Among patients with congestive heart failure (CHF) who are undergoing PCI, bivalirudin results in less bleeding and lower mortality compared with heparin when each is paired with a glycoprotein IIb/IIIa inhibitor, according to propensity-matched analysis of data from a large registry published online May 22, 2015, ahead of print in Catheterization and Cardiovascular Interventions. Bivalirudin is also associated with reduced overall hospital costs.

“These findings suggest that bivalirudin [Angiomax; The Medicines Company] is an economically and clinically attractive option, if not the preferred agent, for CHF patients undergoing PCI,” write C. Michael Gibson, MD, MS, of Beth Israel Deaconess Medical Center (Boston, MA), and colleagues.

For the retrospective study, investigators analyzed data on 116,313 PCI patients with CHF (median age 71 years; about 57% men) treated at 315 US centers contributing to the Premier hospital database between January 2004 and June 2012. Of this cohort, 21.2% presented with STEMI, 29.1% NSTEMI, 16.6% unstable angina, 5.7% stable angina, and 24.2% other ischemic heart disease.

Patients were stratified according to anticoagulant use:

• Bivalirudin alone (n = 45,559)
• Bivalirudin plus GPI (n = 8,115)
• Heparin alone (n = 27,972)
• Heparin plus GPI (n = 34,667)

Overall, rates of clinically apparent bleeding, transfusion, and the combination of the 2 were reduced with bivalirudin monotherapy compared with heparin alone (table 1).

When each of the anticoagulants was combined with a GPI, only clinically apparent bleeding was lower with bivalirudin (13.8% vs 15.0%; P = .009).

Inpatient mortality was lowest in those who received bivalirudin monotherapy and rose progressively with use of heparin monotherapy, bivalirudin plus GPI, and heparin plus GPI (P < .0001 for trend). Likewise, hospital length of stay was shortest and costs were lowest with bivalirudin monotherapy.

Morality Benefit for Bivalirudin Plus GPI

Propensity analysis was performed on 42,474 matched pairs of patients who received either bivalirudin or heparin along with a GPI; approximately 65.5% in each group were implanted with DES. Bivalirudin plus GPI use was associated with lower mortality and less clinically apparent bleeding with or without transfusion as well as shorter hospital stay and lower total hospitalization cost (table 2).

Sensitivity analysis of 25,631 propensity-score–matched pairs of patients who received either bivalirudin or heparin monotherapy showed similar results except for clinically apparent bleeding, which did not differ between the groups. Hospitalization costs were not compared.

Multivariate regression modeling identified several factors associated with death, transfusion, bleeding, and cost. Compared with heparin with or without a GPI, bivalirudin use—whether alone or with a GPI—predicted reduced risk of death (OR 0.76; 95% CI 0.71-0.82). Transfusion and bleeding without transfusion were linked to increased mortality (OR 1.79; 95% CI 1.66-1.94 and OR 1.32; 95% CI 1.19-1.45, respectively). In addition, bivalirudin with or without a GPI was linked to a cost reduction of $635, while bleeding alone was tied to an increase of $8,524 and transfusion to an increase of $13,805.

“Our findings support the results from randomized clinical trials and observational analyses where bivalirudin has been associated with lower rates of bleeding and transfusion compared with heparin [with or without] GPI,” the authors say.

While the current study backs previous evidence linking bleeding and transfusion with adverse events, including death, it “does not provide incremental data as to causality,” they note.

Furthermore, “multivariate analysis adjusting for known confounders and sensitivity analyses evaluating bivalirudin and heparin monotherapy suggest that the benefit of bivalirudin over heparin monotherapy is independent of GPI use,” Dr. Gibson and colleagues observe.

A Bivalirudin Bonus?

“It has been hypothesized that the big benefit of bivalirudin is in [reducing] bleeding,” Dr. Gibson told TCTMD in a telephone interview. “But myocytes have thrombin receptors, and if thrombin binds to them, it triggers cell death, called apoptosis…. If you block those receptors [with the direct thrombin inhibitor bivalirudin], you actually preserve heart muscle by preventing apoptosis.

“So I think the exciting thing about these data is that they speak to an alternate mechanism of benefit of bivalirudin in addition to bleeding [reduction],” he said.

As to why the study failed to include ischemic endpoints like stent thrombosis and urgent revascularization—which were increased with bivalirudin in several earlier studies—Dr. Gibson noted that these events require adjudication, which was not possible when relying on hospital records. However, he stressed, “You don’t need to adjudicate death. Death integrates safety and efficacy, and there you do see a benefit.”

The investigators chose to focus on comparison of bivalirudin and heparin when a GPI was added—either routinely or as bailout—“because once the decision had been made to use a GPI, that removed a little of the confounding [of patient selection],” Dr. Gibson observed.

Asked if part of the motivation for the study was to address economic objections to bivalirudin use, Dr. Gibson acknowledged that cost is a consideration, especially for hospital pharmacy managers. “But the big win is in mortality,” he said.

Overall, Dr. Gibson said, the results suggest that bivalirudin “offers a very safe and effective alternative” to heparin in CHF patients.

Current Equipoise

According to Matthew A. Cavender, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), “It is clear that GPIs increase the risk of bleeding. In this analysis, when bivalirudin was compared to heparin only, there was no difference in the rates of clinically apparent bleeding,” although importantly mortality was lower with bivalirudin.

“As interventional cardiologists have moved away from the routine use of [GPIs], randomized studies are needed that compare bivalirudin and heparin while limiting [GPIs] to provisional use in both treatment groups,” he said in an email with TCTMD.

Currently, there is “clinical equipoise regarding the choice of anticoagulation used in patients undergoing PCI,” contended Dr. Cavender, who is the lead author of a recent meta-analysis of randomized trials comparing bivalirudin and heparin. “It is likely that bivalirudin reduces bleeding even when compared to patients treated with heparin only; however, this reduction… is counterbalanced by an increase in the risk of [MI] and acute stent thrombosis. As such, we need to develop strategies to better understand the patients most likely to benefit from therapies that reduce bleeding and the patient populations most likely to benefit from therapies that are more effective in reducing ischemic and thrombotic complications of PCI.”

Note: Two coauthors are faculty members of the Cardiovascular Research Foundation, which owns and operates TCTMD.

Pinto DS, Kohli P, Fan W, et al. Bivalirudin is associated with improved clinical and economic outcomes in heart failure patients undergoing percutaneous coronary intervention: results from an observational database. Catheter Cardiovasc Interv. 2015;Epub ahead of print.

Disclosures:

• Dr. Gibson reports serving as a consultant to The Medicines Company.
• Dr. Cavender reports no relevant conflicts of interest.

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