6/21/2016

2015 (and early 2016) How to make this talk…. The Year in Review No conflicts of interest Areas Searched • Medline • ACP Journal Club • Residency Journal Clubs • Faculty Suggestion • Practical, Applicable, Interesting • Whatever is not being covered elsewhere….

Topics! Afib, GIB and Warfarin- dangerous brew 1- Therapeutics A 75 year old woman with hypertension and diabetes arrives a week -Afib, GIB and Warfarin- dangerous brew after being sent home after a three day hospitalization after having a upper GIB from a gastric ulcer. Biopsy pathology was benign and her -PPI’s- well tolerated? H.Pylori testing was negative. She has longstanding atrial fibrillation and was taking warfarin which was stopped upon her admission. She 2- Screening Update feels well and wonders if she should restart her anticoagulation. You - The dreaded AAA recommend which of the following: 57% 3- When to refer to ortho A. Treat with clopidogrel monotherapy B. Treat H. Pylori infection 26% 3a- Meniscal tears C. Restart warfarin for INR of 2-3 15% D. Change to a novel oral anticoagulant 2% 0% 3b- Knee replacements E. Reconsider anticoagulation a month after her

...... a t i . bleed l . . e c t i o n R o a f IN g r e n o r 4- Post-op analgesia f y l o r i i n P a r i . r f a novel oral r anticoagul t h c l o p i d o t H e i a t o d w a g e s i r e r t n T c o n e s t a h a T r e a t w R C R e

1 6/21/2016

Stroke Prevention in A. Fib-Rx Meta-analysis Data – 9874 participants, 16 trials 1. Warfarin vs. Placebo
62-68% RRR INR 2-3 - Absolute risk bleeding 0.3%/year - Reduction of all cause mortality 26% (ARR 1.6%/Year) 2. Aspirin vs. Placebo
21-25% RRR ANY Dose -Common disorder, increases with age - Absolute risk bleeding 0.2%/Year -AR% increases dramatically with age - No overall reduction of mortality - Circulation 2010: 103:162-182 -Our patient- 75, DM, HTN WHEN/IF Restart anticoagulation? -CHADS2 = 3

- ~6-8%/year stroke Annals of Int. Medicine Vol. 131, No. 7 October 5, 1999

Mortality after Outcomes: GIB with Afib + 61% 59% -Mortality RRR RRR anticoagulation RRR 61% HR=0.39- Warfarin -Thrombosis - Post-d/c cohort (0.76- antiplatelet RRR 59% - 4600 Danes, alone) X=78yo, 45% women - f/u started 90 days Harms: post discharge -Major Bleed - Two years follow-up RRI 37% 37% 34% -49% mortality nd RRI - 2 GIB RRI - All-cause mortality RRI 34%

-Staerk. BMJ -Staerk. BMJ 2015;351:h5876 2015;351:h5876

2 6/21/2016

Timing of Restarting Anticoagulation Survival analysis showing 1-year mortality -Findings similar stratified by duration of interruption of warfarin

1.18 RRI recurrent GIB P=0.47 33% mortality RRR Mortality Recurrent GIB

29% thrombosis RRR Retrospective Cohort 1329 pts - Increased GIB risk <7days - Southeast Michigan - Increased Death or - 2005-2010 Thromboembolism >30 days - X=76 years - 45% women -Recommend 7-21 days - Anticoag 49% restarted - Controlled for chads/hasbled Thromoboembolism Quereshi et al. AJC, Volume Quereshi et al. AJC, Volume 113, Issue 4, 2014, 662–668 113, Issue 4, 2014, 662–668

Anticoagulation on Discharge Anticoagulation after UGIB

• Mortality Benefit to restarting! • 7-15 days seems to be sweet-spot No Statistical Difference- • Some increase to bleeding- carefully BUT power? council and ensure INR in range

• Case resolution: 76 yo woman 10 days post-UGIB. Restart warfarin for INR=2-3 Sengupta, Am J Gastroenterol 2015; 110:328–335 with close follow-up Prospective Cohort restarted on anticoagulation on discharge - 90 day outcomes, 197 patients

3 6/21/2016

Case #2 Risk of C.

60 year old woman is concerned about her medications. Dif with She has heard that her chronic omeprazole that she has PPI Use taken for several years for her heartburn can cause other medical problems. You say she is right and tell her PPIs • OR = 1.74 are associated with the following complications except: 44% increase in A. Increased risk for C. Dificile infection CID with PPI B. Renal insufficiency 19% C. Drug interaction leading to Clopidogrel 14% 8% 8% failure 6% • Heterogeneity D. Dementia • Consistency E. All of the above c y y Also CAP, B12 deficiency, fracturen . .risk e g i n f i c i d D e m e n t i a l e a across studies F. A and C only n A and C onl i sk fo r C . D ifici.. A ll of the above Renal insuf s e d r a r e Kwok et al. Am J. Gastro I n c D rug interactio 2012;107:1011-19

Retrospective cohort study of 8205 VA patients with ACS 5244 on plavix and PPI/2961 without PPI (VA formulary=omeprazole) Ho, P. M. et al. JAMA 2009;301:937-944. PPI and Renal Damage?

NNH=11 !! • Chronic kidney disease (CKD) affects approximately 13.6% of adults in United States • Increased risk of death and cardiovascular events • PPIs amongst most commonly used drugs worldwide Re-ACS or death = 29.8% PPI – 40% to 60% no appropriate indication = 20.8% no PPI

• Large database study examines relationship • Atherosclerosis Risk in Communities ( ARIC ) prospective cohort study 10,482 participants, 63.0 yo, 56% women • Replication Cohort 248,751 patients with an outpatient eGFR of at least 60 Clopidogrel activated by CYP2C19 – Lazarus et al. JAMA Intern Med. 2016;176(2) Enzyme metabolized/inhibited by omeprazole

4 6/21/2016

Rapid Rise of PPI Use Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease

Up to 25% of American adults >55 use PPI’s!!!!

Prevalence of Proton Pump Inhibitor (PPI) Ever Use Table Title: Over Time in the Atherosclerosis Risk in Communities Study

Lazarus et al. JAMA Intern Med. 2016;176(2). Lazarus et al. JAMA Intern Med. 2016;176(2)

Proton Pump Inhibitor Use and the Risk of Incident Chronic Kidney Disease PPI and Dementia

• German Study on Aging, Cognition and Dementia in Primary Care Patients • 73K participants free of dementia • X=83 yo, 74% women • Community dwelling at enrollment • q18 month follow up • Memory testing

JAMA Intern Med. 2016;176(2). doi:10.1001/jamainternmed.2015.7193

5 6/21/2016

From: Association of Proton Pump Inhibitors With Risk of Dementia: A Pharmacoepidemiological Claims Data From: Association of Proton Pump Inhibitors With Risk of Dementia: A Pharmacoepidemiological Claims Data Analysis Analysis

JAMA Neurol. 2016;73(4):410-416. doi:10.1001/jamaneurol.2015.4791

hazard ratio 1.44

44% increase risk of dementia with PPI use over 6 years

Figure Legend: Table Title:

Dementia increase: Gomm et al. JAMA Neurol. 2016;73(4):410-416. 69% RRI 75-79, 49% RRI 80-84, 32% RRI >85 years

Bottom Line:

• Long Term PPI Indications: – Barrett ’s or Erosive esophagitis, Hypergastrinemic states, Long term NSAIDS in high risk patients, DAPT – AGA recommends lowest shortest exposure possible • Re-evaluate: • Needs assessment for PPI- frequently • Try protocol

Gastroenterol Hepatol (N Y). 2008 May; 4(5): 322–325 Ther Adv Gastroenterol. 2012;5(4):219-232.

Anderson and Kotwani- reproduced with permission

6 6/21/2016

Case #3- Abdominal Aortic Aneurysm When talking about Abdominal Aortic Aneurysms which of the following statements is true? • AAA >2.9 cm 6% at 65yo – Increases 6%/decade A. Risk of rupture increases exponentially when AAA measures >4.5cm 40% – 90% smokers 35% B. Smoking is the biggest risk factor for AAA – Ehlers Danlos, Marfans – Familial (30%, 6%) C. Family history of AAA is not a risk factor 20% D. Screening for AAA has no impact on disease • Obvious risk=rupture specific mortality 5% – 90% mortality! 0% E. All of the above are false 9K deaths

e ...... s a s e t r i . e s – 2-6% operative mortality r e i n c r u above are fal s t h e b i g g e for A AA has en. i n g o f r u p t 1400-2800 deaths l y history of AA A is ... s k A l l o f t h Aorta Rupture R i S m o k i n g i F a m i S c r e e n www.pennhealth.com/ int_rad/health_info/aaa.html

When to repair a AAA?? Who to screen for AAA?

• Poking a skunk… • Ultrasound Sn=95%, Sp=99% – CT- similar test characteristics, more dye • USPSTF – Male smoker 65-75 years- Grade B (fair data) – Family Hx, Erhlers Danlos, Marfans – AAA mortality screened- OR = 0.57 – Non-smoking Males- Grade C- no rec. – Females 65-75 years- Grade D • OR = 0.98 mortality.. Only one trial Surgical benefit>>Surgical risk when aneurysm is 5.5-6cm • Fleming et al. Ann Intern Med. 2005 Feb 1;142(3):203-11. >1cm expansion/12mos Powell et al. NEJM 348;19, May 8, 2003

7 6/21/2016

How to repair a AAA? MASS Trial (multicenter aneurysm screening study) DREAM Trial- >5 cms 0.87% 68K men in (Dutch Randomized EVR Aneurysm Trial) UK 65-75yrs, 10 yrs of 345 patients follow-up 0.46% Open-174 EVR-171 -HR=0.52 4.6% (8) 1.2% (2) (intention to screen) Mortality -HR=0.40 (actually screened) 9.8% (17) 4.7% (8) -NNS= 243 Mortality or severe -$11,400 per complications @30 days Thompson et al. BMJ 2009;338:b2307 www.marketwire.com/ QALY NEJM 351;16, Oct 14, 2004 mw/release_html_b1?release...

Not so Sweet DREAM- 2 year outcomes Long-Term Outcomes of Abdominal Aortic Aneurysm in the Medicare Population

• Large retrospective Medicare database evaluation • 40K matched pairs of patients who had undergone either open repair or endovascular repair. • Perioperative mortality 1.6%-EVR vs. 5.2% with open repair (P<0.001) 3 Possible Explanations • From 2001 through 2008, perioperative mortality 1- Chance driving outcomes since small study decreased 1% both 2- Frail patients survived EVR but later died • 8 years of follow-up 3- Long term EV repair inferior to open? – Schermerhorn ML et al. N Engl J Med 2015;373:328-338 NEJM 352:23 June 9 2005

8 6/21/2016

Freedom from Rupture, Aneurysm, or Reintervention for Complications Related to Laparotomy. Bottom Line- AAA NN Burst=25 8 year outcomes Over 6 years Aneurysm • Screen smoking men 65-75, +FH, Marfans rupture: – Non-smokers, women?? 5.4% EVR 1.4% open • >5.4 cm refer for repair repair (P<0.001) – (or for >1cm expansion/yr) – Short term survival benefit for EVR – Endovascular repair high risk patients

– Mortality risk crosses between 2-3 years – Annual U/S post procedure

Schermerhorn ML et al. N Engl J Med 2015;373:328-338.

Case 5 Fidelity Study- what is known

60 yo woman arrives in your office complaining of right RCT- sham-controlled knee pain that began while playing golf where she twisted meniscetomy. after hitting the ball. The pain has persisted despite 2 weeks of APAP. She endorses her knee catches with - 146 patients 35-65 yo walking and occasionally feels like it could collapse. Xrays - Degenerative medial show no fractures or significant DJD. You advise. meniscus tear 70% - Arthroscopic partial A. Vitamin D 800iu daily meniscectomy vs. B. Physical therapy sham arthroscopy 26% - Pain scores 12 mos. C. Arthroscopic partial meniscectomy D. Glucosamine sulfate orally 2% 2% - NO DIFFERENCE

p y . . e r a i u d a i l y 0 t h l m e n . a a l t i a r N Engl J Med 2013; p m i n D 8 0 P h y s i c t a o p i c V i s c o 369:2515-2524 h r G lucosam ine sulfate orally A r t

9 6/21/2016

Meniscectomy for Tears Fidelity Subgroup- Mechanical s/s

• 700,000 annually • Previous research no difference from PT and fewer complications • NOT examined for mechanical symptoms Mechanical symptoms: manifest by: locking, -32 patients (46%) in the APM vs. 37 (49%) sham popping or collapse -No Difference post procedure… – May represent larger tears CAUTION in using surgery for reported mechanical s/s… Sihvonen et al. Ann Intern Med. 2016 Apr 5;164(7):449-55

Case 5 Total Knee Replacement 80 yo woman arrives in your office complaining of right knee pain that is ongoing. You recently diagnosed her with • Effective for severe knee DJD severe DJD for which she has had only transient relief from – 670K TKA’s in 2012, 900+K in 2015 APAP. You advise. 50% – Aggregate charges $ 36 billion A. Vitamin D 800iu daily (neg RCT**) • Multi-specialty care also B. Physical therapy, 24% nutrition 21% effective C. Total knee replacement – Exercise, diet, insoles, pain relief 5% D. Foot insoles 0% – AGS step care approach endorsed E. B and D l y e s a i i o n e n t • Comparison study needed d r i t m u t B a n d D l a c e 8 0 0 i D r e p F o o t i n s o l **Jin et al. JAMA. 2016:315(10):1005-13 a p y , n u n r e e n t a m i k V i T o t a l Physical the

10 6/21/2016

RCT Total Knee Replacement RCT Total Knee Replacement

100 Patients mod-to-severe knee osteoarthritis KOOS improvement: -both groups TKA + 12 Vs. 12 weeks non- improved weeks non- surgical Rx -32.5 surgery surgical Rx -16 non surgical (PT, nutrition, -Only 26% crossed exercise, over to surgery NNT 5.7 education, for 15% improvement insoles, pain rx) Skou et al. N Engl J Med 2015; 373:1597- 1606 Outcome: 4 Knee Injury and Osteoarthritis Outcome Score subscales , covering pain, symptoms, activities of daily living, and QOL (KOOS4)

More side effects in surgical group Pre-op pain advice for TKA Your 80 yo woman decides to go for TKA after only DVT, deep mild relief from intensive non-surgical intervention. infection, femur fx, She wants to minimize pain medications. What do mobilization procedure you advise? 89% A. Avoid narcotics to prevent addiction B. General rather than regional Bottom Line: Better outcomes anesthesia with surgery BUT C. Go to low volume center to ensure 70% avoided 9% 2% 0% surgery with intense more personalized care non-surgical D. Listen to music post-operatively intervention- trial

post-oper... r than regi... um e center .. everyone first! e l s i c v o u m r a t h o a l r n t A void narcotics to preve.. o t o l o w G e n e G L i s t e

11 6/21/2016

Last case: Post-op pain relief Final Review

• Meta-analysis of 73 • Therapeutics RCTs – Restart anticoagulation 7-14 days post UGIB in afib • Music type, timing, – Review needs for PPI frequently and minimize use duration variable • Imaging • Reduced pain, anxiety, analgesic – Ultrasound imaging AAA in smokers use – Endovascular repair outcomes cross over after 3 years • Improved patient • Surgery for Knees satisfaction – No meniscectomy for most mechanical symptoms – TKA only after intensive non-surgical intervention Lancet: Volume 386, – Music for post-op pain is good! Issue 10004, 24–30 October 2015

Thanks for your attention!!

12 6/21/2016

Match Trial CHADS 2 Prediction Rule Secondary Prevention: Plavix + Aspirin or AFI, SPAF - 2 large prediction rule trials Plavix + Placebo ’ - don t always agree • N=7599 followed for 18 months - Framingham hard to use • Outcomes: CVA, MI, hospitalization or death – CHF in last 100 days C – Dual Rx. 596/3793 (15.7%) – Clopidogrel 636/3802 (16.7%)- no asa alone arm…. – Hypertension H – RRR 6.4% (-4.6-16.3) – Significant increase in bleeding on dual therapy A – Age >75 Years Score 0=1% D – Diabetes 1=2.5%/year 4=8% • Conclusions: Dual Rx no better than clopidogrel alone 2=4% 5=12% – VA Neuro- change antiplatelet agent » Lancet Vol. 364 July, 2004 S2 – x2 previous Stroke or TIA 3=6% 6=18% Gage et al. JAMA June 13, 2001

How to follow a AAA.. • Society of Vascular Surgery – U/S annually 3-4cm – U/S q6 mos. 4-4.5cm – U/S q6 mos. and vascular referral for >4.5 cm Patient- 5.8cm AAA on U/S Aorta Rupture

Ann Intern Med. 2005 Feb 1;142(3):203-11

13