Challenging the expanded use of Statins

[Guest guest]

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)Promoting Openness, Full Disclosure, and Accountabilityhttp://www.ahrp.org FYIA Commentary in the Lancet by John Abramson, MD, of Harvard Medical School,author of Overdosed America, and James Wright, MD, University of BritishColumbia, challenges the validity of the U.S. clinical practice guidelinesrecommending the expanded use of statins by healthy people.The authors argue that recommendations for the expanded use of statins tostave off cardiovascular disease are NOT supported by the evidence. It should be noted that: "For adults aged between 30 and 80 years old whoalready have occlusive vascular disease, statins confer a total andcardiovascular mortality benefit t and are not controversial." But the revised U.S. guidelines (2001) increased the target population tobe treated with statins from 13 million to 36 million Americans.That increase offers huge economic implications for the manufacturers ofstatins.The guidelines, the authors say, "are based on the assumption thatcardiovascular risk is a continuum and that evidence of benefit in peoplewithocclusive vascular disease (secondary prevention) can be extrapolated toprimary prevention populations. This assumption, plus the assumption thatcardiovascular risk can be accurately predicted, leads to the recommendationthat a substantial proportion of the healthy population should be placed onstatin therapy."The controversy involves this question: which people without evidentocclusive vascular disease (true primary prevention) should be offeredstatins? The authors note that in formulating recommendations for primaryprevention, the authors of the guidelines did not rely on the data thatalready exist from the primary prevention trials. Indeed, the authors notethat the guidelines cite seven and nine randomised trials, in support ofstatin therapy for the primary prevention of this disease in women andpeople aged over 65 years. Yet NOT ONE of the studies provides suchevidence.Furthermore, they note: "the absolute risk reduction of 1.5% is small andmeans that 67 people have to be treated for 5 years to prevent one suchevent. Further analysis revealed that the benefit might be limited tohigh-risk men aged 30-69 years. Statins did not reduce total coronary heart disease events in 10,990 womenin these primary prevention trials. Similarly, in 3,239 men and women older than 69 years, statins did notreduce total cardiovascular events (relative"Our analysis suggests that lipid-lowering statins should not be prescribedfor true primary prevention in women of any age or for men older than 69years. High-risk men aged 30-69 years should be advised that about 50patients need to be treated for 5 years to prevent one event."Contact: Vera Hassner Sharav212-595-8974veracare www.thelancet.com THE LANCETVol 369 January 20, 2007 169CommentAre lipid-lowering guidelines evidence-based?The last major revision of the US guidelines, in 2001,1 increased the numberof Americans for whom statins are recommended from 13 million to 36 million,most of whom do not yet have but are estimated to be at moderately elevatedrisk of developing coronary heart disease.2 In support of statin therapy forthe primary prevention of this disease in women and people aged over 65years, the guidelines cite seven and nine randomised trials, respectively.Yet not one of the studies provides such evidence.For adults aged between 30 and 80 years old who already have occlusivevascular disease, statins confer a total and cardiovascular mortality benefit and are not controversial. The controversy involves this question: whichpeople without evident occlusive vascular disease (true primary prevention)should be off ered statins? With about threequarters of those taking statinsin this category,3 the answer has huge economic and health implications. Informulating recommendations for primary prevention, why do authors ofguidelines not rely on the data that already exist from the primaryprevention trials?We have pooled the data from all eight randomised trials that comparedstatins with placebo in primary prevention populations at increased risk.4Unfortunately, our analysis is imperfect because these trials are not solelyprimary prevention: 8.5% of patients had occlusive vascular disease atbaseline.5 We used two outcomes to estimate overall benefi t (benefi t minusharm): total mortality and total serious adverse events (SAEs). Totalmortality was not reduced by statins (relative risk 0.95, 95% CI 0.89-1.01).In the two trials that reported total SAEs, such events were not reduced bystatins (1.01, 0.97-1.05) (data on SAEs from the other trials were notreported). The frequency of cardiovascular events, a less encompassing outcome, wasreduced by statins (relative risk 0.82, 0.77-0.87). However, the absoluterisk reduction of 1.5% is small and means that 67 people have to be treatedfor 5 years to prevent one such event. Further analysis revealed that thebenefi t might be limited to high-risk men aged 30-69 years. Statins did notreduce total coronary heart disease events in 10 990 women in theseprimary prevention trials (relative risk 0.98, 0.85-1.12).6 Similarly, in3239 men and women older than 69 years, statins did not reduce totalcardiovascular events (relative risk 0.94, 0.77-1.15).7Our analysis suggests that lipid-lowering statins should not be prescribedfor true primary prevention in women of any age or for men older than 69years. High-risk men aged 30-69 years should be advised that about 50patients need to be treated for 5 years to prevent one event. In ourexperience, many men presented with this evidence do not choose to take astatin, especially when informed of the potential benefi ts of lifestylemodifi cation on cardiovascular risk and overall health.8 This approach, based on the best available evidence in the appropriatepopulation, would lead to statins being used by a much smaller proportion ofthe overall population than recommended by any of the guidelines.9Why the disagreement? The current guidelines are based on the assumption that cardiovascular riskis a continuum and that evidence of benefi t in people with occlusivevascular disease (secondary prevention) can be extrapolated to primaryprevention populations. This assumption, plus the assumption thatcardiovascular risk can be accurately predicted, leads to the recommendationthat a substantial proportion of the healthy population should be placed onstatin therapy.A similar set of assumptions underlie the conclusions of the CholesterolTreatment Trialists' (CTT) collaboration, a group that undertakes periodicmeta-analyses of individual participants' data on morbidity and mortalityfrom all relevant large-scale randomised trials of lipidmodifyingtreatment.5 The CTT Collaborators included seven trials of statins forsecondary prevention and seven trials of statins for mostly primaryprevention. However, instead of analysing these two groups of studies separately, theycombine all the studies and report the overall eff ect. Because they haveindividual participants' data, the CTT Collaborators have the uniqueopportunity to analyse the data for the 41 354 people in the true primaryprevention group that they have identifi ed as included in these studies.5However, they do not report on this pure primary prevention population. Instead they calculate and report the absolute benefit of statins in 47 925patients with no coronary heart disease at baseline; however, this groupincludes about 6570 patients with pre-existing cerebrovascular or peripheralvascular disease. Combination of these second ary prevention patients(5-year frequency of major vascular events 25-30%) with the true primaryprevention group (5-year incidence of major vascular events 9%) infl atesthe estimate of absolute benefi t from 1.5% (our estimate) to 2.5%.The CTT collaborators have primary prevention outcome data that can resolvethe issues we raise. Subpopulations of particular interest include: men,women, men aged 70 years or older, women below the age of 70 years, peoplewith diabetes mellitus, 20% of people with the lowest bodyweight, peopletaking more than fi ve drugs, and tertiles of cardiovascular risk atbaseline. The following are the outcomes that would be most informative:total mortality, total SAEs, total incidence of cancer, and totalcardiovascular events. This analysis would answer the key outstandingquestions.First, do the data on primary prevention confi rm that there is no overallbenefi t in adult women of any age and in men aged 70 years and older? And,second, is there signifi cant heterogeneity between the statin treatmenteffect in primary prevention subgroups compared with that in secondaryprevention subgroups? If the answer to both these questions is yes, theassumption that the benefi ts for secondary prevention populations can beextrapolated to primary prevention populations is false and the cholesteroltreatment guidelines based on this assumption should be revised.J Abramson, *J M Wright Harvard Medical School, Cambridge, Massachusetts,USA (JA); and Department of Anesthesiology, Pharmacology & Therapeutics andMedicine, University of British Columbia, Vancouver, BC, Canada V6T 1Z3(JMW) jmwrightJMW declares no confl ict of interest. JA is an expert consultant toplaintiffs' attorneys on litigation involving the drug industry, includingPfi zer for itsmarketing of atorvastatin.1 Third report of the National Cholesterol Education Program (NCEP) expertpanel on detection, evaluation, and treatment of high blood pressure inadults (adult treatment panel III) fi nal report: table II.2-3. September,2002: http://www.nhlbi.nih.gov/guidelines/cholesterol (accessed Jan 2,2007).2 Third report of the National Cholesterol Education Program (NCEP) expertpanel on detection, evaluation, and treatment of high blood cholesterol inadults. Adult treatment panel III, fi nal report. September, 2002.http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf (accessed Jan2, 2007).3 Savoie I, Kazanjian A. Utilization of lipid-lowering drugs in men andwomen: a refl ection of the research evidence? J Clin Epidemiol, 2002; 55:95-101.4 Jauca C, Wright JM. Therapeutics letter: update on statin therapy. Int SocDrug Bull Newsletter 2003; 17: 7-9.5 Cholesterol Treatment Trialists' (CTT) Collaborators. Effi cacy and safetyof cholesterol-lowering treatment: prospective meta-analysis of data from90 056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78.6 Walsh JME, Pigame M. Drug treatment of hyperlipidemia in women. JAMA 2004;291: 2243-52.7 Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individualsat risk of vascular disease (PROSPER): a randomised controlled trial. Lancet2002;360: 1623-30.8 Chiuve SE, McCullough ML, Sacks FM, Rimm EB. Healthy lifestyle factors inthe primary prevention of coronary heart disease among men: benefi tsamong users and nonusers of lipid lowering and antihypertensive medications.Circulation 2006; 114: 160-67.9 Manuel DG, Kwong K, Tanuseputro P, et al. Eff ectiveness and effi ciencyof diff erent guidelines on statin treatment for preventing deaths fromcoronary heart disease: modelling study. BMJ 2006; 332: 1419-22.FAIR USE NOTICE: This may contain copyrighted (C ) material the use of whichhas not always been specifically authorized by the copyright owner. Suchmaterial is made available for educational purposes, to advanceunderstanding of human rights, democracy, scientific, moral, ethical, andsocial justice issues, etc. It is believed that this constitutes a 'fairuse' of any such copyrighted material as provided for in Title 17 U.S.C.section 107 of the US Copyright Law. This material is distributed withoutprofit.