AntiPlatelet Therapy: Widening Options & Opinions

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The FDA approved the third thienopyridine agent, prasugrel (Effient, Eli Lilly/Daiichi Sankyo), in July 2009, challenging the U.S. market dominance of clopidogrel (Plavix, Bristol Myers Squibb/Sanofi Aventis). Yet, some cardiologists are being cautious about rapid, widespread adoption, and uptake has been slower than expected. Meanwhile, other options—such as reversible agents—loom on the horizon.

Cath lab decisions broaden

Now that prasugrel has become available in most hospitals, interventionalists, along with their cath lab managers, have to decide when and how to utilize the newest antiplatelet drug.

Three concerns remain obstacles to wider adoption of prasugrel, says Paul A. Gurbel, MD, director of the Sinai Center for Thrombosis Research at the Sinai Hospital in Baltimore. Those include the dosing regimens utilized in the TRITON-TIMI 38 trial, bleeding risks and uncertainty about the optimal duration of therapy.

Steven V. Manoukian, MD, medical director of cardiology at Hospital Corporation of America and director of cardiovascular research at Sarah Cannon Research Institute in Nashville, Tenn., says that while cost is always a consideration, confusion exists “about the relative efficacy and safety between clopidogrel and prasugrel, and clinicians are looking to better understand the results of recent clinical trials.” As a result, purchasing groups, who rely on the expertise of their clinicians, are poised in a wait-and-see mode until clinicians have a more clear consensus.

David J. Cohen, MD, director of cardiovascular research for Saint Luke’s Mid America Heart Institute in Kansas City, Mo., concurs that a cath lab’s bottom line isn’t influencing their choice of adoption. “From the hospital perspective, the cost difference is trivial, as prasugrel costs 60 cents more per pill,” says Cohen. If a patient is in the hospital for two days, and he or she receives a loading dose and a single maintenance dose, it would be a difference of $4 for the patient’s visit. “Hospitals drop that much in gauze pads on the floor during every procedure,” he says.

Clinically, physicians are trying to weigh the tradeoff between ischemic versus bleeding events in making the daily decisions about who receives which drug, says Cohen, an investigator for TRITON-TIMI 38.

As a result of these clinical considerations, prasugrel is experiencing slow adoption in the U.S., according to Robert A. Harrington, MD, director of the Duke Clinical Research Institute at Duke University Medical Center in Durham, N.C. While clinicians may gain experience with the agent in higher risk subgroups, he predicts that the uptake may remain flat for awhile.

TRITON questions reign

There is still “a lot of controversy” about whether prasugrel would remain superior to clopidogrel if patients were given the standard 600 mg dose, as opposed to the 300 mg dose administered in the TRITON-TIMI trial, says Gurbel. He adds that prasugrel should only be used in the two doses that were studied in TRITON-TIMI (60 mg loading dose and 10 mg maintenance dose).

“If TRITON had emerged in the clinical trial vacuum of the previous years, and if standard-dose clopidogrel were the only foreseeable alternative, the results of the trial would have been more compelling through its reduction in clinical events—albeit at the expense of clinically significant bleeding,” states Manoukian, who was an investigator in the earlier prasugrel trial, JUMBO. “Confounding TRITON results, the recently reported CURRENT OASIS-7 trial revealed that the way clopidogrel was studied in TRITON doesn’t mimic clinical practice and that double-dose clopidogrel is often the norm.”

Most practices administer 600 mg of clopidogrel and a large percentage of patients are pretreated with clopidogrel several hours prior to an elective or urgent PCI. In TRITON, 75 percent of patients received clopidogrel peri-procedurally and all patients received a clopidogrel loading dose of 300 mg.

CURRENT OASIS-7 showed an early administration of clopidogrel with a 600 mg dose around the time of PCI, followed by 75 mg twice a day for one week, could achieve “prasugrel-like results—an increase in efficacy, but also with a potential for excess bleeding, although not by the commonly used TIMI bleeding scale,” Manoukian says.

Additionally, Gurbel disagrees with the FDA’s decision to consider lowering the maintenance dose of prasugrel to 5 mg in patients weighing less than 60 kg. “It’s a totally inappropriate and premature