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Patients with concomitant atrial fibrillation (AF) account for 5%–10% of those receiving percutaneous coronary intervention (PCI); this prevalence is likely to increase in the future due to the advancing age of the population and attendant comorbidities. Given the great number of possible therapeutic combinations, observational data on patients with AF suffering from acute myocardial infarction (MI) and/or receiving PCI have indicated a large variability of antithrombotic strategies among different countries and centres. Furthermore, available evidence often derives from single-centre registries or small case-controlled series, and refers to patient populations with different characteristics and risk profiles.
Triple antithrombotic therapy for a long time has been empirically considered the ‘ideal’ treatment in this setting of patients, as it may provide protection from both AF-related thromboembolic complications and ischaemic cardiac events, that is, oral anticoagulant therapy to prevent stroke or systemic embolism and dual antiplatelet therapy with aspirin plus clopidogrel to reduce MI and stent thrombosis. However, a close correlation between bleeding events and number or doses of antithrombotic agents has been clearly documented. In particular, studies have shown a greater than threefold elevation in the risk of major bleeding with use of triple versus dual antithrombotic therapy; notably, the occurrence of haemorrhagic complications may negatively affect the prognosis during follow-up. Thus, three randomised trials have recently evaluated whether in patients with AF undergoing PCI a dual antithrombotic treatment (an oral anticoagulant drug plus a P2Y12 inhibitor, usually clopidogrel, withdrawing aspirin) reduces the rates of bleeding events without increase in ischaemic events compared with triple therapy.1–3 Those investigations showed a safety benefit with dual therapy, apparently with no signal of lower efficacy, but they were individually underpowered for ischaemic events and more data are needed to draw definite conclusions. Of note, the 2017 European Society of Cardiology update on dual antiplatelet therapy in coronary artery disease recommends triple therapy (with vitamin K antagonist (VKA) anticoagulants, or non-VKA oral anticoagulants (new oral anticoagulants, NOAC), as anticoagulant agent) up to 6 months after PCI when the ischaemic risk prevails and triple therapy for 1 month (IIa B) or dual antithrombotic therapy (IIa A) when the bleeding risk prevails.4 To date, in patients with AF undergoing PCI no extensive real-world data were available on the penetration of NOAC utilisation, neither on strategies for associating NOACs and antiplatelet agents nor on patterns of NOAC dosages.
In their Heart paper, Sindet-Pedersen et al 5 published data from a large observational study using Danish nationwide registries; in particular, the authors explored prevalence and temporal trends from 2011 to 2016 of NOAC versus VKA utilisation, with either single or dual antiplatelet therapy, among 2946 patients with AF surviving 30 days after discharge from MI and/or PCI. The study appears adequately sized and methodologically well conducted, registries used were associated with high internal validity, and the risk of inclusion, treatment and misclassification biases was limited. The investigation is focused on a contemporary and debated topic; the results are relevant inasmuch as they provide a real-world snapshot of the different antithrombotic strategies applied in patients with AF with concomitant coronary artery disease, and, importantly, how those strategies have changed after the introduction of the newer and safer anticoagulant drugs (NOACs). The authors report that in the overall study period the prevalence of triple therapy was higher in patients receiving PCI with stent implantation compared with those with MI (68% vs 41%), and the opposite was for dual antithrombotic treatment; this is in line with the physicians’ concern to give up therapy with aspirin plus P2Y12 inhibitor after coronary stenting due to the risk of stent thrombosis in the first months after the intervention. Unexpectedly, the use of dual antithrombotic therapy instead of triple therapy was not particularly addressed to patients with high HAS-BLED score; thus, in the real-world context other features of increased bleeding risk beyond those included in the currently available scores may drive the choice of antithrombotic strategies and/or, regardless of the bleeding risk, the prescription of antithrombotic treatment is guided by the ischaemic risk more than the bleeding risk.
The study results on temporal trends are also interesting; over a 5-year period there was a progressive decline of dual antithrombotic therapy utilisation, paralleled by an increase in triple therapy (from 43% to 60%); this raise mainly occurred in patients undergoing PCI and tended to be higher in younger patients. In the context of triple therapy, there was an overtime reduction of VKA use and a continuous, incremental prescription of NOACs. Importantly, the increase of triple therapy penetration, especially with NOAC as anticoagulant agent, was also observed in patients with older age, high bleeding risk and history of previous bleeding. Moreover, from 2011 to 2016 the elevation in the association NOACs plus antiplatelet therapy was driven by an increased prescription of NOACs added to dual (from 4% to 32%) rather than to single antiplatelet treatment.
Thus, the improvement in physicians’ experience and familiarity with NOAC use, together with the clear evidence concerning the safety of these agents compared with VKAs, has progressively led to prefer the prescription of NOACs instead of VKAs in patients at higher risk of bleeding, also including those with concomitant antiplatelet therapy. Indeed, in the Randomized Evaluation of Long-Term Anticoagulant Therapy trial, patients with AF receiving oral anticoagulation plus dual antiplatelet therapy (figure 1) had a 40% and 130% relative increase in the risk of major bleeding compared with those on anticoagulant plus single antiplatelet therapy and on anticoagulant therapy alone, respectively6; notably, in the Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation trial, the absolute risk reduction of any bleeding with apixaban versus warfarin was more pronounced in patients with versus those without concomitant aspirin therapy (10.2% vs 7.1%).7 In the real world, a concern related to the NOAC use is represented by the risk of bleeding in patients with chronic renal failure; accordingly, Sindet-Pedersen et al report that, among patients with renal failure who were given triple therapy, the prescription of VKAs was prevalent (14% vs 6% for NOACs).5
In the study by Sindet-Pedersen et al the majority of patients received NOACs at standard dosage before the index coronary event (60%), whereas the majority was on a reduced NOAC dose when antiplatelet therapy was added (64%).5 This may be at least in part due to the recommendation of the latest guidelines of the European Society of Cardiology on AF,8 indicating after acute coronary syndromes and PCI in patients requiring oral anticoagulation to use a NOAC at the lowest dose effective for stroke prevention in AF. However, observational real-world registries have reported high rates of NOACs prescribed at inappropriate dosing (ie, inappropriate dose reduction, beyond the approved dosing tested in phase III trials), mainly in patients at high risk of bleeding9; this occurrence cannot be excluded also in the investigation by Sindet-Pedersen et al. Importantly, an inappropriate reduction of NOAC dosage may cause a suboptimal, inadequate protection from stroke and other thromboembolic events.9
The study by Sindet-Pedersen et al did not evaluate other relevant issues related to antithrombotic therapy in patients with AF candidates to antiplatelet therapy because of concomitant coronary artery disease. In particular, no correlation was performed between the extension of coronary artery disease, the coronary risk profile, the type of implanted stents and the prevalence of different antithrombotic approaches. Moreover, no specific data on clinical outcome with the use of NOACs in this setting of patients were provided; this is a ‘burning’ unmet need, and future prospective, large-sized, real-world studies exploring such an issue are welcome.
Competing interests GP: speaker/consultant/advisory board for Amgen, Sanofi, Bayer, Boehringer-Ingelheim, BMS-Pfizer, Daiichi Sankyo, Astra Zeneca, Sigma-Tau, Malesci, PIAM and MSD.
Provenance and peer review Commissioned; internally peer reviewed.
- Arrhythmias and sudden death