A newly approved drug thins the blood faster, more consistently, and more powerfully than the standard drug, which can fail to prevent deadly blood clots in patients after they undergo a common procedure to avoid or treat a heart attack. But the new drug, prasugrel (Effient), is also more likely to cause potentially fatal bleeding.
Overall, prasugrel may be superior to the approved dose of the older drug, clopidogrel (Plavix), in many cases. But more doctors have been using an initial, higher-than-standard dose of clopidogrel to boost its efficacy, and how that regimen stacks up against prasugrel on key clinical outcomes is unclear. Deciding who is likely to be helped—or harmed—by the various options requires careful consideration of many factors.
Acute coronary syndrome—either unstable angina (escalating heart-related chest pain) or a heart attack in progress—is often treated by percutaneous coronary intervention (PCI), or angioplasty, in which cardiologists inflate a tiny balloon inside a blocked artery. When inflated, the obstruction is pushed against the artery wall, the passageway widens, and blood flows freely. To help prevent blood clots that can block the artery again after the procedure, doctors prescribe medication that inhibits the action of platelets, or clot-forming blood cells.
The body converts prasugrel to its active form considerably faster than it does clopidogrel. Indeed, the approved, 300-mg dose of clopidogrel takes hours to reach full strength—a potentially significant drawback during a coronary crisis. Moreover clopidogrel, at least at the lower dose, doesn't work adequately in a significant minority of patients who may be genetically resistant to the medication.
But there is a hitch: antiplatelet blood thinners increase the chance of hemorrhages—and prasugrel seems to raise that risk more than the approved dose of clopidogrel. Indeed, the package insert for prasugrel contains a black-box warning, the strongest kind, about this bleeding risk, which is sometimes fatal.
The Food and Drug Administration based its approval of prasugrel largely on a 13,608-patient, multicenter clinical trial that compared it with the approved dose of clopidogrel for acute coronary syndrome patients scheduled for PCI; they all received aspirin as well. During the next six to 15 months, the advantages of prasugrel generally outweighed its risks. For every 1,000 patients treated, it prevented 24 more heart attacks, strokes, and cardiovascular deaths than clopidogrel did, while it caused only 10 more cases of serious or fatal bleeding.
Prasugrel was particularly beneficial for people with diabetes. But the risk of bleeding exceeded the benefits in those with a history of strokes or transient ischemic attacks (fleeting, strokelike symptoms). It had no advantage over clopidogrel in two other groups with increased bleeding risk: people older than age 75 or weighing less than about 130 pounds. And those who needed coronary artery bypass surgery after the PCI had substantially higher risks with prasugrel than with the older drug.
But that study leaves at least one major question unanswered: How does prasugrel compare with a larger, 600-mg dose of clopidogrel? The American College of Cardiology and the American Heart Association now recommend it as the generally preferred option before or when PCI is performed. And results of a recent clinical trial suggest that this doubled dose may be generally superior to the approved dose. (Doctors can legally prescribe unapproved but reasonable doses and uses of any approved medication.)
One study found that prasugrel may inhibit platelet activity more than even the doubled clopidogrel dose; experts say that resistance will occur with even higher clopidogrel doses in some patients. But whether that potential advantage translates into fewer blood clots, heart attacks, and strokes remains unknown. Which regimen causes less bleeding has also not been determined.
Potential prasugrel users should know about another research observation: After four months, prasugrel users seemed to experience an increased risk of cancerous tumors than clopidogrel users. That may have occurred either by chance or because higher bleeding rates lead to more scrutiny and detection of cancer. The FDA did not include cancer among the risks listed in the package insert, though it briefly mentioned the possibility elsewhere. But it did order the manufacturer to continue work on another clinical trial, already under way, to assess the drug's cancer-causing potential.