Prasugrel for acute coronary syndromes: Faster, more potent, but higher bleeding risk
ABSTRACTPrasugrel (Effient) has been approved for reducing the risk of thrombotic complications in patients with acute coronary syndromes who are to undergo percutaneous coronary intervention. In a large clinical trial (N Engl J Med 2007; 357:2001–2005), prasugrel was superior to clopidogrel (Plavix), another drug of its class, in this situation. However, bleeding complications were more frequent with prasugrel, and so this drug should be avoided in patients at higher risk of bleeding.
KEY POINTS
- The thienopyridines—ticlopidine (Ticlid), clopidogrel (Plavix), and now prasugrel—reduce the risk of death from and serious complications of acute coronary syndromes by inhibiting platelet aggregation.
- Compared with clopidogrel, prasugrel is more potent, faster in onset, and more consistent in inhibiting platelets.
- Prasugrel should be avoided in patients at higher risk of bleeding, including those with a history of stroke or transient ischemic attack, those age 75 or older, or those who weigh less than 60 kg.
TAKE-HOME POINTS
Prasugrel is more potent, more rapid in onset, and more consistent in inhibiting platelet aggregation than clopidogrel. A large clinical trial17 found prasugrel to be superior to clopidogrel for patients with moderate-to high-risk acute coronary syndromes with high probability of undergoing a percutaneous coronary intervention.
Who should receive prasugrel, and how?
Prasugrel should be given after angiography to patients with non-ST-elevation acute coronary syndromes or at presentation to patients with ST-elevation MI. When used for planned percutaneous coronary intervention, prasugrel should be given at least 30 minutes before the intervention, as was done in phase 2 trials (although its routine use in this situation is not recommended—see below).
It is given in a one-time loading dose of 60 mg by mouth and then maintained with 10 mg by mouth once daily for at least 1 year. (At least 9 months of treatment with a thienopyridine is indicated for patients with acute coronary syndromes who are medically treated, and at least 1 year is indicated following urgent or elective percutaneous coronary intervention, including balloon angioplasty and placement of a bare-metal or drug-eluting stent.)
Who should not receive prasugrel?
For now, prasugrel should be avoided in favor of clopidogrel in patients at higher risk of bleeding. It is clearly contraindicated in patients with prior transient ischemic attack or stroke, for whom the risk of serious bleeding seems to be prohibitive. It should generally be avoided in patients age 75 and older, although it might be considered in those at particularly high risk of stent thrombosis, such as those with diabetes or prior MI. In patients weighing less than 60 kg, the package insert advises a reduced dose (5 mg), although clinical evidence for this practice is lacking.
As yet, we have no data assuring that prasugrel is safe to use in combination with fibrinolytic agents, so patients on thrombolytic therapy for acute MI should continue to receive clopidogrel starting immediately after lysis. Furthermore, in patients who proceeded to coronary artery bypass grafting, the rate of major bleeding was more than four times higher in the prasugrel group than in the clopidogrel group in the TRITON-TIMI 38 trial.17 No thienopyridine should be given to patients likely to proceed to coronary artery bypass grafting.
Only clopidogrel has evidence supporting its use as an alternative to aspirin for patients with atherosclerotic disease who cannot tolerate aspirin. Neither drug has evidence for use for primary prevention.
Other areas of uncertainty
Prior to angiography. Indications for prasugrel are currently limited by the narrow scope of the trial data. TRITON-TIMI 38,17 the only large trial completed to date, randomized patients to receive prasugrel only after their coronary anatomy was known, except for ST-elevation MI patients. It is unknown whether the benefits of prasugrel will outweigh the higher risk of bleeding in patients with acute coronary syndromes who do not proceed to percutaneous coronary interventions.
A clinical trial is currently under way comparing prasugrel with clopidogrel in 10,000 patients with acute coronary syndromes who will be medically managed without planned revascularization: A Comparison of Prasugrel and Clopidogrel in Acute Coronary Syndrome Subjects (TRILOGY ACS), ClinicalTrials.gov Identifier: NCT00699998. The trial has an estimated completion date of March 2011.
In cases of non-ST-elevation acute coronary syndrome, it is reasonable to wait to give a thienopyridine until after the coronary anatomy has been defined, if angiography will be completed soon after presentation. For example, a 1-hour delay before giving prasugrel still delivers antiplatelet therapy more quickly than giving clopidogrel on presentation. If longer delays are expected before angiography, however, the patient should be given a loading dose of clopidogrel “up front,” in accordance with guidelines published by the American College of Cardiology, American Heart Association, and European Society of Cardiology,20 which recommend starting a thienopyridine early during hospitalization based on trial data with clopidogrel.
Patients undergoing elective percutaneous coronary intervention are at lower risk of stent thrombosis and other ischemic complications, so it is possible that the benefits of prasugrel would not outweigh the risks in these patients. Thus, prasugrel cannot yet be recommended for routine elective percutaneous coronary intervention except in individual cases in which the interventionalist feels that the patient may be at higher risk of thrombosis.
