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Simvastatin has long-term survival benefit: heart disease & cancer examined
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NEW YORK (Reuters Health) - The survival advantage for patients treated with simvastatin persists for at least 10 years, according to the results of the longest follow-up study to date of patients taking a statin drug. The study detected no excess cancer risk.
Most statin trials have lasted only 5 to 6 years, Dr. Timo E. Strandberg, at the University of Helsinki, Finland, and co-authors note in the August 28th issue of The Lancet. Concern was raised when some studies suggested an excess of cancer deaths among statin users, but others have linked statin use to reductions in cancer incidence and improved cancer survival (see Reuters Health reports, August 22, 2000 and June 2, 2003).
Dr. Strandberg's group extended post-trial follow-up of participants in the Scandinavian Simvastatin Survival Study. The double-blind phase had taken place between 1989 and 1994 and included patients with previous MI or angina pectoris and serum total cholesterol 5.5 to 8.0 mmol/L.
During the double-blind trial, active treatment reduced all-cause mortality by 30%, cardiovascular mortality by 36% and coronary mortality by 43%, the authors note. There were 1967 survivors in the placebo group and 2039 in the simvastatin group at the end of the first 5 years.
Most of the patients in both arms of the study received open-label lipid-lowering drugs during the 5-year extension.
"The absolute differences in all-cause, cardiovascular, and coronary mortality achieved during the double-blind trial changed little during the 5-year extension of the follow-up," they maintain.
Over the course of the entire trial, cancer was diagnosed in 12% of subjects in the placebo group and in 11% of those in the simvastatin group. Deaths from cancer occurred in 5.1% and 4.3%, respectively. Although the differences were not statistically significantly, "these findings are reassuring," Dr. Strandberg's group concludes.
Lancet 2004;364:771-777.
Mortality and incidence of cancer during 10-year follow-up of the Scandinavian Simvastatin Survival Study (4S)
Timo E Strandberg, Kalevi Pyörälä, Thomas J Cook, Lars Wilhelmsen, Ole Faergeman, Gudmundur Thorgeirsson, Terje R Pedersen, John Kjekshus, for the 4S Group*
Summary
Background: The effects of cholesterol-lowering treatment with statins on mortality and risk of cancer beyond the usual 5-6-year trial periods are unknown. We extended post-trial follow-up of participants in the Scandinavian Simvastatin Survival Study (4S) to investigate cause-specific mortality and incidence of cancer 5 years after closure of the trial.
Methods: 4S was a randomised double-blind trial of simvastatin or placebo in patients with coronary heart disease, serum total cholesterol 5·5-8·0 mmol/L, and serum triglycerides 2·5 mmol/L or lower. The double-blind period lasted for a median of 5·4 years (range for survivors 4·9-6·3) and ended in 1994. After the trial, most patients in both groups received open-label lipid-lowering treatment. National registers were used to assess mortality and causes of death and cancer incidence in the original treatment groups for a median total follow-up time of 10·4 years (range for survivors 9·9-11·3). Analysis was by intention to treat.
Findings: 414 patients originally allocated simvastatin and 468 assigned placebo died during the 10·4-year follow-up (relative risk 0·85 [95% CI 0·74-0·97], p=0·02), a difference largely attributable to lower coronary mortality in the simvastatin group (238 vs 300 deaths; 0·76 [0·64-0.90], p=0·0018). 85 cancer deaths arose in the simvastatin group versus 100 in the placebo group (0·81 [0·60-1·08], p=0·14), and 227 incident cancers were reported in the simvastin group versus 248 in the placebo group (0·88 [0·73-1·05], p=0·15). Incidence of any specific type of cancer did not rise in the simvastatin group.
Interpretation: Simvastatin treatment for 5 years in a placebo-controlled trial, followed by open-label statin therapy, was associated with survival benefit over 10 years of follow-up compared with open-label statin therapy for the past 5 years only. No difference was noted in mortality from and incidence of cancer between the original simvastatin group and placebo group.
Introduction
Publication of the Scandinavian Simvastatin Survival Study (4S) in The Lancet in 19941 was early trial evidence of the benefits of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) in the prevention of coronary events and in the reduction of all-cause mortality. The benefits of statin treatment both in primary and secondary prevention of coronary heart disease and other forms of atherosclerotic disease have since then become well established.
In general, the safety profile of statins has been good, but not all concerns have been silenced, particularly with respect to the possible increased risk of cancer associated with pronounced cholesterol lowering. This concern originated in the early 1990s from findings of prospective epidemiological studies showing some rise in non-cardiovascular mortality, particularly cancer deaths, in people with low cholesterol concentrations, and from results of early trials of cholesterol lowering.16 Furthermore, some researchers showed that lipid-lowering drugs, including statins, increase the occurrence of several types of cancer in rodents. Most statin trials, which generally last 5-6 years, have not shown any rise in cancer incidence in statin-treated participants, but in two studies some excess of cancer was reported. In the CARE trial, incidence of female breast cancer rose, and in the PROSPER trial in elderly people,9 incidence of all cancers increased in patients given pravastatin. However, meta-analyses of data from pravastatin and statin studies, and the large Heart Protection Study with simvastatin, did not show any significant excess of cancers. The average duration of randomised double-blind trials of statin treatment is, however, a fairly short period to study incidence of cancer. Therefore, longer follow-up of participants in statin trials has been called for.
After completion of 4S in 1994, we decided that follow-up of the randomised patients would be extended by 5 years after the end of the double-blind period. Our aim was to investigate cause-specific mortality and cancer incidence in the original simvastatin and placebo groups on the basis of data from national registers in the five participating countries. Here, we report our 10-year follow-up results.
AUTHOR DISCUSSION
The main finding of this 10-year follow-up study of the participants of 4S was that the survival benefit of patients allocated simvastatin compared with those allocated placebo that accrued during the double-blind trial period persisted during follow-up. The reduction in the relative risk between the two original treatment groups was not unexpected, because open-label treatment with lipid-lowering drugs (mostly statins) was given to most patients when the trial ended. After 3 years, more than 80% of patients in both groups were using these drugs. Nevertheless, the absolute differences in all-cause, cardiovascular, and coronary mortality achieved during the double-blind trial changed little during the 5-year extension of the follow-up. Another important finding of our study was that during the 10-year follow-up, mortality from and incidence of cancer were slightly, although non-significantly, reduced in the original simvastatin group relative to the original placebo group. Although this finding should be interpreted with caution, the 95% CIs (0·60-1·08 for cancer mortality, 0·73-1·05 for cancer incidence) nevertheless suggest that even if the effect were in the other direction, it would be clinically negligible.
The strength of our study is that we have been able to achieve complete follow-up of the original 4S patient groups with respect to cause-specific mortality and virtually complete follow-up with respect to incident cancer, because we could use, with approval of data protection authorities, the unique social security number of every individual to link study register data with national cause-of-death and cancer register data.
Among statin trials, our study, with its median follow-up period of 10·4 years, is so far the longest follow-up of patients originally randomised to receive statin or placebo. However, it has unavoidable weaknesses, which make interpretation of findings complex. First, during the double-blind period, the simvastatin-treated group became larger than the placebo-treated group, mainly because of a pronounced reduction of coronary deaths in the simvastatin-treated group. Second, after closure of the double-blind trial, the original placebo group received open-label lipid-lowering drug treatment.
The use of Cox proportional-hazards models as the main method of data analysis can be criticised, because the proportional-hazards assumption does not hold in strict sense over the entire 10-year follow-up. However, as we have shown, the results are essentially similar, if the original simvastatin and placebo groups comparisons are done by comparing Kaplan-Meier point estimates for mortality categories at the end of the double-blind trial and at the end of the entire follow-up. The advantage of Cox-model analyses is that the relative risks can be adjusted for the effect of important covariates.
During the double-blind period of the 4S, the survival curves for all-cause, cardiovascular, and coronary mortality in the simvastatin group and the placebo group began to diverge early and progressively until closure of the trial. Thereafter, during the 5-year extension of the follow-up, the survival curves took a more parallel course. For the reasons mentioned above, interpretation of the evolution of cause-specific mortality during the post-trial follow-up has to be made with caution. However, it is noteworthy that during the 5-year extension the number of cardiovascular deaths, and specifically the number of coronary deaths, was lower in the original placebo group, which could indicate an accruing benefit from lipid-lowering drug treatment in these patients whose cholesterol concentrations had remained in the high-risk range during the trial. On the other hand, in the original simvastatin group some coronary deaths could have been delayed into the follow-up period. These deaths could account for the almost similar coronary mortality in the placebo and simvastatin groups during the 5-year extension.
Competition between cardiovascular and non-cardiovascular causes of death could potentially take place during long-term follow-up of an ageing study population, such as the 4S participants, of whom about half were age 60 years or older at the time of randomisation. The original simvastatin group could be expected to be at an increased risk of non-cardiovascular death during the extended follow-up because their survival improved during the trial through the reduction of cardiovascular deaths. Yet, no increase in non-cardiovascular mortality was recorded in the original simvastatin group during the 5-year extension or the whole 10-year follow-up period. During the 10-year follow-up, mortality from cancer, forming the largest proportion of non-cardiovascular deaths, was actually lower in the original simvastatin group than in the original placebo group, although this difference was not significant.
In accordance with the cancer mortality data, our 10-year follow-up study also showed that the incidence of cancer was similar in the original simvastatin group and in the original placebo group. These findings are reassuring and in accordance with the negative findings on the risk of cancer in the Heart Protection Study7 and in the meta-analyses of statin trials The effects of statins beyond 10 years remain, so far, unknown. However, we should note in this context that studies of cancer cell biology and animal work have shown mechanisms by which statin drugs might have anticancer effects.
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