There is no evidence that using cholesterol-lowering statins can reduce the risk of death in people at high risk of cardiovascular disease (CVD) but without any prior history of CVD, a meta-analysis by UK and Dutch researchers has concluded.

Current prevention guidelines recommend statin therapy to ward off fatal and non-fatal vascular events in individuals at high global risk of incident CVD, note the authors of the meta-analysis published in the latest issue of Archives of Internal Medicine. “Due consideration is needed in applying statin therapy in lower-risk primary prevention populations,” they warn.

Advocates of primary prevention strategies with statins come in for more flak in a critical re-appraisal of the pivotal JUPITER (Justification for the Use of Statins in Primary Prevention) trial, published in the same issue of the Archives.

In the JUPITER study, AstraZeneca’s Crestor (rosuvastatin) was found to reduce the risk of cardiovascular death and heart attacks by 44% versus placebo, as well as cutting all-cause mortality by 20%, in patients with elevated high-sensitivity levels of C-reactive protein but low-to-normal cholesterol levels.

However, an international team led by Dr Michel de Lorgeril, from the Université Joseph Fournier and the Centre National de la Recherche Scientifique in La Troche, France, argues that the trial methodology was flawed and its outcomes both clinically inconsistent and subject to commercial bias.

The long-term implications of these two articles, suggests an accompanying editorial by Dr Leo Green of the University of Michigan Medical School in Ann Arbor, US, is that physicians remain in the dark about the real benefits or otherwise of pharmacological lipid-lowering for coronary primary prevention.

“We need good research to find out and, as de Lorgeril and colleagues point out, that research must be free of incentives to find any particular desired answer,” Dr Green writes.

The meta-analysis led by Dr Kausik Ray from the University of Cambridge and the Department of Cardiology at Addenbrooke’s Hospital, Cambridge looked at data from 11 studies involving 65,229 participants, of whom 32,623 were assigned to statins and 32,606 to placebo.

As the researchers note, previous systematic reviews of statin trials for primary prevention in high-risk populations have “either principally attempted to evaluate heterogeneity of effect estimates between statins, and thus have not reported combined effect estimates across statin trials, or have included populations with prevalent CVD and/or have included trials with incomplete randomisation”.

No significant reduction

Over an average of 3.7 years’ follow-up, Ray et al found, 2,793 of the trial participants died, including 1,447 allocated to placebo and 1,346 on statins. This did not constitute a statistically significant reduction in the risk of mortality associated with statin use, they said. The risk ratio for all-cause mortality with statin use was 0.91 (95% confidence interval, 0.83-1.01)

Low-density lipoprotein levels were higher among the trial participants on placebo than in those taking statins (134 mg/dL versus 94mg/dL), but there was no significant association between the risk of death and either mean LDL levels at baseline or the average reduction in LDL levels, Ray et al determined.

JUPITER re-appraised

The re-appraisal of the JUPITER trial by de Lorgeril et al concludes that the results do not support the use of statins for primary prevention of cardiovascular disease. On the contrary, the authors contend, the outcomes are clinically inconsistent and “support concerns that commercially sponsored clinical trials are at risk of poor quality and bias”.

Among their objections are that the JUPITER study was terminated after two years of follow-up, “with no differences between the two groups on the most objective criteria”. The data also showed a “major discrepancy” between significant reduction of non-fatal stroke and myocardial infarction (MI) with Crestor on the one hand, and no effect on mortality from stroke and MI on the other.

Moreover, cardiovascular mortality was “surprisingly low” compared with total mortality – between 5-18%, whereas “the expected rate would have been close to 40%”, the authors say. Moreover, the case-fatality rate for myocardial infarction was “very low … far from the expected number of close to 50%”.

Documentation of the “failure of the JUPITER trial to demonstrate a protective effect of rosuvastatin is all the more important as it occurred in the context of the failure of more than 12 other cholesterol-lowering trials published in recent years and in various clinical settings”, de Lorgeril et al contend.

None of these trials provided significant evidence of protection against CHD [coronary heart disease] complications, and especially fatal complications, through cholesterol-lowering, they add. Two other cholesterol-lowering studies were either not published or were “abruptly halted” due to lack of effect.

“These failures strongly suggest that the presumed preventive effects of cholesterol-lowering drugs have been considerably exaggerated,” conclude de Lorgeril et al, who suggest that the emphasis on pharmaceutical intervention to keep CHD at bay “diverts individual and public health attention away from the proven efficacy of adopting a healthy lifestyle, including regular physical activity, not smoking, and a Mediterranean-style diet”.