Triple antithrombotic therapy and dual therapy – What is the evidence base?

A 78-year-old woman with atrial fibrillation (AF) and hypertension presented to the emergency department with chest pain. Her medications include amlodipine 5 mg once daily and apixaban 5 mg twice daily. The admission ECG demonstrated T-wave changes in the lateral leads with a raised troponin (200 ng/L [cut-off 14 ng/L]) consistent with a non-ST segment elevation myocardial infarction (NSTEMI). She was reviewed by the local cardiologist and an invasive treatment strategy was selected. She was subsequently treated with aspirin/clopidogrel and treatment dose anticoagulation. Triple antithrombotic therapy (TAT) refers to the concurrent use of an oral anticoagulant (OAC) in combination with dual antiplatelet therapy (DAPT), such as aspirin and clopidogrel. Overall, it is estimated that 6–8% of patients with acute coronary syndrome (ACS) have a pre-existing indication for OAC therapy.1-3 This combination is most frequently encountered in the context of pre-existing AF, in whom up to 40% have concomitant coronary artery disease (CAD).4 The co-existence of AF with CAD represents a challenge in clinical practice due to the difficulty and risks associated with evidence-based anti-thrombotic choice.5-7 Underpinning the need for TAT in this population is the differential mechanism of thrombosis in the venous and arterial system. In AF, venous thrombi consist of fibrin and are promoted by stasis whilst in CAD, arterial thrombosis is usually initiated by plaque formation in the arterial wall.8 Therefore, therapeutic agents need to target different mechanisms to offer protection against both arterial and venous events. However, it is well recognised that the bleeding risk increases dramatically as the number of antithrombotic agents increases.2, 9 Efforts to quantify this risk have found that the incidence of all major bleeding per 100 patient-years was 2.5 for aspirin monotherapy, 2.2 for DOAC (direct OAC), 3.8 for DAPT, 4.0 for DOAC + single antiplatelet therapy (SAPT) and 8.8 for DOAC TAT9 (for every 100 patients treated with DOAC TAT for a year, around 8.8 will suffer a major bleed as compared to 2.5 patients on aspirin SAPT). Interestingly, vitamin K antagonists (VKA) triple therapy harbours the highest risk of bleeding of 9.0 per 100-patient-years. The need for TAT is based on the fact that ischaemia risk is highest immediately post ACS and slowly tapers off, while bleeding risk stays static/increases with age and advancing comorbidities. The optimal duration of TAT following ACS is controversial. New randomised control trials (RCTs) and subgroup analyses of existing trials produce more evidence pertaining to the benefits and risks of TAT and the optimal duration. The rapid growth of the evidence base in recent years has resulted in updated guidance in the form of a North American Consensus document in 202110 and a European Society of Cardiology (ESC) guideline document in 20207 (summarised in Table 1). Both have trended towards shorter durations of TAT than the documents they have replaced. Based on these documents, it can be advised that TAT should be utilised as the default strategy in all ACS patients with an indication for OAC independent of bleeding/ischaemia risk. The default duration advised by the ESC is 1 week whilst the North American Consensus advises utilisation of TAT peri-procedurally up to 1 week post stenting. (Peri-percutaneous coronary intervention [PCI] is defined as from the start of the inpatient stay, until time of discharge, and up to 1 week after PCI.10 The definition is based on the heterogeneous duration of TAT in the trials that formulate the evidence). Subsequent to this period, patients should be on dual therapy (OAC + antiplatelet combination [preferably clopidogrel over aspirin)] for 12 months and then stepped down to OAC therapy only lifelong. AF patients undergoing PCI on OAC + aspirin + clopidogrel 1 week Followed by OAC + SAPT for 12 months 1 month (can be considered for longer if extremely high ischaemic risk) Followed by OAC + SAPT to complete 12 months 1 week Followed by OAC + SAPT for 6 months Peri-PCI Followed by OAC + SAPT to complete 12 months 1 month Followed by OAC + SAPT to complete 12 months Peri-PCI Followed by OAC + SAPT for up to 6 months Case continued … She proceeded to have percutaneous coronary intervention (PCI) with stenting of her left anterior descending coronary artery. On discharge, the interventional cardiologist advised that the patient should continue with aspirin/clopidogrel and apixaban for 7 days total following her NSTEMI. Subsequent to this she should continue on clopidogrel and apixaban for 12 months and stop the clopidogrel hereafter. Nuances in the duration and dose of TAT/dual therapy exist for patients at a high risk of thrombosis or high risk of bleeding (as defined by a validated risk assessment score such as HASBLED11), where the treating cardiologist can alter the duration and dose of TAT slightly. This is particularly utilised in a high-risk bleeding patient where a lower dose of OAC can be utilised, or in a high risk ischaemic patient where a longer duration of TAT can be considered.7, 10 The definitions of high-risk ischaemia/bleeding patients are beyond the scope of this document and are well described in the literature.12, 13 The decision to be placed on TAT should be made by the treating cardiologist and the duration of this therapy should be clearly stated when patients are discharged. These recommendations are based on an influx of RCTs in the past decade in the form of WOEST14 (Dual therapy vs TAT), ISAR-TRIPLE15 (VKA and DAPT), PIONEER AF-PCI16 (rivaroxaban and DAPT), RE-DUAL PCI17 (dabigatran and DAPT), AUGUSTUS18 (apixaban and DAPT), ENTRUST-AF-PCI19 (edoxaban and DAPT) and a sub-analysis of the MASTER-DAPT20 trial (DAPT for 1 month vs 3–12 months), all demonstrating a significant consistent reduction in bleeding complications with dual therapy as compared to triple therapy. Furthermore, data from these trials demonstrate significant lower risk of bleeding with an OAC + DAPT combination as compared to a VKA + DAPT combination.21 Notably, there was no significant increase in ischaemic events associated with dual therapy (albeit none were powered to assess major adverse ischaemic events or stent thrombosis). However, two large meta-analyses of these trials have both demonstrated that dual therapy potentially increases thrombotic complications as compared with triple therapy.22, 23 Table 2 demonstrates a breakdown of these trials and their findings. Meta-analysis data from Galli et al. estimates that the number needed to treat (NNT) with dual therapy as compared to triple therapy to prevent one bleeding event was 17.22 The NNT to prevent one intracranial haemorrhage was estimated at 314. On the other hand, the number needed to harm to cause an ST event was 274. This demonstrates the decision on dual therapy/TAT is always a balancing act between ischaemia and bleeding.22 WOEST14 NCT00769938 ISAR-TRIPLE15 NCT00776633 PIONEER AF-PCI16 NCT01830543 18% in rivaroxaban + SAPT group vs 26.7% in TAT group P < .001 RE-DUAL PCI17 NCT02164864 ENTRUST-AF-PCI19 NCT02866175 AUGUSTUS18 NCT02415400 Dual therapy results in less bleeding without significant differences in ischaemic events. The first 12 months after ACS have a significant evidence base for decision making on choice of OAC/anti-platelet agent. What is less clear is what the optimum strategy is after 12 months. The OAC-alone24 trial randomised people to OAC + SAPT vs OAC alone. Unfortunately, this trial was underpowered and inconclusive because of premature termination. The subsequent AFIRE25 randomised patients to rivaroxaban + SAPT vs rivaroxaban alone. This trial was terminated early due to excessive bleeding risk in the combination group, suggesting that OAC alone may be the optimal strategy. Case continued … One year after her NSTEMI, the patient was reviewed by her general physician. She was found to have well controlled lipid levels and a normal blood pressure. She had successfully given up smoking and lost weight. During her review it transpires that she has not had any further episodes of chest pain. She had remained well on dual therapy with apixaban and clopidogrel and, following her review, her clopidogrel was stopped. H.E. and L.W. have nothing to declare. R.S. reports speaker fees from Novartis, Astra Zeneca, Vyfor, BMS/Pfizer and research grants from Biotronik UK and the British Heart Foundation outside the submitted work. HE drafted and wrote the manuscript. RS and LW edited the manuscript and provided supervision.