London Health Sciences Centre
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.
PHYSICIAN PERSPECTIVE - Get with the GUIDELINES - A Regional Perspective on the Evidence and Resulting Changes in ACS Protocol
Reviewed and edited by:
Dennis Humen, MD, FRCPC
London Health Sciences Centre
Professor of Medicine
University of Western Ontario
Care pathways that include antiplatelet therapy in the management of acute coronary syndromes (ACS) are in place at the London Health Sciences Center (LHSC). These pathways are designed to reduce the risk of major cardiovascular (CV) events by including use of the newer antiplatelet agents in appropriate patients over the previous standard of clopidogrel and ASA. These care pathways specify where prasugrel and ticagrelor should be employed to provide additional protection against major CV events. Guided by the large clinical trials that underlie the changes, the specific recommendations allow for the clinical gains from greater antiplatelet effect, including in some cases, a lower risk of death. They also balance benefit with an acceptably low risk of major or minor bleeding. Due to the fundamental importance of deactivating platelets to alter the natural history of evolving ACS events, optimal use of antiplatelet therapy should be considered an essential strategy for improving the prognosis of ACS. The new protocol is consistent with revisions in national guidelines.
Previous Standard: Need for Improvement
The dual antiplatelet strategy of clopidogrel and ASA in patients presenting with ACS has been a widely employed standard for more than 10 years. However, rates of CV events in ACS populations remain substantial. In the landmark CURE study, 10% of those receiving clopidogrel plus ASA went on to a recurrent myocardial infarction (MI), a persistent arterial occlusion or died of a CV cause despite the 20% reduction with the combination relative to ASA alone.1 This study was performed in patients with non-ST elevation MI (NSTEMI). In the CLARITY-TIMI 28 trial, conducted in patients with ST elevation MI (STEMI), the residual risk of death, stroke or MI was 9% in the group receiving clopidogrel plus ASA despite a 31% reduction in risk of a major CV event relative to ASA alone.2
Since those studies established dual antiplatelet combination as a standard in ACS, two large ACS trials have proven that more effective antiplatelet therapy will further reduce CV risk. One trial tested ticagrelor in an all-comer population of ACS patients.3 The other study tested prasugrel in ACS patients scheduled for a percutaneous coronary intervention (PCI).4 Data from these trials provide an opportunity to improve outcomes over the previous clopidogrel plus ASA standard.
In the TRITON-TIMI 38 study, 13,608 ACS patients scheduled for PCI were randomized. In the experimental arm, patients received a loading dose of prasugrel (60 mg) followed by maintenance prasugrel (10 mg daily). The comparator arm received a loading dose of clopidogrel (300 mg) followed by maintenance clopidogrel (75 mg daily). Both groups received ASA. Approximately 25% of the ACS events were STEMI and the remaining NSTEMI.
Relative to clopidogrel, prasugrel reduced the risk of the composite end point of death from CV cause, MI or stroke by 19% (HR 0.81; P<0.001). The risk of major bleeding on prasugrel was increased by 32% (HR 1.32; P=0.03) relative to clopidogrel. There was no difference in mortality. The authors concluded that the greater protection against ischemic events must be weighed against an increased risk of bleeding, but post-hoc analyses provided guidance for candidate selection.
In the PLATO trial, all individuals admitted to hospital with ACS were randomized regardless of planned procedure or pre-hospital antiplatelet treatment. The experimental arm received a loading dose of ticagrelor (180 mg) followed by maintenance ticagrelor (90 mg twice daily). The comparator arm received a loading dose of clopidogrel (300 or 600 mg) followed by maintenance clopidogrel (75 mg daily). Both groups received ASA. Approximately 37% of the 18,624 patients randomized had STEMI and the remaining had NSTEMI.
Relative to clopidogrel, ticagrelor reduced the risk of the composite end point of death from vascular causes, MI or stroke by 16% (HR 0.84; P<0.001). The difference in total major bleeding (11.6% vs. 11.2%; P=0.43) did not reach statistical significance. Unique to antiplatelet trials, ticagrelor was associated with a 16% reduction (HR 0.84; nominal P<0.001) in all-cause mortality.
New Data Translated into Clinical Practice
The care pathways for antiplatelet therapy in ACS patients are designed to capture the opportunity to improve outcome based on the PLATO and TRITON-TIMI 38 trials. While all ACS patients should be initiated on ASA immediately, the second antiplatelet agent is defined by the diagnosis, the planned strategies for intervention and specific patient characteristics. Several large organizations have altered ACS antiplatelet guidelines on the basis of the PLATO and TRITON-TIMI 38 trials, but specific recommendations at the regional or hospital level are appropriate because of differences in ACS care.
At regional centres, including the LHSC, the data generated by the PLATO and TRITON-TIMI 38 trials can be applied directly. In NSTEMI patients, ticagrelor is now the dominant partner in a dual antiplatelet strategy with ASA with important exceptions. These exceptions include patients on an anticoagulant or who have had a prior intracranial hemorrhage (Figure 1). In those patients who are not candidates for ticagrelor, clopidogrel remains the preferred partner with ASA. In those initiated on clopidogrel who are candidates for ticagrelor according to the algorithm, the therapy may be switched.
Figure 1. LHSC: ACS Antiplatelet Care Pathway
In STEMI patients scheduled for PCI, prasugrel has been found more effective than clopidogrel in a dual antiplatelet strategy with ASA, but the benefit-to-risk ratio varied across subpopulations in the registration trial, producing some important exceptions. As a result, clopidogrel not only remains the preferred partner with ASA in individuals who have received anticoagulants or prior treatment with a fibrinolytic agent but in those over the age of 75 years, those who weigh <60 kg and those with a prior transient ischemic attack or stroke. In these individuals, the evidence suggests that the greater risk of major bleeding negates the clinical benefit provided by the relative reduction in CV events.
Relevance of New Algorithm to Regional Centres
The objective evidence that newer antiplatelet therapies can improve the outcome in ACS patients informs but does not dictate adjustments in patient care. Due to substantial regional disparities in the care of ACS driven largely by variability in resources, such as the proximity of rapid response teams and differences in transfer intervals to catheterization laboratories, treatment guidelines must be adjusted for relevance to current practice. At regional centres, treatment recommendations must be adjusted for these variables. The same opportunities to improve outcome with more effective antiplatelet regimens should not be overlooked. Current practice at regional facilities is relevant to community hospitals whether or not the transfer of patients is common.
The new guidelines at LHSC include several assumptions that may or may not be relevant to nearby community centres. For example, the improvement in outcome associated with prasugrel in STEMI patients scheduled for PCI is based on the availability of PCI. However, the revised algorithm is evidence-based and does specifically outline areas in which clopidogrel plus ASA should no longer be considered the standard.
There are compelling data to conclude that implementation of more modern strategies for appropriate candidates will improve ACS outcomes including a reduction in mortality. The implementation and adherence to treatment guidelines in the management of ACS has been associated with statistically significant improvements in outcome. In an observational analysis that included 350 academic and non-academic centres, a stepwise 10% reduction in in-hospital mortality rates was associated with each 10% increase in adherence to evidence-based guidelines (Figure 2).5
Figure 2. Association Between Hospital Composite Guideline Adherence Rate and In-hospital Mortality
The first-line antiplatelet strategies in ACS patients have been revised. The newer agents ticagrelor and prasugrel provide an important opportunity to improve outcome relative to clopidogrel when any of these agents is combined with ASA. In NSTEMI patients, the advantage of ticagrelor over clopidogrel in appropriately selected patients includes a mortality reduction. The recommendations developed by LHSC were designed specifically to identify these opportunities in a readily applied care pathways.
Question & Answers
Q: What is your perspective on the benefit-to-risk ratio that the newer antiplatelet agents offer within the revised algorithm for reducing the risk of thrombosis within an acceptable rate of bleeding?
A: The added bleeding risk attributable to ticagrelor is very small and is acceptable given the mortality benefit attributable to the drug compared to clopidogrel. The bleeding risk attributable to prasugrel is higher than ticagrelor but would be acceptable when the effectiveness of either ticagrelor or clopidogrel is thought to be compromised.
Q: The studies that led to changes in the guidelines compared therapies in different populations. What insights can you offer on why it was important to prove superiority of prasugrel or ticagrelor over clopidogrel in different ACS groups (STEMI, NSTEMI, unstable angina, etc)?
A: Clopidogrel has therapeutic deficiencies and the newer agents seek to improve efficacy. In the case of ticagrelor this has translated into a mortality benefit.
Q: What is your point of view on the possible side effects associated with the newer agents vs. the opportunity to improve outcomes?
A: The side effects are not common and rarely lead to drug discontinuance.
Q: The algorithm introduces some decision points not previously required when all patients were treated with clopidogrel plus ASA. What action needs to be taken to improve outcomes?
A: The algorithm is best managed in a clinical pathway management structure.
1. Yusuf et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without
ST-segment elevation. N Engl J Med 2001;345(7):494-502.
2. Sabatine et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005;352(12):1179-89.
3. Wallentin et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361(11):1045-57.
4. Wiviott et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357(20):2001-15.
5. Peterson et al. Association between hospital process performance and outcomes among patients with acute coronary syndromes. JAMA 2006;295(16):1912-20.