Study fails to close divide on statins
AMAJOR new British study in the Lancet journal claims finally to put to rest the rancorous debate worldwide over the risk-versus-benefit profile of statins. The authors say the evidence is “overwhelming” that statins are safe and effective for primary and secondary prevention — to prevent a first heart attack or stroke in otherwise healthy people, or to prevent a second attack or stroke.
Statins are cholesterol-lowering drugs used to treat or prevent heart disease and stroke. They have become the world’s most prescribed drugs and generate billions in revenue for the drug companies that make them.
The Lancet review is led by Rory Collins of Oxford University’s clinical trial service unit. It has revived concerns about the serious side effects of statins that include muscle, nerve, liver and cardiovascular damage, endocrine disruption, erectile dysfunction and an increased risk of diabetes, cancer, cataracts and birth defects.
Top experts worldwide say the new review is dangerous and misleading because it overplays the benefits of statins for primary prevention and downplays significant evidence of harm.
Collins and his co-authors say doctors and patients have repeatedly underestimated its benefits and exaggerated the harm. They say there has been “misinterpretation of the evidence”, in particular a failure to “acknowledge properly the wealth of evidence from randomised controlled trials [the so-called goldstandard of scientific trials], and the limitations of other types of observational studies”.
Their review covers data over 30 years and has 300 references that include randomised controlled trials.
The authors explain how available evidence on the efficacy and safety of statin therapy should be interpreted.
Collins says the review shows 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”. Most side effects can be reversed with no residual effects by stopping the statin, he says.
The effects of a heart attack or stroke not being prevented are “irreversible and can be devastating”, he says.
“Consequently, there is a serious cost to public health from making misleading claims about high sideeffect rates that inappropriately dissuade people from taking statin therapy despite the proven benefits,” Collins says. THE
authors conclude that lowering cholesterol by 2mmol a litre with an effective low-cost statin therapy (such as atorvastatin 40mg daily, which costs about £2 per month in the UK) for five years in 10,000 patients would:
Prevent major cardiovascular “events” (heart attacks, ischaemic strokes, coronary artery bypasses) in 1,000 people with pre-existing vascular disease (secondary prevention), and in 500 people who are at increased risk (due to their age or having hypertension or diabetes) but who have not yet had a “vascular event” (primary prevention);
Cause five cases of myopathy (muscle weakness, one of which might progress to the more severe condition of rhabdomyolysis, if the statin is not stopped), five to 10 haemorrhagic strokes, 50-100 new
cases of diabetes and up to 50-100 cases of symptomatic adverse events (such as muscle pain).
They say although further research may identify small additional beneficial or adverse effects, this is unlikely “to materially alter the balance of benefits and harms for patients because of the evidence generated so far”.
Sunninghill cardiologist Jeff King says the Lancet review provides “an excellent, balanced appraisal of the current status therapy for primary and secondary cardiovascular protection”. It follows the latest European Cardiology Society’s 2016 revision of the lipid guidelines published in the European Heart Journal in August.
Both publications “validate and substantiate” the results of 30 years of medical research on the benefits of statins and the “actual significance of side effects”, King says. He is concerned about underuse of statins in SA, due in part to medical schemes’ trustees who do not govern administrators’ adherence to up-to-date evidencebased medicine with “proper corporate governance and fiduciary responsibilities”. Schemes rely on “outdated lipid management algorithms” and poor reimbursement practices, King says. An “unethical code of management” has led to lower therapeutic targets, poorer outcomes, and higher hospitalisation and onward costs.
South African-born US lipidologist and cardiologist Dennis Goodman says “the conundrum for physicians remains: how low should we take LDL cholesterol”? By lowering LDL cholesterol (lowdensity lipoprotein, so-called “bad cholesterol”), statin therapy has been “a cornerstone” of secondary cardiovascular disease prevention, says Goodman, clinical professor and director of integrative medicine at New York University.
From 5% to 10% of patients cannot tolerate statins because of muscle-related adverse effects.
New-generation cholesterollowering drugs, PCSK9 inhibitors, are being tested in large, phase-3 outcome studies. They have demonstrated excellent efficacy (further 70% reduction of LDL cholesterol in addition to statin therapy) and an excellent short-term safety profile, he says.
Indications are for patients with cardiovascular disease who are already on maximally tolerated doses of statin and not at LDL goal, and patients with the genetic condition, familial hyperlipidemia. The results are expected next year. PCSK9
inhibitors are “expensive agents”, says Goodman. Outcomes data are likely to determine whether the medical community and insurance companies “will embrace or reject them”.
Sherif Sultan, president elect of the International Society for Vascular Surgery, is critical of the Lancet paper. “It does not encompass any substantial new information or data and it lacks independence,” says Sultan, professor of vascular surgery at the University of Ireland.
“It is a review by the triallists who published all these data before, with the long declaration of interests and whose research is paid generously by the drug industry.”
The Oxford clinical trials unit receives “hundreds of millions of pounds of support from the pharmaceutical industry”, he says.
Statins’ harmfulness is “clear and data-driven”, says Sultan.
The authors have downplayed their harm and do not make clear “when there is an absence of evidence and evidence of absence”.
Several independent researchers have documented that the number of side effects are much higher than the Lancet paper describes, says Sultan. For example, the risk of myopathy (muscle damage) is shown to be at least 10% to 20%, not 0.01% as described in the Lancet.
Muscular side effects are not “benign phenomena”, he says.
“They may have a deleterious effect on elderly people, because the least expensive and the least risky way to prevent heart disease is regular exercise.”
Several studies have shown that the risk of diabetes is at least 25 times higher than the 0.1%-0.2% averred in the Lancet, he says.
Data on statin benefits derives from an analysis based on individual patient data by the cholesterol treatment triallists’ collaboration, which Collins leads.
Despite numerous requests, this has not been published — or included in the Lancet paper, says Sultan. This means the evidence on statin harm is “not as rigorous as the evidence for statin benefits”.
“Ideally, all clinical trial data should be available for third-party scrutiny and published for public scrutiny,” Sultan says.
The need for independent review is “especially pressing in this case, given the public health implications of the call for widespread use of statins for primary prevention”.
Sultan’s prescription for a healthy heart is primary prevention: a Mediterranean-style diet, regular physical activity, no smoking, no alcohol, lots of “good water” daily, no refined sugar, no heavy meal after 7pm, and lots of “good love”.
Top British cardiologist Aseem Malhotra is similarly dismissive of the Lancet review.
“There is great concern among doctors about the reliability of industry-sponsored trials,” says Malhotra. “Such studies should be seen as marketing until proven to be otherwise.”
The Lancet review appears aimed at shutting down the debate on statins despite considerable controversy that still swirls around the drugs.
In effect, it is “antiscience”, Malhotra says. There is “an epidemic of misinformed doctors and misinformed patients” globally, he says.