https://orcid.org/0000-0001-9808-5492
Abstract
To investigate the effects of aspirin-omitted dual antithrombotic therapy (DAT) on myocardial infarction and stent thrombosis in non-valvular atrial fibrillation (NVAF) patients presenting with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI).
A systematic review and meta-analysis were performed using PubMed to search for randomized clinical trials comparing DAT with triple antithrombotic therapy (TAT) in this setting. Three trials involving 8845 patients were included (4802 and 4043 patients treated with DAT and TAT, respectively). There were no significant differences in all-cause death and stroke between the aspirin-omitted DAT group and TAT group. Otherwise, the incidence of myocardial infarction was significantly higher with aspirin-omitted DAT vs. TAT [odds ratio (OR): 1.29, 95% confidence interval (CI): 1.02–1.63; P = 0.04; I2 = 0%]. Similarly, the incidence of stent thrombosis increased in patients treated with aspirin-omitted DAT vs. TAT (OR: 1.61, 95% CI: 1.02–2.53; P = 0.04; I2 = 0%). The occurrence of major bleeding and clinically relevant non-major bleeding events, as defined by the International Society on Thrombosis and Haemostasis, was significantly lower with aspirin-omitted DAT vs. TAT (OR: 0.61, 95% CI: 0.48–0.78; P = 0.02; I2 = 76%). Similar results were found according to the International Society on Thrombosis and Haemostasis major bleeding, Thrombolysis in Myocardial Infarction major or minor bleeding, and Thrombolysis in Myocardial Infarction major bleeding scales.
Aspirin-omitted DAT reduces the occurrence of bleeding episodes, with a higher rate of myocardial infarction and stent thrombosis in NVAF patients presenting with ACS or undergoing PCI.
Introduction
Approximately 20% of patients with atrial fibrillation (AF) develop acute coronary syndrome (ACS) or undergo percutaneous coronary intervention (PCI).1 In patients with AF at high risk of stroke, oral anticoagulation (OAC) therapy prevents stroke and systemic embolism.2–4 In contrast, dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor prevents platelet-mediated coronary events (e.g. myocardial infarction and stent thrombosis) in patients with ACS5 or after PCI.6 In these conditions, DAPT with a P2Y12 inhibitor, in addition to aspirin, is recommended for ≥12 months unless contraindicated (e.g. high risk of bleeding). A similar consensus has been reached for patients with stable coronary artery disease for 6 months.7,8 Although OAC is superior to DAPT for the prevention of ischaemic stroke and non-central nervous system systemic embolism in patients with AF at high risk of stroke,9 OAC is less efficacious for secondary prevention after ACS and prevention of stent thrombosis.10 Theoretically, patients with AF undergoing ACS or PCI would require triple antithrombotic therapy (TAT) (i.e. a combination of OAC and DAPT) to prevent the occurrence of cardioembolic and coronary thrombotic complications.11,12 However, TAT with a vitamin K antagonist (VKA), aspirin and clopidogrel results in excessive and major bleeding.13,14 Therefore, the therapeutic strategy for patients with AF undergoing ACS or PCI must carefully balance the risk of stent thrombosis and ischaemic stroke with the risk of bleeding. The What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing (WOEST) study showed that dual antithrombotic therapy (DAT) with OAC and clopidogrel decreased the occurrence of bleeding episodes by 64% in patients treated with OAC undergoing PCI vs. TAT with OAC, clopidogrel, and aspirin.15 Those results indicated that omitting aspirin from the antithrombotic regimen may reduce the rate of bleeding events. However, in the Open-Label, 2 × 2 Factorial, Randomized, Controlled Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin vs. Aspirin Placebo in Patients with Atrial Fibrillation and Acute Coronary Syndrome and/or Percutaneous Coronary Intervention (AUGUSTUS) trial, aspirin omitted from the antithrombotic regimen resulted in a numerical increase in the incidence of myocardial infarction and stent thrombosis.16 Therefore, we performed a systematic review and meta-analysis of randomized controlled trials that compared aspirin-omitted DAT with TAT in non-valvular atrial fibrillation (NVAF) patients presenting with ACS or undergoing PCI, specifically focusing on the effect of aspirin-omitted DAT on coronary ischaemic events.
Methods
Search strategy and selection criteria
For this meta-analysis, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.17 We developed a protocol which was submitted to PROSPERO on 11 October 2019 (ID 157962). A search was conducted in PubMed until 30 September 2019, using the following search terms in various combinations: ‘atrial fibrillation’, ‘AF’, ‘percutaneous coronary intervention’, ‘coronary stenting’, ‘PCI’, ‘acute coronary syndrome’, ‘ACS’, ‘apixaban’, ‘rivaroxaban’, ‘edoxaban’, ‘dabigatran’, ‘non-vitamin K oral anticoagulants’, ‘new oral anticoagulants’, ‘NOAC’, ‘direct oral anticoagulants’, ‘DOAC’, ‘vitamin k antagonist’, ‘VKA’, ‘aspirin’, ‘clopidogrel’, ‘ticagrelor’, ‘prasugrel’, ‘triple antithrombotic therapy’, ‘dual antithrombotic therapy’, ‘triple therapy’, and ‘dual therapy’.
In addition, references of prior systematic reviews and meta-analyses, as well as abstracts from major cardiology meetings, were screened for related studies. Two investigators (C.F.L. and P.M.) independently reviewed the titles, abstracts, and studies to determine their eligibility for inclusion in the present analysis.
We included articles that met the following criteria: (i) randomized controlled trials involving NVAF patients with ACS or undergoing PCI; (ii) at least two groups involved: DAT (single antiplatelet therapy + OAC) and TAT (DAPT + OAC); (iii) a P2Y12 inhibitor selected as long-term antiplatelet therapy, but not aspirin; and (iv) outcomes including all-cause death, stroke, myocardial infarction, stent thrombosis, and bleeding events. The following information was extracted from each included article: study characteristics (i.e. authors, year of publication, study design, sample size, time after ACS or PCI) and antithrombotic therapy regimen.
Statistical analysis
Odds ratios (ORs) with 95% confidence intervals (CIs) using both random- and fixed-effects models were calculated with the RevMan software version 5.3 (Cochrane Collaboration). Significant heterogeneity was identified in both analyses, as indicated by the I2 values. In general, the I2 values of 25%, 50%, and 75% indicate low, moderate, and high degrees of heterogeneity, respectively. The random-effects model with inverse variance weighting was used when the degree of heterogeneity was high or moderate; otherwise, the fixed-effects model with the Mantel–Haenszel method was preferred. Funnel plots were examined for publication bias.
Results
Studies and patient characteristics
Using the search strategy, 763 potentially relevant articles were screened focusing on antithrombotic therapy in NVAF patients undergoing ACS or PCI. Three articles16,18,19 met our inclusion criteria and were pooled for meta-analysis (Supplementary material online, Figure S1). The WOEST trial included patients in whom long-term OAC and PCI were indicated. Although 69% of enrolled patients had AF or atrial flutter, patients with mechanical valve, pulmonary embolus, and other OAC indication were also included.15 In the PIONEER AF-PCI trial (Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous Coronary Intervention), patients with NVAF undergoing PCI with stenting received low-dose rivaroxaban plus a P2Y12 inhibitor for 12 months; very-low-dose rivaroxaban plus DAPT for 1, 6, or 12 months; or a dose-adjusted VKA plus DAPT for 1, 6, or 12 months, respectively. After 1 or 6 months of DAPT, treatment with the P2Y12 inhibitor was discontinued, and aspirin coupled with OAC or rivaroxaban were administered for the remaining 12 months of the treatment period.10 These two trials did not meet our inclusion criteria and were excluded from the meta-analysis.
The RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran vs. Triple Therapy with Warfarin in Patients with Non-valvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial included two dabigatran-based groups (110 mg bid and 150 mg bid) with 981 patients and 763 patients,18 respectively; these two groups were pooled for meta-analysis.
All-cause death and stroke
In patients treated with aspirin-omitted DAT or TAT, the rate of all-cause death was 4.4% and 3.9%, respectively (OR: 1.10; 95% CI: 0.89–1.36) (Figure 1A), while the rate of stroke was 1.1% and 1.1%, respectively (OR: 0.98; 95% CI: 0.66–1.47) (Figure 1B). This indicates that aspirin-omitted DAT did not significantly increase the occurrence of all-cause death or stroke in patients with NVAF undergoing ACS or PCI vs. TAT, in which OAC or a non-vitamin K antagonist oral anticoagulant (NOAC) was involved.
All-cause death (A) and stroke (B) in dual antithrombotic therapy vs. triple antithrombotic therapy. CI, confidence interval; DAT, dual antithrombotic therapy; PCI, percutaneous coronary intervention; TAT, triple antithrombotic therapy.
Myocardial infarction and stent thrombosis
The RE-DUAL PCI, AUGUSTUS, and ENTRUST-AF PCI trials reported cases of myocardial infarction during the follow-up. By pooling the three trials, there were 183 and 120 cases (3.8% and 3.0%, respectively; OR: 1.29; 95% CI: 1.02–1.63) complicated with myocardial infarction among patients receiving aspirin-omitted DAT and TAT, respectively (Figure 2A). Furthermore, there were 56 and 29 cases (1.2% and 0.7%, respectively; OR: 1.61; 95% CI: 1.02–2.53) complicated with definite or probable stent thrombosis among patients treated with aspirin-omitted DAT and TAT, respectively (Supplementary material online, Figure S2). In the AUGUSTUS trial, 1746 and 1752 patients underwent PCI in the aspirin and placebo groups, respectively. Considering that not all patients underwent PCI, the rate of definite or probable stent thrombosis was 1.3% and 0.8%, respectively (OR: 1.61; 95% CI: 1.02–2.53) (Figure 2B). This suggests that aspirin-omitted DAT may increase the occurrence of myocardial infarction and definite or probable stent thrombosis in NVAF patients after ACS or PCI, compared with TAT.
Myocardial infarction (A) and stent thrombosis (B) in dual antithrombotic therapy vs. triple antithrombotic therapy. CI, confidence interval; DAT, dual antithrombotic therapy; PCI, percutaneous coronary intervention; TAT, triple antithrombotic therapy.
Bleeding events
In patients treated with aspirin-omitted DAT or TAT, the rate of major bleeding or clinically relevant non-major (CRNM) bleeding event, defined by the International Society on Thrombosis and Haemostasis (ISTH), was 13.3% and 19.5%, respectively (OR: 0.61; 95% CI: 0.48–0.78) (Figure 3A). The rate of ISTH major bleeding event was 4.2% and 6.1%, respectively (OR: 0.63; 95% CI: 0.52–0.77) (Figure 3B). The rate of major or minor bleeding event, defined by Thrombolysis in Myocardial Infarction (TIMI), was 5.5% and 8.7%, respectively (OR: 0.59; 95% CI: 0.40–0.86) (Figure 3C). The rate of TIMI major bleeding event was 1.6% and 2.9%, respectively (OR: 0.51; 95% CI: 0.38–0.69) (Figure 3D). The rate of intracranial haemorrhage event was 0.4% and 0.7%, respectively (OR: 0.57; 95% CI: 0.31–1.02) (Figure 3E). Importantly, the regimen of DAT was NOAC (dabigatran or edoxaban) plus a P2Y12 inhibitor, except in the AUGUSTUS trial (i.e. apixaban or VKA plus a P2Y12 inhibitor). If the results of the AUGUSTUS trial are excluded, the pooled analysis of the data obtained from the RE-DUAL PCI and ENTRUST-AF PCI trials revealed that aspirin-omitted DAT reduced the incidence of intracranial haemorrhage (OR: 0.31; 95% CI: 0.14–0.72) (Supplementary material online, Figure S3). These results suggest that aspirin-omitted DAT decreased the occurrence of bleeding events in NVAF patients after ACS or PCI, compared with TAT. In addition, aspirin-omitted DAT numerically reduced the occurrence of intracranial haemorrhage.
Bleeding events in dual antithrombotic therapy vs. triple antithrombotic therapy. CI, confidence interval; CRNM, clinically relevant non-major; DAT, dual antithrombotic therapy; ISTH, International Society on Thrombosis and Haemostasis; PCI, percutaneous coronary intervention; TAT, triple antithrombotic therapy; TIMI, thrombolysis in myocardial infarction.
Discussion
In the present meta-analysis, we focused on aspirin-omitted DAT for NVAF patients presenting with ACS or undergoing PCI. The results showed that aspirin-omitted DAT decreased the occurrence of ISTH major bleeding or CRNM bleeding, compared with TAT. Aspirin-omitted DAT was also associated with a lower rate of TIMI major or minor bleeding, and numerically decreased the rate of intracranial haemorrhage episodes. If the results of the AUGUSTUS trial are excluded, the pooled analysis of the data obtained from the RE-DUAL PCI and ENTRUST-AF PCI trials revealed that aspirin-omitted DAT reduced the incidence of intracranial haemorrhage. In the AUGUSTUS trial, the regimen of DAT was apixaban or VKA plus a P2Y12 inhibitor. Apixaban decreased the occurrence of intracranial haemorrhage compared with warfarin in patients with AF.20 In patients receiving VKA, the target international normalized ratio was within a range of 2.0–3.0 in all included trials.16,18,19 However, a lower therapeutic range (i.e. 2.0–2.5) is recommended by North American21 and European22 expert consensus, especially in patients receiving TAT.22 The lower end of the therapeutic range of VKA is linked to a lower rate of bleeding episodes.
For the endpoint event of all-cause death and stroke, the pooled results showed that there was no increase in the rate of events among patients receiving aspirin-omitted DAT. Therefore, omission of aspirin from TAT appears safe and effective for NVAF patients presenting with ACS or undergoing PCI. Unfortunately, the pooled analysis showed that aspirin-omitted DAT increased the occurrence of myocardial infarction or stent thrombosis, compared with TAT. It is established that platelets play a key role in the development of ACS. DAPT with a P2Y12 inhibitor and aspirin is the cornerstone of therapy for ACS or PCI. It is recommended to prevent myocardial infarction and stent thrombosis though advances in stent technology and stent implantation guided by intravascular ultrasound or optical coherence tomography.23 In clinical practice, the administration of an optimal antithrombotic therapy regimen in NVAF patients presenting with ACS or undergoing PCI is challenging. It is necessary to balance the cardioembolic and coronary ischaemic risk with the bleeding risk. For the secondary prevention of cardiovascular disease, the administration of aspirin reduced the incidence of vascular events and was associated with a significantly increased incidence of major bleeding events.24 A previous study reported that withdrawal of aspirin in patients with coronary artery disease increased the occurrence of a new coronary event, including stent thrombosis.25 The combination of aspirin with other antithrombotic drugs may be more effective in preventing cardiovascular events vs. aspirin monotherapy. Based on the development of new antithrombotic agents, aspirin-omitted regimens may have an increased net benefit for patients owing to the reduction in the risk of bleeding.26 In the RE-DUAL PCI trial, DAT with dabigatran (110 mg or 150 mg bid) plus clopidogrel reduced ISTH major or CRNM bleeding by 48% and 28%, respectively, compared with TAT including VKA plus clopidogrel and aspirin. This effect was accompanied by a numerical increase in the occurrence of myocardial infarction and definite stent thrombosis in patients treated with 110 mg dabigatran plus clopidogrel.18 In the AUGUSTUS trial, there was a 49% decrease in ISTH major or CRNM bleeding in patients treated with aspirin-omitted DAT vs. TAT including VKA or apixaban plus clopidogrel and aspirin. This effect was accompanied by a numerical increase in the occurrence of myocardial infarction and definite or probable stent thrombosis.16 The results of the pooled analysis showed that the rates of myocardial infarction and definite or probable stent thrombosis were significantly increased in patients treated with aspirin-omitted DAT. In the three analysed trials, patients were enrolled 5–14 days after ACS or PCI. Therefore, aspirin was withdrawn very early in patients treated with DAT. It is established that increased platelet activity is observed in patients with ACS, especially in the first 30 days following stent implantation. This effect results in an increased risk of early stent thrombosis and is associated with the highest risk of mortality.27 Accordingly, according to a European consensus statement, TAT should be considered for ≥4 weeks in patients with NVAF and ACS undergoing PCI, except in those at very high risk of bleeding. For the latter group of patients, the administration of DAT with omission of aspirin after index PCI should be considered.22
Recently, results showed that P2Y12 inhibitor monotherapy after 1 or 3 months of DAPT did not significantly increase the occurrence of myocardial infarction or stent thrombosis in patients after stent implantation, compared with 12 months of DAPT.28,29 With respect to reducing the incidence of coronary ischaemic events or stent thrombosis, it is reasonable to administer TAT for ≥4 weeks in NVAF patients presenting with ACS or undergoing PCI, but not for patients carrying a very high risk of bleeding (e.g. recent bleeding event). The clinical decision regarding the duration of TAT should be based on a balanced assessment of the cardioembolic, coronary ischaemic, and bleeding risks. In NVAF patients with ACS or after PCI at a low risk of bleeding and high ischaemic risk, TAT should last for 3–6 months. Certainly, NOAC is the preferred OAC agent for anticoagulative therapy.
Clopidogrel is the most common P2Y12 inhibitor used in NVAF patients presenting with ACS or undergoing PCI. Only 12%, >8%, and 7–8% of patients received treatment with ticagrelor or prasugrel in the RE-DUAL PCI, AUGUSTUS, and ENTRUST-AF PCI trials, respectively. Ticagrelor30 and prasugrel31 are associated with a higher rate of bleeding than clopidogrel. Therefore, their use may only be considered in selected patients, such as those with definite stent thrombosis while receiving clopidogrel, aspirin, and OAC.22
Lopes et al.32 carried out a network meta-analysis of randomized controlled trials to study the safety and efficacy of different antithrombotic regimens in patients with AF and ACS and/or PCI. Four randomized trials (WOEST, PIONEER AF-PCI, RE-DUAL PCI, and AUGUSTUS) were included. Results indicated that a regimen of NOACs plus a P2Y12 inhibitor was associated with less bleeding compared with that of VKAs plus DAPT. Strategies omitting aspirin caused less bleeding (including intracranial bleeding) without a significant difference in trial-defined major adverse cardiovascular events compared with strategies that included aspirin. Gargiulo et al.33 undertook a meta-analysis of NOAC-based randomized clinical trials to investigate the safety and efficacy of DAT vs. TAT in patients with AF and ACS, or who had undergone PCI. Four trials (PIONEER AF-PCI, RE-DUAL PCI, AUGUSTUS, and ENTRUST-AF PCI) were included. Results indicated that DAT, particularly if it consisted of a NOAC instead of VKA and a P2Y12 inhibitor, was associated with a reduction of bleeding. This benefit, however, was counterbalanced by a significant increase in the prevalence of stent thrombosis and a trend towards a higher risk of myocardial infarction with DAT. Here, we focused on the effects of aspirin-omitted strategies on ischaemic coronary events in patients with AF and ACS or undergoing PCI. Only 69% of enrolled patients had AF or atrial flutter in the WOEST trial. In the PIONEER AF-PCI trial, a P2Y12 inhibitor was discontinued in TAT after 1 or 6 months of DAPT, and aspirin coupled with OAC or rivaroxaban were administered for long-term treatment. Therefore, the WOEST and PIONEER AF-PCI trials were excluded. Those results confirmed that aspirin-omitted DAT significantly increased the occurrence of myocardial infarction and stent thrombosis.
The present meta-analysis had several limitations. Firstly, heterogeneity was found in the analysis of all bleeding events. Secondly, the follow-up periods were not identical in all the studies. Thirdly, the rate of stent thrombosis was low, especially in patients who received second-generation stents. Additional randomized trials with larger sample sizes are warranted to confirm the results of the present meta-analysis.
In summary, the present meta-analysis showed that aspirin-omitted DAT with OAC plus a P2Y12 inhibitor significantly decreased the incidence of bleeding episodes in NVAF patients presenting with ACS or undergoing PCI vs. TAT. However, treatment with this regimen significantly increased the occurrence of myocardial infarction or stent thrombosis.
Supplementary material
Supplementary material is available at European Heart Journal – Cardiovascular Pharmacotherapy online.
Conflict of interest: none declared.
