Dissolving the dilemma: Management of Antithrombotic Therapy after Acute Coronary Syndromes

The management of antithrombotic agents for patients after an acute coronary syndrome is becoming increasingly complex. The data suggesting better drugs or better combinations for extended or limited durations needs to be simplified for everyday use by clinicians. Further, since the trials may not represent the entire diversity of patients presenting to a cardiologist, due to their stringent inclusion/exclusion criteria, hence individualization of therapy may be needed in many cases. This discussion aims to assimilate the recent evidence of antiplatelet and antithrombotic use in post-acute coronary syndrome (ACS) patients and touches upon the aspects of personalizing such therapy according to a given clinical scenario.

1. Choice of antiplatelets: The 2014 AHA guidelines recommend either clopidogrel or ticagrelor for the management of a non-STE acute coronary syndrome , with a preference for ticagrelor. Prasugrel is recommended mainly when a percutaneous coronary intervention (PCI) is planned in patients who are not considered to be at high risk for bleeding. This recommendation is based on findings from TRITON-TIMI and PLATO trials which documented a benefit of ticagrelor over clopidogrel for patients at moderate-to-high risk for ischemia with or without revascularization. The 2020 European Society of Cardiology (ESC) treatment guidelines for non-STE acute coronary syndrome preferentially recommend ticagrelor or prasugrel as the standard treatment for all patients presenting with an acute coronary syndrome (class I recommendation, level of evidence B) unless this agent is contraindicated.

In 2019, the ISAR-REACT 5 trial randomly assigned 4018 patients presenting with ACS to either ticagrelor (loading dose given right away) or prasugrel (loading dose given right away for STE myocardial infarction and loading dose given after delineation of coronary anatomy for other acute coronary syndromes). The investigators concluded that prasugrel was superior to ticagrelor, with a lower rate of death, myocardial infarction, or stroke at 1 year and no increase in the risk of bleeding. The ESC guidelines thus recommend considering prasugrel over ticagrelor for patients with non-STE acute coronary syndrome who undergo PCI (class IIa recommendation, level of evidence B.)

2. Duration of DAPT: The recommended duration of DAPT after an acute coronary syndrome and PCI is a moving target. For most patients, DAPT is recommended for a minimum of 12 months after an acute coronary syndrome; exceptions include patients for whom surgery is urgently needed, anticoagulation is needed for atrial fibrillation, or the risk of bleeding is too high for other reasons, such as thrombocytopenia, liver disease, or renal disease. The adequate dose of aspirin for long-term therapy in patients with coronary artery disease is currently being studied in a pragmatic clinical trial, ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness), with results expected in 2021. As of now, a dose ranging from 75-100 mg is mostly used.

Patients with complex coronary anatomy, other vascular disease, or untreated residual coronary disease who are not at high risk for bleeding may benefit from a longer duration of DAPT (beyond 12 months), particularly if they have not had a major bleeding event during 1 year of DAPT. The alternative approach of discontinuing aspirin instead of the P2Y12 inhibitor has been studied in several recent trials like TWILIGHT and TICO. A recent meta-analysis by O'Donoghue et al. similarly concluded that discontinuation of aspirin with continued P2Y12 monotherapy (after 1 to 3 months of DAPT) reduced the risk of bleeding and was not associated with an increased risk of ischemic events among patients presenting with acute coronary syndromes.

3. Anticoagulation: Current clinical practice guidelines recommend the combination of DAPT and anticoagulant therapy for hospitalized patients with acute coronary syndromes, irrespective of whether invasive or conservative treatment strategies are planned.

Parenteral anticoagulant agents — enoxaparin, bivalirudin, fondaparinux, or unfractionated heparin — are a class I recommendation for treatment during the initial period (up to 48 hours after the event or until PCI is performed). The choice of anticoagulant may be guided by concurrent decision making regarding the use and timing of an early invasive strategy. For example, a patient for whom an invasive strategy is planned, with a very rapid transition (within a few hours) to the catheterization laboratory for PCI, might best be treated with unfractionated heparin or bivalirudin, whereas a patient for whom a medical strategy is planned might be more appropriately treated with enoxaparin or fondaparinux.

It is estimated that atrial fibrillation develops in up to 20% of patients with acute coronary syndromes, and these patients have higher stroke rates and in-hospital mortality than patients without atrial fibrillation. With the increasing use of direct oral anticoagulants (DOACs) for the management of atrial fibrillation, several trials like REDUAL-PCI, PIONEER AF, AUGUSTUS and ENTRUST AF PCI have now documented a reduction in bleeding when a DOAC and a P2Y12 inhibitor are used together, as compared with warfarin-based triple therapy, in patients undergoing PCI.

For patients with an acute coronary syndrome and atrial fibrillation, the totality of the evidence favors a short duration of triple therapy in most cases and then dual antithrombotic therapy with a P2Y12 inhibitor (clopidogrel) and a DOAC for at least 12 months. The results of the AFIRE (Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease) trial suggest that rivaroxaban monotherapy may be a safe alternative for longer-term management of atrial fibrillation and stable coronary artery disease (at least 1 year after PCI or bypass surgery).

When and how to individualize? It is important to remember that the evidence base informing practice guidelines reflects population-level data. However, many patients seen in clinical practice do not perfectly meet trial inclusion criteria and have sociodemographic, clinical, or other characteristics that require special consideration.

A schematic for such individualized decision-making is shown in the accompanying figure.

Several areas are under active investigation. Almost all the reported studies of DAPT and triple therapy after an acute coronary syndrome have assessed the combination of clopidogrel plus aspirin. We do not know the adequate duration of DAPT with more potent, newer-generation P2Y12 inhibitors.

Newer-generation stents, which have essentially replaced bare-metal stents, are likely to require less potent platelet inhibition, yet the benefits of antithrombotic therapy after an acute coronary syndrome are independent of stenting. Active clinical trials are evaluating investigational agents that might improve the risk–benefit balance of current antithrombotic strategies. In addition, we need more rigorous and pragmatic clinical trials that recruit populations as diverse as the patients we care for in clinical practice, with broad representation of race or ethnic group, sex, coexisting conditions, age, and sociocultural characteristics.

A one-size-fits-all approach is not suited to the management of antithrombotic therapies after acute coronary syndrome. A careful assessment of thrombotic risk versus bleeding risk is required for each patient as part of a tailored, potentially dynamic treatment plan that uses the tools of risk stratification in the context of the patient's values and preferences.

Source:NEJM:NEnglJMed2021;384:452-460

DOI: 10.1056/NEJMra1607714