Optimal Timing for Anticlotting Drugs in Acute Coronary Syndromes Still Unclear

NEW YORK, Feb 13 -- The ideal timing for the use of platelet-inhibiting drugs for patients with acute coronary syndromes undergoing invasive treatment remains an open question after an international trial.

Among those with moderate- and high-risk acute coronary syndromes, deferring routine upstream use of platelet inhibitors (glycoprotein IIb/IIIa inhibitors) prior to angiography to selective use just prior to angioplasty found the delay produced a statistically nonsignificant increase in composite ischemia, the investigators reported in the Feb 14 issue of the Journal of the American Medical Association.

However, this finding was offset by a significant reduction in major bleeding, said Gregg Stone, M.D., of Columbia University, and colleagues in the ACUITY Timing Trial.

Standard guidelines recommend the use of these platelet inhibitors, either upstream for all patients prior to angiography or deferred for selective use in the cath lab just prior to angioplasty. The preferred approach has not been determined, and in this trial the results for the deferred approach did not meet the criterion for noninferiority, the researchers said.

The findings came from a prospective, randomized, open-label trial with a 30-day clinical follow-up of 9,207 patients from 450 academic and community-based institutions in 17 countries, from August 2003 to December 2005.

Of the patients with moderate- and high-risk acute coronary syndrome undergoing an invasive treatment strategy, 4,605 were randomly assigned to receive routine upstream administration, while 4,602 received deferred selective administration of the Gp IIb/IIIa inhibitor.

Among patients in the upstream group, compared with those in the deferred group, glycoprotein IIb/IIIa inhibitors were used more frequently (98.3% versus 55.7%, respectively) and for a significantly longer duration (median, 18.3 versus 13.1 hours; P

Other potential limitations include the open-label design, introducing the potential for bias, although the use of adjunctive medications and revascularization strategies was well balanced between the two groups, the researchers said.

Finally, given the heterogeneity of the patients and the treatments received, including decisions about the choice of the platelet inhibitor and the selection of medical therapy--percutaneous coronary intervention versus coronary artery bypass--definitive conclusions regarding the relative safety and efficacy of the two assigned treatment in all scenarios is "problematic," the researchers said.

In this regard, they added, subgroup analysis is limited, and "any trends (or lack thereof) in underpowered subgroups should be considered hypothesis-generating only," Dr. Stone's team said.

"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 researchers concluded.

In a related editorial, Kenneth Mahaffey, M.D., and Robert Harrington, M.D., of the Duke Clinical Research Institute in Durham, N.C., said that even though the results of the ACUITY Timing Trial should not fundamentally change the use of Gp IIb/IIIa inhibitors in clinical practice, the ACUITY investigators have addressed an important question within the framework of a large clinical trial.

Because of varying results from other trials, clinicians currently struggle with what constitutes the optimum antithrombin/antiplatelet strategy for patients with acute coronary syndrome, they said.

The ACUITY Timing Trial was not designed to allow comparisons among agents, and these considerations are appropriately absent from this report.

Furthermore, they said, clinical decisions were left to the discretion of the treating physicians, a common and preferred approach, which produced some limitations, however.

Also, the use of antithrombin therapy was open-label and the decision about which Gp IIb/IIIa inhibitor to use upstream or during PCI was left to the discretion of the treating physician. Finally, two-thirds of the patients received antithrombin therapy prior to randomization, and nearly 10% of the patients were being treated with the glycoprotein IIb/IIIa inhibitor prior to randomization, they said.

"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," Drs. Mahaffey and Harrington concluded.

Dr Stone reported having received consulting fees from the Medicines Company, Boston Scientific, Guidant, Abbott, Volcano, St Jude, and BMS Imaging and lecture fees from the Medicines Company, Nycomed, Guidant, Medtronic,and Abbott. Co-author Michel Bertrand, M.D. reported receiving consulting and lecture fees from Servier Laboratories and Sanofi Aventis. Jeffrey Moses, M.D., received consulting fees from Johnson & Johnson and is on the speaker's bureau for AstraZeneca. E. Magnus Ohman, M.D., has received consulting fees from Inovise Medical, Response Biomedical, and Savacor; he has equity/ownership in Medtronic and Savacor, and has received lecture fees from Schering-Plough, Bristol-Myers Squibb, and Datascope, as well as grant support from Bristol-Myers Squibb and Sanofi-Aventis, Schering-Plough Millenium, and Berlex.

A. Michael Lincoff, M.D., has received research support from the Medicines Company, Sanofi-Aventis, Eli Lilly, Centocor, and Pfizer, consulting fees from the Medicines Company, Medicure, Eli Lilly, Sanofi-Aventis, and Pfizer, and lecture fees from the Medicines Company. James Ware, Ph.D., has received consulting fees from Infra-ReDX, Biogen, the Medicines Company, Pfizer, Schering-Plough, and Proctor & Gamble. Stuart Pocock, Ph.D., received consulting fees from the Medicines Company. Dr. Cox reported receiving consulting and lecture fees from Boston Scientific, Guidant, St Jude, Cordis, and the Medicines Company. M. Zubair Jafar, M.D., is on the speaker's bureau for the Medicines Company, Schering-Plough, Sanofi, KOS, and Pfizer. Martin Desaga, M.D., has received lecture fees from Nycomed. David Cohen, M.D., has received grant support from the Medicines Company, Schering-Plough, Eli Lilly, and BMS/Sanofi and is on the speaker's bureau for the Medicines Company and Schering-Plough. Roxana Mehran, M.D., is on the speaker's bureau for the Medicines Company, Cordis, and Boston Scientific. Harvey White, M.D., has received consulting and lecture fees from Sanofi-Aventis and the Medicines Company and has received grant support from Alexion, Sanofi-Aventis, Eli Lilly, Merck Sharpe and Dohme, the Medicines Company, Neuren Pharmaceuticals, the National Institutes of Health, GlaxoSmithKline, Pfizer, Roche, Fournier Laboratories, Johnson & Johnson, Procter & Gamble, and Schering-Plough.

The editorial writers, Drs. Mahaffey and Harrington, reported receiving funding from AstraZeneca, Bayer, Bristol-Myers Squibb, Johnson & Johnson, Lilly, Merck, Sanofi- Aventis, Schering-Plough, Scios, and the Medicines Company. Dr. Mahaffey has received consulting or speaker fees from Johnson & Johnson, Sanofi-Aventis, Scios, and the Medicines Company. Dr. Harrington has received consulting or speaker fees from Bristol-Myers Squibb, Sanofi-Aventis, and Schering-Plough. He also reported that since October 4, 2006, all personal monies related to industry-supported activities are donated to educational charities.