Sometimes the simplest questions in medicine have the most elusive answers. Coronary thrombosis has long been recognized as an important mechanism leading to myocardial infarction (MI), and antithrombotic therapy is a cornerstone of acute coronary syndrome management. Alongside the benefit of antithrombotic therapy comes the tradeoff of increased risk for bleeding, and in the era of primary percutaneous coronary intervention (PCI), the goals of administration of antithrombotic agents also include prevention of stent thrombosis. Intravenous anticoagulation, most commonly with bivalirudin or heparin, is an essential component of antithrombotic therapy in this setting.
For many years, researchers have examined which anticoagulant is better to use during PCI. Early trials showed fewer bleeding events with bivalirudin, but they were conducted when potent P2Y12 inhibitors were not available and glycoprotein IIb/IIIa inhibitors were routinely given with heparin. Furthermore, radial artery access, which is associated with lower rates of bleeding complications than femoral artery access, was not widely used. More recent trials have had varying results due to design differences, but suggest that bivalirudin is associated with lower rates of bleeding than heparin at the cost of more stent thrombosis. In this week’s NEJM, the results of the VALIDATE-SWEDEHEART trial, presented in August 2017 at the European Society of Cardiology Congress, attempts to clarify the uncertainties about anticoagulation at the time of PCI.
VALIDATE-SWEDEHEART is a recent addition to a series of randomized clinical trials that take advantage of the unique SWEDEHEART registry of pooled data from all Swedish hospitals that treat patients with acute coronary syndrome. The online platform allows enrollment, randomization, and collection of data for an entire population of patients. In VALIDATE-SWEDEHEART, 6006 patients with planned PCI for acute MI were randomized to receive bivalirudin (n = 3004) or heparin (n = 3002); 3005 patients had ST-segment elevation myocardial infarction (STEMI) and 3001 had non-STEMI (NSTEMI). Before the procedure, all patients received a potent P2Y12 inhibitor (ticagrelor, 94.9%; prasugrel, 2.1%, or cangrelor, 0.3%) and 90% of PCIs were performed with radial access. In the bivalirudin group, 65% of patients received a prolonged infusion. Rates of rescue glycoprotein IIb/IIIa inhibitor use were 2.4% in the bivalirudin group and 2.8% in the heparin group.
The primary outcome — a composite of death, MI, and major bleeding at 180 days — occurred in 12.3% of patients in the bivalirudin group versus 12.8% of patients in the heparin group (hazard ratio, 0.96; P=0.54). Individual secondary endpoints of death (2.9% vs. 2.8%), MI (2.0% vs. 2.4%), major bleeding (8.6% vs. 8.6%), and stent thrombosis (1.9% vs. 2.0%) did not differ significantly. Similar findings were observed at 30 days for the primary composite outcome (7.2% vs. 8.0%), death (1.9% vs. 1.7%), MI (0.8% vs. 1.1%), major bleeding (5.1% vs. 5.6%), and stent thrombosis (1.7% vs. 1.8%). There was no indication of a differential effect of therapy in various subgroups, including STEMI versus NSTEMI.
In an accompanying editorial, Dr. Gregg Stone identifies some limitations of the study that could have contributed to a null finding, such as lower-than-expected event rates, particularly at 30 days, which may be a more meaningful time point than 180 days for comparing procedural anticoagulants. Consequently, the study may be underpowered to detect a difference between agents if one exists. Furthermore, the combination of efficacy and safety measures in the primary endpoint could bias the outcome toward no net difference.
VALIDATE-SWEDEHEART offers some reassurance to cardiologists that in contemporary practice, either bivalirudin or heparin can be used at the time of PCI for acute MI without any significant difference in outcomes. However, the jury is still out on the final answer to the seemingly simple question of which drug to use during PCI. Fortunately, as Dr. Stone notes, investigators of the major randomized trials of the two therapies have agreed to pool all individual patient data to help clinicians decide which patients, depending on specific characteristics, would most benefit from one drug versus the other.
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Mike is a 2017-2018 NEJM Editorial Fellow and a hospitalist at Beth Israel Deaconess Medical Center. He graduated from Harvard Medical School and completed his internal medicine training at BIDMC.