FDA Clears Effient, May be Serious Competitor to Plavix

Studies show prasugrel is more effective than clopidogrel in reducing stent thrombosis, but has more bleeding.
By: 
Dave Fornell

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September 17, 2009
Effient (prasugrel) 10 mg tablet

In August Daiichi Sankyo and Eli Lilly and Company launched U.S. sales of Effient (prasugrel), a new antiplatelet medication to prevent stent thrombosis, which clinical studies show to be more effective and better tolerated than Plavix (clopidogrel).

The FDA approved Effient tablets in July for the reduction of thrombotic cardiovascular events in patients who undergo PCI, and for patients who have acute coronary syndrome, including unstable angina and myocardial infarction.

Effient is expected to give major competition to Plavix, which is comarketed in the U.S. by Bristol-Myers Squibb and sanofi-aventis. Plavix was FDA cleared in October 1997 and is among the world’s top three best-selling drugs. In 2008 Plavix had total sales of about $5.6 billion. In the U.S. alone, 57.9 million prescriptions were issued for Plavix in 2008. (1)

“I think it’s a major advance. Effient with aspirin was clearly a better treatment than with Plavix and aspirin,” said Dean Kereiakes, M.D., FACC, coinvestigator of the pivotal TRITON-TIMI 38 clinical study, medical director at The Christ Hospital Heart and Vascular Center in Cincinnati, Ohio, medical director of the Carl and Edyth Lindner Center for Research and Education at The Christ Hospital, and professor of clinical medicine at Ohio State University.

He said the head-to-head trial showed Effient reduced the risk of cardiovascular death, heart attack and stroke by 19 percent compared with Plavix in patients with ACS managed with PCI. Effient was responsible for a 50 percent decrease in stent thrombosis cases as compared to Plavix. He said in diabetics the results were even better.

Prasugrel is a rapidly-acting thienopyridine that works faster than clopidogrel. Dr. Kereiakes said Effient is absorbed by the body more quickly through the intestines and only requires one chemical conversion process in the liver. Plavix requires two chemical reactions to convert it from a prodrug to an active drug. “The major difference is that Effient is faster and more effective in preventing platelets from sticking together,” Dr. Kereiakes said.

“The data from the TRITON-TIMI 38 Phase III pivotal trial provide compelling evidence that treatment with prasugrel significantly reduced the combined risk of cardiovascular death, heart attack or stroke over the current standard of care, clopidogrel, across a wide variety of patient types,” said lead TRITON-TIMI 38 investigator Elliott Antman, M.D., professor of medicine at Brigham and Women’s Hospital in Boston and senior investigator with the BWH TIMI Study Group. “Prasugrel is an important new option for patients with ACS who are managed with PCI.”


Drug Interactions

“There don’t appear to be any drug interactions with Effient, where there is a problem with Plavix,” Dr. Kereiakes said. “Different patients respond differently to medications, so it’s important to have multiple options for treating heart disease given how pervasive and costly this condition is.”

Proton pump inhibitors (PPIs) decrease the effectiveness of Plavix by as much as 50 percent, according to results of a study released in May at the meeting of the Society for Cardiovascular Angiography and Interventions. The study, conducted by Medco Health Solutions Inc. and the Indiana University School of Medicine, showed the four most commonly used PPIs, Nexium, Prevacid, Prilosec and Protonix, reduced the effectiveness of Plavix and increased the risk of heart attack and stroke by 50 percent. Clopidogrel requires activation in the liver by cytochrome P450, and PPIs block cytochrome P450. (2)

Clinical data so far shows prasugrel has no interaction with PPIs or any other drugs. Dr. Kereiakes said this means Effient also avoids the so-called “smokers paradox” with Plavix, where smoking actually increases the effectiveness of the drug. However, as with many drugs, he expects down the road as more patients start using Effient, some side effects may surface.

Plavix has many more trade offs than Effient. One in four patients do not respond to Plavix and there is no good bedside test to determine which patients will respond, Dr. Kereiakes said.

“We don’t know which patient of the one in four will be a poor responder to Plavix,” he said. “Effient takes the guess work out. Patients who are not responsive to Plavix will be responsive to Effient, and that is really powerful.”


Increased Bleeding Complications

While Effient lowers the risk of stroke, AMI and cardiovascular death, it increases the risk of serious bleeding. “That is the trade off,” Dr. Kereiakes said.

Eli Lilly said its studies show the bleeding is sometimes life-threatening or fatal in patients treated with Effient compared with Plavix (2.2 percent vs. 1.7 percent). When the efficacy benefits were compared with the risk of serious bleeding events, it was noted that for every 1,000 people treated with Effient compared with Plavix, there were six more major bleeding events, but 23 fewer heart attacks.

“There has been a progressive decline in these bad outcomes of stroke, heart attack and death using aspirin, then Plavix and now Effient, but there has also been an incremental increase in bleeding events,” Dr. Kereiakes said

Effient is not suggested for patients with active bleeding or a history of transient ischemic attack or hemorrhagic stroke. It is also not recommended for patients over the age of 75. However, Dr. Kereiakes said diabetics respond very well to the drug and he would still consider them for the drug over age 75 because of the benefit. Increased bleeding was also found in patients who weigh less than 130 pounds, so it is recommended the daily dose in these patients be reduced to 5 mg instead of the standard 10 mg. The manufactures said Effient should not be used in patients with active pathological bleeding.


Effient Has a Limited Indication

The FDA has only indicated Effient for a limited segment of patients with acute coronary syndromes who are undergoing PCI, which may limit its immediate impact on Plavix.

“We believe that prasugrel’s indication limits its use to a narrow patient population,” said Elizabeth Schupp-Baxter, director of U.S. communications for sanofi-aventis, the maker of Plavix. “Plavix is indicated for a much broader population of patients across the full spectrum of ACS, recent MI, recent ischemic stroke, and established peripheral artery disease.”

She points to recent data from the CRUSADE Registry, which showed about half (52 percent) of UA/NSTEMI patients in the United States undergo PCI. Worldwide less than 40 percent of the total ACS patient population is treated with PCI.

She said Plavix has been proven effective and the safe by four large clinical studies involving 81,000 patients across the entire spectrum of its cardiovascular indications. Prasugrel has only been studied in ACS patients undergoing PCI, which is only a segment of the Plavix ACS indication. Schupp-Baxter also said Plavix has been prescribed to more than 90 million patients worldwide during the 11 years it has been on the market.

Dr. Kereiakes said these other indications for Plavix will likely be added in the future as Effient completes more trials.

Comparing Effectiveness

Prasugrel will be compared again with clopidogrel in the Dual Antiplatelet Therapy (DAPT) Trial, an industry-wide collaboration with medical device and pharmaceutical companies. The first patient will be treated this fall, and results are expected to help establish definitive antiplatelet medication guidelines.

DAPT is an independent, large-scale study of 20,000 or more patients to determine the appropriate duration for dual antiplatelet therapy (the combination of aspirin and a second anticlotting medication) to protect patients from stent thrombosis. The DAPT Trial was developed by a consortium of eight companies (four major stent manufacturers and four manufacturers of antiplatelet medications). The Harvard Clinical Research Institute is responsible for the overall study.

References:

(1). IMS Health National Sales Perspectives 2008, and IMS Health National Prescription Audit 2008, www.imshealth.com

(2.) “A Population-Based Study of the Drug Interaction Between Proton Pump Inhibitors and Clopidogrel,” Juurlink DN, et al. Canadian Medical Association Journal, June 2009, vol. 180, pages 1228–29.

(3.) “Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes.” Wiviott, S, Braunwald, E, et al. New England Journal of Medicine, Nov. 2007, vol. 357, pages 2001-15.

For More Information:

www.effient.com

www.plavix.com

www.hcri.harvard.edu