ACC: Evidence Suggests Many Pathways for Thrombin Control in Acute Coronary Syndrome

NEW ORLEANS, March 30 -- When patients are being evaluated for antithrombin therapy in association with percutaneous coronary interventions, doctors have multiple choices that make it possible to tailor therapy, said a Cleveland Clinic investigator.

These choices include heparin, low molecular weight heparin, glycoprotein IIb/IIIa inhibitors, bivalirudin, and fondaparinux said A. Michael Lincoff, M.D, who is vice chairman for cardiovascular research at the clinic.

He discussed differing management strategies for antithrombin therapy at an industry symposium, held in conjunction with the American College of Cardiology meeting here.

"Acute coronary syndrome management is complicated because we don't have one-size-fits-all antithrombotic pathway because patients and conditions are different," said Dr. Lincoff, who served as moderator at the symposium, which was sponsored by the Medicines Company.

The foundation for treatment of patients with acute coronary syndromes is aspirin and on top of that is clopidogrel (Plavix), but even with aspirin and clopidogrel, which are considered relatively simple therapies, dose titration should be carefully monitored, Dr. Lincoff said.

Beyond aspirin and clopidogrel, doctors have to determine whether they should use glycoprotein IIb/IIIa inhibitors either upfront or during the procedure. Then, he said, comes the difficult choice--heparin or low molecular weight heparin or bivalirudin or fondaparinux?

"It used to be fairly straightforward as to how we treat patients going to the cath lab, but as the situation has matured with data we end up with clarifying questions, and with the addition of new agents the questions become progressively more complicated," he said.

The condition of the patients and the seriousness of their syndrome probably require different regimens, Dr. Lincoff said.

He said general agreement now leans toward pre-treatment with clopidogrel in a broad spectrum of patients from elective to emergent procedures.

Dr. Lincoff said that at one time clinicians accepted the idea of higher bleeding rates among patients undergoing percutaneous coronary interventions in order to maintain antithrombin levels in their patients. "However, newer studies are challenging that position," he said. It is even more important in clinical practice where, he said, bleeding rates are, if anything, higher than in clinical trials.

He cited the REPLACE-2 trial (Lincoff et all JAMA 2003; 289:853). The bleeding rate with bivalirudin was less than with heparin and GP IIb/IIIa inhibitors as was one-year mortality.

In the OASIS-5 Trial, Dr. Lincoff noted that fondaparinux appeared to show non-inferiority and borderline superiority to enoxaparin with less major bleeding in patients with acute coronary syndromes. Then in OASIS-6, more problems were seen with fondaparinux compared with heparin.

"This agent remains problematic in the setting of coronary interventions and clear indications on how is should be used are not elicited at this point," Dr. Lincoff said.

In ACUITY, three treatment arms were employed in acute coronary syndrome patients. The study enrolled 13,819 patients, with 4,603 randomized to receive heparin or enoxaparin plus GP IIb/IIIa; bivalirudin plus GP IIb/IIIa or bivalirudin alone. About 57% of patients were treated with percutaneous coronary intervention; 11% went to coronary artery bypass surgery and 32% were treated medically in each of the groups.

Event rates were lower with bivalirudin alone and in major bleeding episodes, but otherwise the study showed non-inferiority between the modalities.

"The benefit of bivalirudin seems to be its ability to withhold GP IIb/IIIa without losing efficacy," Dr. Lincoff said.

He said that recent randomized clinical trials indicate that fondaparinux is associated with less bleeding than enoxaparin at 1 mg/kg; is non-inferior in regards to ischemic outcomes, and is associated with less death or myocardial infarction at six months, but requires co-administration with unfractionated heparin when being used in percutaneous coronary interventions.

Bivalirudin, De. Lincoff said, shows comparable ischemic outcomes to heparin combined with GP IIb/IIIa inhibitors; consistent reduction in bleeding when compared with GP IIb/IIIa inhibitors; and there was no benefit in substituting bivalirudin for the combination of heparin and GP IIb/IIIa inhibitors.

Following the overview of the science behind antithrombin treatment in connection with acute coronary syndromes, Dr. Lincoff and the panelists discussed various case histories, altering them as needed to show how different strategies could be used depending on patient characteristics.

The panelists were Peter Berger, M.D., the associate chief for clinical research at Geisinger Hospitals and Clinics in Danville, Pa.; E. Magnus Ohman, M.D., a professor of medicine at Duke University Medical Center in Durham, N.C.; and Elliott Antman, a professor of medicine at Harvard Medical School.