Exaggerated benefit of statin treatment in the elderly?
PhD (corresponding author), Magle Stora Kyrkogata 9, S-22350 Lund, Sweden.
Tel/fax +46 46145022 (call before faxing) , e-mail: ravnskov+tele2.se (exchange
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his editorial about cholesterol lowering in the elderly Scott Grundy pleads
for aggressive statin treatment with the argument that statins reduce the
risk for major coronary events by at least one third.1 However,
this end-point includes non-fatal myocardial infarction and instable angina,
conditions that may heal with little discomfort or residual damage. Since
what most patients care about is whether treatment will prolong life, a more
appropriate end-point would be total mortality, which also has the advantage
of being free of bias. Furthermore, to report treatment results in terms of
relative risk reduction is misleading because it exaggerates the benefit for
the individual patient. A more honest way to inform the patient is to
calculate his/her chance of surviving with and without treatment. These
odds, as well as the relative and the absolute reduction or increase of
total mortality in the five trials2-6 that were used by Grundy as
evidence and in the statin trial, EXCEL,7 that he ignored are
shown in the following table.
As can be seen, the optimistic figures for relative risk reduction
actually reflect unimpressive absolute risk reductions. These small benefits
are also illustrated by the trivial differences between the survival rates
with and without treatment. In two of the three trials that included healthy
people only,5,7 the chance of surviving was even better without
According to Grundy the results from the Heart Protection Study (HPS)8
demonstrated that older persons achieved the same relative benefit from
LDL-lowering therapy as did other subgroups. Unfortunately the data given by
the HPS directors do not allow a calculation of the chance of surviving for
the individual age groups, but as the results from HPS were only half as
good as the results from the previous simvastatin trial,9 the
increased chance of surviving for old people must have been even lower than
given in the table.
That senior citizens with coronary heart disease, non-coronary
atherosclerotic disease and diabetes deserve intensive LDL-lowering therapy,
as suggested by Grundy, is questionable since recent studies have shown that
a low, not a high cholesterol, is more predictive of coronary heart disease
in the elderly.10,11 How is it possible to prevent CHD by
cholesterol lowering if a low cholesterol predicts future CHD? The answer is
that the cardioprotective benefits associated with statin therapy are
obviously not the result of lipid-lowering but rather other advantageous
effects, some of which Grundy referred to.
That cholesterol lowering has any effect by itself is also
contradicted by the observation of a general lack of exposure-response in
the statin trials. Exposure-response has often been claimed because the
outcome of a trial was associated with the initial or pre-trial cholesterol
level. However, true exposure-response demands that the outcome is
associated with the degree of total or LDL-cholesterol lowering, whether
outcome is expressed by clinical events or by degree of atherosclerosis
growth, and such associations are rarely found. Thus, the p values for the
relationships between the outcome, and the percentage or the absolute change
in LDL cholesterol, as calculated in one of the trial reports, were 0.76 and
0.97, respectively;12 and with one exception. none of 18
cholesterol lowering angiographic trials found exposure-response for LDL,
total cholesterol or any other lipid fraction.13
One may question whether statin treatment should be used at all
because the small absolute risk reduction rewards may be outweighed by
potential serious long-term side effects. One statin drug has already been
withdrawn because of a large number of fatal cases of rhabdomyolysis and
another serious side effect is peripheral neuropathy. In a recent case
control study the relative risk of idiopathic polyneuropathy for patients
treated with statins for two years or longer was 26.4 (7.8 to 45.4), and the
risk was strongly associated with duration of treatment and cumulative dose.14
It was calculated that one new case of neuropathy could be expected for each
2200 patient years among those aged 50 years or older, a figure that by time
easily may exceed the small number of lives saved in the statin trials, in
particular in those that included healthy individuals.
Should properly informed patients still request statins, then the
lowest effective dose should be prescribed rather than trying to reduce LDL
to an arbitrary level as the end point.15
Risk reduction (total mortality) in six clinical statin trials
SM. Statin Therapy in Older Persons. Pertinent Issues. Arch Intern Med 2002;162:1329-1331.
Randomised trial of cholesterol lowering in 4444 patients with coronary
heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet
3. Shepherd J, Cobbe SM, Ford I, et al. for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;333:1301-1307.
4. Sacks FM, Pfeffer MA, Moye LA, et al. for the Cholesterol and Recurrent Events Trial investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001-1009.
Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute
coronary events with lovastatin in men and women with average cholesterol
levels: results of AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis
Prevention Study. JAMA 1998;279:1615-1622.
6. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:489-497.
Bradford RH, Shear CL, Chremos AN, et al. Expanded Clinical
Evaluation of Lovastatin (EXCEL) study results. I. Efficacy in modifying
plasma lipoproteins and adverse event profile in 8245 patients with moderate
hypercholesterolemia. Arch Intern Med 1991;151:43-49.
Heart Protection Study Collaborative Group. MRC/BHF heart protection study
of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a
randomised placebo-controlled trial. Lancet 2002;360:7-22.
Ravnskov U. Statins as the new Aspirin. Conclusions from the heart
protection study were premature. BMJ
Krumholz HM, Seeman TE, Merrill SS, et al. Lack
of association between cholesterol and coronary heart disease mortality and
morbidity and all-cause mortality in persons older than 70 years. JAMA 1994;272:1335-1340.
Schatz IJ, Masaki K, Yano K, Chen R, Rodriguez BL, Curb JD. Cholesterol and
all-cause-mortality in elderly people from the Honolulu Heart Program: a
cohort study. Lancet 2001; 358: 351-55
Sacks FM, Moyé LA, Davis BR, et al. Relationship
between plasma LDL concentrations during treatment with pravastatin and
recurrent coronary events in the cholesterol and recurrent events trial. Circulation 1998;97:1446-1452
Ravnskov U. Is atherosclerosis caused by high cholesterol? QJM
2002; 95: 397-403.
Gaist D, Jeppesen U, Andersen, M, Rodríguez LAG, Hallas J, Sindrup, SH.
Statins and risk of polyneuropathy. A case-control study. Neurology
Rosch PJ. Guidelines for
diagnosis and treatment of high cholesterol. JAMA 2001;286:2401.
Sept. 25, 2002
Dear Dr. Ravnskov
Thank you for your recent letter to the editor. Unfortunately, because of
the many submissions we receive and our space limitations in the letter
section, we are unable to publish your letter in the Archives of Internal
After considering the opionion of our editorial staff, we
determined your letter did not receive a high enough priority rating for
publication in THE ARCHIVES. We are able to publish only a small fraction of
the many letters submitted to us each year, which means that published
letters must have an extremely high rating. We appreciate your interest and
thank you for the opportunity to review your letter
James E.Dalen, MD, MPH