New Data Confirm Lovenox(R) is an Effective Antithrombotic for Treatment of Acute Coronary Syndromes SYNERGY, A to Z and a Systematic Overview of Six Randomized Trials Published in JAMA BRIDGEWATER, N.J., July 7 /PRNewswire-FirstCall/ -- Results of two new randomized clinical studies confirm that Lovenox(R) (enoxaparin sodium injection) is an effective and safe antithrombotic agent in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) undergoing an invasive management strategy. In addition, a systematic overview of six clinical trials involving approximately 22,000 patients with NSTE ACS showed that overall, Lovenox(R) is superior to unfractionated heparin (UFH) in preventing nonfatal myocardial infarction (MI) and the composite of death or nonfatal MI regardless of management strategy, with similar safety. Results of the SYNERGY trial, the "A" phase of the A-to-Z (Aggrastat(R) to Zocor(R)) trial, and the systematic overview were published in the July 7 issue of the Journal of the American Medical Association. (Logo: http://www.newscom.com/cgi-bin/prnh/20000501/NYM197 ) "The results of SYNERGY, A-to-Z and the systematic overview confirm the benefit of enoxaparin across the spectrum of high- and low-risk ACS patients intended for aggressive or conservative management strategies," said Kenneth W. Mahaffey, MD, associate professor of medicine, Duke Clinical Research Institute at Duke University Medical Center, Durham, NC, and one of the lead authors of both the SYNERGY study and the systematic overview. "The benefits appear to be enhanced in patients who receive enoxaparin as their initial therapy." The SYNERGY Trial SYNERGY was a prospective, randomized, open-label study of Lovenox(R) versus UFH in more than 10,000 high-risk patients presenting with NSTE ACS and treated with an early invasive strategy. All patients enrolled in the study received treatment with aspirin and either Lovenox(R) or UFH. Clopidogrel and platelet glycoprotein IIb/IIIa inhibitors were administered at the treating physician's discretion. Lovenox(R) was established to be at least as effective as UFH in reducing the incidence of death or nonfatal MI at 30 days, the primary endpoint (14.0% vs. 14.5%, p=0.396). Bleeding was modestly increased in patients assigned to Lovenox(R), with a statistically nonsignificant excess in GUSTO severe events (2.7% vs. 2.2%, p=0.084), although TIMI major bleeding was significantly higher in patients treated with Lovenox(R) (9.1% vs. 7.6%, p=0.008). The majority of the bleeding excess resulted from coronary bypass artery graft (CABG)-related events. No significant differences in transfusion, intracranial hemorrhage or thrombocytopenia were observed. Importantly, with greater than 90 percent of patients undergoing coronary angiography and 47 percent undergoing percutaneous coronary intervention, no increase was observed in ischemic complications at the time of procedure, including thrombus formation, abrupt closure, stroke or need for urgent CABG. A series of comprehensive secondary analyses was conducted to remove the confounding influence of pre-randomization antithrombin therapy or postrandomization "crossovers" to alternate antithrombin therapy. Lovenox(R) appeared to have a relative advantage with no excess of bleeding in these analyses. In patients who did not receive antithrombin therapy prior to randomization, Lovenox(R) was associated with a 16 percent relative risk reduction in death and nonfatal MI at 30 days compared with UFH (12.6% vs. 14.8%, p=0.116). In patients who did not receive prior antithrombin therapy or who were randomized to the same antithrombin therapy as they were on prior to randomization, Lovenox(R) resulted in a statistically significant 18 percent relative reduction in death or nonfatal MI compared to patients who received UFH (13.3% vs. 15.9%, p=0.039). Bleeding events in these two groups of patients were similar. The A Phase of the A-to-Z Trial The A phase of the 4,000- patient A-to-Z study was designed as an open- label comparison of the efficacy and safety of Lovenox(R) and UFH when administered concomitantly with tirofiban (Aggrastat(R)), a platelet glycoprotein IIb/IIIa inhibitor, and aspirin. Approximately 55 percent of patients in each arm were recommended for an early invasive treatment strategy, and by 48 hours, approximately 42.5 percent in the Lovenox(R) arm and 43.8 percent in the UFH arm had undergone cardiac catheterization. At 7 days, the primary endpoint (death, myocardial infarction or refractory ischemia) occurred in 8.4 percent of patients receiving Lovenox(R) and 9.4 percent of patients receiving UFH in the intention-to-treat population (p=0.16). Patients treated with Lovenox(R) who received no antithrombotic agent within 24 hours before randomization also experienced a trend toward risk reduction (8.1% vs. 10.2%), though not statistically significant. Combined rates of clinically significant bleeding (TIMI major or minor bleeding) in the as-treated population were 3.0 percent in the Lovenox(R) arm vs. 2.2 percent in the UFH arm (p=0.134). There was no difference in major bleeding rates between Lovenox(R) and UFH for any individuals who underwent early intervention, but there was a significant increase in reports of "any bleed" in Lovenox(R)-treated patients, driven primarily by investigator- identified minor bleeding episodes. Systematic Overview of Lovenox(R) in Non-ST-Segment Elevation ACS "Recent studies have demonstrated that enoxaparin is an effective and safe alternative to unfractionated heparin in patients with unstable angina or non- ST-segment elevation myocardial infarction, though these efficacy and safety results were less robust than the significant reductions in death and myocardial infarction seen in earlier large clinical trials," said Dr. Mahaffey. "To investigate whether the treatment effect of enoxaparin has changed as strategies have evolved to include concomitant antiplatelet agents and more aggressive invasive treatment, we undertook a systematic overview of the ESSENCE, TIMI 11B, ACUTE II, INTERACT, SYNERGY and A-to-Z trials examining enoxaparin versus UFH in ACS." Investigators conducted an analysis of data from these six clinical trials comparing Lovenox(R) to UFH in the treatment of approximately 22,000 patients with NSTE ACS. The systematic evaluation was performed for the endpoints of death and nonfatal MI, transfusion, and major bleeding in the overall trial populations and in the subpopulation receiving no antithrombin therapy prior to randomization. In patients treated with Lovenox(R), there was a significant reduction in the composite of death or MI, which translates into a relative risk reduction of 8.2 percent. There was no difference in mortality at 30 days in the intention-to-treat populations. Among patients who did not receive any antithrombin therapy prior to randomization, there was a trend toward a decrease in mortality in favor of Lovenox(R) (2.8% in the Lovenox(R) arm vs. 3.2% in UFH arm). A statistically significant 14.6 percent relative risk reduction in the combined endpoint of death and MI was observed in patients in the group treated with Lovenox(R). The treatment effect was consistent across trials with varying protocol designs over the past eight years of NSTE ACS trial experience. The primary safety analysis examined endpoints occurring through day 7 after randomization. No significant difference was detected in transfusion or major bleeding in the overall safety population or in the population receiving no antithrombin therapy prior to randomization. In the analyses of both the overall safety populations of all six trials and the overall safety population of trials assessing CABG-related bleeding, no significant difference was detected in in-hospital blood transfusion or major bleeding. A modest but statistically significant increase in major bleeding during hospitalization was detected in the analysis of patients who did not receive antithrombin therapy prior to randomization, but no difference in blood transfusion was noted. About Lovenox(R) The No. 1-selling low-molecular-weight heparin in the world, Lovenox(R) was approved in the United States and Canada in 1993. It has been available in Europe since 1987 and is known under the brand names Lovenox(R), Clexane(R) and Klexane(R). Lovenox(R) is the only low-molecular-weight heparin approved by the FDA for all of the following indications: * Prophylaxis of deep-vein thrombosis, which may lead to pulmonary embolism: -- for medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness; -- for patients undergoing abdominal surgery who are at risk for thromboembolic complications; -- for patients undergoing hip replacement surgery, during and following hospitalization; -- for patients undergoing knee replacement surgery. * Prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin. * Inpatient treatment of acute deep-vein thrombosis with or without pulmonary embolism, when administered in conjunction with warfarin sodium. * Outpatient treatment of acute deep-vein thrombosis without pulmonary embolism when administered in conjunction with warfarin sodium. Important Safety Information 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. (See boxed WARNING) As with other anticoagulants, use with extreme caution in patients with conditions that increase the risk of hemorrhage. Dosage adjustment is recommended in patients with severe renal impairment. Unless otherwise indicated, agents that may affect hemostasis should be discontinued prior to LOVENOX(R) therapy. Bleeding can occur at any site during LOVENOX(R) therapy. An unexplained fall in hematocrit or blood pressure should lead to a search for a bleeding site. (See WARNINGS and PRECAUTIONS) Thrombocytopenia can occur with LOVENOX(R). In patients with a history of heparin-induced thrombocytopenia, LOVENOX(R) should be used with extreme caution. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm3, LOVENOX(R) should be discontinued. Cases of heparin-induced thrombocytopenia have been observed in clinical practice. (See WARNINGS) The use of LOVENOX(R) has not been adequately studied for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves. (See WARNINGS) LOVENOX(R) is contraindicated in patients with hypersensitivity to enoxaparin sodium, heparin, or pork products, and in patients with active major bleeding. Please see accompanying information or go to http://www.lovenox.com/ for complete prescribing information, including boxed WARNING, and additional important information. About Aventis Aventis is dedicated to treating and preventing disease by discovering and developing innovative prescription drugs and human vaccines. In 2003, Aventis generated sales of euro 16.79 billion (US $18.99), invested euro 2.86 billion (US $3.24) in research and development and employed approximately 69,000 people in its core business. Aventis corporate headquarters are in Strasbourg, France. The company's prescription drugs business is conducted in the U.S. by Aventis Pharmaceuticals Inc., which is headquartered in Bridgewater, New Jersey. For more information, please visit: http://www.aventis-us.com/. Statements in this news release containing projections or estimates of revenues, income, earnings per share, capital expenditures, capital structure, or other financial items; plans and objectives relating to future operations, products, or services; future economic performance; or assumptions underlying or relating to any such statements, are forward-looking statements subject to risks and uncertainties. Actual results could differ materially depending on factors such as the timing and effects of regulatory actions, the results of clinical trials, the company's relative success developing and gaining market acceptance for new products, the outcome of significant litigation, and the effectiveness of patent protection. Additional information regarding risks and uncertainties is set forth in the current Annual Report on Form 20-F of Aventis on file with the Securities and Exchange Commission and in the current Annual Report -"Document de R�f�rence" -- on file with the "Autorit� des march�s financiers" in France. Aggrastat(R) and Zocor(R) are registered trademarks of Merck and Co., sponsor of the A-to-Z study. http://www.newscom.com/cgi-bin/prnh/20000501/NYM197DATASOURCE: Aventis CONTACT: Terri Pedone, +1-908-243-6578, , or Susan Brooks, +1-908-243-7564, , both of Aventis Web site: http://www.aventis.com/ http://www.lovenox.com/

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