Patient-Level Pooled Analysis Supports Bivalirudin Use in Primary PCI

Anticoagulation with bivalirudin compared with heparin plus a glycoprotein IIb/IIIa inhibitor (GPI) reduces cardiac mortality and bleeding in STEMI patients undergoing primary PCI at the cost of more acute stent thrombosis, according to a patient-level analysis of 2 trials published in the January 6/13, 2015, issue of the Journal of the American College of Cardiology.

The results support bivalirudin (Angiomax; The Medicines Company) use in this setting “independently of vascular access site, choice of P2Y12 inhibitor, and timing of drug initiation and discontinuation,” the authors assert.

Researchers led by Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), grouped 5,800 patients enrolled in the multicenter, international HORIZONS-AMI or EUROMAX trials who were randomized to unfractionated heparin (60 IU/kg IV bolus) or enoxaparin (0.5 mg/kg IV bolus) with or without GPI (n = 2,911) or bivalirudin (0.75 mg/kg IV bolus, followed by either 0.25 or 1.75 mg/kg/h; n = 2,889). GPIs were used by 8.8% of the bivalirudin arm and 84.8% of the heparin arm. Prasugrel or ticagrelor were used as a loading dose in 18.1% of patients and as a maintenance dose in 20.5%.

Baseline characteristics were well balanced between treatment groups, and average patient age was 60.6 years. About one-quarter of patients were women, and 73.3% were enrolled in Europe. Radial access was used in 21.3%, and PCI with DES was the most common management strategy at 91.1%.

Advantages of Bivalirudin

Bivalirudin was associated with lower cardiac mortality at 30 days compared with heparin but higher rates of acute stent thrombosis. Additionally, there were decreases in non-CABG major bleeding and thrombocytopenia. Net adverse clinical events (MACE or protocol-defined non-CABG major bleeding) were reduced with bivalirudin (table 1).

 

There was no heterogeneity between the 2 studies in any of the major clinical endpoints. Moreover, there was consistency for all 30-day outcomes among several prespecified subgroups.

EUROMAX Changes the Game

The “increased acute stent thrombosis rate, occurring within the first 4 [hours] after abrupt discontinuation of bivalirudin infusion, may be due to residual thrombin activity after bivalirudin cessation and/or inadequate inhibition of adenosine diphosphate-induced platelet aggregation, attributable to the slow onset of action and inherent variability in response of clopidogrel,” Dr. Stone and colleagues write. “Moreover, stent thrombosis after 24 [hours] was more common in patients treated with heparin + GPI, representing a catch-up phenomenon after GPI infusion discontinuation.” Hence, stent thrombosis rates did not differ between treatment groups at 30 days or at 1 or 3 years, they say.

The authors outline several treatment advances incorporated into EUROMAX but not used in HORIZONS-AMI “[that] might affect the safety versus efficacy tradeoffs of bivalirudin during primary PCI.” These include:

 

• The use of faster acting and more potent P2Y12 inhibitors prasugrel and ticagrelor
• The routine use of extended bivalirudin infusion
• No prerandomization use of heparin compared with more than two-thirds in HORIZONS-AMI
• Growing use of radial access

 

With regard to newer P2Y12 inhibitors, though, Dr. Stone and colleagues write, “cangrelor…might be of greater benefit.” Furthermore, they add, “because preprocedural heparin was not administered in EUROMAX, we cannot completely exclude benefit from this practice in patients also treated early with potent adenosine diphosphate antagonists or with other procedures used only in this trial.”

Lastly, the authors observe, as the effect of bivalirudin on bleeding was independent of access site, this also reflects that “the majority of major hemorrhagic complications of PCI are unrelated to the access site.”

Overall, they note that the study may have been underpowered “to elucidate small differences in low-frequency safety events (or small subgroups), and the use of study-specific definitions, which may slightly vary (eg, reinfarction), adds some imprecision…. Longer-term follow-up from EUROMAX is required to further assess the durability and late benefits of bivalirudin.”

Editorial Identifies Several Issues

In an accompanying editorial, Sanjay Kaul, MD, of Cedars-Sinai Medical Center (Los Angeles, CA), questions whether these conclusions are justified.

Use of patient-level data, he notes, is a “particular strength [as they]… permit evaluation of each study’s quality and eligibility for inclusion in a meta-analysis, allowing confirmation of study outcomes, particularly time-to-event outcomes, and facilitating evaluation of the consistency of treatment effects across subgroups.”

However, because the EUROMAX trial alone did not show a bleeding reduction with bivalirudin, “it is much less certain whether there is a true mortality reduction,” Dr. Kaul observes, and unlike HORIZONS-AMI, EUROMAX did not show a reduction specifically in TIMI major bleeding. Thus, he concludes, “pooling results can yield misleading inferences of consistent treatment effects… across the 2 trials.

“Second, unconventional use of a composite efficacy (ischemic) and safety (bleeding) outcome, net adverse clinical events (NACE), biased the results of both trials in favor of bivalirudin,” Dr. Kaul writes, adding that similar “misleading” outcomes were utilized in both the REPLACE-2 and ACUITY trials, “where the difference in major bleeding events… exceeded the difference in MIs,… resulting in the NACE quadruple composite endpoint favoring bivalirudin.”

‘Out With the New’

Some argue that the observed reduction in cardiac mortality with bivalirudin in HORIZONS-AMI is adequate rationale for using bivalirudin during primary PCI, he continues. “However, its reliability is questionable; it was not a prespecified endpoint and therefore not adequately powered for comparison…. Furthermore, 2 mechanisms by which bivalirudin could potentially yield a mortality benefit, biomarker-determined or [MRI]-determined infarct size or [LVEF], were no different.”

Concluding, Dr. Kaul acknowledges certain proven benefits of bivalirudin but underlines its high cost “with no discernable efficacy or substantial safety advantage.

“Arguably, a new, carefully designed trial is required to cut the Gordian knot and adjudicate the uncertainties,” he writes. “Until then, like fine wine that never goes out of fashion, it is time for out with the new (bivalirudin), in with the old (heparin monotherapy with bailout GPI).”

Note: Dr. Stone and several of the study’s co-authors are faculty members of the Cardiovascular Research Foundation, which owns and operates TCTMD.

 

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Sources:
1. Stone GW, Mehran R, Goldstein P, et al. Bivalirudin versus heparin with or without glycoprotein IIb/IIIa inhibitors in patients with STEMI undergoing primary percutaneous coronary intervention: pooled patient-level analysis from the HORIZONS-AMI and EUROMAX trials. J Am Coll Cardiol. 2015;65:27-38.

 

2. Kaul S. Choice of optimal anticoagulant to support primary PCI: out with the new, in with the old [editorial]. J Am Coll Cardiol. 2015;65:39-42.

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• Meta-analysis: Less Bleeding, More Stent Thrombosis with Bivalirudin vs. Heparin After PCI
• BRIGHT: Prolonged Bivalirudin Results in Comparable Stent Thrombosis, Reduced Bleeding vs. Heparin
• HEAT-PPCI Published: Discrepant Finding of Heparin’s Superiority over Bivalirudin in Primary PCI Still Puzzles