Drugs Log

A new blood thinner proved better than Plavix, one of the world’s top-selling drugs, at preventing heart problems after procedures to open clogged arteries, doctors reported Sunday. But the new drug also raised the risk of serious bleeding.

People given the experimental drug, prasugrel, were nearly 20 percent less likely to suffer one of the problems in a combined measure — heart attack, stroke or heart-related death — than those given Plavix, a drug that millions of Americans take to prevent blood clots that cause these events.

However, for each heart-related death that prasugrel (PRASS-uh-grell) prevented, compared to Plavix, almost one additional bleeding death occurred.

“There is a price to pay” for greater effectiveness, Dr. Deepak Bhatt, a Cleveland Clinic cardiologist, wrote in an editorial accompanying the results, which were published online by The New England Journal of Medicine and presented at an American Heart Association conference in Florida.

Still, many doctors said that on balance, the new drug comes out ahead, and offers great promise as a more potent alternative to Plavix, which costs $4 a day and does not work for many patients.

“I’m encouraged by the results” and think prasugrel should win Food and Drug Administration approval because it so dramatically cuts non-fatal heart attacks, said the Cleveland Clinic’s Dr. Steven Nissen, a frequent government adviser.

Doctors can sort out who might most benefit from it, such as diabetics, and who might face too much bleeding risk to use it, like the elderly, people who previously had strokes and those with kidney problems, he said. (The Cleveland doctors give to charity or the clinic the consulting and research fees they earn from drugmakers.)

Doctors also were waiting for prasugrel’s makers to clarify why they stopped two small studies of it a week ago. They said it was due to dosing problems but did not explain.

Prasugrel is being developed by Indianapolis-based Eli Lilly and Co. and a Japanese firm, Daiichi Sankyo Co. It could be a hugely important drug, and the study has been one of the most-watched tests of a novel heart medication in recent years.

Like Plavix, prasugrel prevents blood components called platelets from sticking together and forming a clot. Anti-platelet drugs are advised for most people with stents — tiny mesh tubes that keep arteries open after balloon angioplasty, an artery-clearing procedure that more than a million Americans have each year.

Plavix, sold by Sanofi-Aventis SA and Bristol-Myers Squibb Co., has been the most effective drug of this type. More than 70 million people have taken it since it went on sale a decade ago.

Plavix had 18.6 million prescriptions and nearly $3 billion in U.S. sales last year, according to IMS Health, a healthcare information firm. Worldwide sales were nearly $6 billion.

The study comparing it to prasugrel involved 13,608 patients from 30 countries and was led by Dr. Elliott Antman at Harvard Medical School and Brigham and Women’s Hospital in Boston. Prasugrel’s makers paid for the study; many of the researchers work or consult for them.

Study participants were having angioplasty due to heart attacks or blockages causing sudden or worsening chest pain, and were randomly assigned to one drug or the other for six to 15 months.

The results: about 12 percent of people taking Plavix but only 10 percent on prasugrel suffered heart attacks, strokes or heart-related deaths — a 20 percent reduction in risk. Only 1.1 percent on the new drug developed blood clots in stents versus 2.4 percent on Plavix — a 52 percent lower risk. Prasugrel also worked faster than Plavix and showed more effectiveness at the first checkpoint — three days.

However, major bleeding occurred in 2.4 percent of those on prasugrel versus 1.8 percent of those on Plavix. This included brain or gastrointestinal bleeding, or after falls. Fatal bleeding was uncommon, but four times more frequent with the new drug.

Results hinted that some people might be in greater danger — those who had a previous stroke, were elderly, or weighed less than 132 pounds.

These signs are why prasugrel’s makers suspended two small studies a week ago to see whether such patients should be included in the study or should get a lower dose, said Dr. Anthony Ware of Eli Lilly.

“It was a precaution … because of a risk of a safety problem rather than an actual one,” he said.

Lilly will conduct another big study of prasugrel in people not having angioplasty but on medications because they are at risk of having a heart attack, Ware said.

That 10,000-person study will be led by Dr. E. Magnus Ohman at Duke University Medical Center.

In the study reported on Sunday, “the benefit clearly outweighs the risk” for most patients, Ohman said.

Bhatt of Cleveland Clinic noted that even aspirin — which is widely recommended to prevent clots and was prescribed to all patients in this study — carries a risk of bleeding.

Dr. Spencer King, a heart specialist at Piedmont Hospital in Atlanta and spokesman for the American College of Cardiology, was on the safety monitoring committee for the study. He said prasugrel would be “a little bit of a tough sell” to doctors who are comfortable with using Plavix, but that competition could give patients drugs more closely matched to their needs.

“We’ve had one size fits all … now we’ll have two choices,” King said.

Dr. Harlan Krumholz, a Yale University cardiologist with no role in the study, noted that “in absolute numbers, for every 1,000 people you treat, you’d save a lot more heart events than you’d cause bleeds,” because heart problems are more common.

Cost also keeps many people from taking Plavix now. Prasugrel’s makers have not said what it would cost, but “if they start competing on price, it could be a boon for the health care system,” Krumholz said.

Lilly’s Prasugrel Reduces Heart Risks But Has Higher Bleeding Rate

An experimental Eli Lilly & Co. blooding-thinning drug, prasugrel, was effective at reducing the number heart attacks, strokes and cardiovascular deaths, but carries a risk of serious bleeding, according to a new study released Sunday.

The study compared prasugrel and a similar anti-clotting drug, Plavix, by Bristol-Myers Squibb Co. and Sanofi-Aventis SA in 13,608 patients set to undergo a procedure to open blocked coronary arteries. Most patients then received a stent to keep the arteries open.

Overall, the study showed prasugrel was better than Plavix at reducing the number of heart attacks, strokes and cardiovascular deaths, but prasugrel had a higher rate of bleeding including fatal bleeding.

One of the study’s researchers, Elliott Antman, the director of the Brigham and Women’s Hospital’s cardiac unit, said patients on Prasugrel were 19% less likely to have a stroke, heart attack or death from a cardiovascular cause compared with patients on Plavix, but were 32% more likely to suffer a serious bleeding event. Patients on prasugrel were 24% less likely to suffer a heart attack compared with those on Plavix, Dr. Antman said.

Both drugs are designed to keep blood platelets from sticking together to form dangerous blood clots that can cause heart attacks and strokes. But they also carry a risk of bleeding if the drugs go too far at inhibiting platelets. Aspirin is also an anti-clotting agent and is commonly prescribed with Plavix.

The study, known as Triton, was presented Sunday at the American Heart Association’s annual meeting in Orlando and is also being published online in the New England Journal of Medicine.

Researchers, led by Harvard Medical School and Brigham and Women’s Hospital in Boston, said the net clinical benefit, which takes into account the benefits and risks of a drug, favors prasugrel. Dr. Antman said that for every 1,000 patients treated with prasugrel compared with Plavix, prasugrel would prevent an additional 23 heart attacks, but would likely cause six additional cases of serious bleeding.

Lilly, which is developing prasugrel with Daiichi Sankyo Co. of Japan, said Oct. 24 it halted two smaller studies of prasugrel amid concerns about the dosage used in certain patient groups, rattling investors and in turn, putting an even greater focus on the Triton data. Both Lilly and Daiichi funded the study.

Specifically, the Triton study showed that 12.1% of patients on Plavix had a heart attack, stroke or death from a cardiovascular cause during the study, compared with 9.9% of patients receiving prasugrel, which translates into an overall difference of 19%. Patients in the study were either given a one-time “loading” dose of prasugrel at 60 milligrams and maintenance doses of 10 milligrams, or a 300 milligram loading dose of Plavix followed by 75 milligram maintenance doses. Patients were treated for six to 15 months.

The rate of major bleeding among patients receiving prasugrel was 2.4% compared with 1.8% receiving Plavix. The study showed the rate of life-threatening bleeding was 1.4% for patients on prasugrel and 0.9% for patients on Plavix. That included fatal bleeding, which occurred among 0.4% of patients receiving prasugrel and 0.1% of patients on Plavix, along with non-fatal bleeding, which was 1.1% in the prasugrel group and 0.9% in the Plavix group.

Lilly has said it plans to submit an application for Food and Drug Administration approval of prasugrel by the end of this year.

“We are very pleased with the trial’s outcome and are excited by the potential for these results to help us further tailor prasugrel therapy to assure the greatest benefit from this novel treatment,” said J. Anthony Ware, Lilly’s cardiovascular platform leader for prasugrel.

Researchers said there were “significant reductions” in stent thrombosis and repeat procedures to reopen clogged arteries among patients on prasugrel compared with those on Plavix. The stent thrombosis rate, or blood clots attributed to the stent, was 1.1% for those receiving prasugrel and 2.4% for the Plavix patients, or a 52% reduction in the stent thrombosis rate for patients on Plavix. Urgent target vessel revascularization among prasugrel patients was 2.5% compared with 3.7% for those on Plavix, a 34% reduction.

In an accompanying editorial in the New England Journal of Medicine, Dr. Deepak Bhatt of The Cleveland Clinic, said for each additional cardiovascular death prevented by the use of prasugrel compared with Plavix, “approximately one additional episode of fatal bleeding was caused by prasugrel.” He wrote that prasugrel would probably benefit patients who are at high risk of additional heart problems such as a heart attack and at low risk of bleeding, while patients with a high risk of bleeding and at lower risk for heart attacks or strokes “may be better served by” Plavix.

Indeed, researchers wrote that an analysis of subgroups of patients in the study suggested those with a history of smoking, stroke, those age 75 and older as well as those who weighed less than 60 kilograms (132 pounds) had “less clinical efficacy and greater absolute levels of bleeding than the overall cohort.”

Dr. Antman said most of the excess bleeding and fatal bleeding occurred in patients who’ve suffered a previous stroke and said if approved, the drug shouldn’t be used in that group.

Plavix, which generated almost $6 billion in global sales last year, is among the world’s top-selling drugs. Lilly is hoping prasugrel, which some researchers said might work more consistently than Plavix, could take market share away from Plavix if it’s approved later next year.

In a statement, Bristol-Myers said “with the wealth of safety and efficacy data on Plavix, this drug is well understood by phsyicians in a real-world setting. The bleeding rate observed with prasugrel in Triton raises important questions.”

Lilly’s best selling drug Zyprexa loses U.S. patent protection in 2011 and prasugrel is widely viewed as the company’s most promising drug in its pipeline. Zyprexa treats schizophrenia and bipolar disorder.

Other companies also are developing anti-clotting drugs, including AstraZeneca PLC and Schering-Plough Corp. along with Bayer AG and Johnson & Johnson, which are jointly working on a product.