Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis
BMJ 2003; 326 doi: https://doi.org/10.1136/bmj.326.7404.1423 (Published 26 June 2003) Cite this as: BMJ 2003;326:1423All rapid responses
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Statins are a key element of vascular prevention. Some RCTs suggest
that they are effective in reducing coronary event rates and overall
mortality also in high–risk patients with average cholesterol levels,
regardless of sex. Prescription data show that this conclusion has already
been adopted in clinical practice, since statins are commonly (and evenly)
prescribed to people of both sexes: in our area (Province of Modena, in
Northern Italy, 630,000 inhabitants and 520 General Practitioners) 9,164
and 9,045 Defined Daily Doses (DDD) of the drugs have been prescribed in
2002 to female and male patients, respectively.
We believe, however, that statins’ efficacy in females is still to be
convincingly demonstrated. A previous meta-analysis (1999) on 5 studies
showed that statins are beneficial in both sexes (1) , but a cost-
effectiveness analysis (including 2 out of 5 studies considered in the
former meta-analysis) raised doubts on their use in females in primary
prevention (2). Newly published RCTs add further uncertainty on this
issue. In their meta-analysis, Law et al (3) included data from three
large RCTs (4-6)(of either primary or secondary prevention) showing lower
efficacy in females who may not even get a statistically significant
benefit (table).
Indeed low statistical power may hinder gender-related differences in
treatment effect and prevent trialists in highlighting these “by sex”
differences: the vascular event rate in females is lower than males and
trialists tend to prefer the inclusion of male subjects to increase power.
In absence of a convincing empirical demonstration, however, this is not a
good reason to conclude that statins work equally well in both sexes. Meta
-analyses might in fact help overcoming the “low power” issue. The meta-
analysis from Law et al3, including data from new RCTs, could help in this
regard. We invite trialists to provide results stratified by gender so
that readers can evaluate whether females benefit from statins and a
relevant public health benefit could be expected for this subgroup.
Waiting for this a generalisation of statins’ effects on female does not
seem warranted.
Table 1: Effects of statins ( overall and in gender |
|||||||
Study Acronym |
Total n. |
Males n. |
Females n. |
Male/ Female ratio |
Relative Risk (95% CI) |
||
All subjects |
Only males |
Only females |
|||||
ASCOT - LLA |
10305 |
8347 |
1958 |
4,26 |
0,64 (0,50-0,83) |
0,59 (0,44-0,77) |
1,10 (0,57-2,12) |
AFCAPS/ TexCAPS |
6605 |
5746 |
859 |
6,69 |
0,63 (0,50-0,79) |
0,64 (0,51-0,81) |
0,54(0,22-1,34) |
Patients enrolled with or without known vascular disease on entry |
|||||||
ALLHAT – LLT |
10355 |
5281 |
5074 |
1,05 |
0,91 (0,79-1,04) |
0,84 (0,71-1,00) |
1,02 (0,81-1,28) |
Patients enrolled with known vascular disease on entry |
|||||||
HPS |
20536 |
15402 |
5134 |
3,04 |
0,76 (0,72-0,81) |
0,78 (0,74-0,83) |
0,81 (0,72-0,92) |
PROSPER |
5804 |
2804 |
3000 |
0,93 |
0,85 (0,74-0,97) |
0,77 (0,65-0,92) |
0.96 (0,79-1,18) |
LIPID |
9014 |
7482 |
1532 |
4,88 |
0,78 (0,70-0,86) |
0,76 (0,68-0,85) |
0,87( 0,67-1,13) |
MIRACL |
3086 |
2006 |
1080 |
1,86 |
0,92 (0,75-1,13) |
NOT REPORTED |
NOT REPORTED |
4S |
4444 |
3617 |
827 |
4,38 |
0,70 (0,62-0,80) |
0,70 (0,62-0,78) |
0,67 (0,50-0,90) |
CARE |
4159 |
3577 |
582 |
6,14 |
0,77 (0,65-0,91) |
0,82 (0,72-0,92) |
0,60 (0,37-0,97) |
REFERENCES
(1) LaRosa JC, Jiang He, Vupputuri S. Effect of Statins on Risk of
Coronary Disease. A Meta-analysis of Randomized Controlled Trials JAMA
1999; 282: 2340-6
(2) Prosser LA, Stinnett AA, Goldman PA, et al. Cost-effectiveness of
cholesterol-lowering therapies according to selected patient
characteristics. Ann Intern Med. 2000; 132: 769-79
(3) Law MR, Wald NJ, Rudnicka AR Quantifying effect of statins on low
density lipoprotein cholesterol, ischaemic heart disease, and stroke:
systematic review and meta-analysis BMJ 2003; 326: 1423-1427
(4) Shepherd J, Blauw GJ, Murphy MB, et al. Prospective Study of
Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at
risk of vascular disease (PROSPER): a randomised controlled trial. Lancet.
2002; 360:1623-30
(5) ALLHAT Officers and Coordinators for the ALLHAT Collaborative
Research Group. The Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial. Major outcomes in moderately
hypercholesterolemic, hypertensive patients randomized to pravastatin vs
usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial (ALLHAT-LLT). JAMA. 2002; 288: 2998-3007
(6) Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and
stroke events with atorvastatin in hypertensive patients who have average
or lower-than-average cholesterol concentrations, in the Anglo-
Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a
multicentre randomised controlled trial Lancet. 2003; 361:1149-58
Competing interests:
None declared
Competing interests: No competing interests
The article of Law et al1 heaped up all evidence on the cholesterol
lowering properties of statin therapy for cardiovascular risk management.
Strangely, the reductions of hard disease events, as observed in major
trials and compiled in a meta-analysis,2 figure only in footnote.
Cohort studies studying correlations of cholesterol with mortality
are not randomised clinical trials (RCT) of statins. A cohort involves
people, whose cholesterol level is one of many risk factors predicting
heart disease, some known, some unknown, to which these people are exposed
for life. A RCT observes the unconfounded effects of statins, a drug with
manifold and uncertain activities, in randomised populations. The history
of female hormone replacement therapy in the prevention of vascular
disease must not be forgotten: a wealth of observational evidence of
benefit, but only experimental evidence of harm. Equating short term
effects of complex drugs with poorly understood effects such as statins
with lifelong correlations of LDL with CHD mortality shows a naive belief
in simplistic linear models 3 .
And why would we wish to calculate the health effects of a belief, if
we have hard data? In table 3, Law et al show convincingly, once more,
that the observed risk reduction in coronary heart disease is nearly
constant and somewhat over 30 percent for all time periods of three years
and more. Reductions in stroke incidence are supported by the same hard
evidence4 5. There is little evidence that event reduction by statin use
differ either by type of drug, duration taken (after 2 years of use) or
dose. Only in the 4S trial reductions over 40 percent have been observed
in myocardial infarction survivors with increased cholesterol and very
high risks. Evidence of benefits even higher than this do not exist. Why
would we want to exaggerate the great benefits of statins?
Indeed, if this issue of the BMJ is worth keeping, it is as an
historical example of the dangers of extrapolation. Extrapolate LDL
cholesterol into nothingness, and eradicate 99.9 percent of coronary heart
disease. Extrapolate one century of world records of the 100 metres
sprint into the far future, and in thousand years we will run 100 meters
in less than 1 second.
References
1. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low
density lipoprotein cholesterol, ischaemic heart disease, and stroke:
systematic review and meta-analysis. Bmj 2003;326(7404):1423.
2. LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary
disease: a meta-analysis of randomized controlled trials. Jama
1999;282(24):2340-6.
3. Libby P, Aikawa M. Mechanisms of plaque stabilization with statins. Am
J Cardiol 2003;91(4A):4B-8B.
4. Corvol JC, Bouzamondo A, Sirol M, Hulot JS, Sanchez P, Lechat P.
Differential effects of lipid-lowering therapies on stroke prevention: a
meta-analysis of randomized trials. Arch Intern Med 2003;163(6):669-76.
5. Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with
statin drugs, risk of stroke, and total mortality. An overview of
randomized trials. Jama 1997;278(4):313-21.
Competing interests:
None declared
Competing interests: No competing interests
The approach taken by Wald and Law assumes that the effects of the
various treatments proposed are additive, yet there is little evidence
presented that this is, in fact, the case. Without this assumption it is
not valid to multiply the relative risks of the various treatment
strategies in order to determine the overall effect of the combined
treatments. There may be interactions between the treatments, whereby one
treatment may negate the effect of one or more of the other treatments.
This could only be determined if comparative trials, with combined
treatment arms, had been performed. Hence, the authors have proposed an
interesting hypothesis that deserves to be tested, but they have not
provided convincing evidence that their proposed combination of treatments
should be adopted into clinical practice.
Competing interests:
None declared
Competing interests: No competing interests
The authors state that there is a paradox in that the use of statins
has been shown to reduce the incidence of stroke, but that studies show no
association with cholesterol concentration and stroke. May this not be due
to the fact that statins work not because they lower cholesterol, but
because they do something else, something we may not know about yet. I
speak as a sceptic about the cholesterol hypothesis, but one willing to
accept that statins work for whatever reason, and it seems to me that the
evidence increasingly points to the fact that the treatment is statins
even if we don't quite know the diagnosis or its cause.
Competing interests:
None declared
Competing interests: No competing interests
Cholesterol and Ischemic heart disease
A recent study by Ward et al published in the BMJ about the variation
in how the variation in Cholesterol levels overtime decreases the
estimation of the link between ischemic heart disease and Cholesterol. On
correcting for both the variation in Cholesterol and the variation in LDL
(which has a stronger link to heart disease) in a cohort of more than 5000
patients they established that the link to IHD is underestimated. They
also found that interventions to reduce LDL may be more useful in reducing
Cholesterol than previously thought. According to their data in middle
aged men lowering LDL by 0.6 mmol/l may reduce IHD risk by 25-30%.[1]
[1]BMJ 1994;308:363-366 Systematic underestimation of association
between serum cholesterol concentration and ischemic heart disease in
observational studies: data from the BUPA study
M R Law, N J Wald, T Wu, A Hackshaw, A Bailey
Competing interests:
None declared
Competing interests: No competing interests