Statin Safety Claims in Lancet Reignite Acrimony, Scientific Divide

Patrice Wendling

September 22, 2016

OXFORD, UK — A review of statin safety and efficacy data intended to help clinicians and patients make informed decisions is embroiled in controversy and reopened wounds among Britain's leading medical journals[1].

The first third of the review, led by Prof Rory Collins (University of Oxford, UK), is an academic look at the generic strengths and limitations of nonrandomized evidence, but the grist of the 25-page document lies in the later assertion that the benefits of statins have been underestimated and the risks exaggerated.

The investigators argue that claims of "so-called" statin intolerance in up to 20% of patients—which sparked a very public feud after being repeated in two papers published in the BMJ in 2013—are not supported by large-scale evidence from randomized trials.

"Statin therapy has generally been found to be no less well tolerated than placebo," Collins et al wrote online September 8, 2016 in the Lancet.

By their calculations, treatment of 10,000 patients for 5 years with an effective statin regimen such as atorvastatin 40 mg daily would typically cause "about five extra cases of myopathy (one of which might progress to rhabdomyolysis), 50 to 100 cases of diabetes, and five to 10 hemorrhagic strokes."

Collins told heartwire from Medscape that his group has spent the last year and a half working on the review in an effort to try to set the record straight regarding statin therapy. Further, the controversy about statin intolerance and myopathy rates emerged only in the past 2 or 3 years as manufacturers began marketing newer and "very expensive" cholesterol-lowering agents such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for patients classified as statin intolerant.

"It's certainly the case that there has been industry funding for reports on statin intolerance; for example, the European Atherosclerosis Society's report[2] has funding from the makers of PCSK9 inhibitors, and in fact the meetings of that group were coordinated by a commercial entity that is funded by the manufacturers," he said.

Collins pointed out that any adverse impact of statin side effects on major vascular events was already taken into account in their estimates of the absolute benefits of statins. These benefits generally depend on a person's absolute risk of atherosclerotic events and absolute reduction in LDL cholesterol, he said, but one could expect that 5 years of a statin regimen that lowers LDL cholesterol by 2 mmol/L would prevent major vascular events in about 1000 of 10,000 secondary-prevention patients and about 500 of 10,000 primary-prevention patients, with a bigger benefit to be expected with lifelong statin usage.

"In addition, whereas many of the adverse effects (such as myopathy) can be reversed with no residual effects by stopping the statin therapy, the effects of a heart attack or stroke are often irreversible," the investigators write.

Commenting on the review in the BMJ[3], Dr Harlan Krumholz (Yale University, New Haven, CT) said the "findings strongly support the benefits of statins in comparison with very modest risks." He added, however, that "there is little consideration of the limitations of the trial evidence," most notably a lack of good data on elderly patients, individual trials unpowered to detect many relevant harms, and variation in how adverse event data were collected.

Asked to comment, Dr Aseem Malhotra (Lister Hospital, Stevenage, UK), who has been a vocal critic of the review and author of one of the 2013 BMJ papers[4], told heartwire that the Clinical Trials Service Unit at Oxford has received hundreds of millions of pounds in funding from statin manufacturers and that Collins's group has not released raw data on the major statin randomized controlled trials for independent scrutiny.

"Using predominantly industry-sponsored trials designed for the purpose of determining the benefits of statins to assess side effects, which is what this review has done, simply adds false precision to biased estimates," he said.

He noted that Pfizer's own patient leaflet on atorvastatin states "common side effects [that] may affect up to one in 10 people" include sore throat, nausea, digestive problems, and muscle and joint pains.

A recent systematic review coauthored by Malhotra also reveals that in those over age 60, LDL-C is not associated with CVD and is inversely correlated with all-cause mortality[5].

"I have no doubt that statins have a benefit, but focusing on LDL lowering as if this was the end in itself is counterproductive, especially when insulin resistance is a more important risk factor for myocardial infarction," Malhotra said.

He added, "In my view the Lancet review is a total whitewash. The editor in chief of the BMJ Fiona Godlee has described this as 'the trialists marking their own homework,' and I completely agree."

Old Wounds Reopened

Godlee and Collins have been at odds ever since Collins called on the BMJ to correct and ultimately withdraw the two 2013 studies that repeated claims made in a paper by Abramson et al[6] that side effects of statins occur in 18% to 20% of people.

The statements were corrected in the two studies, but Godlee passed the decision on whether to retract on to an independent panel of experts appointed by the journal. That panel unanimously rejected Collins's request for retraction in June 2014, although it did make numerous suggestions for improving editorial processes at the journal.

In October 2014, Collins and several coauthors of the new Lancet statin review sent a letter of complaint about the BMJ's handling of the two papers to the UK's Committee on Publication Ethics (COPE). In April 2016, COPE ultimately determined that the BMJ "acted with due diligence and in line with the expectations under the COPE Code of Conduct."

In a comment accompanying the statin review[7], Lancet editor in chief Dr Richard Horton, however, calls into question "the independence of the panel's judgment," noting that its chair had previously written critically about the use of statins among older patients.

He wrote that "after 2 years of frustrating exchange, including a direct request that COPE conduct an independent investigation, COPE declined to act further, emphasizing that it is a charitable member organization, not a regulatory authority."

Horton observes that "more than 200,000 patients were estimated to have stopped taking a statin in the 6 months after adverse media coverage" following publication of the disputed research. He also drew parallels between "this statin scare" and the MMR vaccine scare that began with a now-retracted research paper and led to widespread vaccine hesitancy.

But it was Horton's comment about COPE's conduct that prompted Godlee to fire back in a September 14, 2016 rapid response letter[8] that "COPE did not decline to act. It deliberated on the concerns raised by Collins et al and the BMJ's response and came to a clear conclusion: that the BMJ had acted appropriately in this matter."

Godlee has also written to England's chief medical officer, Dr Sally Davies, asking for an inquiry into the statins saga and an independent review of the evidence on statins.

"Independent third-party scrutiny of the statins trial data remains an essential next step if this increasingly bitter and unproductive dispute is to be resolved," she wrote in her weekly column.

Godlee also took this opportunity to publish a treasure trove of documents and correspondence relating to the complaint that she said "will serve to correct the public record."

Collins reported work in the Clinical Trial Service Unit & Epidemiological Studies Unit at the University of Oxford, which has received grants from Abbott, AstraZeneca, Bayer, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, Schering, and Solvay; and being the coinventor of a genetic test for statin-related myopathy risk. Disclosures for the coauthors are listed in the article. Malhotra reported no relevant financial relationships.

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