Reports

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22nd Annual Cardiovascular Conference at Lake Louise

Lake Louise, Alberta / March 26-30, 2006

Dr. Allan Ross, Professor of Medicine, George Washington University, Washington, DC, discussed at length the findings of the ASSENT-4 PCI (Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention). Because there can be a significant delay, perhaps even of several hours from the time a patient first experiences symptoms of myocardial infarction (MI) to treatment onset, facilitated PCI seeks to mitigate the effects of this delay. By administering a pharmacological reperfusion—in this case, tenecteplase (TNK) and unfractionated heparin—prior to transfer of the patient to a PCI lab, the reduction in benefit imposed by the delay could be mitigated. The rationale behind the recent ASSENT-4 PCI trial “was to investigate whether the administration of full-dose TNK before a delayed PCI could mitigate the negative effect of this delay” (Lancet 2006; 18(367):569-78). The primary end point of the study was the incidence of death, shock, and new congestive heart failure (CHF) at 90 days. However, the trial had to be terminated prematurely due to adverse events associated with facilitated PCI. Among the reasons for early cessation was the finding that there was significantly higher in-hospital mortality in the facilitated PCI group of 6% (43 of 664 patients) when compared to the standard PCI group of 3% (22 of 656 patients, P=0.0105). These findings led the researchers to conclude that facilitated PCI “cannot be recommended,” particularly when compared to PCI alone.

Dr. Ross described for delegates some of the reasons regarding the study design of the ASSENT-4 trial that might have resulted in the outcome. Specifically, Dr. Ross attributed the findings to the “delays encountered in this experience [which] were not of magnitude expected to negatively impact the excellent outcomes associated with mechanical reperfusion.” In essence, the time intervals chosen for the ASSENT-4 PCI study were not appropriate for comparing the standard PCI and facilitated PCI procedures.

“I thought—and I think everyone did—that the majority of patients in this trial would come from the non-PCI community hospitals, which would transfer their patients after diagnosis to a tertiary care facility. But only 35% of patients in ASSENT-4 were of that group,” Dr. Ross told delegates. He also indicated that the “adjunctive anticoagulation regimen might have been too conservative for the thrombogenic milieu,” perhaps resulting in unanticipated adverse events.

Another reason may have been chance itself. Given that the study anticipated enrolling 4000 patients but was stopped at 1667 patients, there was a risk of an inadequate statistical data pool. “When you do a trial intended to be 4000 patients strong, it is because your sample size calculation tells you that you need that many patients in order to have a reasonably firm conclusion. If you only have a third of them, then the possibility of what you see as being fallacious is very real,” Dr. Ross stated. “So in my opinion, time intervals, place of enrolment and lower-than-expected reperfusion rate in the facilitated group certainly provide some insight, perhaps, into the results of ASSENT-4 PCI. The very question we set out to ask is still, in my opinion, unanswered.”

WEST Study

The WEST (Which Early ST Elevation Myocardial Infarction Therapy) trial examined the hypothesis that optimal pharmacological therapy, instigated at the earliest point of care, with prompt TNK administration together with enoxaparin, would be comparable to timely PCI intervention. Dr. Paul Armstrong, Professor of Medicine, University of Alberta, Edmonton, told delegates, “The most appropriate therapy remains unclear for the large majority of STEMI patients in clinical environments where PCI within 60 minutes of presentation is not feasible.” Dr. Armstrong and his team stated the principal hypothesis as “Optimal pharmacologic therapy, at the earliest point of care, with prompt administration of TNK and enoxaparin [low molecular-weight heparin] will be non-inferior to the outcome achieved with timely direct PCI.”

Patients at high risk for acute MI within six hours from onset were enrolled and randomized at initial presentation. Patients were excluded if they were able to undergo PCI within 60 minutes of randomization or if they were contraindicated for fibrinolysis. “We emphasized early recognition and treatment,” said Dr. Armstrong. The primary end point of the study measured at 30 days was the incidence of death, recurrence of MI, refractory ischemia, CHF, cardiogenic shock or major ventricular arrhythmia. The trial randomized 304 patients into one of three treatment arms: Group A (n=100) patients received TNK, enoxaparin, ASA and “usual care” in the primary care setting, including PCI as indicated; Group B (n=104) patients were administered an initial dose of TNK, enoxaparin and ASA, transferred to a PCI-equipped hospital facility within 24 hours and given PCI as required; and Group C (n=100) patients were given enoxaparin, clopidogrel and ASA and treated by PCI as soon as possible, within three hours from randomization.

Dr. Robert Welsh, Assistant Professor of Medicine, University of Alberta Hospital, presented some of the latest findings from the WEST trial. The results at 30 days demonstrated similar primary efficacy end points: Group A at 25%, Group B at 24% and Group C at 23%. He reported that the WEST trial decreased by 47 minutes the time from onset of symptoms to first drug administration. Additionally, the time from symptom onset to PCI was decreased by 57 minutes. Even though challenges persist regarding the pre-hospital and in-hospital delays, Dr. Welsh pointed out that, “There is a therapeutic ‘sweet spot’ within the ambulance we should all be focusing in on moving forward. Especially notable are the opportunities provided through pre-hospital management with initiation of therapy, triage to appropriate hospitals or both, as major potential avenues to further enhance patient outcomes.” (Welsh et al. Am Heart J 2003; 145(1):1-8).

According to Dr. Welsh, the incidence of death was 4% among Group A patients and 1% each among Group B and Group C patients. “To my knowledge this is the lowest mortality ever published in a trial of 300 patients. In my opinion, it is achieved due to the very rapid time to treatments,” Dr. Welsh noted. In situations where time is of the essence, Dr. Welsh concluded that empowering decision makers might help “avoid reperfusion paralysis.”

With respect to angiographic imaging in the WEST trial, Dr. John Mancini, Division of Cardiology, Department of Medicine, University of British Columbia Vancouver Hospital and Health Sciences Centre, told delegates, “The WEST study shows flow/perfusion effects are intuitively in keeping with the expected results.”

Dr. Armstrong noted several implications of the WEST study findings. The first is that a pharmacologic catheter co-intervention strategy applied at an early point in care is safe and effective, even in a high-risk population; the second is that this type of care is especially relevant to pre-hospital settings, such as the ambulance, as well as in community hospitals. Based upon these findings, Dr. Armstrong concluded, “The WEST strategy deserves large-scale investigation.”

Summary

“Although the approach [facilitated PCI] as investigated in ASSENT-4 did not support the concept, it has by no means been fully and conclusively evaluated,” Dr. Ross stated. In describing the importance of PCI-related research, “The results have been rather encouraging in the modern era, suggesting that as we treat patients with our devices and our drugs today, facilitated PCI is actually quite good.” He added that these particular data has emerged from registries, retrospective analyses and some smaller trials, “None of them by themselves can be conclusive. But when they are looked at in the aggregate, they do favour PCI.” Dr. Ross posited that there is a need for future PCI research. “Facilitated PCI should have at least a future clinical trial.” Dr. Welsh concluded that “a systems-based approach” supports a “very effective and rapid therapy.”