Nov. 17--CHICAGO -- An experimental drug dramatically raised good HDL cholesterol, but before it gets on the market researchers first must be sure that doing so saves lives rather than takes them, as a similar drug did several years ago.
The long-awaited clinical trial results presented Wednesday are a crucial advance in what doctors say may be the next big breakthrough in treating and preventing heart disease, one that eventually could resolve a longstanding theory about HDL cholesterol and artery health.
Years of observational research has showed that people with naturally high levels of HDL have fewer heart attacks and strokes. But will increases in HDL brought about by a drug do the same thing?
Doctors warn that the physiology of HDL cholesterol, which actually is a family of particles, is complicated and far from fully understood.
"There are so many functions (of HDL cholesterol)," said Eliot Brinton, a researcher at the University of Utah School of Medicine, Merck consultant and co-author of the study of the drug, anacetrapib. "There is a lot of confusion and no consensus in the field."
The pharmaceutical industry is betting that raising HDL will save lives.
Merck, whose 18-month clinical trial results with 1,623 people were presented at the annual meeting of the American Heart Association, now is planning to start a 30,000-patient, four-year trial of anacetrapib next year.
Two other drug companies, Hoffman-LaRoche and Eli Lilly, also are testing drugs from the same class of HDL-raising agents.
However, they all are proceeding with caution and it could be several years before any of them reach the marketplace.
In 2006, Pfizer had to halt a large clinical trial of a similar drug because of deaths that are believed to have been caused by increases in blood pressure brought on by its drug, torcetrapib.
The new research will test the Food and Drug Administration's resolve in demanding that drug companies show true benefits as measured by fewer heart attacks, strokes and deaths rather than just impressive improvements in cholesterol numbers.
Anacetrapib increased HDL cholesterol by an unprecedented 138%, while also reducing LDL cholesterol by 40% -- and that was in people who already were on cholesterol medication. The study also was published online in the New England Journal of Medicine.
"We need to know more," said Harlan Krumholz, a cardiologist with Yale School of Medicine. "They are not going to get approval based on the lab results. It could also cause harm."
Cholesterol-lowering statin drugs generally reduce heart attacks and strokes by about 30%. Anacetrapib has the potential to reduce risk even more, he said, but Merck must do a much larger study to prove that.
"The amount of money they are going to spend on the trial will be dwarfed if it is successful," he added.
There were four deaths from cardiovascular causes in the 808 people in the anacetrapib group and one death in the placebo group. Also, there were 11 deaths from any cause in the anacetrapib group and eight in the placebo group. However, the trial was not large enough to show the drug's effect on deaths or heart attacks.
Christopher Cannon, the study's lead author, also pointed to the lower number of procedures that were done to open coronary arteries of patients getting anacetrapib, eight vs. 28 in the placebo group.
However, such procedures often are elective. If patients and their doctors had their cholesterol checked, they could probably figure out if they were getting the drug or the placebo, which, in turn could influence a decision to undergo a procedure, doctors said.
"If this works, it may take cardiovascular disease away from being the number one killer," said Cannon, a Harvard cardiologist and researcher with the TIMI Study Group. The trial was defined to test the safety of the drug. An analysis done by the researchers, who are consultants to Merck, found that there was a 94% likelihood that the drug would not cause a significant increase in cardiovascular events as the Pfizer drug did.
Yale Mitchel, Merck's vice president for cardiovascular disease research, said the company is on record as saying it would not seek FDA approval for anacetrapib before 2015.
However, he would not directly answer whether there were circumstances in which it would seek to get the drug on the market before then.
Merck came close to abandoning research on the drug after the Pfizer drug trial was halted in 2006. Both drugs are from the class of agents known as CETP inhibitors.
But, Mitchel said, Merck had its own research suggesting that its drug did not work in the same detrimental way as the Pfizer drug, increasing levels of the hormone aldosterone and affecting electrolyte levels as well as blood pressure.
Even today, he acknowledged, raising HDL remains poorly understood. The prevailing theory is that HDL removes cholesterol from arteries, taking it back to the liver, where it is excreted.
Many doctors find HDL frustrating.
Michael Cinquegrani, a cardiologist at Froedtert Hospital in Wauwatosa, said he often sees patients with high LDL and low HDL levels.
While he can get substantial reductions in LDL, raising HDL is a problem.
In addition, a perplexing group of substances, including saturated fat, alcohol, estrogen and niacin, will raise HDL.
The drug that has the biggest effect is niacin, but many patients can't tolerate it because it causes a flushing sensation in the skin, he said.
Kooroush Saeian, a cardiologist with Waukesha Memorial Hospital, said a new drug that raises HDL and reduces heart attacks would be revolutionary.
But, he added, "As physicians so many times we've been sold a drug and then have gotten burned."
The anacetrapib trial was funded by Merck and eight of the 12 authors of the study were Merck employees. Some of the other authors are consultants to Merck.
In addition, the analysis of the trial's results were done by a firm hired by Merck, said co-author Philip Barter, a physician with the Heart Research Institute in Sydney, Australia. Both Merck and that firm also collected the trial's data, he said.
Such arrangements have received criticism because they raise questions about whether research is being done in a truly independent manner.
Barter said the 30,000-patient trial of anacetrapib that will start next year will be done differently with the outside investigators controlling the study analysis, data collection and design.
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