Heart attack patients who received a new therapy regimen consisting of the single-bolus thrombolytic agent TNKase(TM)/Metalyse(R) (tenecteplase) and the low-molecular-weight heparin Lovenox(R) (enoxaparin sodium) Injection experienced the most significant clinical efficacy and safety benefits in the ASSENT 3 (ASsessment of the Safety and Efficacy of New Thrombolytic regimens) trial. The treatment regimen also yielded the lowest 30-day mortality rate (5.35 percent) ever reported in a large-scale clinical trial of acute myocardial infarction (AMI). Results of the study are published in the 25 August 2001 issue of The Lancet.

ASSENT 3 enrolled 6,095 heart attack patients at more than 500 sites worldwide. Patients were randomized to receive one of three treatments within six hours of the onset of symptoms. Treatment arms included full-dose TNKase/Metalyse plus Lovenox (Group A); half-dose TNKase/Metalyse plus weight-adjusted, reduced-dose unfractionated heparin (UFH) in combination with a 12-hour infusion of the glycoprotein IIb/IIIa inhibitor ReoPro(R) (abciximab) (Group B); and full-dose TNKase/Metalyse plus weight-adjusted UFH (Group C).

ASSENT 3 had two primary composite endpoints: primary efficacy and primary efficacy plus safety. The primary efficacy endpoint was measured as a reduction in the composite of 30-day mortality, in-hospital reinfarction or in-hospital ischemia. The primary safety endpoint was measured as a reduction in the composite of the primary efficacy endpoint plus safety events, including in-hospital intracranial hemorrhage (ICH) or in-hospital major bleeding complications (other than ICH).

"Taking into account efficacy and safety, full-dose tenecteplase with enoxaparin emerged as the most promising reperfusion therapy regimen in this trial," said ASSENT 3 principal investigator Frans J. Van de Werf, MD, chairman, department of cardiology, University Hospital Gasthuisberg, Leuven, Belgium. "This combination successfully lowered event rates, exhibited an excellent safety profile and was easy to administer."

TNKase/Metalyse is the only available thrombolytic that is administered as a single bolus over five seconds in a dose based on the patient's estimated weight. In ASSENT 3, Lovenox was administered as an initial bolus followed by twice-daily subcutaneous injections until discharge or revascularization for a maximum of seven days. Unlike unfractionated heparin, Lovenox does not require ongoing monitoring of blood-clotting factors.

While the Group B regimen reduced efficacy plus safety endpoint events, this reduction did not achieve statistical significance after adjustments for multiple comparisons. Investigators reported that the Group B arm was associated with an increase in major bleeding complications, including non-cerebral bleeding, need for transfusions and the occurrence of thrombocytopenia (bleeding disorder due to low platelet count), particularly in patients with diabetes or who were older than 75 years of age.

For the primary efficacy endpoint, both experimental arms of the trial yielded statistically significant reductions in events (Group A, 11.44 percent; Group B, 11.06 percent) compared with Group C (15.41 percent), p<0.0001. Total stroke and intracranial hemorrhage rates were similar across all three groups. The mortality rate, which was part of the combined efficacy plus safety endpoint, was lowest in Group A, the full-dose TNKase/Metalyse plus Lovenox therapy regimen, at 5.35 percent, compared to half-dose TNKase/Metalyse plus reduced-dose UFH and abciximab (Group B) at 6.59 percent and full-dose TNKase/Metalyse plus weight-adjusted UFH (Group C) at 5.99 percent, although these differences were not statistically significant.

"The consistent efficacy and safety results achieved with enoxaparin suggest that this agent might be considered the adjunctive therapy of choice when administered with a fibrin-specific thrombolytic such as tenecteplase," said Prof. Van de Werf.

ASSENT 3 was sponsored by Aventis Pharma AG (maker of enoxaparin, marketed in the U.S. as Lovenox and worldwide as Clexane), Boehringer Ingelheim (developer and marketer of Metalyse in Europe and other regions) and Genentech, Inc. (developer and marketer of TNKase in the United States). U.S. coordination of the ASSENT 3 trial was through the Duke Clinical Research Institute. Results from ASSENT 3 will be presented on September 2, 2001, at the XXIII Congress of the European Society of Cardiology in Stockholm, Sweden.

According to the World Health Organization, cardiovascular diseases account for 12 million deaths in the world each year. Currently, heart attack is a leading killer of men and women in developed countries. It is projected that by 2010, heart disease will be the number-one cause of death in developing countries. This year, as many as 1.1 million people in the United States will have a coronary attack (includes heart attack and fatal coronary disease), and 4 million people throughout Europe will die of cardiovascular disease.

In the last decade, thrombolytic therapy has emerged as the standard of care for the pharmacological management of AMI. To continue to build upon the success of these products in improving treatment outcomes, cardiologists now are investigating various combinations of thrombolytics with other pharmacological agents used in the armamentarium against ischemic heart disease. The quest for this combination, or "optimal AMI cocktail," has led researchers to combine multiple therapies, such as thrombolytics, antithrombotics and antiplatelet agents, in an attempt to maximize artery-opening patency and improve patient outcomes.

For Metalyse full prescribing information in Europe, please call Boehringer Ingelheim at +49 (6132) 77 3582.

For Lovenox full prescribing information, visit the Aventis Pharmaceuticals U.S. Web site at http://www.aventispharma-us.com.

Lovenox (R) (enoxaparin sodium) Injection is indicated for the prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin.

Lovenox(R) (enoxaparin sodium) Injection cannot be used interchangeably with other low-molecular-weight heparins or unfractionated heparin, as they differ in their manufacturing process, molecular weight distribution, anti-Xa and anti-IIa activities, units, and dosage.

When epidural/spinal anesthesia or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low-molecular-weight heparins or heparinoids are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis.

The risk of these events is increased by the use of postoperative indwelling epidural catheters or by the concomitant use of drugs affecting hemostasis. Patients should be frequently monitored for signs and symptoms of neurological impairment.

As with other anticoagulants, use with extreme caution in patients with conditions that increase the risk of hemorrhage. Unless otherwise indicated, agents that may affect hemostasis should be discontinued prior to Lovenox therapy.

Bleeding can occur at any site during Lovenox therapy. An unexplained fall in hematocrit or blood pressure should lead to a search for a bleeding site.

Thromobocytopenia can occur with Lovenox. In patients with a history of heparin-induced thrombocytopenia, Lovenox should be used with extreme caution.

Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm3, enoxaparin should be discontinued. Cases of heparin-induced thrombocytopenia have been observed in clinical practice.

Lovenox is contraindicated in patients with hypersensitivity to enoxaparin sodium, heparin, or pork products, and in patients with active major bleeding. Statements in this news release other than historical information are forward- looking statements subject to risks and uncertainties.