University of Ottawa Heart Institute
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 PROTOCOL - A Regional Perspective on the Evidence and Resulting Changes in ACS Protocol
Reviewed and edited by:
Michel Le May, MD, FRCPC
Director, Coronary Care Unit, and University of Ottawa Heart Institute Regional STEMI Program
Professor of Medicine
University of Ottawa Heart Institute
Antiplatelet therapy in the management of acute coronary syndromes (ACS) has recently been revised at the University of Ottawa Heart Institute (UOHI). The new strategy is designed to provide significant reductions in risk of major cardiovascular (CV) events by primarily employing a newer antiplatelet agent compared to the previous standard of clopidogrel. 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 standard for more than 10 years. However, rates of CV events in ACS populations remain substantial. In the landmark CURE study, 9.3% of those receiving clopidogrel plus ASA experienced a recurrent myocardial infarction (MI), stroke or death from 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, recurrent MI or recurrent ischemia leading to urgent revascularization was 11.6% in the group receiving clopidogrel plus ASA despite a 20% reduction in risk as compared to the placebo group.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.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.
Compared to clopidogrel, prasugrel reduced the relative risk of the composite end point of death from CV cause, MI or stroke by 19% (HR 0.81; P<0.001) and the absolute risk by 2.2% (primary end points in 9.9% of the prasugrel group vs. 12.1% of the control group). The relative risk of major bleeding on prasugrel was increased by 32% (HR 1.32; P=0.03) while the absolute risk was increased by 0.6% (major bleeding events in 2.4% of those receiving prasugrel and 1.8% of controls). 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, 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.
Compared to clopidogrel, ticagrelor reduced the relative risk of the composite end point of death from vascular causes, MI or stroke by 16% (HR 0.84; P<0.001) and the absolute risk by 1.9% (primary end points in 9.8% vs. 11.7% of the ticagrelor and clopidogrel groups, respectively). The difference in total major bleeding with ticagrelor (11.6% vs. 11.2%; P=0.43) did not reach statistical significance but non-CABG major bleeding was significantly increased (4.5% vs. 3.8%; P=0.026) Unique to antiplatelet trials, ticagrelor was associated with a 22% reduction in death from any cause, 5.9% to 4.9% (HR 0.78; nominal P<0.001).
New Data Translated into Clinical Practice
Revised treatment standards for antiplatelet therapy in ACS patients are designed to capture the opportunity to improve outcomes based on 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 PLATO and TRITON-TIMI 38 trials, but algorithms at the regional or hospital level are appropriate because of differences in ACS care.
At the UOHI, we have opted for ticagrelor as a standard replacement for clopidogrel in a dual antiplatelet strategy with ASA for most ACS patients. It is important to exercise caution when using any dual antiplatelet therapy in patients already taking an oral anticoagulant. Exceptions for which the interventional cardiologist may consider clopidogrel over ticagrelor include those who are taking an oral anticoagulant, including warfarin, or those who have had a prior intracranial hemorrhage.
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, especially in those over the age of 75 years and those who weigh <60 kg. Results from both TRITON-TIMI 38 and PLATO trials were taken into consideration; however, to simplify and streamline the treatment process, ticagrelor was selected as the preferred agent in STEMI at UOHI. In patients were the attending physician deems ticagrelor inappropriate, clopidogrel remains an option.
Relevance of New Algorithm to Regional Centres
Guidelines for the use of antiplatelet therapies in ACS patients were made available by the Canadian Cardiovascular Society (CCS) in 2012.5 In these guidelines, which strongly influenced practice at UOHI, emphasis was placed on replacing clopidogrel with ticagrelor in both STEMI and NSTEMI (class 1). Clopidogrel has now been relegated to second choice. Prasugrel is identified as an option in STEMI patients, but this is based on data from the TRITON-TIMI 38 trial in which the cardiac anatomy was known prior to initiating therapy.
The new guidelines at UOHI include several assumptions that may or may not be relevant to nearby community centres. In particular, the use of prasugrel in STEMI patients is dependent on the availably of a catheterization laboratory and the ability to perform PCI. Naturally, due to regional disparities in ACS care driven largely by availability of resources, which also include the proximity of rapid response teams, treatment must be adjusted for these variables. Keeping the above in mind, current practice at regional facilities is relevant to community hospitals and the same opportunities to improve outcome with more effective antiplatelet regimens should not be overlooked.
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 centers, a stepwise 10% reduction in in-hospital mortality rates was associated with each 10% increase in adherence to evidence-based guidelines (Figure 1).6
Figure 1. 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, when combined with ASA, provide an important opportunity to improve outcomes relative to clopidogrel. In ACS patients, the advantage of ticagrelor, including a nominal reduction in mortality, has made it the agent of choice. The guidelines developed by UOHI were designed specifically to identify these opportunities in a simplified and readily applied strategy.
Question & Answers
Q: What is your perspective on the benefit-to-risk ratio that the newer antiplatelet agents offer within the revised guidelines for reducing the risk of thrombosis within an acceptable rate of bleeding?
A: In TRITON-TIMI 38, prasugrel reduced the rate of stent thrombosis measured at 15 months, 1.1% vs. 2.4% for clopidogrel, P<0.001. However, the rate of non-CABG TIMI major bleed in patients treated with prasugrel was 2.4% against 1.8% in patients treated with clopidogrel, P=0.03; the rate of fatal bleed was 0.4% vs. 0.1% respectively, P=0.002. Patients with a history of prior stroke or TIA had an excessive rate of intracranial bleed when treated with prasugrel (2.3% vs. none for clopidogrel, P=0.02). These results have led to a recommendation that prasugrel should not be prescribed to a patient with a history of TIA or stroke.
In the PLATO trial, there was also a significant reduction in probable or definite stent thrombosis with ticagrelor 2.2% vs. 2.9% for clopidogrel, P=0.02. Major bleeding, using PLATO study criteria, was measured in 11.6% of the ticagrelor group vs. 11.2% of the clopidogrel group, P=0.43. Major bleeding using TIMI definition was recorded in 7.9% and 7.7% of ticagrelor and clopidogrel patients, respectively, P=0.57. However, the rates of non-CABG TIMI major bleeding were significantly higher with ticagrelor 2.8% vs. clopidogrel 2.2%, P=0.03. Finally, there was no increase in intracranial bleed in patients treated with ticagrelor who had a past history of stroke and fatal bleeding was reported as 0.3% for each group.
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: Although STEMI and non-STEMI share a common trigger i.e. a ruptured plaque, the two clinical presentations have some differences. Patients with STEMI generally present with a higher level of acuity and a more “inflammatory” state which may alter absorption and metabolism significantly. Thus the pharmacokinetic and pharmacodynamic properties of antiplatelet agents may be altered as well in these patients. In the context of primary PCI the drug needs to work quickly to prevent stent thrombosis. The two landmark trials, TRITON TIMI-38 and PLATO, both showed that the novel antiplatelet agents, prasugrel and ticagrelor respectively, provided significant benefit over clopidogrel in the STEMI patients and in non-STEMI patients. Hence the benefits of these novel agents apply to both STEMI and non-STEMI patients.
Q: What is your point of view on the possible side effects associated with the newer agents vs. the opportunity to improve outcomes?
A: Combining either ticagrelor or prasugrel with ASA (dual antiplatelet therapy) is more likely associated with bleeding complications as compared with ASA alone. Nuisance bleeding such as easy bruising, is certainly increased with dual antiplatelet therapy.
In the TRITON TIMI-38 study, prasugrel was associated with more bleeding than with clopidogrel. Furthermore, patients with a previous history or stroke or TIA, were at greater risk of intracranial bleeding. Hence prasugrel is contraindicated if there is a history of previous stroke or TIA. In addition, patients referred for bypass surgery had increased bleeding with prasugrel. Bleeding complications associated with prasugrel need to be balanced against its effectiveness in reducing death, reinfarction or stroke, and stent thrombosis.
In PLATO, ticagrelor was not associated with increased bleeding. However when looking at the subset of patients who did not require bypass surgery, the rate of non-CABG bleeding was higher with ticagrelor. Dyspnea was noted in 13.8% of patients treated with ticagrelor vs. 7.8% treated with clopidogrel. Dyspnea related to ticagrelor appears to be mediated by adenosine. This symptom was not associated with changes in pulmonary testing and is usually mild and often self-limiting. In a few cases, it can be severe and the drug needs to be stopped and replaced by clopidogrel. Of note, in PLATO, ticagrelor was discontinued because of dyspnea in only 0.9% of the patients. The side effects of ticagrelor need to be weighed against the benefits ie a reduction in ischemic events, including stent thrombosis and most importantly mortality.
Q: The new standard 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 newer agents were studied in the context of ACS. The new Canadian guidelines recommend that ticagrelor or prasugrel replace clopidogrel for the management of ACSand the duration of therapy with the novel agents is 1 year. One exception to this applies to patients treated with fibrinolytic therapy. The standard for these patients continues to be a loading dose of clopidogrel 300 mg in patients <75 years of age at the time of administration of fibrinolytic therapy followed by maintenance clopidogrel 75 mg daily. In patients ≥75 years of age, the recommendation is to start with 75 mg of clopidogrel only, i.e. no loading dose. There is currently no data to support prescribing the newer agents to patients with stable angina. Patients referred for elective PCI should be managed with a combination of clopidogrel and ASA. There is also no data available for chronic maintenance with dual antiplatelet therapy with the new agents. The PEGASUS trial is currently evaluating the ticagrelor/ASA combination in stable patients with a prior history of MI. Enrollment for this trial has just been completed.
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.
6. Peterson et al. Association between hospital process performance and outcomes among patients with acute coronary syndromes. JAMA 2006;295(16):1912-20.