Within and beyond 12-month efficacy and safety of antithrombotic strategies in patients with established coronary artery disease: two companion network meta-analyses of the 2022 joint clinical consensus statement of the European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Association for Acute CardioVascular Care (ACVC), and European Association of Preventive Cardiology (EAPC)

Abstract

Aims

To appraise all available antithrombotic treatments within or after 12 months following coronary revascularization and/or acute coronary syndrome in two network meta-analyses.

Methods and results

Forty-three (N = 189 261 patients) trials within 12 months and 19 (N = 139 086 patients) trials beyond 12 months were included for efficacy/safety endpoints appraisal. Within 12 months, ticagrelor 90 mg bis in die (b.i.d.) [hazard ratio (HR), 0.66; 95% confidence interval (CI), 0.49–0.88], aspirin and ticagrelor 90 mg (HR, 0.85; 95% CI, 0.76–0.95), or aspirin, clopidogrel and rivaroxaban 2.5 mg b.i.d. (HR, 0.66; 95% CI, 0.51–0.86) were the only treatments associated with lower cardiovascular mortality, compared with aspirin and clopidogrel, without or with greater bleeding risk for the first and the other treatment options, respectively. Beyond 12 months, no strategy lowered mortality; compared with aspirin; the greatest reductions of myocardial infarction (MI) were found with aspirin and clopidogrel (HR, 0.68; 95% CI, 0.55–0.85) or P2Y₁₂ inhibitor monotherapy (HR, 0.76; 95% CI: 0.61–0.95), especially ticagrelor 90 mg (HR, 0.54; 95% CI, 0.32–0.92), and of stroke with VKA (HR, 0.56; 95% CI, 0.44–0.76) or aspirin and rivaroxaban 2.5 mg (HR, 0.58; 95% CI, 0.44–0.76). All treatments increased bleeding except P2Y₁₂ monotherapy, compared with aspirin.

Conclusion

Within 12 months, ticagrelor 90 mg monotherapy was the only treatment associated with lower mortality, without bleeding risk trade-off compared with aspirin and clopidogrel. Beyond 12 months, P2Y₁₂ monotherapy, especially ticagrelor 90 mg, was associated with lower MI without bleeding trade-off; aspirin and rivaroxaban 2.5 mg most effectively reduced stroke, with a more acceptable bleeding risk than VKA, compared with aspirin.

Registration URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifiers: CRD42021243985 and CRD42021252398.

Graphical Abstract

The two best-in-class treatments for each outcome. Number needed to treat (NNT) and number needed to harm (NNH) with 95% confidence intervals were generated from the within and beyond 12 months network meta-analyses (NMAs) and adjusted according to baseline risk profile (low and high risks). Best-in-class antithrombotic regimens for patients at high and low risk of all-cause mortality, myocardial infarction, stroke, or major bleeding are presented in hierarchical order in terms of net benefit (NNH/NNT ratio). The average follow-up for the within and beyond 12 months NMA was 12 and 30 months, respectively. * denotes statistically significant differences in the NMA.

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Introduction

Antithrombotic therapy is the cornerstone of secondary and tertiary prevention among patients with established coronary artery disease (CAD).^1,2 Societal guidelines generally provide different recommendations for oral antithrombotic therapy during the early (i.e. within 1 year) and late (i.e. after 1 year) periods after a cardiovascular event, including myocardial infarction (MI) or coronary revascularization.^1–3 This distinction is principally due to a heightened risk of recurrent ischaemic events in the early period prompting intensification of antithrombotic therapy during this timeframe.⁴ Long-term use of aspirin monotherapy remains the most frequently adopted regimen in this clinical setting. Current 2020 European Society of Cardiology (ESC) Guidelines for the management of acute coronary syndrome (ACS) in patients without persistent ST-segment elevation state that treatment intensification with an additional antithrombotic drug, such as a P2Y₁₂ inhibitor or rivaroxaban, may or should be considered instead of aspirin monotherapy for a time window up to 12–36 months if the bleeding risk is not high, depending on whether the ischaemic risk is moderate or high, respectively.³ Due to the lack of head-to-head trials among these treatments, no further guidance is provided on strategy selection among these treatment options in individual patients.

With the aim to inform the 2022 European consensus document on antithrombotic treatment strategies for secondary or tertiary prevention in patients with established CAD, we performed two separate network meta-analyses (NMAs) of the totality of randomized evidence with a focus on acute (within 12 months) and post-acute (>12 months) CAD, including ACS, coronary revascularization, or medically managed chronic coronary syndrome (CCS).

Methods

Established methods recommended by the Cochrane Collaboration were used to conduct the two meta-analyses.⁵ The findings were reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement.⁶ The following databases were searched: MEDLINE, EMBASE, TCTMD (https://www.tctmd.com/), and ClinicalTrials.gov, from database inception date through 29 December 2021 (PROSPERO CRD42021243985 and CRD42021252398).

The detailed search algorithms are provided in Supplementary material online, Tables S1 and S2. Additional information on search strategies, detailed inclusion and exclusion criteria, quality assessment, and data extraction is provided in the Supplementary material, including Supplementary material online, Figures S1–S3 for network flow charts of compared treatments and PRISMA flow diagrams.

Outcome measures at follow-up

Pre-specified efficacy and safety endpoints were separately analysed at 1 year and at the longest available follow-up. A detailed description of efficacy [all-cause and cardiovascular (CV) mortality, MI, or stroke] and safety outcomes (major bleeding and primary bleeding definition according to each trial) is reported in the Supplementary material. The definitions of MI and bleeding across trials are provided in Supplementary material online, Table S3.

Statistical analysis

We performed frequentist NMAs to generate direct and indirect evidence among interventions. A detailed description of statistical analysis is provided in the Supplementary material.

The consistency between direct and indirect sources of evidence was examined by the node-splitting method for the within (Supplementary material online, Figure S4a–e) and beyond 12-month meta-analysis (Supplementary material online, Figure S5a–e). The results were regarded as significant when the 95% CIs of the HRs did not include the unit value.

Publication bias was estimated using funnel plot (Supplementary material online, Figures S6a–e and S7A–F) and Egger's regression test (Supplementary material online, Tables S4 and S5). Stratified NMAs for all outcomes by type of P2Y₁₂ agent given as monotherapy (clopidogrel or ticagrelor 90 mg) were pre-specified. Bias assessment is shown in Supplementary material online, Table S6. Meta-regressions with a Bayesian framework were carried out to assess the impact of age, proportion of patients with ACS on outcomes. The goodness-of-fit of the regression models was compared with that of the original model by means of the deviance information criterion (DIC), considering a five-unit DIC reduction suggestive for a goodness-of-fit improvement (Supplementary material online, Table S7).

All analyses were performed using R Project version 4.0.3 for statistical computing -‘netmeta’ and ‘Bugsnet’ packages and Microsoft Excel.

Results

Within 12-month NMA: study selection and patient population

Of 12 058 articles, 43 trials (189 261 patients) met inclusion criteria (Supplementary material online, Figure S2). References of included trials are provided in the Supplementary material. The average follow-up was 12 months. The antithrombotic regimens used in the included trials are shown in Table 1. A detailed description of employed drug regimens in the NMA is provided in Supplementary material online, Table S8.

Beyond 12-month NMA: study selection and patient population

Of 12 058 articles, 19 trials (139 086 patients) met the inclusion criteria (Supplementary material online, Figure S3). References of included trials are provided in the Supplementary material. The data of the THEMIS study were appraised as aspirin and ticagrelor 60 mg bis in die regimen vs. aspirin monotherapy.⁷

Main characteristics of included studies are shown in Table 2. Average follow-up was 30 months (Table 2). Mean age of study participants was 55 years. Bias assessment is shown in Supplementary material online, Table S6. Employed drug regimens of the NMA and events in the RCTs are provided in Supplementary material online, Table S8.

All-cause and cardiovascular mortality

Twelve-month treatment effect appraisal

All-cause mortality was available in 43 trials (189 261 patients) with a total of 9357 events (4.94%). CV mortality with 4612 events (2.91%) was obtained from a total of 36 trials (158 319 patients). There was no heterogeneity across treatments (τ² = 0), with no publication bias (Supplementary material online, Table S4).

Aspirin comparator: All-cause mortality was lower with ticagrelor 90 mg monotherapy [HR, 0.68 (95% CI, 0.52–0.89)], aspirin and ticagrelor 90 mg dual therapy [HR, 0.84 (95% CI, 0.71–1.00)], and rivaroxaban 2.5 mg, aspirin, and clopidogrel triple therapy [HR, 0.66 (95% CI, 0.50–0.88)] (Supplementary material online, Figure S8a). Results were consistent for CV mortality (Figure 1a). Ticagrelor 90 mg and triple therapy with rivaroxaban 2.5 mg, aspirin and clopidogrel ranked as the two best strategies for reducing CV (P score = 0.89 for both, Supplementary material online, Figure 9a) and all-cause mortality (Supplementary material online, Figure S9b) (P score = 0.89 and P score = 0.91, respectively).

Aspirin and clopidogrel for 12-month comparator: All-cause mortality was lower with ticagrelor 90 mg monotherapy [HR, 0.70 (95% CI, 0.55–0.89)], aspirin and ticagrelor 90 mg dual therapy [HR, 0.87 (95% CI, 0.79–0.96)] and rivaroxaban 2.5 mg, aspirin and clopidogrel triple therapy [HR, 0.68 (95% CI, 0.53–0.87)] (Supplementary material online, Figure S8a). Results were consistent for CV mortality (Figure 1a).

Beyond 12-month treatment effect appraisal

A total of 16 trials (128 047 patients) contributed to CV mortality with 4064 cardiovascular deaths (3.17%). There was low-to-moderate heterogeneity among treatments (τ² = 0.02), with no publication bias (Supplementary material online, Table S5).

Placebo comparator: None of the investigated treatments affected all-cause or CV mortality (Supplementary material online, Figure S8b and Figure 1b).

Aspirin comparator: None of the investigated treatments affected all-cause or CV mortality (Supplementary material online, Figure S8b and Figure 1b).

Myocardial infarction

Twelve-month treatment effect appraisal

Forty trials (169 548 patients) reported 7822 (4.61%) MI events. There was low heterogeneity across treatments (τ² = 0.01) and no evidence of publication bias (Supplementary material online, Table S4).

Aspirin comparator:Several combination strategies including antiplatelet and anticoagulant medications yielded a significant reduction of MI risk, including aspirin and prasugrel [HR, 0.62 (95% CI, 0.47–0.82)], with ticagrelor 90 mg [HR, 0.69 (95% CI, 0.50–0.95)], triple therapy with rivaroxaban 2.5 mg, aspirin and clopidogrel [HR, 0.69 (95% CI, 0.48–1.00)], aspirin and ticagrelor 90 mg [HR, 0.75 (95% CI, 0.57–0.99)] or aspirin and clopidogrel for 12 months [HR, 0.77 (95% CI, 0.60–0.97)], but not for 6 or 3 months (Figure 2a). DAPT with aspirin and prasugrel ranked the most effective treatment to reduce MI (P score = 0.92), followed by ticagrelor 90 mg monotherapy (P score = 0.79)

Aspirin and clopidogrel for 12-month comparator:Only aspirin and prasugrel [HR, 0.81 (95% CI, 0.70–0.94)] (Figure 2a) yielded a significant MI reduction.

Beyond 12-month treatment effect appraisal

Nineteen trials (139 086 patients) reported 4746 (3.41%) MI events. There was low heterogeneity among treatments (τ² = 0.015) and no evidence of publication bias (Egger's test P = 0.36, Supplementary material online, Table S5).

Placebo comparator: All investigated strategies yielded a significant reduction of MI rates, except vitamin K antagonist (VKA) [HR, 0.68 (95% CI, 0.45–1.02)] and rivaroxaban 5 mg [HR, 0.68 (95% CI, 0.46–1.00)] monotherapies. The treatment effects varied among the treatment options and were highest with aspirin and clopidogrel dual therapy [HR, 0.51 (95% CI, 0.37–0.71)], and P2Y₁₂ inhibitor monotherapy [HR, 0.58 (95% CI, 0.42–0.80)], especially ticagrelor [HR, 0.41 (95% CI, 0.23–0.73)] and lowest with aspirin monotherapy [HR, 0.76 (95% CI, 0.60–0.96)] (Figure 2b).

Aspirin comparator: A significant MI risk reduction was found with aspirin and clopidogrel dual therapy [HR, 0.68 (95% CI, 0.55–0.85)] and P2Y₁₂ monotherapy [HR, 0.76 (95% CI, 0.61–0.95)], which was more pronounced with ticagrelor [HR, 0.54 (95% CI, 0.32–0.92)] than with clopidogrel monotherapy [HR, 0.81 (95% CI, 0.65–1.01)]. No significant differences in MI risk occurred with the other strategies in comparison with aspirin (Figure 2b). Ticagrelor 90 mg monotherapy had the highest ranking in preventing MI (P score = 0.92, Figure 3a), followed by aspirin and clopidogrel dual therapy (P score = 0.90) and aspirin and ticagrelor 90 mg dual therapy (P score = 0.62). Bayesian probability curves of individual treatments showed that ticagrelor 90 mg monotherapy had a 75.2% probability to be the first treatment in the hierarchy, followed by dual antiplatelet therapy with aspirin and clopidogrel with a probability of 20.1% (Figure 3b).

Stroke

Twelve-month treatment effect appraisal

A total of 40 trials assessed stroke (N = 169 266). A total of 1625 stroke episodes occurred (1.00%). Heterogeneity across trials was absent (τ² = 0).

Aspirin comparator: No treatment decreased the risk of stroke compared with aspirin (Figure 4a).

Aspirin and clopidogrel for 12-month comparator: No treatment decreased the risk of stroke compared with 12-month aspirin and clopidogrel (Figure 4a).

Beyond 12-month treatment effect appraisal

Eighteen trials (132 620 patients) reported 2877 (2.17%) strokes. Heterogeneity was low-to-moderate (τ² = 0.026). No publication bias was observed (Egger's test P = 0.35, Supplementary material online, Table S5).

Placebo comparator: Aspirin and ticagrelor 60 mg dual therapy, aspirin and VKA dual therapy, P2Y₁₂ monotherapy, aspirin and rivaroxaban 2.5 dual therapy, and VKA monotherapy reduced stroke. The treatment effects varied among the treatment options and were highest with VKA monotherapy [HR, 0.40 (95% CI, 0.19–0.84)] or aspirin and rivaroxaban 2.5 mg dual therapy [HR, 0.42 (95% CI, 0.24–0.73)], and lowest with aspirin monotherapy [HR, 0.72 (95% CI, 0.50–1.04)] (Figure 4b).

Aspirin comparator: The lowest stroke risk was observed with VKA monotherapy [HR, 0.56 (95% CI, 0.44–0.76)] or aspirin and an anticoagulant dual therapy, consisting of either rivaroxaban 2.5 mg [HR, 0.58 (95% CI, 0.44–0.76)] or VKA [HR, 0.64 (95% CI, 0.49–0.83)] (Figure 4b).

Treatment with aspirin and rivaroxaban 2.5 mg dual therapy was the highest-ranked treatment option (P score = 0.84, Figure 3e), immediately followed by VKA monotherapy (P score = 0.82). Bayesian probability curves of individual treatments showed VKA monotherapy (Figure 3f) to be the first treatment in the hierarchy, with a probability of 53%, followed by aspirin and rivaroxaban 2.5 mg dual therapy.

Bleeding endpoints

Twelve-month treatment effect appraisal

Thirty-eight trials (166 740 patients) were included in the analysis of major bleeding (4553 events, 2.73%). Heterogeneity was low (τ² = 0.02). There was no evidence of publication bias (Egger's test P = 0.27, Supplementary material online, Table S4).

Aspirin comparator: Major bleeding risk was more than three-fold higher with triple therapies, either in the form of apixaban, aspirin and clopidogrel [HR, 3.92 (95% CI, 2.15–7.13)] or rivaroxaban 2.5 mg, aspirin and clopidogrel [HR, 3.50 (95% CI, 1.99–6.15)]; more than two-fold higher with rivaroxaban in combination with ticagrelor [HR, 2.86 (95% CI, 1.20–6.85)] or clopidogrel [HR, 2.09 (95% CI, 0.78–5.57)]; less than two-fold higher with aspirin and prasugrel [HR, 1.81 (95% CI, 1.26–2.59)], aspirin and ticagrelor 90 mg [HR, 1.84 (95% CI, 1.30–2.59)], or VKA and aspirin [HR, 1.56 (95% CI, 1.14–2.14)]; similar with monotherapies with clopidogrel or ticagrelor or dual therapy with aspirin and clopidogrel (Figure 5a).

Aspirin and clopidogrel for 12-month comparator: Clopidogrel monotherapy [HR, 0.62 (95% CI, 0.40–0.96)], aspirin monotherapy [HR, 0.71 (95% CI, 0.53–0.96)], and 6-month aspirin and clopidogrel [HR, 0.73 (95% CI, 0.53–0.99)] were associated with a significant reduction of major bleeding. Apixaban, aspirin and clopidogrel [HR, 2.79 (95% CI, 1.66–4.70)], rivaroxaban 2.5 mg, aspirin and clopidogrel [HR, 2.49 (95% CI, 1.54–4.03)], aspirin and prasugrel [HR, 1.29 (95% CI, 1.05–1.58)], or aspirin and ticagrelor 90 mg [HR, 1.31 (95% CI, 1.08–1.58)] resulted in a significant increase in the risk of major bleeding (Figure 5a). Results on study-defined bleeding were consistent (Supplementary material online, Figure S10A).

Beyond 12-month treatment effect appraisal

Seventeen trials with 133 033 patients were analysed for major bleeding with a total of 2204 events (1.66%). Heterogeneity was absent (τ² = 0.0014). There was no evidence of publication bias (Egger's test p = 0.54, Supplementary material online, Table S5).

Placebo comparator: Aspirin monotherapy or P2Y₁₂ inhibitor monotherapy, either clopidogrel or ticagrelor, were the only treatment options that were not associated with statistically significant increased bleeding risk. The bleeding risk was highest with VKA [HR, 5.12 (95% CI, 2.03–12.91)] (Figure 5b).

Aspirin comparator: Major bleeding was greater with all treatment combinations and with VKA or rivaroxaban 5 mg monotherapies. The bleeding risk did not differ with placebo or P2Y₁₂ monotherapy, albeit it was numerically lower with clopidogrel [HR, 0.83 (95% CI, 0.68–1.02)] and higher with ticagrelor [HR, 1.34 (95% CI, 0.73–2.46)] monotherapies (Figure 5b). Results on study-defined bleeding were consistent (Supplementary material online, Figure S10B).

Network consistency and additional analyses

By node-splitting, both NMAs showed consistency between direct and indirect estimates (Supplementary material online, Figures S4a–E and S5A–E). Among the included antithrombotic strategies, the two best-in-class agents for each explored outcome expressed in terms of net benefit (number needed to treat for all-cause mortality, MI, or stroke with corresponding number needed to harm for major bleeding) derived from the NMAs are depicted in the Graphical abstract. Bayesian meta-regression analyses did not show any significant impact of age or percentage of patients with ACS with less than five-unit DIC changes in comparison to the original model (Supplementary material online, Table S7).

Discussion

To the best of our knowledge, for the first time all available treatment options for secondary and tertiary prevention in CAD patients are compared by NMAs, with a distinct focus on within and beyond 12 months treatment effects.

In within 12-month NMA, including randomized trials and 189 261 patients, we addressed the efficacy and safety of 14 antithrombotic treatments within 1 year after ACS and/or coronary revascularization. The main findings are the following:

• Compared with aspirin or 12-month aspirin and clopidogrel, ticagrelor 90 mg monotherapy, aspirin and ticagrelor 90 mg dual therapy, and rivaroxaban 2.5 mg, aspirin and clopidogrel triple therapy reduced CV and all-cause death. No other treatment, in isolation or combination, affected mortality.

• Compared with aspirin, several antithrombotic treatment combinations, including triple therapies (rivaroxaban 2.5 mg, aspirin and clopidogrel or apixaban, aspirin and clopidogrel), dual therapies (aspirin and ticagrelor 90 mg or aspirin and clopidogrel for 12 months but not for 3 or 6 months), and a single monotherapy option (ticagrelor 90 mg) reduced the risk of MI. Only aspirin and prasugrel dual therapy reduced the risk of MI compared with 12-month aspirin and clopidogrel.

• No antithrombotic treatment reduced stroke risk either compared with aspirin or 12-month aspirin and clopidogrel.

• Bleeding risk increased progressively from single, through dual to triple antithrombotic treatments. Monotherapies with clopidogrel or ticagrelor were not associated with greater bleeding than aspirin. Compared with 12-month aspirin and clopidogrel, clopidogrel or ticagrelor 90 mg monotherapies were associated with lower and similar bleeding risks, respectively.

Over the years, current practice of antithrombotic therapy has been shifting from ischaemia prevention only to a net clinical benefit perspective, including the estimation of the bleeding risk trade-off, which is associated with increased mortality.⁸ Mortality is, therefore, the most solid endpoint in assessing the balance between benefits and risks when considering antithrombotic treatments. Ticagrelor 90 mg monotherapy and rivaroxaban 2.5 mg, aspirin and clopidogrel triple therapy were ranked as the best strategies for reducing all-cause and cardiovascular mortality. A considerable bleeding risk trade-off was noted, however, for rivaroxaban 2.5 mg, aspirin and clopidogrel, which explains why it is infrequently implemented in practice. Our findings suggest that ticagrelor 90 mg monotherapy provides a mortality benefit without increasing the bleeding risk compared with aspirin and clopidogrel. Combining ticagrelor 90 mg with aspirin did not improve protection from fatal or non-fatal ischaemic events, as shown in prior meta-analyses^9,10 and was associated with greater bleeding compared with ticagrelor 90 mg monotherapy.¹⁰

Clopidogrel monotherapy is an attractive treatment especially in patients at high risk for bleeding, whereas aspirin and prasugrel may be selected in patients in whom the bleeding risk is low and concerns over the MI risk prevail.

In beyond 12-month NMA, encompassing 139 086 patients from 19 trials, we examined the efficacy and safety profile of nine available antithrombotic strategies in CCS patients.

In comparison with aspirin:

1. Aspirin and clopidogrel dual therapy or P2Y₁₂ inhibitor monotherapy, especially ticagrelor, were associated with lower MI risk.

2. VKA monotherapy, aspirin and VKA, aspirin and rivaroxaban 2.5 mg dual therapies were associated with a lower risk of stroke.

3. All treatment options except P2Y₁₂ inhibitor monotherapy were associated with enhanced bleeding risk, with a gradient of risk that was highest for VKA.

Patients with CAD remain at risk over long-term for recurrent cardiovascular and cerebrovascular events, which prompted the endorsement of the CCS terminology in preference to stable CAD, to highlight the dynamic nature of the disease and the continuous risk of recurrent events.¹¹ While aspirin is perceived as the standard antithrombotic long-term treatment for CCS patients, our study findings reinforce the notion that this strategy offers the lowest protection for MI and stroke risks when compared with alternative treatments in CCS patients.^12,13 Yet, the bleeding risk with alternative treatments is also generally higher than with aspirin alone. Our results confirm this prior knowledge with all tested alternative antithrombotic regimens except P2Y₁₂ monotherapy, which offers overall greater MI protection without concomitant higher bleeding risk than aspirin. P2Y₁₂ monotherapy may therefore be preferred to aspirin as beyond 12-month treatment in both patients with or without high bleeding risk features. When the type of P2Y₁₂ inhibitor was separately appraised, the MI risk trended but was not significantly lower with clopidogrel than aspirin, whereas the bleeding risk also was numerically but not significantly lower in favour of clopidogrel. Therefore, clopidogrel is likely to provide a net benefit compared with aspirin, although this composite endpoint was not appraised in our analysis. Ticagrelor monotherapy was associated with a significant MI reduction compared with aspirin. On the other hand, ticagrelor was associated with numerically, albeit not significantly, greater bleeding than aspirin. Hence, the individual bleeding risk profile and the need for protection from recurrent MI (i.e. in patients with prior MI) may inform the selection of the specific P2Y₁₂ inhibitor type for monotherapy. Our data do not suggest that the combination of aspirin and a P2Y₁₂ inhibitor provides greater ischaemic protection than the P2Y₁₂ inhibitor alone. This finding was generally consistent when clopidogrel or ticagrelor monotherapies were separately appraised compared with their combination with aspirin dual therapies and has been replicated in recent individual patient data meta-analyses.^9,10 Bayesian probability curves of individual treatments by providing a ranking of treatments showed that ticagrelor 90 mg monotherapy had greater probability than ticagrelor 90 mg and aspirin dual therapy of being the best treatment for MI prevention. This finding may reflect the different experimental settings, in which these two treatment options were tested and is consistent with a post-hoc analysis from the PLATO trial, suggesting that aspirin may diminish rather than potentiate ticagrelor treatment effect towards ischaemic risk protection.¹⁴

Unlike previous direct or NMAs,^9,10,15,16 our study is unique on the fact that it did not only address DAPT duration or type therefore, rather appraised all available treatment options that have been tested in the setting of at least one medium-to-large size randomized clinical trial with two distinct time frames (i.e. within and beyond 12 months).

Limitations

The current NMA has limitations. As for study-level meta-analyses, the results are derived from pooled patient data as no individual patient data were collected for this analysis. The absence of direct comparisons for some of the examined treatment options due to the limited number of available trials precluded a more robust assessment of network coherence in some instances. On the other hand, the consistency of results in the main and sensitivity analyses suggests robustness of findings. Some of the investigated treatment options were investigated in single trial, which limits the precision and the generalizability of the results. However, the consistency between direct and indirect estimates corroborated the findings. We did not perform multiplicity adjustments; therefore, the chance of type I error inflation cannot be dismissed. We included studies conducted decades ago, which no longer reflect current practice, especially for the aspirin vs. no aspirin/placebo and VKA treatment effects. The definition of MI evolved over time with the use of more sensitive biomarkers. Similarly, despite our attempts to homogenize the bleeding metrics, the bleeding definitions were not consistent across trials. This NMA was not designed to investigate separately the clinical effect in patients with or without an ACS that could be addressed with large-scale individual patient data. On the other hand, by Bayesian meta-regressions, the percentage of ACS across trials did not have a significant impact on outcomes.

Conclusions

Within 12 months after coronary revascularization and/or ACS, ticagrelor 90 mg monotherapy was the only treatment associated with lower mortality, without increased bleeding risk compared with aspirin and clopidogrel. Beyond 12 months, P2Y₁₂ monotherapy, especially ticagrelor 90 mg, was associated with lower MI without a bleeding risk trade-off; rivaroxaban 2.5 mg and aspirin most effectively reduced stroke risk, with a more acceptable bleeding risk than VKA, compared with aspirin. The use of aspirin monotherapy as routine beyond 12-month antithrombotic treatment in patients with established CAD does not appear justifiable based on the cardiovascular and cerebrovascular ischaemic risks, nor the bleeding risk.

Acknowledgement

None.

Funding

None.

Conflict of interest: E.P.N. reports research grants from Abbott and Amgen and lecture fees/honoraria from Amgen, AstraZeneca, Bayer, Pfizer, and Sanofi-Regeneron, outside the submitted work. V.A. reports speaker honoraria from Amgen, Novartis, and Pfizer and is consultant/advisory board for Bayer Healthcare, Novo Nordisk, Sanofi, AstraZeneca, Boehringer Ingelheim, and BMS, outside the submitted work. D.J.A. declares that he has received consulting fees or honoraria from Abbott, Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company and has received payments for participation in review activities from CeloNova and St Jude Medical, outside the present work. D.J.A. also declares that his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation. D.C. declares that he has received consulting and speaking fees from Amgen, Boehringer Ingelheim, Biotronik, Daiichi Sankyo, and sanofi-aventis, outside the present work. K.A.A.F. has received grants and personal fees from Bayer/Janssen and AstraZeneca and personal fees from Sanofi/Regeneron and Verseon, outside the submitted work. S.H. has received speaking fees from Boehringer Ingelheim, BMS, Pfizer, and Sanofi, outside the submitted work. S.J. reported grants from AstraZeneca, outside the submitted work. P.J. serves as an unpaid steering committee member of trials funded by Abbott Vascular, AstraZeneca, Biotronik, Biosensors, St Jude Medical, Terumo, and The Medicines Company; receives institutional research grants from Appili Therapeutics, AstraZeneca, Biotronik, Biosensors International, Eli Lilly, and The Medicines Company; and receives institutional honoraria for participation in advisory boards or consulting from Amgen, Ava, and Fresenius, but has not received personal payments by any pharmaceutical company or device manufacturer. V.K. has received personal fees/honoraria from Bayer, AstraZeneca, Abbott, Amgen, and Daiichi Sankyo, all outside the submitted work. S.L. reports grants and personal fees from AstraZeneca, Daiichi Sankyo, Bayer, Pfizer/BMS, ICON, Chiesi, and Novo Nordisk, all outside the submitted work. R.M. reports institutional research grants from Abbott, Abiomed, Applied Therapeutics, Arena, AstraZeneca, Bayer, Biosensors, Boston Scientific, Bristol Myers Squibb, CardiaWave, CellAegis, CERC, Chiesi, Concept Medical, CSL Behring, DSI, Insel Gruppe AG, Medtronic, Novartis Pharmaceuticals, OrbusNeich, Philips, Transverse Medical, Zoll; personal fees from ACC, Boston Scientific, California Institute for Regenerative Medicine (CIRM), Cine-Med Research, Janssen, WebMD, SCAI; consulting fees paid to the institution from Abbott, Abiomed, AM-Pharma, Alleviant Medical, Bayer, Beth Israel Deaconess, CardiaWave, CeloNova, Chiesi, Concept Medical, DSI, Duke University, Idorsia Pharmaceuticals, Medtronic, Novartis, Philips; equity 1% in Applied Therapeutics, Elixir Medical, STEL, and CONTROLRAD (spouse); Scientific Advisory Board for AMA, Biosensors (spouse), all outside the submitted work. G.M. reports institutional research funds or fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cell Prothera, CSL Behring, Europa, Idorsia, IRIS-Servier, Medtronic, MSD, Novartis, Pfizer, Quantum Genomics, and Sanofi, outside the submitted work. R.F.S. reports institutional research grants/support from AstraZeneca, Cytosorbents, and GlyCardial Diagnostics; consultancy fees from AstraZeneca, Bayer, Bristol Myers Squibb/Pfizer, CSL Behring, Cytosorbents, GlyCardial Diagnostics, Hengrui, Idorsia, Novartis, PhaseBio, Portola, sanofi-aventis, and Thromboserin; and honoraria from AstraZeneca, Bayer, Bristol Myers Squibb/Pfizer, Intas Pharmaceuticals, and Medscape, all outside the submitted work. P.V. reports personal fees from Bayer, personal fees from Daiichi Sankyo, and personal fees from CLS Behring, outside the submitted work. S.W. reports research and educational grants to the institution from Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardinal Health, CardioValve, Corflow Therapeutics, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Guerbet, InfraRedx, Janssen-Cilag, Johnson & Johnson, Medicure, Medtronic, Merck Sharp & Dohm, Miracor Medical, Novartis, Novo Nordisk, Organon, OrPha Suisse, Pfizer, Polares, Regeneron, sanofi-aventis, Servier, Sinomed, Terumo, Vifor, and V-Wave. S.W. serves as an unpaid advisory board member and/or unpaid member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Boston Scientific, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, Janssen, MedAlliance, Medtronic, Novartis, Polares, Recardio, Sinomed, Terumo, V-Wave, and Xeltis, but has not received personal payments by pharmaceutical companies or device manufacturers. He is also a member of the steering/executive committee group of several investigator-initiated trials that receive funding by industry without impact on his personal remuneration. M.V. reports grants and/or personal fees from AstraZeneca, Terumo, Alvimedica/CID, Abbott Vascular, Daiichi Sankyo, Bayer, CoreFLOW, Idorsia Pharmaceuticals Ltd, Universität Basel Department Klinische Forschung, Vifor, Bristol Myers Squib SA, Biotronik, Boston Scientific, Medtronic, Vesalio, Novartis, Chiesi, and PhaseBio, outside the submitted work. The other authors report no relationships relevant to the contents of this paper to disclose.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.

Notes

Twitter handles: @vlgmrc (Marco Valgimigli), @ElianoNavarese (Eliano Navarese), @antoniolandii (Antonio Landi), @DFCapodanno (Davide Capodanno), @Drroxmehran (Roxana Mehran).

References

Author notes