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PHYSICIAN PERSPECTIVE - Get with the PROTOCOL - Dual-antiplatelet Therapies for Acute Coronary Syndromes: A Regional Perspective on the Evidence and Resulting Changes

June 2014

Guest Editor:

Madhu Natarajan, MD
Interventional Cardiologist
Director, Hamilton-Niagara Integrated Heart Investigation Unit 
Hamilton Health Sciences
McMaster University
Hamilton, Ontario

Introduction

The protocol for antiplatelet therapy in the management of acute coronary syndromes (ACS) has been revised at Hamilton Health Sciences. The altered algorithm is designed to provide significant reductions in risk of major cardiovascular (CV) events when compared to the previous standard of aspirin (ASA) and clopidogrel. The new algorithm specifies when the newer antiplatelet agent, 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 clinical gains from greater antiplatelet effect, including, in some cases, a lower risk of death, to be achieved with an acceptable risk of bleeding. Due to the fundamental importance of blocking platelet activity to alter the natural history of an evolving ACS event, optimal use of antiplatelet therapy should be considered an essential strategy for improving the prognosis in patients with ACS. The new protocol is consistent with revisions in national guidelines.

 

Previous Standard: Need for Improvement

The dual antiplatelet strategy of ASA and clopidogrel in patients presenting with ACS has been widely employed for more than 10 years. However, rates of CV events in ACS populations remain substantial. In the landmark CURE study, performed in patients with non-ST elevation MI (NSTEMI), approximately 10% of those receiving ASA and clopidogrel went on to a recurrent myocardial infarction (MI), stroke  or CV death at 12 months  despite the 20% reduction with the combination compared with ASA alone.1 In the CLARITY-TIMI 28 trial, conducted in patients with ST elevation MI (STEMI), the residual risk was approximately 12% in the group receiving ASA plus clopidogrel despite a 20% reduction in risk of a major CV event at 30 days relative to ASA alone.2

Since those studies established dual antiplatelet therapy with ASA and clopidogrel as a standard in ACS, two recently completed ACS trials have proven that more potent antiplatelet therapy will further reduce CV risk.  The PLATO trial evaluated ASA and ticagrelor, an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12, versus ASA and clopidogrel in an all-comer population of ACS patients.3 The other study, TRITON-TIMI-38, tested ASA and prasugrel in ACS patients scheduled for percutaneous coronary intervention (PCI) versus ASA and clopidogrel.4 Data from these trials demonstrated that newer, more potent, and rapid-acting antiplatelet agents provide an opportunity to improve outcomes in ACS over the previous ASA and clopidogrel combination.

In the PLATO trial, all individuals admitted to a hospital with ACS were randomized regardless of planned procedure or prior clopidogrel treatment. The experimental arm received a loading dose (LD) of ticagrelor (180 mg) followed by maintenance ticagrelor (90 mg twice daily). The comparator arm received a LD of clopidogrel (300 or 600 mg) followed by a maintenance clopidogrel (75 mg daily). Both groups received ASA. Approximately 37% of the 18,624 patients randomized were diagnosed with STEMI and the remaining were diagnosed with NSTEMI.

Relative to clopidogrel, ticagrelor reduced the risk of the composite endpoint of death from vascular causes, MI or stroke at 12 months, by 16% (9.8% vs 11.7%, 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, but ticagrelor was associated with a higher rate of non-CABG related major bleeding (4.5% vs 3.8%, P=0.03). Unique to recent antiplatelet trials, ticagrelor was associated with a 16% reduction (5.8 % vs 6.9%, HR 0.84; P<0.001) in all-cause mortality.

In the TRITON-TIMI 38 study, 13,608 ACS patients scheduled for PCI were randomized. In the experimental arm, patients received a LD of prasugrel (60 mg) followed by maintenance prasugrel (10 mg daily). The comparator arm received a LD of clopidogrel (300 mg) followed by maintenance clopidogrel (75 mg daily). Both groups received ASA. Approximately 26% of the ACS events were STEMI and the remaining NSTEMI or other ACS.

Relative to clopidogrel, prasugrel reduced the risk of the composite endpoint of death from CV cause, MI or stroke by 19% (9.9% vs 12.1%, HR 0.81; P<0.001). The risk of non-CABG related major bleeding on prasugrel was increased by 32% (2.4% vs 1.8%, 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, and utilized post-hoc analyses to provide guidance for candidate selection.

New Data Translated into Clinical Practice

The revised treatment algorithms for antiplatelet therapy in ACS patients are designed to capture the opportunities to improve outcomes based on this information. While all ACS patients should be administered ASA immediately, the second antiplatelet agent is defined by the diagnosis, the planned strategies for intervention, and specific patient characteristics. Several national and international organizations have altered ACS antiplatelet guidelines on the basis of the PLATO and TRITON-TIMI 38 trials, but specific algorithms at the regional or hospital level are appropriate, to reflect regional differences in ACS care.

At tertiary centres, including Hamilton Health Sciences (HHS), these data can been applied directly. In NSTEMI patients, ticagrelor is now an acceptable first-line option in a dual antiplatelet strategy with ASA. There are exceptions for those with increased bleeding risk, such as patients on an oral anticoagulant or who have had a prior intracranial hemorrhage. While ticagrelor is the favoured partner with ASA overall, clopidogrel is preferred in those with increased risk for bleeding. In those initiated on clopidogrel who are candidates for ticagrelor, switching to ticagrelor is also a reasonable strategy to achieve the greater expected protection against thrombotic events.

In STEMI patients referred for primary or direct PCI, newer agents have been associated with a greater reduction in risk of events than clopidogrel in a dual antiplatelet strategy with ASA. Prasugrel has not been included in the HHS algorithm because of a more complex benefit-to-risk ratio across subpopulations, such as in patients ≥75 years of age, having prior stroke or TIA and or a body weight ≤60 kg. Unlike ticagrelor in PLATO, prasugrel in TRITON-TIMI 38 did not show a mortality benefit. In the HHS algorithm, ASA and ticagrelor is an acceptable first-line option in patients who are candidates for primary PCI.

Relevance of New Algorithm to Regional Centres

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

Current practice in ACS at tertiary facilities such as HHS is relevant to regional community hospitals as emergency and urgent transfer of patients for cardiac catheterization and PCI is integral to the optimal management of these patients. While there are many regional disparities in the care of ACS driven largely by geography and variability in resources (e.g. the proximity of rapid response teams, medical directives for redirection to a PCI centre and differences in transfer intervals to catheterization laboratories.), regional standardization of antiplatelet therapies provides an opportunity to improve outcomes. The revised algorithm is evidence-based and does specifically outline areas in which ASA plus ticagrelor should be considered as first-line therapy instead of ASA plus clopidogrel.

Conclusion

The first-line antiplatelet strategies in ACS patients have been revised. The combination of ASA and ticagrelor provides an important opportunity to improve outcomes relative to ASA and clopidogrel in ACS patients, with or without ECG ST segment elevation. The advantage of ticagrelor over clopidogrel in appropriately selected patients includes a mortality reduction. The guidelines developed by HHS are evidence based and 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 with an acceptable risk from more effective antiplatelet therapy?

A: There is randomized trial evidence that some specific high-risk patients achieve a reduction in risk of thrombotic events with an acceptable risk of adverse events from newer more effective antiplatelet therapy. In the algorithm we developed, based on this evidence, the goal is to provide a clear pathway for making choices that will provide an optimal balance of risks versus benefits. For example, the data favour ASA and ticagrelor in STEMI patients undergoing primary PCI, but ASA and clopidogrel is preferred in patients with a high risk of bleeding, such as those who are administered fibrinolysis. The risk of bleeding in patients treated with fibrinolysis may negate the advantage of greater antiplatelet activity.

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 the newer antiplatelet therapies over clopidogrel in different ACS groups (STEMI and NSTEMI ACS)?

A: Even if we can differentiate types of ACS by clinical findings, we assume that the pathophysiology is similar. In general, the advantage of greater antiplatelet effect will be greatest in those at highest risk of a thrombotic event. Our algorithm is based on the benefit-to-risk ratio derived from the clinical trials. In addition to antiplatelet activity, the speed of antiplatelet inhibition is also an important consideration. Clearly, the faster onset of ticagrelor is very important in STEMI patients who are reaching the cath lab within 90 to 120 minutes of diagnosis, because it is critical to achieve greater antiplatelet effect when it is needed most. But even in the NSTEMI patient who may not have an angiogram until day 2 or day 3 after diagnosis, the rapid onset of antiplatelet activity is important to maximize the initial benefits of medical therapies.

Q: What is your point of view on the possible side effects associated with the newer agents vs. the opportunity to improve outcomes?

A: In the PLATO study, side-effects such as dyspnea and ventricular pauses in the first week were more common in the ticagrelor group, but few patients discontinued the drug because the dyspnea and pauses were rarely associated with symptoms or events. It is important to be aware of these potential side-effects as part of routine clinical practice, but decisions to discontinue ticagrelor must be balanced with the potential benefits of administering appropriate evidence based therapies.

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: It is true that the upfront decisions in ACS are getting more complex, but the algorithm is organized into a stepwise decision tree that is designed to allow clinicians to rapidly and rationally select the appropriate antiplatelet therapy in the context of their ACS care. In our Local Health Integration Network (LHIN), we  have two centres that offer PCI, but there are several centres that are not equipped to provide PCI. One of the key issues in ACS is the timing of cardiac catheterization. The selection of antiplatelet agent not only depends on patient profile but on the expected course of management. The algorithm we developed accommodates appropriate decisions in different settings. 

Sometimes there is a need to switch from one antiplatelet to another based on the clinical context.  The following are examples of clinical scenarios that may arise:

a) Starting ticagrelor in a patient who has already been treated with clopidogrel:

- After LD of clopidogrel has been given, it is reasonable to treat with 180 mg LD ticagrelor and then continue with 90 mg b.i.d.

- After LD and at least one maintenance dose of clopidogrel has been given.

•     If clinical circumstances require rapid and high level platelet inhibition: 180 mg LD ticagrelor and then 90 mg b.i.d.

•   If clinically do NOT require rapid and high level platelet inhibition: No LD of ticagrelor and start 90 mg bid the day after receiving their last dose of clopidogrel.

b) Starting clopidogrel in a patient who has already been treated with ticagrelor:

-Wait 12-24 hr from last ticagrelor dosing and start 300 mg LD clopidogrel and then 75 mg daily in AM.  This group may include patients with newly identified atrial fibrillation who may be initiated on warfarin or another novel oral anticoagulant to reduce their risk of stroke. By using clopidogrel rather than ticagrelor in groups with potential bleeding issues, we accept reduced protection against stent thrombosis for a reduced risk of bleeding.   

References:

1. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. 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 MS, Cannon CP, Gibson CM, 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 L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361(11):1045-57.

4. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357(20):2001-15.

5. Peterson ED, Roe MT, Mulgund J, et al. Association between hospital process performance and outcomes among patients with acute coronary syndromes. JAMA 2006;295(16):1912-20.

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