Author + information
- Dominick J. Angiolillo, MD, PhD∗ (, )
- Fabiana Rollini, MD and
- Francesco Franchi, MD
- ↵∗Address for correspondence:
Dr. Dominick J. Angiolillo, University of Florida College of Medicine-Jacksonville, 655 West 8th Street, Jacksonville, Florida 32209.
- acute coronary syndrome
- glycoprotein IIb/IIIa inhibitors
- percutaneous coronary intervention
The early phase of an acute coronary syndrome (ACS) is characterized by an increased risk of thrombotic complications, underscoring the need for fast-acting, safe, and efficacious antithrombotic therapies, particularly among patients undergoing percutaneous coronary intervention (PCI) (1,2). Because of the central role of thrombin on enhancing the prothrombotic milieu, strategies that target thrombin-mediated effects have become essential in this setting (1,2). To this extent, unfractionated heparin (UFH) and bivalirudin are fast-acting intravenous anticoagulants available in clinical practice. UFH is an indirect thrombin and factor Xa inhibitor, the pharmacokinetic and pharmacodynamic profiles of which are characterized by high intra- and interpatient variability (2). Moreover, UFH has been associated with an increase in platelet reactivity (3). Before the introduction of the more effective oral P2Y12 inhibitors, glycoprotein IIb/IIIa inhibitors (GPIs) were commonly used in adjunct to UFH to reduce periprocedural thrombotic events. However, the increased rates of major bleeding complications with GPI use and the ever-increasing awareness of the poor prognostic implications associated with bleeding, including increased mortality, have reinforced the importance of bleeding reduction strategies (4,5). Bivalirudin is a direct thrombin inhibitor with a linear dose−response profile that leads to more predictable anticoagulant effects (2). Several clinical trials have supported the superior safety (i.e., reduced bleeding), without a tradeoff in efficacy, of bivalirudin compared with UFH plus routinely administered intravenous GPIs in ACS patients who are undergoing PCI (6). However, the evolution in technical expertise and devices, as well as the expansion of the armamentarium of antithrombotic therapies available for patients undergoing PCI, have led to a decline in GPI use (4). This has inevitably questioned the role of bivalirudin in the modern era of interventional pharmacology, which is largely characterized by only provisional GPI use.
With this background, in the MATRIX (Minimizing Adverse Hemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox) trial, patients with an ACS who underwent PCI were randomized to receive either bivalirudin or UFH with or without GPIs at operator discretion. The MATRIX trial was designed to demonstrate the superiority of bivalirudin over UFH ± GPI on the coprimary endpoints of major adverse cardiovascular events (MACEs; a composite of death, myocardial infarction, or stroke) and net adverse clinical events (NACEs; a composite of MACEs or major bleeding not related to coronary artery bypass graft) (Bleeding Academic Research Consortium [BARC] type 3 or 5) at 30 days. However, despite a significant reduction in major bleeding, all-cause death, and cardiac death, neither of the primary endpoints were met (7).
In this issue of the Journal, Gargiulo et al. (8) report the results of a pre-specified analysis of MATRIX that compared bivalirudin versus UFH with or without planned GPI use. Among the 7,213 randomized patients, 3,610 patients were assigned to bivalirudin and 3,603 to UFH. By nature of the trial design, the use of GPI was not balanced between the groups; among those who received UFH, 781 patients (21.7%) had planned GPI treatment, whereas bailout use of GPI was similar between the groups (4.5% with bivalirudin and 5.4% with UFH). After multivariable and propensity score adjustments, the rates of both MACEs and NACEs were not significantly lower with bivalirudin than with UFH, regardless of planned GPI use. However, bivalirudin significantly reduced major bleeding complications, including fatal bleeding, nonaccess site−related bleeding, and need for transfusion, regardless of planned GPI use. In addition, the unadjusted and propensity score adjusted analyses showed a trend toward a reduction in all-cause and cardiovascular mortality with bivalirudin compared with UFH alone (8).
Although in the setting of a trial that was negative for its primary endpoints no claim of superiority on secondary endpoints can be made, the findings of this elegant analysis are noteworthy and of clinical value. These results are assertive of the bleeding risk reduction achieved with the use of bivalirudin compared with UFH, which is consistent regardless of GPI use. Reduced bleeding with bivalirudin is a finding in line with several other major ACS trials (9). It has been argued that the benefit of bivalirudin on major bleeding and mortality could be attributed to a reduction of access site bleeding in patients undergoing PCI through femoral access, an approach that is now largely in decline (10). However, in the current analysis, bivalirudin reduced mainly BARC 3 or 5 nonaccess site−related bleeding, regardless of GPI use. In addition, access site bleeding was reduced, despite the approach used (radial or femoral).
Although the reduction in bleeding observed in MATRIX is consistent with many historical studies, the more recent HEAT-PPCI (How Effective are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention) and VALIDATE-SWEDEHEART (Bivalirudin versus Heparin in ST-Segment and Non–ST-Segment Elevation Myocardial Infarction in Patients on Modern Antiplatelet Therapy in the Swedish Web System for Enhancement and Development of Evidence-based Care in Heart Disease Evaluated according to Recommended Therapies Registry Trial) trials, which were conducted with a contemporary approach of predominantly radial access and bailout-only use of GPI, did not show any benefit of bivalirudin compared with UFH (11,12). The results of these studies resulted in reduced enthusiasm toward the use of bivalirudin also in light of its costs. The inconsistency in results with MATRIX could be attributed to several factors. HEAT-PPCI was a relatively small, open-label, single-center trial that was conducted in only primary PCI patients (11). VALIDATE-SWEDEHEART was a registry-based, open-label clinical trial conducted in ACS patients. Although the trial did not meet its primary endpoint at 6 months, at 30 days, which is a more sensitive time point to detect differences between periprocedural antithrombotic agents on bleeding, there was a trend toward reduced bleeding with bivalirudin. Moreover, in the trial, UFH could be administered in the bivalirudin arm both upstream and during PCI, which might have mitigated these differences (12).
Some considerations need to be made when interpreting the results from Gargiulo et al. (8). First, in MATRIX, upstream administration of UFH was also allowed in the bivalirudin arm, which occurred in one-third of patients. Second, the allocation into the 3 groups (bivalirudin, UFH, or UFH+GPI) was not randomized, and use of planned GPI was at the discretion of the treating physician, which made the groups imbalanced in number and characteristics. Although the investigators performed detailed multivariate and propensity adjusted analyses, there were several known and unknown confounders, which could have affected the study endpoints, and even sophisticated statistical methods could not eliminate potential selection bias. Finally, the investigators did not provide information on the impact of duration and dose of bivalirudin infusion nor added these to their multivariable models.
In conclusion, despite the inability of more recent clinical trial data to demonstrate the superiority of bivalirudin compared with alternative antithrombotic regimens, the findings of MATRIX remain noteworthy in light of the non-negligible impact of bivalirudin on reducing bleeding complications. The well-established impact of bleeding on adverse outcomes, including mortality (5), is in line with the findings of the current analysis, although this needs to be interpreted with caution in the context of a trial that did not meet its primary endpoint and was not powered for mortality. Because of the unlikelihood of dedicated trials to address this aspect, the findings of MATRIX do open avenues for large-scale, patient-level analyses on the impact of bivalirudin on bleeding reduction and mortality. A benefit in terms of reduced mortality would trump the increased cost considerations associated with bivalirudin use. Moreover, although the MATRIX trial was not selectively conducted in patients at high bleeding risk, the results of this trial support dedicated investigations on the role of bivalirudin in high bleeding risk settings. Several ongoing trials are currently investigating strategies (e.g., different durations of dual antiplatelet therapy and stent platforms) to optimize outcomes in patients with high bleeding risk, and a clinical trial of periprocedural antithrombotic therapy conducted specifically in high bleeding risk patients is an unmet need.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Angiolillo is funded by the Scott R. MacKenzie Foundation and the NIH/NCATS Clinical and Translational Science Award to the University of Florida UL1 TR000064 and NIH/NHGRI U01 HG007269; has received consulting fees or honorarium from Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Janssen, Merck, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; has participated in review activities from CeloNova and St. Jude Medical; and has received institutional payments for grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli-Lilly, Gilead, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, and Renal Guard Solutions. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation
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