Article

Will This Trial Change My Practice?

Abstract

At EuroPCR, 2014, Paris, a new session format was introduced to analyse how results of clinical trial results impact on clinical practice. While cardiologists receive a large amount of scientific information from clinical studies, only a small part of it will impact on the decision-making process for individual patients. The aims of these sessions was therefore to achieve a detailed understanding of a particular published trial, to evaluate the relevance of new results for daily practice and to share current and future practice

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Citation:RadcliffeCardiology.com, August 2014

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Introduction
At EuroPCR, 2014, Paris, a new session format was introduced to analyse how results of clinical trial results impact on clinical practice. While cardiologists receive a large amount of scientific information from clinical studies, only a small part of it will impact on the decision-making process for individual patients. The aims of these sessions was therefore to achieve a detailed understanding of a particular published trial, to evaluate the relevance of new results for daily practice and to share current and future practice.

The ACCOAST Study
Before discussing the study, the chairperson, Professor Thomas Cuisset, asked the audience who had changed their daily practice in non-ST elevation myocardial infarction (NSTEMI) management since publication of the a Comparison of prasugrel at PCI or time of diagnosis of Non-ST elevation myocardial infarction (ACCOAST) study data. A substantial minority raised their hands.

What was Known Before this Trial?
Dr Rod Stables of the Liverpool Heart and Chest Hospital, United Kingdom presented a summary of current knowledge. Oral antiplatelet therapy is a core concept in cardiology. The clopidogrel in unstable angina to prevent recurrent ischemic events (CURE) Trial found that in the first 24 hours, the relative risk reduction is 34 % and suggested that all patients presenting with acute coronary syndrome (ACS) should receive clopidogrel on admission.1 Furthermore, the Intracoronary stenting with antithrombotic regimen cooling off (ISAR-COOL) study in high-risk ACS patients showed that delaying intervention for prolonged antithrombotic treatment is not beneficial.2 A recent study found that upstream clopidogrel treatment prior to catheterisation laboratory arrival is associated with a significant decrease in the prevalence and extent of microvascular obstruction.3 Another study found that a loading dose of prasugrel 60 mg results in more rapid, potent, and consistent inhibition of platelet function than clopidogrel 300 mg.4 In summary, current evidence supports the use of oral antiplatelet therapy prior to coronary intervention in patients with ACS.

Trial Review – the Data, Statistics and Conclusions
Professor Peter Jüni of the University of Bern, Switzerland, described the ACCOAST trial. Patients (n=4022) with non-ST elevation ACS and a positive troponin level who were scheduled to undergo coronary angiography within 2–48 hours after randomisation, were randomly assigned to receive prasugrel (a 30 mg loading dose) before the angiography (pretreatment group) or placebo (control group).5 When percutaneous coronary intervention (PCI) was indicated, additional prasugrel (30 mg) was given in the pretreatment group at the time of PCI and prasugrel (60 mg) was given in the control group. The primary composite endpoint was death from cardiovascular causes, myocardial infarction (MI), stroke, urgent revascularisation and the need for glycoprotein IIb/IIIa bailout within the first seven days after randomisation. Safety endpoints were: thrombolysis in myocardial infarction (TIMI) bleeds and additional Safety and efficacy of enoxaparin in PCI Patients, an international randomised evaluation (STEEPLE) and Global use of strategies to open occluded arteries (GUSTO) bleeding criteria. Patient profiles and treatment timelines were representative of those seen in daily practice.

At 30 days, the rate of the primary efficacy end point did not differ significantly between the two groups (hazard ratio [HR] with pretreatment, 1.02) The result was therefore clear-cut: no evidence of benefit. The rate of the key safety end point of all TIMI major bleeding episodes through day seven was increased with pretreatment (HR, 1.90 p=0.006). Pretreatment did not reduce the rate of the primary outcome among patients undergoing PCI (69 % of the patients) but increased the rate of thrombolysis in myocardial infarction (TIMI) major bleeding at seven days. The study concluded that, in non-ST-elevation (NSTE) ACS patients managed invasively within 48 h of admission, pre-treatment with prasugrel does not reduce major ischaemic events within 30 days but increases major bleeding complications. Therefore a reappraisal of routine pre-treatment strategies in HSTE-ACS is needed.

ACCOAST – Take-home Message
Following the discussion of ACCOAST, most of the audience would still pretreat their patients. ACCOAST is an interesting clinical trial that asks a clinically relevant question, but is based on only drug. It is not known whether we can extrapolate these results to pre-treatment with established drugs that have been shown to be beneficial in other trials. The fact that an excess of bleeding complications were seen could be explained by the fact that many patients are not good candidates for prasugrel. A trial with ticagrelor would be interesting. An important message of ACCOAST is that getting patients into the catheterisation laboratory as soon as possible avoids many problems. However, many don’t have that opportunity. In these cases, the use of clopidogrel avoids coronary events. In conclusion, the trial is relevant but further study is required to determine whether we can advance current treatment for patients with ACS.

The PRAMI Trial – Treatment of Bystander Coronary Lesions in Patients Undergoing Primary PCI for Acute STEMI
The session, chaired by Dr Andreas Baumbach of the UK, began by a show of hands among the audience. Few would stent all lesions in primary PCI, which was the treatment arm in preventive angioplasty in myocardial infarction (PRAMI), while no-one would only stent the culprit lesion and not follow up or investigate, the control arm.

What was Known Before this Trial?
Professor Gabriel Steg of the University of Paris, France discussed what was known before PRAMI. People with multi-vessel disease have worse outcomes than patients with single vessel disease.6 Non-culprit lesions carry overall the same risk of subsequent events as the culprit lesion.7 Routine revascularisation of stable lesions does not produce clinical benefit, even when they produce ischaemia – a meta-analysis found that, in patients with stable CAD and myocardial ischaemia, adding PCI with medical therapy did not reduce in a reduction in death, nonfatal MI, unplanned revascularisation, or angina compared with medical therapy alone.8 Observational studies of single vessel vs multivessel PCI in STEMI provide conflicting results. Two studies of primary PCI patients found better outcomes in those that undergo multivessel revascularisation compared with patients undergoing culprit PCI only.9,10 Conversely, another study found that non-culprit coronary interventions performed at the time of primary PCI were significantly associated with increased mortality.11 A pooled analysis suggested that a staged approach may be beneficial, but the level of evidence was weak. Multivessel PCI is associated with increased mortality in the acute setting, but that as a staged procedure, multivessel PCI improves short- and long-term survival and reduced repeat PCI12. Current guidelines do not recommend same sitting multivessel PCI in STEMI.13

Trial Review – the Data, the Statistics, the Conclusions
Dr Alexandra Lansky of the Yale-New Haven Hospital, New Haven, CT, presented a critical analysis of PRAMI. The trial randomised 65 patients with acute STEMI to either preventive PCI or no preventive PCI.14 The primary outcome was a composite of death from cardiac causes, nonfatal myocardial infarction (MI), or refractory angina. During a mean follow-up of 23 months, the primary outcome occurred in 21 patients assigned to preventive PCI and in 53 patients assigned to no preventive PCI (infarct-artery-only PCI), which translated into a hazard ratio [HR] in the preventive-PCI group of 0.35 (p<0.001). The study concluded that in patients with STEMI and multivessel coronary artery disease undergoing infarct-artery PCI, preventive PCI in noninfarct coronary arteries with major stenoses In terms of whether the trial reflects clinical practice, it is necessary to question the strategies used in PRAMI. The preventative strategy involved successful culprit primary PCI (PPCI) and PCI of any other lesion of >50 % but <100 % at the same setting. The control strategy involved successful culprit PPCI and conservative treatment. Neither is common practice.

Although 600 patients were planned, the trial was stopped at 465 patients following evidence of overwhelming benefit of the primary endpoint (p<0.001). Terminating a trial due to unexpectedly large treatment effect tends to overestimate its benefit: the fewer events in a trial, the greater the overestimation. There were only 74 events at PRAMI, suggesting a large overestimation. Of patients screened, 80 % were not eligible. In 269 cases, the nonculprit lesions were deemed unsuitable, which raises questions. Interestingly, refractory angina was 50 % of the primary endpoint, a soft endpoint and not related to cardiac death, and endpoints such as cardiac death did not reach statistical significance. The challenge of interpretation was also worsened by composite endpoints. In PRAMI, the component event frequency was inversely important to the patient (14 deaths, 27 MI, 42 angina events). Only three more MIs in the preventative PPCI group would have made the results nonsignificant.

PRAMI – Take Home Message
PRAMI was a important in that it demonstrated the safety of preventative PCI and challenged historic wisdom and adds to the body of evidence that favours complete revascularisations. Although the discussions raised concerns about the trial design and the impact of premature cessation of the study, this trial will lead to a larger, prospective, multicentre study that may challenge current STEMI practice.

Conclusion
Good evidence is needed to deviate from established treatment regimens, and there is a need to translate trial data into meaningful messages for daily practice. These sessions showed that the ACCOAST and PRAMI trials are both relevant, but are unlikely to be practicechanging for the majority of interventional cardiologists. However, both should enable larger clinical studies, which may have implications for future practice.

References

  1. Mehta SR, Yusuf S, Peters RJ, et al., Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study, Lancet, 2001;358:527-33.
  2. Neumann FJ, Kastrati A, Pogatsa-Murray G, et al., Evaluation of prolonged antithrombotic pretreatment (“cooling-off” strategy) before intervention in patients with unstable coronary syndromes: a randomized controlled trial, JAMA, 2003;290:1593-9.
  3. de Waha S, Eitel I, Desch S, et al., Association of upstream clopidogrel administration and myocardial reperfusion assessed by cardiac magnetic resonance imaging in patients with ST-elevation myocardial infarction, Eur Heart J Acute Cardiovasc Care, 2014;3:110-7.
  4. Brandt JT, Payne CD, Wiviott SD, et al., A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation, Am Heart J, 2007;153:66 e9-16.
  5. Montalescot G, Bolognese L, Dudek D, et al., Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes, N Engl J Med, 2013;369:999-1010.
  6. Parodi G, Memisha G, Valenti R, et al., Five year outcome after primary coronary intervention for acute ST elevation myocardial infarction: results from a single centre experience, Heart, 2005;91:1541-4.
  7. Stone GW, Maehara A, Lansky AJ, et al., A prospective natural-history study of coronary atherosclerosis, N Engl J Med, 2011;364:226-35.
  8. Stergiopoulos K, Boden WE, Hartigan P, et al., Percutaneous coronary intervention outcomes in patients with stable obstructive coronary artery disease and myocardial ischemia: a collaborative meta-analysis of contemporary randomized clinical trials, JAMA Intern Med, 2014;174:232-40.
  9. Hannan EL, Samadashvili Z, Walford G, et al., Culprit vessel percutaneous coronary intervention versus multivessel and staged percutaneous coronary intervention for ST-segment elevation myocardial infarction patients with multivessel disease, JACC Cardiovasc Interv, 2010;3:22-31.
  10. Hannan EL, Wu C, Walford G, et al., Incomplete revascularization in the era of drug-eluting stents: impact on adverse outcomes, JACC Cardiovasc Interv, 2009;2:17-25.
  11. Toma M, Buller CE, Westerhout CM, et al., Non-culprit coronary artery percutaneous coronary intervention during acute ST-segment elevation myocardial infarction: insights from the APEX-AMI trial, Eur Heart J, 2010;31:1701-7.
  12. Bainey KR, Mehta SR, Lai T, et al., Complete vs culprit-only revascularization for patients with multivessel disease undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: a systematic review and meta-analysis, Am Heart J, 2014;167:1-14 e2.
  13. Task Force on the management of STseamiotESoC, Steg PG, James SK, et al., ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation, Eur Heart J, 2012;33:2569-619.
  14. Wald DS, Morris JK, Wald NJ, et al., Preventive angioplasty in myocardial infarction, N Engl J Med, 2014;370:283.