By: Ed Susman

STOCKHOLM, SWEDEN – A lower dose of heparin appears to reduce the risk of bleeding when used to prevent thrombotic events during percutaneous coronary interventions, researchers said at the European Society of Cardiology Congress 2010.

Researchers noted that in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 3 trial, unfractionated heparin 140 U/kg appeared equivalent in efficacy to bivalirudin, but that the dose of heparin came with a cost of increased bleeding events.

“We speculated that a lower dose of heparin might be as effective and yet would result in less bleeding,” said Stephanie Schulz, MD, Deutches Herzzentrum, Munich, Germany. “We found that the lower unfractionated heparin dose — 100 U/kg rather than 140 U/kg — provided noninferior net clinical outcome compared with the bivalirudin group.”

The ISAR-REACT 3A trial enrolled 2,505 biomarker-negative patients who were undergoing percutaneous coronary intervention. After clopidogrel pretreatment, the patients received a single bolus of unfractionated heparin 100 U/kg.

The quadruple primary endpoint was net clinical outcome (ie, death, myocardial infarction, urgent target-vessel revascularisation within 30 days, or inhospital major bleeding). The primary comparison was with the historical unfractionated heparin group from ISAR-REACT 3 (n = 2,281). A second analysis checked for noninferiority against the historical bivalirudin arm of ISAR-REACT 3 (n = 2,289).

The mean age of the participants was 68 years, and about 23% of the patients were women. About 30% of the patients had diabetes, 90% had hypertension, >70% had high cholesterol, and 15% smoked.

About 7.3% of the patients who received the low dose of heparin experienced the primary endpoint versus 8.7% of the patients who received 149 U/kg in the earlier trial, which translated to a 19% reduction in the risk for 1 of the primary outcome event (adjusted P =.007).

The incidence of major bleeding was 3.6% among patients who received the lower heparin dose and 4.6% in the higher-dose group (P =.11). The lower dose was noninferior to bivalirudin (P <.001).

In biomarker-negative patients undergoing percutaneous coronary intervention, a reduction in heparin dose from 140 to 100 U/kg provided a net clinical benefit, compared with a higher dose, that was primarily driven by a reduction in bleeding.

Dr. Schulz said that on the basis of the ISAR-REACT 3a trial, patients undergoing percutaneous coronary intervention at her facility are now given the 100-U/kg dose of unfractionated heparin.

- MFP Wire Services
- 09-04-2010

By: Ed Susman

STOCKHOLM, SWEDEN – The investigate antiplatelet agent elinogrel, in both oral and intravenous formulations, can produce a greater effect more rapidly than clopidogrel without an excess in bleeding, researchers said at the European Society of Cardiology Congress 2010.

Although the phase 2 trial was not powered for efficacy, the researchers demonstrated that the event rate — a composite of death, myocardial infarction, stroke, the need for revascularisation, and additional therapies — was comparable for clopidogrel (n = 208), intravenous elinogrel 80 mg (n = 118), and intravenous elinogrel 120 mg (n = 312).

“We saw no significant differences in efficacy at 24 hours or 120 days,” said Sunil Rao, MD, Duke University, Durham, North Carolina.

“Although clopidogrel is a well-established and effective therapy,” he explained, “it does not work for all patients, so it is important that we explore alternatives to improve efficacy and help prevent serious complications.”

Dr. Rao noted that elinogrel is the only reversible and competitive P2Y12 receptor antagonist that is directly acting on platelets, requiring no conversion to an active metabolite as required with clopidogrel.

“[Elinogrel] is available for intravenous and oral administration, enabling acute and chronic use,” said Dr. Rao.

The researchers enrolled patients who were undergoing nonurgent percutaneous coronary interventions. Patients were originally randomised to 3 doses, but the 80-mg intravenous loading dose was increased to 120 mg and the low 50-mg oral dose was discontinued based on recommendations of the Data Safety and Monitoring Committee.

The chronic phase of treatment was also extended from 60 to 120 days; 590 patients were followed for 60 days, and 328 for 120 days.

In pharmacokinetic studies, patients dosed with elinogrel achieved nearly complete platelet aggregation inhibition within 30 minutes to a greater extent than clopidogrel (P <.0025). The difference remained statistically significant at 2 and 20 hours, Dr. Rao said.

No major bleeding episodes occurred for any doses of elinogrel or clopidogrel. However, a trend toward a dose-dependent increase in less severe bleeds was seen with elinogrel, mostly at the vascular access site in the periprocedural area.

- MFP Wire Services
- 09-04-2010

By: Ed Susman

STOCKHOLM, SWEDEN – The investigative Factor Xa inhibitor apixaban reduces the risk of stroke or systemic embolic events by 54% when compared with at-risk patients who are being treated with aspirin, researchers said at the European Society of Cardiology Congress 2010.

In reporting the results from the Apixaban Versus Acetylsalicylic Acid to Prevent Stroke (AVERROES) study, Stuart Connolly, MD, University of Hamilton, Hamilton, Ontario, said 3.9% of patients on aspirin experienced either a stroke or systemic embolic events — the combination of which was the primary endpoint of the study — compared with a rate of 1.7% among those being treated with apixaban (P <.001).

Researchers enrolled patients with atrial fibrillation and at least 1 other risk factor for stroke, and who were unable to successfully use Vitamin K antagonists as an anticoagulant or who were deemed unsuitable for Vitamin K antagonist therapy.

Patients were randomised to receive apixaban 5 mg twice daily (n = 809) or aspirin 81 to 324 mg/day (n = 2,791).

The mean age of the patients was 70 years and about 60% were men. More than 85% of the patients had hypertension; about 40% had heart failure, and about 20% were diabetic.

The trial was truncated after 21 months when it became apparent that treatment with apixaban was superior to aspirin in this patient population, Dr. Connolly said in presenting his findings.

"If we treated 1,000 patients with apixaban instead of aspirin we would expect to prevent 18 strokes, mainly larger ones, prevent 10 deaths, and prevent 31 cardiovascular hospitalisations," Dr. Connolly said. Two major bleeding episodes were also likely to occur within that year of treatment, he said.

In addition to achieving a positive result for its primary endpoint, treatment with apixaban also:
· Significantly (P <.001) reduced the risk of experiencing the composite events of stroke, systemic embolic events, myocardial infarction or vascular death by 34% compared with aspirin.
· Significantly reduced (P <.001) cardiovascular hospitalisations.
· Tended to reduce (P =.07) total mortality.
· Didn't increase risk of major bleeding (P =.56).

Funding for this study was provided Bristol-Myers Squibb and Pfizer.

- MFP Wire Services
- 09-04-2010