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Statins
No benefit in primary prevention trials?
From Dr S. Mann, MB BS, FFPM, and Mr J. Cottrell, MSc
In responding to Hemant Patel’s letter (PJ, 22 May, p638), Peter
Burrill promotes himself as the voice of reason (PJ, 29 May, p670), but
his assertions require some comment.
Crucially he questions the benefit of statins in primary prevention of
coronary heart disease, citing the views of a Canadian university bulletin,
Therapeutics Letter, as support. The four main placebo-controlled primary
prevention statin trials,1–4 involving a total of 32,519 subjects,
all found substantial and significant reductions in rates of CHD events
compared with placebo. Published meta-analyses, for example in a recent
BMJ,5 also support primary prevention, as do guidelines issued by the Joint
British Societies,6 Scottish Intercollegiate Guideline Network,7 the British
Hypertension Society,8 the Third Joint Task Force of the European Societies,9 and as does the National Service Framework for CHD.10 Interestingly, so
does a Canadian national guideline.11 Despite this consensus the Canadian
bulletin contrived to conclude that “statins have not been shown
to provide an overall health benefit in primary prevention trials”,
by creating its own non-significant endpoints combining CHD events with
all-cause mortality and stroke. These latter endpoints are predictably
elusive in primary prevention studies because of low event rates in lower
risk populations. Prescribing bulletins may have a role in limiting use
of health care resources but it may be wiser to rely on peer-reviewed publications
and expert guidelines for scientific evaluation of evidence. There are,
after all, plenty from which to choose.
Mr Burrill refers to another bulletin in support of a 40mg dose. However
this bulletin was written in the context of prescribing advice under current
UK NSF guidelines — currently aimed at secondary prevention, and
for primary prevention in people with a 30 per cent 10-year CHD risk. These
are clearly high-risk individuals and few would dispute that such individuals
merit aggressive cholesterol reduction as the primary means of driving
down their risk.
The dose-response of simvastatin is non-linear: 10mg reduces LDL-C by 27
per cent, but doubling the dose only results in a 32 per cent reduction
with 20mg and 37 per cent with 40mg. In other words 10mg delivers 73 per
cent of the LDL-C reduction compared with that of the 40mg dose, at one-quarter
of the dose.5 In the context of an OTC switch for a long-term treatment,
this trade-off seems reasonable in the context of reducing the potential
for the rare but dose-related adverse event of myositis.
Mr Burrill states he has “found no evidence to suggest that simvastatin
10mg daily reduces vascular events”. In fact the various guidelines
support the principle of cholesterol reduction for primary prevention without
specifying particular statins or doses — the degree of reduction
is the focus. The reclassification proposal for simvastatin 10mg is based
firstly on the abundant evidence base for the effect of the dose on LDL-C,
and secondly on the overall evidence base for LDL-C reduction and reduction
in coronary risk. Why is it reasonable to do this? The observed reduction
of CHD risk related to LDL-C reduction with statins is remarkably consistent
across populations and between equivalent doses of different statins – the “cholesterol
hypothesis” has long been proven. Extrapolation on the basis of the
extensive and consistent database for statins can be undertaken with considerable
confidence. Conversely it is nonsense to suggest that we must re-prove
the cholesterol hypothesis every time we define a population suitable for
statin treatment in a new context.
It has been estimated from meta-analysis of all the available data that
a 1mmol/L reduction in LDL-C (simvastatin 10mg gives around a 1.3mmol/L
reduction) provides about a one-third reduction in risk of major CHD events
over three years.5 This cannot be said to be a “limited benefit”.
Mr Burrill claims “it is likely hundreds would be needed to be treated
to prevent one event”. For the two most relevant primary prevention
studies the number needed to treat (NNT) was 49 (or 87, depending on the
endpoint used) in a low risk (6 per cent) population,1 and 42 in an intermediate
risk (16 per cent) population.2 The range of risk proposed for self-medication
is 10 to 15 per cent. NNT may be useful for deciding how to allocate scarce
NHS resources, but is it relevant for an OTC medicine where the individual
makes the decision and bears the cost? Therapy decisions based on NNT favour
high-risk individuals and given resource limitations typically lead to
the setting of treatment thresholds. Many individuals will have accumulated
most of their CHD risk before they become eligible for treatment on the
basis of thresholds. An individual at moderate risk might legitimately
ask: “Why do I have to wait until I have reached a ‘threshold’ risk
before acting when I could prevent myself from even getting to that level?”
Mr Burrill concludes by asking “Would you spend £10 to £15
per month for several years if this was made clear to you?” In the
context of a rising prevalence of CHD and risk factors for CHD, and with
UK mortality amongst the highest of Western countries, the answer should
be a resounding “yes” for most people.
Stephen Mann
Jeremy Cottrell
Research and Development
Johnson & Johnson MSD Consumer Pharmaceuticals
References
1. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et
al. Primary prevention of acute coronary events with lovastatin in men
and women with average cholesterol levels. Journal of the American Medical
Association 1998;279:1615–22.
2. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW,
et al. Prevention of coronary heart disease with pravastatin in men with
hypercholesterolemia.
New England Journal of Medicine 1995;333:1301–7.
3. Sever P, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, 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 trial. Lancet 2003;361:1149–58.
4. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, et
al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER):
a randomised controlled trial. Lancet 2002;360:1623–30.
5. Law M, Wald N, Rudnicka A. Quantifying effect of statins on low density
lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic
review and meta-analysis. BMJ 2003;326:1423–9.
6. Wood D, Durrington P, McInnes G, Poulter N, Rees A, Wray R. Joint British
recommendations on prevention of coronary heart disease in clinical practice.Heart
1998;80(suppl
2):S1–29.
7. Scottish Intercollegiate Guidelines
Network. Lipids and the Primary
Prevention of Coronary Heart Disease: A National Clinical Guideline. SIGN
Publication No. 40, September 1999.
8. Williams B, Poulter NR, Brown MJ, Davis M, McInnes GT, Potter JF, et
al. Guidelines for management of hypertension: report of the fourth working
party of the British Hypertension Society, 2004-BHS IV. Journal of Human
Hypertension 2004;18:139–85.
9. Third Joint Task Force of European and other Societies on Cardiovascular
Disease Prevention in Clinical Practice. European guidelines on cardiovascular
disease prevention in clinical practice. European Heart Journal 2003;24:1601–10.
10. Department of Health. National
Service Framework for Coronary Heart
Disease. London: The Department; March 2000.
11. Fodor JG, Frohlich JJ, Genest JJG, McPherson PR. Recommendations for
the management and treatment of dyslipidemia. Canadian Medical Association Journal 2000;162:1441–7. |
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