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Study finds bivalirudin efficacy for PCI no better than heparin

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Bivalirudin no better than heparin?

After considering the findings of the VALIDATE-SWEDEHEART trial, Gregg W. Stone, MD, said in an accompanying editorial, “there is no definitive answer to the question of whether to use bivalirudin or heparin during PCI.”

Dr. Stone, of New York–Presbyterian Hospital, Columbia University Medical Center, and the Cardiovascular Research Foundation, New York, noted four potential flaws in the study findings. One, the 30-day interval may be a better for evaluating procedural anticoagulation than 180 days – and at 30 days the Swedish study showed “a nonsignificant trend in favor of bivalirudin.” Two, the composite primary endpoint could bias outcomes because individual measures could essentially cancel each other out. Three, differences between treatment groups could have been further minimized because 91% of patients who received bivalirudin also received a substantial dose of heparin before and during PCI. Finally, Dr. Stone said, the study was underpowered to examine the individual components of outcomes.

The data comparing outcomes in STEMI and NSTEMI patients did not show separate results for death, bleeding, and stent thrombosis. Dr. Stone pointed to a meta-analysis of six randomized trials of 14,095 patients with STEMI, showing that bivalirudin had lower rates of major bleeding and 30-day death but higher rates of stent thrombosis than heparin, and that mortality was lower regardless of the use of femoral artery or radial-artery access or other procedural factors. By contrast, previous trials did show similar rates of death, MI, and stent thrombosis between both treatment groups, although lower bleeding rates were seen with bivalirudin.

More definitive answers may lie in investigators from the large-scale randomized trials comparing the anticoagulant agents, including the Swedish authors, combining their data on more than 36,000 patients into a single database, as they have agreed to do, Dr. Stone said. That “should provide robust evidence to guide decisions regarding anticoagulation among patients with STEMI and NSTEMI,” he concluded.

Dr. Stone had no relevant financial relationships to disclose. He made his comments in an invited editorial in the New England Journal of Medicine (doi: 10.1056/NEJMe1709247).



A large study of more than 6,000 heart patients in Sweden has found that patients having percutaneous coronary intervention who received bivalirudin did not have lower rates of deleterious outcomes – death, heart attack, or major bleeding – than did patients who received heparin monotherapy, a contrast to previous trials that found that bivalirudin had a lower bleeding risk than heparin alone after PCI.

The findings were presented at the annual congress of the European Society of Cardiology and published simultaneously in the New England Journal of Medicine.

The study sought to explain the conflicting findings of previous trials investigating the efficacy of bivalirudin vs. heparin monotherapy. The VALIDATE-SWEDEHEART trial evaluated 6,006 patients who had PCI from June 2014 to September 2016, 90.3% via radial-artery access. This trial differed from previous studies because it was conducted after radial-artery access was routine and potent P2Y12 inhibitors were available, and earlier trials did not compare bivalirudin to heparin monotherapy, said David Erlinge, MD, PhD, of Lund (Sweden) University, and 38 coauthors (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1706443).

The Swedish investigators evaluated the primary endpoint – the composite of any-cause death, MI or major bleeding – during 180 days of follow-up. Among the study patients, 3,005 had ST-segment elevation MI (STEMI) and 3,001 non-STEMI (NSTEMI). All had undergone urgent PCI and most were also on P2Y inhibitors. The P2Y12 inhibitors used were ticagrelor in 5,697 patients (94.9%), prasugrel in 125 (2.1%) and cangrelor in 21 (0.3%).

Study patients with STEMI were permitted to receive up to 5,000 U of intravenous unfractionated heparin before arrival in the catheterization laboratory, and both STEMI and non-STEMI patients who had not received heparin previously could receive up to 3,000 U of intra-arterial heparin before angiography. All patients received aspirin pretreatment, and 62% received potent P2Y12 inhibitors at least one hour before PCI.

After angiography, but before PCI, patients were randomized 1:1 to receive in an open-label fashion either intravenous bivalirudin (The Medicines Company), or intra-arterial unfractionated heparin (LEO Pharma). Bivalirudin was administered as a bolus of 0.75 mg/kg of body weight followed by an infusion of 1.7 mg/kg per hour.

Research nurses contacted patients by phone 7 and 180 days after PCI. Baseline characteristics were similar between the bivalirudin and heparin groups. For example, around 31% of both groups had hyperlipidemia, and 15.2% of the bivalirudin group and 14.2% of the heparin group had a previous PCI.

“The rate of the primary endpoint did not differ significantly between the treatment groups at 30 days after PCI,” Dr. Erlinge and his coauthors noted. At 30 days, 7.2% of the bivalirudin patients and 8% of the heparin group had one of the primary endpoint outcomes, a nonsignificant difference. At 180 days, 12.3% of the bivalirudin group and 12.8% of those receiving heparin had one of the primary endpoint outcomes, also a nonsignificant difference.

Specific outcomes in the bivalirudin vs. heparin patients, respectively, at 180 days were: MI, 2% vs. 2.4%; major bleeding, 8.6% in both groups; stent thrombosis, 0.4% vs. 0.7%; and death from any cause, 2.9% vs. 2.8%, all nonsignificant differences.

“Results were consistent between patients with STEMI and those with NSTEMI and across all other prespecified subgroups,” the researchers wrote. They noted that women in the bivalirudin group had a lower, although not statistically significant, primary endpoint rate than did women in the heparin group.

In this trial, the high rate of radial-artery access and the low use of glycoprotein IIb/IIIa inhibitors may explain the low bleeding rates, the researchers said.

Among the study limitations were that patients excluded from the trial were at higher risk for a primary endpoint than those enrolled, the open-label design may have biased participating physicians in identifying outcomes, the telephone call-based follow-up may have been inherently unreliable, and the fact that most patients received a small dose of heparin before randomization may have reconciled any differences between the two drugs.

Coauthors Stefan James, MD, and Ollie Ostlund, MD, disclosed receiving grants from Astra Zeneca, and The Medicines Company. Dr. Erlinge and other coauthors had no financial relationships relevant to the work.

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