Dyslipidemia: Lots of Good Evidence, Less Good Interpretation. G Michael Allan Evidence & CPD Program, ACFP Associate Professor, Dept of Family, U of A.
CFPC CoI Templates: Slide 1 Faculty/Presenter Disclosure Faculty: G Michael Allan (Mike) Relationships with commercial interests: Grants/Research Support: None Speakers Bureau/Honoraria: None Consulting Fees: None Other: None
CFPC CoI Templates: Slide 2 Disclosure of Commercial Support This program has received financial support from Ontario College of Family Physicians in the form of honorarium and flight. This program has received in-kind support from Alberta College of Family Physicians and the U of A in the form of My team grant and my salary, respectively. Potential for conflict(s) of interest: Mike has received nothing from anyone with a commercial interest. a product that will be discussed in this program: Not relevant.
CFPC CoI Templates: Slide 3 Mitigating Potential Bias I will try not to talk (too much) about the merits of primary care.
Case: Mr Chole needs some help Mr Chole is 50 years old. He is thick around the middle, has elevated sugar (but not Diabetes), is on 2 drugs for hypertension, and thinks beer is staving off heart disease. Non-smoker & no family history. Total cholesterol: 6.2 mmol/l HDL: 0.75mmol/L LDL: 4.5 mmol/l Triglycerides: 5 mmol/l What is his 10-year risk of any CVD It is about a 22% 10-year risk of CVD What drug would you consider & what are the benefits of treatment?
Statins: Primary Prevention Hard to get Clean data, lots of heterogeneity, Meta-analysis of DM 1 : 37% of Diabetics, History of CVD Meta-analysis of Primary Prevention 2 : Includes diabetics Meta-analysis of all 3 Complete mix of patients Done per mmol/l reduction 1. Lancet 2008; 371: 117 25. 2. BMJ 2009;338:b2376. doi:10.1136/bmj.b2376 3. Lancet 2005; 366: 1267 78
Statin: Primary Prevention 10 RCT (70 K pts) 1 ; mean 4.1 yrs, low-mid dose, CVD 5.3% vs 3.8%, NNT 66 Others find (for 5 yrs) CVD NNT = 40 primary prevention But NNT will change based on base-line risk Relative risk reduction is stable: 25% 1. BMJ 2009;338:b2376. ACP J Club 2009; 151(4): 14. 2. Lancet 2005; 366: 1267 78. 3) Cochrane Database Syst Rev. 2013 Jan 31;1:CD004816.
1. Am J Med. 2008;121:24-33. ACP J Club 2008; 149(1): 7. Lancet Neurol 2009; 8: 453 63 2. Cochrane Database Syst Rev. 2013 Jan 31;1:CD004816. CMAJ. 2011 Nov 8;183(16):E1189- Stroke (& MI) Individually Stroke: Mixed population (Primary & Secondary) Meta-analysis (121 K pts) 1 : 3.0% vs 3.6%, NNT 174 Relative reductions of stroke and MI are 2 27% - 36% for MI 19% - 22% for stroke.
A closer look at the statins don t reduce mortality (in primary prevention)?
Primary Prevention & Statin Bottom-line: In primary prevention, statins reduce Mortality about 0.5% over 5 years (or about 10% relative). They reduce CVD by 25%. In our case, Mr Chole would have his risk go from 22% to 16.5%, A reduction of 5.5% or NNT of 19 over 10 years.
1. N Engl J Med 2008;358:1431-43. 2. N Engl J Med 2009;361:2113-22. 3. N Engl J Med 2008;359:1343-56. 4. Lancet. 2011;377(9784):2181-92. 5. N Engl J Med 2008;359:1357-66. Ezetimibe Statin + Ezetimibe vs Statin + placebo RCT 1, 720 pts, fam. hyperchol, 46y.o, 50% : Nothing RCT 2, 363 pts (208 analyzed for part), CAD (77%) or equiv. CVD events: 5% Ezetimibe vs 1% Niacin. NNT 24 Statin +Ezetimibe vs placebo SEAS trial 3 : 1873pts, asymptomatic aortic stenosis x4.5 yrs, Nothing SHARP 4 : 9438 renal impaired pts, 5 years, 11.3% vs 13.4% combined CVD events. (no diff in mortality) Cancer: 3 largest studies combined, Concern of more cancer deaths (0.2%/year extra) 5
Ezetimibe Bottom-line: It should not be used until we have some better data to support it Most Important: IMPROVE-IT (Primary trial - 2005) Does ezetimibe add anything to CAD patients on statin? 2011: No benefit, Extend 1 year 2012: No benefit, Extend 2 years.
Fibrates 8 systematic reviews evaluate fibrates. 1-8 Heterogeneity common but trial results similar Meta-analysis 1 of 18 trials (45,058 pts) x1-6 years RRR 10% (0-18%) in CVD Primarily due to a 20% RRR in non-fatal coronary events No effect on all-cause or vascular mortality, or stroke When added to a statin (5518 diabetics x 4.7 yrs) No difference in any outcome 1) Lancet. 2010;375:1875-84. 2) Am J Med. 2009;122:962.e1-962.e8. 3) Am Heart J. 2007;154:943-53. 4) Curr Opin Lipidol. 2006;17(4):431-9. 5) Am J Ther. 2010;17(6):e182-8 6) Int J Cardiol. 2010;141(2):157-66. 7) J Am Coll Cardiol 2005;45:185 97. 8) Arch Intern Med. 2005;165:725-730. 9) N Engl J Med. 2010 Apr 29;362(17):1563-74
Fibrates Reduce pancreatitis (by reducing triglycerides). The best evidence 13 suggests the opposite: Statins reduce pancreatitis (NNT 1200 at 5 years) Fibrates increase pancreatitis (NNH 935 at 5 years) Bottom-line: Seems to improve non-fatal MI in mixed group with higher risk, no help with mortality and some concerns linger. JAMA. 2012;308:804-11.
Niacin: Vitamins, Always healthy RCT 3414 pts CVD hx, x3 yr, Niacin added statin Outcomes: Stopped early as no benefit Strokes approaching borderline stat sign worse Flushing 3.3% vs 1.4% Otherwise, research is old (late 1960 s): Coronary Drug Project (15 years), 3908 x 4 arms 27% relative reduction CVD outcomes 2 (esp non-fatal MI) Bottom-Line: Probably no place at this time. Boden WE et al. N Engl J Med. doi:10.1056/nejmoa11075791 EurJ Clin Pharmacol (1991) 40 [Suppl 1]: S49-S51. 2. J Am Coll Cardiol 2005;45:185 97. 3. N Engl J Med 2009;361:2113-22
Omega 3 or n-3 Fatty Acids Meta-analysis 1 : 14 RCTs, 20 485 pts, No benefit on overall CV events RR 0.99 (CI 0.89-1.09) No benefit all cause mortality, MI, stroke, etc RCT 12,536 diabetics (60% with CVD): no effect RCT 12,513 CVD (non-mi): No effect Only cohort data & weakest RCTs support benefit 3 Bottom-Line: No effect. 1) Arch Intern Med. 2012 Apr 9. 2) Lancet 1971;1(7710):1143-1145. 3) BMJ 2006; 332: 752-760.
Diet No data for any but the Mediterranean Diet. Primary Prevention Med Diet (PREDIMED) 7447 pts, 57% women, age 55-80 yrs, 4.8 yrs. Fresh fruit 3 + /d, vegies 2 + /d, legumes 3 + /wk, fish-seafood 3 + /wk, white meat vs red (red & processed <1/d) All CV events: 29% relative reduction, 4% vs 5.6%, NNT 77 Countries Risk CVD Mortality Lancet 1994 France Secondary (MI within 6 months) 0.27 (0.12-0.59) 0.30 (0.11-0.82) Lancet 2002 Northern India Mixed ( 1 risks (BP, Chol, DM), or angina or MI)* 0.50 (0.34-0.73) 0.63 (not sign, p=0.064) BMJ 2008;337:a1344 Lancet 1994; 343: 1454-59. Lancet 2002; 360: 1455-61. Estruch NEJM 2013
Torcetrapib: The Lipid King Cholesteryl ester transfer protein (CETP) Inhibitor HDL up 72% (34 mg/dl), LDL down 25% (22mg/dL) Unfortunately 1 : CVD events sign 25%, AR = 1.2%, NNH 84 Mortality sign 58%, AR = 0.45%, NNH 222 Withdrawn Dalcetrabip also developed stopped Anacetrapib still in development 2 Good Lesson about Surrogates and Targets 1. N Engl J Med 2007;357:2109-22. 2. Canon CP et al, N Engl J Med 2010.
Secondary Prevention
Is bigger better: High Dose Statin At least 6 meta-analyses 1-6 Most recent: 10 trials, 41,778 patients with cardiovascular disease (CVD). Mean trial duration 2.5 years. High dose usually Atorvastatin 80mg. Low-moderate dose varies: pravastatin 40 mg to lovastatin 5mg. Outcomes No difference Death, CVD death, or fatal MI. High dose Heart disease: 9.4% vs 10.5%, NNT 91 over 2.5 yrs Others add some clarity but little difference. High dose, Reduced mortality: NNT 91 over 2 years in ACS patients 1,3 Increased adverse events leading to stopping therapy: NNH 47
Is Bigger Better? Statin (low-moderate: 40mg Pravastatin or 20-40mg Simvastatin) vs placebo CHD: 7 Reduced CHD: NNT 27 Reduced Mortality: NNT 56 Benefits of low-moderate dose vs placebo are much more than high dose vs low-moderate dose (relative benefits 25% 7 vs 10% 1 ). Adherence to statin therapy in the community is poor: Up to 50% stop taking statins by 3 years adverse events play a role in these discontinuations. 8-10 Muscle-related side effects and transaminase abnormalities increase 4-5 fold going from atorvastatin 40 mg to 80 mg. 11,12 1) European Heart Journal (2011) 32, 1409 1415. 2) Lancet 2010;376:1670 1681. 3) CMAJ
Is Bigger Better? Bottom-line: In patients with coronary artery disease, using high dose statins (compared to low-moderate dose) prevents one CHD event for every 91 patients, but results in one in 47 patients discontinuing therapy due to adverse events. However, low-moderate dose statin (compared to placebo) provides 2-3 times greater benefit that increasing to high dose. Therefore, getting and keeping patients on any statin is key, with dose adjusted up to tolerable levels. 1) European Heart Journal (2011) 32, 1409 1415. 2) Lancet 2010;376:1670 1681. 3) CMAJ 2008;178: 576-84. 4) Clin Ther 2007;29:253 260. 5) Heart 2007;93:914 921. 6) J Am Coll Cardiol 2006;48:438 445. 7) Arch Intern Med. 2004 ;164(13):1427-36. 8) Expert Opin. Pharmacother. 2009;10(18):2973-2985. 9) J Epidemiol Community Health 2010;64:109e113. 10) Stroke. 2007;38:2652-2657. 11) Expert Opin Drug Saf 2010; 9(4): 667-74. 12) Am J Cardiol 2002; 90 Suppl:50K-60K
What Experts Say Low Risk: Recommend pharmacotherapy for LDL 5.0 mmol/l, or if genetic dyslipidemia (Strong Rec, Moderate- Evidence). Target 50% reduction of LDL (Strong Rec, Mod- Evid). Intermediate Risk (Framingham risk score 10-20%): Treat for LDL 3.5 mmol/l (Strong Rec, Mod- Evid). Target LDL 2.0 mmol/l or 50% reduction of LDL-C (Strong Rec, Mod Evid). High Risk (Framingham 20%) Target LDL 2.0 mmol/l or 50% reduction of LDL-C (Strong Recommendation, High- Evid). Plus Other testing optional (apo, etc) Canadian Journal of Cardiology 29 (2013) 151 167
Reviewing the Target trials Trials that target lipid levels (please fill in when we get a single study) Trials that triage & treat based on other markers (please fill in when we get a single study) Jupiter enrolled moderate risk pts with higher CRP but did not treat or randomize by this selection The Actual evidence is low quality
Struggling for Clarity