CardioSource WorldNews Interventions | It has been a 20-year battle between heparin and bivalirudin. Heparin was the workhorse for preventing closure of the dilated vessel after coronary angioplasty. One issue was the 5% to 10% rate of ischemic or hemorrhagic complications among heparin-treated patients. So, investigators set out to determine whether these complications could be prevented by using the direct thrombin inhibitor bivalirudin instead of heparin.

There were a pair of large multicenter trials (with identical designs) that compared the safety and efficacy of bivalirudin and heparin in 4,672 patients with unstable angina undergoing angioplasty. Both showed that bivalirudin was at least as effective as high-dose heparin in preventing ischemic complications and it carried a lower risk of bleeding (3.8% vs. 9.8% and p < 0.001 in one trial, for example).¹

Nevertheless, in a split vote, a Food and Drug Administration (FDA) panel originally recommended against approval for bivalirudin. Despite the large number of patients, neither study—nor in an analysis of the 2 datasets combined—demonstrated a significant difference between bivalirudin and heparin for the primary endpoint, defined as death, myocardial infarction (MI) during hospitalization, need for revascularization, or angiographic evidence of established or impending abrupt vessel closure. Yes, the FDA panel acknowledged, bivalirudin use led to fewer and less severe bleeding events in both trials, but this was not a primary endpoint.

In a short published item, Ileana Pina, MD, FACC, explained the panel’s decision.² She wrote that although heparin has become standard therapy during angioplasty, there had been no well-controlled trials demonstrating its effectiveness in this setting and was, in fact, not labeled for that indication.

In addition, there was no standard regimen or accepted schedule of heparin administration during angioplasty. In the submitted trials, the patients on heparin tended to have longer clotting times, which may have increased bleeding and prolonged hospitalization. Finally, the dosing regimen of heparin was amended in both trials, which the committee felt was further evidence of uncertainty in the standardization of heparin administration.

Even the pharmaceutical company that sponsored the original trial was disappointed in the results and halted the drug’s development. However, a couple of individuals decided the drug was worth further study; they started their own company, gained control of bivalirudin, and initiated a robust clinical trial program.

Debate Continued

In 2000, the FDA did approve the drug for unstable angina, providing an alternative to heparin in the catheterization lab. In subsequent studies another issue emerged. Clopidogrel, ticagrelor, and prasugrel do not break apart existing thrombus; yes, they prevent platelets from getting activated, but once aggregated these drugs do not break it apart. On the other hand, the glycoprotein IIb/IIIa inhibitors (GPI) do disaggregate and the use of these drugs made it more difficult to tease out the findings when they are used in trials ostensibly designed to evaluate bivalirudin versus heparin.

The MATRIX (Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX) trial, for example, was a large, ambitious trial enrolling 7,213 patients at 78 European centers. There were no differences in outcome between patients who received bivalirudin and those who received heparin before angiography and anticipated percutaneous coronary intervention (PCI).³

In an editorial accompanying the MATRIX results in the setting of acute coronary syndrome (ACS),⁴ Peter B. Berger, MD, FACC, noted that the authors provided no information about why investigators administered GPIs to more than one-quarter of the patients in the heparin group (vs. 4.6% in the bivalirudin arm) or how these patients differed from those who did not receive 1 of those drugs. Furthermore, the trial was confounded, as nearly all such trials have been, in that many patients in the bivalirudin group also received heparin, either upstream (in 32.3% of the patients) or in or after the catheterization laboratory (in 6.9% of the patients).

Wrote Dr. Berger: “The investigators properly conclude that the trial did not produce a clear winner — neither in the comparison of the 2 regimens for the prevention of a composite endpoint of cardiovascular adverse events or bleeding nor in the comparison of in-laboratory versus prolonged bivalirudin infusion.”

At this point, in 2016, we have a library of bivalirudin trial data: in the setting of PCI that includes CACHET, REPLACE-1, REPLACE-2, ISAR-REACT-3, NAPLES, and NAPLES 3; in ACS, the data come from ACUITY, PROTECT TIMI 30, ISAR-REACT-4, and TENACITY; in acute MI the trials include BRIGHT and MATRIX; and in ST-elevation MI, the list includes HORIZONS-AMI, EUROMAX, HEAT-PPCI, and BRAVE-4.

Both dosing regimens and endpoints studied have evolved. There have been plenty of meta-analyses, too, with no difference reported in major acute cardiac events, death or MI, but for subacute stent thrombosis (especially in the first 24 hours) that has been higher with bivalirudin and for major bleeding that has been lower with bivalirudin. That’s not to say the bleeding advantage is always present; in the setting of radial access, a lower dose of unfractionated heparin (< 75 vs. > 100 U/kg), or provisional use of GPIs, evidence suggests there really may be no bleeding benefit at all to bivalirudin use.

Then there is the issue of cost. At ACC.16, Eric R. Bates, MD, FACC, a professor of internal medicine at the University of Michigan Medical Center, Ann Arbor, noted that a vial of brand name bivalirudin is $958, its generic is $525, and cangrelor is $750 versus a bolus of eptifibatide at $150 or heparin at about $2.

So, in the battle between bivalirudin and heparin, is the war over? Dr. Bates suggested it depends, based on your ideological position. Are you looking at study data or a meta-analysis? What endpoints are of concern to you? What are your access site skills? What dose of unfractionated heparin are you considering? Is GPI use planned or provisional? And is cost a consideration?

Thus, after all this, the war may not be over as much as it has just petered out and plodded to a draw. Some interventionalists may still find a rationale for using bivalirudin while others can confidently continue to use heparin along with efforts aimed at reducing ischemic and hemorrhagic complications seen among heparin-treated patients.

References

1. Bittl JA, Strony J, Brinker JA, et al. N Engl J Med. 1995;333:764-9.
2. Piña I. Circulation. 1999;99:1277.
3. Valgimigli M, Frigoli E, Leonardi S, et al. N Engl J Med. 2015;373:997-1009.
4. Berger PB. N Engl J Med. 2015;373:1069-70.

Read the full November/December issue of CardioSource WorldNews Interventions at ACC.org/CSWNI

Keywords: CardioSource WorldNews Interventions, Angina, Unstable, Angioplasty, Antithrombin Proteins, Heparin, Hirudins, Hospitalization, Myocardial Infarction, Peptide Fragments, United States Food and Drug Administration

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