Registry Data Show Rise and Fall of Bivalirudin vs Heparin for Primary PCI

Bivalirudin use in primary PCI rose steadily between 2009 and 2013 but more recently, physicians in the United States have begun to return to unfractionated heparin, according to national registry data.

Several discordant studies have been published supporting one anticoagulant over the other in terms of bleeding and mortality benefits—not to mention cost—but as evidenced in a recent survey and at a debate session at TCT 2016, many interventionalists are still not convinced either way.

For this study, published online November 9, 2016, ahead of print in JACC: Cardiovascular Interventions, Eric Secemsky, MD, MSc (Massachusetts General Hospital, Boston), and colleagues looked at 513,778 patients undergoing PCI for STEMI between July 2009 and December 2014 within the NCDR CathPCI Registry. In 2009, bivalirudin was used in less than one-third of cases, but up until 2013 its use linearly increased, such that 44.7% of PCIs were performed with bivalirudin and 27.2% with unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor (GPI) at the end of 2013. During this time, evidence from trials like EUROMAX and HORIZONS-AMI seemed to convince clinicians that the novel antithrombotic was the better choice.

But this period coincides with the rise of transradial PCI, which was finding its way into more cath labs and bringing fewer bleeding complications with it, according to senior author Robert Yeh, MD (Beth Israel Deaconess Medical Center, Boston, MA). Then in 2014, the HEAT-PPCI study caused a rethink of bivalirudin’s popularity, demonstrating better efficacy and comparable safety with heparin. Though the study was criticized for its methodology, it’s clear that its publication had an effect on practice, Yeh told TCTMD.

In Secemsky et al’s analysis, bivalirudin use by the end of 2014 was 37.7% while heparin monotherapy use was 20.8%.

The study also looked at bleeding risk associated with both therapies. While bivalirudin was associated with decreased in-hospital bleeding and mortality compared with heparin in unadjusted analyses (P < 0.001 for both), it only remained associated with reduced bleeding (-3.75%; P < 0.001)—not mortality—in instrumental variable analyses. Additionally, when the greater use of GPIs with heparin was taken into account, bivalirudin’s bleeding benefit was halved (-1.75%; P < 0.001). For patients treated transradially, there was no bleeding benefit to using bivalirudin regardless of GPI use.

It’s increasingly believed that patients studied in older randomized trials had a much higher bleeding risk on heparin compared with bivalirudin because GPIs were then mandatory for the former and only used for bailout in the latter, Yeh observed. “So maybe the bad factor for bleeding is really the GPI and maybe has less to do with the anticoagulant of choice,” he said, commenting that the authors of HEAT-PPCI “were cognizant of this” and did not mandate GPI use for either arm.

This data reflects the “humongous variation” in practice that has been observed, Yeh said. “There were operators who used [bivalirudin] 100% of the time in their STEMIs, there were operators who used it 0% of the time, and there was everything in between. [This] really reflects the different opinions people have about the strength of the evidence supporting its use.”

As more operators move toward transradial procedures, Yeh said, this issue might become moot. “Right now, about a quarter of our STEMIs in the United States are treated transradially. That's too few,” he said. “If we were to drive up that transradial number, then I think we would be steadily decreasing the benefit associated with bivalirudin in this population because it looks like the absolute benefit of bivalirudin is significantly less when you eliminate access-site complications compared to heparin.”

This still needs to be confirmed “on the national scale,” he added.

Methodology Questions

In an accompanying editorial, John Bittl, MD (Munroe Regional Medical Center, Ocala, FL), says the study “contains a critical new clue . . . to answer the central unsettled question about antithrombotic therapy: What is more grave, bleeding or ischemic events?”

However, he expresses some skepticism about the methods used here, specifically the instrumental variable analysis, which might “give the impression of trying to obscure a mortality advantage of bivalirudin.” Also, after explaining the thought process behind this kind of statistical analysis, he comments that the results received remain “a mystery.”

In response, Yeh agreed that though this kind of analysis might be “complicated” and unfamiliar to many, it involves “well-described methods that have been used for decades in the literature [with] a strong mathematical basis.” He said his team used the approach because they thought it was “the best way of analyzing the data. So we didn’t want to sacrifice accuracy for the sake of simplicity.”

But given the lack of randomization in the study, “some type of adjustment seems reasonable,” Bittl says. Both this study and “a raft of RCTs” all suggest “that when a treatment decision is associated with a compromise between bleeding and ischemic events, the primacy of all-cause mortality can help clinicians and patients choose the best approach,” he concludes.

Note: Co-author Ajay Kirtane, MD, SM (Columbia University Medical Center, New York, NY), is a faculty member of the Cardiovascular Research Foundation, the publisher of TCTMD.