The most effective antithrombotic regimen for preventing ischemic complications while limiting bleeding risk in patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS) remains uncertain. Recent studies comparing the use of unfractionated heparin (UFH) with or without glycoprotein IIb/IIIa inhibitors (GPI) and bivalirudin in ACS patients have come to conflicting results in terms of ischemic, bleeding, and combined outcomes. Given the absence of clear evidence for anticoagulant selection in ACS, the Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of AngioX (MATRIX) program aimed to clarify the impact of bivalirudin selection on both thrombotic and bleeding events.

The MATRIX antithrombotic study was designed to determine the role of bivalirudin administration across the whole spectrum of ACS intended for an early invasive strategy, including clarifying the optimal duration of bivalirudin infusion in patients undergoing PCI. The MATRIX trial randomly assigned patients with ACS to receive either bivalirudin or UFH. Patients in the bivalirudin arm were randomized again to receive or not to receive a post-PCI bivalirudin infusion. The second randomization aimed to test the superiority of a strategy of pursuit of bivalirudin after PCI as compared to a strategy of interruption. The primary objective of the MATRIX antithrombotic arm was to assess whether bivalirudin, as compared with UFH plus provisional GPI, decreases the 30-day incidence of an ischemic (i.e., death, myocardial infarction [MI], or stroke) or an ischemic and bleeding composite endpoint (i.e., death, MI, stroke, or major bleeding defined by Bleeding Academic Research Consortium [BARC] 3 or 5 bleeding events). The primary outcome for the comparison of a post-PCI bivalirudin infusion with no post-PCI infusion was a composite of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events. Over three years, 7,213 patients undergoing PCI at 105 sites in Europe were prospectively recruited. Overall, 26% of patients in the UFH arm and 4.6% of patients in the bivalirudin arm received a GPI. A prolonged bivalirudin infusion after PCI has been proposed in 47.7% of the bivalirudin-treated patients. Bivalirudin in ACS patients undergoing invasive management failed to significantly reduce the 30-day risk of the primary ischemic endpoint (10.3% of the bivalirudin group vs. 10.9% of the heparin group, relative risk (RR) = 0.94, 95% confidence interval [CI] 0.81-1.10, p = 0.45) or the co–primary ischemic and bleeding endpoint (11.2% in the bivalirudin group vs. 12.4% in the heparin group, RR = 0.89, 95% CI 0.78-1.10, p = 0.12), when compared with patients who received UFH. Definite stent thrombosis rates were significantly higher in the bivalirudin group (1.0% vs. 0.6%, p = 0.048). Surprisingly, treatment with bivalirudin did significantly reduce all-cause mortality (RR = 0.71, 95% CI 0.51-0.99, p = 0.042), including a statistically significant 30% (CI 0.50-0.98, p = 0.037) relative reduction in the risk of cardiovascular death and a 32% (CI 0.48-0.97, p = 0.032) reduction in the risk of cardiac death HR. In addition, bleeding rates were significantly reduced with bivalirudin. In MATRIX, investigators observed a 47% relative reduction in non-access-site bleeding (RR = 0.53 CI 0.34-0.83, p = 0.05), a 39% relative reduction in BARC 3 (RR = 0.61 CI 0.42-0.88, p = 0.008), and a 69% relative reduction in BARC 5 bleeding (RR = 0.31 CI 0.11-0.85, p = 0.0016). Thrombolysis in Myocardial Infarction (TIMI) and Global Utilization Of Streptokinase And Tpa For Occluded Arteries (GUSTO) bleeding measures were also significantly reduced. These findings were consistent across subgroups, including access site. Regarding the impact of bivalirudin treatment duration, post-PCI bivalirudin infusion did not significantly decrease the rate of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events compared with no post-PCI infusion (11.0% and 11.9%, respectively, RR = 0.91, 95% CI 0.74-1.11, p = 0.34). Moreover, post-PCI bivalirudin infusion was paradoxically associated with a higher rate of subacute stent thrombosis compared with no post-PCI bivalirudin infusion (RR = 4.37 CI 1.24-15-35, p = 0.01).

While showing no difference in terms of ischemic events during one-month follow-up between the two antithrombotic regimens, the main result of the MATRIX trial is consistent with previous studies. Among all the accumulated data on bivalirudin, no study demonstrated bivalirudin-based regimens that resulted in a lower rate of ischemic events. A pooled meta-analysis actually found opposite results with an increased risk of major adverse cardiac events in bivalirudin-treated patients versus Heparin-treated patients regardless of the ACS type or GPI use in the heparin arm.¹ A high proportion of the events of both co-primary endpoints were type 4a MI in the MATRIX study. Effect of bivalirudin seems to be neutral on MI in this trial, thus contributing to a negative overall trial for both endpoints.

Despite adequate antithrombotic management (use of anticoagulants in more than half of the patients before randomization, high rate of pretreatment with P2Y₁₂ inhibitors including a large proportion with ticagrelor and use of prolonged infusion in nearly half of the bivalirudin-treated patients), patients from the MATRIX trial experienced more acute or subacute definite stent thrombosis in the bivalirudin arm compared with the heparin arm. Use of bivalirudin has been consistently associated with increased risk of acute stent thrombosis in primary PCI studies.^2-4 Post-PCI prolonged bivalirudin infusion has been proposed to decrease acute stent thrombosis risk. Results of the MATRIX trial curiously showed the opposite.

One of the most striking findings of the MATRIX study is the dramatic reduction of bleeding events associated with bivalirudin compared with UFH and provisional use of GPI despite an optional use of GPI in the heparin arm. A consistent reduction in major bleeding risk across the first bivalirudin trials has been reported.^5-7 Interestingly, a recent meta-analysis including 16 trials comparing bivalirudin-versus UFH-based regimens demonstrated that the reduction of bleeding with bivalirudin largely depended on the concomitant use of GPI with UFH. Bleeding rates were reduced by almost half when bivalirudin was compared with UFH and planned GPI use (risk ratio, 95% CI: 0.53, 0.47-0.61). However, bleeding rates were similar when GPI use was provisional or planned in both arms.¹

This meta-analysis did not report any difference in the incidence of death in patients treated with bivalirudin compared with UFH. Surprisingly, bivalirudin was associated with a significant reduction of mortality in the MATRIX trial. This mortality benefit of the bivalirudin arm has been interpreted as a proof of concept that bleeding reduction finally translates into an improved survival.

Given the comparison with a control arm treated according to standard of care and the inclusion of high-risk patients, the MATRIX trial can be considered as a suitable reflection of current practice. The study is clearly limited in that it relied on a composite endpoint, and it was not powered for mortality or major bleeding alone. Drawing conclusions from secondary endpoints in a overall negative trial is obviously not rational. According to the main result of this study, routine use of bivalirudin does not offer a clear advantage over heparin among patients undergoing PCI in ACS. Results concerning mortality and bleeding are intriguing but should be considered as hypothesis generating data. Unfortunately, another randomized trial on bivalirudin versus heparin is not in the pipeline, and it is unlikely that new insights for anticoagulant selection in ACS will emerge in the near future.

References

1. Cavender MA, Sabatine MS. Bivalirudin versus heparin in patients planned for percutaneous coronary intervention: a meta-analysis of randomised controlled trials. Lancet 2014;384:599-606.
2. Steg PG, van 't Hof A, Hamm CW, et al. Bivalirudin started during emergency transport for primary PCI. N Engl J Med 2013;369:2207-17.
3. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218-30.
4. Shahzad A, Kemp I, Mars C, et al. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet 2014;384:1849-58.
5. Lincoff A, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein iib/iiia blockade compared with heparin and planned glycoprotein iib/iiia blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853-63.
6. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203-16.
7. Kastrati A, Neumann F-J, Schulz S, et al. Abciximab and heparin versus bivalirudin for non–ST-elevation myocardial infarction. N Engl J Med 2011;365:1980-9.

Keywords: Acute Coronary Syndrome, Adenosine, Angiography, Anticoagulants, Arteries, Follow-Up Studies, Heparin, Hirudins, Incidence, Myocardial Infarction, Peptide Fragments, Percutaneous Coronary Intervention, Platelet Glycoprotein GPIIb-IIIa Complex, Research Personnel, Risk, Standard of Care, Stents, Streptokinase, Stroke, Thrombosis

< Back to Listings