Canibais e Reis

Há muito mais cartas destas, que nunca vêm a luz do dia (porque será?), aqui.

Letter to Archives of Internal Medicine, submitted on July 20, 2002

Exaggerated benefit of statin treatment in the elderly?   

by

Uffe Ravnskov, MD, PhD (corresponding author), Magle Stora Kyrkogata 9, S-22350 Lund, Sweden. Tel/fax +46 46145022 (call before faxing) , e-mail: ravnskov+tele2.se (exchange + with @)
Joel M. Kauffman; PhD, Professor of Chemistry Emeritus, University of the Sciences in Philadelphia
Peter H. Langsjoen, M.D., F.A.C.C., 1107 Doctors Drive, Tyler, Texas  
Kilmer S. McCully, M.D., Chief, Pathology & Laboratory Medicine Service, Boston Area Consolidated Laboratories, US Department of Veterans Affairs
Paul J. Rosch, Clinical Professor of Medicine and Psychiatry, New York Medical College; President, The American Institute of Stress

 In 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 trials^2-6 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 treatment.

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

 

Table 1. Risk reduction (total mortality) in six clinical statin trials

	Relative risk; %	Absolute risk; %	Chance of surviving without treatment; %	Chance of surviving with treatment; %
4S2	-29	-3.3	88.5	91.8
WOSCOPS3	-21	-0.9	95.9	96.9
CARE4	-8	-0.78	90.57	91.35
AFCAPS/TexCAPS5	+3.9	+0.09	97.7	97.6
LIPID6	-21	-3.0	85.9	89
EXCEL7	+150	+0.3	99.8	99.5

 

Literature

1. Grundy SM. Statin Therapy in Older Persons. Pertinent Issues. Arch Intern Med 2002;162:1329-1331.

2. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-1389.

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.

5. 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.

7. 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.

8. 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.

9. Ravnskov U. Statins as the new Aspirin. Conclusions from the heart protection study were premature. BMJ 2002;324:789.

10. 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.

11. 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

12. 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

13. Ravnskov U. Is atherosclerosis caused by high cholesterol? QJM 2002; 95: 397-403.

14. Gaist D, Jeppesen U, Andersen, M, Rodríguez LAG, Hallas J, Sindrup, SH. Statins and risk of polyneuropathy. A case-control study. Neurology 2002;58:1333–1337

15. Rosch PJ. Guidelines for diagnosis and treatment of high cholesterol. JAMA 2001;286:2401.

 

Editor’s response:

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 Medicine.

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

Sincerely

James E.Dalen, MD, MPH
Editor