A class of cholesterol-lowering drug that had been implicated in a cancer scare has been given the all-clear signal by epidemiologists.
Using the results from two large ongoing clinical trials, the research led by Richard Peto of the University of Oxford, UK, has been published online by the New England Journal of Medicine1, along with full results of the trial that first raised the scare.
The trial that raised the scare were also presented today at the European Society of Cardiology congress in Munich, Germany, reports Nature.
The trial was designed to investigate whether a combination of these two cholesterol-lowering drugs would help in cases of aortic stenosis, where a key heart valve is partially blocked.
Simvastatin, a statin that has already been used in other drugs, works by blocking cholesterol synthesis in the body. The newer ezetimibe works by blocking the absorption of cholesterol from the gut.
An unusual pre-publication announcement from the SEAS study reported that, while the therapy did not help very much in aortic stenosis, cancer appeared more frequently in the treated groups.
In the research of 1,873 people in seven European countries with mild or moderate aortic stenosis, all the participants were treated with either a combination of both drugs or a placebo, and followed for at least four years.
The progress of stenosis appeared unaffected by the choice of treatment, although fewer of those treated needed bypass surgery for acute ischaemic heart disease over this period.
However, 105 people from the treated groups developed a cancer within the four years, whereas only 70 in the placebo group did.
There were also more cancer deaths in the treatment group.
When so ever, a clinical trial raises a major safety concern, the sponsors - in this case the companies Merck and Schering-Plough who market the drug combination under the names Vytorin and Inegy - are required to inform the US Federal Drug Administration (FDA) and other national drug agencies within 15 days.
Therefore, the managers of SEAS reported the cancer observations to the FDA and the European Medicines Authority on 21 July.
"By coincidence, this was also the day that Merck and Schering were obliged to update the stock exchange on the progress of their joint trial," says Terje Pedersen, a cardiologist from the Ulleval University Hospital in Oslo, Norway, and principal investigator in SEAS.
"We estimated that there wasn't much hope of retaining confidentiality, so we decided it was probably best to go public with the data ourselves, without waiting for the full trial to be published," he added.
He said that he wasn't surprised by the subsequent media alarm.
But Pedersen says he was also unsurprised when the apparent association turned out to be a statistical blip2, as the sample size in the SEAS study was far too small to detect modest increases in risk with any certainty.
The media alarm and associated political pressure prompted the management teams of two large ongoing double-blind clinical trials involving ezetimibe to take the unusual step of 'unblinding' their trials several years before they are due to end.
They provided data on cancer incidence for analysis.
Those two trials were the UK-based Study of Heart and Renal Protection (SHARP) study, with 9,264 patients, and the US-based Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) study, with 11,353 patients so far. The link with cancer did not emerge in these larger groups.