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- Heart rate variability
- oxidative stress
- risk factors
- acute coronary syndrome
Despite recent substantial advances in risk factor management and cardiac care, the incidence of myocardial infarction remains a major public health concern across the globe. Recent European registry data demonstrate the incidence of all acute myocardial infarction to be around 190/100 000 people/year, with ST segment elevation myocardial infarction (STEMI) representing around 40% of that number.1 In multiple clinical trials, primary percutaneous coronary intervention (PCI) has been shown to be better than thrombolysis in the treatment of STEMI, and indeed the ESC, ACC and AHA all recommend primary PCI as first-line reperfusion treatment.2 3 Although primary PCI is first line of treatment for STEMI, adjuvant antithrombotic pharmacotherapy varies widely, and the optimal antithrombotic regimen is still the source of debate as head-to-head trial evidence of all the options is limited.
Recent studies have demonstrated that the use of bivalirudin, a hirudin-type drug which acts as a direct thrombin inhibitor, before and during primary PCI is associated with reduced cardiovascular mortality and morbidity as compared with the use of unfractionated heparin and GpIIb/IIIa inhibitors.4 In the open-label HORIZONS-AMI trial, 3602 patients presenting with STEMI were randomised to receive either bivalirudin or unfractionated heparin with a GpIIb/IIIa inhibitor as adjunctive antithrombotic treatment. The authors prespecifed two primary end points, the incidence of major bleeding and a composite end point of the combination of major bleeding and the incidence of major adverse cardiovascular events, including death, reinfarction, target vessel revascularisation for ischaemia and stroke. They demonstrated a 24% RR reduction (9.2% vs 12.1%) in the composite end point in the bivalirudin group as compared with the heparin and GpIIb/IIIa inhibitor group. This difference was driven mainly by the reduction in major bleeding events, with a 40% RR reduction (4.9% vs 9.3%) in major bleeding as in previous trials such as ACUITY.5 It is interesting that in the bivalirudin group, there was a significant increase in the incidence of acute stent thrombosis occurring in the first 24 h after intervention (1.3% vs 0.3%), a difference no longer evident at the 30-day point, where major cardiovascular events were lower in this group. The authors concluded that adjuvant antithrombotic treatment during primary PCI with bivalirudin offers a significant clinical benefit over the combination of unfractionated heparin and GpIIb/IIIa inhibitors.
It is interesting to note, however, that in the HORIZONS-AMI trial, two-thirds of patients received a bolus of heparin before receiving bivalirudin in the ‘bivalirudin alone’ group, and therefore the impact of the additional heparin in this group is unknown. In their paper published in this issue of Heart, Koutouzis and colleagues present a study that examines this issue (see page 1484).6 In a ‘real-world’ report from the Swedish Coronary Angiography and Angioplasty Registry, the authors report data from all patients in Sweden presenting with acute STEMI over a 52-month period who were treated with bivalirudin as the primary adjuvant antithrombotic treatment to primary PCI. Of the 19 687 primary PCIs carried out in the study period, bivalirudin was used in 3379 procedures (17%), although 2996 procedures were finally analysed as meeting all the study inclusion and exclusion criteria (15%). In this group, approximately two-thirds received bivalirudin alone, and a third received additional unfractionated heparin either before or during the PCI procedure. The primary end point specified was the combination of death or definite target lesion thrombosis at 30 days after the index procedure.
In this observational (non-randomised) analysis it is important to note that these two groups differed, as expected, and the patients treated with bivalirudin alone tended to be older, have more comorbidities including diabetes mellitus, previous myocardial infarction, previous coronary artery bypass surgery and they were more likely to have three-vessel or left main stem stenoses than the bivalirudin and heparin group. Furthermore, these patients were less likely to receive complete revascularisation, consistent with more advanced coronary atheroma, and were significantly more likely to require the use of an intra-aortic balloon pump. One would therefore expect these patients to represent a more high-risk population, in whom the primary end point of death or target lesion thrombosis would be reached more often. Furthermore, when analysing the occurrence of bleeding complications, it should be noted that in the bivalirudin-alone group 82% of patients were treated by the femoral route, compared with only 47% of those in the combination treatment group. Recent evidence indicates that the use of the transradial route reduces the incidence of bleeding complications7 during and after coronary intervention.
With these important clinical differences in mind, the authors report an unadjusted 45% RR reduction (HR=0.55, 95% CI 0.41 to 0.72) in the occurrence of the primary end point of death or target lesion thrombosis when patients were treated with heparin in addition to bivalirudin as compared with bivalirudin alone. After adjustment this benefit remained significant, with a RR reduction of 36% (HR=0.64, 95% CI 0.44 to 0.95), although neither death alone, or target lesion thrombosis alone reached statistical significance. Furthermore, the incidence of major bleeding events (not a prespecified end point) was not increased significantly with the addition of heparin to bivalirudin, although it should be noted that the overall event rate was low and therefore the study was not adequately powered to detect small increases in bleeding risk.
Large international clinical registries such as GRACE8 and smaller registry studies such as that reported by Koutouzis and colleagues6 are important in evaluating the real-world benefit of new treatments outside the clinical trial environment. In clinical trials, the population studied is highly selected and deliberately chosen to show the maximal benefit, or harm, of a particular treatment strategy and hence allow definite statements to be made about the trial comparisons. While such studies are crucially important in forwarding medical science and clinical treatment regimens, questions always remain about the benefits of these new treatments in a real-world setting where patients are more likely to have multiple medical complaints, to be older and to be taking other drugs and likely to have more extensive coronary and systemic vascular disease. The fact that the Swedish Coronary Angiography and Angioplasty Registry study showed significant benefits in the real-world setting is an important strength, and helps to underline the benefit of the combination of heparin and bivalirudin as adjuvant antithrombotic treatment in the treatment of acute STEMI.
The findings of Koutouzis and colleagues suggest that for those patients treated with bivalirudin as the primary antithrombotic treatment during primary PCI, addition of a bolus of unfractionated heparin is both safe—without significant increase in bleeding events—and offers a small clinical benefit by reducing death or target lesion thrombosis. The underlying mechanism of this effect remains unexplained, although it is clear that this is driven by events in the first 30 days, as the authors also present data from the subsequent 11 months, showing no difference in death or target lesion thrombosis beyond the first 30 days. As discussed earlier, randomised clinical trials of bivalirudin demonstrated that there was a small increase in acute stent thrombosis immediately after the index procedure. Although Koutouzis and colleagues did not demonstrate a significant reduction in definite target lesion thrombosis alone, this was defined as angiographically proven thrombotic occlusion of the previously deployed coronary stent. It is likely that abrupt closure of the previously treated artery could have led to some adverse outcomes and a proportion of these patients would not have survived to repeat angiography, or might have had an ischaemic event and been treated conservatively with additional antithrombotic treatments. It seems logical that this clinical benefit is driven by a reduction in thrombotic events in patients treated with the combination treatment, and indeed this is supported by the post hoc analysis of HORIZONS-AMI where there was a significant reduction in the incidence of stent thrombosis in patients pretreated with unfractionated heparin.9
Overall, the results presented by Koutouzis and colleagues provide an important advance in the use of bivalirudin as the primary adjuvant antithrombotic treatment during primary PCI and suggest that this should be combined with a bolus of unfractionated heparin either before or during the procedure itself.
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