Abstract
Aims
After percutaneous coronary intervention (PCI) in patients with atrial fibrillation, safety and efficacy with dabigatran dual therapy were evaluated in pre-specified subgroups of patients undergoing PCI due to acute coronary syndrome (ACS) or elective PCI, and those receiving ticagrelor or clopidogrel treatment.
Methods and results
In the RE-DUAL PCI trial, 2725 patients were randomized to dabigatran 110 mg or 150 mg with P2Y12 inhibitor, or warfarin with P2Y12 inhibitor and aspirin. Mean follow-up was 14 months, 50.5% had ACS, and 12% received ticagrelor. The risk of the primary endpoint, major or clinically relevant non-major bleeding event, was reduced with both dabigatran dual therapies vs. warfarin triple therapy in patients with ACS [hazard ratio (95% confidence interval), 0.47 (0.35–0.63) for 110 mg and 0.67 (0.50–0.90) for 150 mg]; elective PCI [0.57 (0.43–0.76) for 110 mg and 0.76 (0.56–1.03) for 150 mg]; receiving ticagrelor [0.46 (0.28–0.76) for 110 mg and 0.59 (0.34–1.04) for 150 mg]; or clopidogrel [0.51 (0.41–0.64) for 110 mg and 0.73 (0.58–0.91) for 150 mg], all interaction P-values >0.10. Overall, dabigatran dual therapy was comparable to warfarin triple therapy for the composite endpoint of death, myocardial infarction, stroke, systemic embolism, or unplanned revascularization, with minor variations across the subgroups, all interaction P-values >0.10.
Conclusion
The benefits of both dabigatran 110 mg and 150 mg dual therapy compared with warfarin triple therapy in reducing bleeding risks were consistent across subgroups of patients with or without ACS, and patients treated with ticagrelor or clopidogrel.
Keywords: Atrial fibrillation, Acute coronary syndrome, Coronary artery disease, Percutaneous coronary intervention, Oral anticoagulants, P2Y12 inhibitors
See page 1563 for the editorial comment on this article (doi: 10.1093/eurheartj/ehz192)
Introduction
Recent estimates suggest an atrial fibrillation (AF) prevalence of ∼3% in adults above the age of 20 years.1,2 Coronary artery disease commonly co-exists with AF and at least 5% of unselected patients undergoing percutaneous coronary interventions (PCIs) have AF, which poses an antithrombotic treatment dilemma.3,4 Oral anticoagulation for prevention of stroke is indicated in the majority of patients with AF,5,6 whereas dual antiplatelet therapy with a P2Y12 inhibitor plus aspirin is indicated for patients undergoing PCI with stent implantation and/or after an acute coronary syndrome (ACS).7
Contemporary guidelines5–9 recommend a short period of triple therapy with both oral anticoagulation and dual antiplatelet therapy with aspirin and clopidogrel, although these triple regimens are inevitably associated with higher rates of major bleeding. The use of the newer P2Y12 inhibitors prasugrel or ticagrelor as part of triple therapy is discouraged,6,7,9,10 given the lack of evidence of the safety of those drugs in combination with oral anticoagulation therapy.
Results of observational studies, randomized trials, and meta-analyses suggest that dual antithrombotic treatment, i.e. an oral anticoagulant—either a non-vitamin K antagonist oral anticoagulant (NOAC) or a vitamin K antagonist (VKA)—in combination with one antiplatelet agent, most commonly a P2Y12 inhibitor, reduces bleeding events without increased risk of thromboembolic events compared with triple treatment.11–15 More recently, the RE-DUAL PCI (Randomized Evaluation of DUAL Antithrombotic Therapy With Dabigatran vs. Triple Therapy With Warfarin In Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial showed that the risk of major or clinically relevant non-major bleeding events was reduced by 48% with dabigatran 110 mg dual therapy without aspirin, and by 28% with dabigatran 150 mg dual therapy without aspirin, respectively, with non-inferiority for overall thromboembolic events with dabigatran (both doses combined) dual therapy compared with warfarin triple therapy with both aspirin and a P2Y12 inhibitor.16,17 In the present analysis, we evaluated the safety and efficacy of dabigatran dual vs. warfarin triple therapy in the pre-specified patient subgroups with PCI due to ACS or undergoing elective PCI, and those treated with ticagrelor or clopidogrel.
Methods
The RE-DUAL PCI trial was a prospective, randomized, open-label study comparing the safety and efficacy of dabigatran dual antithrombotic therapy vs. warfarin triple therapy. The detailed design and primary results of RE-DUAL PCI have been published (RE-DUAL PCI ClinicalTrials.gov number, NCT02164864).16,17 Men and women who were at least 18 years of age were eligible for inclusion if they had non-valvular AF and had been successfully treated with PCI with a bare-metal or drug-eluting stent within the prior 120 h. Non-valvular AF could be paroxysmal, persistent, or permanent, but not secondary to a reversible disorder unless long-term treatment with an oral anticoagulant was anticipated. Patients could be either treatment-naïve or receiving an oral anticoagulant prior to PCI. The indication for PCI could be either an ACS or stable coronary artery disease. Exclusion criteria included patients with bioprosthetic or mechanical heart valves, severe renal insufficiency (creatinine clearance <30 mL/min), or other major comorbidities.
Patients were randomized to dabigatran 110 mg twice daily plus either clopidogrel or ticagrelor (dabigatran 110 dual therapy); dabigatran 150 mg twice daily plus either clopidogrel or ticagrelor (dabigatran 150 dual therapy); or warfarin plus either clopidogrel or ticagrelor, and aspirin at a daily dose of 100 mg or less (warfarin triple-therapy) in a 1:1:1 ratio. In the warfarin arm, aspirin was discontinued after 1 month in patients implanted with a bare-metal stent, and after 3 months in patients implanted with a drug-eluting stent. Outside the USA, patients aged ≥80 years (≥70 years in Japan) were only randomized to the 110-mg dabigatran dose vs. warfarin in a 1:1 ratio. All patients received either clopidogrel 75 mg daily or ticagrelor 90 mg twice daily for at least 12 months following randomization, with the choice of agent at the discretion of the investigator, but the protocol specified that this decision was to be taken prior to randomization. Prasugrel was not allowed in the study. The dose of warfarin was adjusted to ensure the patient’s international normalized ratio was in the range of 2.0–3.0.
The present subgroup analyses of patients with or without ACS at index PCI and patients treated with ticagrelor or clopidogrel were pre-specified. The RE-DUAL PCI trial primary endpoint was time to first International Society on Thrombosis and Haemostasis (ISTH) major18 or clinically relevant non-major19 bleeding event. Further safety endpoints included major bleeding events according to ISTH18 and Thrombolysis in Myocardial Infarction (TIMI)20 definitions; and efficacy outcomes including the composite of death or thromboembolic events (myocardial infarction, stroke, or systemic embolism), or unplanned revascularization (PCI/coronary artery bypass graft), myocardial infarction and all-cause death. All clinical endpoints were adjudicated by an independent committee blinded to treatment assignment.
Statistics
Patients were grouped according to the index PCI indication, i.e. patients either undergoing PCI due to ACS, or undergoing elective PCI due to stable angina and/or positive stress test, staged procedure, or other, and according to the P2Y12 inhibitor use at baseline. The latter subgroup analysis was performed by grouping the patients uniquely into patients who received ticagrelor at baseline (further referred ‘ticagrelor’), which included 58 patients who took both ticagrelor and clopidogrel on the day of randomization (i.e. at baseline), and patients who did not receive ticagrelor at baseline (further referred ‘clopidogrel’), which included 93 patients who received neither ticagrelor nor clopidogrel at baseline.
The clinical characteristics were summarized descriptively by ACS or elective PCI at index event as well as by treatment with ticagrelor or clopidogrel at baseline, with P-values using the t-test for continuous variables and the χ2 test for categorical variables. For the comparison of treatment groups within the index PCI indication and P2Y12 inhibitor subgroups, stratified Cox proportional hazards regression models including age group as a stratifying factor [non-elderly or elderly (<70 years or ≥70 years old in Japan and <80 years or ≥80 years old elsewhere)] and treatment (dabigatran 110 dual therapy vs. warfarin triple therapy) as explanatory factor were applied. For the dabigatran 150 dual therapy vs. warfarin triple therapy comparison, unstratified models were applied. A corresponding triple-therapy warfarin group that included only patients eligible for dabigatran 150 dual therapy (i.e. not elderly patients outside the USA) was used for this comparison. Hazard ratios (HRs) and two-sided 95% Wald confidence intervals (CIs) for HRs resulting from Cox proportional hazard models were calculated within the index PCI indication and P2Y12 inhibitor subgroups. Exploratory treatment by subgroup interaction P-values resulting from Cox proportional hazard regression models stratified by age for dabigatran 110 dual therapy vs. warfarin triple therapy and unstratified for dabigatran 150 dual therapy vs. warfarin triple therapy, respectively, were provided. Additionally, the risk of the primary endpoint (ISTH major or clinically relevant non-major bleeding events) and of the composite efficacy endpoint of death, thromboembolic events, or unplanned revascularization, respectively, was compared between ticagrelor- and clopidogrel-treated patients as well as between patients with ACS and elective PCI with a multivariable adjusted treatment-independent and stratified (non-elderly or elderly) Cox proportional hazard regression model. For the bleeding endpoint, the Cox model was adjusted for bleeding risk factors, i.e. age, creatinine clearance, previous stroke, prior major bleeding events or bleeding predisposition, diabetes, and ACS or ticagrelor use, respectively. For the composite efficacy endpoint, adjustment was performed for risk factors of death and thromboembolic events, i.e. age, creatinine clearance, prior myocardial infarction, previous stroke, diabetes, multi-vessel disease, and ACS or ticagrelor use, respectively. HRs and two-sided 95% CIs from this Cox model were provided.
Results
Baseline characteristics
Baseline characteristics of the 2725 patients enrolled in RE-DUAL PCI are presented by ACS or elective PCI at index event in Table 1, and by treatment with ticagrelor or clopidogrel are presented in Table 2.
Table 1.
Baseline characteristics by indication for percutaneous coronary intervention
| ACS (N = 1375) | Elective PCIa (N = 1349) | P-value | |
|---|---|---|---|
| Age (years), mean (SD) | 70.9 (9.1) | 70.6 (8.1) | 0.3406 |
| Male, n (%) | 1010 (73.5) | 1059 (78.5) | 0.0021 |
| Type of atrial fibrillation, n (%) | 0.1047 | ||
| Paroxysmal | 708 (51.5) | 643 (47.7) | |
| Persistent | 229 (16.7) | 255 (18.9) | |
| Permanent | 437 (31.8) | 451 (33.4) | |
| Type of ACS, n (%)b | NA | ||
| Unstable angina | 462 (33.6) | NA | |
| STEMI | 305 (22.2) | NA | |
| NSTEMI | 582 (42.3) | NA | |
| Diabetes, n (%) | 492 (35.8) | 501 (37.1) | 0.4620 |
| Prior stroke, n (%) | 106 (7.7) | 120 (8.9) | 0.2617 |
| Prior myocardial infarction, n (%) | 390 (28.4) | 309 (22.9) | 0.0011 |
| Creatinine clearance (mL/min), mean (SD)c | 77.2 (29.9) | 78.8 (29.6) | 0.1832 |
| CHA2DS2-VASc, mean (SD) | 3.6 (1.6) | 3.6 (1.5) | 0.3887 |
| Modified HAS-BLED, mean (SD) | 2.7 (0.7) | 2.7 (0.7) | 0.1105 |
| OAC treatment at baseline, n (%) | <0.0001 | ||
| Long-term | 354 (25.7) | 574 (42.6) | |
| Treatment naïved | 1021 (74.3) | 775 (57.4) | |
| Complexity factors, n (%)e | <0.0001 | ||
| No clinical/procedural factors | 0 | 1007 (74.6) | |
| Clinical complexity factors only | 1114 (81.0) | 60 (4.4) | |
| Procedural complexity factors only | 0 | 270 (20.0) | |
| Both clinical and procedural factors | 261 (19.0) | 12 (0.9) | |
| Type of stent,fn (%) | 0.0006 | ||
| DES only | 1099 (79.9) | 1152 (85.4) | |
| BMS only | 239 (17.4) | 165 (12.2) | |
| DES and BMS, or other | 33 (2.4) | 29 (2.1) |
Information on indication for PCI was missing for one patient. Statistics: using the t-test for continuous variables and the χ2 test for categorical variables.
ACS, acute coronary syndrome; BMS, bare-metal stent; DES, drug-eluting stent; NA, not applicable; NSTEMI, non-ST-elevation myocardial infarction; OAC, oral anticoagulant; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction.
Elective PCI includes stable angina and/or positive stress test, staged procedure, or other indication.
Data missing for 26 patients.
Mean creatinine clearance missing at baseline for 138 patients in ACS and 93 patients in elective PCI group.
Less than 14 days’ consecutive OAC treatment.
Clinical complexity factors considered are acute coronary syndrome, acute ST-elevation myocardial infarction, renal insufficiency/failure, and left ventricular ejection fraction <30%. Procedural (including lesion) complexity factors are >2 vessels stented, in-stent restenosis of a drug-eluting stent, prior brachytherapy, unprotected left main stenting, >2 lesions per vessel, lesion length ≥30 mm, bifurcation lesion with side branch ≥2.5 mm, vein bypass graft, and thrombus-containing lesion (from Yeh et al.21).
Type of stent missing for four patients in ACS and three patients in elective PCI group.
Table 2.
Baseline characteristics by treatment with ticagrelor or clopidogrel
| Ticagrelora (N = 327) | Clopidogrelb (N = 2398) | P-value | |
|---|---|---|---|
| Age (years), mean (SD) | 69.7 (9.6) | 70.9 (8.5) | 0.0323 |
| Male, n (%) | 253 (77.4) | 1817 (75.8) | 0.5257 |
| Type of atrial fibrillation, n (%) | 0.0197 | ||
| Paroxysmal | 185 (56.6) | 1166 (48.6) | |
| Persistent | 53 (16.2) | 431 (18.0) | |
| Permanent | 88 (26.9) | 800 (33.4) | |
| Indication for PCI, n (%) | <0.0001 | ||
| Elective PCIc | 87 (26.6) | 1262 (52.6) | |
| ACS | 240 (73.4) | 1135 (47.3) | <0.0001 |
| Type of ACS, n (%)d | |||
| Unstable angina | 54 (22.5) | 408 (35.9) | |
| NSTEMI | 105 (43.8) | 477 (42.0) | |
| STEMI | 79 (32.9) | 226 (19.9) | |
| Diabetes, n (%) | 123 (37.6) | 870 (36.3) | 0.6419 |
| Prior stroke, n (%) | 20 (6.1) | 206 (8.6) | 0.1275 |
| Prior myocardial infarction, n (%) | 91 (27.8) | 608 (25.4) | 0.3365 |
| Creatinine clearance (mL/min), mean (SD) | 80.5 (32.2) | 77.7 (29.4) | 0.1507 |
| CHA2DS2-VASc, mean (SD) | 3.4 (1.6) | 3.6 (1.5) | 0.0282 |
| Modified HAS-BLED, mean (SD) | 2.6 (0.7) | 2.7 (0.7) | 0.0057 |
| OAC treatment at baseline, n (%) | <0.0001 | ||
| Long-term | 78 (23.9) | 851 (35.5) | |
| Treatment naïvee | 249 (76.1) | 1547 (64.5) | |
| Complexity factors, n (%)f | <0.0001 | ||
| No clinical/procedural factors | 67 (20.5) | 941 (39.2) | |
| Clinical factors only | 193 (59.0) | 981 (40.9) | |
| Procedural factors only | 16 (4.9) | 254 (10.6) | |
| Both clinical and procedural factors | 51 (15.6) | 222 (9.3) | |
| Type of stent, n (%)g | 0.1556 | ||
| DES only | 275 (84.1) | 1976 (82.4) | |
| BMS only | 40 (12.2) | 364 (15.2) | |
| DES and BMS, or other | 11 (3.4) | 51 (2.1) |
Statistics: using the t-test for continuous variables and the χ2 test for categorical variables.
ACS, acute coronary syndrome; BMS, bare-metal stent; DES, drug-eluting stent; NSTEMI, non-ST-elevation myocardial infarction; OAC, oral anticoagulant; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction.
Fifty-eight patients who received ticagrelor + clopidogrel are included in the ticagrelor subgroup.
Ninety-three patients who received neither clopidogrel nor ticagrelor are included in the clopidogrel subgroup; data on atrial fibrillation, diabetes, prior stroke, and indication for PCI were missing for one patient in the clopidogrel group.
Elective PCI includes stable angina and/or positive stress test, staged procedure, or other indication.
Data missing for two patients in the ticagrelor and for 24 patients in the clopidogrel group.
Less than 14 days’ consecutive OAC treatment.
Clinical complexity factors considered are acute coronary syndrome, acute ST-elevation myocardial infarction, renal insufficiency/failure, and left ventricular ejection fraction <30%. Procedural (including lesion) complexity factors are >2 vessels stented, in-stent restenosis of a drug-eluting stent, prior brachytherapy, unprotected left main stenting, >2 lesions per vessel, lesion length ≥30 mm, bifurcation lesion with side branch ≥2.5 mm, vein bypass graft, and thrombus-containing lesion (from Yeh et al.21).
Type of stent was missing for one patient in the ticagrelor and seven patients in the clopidogrel group.
The index indication for PCI was ACS in 1375 (50.5%) patients; within the treatment groups, the index indication for PCI was ACS for 509 (51.9%) of the 981 patients randomized to dabigatran 110 mg dual therapy, 391 (51.2%) of the 763 patients randomized to dabigatran 150 mg dual therapy, 475 (48.4%) of the 981 patients randomized to warfarin triple therapy, and 369 (48.3%) of the 764 patients randomized to warfarin triple therapy excluding elderly patients outside the USA. Patients in the ACS and elective PCI subgroups were of similar age but a lower proportion of ACS patients were males (73.5% vs. 78.5%). The most common type of ACS was non-ST-elevation myocardial infarction (42.3%), followed by unstable angina (33.6%) and ST-elevation myocardial infarction (22.2%). The proportions of oral anticoagulant treatment-naïve patients at baseline, defined as having <14 days of consecutive oral anticoagulant treatment, were 74.3% in the ACS subgroup and 57.4% in the elective PCI group. Clinical and procedural complexity factors21 and prior myocardial infarction were more common in the ACS group, Table 1. Drug-eluting stents were predominantly used in all patients but slightly more commonly in the elective PCI group than the ACS group.
Ticagrelor was chosen (by the investigators) as the P2Y12 inhibitor in 327 (12.0%) patients; within each treatment group, ticagrelor was chosen in 132 (13.5%) of the 981 patients randomized to dabigatran 110 mg dual therapy, in 104 (13.6%) of those 763 patients randomized to dabigatran 150 mg dual therapy, in 91 (9.3%) of those 981 patients randomized to warfarin triple therapy, and in 73 (9.6%) of those 764 patients randomized to warfarin triple therapy excluding elderly patients outside the USA. Mean age was 69.7 years and 70.9 years in the ticagrelor- and clopidogrel-treated patients. Type of AF was paroxysmal in 56.6% and 48.6%, and permanent in 26.9% and 33.4%, of patients treated with ticagrelor or clopidogrel, respectively. The proportions of patients with prior stroke were 6.1% in the ticagrelor group and 8.6% in the clopidogrel group, and 76.1% and 64.5% were oral anticoagulant treatment-naïve, respectively. In the ticagrelor group, 73.4% of the patients had an ACS at index event, and 47.3% had ACS at index in the clopidogrel group. Mean CHA2DS2-VASc and modified HAS-BLED scores were slightly higher in patients treated with clopidogrel, but clinical complexity factors, and the combination of clinical and procedural factors, were more common in those treated with ticagrelor, Table 2.
Bleeding events
The overall incidence (independent of study treatment, i.e. dabigatran or warfarin) of the first ISTH major or clinically relevant non-major bleeding event was 20.9% in patients with PCI due to ACS, and 20.9% in those who had undergone elective PCI; multivariable adjusted treatment independent HR 0.97 with a two-sided 95% CI of 0.81–1.15. The risk of experiencing ISTH major or clinically relevant non-major bleeding was reduced with dabigatran dual therapy vs. warfarin triple therapy in patients with ACS and undergoing elective PCI, Figure 1. Compared with warfarin triple therapy, the risks of experiencing ISTH major bleeding events alone and TIMI major bleeding events were also consistently reduced with both dabigatran 110 mg dual therapy and dabigatran 150 mg dual therapy for patients with ACS and undergoing elective PCI. All interaction P-values were non-significant; thus no interaction between study treatment and index PCI indication could be detected.
Figure 1.
Bleeding events by percutaneous coronary intervention indication at index event. aFrom Cox proportional hazard model stratified by age (elderly vs. non-elderly). bFor the comparison with dabigatran 150 mg dual therapy, elderly patients outside the USA were excluded. cFrom unstratified Cox proportional hazard model. ACS, acute coronary syndrome; CI, confidence interval; CRNM, clinically relevant non-major; ISTH, International Society on Thrombosis and Haemostasis; PCI, percutaneous coronary intervention; TIMI, thrombolysis in myocardial infarction.
In the group of patients treated with ticagrelor, the study treatment-independent incidence of the first ISTH major or clinically relevant non-major bleeding event was 26.3%, and in those treated with clopidogrel 20.1%; multivariable adjusted HR 1.35, 95% CI 1.05–1.72. Across the subgroups of patients with ticagrelor or clopidogrel, the risks of experiencing the primary outcome of ISTH major or clinically relevant non-major bleeding, as well as ISTH major bleeding events alone, and TIMI major bleeding events, were consistently reduced with dabigatran 110 mg dual therapy and dabigatran 150 mg dual therapy vs. warfarin triple therapy, Figure 2 and Supplementary material online, Figure S1. All interaction P-values were non-significant.
Figure 2.
Bleeding events by treatment with ticagrelor or clopidogrel. Fifty-eight patients who received ticagrelor + clopidogrel are included in the ticagrelor subgroup; 93 patients who received neither clopidogrel nor ticagrelor are included in the clopidogrel subgroup. The choice of ticagrelor or clopidogrel was at the discretion of the investigator, these groups are not directly comparable due to allocation bias. aFrom Cox proportional hazard model stratified by age (elderly vs. non-elderly). bFor the comparison with dabigatran 150 mg dual therapy, elderly patients outside the USA were excluded. cFrom unstratified Cox proportional hazard model. ACS, acute coronary syndrome; CI, confidence interval; CRNM, clinically relevant non-major; ISTH, International Society on Thrombosis and Haemostasis; PCI, percutaneous coronary intervention; TIMI, thrombolysis in myocardial infarction.
Death, thromboembolic events, or unplanned revascularization
The study treatment-independent incidence of death, thromboembolic events, or unplanned revascularization was 14.8% in patients with ACS and 12.4% in patients undergoing elective PCI; multivariable adjusted HR 1.13, 95% CI 0.91–1.41. The study treatment independent incidence of death, thromboembolic events, or unplanned revascularization was 18.7% in those treated with ticagrelor and 12.9% in those treated with clopidogrel; multivariable adjusted HR 1.34, 95% CI 1.00–1.82.
Minor variations were observed for the composite endpoint of death, thromboembolic events, or unplanned revascularization, for dabigatran 110 mg or 150 mg dual therapy vs. warfarin triple across subgroups of ACS and elective PCI, Figure 3, and those treated with ticagrelor or clopidogrel, Figure 4andSupplementary material online, Figure S2, but all interaction P-values were non-significant. Numerical differences in the composite of death or thromboembolic events, and for the individual thromboembolic endpoints stroke and all-cause mortality, respectively, were also observed for dabigatran 110 mg or 150 mg dual therapy vs. warfarin triple therapy across subgroups of ACS and elective PCI, Figure 3, but all interaction P-values were non-significant. In the ACS subgroup, numerically higher rates of myocardial infarction and stent thrombosis were observed with dabigatran 110 mg dual therapy vs. warfarin triple therapy, interaction P = 0.20 and 0.07, respectively. Numerical differences in the composite of death or thromboembolic events and the individual thromboembolic endpoints were also observed for those patients treated with ticagrelor or clopidogrel, Figure 4, but all interaction P-values were non-significant.
Figure 3.
Death, thromboembolic events, and unplanned revascularization by percutaneous coronary intervention indication at index event. aFrom Cox proportional hazard model stratified by age (elderly vs. non-elderly). bFor the comparison with dabigatran 150 mg dual therapy, elderly patients outside the USA were excluded. cFrom unstratified Cox proportional hazard model. ACS, acute coronary syndrome; CI, confidence interval; DTE, death or thromboembolic event (myocardial infarction, stroke, or systemic embolism); PCI, percutaneous coronary intervention.
Figure 4.
Death, thromboembolic events, and unplanned revascularization by treatment with ticagrelor or clopidogrel. The choice of ticagrelor or clopidogrel was at the discretion of the investigator, these groups are not directly comparable due to allocation bias. aFrom Cox proportional hazard model stratified by age (elderly vs. non-elderly). bFor the comparison with dabigatran 150 mg dual therapy, elderly patients outside the USA were excluded. cFrom unstratified Cox proportional hazard model. CI, confidence interval; DTE, death or thromboembolic event (myocardial infarction, stroke, or systemic embolism); HR, hazard ratio; n.d., not done (one treatment group had zero events and HR is not given).
Take home figure.
The benefits of both dabigatran 110 mg and 150 mg dual therapy compared with warfarin triple therapy in reducing bleeding risks were consistent across subgroups of patients with or without ACS, and patients treated with ticagrelor or clopidogrel. ACS, acute coronary syndrome; ASA, aspirin; CI, confidence interval; ISTH, International Society on Thrombosis and Haemostasis; PCI, percutaneous coronary intervention.
Discussion
The benefits of both dabigatran 110 mg and 150 mg dual therapy, with substantial reduction in major and clinically relevant non-major bleeding events, and ISTH and TIMI major bleeding events, compared with warfarin triple therapy were consistent across the pre-specified subgroups of patients with ACS or elective PCI and in those treated with the P2Y12 inhibitors ticagrelor or clopidogrel.
At least 5% of unselected patients undergoing PCI have AF,4 and ∼15% of AF patients have a history of myocardial infarction.22,23 In patients hospitalized for an ACS, an AF incidence up to 21% has been reported, and this combination is associated with worse outcome including higher risk for stroke, myocardial infarction, and death.24,25 Therefore, patients with AF undergoing PCI with stent implantation are most often at sufficient increased risk for thromboembolic complications warranting long-term oral anticoagulation therapy, irrespective of the indication for PCI being ACS or elective PCI. However, the choice of antiplatelet drugs and treatment durations may differ after an ACS or an elective PCI.
In the RE-DUAL PCI trial, the equally sized subgroups of patients with ACS or elective PCI as the index event had similar baseline characteristics, mean CHA2DS2-VASc and modified HAS-BLED scores, and primary safety outcome incidences. Both dabigatran dual therapies were associated with substantially reduced risk of bleeding events compared with warfarin triple therapy without signs of interaction between study treatment and the indication for PCI (ACS or elective). The risk of the composite of death, thromboembolic events, or unplanned revascularization with dabigatran dual therapies seemed comparable to warfarin triple therapy in the ACS and elective PCI subgroups. While there was substantially less bleeding with dabigatran 110 mg dual therapy compared with warfarin triple therapy, numerically higher risks of myocardial infarction and stent thrombosis were observed in the ACS population, although the number of events was small and interaction P-values were non-significant. These differences should be interpreted with caution as the main RE-DUAL PCI study was not adequately powered for individual thromboembolic events, and the results in the present analysis are based on even smaller numbers of patients and events within each subgroup. Importantly, both dabigatran doses in the dual therapy groups have previously been evaluated for stroke prevention compared with warfarin. In the pivotal RE-LY study,26 dabigatran 150 mg was superior to warfarin with a 35% risk reduction in stroke, whereas dabigatran 110 mg was non-inferior to warfarin for stroke prevention. Thus, irrespective of ACS or elective PCI at the index event, dabigatran 150 mg dual therapy is an attractive option after PCI in patients with AF,9 whereas dabigatran 110 mg dual therapy should be considered in very elderly patients and those at increased bleeding risk.
In the PIONEER-AF PCI trial,13 both dual therapy with rivaroxaban 15 mg once daily and triple therapy with rivaroxaban 2.5 mg twice daily also reduced clinically relevant bleeding events compared with VKA triple therapy in patients with AF after PCI. Similar to the present trial, the groups of patient with or without ACS at index PCI intervention were of equal size in PIONEER-AF PCI, and the authors reported consistent results in the ACS subgroup.
In the RE-DUAL PCI trial, the choice of the P2Y12 inhibitors clopidogrel or ticagrelor was at the discretion of the investigator. The vast majority of the study patients were treated with clopidogrel, but 12% of the patients received ticagrelor as part of their antithrombotic regimen. In the PIONEER-AF PCI trial,13 the choice of P2Y12 inhibitor was likewise at the investigators’ discretion, but only 4.3% of the patients received ticagrelor and 1.3% received prasugrel (the latter not allowed in RE-DUAL PCI). In the present study, the majority of patients treated with ticagrelor (73%) had an ACS at index event, in line with contemporary guidelines recommending ticagrelor in preference to clopidogrel on top of aspirin after an ACS episode.7 Not surprisingly, patients treated with ticagrelor had a higher bleeding risk than the patients who the physician treated with clopidogrel. A higher risk of bleeding in patients with ACS treated with ticagrelor (but not on oral anticoagulants) compared with clopidogrel has also been reported in the PLATO trial.27
Patients treated with ticagrelor at investigator’s discretion were also associated with higher risk of the composite of death, thromboembolic events, or unplanned revascularization, of borderline statistical significance, than patients receiving clopidogrel in the present study. In contrast, ticagrelor was significantly associated with 16% lower risk for the primary composite outcome of cardiovascular death, myocardial infarction, or stroke, compared to clopidogrel in the aforementioned randomized PLATO trial.27 Despite multivariable statistical adjustments, our findings may merely reflect that patients receiving ticagrelor, at the choice of the investigator, were at higher risk for thromboembolic and bleeding events, e.g. because of clinical and procedural complexity factors.
Despite the higher bleeding risk observed in patients treated with ticagrelor, the benefits of both dabigatran 110 mg and 150 mg dual therapy compared with warfarin triple therapy were consistent across the ticagrelor and clopidogrel subgroups. In patients with AF where more intensive platelet inhibition is warranted, e.g. after an ACS with high risk for new coronary events, or in patients who are non-responders to clopidogrel and thereby at high risk for thromboembolic events,28 dabigatran dual therapy with ticagrelor might be an attractive alternative after PCI as recently suggested in a North American consensus document.10 Notably the trend for higher risk for myocardial infarction and stent thrombosis in patients treated with dabigatran 110 mg dual therapy compared with warfarin triple therapy seemed attenuated in those patients receiving ticagrelor, with the caveat that this finding is based on a small subgroup of patients.
Approximately 10% of patients in the warfarin triple therapy group received ticagrelor in combination with aspirin and warfarin in the present study. Albeit based on modest numbers, the high bleeding rates in these patients support current guideline recommendations to avoid newer P2Y12 inhibitors as part of oral anticoagulant triple therapy.6,7,9,10 In addition, in previous small observational studies,29–31 VKA or NOAC triple therapy with ticagrelor or prasugrel have been associated with up to three times higher risk of bleeding events compared to triple therapy with clopidogrel.
This report has limitations. Subgroup analyses, albeit pre-specified, should always be interpreted cautiously as these individual subgroups were not powered for formal statistical testing of each individual subgroup, and therefore the CIs were inevitably wider than in the main study due to the smaller numbers of patients and events, especially in the relatively small subgroup of patients receiving ticagrelor. Also, interaction P-values should be regarded as exploratory. The magnitude of increased bleeding risk with ticagrelor compared to clopidogrel was somewhat higher in the present study than in the randomized post-ACS trial comparing ticagrelor vs. clopidogrel on top of aspirin but not oral anticoagulant treatment.27 This might imply an incremental bleeding risk with ticagrelor in combination with oral anticoagulants, also indicated by small observational studies.29–31 However, this interpretation is limited by the non-randomized comparisons of P2Y12 inhibitors in the present study, as well as in the observational studies, and the small subgroup of patients receiving ticagrelor. Lastly, the assignment of patients to the P2Y12 inhibitor was not randomized but chosen at the discretion of the investigator, so that residual confounding or classification bias cannot be excluded.
Conclusions
In patients with AF who had undergone PCI, the benefits of both dabigatran 110 mg and 150 mg dual therapy compared with warfarin triple therapy in reducing bleeding risks were consistent across subgroups of patients with or without ACS at index event, and those treated with ticagrelor or clopidogrel.
Supplementary Material
Acknowledgements
Editorial assistance consisting of formatting and collation of author comments was provided by Sarah Petit, PhD from PAREXEL, with funding from Boehringer Ingelheim. Assistance with statistical analyses was provided by Corinna Miede, an employee of HMS Analytical Software GmbH, with funding from Boehringer Ingelheim. Assistance with programming was provided by Clemens Tilke from Boehringer Ingelheim.
Funding
This work was supported by Boehringer Ingelheim International GmbH.
Conflict of interest: J.O. reports fees to his institution from AstraZeneca, Boehringer Ingelheim, Bayer, Bristol-Myers Squibb, Daichii Sankyo, Pfizer, Portola, Roche Diagnostics, and Sanofi. P.G.S. reports research grant from Bayer, Merck, Sanofi, and Servier, speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer Ingelheim, Bristol-Myers-Squibb, Lilly, Merck, Novartis, Novo-Nordisk, Pfizer, Regeneron, Sanofi, and Servier; S.H.H. reports personal fees from Bayer HealthCare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Medtronic, Pfizer, SJM, and Zol; G.Y.H.L. has served as a consultant for Bayer/Janssen, BMS/Pfizer, Medtronic, Boehringer Ingelheim, Novartis, Verseon and Daiichi Sankyo, and has been on the speaker’s bureau for Bayer, BMS/Pfizer, Medtronic, Boehringer Ingelheim, and Daiichi Sankyo; T.K. reports grants from Boehringer Ingelheim GmbH; M.N., M.B., and E.K. are employees of Boehringer Ingelheim; J.M.t.B. reports advisory/consulting/speakers’ fees from Accumetrics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lily, The Medicines Company, and Pfizer, and research grants from AstraZeneca and ZonMw; D.L.B. discloses the following relationships—Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, and The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo-Nordisk, PLx Pharma, Takeda; C.P.C. reports research grants from Amgen, Boehringer Ingelheim (BI), Bristol-Myers Squibb (BMS), Daiichi Sankyo, Janssen, Merck and consulting fees from Alnylam, Amarin, Amgen, BI, BMS, Eisai, Janssen, Kowa, Merck, Pfizer, Regeneron, Sanofi.
References
- 1. Bjorck S, Palaszewski B, Friberg L, Bergfeldt L.. Atrial fibrillation, stroke risk, and warfarin therapy revisited: a population-based study. Stroke 2013;44:3103–3108. [DOI] [PubMed] [Google Scholar]
- 2. Haim M, Hoshen M, Reges O, Rabi Y, Balicer R, Leibowitz M.. Prospective national study of the prevalence, incidence, management and outcome of a large contemporary cohort of patients with incident non-valvular atrial fibrillation. J Am Heart Assoc 2015;4:e001486.. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Goto S, Bhatt DL, Rother J, Alberts M, Hill MD, Ikeda Y, Uchiyama S, D'Agostino R, Ohman EM, Liau CS, Hirsch AT, Mas JL, Wilson PW, Corbalan R, Aichner F, Steg PG; REACH Investigators. Prevalence, clinical profile, and cardiovascular outcomes of atrial fibrillation patients with atherothrombosis. Am Heart J 2008;156:855–863.e852. [DOI] [PubMed] [Google Scholar]
- 4. Pilgrim T, Kalesan B, Zanchin T, Pulver C, Jung S, Mattle H, Carrel T, Moschovitis A, Stortecky S, Wenaweser P, Stefanini GG, Raber L, Meier B, Juni P, Windecker S.. Impact of atrial fibrillation on clinical outcomes among patients with coronary artery disease undergoing revascularisation with drug-eluting stents. EuroIntervention 2013;8:1061–1071. [DOI] [PubMed] [Google Scholar]
- 5. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW.. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. Circulation 2014;130:e199–e267. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener H-C, Heidbuchel H, Hendriks J, Hindricks G, Manolis AS, Oldgren J, Popescu BA, Schotten U, Van Putte B, Vardas P, Agewall S, Camm J, Baron Esquivias G, Budts W, Carerj S, Casselman F, Coca A, De Caterina R, Deftereos S, Dobrev D, Ferro JM, Filippatos G, Fitzsimons D, Gorenek B, Guenoun M, Hohnloser SH, Kolh P, Lip GYH, Manolis A, McMurray J, Ponikowski P, Rosenhek R, Ruschitzka F, Savelieva I, Sharma S, Suwalski P, Tamargo JL, Taylor CJ, Van Gelder IC, Voors AA, Windecker S, Zamorano JL, Zeppenfeld K.. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–2962. [DOI] [PubMed] [Google Scholar]
- 7. Valgimigli M, Bueno H, Byrne RA, Collet J-P, Costa F, Jeppsson A, Jüni P, Kastrati A, Kolh P, Mauri L, Montalescot G, Neumann F-J, Petricevic M, Roffi M, Steg PG, Windecker S, Zamorano JL, Levine GN; ESC Scientific Document Group; ESC Committee for Practice Guidelines (CPG); ESC National Cardiac Societies. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. Eur Heart J 2018;39:213–260. [DOI] [PubMed] [Google Scholar]
- 8. Steffel J, Verhamme P, Potpara TS, Albaladejo P, Antz M, Desteghe L, Haeusler KG, Oldgren J, Reinecke H, Roldan-Schilling V, Rowell N, Sinnaeve P, Collins R, Camm AJ, Heidbüchel H, Lip GYH, Weitz J, Fauchier L, Lane D, Boriani G, Goette A, Keegan R, MacFadyen R, Chiang C-E, Joung B, Shimizu W.. The 2018 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018;39:1330–1393. [DOI] [PubMed] [Google Scholar]
- 9. Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U, Byrne RA, Collet JP, Falk V, Head SJ, Juni P, Kastrati A, Koller A, Kristensen SD, Niebauer J, Richter DJ, Seferovic PM, Sibbing D, Stefanini GG, Windecker S, Yadav R, Zembala MO; ESC Scientific Document Group. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2018; doi:10.1093/eurheartj/ehy394. [Epub ahead of print]. [DOI] [PubMed] [Google Scholar]
- 10. Angiolillo JD, Goodman SG, Bhatt DL, Eikelboom JW, Price Matthew J., Moliterno DJ, Cannon CP, Tanguay J-F, Granger CB, Mauri L, Holmes DR, Gibson CM, Faxon DP.. Antithrombotic therapy in patients with atrial fibrillation treated with oral anticoagulation undergoing percutaneous coronary intervention: a North American perspective—2018 update. Circulation 2018;38:527–536. [DOI] [PubMed] [Google Scholar]
- 11. Lamberts M, Gislason GH, Olesen JB, Kristensen SL, Schjerning Olsen AM, Mikkelsen A, Christensen CB, Lip GY, Kober L, Torp-Pedersen C, Hansen ML.. Oral anticoagulation and antiplatelets in atrial fibrillation patients after myocardial infarction and coronary intervention. J Am Coll Cardiol 2013;62:981–989. [DOI] [PubMed] [Google Scholar]
- 12. Dewilde WJM, Oirbans T, Verheugt FWA, Kelder JC, De Smet BJGL, Herrman J-P, Adriaenssens T, Vrolix M, Heestermans AACM, Vis MM, Tijsen JGP, van't Hof AW, ten Berg JM; WOEST Investigators. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013;381:1107–1115. [DOI] [PubMed] [Google Scholar]
- 13. Gibson CM, Mehran R, Bode C, Halperin J, Verheugt FW, Wildgoose P, Birmingham M, Ianus J, Burton P, van Eickels M, Korjian S, Daaboul Y, Lip GY, Cohen M, Husted S, Peterson ED, Fox KA.. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med 2016;375:2423–2434. [DOI] [PubMed] [Google Scholar]
- 14. Agarwal N, Jain A, Mahmoud AN, Bishnoi R, Golwala H, Karimi A, Mojadidi MK, Garg J, Gupta T, Patel NK, Wayangankar S, Anderson RD.. Safety and efficacy of dual versus triple antithrombotic therapy in patients undergoing percutaneous coronary intervention. Am J Med 2017;130:1280–1289. [DOI] [PubMed] [Google Scholar]
- 15. Batra G, Friberg L, Erlinge D, James S, Jernberg T, Svennblad B, Wallentin L, Oldgren J.. Antithrombotic therapy after myocardial infarction in patients with atrial fibrillation undergoing percutaneous coronary intervention. Eur Heart J Cardiovasc Pharmacother 2018;4:36–45. [DOI] [PubMed] [Google Scholar]
- 16. Cannon CP, Bhatt DL, Oldgren J, Lip GYH, Ellis SG, Kimura T, Maeng M, Merkely B, Zeymer U, Gropper S, Nordaby M, Kleine E, Harper R, Manassie J, Januzzi JL, Ten Berg JM, Steg PG, Hohnloser SH; RE-DUAL PCI Investigators. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med 2017;377:1513–1524. [DOI] [PubMed] [Google Scholar]
- 17. Cannon CP, Gropper S, Bhatt DL, Ellis SG, Kimura T, Lip GY, Steg PG, Ten Berg JM, Manassie J, Kreuzer J, Blatchford J, Massaro JM, Brueckmann M, Ferreiros Ripoll E, Oldgren J, Hohnloser SH.. Design and rationale of the RE-DUAL PCI trial. Clin Cardiol 2016;39:555–564. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Schulman S, Kearon C. Subcommittee on Control of Anticoagulation, The Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005;3:692–694. [DOI] [PubMed] [Google Scholar]
- 19. Kaatz S, Ahmad D, Spyropoulos AC, Schulman S; Subcommittee on Control of Anticoagulation. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 2015;13:2119–2126. [DOI] [PubMed] [Google Scholar]
- 20. Bovill EG, Terrin ML, Stump DC, Berke AD, Frederick M, Collen D, Feit F, Gore JM, Hillis LD, Lambrew CT, Leiboff R, Mann KG, Markis JE, Pratt CM, Sharkey SW, Sopko G, Tracy RP, Chesebro JH. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI), Phase II Trial. Ann Intern Med 1991;115:256–265. [DOI] [PubMed] [Google Scholar]
- 21. Yeh RW, Kereiakes DJ, Steg PG, Cutlip DE, Croce KJ, Massaro JM, Mauri L; DAPT Study Investigators. Lesion complexity and outcomes of extended dual antiplatelet therapy after percutaneous coronary intervention. J Am Coll Cardiol 2017;70:2213–2223. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Oldgren J, Healey JS, Ezekowitz M, Commerford P, Avezum A, Pais P, Zhu J, Jansky P, Sigamani A, Morillo CA, Liu L, Damasceno A, Grinvalds A, Nakamya J, Reilly PA, Keltai K, Van Gelder IC, Yusufali AH, Watanabe E, Wallentin L, Connolly SJ, Yusuf S; RE-LY Atrial Fibrillation Registry Investigators. Variations in cause and management of atrial fibrillation in a prospective registry of 15, 400 emergency department patients in 46 countries: the RE-LY Atrial Fibrillation Registry. Circulation 2014;129:1568–1576. [DOI] [PubMed] [Google Scholar]
- 23. Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM.. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383:955–962. [DOI] [PubMed] [Google Scholar]
- 24. Schmitt J, Duray G, Gersh BJ, Hohnloser SH.. Atrial fibrillation in acute myocardial infarction: a systematic review of the incidence, clinical features and prognostic implications. Eur Heart J 2009;30:1038–1045. [DOI] [PubMed] [Google Scholar]
- 25. Batra G, Svennblad B, Held C, Jernberg T, Johanson P, Wallentin L, Oldgren J.. All types of atrial fibrillation in the setting of myocardial infarction are associated with impaired outcome. Heart 2016;102:926–933. [DOI] [PubMed] [Google Scholar]
- 26. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–1151. [DOI] [PubMed] [Google Scholar]
- 27. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, Freij A, Thorsén M; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–1057. [DOI] [PubMed] [Google Scholar]
- 28. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA, Costa MA.. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 2007;49:1505–1516. [DOI] [PubMed] [Google Scholar]
- 29. Sarafoff N, Martischnig A, Wealer J, Mayer K, Mehilli J, Sibbing D, Kastrati A.. Triple therapy with aspirin, prasugrel, and vitamin K antagonists in patients with drug-eluting stent implantation and an indication for oral anticoagulation. J Am Coll Cardiol 2013;61:2060–2066. [DOI] [PubMed] [Google Scholar]
- 30. Sra S, Tan MK, Mehta SR, Fisher HN, Dery JP, Welsh RC, Eisenberg MJ, Overgaard CB, Rose BF, Siega AJ, Cheema AN, Wong BY, Henderson MA, Lutchmedial S, Lavi S, Goodman SG, Yan AT; Canadian Observational AntiPlatelet sTudy I. Ischemic and bleeding events in patients with myocardial infarction undergoing percutaneous coronary intervention who require oral anticoagulation: insights from the Canadian observational AntiPlatelet sTudy. Am Heart J 2016;180:82–89. [DOI] [PubMed] [Google Scholar]
- 31. Verlinden NJ, Coons JC, Iasella CJ, Kane-Gill SL.. Triple antithrombotic therapy with aspirin, P2Y12 inhibitor, and warfarin after percutaneous coronary intervention: an evaluation of prasugrel or ticagrelor versus clopidogrel. J Cardiovasc Pharmacol Ther 2017;22:546–551. [DOI] [PubMed] [Google Scholar]
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