Assessment of Prevention, Diagnosis, and Treatment Options

Research Prioritization Topic Briefs

PCORI Scientific Program Area: Assessment of Prevention, Diagnosis, and Treatment Options

Prepared for PCORI by Dr. Gillian Sanders Schmidler, PhD, and Team The Duke Clinical Research Institute

April 18, 2013

Contents

Topic 1: “Attention Deficit Hyperactivity Disorder (ADHD)” ...... 2 Topic 2: “Bipolar Disorder” ...... 9 Topic 3: “Hip Fracture” ...... 15 Topic 4: “Carotid Artery Disease” ...... 21 Topic 5: “Cerebral Adrenoleukodystrophy (ALD )” ...... 28 Topic 6: “Coronary Artery Disease (CAD)” ...... 35 Topic 7: “Ductal Carcinoma” ...... 45 Topic 8: “Gestational Diabetes”...... 51 Topic 9: “Eczema” ...... 61 Topic 11: “Generalized Anxiety Disorder (GAD)” ...... 77 Topic 12: “Hearing Loss” ...... 84 Topic 13: “Chronic Kidney Disease” ...... 90 Topic 14: “Treatments for Liver Cancer” ...... 97 Topic 15: “Macular Degeneration” ...... 105 Topic 16: “Melanoma” ...... 111 Topic 17: “Migraine Headache” ...... 118 Topic 18: “Multiple Sclerosis” ...... 126 Topic 19: “Obstructive Sleep Apnea” ...... 134 Topic 20: “Osteoarthritis” ...... 143

Topic 1: “Attention Deficit Hyperactivity Disorder (ADHD)”

Comparative effectiveness of treatment options for attention deficit hyperactivity disorder (ADHD) in children.

Criteria Brief Description Introduction Overview/definition DESCRIPTION OF CONDITION of topic • Attention Deficit Hyperactivity Disorder (ADHD) is a neurobehavioral disorder ( ie, pertaining to a person’s neurological state by observation of his/her behavior) that begins in childhood and could affect the entire lifespan • ADHD is a highly heritable condition1 with genetic, biologic, and developmental factors all playing a role • There is no single diagnostic or genetic test for ADHD, therefore early diagnosis is often impossible • Diagnosis is based on behavioral signs or symptoms Relevance to SYMPTOMS patient-centered • Difficulties with paying attention, controlling impulsive behaviors, and/or being overly active outcomes PATIENT-CENTERED OUTCOMES2,3 • Children with ADHD are at increased risk of: o Learning problems and academic underachievement o Difficulties relating to peers and forming friendships o Major injuries o Early sexual activity and pregnancy o Substance abuse and/or dependence o Legal difficulties o Occupational difficulties Burden on Society Recent prevalence in PREVALENCE3 populations and • One of the most common chronic health conditions affecting school-age children subpopulations o Approximately 9.5% of children ages 4-17 (5.4 million) diagnosed as of 2007 o Prevalence of reported cases is increasing • Boys (13.2%) more likely to be affected than girls (5.6%) • Highest rates of ADHD are among children covered by Medicaid and multiracial children

Effects on patients’ QUALITY OF LIFE quality of life, • When untreated, ADHD has a significant impact on quality of life, psychosocial functioning, productivity, and family life functional PRODUCTIVITY capacity, • When untreated, ADHD significantly affects the productivity of both patients and their family mortality, use of members health care HEALTH CARE SERVICE UTILIZATION services • As of 2007, 2.7 million children ages 4-17 (66.3% of those diagnosed with ADHD) were receiving drug treatment3 • Children with ADHD are more likely to have hospital inpatient, hospital outpatient, and emergency department admissions3 • Children with ADHD are more likely to have contact with a mental health professional, use prescription drugs, and have frequent health care visits3 • Average ADHD-related expenditures were $1,319 per patient in 200710 How strongly does ADHD is a common disorder affecting a large number of individuals that can have a significant this overall impact on psychosocial, social, educational, and/or occupational functioning throughout the societal burden lifespan. While drug treatment is most often used, wider implementation of behavioral suggest that CER treatment with or without drug treatment may improve outcomes, reduce need for medication on alternative treatment, and reduce associated side effects. approaches to this problem should be given high priority? Options for Addressing the Issue

Based on recent For children under 6 years of age at risk of developing ADHD: systematic • There is strong evidence for parent-administered behavior training (training parents to use reviews, what is effective discipline strategies such as rewards and nonpunitive consequences to manage known about the their child’s behavior). There are four different programs of behavior training interventions relative benefits for parents, with some shared common therapeutic components.4 4 and harms of the o Potential harms: no evidence There is limited evidence for methylphenidate (MPH) available therapy (only one good study)4 Preschool ADHD Treatment Study (PATS) showed MPH to management be effective5,6 options? o Potential harms: Young children have more dose-related side effects and interference with growth.4 In addition, MPH is less effective in children with three or more psychological conditions in addition to ADHD.4 For those 6 years of age and older with a diagnosis of ADHD: • Drugs used for controlling inattention, overactivity, and impulsivity have been shown to maintain effectiveness and safety for 12 to 24 months.4 • It is less certain whether drugs are effective and safe over the longer term.4 • Drug treatments and interventions that combine drug and behavioral treatments are more effective than behavioral treatments alone.4 This finding is based largely on the Multimodal Treatment Study of Children with ADHD (MTA).7 o The MTA study also suggests that (1) children with ADHD and comorbid anxiety respond equally well to behavioral treatment and medication; (2) children with ADHD and comorbid oppositional defiant disorder (ODD) or conduct disorder (CD) require medication for benefit; and (3) behavioral treatments in addition to medication may be most important for minorities8 • There is insufficient evidence to comment on longer-term outcomes for ADHD symptoms following behavioral training for parents, children, or for academic interventions4 What could new For children under 6 years of age: research • There is a need for studies that compare drug treatments to behavioral treatments or contribute to combined drug and behavioral treatment as in the MTA study (which looked at intensive achieving better medication management alone, intensive behavioral treatment alone, and a combination of patient-centered both) in older children. For the youngest children, it would be beneficial to assess which outcomes? strategies have the best patient-centered outcomes • Since most studies have used different behavioral strategies it would also be beneficial to assess the relative efficacy of key components of behavioral treatment programs in an effort to see what strategies are most practical For those over 6 years of age: • There is a need for more information on the long-term outcomes of behavioral and pharmacologic therapies • The optimal follow-up and monitoring schedule for patients with ADHD is not known.9

Have recent • Existing studies of drug treatments tested older, short-acting stimulant medications, such as innovations made methylphenidate and amphetamine. research on this • Studies of newer, long-acting medications (eg extended release methylphenidate, extended topic especially release dextroamphetamine, extended release amphetamine, dextroamphetamine mixed compelling? salts, amphetamine, dextroamphetamine mixed salts atomoxetine, and lisdexamfetamine dimesylate) are needed. Such studies should ideally compare these medications to short- acting stimulant medications as well as behavioral therapies. How widely does • Rates of diagnosis vary considerably in relation to access to local health care services and care now vary? availability of medical providers.9 • Rates of drug usage vary by age and sex; children age 11-17 years are more likely than those age 4-10 to take medication; boys are 2.8 times more likely than girls to take medication.3 • Children of relatively low socioeconomic status are more likely to have ADHD and less likely to receive treatment than children of relatively high socioeconomic status9 • Low socioeconomic and minority status are both associated with shorter duration of drug use, thus reducing treatment efficacy.9 What is the pace of ClinicalTrials.gov: other research on • Ongoing trials: 215 this topic (as • Completed trials: 394 indicated by recent NIH reporter: publications and 544 projects/ 307 publications ongoing trials)? How likely is it that For children under 6 years of age, new CER could provide better data on: new CER on this • The comparative effectiveness of behavioral strategies versus drug versus a combination of topic would the two provide better • The comparative effectiveness of newer ADHD medications, which are approved for children information to over 6 years of age but are being prescribed off-label to children younger than 6, although guide clinical they have not been studied in this population decision making? • Which components of behavioral treatment programs are most practical For people over 6 years of age, new CER could provide better data on: • Long-term outcomes of behavioral versus drug therapies • Differences in outcomes based on age, sex, race, ethnicity, socioeconomic status, or other comorbid conditions Potential for New Information to Improve Care and Patient-Centered Outcomes What are the FACILITATORS: facilitators and • Large numbers of children and adults with ADHD barriers that • Significant impact on psychosocial function would affect the • Desire for alternatives to drug treatments because of concerns about side effects implementation of BARRIERS: new findings in • Lack of time for medical providers to adequately assess patients practice? • Lack of training for medical providers in diagnosis and treatment of ADHD • Lack of availability of behavioral treatment programs in certain locations • Reimbursement for treatment • Cost and practicality of conducting long-term follow-up studies 6

How likely is it that • It is likely that new data suggesting superiority of particular medications over others could be the results of new implemented quickly in people over the age of 6, as these medications are already approved research on this for this age group topic would be • It is likely that new data on the effectiveness of different drug treatments would not be implemented in implemented quickly in children under the age of 6, as these medications would need FDA practice right approval in this age group and there is likely to be considerable concern regarding side away? effects. However, since many of these agents are already being used off-label in this age group, it may be possible to expedite this process. • It is likely that new data on the effectiveness of different behavioral programs or their component parts could be implemented quickly if these programs are already available • It is unlikely that new data on the effectiveness of different behavioral programs or their component parts could be implemented quickly if these programs are not already available as there would be delay while these programs are created Would new • There are a large number of completed and ongoing studies in this topic area; however, information from many studies are small in size. CER on this topic • Both the larger PATS and MTA studies have remained current for many years. It is likely that remain current for new information with more current therapies (medication and psychosocial) would remain several years, or relevant for many years. would it be rendered obsolete quickly by subsequent studies?

REFERENCES:

1. Larsson H, Lichtenstein P, Larsson JO. Genetic contributions to the development of ADHD subtypes from childhood to adolescence. J Am Acad Child Adolesc Psychiatry. 2006;45(8):973-981. 2. Biel MG, McGee ME. Assessment of attention-deficit/hyperactivity disorder. Pediatr Ann. 2011;40(10):493-498. 3. Centers for Disease Control and Prevention. Attention-Deficit / Hyperactivity Disorder (ADHD): Data & Statistics. Centers for Disease Control and Prevention. www.cdc.gov/ncbddd/adhd/data.html. Accessed April 10, 2013. 4. Charach A, Dashti B, Carson P, Booker L, Lim CG, Lillie E, Yeung E, Ma J, Raina P, Schachar R. Attention Deficit Hyperactivity Disorder: Effectiveness of Treatment in At-Risk Preschoolers; Long-Term Effectiveness in All Ages; and Variability in Prevalence, Diagnosis, and Treatment. Comparative Effectiveness Review No. 44. (Prepared by the McMaster University Evidence-based Practice Center under Contract No. MME2202 290-02-0020.) AHRQ Publication No. 12-EHC003-EF. Rockville, MD: Agency for Healthcare Research and Quality; October 2011. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published October 2011. Accessed April 10, 2013. 5. Abikoff HB, Vitiello B, Riddle MA, Cunningham C, Greenhill LL, Swanson JM, Chuang SZ, Davies M, Kastelic E, Wigal SB, Evans L, Ghuman JK, Kollins SH, McCracken JT, McGough JJ, Murray DW, Posner K, Skrobala AM, Wigal T. Methylphenidate effects on functional outcomes in the Preschoolers with Attention-Deficit/Hyperactivity Disorder Treatment Study (PATS). J Child Adolesc Psychopharmacol. 2007;17(5):581-592. 6. Vitiello B, Abikoff HB, Chuang SZ, Kollins SH, McCracken JT, Riddle MA, Swanson JM, Wigal T, McGough JJ, Ghuman JK, Wigal SB, Skrobala AM, Davies M, Posner K, Cunningham C, Greenhill LL. Effectiveness of methylphenidate in the 1-month continuation phase of the Preschoolers with Attention-Deficit/Hyperactivity Disorder Treatment Study (PATS). J Child Adolesc Psychopharmacol. 2007;17(5):593-604. 7

7. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry. 1999;56(12):1073- 1086. 8. Murray DW, Arnold LE, Swanson J, Wells K, Burns K, Jensen P, Hechtman L, Paykina N, Legato L, Strauss T. A clinical review of outcomes of the multimodal treatment study of children with attention-deficit/hyperactivity disorder (MTA). Curr Psychiatry Rep. 2008;10(5):424-431. 9. Subcommittee on Attention-Deficit/Hyperactivity Disorder; Steering Committee on Quality Improvement and Management, Wolraich M, Brown L, Brown RT, DuPaul G, Earls M, Feldman HM, Ganiats TG, Kaplanek B, Meyer B, Perrin J, Pierce K, Reiff M, Stein MT, Visser S. ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2011;128(5):1007-1022. 10. Soni, A. Attention-Deficit Hyperactivity Disorder (ADHD) in children, ages 5-17: use and expenditures, 2007. Statistical Brief #276. Rockville, MD: Agency for Healthcare Research and Quality; 2009. www.meps.ahrq.gov/mepsweb/data_files/publications/st276/stat276.shtml. Published December 2009. Accessed April 10, 2013.

APPENDIX: TOPIC QUESTIONS

Nominated by Agency for Healthcare Research and Quality (AHRQ):

1) For children less than 6 years of age with disruptive behavior disorder or ADHD, what is the comparative efficacy and effectiveness of specific psychosocial treatments alone compared with pharmacological treatments alone or in combination with psychosocial treatments for patient outcomes? 2) For people ages 6 years or older with ADHD, what are the comparative long-term outcomes for the available psychosocial and pharmacological treatments? 3) Among children less than 6 years of age with disruptive behavior disorder or ADHD, what is the relative/comparative efficacy of key components of psychosocial treatment programs? These might include the relative efficacy of specific parent training compared with treatment components targeting the child, or the efficacy of variants in psychosocial treatment service delivery that allow flexibility for parental preferences compared with those that do not. 4) For people ages 6 years or older with ADHD, which specific sociodemographic, baseline clinical characteristics, and neurobiological features predict a positive treatment response with respect to patient outcomes?

Topic 2: “Bipolar Disorder”

Comparative effectiveness of antipsychotics for adolescents and young adults with bipolar disorder.

Criteria Brief Description Introduction Overview/definition DESCRIPTION OF CONDITION of topic • Bipolar disorder, commonly called “manic depression,” is a serious brain disorder that causes extreme and unusual changes in moods and behaviors. • Bipolar disorder that starts in childhood or the early teen years seems to be more severe than when the disorder starts in older teens and adults.1,2 • There is no cure for bipolar disorder. • Antipsychotic medications are used to control symptoms of bipolar disorder and provide symptom relieve compared to no treatment in adolescents and young adults (defined as youths under 25 years of age). However, antipsychotics carry significant side effects. Relevance to SYMPTOMS/OUTCOMES patient-centered • Symptoms outcomes o Episodes of extreme elevated moods o Episodes of major depression • Outcomes o Adolescents and young adults with bipolar disorder experience higher rates of attempted and completed suicide, substance abuse, hospitalizations, legal issues, and poor academic and psychosocial functioning • Worse outcomes are associated with patients who are an early age at first episode, who suffer long duration, who have comorbid disorders, are low socioeconomic status, or who have negative life events (like abuse) Burden on Society Recent incidence BIPOLAR DISODER INCIDENCE (NEW CASES) & PREVALENCE (PROPORTION OF and prevalence in POPULATION LIVING WITH THE CONDITION) populations and • A recent meta-analysis found that 2.7% of youths aged 12 to 21 have bipolar disorder. subpopulations Rates of bipolar disorder jump to as much as 5% when subsyndromal manic symptomatology is included in the estimates.3 • Recovery in most youths, defined as no significant symptoms for 2 months following first episode,4-7 is achievable • Almost 80% of affected youth, however, will have a relapse of bipolar disorder within 2 to 5 years.6 Effects on patients’ QUALITY OF LIFE quality of life, • Affects family relationships and family’s overall financial security productivity, • Difficulties with interpersonal relationships functional capacity, • Antipsychotic drugs have side effects that negatively affect quality of life. mortality, use of health care PRODUCTIVITY services • Poor school and social performance • Difficulties obtaining and retaining a job

MORTALITY • Higher rates of attempted and completed suicide 10

USE OF HEALTH CARE SERVICES • Higher number of hospitalizations compared to youths without bipolar disorder • Estimated $2.82 billion were spent in 2003 in the United States on antipsychotic medications8 • Use of antipsychotics in youths has increased dramatically over the last 20 years9,10 How strongly does This is a serious disorder affecting approximately 3% of adolescents and young adults, with this overall societal significant implications for patients, families, and society. Antipsychotics have the potential to burden suggest control symptoms but the majority of research has been conducted with adult populations. that CER on While there are multiple head-to-head comparison studies of the benefits and harms of alternative antipsychotics for adults, few high-quality comparative effectiveness trials have tested these approaches to this medications in younger populations. problem should be given high priority? Options for Addressing the Issue Based on recent SCREENING/EARLY DIAGNOSIS systematic reviews, • Diagnosing bipolar disorder in children and adolescents is complex and requires longitudinal what is known assessments about the relative • Psychiatric interviews and rating scales can be used by trained clinicians for screening benefits and harms • Parent-report instruments have also been used to screen for bipolar disorder in youths of the available management TREATMENT options? Overview • Antipsychotic drugs are one class of drugs used to treat bipolar disorder. These are commonly categorized into two classes, which have different side-effect profiles. o First-generation antipsychotics (FGA) or typical antipsychotics (developed in the 1950s) . Side effects: movement disorders (repetitive, involuntary muscle movements: eye blinking, finger movement, lip smacking), uncontrollable muscle contractions, liver problems, irregular heartbeat, constipation, loss of appetite, and sedation o Second-generation antipsychotics (SGA) or atypical antipsychotics (1980s) . Side effects: weight gain, elevated lipids, increased risk for type 2 diabetes . Lower risk of movement side effects with SGA than with FGA

Systematic Reviews • A recent systematic review identified only 11 randomized controlled trials (RCTs) evaluating antipsychotic drugs in adolescents and young adults. These trials compared different doses of the same SGA (4 trials), one SGA versus another (2 trials), or an SGA versus placebo (8 trials).8 (Total number of comparisons exceeds 11 as some trials had 3 or 4 group designs that assessed multiple comparisons.) o No studies compared FGAs to SGAs. o Few studies reported on important patient-centered outcomes (eg, sedation, restlessness), even though they are vital to patient compliance

o Few studies assessed long-term outcomes. o Little data on benefits and harms of antipsychotics among key subgroups of patients o Across all comparisons and outcomes the volume and quality of evidence were low.

What could new New research could contribute to achieving better patient-centered outcomes: research • Data on the relative benefits and harms of different treatments contribute to • Data on important patient and family outcomes achieving better patient-centered outcomes? Have recent Recent innovations: innovations made • There have been multiple head-to-head comparison studies of the benefits and harms of research on this antipsychotics for adults, however, few high-quality comparative effectiveness trials have topic especially tested these medications in younger populations. compelling? How widely does VARIABILITY IN CARE care now vary? • Diagnosis is complex and requires ongoing evaluation which could lead to variability in care. While relatively few antipsychotics are FDA-approved for use in youths with bipolar disorder, use of medications is often driven by side-effects leading to variability in care. What is the pace of RECENT PUBLICATIONS other research on • MEDLINE search from 1/1/2008-3/31/2013: total of 1250 citations this topic (as o 207 randomized controlled trials (RCTs) indicated by recent o 369 observational/cohort trials publications and o 60 systematic reviews ongoing trials)? ONGOING TRIALS • ClinicalTrials.gov: 254 ongoing trials • NIH Reporter: 570 projects How likely is it that KEY UNCERTAINTIES IN CLINICAL DECISION MAKING new CER on this • What are the comparative harms and benefits of FGAs and SGAs? topic would • What are the long-term outcomes of these medications on youths across a wide variety of provide better clinical, developmental, and social domains? information to • Do effects of these treatments vary by important subgroups (age, sex)? guide clinical decision making? LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES There is a high likelihood that CER would reduce uncertainly. • Few head-to-head comparisons of antipsychotics • Few high-quality longitudinal studies of antipsychotics • Little information to guide clinical practice on how treatment effects vary across key subgroups Potential for New Information to Improve Care and Patient-Centered Outcomes What are the FACILITATORS facilitators and • Few FDA-approved treatments at this time. CER could provide needed information on which barriers that would of the currently available treatments should be added to the FDA-approved list and give 12

affect the needed comparative information on side-effect profiles. Expanding the choice of treatments implementation of with better side-effect profiles could potentially be embraced by clinical, patient, and new findings in caregiver populations. practice? BARRIERS • Social stigma associated with having a mental health disorder • Noncompliance with taking antipsychotics may occur for many reasons, including side effects from medication and a lack of improvement in symptoms How likely is it that EVIDENCE OF BENEFIT the results of new • Highly likely that treatments with evidence of benefits would be implemented. research on this EVIDENCE OF NO BENEFIT OR HARM topic would be • Highly likely that finding of no benefits or of greater harms would be implemented. implemented in practice right away? Would new Despite the sizable number of studies in this area, there are few head-to-head comparisons and information from the quality of these studies is generally low. Thus, high-quality, CER studies that report on CER on this topic important short- and long-term clinical and patient-centered outcomes are likely to be relevant remain current for for several years. several years?

REFERENCES: 1. Perlis RH, Miyahara S, Marangell LB, Wisniewski SR, Ostacher M, DelBello MP, Bowden CL, Sachs GS, Nierenberg AA. Long-term implications of early onset in bipolar disorder: data from the first 1000 participants in the systematic treatment enhancement program for bipolar disorder (STEP-BD). Biol Psychiatry. 2004 May 1;55(9):875-881. 2. Birmaher B, Axelson D, Strober M, Gill MK, Valeri S, Chiappetta L, Ryan N, Leonard H, Hunt J, Iyengar S, Keller M. Clinical course of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry. 2006 Feb;63(2):175-183. 3. Van Meter AR, Moreira AL, Youngstrom EA: Meta-analysis of epidemiological studies of pediatric bipolar disorder. J Clinical Psychiatry 72:1250–1256, 2011. 4. Birmaher B, Axelson D, Goldstein B, et al. Four-year longitudinal course of children and adolescents with bipolar spectrum disorders: the Course and Outcome of Bipolar Youth (COBY) study. Am J Psychiatry 2009; 166:795. 5. DelBello MP, Hanseman D, Adler CM, et al. Twelve-month outcome of adolescents with bipolar disorder following first hospitalization for a manic or mixed episode. Am J Psychiatry 2007; 164:582. 6. Birmaher B. Longitudinal course of pediatric bipolar disorder. Am J Psychiatry 2007; 164:537. 7. Geller B, Tillman R, Bolhofner K, Zimerman B. Child bipolar I disorder: prospective continuity with adult bipolar I disorder; characteristics of second and third episodes; predictors of 8-year outcome. Arch Gen Psychiatry 2008; 65:1125. 8. Abou-Setta AM, Mousavi SS, Spooner C, Schouten JR, Pasichnyk D, Armijo-Olivo S, Beaith A, Seida JC, Dursun S, Newton AS, Hartling L. First-Generation Versus Second-Generation Antipsychotics in Adults: Comparative Effectiveness. Comparative Effectiveness Review No. 63. (Prepared by the University of Alberta Evidence-based Practice Center under Contract No. 290-2007-10021.) AHRQ Publication No. 12-EHC054-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2012. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published August 2012.

9. Zito JM, Safer DJ, dosReis S, et al. Trends in the prescribing of psychotropic medications to preschoolers. JAMA 2000;238(8):1025-1030. 10. Pathak S AS, Danielyan A, et al. Psychotropic utilization and psychiatric presentation of hospitalized very young children. J Child Adolesc Psychopharmacol 2004;14(3):433-442.

Appendix: Topic Question

Nominated by Agency for Healthcare Research and Quality (AHRQ)

1) What is the efficacy and effectiveness of first or second generation antipsychotics for adolescents and young adults with bipolar disorder in the following outcome domains: core features of the disorder, its commonly associated comorbidities and behavioral features, social/occupational functioning, patient- and parent-reported outcomes, those related to high risk behaviors, and suicide-related behavior?

Topic 3: “Hip Fracture”

Comparative effectiveness of surgical options for hip fracture in the elderly.

Criteria Brief Description Introduction Overview/definition DESCRIPTION OF CONDITION1,2,3 of topic • “Hip fracture” refers to a break of the upper part of the femur (large bone of the upper thigh) • Classified into different types depending on location • Treatment options vary by fracture type • Two main causes: o Simple falls (90%)—affect mostly the elderly, more common in women o Major trauma ( eg, motor vehicle accident)—mostly younger, more common in men

Patient-centered SYMPTOMS/OUTCOMES1,2,3 outcomes • Hip fracture can result in: o Pain o Functional impairment o Prolonged rehabilitation o Loss of ability to live independently o Premature death • Goal of treatment usually to return patients to pre-fracture level of functioning Burden on Society Recent incidence INCIDENCE (NEW CASES)1,2 and prevalence in • 957 per 100,000 for women and 414 per 100,000 for men from 1986 to 2005 populations and • Increased risk in women due to changes in bone strength (osteoporosis) after menopause subpopulations o Unclear if decreased use of postmenopausal hormone replacement therapy after findings of Women’s Health Initiative in 2002 will lead to increased incidence in women Effects on patients’ QUALITY OF LIFE1,2,3 quality of life, • 80% of elderly women surveyed preferred death to a “bad” hip fracture that would result in productivity, nursing home need functional FUNCTIONAL CAPACITY capacity, • 50% of previously independently living elderly patients able to walk unaided after fracture, mortality, use of but many (25–75%) never completely recover full pre-injury functional status health care MORTALITY services • 20% one-year mortality after a hip fracture • 2–3% in-hospital mortality among patients 65 and over4 USE OF HEALTH CARE SERVICES4 • 304,000 hospitalizations in the United States (in 2010) secondary to hip fractures o Ages 65–84: 0.9% of all hospitalizations for men, 1.8% for women o Ages 85 and older: 2.7% of all hospitalizations for men, 4.5% for women

How strongly does • Common condition with potential for severe consequences and overall high societal burden this overall • Also high potential for decreasing the incidence of hip fractures via fall prevention measures societal burden • Multiple different treatment options and potential for wide variety of different outcomes suggest that CER depending on nature, quality, and extent of medical/surgical care provided on alternative • CER on alternative approaches may have significant impact on clinical outcomes, societal approaches to this costs, and patient and provider decision making problem should be given high priority?

Options for Addressing the Issue Based on recent Four Key Questions in 2009 AHRQ “Treatment of Common Hip Fractures” report 3 systematic 1) Relationship between patient variables, fracture type, and patient outcomes reviews, what is 2) Relationship between fracture type and patient outcomes known about the 3) Relationship between implant variables and patient outcomes relative benefits 4) Relationship between intervention type and patient outcomes and harms of the Results: available • Five of the included trials were conducted in the United States management • Limited evidence to answer most of the key questions options? • High degree of uncertainty regarding the best way to treat unstable hip fractures and about which treatment options are most appropriate for various clinical populations What could new 2010 AHRQ “Future Needs for the Treatment of Common Hip Fractures” report5 identified the research following research gaps: contribute to • Predictors of short time-to-recovery and functional outcomes achieving better • Impact of suboptimal surgical quality on functional outcomes patient-centered • Optimal treatment for different types of fractures ( eg, unstable intertrochanteric hip outcomes? fractures) or defined populations ( eg, frail elderly, patients with dementia) • Between-class and within-class comparisons ( eg, intramedullary nail vs. screws, cement vs. not, number and placement of screws, plate length and position, nail length, and other parameters) Have recent • Comanaged geriatric fracture centers and organized geriatric fracture programs represent innovations made novel approaches that are associated with shorter times to surgery, fewer postoperative research on this infections, fewer complications overall, and shorter lengths of stay.6 topic especially • Further research on health care redesign involving multidisciplinary collaboration is timely compelling? and may result in both improved outcomes and more efficient use of health care resources. How widely does VARIABILITY IN CARE care now vary? • Very large variation in quality, nature, and extent of care provided across the many clinical settings throughout the United States that offer hip fracture repair • High variability in training and quality of surgeons and hospital-based clinicians who provide medical care to elderly patients with multiple comorbidities during hospitalization for hip fracture repair

What is the pace of RECENT PUBLICATIONS other research on • Treatment of Common Hip Fractures (AHRQ, 2009)3 this topic (as • Future Needs for the Treatment of Common Hip Fractures (AHRQ, 2010)5 indicated by • Pain Management Interventions for Hip Fractures (AHRQ, 2011)7 recent ONGOING TRIALS publications and • FAITH (Fixation using Alternative Implants for the Treatment of Hip Fractures)8 ongoing trials)? • HEALTH (Comparing Total Hip Arthroplasty and Hemi-Arthroplasty on Revision Surgery and Quality of Life in Adults with Displaced Hip Fractures)9 How likely is it that • The research gaps listed above were identified by key stakeholders. This suggests that CER on new CER on this these topics is likely to inform stakeholder clinical decision making. topic would • Many areas of uncertainty involve technical issues regarding surgical management; relative provide better involvement of patients/capacity for shared decision making may vary information to guide clinical decision making?

Potential for New Information to Improve Care and Patient-Centered Outcomes What are the FACILITATORS facilitators and • The current lack of consensus on questions identified by stakeholders as being important is barriers that likely to facilitate implementation of new, compelling findings. would affect the • 80% of hospitalizations have Medicare as primary payer—potential for CMS to help facilitate implementation of implementation new findings in BARRIERS practice? • Cost of implementation ( eg, to payers, providers, patients, caregivers, and others) • Lower barriers to market entry for surgical instruments and devices ( eg, hip implants), as opposed to drugs • Reimbursement structure for providers and financial incentives/disincentives associated with changing existing practices • Dissemination of findings across a large spectrum of providers, payers, and patients How likely is it that EVIDENCE OF BENEFIT the results of new • Highly likely to be implemented because most stakeholders likely to be motivated to improve research on this decision making and patient outcomes topic would be • General sense that orthopedic surgeons are open to—and would welcome—greater clarity implemented in on treatment options practice right EVIDENCE OF NO BENEFIT OR HARM away? • Depending on balance, may be less likely to be implemented if findings do not provide additional clarity o Especially true if current financial/other incentives favor continued use of intervention with no benefit relative to other options Would new • New information from CER on this topic may remain current if it is compelling and clear, and information from if it addresses questions deemed relevant by stakeholders. CER on this topic • CER on certain technical questions may be rendered obsolete by unforeseeable technological remain current for advances ( eg, availability of new materials for hip replacement). several years?

REFERENCES:

1. Brauer AC, Coca-Perraillon M, Cutler DM, Rosen AB. Incidence and mortality of hip fractures in the United States. JAMA. 2009;302:1573-1579. 2. Braithwaite RS, Col NF, Wong JB. Estimating hip fracture morbidity, mortality and costs. J Am Geriatr Soc. 2003;51:364-70. 3. Butler M, Forte M, Kane RL, Joglekar S, Duval SJ, Swiontkowski M., Wilt T. Treatment of Common Hip Fractures. Evidence Report/Technology Assessment No. 184 (Prepared by the Minnesota Evidence-based Practice Center under Contract No. HHSA 290 2007 10064 1.) AHRQ Publication No. 09-E013. Rockville, MD. Agency for Healthcare Research and Quality. 2009. www.ahrq.gov/research/findings/evidence-based-reports/hipfrac-evidence-report.pdf. Published August 2009. Accessed April 10, 2013. 4. HCUPnet, Healthcare Cost and Utilization Project. Agency for Healthcare Research and Quality, Rockville, MD. Available at: http://hcupnet.ahrq.gov. Accessed April 10, 2013.

5. Butler M, Forte ML, Kane RL, Swiontkowski MF. Future Research Needs for the Treatment of Common Hip Fractures. Future Research Needs Paper No. 2. (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-2007-10064-I.) AHRQ Publication No. 10-EHC071-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2010. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published September 2010. Accessed April 10, 2013. 6. Friedman, S.M., et al., Geriatric co‐management of proximal femur fractures: total quality management and protocol‐driven care result in better outcomes for a frail patient population. J Am Geriatr Soc. 2008;56:1349‐1356. 7. Abou-Setta AM, Beaupre LA, Jones CA, Rashiq S, Hamm MP, Sadowski CA, Menon MR, Majumdar SR, Wilson MD, Karkhaneh M, Wong K, Mousavi SS, Tjosvold L, Dryden DM. Pain Management Interventions for Hip Fracture. Comparative Effectiveness Review No. 30. (Prepared by the University of Alberta Evidence-based Practice Center under Contract No. 290-02-0023.) AHRQ Publication No. 11-EHC022-EF. Rockville, MD: Agency for Healthcare Research and Quality. 2011. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published May 2011. Accessed April 10, 2013. 8. Fixation Using Alternative Implants for the Treatment of Hip Fractures [FAITH]: A Multi-Centre Randomized Trial Comparing Sliding Hip Screws and Cancellous Screws on Revision Surgery Rates and Quality of Life in the Treatment of Femoral Neck Fractures. ClinicalTrials.gov ID: NCT00761813. http://clinicaltrials.gov/ct2/show/NCT00761813. Accessed April 10, 2013. 9. Comparing Total Hip Arthroplasty and Hemi-Arthroplasty on Revision Surgery and Quality of Life in Adults With Displaced Hip Fractures (The HEALTH Study). ClinicalTrials.gov ID: NCT00556842. http://clinicaltrials.gov/ct2/show/NCT00556842. Accessed April 10, 2013.

APPENDIX: TOPIC QUESTIONS

Nominated by the Agency for Healthcare Research and Quality (AHRQ)

1. What predicts short time-to-recovery after hip fracture? 2. What predicts functional outcomes after one year, especially one to two years after hip fracture? 3. What is the impact of suboptimal surgical quality on functional outcomes? 4. Do certain procedures ( eg, internal fixation) work better than others for frail older patients? 5. Are most fragile patients more or less likely to have suboptimal fracture reduction/implant position than the most active, mobile patients (making them higher risk for implant failure?) 6. Which procedures are better for patients with dementia? 7. What is the optimal treatment for displaced femoral neck fractures? 8. What is the optimal treatment for unstable‖ intertrochanteric hip fractures? 9. What is the optimal treatment for subtrochanteric hip fractures? 10. Between class comparisons ( eg, IM nail vs. screws) 11. Within-class comparison of arthroplasty—c ement vs. not 12. Within-class comparison of number and placement of screws 13. Within-class comparison of plate length, position 14. Within-class comparison of nail length (IMN)

Topic 4: “Carotid Artery Disease”

Comparative effectiveness of medical and surgical treatment options of patients with asymptomatic carotid artery stenosis.

Criteria Brief Description Introduction Overview/definition DESCRIPTION OF CONDITION of topic Overview • The carotid arteries, which carry blood to the brain, are prone to blockage from arteriosclerosis (thickening/hardening of the arteries). Atherosclerotic plaque in the carotid arteries can lead to ischemic strokes or transient ischemic attacks (TIAs). • The risk of stroke related to carotid artery disease is higher with: o Higher degrees of stenosis (narrowing of the carotid artery) o Neurologic symptoms o Evidence of asymptomatic cerebral embolism or presence of ulcerations of carotid artery • Peripheral vascular disease and ischemic heart disease are common comorbid conditions.

Screening/Diagnosis • Carotid stenosis can be identified through diagnostic evaluation: o In persons with neurologic symptoms o By hearing a neck bruit (abnormal sound) o Via screening tests (Doppler ultrasound)

Treatment • Three main treatments are used to prevent stroke in patients with carotid artery disease: (1) medical therapy (using various drugs) for risk factor reduction, (2) carotid endarterectomy (CEA) or, more recently, (3) percutaneous carotid artery angioplasty and stenting (CAS). CEA and CAS are two different types of revascularization procedures. Relevance to SYMPTOMS/OUTCOMES patient-centered • Neurologic symptoms sometimes last <24 hours. outcomes • For patients who progress to a stroke, outcomes include: o Loss of use of arms or legs o Loss of ability to speak (aphasia) o Functional deficits, including in relation to ambulation or ability to care for self o Death (with large severe strokes) Burden on Society Recent incidence PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE CONDITION) and prevalence in • Prevalence of asymptomatic carotid artery stenosis is up to 7.5%, with higher prevalence in populations and men and in older patients1 subpopulations

Effects on patients’ QUALITY OF LIFE quality of life, • Quality-of-life benefit from CEA is delayed, with initial risk of perioperative morbidity productivity, (including strokes caused by the surgery), but with benefit that is significant at two years and functional longer after procedure. Limited data are available on CAS. capacity, PRODUCTIVITY mortality, use of • Stroke is the leading cause of serious long-term disability in the United States. health care MORTALITY services • 30-day mortality rates directly related to CEA and CAS among Medicare patients were 1.2% for CEA and 2.3% for CAS in 2005.2 USE OF HEALTH CARE SERVICES AND COSTS • In 2008, total direct and indirect costs related to stroke in the United States were over $65 billion. • The majority of direct medical costs arise during the first few months after a stroke and include acute hospital costs (~50%), nursing home, and home health care costs (35%).3 • The majority of lifetime stroke-related costs are from indirect costs, including lost earnings, informal care, or the care required for assistance in the home by a relative or unpaid nonrelative.3 • Among Medicare beneficiaries, CEA was performed on over 66,000 patients for symptomatic or asymptomatic indication in 2005;CAS in over 7000 patients.2 • Given the success of medical therapy and risk factor reduction, the overall rate of carotid revascularization procedures (CEA and CAS) has declined between 1998 and 2008. A large decrease in the use of CEA during this period has been accompanied by a sharp increase in the use of CAS.4 How strongly does The detection of asymptomatic carotid artery stenosis provides an opportunity to avoid many of this overall the costs associated with a stroke through prevention, particularly the lifetime indirect costs societal burden associated with lost productivity and informal care. However, detection and management of this suggest that CER asymptomatic condition also impose direct and indirect costs associated with the screening on alternative process, treatment, and lost productivity associated with both of these. approaches to this problem should be given high priority? Options for Addressing the Issue Based on recent SCREENING/DIAGNOSIS systematic • The United States Preventive Services Task Force (USPSTF) does not recommend screening reviews, what is by ultrasound for the general population.5 known about the relative benefits TREATMENT and harms of the Medical Therapy available • Medical therapy with antiplatelet agents (aspirin, ticlopidine, clopidogrel, or aspirin and management dipyridamole) and risk factor reduction are generally accepted as being effective for all options? patients with carotid artery disease. • Medical therapy is preferred for symptomatic patients with <50% stenosis. • One systematic review of 11 prospective studies (but no random controlled trials [RCTs])

found that treatment with medical therapy led to stroke rates in follow-up that are comparable to rates achieved with CEA.6

Carotid Endarterectomy (CEA) • CEA is recommended for patients who have experienced symptoms (stroke or TIA) associated with carotid stenosis of 70-99% (strongly recommended) or 50-69% (when life expectancy is >5 years and probability of stroke during surgery is <6%).7 • CEA is also a consideration for appropriate patients who are asymptomatic with 60-99% stenosis (when life expectancy is >5 years and probability of stroke during surgery is <3%). • Trials comparing CEA to medical therapy (aspirin) concluded that patients undergoing CEA for asymptomatic carotid artery disease should have the procedure done in centers with a perioperative rate of death and stroke of <3% and with surgeons whose complication rates are <3%.8-10 • Certain subgroups of patient are shown not to benefit from CEA (compared to aspirin therapy) including patients with: o Significant comorbidity o Prior stroke and persistent neurologic deficits on the same side o Total occlusion of the internal carotid artery (same side CEA) o Total occlusion of contralateral internal carotid artery (opposite side CEA) • Based on data from meta-analysis, women may not benefit from CEA for asymptomatic carotid artery disease, based on five-year risk of stroke or perioperative death, whereas men do seem to benefit from CEA, especially if their life expectancy is ≥5 years.11 • Patients with evidence of asymptomatic cerebral embolism, presence of ulcerations of carotid artery plaques, and higher degrees of stenosis are at higher risk of stroke and may benefit more from CEA.

Percutaneous Carotid Artery Angioplasty and Stenting (CAS) • There is an overall similar risk of stroke or death with CEA and CAS. • CEA is favored over CAS for patients older than 70 years of age, with higher rates of stroke especially associated with age ≥80. • Based on observational data, CAS may be appropriate for patients with prior neck radiation therapy, high cervical carotid bifurcations, and those with complete occlusion of contralateral internal carotid artery. • A systematic review in patients with symptomatic and asymptomatic carotid artery disease found that CAS had a higher risk of stroke at 30 days compared to CEA, lower risk of MI, and no significant difference in mortality at 30 days.12 Other systematic reviews confirm the higher risk of stroke and lower risk of MI with CAS compared to CEA. • A recent Cochrane review13 found: o Among asymptomatic patients, no statistically significant difference was found between CEA and CAS for the primary safety outcome of stroke or death at 30 days, or for combined efficacy and safety outcomes including MI, cranial nerve palsy, and access-site hematomas. o Among symptomatic patients, there was a higher risk of the composite outcome of stroke or death associated with CAS only among older patients (≥70 years old). o In patients not suitable for CEA, there was no significant difference between CAS and 24

medical therapy. What could new • Current optimal medical therapy has been shown to be as good as or superior to CAS and research CEA in two recent RCTs in patients with symptomatic carotid artery disease.14-15 However, contribute to trials comparing CEA or CAS to optimal medical therapy in patients with significant achieving better asymptomatic carotid artery disease have not been done. patient-centered • Trials comparing CEA and CAS in specific subgroups of patients based on sex, race, and outcomes? comorbidities, all which have been found to affect outcome of the invasive procedures, have not been done. • Better evidence based on RCTs to determine if medical therapy is adequate or even better compared to CEA and CAS would be very important to the care of patients with asymptomatic carotid artery disease. It could potentially expose patients to less risk and improve outcomes; it could also lead to decreased health care costs. Have recent • Improved medical therapy for atherosclerotic disease has been developed, including the innovations made widespread use of statins and more aggressive risk factor management. These improvements research on this in medical therapy have rendered landmark trials comparing CEA with medical therapy topic especially possibly obsolete. compelling? • Recent data suggest that stroke rates are lower with more aggressive risk factor reduction, potentially reducing or eliminating the benefit of CEA (or CAS) over medical therapy14-15 How widely does • Based on Medicare beneficiaries data from 2004-2006:2 care now vary? o CEA and CAS were performed more often in men than women; both were performed more often in patients with peripheral vascular disease. o CEA and CAS were performed more often in the East North Central region than in New England. What is the pace of RECENT PUBLICATIONS other research on • The USPSTF is updating its 2007 guidance5 with a new review of evidence in 2013. this topic (as indicated by ONGOING TRIALS recent • ClinicalTrials.gov lists 68 trials of CEA and 81 trials of CAS as completed or ongoing, but only publications and one is a comparative trial (CAS vs. CEA, still recruiting), and none compares medical ongoing trials)? treatment with CAS or CEA. • Multiple technology evaluations of devices to reduce embolization associated with CAS procedures are underway. How likely is it that • New comparative-effectiveness research (CER) evaluating current aggressive medical therapy new CER on this and risk factor reduction vs. procedure-based management (CEA or CAS), particularly for topic would patients with asymptomatic carotid artery stenosis and possibly for patients with noncritical provide better (50-69%) symptomatic stenosis, would help to resolve uncertainty. information to • Trials comparing these treatments in specific subgroups of patients based on sex, race, and guide clinical comorbidities, all which have been found to affect outcome of the invasive procedures, have decision making? not been done. Potential for New Information to Improve Care and Patient-Centered Outcomes

What are the FACILITATORS facilitators and • Implementation of medical therapy to treat asymptomatic carotid artery disease could likely barriers that be easy, as similar treatments are already used for other atherosclerotic diseases. would affect the • Medical therapy vs. a procedure would result in less stress to patients, lower risk of implementation of procedure-related complications, and reduced direct and indirect health care costs. new findings in BARRIERS practice? • Existing referral patterns and recently expanded use of CAS among interventional cardiologists, radiologists, and neurologists may be resistant to change. • There are no definite recommendations regarding screening procedures for asymptomatic carotid artery disease, which may prevent eligible patients from receiving the best treatment. How likely is it that • Implementation of medical therapy to treat asymptomatic carotid artery disease could likely the results of new be easy, as similar treatments are already used for other atherosclerotic diseases. research on this • Similarly, research supporting expanded indications for revascularization procedures would topic would be likely be easily and quickly implemented as the relatively rapid uptake of CAS illustrates. implemented in practice right away? Would new New research comparing medical and revascularization procedures for asymptomatic stenosis, information from particularly in those subgroups of patients at high or low risk, for complications related to these CER on this topic procedures have a great potential benefit to patients and the health care system and would likely remain current for be relevant for several years. several years, or would it be rendered obsolete quickly by subsequent studies?

REFERENCES:

1. de Weerd M, Greving JP, Hedblad B, et al. Prevalence of asymptomatic carotid artery stenosis in the general population: an individual participant data meta-analysis. Stroke. 2010;41(6):1294-1297. 2. Patel MR, Greiner MA, DiMartino LD, et al. Geographic variation in carotid revascularization among Medicare beneficiaries, 2003-2006. Arch Intern Med. 2010;170(14):1218-1225. 3. Demaerschalk BM, Hwang HM, Leung G. US cost burden of ischemic stroke: a systematic literature review. Am J Manag Care 2010;16(7):525-533. 4. Goodney PP, Travis L, Lucas FL, et al. Trends and regional variation in carotid revascularization. The Dartmouth Institute for Health Policy and Clinical Practice. A Dartmouth Atlas Surgery Report. Jan 26, 2010. 5. U.S. Preventive Services Task Force. Screening for Carotid Artery Stenosis: Clinical Summary of U.S. Preventive Services Task Force Recommendation. AHRQ Publication No. 08-05102-EF-3. Rockville, MD: U.S. Preventive Services Task Force; 2007. www.uspreventiveservicestaskforce.org/uspstf07/cas/cassum.htm. Published December 2007. Accessed April 11, 2013.

6. Abbott AL. Medical (nonsurgical) intervention alone is now best for prevention of stroke associated with asymptomatic severe carotid stenosis: results of a systematic review and analysis. Stroke 2009; 40(10):e573-583. 7. Brott TG, Halperin JL, Abbara S, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/ SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary. Stroke. 2011;42(8):e420-463. 8. Gorelick PB. Carotid endarterectomy: where do we draw the line? Stroke 1999;30(9):1745-1750. 9. Goldstein LB, Moore WS, Robertson JT, et al. Complication rates for carotid endarterectomy. A call to action. Stroke 1991; 22(11):1353-1357. 10. Barnett HJ. The inappropriate use of carotid endarterectomy. CMAJ 2004;171(5):473-474. 11. Rothwell PM, Goldstein LB. Carotid endarterectomy for asymptomatic carotid stenosis: asymptomatic carotid surgery trial. Stroke 2004;35(10):2425-2427. 12. Guay J. Endovascular stenting or carotid endarterectomy for treatment of carotid stenosis: a meta-analysis. J Cardiothorac Vasc Anesth. 2011;25(6):1024-1029. 13. Bonati LH, Lyrer P, Ederle J, et al. Percutaneous transluminal balloon angioplasty and stenting for carotid artery stenosis. Cochrane Database Syst. Rev. 2012;9:CD000515. 14. Chimowitz MI, Lynn MJ, Derdeyn CP, et al.; SAMMPRIS Trial Investigators. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 2011;365(11):993-1003. 15. Powers WJ, Clarke WR, Grubb RL Jr, et al; COSS Investigators. Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial. JAMA. 2011;306(18):1983-1992. APPENDIX: TOPIC QUESTIONS Nominated by ‘Web’ 1) What is the optimal management of patients with asymptomatic carotid artery stenosis?

Population: Older patients of both genders and any ethnicity should be included in studies

Importance: The most relevant randomized trial addressing asymptomatic carotid disease is arguably obsolete (ACAS, 1995) since it was completed before use of statin agents became widespread. Because the margin of benefit of intervention over medical therapy was already narrow at that time, more effective medical therapy may have made intervention equivalent to medical therapy.

Nominated by National Institute of Health (NIH) 1) Revascularization vs. intensive medical management of asymptomatic carotid disease.

Topic 5: “Cerebral Adrenoleukodystrophy (ALD )”

Comparative effectiveness of early versus late bone marrow transplant treatment for children affected by adrenoleukodystrophy (ALD).

Criteria Brief Description Introduction Overview/definition DESCRIPTION OF CONDITION of topic • Adrenoleukodystrophy (ALD) is an inherited disorder that affects how cells break down nutrients called very long chain fatty acids. These acids accumulate in cells and affect organs including the brain, adrenal glands, and testes. The childhood cerebral form of the disease is the most severe form. • ALD may be familiar from the movie “Lorenzo’s Oil.” • ALD is linked to the X chromosome: o Boys have only one X chromosome, so carriers almost always develop symptoms. o Girls have two X chromosomes, but 50-65% of carriers may still develop symptoms later in life. Relevance to SYMPTOMS/OUTCOMES patient-centered • Symptoms vary in severity and timing: outcomes o 35% of male patients develop severe nerve symptoms during childhood, starting with behavioral problems and progressing to cognitive deficits, blindness, and quadriplegia. The adrenal glands are often affected. . Average age of onset is 7 years. . Progresses to vegetative state (similar to a coma) within one to two years. . Death occurs within five to ten years. o 45-50% of male patients develop a less severe form of the disease during adulthood (called adrenomyeloneuropathy or AMN). This causes a slowly progressing paralysis and can affect the adrenal glands. When female patients develop symptoms, it resembles AMN. o 5-10% of patients develop adrenal gland problems only. • Other outcomes: o Decreased quality of life for both patient and family o Reproductive concerns (female carrier has 50% chance of having an affected son and a 50% chance of passing the gene to a daughter) o Considerable uncertainty about benefits and harms of screening (among male patients, there is no good way to predict who is going to develop symptoms, when they will occur, or their severity) Burden on Society Recent incidence INCIDENCE (NEW CASES)1 and prevalence in o 1 in 42,000: hemizygotes (having only one of a given pair of genes, ie, males) populations and o 1 in 16,800: including both hemizygotes and heterozygotes (having two different forms of subpopulations the gene, ie, females) PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE CONDITION) o Approximately 27,000 people in the United States (0.001-0.009% of population) Effects on patients’ QUALITY OF LIFE quality of life, • Severity of ALD varies, but all patients who develop symptoms experience some decrease in productivity, quality of life. In the severe childhood form (30-35% of patients), the impact on quality of life functional is major.

capacity, • Like all childhood illnesses, cerebral ALD has substantial effects on the whole family. mortality, use of PRODUCTIVITY health care • Affected children have an impact on parents’ productivity. services • The impact for affected adults depends on the severity of symptoms. FUNCTIONAL CAPACITY • The severe childhood form limits patients’ ability to do normal daily activities. • The less severe form (AMN) can lead to total disability in up to 20% of cases. MORTALITY • Mortality is close to 100% within five to ten years of diagnosis for the severe childhood form. AMN is also associated with early death in up to 20% of cases. How strongly does Though ALD is rare, it carries a severe burden for people who have it and their families. this overall societal burden suggest that CER on alternative approaches to this problem should be given high priority? Options for Addressing the Issue Based on recent There are no systematic reviews on the severe childhood form of ALD, although there was a systematic narrative review in 2012 of hematopoietic stem cell transplantation (HSCT) as a treatment in reviews, what is pediatric populations.2 This report attempted to conduct a systematic review of AMN, but known about the pediatric data were too limited. A summary of the available evidence follows. relative benefits and harms of the SCREENING/EARLY DIAGNOSIS available • Tests are available, but there is no direct evidence of improved outcomes for symptoms or management mortality based on identification of ALD in newborns. options? o Potential benefits include family planning, avoiding a lengthy process of diagnosis after symptoms develop. o Potential harms include false-positive results, identification of newborns who will not develop symptoms until later in life, complications of unproven therapies, identification of carriers and the resulting potential negative impact on quality of life. TREATMENT 3,4 o Replacement of adrenal gland hormones o No uncertainty; benefits (prevention of mortality) greatly outweigh harms when adrenal insufficiency is present (70% of patients with ALD). 3,5 o Dietary therapy (Lorenzo’s oil) o Uncontrolled studies have been conducted in asymptomatic boys discovered on screening, boys with the severe childhood form, and adults with AMN. o Potential benefits include a reduction or delay in onset of developing cerebral disease in asymptomatic patients (but no benefit if already present); may also slow pace of symptom progression in AMN. o Potential harms include causing low platelet count, abnormal liver tests. 30

3,6-11 o HSCT o Potential benefits include improving neurologic symptoms and mortality in boys with early symptoms or mild abnormalities on MRI: . Little evidence for benefit in patients with advanced symptoms or MRI findings. . Not recommended for patients with no abnormality on MRI, since half will not develop brain disease. o Potential harms include death, severe infections, graft-versus-host disease, need for immunosuppression drugs. o Medical treatments with lovastatin or phenylacetate show minimal evidence of benefits and harms. o Gene therapy shows minimal evidence of benefits and harms. What could new New research in three main areas could contribute to better patient-centered outcomes: research 1) Better understanding of benefits, harms, and costs associated with screening for ALD in contribute to newborn males would potentially facilitate starting dietary therapy early and improving achieving better survival and neurologic outcomes. Additional outcomes to study could be patient and family patient-centered quality of life and reproductive decisionmaking. outcomes? 2) Further study is needed to define which patient subgroups benefit most from HSCT in terms of neurologic symptoms and survival. Existing data are limited to case series studies.6-9 Clinical trials to evaluate HSCT in predefined patient subgroups (for example, patients with severe childhood ALD with minimal symptoms, patients with severe childhood ALD with moderate-to-severe symptoms, and patients with less severe forms such as AMN) could examine outcomes such as survival, neurologic symptoms, and quality of life. 3) Research comparing novel, less-established therapies (gene therapy, treatment with lovastatin) to better established therapies (HSCT, dietary therapy) in predefined patient subgroups is needed to increase understanding of whether and how these therapies improve patient-centered outcomes. Have recent The development of gene therapy as an option for treating ALD is a promising innovation and innovations made merits further research. research on this topic especially compelling? How widely does VARIABILITY IN CARE care now vary? o Because ALD is a rare disease with variable presentation among patients, care requires special expertise. Variability in care exists now but likely is appropriate given that patients present very differently. What is the pace of RECENT PUBLICATIONS 2 other research on o In 2012 there was a comparative effectiveness review that evaluated four case-series this topic (as studies of HSCT in pediatric patients with severe childhood form of ALD.6-9 One additional indicated by case-series report of HSCT on the severe form of ALD has since been published. recent ONGOING TRIALS publications and o There are at least eight ongoing studies in ClinicalTrials.gov relating to ALD, three of which ongoing trials)? address HSCT, and two which address dietary or medical therapies. There is a recently completed study comparing Lorenzo’s oil with placebo in adults with AMN, but results are not yet available. Outcomes assessed in these studies include neurological function and survival. 31

How likely is it that The greatest limitation is the lack of randomized controlled trials and other controlled studies of new CER on this HSCT, dietary therapy, gene therapy, and other treatments. Carrying out controlled studies may topic would be difficult, however, due to the rarity of ALD and ethical concerns about withholding treatment provide better in control patients for this often-fatal disease. Another limitation is that variation in disease information to symptoms from patient to patient makes it difficult to generalize findings of existing studies to all guide clinical patients. decision making? KEY UNCERTAINTIES IN CLINICAL DECISIONMAKING: • What are the comparative benefits and harms of screening with different tests compared with each other and with no screening? • Do the benefits of HSCT outweigh the potential harms in specific subgroups of patients with ALD? • What is the role of newer therapies for ALD, such as gene therapy, compared with other therapies?

LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES: o Because accurate screening tests exist, additional well-designed studies would likely be able to reduce uncertainty in the area of ALD screening. Well-designed studies comparing different therapies (HSCT, dietary therapy, gene therapy) in different patient subgroups would help reduce uncertainty in treating ALD. Potential for New Information to Improve Care and Patient-Centered Outcomes What are the FACILITATORS facilitators and o Technical experience with HSCT at specialized centers for ALD and other conditions barriers that o Potential high degree of acceptance for positive findings since ALD is a condition with would affect the extremely poor prognosis and high impact on families implementation of BARRIERS new findings in • Variability in clinical presentation making it difficult to generalize findings to all patients practice? • Costs of treatment • Availability of donor stem cells and access to specialized therapies such as HSCT o Potential for reluctance to accept negative findings since ALD is a condition with extremely poor prognosis and high impact on families How likely is it that EVIDENCE OF BENEFIT the results of new o If there is evidence of benefit, it is extremely likely that research results would be research on this implemented quickly. topic would be EVIDENCE OF NO BENEFIT OR HARM implemented in o Depending on the balance of benefits and harms, implementation may be less likely if there practice right is insufficient patient demand or provider uncertainty. away? Would new Because ALD is a rare disease, often having a long delay between diagnosis and outcomes, the information from number of studies is necessarily small, and so findings from completed studies are likely to be CER on this topic relevant for a relatively long period compared with more common diseases having a shorter time remain current for to measurement of outcomes. several years, or would it be

rendered obsolete quickly by subsequent studies?

REFERENCES: 1. Bezman L, Moser AB, Raymond GV, Rinaldo P, Watkins PA, Smith KD, Kass NE, Moser HW. Adrenoleukodystrophy: incidence, new mutation rate, and results of extended family screening. Ann Neurol. 2001;49(4):512-517. 2. Ratko TA, Belinson SE, Brown HM, Noorani HZ, Chopra RD, Marbella A, Samson DJ, Bonnell CJ, Ziegler KM, Aronson N. Hematopoietic Stem-Cell Transplantation in the Pediatric Population. Comparative Effectiveness Review No. 48. (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. HHSA 290-2007-10058.) AHRQ Publication No. 12-EHC018-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2012. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published February 2012. Accessed datexx. 3. Moser HW, Raymond GV, Dubey P. Adrenoleukodystrophy: new approaches to a neurodegenerative disease. JAMA. 2005;294(24):3131-3134. 4. Dubey P, Raymond G, Moser AB, Kharkar S, Bezman L, Moser HW. Adrenal insufficiency in asymptomatic adrenoleukodystrophy patients identified by very long chain fatty acid screening. J Pediatr. 2005;146:528-532. 5. Moser HW, Raymond GV, Lu SE, Muenz LR, Moser AB, Xu J, Jones RO, Loes DJ, Melhem ER, Dubey P, Bezman L, Brereton NH, Odone A. Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with Lorenzo’s oil. Arch Neurol. 2005;62:1073-1080. 6. Aubourg P, Blanche S, JambaquéI, Rocchiccioli F, Kalifa G, Naud-Saudreau C, Rolland MO, DebréM, Chaussain JL, Griscelli C. Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation. N Engl J Med. 1990;322(26):1860-1866. 7. Loes DJ, Stillman AE, Hite S, Shapiro E, Lockman L, Latchaw RE, Moser H, Krivit W. Childhood cerebral form of adrenoleukodystrophy: short-term effect of bone marrow transplantation on brain MR observations. AJNR Am J Neuroradiol 1994;15(9):1767-1771. 8. Shapiro E, Krivit W, Lockman L, Jambaqué I, Peters C, Cowan M, Harris R, Blanche S, Bordigoni P, Loes D, Ziegler R, Crittenden M, Ris D, Berg B, Cox C, Moser H, Fischer A, Aubourg P. Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy. Lancet. 2000;356:713-718. 9. Peters C, Charnas LR, Tan Y, Ziegler RS, Shapiro EG, DeFor T, Grewal SS, Orchard PJ, Abel SL, Goldman AI, Ramsay NK, Dusenbery KE, Loes DJ, Lockman LA, Kato S, Aubourg PR, Moser HW, Krivit W. Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999. Blood. 2004;104:881-888. 10. Miller WP, Rothman SM, Nascene D, Kivisto T, DeFor TE, Ziegler RS, Eisengart J, Leiser K, Raymond G, Lund TC, Tolar J, Orchard PJ. Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. Blood. 2011;118(7):1971-1978. 11. Mahmood A, Dubey P, Moser HW, Moser A. X-linked adrenoleukodystrophy: therapeutic approaches to distinct phenotypes. Pediatr Transplant. 2005;9 Suppl 7:55-62.

Appendix: Topic Question

Nominated by ‘Web’

1) Adrenoleukodystrophy (ALD) is an X-linked disorder with an incidence of 1 in 17,000 males. It is characterized by an increase in very long chain fatty acids (VLCFA) in plasma and brain. In approximately 40% of boys with ALD, an acute inflammatory process develops within the central nervous system (CNS). The median age of onset of this neuroinflammatory process is age 7. Untreated, it is rapidly progressive and lethal, generally within several years of onset. Early in the course of cerebral ALD (C-ALD), bone marrow transplantation is effective in achieving disease stabilization. While patients early in the course of their disease have good outcomes with transplantation, many boys are not diagnosed until they are more advanced, limiting the ability of transplantation to stabilize the disease process. The question therefore becomes “Can we tell parents making decisions for their affected boys who is likely to have a reasonable outcome, and who is not?”

a. Population: This disease is limited to boys, based on how it is inherited. In regards to demographics, it affects all ethnic groups relatively similarly.

b. Importance: Imagine that you have a boy that you have always thought is absolutely healthy, but he starts doing worse in school, is complaining of vision issues or hearing issues, and at some point an MRI is done. The MRI scan suggests ALD and the disease is confirmed with a blood test. Then the parents learn that not only does their son have an inherited disease affecting the brain, but that it is progressive and will be lethal within a few years. There is one potential intervention, which is bone marrow transplantation. However, in some situations, a transplant may stop the disease from getting worse, but in others a transplant may lead to a boy that is devastated neurologically and will require virtually total care, possibly for decades. It is extremely important to develop methods to determine who should be transplanted and who should not. This is the goal of our proposed study.

Topic 6: “Coronary Artery Disease (CAD)”

Comparative effectiveness of coronary artery bypass surgery (CABG) and percutaneous coronary intervention (PCI) for treatment of adults with coronary artery disease.

Criteria Brief Description Introduction Overview/definition DESCRIPTION OF CONDITION of topic • Coronary artery disease (CAD) is caused by atherosclerosis, a thickening or hardening of the coronary arteries, which can lead to narrowing and obstruction of blood flow to the heart muscle.

• CAD can be present but not cause symptoms (asymptomatic).

• CAD can result in chest pain (angina) or a heart attack (myocardial infarction or MI for short).

• Treatment of CAD depends on the individual patient:

o All patients are given medications as needed for conditions they have that contribute to CAD, such as medications to prevent blood clots (blood thinners), treat high blood pressure, treat diabetes, and lower their cholesterol if it is too high.

o As the disease progresses, some patients require invasive treatments, such as percutaneous coronary interventions (PCI), or coronary artery bypass graft (CABG) surgery, which is even more invasive and with a longer recovery.1

Relevance to patient- SYMPTOMS centered outcomes • Shortness of breath

• Chest pain (angina)

• Heart attack (or MI), symptoms of which can include chest pain or crushing chest pain, pain and numbness down an arm, neck pain, back pain, jaw pain, nausea, sweating

OUTCOMES • Quality of life (freedom from chest pain, ability to do self-care and activities), prevention of future heart attacks or strokes, survival, and prevention of complications (such as prolonged hospital stay, infection, bleeding) from the invasive treatments of PCI and CABG

PATIENT CHARACTERISTICS • Characteristics include, sex, race, age, comorbidities (hypertension, diabetes, high cholesterol, chronic kidney disease, congestive heart failure), and lifestyle choices (heavy alcohol consumption, tobacco use, sedentary lifestyle).

• These characteristics affect disease progression and thus treatment of the patient.

SEVERITY OF CAD 36

• Determined by assessing the number and location of vessels with CAD and the degree of constriction (stenosis) of the diseased vessels

PROCEDURE/HEALTH CARE CENTER VARIABLES • PCI variables include choice of opening a vessel with balloon angioplasty or placing a stent (small device to help hold vessels open)

• CABG variables include open-bypass (chest bone is opened), performed either

o “On pump” (heart is stopped, heart-lung bypass machine is used)

o “Off pump” (heart remains beating, no pump needed, heart does not need to be restarted but is technically more difficult for surgeon)

• MIDCAB procedure, a relatively new type of bypass, is less invasive (chest bone is not opened); it involves:

o Small cuts made on the left side of the chest between the ribs

o Repair limited to one or two coronary arteries

o Performing “on pump” or “off pump” • Centers where more PCI and CABG procedures are performed have better outcomes, suggesting that experience is an important factor in improving how well a patient does after the procedure.

Burden on Society Recent incidence and INCIDENCE (NEW CASES) prevalence in • Rates of first heart attack or stroke in men rise from 3 per 1000 (aged 35-44) to 74 per populations and 1000 (aged 85 to 94).2 subpopulations • For women, comparable rates occur 10 years later in life.

• The gap between men and women narrows with advancing age.2

• 600,000 Americans die from heart disease each year, which is one in every four deaths.3 • CAD is the most common type of heart disease, killing more than 385,000 people annually.3

PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE CONDITION) • Age-adjusted prevalence of CAD in a general US population was estimated at about 6% in 2010, with higher prevalence in certain subgroups including patients over 65 years of age (19.8%), patients with diabetes (35%), and patients with chronic kidney disease (38- 37

65%).

Effects on patients’ QUALITY OF LIFE quality of life, • Quality of life is associated with not having chest pain (known as angina). productivity, functional capacity, o Patients undergoing CABG (rather than PCI) had less angina during the period from six mortality, use of months to three years after the procedure. health care services o The amount of chest pain was the same for both procedures after three years.

o Older patients had less angina in general. PRODUCTIVITY • Lost productivity cost about $172 billion in 2010.4

FUNCTIONAL CAPACITY • CAD is one of the top three conditions causing disability in the United States.

MORTALITY • CAD is the leading cause of death in the United States in both men and women.

• Rate of death attributable to CAD decreased by 30% (from 1999 to 2009).

• African Americans with CAD die at a faster rate than Caucasians with CAD.

USE OF HEALTH CARE SERVICES • In the United States in 2009, ~596,000 patients underwent PCI, and ~242,000 patients underwent CABG.

• PCI usually involves placement of a stent to keep a diseased vessel open.

• In 2010, CAD was the leading diagnosis across US hospitalized patients.

How strongly does BURDEN this overall societal • Given the large number of CAD patients and the aging society, priority should be given to burden suggest that comparative-effectiveness research to determine the treatments with the best outcomes CER on alternative based on patient characteristics and severity of CAD. approaches to this problem should be given high priority?

Options for Addressing the Issue Based on recent Knowledge about benefits and harms of treatment options, based on a recent systematic systematic reviews, review,5 include: what is known about BENEFITS the relative benefits • Overall survival after PCI and CABG are now quite similar, with PCI being the less invasive and harms of the option. available management • Patients with 1-vessel disease (non-left anterior descending vessel) have better survival options? with PCI.

• Patients with 3-vessel, or left main, disease have better survival with CABG.

• In patients with diabetes and heart failure, there was no clear difference between PCI and CABG in terms of survival.

HARMS • Risk of periprocedural heart attack was not significantly different with CABG compared to PCI.

• Risk of periprocedural stroke was higher with CABG compared to PCI.

• Complications were higher in older patients for both CABG and PCI.

• Patient results were worse for both procedures at hospitals where they were performed infrequently.

What could new An AHRQ report in 20106 identified four areas where future research is indicated to answer research contribute areas of uncertainty: to achieving better 1 Studies of the comparative effectiveness and safety of PCI vs. CABG should be done using patient-centered existing data (performing meta-analyses of individual patient data available from prior outcomes? research projects).

2 Studies should evaluate the ability of tests to predict how well a person will do with different types of revascularization procedures. Such tests would include both invasive tests (arteriography) and noninvasive tests (magnetic resonance [MRI or computed tomography angiography], CT scan, and exercise treadmill testing).

3 Studies should enhance patient participation by asking for and measuring patient preferences as well as involving patients in decisions regarding their care.

4 Studies should develop performance measures that provide feedback to health care providers in order to improve outcomes for their patients.

Have recent • Drug-eluting stents (DES) are a newer technology than bare-metal stents (BMS). innovations made research on this • Use of DES with PCI has increased markedly over the past decade. topic especially compelling? • Most doctors who do PCI and CABG believe that there are fewer heart attacks and strokes in patients who receive DES (compared with BMS), but there are not enough data to support this belief.

• A 2007 AHRQ report5 included only one DES trial, but there are now six DES vs. CABG studies completed, with additional available data.

• An updated comparative-effectiveness report comparing DES with CABG could help determine whether DES is truly superior to BMS and further help define which populations of CAD patients do better with the less invasive PCI treatment (rather than CABG).

How widely does care VARIABILITY IN CARE now vary? • Overall, there are fewer invasive procedures being done, and of those performed, rates for the less invasive PCI have increased.

o An analysis of Medicare patients from 2001 to 2009 showed an increase for PCI of 1.3% per 1000 beneficiaries.

o During the same period, there was an annual decrease of CABG by 5%.

• An analysis of North Carolina data from 2003 to 20097 showed that rates of all invasive procedures per 100,000 population declined:

o 24% decrease in catheterization rates

o 16% decrease in PCI rates

o 35% decrease in CABG rates What is the pace of RECENT PUBLICATIONS other research on • In a MEDLINE search over the past 5 years, 26,550 citations were identified related to this topic (as treatment of CAD: indicated by recent publications and o Randomized controlled trials (RCTs): 2853 ongoing trials)? o Cohort studies: 9831

o Systematic reviews: 1827 • In 2007, AHRQ published a comparative-effectiveness report of PCI vs. CABG for CAD5; an 40

addendum was published in February 2010 with meta-analysis of individual patient data from 10 of the 12 trials included in the 2007 report.

• In September 2010, AHRQ published a future research needs report about PCI vs. CABG for CAD.6

ONGOING TRIALS • A search of ClinicalTrials.gov lists 167 ongoing trials.

• Several projects are evaluating comparisons of single modalities; for example, DES vs. BMS in subgroups (elderly, diabetes); off-pump vs. on-pump CABG.

• There are few RCTs of PCI vs. CABG due to the difficulty in recruiting cardiologists and cardiac surgeons who are willing to randomize patients.

• An indirect or network meta-analysis combining single-modality studies of DES vs. BMS and the various CABG modalities could be performed to increase the number of PCI vs. CABG studies available for comparison.

How likely is it that KEY UNCERTAINTIES IN CLINICAL DECISION MAKING new CER on this • Previous systematic reviews were based on older technologies (balloon angioplasty or topic would provide BMS). better information to guide clinical • DES use has increased over the past decade. decision making? • Findings from RCTs may not translate to results in real-world settings, where patients with multiple comorbidities are treated for CAD.

• RCTs have not been large enough to evaluate effectiveness in subgroups.

• Provider and patient preferences—rather than evidence—are used in determining the choice of invasive therapy to treat individual CAD patients.

REDUCING UNCERTAINTIES • Updated CER comparing DES and BMS, by looking at earlier data from BMS vs. CABG studies and then newer data comparing DES vs. CABG, would reduce uncertainty about newer technologies.

• Pooling patient-level data would make it possible to have more information about optimal care for certain patient subgroups.

• Providers may be able to help patients make more informed decisions with better evidence.

Potential for New Information to Improve Care and Patient-Centered Outcomes What are the FACILITATORS facilitators and • Professional societies and patient advocacy groups help to implement new guidelines as barriers that would more information is obtained. affect the implementation of • Educational initiatives, similar to “Get With the Guidelines” for MI and heart failure care, new findings in could be implemented. practice?

BARRIERS • Physician and patient preferences, regardless of what the evidence may show, will always factor into decisions about the use of invasive procedures.

• Some patients may choose a certain procedure due to insurance requirements, fear of surgery, or inability to take time away from work and caregiver responsibilities.

How likely is it that • Physician and patient preferences influence much of the variability in PCI and CABG use the results of new across the nation. This situation mandates additional research to increase our research on this understanding of how particular types of disease, demographics, and comorbidities affect topic would be outcomes. This knowledge will help patients to optimize their treatments. implemented in practice right away? • Implementation would require collaborative effort among professional societies and patient advocacy groups as well as health care providers in order to educate patients and determine the best care for them.

Would new • PCI and CABG have been the main invasive treatments for over two decades. information from CER on this topic • While advances in PCI and CABG techniques are still being developed, it is likely that results remain current for from CER on this topic will be relevant for several years. several years, or would it be rendered • Further, this is a prime group to work on this type of shared decision making model, obsolete quickly by because there are already strong professional societies and guideline groups in place. subsequent studies?

References:

1. Incidence and Prevalence: 2006 Chart Book on Cardiovascular and Lung Diseases. Bethesda, MD: National Heart, Lung, and Blood Institute; 2006.

2. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation. 2013;2127(1):e6-e245. PMID: 23239837.

3. Kochanek KD, Xu JQ, Murphy SL, Miniño AM, Kung HC. Deaths: final data for 2009. National vital statistics reports. 2011;60(3).

4. Fang J, Shaw, KM, Keenan NL. Prevalence of Coronary Heart Disease – United States, 2006-2010. MMWR October 14, 2011;60(40):1377-1381.

5. Bravata DM, McDonald KM, Gienger AL, et al. Comparative Effectiveness of Percutaneous Coronary Interventions and Coronary Artery Bypass Grafting for Coronary Artery Disease. Comparative Effectiveness Review No. 9. (Prepared by Stanford-UCSF Evidence-based Practice Center under Contract No. 290-02-0017.) Rockville, MD: Agency for Healthcare Research and Quality; 2007. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published October 2007.

6. Trikalinos TA, Dahabreh IJ, Wong J, et al. Future Research Needs for the Comparison of Percutaneous Coronary Interventions with Bypass Graft Surgery in Nonacute Coronary Artery Disease. Future Research Needs Paper No. 1. (Prepared by the Tufts Evidence-based Practice Center under Contract No. 290-2007-10055-I.) AHRQ Publication No. 10-EHC068-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2010. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published September 2010.

7. Jones WS, Patel MR, Holleran SA, et al. Trends in the use of diagnostic coronary angiography, percutaneous coronary intervention, and coronary artery bypass graft surgery across North Carolina. Am Heart J. 2011;162(5):932-937. PMID: 22093211.

APPENDIX: Topic Questions

Nominated by ‘Web’

1) How can we be certain that patients are being offered the proper treatment for coronary artery disease … percutaneous coronary intervention vs. coronary artery bypass surgery? How can we know whether guidelines are being followed in every institution?

Population: All patients who have coronary artery disease, which would affect men and women of all ethnicities, but usually in the relatively elderly population.

Importance: We know outcomes are affected by approach ... PCI vs. CABG. Are we using concordant decision making to assure that patients are being referred for the proper treatment? Best care would be most cost- effective in the long run.

Nominated by NIH

Comparative effectiveness of PCI vs. CABG [specifically for]:

Subpopulations: 43

• Age >75 years • Prior PCI • Diabetes • Women • Congestive heart failure • Stage 3 or 4 of chronic kidney disease

Comparisons: • BMS vs. on-pump traditional CABG with arterial grafts • DES vs. on-pump traditional CABG with arterial grafts

Topic 7: “Ductal Carcinoma”

Comparative effectiveness of management strategies for ductal carcinoma in situ (DCIS) among women who have had screening mammography.

Criteria Brief Description Introduction Overview/definition DESCRIPTION OF CONDITION of topic • Ductal carcinoma in situ (DCIS): o Abnormal cells that look like cancer cells lining the milk ducts of the breast that have not invaded the underlying breast tissue • DCIS itself is not an invasive cancer, but may become an invasive breast cancer • Main clinical issue is that there is no reliable way to predict which patients with DCIS will go on to develop invasive cancer and which will not Relevance to SYMPTOMS/OUTCOMES patient-centered • Symptoms outcomes o Most DCIS is asymptomatic and detected through screening mammography o Some women have nipple discharge or feel a lump • Outcomes o Various treatment options for DCIS present trade-offs relevant to patient-centered outcomes such as symptoms, function, and well-being Burden on Society Recent incidence • INCIDENCE (NEW CASES) & PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE and prevalence in CONDITION) populations and o Approximately 54,944 new cases of DCIS are expected to occur among US women in subpopulations 2013 o While the annual incidence of DCIS is less than that of invasive breast cancers, expanded use of screening mammography has led to a dramatic increase in the diagnosis of DCIS (32.5 cases per 100,000 women).1 . 25% of all breast “cancers” diagnosed in the United States are DCIS • KEY SUBPOPULATIONS 1 o Increased risk of DCIS is associated with: . Use of screening mammography . Older age (peaks at ages 60-74) . Race (Caucasian vs. African American) . Family history of DCIS or positive for BRCA 1/2 genes . Increased breast density . None or one child and older age at birth of first child Effects on patients’ QUALITY OF LIFE quality of life, • Anxiety/uncertainty surrounding significance of diagnosis productivity, • Need for long-term follow-up functional • Treatments may have impact on body image, sexual functioning capacity, • Other potential side effects include lymphedema (swelling of arm because of blockage of mortality, use of lymphatic flow) if extensive lymph node biopsy performed health care MORTALITY services • 98% survival after diagnosis of DCIS

How strongly does • Continued use of screening mammography, along with increasing prevalence of risk factors this overall (baby boom population in highest risk group, later age at first birth) suggests overall societal burden incidence is likely to rise suggest that CER • Low effect on mortality means that number of women living with diagnosis of DCIS will be on alternative very high approaches to this problem should be given high priority?

Options for Addressing the Issue Based on recent Four recent systematic reviews explored diagnosis and treatment options.1-4 They found: systematic reviews, what is SCREENING/EARLY DIAGNOSIS known about the • DCIS is primarily detected through screening mammography relative benefits • There are no reliable methods for distinguishing clinically-relevant DCIS (likely to progress to and harms of the invasive cancer) from DCIS that would never become symptomatic or develop into invasive available cancer management options? CLINICAL MANAGEMENT AND TREATMENT • Decisions about clinical management and treatment (and evaluation of harms and benefits) are complicated by the fact that the proportion of untreated DCIS that would develop into invasive cancers of the breast is not known. • Current clinical options include: o Mastectomy o Breast-conserving therapy alone o Breast-conserving therapy plus radiation therapy o Breast-conserving therapy plus radiation therapy, plus tamoxifen • Benefits: o Most important potential benefit for any treatment is prevention of mortality from invasive breast cancer, but without knowing prognosis for individual cases of DCIS, this is difficult to evaluate o Additional potential benefits include: . For DCIS destined to become invasive cancer, earlier treatments may be less disfiguring and/or have fewer side effects . Prevention of recurrence of DCIS (but if DCIS was never going to become invasive cancer, this may not really be a benefit) • Harms: o Effects of mastectomy on body image, relationships, and other factors o Lymphedema o Menopausal symptoms from tamoxifen o Increased risk of abnormal growth of lining of uterus with tamoxifen, leading to abnormal bleeding or endometrial cancer What could new There are limited randomized studies of DCIS treatment on which to base decisions regarding the

research trade-offs between the various treatment options. contribute to achieving better patient-centered outcomes? Have recent No recent innovations, but to date there have been limited randomized studies of existing DCIS innovations made management and treatment options research on this topic especially compelling? How widely does VARIABILITY IN CARE care now vary? • Variability in both surgical and postoperative management, with resulting variability in outcomes5-11 What is the pace of RECENT PUBLICATIONS other research on • MEDLINE search from 1/1/2008–3/27/2013: total 136 this topic (as o 6 randomized controlled trials/therapy indicated by o 65 cohort studies recent o 12 meta-analyses or systematic reviews publications and ongoing trials)? ONGOING TRIALS • There are at least 25 ongoing studies listed in ClinicalTrials.gov • NIH Reporter (a database of NIH funded studies) lists: o 89 projects o 43 publications How likely it is that KEY UNCERTAINTIES IN CLINICAL DECISION MAKING new CER on this • Biggest uncertainty in clinical decision making is which DCIS cases are truly “pre-cancers” topic would • Patient preferences for different outcomes also unclear provide better LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES information to • There are few randomized controlled trials of promising treatments for women with DCIS. guide clinical • CER unlikely to reduce uncertainty about clinical significance—identifying biomarkers, impact decision making? of management on invasive cancer/mortality more of a basic science, NIH issue • Patient-centered CER could be highly useful if it focused on patient preferences, quality-of- life, and anxiety issues rather than on traditional cancer outcomes Potential for New Information to Improve Care and Patient-Centered Outcomes What are the FACILITATORS facilitators and • High degree of uncertainty barriers that • Given the high survival rate, many of the most important outcomes relevant to CER are would affect the related specifically to patient preferences implementation of BARRIERS new findings in • Significant anxiety about potential breast cancer diagnosis may contribute to preferences for practice? overly aggressive treatment options • Possibly provider incentives/disincentives for maintaining current practice patterns How likely is it that EVIDENCE OF BENEFIT the results of new • High likelihood of implementation if evidence of benefit 48

research on this EVIDENCE OF NO BENEFIT OR HARM topic would be • Implementation of less aggressive practices related to screening/treatment often more implemented in difficult because of residual patient anxieties about risk and potential provider incentives for practice right recommending specific treatments away? • Relative weighting of harms may also create barriers (eg, some patients/providers may feel that “over-diagnosis” is worth preventing cancer) Would new There are few randomized controlled trials of promising treatments for women with DCIS. It is information from highly likely that new information on the management of DCIS will be current for several years. CER on this topic remain current for several years, or would it be rendered obsolete quickly by subsequent studies?

REFERENCES:

1. Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal carcinoma in situ of the breast: a systematic review of incidence, treatment, and outcomes. J Natl Cancer Inst. 2010;102(3):170-178. 2. Early and locally advanced breast cancer: diagnosis and treatment. Clinical guidelines CG80. UK National Institute for Health and Care Excellence (NICE); February 2009. 3. Goodwin A, Parker S, Ghersi D, Wilcken N. Post-operative radiotherapy for ductal carcinoma in situ of the breast. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD000563. DOI:10.1002/14651858.CD000563.pub6. 4. Staley H, McCallum I, Bruce J. Postoperative tamoxifen for ductal carcinoma in situ. Cochrane Database of Systematic Reviews 2012, Issue 10. Art. No.: CD007847. DOI: 10.1002/14651858.CD007847.pub2. 5. Baxter NN, Virnig BA, Durham SB, Tuttle TM. Trends in the treatment of ductal carcinoma in situ of the breast. J Natl Cancer Inst. 2004;96(6):443–448. 6. Katz J, Lantz PM, Janz NK, et al. Patterns and correlates of local therapy for women with ductal carcinoma-in-situ. J Clin Oncol. 2005;23(13):3001–3007. 7. Partridge A, Winer JP, Golshan M, et al. Perceptions and management approaches of physicians who care for women with ductal carcinoma in situ. Clin Breast Cancer. 2008;8(3):275-280 8. Rakovitch E, Pignol JP, Chartier C, et al. The management of ductal carcinoma in situ of the breast: a screened population-based analysis. Breast Cancer Res Treat. 2007;101(3):335–347. 9. Tuttle TM, Jarosek S, Habermann EB, et al. Increasing rates of contralateral prophylactic mastectomy among patients with ductal carcinoma in situ. J Clin Oncol. 2009;27(9):1362–1367. 10. Gold HT, Dick AW. Variations in treatment for ductal carcinoma in situ in elderly women. Med Care. 2004;42(3):267- 275. 11. Dick AW, Sorbero MS, Ahrendt GM, et al. Comparative effectiveness of ductal carcinoma in situ management and the roles of margins and surgeons. J Natl Cancer Inst. 2011;103(2):92-104.

APPENDIX: TOPIC QUESTIONS 49

Nominated by the Institute of Medicine (IOM):

• Compare the effectiveness of management strategies for ductal carcinoma in situ (DCIS).

Topic 8: “Gestational Diabetes”

Comparative effectiveness of medical, surgical and lifestyle treatment options in the prevention and treatment of gestational diabetes.

Criteria Brief Description Introduction Overview/definition DESCRIPTION OF CONDITION of topic • Normal pregnancy increases the body’s need for insulin, resulting in increases in blood sugar. • Some women do not produce enough insulin, or their bodies cannot use the insulin well enough. • As blood sugar rises, the risk of certain adverse outcomes for mother and infant increase. • Although the association between increasing blood sugar and increasing risk of adverse outcomes is continuous, there are different definitions for the threshold for distinguishing “gestational diabetes” (GDM) from “normal” elevations in blood sugar. Relevance to SYMPTOMS/OUTCOMES patient-centered • Increased blood sugar  more sugar available to the baby  larger baby than normal outcomes (relative proportions of different parts of baby’s body also different, affecting labor and delivery) • Most common adverse outcomes of GDM related to larger babies • Outcomes for babies o Short term . Shoulder dystocia During labor, the head delivers but the baby’s shoulders get stuck—this is potentially fatal. However, the most common adverse outcome is injury to the nerves around the baby’s neck/shoulders, which can result in permanent disability to the baby. . Postdelivery hypoglycemia (low blood sugar) . Other respiratory and metabolic complications o Long term . Higher rates of obesity, hyperactivity/attention disorders, diabetes later in life (although unclear if treatment during pregnancy affects these outcomes) • Outcomes for mothers o Short term . Association with preeclampsia (high blood pressure and protein in the urine, occasionally leading to seizures); increases risk of death for both mother and baby, sometimes necessitating premature delivery of the baby . Increased risk of Cesarean section (C-section), both because of difficult labor due to large baby and lower physician threshold regarding performing C-sections because of concerns about shoulder dystocia . Injury to the vagina, bladder, and/or rectum from large baby, which may lead to problems with incontinence, prolapse . NIH Consensus Panel noted paucity of data on quality of life, particularly anxiety1 2 o Long term . 5-10% of women diagnosed with GDM have overt diabetes, usually type 2, diagnosed immediately after pregnancy . 35-60% chance of developing overt diabetes in next 10-20 years

Burden on Society Recent incidence INCIDENCE (NEW CASES) & PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE and prevalence in CONDITION) populations and • Rates of GDM vary across studies (in part due to varying definitions for GDM) subpopulations • Using older definitions, rates of GDM range from 2-10% of pregnancies in the United States (of the approximately four million deliveries, 80,000-400,000 women, annually)2 • New proposed definition would increase proportion of women diagnosed with GDM to 15- 20% of pregnancies (600,000-800,000 women annually)3 • Risk increased in some ethnic populations o African American o Hispanic/Latino American o Native American o Pacific Islander • Risk increased in older women, obese women, and women with family history of diabetes o Incidence increasing over time as average age of pregnancy increases and prevalence of obesity in population increases Effects on patients’ • QUALITY OF LIFE quality of life, o Diagnosis of GDM carries significant self-management burden for mothers (checking productivity, sugar levels multiple times a day) functional o Having a larger baby can cause birth trauma or more C-sections, which impact mother’s capacity, quality of life and recovery from birth mortality, use of o History of GDM is linked to a greater risk of the mother developing type 2 diabetes, type health care 1 diabetes, and cardiovascular disease later in life services o Diagnosis of GDM may cause significant anxiety/concern over and above normal concerns about pregnancy • PRODUCTIVITY o In the short term, C-sections have longer recovery than vaginal delivery and may interfere with mother-infant interaction in the delivery room. o In the longer term, a history of GDM increases the risk of other chronic illnesses (diabetes, cardiovascular disease). Developing these chronic conditions may impact mother’s future productivity. • FUNCTIONAL CAPACITY o C-sections is associated with a higher rate of injury to some organs (bladder, bowel, blood vessels), infections (wound, uterus, urinary tract), and blood clotting complications (although absolute risks are low). o Children of mothers with GDM have higher rates of childhood obesity, hyperactivity/inattention disorders, and higher rates of developing diabetes later in life. • MORTALITY o For fetus, greater risk of death near time of delivery o For mothers, greater risk life-threatening preeclampsia o Absolute risk for death in both mother and infant low

How strongly does • GDM is relatively common, and new definitions may make it even more common this overall • Short- and long-term effects on mother and infant societal burden o Significant impact on C-section utilization alone suggest that CER • Major source of uncertainty is effect of changing screening practices/definitions, with –two- on alternative to three-fold increase in number of women diagnosed with GDM and relative lack of data on approaches to this benefits and harms in this broader population problem should be given high priority? Options for Addressing the Issue Based on recent SYSTEMATIC REVIEWS/AVAILABLE DATA systematic • Ample systematic review data available regarding screening/diagnosis, prevention, and reviews, what is treatment of GDM known about the • However, available data based on studies conducted using different screening/diagnostic relative benefits criteria—unclear how they would apply if criteria change and harms of the SCREENING/EARLY DIAGNOSIS available • Two main options for screening (usually between 24-28 weeks gestation, earlier for high-risk management women) options? o “Two-step” approach traditional in the United States, recommended by American Congress of Obstetricians and Gynecologists (ACOG)4-5 . 50 grams of glucose taken orally without regard to whether woman has recently eaten . Blood glucose (sugar) measured 1 hour later − If less than cutoff, patient is “negative” and no further testing − If above cutoff, a second step (on another day) is performed, using 100 grams of glucose while patient is fasting; blood glucose measured before the dose and 1, 2, and 3 hours after and compared to cutoffs to make diagnosis. . This approach was originally developed to identify women at risk for developing diabetes later in life, not to identify women at high risk for GDM-related complications during pregnancy . Minimizes the number of women needed to fast for testing (can be difficulty/inconvenient during pregnancy) o “One-step” approach used internationally, recommended by International Association of Diabetes and Pregnancy Study Group (IADPSG) and American Diabetes Association (ADA)3,6 . 75 grams of glucose given while fasting . Fasting, 1-, and 2-hour levels compared against criteria . Some minor differences in definitions between two groups . IADPSG cutoffs based on pregnancy outcomes (glucose values associated with 1.75- fold increase in selected adverse outcomes) o Adoption of “one-step” approach would make US practice consistent with rest of world, but would increase number of women with diagnosis of GDM two- to three-fold o Recent NIH Consensus Conference (March 2013) concluded too little data about relative benefits and harms to recommend change1 PREVENTION OF GDM 54

• Lack of clear evidence on weight loss, diet, or physical activity before or during pregnancy to prevent GDM TREATMENT • According to a recent AHRQ-sponsored systematic review, there is moderate evidence for reduction of preeclampsia, macrosomia (big baby), and shoulder dystocia with receipt of treatment for GDM (defined as treatments reducing maternal blood sugar levels)7 o Diet/activity may be sufficient o If no response, insulin is standard of care, but uncertainty about safety of some preparations o Limited data on oral agents in the United States, none FDA-approved o Limited data on harms/benefits of different delivery management strategies (eg, induction of labor) PREVENTION OF LONG-TERM MATERNAL DIABETES • No data on effectiveness of strategies aimed at preventing long-term development of diabetes in women

What could new New research could contribute to achieving better patient-centered outcomes in certain key research areas: contribute to • Diagnosis/screening: achieving better o Further comparative-effectiveness research (CER) evaluating the timing of assessment patient-centered for GDM could improve patient-centered outcomes (for both mothers and babies) outcomes? o Further CER evaluating strategies for assessment of GDM (for example one-step vs. two- step strategy, 100 gram vs. 75 gram glucose tolerance tests) could improve patient- centered outcomes for both mothers and babies • Prevention o Further CER exploring prevention of GDM through nutritional, exercise, and drug treatment strategies could improve patient-centered outcomes for both mothers and babies • Treatment o Further CER exploring treatment of GDM through nutritional, exercise, and different pharmacologic strategies (including insulin, more established medications like glyburide and metformin, and newer medication classes) could improve patient-centered outcomes for both mothers and babies o In particular, further CER to identify safe and effective alternatives to insulin could improve patient-centered outcomes such as quality of life (because insulin imposes a greater self-management burden on mothers) • Development of GDM and overt diabetes o Research to identify risk factors for GDM and subsequent development of overt diabetes could improve patient-centered outcomes for both mothers and babies o Potential risk factors could include maternal health behaviors (such as diet, physical activity, or breastfeeding), maternal metabolic measures (such as glucose tolerance test, insulin levels, or cortisol levels), comorbid conditions (such as advanced maternal age, hypertension, or hyperlipidemia), genetic factors (such as gene mutations, epigenetic factors, and gene-environment interactions) o Further CER exploring prevention of subsequent development of overt diabetes following GDM (through behavioral change strategies, lifestyle interventions, or pharmacologic strategies) could improve patient-centered outcomes for both mothers and babies Have recent Recent innovations: innovations made • With the availability of new classes of non-insulin-dependent diabetes medications in research on this addition to better-established non-insulin-dependent diabetes medications, research on topic especially prevention and non-insulin-dependent treatment of GDM using these therapies is compelling compelling? • As our understanding of the role of genetic factors in development of disease expands, new opportunities exist to explore novel questions about risk factors for the development of GDM and the development of overt diabetes after GDM (including gene mutations, epigenetic factors, and gene-environment interactions) How widely does VARIABILITY IN CARE care now vary? • Widespread variation in delivery practices between types of providers (obstetricians, family practice physicians, nurse midwives) and within different groups • Variability in postdelivery screening/testing

What is the pace of RECENT PUBLICATIONS other research on • MEDLINE search, 1/1/2008 – 4/3/2013: total 575 this topic (as o 53 randomized controlled trials (RCTs) indicated by o 58 meta-analyses or systematic reviews recent ONGOING TRIALS publications and • There are at least 125 ongoing studies listed in ClinicalTrials.gov ongoing trials)? • NIH Reporter (a database of NIH funded studies) lists: o 129 projects o 146 publications

How likely is it that KEY UNCERTAINTIES IN CLINICAL DECISION MAKING new CER on this • What is the optimal timing and mode of GDM screening? topic would • What are the comparative benefits and harms of different behavioral strategies (diet, provide better exercise) and drug treatments on mother and child outcomes? information to • What is the optimal management of women diagnosed with GDM after delivery? guide clinical • What is the optimal management of children born to women with GDM? decision making? LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES • While there have been many systematic reviews on GDM, most point to a lack of well- designed, higher-quality studies. New, high-quality CER could contribute significantly to this area and provide needed guidance for clinical decision making. Potential for New Information to Improve Care and Patient-Centered Outcomes What are the FACILITATORS facilitators and • Common condition with serious outcomes that impact both mother and child. barriers that • Pregnancy is a time of heightened patient activation. Thus, patient may be adherent to new would affect the behaviors at this time if prompted by physician. implementation of new findings in BARRIERS practice? • Variability in screening and diagnostic criteria may lead to differential implementation • Cost of treatments • Patient compliance with taking medications during pregnancy • Uncertain how patients and providers weigh relative benefits/harms to mother vs. infant in event of competing risks; further research on this alone would be critical and have applicability beyond management of GDM How likely is it that EVIDENCE OF BENEFIT the results of new • Likely to be implemented if clear evidence of better mother-child outcomes research on this topic would be EVIDENCE OF NO BENEFIT OR HARM implemented in • Depending on practice, likelihood of stopping/decreasing practice may be variable. For practice right example, to the extent that C-section rates are driven by provider concern about adverse away? outcomes and subsequent malpractice litigation, lack of evidence of benefit may still not lead to changes in practice.

Would new • GDM is a relatively common condition with multiple uncertainties in diagnosis and information from treatment. It is likely that high-quality RCT evidence would remain current for several years. CER on this topic • At current time, greatest controversy in this field is whether to adapt one-step screening, remain current for with consequent two- to three-fold increase in number of women diagnosed with GDM several years, or o Because the likelihood of benefits and harms and the ratio of benefits and harms will would it be vary based on the underlying population, new research on prevention, treatment, and rendered obsolete postpregnancy management would all need to be conducted. quickly by subsequent studies?

REFERENCES:

1. National Institutes of Health Consensus Development Conference: Diagnosing Gestational Diabetes Mellitus Conference; March 4–6, 2013. Draft Statement. http://prevention.nih.gov/cdp/conferences/2013/gdm/resources.aspx. Published March 2013. Accessed April 11, 2013. 2. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011. http://www.cdc.gov/diabetes/pubs/factsheet11.htm. Published 2011. Accessed April 11, 2013. 3. Metzger BE, Gabbe SG, Persson B, Buchanan TA, Catalano PA, Damm P, Dyer AR, Leiva A, Hod M, Kitzmiler JL, Lowe LP, McIntyre HD, Oats JJ, Omori Y, Schmidt MI. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33(3):676-682. 4. Anonymous. Committee opinion no. 504: screening and diagnosis of gestational diabetes mellitus. Obstet Gynecol. 2011;118(3):751-753. 5. American College of Obstetricians and Gynecologists Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. Number 30, September 2001 (replaces Technical Bulletin Number 200, December 1994). Gestational diabetes. Obstet Gynecol. 2001;98(3):525-538. 6. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2013;36 Suppl 1:S67-74. 7. Hartling L, Dryden DM, Guthrie A, Muise M, Vandermeer B, Aktary WM, Pasichnyk D, Seida JC, Donovan L. Screening and Diagnosing Gestational Diabetes Mellitus. Evidence Report/Technology Assessment No. 210. (Prepared by the University of Alberta Evidence-based Practice Center under Contract No. 290-2007-10021-I.) AHRQ Publication No. 12(13)-E021-EF. Rockville, MD: Agency for Healthcare Research and Quality;2012.www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published October 2012. Accessed April 11, 2013.

APPENDIX: TOPIC QUESTIONS

Nominated by AHRQ

1. What are the effectiveness and safety of any of the second generation sulfonylureas compared to any insulin in the treatment of gestational diabetes with regard to the following: short- and long-term maternal outcomes, neonatal outcomes, and long-term offspring outcomes? 2. What are the effectiveness and safety of metformin compared to any insulin in the treatment of gestational diabetes with regard to the following: short- and long-term maternal outcomes, neonatal outcomes, and long- term offspring outcomes? 3. What are the comparative effectiveness and safety of various insulin regimens in terms of type/duration, dosing, and frequency of administration in the treatment of gestational diabetes with regard to the following: short- and long-term maternal outcomes, neonatal outcomes, and long-term offspring outcomes? 4. What are the effectiveness and safety of other hypoglycemic drug classes (eg, thiazolidinediones, DPP-4 inhibitors, GLP-1 agonists, meglitinides) compared to any insulin or other hypoglycemic drugs in the treatment of gestational diabetes with regard to the following: short- and long-term maternal outcomes, neonatal outcomes, and long-term offspring outcomes? 5. What are the effectiveness and safety of elective labor induction at 40 weeks compared to expectant management in women with gestational diabetes with regard to the following: maternal and neonatal outcomes? 6. What are the effectiveness and safety of elective cesarean delivery at 40 weeks compared to expectant management in women with gestational diabetes with regard to the following: maternal and neonatal outcomes? 7. What is the evidence that maternal health behaviors (such as breastfeeding, physical activity, diet) are associated with the risk of developing type 2 diabetes or glucose intolerance/ impaired fasting glucose following a pregnancy with gestational diabetes? 8. What is the evidence that maternal metabolic measures (eg, fasting insulin levels, OGTT measures, HPA axis stress (subclinical hypercortisolism)) are associated with the risk of developing type 2 diabetes or glucose intolerance/impaired fasting glucose following a pregnancy with gestational diabetes? 9. What is the evidence that comorbid conditions (eg, advanced maternal age, obesity, hypertension, hypercholesterolemia) are associated with the risk of developing type 2 diabetes or glucose intolerance/impaired fasting glucose following a pregnancy with gestational diabetes? 10. What is the evidence that family history, gene mutations, genotypes, gene-environment interactions, epigenetic modifications, or other biomarkers are associated with the risk of developing type 2 diabetes or glucose intolerance/impaired fasting glucose among women with gestational diabetes? Are there differences in these associations by race or ethnic group? 11. What is the comparative effectiveness of various lifestyle interventions (eg, diet, physical activity, smoking) for prevention of type 2 diabetes, glucose intolerance/impaired fasting glucose, and obesity in women with a history of gestational diabetes? 12. What is the comparative effectiveness of various educational and behavioral change strategies (eg, patient education about diabetes risk, lactation support, diet, physical activity) for prevention of type 2 diabetes and glucose intolerance/impaired fasting glucose in women with a history of gestational diabetes? 13. What are the performance characteristics (sensitivity, specificity, and reproducibility) of a single fasting blood glucose test compared to the full 2-hour 75-gm OGTT in screening for type 2 diabetes and glucose intolerance/impaired fasting glucose following a pregnancy with gestational diabetes? Does the accuracy of the

fasting blood glucose test compared to the full 2-hour 75-gm OGTT vary with the postpartum testing interval in screening for type 2 diabetes and glucose intolerance/impaired fasting glucose following a pregnancy with gestational diabetes? 14. What are the performance characteristics (sensitivity, specificity, and reproducibility) of the HbA1c test compared to the 2-hour 75-gm OGTT in screening for type 2 diabetes and glucose intolerance/impaired fasting glucose following a pregnancy with gestational diabetes? Does the accuracy of the HbA1c test compared to the full 2 hour 75- gm OGTT vary with the postpartum testing interval in screening for type 2 diabetes and glucose intolerance/impaired fasting glucose following a pregnancy with gestational diabetes?

Topic 9: “Eczema”

Comparative effectiveness of treatment options for topical or systemic eczema in children and adults.

Criteria Brief Description Introduction Overview/definition DESCRIPTION OF CONDITION1,2 of topic • Eczema (also known as atopic dermatitis) is a chronic inflammatory skin condition. • It is often the first manifestation of other allergic diseases (allergic rhinitis or hay fever, asthma, food allergy). • It typically presents in early childhood but can develop in adulthood. • It is characterized by defects in the skin’s protective outer layer. These defects can either develop over time (acquired) or be something a patient is born with (genetic). • An inadequate immune response may increase one’s susceptibility to infections. Relevance to SYMPTOMS1,2 patient-centered • Three recurring phases of itchy skin lesions: outcomes o Acute—weeping, crusted skin lesions o Subacute—dry, scaly, red skin lesions o Chronic—thickened skin lesions from scratching • Can be exacerbated by temperature, humidity, irritants, infections, food, allergens and emotional stress. DIAGNOSIS • No objective diagnostic test • Diagnosis based on clinical features COMPLICATIONS • Sleep disturbance • Chronic skin changes • Scarring from picking and scratching • Secondary skin infections (bacterial and viral) Burden on Society Recent prevalence in PREVALENCE2,3 populations and • 17.8 million people in the United States are living with eczema subpopulations • 10-20% of US children • Prevalence is increasing • Study of US children 17 years of age or younger: o Prevalence ranged from 8.7% to 18.1% from state to state o Higher disease prevalence associated with metropolitan living, African American population, and educational levels in the household greater than high school Effects on patients’ QUALITY OF LIFE1,4 quality of life, • Significant impact on patients (and difficult for caregivers to manage in children) productivity, • Sleep disruption (from itching) functional • Inhibited bonding and touching between parent and affected infant capacity, • Parental feelings of inadequacy about caring for their affected child mortality, use of • Embarrassment and avoidance of daily activities health care • Emotional distress and at risk for behavioral problems, anxiety, and depression services • Financial costs, time demands, and lifestyle changes associated with disease management 62

PRODUCTIVITY4 • Missed school or work days • Lost work days for medical appointments and when children miss school USE OF HEALTH CARE SERVICES4 • Moderate disease—13 physician visits per year and annual cost of $1700 for family • Severe disease—23 physician visits per year and annual cost of $2500 or more How strongly does US costs are estimated between $364 million and $3.8 billion annually.5 this overall societal burden suggest that CER on alternative approaches to this problem should be given high priority? Options for Addressing the Issue Based on recent MANAGEMENT OPTIONS systematic Standard therapy for eczema includes skin hydration, topical corticosteroids, and antihistamines. reviews, what is Studies comparing topical corticosteroids with calcineurin inhibitors have shown that calcineurin known about the inhibitors are more effective at reducing skin inflammation than low-potency topical relative benefits corticosteroids; but have similar efficacy to mid-potency topical corticosteroids. and harms of the available Other therapies are introduced if the eczema does not respond to standard therapy. Costs and management side effects influence the choice of therapy. For example, calcineurin inhibitors are expensive, options? and the side effect profile includes immunosuppression and increased risk of skin cancer. Brief descriptions of the benefits and harms of routine therapies follow.1,2

• Skin hydration: Warm, soaking baths and application of a moisturizer: o Potential benefits are improvement of skin-barrier function, decreased itching, maintenance of skin texture, decreased need to use corticosteroids. o Potential harms are skin irritation or drying (if lotion or cream) and interfering with sweat ducts (if occlusive ointment). • Topical corticosteroids: Seven levels of medication strength, which should be tailored to disease severity: o Potential benefits include effective treatment (low potency used for maintenance, high potency for treatment of exacerbations over short periods). o Potential harms are systemic and local: . Systemic (suppression of hypothalamic-pituitary-adrenal axis) harms vary with potency, application site, percent of body covered, and duration of use (and is more likely in small children and infants (who have a higher body surface area ratio than adults). . Local harms are thinning of the skin; rash around mouth; bumpy, acne-like rash on nose; and contact dermatitis. • Calcineurin inhibitors: Tacrolimus and pimecrolimus, approved for use in patients older than

2 years of age. These are particularly useful for eczema on the face that is not responsive to low-potency topical steroids: o Potential benefits include reduced itchiness, no skin atrophy, and greater therapeutic margin of safety than medium-strength glucocorticoids for facial and eyelid eczema. o Potential harms are transient local burning and itching in the first week, facial flushing after drinking alcoholic beverages, possible increase in viral skin infections (herpes simplex, molluscum contagiosum), possible immunosuppression, and possible link to lymphoma and skin cancer (but no conclusive evidence for lymphoma and skin cancer). • Tar preparations: No randomized controlled studies demonstrating efficacy; tar preparations can potentially irritate the skin. • Antihistamines: Little objective evidence demonstrating relief of itching for sedating or nonsedating oral antihistamines. Additionally, topical antihistamines can potentially cause skin to become increasingly inflamed and reactive to irritants. • Food allergy testing: Recommended only if patient has persistent eczema despite optimal management, or if there is a reliable history of an immediate allergic reaction after ingestion of food. • Extensive elimination diets: Based on positive skin tests or specific immunoglobulin-E test results, not recommended because of potential development of nutritional deficiencies. • Nutritional supplementation and Probiotics: Fish oil, zinc sulphate, selenium, vitamin E, vitamin D, pyridoxine, buckthorn seed oil, buckthorn pulp oil, hempseed oil, sunflower oil, DHA, and probiotics:1,2,6,7 o There is no convincing evidence for benefits of nutritional supplements or existing probiotics. o Nutritional studies were small with low numbers of participants and of poor quality. o Two trials of fish oil found some slight improvement in terms of itchiness and quality of life; but these were small trials and larger trials are needed before recommendations can be made. o There is also ongoing research regarding giving supplemental Vitamin D if the patient has low vitamin D levels confirmed by a blood test. o There is no evidence for harms in nutritional supplementation studies except: . There is a potential for vitamin D toxicity if taken in high doses. . Probiotics can cause infections and digestion problems. • Therapies for difficult-to-manage patients:1,2 o Systemic immunomodulating agents (medications that help regulate your immunity) include cyclosporine A, mycophenolate mofetil, azathioprine, interferon-gamma, systemic corticosteroids, and methotrexate. . All have potential for serious adverse effects. o Phototherapy (ultraviolet therapy, made up of mostly UVA rays), the benefit has to be weighed against the potential skin damage caused by these treatments (similar to sun exposure and tanning beds).

What could new • Itching is the most significant complaint of patients with eczema; therefore improved patient research outcomes must include evaluating therapies that can control itching. contribute to • A recent meta-analysis8 suggests that topical therapies were preferable to systemic therapies achieving better at controlling itching. patient-centered o Further, calcineurin inhibitors were the most effective agent at controlling itching. outcomes? o Studies designed to evaluate the safe use of these agents in children and patients younger than two years of age are needed. • The role of omega-3 fatty acids in the treatment of eczema symptoms has been evaluated only in small studies. Larger studies are needed that assess the potential role of these dietary supplements. Have recent • The most recent innovation has been the approval of calcineurin inhibitors. innovations made • However, the black-box warning for these topical agents (lack of long-term safety data and research on this the potential risk of the development of skin cancer) has likely limited their use, particularly topic especially in children. compelling? • Attempting to better define the role of calcineurin inhibitors in treating childhood eczema is compelling. How widely does Care varies widely: care now vary? • Eczema is a common condition for which patients seek care from health care providers representing a wide variety of different specialties. • Many patients self-treat with over-the-counter creams without consultation from health care professionals. What is the pace of Clinicaltrials.gov: Clinicaltrials.gov: other research on this topic (as Search: Eczema Search: Dermatitis indicated by Total ongoing trials: 75 Total ongoing trials: 139 recent Completed trials: 122 Completed trials: 339 publications and ongoing trials)? How likely is it that • New comparative-effectiveness research (CER) that provides compelling information about new CER on this treatment or prevention approaches that can be easily understood and implemented by topic would patients or caregivers is likely to guide patient-driven clinical decisions. provide better • There is a need for better, faster ways to identify the allergen causing the eczema to reduce a information to patient’s exposure to the allergen or to identify a medication that will treat the reaction. guide clinical Until we have better diagnostic methods, clinical treatments are chosen by trial and error decision making? (that is, “Let’s see if this works, and if not, we’ll try something else”). Potential for New Information to Improve Care and Patient-Centered Outcomes What are the FACILITATORS facilitators and • Desire by stakeholders to improve care barriers that • Generally well-informed patients who may be able to access new findings via the Internet would affect the BARRIERS implementation of • Diversity of health care providers (dermatologists, general internists, family physicians, new findings in gynecologists, alternative medicine practitioners, and the like) who treat eczema practice? • Large amount of currently available information on the Internet • Wide variation of beliefs about what causes eczema and what are plausibly effective 65

treatment options How likely is it that • Results of new research on this topic would need to be disseminated to a diverse group of the results of new stakeholders. research on this • However, with targeted efforts towards dermatologists and allergists (who see a large topic would be volume of eczema in their practices), this information would be helpful for discussing the implemented in risks and benefits of treatment options with those who suffer with eczema. practice right away? Would new • Eczema seems to be a relatively active topic in ongoing research. information from • Many different claims of efficacy and harms associated with a variety of different treatment CER remain approaches are readily available on the Internet. current, or would • In order for new CER information on this topic to remain current, it would have to be it be rendered perceived by stakeholders as compelling in order to compete with existing and future obsolete quickly information (substantiated by evidence or not). by subsequent studies?

REFERENCES 1) Schneider L, Tilles S, Lio P et al. Atopic dermatitis: A practice parameter update 2012. J Allergy Clin Immunol 2013;131:295-299. 2) Berke R, Singh A, Guralnick M et al. Atopic dermatitis: An overview. Am Fam Physician. 2012;86(1)35-42. 3) Eichenfield LF, Ellis CN, Mancinin AJ, Paller AS, Simpson EL. Atopic dermatitis. Epidemiology and Pathogenesis Update. 2012 Semin Cutan Med Surg 31 (suppl 3):S3-5. 4) O’Connell EJ. The burden of atopy and asthma in children. Allergy 2004 59 (Suppl.78):7-11. 5) Mancini AJ. Kaulback K, Chamlin SL. The socioeconomic impact of atopic dermatitis in the United States: A systematic review. Pediatric Dermatology 2008;25(1) 1-6. 6) Bath-Hextall FJ, Jenkinson C, Humphreys R, Williams HC. Dietary supplements for established atopic eczema. 2012 The Cochrane Collaboration. 7) Boyle RJ, Bath-Hextall FJ, Leonardi-Bee J, Murrell DF, Tang MLK. Probiotics for treating eczema (Review). 2008. The Cochrane Collaboration. 8) Sher LG, Chang J, Patel IB, Balkrishnan R, Fleischer AB Jr. Relieving the pruritis of atopic dermatitis: a meta- analysis. Acta Derm Venereol. 2012 Sep;92(5):455-461.

APPENDIX: Topic Question

Nominated over the Web

1) What safe therapies are there to stop the itch associated with eczema, either topical or systemic? Topical corticosteroids do not work for everyone, and they are not appropriate for the face. For infants, it is not always a great option to cover the entire body and does not stop the itching. 66

Population: All ages and ethnic groups. Importance: Because there are so many people still suffering with eczema.

2) I would like to see more research on eczema, what causes it, and most importantly nonmedication treatment options. I am particularly interested in the link between nutrition, omega-3 fatty acids and eczema. Thank you!

Population: Adults and children Importance: Both my daughter and I suffer from eczema and have spent countless hours researching this very common condition. We accidentally discovered a link between fats and eczema, and use a self-prescribed treatment, consisting of bumping up fatty acids in our diet. I would like to see a more scientific study on this topic. It seems, at least based on our experiences, and those of the many people posting in Internet forums, that the omega-3 could be a cure for eczema! Much simpler and probably safer than the many medications (creams) that we have been prescribed, unsuccessfully, over the years.

Research Prioritization Topic Brief

Topic 10: “Epilepsy”

Comparative effectiveness of treatment options for epilepsy in adults.

PCORI Scientific Program Area: Assessment of Prevention, Diagnosis and Treatment Options

Dr. Gillian Sanders Schmidler, PhD and Team The Duke Clinical Research Institute

April 18, 2013

Criteria Brief Description Introduction Overview/definition DESCRIPTION OF CONDITION of topic • Epilepsy is a condition in which a person experiences recurrent seizures1 • Seizures are temporary disturbances in brain function in which groups of nerve cells in the brain signal abnormally and excessively1-2 • People with epilepsy are at special risk for status epilepticus (a potentially life-threatening condition in which a person either has an abnormally prolonged seizure or does not fully regain consciousness between recurring seizures) and sudden unexplained death in epilepsy (SUDEP)2 Relevance to SYMPTOMS/OUTCOMES patient-centered • Symptoms outcomes o Seizures may cause change in awareness or sensation, involuntary movements, or other changes in behavior1-2 o There are two main types of seizures: . Primary generalized seizures—begin with widespread involvement of both sides of the brain . Partial seizures—begin with involvement of a smaller, localized area of the brain o 30-40% of people with epilepsy continue to have seizures even when treated with antiepileptic drugs3 • Other outcomes o People with severe seizures that resist treatment have, on average, a shorter life expectancy and an increased risk of cognitive impairment, particularly if the seizures developed in early childhood.2 o It is not uncommon for people with epilepsy, especially children, to develop behavioral and emotional problems.2 2 o Epilepsy can affect both school and work performance. o Even when seizures are controlled, side effects of drugs or surgical interventions can further diminish quality of life. Burden on Society Recent incidence • INCIDENCE (NEW CASES)3 and prevalence in o 200,000 people in the United States develop epilepsy each year. populations and • PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE CONDITION)3 subpopulations o Third most common neurological disorder in the United States o 2.5 million people in the United States have epilepsy o Affects more than 300,000 children under the age of 15, more than 90,000 of whom have seizures that cannot be adequately treated Effects on patients’ • QUALITY OF LIFE quality of life, o People with epilepsy have an increased risk of poor self-esteem, depression, and productivity, suicide.2 functional o Most states and the District of Columbia will not issue a driver's license to someone with capacity, epilepsy unless the person can document that they have gone a specific amount of time mortality, use of without a seizure.1-2 69

health care • PRODUCTIVITY services o According to one survey, only about 56% of people with epilepsy finish high school, and about 15% finish college (rates much lower than those for the general population), and about 25% of working-age people with epilepsy are unemployed2 • FUNCTIONAL CAPACITY o Cognitive impairment, behavioral and emotional problems o Environmental restrictions (eg, no driving, work at heights, use of heavy equipment or hazardous machinery) • MORTALITY o Mortality rate among people with epilepsy is 2-3 times higher than the general population, and the risk of sudden death is 24 times higher3 How strongly does • This is a common neurological disorder that can have a significant impact on psychosocial, this overall social and/or educational or occupational functioning throughout the lifespan. societal burden suggest that CER on alternative approaches to this problem should be given high priority? Options for Addressing the Issue Based on recent SYSTEMATIC REVIEWS systematic • 381 MEDLINE; 107 Cochrane reviews reviews, what is SCREENING/EARLY DIAGNOSIS known about the • People are usually not screened or tested for epilepsy unless they have an unexplained loss relative benefits of consciousness or a strong family history of epilepsy. However, research into finding genes and harms of the and genetic disorders that cause epilepsy may allow genetic screening and prenatal diagnosis available of epilepsy in the future. management TREATMENT options? • Newer antiepileptic drugs significantly reduce the risk of mortality compared to older drugs (carbamazepine, phenytoin, or valproic acid).4 • Based on four controlled clinical trials:4 o Switching from a brand name to a generic antiepileptic drug may increase the risk of hospitalization and hospital stay duration, but may not increase outpatient service utilization. o When comparing brand name antiepileptic drugs with their respective generic versions, seizure occurrence and frequency were not significantly different between groups. o There were no significant differences between brand name antiepileptic drugs and their respective generic versions in terms of total withdrawals or withdrawals due to lack of efficacy. o No significant differences were noted between brand name and generic antiepileptic drugs for evaluated side effects, including headache, somnolence, diplopia, or skin rash. • In children, the ketogenic diet (high-fat, adequate-protein, low-carbohydrate diet) results in short- to medium-term benefits in seizure control, the effects of which are comparable to

modern antiepileptic drugs. Limited data are available for adults.5 • A meta-analysis of surgery for epilepsy reported median proportions of long-term (>5 years) seizure remission of 27% for frontal lobe resections, 46% for occipital or parietal resections, and 66% for temporal lobe resections.6 • For nonresective surgeries, callostomy (a procedure that severs the fiber bundle connection between the right and left cerebral hemispheres) resulted in 35% freedom from seizures and subpial transections (cutting nerve fibers in the outer layers of the brain) a 16% freedom from seizures.6 • The only complete randomized controlled trial (RCT) of epilepsy surgery showed a statistically significant advantage of surgery over medical management in seizure remission (58 vs. 8%, respectively).7 A systematic review of nonrandomized comparative studies and an RCT that was terminated early also reported significant improvements in the seizure frequency in the surgery group compared with nonsurgery group.8 • In the Nationwide Inpatient Sample hospital discharge database, anterior temporal lobectomy for epilepsy performed between 1988 and 2003 was associated with a 10.8% overall morbidity and no mortality.9 • Early antiepileptic drug withdrawal resulted in a 32% increase in seizure relapse compared with late withdrawal. Early discontinuation was also associated with greater relapse rates in people with partial seizures or an abnormal EEG.10 What could new New research could contribute to achieving better patient-centered outcomes: research • What is the comparative effectiveness of early surgery vs. medical management in patients contribute to with difficult-to-control seizures? Or, what is the comparative effectiveness of early surgery achieving better vs. later surgery in seizure remission and quality of life? patient-centered [To date, only one RCT looking at comparative-effectiveness research (CER) between the outcomes? surgery vs. medical management strongly favoring surgery, but there could be benefit in conducting studies looking at the timing of referral for surgical evaluation.] • What is the comparative effectiveness of different surgical methods in remission of seizures? [Studies comparing different surgical interventions and/or preoperative screening methods to determine the most appropriate surgical intervention may be useful.] • What is the comparative effectiveness of different generic versions of seizure medications? [No studies available comparing generic medications made by different manufacturers but anecdotal evidence suggests people may respond differently.] • What is the comparative effectiveness of different treatments for mood disorders associated with seizure disorders? [Given the significant association between epilepsy and mood disorders, it would be helpful to know if certain treatments are more effective than others in this population.] • What is the optimal timing of antiepileptic drug withdrawal and what are the risk factors predictive of relapse among seizure-free adults? Have recent Recent innovations: innovations made • The use of preoperative imaging and EEG monitoring has helped to identify those patients research on this with the highest likelihood of benefit from surgical resection. topic especially • Improvements in drugs and drug delivery methods (providing potentially more effective compelling? alternatives to current oral or IV routes).

How widely does VARIABILITY IN CARE11 care now vary? • According to a recent study (Quality Indicators in Epilepsy Treatment [QUIET]), patients with epilepsy received 40.9% of recommended care • Black patients were two times more likely to receive 50% or more recommended care compared with non-Hispanic whites • Black patients scored significantly worse than non-Hispanic whites for two patient-reported measures: perceived racial/ethnic disparities and difficulties getting follow-up appointments What is the pace of ONGOING TRIALS other research on • ClinicalTrials.gov lists 300 Ongoing Trials and 432 Completed trials. this topic (as • Phase II/III clinical trials are ongoing for several antiepileptic drugs.12 indicated by • RCTs are underway for few alternative, non-drug therapies, e.g., ketogenic diet (high-fat, recent adequate-protein, low-carbohydrate), yoga, P- glycoprotein blockers, and polyunsaturated publications and fatty acids.12 ongoing trials)? How likely is it that KEY UNCERTAINTIES IN CLINICAL DECISION MAKING new CER on this • Do outcomes differ based on timing of referral for surgical evaluation? topic would • What is the optimal timing for discontinuing antiepileptic drugs in patients who have been provide better free of seizures? information to • Do different surgical techniques result in different outcomes? guide clinical • What are the most effective techniques for identifying epileptic foci prior to surgery? decision making? • What are the predictors of response to surgery? • Is the ketogenic diet effective in controlling seizures in the adult population? • Are there any medications to treat mood disorders that are more effective than others in patients with seizures? • Do generic antiepileptic drugs differ in their effectiveness? LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES • CER looking at early referral vs. late referral for surgical evaluation could provide useful information if outcomes do differ • New CER may provide useful information regarding which surgical techniques are more effective than others • New CER may provide useful information regarding which techniques best identify the areas of focus for surgical intervention • It is unlikely that even if it were feasible to do a study comparing generic medications from different manufacturers that this would change clinical care • New CER research looking at various medications to treat mood disorders may provide useful information regarding which medications may be more effective in patients with epilepsy • New CER on specialized diets (such as the ketogenic diet) in the adult population may provide useful information to determine if this is an effective treatment • New CER on discontinuation of antiepileptic drugs in seizure-free patients may help to identify the ideal timing to stop these medications Potential for New Information to Improve Care and Patient-Centered Outcomes What are the FACILITATORS facilitators and • Effective surgical interventions for intractable epilepsy already in use barriers that • Multiple medications for treating mood disorders currently available 72

would affect the implementation of BARRIERS new findings in • Insurance coverage practice? • Education of providers • Inability of providers to direct which manufacturers’ generic medication is used • Even if determined to be effective in adults, studies have shown poor compliance with a ketogenic diet, so its utility may be limited How likely is it that • It is very likely that information regarding significant differences in medications to treat the results of new mood disorders associated with epilepsy could be implemented right away as these research on this medications are available and most are covered by most insurance plans topic would be • It is likely that with appropriate education, changes in timing of referral for surgical implemented in intervention could be implemented if significant differences were found practice right • It is unlikely that even if significant differences were found between generic medications away? from different manufacturers that providers will have the liberty to prescribe a specific manufacturer’s medications Would new • It is likely that any new information from CER on this topic would stay current for several information from years, as it will provide information on the appropriate use of existing treatments (surgery CER on this topic for epilepsy, medications for mood disorders) and no significant changes in these treatments remain current for are expected in the near future several years, or would it be rendered obsolete quickly by subsequent studies?

REFERENCES:

1. Centers for Disease Control and Prevention. Epilepsy Basics. www.cdc.gov/epilepsy/basics/faqs.htm. Accessed April 11, 2013. 2. National Institute of Neurological Disorders and Stroke. Seizures and Epilepsy: Hope Through Research. www.ninds.nih.gov/disorders/epilepsy/detail_epilepsy.htm. Accessed April 11, 2013. 3. National Clearinghouse Quality Measures, Epilepsy: percentage of visits for patients with a diagnosis of epilepsy who had the type(s) of seizure(s) and current seizure frequency for each seizure type documented in medical record. 2009 Aug. NQMC: 006895. American Academy of Neurology—Medical Specialty Society. www.qualitymeasures.ahrq.gov/content.aspx?id=32700&search=epilepsy. Published 2009. Accessed April 11, 2013. 4. Talati R, Scholle JM, Phung OJ, et al. Effectiveness and Safety of Antiepileptic Medications in Patients with Epilepsy. Comparative Effectiveness Review No. 40. (Prepared by the University of Connecticut/Hartford Hospital Evidence- based Practice Center under Contract No. 20-2007-10067-I.) AHRQ Publication No. 11(12)-EHC082-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2011. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published December 2011. Accessed April 11, 2013. 5. Levy RG, Cooper PN, Giri P, Pulman J. Ketogenic diet and other dietary treatments for epilepsy. Cochrane Database of Systematic Reviews 2012, Issue 3. Art. No.: CD001903. DOI: 10.1002/14651858.C D001903.pub2.

6. Tellez-Zenteno JF, Dhar R, Wiebe S. Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis. Brain 2005;128:1188-1198. 7. Wiebe S, Blume WT, Girvin JP, et al. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med 2001;345:311-318. 8. Health Quality Ontario. Epilepsy surgery: an evidence summary. Ont Health Technol Assess Ser [Internet]. 2012;12(17):1-28. http://www.hqontario.ca/en/documents/eds/2012/full-report-epil-surg.pdf. Published 2012. Accessed April 11, 2013. 9. McClelland S III, Guo H, Okuyemi KS. Population-based analysis of morbidity and mortality following surgery for intractable temporal lobe epilepsy in the United States. Arch Neurol 2011;68:725-729. 10. Sirven J, Sperling MR, Wingerchuk DM. Early versus late antiepileptic drug withdrawal for people with epilepsy in remission. Cochrane Database of Systematic Reviews 2001, Issue 3. Art. No.: CD001902. DOI: 10.1002/14651858. CD001902. 11. Avetisyan R, Cabral H, Montouris G, et al. Evaluating racial/ethnic variations in outpatient epilepsy care. Epilepsy Behav 2013;27:95-101. 12. Epilepsy Research Benchmarks Progress Update (2007-2009). National Institute of Neurological Disorders and Stroke. www.ninds.nih.gov/research/epilepsyweb/2010_benchmarks.htm. Accessed: April 11, 2013. APPENDIX: TOPIC QUESTIONS

Nominated by Institute of Medicine (IOM) 1. Compare the effectiveness of monotherapy and polytherapy (ie, use of two or more drugs) on seizure frequency, adverse events, quality of life, and cost in patients with intractable epilepsy.

Nominated by National Institute of Health (NIH) 2. Quality of life for patients with difficult to control epilepsy: comparison of surgery vs. medical management.

Nominated by ‘Web’ 3. Should I go to my neurologist, therapist, or primary health physician when finding out if panic attacks are really seizures or just panic attacks? • Population: Younger patients. • Importance: It's what I've been experiencing myself recently. The Internet is not giving any help and it is a question that, when answered, will give me a lot of help and peace of mind. 4. My grand mal and complex partial seizures, which come from my left temporal lobe, have re-emerged back into my life after being dormant for 9.5 years. The neurologist wants to do the research to see if I am a good candidate for surgery. Should I proceed with the research or continue on the drugs that he has me on? I can still function fine, but the occasional seizure is holding me back. • Population: This would help everyone (from all backgrounds) who has to face the same decision I do. There are risks of the surgery but there are also risks of continuing regular drugs or something else as treatment, but everyone must weigh the pros and cons. If I go through with it and come out fine, I would love to be a voice for the Epilepsy Foundation to help support the idea of people doing the testing. Right now I am leaning towards going forward with the research. 5. How many different medications have you taken? Which ones? What dosage? Where they brand name, generic, or have they been changed from brand name to generic? Did they cause side effects, if so what? If you changed to generic, could you feel a difference between the medications? While taking the generic did the pharmacy change the manufacturer? After changing manufacturer of the medication, did this change the outcome,

reasons, or "feelings" the medication was used for? I want to be able to prove there is a difference between manufacturer's generic medication in the way they treat patient's need for the medication. • Population: This will include anyone that is able to switch brand name medication with generic medication. Over a period of time, we will switch one generic manufacturer with another generic manufacturer. This will prove which generic is the closest to the brand name for treatment. • Importance: I was able to take a generic (Teva) brand Epilepsy medication. The pharmacy switched brands to another generic (Mylan). I was able to drive because I was epilepsy free for five years. Since the pharmacy switched generic brands I had a seizure while driving. My fourteen your old daughter was with me. She had to have her ankle fused after three surgeries. After this, I want know if generic medications cause differences in other health issues. 6. I am caregiver for my 60-year-old sister, diagnosed with Lennox-Gastaut seizure disorder. Because of multiple foci in the brain from which seizures precipitate, current meds are not effective for total seizure control. Currently, she has the best seizure control since the age of 11. but it has been a "hit and miss" project over the years trying different meds and wondering if we were missing just the right combination of meds that would be effective for her. Onfi, the latest addition to her regime (Lamictal, Keppra, and Banzel) has resulted in the most notable seizure reduction. She now averages a 3-10 partial seizures weekly and 1-2 cluster seizures monthly. It would be helpful to be able to access information from other patients with the same diagnosis regarding meds, diet, exercise, and prevention techniques that have been effective as well as "triggers" for seizure activity. Although each patient is different, I suspect there are some similarities within similar diagnoses. Thank you. • Population: It would help all patients with epilepsy to have access to information about what has been effective for other patients with similar seizure disorders. Importance: It is important because the information is not currently available and choosing the best med is largely trial and error process, even for neurologists. 7. How does the ketogenic diet control seizures in epilepsy? • Population: All patients affected by seizures, especially children. • Importance: The diet has been used for many years with great success, yet only a superficial understanding of its exact mechanism exists. This information could be used to develop safer antiepileptic medications and permit more patients to improve their seizure control. 8. Is there evidence that any specific diet controls seizures better for different causes of epilepsy? Low glycemic index, modified Atkins, ketogenic diet... • Population: Severe drug resistant epilepsy, children • Importance: Lack of funding for diet studies, avoids drug toxicity issues 9. Do anti-suffocation pillows effectively prevent hypoxia during nocturnal seizures? • Population: All ages, especially cognitively impaired, residential community dwelling • Importance: Class 1 medical device in the UK, not approved in the US, lack of information 10. Improve health care and community services for persons with epilepsy in rural and underserved populations. • Population: Patients residing in rural areas. Patients of low socioeconomic status • Importance: Although many new treatments have been developed for epilepsy, people residing in underserved rural areas lack access to specialty care or specialty care is delayed due to lack of health professional knowledge about epilepsy. Through expansion of access to comprehensive epilepsy care and timely diagnosis can improve patient health outcomes, potentially reduce mortality, improve quality of life and ultimately reduce the burden of epilepsy. 11. Patients with epilepsy often experience changes in mood and psychoses from the anti-seizure drugs they take. Is it correct to identify these as "side effects," or would it be better to view the changes as symptoms of what Hans Landolt called "forced normalization"? 75

• Population: younger. Refractory epileptics • Importance: Doctors would better know what to expect from treatments a patient has not yet tried. Doctor and patient could make better choices in treatment. Identifying "forced normalization" as a serious problem would indicate the need for complete seizure control earlier in childhood. Patients' self- esteem may be less damaged by understanding the causes of multiple drug failures and uncontrolled mood. 12. How many patients with epilepsy are able to take one generic brand medication that keeps their seizures under control, then start having seizures when the medication is switched to another generic brand medication? What is the difference between the generic brand medications that make patients start having the seizures? Is there a difference in the type of seizures that they were having previously? • Population: Patients with all types of epilepsy and are able to keep track of their seizures or have someone with them who can for them. Patients or people who stay with them that are able to tell to the difference between their seizures. Patients of all ages, race, and sex. • Importance: I was able to take one generic brand medication then was switched another brand generic. I had been able to drive for five years because I had been seizure free. The drug store switched my generic brand medication to another company that made that medication. While I was driving, I had a seizure which was not like my others that I had before. This caused me to have a wreck and with my daughters in the car. One had to have surgery on her ankle. This is why I am working hard on discovering more information on generic medications. Thank You 13. What should patients with epilepsy (children and adolescents) do about the conflicting information about suicidality induced by the antidepressants and the antiepileptics: If the patient is diagnosed with MDD, and you look on the Internet, there are two black box warnings about the AED and the SSRIs. It is really hard for parents to make an informed decision when they have to deal with this, is it the medication that makes them suicidal or the disease?? • Population: Younger, adolescents, early adults • Importance: I deal with this question every day, suicidality is very frequent in patients with epilepsy and parents feel with the information out there is really hard for them to make an informed decision

Topic 11: “Generalized Anxiety Disorder (GAD)”

Comparative effectiveness of treatment options for generalized anxiety disorder (GAD) in adults.

Criteria Brief Description Introduction Overview/definition DESCRIPTION OF CONDITION of topic • Generalized anxiety disorder (GAD) is a clinical condition characterized by excessive and persistent worry or anxiety that is difficult to control. • GAD can be chronic (always feel anxiety) or the symptoms can come and go (remittent). • 66% of people with GAD have other disorders, such as social phobia, panic disorder, substance abuse, or posttraumatic stress disorder. Relevance to patient- SYMPTOMS centered outcomes • People with GAD may have similar symptoms to those experienced by people with panic disorder, and these symptoms are often their presenting issues that make them seek medical care. • According to the psychological classification system (DSM-IV-TR1), diagnosis of GAD requires the presence of excessive worry accompanied by three or more of the following symptoms: restlessness, fatigue, difficulty concentrating, irritability, muscle tension, sleep disturbance. Burden on Society Recent incidence and • Lifetime prevalence of GAD is 5-12% in the United States.2,3 prevalence in • GAD is about twice as common among women compared with men. populations and • GAD is more common in middle age, with prevalence rates rising after age 35 in women and subpopulations age 45 in men. • Nearly 8% of patients consulting a primary care physician have GAD.4 Effects on patients’ QUALITY OF LIFE quality of life, • GAD can be debilitating and lead to agoraphobia and other avoidance behaviors. productivity, • GAD has been associated with impaired social functioning and quality of life.5 functional capacity, PRODUCTIVITY mortality, use of • GAD can result in decreased productivity due to days missed from work. health care services FUNCTIONAL CAPACITY • GAD is associated with a significant degree of functional impairment, similar to that seen with major depression.6 MORTALITY • GAD may be associated with severe mental illness (eg, major depression), which can lead to premature death. USE OF HEALTH CARE SERVICES • GAD has been shown to be associated with increased use of health care services. How strongly does GAD is a highly prevalent condition with significant overall societal burden due to the persistent this overall societal nature of impairments. burden suggest that CER on alternative approaches to this problem should be given high priority?

Options for Addressing the Issue Based on recent There are few randomized controlled trials (RCTs) comparing treatment options, including both systematic reviews, medication and nonmedication interventions for GAD. Systematic reviews in this field have what is known primarily evaluated comparisons either with placebo (in medication trials) or with no-treatment about the relative controls (for instance, in psychological treatment options). Many systematic reviews have benefits and harms combined pretreatment-to-posttreatment improvements in the same patient, in order to of the available estimate the effect of treatment. management TREATMENT options? • Medication treatments for GAD: o A systematic review concluded that selective serotonin reuptake inhibitors (SSRIs)—the usual first-line medication treatment for GAD—were effective in one out of every five patients treated. 7 o There are few trials comparing different medication treatments, but an indirect comparison in a meta-analysis of placebo-controlled trials of patients with GAD reported similar effect sizes for SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), benzodiazepines, buspirone, and hydroxyzine.8 8 o The effect of the medications was higher for children and adolescents than for adults. o Another meta-analysis assessed remission rates for first-, second-, and third-line medication treatments in patients with GAD and showed that higher remission rates were reported in studies of first-line SSRI and SNRIs compared with second-line tricyclic antidepressants, benzodiazepines, buspirone, and pregabalin.9 • Psychological treatment for GAD: o Cognitive behavioral therapy (CBT) is the most studied and appears to be most effective psychotherapy for GAD.10,11 Meta-analyses of RCTs and nonrandomized controlled trials have found that CBT was superior to no treatment or placebo controls for improvement in anxiety and depressive symptom severity measures.12-14 o One meta-analysis that compared medications and CBT found mostly the same results, but this was based on indirect comparisons. 12 • Complementary and alternative therapies for GAD: o Mindfulness- and acceptance-based interventions: . In a 19-study meta-analysis of within-group pretreatment-to-posttreatment effects showed substantial reductions in anxiety and depression symptoms.15 o Meditative therapies: . A meta-analysis showed effect sizes for reducing anxiety symptoms of -0.52 compared with wait-list control (25 RCTs); -0.59 compared with attention control (7 RCTs); and -0.27 compared with alternative treatments (10 RCTs). However, most studies measured only improvement in anxiety symptoms.16 o Lifestyle modifications: . There is strong support for lifestyle modifications including moderate exercise and mindfulness meditation. 17 . There is also some support for the herbal medicine kava. 17 . There is currently little evidence for naturopathic medicine; acupuncture; yoga; tai chi; dietary improvement; and avoidance of caffeine, alcohol, and nicotine. 17 . Homeopathy was not supported.17 79

What could new • New research on nonmedication treatment options for GAD may contribute to better research contribute patient-centered outcomes among people for whom medical management is not sufficiently to achieving better effective or who have intolerable side effects to the prescribed medication. patient-centered • New research on the efficacy of medication or nonmedication treatment for subgroups of outcomes? patients could contribute to better patient-centered outcomes. Have recent There is preliminary evidence showing several complementary and alternative approaches for innovations made the treatment of GAD and its associated symptoms (eg, mindfulness meditation, acupuncture, research on this exercise, yoga, herbal therapies) may be effective.15-17 topic especially compelling? How widely does care VARIABILITY IN CARE now vary? • A large proportion of cases of GAD are undiagnosed; many people try to alleviate symptoms using home remedies, over-the-counter medications, self-medicating with alcohol and tobacco, and/or by using other alternative medicine approaches (yoga, meditation, and so forth). • In a longitudinal study in primary care of patients with anxiety disorders, including 25% with GAD, almost half (47%) of patients were untreated. When patients did receive treatment, the most common approach involved a combination of medication and psychotherapy (25%), with 21% receiving medication alone and 7% receiving psychotherapy alone.18 • People who seek health care for GAD do so through a wide range of medical specialties, resulting in highly variable types and quality of care. What is the pace of RECENT PUBLICATIONS (Medline Search of Past five years) other research on Total: 2,185 citations this topic (as Citations labeled as RCT: 653 indicated by recent Citations labeled as Meta-Analysis or Systematic Reviews: 265 publications and ongoing trials)? ONGOING TRIALS (Search on ‘clinicaltrials.gov’) Search: Generalized Anxiety Disorder Ongoing Trials: 113 trials that are recruiting subjects and therefore do not have results published yet nor are included in any of the above mentioned meta-analyses How likely is it that KEY UNCERTAINTIES IN CLINICAL DECISION MAKING new CER on this • There are many uncertainties pertaining to the comparative effectiveness and safety of topic would nonmedication treatment options for GAD, especially for the comparative effectiveness of provide better medication and nonmedication treatments (with very few direct comparison studies). information to • There is also uncertainty pertaining to patient preference for treatment options, as well as guide clinical patients’ willingness and ability to engage in lifestyle modifications or behavioral decision making? interventions that could prove to be potentially effective. LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES • There is a high likelihood that new comparative-effectiveness research (CER) on nonmedication approaches to GAD could help inform patients and health care providers about treatment options and facilitate decision making. Potential for New Information to Improve Care and Patient-Centered Outcomes What are the FACILITATORS facilitators and • GAD is a highly prevalent condition, and patients do often seek relief from unpleasant 80

barriers that would symptoms. affect the • There are increasing numbers of patients interested in nonmedication approaches to disease implementation of management and relief of symptoms. new findings in • No obvious avenue exists for disseminating findings to patients and health care providers, practice? however professional societies related to psychiatry/psychology and support and advocacy groups for those who have GAD should be potential resources to facilitate dissemination. BARRIERS • There is a general lack of industry support for nonmedication approaches to treating clinical conditions. How likely is it that EVIDENCE OF BENEFIT the results of new • The apparently growing population of those seeking information from sources other than research on this conventional health care providers might access and implement results of new research right topic would be away. implemented in • Physicians and other health care providers, however, may tend to wait for additional practice right information about nonmedication approaches before changing their recommendations. away? • Insurance companies may also be relatively slow to implement changes involving nonmedication treatments. EVIDENCE OF NO BENEFIT OR HARM • Evidence of no benefit may be largely overlooked by patients, providers, and payers. • Evidence of harm associated with nonmedication approaches is likely to be addressed quickly by health care providers and have bearings on their recommendations regarding treatment options for an individual patient. Would new There are many important clinical uncertainties associated with this topic. information from New information may be rendered obsolete quickly, but may also encourage further research CER on this topic that may ultimately have an impact on patient-centered outcomes. remain current for several years, or would it be rendered obsolete quickly by subsequent studies?

REFERENCES 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.) (DSM- IV-TR). Washington, DC: American Psychiatric Press Inc, 2000. 2. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005; 62:593. 3. Kessler RC, Gruber M, Hettema JM, et al. Co-morbid major depression and generalized anxiety disorders in the National Comorbidity Survey follow-up. Psychol Med. 2008; 38:365. 4. Üstün TB, Sartorius N. Mental Illness in General Health Care: An International Study. Chichester, United Kingdom: Wiley; 1995. pp. 323–335. 5. Massion AO, Warshaw MG, Keller MB. Quality of life and psychiatric morbidity in panic disorder and generalized anxiety disorder. Am J Psychiatry. 1993;150(4):600–607.

6. Wittchen HU, Carter RM, Pfister H, et al. Disabilities and quality of life in pure and comorbid generalized anxiety disorder and major depression in a national survey. Int Clin Psychopharmacol. 2000; 15:319. 7. Kapczinski F, Lima MS, Souza JS, Schmitt R. Antidepressants for generalized anxiety disorder. Cochrane Database Syst Rev. 2003; CD003592. 8. Hidalgo RB, Tupler LA, Davidson JR. An effect-size analysis of pharmacologic treatments for generalized anxiety disorder. J Psychopharmacol. 2007; 21:864. 9. Bereza BG, Machado M, Ravindran AV, Einarson TR. Evidence-based review of clinical outcomes of guideline- recommended pharmacotherapies for generalized anxiety disorder. Can J Psychiatry. 2012 Aug;57(8):470-478. 10. Hunot V, Churchill R, Silva de Lima M, Teixeira V. Psychological therapies for generalised anxiety disorder. Cochrane Database Syst Rev. 2007; CD001848. 11. Hendriks GJ, Oude Voshaar RC, Keijsers GP, et al. Cognitive-behavioural therapy for late-life anxiety disorders: a systematic review and meta-analysis. Acta Psychiatr Scand. 2008; 117:403. 12. Mitte K. Meta-analysis of cognitive-behavioral treatments for generalized anxiety disorder: a comparison with pharmacotherapy. Psychol Bull. 2005; 131:785. 13. Norton PJ, Price EC. A meta-analytic review of adult cognitive-behavioral treatment outcome across the anxiety disorders. J Nerv Ment Dis. 2007; 195:521. 14. Hofmann SG, Smits JA. Cognitive-behavioral therapy for adult anxiety disorders: a meta-analysis of randomized placebo-controlled trials. J Clin Psychiatry. 2008; 69:621. 15. Vøllestad J, Nielsen MB, Nielsen GH. Mindfulness- and acceptance-based interventions for anxiety disorders: a systematic review and meta-analysis. Br J Clin Psychol. 2012 Sep;51(3):239-60. doi: 10.1111/j.2044- 8260.2011.02024.x. Epub 2011 Sep 9. 16. Chen KW, Berger CC, Manheimer E, Forde D, Magidson J, Dachman L, Lejuez CW. Meditative therapies for reducing anxiety: a systematic review and meta-analysis of randomized controlled trials. Depress Anxiety. 2012 Jul;29(7):545-62. doi: 10.1002/da.21964. Epub 2012 Jun 14. 17. Sarris J, Moylan S, Camfield DA, Pase MP, Mischoulon D, Berk M, Jacka FN, Schweitzer I. Complementary medicine, exercise, meditation, diet, and lifestyle modification for anxiety disorders: a review of current evidence. Evid Based Complement Alternat Med. 2012;2012:809653. doi: 10.1155/2012/809653. Epub 2012 Aug 27. 18. Weisberg RB, Dyck I, Culpepper L, et al. Psychiatric treatment in primary care patients with anxiety disorders: a comparison of care received from primary care providers and psychiatrists. Am J Psychiatry. 2007;164(2):276–282.

APPENDIX: Topic Questions

Nominated by ‘Web’

1) What other options for treatment are there for GAD besides pills, if a person also suffers from GERD, or other intestinal disorders which prevent digestion of pills?

Population: Patients who suffer from gastrointestinal disorders. Importance: This question is important, because taking pills is impeding the speed at which I can respond to a pill- oriented treatment regimen.

Note: We could find no specific link between GERD and GAD, other than the higher rate of somatic (bodily) complaints in people with GAD. Furthermore, there is no evidence that GERD prevents the digestion of pills which might be used for 82

treatment of GAD. Hence, we focused this topic brief on the comparison between medication and nonmedication treatment for GAD

Topic 12: “Hearing Loss”

Comparative effectiveness of treatments for hearing loss in children and adults.

Criteria Brief Description Introduction Overview/definition of DESCRIPTION OF CONDITION topic • There are three types of hearing loss.1 o Sensorineural hearing loss (SNHL) involves inner ear, cochlea, and auditory nerve o Conductive hearing loss involves middle ear bones or other processes that prevent sound from being transmitted from external ear to inner ear. o Mixed loss is a combination of sensorineural and conductive causes of hearing loss • In children, there is a fourth type of hearing loss, auditory neuropathy spectrum disorder, which, because of damage to the inner ear or the hearing nerve, sound is not organized in a way that the brain can understand. CAUSES • Hearing loss can result from genetic causes, trauma, infections, and other exposures.2 TREATMENTS • Treatments vary depending on the type and cause of hearing loss, as well as a patient’s culture, language, medical, and developmental backgrounds.2 • Treatments for hearing loss include: o Antibiotics (for external or middle ear infections) o Oral corticosteroids (for inflammatory or sudden hearing loss) o Conventional hearing aids o Contralateral routing of signals (CROS) hearing aids, which transmit sound from a microphone in the hearing-impaired ear to a receiver in the hearing ear o Bone-anchored hearing aids (BAHA), which involve a sound processor implanted in the skull behind the ear that carries sound vibrations directly to the cochlear nerve o Cochlear implant devices, which involve an externally worn microphone, sound processor and transmitter system, and implanted receiver and electrode system containing the electronic circuits that receive signals from the external system and send electrical currents to the inner ear Relevance to patient- Hearing loss has a significant effect on the ability to communicate, work, and learn. centered outcomes Comparative-effectiveness research (CER) to identify the most effective treatments could lead to dramatic improvements in functioning and quality of life for patients. Burden on Society Recent incidence and PREVALENCE prevalence in • Hearing loss affects 360 million people worldwide.2 populations and • Approximately two to three out of every 1,000 children in the United States are born deaf subpopulations or hard-of-hearing.3 • Approximately 17% (36 million) of American adults report some degree of hearing loss.3 • There is a strong relationship between age and reported hearing loss: 18% of American adults 45-64 years old, 30% of adults 65-74 years old, and 47% of adults 75 years old or older report hearing loss.3 • The prevalence of hearing loss is higher among people who are male, white, older, less educated, diabetic, hypertensive, or, are a long-time smoker.4

Effects on patients’ QUALITY OF LIFE/PRODUCTIVITY/FUNCTIONAL CAPACITY/MORTALITY quality of life, • Spoken language development is often delayed in children with deafness.2 productivity, • Hearing loss can have a significantly adverse effect on the academic performance of functional capacity, children.2 mortality, use of • Exclusion from communication can cause feelings of loneliness, isolation, and frustration, health care services particularly among older people with hearing loss.2 • If a person with congenital deafness has not been given the opportunity to learn sign language as a child, they may feel excluded from social interaction.2 • Sensorineural hearing loss is the third leading cause worldwide of years lived with disability.5 • Adults with hearing loss have a much higher unemployment rate.2 • Among those who are employed, a higher percentage of people with hearing loss are in the lower grades of employment compared with the general workforce.2 • In the United States, severe to profound hearing loss is expected to cost society $297,000 over the lifetime of an individual. Most of these losses (67%) are due to reduced work productivity; the use of special education resources for children contributes an additional 21%.6 • People with severe hearing loss in the workplace are expected to earn only 50-70% of their non-hearing-impaired peers and lose between $220,000 and $440,000 in earnings over their working life.6 • Lifetime costs for those with prelingual onset exceed $1 million.6 • The lifetime educational cost of hearing loss (more than 40 decibels permanent loss without other disabilities) has been estimated at $115,600 per child (year 2007 value).1 USE OF HEALTH CARE SERVICES • Only one out of five people who could benefit from a hearing aid actually wears one.3 • Approximately 188,000 people worldwide have received cochlear implants. In the United States, roughly 41,500 adults and 25,500 children have received them.3 In adults and children, both multichannel and bilateral cochlear implants were rated as cost-effective treatments for hearing loss.7 • Cochlear implants yielded a calculated net savings of $53,198 per child in indirect costs such as reduced educational expenses.7 How strongly does this Hearing loss can have a profound effect on an individual’s ability to achieve his or her full overall societal burden potential, which in turn can result in significant overall economic and societal costs to the suggest that CER on larger community. This very common disorder should be given high priority in the research alternative agenda. approaches to this problem should be given high priority? Options for Addressing the Issue Based on recent • Corticosteroids are a validated treatment of hearing loss caused by autoimmune and systematic reviews, inflammatory disease; they also remain the primary treatment of idiopathic sudden what is known about SNHL.8 the relative benefits • There is limited evidence that hyperbaric therapy improves hearing in patients with and harms of the idiopathic sudden SNHL and no evidence of a functionally significant improvement.9 available management • BAHA surgery may be preferred by patients over air-conduction CROS hearing aids for 86

options? asymmetric hearing loss.10 • There is no significant improvement in auditory localization with either BAHA or CROS hearing aids, but BAHA provides an advantage with both speech discrimination in noise and subjective auditory abilities.11 • There is significant improvement in auditory localization with bilateral cochlear implantation compared with unilateral cochlear implantation.12 • Bilateral cochlear implants were beneficial for speech perception in noise under certain conditions and several self-reported measures.12 • Statistically significant improvement in mean speech scores as measured by open-set sentence or multisyllable word tests in most studies looking at unilateral implantation.5 • There is significant improvement in quality of life after unilateral implantation.5 • Results from studies assessing bilateral implantation showed improvement in communication-related outcomes compared with unilateral implantation and additional improvements in sound localization compared with unilateral device use or implantation only.5 • Based on a few studies, quality-of-life outcomes varied across tests after bilateral implantation.5 • Bilateral BAHA provides additional objective and subjective benefit compared with unilateral BAHA.13 What could new • Comparative effectiveness of long-term outcomes for unilateral vs. bilateral cochlear research contribute to implants achieving better • Comparative effectiveness of BAHA vs. CROS in a randomized controlled trial format patient-centered • Comparative effectiveness of long-term outcomes for BAHA vs. CROS outcomes? • Comparative effectiveness of unilateral or bilateral cochlear implant devices vs. assistive listening devices • Comparative effectiveness of unilateral or bilateral cochlear implant devices vs. electric- acoustic devices • Comparative effectiveness of unilateral or bilateral cochlear implant devices vs. habilitation/rehabilitation therapy Have recent innovations Increased numbers of patients are receiving bilateral cochlear implants; studies to date have made research on this shown significant benefit over unilateral implantation. There is ongoing research that topic especially continues attempts to improve the technology of existing hearing devices.14 compelling? How widely does care We were unable to find any publications describing the variation in care for hearing loss now vary? treatment. There were a few publications on quality improvement strategies to improve newborn screening of hearing as well as a few publications describing primary care referral patterns to audiology and otolaryngology for hearing loss. What is the pace of ClincalTrials.gov: NIH Reporter: other research on this Search: Hearing Loss Projects: 743 topic (as indicated by Total ongoing trials: 186 Publications: 436 recent publications Completed trials: 154 and ongoing trials)? Search: Deafness Total ongoing trials: 183 Completed trials: 149 87

How likely is it that new New CER could provide useful information regarding the comparative effectiveness of CER on this topic unilateral vs. bilateral cochlear implants as well as useful information comparing these devices would provide better with other treatment modalities for hearing loss. New CER could provide additional information to guide information comparing the BAHA cochlear stimulator with the CROS hearing aid. clinical decision making? Potential for New Information to Improve Care and Patient-Centered Outcomes What are the facilitators FACILITATORS and barriers that • Existing technology will allow easier implementation if specific devices are found to be would affect the more effective. implementation of BARRIERS new findings in • Uncertain coverage by insurance for some devices makes it hard for patients to know practice? what to do if the device that is recommended by the specialist is not covered by their insurance (should they pay for the out-of-pocket cost, or ask the specialist to recommend a different one that is covered?). • Experts (audiologists and otolaryngologists) understand the advantages/disadvantages and differences among these devices, but patients have little information to make decisions on which devices are best for their hearing loss. • Primary care providers are focused on screening for hearing loss and referrals to specialists; therefore their knowledge of appropriate treatment options for specific patients is limited. How likely is it that the It is likely that if covered by insurance, more effective devices or practices (such as bilateral results of new cochlear implantation) would be adopted readily because the technology and expertise already research on this topic exist. would be implemented in practice right away? Would new information There is ongoing research to improve hearing aid technology to provide better speech from CER on this topic discrimination and better discrimination in noisy environments which could help to improve remain current for existing hearing devices, but not necessarily render any results regarding comparative several years, or effectiveness obsolete.14 would it be rendered obsolete quickly by subsequent studies?

REFERENCES 1. Centers for Disease Control. http://www.cdc.gov/ncbddd/hearingloss/types.html. Accessed 4/2/2013. 2. World Health Organization. http://www.who.int/mediacentre/factsheets/fs300/en/. Accessed 4/1/2013. 3. National Institute for Deafness and other Communication Disorders. http://www.nidcd.nih.gov/health/statistics/Pages/quick.aspx. Accessed 4/1/2013. 4. Agrawal Y, Platz EA, Niparko JK. Prevalence of Hearing Loss and Differences by Demographic Characteristics Among US Adults Data From the National Health and Nutrition Examination Survey, 1999-2004. Arch Intern Med. 2008;168(14):1522-1530.

5. Gaylor JM, Raman G, Chung M, et al. Cochlear Implantation in Adults: A Systematic Review and Meta-analysis. JAMA Otolaryngol Head Neck Surg. 2013 Mar 1;139(3):265-72. DOI: 10.1001/jamaoto.2013.1744. 6. Mohr PE, Feldman JJ, Dunbar JL, et al. The societal costs of severe to profound hearing loss in the United States. Am J Audiol. 2012 Dec;21(2):329-330. 7. Semenov YR, Martinez-Monedero R, Niparko JK. Cochlear Implants Clinical and Societal Outcomes. Otolaryngol Clin N Am 2012;45:959–981. 8. Chau JK, Cho JJ, Fritz DK. Evidence-based practice: management of adult sensorineural hearing loss. Otolaryngol Clin North Am. 2012 Oct;45(5):941-958 9. Bennett MH, Kertesz T, Yeung P. Hyperbaric oxygen for idiopathic sudden sensorineural hearing loss and tinnitus. Cochrane Database Syst Rev. 2007;(1):CD004739. 10. Bishop CE, Eby TL. The current status of audiologic rehabilitation for profound unilateral sensorineural hearing loss. Laryngoscope. 2010;120(3):552–556. 11. Baguley DM, Bird J, Humphriss RL, et al. The evidence base for the application of contralateral bone anchored hearing aids in acquired unilateral sensorineural hearing loss in adults. Clin Otolaryngol. 2005;31(1):6–14. 12. van Schoonhoven J, Sparreboom M, van Zanten BG, et al. The effectiveness of bilateral cochlear implants for severe- to-profound deafness in adults: a systematic review. Otol Neurotol. 2013 Feb;34(2):190-198. 13. Janssen RM, Hong P, Chadha NK. Bilateral bone-anchored hearing aids for bilateral permanent conductive hearing loss: a systematic review. Otolaryngol Head Neck Surg. 2012 Sep;147(3):412-22. 14. National Institutes of Health.http://report.nih.gov/nihfactsheets/viewfactsheet.aspx?csid=95. Accessed 4/2/2013.

APPENDIX: Topic Question

Nominated by Institute of Medicine (IOM)

1) Compare the effectiveness of the different treatments (eg, assistive listening devices, cochlear implants, electric- acoustic devices, habilitation and rehabilitation methods [auditory/oral, sign language, and total communication]) for hearing loss in children and adults, especially individuals with diverse cultural, language, medical, and developmental backgrounds.

Topic 13: “Chronic Kidney Disease”

Comparative effectiveness of treatment and prevention options for patients with chronic kidney disease.

Criteria Brief Description Introduction Overview/definition of DESCRIPTION OF CONDITION topic • Chronic kidney disease (CKD) is a condition in which the kidneys are damaged and cannot filter blood as well as in normal functioning kidneys.1 • There are five stages of CKD based on level of functional impairment. Relevance to patient- SYMPTOMS centered outcomes • CKD is usually asymptomatic in the early stages.1 • In more advanced kidney disease stages, symptoms can include lack of energy, difficulty concentrating, poor appetite, insomnia, muscle cramping, edema (swelling), dry skin, increased urinary frequency, bruising, shortness of breath, and bone pain.2 OUTCOMES • CKD can cause wastes to build up in the body and lead to other health problems, including cardiovascular disease, anemia (low red blood cells), and bone deformities and weakening.1 • CKD is usually irreversible and progressive. • If not treated, over time it can lead to kidney failure, also called end-stage kidney disease (ESKD).1 Burden on Society Recent incidence and INCIDENCE (NEW CASES) prevalence in • The incidence of CKD is increasing most rapidly in people aged 65 and older—more than populations and doubling in this age group between 2000 and 2008, to nearly 4.5%.3 subpopulations • The incidence of recognized CKD among 20-64 year olds is 0.5%.3 PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE CONDITION)1 • In the United States, more than 20 million people aged 20 years or older (>10%) have CKD. • CKD is more common among women than men. • African Americans were nearly four times more likely to develop ESKD than whites in 2007; however, this disparity in ESKD incidence had narrowed from 1998 to 2005. • The Hispanic population has 1.5 times the rate of kidney failure compared to the non- Hispanic white population. Effects on patients’ QUALITY OF LIFE quality of life, • Multiple studies have shown that CKD is associated with decreased health-related quality productivity, of life (QOL), most showing a worse QOL decreasing with progressive kidney disease.4-6 functional capacity, PRODUCTIVITY mortality, use of o One study showed that patients with CKD reported 18% absenteeism and 35% health care services productivity loss.7 MORTALITY o Premature death from both cardiovascular disease and from all causes is higher in adults with CKD compared to adults without CKD.1 1 o Individuals with CKD are 16-40 times more likely to die before progressing to ESKD. o The number of annual deaths from ESKD increased from 10,478 in 1980 to 90,118 in 2009.3 91

COST o The overall medical and economic cost of CKD in the United States was approximately $82.9 billion in 2007.8 8 o Expenditures for patients with CKD accounts for nearly 28% of all Medicare spending.

How strongly does this CKD is an increasingly common medical condition, which results in significant economic costs overall societal burden to society and impact on the quality of life of individual who have it. High priority should be suggest that CER on given to this research topic. alternative approaches to this problem should be given high priority? Options for Addressing the Issue Based on recent • For CKD patients with large amounts of protein in their urine—nearly all with diabetes systematic reviews, and hypertension—angiotensin converting enzyme inhibitors (ACEIs) and angiotensin what is known about receptor blockers (ARBs) significantly reduced the risk of progressing to ESKD compared the relative benefits with placebo.9 and harms of the • For CKD patients with small amounts of protein in their urine who have cardiovascular available management disease or diabetes with other cardiovascular risk factors, ACEIs treatment reduced options? mortality risk compared with placebo.9 • In randomized controlled trials that directly compared different treatments for hypertension, diabetes, and high cholesterol, it was unclear whether increasing treatment improves clinical outcomes.9 • Despite substantial focus on the early identification and proactive management of CKD in the last few years, there are significant areas where more research is needed in order to know how best to manage people with CKD.10 What could new • Examining different strategies to screen for CKD or monitor CKD progression could lead research contribute to to earlier detection of kidney disease, faster initiation of preventive medicine, and better achieving better patient-centered outcomes (such as QOL and delayed progression of CKD). patient-centered • Evaluating the comparative effectiveness of various treatments for CKD risk factors such outcomes? as hypertension, diabetes, and high cholesterol could help to determine the best treatment of these conditions to prevent progression of CKD and improve patient- centered outcomes. • Evaluating available treatment for slowing progression of CKD at different stages could help determine the optimal timing for initiation of treatment to slow CKD progression and improve patient-centered outcomes. • Evaluating available treatment for slowing progression of CKD among patients in different demographic subgroups and with different comorbidities could lead to more effective and better tolerated treatment, thus improving patient-centered outcomes. • Evaluating harms of treatments to slow progression of CKD could potentially improve patient adherence and quality of life.

• Although research exists showing improvement in diabetes treatment (a known risk factor for CKD) with medical nutrition therapy (MNT), additional research assessing the comparative effectiveness of MNT vs. (or in addition to) other treatments for diabetes may provide useful information for determining how to best manage diabetes in order to optimize kidney functioning. Have recent innovations Newer drug classes, several of them “first-in-class” drugs (ie, drugs which, for example, use a made research on this new and unique mechanism of action for treatment) that are being tested have less topic especially supportive data and would make compelling areas for additional research. compelling? How widely does care VARIABILITY IN CARE now vary? • Among people with CKD in the United States, lower socioeconomic status is associated with greater risk of disability. This is found regardless of a patient’s race or ethnicity, health care access, and comorbid conditions.11 • The mechanisms by which socioeconomic status influences the development of risk factors for CKD throughout the course of an individual’s life are not entirely clear.11 What is the pace of Clinicaltrials.gov: NIH Reporter: other research on this o Total ongoing trials: 548 o Projects: 250 topic (as indicated by o Completed trials: 778 o Publications: 596 recent publications and ongoing trials)? How likely is it that new KEY UNCERTAINTIES IN CLINICAL DECISION MAKING CER on this topic • Does systematic CKD screening improve clinical outcomes? would provide better • Does systematic CKD monitoring for worsened kidney function or damage improve information to guide clinical outcomes? clinical decision • What medications used to treat diabetes, hypertension, and high cholesterol have an making? effect on progression of renal disease? • Does the effectiveness of available medical treatments differ based on severity of CKD stage? • Do medical treatments have different risks vs. benefits in clinical outcomes for patients with recently worsened kidney function or damage (as detectable by monitoring) compared with those with stable CKD? • Do medical treatments improve outcomes in CKD subgroups for which treatment is not already indicated? • How effective is MNT alone or in combination with other treatment in preventing or slowing progression of CKD? • What is the effect of MNT on clinical outcomes in patients with CKD stages 1–3 vs. later stage CKD? • Does effectiveness of medical treatments vary based on stage of kidney disease? • What is the optimal timing (stage of kidney disease) of referral to a nephrologist (kidney specialist) for management of CKD? LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES • New research would likely be able to identify ideal screening and monitoring strategies. • New research could clarify ideal treatment for those risk factors such as diabetes, hypertension, and high cholesterol that would prevent progression of kidney disease.

• New research could clarify effectiveness of treatment in different stages of kidney disease. • New research could clarify the comparative effectiveness of MNT in preventing or slowing progression of kidney disease. Potential for New Information to Improve Care and Patient-Centered Outcomes What are the facilitators FACILITATORS and barriers that • Diabetes, hypertension, and high cholesterol are all already high-priority conditions. would affect the • Many medications exist to treat these conditions and potentially prevent complications. implementation of • MNT is covered by Medicare. new findings in • Most patients with kidney disease are on Medicare and/or Medicaid, so some practice? information may be able to be obtained from their databases. BARRIERS • Studies of earlier stage CKD would require years of follow-up, which could be expensive. • The number of available treatments and many different patient subgroups could make designing generalizable studies challenging. • There is a potential lack of workers to provide MNT to all qualified patients. • There is a potential lack of coverage for MNT by insurance plans other than Medicare. • Providers lack knowledge about MNT. • Providers lack knowledge about current CKD management guidelines. How likely is it that the • It is likely that new information regarding optimal treatments for diabetes, hypertension, results of new and high cholesterol in patients with CKD could be implemented quickly with education. research on this topic • If MNT were shown to be effective in preventing or slowing progression of kidney disease, would be it is likely that new information could be implemented quickly if there is an adequate implemented in number of trained workers to provide nutrition counseling. practice right away? Would new information It is likely that new information from comparative-effectiveness research (CER) would remain from CER on this topic current for several years. remain current for several years, or would it be rendered obsolete quickly by subsequent studies?

REFERENCES

1. Centers for Disease Control and Prevention. National Chronic Kidney Disease Fact Sheet: General Information and National Estimates on Chronic Kidney Disease in the United States, 2010. Atlanta, GA: U.S. Department of Health and Human Services, CDC; 2010. http://www.ihpm.org/pdf/CKD_HPM%20_2010.pdf. Published 2010. 2. Chronic Kidney Disease. Institute for Health and Productivity Management. http://www.ihpm.org/pdf/CKD_HPM%20_2010.pdf. Published 2010. Accessed 4/8/2013. 3. Kidney Disease Statistics for the United States. National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC). http://kidney.niddk.nih.gov/kudiseases/pubs/kustats/. Accessed 4/6/2013. 4. Perlman RL, Finkelstein FO, Liu L, et al. Quality of life in chronic kidney disease (CKD): a cross-sectional analysis in the Renal Research Institute-CKD study. Am J Kidney Dis. 2005 Apr; 45(4):658-666. 94

5. Mujais SK, Story K, Brouillette J, et al. Health-related Quality of Life in CKD Patients: Correlates and Evolution over Time. Clin J of the Am Soc of Nephrology. 2009 Aug; 4(8): 1293–1301. 6. Pagels AA, Soderkvist BK, Medin C, et al. Health-related quality of life in different stages of chronic kidney disease and at initiation of dialysis treatment. Health and Quality of Life Outcomes. 2012 Jun;10:71. 7. Assessing Work Productivity Loss and Disability Among Chronic Kidney Disease Sufferers in the United States. Poster presentation at the American Occupational Health Conference. 2010 May. 8. U.S. Renal Data System. USRDS 2009 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2009. 9. Fink HA, Ishani A, Taylor BC, et al. Chronic Kidney Disease Stages 1–3: Screening, Monitoring and Treatment. Comparative Effectiveness Review No. 37. (Prepared by the Minnesota Evidence-based Practice Center under Contract No. HHSA 290-2007-10064-I.) AHRQ Publication No. 11(12)-EHC075-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2012. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published January 2012. 10. Black C, Sharma P, Scotland G, et al. Early referral strategies for management of people with markers of renal disease: a systematic review of the evidence of clinical effectiveness, cost-effectiveness and economic analysis. Health Technology Assessment. 2010; 14(21): 1-184 11. Plantinga LC, Johansen KL, Schillinger D, Powe NR. Lower Socioeconomic Status and Disability Among US Adults With Chronic Kidney Disease, 1999-2008. Prev Chronic Dis. 2012;9:E12.

APPENDIX: Topic Questions

Nominated by ‘Web’

1) What are the best strategies for delaying the progression of chronic kidney disease, maintaining the patient's quality of life, and decreasing morbidity?

Importance: Chronic kidney disease (CKD) is common, affecting approximately 20 million (one out of every nine) people in the United States.

2) Is Diabetes Self-Management Training (DSMT) and/or dietetic consultation (including, but not limited to, Medicare Medical Nutrition Therapy) effective in empowering patients to avoid morbidity/mortality from chronic kidney disease (CKD) associated with diabetes?

Population: The burden of CKD is greatest among senior citizens, including Medicare beneficiaries, as well as among members of racial and ethnic minority groups, and among populations with lower socioeconomic status. The growth of CKD in the United States is related to the increase in both diabetes and hypertension at the population level.

Importance: Medical Nutrition Therapy (MNT) is Medicare coverage for consultation with a nutritionist that was authorized by the Benefits Improvement and Protection Act of 2000 and is available to individuals with diabetes and/or impaired kidney function (eGFR below 50). Utilization of MNT benefits has been far below expectations. However, MNT and DSMT provide excellent opportunities for patient empowerment. Proof that DSMT and MNT are effective in improving outcomes (eg, preventing/delaying End Stage Renal Disease, improving blood pressure control, enhancing glycemic control, reducing avoidable hospitalizations from CKD associated with diabetes) 95

should enhance utilization of these benefits. In addition, this kind of research could incentivize group health plans to include similar initiatives as part of the wellness programs they provide pursuant to the Affordable Care Act.

Topic 14: “Treatments for Liver Cancer”

Comparative effectiveness of medical and surgical treatment options in patients with primary or metastatic malignancies of the liver in adults.

Criteria Brief Description Introduction Overview/definition DESCRIPTION OF CONDITION of topic • Two different types of liver cancer: primary and secondary • Primary liver cancer (cancer arising from the cells of the liver) Most commonly hepatocellular carcinoma (HCC) o 1-2 o HCC almost always arises in patients with chronic liver disease (from other causes): . Alcohol addiction/abuse/overuse . Chronic infection with Hepatitis B or C . Nonalcoholic fatty liver disease (associated with obesity and Type 2 diabetes) . Less common exposures such as arsenic, certain chemicals in plastics, abuse of anabolic steroids (testosterone derivatives), rare metabolic/genetic conditions • Secondary liver cancer (other cancer has spread to liver; called liver metastases) Cancer cells from another organ cause tumors in the liver o 3 o Most common original cancer site is the colon . 60-70% of colon cancer patients eventually develop liver metastases . 20-25% have liver metastases at time of diagnosis . 40-50% develop liver metastases despite colon cancer treatment o Other cancers that spread to the liver include breast, esophagus, stomach, pancreas, skin, and lung o Treatment of secondary liver cancer is based on treatment of original cancer Relevance to • Symptoms patient-centered o Primary liver cancer (HCC) outcomes . Jaundice (skin and whites of eyes become yellow, urine darkens, color of stool becomes lighter than normal) . General feelings of poor health, weakness, and fatigue . Loss of appetite and/or weight loss . Abdominal bloating . Itching of skin . Abdominal pain or discomfort . Swelling of legs o Secondary liver cancer (liver metastases) . Similar to HCC . May have symptoms related to original type of cancer or from its treatment

• Other outcomes o Mortality o Quality of life (affected both by underlying disease and by treatments) Burden on Society Recent incidence INCIDENCE (new cases)/PREVALENCE (proportion of population with condition) and prevalence in • Incidence approximates prevalence for both primary and secondary liver cancer due to high populations and mortality rates subpopulations • Primary liver cancer (HCC) 98

o Age-adjusted incidence 3.2 per 100,000 in the United States in 2006 and increasing due to rise in rate of hepatitis B and C (present in 80% of HCC cases)4 o Incidence and prevalence are much higher in other parts of the world (eg, Asia, Africa), mirroring higher rates of hepatitis B and C5 o In the United States, more common in men than women and more common among Asian/Pacific Islanders, Native Americans/Alaska Natives, blacks, and Hispanic people than in whites (age-adjusted incidence per 100,000)6

• Secondary liver cancer (liver metastases): Difficult to estimate overall, as multiple cancers can cause liver metastasis o Overall incidence of colon cancer is 46.3 per 100,000, and about 20-25% of these patients have metastases7-8 o Assuming 65% of all cases eventually develop liver metastases (age-adjusted incidence per 100,000)6 o By race/sex, secondary liver cancer (liver metastases) are between 1.5 to more than 10 times more likely than primary liver cancer (HCC) o Metastases at time of diagnosis are slightly more common in blacks than in whites Effects on patients’ QUALITY OF LIFE quality of life, • Both primary (HCC) and secondary liver cancer (liver metastases) have a major impact on productivity, quality of life, with impact increasing with worsened tumor cancer stage8-9 functional capacity, FUNCTIONAL CAPACITY/PRODUCTIVITY mortality, use of • Primary liver cancer/HCC: Functional capacity reduced; impact on functional capacity often health care worse among patients with advanced liver disease due to hepatitis B or C infections and/or services other illnesses10-11 • Secondary liver cancer (liver metastases): Major impact on functional capacity; patients often debilitated from their cancer treatments (which can include surgery, chemotherapy, and radiation) as well as from underlying illness8,10

MORTALITY • Primary liver cancer (HCC): 11-12 o One-year survival rate remains <50%, five-year survival rate 14.4% o Age-adjusted death rate is estimated at 5.2 per 100,000 people per year in the United States7 • Secondary liver cancer: Varies by tumor type; for colon cancer that spreads to the liver, one- year survival is ~40%, and five-year survival is ~6-8%8,13 How strongly does • Incidence of primary liver cancer (HCC) is increasing as prevalence of hepatitis B and hepatitis this overall C increase societal burden o Primary liver cancer (HCC) is a high-mortality condition suggest that CER . There is a range of available treatments, lending high priority to CER on alternative . However, relative burden of primary liver cancer much smaller than for secondary approaches to this liver cancer problem should be . Other strategies available for preventing morbidity/mortality from primary liver given high cancer priority? • Primary prevention of hepatitis B and C through vaccination (currently available 99

only for hepatitis B), screening, measures to prevent the spread of hepatitis infections between people, improved treatments for chronic hepatitis infection • Prevention and treatment of other conditions (alcoholism, type 2 diabetes, and other liver diseases) o Secondary liver cancer (liver metastases) can result from multiple other types of cancers . Colon cancer with associated liver metastasis is a relatively common, high-mortality condition. This also makes colon cancer a high priority for CER. Options for Addressing the Issue Based on recent SYSTEMATIC REVIEWS systematic • Imaging Techniques for the Surveillance, Diagnosis, and Staging of Hepatocellular Carcinoma reviews, what is (HCC) (EPC Project In Process)11 known about the • Local Therapies for Unresectable Primary Hepatocellular Carcinoma: Comparative relative benefits Effectiveness Review (Draft 2012)14 and harms of the • Belinson S, Chopra R, Yang Y, Shankaran V, Aronson N. Local Hepatic Therapies for available Metastases to the Liver From Unresectable Colorectal Cancer. Comparative Effectiveness management Review No. 93. AHRQ Publication No. 13-EHC014-EF. Rockville, MD: Agency for Healthcare options? Research and Quality. December 2012.8

SCREENING/EARLY DIAGNOSIS • Primary liver cancer (HCC)11 o Among patients with hepatitis B or C, screening is typically done using ultrasonography (u/s), computerized tomography (CT, aka CAT scan), and magnetic resonance imaging (MRI) o Otherwise, primary liver cancer is most often found incidentally on imaging studies done for other reasons • Secondary liver cancer (liver metastases) o Liver metastases not typically screened for, though primary cancers that lead to liver metastases often have established screening tests (eg, colon cancer and screening with a colonoscopy)

TREATMENT • Primary liver cancer (HCC): In cases where HCC is detected early enough and the patient’s liver function is sufficient to allow a procedure, a variety of procedural treatments may be possible. o Medical treatment (most commonly a drug called sorafenib) is sometimes an option, but HCC tends to be resistant to standard drug therapy14-15 o Surgery: If a tumor meets certain criteria for size and location, surgical removal may be an option, and may prolong survival or even be curative. o Liver transplantation: This is the treatment of choice for some patients with poor liver function who cannot tolerate surgery. o Treatment with one of the below therapies may be used as a bridge to transplant. o Ablation: Destruction of liver cancer tissue through chemical injury or heating. o Embolization: Blockage of blood vessels that supply the liver cancer. o Radiotherapy: Directed radiation to destroy liver cancer tissue. 100

• Secondary liver cancer (liver metastasis): In cases where metastases are confined to the liver, local treatment may be possible, along with treatment of the primary cancer and chemotherapy (focus here is on colon cancer, as this is the most common cause for liver metastases).8 o Surgery: If a metastatic tumor in the liver meets certain criteria for size and location, surgical removal may be an option, and may prolong survival or even be curative. Pretreatment with chemotherapy may also shrink metastatic tumors so that they can be treated surgically. o Ablation: Destruction of liver cancer tissue through chemical injury or heating. o Embolization: Blockage of blood vessels that supply the liver cancer. o Radiotherapy: Directed radiation to destroy liver cancer tissue.

What could new New research could contribute to achieving better patient-centered outcomes by evaluating:8,14 research • Comparative effectiveness (regarding survival and quality of life) of the various liver-directed contribute to therapies in patients with primary or secondary liver cancer who are not otherwise achieving better candidates for surgical resection (or liver transplantation for primary liver cancer) patient-centered Comparative harms (regarding side effects) of the various liver-directed therapies in patients outcomes? with primary or secondary liver cancer who are not otherwise candidates for surgical resection (or transplantation) • Effect of specific patient and tumor characteristics, such as age, sex, disease etiology, and liver function on comparative effectiveness of various liver-directed therapies in patients with primary or secondary liver cancer who are not otherwise candidates for surgical resection (or transplantation) • Role of the various liver-directed therapies in patients who are candidates for liver-directed therapy as an adjunct to chemotherapy for metastases to the liver that cannot be operated on Have recent Recent innovations: innovations made • Many available procedural therapies for primary or secondary liver cancer represent recent research on this innovations, and procedural techniques continue to evolve. topic especially • New comparative-effectiveness research (CER) will likely be needed to establish which of the compelling? options is preferred in specific clinical situations and in specific patient subgroups. How widely does VARIABILITY IN CARE care now vary? • While the indications for surgery for primary or secondary liver cancer are reasonably well- understood, there is likely more variability in the use of other newer procedural therapies due to variation in local expertise and access to advanced care. o Care may be provided by different specialties (surgeons, medical oncologists, interventional radiologists, radiation therapies) o Local practices, financial incentives/disincentives may contribute to variability in care What is the pace of RECENT PUBLICATIONS other research on • MEDLINE search 1/1/08-4/16/13: this topic (as o Total: 6,442 citations indicated by o Labeled as randomized controlled trial (RCT): 224 recent o Labeled as meta-analysis or systematic review: 386 publications and ongoing trials)? 101

ONGOING TRIALS • Clinicaltrials.gov: search term ‘liver cancer’ o Ongoing trials: 645 o Completed trials: 414 • Clinicaltrials.gov: search term ‘hepatocellular carcinoma’ o Ongoing trials: 397 o Completed trials: 226 • NIH reporter: Hepatic carcinoma o Projects: 662 o Publications: 143 How likely is it that KEY UNCERTAINTIES IN CLINICAL DECISION-MAKING new CER on this • Optimal strategy for screening/early diagnosis topic would • Comparative effectiveness of treatment options (surgery, medical therapy, ablation, or provide better observation) on disease-free survival and overall survival, tumor recurrence, and quality of information to life in patients with: guide clinical o Primary liver cancer decision making? o Secondary liver cancer • Optimal treatment for primary and secondary liver cancer that cannot be operated on

LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES • Appropriately designed studies would have a high likelihood of answering the above questions and reducing key areas of uncertainty • Randomized trials of easily measured outcomes (like disease-free survival and overall survival) usually sponsored by National Cancer Institute or manufacturer (especially chemotherapeutic drugs) o Treatments based on surgical procedures (eg, cutting off tumor blood supply with embolization) are less likely to be subjected to RCTs, because either no regulatory requirements (surgical procedures) or fewer restrictive regulatory requirements (devices) compared to drugs • CER by PCORI focused on patient-centered outcomes, particularly quality of life, preferences for different treatments, as well as other factors, more feasible than large-scale RCTs with mortality as primary outcome Potential for New Information to Improve Care and Patient-Centered Outcomes What are the FACILITATORS facilitators and • Acceptance of evidence-based treatment results generally better in cancer treatment than barriers that other areas of medicine would affect the • Evidence of improved survival and other outcomes likely to be well accepted by both implementation of patients and health care providers new findings in practice? BARRIERS • Treatment options may be expensive and uncovered or only partially covered by third-party payers • Access to different treatments may be affected by availability of appropriately trained and experienced clinicians 102

• Different financial incentives/disincentives for treatment options, competition between different types of practitioners How likely is it that EVIDENCE OF BENEFIT the results of new • Evidence of benefit, particularly for survival, likely to be rapidly implemented research on this topic would be EVIDENCE OF NO BENEFIT OR HARM implemented in • Evidence of no benefit may or may not be rapidly implemented (ie, treatment with no practice right benefit compared to other available treatments may continue to be used) based on issues of away? access, provider incentives, and other factors. • Evidence of harm may or may not be rapidly implemented depending on types of harm (decreased survival likely to be implemented, increased risk of side effects or negative impact on quality of life possibly less likely to be implemented depending on other factors) Would new • Primary Liver Cancer (HCC) information from o Incidence attributable to chronic hepatitis likely to continue to rise even if vaccine for CER on this topic hepatitis C is discovered, given high prevalence in other parts of world and difficulty in remain current for establishing vaccination program several years, or o Incidence related to other causes, particularly nonalcoholic fatty liver disease, also likely would it be to continue to increase rendered obsolete quickly by • Secondary Liver Cancer (liver metastases) subsequent o Given that colon cancer is the third most common cancer in the United States, high rate studies? of metastases, and variability in cancer outcomes even for same treatment in same cancer type, CER results unlikely to become obsolete . CER results may be modified if genetic or other biomarkers predictive of treatment response become available

REFERENCES: 1. Liver cancer. Memorial Sloan Kettering Cancer Center. www.mskcc.org/cancer-care/adult/liver/about-liver. Accessed April 16, 2013. 2. Liver cancer. National Cancer Institute. www.cancer.gov/cancertopics/types/liver/. Accessed April 16, 2013. 3. Liver metastases (secondary liver cancer). Memorial Sloan Kettering Cancer Center. www.mskcc.org/cancer- care/adult/liver-metastases-secondary-liver/about-liver-metastases. Accessed April 16, 2013. 4. Centers for Disease Control and Prevention (CDC). Hepatocellular carcinoma - United States, 2001-2006. MMWR Morb Mortal Wkly Rep. 2010;59(17):517-520. 5. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69- 90. 6. Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 18 Regs Research Data + Hurricane Katrina Impacted Louisiana Cases, Nov 2011 Sub, Vintage 2009 Pops (2000-2009). National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2012, based on the November 2011 submission. 7. SEER Stat Fact Sheets: Colon and Rectum. http://seer.cancer.gov/statfacts/html/colorect.html. Accessed April 16, 2013. 8. Belinson S, Chopra R, Yang Y, Shankaran V, Aronson N. Local Hepatic Therapies for Metastases to the Liver From Unresectable Colorectal Cancer. Comparative Effectiveness Review No. 93. (Prepared by Blue Cross and Blue Cross Blue Shield Association Technology Evaluation Center under Contract No. 290-2007-10058-I.) AHRQ 103

Publication No. 13-EHC014-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2012. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published December 2012. 9. Qiao CX, Zhai XF, Ling CQ, Lang QB, Dong HJ, Liu Q, Li MD. Health-related quality of life evaluated by tumor node metastasis staging system in patients with hepatocellular carcinoma. World J Gastroenterol. 2012;18(21):2689- 2694. 10. Stafford RS, Cyr PL. The impact of cancer on the physical function of the elderly and their utilization of health care. Cancer. 1997;80(10):1973-1980. 11. Imaging Techniques for the Surveillance, Diagnosis, and Staging of Hepatocellular Carcinoma (HCC) (EPC Project In Process) (www.effectivehealthcare.ahrq.gov/search-for-guides-reviews-and- reports/?pageaction=displaytopic&topicid=479&search=liver%20cancer). Accessed April 16, 2013. 12. Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol. 2009;27(9):1485-1491. 13. O'Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst. 2004;96(19):1420. 14. Local Therapies for Unresectable Primary Hepatocellular Carcinoma: Comparative Effectiveness Review (Draft 2012) (http://www.effectivehealthcare.ahrq.gov/ehc/products/360/1012/HCC_protocol- amendment_20121212.pdf). Accessed April 16, 2013. 15. Clavien PA, Lesurtel M, Bossuyt PM, et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol. 2012;13:e11-22.

APPENDIX: TOPIC QUESTIONS Nominated by Institute of Medicine 1) Compare the effectiveness of surgical resection, observation, or ablative techniques on disease-free and overall survival, tumor recurrence, quality of life, and toxicity in patients with liver metastases.

Nominated by ‘Web’ 1) Treatments for Unresectable Liver Cancer - This is a Center for Medical Technology Policy (CMTP)-identified CER priority

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Topic 15: “Macular Degeneration”

Comparative effectiveness of treatment for patients with age-related macular degeneration (AMD).

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Criteria Brief Description Introduction Overview/definition DESCRIPTION OF CONDITION 1,2 of topic • Macular degeneration is a degenerative disease of the central portion of the retina (macula). • Age-related macular degeneration (AMD) is the most common form. • Two types of AMD: o Dry (atrophic) is chronic. o Wet (neurovascular or exudative) is an abrupt onset that can rapidly progress to blindness if untreated. • Dry AMD is a risk factor or precursor state for wet AMD, with early dry phase converting to more severe wet form in 10-20% of patients. • Early stage of dry AMD is asymptomatic. Relevance to SYMPTOMS1 patient-centered • With AMD, there is progressive visual loss, primarily of the central (rather than peripheral) outcomes vision • Central vision is needed for reading and driving. • Central vision loss is associated with increased falls and hip fractures. Burden on Society Recent prevalence in PREVALENCE1,2 populations and • 10-15 million people in the United States are living with AMD, two million of whom have subpopulations advanced disease. • Prevalence is increasing (by 2020, three times as many people will have AMD than in 1995). • Prevalence increases with age, with 2% of people at age 40 to 25% at age 80. • Risk factors include age, smoking, family history, cardiovascular disease, lightly pigmented skin, and female sex. INCIDENCE • 15-year cumulative incidence is 14% for early AMD and 3% for late AMD. Effects on patients’ QUALITY OF LIFE (QOL)2,3 quality of life, • AMD is the leading cause of blindness in the United States. productivity, • AMD is associated with impairment in driving, ambulation, reading, recognizing faces, and all functional activities of daily living. capacity, PRODUCTIVITY mortality, use of • Condition can result in loss of independent living. health care FUNCTIONAL CAPACITY services • Leads to vision impairment or blindness. USE OF HEALTH CARE SERVICES4 • Among Medicare beneficiaries diagnosed with wet AMD between 2004 and 2008, the mean cost per case for the year after diagnosis was $12,422 ($4,884 higher than the year before diagnosis).

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How strongly does There is a high overall societal burden caused by AMD-associated blindness, decreased QOL, and this overall caregiver burden. Comparative-effectiveness research (CER) on alternative approaches for the societal burden prevention of progression of AMD could decrease societal burden through preservation of a suggest that CER patient’s sight. on alternative approaches to this problem should be given high priority? Options for Addressing the Issue Based on recent TREATMENT OPTIONS systematic • There are no proven effective treatments for dry AMD, which is asymptomatic in the early reviews, what is stages. known about the • For wet AMD, treatment options include: relative benefits o Laser photocoagulation prevents further vision loss by destroying the new vessels that and harms of the develop in AMD. Introduced in the 1980s and less commonly used now, in part because available it is generally not indicated for disease at the center of the macula. management o Photodynamic therapy uses a combination of laser and injected medicine. Requires options? evaluation by a retina specialist to determine eligibility. o Macular translocation surgery involves moving the macula to a different part of the retina to restore central vision. Still largely experimental. o Intravitreal injections with vascular endothelial growth factor (VEGF) inhibitors (prevent or inhibit VEGF; which are proteins that stimulate the creation of new blood vessels) such as ranibizumab, pegaptanib, bevacizumab, or aflibercept. In the past six years, VEGF inhibitors have largely replaced laser photocoagulation and photodynamic therapy.5 Ranibizumab has been shown in a randomized sham-controlled study to be effective in the treatment of AMD. Bevacizumab has been used off-label to treat AMD, despite the absence of similar supporting data. A recent comparison of AMD treatments trials (CATT study) showed that ranibizumab and bevacizumab did not differ in effects on visual acuity for wet AMD when administered according to the same schedule,6 and suggests that modification of monthly dosing regimens is feasible.7 Uncertainties include: . Dosing regimen . Cost . Safety concerns, including possible increased risk of systemic vascular events o Diet and supplements such as omega-3 fatty acids and/or high doses of antioxidants and minerals such as vitamins C and E, beta-carotene, and zinc. A meta-analysis suggests that foods rich in omega-3 fatty acids may be associated with a lower risk of AMD, there is insufficient evidence (few prospective studies and no randomized controlled trials [RCTs]), to support their consumption for AMD prevention.8 9 o Visual rehabilitation using visual aids can be effective in managing vision loss.

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What could new • New research on comparative effectiveness, safety, and cost of management options could research inform providers and patients. Research on prevention of AMD as well as management of contribute to vision loss might also improve patient-centered outcomes. achieving better • A technology assessment published in 2009 by the Canadian National Institutes for Health patient-centered Research evaluated cost-effectiveness associated with different dosing regimens of VEGF outcomes? inhibitors10; additional research in this area could help inform dosing decisions. Have recent The most recent innovation has been the approval of VEGF inhibitors for the treatment of AMD. innovations made Current uncertainties regarding comparative effectiveness, safety, and cost of different VEGF research on this inhibitors, as well as unanswered questions about optimal dosing regimens, may make this topic topic especially compelling for new CER. Advances in retinal imaging represent another innovation that could compelling? lead to improved screening and management. How widely does Management of AMD in the United States is generally provided by ophthalmologists with care now vary? appropriate expertise. There is evidence that black patients are less likely than white patients to receive VEGF inhibitor therapy,11 What is the pace of Medline search from 1/1/2008 to 12/31/2013: other research on • Total: 2,341 citations this topic (as o Labeled as RCTs: 333 citations indicated by o Systematic Reviews: 159 citations recent publications and Search on ‘clinicaltrials.gov”: ongoing trials)? • Ongoing trials: 420* • Completed trials: 398

*The AREDS2 trial is an ongoing RCT designed to evaluate whether the vitamin supplements lutein, zeaxanthin, or omega-3 fatty acids affect the course of dry AMD. How likely is it that • New CER that provides compelling information about screening or prevention measures new CER on this could inform clinical decision making by patients and providers. topic would • More information about different responses to treatment by patient subgroups may also provide better guide clinical decision making. information to • Primary care providers might encourage routine eye exams to more patients (eg, patients guide clinical older than 50, relatives of affected individuals) if new findings supported that approach. decision making? • If patients knew that they should be screened based on age or risk factors, they might be willing to get their eyes examined more often. • If people knew, they could prevent AMD by engaging in lifestyle changes (like changing their diet or taking vitamins) Potential for New Information to Improve Care and Patient-Centered Outcomes

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What are the FACILITATORS facilitators and • Most care is provided by ophthalmologists, so rapid dissemination of new findings to the barriers that target audience is feasible with a targeted audience of one type of health care provider. would affect the • Active patient advocacy groups (AMD Alliance, Macular Degeneration Foundation, and implementation of Macular Degeneration International) could assist with dissemination to patients new findings in BARRIERS practice? • New findings would likely need to be strongly compelling to result in changes in decision making by ophthalmologists. How likely is it that • There are certainly knowledge gaps, but there may not be a strong sense among the results of new ophthalmologists with expertise in AMD that current treatment practice needs to change research on this (unless there is compelling research showing new and improved screening and treatments). topic would be • Also, if new research findings support that lifestyle changes or taking vitamins or omega-3 implemented in supplements would prevent or reduce worsening of AMD, then research findings might be practice right implemented quickly by patients. away? Would new • This is a relatively active area of research, with 424 ongoing trials identified in information from clinicaltrials.gov and identified by the search terms “macular degeneration.” CER on this topic • New information about the most effective prevention and treatment therapies, including remain current for optimal dose and timing of treatments, may remain current for several years. several years, or would it be rendered obsolete quickly by subsequent studies?

REFERENCES

1. Lim LS, Seddon J, Holz FG, Wong TY. Age-related macular degeneration. Lancet. 2012; 379:1728-1738. 2. Technology Assessment: Quality of Life in Macular Degeneration (2006) (http://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/id30TA.pdf) 3. Bennion AE, Shaw RL, Gibson JM. What do we know about the experience of age related macular degeneration? A systematic review and meta-synthesis of qualitative research. Social Science and Medicine. 2012; 75:976-985. 4. Qualls LG, Hammill BG, Wang F, Lad EM, Schulman KA, Cousins SW, Curtis LH. Costs of newly diagnosed neovascular age-related macular degeneration among Medicare beneficiaries, 2004-2008. Retina. 2013 Apr;33(4):854-861. 5. Campbell RJ, Bronskill SE, Bell CM, Paterson JM, Whitehead M, Gill SS. Rapid expansion of intravitreal drug injection procedures, 2000 to 2008: a population-based analysis. Arch Ophthalmol. 2010 Mar;128(3):359-362. 6. CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011 May 19;364(20):1897-908. 7. Davis J, Olsen TW, Stewart M, Sternberg P Jr. How the comparison of age-related macular degeneration treatments trial results will impact clinical care. Am J Ophthalmol. 2011 Oct;152(4):509-514. 8. Dietary omega-3 fatty acid and fish intake in the primary prevention of age-related macular degeneration: a systematic review and meta-analysis. (2008) (http://www.ncbi.nlm.nih.gov/pubmed/18541848)

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9. Decarlo DK, McGwin G Jr, Searcey K, Gao L, Snow M, Stevens L, Owsley C. Use of prescribed optical devices in age- related macular degeneration. Optom Vis Sci. 2012 Sep;89(9):1336-1342. 10. www.cadth.ca/media/pdf/htis/L0026%20Pharmacological%20Management%20in%20AMD%20final.pdf 11. Curtis LH, Hammill BG, Qualls LG, DiMartino LD, Wang F, Schulman KA, Cousins SW. Treatment patterns for neovascular age-related macular degeneration: analysis of 284 380 medicare beneficiaries. Am J Ophthalmol. 2012 Jun;153(6):1116-1124.e1.

APPENDIX: Topic Questions

Nominated by ‘Web’

1) What is the optimal treatment and dosing schedule as a patient with AMD? Does it vary based on age, gender, ethnicity, etc.?

Population: Typically, these are older white patients. Importance: This is an important question because of the significant impact that age-related macular degeneration has on the United States’ population, and the implication for patients (number of visits, out-of- pocket costs) and for third-party payers.

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Topic 16: “Melanoma”

Comparative effectiveness of using surgical treatment options to prevent recurrence of melanoma.

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Criteria Brief Description Introduction Overview/definition DESCRIPTION OF CONDITION of topic • Melanoma is the most fatal form of skin cancer, with a rising incidence in the United States, as well as in people of European descent worldwide. • Prognosis and treatment of melanoma both depend on the stage (or thickness) of the melanoma at the time of diagnosis. o There is currently some controversy over the best surgical treatments for patients who have evidence of melanoma in their lymph nodes. o Other types of skin cancer treatment include phototherapy (using laser treatment), radiation therapy, biologic therapy (using medicines to help the immune system fight the cancer), and chemotherapy. o Focus of the nomination and topic brief document is on the comparative effectiveness of surgical resection of the skin cancer based on lymph node involvement. Relevance to SYMPTOMS1 patient-centered • Melanomas appear as irregularly shaped, dark (hyperpigmented) skin moles. outcomes • Melanoma does not cause any symptoms to the patient unless it has spread to other organs (ie, becomes metastatic). • A mole should be examined for possible melanoma if it has a suspicious appearance based on the “ABCDE” criteria—an uneven appearance, irregular border, color variation, bigger than 6mm in diameter, and evolving (or changing) appearance.

OUTCOMES1 • Outcomes that are commonly reported include spread to lymph nodes (local or distant), spread to other organs, complications from surgery, and survival. • Important patient-centered outcomes that are not commonly reported in the medical literature include disfiguration from surgery, fatigue and side effects from chemotherapy, and psychological distress from concerns about survival and recurrence of the cancer. • Patients with melanoma that has spread to distant lymph nodes or organs have worse outcomes than those with disease limited to the skin. Burden on Society Recent incidence INCIDENCE (NEW CASES)2 and prevalence in • Incidence of melanoma has been increasing over the past three decades, with 19.2 cases in populations and the United States per 100,000 people from 2004-2006. subpopulations • Incidence and severity vary by patient characteristics including sex, age, race, and socioeconomic status. • Males have a higher incidence and greater severity of the condition compared with women. • In 2008, the incidence of melanoma was 29.1 cases per 100,000 males compared with 19 cases per 100,000 females. • There is a greater incidence with older age, but men continue to have a higher incidence in all age groups except those younger than age 44. • Though melanoma affects whites more than other races, it does affect other races/ethnicities (Hispanic people had 3.9 cases and Native Americans had 3.7 cases per 112

100,000 people between 2004 and 2008). • There is a higher incidence of melanoma among people of higher socioeconomic status, although the incidence seems to be rising among people of all socioeconomic groups.

PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE CONDITION) • In the United States, melanoma is the fifth most common cancer in men and seventh most common cancer in women. • It is estimated that about 9500 people died from melanoma in the United States in 2011. Effects on patients’ QUALITY OF LIFE quality of life, • A patient’s quality of life can be affected by the treatment regimen (surgery and productivity, chemotherapy). functional • With regard to surgical treatments and lymph node dissections, patients can experience capacity, complications including lymphedema (severe swelling of the extremity requiring ongoing mortality, use of care to manage), pain, decreased ability to care for oneself while recovering, activity health care restrictions, infection, and wound complications. services PRODUCTIVITY o Based on data from the Centers for Disease Control and Prevention as well as Prevention National Vital Statistics Surveillance System from 2000-2006, the decrease in productivity related to all melanoma-related deaths in the United States during this time was estimated at $3.5 billion, with an average cost for lost productivity per death of $413,370.3

FUNCTIONAL CAPACITY o Patients undergoing treatment for melanoma have decreased functional capacity. o This can be an ongoing problem depending on the extent of surgical revision and if there is ongoing lymphedema that requires chronic management and possibly limited range of movement.

MORTALITY o In general, a thin melanoma of ≤1.0mm is associated with a 96% melanoma-specific survival at 20 years. o Thicker melanomas are associated with a higher incidence of spreading, particularly to local lymph nodes. o For patients with small amounts of cancer spreading to lymph nodes, survival is based on the number of lymph nodes involved, with overall five-year survival of 71% (one lymph node), 65% (two lymph nodes), and 61% (three lymph nodes). o For patients with larger amounts of cancer spreading to local lymph nodes, the prognosis is worse, with overall five-year survival of 50% (one lymph node), 43% (two lymph nodes), and 40% (three lymph nodes). o Prognosis of patients with distant metastases is generally worse but also is dependent on characteristics of the tumor, patient, and markers described briefly above.

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How strongly does • Given the rising incidence of melanoma, it is important to find the optimal treatments for the this overall different stages of disease and to determine the risks and benefits for the different societal burden treatment options. suggest that CER • In particular, with regard to patients with melanoma that has spread to a lymph node, (but on alternative only in a small amount or to a few lymph nodes), it is unclear if surgically removing and approaches to this testing many lymph nodes is needed—and if the benefits of doing this more invasive surgery problem should be with increased complication risks, such as the chronic swelling caused by lymphedema, is given high worthwhile compared with less extensive surgery. priority? Options for Addressing the Issue Based on recent Systematic reviews systematic o Current guidelines recommend that patients with intermediate-thickness melanomas reviews, what is undergo a lymph node dissection, and if that node shows signs of cancer, the patient should known about the have an extensive, complete lymph node dissection.4 relative benefits o No systematic review was identified pertaining to lymph node dissections for skin cancer. and harms of the o One clinical review describes clinical trials and observational studies regarding the surgical available treatment of intermediate-thickness melanoma that has only begun to spread management (micrometastasis). options? o The Multicenter Selective Lymphadenectomy Trial (MSLT 1) evaluated patients with intermediate-thickness melanoma and found that a sentinel lymph node biopsy (SLNB), or biopsy of the first lymph node that is draining from the cancer site, was a good indicator of prognosis. o This study found that survival was better among the patients who underwent SLNB along with wide excision of the tumor. o There was also improved survival among patients who underwent complete lymph node dissection if the SLNB was positive compared with patients who underwent only wide excision of tumor with observation and treatment of nodal disease only when it became obvious that the cancer had spread. o There are harms associated with the SLNB procedure: . In a review of over 400 SLNB biopsies, the complication rate was found to be 4.26% with complications including hematoma (collection of blood/bruising), lymphedema (severe swelling of involved extremity), seroma (pockets of clear fluid collecting around surgical site), wound infection, thick scars, and pain.5 o It is not clear that extensive lymph node dissection is needed for all positive sentinel lymph nodes. o The potential harm of increased risk of recurrent disease without extensive lymph node dissection could be worse than surgical complications. What could new Further studies about prognosis for recurrence of melanoma for patients with positive sentinel research lymph nodes are needed to determine if specific markers of disease can help to identify the contribute to patients who would benefit from more extensive surgical dissection vs. less invasive surgery. achieving better patient-centered outcomes? Have recent Recent innovations: innovations made • New markers of the disease have been identified in patients’ blood work. 114

research on this • Measures of the extent of disease with tissue samples, radiologic findings, and gene topic especially mutations have been found that are also associated with prognosis. compelling? • These markers may be able to help determine the best treatment for individual patients. How widely does VARIABILITY IN CARE care now vary? • There are no publications assessing variation in regional vs. extensive lymph node dissection in the melanoma population in the United States. • Studies have evaluated the use of SLNB in patients with melanoma for surgical staging (ie, diagnosis phase of the disease) and found practice variations in SLNB, with underutilization in the elderly and minority populations, in patients with head, neck, or trunk melanomas, and in some geographic regions of the United States.6 What is the pace of PACE OF RESEARCH other research on this topic (as Search on Medline: indicated by • Total citations: 843 recent • Labeled as randomized controlled trial (RCT): 50 publications and • Labeled as meta-analysis or systematic review: 67 ongoing trials)? Search on Clinicaltrials.gov: • “Melanoma” AND “(nodal dissection OR lymph node excision OR lymph node dissection OR node dissection)” o Total ongoing trials: 24 . The MSLT II trial is evaluating patients with a positive SLNB and randomizing them to either complete lymph node dissection or observation with ultrasound surveillance. Outcomes include disease-free survival as well as quality of life. . The European Organisation for Research and Treatment of Cancer melanoma group MINITUB (Minimal Tumor Burden) is a registry that is following patients with a positive SLNB but with minimal tumor size, thickness, and spread who did not undergo complete lymph node dissection. o Completed trials: 14

How likely is it that KEY UNCERTAINTIES IN CLINICAL DECISION MAKING new CER on this For patients with a positive SLNB, it is unclear if extensive lymph node dissection is needed topic would for all of these patients or if ongoing surveillance, less extensive surgery, or potentially provide better nonsurgical treatments would be suitable treatments associated with fewer complications. information to guide clinical LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES decision making? • Some studies have found that the use of certain biomarkers and additional imaging studies7 may help determine the significance of a positive SLNB. • New clinical trials and comparative-effectiveness research (CER) are needed to determine the best method of performing SLNB as well as the best treatment options— both surgical and nonsurgical—for patients with a positive SLNB. Potential for New Information to Improve Care and Patient-Centered Outcomes

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What are the FACILITATORS facilitators and • There is great interest in optimizing treatment for melanoma, which is rising in incidence. barriers that would affect the BARRIERS implementation of • Surgeons may be resistant to less aggressive surgical interventions unless there are data to new findings in confirm that benefits outweigh risks. practice? How likely is it that • Given the rising incidence of melanoma and the high mortality associated with intermediate- the results of new thickness and advanced melanomas, any progress made to better understand the risk of research on this recurrence and how to decrease that risk with minimal morbidity would likely be readily topic would be implemented by specialists treating this condition. implemented in practice right away? Would new • One ongoing trial (MSLT II) is addressing this specific question. information from • Further trials addressing this topic would help support or dispute any trends seen in this one CER on this topic trial. remain current for several years, or would it be rendered obsolete quickly by subsequent studies?

REFERENCES 1. http://www.uptodate.com/contents/screening-and-early-detection-of- melanoma?source=search_result&search=melanoma&selectedTitle=5%7E150 2. Little EG, Eide MJ. Update on the current state of melanoma incidence. Dermatol Clin. 2012;Jul;30(3):355-361. doi: 10.1016/j.det.2012.04.001. Epub 2012 Jun 8. 3. Ekwueme DU, Guy GP Jr, Li C, Rim SH, Parelkar P, Chen SC. The health burden and economic costs of cutaneous melanoma mortality by race/ethnicity-United States, 2000 to 2006. J Am Acad Dermatol. 2011;Nov;65(5 Suppl 1):S133-143. doi: 10.1016/j.jaad.2011.04.036. 4. Wong SL, Balch CM, Hurley P, Agarwala SS, Akhurst TJ, Cochran A, Cormier JN, Gorman M, Kim TY, McMasters KM, Noyes RD, Schuchter LM, Valsecchi ME,Weaver DL, Lyman GH. Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. J Clin Oncol. 2012;Aug 10;30(23):2912-2918. doi: 10.1200/JCO.2011.40.3519. Epub 2012 Jul 9. 5. Cigna E, Gradilone A, Ribuffo D, Gazzaniga P, Fino P, Sorvillo V, Scuderi N. Morbidity of selective lymph node biopsy for melanoma: meta-analysis of complications. Tumori. 2012;Jan-Feb;98(1):94-98. doi: 10.1700/1053.11506. 6. Cormier JN, Xing Y, Ding M, Lee JE, Mansfield PF, Gershenwald JE, Ross MI, Du XL. Population-based assessment of surgical treatment trends for patients with melanoma in the era of sentinel lymph node biopsy. J Clin Oncol. 2005;Sep 1;23(25):6054-6062.

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7. Stoffels I, Boy C, Pöppel T, Kuhn J, Klötgen K, Dissemond J, Schadendorf D, Klode J. Association between sentinel lymph node excision with or without preoperative SPECT/CT and metastatic node detection and disease-free survival in melanoma. JAMA. 2012;Sep 12;308(10):1007-1014. doi: 10.1001/2012.jama.11030.

APPENDIX: Topic Question

Nominated by ‘Web’

• Use of Extensive or Limited Lymph Node Dissection to Prevent Recurrence of Melanoma (Friends of Cancer Research, CER priority)

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Topic 17: “Migraine Headache”

Comparative effectiveness of different treatment strategies for adults with frequent migraine headaches.

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Criteria Brief Description Introduction Overview/ DESCRIPTION OF CONDITION1-2 definition of • Migraine is a recurring disorder characterized by severe headache, generally associated with nausea, topic vomiting, and other neurologic symptoms during attacks, with no symptoms between attacks • “Chronic migraine” is diagnosed if migraine headaches occur on 15 or more days per month for more than three months o Chronic migraine is diagnosed only if painkiller medication overuse has been excluded o Still a controversial diagnosis, with no universally agreed definition Relevance to SYMPTOMS2 patient- • Phases of migraine episode: centered 1. Premonitory or prodrome (hyper- or hypo-activity, depression, food cravings, repetitive outcomes yawning) 2. Aura or perceptual disturbance (visual, sensory, verbal, or motor disturbances)—may or may not be present 3. Headache is typically one-sided, throbbing, moderate to severe in intensity, lasting hours to days, and aggravated by physical activity (nausea and vomiting, intolerance to light and noise) 4. Postdrome (extreme fatigue, loss of appetite, depression) • Commonly mentioned precipitating factors include stress, menstruation, visual stimuli, weather changes, nitrates, fasting, and wine (aged or fermented food/drink) DIAGNOSIS • No objective diagnostic tests • Diagnosis based on clinical features, medical history, and physical exam; diagnostic criteria defined by the International Headache Society2 Burden on Society Recent INCIDENCE prevalence in • Each year, approximately 2.5% of patients with episodic migraine develop new-onset chronic populations migraine3 and subpopulations PREVALENCE4-6 • Episodic migraine affects up to 12% of population (8% of children) o More frequent in women (17%) than in men (6%) o Prevalence is . higher in whites than in blacks . inversely related to household income . highest in middle life (30-49 years) o Chronic migraine is less common (1.3% of women and 0.5% of men) o Prevalence highest among females, in mid-life, and in households with the lowest annual income7 o Severe headache-related disability is more common among persons with chronic migraine than episodic migraine, especially among women7 Effects on QUALITY OF LIFE5,8 patients’ • Migraine causes impairment in activity and may require bed rest during attacks 119

quality of life, • Compared with patients with episodic migraine, those with chronic migraine have worse productivity, socioeconomic status, reduced health-related quality of life, increased headache-related burden functional (including impairment in occupational, social, and family functioning), and greater psychiatric and capacity, medical comorbidities3 mortality, use of health care PRODUCTIVITY5 services • Missed school or work days • Reduced work or school productivity • National annual indirect burden of illness, excluding being at work but being less productive, estimated to be $12 billion (mostly attributed to absenteeism)11

HEALTH CARE SERVICE UTILIZATION8 • More frequent health care usage among persons with migraine. • Estimated annual US migraine-related health care costs in 2010 were $3.2 billion for outpatient visits, $700 million for emergency room visits, and $375 million for hospitalizations.10 • Headache among top 20 reasons for outpatient office visits (1.2% of office visits) o Approximately 12.1 million office visits for headache annually • Estimated 6.2 million prescriptions for antimigraine drugs in 2009 • 80% of prescription for triptans (nearly half for sumatriptan) • Headache or head pain fifth is the leading cause of visits to emergency department • Chronic migraine was associated with higher medical resource use and total costs compared to episodic migraine.9 How strongly • For episodic migraine, the burden in both direct costs and indirect costs is high because of the high does this prevalence in working-age persons. overall • For chronic migraine, a small portion of this population is more severely affected. This suggests societal alternative approaches should be considered or more effective treatment identified. burden suggest that CER on alternative approaches to this problem should be given high priority? Options for Addressing the Issue Based on recent MANAGEMENT OPTIONS systematic • The focus of management for chronic migraine is prevention reviews, what • Evidence-based guidelines based on systematic reviews suggest that preventive therapy should be is known considered for patients who have contraindications or intolerance to acute treatment therapies, about the headaches symptoms occurring more than two days per week, headaches that severely limit quality relative of life, or if uncommon migraine conditions or complications are present.4,13-17 benefits and • Clinical trial literature focuses on episodic migraine and tension-type headaches, the most harms of the common headache disorders, with relatively less attention to chronic migraine 120

available • Clinical trial literature focuses heavily on placebo-controlled drug studies, with little direct management comparisons between active therapies; also little clinically useful research on psychological and options? alternative medical therapies. Comparative studies—especially between drug and nondrug treatments—are few and inconclusive.

DRUG TREATMENTS • Antiepileptic drugs (AEDs) o Benefits: Divalproex sodium, sodium valproate, and topiramate have been shown to be effective for preventing episodic migraine. Other AEDs ( eg, lamotrigine) have been shown to be ineffective; there is insufficient evidence regarding other AEDs. o Harms: Weight gain or loss, paresthesias (abnormal sensation of tingling, numbness, or burning), drowsiness, need for monitoring for liver disease and pancreatitis, and potential birth-defect risks. o Comparisons: Topiramate as effective as valproate, propranolol, or amitriptyline • Antidepressants o Benefits: Amitriptyline and venlafaxine have been shown to likely be effective but there remains conflicting evidence for other antidepressants. o Harms: Nausea, vomiting, drowsiness, sedation, urinary retention, constipation, dry mouth, dizziness, liver enzyme elevation, arrhythmia o Comparisons: Venlafaxine possibly as effective as amitriptyline. Amitriptyline probably as effective as topiramate. • Beta-Blockers o Benefits: Metoprolol, propranolol, and timolol have been shown to be effective; atenolol and nadalol also probably effective o Harms: Sleep disturbance, weight gain, fatigue, dry mouth • Triptans—short-term use for prevention of menstrual-associated migraines o Benefits: Some effective (frovatriptan) or probably effective (zolmitriptan, naratriptan) o Harms: Weakness, headache, dizziness, nausea • Other drugs: o Some ACE inhibitors (lisinopril), angiotensin-receptor blockers (candesartan), alpha-agonists (clonidine, guanfacine), and antihistamines (cyproheptadine) are possibly effective

NONDRUG TREATMENTS • Behavioral therapies: o Benefits: Relaxation training, thermal biofeedback combined with relaxation training, electromyographic (EMG) biofeedback, and cognitive-behavioral therapy are all modestly effective in preventing migraine headaches when compared to a control. • Botulinum toxin A: o Benefits: Botulinum toxin A compared with placebo was associated with a small-to-modest benefit for chronic daily headaches and chronic migraines, but was not associated with fewer episodic migraine or chronic tension-type headaches per month. o Harms: Drooping of upper eyelid, skin tightness, paresthesias (abnormal sensation of tingling, numbness, or burning), neck stiffness, muscle weakness, and neck pain • Spinal manipulation: o Current evidence is limited, inconsistent, and does not support the use of spinal 121

manipulation for the prevention of migraine headaches • Other physical treatments: o There are insufficient data to draw conclusions about the possible benefits and harms of other physical treatments ( eg, transcutaneous electrical nerve stimulation [TENS], mobilization, physical therapy, massage, and hyperbaric oxygen) What could new KEY UNCERTAINTIES IN CLINICAL DECISION-MAKING research • Which drugs (migraine-specific or nonmigraine-specific) are most effective in reducing the frequency contribute to of chronic migraine headaches or improving quality of life? achieving • Which nondrug therapies are most effective in reducing the frequency of chronic migraine better headaches or improving quality of life? patient- • Are drug or nondrug treatments more effective in reducing the frequency of chronic migraine centered headaches or improving quality of life? outcomes? LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES A multitude of treatments are currently used to treat migraines, but there are limited comparative data to recommend one therapy over another. The vast majority of existing research is on episodic migraine, rather than chronic migraine, the definition of which has only been somewhat standardized since 2006. New research in this area has the potential to significantly improve patient health and quality of life. Have recent The quality of evidence for many preventive drugs is either inadequate or is conflicting, leaving room for innovations studies of novel treatments, particularly angiotensin-receptor blockers, angiotensin-converting-enzyme made inhibitors, alpha-agonists, antiepileptics, calcium channel blockers and botulinum toxin A, as well as research on various nondrug treatments, such as biofeedback, relaxation therapy, and cognitive-behavioral therapy. this topic especially compelling? How widely • Evidence suggests only a small fraction of those with episodic migraine who might benefit from does care now preventive therapy are receiving it. vary? • 80% of patients meeting criteria for chronic migraine were not properly recognized as such.18

What is the RECENT PUBLICATIONS pace of other • MEDLINE search from 1/1/2008 – 4/4/2013: total 1,462 citations research on o Labeled as randomized controlled trial (RCT): 249 this topic (as o Labeled as meta-analysis or systematic review: 146 indicated by recent ONGOING TRIALS publications • There are at least 121 ongoing studies listed in ClinicalTrials.gov and ongoing • NIH Reporter (a database of NIH funded studies) lists: trials)? o 127 projects o 103 publications How likely is it • Due to the wide variety of treatments currently in use for prevention of chronic migraine headaches, that new CER new comparative-effectiveness research (CER) that could identify the most effective treatments on this topic would provide helpful guidance for clinical decision making. would provide • It is important to note that AHRQ is currently sponsoring a Comparative Effectiveness Review better designed to address preventive treatment for migraine—including chronic migraine—in children and

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information to adults.19 guide clinical decision making? Potential for New Information to Improve Care and Patient-Centered Outcomes What are the FACILITATORS facilitators • Migraine headaches are difficult and frustrating for both clinicians and patients, and evidence and barriers regarding the most effective preventive treatments is highly desired by both that would • Current medications used to prevent migraine are already FDA-approved for this or other affect the conditions (such as depression, hypertension and seizure disorder) and would be easily implementati accessible on of new findings in BARRIERS practice? • Many nondrug treatments ( eg, biofeedback, relaxation therapy, and cognitive-behavioral therapy) may not be accessible in all areas • Patients with migraine often have other comorbidities and require medications that may interact with preventive treatments for migraines, making selection of appropriate treatment more difficult • It is likely that access to botulinum treatment, if effective, would be limited by providers trained in this technique and possibly by insurance coverage How likely is it • It is very likely that new data showing increased effectiveness of one or more drugs in preventing that the chronic migraine headaches would be implemented very quickly provided there was appropriate results of new and timely dissemination of the data, as well as insurance coverage for use in chronic migraine. research on • Current evidence for nondrug treatments is sparse and lacks clinically meaningful comparisons. If this topic CER were to show effectiveness, implementation of nondrug treatments may be hampered by would be availability of properly trained providers and health insurance coverage. implemented in practice right away? Would new • Further basic research may be able to better characterize the cause(s) of chronic migraine, which information could lead to a greater ability to identify or create more targeted therapies. from CER on • Given such new basic science discoveries: this topic o CER exploring the comparative safety and effectiveness of novel targeted therapies for remain chronic migraine is likely to remain current for several years. current for several years, or would it be rendered obsolete quickly by subsequent studies?

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REFERENCES:

1. Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL. Jamesone JL (eds). Harrison’s Principles of Internal Medicine, 15th ed. New York:McGraw-Hill: 2001 2. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24 Suppl 1:1-160. http://ihs-classification.org/en/. Accessed April 16, 2013. 3. Manack AN, Buse DC, Lipton RB. Chronic migraine: epidemiology and disease burden. Curr Pain Headache Rep. 2011;15(1):70-78. 4. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF; AMPP Advisory Group. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68(5):343-349. 5. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache. 2001;41(7):646-567. 6. Howard Jacobs, MD; Jack Gladstein, MD. Pediatric headache: a clinical review. Headache. 2012;52(2):333-339. 7. Buse DC, Manack AN, Fanning KM, Serrano D, Reed ML, Turkel CC, Lipton RB. Chronic migraine prevalence, disability, and sociodemographic factors: results from the American Migraine Prevalence and Prevention Study. Headache. 2012 Jun 22. doi: 10.1111/j.1526-4610.2012.02223.x. [Epub ahead of print]. 8. Smitherman TA, Burch R, Sheikh H, Loder E. The prevalence, impact, and treatment of migraine and severe headaches in the United States: a review of statistics from national surveillance studies. Headache. 2013;53(3):427-436. 9. Stokes M, Becker WJ, Lipton RB, et al. Cost of health care among patients with chronic and episodic migraine in Canada and the USA: results from the International Burden of Migraine Study (IBMS). Headache. 2011;51(7):1058-1077. 10. Insinga RP, Ng-Mak DS, Hanson ME. Costs associated with outpatient, emergency room and inpatient care for migraine in the USA. Cephalalgia. 2011;31(15):1570-1575. 11. Hawkins K, Wang S, Rupnow MF. Indirect cost burden of migraine in the United States. J Occup Environ Med. 2007;49(4):368-374. 12. Gilmore B. Michael M. Treatment of acute migraine headache. American Family Physician. 2011;83(3) 271-80. 13. Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;55(6):754-762. 14. Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E; Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337-1345. 15. Jackson JL, Kuriyama A, Hayashino Y. Botulinum toxin A for prophylactic treatment of migraine and tension headaches in adults: a meta-analysis. JAMA. 2012;307(16):1736-1745. 16. Posadzki P, Ernst E. Spinal manipulations for the treatment of migraine: a systematic review of randomized clinical trials. Cephalalgia. 2011;31(8):964-970. 17. Duke University, Center for Clinical Health Policy Research. Behavioral and Physical Treatments for Migraine Headache. Technical Review 2.2. February 1999. (Prepared for the Agency for Health Care Policy and Research under Contract No. 290-94-2025. Available from the National Technical Information Service; NTIS Accession No. PB99-127946).

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18. Bigal ME, Serrano D, Reed M, Lipton RB. Chronic migraine in the population: burden, diagnosis, and satisfaction with treatment. Neurology. 2008;71(8):559-566. 19. Research Protocol: Comparative Effectiveness of Preventive Pharmacological Treatments for Migraine. November 3, 2011. http://effectivehealthcare.ahrq.gov/index.cfm. Published November 3, 2011. Accessed April 16, 2013.

APPENDIX: TOPIC QUESTIONS

Nominated by Institute of Medicine (IOM):

1) Compare the effectiveness of different treatment strategies on the frequency and lost productivity in people with chronic, frequent migraine headaches.

Nominated by ‘Web’:

1) Where is the best information about the treatment of constant migraine headache? Population: All patients Importance: It seems that the treatments are diverse and not a single source of information to standardize the efforts.

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Topic 18: “Multiple Sclerosis”

Comparative effectiveness of treatment programs for recurring/remitting multiple sclerosis (MS).

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Criteria Brief Description Introduction Overview/definition DESCRIPTION OF CONDITION of topic • Multiple sclerosis (MS) is a neurologic condition typically affecting young adults and is characterized by an autoimmune disorder that causes damage (by demyelination) of nerves within the central nervous system (CNS). Patients have one of four types of MS: o relapsing-remitting (most common) o secondary progressive o primary progressive o progressive relapsing • Patients have distinct episodes of CNS dysfunction (or relapses) that, at least partially, resolve over time. • Most patients with relapsing-remitting MS will eventually enter a secondary progressive phase in which recovery between relapses becomes less often and for shorter periods of time. • MS is a leading cause of disability in young adults; treatments for this condition are costly, including expensive medications and ongoing rehabilitation. Relevance to SYMPTOMS1,2 patient-entered • Patients have episodes of CNS dysfunction, lasting at least 24 hours, which at least partially outcomes resolve over time. • CNS dysfunction most commonly first appears as sensory disturbances or visual loss, often due to optic neuritis (inflammation of the optic nerve), but also as motor weakness, diplopia (double vision), gait disturbances, or other neurologic symptoms. • MS is associated with increased mortality, higher rates of cognitive decline, depression, and global fatigue. OUTCOMES • Radiologic findings are used to diagnose MS (multiple characteristic T2 lesions seen with magnetic resonance imaging (MRI) in areas of the CNS that vary over time). • The extent of disability resulting from MS varies depending on the type of MS. Burden on Society Recent incidence INCIDENCE (NEW CASES)3 and prevalence in • More than 200 cases of MS are diagnosed weekly in the United States.3 populations and • Incidence generally occurs between 20 and 50 years of age, peaking at about 30 years of subpopulations age.4 • Incidence is increasing, particularly among women. PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE CONDITION)3 • Highest prevalence occurs among white people of Nordic origin, in areas with moderate climates, and among higher income people. • Approximately 400,000 adults have MS in the United States, while there are 2.5 million adults with this condition worldwide, with varying prevalence by country.3 • Prevalence peaks at about 50 years of age.4 • Women are affected by MS twice as often as men. • Prevalence of MS is increasing as incidence increases (along with more effective treatments 127

extending survival of patients with MS). Effects on patients’ QUALITY OF LIFE (QOL) quality of life, • Patients’ QOL is affected by disability (such as impaired mobility, chronic pain, cognitive productivity, impairment, depression, and spasticity as well as bowel and bladder dysfunction and other functional neurologic impairments).5 capacity, • Based on a 2006 cost assessment and a quality-adjusted life-years valued at $60,000, the mortality, use of reduction in QOL due to MS was estimated to add $15,315 to annual costs per patient.6 health care PRODUCTIVITY services • Based on a 2009 insurance claims database study, employees with MS had 29.8 disability days per year compared to 4.5 days for employees without MS. • Employees with MS compared with employees without MS also had significantly higher annual disability costs ($3868 vs. $414). • Absenteeism costs ($1901 vs. $1003), and total indirect costs ($5769 vs. $1417) are also increased.7 FUNCTIONAL CAPACITY • The extent of disability varies depending on the type of MS and risk factors. • Natural history studies have also found varying degrees of progressive disability. • Using the Expanded Disability Status Scale as the reference, one study reported that median time to development of significant disability (needing a cane to walk) was 28 years from disease onset.3 MORTALITY • MS is associated with higher mortality with a mean age of death of 58 years.1 • One study from Wales found that patients with MS are almost three times more likely to die prematurely than the general population.9 COSTS • Total direct medical cost for all patients with MS in the United States is estimated to be more than $10 billion per year.10 How strongly does MS has a significant impact on the functional status of young adults. Given the burden that this this overall condition places on the QOL of patients, as well as the economic burden (both direct and indirect societal burden costs) of this condition, it is important to determine the most effective treatments for this suggest that CER condition. on alternative approaches to this problem should be given high priority? Options for Addressing the Issue Based on recent SCREENING/EARLY DIAGNOSIS systematic o There are currently no screening or early diagnostic tests in widespread use. reviews, what is o Disease monitoring typically consists of tracking patient symptoms, recurrent physical known about the examinations, MRI, spinal fluid analysis, and laboratory tests. relative benefits TREATMENT FOR RELAPSING-REMITTING MS and harms of the • Drug treatment: available o Acute attacks (or relapses) are often treated with oral or intravenous glucocorticoids 128

management (type of steroid hormone medication).11 options? o Disease-modifying therapy with a medication that regulates your immunity (since MS is an autoimmune disorder) typically administered soon after diagnosis, with the goal of decreasing the rate of relapse and slowing the accumulation of brain lesions that are seen on MRI. . Six disease- modifying drugs have been approved: interferon-beta, glatiramer acetate, mitoxantrone, natalizumab, fingolimod, and, recently, dimethyl fumarate. 12 These agents have been shown to affect the rate of developing new brain lesions, but there is insufficient evidence to support their effect on functional outcomes. • Physical therapy and rehabilitation: o Physical therapy, exercise, and behavioral interventions have been shown to improve: balance in patients with mild to moderate levels of disability,13 symptoms of fatigue and depression,14 and muscle strength.15 o Exercise therapy compared with no exercise therapy showed improved muscle power, exercise tolerance, and mobility-related activities. There was also moderate evidence found for improving mood.16 o In a meta-analysis of 22 uncontrolled trials of exercise, more benefits were associated with supervised exercise training and with exercise programs that were less than three months long.17 . Exercise training was also shown to be associated with a small improvement in walking mobility.17 o No best “dose” of therapy or superiority of one therapy over another could be identified.18 . Inpatient rehabilitation showed short-term gains in disability despite no change in the level of impairment. . Outpatient -and home-based rehabilitation showed limited short-term improvements in symptoms, disability, and QOL with high-intensity programs. . Low-intensity programs over a longer period showed longer-term gains in QOL.18 What could new • New research could contribute to achieving better patient-centered outcomes by research identifying, developing, improving, and supporting outcome measures that reliably assess contribute to clinically meaningful disease progression, mobility, functional capacity, and QOL. achieving better • New comparative-effectiveness research (CER)could provide data to help MS patients with patient-centered decision making regarding their care (data regarding physical therapy and potential impact outcomes? on disease clinical course, management of symptoms, and resulting disability, as well as QOL). • New CER of treatment options could identify new and more effective treatments. • Patient-centered outcomes might be improved if new research that compares comprehensive care with usual care demonstrates superiority of one of the approaches. Have recent • There have been recent technical innovations that facilitate diagnosis and disease monitoring innovations made (eg, improved imaging techniques and laboratory tests to identify antibodies in the blood research on this and spinal fluid), but there does not appear to be clearly improved methods for examining topic especially treatment options and how they impact patient-centered outcomes. 129

compelling? • The recent increase in medication treatments for MS has increased the need for CER to help guide patient decision making regarding risks and benefits to the variety of medication and nonmedication treatments for managing MS. How widely does There is significant variability in the content of the number of MS clinical guidelines sponsored by care now vary? organizations in both the United States and Europe.19 Also, recommendations for the treatment of MS has been known to change relatively rapidly. What is the pace of RECENT PUBLICATIONS other research on • In the past two years, many systematic reviews have been published that evaluated the this topic (as comparative effectiveness and safety of disease-modifying agents and behavioral indicated by interventions, including exercise and physical therapy. recent • Another oral drug treatment, dimethyl fumarate, received FDA approval for relapsing MS in publications and March 2013. Research at various stages is currently underway for many other new drug ongoing trials)? treatments and use of existing drugs in combination. ONGOING TRIALS • ‘ClinTrials.gov’ lists search for multiple sclerosis showed: o Total ongoing trials: 411 o Completed trials: 451 How likely is it that KEY UNCERTAINTIES IN CLINICAL DECISION MAKING new CER on this • What are the best outcome measures for monitoring disease progression and treatment topic would efficacy, using outcomes that are meaningful to patients? provide better • What are the comparative efficacy, safety, and cost of the FDA-approved disease-modifying information to agents and other agents undergoing clinical development, by disease characteristics (eg, guide clinical relapsing-remitting MS) and by patient subgroups? decision making? • How do these treatments impact patient-centered outcomes? • Do health care delivery innovations (such as comprehensive, coordinated care) improve processes and outcomes? LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES • There is high likelihood that CER would be able to reduce these uncertainties. These are answerable research questions that would guide clinical decision making. Potential for New Information to Improve Care and Patient-Centered Outcomes What are the FACILITATORS facilitators and • Most stakeholders (eg, patients, providers, payers) are likely to be interested in new barriers that information about MS and in implementing new findings that might lead to improvement in would affect the disease monitoring or treatment efficacy and safety. implementation of • A neurologist is likely to participate in the care of most patients under treatment for MS in new findings in the United States. Disseminating new findings to this relatively small group of specialists practice? should not be difficult. BARRIERS • Rapid changes in published clinical guidelines are a potential barrier. • The expected availability of still more drug treatment options could be a barrier. How likely is it that EVIDENCE OF BENEFIT the results of new • Improved patient-centered outcome measures are likely to be used in practice right away if research on this the evidence supporting them is compelling and if the outcomes are considered by both topic would be patients and providers to be meaningful and useful. 130

implemented in EVIDENCE OF NO BENEFIT OR HARM practice right • New evidence that does not demonstrate benefits—or demonstrates harm—would likely be away? incorporated into clinical decision making. Would new • A systematic review titled “Comparative clinical and cost effectiveness of drug therapies for information from relapsing-remitting multiple sclerosis” is listed in the Prospero registry as being underway, CER on this topic with an anticipated completion date of August 2013. The four review questions to be remain current for addressed in that review focus on comparative efficacy, safety, and cost-effectiveness for several years, or both individual disease-modifying agents and combination therapy for relapsing-remitting would it be MS. However, as new drug treatments continue to be approved, any CER that compares rendered obsolete current drug treatments may quickly become outdated. quickly by • Information from CER on the topics of patient-centered outcome measures or coordinated subsequent vs. usual care for MS, however, is likely to remain current for several years because neither studies? topic appears to be an area of currently active research.

REFERENCES 1. UpToDate. http://www.uptodate.com/contents/epidemiology-and-clinical-features-of-multiple-sclerosis-in- adults?source=search_result&search=multiple+sclerosis&selectedTitle=2%7E150 2. Giesser BS. Diagnosis of multiple sclerosis. Neurol Clin. 2011 May;29(2):381-388. 3. Tullman MJ. Overview of the epidemiology, diagnosis, and disease progression associated with multiple sclerosis. Am J Manag Care. 2013 Feb;19(2 Suppl):s15-20. 4. Koch-Henriksen N, Sørensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol. 2010 May;9(5):520-532. doi: 10.1016/S1474-4422(10)70064-8. 5. Zwibel HL, Smrtka J. Improving quality of life in multiple sclerosis: an unmet need. Am J Manag Care. 2011 May;17 Suppl 5:S139-145. 6. Kobelt G, Berg J, Atherly D, Hadjimichael O. Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States. Neurology. 2006;66(11):1696-1702. 7. Ivanova JI, Birnbaum HG, Samuels S, Davis M, Phillips AL, Meletiche D. The cost of disability and medically related absenteeism among employees with multiple sclerosis in the US. Pharmacoeconomics. 2009;27(8):681-669. 8. Tremlett H, Paty D, Devonshire V. Disability progression in multiple sclerosis is slower than previously reported. Neurology. 2006 Jan 24;66(2):172-177. 9. Hirst C, Swingler R, Compston DA, Ben-Shlomo Y, Robertson NP. Survival and cause of death in multiple sclerosis: a prospective population-based study. J Neurol Neurosurg Psychiatry. 2008 Sep;79(9):1016-1021. doi: 10.1136/jnnp.2007.127332. Epub 2008 Feb 26. 10. Mathis SA. Managed Care Aspects of Managing Multiple Sclerosis. Am J Manag Care. 2013;19:S28-S34 11. Burton JM, O’Connor PW, Hohol M, et al. Oral versus intravenous steroids for treatment of relapses in multiple sclerosis. Cochrane Database Syst Rev. 2012(12):CD006921. 12. Luessi F, Siffrin V, Zipp F. Neurodegeneration in multiple sclerosis: novel treatment strategies. Expert Rev Neurother. 2012;12(9):1061-1076. 13. Paltamaa J, Sjögren T, Peurala SH, et al. Effects of physiotherapy interventions on balance in multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials. J Rehabil Med. 2012;44(10):811-823. 14. Heesen C, Köpke S, Kasper J, et al. Behavioral interventions in multiple sclerosis: a biopsychosocial perspective. Expert Rev Neurother. 2012;12(9):1089-1100. 15. Kjølhede T, Vissing K, Dalgas U. Multiple sclerosis and progressive resistance training: a systematic review. Mult Scler. 2012;18(9):1215-1228.

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16. Rietberg MB, Brooks D, Uitdehaag Bernard MJ, et al. Exercise therapy for multiple sclerosis. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2004. http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD00398 17. Snook EM, Motl RW. Effect of exercise training on walking mobility in multiple sclerosis: a meta-analysis. Neurorehabil Neural Repair. 2009 Feb;23(2):108-116. 18. Khan F, Turner-Stokes L, Ng L, et al. Multidisciplinary rehabilitation for adults with multiple sclerosis. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2008. http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD00603 19 Trisolini MG. Comparison of Multiple Sclerosis Guidelines Underscores Need for Collaboration. 2008. http://guidelines.gov/expert/expert-commentary.aspx?id=16443.

APPENDIX: Topic Questions

Nominated by Institute of Medicine (IOM) 1) Compare the effectiveness of comprehensive, coordinated care and usual care on objective measures of clinical status, patient-reported outcomes, and costs of care for people with multiple sclerosis.

Nominated by ‘Web’ 1) The measurement of new lesions and relapses for determining the efficacy of a drug is flawed. The real measurement should include disease progression and mobility Population: All MS patients Importance: Because the treatments available for MS are crazy expensive. A patient can have lesions without progression. The real goal should be preventing or limiting progression.

2) My health insurance company has a $3000 annual cap for physical therapy. I reached that cap in April 2012. I requested additional PT along with copies of my PT progress note and a letter from my neurologist stating that continued therapy is medically necessary. I also included a statement explaining that in 2005 I was denied additional therapy therefore sought out other avenues to improve flexibility and strength. Unfortunately, I sustained a complete spiral fracture of my right femur while my personal yoga instructor assisted me with stretching my left hip. Well, the insurance company denied my 2012 appeal stating the notes do not reflect significant improvement. My question is (the insurance company will not provide detail) how can an insurance reviewer define what is significant improvement for an individual whom they have never met? Also, some conditions benefit from therapy even without improvement because without therapy the condition will deteriorate Population: Persons with chronic progressive disease of all backgrounds. Progressive diseases of the central nervous system will benefit, Importance: This is important because people are denied physical therapy because of arbitrary caps and restorative discrimination and therefore deteriorating not because the disease is progressing but because of disuse. This causes unnecessary pain, surgery and loss of participation in family and community life.

3) Which is (are) the best treatment(s) for recurring/remitting MS? Could MS be effectively treated less expensively? Population: All individuals diagnosed with recurring/remitting MS. Significantly more women than men. Most patients are diagnosed while still relatively young, so effective treatment could improve their quality of life over a long period of time.

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Importance: The treatments, none of which cure the disease or stop the progression, are all very expensive. With so much money being spent per patient to achieve such modest results, choosing the right treatment is critical.

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Topic 19: “Obstructive Sleep Apnea”

Comparative effectiveness of medical and surgical treatment options for obstructive sleep apnea in adults.

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Criteria Brief Description Introduction Overview/definition DESCRIPTION OF CONDITION1 of topic • Individuals with obstructive sleep apnea (OSA) have repeated episodes during sleep where their upper airway collapses and becomes obstructed. This obstruction occurs more frequently among obese individuals, who experience airway narrowing due to fat accumulation. • This results in reduced breathing (hypopnea) or complete stoppage of breathing (apnea). • When breathing stops, oxygen levels drop, causing patients to wake repeatedly through the night. • Over time, poor sleep quality and chronic dropping of oxygen levels lead to many problems. Relevance to SYMPTOMS/OUTCOMES patient-centered • Symptoms (many of these may be noticed by spouse more than patient)1,2 outcomes o Daytime sleepiness o Snoring o Frequent awakening during the night o Awakening with a choking or smothering sensation, dry mouth, sore throat, or chest pain o Irritability o Difficulty concentrating or mental fogging o Memory problems o Morning headaches o Decreased sex drive o Depression o Body aches o History of high blood pressure, diabetes, heart disease, or kidney disease • Other outcomes1 o Cardiovascular disease (heart disease and stroke) o Hypertension o Diabetes mellitus o Higher rates of motor vehicle accidents o Decreased quality of life o Inability to function at a normal level during day due to sleepiness o Higher mortality Burden on Society Recent incidence INCIDENCE (NEW CASES)/PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE and prevalence in CONDITION) populations and • Prevalence of OSA increases with age, from about 10% at age 40 to 20% among those older subpopulations than age 60.1,3 • Rates of OSA are higher in men than in women and African Americans and Asians may be at risk at younger ages compared with Caucasians.3-6 • Rates of OSA are rising, probably related to increasing rates of obesity; up to 25% of adults are at high risk for OSA.5 135

Effects on patients’ QUALITY OF LIFE quality of life, • OSA negatively affects patient quality of life, in a large part because of daytime sleepiness.7 productivity, PRODUCTIVITY functional • Studies using work productivity scales show that OSA negatively affects work productivity, capacity, even in otherwise healthy patients.8 mortality, use of FUNCTIONAL CAPACITY health care • OSA appears to negatively impact exercise capacity, although the contribution of OSA is services difficult to distinguish from that of obesity.9 MORTALITY • OSA, particularly in severe cases and among elderly patients, increases all-cause mortality.1 How strongly does Due to its relationship with obesity, OSA is rising in prevalence. OSA is associated with numerous this overall bothersome symptoms such as daytime sleepiness and poor sleep quality, which reduce patient societal burden quality of life. Further, OSA is associated with devastating complications, including higher rates of suggest that CER cardiovascular disease and mortality. For all of these reasons, comparative-effectiveness on alternative research (CER) to identify optimal treatment approaches should be assigned high priority. approaches to this problem should be given high priority? Options for Addressing the Issue Based on recent Systematic reviews: systematic • AHRQ comparative effectiveness review: Diagnosis and Treatment of Obstructive Sleep reviews, what is Apnea in Adults (2011)1 known about the • Two AHRQ future research needs prioritization projects: Future Research Needs for Diagnosis relative benefits of Obstructive Sleep Apnea (2012) and Future Research Needs for Treatment of Obstructive and harms of the Sleep Apnea (2012)10,11 available • Numerous additional systematic reviews are available management SCREENING/EARLY DIAGNOSIS1,2 options? • Diagnostic testing for OSA should be performed on any patient with typical symptoms of OSA, particularly snoring and daytime sleepiness. It is important for medical providers to ask patients about OSA symptoms, particularly patients who have typical risk factors, such as obesity. • Diagnosis of OSA is based on testing to identify episodes of reduced breathing (hypopnea) or complete stoppage of breathing (apnea): o The apnea-hypopnea index (AHI) is the count of the hourly apnea and hypopnea events during sleep. o The American Academy of Sleep Medicine defines OSA by an AHI of at least 15 events per hour (with or without OSA symptoms) or at least five events per hour with OSA symptoms. • There are two main strategies for diagnosing OSA: o Polysomnography (PSG)—Patients sleep in a special lab with comprehensive brain, breathing, heart monitoring and observation by a technologist. Though this is felt to be the most accurate way to diagnose OSA, disadvantages include cost, patient inconvenience, and differences in standards between labs.

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o Portable monitoring—Smaller monitors that collect data similar to PSG can be used at home or in sleep units. Patient questionnaires may also have a role in identifying patients in whom testing for OSA is indicated.

TREATMENT1,2 • Continuous positive airway pressure (CPAP) is the standard first-line treatment for OSA. CPAP machines improve the airway obstruction that causes OSA by delivering compressed air into the airway (via a nasal or oral mask) to hold it open. 1 o CPAP improves sleep patterns and quality of life when used as directed. o Optimal CPAP settings can be determined during PSG. Biphasic positive airway pressure (BiPAP) masks may be tolerated better by some patient subgroups. o The biggest drawback with CPAP is that patients have trouble tolerating it, often because they find the CPAP mask to be uncomfortable. CPAP only benefits those who use it correctly. Greater adherence is predicted by worse severity as measured by AHI or Epworth Sleepiness Scale.1 1 o The systematic review suggests CPAP is more effective than dental/mandibular devices. • Dental/mandibular devices are fitted by a dentist and worn overnight in the mouth to hold the airway open and prevent collapse. The systematic review suggests moderate effectiveness, but lower than with CPAP.1 o PSG or portable monitoring is recommended to confirm effectiveness of a patient’s device. o Device is generally used in cases where CPAP cannot be tolerated or the patient prefers an oral device. • Surgery can be performed to open up/widen the airway. The most common procedure is uvulopalatopharyngoplasty, in which the soft tissue at the back of the throat is removed, as well as the tonsils and adenoids, if present. o Surgery is generally only performed in cases where CPAP or oral devices have not worked. o The systematic review concluded that there is insufficient evidence to evaluate comparative effectiveness with CPAP or other interventions. • Weight loss—since obesity is a common underlying cause for OSA, weight loss can be effective in reducing symptoms if successful; options include lifestyle interventions and bariatric surgery. • Other treatments—less used treatments for OSA may include devices that hold the head/neck in a certain position, as well as pharmacotherapy. What could new New research could contribute to achieving better patient-centered outcomes: research • Diagnosis-related research:10 contribute to o How do different available tests compare in their ability to diagnose OSA in adults with achieving better symptoms suggestive of disordered sleep? patient-centered o How do these tests compare in different subgroups of patients based on race, sex, body outcomes? mass index, existing noninsulin-dependent diabetes mellitus, existing cardiovascular disease, existing hypertension, clinical symptoms, previous stroke, or airway characteristics? o How does phased testing (screening tests or battery followed by full test) compare with 137

full testing alone? o In adults being screened for OSA, what are the relationships between AHI or oxygen desaturation index and patient characteristics with long-term clinical and functional outcomes? • Treatment-related research:11 o What is the comparative effectiveness of different treatments for OSA in adults? o Does the comparative effect of treatments vary based on presenting patient characteristics, severity of OSA, or other pretreatment factors? o Are any of these characteristics or factors predictive of treatment success? o Does the comparative effect of treatments vary based on the definitions of OSA used by study investigators? o In patients with OSA who were prescribed nonsurgical treatments, what are the associations between pretreatment patient-level characteristics and treatment adherence? o What is the effect of interventions to improve adherence with device use (positive airway pressure, oral appliances, and positional therapy) on clinical and intermediate outcomes? Have recent Recent innovations: innovations made Recently, some improvements in CPAP masks have been developed to improve patient research on this adherence to therapy. topic especially compelling? How widely does VARIABILITY IN CARE care now vary? • Though the American Academy of Sleep Medicine uses a standardized definition for diagnosis of OSA based on AHI,2 different research studies have used different AHI cutoffs.1 • Some differences exist in diagnostic equipment and protocols used by sleep labs as well as in patterns of treatment utilization. What is the pace of RECENT PUBLICATIONS other research on • MEDLINE search 1/1/08-4/9/13—Total: 2,269 this topic (as o Tagged as randomized controlled trial (RCT): 267 indicated by o Tagged as meta-analysis or systematic reviews: 158 recent ONGOING TRIALS publications and • Clinicaltrials.gov—Total ongoing trials: 269, completed trials: 262 ongoing trials)? • NIH reporter—Projects: 166, publications: 232 How likely is it that KEY UNCERTAINTIES IN CLINICAL DECISION MAKING new CER on this • Should there be age- and sex-specific criteria for defining OSA? topic would • What is the optimal test to identify and diagnose OSA? Should this differ in different provide better subgroups (eg, age, obese vs. nonobese, patients with jaw abnormalities)? information to • What is the role for routine (or selected) preoperative screening for OSA? guide clinical • When is it appropriate to skip PSG in diagnosing OSA? decision making? • What are the available objectively-measured predictors of OSA diagnosis (eg, AHI), and which ones are the best? • What are consumer preferences for strategies to diagnose OSA? • What is the value of less common strategies for diagnosing OSA (eg, scoring nasal flow

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limitation in recognizing mild OSA, brain MRI, 4-phase rhinomanometry in identifying patients with high nasal resistance and OSA)? • What is the impact of different available strategies for OSA treatment on major long-term clinical outcomes (including CPAP, dental devices, different surgeries, weight-loss strategies such as lifestyle modification or bariatric surgery, pharmaceutical strategies)? • How do patient characteristics (demographics, comorbidities, OSA severity) affect the likelihood of long-term clinical outcomes? • What is the optimal treatment for OSA in different patient subgroups (differing disease severity, patients who do not tolerate CPAP)? • What is the role of weight-loss programs and bariatric surgery as an adjunctive treatment for OSA? • What CPAP and/or BiPAP masks are optimal for different patient subgroups, and how do they affect adherence to therapy? • What is the role of postoperative CPAP for patients with OSA or at high risk of OSA undergoing any surgery with sedation? LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES • Appropriately designed studies would have a high likelihood of answering these questions and reducing key areas of uncertainty. Potential for New Information to Improve Care and Patient-Centered Outcomes What are the FACILITATORS facilitators and • OSA is a common clinical problem with rising prevalence, so there is high societal motivation barriers that to improve care. would affect the • OSA is associated with many serious clinical complications; these complications may be implementation of prevented or treated through appropriate therapy. new findings in BARRIERS practice? • Diagnostic strategies may inconvenience patients (time, costs, and other factors). • Treatments are costly and often poorly tolerated by patients, which reduces effectiveness. • Many different treatment options are available; effects may differ by patient subgroups, which may make designing good trials challenging. How likely is it that EVIDENCE OF BENEFIT the results of new • It is likely that research would be implemented widely if there is evidence of better patient- research on this centered outcomes topic would be EVIDENCE OF NO BENEFIT OR HARM implemented in • It is likely that research demonstrating no evidence of benefit would also have an impact on practice right practice, particularly because many strategies for diagnosing and treating OSA are costly. away? Would new OSA is a very common problem, and it is increasing in prevalence. Information from well- information from designed randomized controlled trials on this CER topic would likely remain relevant for several CER on this topic years. remain current for several years, or would it be rendered obsolete quickly by 139

subsequent studies?

REFERENCES 1. Balk EM, Moorthy D, Obadan NO, Patel K, Ip S,Chung M, Bannuru RR, Kitsios GD, Sen S, Iovin RC, Gaylor JM, D’Ambrosio C, Lau J. Diagnosis and Treatment of Obstructive Sleep Apnea in Adults. Comparative Effectiveness Review No. 32. (Prepared by Tufts Evidence-based Practice Center under Contract No. 290-2007-10055-1). AHRQ Publication No. 11-EHC052-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2011. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Published July 2011. 2. Epstein LJ, Kristo D, Strollo PJ Jr, Friedman N, Malhotra A, Patil SP, Ramar K, Rogers R, Schwab RJ, Weaver EM, Weinstein MD, Adult Obstructive Sleep Apnea Task Force of the American Academy of Sleep Medicine. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med. 2009;5(3):263-276. 3. Young T, Finn L, Peppard PE et al. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep 2008;31:1071-1078. 4. Punjabi NM, Caffo BS, Goodwin JL, et al. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Medicine/Public Library of Science 2009;6:e1000132. 5. Hiestand DM, Britz P, Goldman M, et al. Prevalence of symptoms and risk of sleep apnea in the US population: Results from the national sleep foundation sleep in America 2005 poll. Chest 2006;130:780-786. 6. Villaneuva AT, Buchanan PR, Yee BJ, Grunstein RR. Ethnicity and obstructive sleep apnoea. Sleep Med Rev. 2005;9(6):419-436. 7. Bulcun E, Ekici A, Ekici M. Quality of life and metabolic disorders in patients with obstructive sleep apnea. Clin Invest Med. 2012;35(2):E105-113. 8. Nena E, Steiropoulos P, Constantinidis TC, Perantoni E, Tsara V. Work productivity in obstructive sleep apnea patients. J Occup Environ Med. 2010;52(6):622-625. 9. Przybyłowski T, Bielicki P, Kumor M, et al. Exercise capacity in patients with obstructive sleep apnea syndrome. J Physiol Pharmacol. 2007;58(suppl 5):563-574. 10. Balk EM, Chung M, Moorthy D, Chan JA, Patel K, Concannon TW, Ratichek SJ, Chang LKW. Future Research Needs for Diagnosis of Obstructive Sleep Apnea. Future Research Needs Paper No. 11. (Prepared by the Tufts Evidence-based Practice Center under Contract No. 290-2007-10055 I.) AHRQ Publication No. 12-EHC031-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2012. www.effectivehealthcare.gov/reports/final.cfm. Published February 2012. 11. Balk EM, Chung M, Chan JA, Moorthy D, Patel K, Concannon TW, Ratichek SJ, Chang LKW. Future Research Needs for Treatment of Obstructive Sleep Apnea. Future Research Needs Paper No. 12. (Prepared by the Tufts Evidence-based Practice Center under Contract No. 290-2007-10055 I.) AHRQ Publication No. 12-EHC033-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2012. www.effectivehealthcare.gov/reports/final.cfm. Published February 2012.

APPENDIX: Topic Questions

Nominated by ‘Web’ 1) A sleep study confirmed I have sleep apnea. I failed CPAP, oral appliances, and other noninvasive measures. Surgery is my next step. What information can you provide to help me decide what type of surgery has the best outcome and the lowest cost, based on my history, morphology, and age. 140

Population: an infant/adolescent; a teenager, adult 25-65 or over 65, regardless of sex or ethnicity Importance: It is well known obstructive sleep apnea leads to decrease day time alertness, physical and mental functioning, mental illness, motor vehicle accidence, and if untreated, diabetes, obesity, heart disease and other diseases or disabilities in the longer term. AHRQ conducted a comparative effectiveness analysis between CPAP and other appliances. Soft-tissue surgery is performed routinely but published study showed it has limited effectiveness and is associated with significant postoperative morbidity and even mortality. Maxillo-mandibular advancement (MMA) surgery, while more costly, appears to be associated with a much higher efficacy rate than soft-tissue surgery. That all surgical studies had limited sample size is part of the issue. Most insurers, however, would only approve MMA after a trial and failure of soft-tissue surgery even though its efficacy is low, increasing cost and subjecting many patients with two surgeries in order to attain relief.

Nominated by Agency for Healthcare Research and Quality (AHRQ) 1) Age- and gender-specific criteria for defining the OSA syndrome (and abnormal breathing)? 2) Effect of routine (or selected) preoperative screening for sleep apnea? 3) Diagnostic approaches to OSA in obese and nonobese patients? 4) Can PSG be skipped in making the diagnosis of sleep apnea? 5) Head-to-head comparisons of portable monitors, questionnaires, and prediction rules? 6) What are the available, objectively-measured predictors of sleep apnea diagnosis? 7) What is consumer willingness to pay for screening and to identify consumer preferences for strategies to diagnose sleep apnea? 8) Value of scoring nasal flow limitation in recognizing mild OSA? 9) Value of brain MRI in evaluating OSA patients? 10) Value of using 4-phase rhinomanometry in recognition of patients with high nasal resistance and OSA? 11) Diagnostic approach to OSA in micrognathia and retrognathia? 12) What is the impact of treatment of sleep-disordered breathing on major long-term clinical outcomes, including mortality, cardiovascular disease, and diabetes? 13) What are long-term outcomes of mandibular advancement devices (MAD) treatment? 14) Comparative studies of different sleep apnea treatments based on patient characteristics a. Analyses of CPAP stratified by disease severity b. Analyses of non-CPAP treatments stratified by disease severity 15) Comparison of alternative treatments for patients who do not tolerate CPAP? 16) What is the association between sleep apnea severity and long-term clinical outcomes? 17) Trials to evaluate weight-loss programs as an adjunctive treatment for sleep apnea? 18) What is the value of bariatric surgery for treatment of sleep apnea? 19) Role of surgery for treatment of OSA? 20) Comparison of surgery vs. CPAP? 21) Role of orthognathic surgery (corrective jaw surgery)? 22) Comparison of genio-tubercle advancement vs. dental devices? 23) Evaluation of postoperative CPAP for all patients with OSA or at high risk of OSA undergoing any surgery with sedation a. Trials comparing CPAP vs. pharmaceutical interventions b. Trials comparing different CPAP masks c. Trials comparing CPAP vs. oropharyngeal exercises d. Trials comparing different degrees of mandibular advancement 141

e. Studies of factors influencing therapist decisions concerning CPAP mask choice

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Topic 20: “Osteoarthritis”

Comparative effectiveness of treatment strategies for stabilization of symptoms from osteoarthritis.

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Criteria Brief Description Introduction Overview/definition DESCRIPTION OF CONDITION of topic • Osteoarthritis (OA) is characterized by damage to cartilage and bones of joints, causing symptoms of pain and stiffness in the affected joints. OA is also referred to as degenerative joint disease or wear-and-tear arthritis. • OA is a very common condition, particularly in people over age 45 and is a major cause of physical disability, decreased quality of life, and increased health care costs. Relevance to SYMPTOMS patient-centered • Pain and stiffness of affected joints—the most commonly affected joints are knees, hips, outcomes hands, spine, and feet • Usually begins in a single joint

OUTCOMES • OA has an impact on many aspects of patients’ lives including: o Quality of life o Daily functioning o Mental health (including depressive symptoms) o Fatigue o Limitations with work o Quality of sleep o Ability to engage in other health behaviors (like physical activity) • Other conditions more common in patients with OA include: . Impact of disease on quality of life: • Impaired functioning (pain, limited mobility) • Depression, anxiety, sleep disorders1 . Related to treatments used for OA symptoms: • Nonsteroidal antiinflammatory drugs (NSAIDs) like aspirin, ibuprofen, and the like, used to treat OA-related pain • Long-term use of these medications can contribute to peptic ulcer disease, kidney disease . Relationship to OA is unclear. Other metabolic disorders (diabetes, hypertension, high cholesterol) are more common in patients with OA.2 Burden on Society Recent incidence INCIDENCE (NEW CASES) and prevalence in • OA increases with age, occurring most often in people over age 45.3. populations and • OA of the hand has one new case per year per 1000 people (0.1%) aged 20-89; higher as age subpopulations increases.1

PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE CONDITION) • 27 million US adults (>10% of population) aged 18 years and older have one or more type of clinical OA.2 • Prevalence varies by definition of OA, location of OA, and populations studied:4 144

. 19% of people aged 45 or older and 37% of people aged 60 or older had knee OA on x- ray.4 . In populations with higher proportions of African American, rural, and obese residents, 28% of people aged 45 or older and 50% aged 75 or older had knee OA on x-ray;4 prevalence of hip OA was similar. . Of those showing OA on x-ray, a smaller proportion report having symptoms (7-17%)4 Key risk subgroups: o Risk of progression and severity of symptoms is greater in African Americans than Caucasians. o There is greater prevalence and associated limitations on activity in women, particularly after menopause. Effects on patients’ QUALITY OF LIFE quality of life, o OA leads to functional limitations, pain, disability, lost earnings, and is associated with other productivity, comorbid conditions, all of which can affect quality of life. functional capacity, PRODUCTIVITY mortality, use of o 5.3% of US adults aged 18-64 report arthritis-attributable work limitations (AAWL). Among health care adults with arthritis, approximately 30% reported AAWL.5 services o In 2003, indirect costs of earning losses due to all rheumatic conditions (with OA being the most common of these) for adults in the United States was over $47 billion.2 o OA is the third leading cause of “years of life lost to disability” (after depression and alcohol overuse).2

FUNCTIONAL CAPACITY2 o Most common functional limitations affect walking, standing, bending, and stooping movements; people with OA are more than three times as likely to have trouble with walking as people without OA. o Among older adults, the risk of disability attributable to knee OA is as great as that due to cardiovascular disease and greater than any other medical condition.6 o Data from the National Health Interview Survey show that people with arthritis-related disability (including disability from OA) have more numerous, longer, and more bothersome disabilities than people with heart disease-related disability.7

MORTALITY o Increased age-specific mortality among patients with OA, particularly symptomatic hip and knee OA,3 compared to those without OA is at least partly attributable to: . Gastrointestinal conditions related to NSAID use . Cardiovascular-related conditions related to obesity8 How strongly does Given the high prevalence of OA and the impact on functional status, productivity, and quality of this overall life, high priority should be given to optimizing treatments to slow progression of disease, reduce societal burden pain, and maintain functional status. suggest that CER on alternative approaches to this problem should be 145

given high priority?

Options for Addressing the Issue Based on recent Four recent systematic reviews explored OA management options.9-12 systematic • limited evidence on the relative benefits and harms of different therapies within each reviews, what is category (drugs, physical therapy/exercise, weight loss, or surgery) known about the • little evidence directly comparing relative effectiveness in terms of patient-centered relative benefits outcomes between different categories, or between different combinations of categories and harms of the available SCREENING/EARLY DIAGNOSIS management • Diagnosing OA can be complex due to a lack of specific physical or laboratory findings and options? discrepancies between symptoms and the results of radiographic examinations. • OA is frequently diagnosed by an overall clinical impression based on the patient's age and history, findings on physical examination, and X-ray or MRI findings.

MANAGEMENT OPTIONS11 • Pain relievers and anti-inflammatory drugs: o Most trials were primarily short-term, conducted in ideal settings (few real-world effectiveness studies) o Potential benefits: . Pain control and reducing swelling o Potential harms: . Gastrointestinal bleeding . Peptic ulcer disease . Hypertension . Swelling . Renal disease • Weight loss: o Identifying effective weight-loss strategies is no easier in an OA population than any other (ie, extremely difficult) • Exercise and physical therapy: o Unclear which type of exercise or physical therapy is best: . Reviews report that no single physical therapy intervention improves all key clinical and patient outcomes. . Studies tended to focus on a single exercise therapy, but typical practice uses combined interventions. . Unclear if effects of exercise therapies on quality of life differ by key patient populations or if outcomes are sustained over time. o Potential benefits for preserving physical function 146

o Few harms were reported except for increased pain or swelling during and after exercise, but these did not deter participation in exercise programs. • Combination management: o Using medications with exercise and physical therapy interventions • Joint Surgery: o When medication and exercise or physical therapy are not enough to decrease pain and improve quality of life, joint surgery is another option. What could new • There are currently few studies that compare multimodal treatments ( eg, combinations of research physical therapies) with exercise alone. contribute to o Few studies explored how effects differed by key subgroups achieving better o Few studies evaluated optimal duration and intensity on interventions patient-centered • Existing evidence does not allow for conclusions about the following: outcomes? o Comparative effectiveness of strategies to help patients engage in key behaviors for managing OA (physical activity, weight management), in real-world settings (community, primary care) o Comparative effectiveness of strategies to increase patient adherence to nonmedication- based strategies o Comparative effectiveness of methods to assist patients with informed decision making regarding OA treatments ( eg, medication use, joint injections, physical therapy, joint replacement surgery), with a focus on individuals with low health literacy and limited health care access o Methods for identifying and engaging patients early in the OA disease process, particularly fostering healthy behaviors (physical activity, weight management) to slow disease progression o Comparative benefits of different exercise and physical therapy interventions o Which exercise therapies work best for key subgroups (sex, severity of disease, age, obesity) o Long-term benefits of exercise therapy interventions and strategies for helping patients adhere to exercise recommendations o How outcomes of pharmacotherapies will work outside of ideal study settings (need for more real-world research) Have recent • There have been no recent high-impact innovations related to strategies for improving innovations made patient-centered outcomes. research on this • Yet, there is a compelling argument for fostering comparative effectiveness research in this topic especially area, given the following: compelling? o High burden of disease and large burden on patient-centered outcomes (pain, functional ability) o Existence of strategies to effectively improve these outcomes o High level of nonadherence to these strategies (both at the patient and health care levels) How widely does VARIABILITY IN CARE care now vary? • Clinical practice often does not reflect guideline recommendations for care.13 • In particular, there is low use of conservative, nonmedication strategies like exercise and weight loss.

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What is the pace of RECENT PUBLICATIONS other research on • MEDLINE search from 1/1/2008 – 4/9/2013: total 4,570 citations this topic (as o 901 labeled as randomized controlled trials/therapy (RCTs) indicated by o 406 labeled as meta-analyses or systematic reviews recent publications and ONGOING TRIALS ongoing trials)? • There are at least 628 ongoing studies listed in ‘clinicalTrials.gov’ • NIH Reporter (a database of NIH funded studies) lists: o 449 projects o 495 publications How likely is it that KEY UNCERTAINTIES IN CLINICAL DECISION MAKING new CER on this • What management strategy or combination of management strategies works best for key topic would subgroups of patients? provide better • What are effective strategies to foster long-term adherence rates to management strategies? information to • What are the comparative benefits and harms of different management strategies? guide clinical • What are the best methods for engaging patients in the decision making process regarding decision making? management strategies?

LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES • Effective treatments and behavioral strategies exist, but methods for employing and sustaining these in real-world clinical settings are lacking; comparative-effectiveness research (CER) can help patients and providers by giving practical guidance in these areas. • There are few comparative effectiveness studies of exercise and physical therapy strategies; understanding the best interventions in this area could improve care and outcomes by establishing a set of “best practices” to be employed in health care and community settings. • Beyond compliance with interventions, there is little evidence regarding which patients do best with what management strategies ( eg, joint injections, pharmacotherapies, physical therapy); CER in this area could help patients and providers to better select strategies according to patient characteristics.

Potential for New Information to Improve Care and Patient-Centered Outcomes What are the FACILITATORS facilitators and • OA is a prevalent disease with wide impact on patient quality of life, functioning, and barriers that productivity. Therefore patients are often motivated to engage in treatments that may would affect the improve their symptoms. implementation of • Many nonmedication therapies can be delivered by individuals other than a physician and new findings in can be delivered in multiple settings to increase patient access. practice? • There are already evidence-based interventions for patients with OA. These “off-the-shelf” programs can be adapted to different settings and patient groups and can be readily used in comparative effectiveness research and implementation strategies.

BARRIERS • OA is primarily treated in primary care settings (until patients need certain types of joint injections or are considering surgery). In primary care settings there are often many 148

competing demands and little time; therefore any strategies need to consider this limitation. • Long-term adherence to exercise and weight loss in OA is a challenge, just as it is among other patient groups. How likely is it that • Provider-based interventions are more likely to be implemented right away if they are easy the results of new to implement for both the provider and the patient. research on this • Several professional societies have developed recommendations for the care and topic would be management of OA, and the core components of these recommendations are in agreement. implemented in However, there is a need to give providers: practice right o Reminders to implement these recommendations away? o Specific guidance on when each management strategy may be appropriate for patients. These types of reminders, particularly if automated and integrated into practice settings, could be feasibly implemented. • Patient-based research that compares the effectiveness of different therapies is likely to be implemented right away if there are improvements in outcomes that are easy to achieve and can be customized to the individual patient. Would new • CER priority areas that seek to identify best strategies for implementing existing information from recommendations for care and patient interventions (physical activity and weight CER on this topic management) are needed. remain current for • Other CER priority areas include comparative effectiveness of specific therapies ( eg, type of several years, or exercise or physical therapy intervention) and identification of optimal strategies for would it be different patient subgroups. rendered obsolete • These types of findings are not likely to become obsolete quickly. quickly by subsequent studies?

REFERENCES: 1. Gore M, Tai KS, Sadosky A, Leslie D, Stacey BR. Clinical comorbidities, treatment patterns, and direct medical costs of patients with osteoarthritis in usual care: a retrospective claims database analysis. J Med Econ. 2011;14(4):497- 507. 2. Murphy L, Helmick CG. The impact of osteoarthritis in the United States: a population-health perspective. Am J Nurs. 2012 Mar;112(3 Suppl 1):S13-19. 3. Hochberg MC. Osteoarthritis year 2012 in review: clinical. Osteoarthritis Cartilage. 2012 Dec;20(12):1465-1469. 4. Suri P, Morgenroth DC, Hunter DJ. PM R. Epidemiology of osteoarthritis and associated comorbidities. 2012 May;4(5 Suppl):S10-9. 5. Theis KA, Murphy L, Hootman JM, Helmick CG, Yelin E. Prevalence and correlates of arthritis-attributable work limitation in the US population among persons ages 18-64: 2002 National Health Interview Survey Data. Arthritis Rheum. 2007 Apr 15;57(3):355-363. 6. Guccione AA, Felson DT, Anderson JJ, et al. The effects of specific medical conditions on the functional limitations of elders in the Framingham Study. Am. J. Public Health. 1997;84:351-358 7. Verbrugge LM, Juarez L. Arthritis disability and heart disease disability. Arthritis Care Res. 2008;59(10):1445-1457. 8. Hochberg MC. Mortality in osteoarthritis. Clin Exp Rheumatol. 2008 Sep-Oct;26(5 Suppl 51):S120-124. 9. Shamliyan TA, Wang S-Y, Olson-Kellogg B, Kane RL. Physical Therapy Interventions for Knee Pain Secondary to Osteoarthritis. Comparative Effectiveness Review No. 77. (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-2007-10064-I.) AHRQ Publication No. 12(13)-EHC115-EF. Rockville, MD: Agency for 149

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APPENDIX: TOPIC QUESTION

Nominated by Institute of Medicine (IOM)

1) Compare the effectiveness of different treatment strategies in the prevention of progression and disability from osteoarthritis.

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