Low-Molecular-Weight Heparin Aids in Acute MI : Reviparin's protective effects extended to 30 days from the start of treatment in the multinational study.


NEW ORLEANS — Antithrombotic treatment, in the form of the low-molecular-weight heparin reviparin, has been shown for the first time to safely improve the outcomes of patients with an acute MI.

“Although heparin is often routinely used to treat patients with an acute myocardial infarction, the incremental benefit from heparin or newer antithrombotics has been poorly defined,” Jeffrey L. Anderson, M.D., said at the annual scientific sessions of the American Heart Association.

The new findings show that reviparin “clearly improves the outcomes of patients who undergo thrombolysis with streptokinase or urokinase,” said Dr. Anderson, associate chief of the division of cardiology at LDS Hospital in Salt Lake City.

But the value of adding reviparin or a similar agent remains in doubt when patients are treated with the fibrin-specific drugs most often used for thrombolysis in the United States, such as alteplase (tissue plasminogen activator), reteplase, and tenecteplase. That's because this new trial, conducted in India, China, Pakistan, and several South American countries and involving 15,570 patients, included only about 100 patients treated with a fibrin-specific thrombolytic drug. Close to 80% of the patients received acute treatment to clear their coronary thrombus, but this treatment was primarily streptokinase in about 50% of patients, urokinase in about 23% of patients, and primary percutaneous intervention in about 6% of patients.

Despite this limitation, the results showed that “reviparin is a simple, inexpensive therapy that is globally applicable for treating acute myocardial infarction,” said Salim Yusuf, D.Phil., director of the division of cardiology at McMaster University in Hamilton, Canada, and lead investigator for the study.

Reviparin is marketed by Abbott Pharmaceuticals under the name Clivarine in several countries in Europe and Asia, but is not approved for U.S. use. Abbott provided the reviparin, but otherwise, the study had no commercial funding.

The study enrolled patients with ST-segment-elevation MI or new bundle branch block who presented within 12 hours of symptom onset. All patients were to be treated with aspirin, and they could also be treated with a regimen designed to produce reperfusion in their blocked coronary arteries. The average age of the patients was 59 years, and the average time from symptom onset to treatment was 4.8 hours, with 61% of patients treated within 6 hours. Aspirin was used on 97% of patients, 72% received an ACE inhibitor, 66% received a lipid-lowering drug, 60% received a β-blocker, and 55% received a thienopyridine, most commonly clopidogrel.

Patients were randomized to treatment with reviparin or placebo by subcutaneous injection b.i.d for 7 days; 76% of patients received the full 7-day course.

The study's primary end point was the incidence of death, repeat MI, or stroke during the 7 days of treatment. The rate of these outcomes was 11.0% in the placebo group and 9.6% in the reviparin group—a statistically significant relative reduction of 13%, Dr. Yusuf reported. Patients treated with reviparin also had a 13% relative reduction in the study's secondary end point, which included death, repeat MI, stroke, or ischemic ECG changes. Treatment with reviparin was also associated with a significant 11% relative reduction in death alone.

The protective effect from reviparin treatment extended to 30 days after the start of treatment. At that time, the rate of death, repeat MI, or stroke was 13.6% in the placebo group and 11.8% in the reviparin group, again a statistically significant 13% relative reduction. These results showed that “stopping therapy after 7 days was not associated with any rebound,” Dr. Yusuf said.

Like all antithrombotic drugs, reviparin boosted the rate of bleeding events. The rate of life-threatening or major bleeds not included in the primary outcomes after 7 days of treatment was 0.1% in the placebo group, compared with 0.2% in the reviparin group. The increased risk of important bleeding events was small, compared with the overall benefit, he noted.

Another noteworthy finding was that the faster treatment with reviparin started the greater the benefit. Patients who started treatment within 2 hours of symptom onset had a 30% relative drop in the primary end point. This relative benefit fell to 20% when treatment began 2–4 hours and to 15% when treatment began within 4–8 hours. The benefit completely disappeared when treatment was delayed beyond 8 hours.

An inevitable question is whether treatment with the low-molecular-weight heparins approved for use in the United States would confer the same benefits. “It's a tricky issue, because low-molecular-weight heparins are very heterogeneous compounds. You need to know the exact dosage to use.” Dr. Yusuf said.