A Commentary in the Lancet by John Abramson, MD, of Harvard Medical School,
author of Overdosed America, and James Wright, MD, University of British
Columbia, challenges the validity of the U.S. clinical practice guidelines
recommending the expanded use of statins by healthy people.

It should be noted that: “For adults aged between 30 and 80 years old who
already have occlusive vascular disease, statins confer a total and
cardiovascular mortality benefit t and are not controversial.”

But the revised U.S. guidelines (2001)  increased the target population to
be treated with statins from 13 million to 36 million Americans.
That increase offers huge economic implications for the manufacturers of
statins.

The guidelines, the authors say, “are based on the assumption that
cardiovascular risk is a continuum and that evidence of benefit in people
with occlusive vascular disease (secondary prevention) can be extrapolated to
primary prevention populations. This assumption, plus the assumption that
cardiovascular risk can be accurately predicted, leads to the recommendation
that a substantial proportion of the healthy population should be placed on
statin therapy.”

The controversy involves this question: which people without evident
occlusive vascular disease (true primary prevention) should be offered
statins? The authors note that in formulating recommendations for primary
prevention, the authors of the guidelines did not rely on the data that
already exist from the primary prevention trials. Indeed, the authors note
that the guidelines cite seven and nine randomised trials, in support of
statin therapy for the primary prevention of this disease in women and
people aged over 65 years. Yet NOT ONE of the studies provides such
evidence.

Furthermore, they note: “the absolute risk reduction of 1.5% is small and
means that 67 people have to be treated for 5 years to prevent one such
event. Further analysis revealed that the benefit might be limited to
high-risk men aged 30-69 years.
Statins did not reduce total coronary heart disease events in 10,990 women
in these primary prevention trials.
Similarly, in 3,239 men and women older than 69 years, statins did not
reduce total cardiovascular events (relative

“Our analysis suggests that lipid-lowering statins should not be prescribed
for true primary prevention in women of any age or for men older than 69
years. High-risk men aged 30-69 years should be advised that about 50
patients need to be treated for 5 years to prevent one event.”

Contact: Vera Hassner Sharav
veracare@ahrp.org
www.thelancet.com
THE LANCET
Vol 369 January 20, 2007 169
Comment
Are lipid-lowering guidelines evidence-based?

The last major revision of the US guidelines, in 2001,1 increased the number
of 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 elevated
risk of developing coronary heart disease.2 In support of statin therapy for
the primary prevention of this disease in women and people aged over 65
years, 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 occlusive
vascular disease, statins confer a total and cardiovascular mortality benefi
t and are not controversial. The controversy involves this question: which
people without evident occlusive vascular disease (true primary prevention)
should be off ered statins? With about threequarters of those taking statins
in this category,3 the answer has huge economic and health implications. In
formulating recommendations for primary prevention, why do authors of
guidelines not rely on the data that already exist from the primary
prevention trials?

We have pooled the data from all eight randomised trials that compared
statins with placebo in primary prevention populations at increased risk.4
Unfortunately, our analysis is imperfect because these trials are not solely
primary prevention: 8.5% of patients had occlusive vascular disease at
baseline.5 We used two outcomes to estimate overall benefi t (benefi t minus
harm): total mortality and total serious adverse events (SAEs). Total
mortality 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 by
statins (1.01, 0.97-1.05) (data on SAEs from the other trials were not
reported).

The frequency of cardiovascular events, a less encompassing outcome, was
reduced by statins (relative risk 0.82, 0.77-0.87). However, the absolute
risk reduction of 1.5% is small and means that 67 people have to be treated
for 5 years to prevent one such event. Further analysis revealed that the
benefi t might be limited to high-risk men aged 30-69 years. Statins did not
reduce total coronary heart disease events in 10 990 women in these
primary prevention trials (relative risk 0.98, 0.85-1.12).6 Similarly, in
3239 men and women older than 69 years, statins did not reduce total
cardiovascular events (relative risk 0.94, 0.77-1.15).7

Our analysis suggests that lipid-lowering statins should not be prescribed
for true primary prevention in women of any age or for men older than 69
years. High-risk men aged 30-69 years should be advised that about 50
patients need to be treated for 5 years to prevent one event. In our
experience, many men presented with this evidence do not choose to take a
statin, especially when informed of the potential benefi ts of lifestyle
modifi cation on cardiovascular risk and overall health.8

This approach, based on the best available evidence in the appropriate
population, would lead to statins being used by a much smaller proportion of
the overall population than recommended by any of the guidelines.9

Why the disagreement?
The current guidelines are based on the assumption that cardiovascular risk
is a continuum and that evidence of benefi t in people with occlusive
vascular disease (secondary prevention) can be extrapolated to primary
prevention populations. This assumption, plus the assumption that
cardiovascular risk can be accurately predicted, leads to the recommendation
that a substantial proportion of the healthy population should be placed on
statin therapy.

A similar set of assumptions underlie the conclusions of the Cholesterol
Treatment Trialists’ (CTT) collaboration, a group that undertakes periodic
meta-analyses of individual participants’ data on morbidity and mortality
from all relevant large-scale randomised trials of lipidmodifying
treatment.5 The CTT Collaborators included seven trials of statins for
secondary prevention and seven trials of statins for mostly primary
prevention.

However, instead of analysing these two groups of studies separately, they
combine all the studies and report the overall eff ect. Because they have
individual participants’ data, the CTT Collaborators have the unique
opportunity to analyse the data for the 41 354 people in the true primary
prevention group that they have identifi ed as included in these studies.5
However, they do not report on this pure primary prevention population.
Instead they calculate and report the absolute benefit of statins in 47 925
patients with no coronary heart disease at baseline; however, this group
includes about 6570 patients with pre-existing cerebrovascular or peripheral
vascular disease. Combination of these second ary prevention patients
(5-year frequency of major vascular events 25-30%) with the true primary
prevention group (5-year incidence of major vascular events 9%) infl ates
the estimate of absolute benefi t from 1.5% (our estimate) to 2.5%.

The CTT collaborators have primary prevention outcome data that can resolve
the issues we raise. Subpopulations of particular interest include: men,
women, men aged 70 years or older, women below the age of 70 years, people
with diabetes mellitus, 20% of people with the lowest bodyweight, people
taking more than fi ve drugs, and tertiles of cardiovascular risk at
baseline. The following are the outcomes that would be most informative:
total mortality, total SAEs, total incidence of cancer, and total
cardiovascular events. This analysis would answer the key outstanding
questions.

First, do the data on primary prevention confi rm that there is no overall
benefi 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 treatment
effect in primary prevention subgroups compared with that in secondary
prevention subgroups? If the answer to both these questions is yes, the
assumption that the benefi ts for secondary prevention populations can be
extrapolated to primary prevention populations is false and the cholesterol
treatment 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 and
Medicine, University of British Columbia, Vancouver, BC, Canada V6T 1Z3
(JMW) jmwright@interchange.ubc.ca

JMW declares no confl ict of interest. JA is an expert consultant to
plaintiffs’ attorneys on litigation involving the drug industry, including
Pfi zer for its
marketing of atorvastatin.

1 Third report of the National Cholesterol Education Program (NCEP) expert
panel on detection, evaluation, and treatment of high blood pressure in
adults (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) expert
panel on detection, evaluation, and treatment of high blood cholesterol in
adults. Adult treatment panel III, fi nal report. September, 2002.
http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf (accessed Jan
2, 2007).
3 Savoie I, Kazanjian A. Utilization of lipid-lowering drugs in men and
women: 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 Soc
Drug Bull Newsletter 2003; 17: 7-9.
5 Cholesterol Treatment Trialists’ (CTT) Collaborators. Effi cacy and safety
of cholesterol-lowering treatment: prospective meta-analysis of data from
90 056 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 individuals
at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet
2002;360: 1623-30.
8 Chiuve SE, McCullough ML, Sacks FM, Rimm EB. Healthy lifestyle factors in
the primary prevention of coronary heart disease among men: benefi ts
among 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 ciency
of diff erent guidelines on statin treatment for preventing deaths from
coronary heart disease: modelling study. BMJ 2006; 332: 1419-22.

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