Results from ASSENT 3 trial, guidelines for heparin from the American Heart Association
It is always difficult to break with tradition. For the past decade, cardiologists have routinely used unfractionated heparin (UFH) along with a thrombolytic agent (e.g., alteplase, recombinant [Activase, Genentech]) to treat acute myocardial infarctions (AMI). According to the American Heart Association (AHA), approximately 1.1 million people in the United States have a heart attack each year, and about every minute someone will die from one.
With such daunting statistics, it's no wonder researchers are continuously searching for new therapies as well as attempting to combine available therapies, such as thrombolytics, antithrombotics, and antiplatelet agents to improve patient outcomes.
Despite the successful use of UFH, there are concerns about potentially serious side effects (excessive bleeding, low platelet count, osteoporosis) and relative unpredictability necessitating close monitoring. To reduce the risk of bleeding, AHA recommends that when UFH is used after thrombolysis or in combination with aspirin or glycoprotein IIb/IIIa inhibitors, the intensity of anticoagulation be reduced. This new recommendation is part of the recently published position statement on heparin therapy released by AHA.
The development of the low molecular weight heparins (LMWHs) has significantly influenced the treatment and prevention of thrombosis. "LMWHs are easier to use [given subcutaneously twice daily as opposed to UFH, which requires a bolus injection followed by continuous intravenous infusion] and do not require anticoagulant monitoring," said Charles Granger, M.D., FACC, associate professor of medicine at Duke University Medical Center. The AHA statement also noted the advantage of a more predictable dose response with LMWHs relative to UFH.
The risk of thromboembolism is often associated with orthopedic surgery (e.g., hip and knee replacement), general and abdominal surgery, spinal cord injury, neurosurgery, and certain medical conditions leading to prolonged inactivity, such as ischemic stroke. Ardeparin (Normiflo, Pharmacia), dalteparin (Fragmin, Pharmacia), and enoxaparin (Lovenox, Aventis) all have indications for prophylaxis for thromboembolism. Tinzaparin (Innohep, DuPont) is approved only for the treatment of deep vein thrombosis (DVT) with or without pulmonary embolism. The AHA statement observes that LMWHs have become the first-line agents for the prevention of venous thrombosis during orthopedic surgery and in anticoagulant-eligible patients after major trauma.
Enoxaparin is now being used more and more in unstable angina, where heparin has been the standard agent, noted Granger. "In almost every setting where there have been direct comparisons with enoxaparin and UFH, enoxaparin has been related to better outcomeslower incidence of death and of recurrent MI," he added. Recent interest in using LMWHs in acute coronary syndromes (unstable angina, non-Q-wave MI, and acute-Q-wave MI) has spurred researchers to explore their use as adjunctive therapy.
The results of the ASSENT 3 Trial (Assessment of the Safety and Efficacy of New Thrombolytic regimens), published in the Aug. 25 issue of Lancet, may provide the evidence needed to break the current standard therapy for AMI. ASSENT 3 enrolled 6,095 heart attack patients who were randomized to receive one of three treatment regimens within six hours of the onset of symptoms. Treatment arms included full-dose TNKase (tenecteplase, Genentech) plus Lovenox (Group A); half-dose TNKase plus UFH in combination with a 12-hour infusion of the glycoprotein IIb/IIIa inhibitor ReoPro (abciximab, Lilly) (Group B); and full-dose TNKase plus UFH (Group C).
Granger, who is also the U.S. lead investigator for the study, noted that this was the largest trial to study therapy regimens for heart attack patients using the latest (1999) American College of Cardiology/AHA guidelines for dosing heparin and LMWH, which stress the use of weight-adjusted dosing.
Group A (TNKase plus Lovenox) demonstrated the best results in reduction of events associated with the "efficacy plus safety" composite end point, including 30-day mortality, in-hospital reinfarction or in-hospital ischemia, and reduction in in-hospital intracranial hemorrhage or major bleeding complications.
"The clinical benefit of enoxaparin with tenecteplase is consistent with the benefit of enoxaparin in unstable angina, providing further confidence that this simple, easy-to-administer combination is an excellent regimen for AMI," concluded Granger. He did add, "There may be important differences between the LMWHs such that one should not use them interchangeably."
The authors of the AHA statement concluded "LMWH preparations are at least as effective and safe as UFH and more convenient" and also recommend LMWH preparations be administered with weight-adjusted dosing (e.g., enoxaparin 1 mg/kg SC every 12 hours) instead of standard doses (e.g., enoxaparin 30 mg SC every 12 hours) in the majority of patients.
Tammy Chernin. Better patient outcomes with low-molecular weight heparin.