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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - American Heart Association (AHA) Scientific Sessions 2011

Orlando, Florida / November 12-16, 2011

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

The quest to identify the most efficacious drug combination to prevent cardiovascular (CV) events has generated many trials comparing the various options. Due to the very high risk of events in patients undergoing either an ST-elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI)—particularly those requiring a percutaneous coronary intervention (PCI)—modest differences in anti-thrombotic efficacy can have a major influence on survival. Although unfractionated heparin (UFH) continues to be widely used in acute coronary syndrome (ACS) populations, new data presented here at the 2011 AHA reinforce a growing body of evidence that this agent is now second-line.

“There is a great deal of data regarding alternatives to UFH in patients undergoing PCI, but the problem has been that few direct comparisons to alternatives have been powered for hard clinical end points, particularly mortality,” reported Dr. Johanne Silvain, Hôpital Pitié-Salpétrière, Paris, France. In particular, he told delegates that although there are data to indicate that low molecular-weight heparins (LWMHs) are associated with a more favourable benefit:risk ratio than UFH, these have not produced a uniform change in practice because of the absence of conclusive studies.

Large Meta-Analysis Undertaken

The approach taken by Dr. Silvain and his colleagues was to develop a large meta-analysis based on all controlled trials conducted with enoxaparin, the most well studied of the LMWH agents in the setting of PCI. Two independent efforts to collect and then extract the data were employed to minimize bias. The objective was to compare enoxaparin to UFH for benefit:risk using hard outcomes, including overall mortality and bleeding events.

Based on an independent search of Medline, the Cochrane Controlled Trials Register database and published abstracts from major CV conferences by 2 reviewers, 229 studies were evaluated. Of these, 34 were of sufficient quality to be evaluated in detail and 22 met the prespecified criteria and quality parameters. The 22 trials evaluated 29,633 patients of which 13,604 received enoxaparin and 16,029 received UFH. The outcomes were expressed in risk ratios (RRs).

Dr. Silvain reported that in ACS patients undergoing PCI, “enoxaparin use was associated with a 34% reduction in death [RR 0.66; 95% CI, 0.57-0.76; P<0.001], a 32% reduction in death or MI [RR 0.68; 95% CI, 0.57-0.81; P<0.001] and a 20% reduction in the risk of major bleeding [RR 0.80; 95% CI, 0.56-0.93; P=0.009].”

In patients undergoing primary PCI for STEMI, the relative advantages were even greater. According to the data presented by Dr. Silvain, the mortality was reduced by 48% (RR 0.52; 95% CI, 0.42-0.64; P<0.001) in those who received enoxaparin vs. UFH, while the reduction in death or MI was 44% (RR 0.56; 95% CI, 0.42-0.76). Even though enoxaparin was associated with these large reductions in risk of events, it was also associated with a 28% reduction in major bleeding (RR 0.72; 95% CI, 0.56-0.93; P=0.01).

“Six studies in this meta-analysis randomized STEMI patients undergoing PCI, and all 6 associated enoxaparin with a reduction in mortality and a reduction in the risk of bleeding,” Dr. Silvain told delegates. Although the relative risk reduction with UFH only reached statistical significance in a few of these studies, the trends were consistent and did provide the robust difference seen when data were collated.

Other Study Findings

In another trial presented here at the AHA, combination UFH+glycoprotein IIb/IIIa inhibitor abciximab was compared to the thrombin inhibitor bivalirudin in patients with an acute NSTEMI undergoing PCI. The multicentre trial randomized 1721 patients. The primary end point was a composite of death, recurrent MI, urgent target vessel revascularization or major bleeding within 30 days. A secondary composite end point included the same end points plus death by any cause.

There was no significant difference in the proportion of patients who reached the primary end point (10.9% in the UFH/antiplatelet arm vs. 11.0% in the bivalirudin arm; P=0.94), but the regimens were not considered equivalent because of an 84% increase in the risk of bleeding (4.7% vs. 2.6%) in those receiving the combination (RR 1.84; 95% CI, 1.10- 3.07; P=0.02).

“UFH+abciximab did not reduce the rate of the primary end point relative to bivalirudin but it did significantly increase the risk of bleeding,” stated Prof. Adnan Kastrati, German Heart Center, Munich, Germany. Based on the fact that “results of PCI are strongly dependent on the efficacy and safety of the anti-clotting drugs used during the procedure,” Prof. Kastrati emphasized the importance of identifying the most efficacious regimens.

In another trial, a phase III evaluation of a new oral protease-activated-receptor 1 (PAR-1) antagonist, the results were less encouraging. Called TRA-CER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome), 12,944 NSTEMI patients, most of whom received PCI, were randomized to the oral PAR-1 antagonist vorapaxar or placebo on top of a standard antiplatelet therapy with ASA and clopidogrel. The primary end point in the phase III trial was a composite of death from CV causes, MI, stroke, hospitalization for recurrent ischemia or urgent revascularization. TRA-CER was published on-line by the New England Journal of Medicine concurrent with the AHA presentation.

After 2 years of follow-up, when the study was terminated prematurely, the end point was reached in 18.5% of those randomized to vorapaxar and 19.9% of those in the placebo group, which was not significantly different. Although there was a significant advantage for vorapaxar on the secondary end point of death from CV causes, MI or stroke (14.7% vs. 16.4%; RR 0.89; 95% CI, 0.81-0.98; P=0.02), the rates of moderate and severe bleeding were higher in the active treatment arm (7.2% vs. 5.2%; RR 1.35; 95% CI, 1.16-1.58; P<0.001). Moreover, rates of intracranial hemorrhage, although low, were much higher in the vorapaxar group (1.1% vs. 0.2%; RR 3.39; 95% CI, 1.78-6.45; P<0.001).

“Based on the phase II experience, we were both surprised and disappointed that we were unable to show a significant benefit on the primary end point in this study,” stated Dr. Robert Harrington, Duke Clinical Research Institute, Durham, North Carolina. Chair of the TRA-CER Steering Committee, he noted that the phase II studies predicted a greater protection against CV events and no increased risk of bleeding when compared to placebo.

Dr. Harrington’s Duke University colleagues and lead investigators of the study, Dr. Pierluigi Tricoci and Dr. Kenneth Mahaffey, agreed. According to Dr. Mahaffey, these results did not necessarily mean that further development of vorapaxar would be abandoned. Rather, he indicated that intensive evaluation of the differences in specific events and the causes of bleeding would be evaluated carefully. Both investigators characterized the lower rate of the secondary end point that included CV death and heart attack and stroke as “promising” and worthy of further evaluation.

Summary

One of the most important variables for reducing the risk of CV events in ACS patients is initiating an optimal antithrombotic regimen as quickly as possible after the diagnosis has been made. In general, the optimal regimen has been defined as one that provides the greatest reduction in events in the context of an acceptable risk of bleeding. However, there is now good evidence from the meta-analysis with enoxaparin vs. UFH that increased protection from events do not necessarily indicate an increased risk of bleeding. Credited to the more predictable effects of LMWH, these and other data suggest that options other than UFH offer advantages in the acute ACS population.