HORIZONS-AMI: Mortality Reduction with Bivalirudin Only Partially Due to Bleeding

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Even in the absence of major bleeding, patients with ST-segment elevation myocardial infarction (STEMI) who receive bivalirudin rather than unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor (GPI) during percutaneous coronary intervention (PCI) are less likely to die of cardiac causes by 3 years. The findings, from a post hoc analysis of HORIZONS-AMI data published online October 16, 2013, ahead of print in the Journal of the American College of Cardiology, suggest that bivalirudin may carry non-hematologic benefits.

In the main HORIZONS-AMI (Harmonizing Outcomes with RevascularIZatiON and Stents in Acute Myocardial Infarction) trial, 3,602 STEMI patients were randomized to bivalirudin (n = 1,800) or heparin plus a GPI (n = 1,802). As reported previously, 3-year follow-up showed an advantage for bivalirudin over heparin plus GPI use in terms of both cardiac mortality (2.9% vs. 5.1%; P = 0.001) and non-CABG major bleeding (6.9% vs. 10.5%; P < 0.0001). Reinfarction also was less common with bivalirudin (6.2% vs. 8.2%; P = 0.04).

For the current analysis, Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), and colleagues sought to understand how much of the decrease in cardiac mortality could be attributed to reduced bleeding.

Patients Without Bleeding Benefit Too

Major bleeding occurred in 7.2% of patients within 30 days and 8.5% within 3 years. Notably, 3-year cardiac mortality was reduced in patients who received bivalirudin whether they experienced major bleeding or not (table 1).

Table 1. Mortality at 3 Years

Cardiac death most often resulted from LV failure or sudden cardiac death, and the etiology of cardiac death did not differ between the randomized treatment arms. In addition, infarct size and LVEF were similar for the 2 groups.

In-hospital thrombocytopenia occurred at an overall rate of 11.7%, affecting more patients in the heparin plus GPI group compared with the bivalirudin group (13.1% vs. 10.4%; P = 0.004). However, patients who developed the complication had higher 3-year cardiac mortality only if they were in the heparin plus GPI group (12.3% vs. 3.5%; HR 4.36; 95% CI 2.73-6.95; P < 0.0001), whereas the bivalirudin group suffered no excess risk (2.3% vs. 2.5%; HR 1.44; 95% CI 0.50-4.12; P = 0.51).

On multivariate analysis adjusting for baseline characteristics as well as in-hospital thrombocytopenia and 3-year major bleeding and reinfarction, bivalirudin treatment was still independently associated with a 3-year reduction in cardiac mortality (adjusted HR 0.57; 95% CI 0.39-0.83; P = 0.003).

Still No Explanation for Long-term Advantage

Lloyd W. Klein, MD, of the Advocate Illinois Medical Center (Chicago, IL), commented to TCTMD in a telephone interview that it is difficult to understand exactly how short-term reductions in bleeding might continue to influence mortality over the long-term. That, he said, is the “difficult thing about HORIZONS. . . . On the surface of it, it really doesn’t make any sense.”

According to Dr. Klein, the link between major bleeding and cardiac mortality is likely an association rather than a causative relationship.

As shown here, bleeding is “only part of the explanation,” Dr. Klein noted. One possibility is that “bleeding is a sign of frailty, and that people who are frail are more apt to have this very easily disrupted balance between bleeding and clotting.” Whether the culprit is frailty itself or some other associated factor is still unknown, he added.

In an e-mail communication with TCTMD, Morton J. Kern, MD, of the University of California, Irvine (Irvine, CA), reported being unsurprised to see an association between major bleeding and long-term mortality. Yet he agreed that it is “mysterious as to how any immediate effect from a cath results in late benefit, but the bleeding may be a marker of more severe vascular disease and hence associated with worse outcomes.”

Mechanism Could Inform Patient Selection

There is no obvious factor other than bleeding to account for the mortality benefit seen with bivalirudin, Dr. Kern added. Regardless of the mechanism, he said, “bivalirudin is a good option and may even be better . . . for those at higher risk.”

Dr. Klein similarly noted that the uncertainty does not in any way weaken the case for using bivalirudin. There is growing support for giving bivalirudin across the board because of its ability to reduce bleeding, he reported. “And that’s perfectly fine,” Dr. KIein said. “But I’m more interested in if there’s a particular subgroup of people in whom bivalirudin has an advantage, and I personally think that there is.”

In a telephone interview with TCTMD, Dr. Stone said that the HORIZONS investigators “had believed that most of the clinical benefit from bivalirudin was due to the prevention of major bleeding and possibly due to the prevention of thrombocytopenia. So we were very interested to see several aspects of this study, most notably the fact that almost half of the reductions in death occurred in patients without any evidence of overt bleeding.”

Based on the current findings, Dr. Stone added, it appears “that there are unmeasured hematologic benefits of bivalirudin, which have been demonstrated experimentally but are difficult to measure in man, such as decreased inflammation, apoptosis, and reperfusion injury and other such mechanisms.” Future trials comparing the 2 anticoagulation strategies should try to prospectively measure differences in these factors and their link to subsequent outcomes, he advised.

Frailty could be important, Dr. Stone acknowledged, but even if that were confirmed, the exact mechanism by which frailty interacts with bivalirudin vs. heparin plus GPI use remains unknown.

Note: Dr. Stone and coauthor Roxana Mehran, MD, are faculty members of the Cardiovascular Research Foundation, which owns and operates TCTMD.

 

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Source:
Stone GW, Clayton T, Deliargyris EN, et al. Reduction in cardiac mortality with bivalirudin in patients with and without major bleeding: The HORIZONS-AMI trial. J Am Coll Cardiol. 2013;Epub ahead of print.

 

 

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