Centre de santé et de services sociaux de Chicoutimi
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PHYSICIAN PERSPECTIVE - Get with the PROTOCOL - A Regional Perspective on the Evidence and Resulting Changes in ACS Protocol
Reviewed and edited by:
Tomás Cieza, MD
Centre de santé et de services sociaux de Chicoutimi
Pierre Bélisle, MD
Centre de santé et de services sociaux de Chicoutimi
Based on data generated by large evidence-based trials, antiplatelet therapy in the management of acute coronary syndromes (ACS) has recently been revised at the Centre de santé et de services sociaux de Chicoutimi (CSSSC). The altered algorithm is designed to provide significant reductions in risk of major cardiovascular (CV) events by employing the newer antiplatelet agents compared to the previous standard of clopidogrel. The new algorithm specifies where prasugrel and ticagrelor should be employed to provide additional protection against major CV events. Guided by the large clinical trials that underlie the revised algorithm, 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 this 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 (except post-thrombolysis patients).3 The other study tested prasugrel in ACS patients scheduled for a percutaneous coronary intervention (PCI).4 Data from these trials provided the rationale for the changes at CSSSC with the goal of improving outcomes over those achieved with the previous standard of clopidogrel plus ASA.
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.
STEMI patients in TRITON TIMI-38 derived particular benefit. Although upfront administration of prasugrel before knowing the coronary anatomy means an increased risk of bleeding from the small proportion of patients who will require CABG, the data support overall benefit.
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 revised treatment algorithms for antiplatelet therapy in ACS patients at CSSSC are designed to capture the opportunity to improve outcome based on the PLATO and TRITON-TIMI 38 trials. While the evidence would have supported the decision to replace clopidogrel across the spectrum of ACS, we preferred to employ ticagrelor preferentially in unstable angina and NSTEMI and prasugrel in STEMI treated with PCI. This is more consistent with the evidence and it allows us to be familiar with all of the available antiplatelet therapies and to change from one to another depending on side effects, availability and issues related to provincial reimbursement. One advantage of the move from clopidogrel to newer P2Y12 inhibitors is that it reduced the use of glycoprotein IIb/IIIa inhibitors. They are now reserved for bail-out situation. Bivalirudin use has also been reserved primarily for use in primary PCI.
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 algorithms at the regional or hospital level are appropriate because of differences in ACS care.
At regional centres, including the CSSSC, 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 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 should be switched.
Figure 1. CSSSC: ACS Algorithm
In STEMI patients scheduled for PCI, prasugrel has been found more effective than clopidogrel in a dual antiplatelet strategy with ASA. That is why prasugrel is used in primary angioplasty. However, the benefit-to-risk ratio varied across subpopulations in the registration trial, producing some important exceptions, notably in individuals: who have received anticoagulants, who have received prior treatment with a fibrinolytic agent, over the age of 75 years, who weigh <60 kg and in individuals 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. Thus, according to our STEMI protocol, the use of ticagrelor is favoured over clopidogrel when there are contraindications to prasugrel.
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. At CSSSC, we sought a regional protocol adapted to local practices and geographical reality that is concordant with national guidelines while remaining simple and easy to apply. As a result, we advocated a unique therapeutic combination for each presentation. This approach is appropriate in the context of the substantial regional disparities in the care of ACS that is driven largely by variability in resources, such as the proximity of rapid response teams and differences in transfer intervals to catheterization laboratories. However, regardless of site, the 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 CSSSC 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.5
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 guidelines developed by CSSSC were designed specifically to identify these opportunities in a readily applied algorithm.
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: For us, it was important to demonstrate this benefit in randomized clinical trials before we could change [the protocol]. This benefit to risk ratio is considered acceptable when we can select patients that can obtain the benefit without increasing the risk of bleeding.
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: We think there are two issues. Firstly, there is increased bleeding with new antiplatelets so a need to demonstrate better efficacy is essential in order to have a better net clinical benefit. Secondly, we have to consider the economic cost compared to clopidogrel, now a genericized drug.
Q: What is your point of view on the possible side effects associated with the newer agents vs. the opportunity to improve outcomes?
A: Once again we have to select the right patient population and avoid in patients with high risk of complications.
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: This is a good question because right now we need more collaboration with our colleagues in the emergency departments in order to choose altogether the best combination for each individual patient. Our protocol was approved for all hospitals in our region in order the have the collaboration at all levels with the goal to improve standard of care for our population.
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.