Percutaneous intervention (PCI) has become standard care for treatment of patients suffering from acute coronary syndrome consisting of ST-elevation myocardial infarction (STEMI), non ST-segment elevation myocardial infarction (NSTEMI) and unstable angina. The procedure demands, for success, adjunctive therapy in the form of antiplatelet agents and anticoagulants. The Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial established the role bivalirudin (a direct thrombin inhibitor); the trial compared bivalirudin with heparin plus a glycoprotein inhibitor (GPI) in patients with STEMI, with bivalirudin recording survival benefit extending to 3 years, albeit with a 5 fold increased incidence of stent thrombosis (ST) (1).
The latest meta-analysis (2), however, comparing bivalirudin with heparin without routine use of glycoprotein IIb/IIIa inhibitors (GPI’s) published in the current EuroIntervention, documents no difference in mortality, reduced rates of bleeding, but significantly increased acute stent thrombosis with bivalirudin. This meta-analysis includes 3 recent randomized trials (HEAT-PPCI , NAPLES III, and BRAVE 4) that had questioned the superiority of bivalirudin over heparin in the setting of acute myocardial infarction as provided by the HORIZONS-AMI trial; and overall 10,065 patients from 10 randomized trials.
The HORIZONS-AMI trial had randomly assigned 3602 patients with ST-segment elevation myocardial infarction to bivalirudin or to heparin plus a GPI. The major net adverse clinical events (NACE) were defined as a combination of major bleeding and combined adverse clinical events (death, reinfarction, target vessel revascularization for ischemia and stroke). The authors had concluded that anticoagulation with bivalirudin alone as compared to heparin and a GPI resulted in significantly reduced 30-day rates of major bleeding and NACE. There was significant reduction in all cause and cardiovascular deaths, and this was presumed to be because of lesser bleeds.
The HEAT-PPCI (3) was a single center study that randomized patients with STEMI to bivalirudin (bolus of 0.75 mg/kg followed by infusion of 1.75 mg/kg/hour or heparin bolus of 70 U/kg pre-procedure. The primary efficacy end point (MACE defined as all cause mortality, cerebrovascular accident, reinfarction, or target lesion revascularization) occurred in 8.7% with bivalirudin and 5.7% of heparin-treated patients, at 4 weeks. Definite or probable ST was observed significantly more with bivalirudin than with heparin (3.4% vs. 0.9%, p=0.001); stent thrombosis was seen almost 4 times more with bivalirudin as compared with heparin. The HORIZONS-AMI trial too had shown 5 times greater ST in bivalirudin treated patients. The major difference in the HEAT-PPCI vs. HORIZONS-AMI was that heparin was employed alone, without routine or mandatory use of a GPI. A GPI was used only as a bailout strategy in the event of a large thrombus burden or no-reflow.
The NAPLES III (4) trial comparing bivalirudin with heparin alone also did not observe differences in major or minor bleeding. NAPLES III was a single center, investigator randomized controlled trial, which studied safety and efficacy of bivalirudin compared with heparin alone in patients considered at increased risk of bleeding; included 837 patients with 419 randomized to heparin and 418 patients to bivalirudin ; the primary end point was the rate of in-hospital major bleeding. At 30 days clinical endpoints, including death, myocardial infarction, ST, and major bleeding were also similar.
The BRAVE 4 (5) not unlike the HEAT-PPCI compared heparin without routine GPI with bivalirudin in STEMI patients. BRAVE 4 also studied synergistic effects of prasugrel plus bivalirudin compared to clopidogrel plus heparin. The researchers were unable to find any difference in the composite of ischemic complications or bleeding complications.
A large Chinese study, BRIGHT, included 2,194 patients with STEMI, and compared bivalirudin with heparin plus routine GPI or heparin alone (6). At 30 days NACE was significantly reduced with bivalirudin compared to heparin plus GPI, and a trend to lower NACE events were seen in the bivalirudin vs. heparin-monotherapy arm. Bleeding events were reduced significantly by 50% to 60%. There were no statistically significant differences between treatments at 30 days between treatments in major adverse cardiac or cerebral events, stent thrombosis, thrombocytopenia. The results prevailed at one year. Bivalirudin used in the BRIGHT trial was manufactured locally in China, and all patients in the bivalirudin treatment arm received a median 3-hour infusion post procedure. This is the only study that did not show increased ST.
The Chinese study however did not use the newer and more powerful oral anti-platelets such as prasugrel or ticagrelor.
The MATRIX study (7) has been the only other study that has observed lower mortality with bivalirudin compared to heparin despite there being no difference in the composite major cardiovascular events at 30 days. There were lesser bleeds with bivalirudin as compared to heparin. It has however been noted that there was higher usage of GPI in the heparin arm (26% vs. 4.6%); also BRIGHT used high doses of heparin (100 U/kg as monotherapy and 60 U/kg with a GPI). But the higher use of a GPI in the heparin arm could imply inferior efficacy of heparin in the dose employed for the patients.
Bivalirudin has also been studied as pre-hospital treatment for patients of STEMI. The EUROMAX trial assigned 2218 STEMI patients to bolus plus infusion of bivalirudin or heparin with optional GPI, started during transportation itself. Bivalirudin was administered as bolus of 0.75 mg/kg and then infusion at 1.75mg/kg/hour for 4 hours post primary PCI procedure, at the same dose or at a reduced dose of 0.25 mg/kg/hour. Heparin was given as 100 U/kg alone or 60 U/kg with a GPI. Bailout GPI was used in presence of a large thrombus or no reflow (microvascular obstruction). Bivalirudin begun in the ambulance reduced major bleeding but raised the incidence of stent thrombosis. There was no significant difference in rates of death or reinfarction (8).
The MATRIX study comparing bivalirudin with heparin, despite not showing any difference in major adverse cardiac events (MACE), net adverse clinical events (NACE), or major bleeding, did record a 32% reduction in cardiac death. The absolute reduction in deaths by bivaluridin was only 0.6%, a reduction from 2.3% in the heparin arm to 1.7% in heparin treated patients. Definite ST was significantly higher with bivalirudin as compared to heparin-1% vs.0.6%The MATRIX study included both patients with STEMI and non-STEMI, and also assessed trans radial vs. trans femoral routes.
A previous meta-analysis of STEMI only patients (9) published in Catheter Cardiovascular Interventions, failed to show reduction in all cause mortality at 30 days despite lesser bleeds with bivalirudin; there was yet again significantly increased acute and 30-day ST. At 30 days, bivalirudin as compared to heparin was associated with similar risk of all cause mortality, bivalirudin significantly increased the risk of definite ST (2.39% vs. 1.06%, p=0.006), leading to significantly higher ischemia driven revascularization (2.5% vs. 1.5%, p=0.04), and increased non-significant reinfarction rates (2% vs. 1.3%, p=0.11). This meta-analysis involved 7,612 patients from 3 randomized STEMI trials. The authors conclude that bivalirudin (in patients with STEMI) did not significantly reduce major bleeding compared to heparin.
On distilling data, we find that by and large, bivalirudin when compared with unfractionated heparin during PCI, does not reduce mortality, may or may not cut down major bleeding, but almost in every study except BRIGHT, significantly increases stent thrombosis. Two German studies ISAR REACT 3(10) and ISAR REACT 4 (11) studying patients with NSTEMI had also not shown difference in stent thrombosis between bivalirudin and heparin groups. The only 2 studies to show reduced deaths with bivalirudin have been HORIZONS and MATRIX; HORIZONS however mandated combined administration of heparin plus a GPI while in MATRIX the lower death rate is considered hypothesis generating because the incidence of reinfarction and stroke were almost identical.
The HEAT-PPCI albeit demonstrating reduced major adverse clinical events with heparin, accompanied by equal bleeds with heparin when compared to bivalirudin was a single center small study. It is therefore imperative an adequately powered multicenter randomized trial is conducted in patients with STEMI to determine optimal antithrombotic and antiplatelet protocol that result in least bleeding and ischemic complications.
The conclusions drawn by the authors of HEAT-PPCI need to be reiterated; compared with bivalirudin heparin reduces incidence of major adverse ischemic events in the setting of PPCI, without increase in bleeding complication; systemic use of heparin rather than bivalirudin would reduce drug cost substantially; particularly in the current climate of crumbling economies and dwindling equity.
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