New Data Confirm Lovenox(R) is an Effective Antithrombotic for Treatment of Acute Coronary Syndromes

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 Référence" -- on file with the "Autorité des marchés
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, [phone], , or

Susan Brooks, [phone], , both of Aventis



Web site:  http://www.aventis.com/

http://www.lovenox.com/ 

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