5 TIWIKLY 5 Things I Wish I Knew Last Year (2015)
Louis Kuritzky, MD University of Florida Family Medicine Residency Program Gainesville, Florida (352)-377-3193 Phone/FAX [email protected]
Disclosure
Louis Kuritzky, MD has NOTHING TO DISCLOSE In reference to the content of this presentation
1 Objectives
• Identify potential therapeutic roles for tranexamic acid • Understand the limitations of AAT replacement therapy • Recognize the weaknesses of current data substantiating triglyceride treatment
Disclosure
Louis Kuritzky has nothing to disclose in reference to the content of this presentation.
2 5 TIWIKLY 2015 Score Card item # Knew Didn’t Know Keep Toss 1) Lung CA Screen Xray Burden 2) Melanoma Adhesive Patch Dx 3) Thermal Rx & Endothelial Fx 4) False + UDT Methadone 5) TRG Rx to ↓ CVD Risk 6) Warfarin & Dental Surgery 7) What is Tranexamic Acid 8) Menorrhagia & Factor VIII 9) A1AT & Emphysema 10) A1AT Replacement $$ 11) A1AT Efficacy 12) TRG & Pancreatitis
How Low Dose is LDCT for Lung Cancer Screening? Arnold is a 62 year old man with a 80 p-y smoking history, who is considering participating in the currently approved protocol for lung cancer screening. He asks you: “It says ‘low dose’ CT. What does that mean?” You would best inform him that a LDCT is equivalent to a) A day in bright sunlight at the beach b)15-20 Chest PA x-rays c) 30-40 Chest PA x-rays d) 110-120 Chest PA x-rays
3 Lung CA Screening: Summary Recommendation
“The USPSTF recommends annual screening for Lung CA with LDCT in adults aged 55-80 years who have a 30 p-y smoking Hx and currently smoke or have quit within the past 15 years.”
Moyer VA, et al Ann Int Med online accessed 013-Dec-30
“Typical” Effective Doses from X-ray Radiographic Dose Equivalent Study (mSv) #CXR ChestPA 0.013 1 L-spine AP 0.44 30 Mammogram (4 view) 0.2 15 Dental Panorama 0.012 1 BE 5 350 CT L-spine 7 550 CT Abdomen 10 750 CT Chest 10 750 LDCT Chest 1.5 113 Adapted from Linet MS et al CA Cancer J Clin 2012;62:75-100
4 Evolution of Radiation Exposure 1980-2006
2006 per capita dose
Other Sources < 0.14 mSv Medical 1980 per capita dose Sources 3.0 mSv Medical Sources Other Sources < 0.05 mSv 0.53 mSv
Natural Sources 2.4 mSv
Linet MSNatural et al Sources CA Cancer 2.4 mSv J Clin 2012;62:75-100
Linet MS et al CA Cancer J Clin 2012;62:75-100
Evolution of Radiation Exposure (mSv) 1980 2006 Natural Sources 2.4 2.4 Medical Sources 0.53 3.0 CT scans 0.03 1.47 Nuclear Medicine 0.1 0.77 Fluoroscopy 0.4 0.76 Other < 0.05 <0.14 Consumer products --- 0.13 Occupational --- 0.005 Nuclear Power --- 0.0005
TOTALLinet MS et al CA Cancer 3.0 J Clin mSv 2012;62:75-100 5.6 mSv Linet MS et al CA Cancer J Clin 2012;62:75-100
5 Estimated Radiation-Related Cancers from Repeated Screening Age X-ray related Test Frequency (years) CA/100,000 Lung LDCT Q1Y 50-70 230 ( ♂) 850 ( ♀) Coronary Ca++ Q1Y 45-70 40 ( ♂) 55-70 60 ( ♀) Mammography Q1Y <55 45-74 90 Q2Y >55
Linet MS et al CA Cancer J Clin 2012;62:75-100
First Glimpses into the Future From Your Dermatology Time Machine • Differentiation of melanoma from other pigmented skin lesions usually requires a tissue sample. Northwestern University (Chicago) has recently published data on a novel non-invasive methodology. It is ♦ Saliva testing for beta-microglobulin ♦ Adhesive patch testing for mRNA ♦ Ultraviolet light reflectometry ♦ Cutaneous DEXA scanning
6 Melanoma: Some Issues
“The incidence of melanoma is ↑ at a rate of 3%-7%/yr for fair-skinned white populations, faster than any other major cancer.”
Gerami P et al J Am Acad Dermatol 2014;71:237-44
Melanoma: Some Issues
Invasive Depth 10-yr Survival Insitu 100% Breslowdepth < 1 mm >90% Breslowdepth > 4mm <50%
Gerami P et al J Am Acad Dermatol 2014;71:237-44
7 Melanoma: Some Issues
“While mortality from almost all preventable cancers has markedly decreased since 1975, melanoma-related mortality remains steady….”
Gerami P et al J Am Acad Dermatol 2014;71:237-44
Melanoma: Some Issues
“A number of studies have shown that early detection through a skin examination allows for Dx at an earlier and more curable state….In 1 study, screening skin examinations reduced mortality by 63%.”
Gerami P et al J Am Acad Dermatol 2014;71:237-44
8 A Noninvasive Adhesive Patch Test for Pigmented Lesions
• Study: Comparison DermTech adhesive patch vs Bx results (n=150) • Patch MOA: captures mRNA from CMIP & LINC00518 genes • Method: apply & remove patch, then Bx
Gerami P et al J Am Acad Dermatol 2014;71:237-44
A Noninvasive Adhesive Patch Test for Pigmented Lesions Patch Bx Classifiction Classification Melanoma Nevus Melanoma 41 6 Nonmelanoma 1 16 Sensitivity 41/42 (97.6%) Specificity 16/22 (72.7%) Gerami P et al J Am Acad Dermatol 2014;71:237-44
9 What About Those False Positives?
“Six of 22 cases with a histologic Dx of nevus had a molecular score consistent with a Dx of melanoma. Interestingly, among those 6 cases, 3 had a histologic reading of dysplastic nevus with severe atypia. Unfortunately, it is impossible to determine whether these 3 cases were truly false positives or actually early melanomas.”
Gerami P et al J Am Acad Dermatol 2014;71:237-44
10 I Know I Have Risk Factors for CAD, but I HATE to Exercise…. • A 62 year old man with T2DM X 10 years, HTN, and dyslipidemia--all Rx appropriately--gives a ‘2 thumbs down’ to the suggestion of exercise. Which of the following interventions has been shown to improve endothelial function in persons with CAD risk factors? ♦ Magnesium Supplementation ♦ Thermal treatment (sauna) ♦ Ginseng tea ♦ Inversion boots (upside-down suspension)
11 Thermal Rx to Improve Endothelial Function
• Study: Japanese men with and without CAD RF (n= 73) • Rx: 15 mins/d dry sauna (60 0 C) X 14 d • Outcome: %FMD (flow-mediated endothelium-dependent dilation)
Imamura M, et al J Am Coll Cardiol 2001;38(4):1083-1088
Thermal Rx to Improve Endothelial Fx: Premises
Ox-LDL DM HTN Smoking
Endothelial Dysfunction
Impaired FMD (Flow Mediated Vasodilation)
Imamura M, et al J Am Coll Cardiol 2001;38(4):1083-1088
12 Thermal Rx to Improve Endothelial Function
* 45% ↑
*emphasis added
Imamura M, et al J Am Coll Cardiol 2001;38(4):1083-1088
Thermal Rx to Improve Endothelial Function
Baseline PostRx p* p** Control CAD RF CAD RF %FMD 8.2 4.0 <0.0001 5.8 <0.001 %NTG 20.4 18.7 0.32 18.1 NS * vs control **vs preRx
Imamura M, et al J Am Coll Cardiol 2001;38(4):1083-1088
13 Thermal Rx & Glucose: Unexpected Payoff?
“A significant decrease in FPG concentration [99 mg/dL → 94 mg/dL, p < 0.05] after two weeks of sauna Rx was observed, consistent with the previous report using hot-tub therapy.”
Imamura M, et al J Am Coll Cardiol 2001;38(4):1083-1088
An Unexpected UDT + for Methadone • A 56 y.o. house painter fell off a ladder fracturing 3 ribs. He has been prescribed tramadol for pain relief. A UDT comes back positive for methadone. The patient claims he has not taken any methadone. ♦ The pt is lying: FP methadone tests are very rare ♦ His tramadol (Ultram) causes a FP UDT ♦ The quetiapine (Seroquel) he takes for depression is causing a FP UDT for methadone ♦ Endogenous opioids induced by acute pain may cause a FP UDT for methadone
14 False Positive Methadone UDT Case Series of 10
“… 10 inpatients……suffering from mood or psychotic disorders who tested + for methadone. Since such false + methadone screenings may seriously affect the therapeutic relationship, this potential interaction is highly relevant for clinicians.
Fischer M et al J Clin Psychiatr 2010;71(12):(LTE)1696-1696
False Positive Methadone UDT Case Series of 10
• All INPATIENTS: methadone access? • All denied methadone use • Gas chromatography-mass spectrometry re-test: methadone negative • All 10 pts Rx with quetiapine (Seroquel)
Fischer M et al J Clin Psychiatr 2010;71(12):(LTE)1696-1696
15 False Positive Methadone UDT Case Series of 10
“…this report strongly suggests that positive methadone drug screenings be confirmed by a second method….especially in patients treated with quetiapine.”
Fischer M et al J Clin Psychiatr 2010;71(12):(LTE)1696-1696
The Triglyceride Story: CVD Risk Reduction • Your new pt Jason W is an obese (BMI 32) 36 y.o. construction worker who requests a fibrate refill for Rx of ↑TRG (off-Rx = 380, on-Rx = 110). He denies pancreatitis. He drinks ‘a couple beers’ after work every day. He has no personal/FH of CVD, but was told by his since-retired GI Doc to take the fibrate to reduce his risk of CVD, which he has done for the last 3 years. He does not have HTN or T2DM. The fibrate causes no AEs. a) Refill the Rx as-is: success is success b) Increase the fibrate dose: his TRGs could be improved c) Decrease the fibrate dose: TRG ≤150 would be OK d) Decline to fill the Rx due to lack of outcomes evidence
16 Two Basic Clinical Questions
• Has pharmacologic Rx of elevated triglycerides been PROVEN to improve CV outcomes? • Has pharmacologic Rx of triglycerides been PROVEN to reduce risk for pancreatitis?
Two Basic Clinical Answers
• ↓ CVD?: No RCT has demonstrated this
17 The Triglyceride Story: UpToDate 2014 CVD Risk Reduction with Rx: Uncertain
“It is uncertain whether pharmacologic therapy targeted at reducing TRG levels will reduce CV risk.”
Rosenson RS “Approach to the patient with hypertriglyceridemia” UpToDate accessed 9/2414
The Triglyceride Story: UpToDate 2014 Preventing Pancreatitis: No High Quality Evidence
“Although high quality evidence is lacking, for primary prevention of pancreatitis, we and others suggest initiating pharmacologic therapy to reduce TRG when fasting concentration is >1000 mg/dL”
Rosenson RS “Approach to the patient with hypertriglyceridemia” UpToDate accessed 9/2414
18 NICE UK Lipid Guidelines 2014 • Do not routinely offer fibrates and do not offer nicotinic acid, a bile acid sequestrant or omega-3 FA compounds for the prevention of CV disease to any of the following ♦ people who are being Rx for 1 0 prevention ♦ people who are being Rx for 2 0 prevention ♦ people with CKD ♦ people with type 1 or type 2 diabetes
NICE Clinical Guideline 181 Updated September 2014
19 NICE 2014 Statin + Fibrate, Nicotinic Acid, Omega-3 FA: NOT
“Do not offer the COMBINATION of a bile acid sequestrant, fibrate, nicotinic acid or omega-3 fatty acid compound with a statin for the primary or secondary prevention of CV disease.”
NICE Clinical Guideline 181 Updated September 2014
The Triglyceride Story: UpToDate 2014 Uncertainty Whether TRG CAUSE Atherosclerosis
“…it now seems clear that elevated TRG levels are independently associated with CV risk,…It remains uncertain, however, whether this association is causal, such that hyperTRG causes atherosclerosis.”
Rosenson RS “Approach to the patient with hypertriglyceridemia” UpToDate accessed 9/2414
20 Fenofibric Acid (Trilipix®) Indications
• In addition to an optimally dosed statin to ↓TG and ↑HDL in mixed dyslipidemia patients with CHD or CHD equivalent • To ↓ TG in severe hypertriglyceridemia • As monotherapy to ↓ LDL, total cholesterol, & Apo B, and ↑ HDL in 1 0 hyperlipidemia or mixed dyslipidemia
Triplix® Prescribing Information 2010
Fenofibrate: Does it Work? Quotes FROM THE PRESCRIBING INFORMATION
• INDICATION: ADD TO STATIN ♦ “No incremental benefit of Trilipix on CV morbidity and mortality over and above that demonstrated for statin monotherapy has been established.”
• INDICATION: ADD TO STATIN…with CHD EQUIV ♦ “Fenofibrate at a dose equivalent to 135 mg of Trilipix was not shown to reduce CHD morbidity and mortality in a large, RCT of patients with type 2 DM.” Triplix® Prescribing Information 2010
21 Where Does This Leave Us Me? Triglycerides and CVD • Triglycerides ARE associated with Atherosclerotic Disease ♦Maybe causal, maybe not • IF causal, it remains to be determined whether modulation improves CV outcomes • We know every medication has toxicity. A risk:benefit ratio, when benefits are indeterminate, cannot be measured
And What About Jason? Obesity, EtOH, no CVD Hx • Jason: in the absence of evidence of CVD risk reduction (and that’s what he is taking it for) I would DECLINE his Rx. • It is unlikely that he has maximized diet or alcohol restraint, either of which might reverse his dyslipidemia
22 Warfarin Management With Dental Surgery?
• Your 72 y.o. patient has been taking warfarin for 3 years because of atrial fibrillation (CHADS score = 3). He is going to undergo two dental extractions, and the dentist has asked that you manage his warfarin for the procedure. His INR has been stable at 2.2-2.6 for 12 months. You should
a) Stop warfarin 5 d before extractions; no bridge b) Stop warfarin 5 d before extractions; enoxaparin bridge c) Stop warfarin 5 d before extractions; clopidogrel bridge d) Continue wafarin; add topical prohemostatic agent
Perioperative Risk From Dental Surgery in Perspective “In reviewing the available literature, there are no well-documented cases of serious bleeding problems from dental surgery in patients receiving therapeutic levels of continuous warfarin… but there were several documented cases of serious embolic complications in patients whose warfarin therapy was withdrawn for dental treatment.”
Wahl MJ “Dental Surgery in Anticoagulated Patients” Arch Intern Med 1998;158:1610 -1616
23 What Do the Antithrombotic Guidelines Say?
“In patients who require a minor dental procedure, we suggest continuing VKAs with coadministration of an oral prohemostatic agent or….”
Douketis JD, et al CHEST 2012;141(2)(Suppl):eS326-e350S
What is Tranexamic Acid?
• Currently under the tradename Lysteda, tranexamic acid has been marketed in the United States since 1986. What is it, and why should you and I know more about it? Tranexamic acid is
a) The more active trans isomer of cis-examic acid, an analgesic b) An antifibrinolytic agent c) An agent to enhance autonomic nerve function d) A synthetic amino acid that activates vitamin D
24 What is Tranexamic Acid?
trans -4-aminomethylcyclohexanecarboxylic acid
What is Tranexamic Acid? trans -4-aminomethylcyclohexanecarboxylic acid
25 Biochemistr-ito
Fe ++
Fe ++ Fe ++
++ Fe Fe ++
26 Ferrous
Wheel Fe ++
Fe ++ Fe ++
++ Fe Fe ++
See How Easy This Is?
27 C3H7NO 2S
cysteine
C3H7NO 2S
28 What’s the Only Element That’s Not On the Periodic Table?
?
What’s the Only Element That’s Not On the Periodic Table?
? The element of SURPRISE
29 What is Tranexamic Acid?
Tranexamic acid Oral Contraceptives Antifibrinolytic Pro-coagulant Plasminogen Activator Inhibitor
Plasminogen
Plasminogen Activator Fibrin Clot Dissolution Plasmin Clot
Efficacy of Tranexamic Acid For Oral Surgery • Study: RDBPCT oral surgery pts (n=94) • Warfarin NOT stopped • Rx: tranexamic acid solution 4.8% ♦10 ml immediately post-op ♦10 ml q.i.d X 2 mins X 7 days • Outcome (Bleeding requiring Rx) ♦Rx group: None ♦Placebo group: 10 patients (p < 0.01)
Ramstrom G et al J Oral Maxillofac Surg 1993;51(11):1211-1216
30 Tranexamic Acid: A Way to Reduce Bleeding Associated with Dental Procedures
Dosing • Tranexamic acid 5% oral solution rinse (500 mg/10 ml) ♦5 ml 5-10 mins pre-procedure ♦5 ml t.i.d.-q.i.d. X 24-48 hrs
Douketis JD et al Chest 2012;141;e326-e350S
CRASH-2 Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage 2 Lancet 2010;376:22-32
31 Trauma or Major Surgery Part of normal hemostatic response Clot Breakdown (fibrinolysis) Sometimes Pathologic Clot Breakdown (hyper-fibrinolysis)
Hemorrhage CRASH-2 Trial Collaborators Lancet 2010;376:22-32
Trauma Issues
“Haemorrhage is responsible for about a third of in-hospital trauma deaths..’”
CRASH-2 Trial Collaborators Lancet 2010;376:22-32
32 Post-trauma Mortality: Hemorrhage vs Other
Deaths Due to Bleeding
Deaths Due to Other Causes # Deaths
N=20,2011
DAYS CRASH-2 Trial Collaborators Lancet 2010;376:23-32
What is Tranexamic Acid?
Tranexamic acid Oral Contraceptives Antifibrinolytic Pro-coagulant Plasminogen Activator Inhibitor
Plasminogen
Plasminogen Activator Fibrin Clot Dissolution Plasmin Clot
33 Effects of Tranexamic Acid in Trauma Patients with Haemorrhage • Study: RDBPCT trauma pts (n=20,211) • Inclusion: ♦ SBP < 90 mm Hg and/or ♦ Pulse > 110 bpm and/or ♦ Considered at risk of significant bleed ♦ Within 8 hr of injury • Rx: tranexamic acid IV 1 g load + 1 g 8hr infusion vs placebo
CRASH-2 Trial Collaborators Lancet 2010;376:22-32
Tranexamic Acid vs Placebo: All-Cause Mortality
Risk Ratio (CI) Time from ≤1 hr 0.87 (0.75-1.00) 1-≤3 hr 0.87 (0.75-1.00) injury >3hr 1.00 (0.86-1.17)
≥90 0.94 (0.82-1.07) SBP mm Hg 76-89 0.94 (0.78-1.14) ≤75 0.87 (0.76-0.99)
0.94 (0.82-1.07) Glasgow Coma Severe 0.94 (0.78-1.14) Moderate 0.87 (0.76-0.99) Score Mild
Blunt 0.92 (0.83-1.02) Injury Type Penetrating 0.86 (0.72-1.03)
N=20,2011 All Patients N = 20,2011 0.91 (0.85-0.97)
0.7 0.8 0.9 1.0 1.1 1.2 CRASH-2 Trial Collaborators Lancet 2010;376:23-32
34 CRASH-2 Thrombotic Outcomes & Transfusions
Tranx Placebo RR p MI 35 (0.3%) 55 (0.5%) 0.64 (0.42-0.97) 0.035 Stroke 57 (0.6%) 66 (0.7%) 0.86 (0.61-1.23) 0.42 PE 72(0.7%) 71 (0.7%) 1.01(0.73-1.41) 0.93 DVT 40 (0.4%) 41 (0.4%) 0.98 (0.63-1.51) 0.91 Transfusion 5,067 (50.4%) 5,160 (51.3%) 0.98 (0.96-1.01) 0.21
CRASH-2 Trial Collaborators Lancet 2010;376:23-32
Evaluation of a Young Woman with Menorrhagia
• You are treating an otherwise healthy 35 y.o. woman for Fe- deficiency anemia secondary to menorrhagia that she has experienced since menarche. She has never had any other signs of excessive bleeding. What are the chances that a bleeding disorder could be causing her menorrhagia? • a) None: she would had had other signs than just the menorrhagia • b) <5% • c)10-15% • d) 20-25%
35 Menorrhagia & von Willebrand Disease
Background & Premises • 5% adult women seek medical care for menorrhagia (insurance claim data) • Menorrhagia = >80 ml blood loss/menses • Menorrhagia Ex not found in 50% • “Menorrhagia is a common Sx of von Willebrand disease.” (17%-37% of English and Swedish women studied for menorrhagia) Dilley A, Drews C, Miller C, et al. “von Willebrand Disease and Other Inherited Bleeding Disorders in Women with Diagnosed Menorrhagia.” Obstet Gynecol 2001;97:630-6
Menorrhagia & von Willebrand Disease
• STUDY: Case-control study (n=244) menorrhagia pts, mean age = 35, from Atlanta HMO • Hx: “No subject reported a previous personal Dx of a bleeding disorder”
Dilley A, Drews C, Miller C, et al. “von Willebrand Disease and Other Inherited Bleeding Disorders in Women with Diagnosed Menorrhagia.” Obstet Gynecol 2001;97:630-6
36 Menorrhagia & von Willebrand Disease
RESULTS • “The overall prevalence of inherited bleeding disorders identified by our laboratory is approximately 11%...for menorrhagia patients….almost entirely due to von Willebrand disease”
Dilley A, Drews C, Miller C, et al. “von Willebrand Disease and Other Inherited Bleeding Disorders in Women with Diagnosed Menorrhagia.” Obstet Gynecol 2001;97:630-6
Menorrhagia & von Willebrand Disease
DISCUSSION “The failure to Dx an underlying inherited bleeding disorder…can have important, and dire, implications…. Many women with unexplained menorrhagia undergo surgery to correct the problem. However, menorrhagia associated with von Willebrand disease can be Rx effectively with desmopressin….””
Dilley A, Drews C, Miller C, et al. “von Willebrand Disease and Other Inherited Bleeding Disorders in Women with Diagnosed Menorrhagia.” Obstet Gynecol 2001;97:630-6
37 Menorrhagia: Tranexamic Acid Rx vs Placebo
Lysteda PI (most recent update 10/2013)
38 Tranexamic Acid (Lysteda): Menorrhagia • Indications: “…an antifibrinolytic indicated for the Rx of cyclic heavy menstrual bleeding” • Dosage (650 mg/tab) : ♦ 1,300 mg t.i.d. for up to 5 days during menstruation ♦Reduce dose for CKD
Lysteda PI (most recent update 10/2013
Enzyme Deficiency Leading to Emphysema?
• Which of the following enzyme deficiencies can lead to chronic lung disease (e.g, emphysema)? • a) biotinidase • b) alpha-1-antitrypsin • c) chymase • d) lactase
39 Glassia (Alpha1-Proteinase Inhibitor [Human] Prescribing Information Updated 3/2014
Glassia PI 2014
INDICATIONS AND USAGE
“Glassia is indicated for chronic augmentation and maintenance therapy in adults with clinically evident emphysema due to severe congenital deficiency of…alpha1-antitrypsin….”
40 Alpha-1-antitrypsin Replacement Costs
• How much does Alpha1-antitrypsin Rx cost? a) $500/month b) $1,000/month c) $2,000/month d) $8,000/month
$8000/month Seems Like a Lot of $$: Does it WORK? “Your are an emphysemologist specializing in alpha- 1-antitrypsin deficiency Rx. The head of accounting at Rock/Paper/Scissors Insurance Company, noticing lots of $$ spent on A1AT replacement asks you “How well does it work?” Your evidence-based response about outcomes should be a) About 10% of patients go into remission b) About 25% of patients go into remission c) >50% of patients go into remission d) Long-term effects on emphysema are not known
41 Glassia PI 2014
INDICATIONS AND USAGE “Clinical data demonstrating the long-term effects of chronic augmentation and maintenance therapy of individuals with Glassia are not available.”
Glassia PI 2014
INDICATIONS AND USAGE “The effect of augmentation therapy with any Alpha1-PI, including Glassia, on pulmonary exacerbations and on the progression of emphysema in alpha1-antitrypsin deficiency has not been conclusively demonstrated in randomized controlled clinical trials.”
42 $8000/month Seems Like a Lot of $$. Does it WORK?
“A recent Cochrane review… concluded that there was no convincing data to support the efficacy of augmentation therapy.”
Stockley RA, Miravitles M, Vogelmeier C Orphanet Journal of Rare Diseases 2013;8:149
NICE 2015 UK Patient Information Leaflet
“The National Institute for Health and Clinical Excellence (NICE) in the UK does not recommend treatment by replacing A1AT at present due to the lack of evidence for its benefit. However, this decision has been criticised by some people. The medicine is available and is used in some other countries.”
http://www.patient.co.uk/health/alpha-1-antitrypsin- deficiency accessed March 17, 2015
43 The Triglyceride Story: Pancreatitis Risk Reduction Because you are such a fine clinician, Jason sends his co- worker Mason, to see you. Mason is a 38 y.o. construction worker, low-normal BMI (19.6), with a Hx of alcoholic pancreatitis and ‘really high TRG’ (600 mg/dL). He has ‘cut way back on alcohol’. Mason asks you to refill his fenofibrate 90 mg/d Rx (on-Rx TRG = 160 mg/dL). He is asymptomatic. You should a) Refill the Rx as-is: success is success b) Refill the Rx but inform him that there is uncertainty about pancreatitis risk reduction c) Refill the Rx but ↑ to 135 mg/d to maximize TRG reduction d) Decline the refill until has entirely eliminated alcohol
The Incomplete Story of Triglycerides & Pancreatitis: Part A • You and I learned: ♦ ↑TG associated with pancreatitis ♦ if TG > 500 mg/dL, must be lowered to prevent pancreatitis ♦ Fibrates, fish oil, diet, nicotinic acid useful in this regard
44 Preiss D et al, JAMA 2012;308(8):804-811
Evidence for TRG Rx?
“HyperTRG has been reported to be the third most common cause of pancreatitis. This has led to major guidelines…advice to commence TRG-lowering Rx, usually fibrates, in persons with moderate and severe hyperTRG (above 400-500 mg/dL).”
Preiss D et al, JAMA 2012;308(8):804-811
45 Evidence for TRG Rx?
“However, high quality evidence for this approach is lacking….”
Preiss D et al, JAMA 2012;308(8):804-811
Evidence for TRG Rx?
“…no convincing trial data exist to support use of any agents for prevention of pancreatitis….”
Preiss D et al, JAMA 2012;308(8):804-811
46 The Triglyceride Story: UpToDate 2014
Preventing Pancreatitis: No High Quality Evidence “Although high quality evidence is lacking, for 10 prevention of pancreatitis, we and others suggest initiating pharmacologic Rx to ↓TRG when fasting concentration is >1000 mg/dL”
Rosenson RS “Approach to the patient with hypertiglyceridemia” UpToDate accessed 9/2414
Fenofibrate: Does it Work? Quotes FROM THE PRESCRIBING INFORMATION
• INDICATION: to ↓TG in patients with SEVERE HYPERTRIGLYCERIDEMIA ♦ “Markedly elevated levels of serum TG…may ↑ the risk of developing pancreatitis. The effect of Trilipix therapy on reducing this risk has not been adequately studied.”
Triplix® Prescribing Information 2010
47 The Incomplete Story of TG & Pancreatitis
• INDICATION: to ↓TG in SEVERE HyperTG ♦ “Markedly elevated levels of serum TG, e.g. > 2,000 mg/dL may ↑ the risk of developing pancreatitis. The effect of Trilipix therapy on reducing this risk has not been adequately studied.”
Triplix® Prescribing Information 2010
The Incomplete Story of TG & Pancreatitis
“Pancreatitis has been reported in patients taking drugs of the fibrate class, including Trilipix. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct.”
Triplix® Prescribing Information 2010 Section 5.6
48 Where Does This Leave Us Me? Triglycerides and Pancreatitis • Triglycerides ARE associated with pancreatitis ♦ Maybe causal, maybe not • IF causal, it remains to be determined whether modulation improves CV outcomes • We know every medication has toxicity. A risk:benefit ratio, when benefits are indeterminate, cannot be measured
And What About Mason? Obesity, EtOH, no CVD Hx
• Alcoholic pancreatitis: probably standard of care to continue Rx, but inform of potential toxicity and no definitive evidence. • More work should be done on his alcohol • No need to ↓ TRG further: same dose OK
49