NEW YORK -- The thrombin-specific anticoagulant Angiomax (bivalirudin) as monotherapy in patients acute coronary syndromes reduced the risk of major bleeding by 47% compared with rates for heparin and glycoprotein IIb/IIIa inhibitors, researchers reported.
NEW YORK, Nov. 22 -- The thrombin-specific anticoagulant Angiomax (bivalirudin) as monotherapy in acute coronary syndromes reduced the risk of major bleeding by 47% compared with rates for heparin and glycoprotein IIb/IIIa inhibitors, researchers reported.
When used alone in acute syndromes, Angiomax, approved to replace heparin in non-emergency percutaneous angioplasty procedures, was as effective as the standard anticoagulants, according to results from the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial reported in the Nov. 23 issue of the New England Journal of Medicine.
In the ACUITY trial, supported by Medicines Company, maker of Angiomax, and Nycomed, the drug's European marketer, 59% of the patients had a myocardial infarction without ST-segment elevation, while 41% had unstable angina, said Gregg Stone, M.D., of Columbia University here, and co-authors in the U.S., Europe, and Australia.
In the 17-country study, 13,819 patients (median age 63, 70% men) with acute coronary syndromes were assigned to one of three antithrombotic regimens: traditional unfractionated heparin or the low-molecular-weight heparin enoxaparin combined with a glycoprotein IIb/IIIa inhibitor; Angiomax plus a glycoprotein IIb/IIIa inhibitor, or Angiomax alone.
The primary endpoints were a composite ischemia endpoint (death, myocardial infarction, or unplanned revascularization for ischemia), major bleeding, and the net clinical outcome (composite ischemia and major bleeding).
Angiomax plus a glycoprotein IIb/IIIa inhibitor, compared with a control group of heparin plus the glycoprotein inhibitor had equivalent (noninferior) 30-day rates for the composite ischemia end point (7.7% and 7.3%, respectively). Major bleeding rates were similar (5.3% and 5.7%), as was the net clinical outcome (11.8% and 11.7%), the researchers reported.
Angiomax alone, compared with heparin plus the glycoprotein inhibitor, produced a noninferior rate of the composite ischemia end point, the researchers said. They found that a 7% decrease in bleeding events offset a 7% increase in ischemic events (7.8% and 7.3%, respectively; P=0.32; relative risk, 1.08; 95% confidence interval 0.93 to 1.24).
On the plus side, the researchers reported that Angiomax had a significant 47% reduced rate of major bleeding (3.0% vs. 5.7%; P<0.001; relative risk, 0.53; CI, 0.43 to 0.65).
The net clinical outcome for Angiomax alone compared with the other anticoagulants was 10.1% vs. 11.7%; P=0.02; relative risk, 0.86; CI, 0.77 to 0.97), the researchers said.
In approximately 64% of the patients, a thienopyridine, in most cases Plavix (clopidogrel), was already in use or was given before angiography or percutaneous coronary intervention. The researchers noted that the point estimate for adverse ischemic events was slightly greater with Angiomax monotherapy than with heparin plus glycoprotein therapy in patients who were not pretreated with a thienopyridine.
Although information about the exact timing of this treatment was not available, Dr. Stone's team suggested that giving a thienopyridine prior to Angiomax monotherapy might be desirable.
Several limitations of the study deserved comment, the investigators said. First, the logistic complexities of the trial required an open-label design, which introduced a potential for bias. Second, 59% of the study cohort presented with myocardial infarction without ST-segment elevation, a percentage lower than that in certain other trials yet similar to still others.
Third, as in other trials, a significant proportion of the patients were pre-treated with some form of heparin before randomization. Nonetheless, the effects of Angiomax monotherapy were consistent, regardless of crossover, as shown in a subgroup analysis.
Finally, the researchers said, the 25% noninferiority margin used in the study may have been too wide. Because the observed rate of ischemic events in the control group was 7.3%, an estimated ischemic-event rate as high as 9.1% in the test groups would have been considered noninferior, even though it might be considered clinically important.
In summary, Dr. Stone said that testing several different combinations of anticoagulant therapies found that Angiomax used alone was as effective at the traditional drugs -- heparin plus glycoprotein IIb/IIIa inhibitors -- in preventing ischemic events, but with significantly lower rates of bleeding.
In an editorial in the same NEJM issue, John Bittl, M.D., of the Ocala Heart Institute, Munroe Regional Medical Center, in Florida, emphasized that patients assigned to Angiomax monotherapy who were not pretreated with Plavix had a significant 29% increase in ischemic events as compared with those treated with traditional drugs. Therefore, he said, patients who require urgent percutaneous coronary intervention but who have not been adequately pretreated with aspirin or Plavix, should receive a glycoprotein IIb/IIIa inhibitor.
"A noninferiority trial like the ACUITY trial, which was designed to test multiple composite outcomes, could be criticized as a shell game," Dr. Bittl wrote. However, he continued, "the significance of the study is its unique ability to evaluate the integrated antithrombotic and invasive therapies used in the contemporary treatment of patients with acute coronary syndromes."
Summing up, Dr. Bittl said, "the ACUITY trial provides strong support" for the use of Angiomax as a substitute for heparin plus glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes who undergo early invasive treatment, in particular if they are pretreated with Plavix.
Dr. Stone reported receiving consulting fees from the Medicines Company, Boston Scientific, Guidant, Abbott, Volcano, St. Jude, and BMS Imaging and lecture fees from the Medicines Company, Boston Scientific, Nycomed, Guidant, Medtronic, and Abbott.
Additional consulting fees, lecture fees, grant support, or equity interests for the more than 20 ACUITY researchers came from the Medicines Company, Boston Scientific, Guidant, St. Jude, Cordis, Servier, Sanofi-Aventis, Mitsubishi Pharmaceuticals, PrognostiX, Pfizer, Sanofi-Synthelabo; Johnson & Johnson, AstraZeneca, Procter &Gamble, Schering-Plough, Eli Lilly, Alexion, Merck, Neuren Pharmaceuticals, GlaxoSmithKline, Pfizer, Roche, Fournier Laboratories, Johnson & Johnson, Biogen, InfraReDx, Millennium Pharmaceuticals, Bristol-Myers Squibb, CSL Alexion, Nycomed, Boehringer Ingelheim, Essex Pharma, Guerbe, Abbott, Terumo, Cordis, Biotronik, Merck, Liposcience, Inovise Medical, Response Biomedical, Savacor, Datascope, Berlex. American Bioscience, Atherogenics, Aventis, Biosite, Converge Medical, Cordis, Glaxo Wellcome, Guilford, Orphan Therapeutics, Pharmacia & Upjohn, Philips, Sankyo, Sanofi, Scios, Takeda America, and Vasogenix.