Statins Improve Long-term Survival Without Increased Cancer Risk

Laurie Barclay, MD

August 27, 2004

Aug. 27, 2004 — Statins are associated with a persistent survival benefit and no increase in the risk of cancer, according to the results of a 10-year follow-up on the Scandinavian Simvastatin Survival Study (4S) trial published in the Aug. 28 issue of The Lancet.

"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," lead author Timo E. Strandberg, from the University of Helsinki in Finland, says in a news release. "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."

In 1994, the 4S trial provided evidence of the benefits of statins in the prevention of coronary events and in the reduction of all-cause mortality, and this has been supported by other studies. The safety profile of statins has been good overall, but there has been concern about the possible increased risk of cancer associated with pronounced cholesterol-lowering.

In the 4S trial, patients with coronary heart disease (serum total cholesterol level of 5.5 - 8.0 mmol/L and serum triglyceride level of 2.5 mmol/L or lower) were randomized to receive simvastatin or placebo for a double-blind median duration of 5.4 years, (range for survivors, 4.9 - 6.3 years), ending in 1994. After the trial, most patients in both groups received open-label, lipid-lowering therapy.

"After three years, more than 80% of patients in both groups were using these drugs," Dr. Strandberg says. "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."

Using national registers, the investigators determined 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 years). Analysis was by intention to treat.

During follow-up, 414 patients originally in the simvastatin group and 468 patients in the placebo group died (relative risk [RR], 0.85; 95% confidence interval [CI], 0.74 - 0.97; P = .02). Lower coronary mortality in the simvastatin group primarily accounted for improved survival (238 vs. 300 deaths; RR, 0.76; 95% CI, 0.64 - 0.90; P = .0018).

The number of deaths from cancer was 85 in the simvastatin group and 100 in the placebo group (RR, 0.81; 95% CI, 0.60 - 1.08; P = .14), and incident cancers occurred in 227 patients in the simvastin group and in 248 patients in the placebo group (RR, 0.88; 95% CI, 0.73 - 1.05; P = .15). There was no increased incidence for any specific type of cancer in the simvastatin group compared with the placebo group.

The authors acknowledge several study limitations. During the double-blind phase, the simvastatin-treated group became larger than the placebo-treated group because there were fewer coronary deaths in the simvastatin-treated group. After the double-blind trial, the original placebo group received open-label, lipid-lowering drug therapy. Finally, using a Cox proportional-hazards models has its own inherent weaknesses.

"Simvastatin treatment for five 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 five years only," the authors write. "No difference was noted in mortality from and incidence of cancer between the original simvastatin group and placebo group."

Merck Research Laboratories, the maker of simvastatin (Zocor), supported the 4S trial and employs one of its authors. Several authors report potential conflicts of interest with Merck, Pfizer, AstraZeneca, Schering-Plough, Novartis, and/or Bristol-Myers Squibb.

Lancet. 2004;364:771-777

Reviewed by Gary D. Vogin, MD

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