Researchers determine timing of administration of platelet-inhibiting drugs

February 13, 2007

Clinicians should carefully weigh the risks and benefits of when to administer platelet glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibitors for patients with acute coronary syndromes undergoing invasive treatment, according to a study in the February 14 issue of JAMA.

"In patients with acute coronary syndromes (ACS; unstable angina or non-ST-segment elevation myocardial infarction [MI or heart attack]), an early invasive strategy, consisting of angiography with subsequent triage to either percutaneous coronary intervention (PCI) [such as balloon angioplasty or stent placement to open narrowed arteries], coronary artery bypass graft (CABG) surgery or medical management, results in reduced rates of death and MI compared with conservative care," the authors provide as background information in the article. "Furthermore, the upstream use of platelet glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibitors (tirofiban or eptifibatide) prior to angiography in patients with ACS further reduces the occurrence of death and MI at 30 days, although at the expense of increased major and minor bleeding complications." The authors add that current guidelines recommend the use of Gp IIb/IIIa inhibitors (which are potent inhibitors of platelet aggregation that act to decrease blood clotting) in certain patients with ACS undergoing an invasive strategy, either administered upstream prior to angiography in all patients or initiated in the catheterization laboratory selectively to patients undergoing PCI.

Gregg W. Stone, M.D., from Columbia University Medical Center, New York, and colleagues performed the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) Timing trial, a large-scale, randomized trial examining the optimal use strategy of Gp IIb/IIIa inhibitors in 9,207 patients with moderate- and high-risk ACS undergoing an early, invasive treatment strategy at 450 medical centers in 17 countries between Aug. 23, 2003, and Dec. 5, 2005. Patients were randomly assigned to receive either routine upstream (n = 4,605) or deferred selective (n = 4,602) Gp IIb/IIIa inhibitor administration.

"Glycoprotein IIb/IIIa inhibitors were used more frequently (98.3 percent vs. 55.7 percent, respectively) and for a significantly longer duration (median [midpoint], 18.3 vs. 13.1 hours) in patients in the upstream group compared with the deferred group," the researchers report. "Composite ischemia (death, MI or unplanned revascularization) at 30 days occurred in 7.9 percent of patients assigned to deferred use compared with 7.1 percent of patients assigned to upstream administration (relative risk 1.12 [a non-significant trend toward a 12 percent increase]); as such, the criterion for noninferiority was not met." The authors add, "...routine upstream compared with deferred selective Gp IIb/IIIa inhibitor use resulted in fewer unplanned revascularization events for ischemia, with no significant differences in the rates of death or MI." In contrast, deferred use compared with routine upstream use resulted in significantly few major bleeding (4.9 percent vs. 6.1 percent) and minor bleeding events. "The 30-day rates of net clinical outcomes (composite ischemia and major bleeding) were nearly identical between the two strategies."

"Deferring the routine upstream use of Gp IIb/IIIa inhibitors for selective administration in the cardiac catheterization laboratory only to patients undergoing PCI resulted in a numerical increase in composite ischemia that, while not statistically significant, did not meet the criterion for noninferiority. This was offset by a significant reduction in major bleeding, minor bleeding and blood transfusions. Given emerging data regarding alternative anticoagulant strategies in ACS and evolving understanding of the relative importance of bleeding and ischemic events, clinicians should carefully weigh the risks and benefits of adjunctive pharmacologic strategies in individual patients," the authors conclude.
(JAMA. 2007; 297:591-602. Available pre-embargo to the media at Editor's Note: This study was sponsored and funded by the Medicines Company, Parsippany, N.J., and Nycomed, Roskilde, Denmark. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Optimal Timing - Questions, Answers and More Questions

"The ACUITY Timing Trial reported by Stone and colleagues in this issue of JAMA is a good example of a clinical investigation that can provide evidence for clinical practice as well as a factual framework that addresses several clinical and research issues," write Kenneth W. Mahaffey, M.D. and Robert A. Harrington, M.D., from Duke Clinical Research Institute, Durham, N.C., in a related editorial.

"In the ACUITY Timing Trial, clinical care decisions were left to the discretion of the treating physicians. This is a common and preferred approach that allows for the testing of research questions in a setting reflective of routine practice, but its use does produce some limitations. In ACUITY, the use of antithrombin therapy was open-label and, in the nonbivalirudin group, the physician had the choice to use unfractionated heparin or low-molecular-weight heparin. In addition, the decision about which Gp IIb/IIIa inhibitor to use upstream or during PCI was left to the discretion of the treating physician. Moreover, two-thirds of patients were already receiving some antithrombin therapy prior to randomization, and nearly 10 percent of patients were being treated with a Gp IIb/IIIa inhibitor prior to randomization."

"Much remains to be learned about optimum care of patients with ACS, and the findings from the ACUITY Timing Trial provide valuable insights for future investigators seeking answers to critical questions of clinical practice." (JAMA. 2007; 297: 636-638. Available pre-embargo to the media at Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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