Statin Trialists Seek To Bury Debate With Evidence

–A Lancet review claims overwhelming evidence in favor of statins for both primary and secondary prevention. Some disagree.

A large group of statin researchers argue forcefully that the debate over statins should be ended because the evidence in favor of statins is overwhelming and incontrovertible. But some outsiders say the issue is more nuanced and that there is still room for debate and discussion.

In a 30-page paper published in the Lancet containing more than 300 references Rory Collins (University of Oxford) and a large group of statin trial leaders present a massive review of the evidence from clinical trials and observational studies involving statins. The paper seeks to demonstrate that misinterpretation of studies, and over-reliance on observational studies, have led both the medical community and the public to underappreciate the enormous benefits of statins and to overestimate adverse effects.

The Lancet defense of statins was prompted by an earlier controversy surrounding papers critical of statins published in the BMJ. Collins demanded that the papers be retracted but his demand was turned down by an advisory panel. The BMJ subsequently published another study showing that media coverage of the earlier papers appeared to have harmed public health by leading people to stop taking statins.

The new paper seeks to end the debate over the benefits and harms of statins. In addition, the authors and, in an accompanying comment, Lancet editor Richard Horton, call for medical editors and the media to sharply curtail and manage “with exquisite care” dissemination of research that might influence people against statins.

Evidence From Randomized Controlled Trials

Collins et al say that the evidence from randomized controlled trials (RCTs) shows that lowering LDL cholesterol by by 2 mmol/L (equivalent to 77 mg/dl) with a statin for 5 years in 10,000 patients will prevent 1,000 cardiovascular events in people with vascular disease and 500 CV events in people at high risk for CV disease who have not yet had an event. The evidence for harms with statins yields 5 cases of myopathy, 5-10 hemorrhagic stroke, 50-100 new cases of diabetes, and, at most, 50-100 symptomatic adverse events such as muscle pain. Given the enormous number of patients already included in randomized clinical trials future research is “unlikely to materially alter the balance of benefits and harms for patients.”

“Our review shows that the numbers of people who avoid heart attacks and strokes by taking statin therapy are very much larger than the numbers who have side-effects with it. In addition, whereas most of the side-effects can be reversed with no residual effects by stopping the statin, the effects of a heart attack or stroke not being prevented are irreversible and can be devastating. Consequently there is a serious cost to public health from making misleading claims about high side-effect rates that inappropriately dissuade people from taking statin therapy despite the proven benefits,” said Collins in a press release.

But The Debate Is Not Over

The Lancet paper does not contain any substantially new information or data. “The big picture of the benefits of statins are very well-described here and have mostly been long known,” said Jeremy Sussman (University of Michigan). “Statins remain among the most important advances in medical history and have prevented untold heart attacks and strokes. They reduce rates of heart attacks and strokes in essentially all people though they prevent non-fatal events at greater rates than fatal ones.”

But, notes Sussman, “the description of the harms of statins is clear and data-driven, but more controversial. The article down-plays accusations of harm caused by statins. In doing so, they are sometimes somewhat unclear on when there is an absence of evidence and when there is evidence of absence. For example, how many studies explicitly looked for statin-related myalgias as opposed to more severe myopathies?”

Rita Redberg (UCSF and editor of JAMA Internal Medicine) pointed out that many of the studies used in the analysis had run-in periods, “which means that people who complained of side effects from statins were excluded from the trial. For example, 35% of the statin users were excluded during the open-label run-in in TNT. Thus, the actual adverse events rate are certainly higher than in the trials.”

Fiona Godlee (editor of the BMJ) pointed out that the data on statin benefits in the paper is dervived from an analysis based on individual patient data by the Cholesterol Treatment Trialists’ (CTT) Collaboration, which is led by Collins. The CTT has promised to perform a similar analysis of adverse effects in the statin trials but this has not been published or included in the Lancet paper so the evidence on statin harms is not as rigorous as the evidence for statin benefits.

More generally, Godlee and Redberg lamented the absence of independent verification of the statin data. Redberg said that “none of the CTT data has been made available to other researchers, despite multiple requests.” “No one has seen these data except the trialists.” Godlee agreed. “Ideally all clinical trial data should be available for third party scrutiny,” she said.

Godlee’s also noted that “this is not an independent review, this is a review by the trialists.” Redberg went further, saying that “the long declaration of interests is telling. The Oxford Clinical Trials Unit receives hundreds of millions of pounds of support from the pharmaceutical industry.”

Godlee said that the need for independent review is especially pressing in this case, given the public health implic  ations of the call for widespread use of statins for primary prevention. Redberg went even further and observed that “all of this data is from industry sponsored studies, with concern for bias.”

The Debate Over Primary Prevention

Redberg was particularly concerned about the wholesale endorsement of statins for primary prevention. “If you accept the data as presented, and their summary, than if 10,000 healthy people take a statin every day for 5 years, 9,500 of them will have absolutely no benefit and 500 will not get some event, such as CABG. None will live any longer, consistent with findings of previous meta-analyses (Ray K et al Arch IM 2010),” said Redberg. “However, a significant number, way upwards of the 200 or so in this review, will suffer from many uncomfortable side effects including fatigue, muscle pains, GI upset, memory loss, diabetes, and possibly ALS, and other problems. Adverse events are underreported in these trials, as they do not ask about the common ones and many use a definition of muscle problems which requires a CPK increase, yet many patients have muscle weakness without CPK bumps. It is estimated that closer to 20% of statin users have muscle problems (Fernandez G et al. Cl Clin Proc 2011). The higher estimate certainly reflects the many patients I see in my faculty practice every week who are or were miserable when put on statins.”

Redberg also pointed out some unintended consequences of statin usage. “data shows that people on statins are more likely to become obese and more sedentary over time than non statin users, likely because people mistakenly think they don’t need to eat a healthy diet and exercise as they can just take a pill to give them the same benefit (Sugiyama et al JAMA IM 2014). So it seems this review affirms that many healthy people who feel perfectly well can take a pill every day, not live any longer, suffer any number of adverse effects, all to treat the ‘disease’ of LDL. I maintain the best way to reduce cardiac risk is to eat a Mediterranean style diet, get regular physical activity, don’t smoke and enjoy yourself.”

Godlee also emphasized the limitations of primary prevention. “Evidence about poor adherence to statins has long been known,” said Godlee. “People don’t want to take a drug forever. The problem didn’t arise with the BMJ study.”

It also seems likely that the Lancet paper  exaggerates the benefits of primary prevention. The long term benefits of primary prevention in the paper are based on modeling. The calculated benefits may be   a best case scenario.

Is There Still Room For Debate?

In his accompanying comment Horton likens the impact of papers critical of statins to the impact of the famous Lancet paper by Andrew Wakefield that set off the panic over vaccines. He urges editors to subject papers critical of statins “to rigorous and extensive challenge”:

“Some research papers are more high risk to public health than others. Those papers deserve extra vigilance. They should be subjected to rigorous and extensive challenge during peer review. The risk of publication should be explicitly discussed and evaluated. If publication is agreed, it should be managed with exquisite care. Authors and editors should be aligned on the messages they wish to convey, and every effort must be made to avoid misinterpretations and misunderstandings in the media. Editors also have to separate their roles as gatekeepers and campaigners.”

But Godlee rejected the comparison of the BMJ papers to the Lancet Wakefield paper and objected to the idea that it’s too dangerous to publish papers critical of statins. “Where do you stop and where does that begin?” she wondered. She also pointed out that public concern over statins in the UK became elevated not after the publication of the BMJ papers but after Collins brought attention to the papers in a public denunciation of the papers on the BBC.

“We have to allow debate, I don’t know where you would draw the line,” she said. “In terms of public debate the statin debate is fascinating and deserves airing.”