Comparison of the Effect of Age (< 75 Versus ≥ 75) on the Efficacy and Safety of Dual Therapy (Dabigatran + Clopidogrel or Ticagrelor) Versus Triple Therapy (Warfarin + Aspirin + Clopidogrel or Ticagrelor) in Patients With Atrial Fibrillation After Percutaneous Coronary Intervention (from the RE-DUAL PCI Trial)

The RE-DUAL PCI trial reported that dabigatran dual therapy (110/150 mg twice daily, plus clopidogrel or ticagrelor) reduced bleeding events versus warfarin triple therapy (warfarin plus aspirin and clopidogrel or ticagrelor) in patients with atrial fibrillation who underwent percutaneous coronary intervention, with noninferiority in composite thromboembolic events. In this prespecified analysis, risks of first major or clinically relevant nonmajor bleeding event and composite end point of death, thromboembolic events, or unplanned revascularization were compared between dabigatran dual therapy and warfarin triple therapy in older (≥ 75 years) and younger (< 75 years) patients, using Cox proportional hazard regression. Of 2,725 patients randomized to treatment, 1,026 (37.7%) were categorized into older and 1,699 (62.3%) into younger age groups. Dabigatran 110 mg dual therapy lowered bleeding risk versus warfarin triple therapy in older (hazard ratio [HR] 0.67; 95% confidence interval [CI] 0.51 to 0.89) and younger patients (HR 0.40; 95% CI 0.30 to 0.54); interaction p value: 0.0125. Dabigatran 150 mg dual therapy lowered bleeding risk versus warfarin triple therapy in younger patients (HR 0.57; 95% CI 0.44 to 0.74), whereas no benefit could be observed in older patients (HR 1.21; 95% CI 0.83 to 1.77); interaction p value: 0.0013. For the thromboembolic end point, there was a trend for a higher risk with dabigatran 110 mg dual therapy in older patients, compared with warfarin triple therapy, whereas the risk was similar in younger patients. For dabigatran 150 mg dual therapy, the thromboembolic risk versus warfarin triple therapy was similar in older and younger patients. In conclusion, the benefits of dabigatran dual therapy differed in the 2 age groups, which may help dose selection when using dabigatran dual therapy. The RE-DUAL PCI trial reported that dabigatran dual therapy (110/150 mg twice daily, plus clopidogrel or ticagrelor) reduced bleeding events versus warfarin triple therapy (warfarin plus aspirin and clopidogrel or ticagrelor) in patients with atrial fibrillation who underwent percutaneous coronary intervention, with noninferiority in composite thromboembolic events. In this prespecified analysis, risks of first major or clinically relevant nonmajor bleeding event and composite end point of death, thromboembolic events, or unplanned revascularization were compared between dabigatran dual therapy and warfarin triple therapy in older (≥ 75 years) and younger (< 75 years) patients, using Cox proportional hazard regression. Of 2,725 patients randomized to treatment, 1,026 (37.7%) were categorized into older and 1,699 (62.3%) into younger age groups. Dabigatran 110 mg dual therapy lowered bleeding risk versus warfarin triple therapy in older (hazard ratio [HR] 0.67; 95% confidence interval [CI] 0.51 to 0.89) and younger patients (HR 0.40; 95% CI 0.30 to 0.54); interaction p value: 0.0125. Dabigatran 150 mg dual therapy lowered bleeding risk versus warfarin triple therapy in younger patients (HR 0.57; 95% CI 0.44 to 0.74), whereas no benefit could be observed in older patients (HR 1.21; 95% CI 0.83 to 1.77); interaction p value: 0.0013. For the thromboembolic end point, there was a trend for a higher risk with dabigatran 110 mg dual therapy in older patients, compared with warfarin triple therapy, whereas the risk was similar in younger patients. For dabigatran 150 mg dual therapy, the thromboembolic risk versus warfarin triple therapy was similar in older and younger patients. In conclusion, the benefits of dabigatran dual therapy differed in the 2 age groups, which may help dose selection when using dabigatran dual therapy. Dabigatran is approved at 110 or 150 mg twice daily doses for the prevention of stroke in atrial fibrillation (AF).1Connolly 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 Steering Committee, InvestigatorsDabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009; 361: 1139-1151Crossref PubMed Scopus (8039) Google Scholar The RE-DUAL PCI trial compared dabigatran dual therapy (110 or 150 mg twice daily, plus clopidogrel or ticagrelor) versus warfarin triple therapy (warfarin with aspirin plus clopidogrel or ticagrelor) in patients with AF who underwent percutaneous coronary intervention (PCI).2Cannon 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 Steering Committee, InvestigatorsDual antithrombotic therapy with dabigatran after PCI in atrial fibrillation.N Engl J Med. 2017; 377: 1513-1524Crossref PubMed Scopus (706) Google Scholar Dabigatran dual therapy at both doses reduced the risk of bleeding—assessed by International Society on Thrombosis and Haemostasis (ISTH) major bleeding events (MBEs) or clinically relevant nonmajor bleeding events (CRNMBEs)—compared with warfarin triple therapy, and was noninferior for the composite efficacy end point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization. The prevalence of AF is increased in older patients due to aging and common predisposing co-morbidities. In this prespecified analysis, we evaluated the influence of patient age on the outcomes in the RE-DUAL PCI trial, using age group as an exploratory variable in an unstratified model, whereas in the main RE-DUAL PCI trial, age was used as a stratifying factor. The design of the RE-DUAL PCI trial (NCT02164864) has been reported previously.3Cannon 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 RE-DUAL PCI Steering Committee, InvestigatorsDesign and rationale of the RE-DUAL PCI trial: a prospective, randomized, phase 3b study comparing the safety and efficacy of dual antithrombotic therapy with dabigatran etexilate versus warfarin triple therapy in patients with nonvalvular atrial fibrillation who have undergone percutaneous coronary intervention with stenting.Clin Cardiol. 2016; 39: 555-564Crossref PubMed Scopus (55) Google Scholar In brief, 2,725 patients aged ≥ 18 years with nonvalvular AF who underwent PCI for acute coronary syndrome or stable coronary artery disease were randomly assigned to dabigatran dual or warfarin triple therapy, with a mean follow-up of 14 months. Aspirin was used for 1 month when a bare-metal stent was used, and for 3 months when a drug-eluting stent was used. Dabigatran 150 mg is not licensed in patients aged ≥ 80 years in Europe or ≥ 70 years in Japan, whereas dabigatran at both 110- and 150-mg doses is approved in the United States regardless of age. Elderly patients in non-US countries (≥ 80 years) or Japan (≥ 70 years) were randomized in RE-DUAL PCI to receive dabigatran 110 mg dual or warfarin triple therapy in a 1:1 ratio, whereas younger patients in non-US countries (< 80 years) and Japan (< 70 years), and all US patients irrespective of age, were randomized to dabigatran 110 mg dual, dabigatran 150 mg dual, or warfarin triple therapy in a 1:1:1 ratio. The primary safety end point in RE-DUAL PCI was the time to first ISTH MBE/CRNMBE. Key efficacy end point was a composite of the time to death, first thromboembolic event, or unplanned revascularization. The current analysis assessed these end points in patients categorized into older (≥ 75 years) and younger (< 75 years) age groups. Cox proportional hazard regression models were used to compare dabigatran 110 or 150 mg dual versus warfarin triple therapy in older and younger age groups. Exploratory treatment-by-subgroup interaction p values were provided from the Cox proportional hazard regression models (p <0.05 was considered statistically significant). Furthermore, the effect of age on the risk of the primary safety end point and of the key composite efficacy end point was investigated with a multivariable Cox proportional hazard regression model that included treatment and age as a continuous variable, as well as the interaction between treatment and age. The resulting hazard ratios (HRs) and confidence intervals (CIs) comparing dabigatran 110 or 150 mg dual versus warfarin triple therapy for varying values of age were visualized via interaction plots. Of the 2,725 patients randomized to treatment, 1,026 (37.7%) were categorized into older and 1,699 (62.3%) into younger age groups (Figure 1). Baseline characteristics of older and younger patients are shown in Table 1. Compared with younger patients, older patients were at higher risk of bleeding and stroke, whereas previous medical history was broadly similar.Table 1Baseline characteristics according to age groupsVariableAge (yrs)(≥ 75 years)(< 75 years)Total (n = 1,026)Total (n = 1,699)Mean age (yrs, ± SD)79.3 ± 3.665.6 ± 6.5Men704 (68.6%)1366 (80.4%)CHA2DS2-VASc*The CHA2DS2-VASc score reflects the risk of stroke, with values ranging from 0 to 9 and higher scores indicating greater risk. score Mean ± SD4.6 ± 1.33.0 ± 1.4 0032 (1.9%) 10171 (10.1%) 238 (3.7%)429 (25.3%) > 2988 (96.3%)1,067 (62.8%)Modified HAS-BLED†The HAS-BLED score reflects the risk of major bleeding in patients with atrial fibrillation who are receiving anticoagulant therapy, with values ranging from 0 to 9 and with higher scores indicating greater risk. score Mean ± SD3.0 ± 0.62.5 ± 0.7 < 3151 (14.7%)792 (46.6%) ≥ 3875 (85.3%)907 (53.4%)Diabetes mellitus‡Data missing from 1 younger patient.343 (33.4%)650 (38.3%)Previous stroke‡Data missing from 1 younger patient.103 (10.0%)123 (7.2%)Previous percutaneous coronary intervention‡Data missing from 1 younger patient.337 (32.8%)575 (33.8%)Previous stent thrombosis§Data missing from 15 older and 29 younger patients.24 (2.3%)44 (2.6%)Previous coronary artery disease‡Data missing from 1 younger patient.692 (67.4%)1136 (66.9%)Previous myocardial infarction247 (24.1%)452 (26.6%)Previous coronary artery bypass graft‡Data missing from 1 younger patient.117 (11.4%)170 (10.0%)Previous pulmonary embolismData missing from 3 older and 5 younger patients.16 (1.6%)20 (1.2%)Previous systemic embolism‡Data missing from 1 younger patient.7 (0.7%)14 (0.8%)SD = standard deviation. The CHA2DS2-VASc score reflects the risk of stroke, with values ranging from 0 to 9 and higher scores indicating greater risk.† The HAS-BLED score reflects the risk of major bleeding in patients with atrial fibrillation who are receiving anticoagulant therapy, with values ranging from 0 to 9 and with higher scores indicating greater risk.‡ Data missing from 1 younger patient.§ Data missing from 15 older and 29 younger patients.|| Data missing from 3 older and 5 younger patients. Open table in a new tab SD = standard deviation. Dabigatran 110 mg dual therapy lowered the risk of MBE/CRNMBE versus warfarin triple therapy in older patients (HR 0.67; 95% CI 0.51 to 0.89) and younger patients (HR 0.40; 95% CI 0.30 to 0.54; Figure 2, Figure 3). Younger patients seem to be favored even more with respect to MBE/CRNMBE by the 110 mg dabigatran dose than older patients, as suggested by the significant interaction p value (0.013; Figure 2). Dabigatran 150 mg dual therapy lowered the risk of MBE/CRNMBE versus warfarin triple therapy in younger patients (HR 0.57; 95% CI 0.44 to 0.74), whereas no benefit could be observed in older patients (HR 1.21; 95% CI 0.83 to 1.77; interaction p value: 0.001; Figure 4, Figure 5). A reliable conclusion is however difficult, because the number of older patients with dabigatran 150 mg dual therapy is low.Figure 3Kaplan-Meier analysis for (A) time to first adjudicated ISTH MBE or CRNMBE and (B) DTE or unplanned revascularization (intent to treat period) by age group: dabigatran 110 mg dual therapy.CRNMBE = clinically relevant nonmajor bleeding event; DE = dabigatran etexilate; DTE = death or thromboembolic event; ISTH = International Society on Thrombosis and Haemostasis; MBE = major bleeding event.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 4Outcomes in older and younger patients according to treatment: dabigatran 150 mg dual therapy.Patients aged ≥ 80 years outside the United States and patients aged ≥ 70 years from Japan were assigned to either DE 110 mg or warfarin in a 1:1 ratio; all other patients are randomized to all 3 treatment groups in a 1:1:1 ratio. *For the comparison with dabigatran 150 mg dual therapy, elderly patients outside the United States aged ≥ 80 years (≥ 70 years in Japan) are excluded. HRs and 95% CIs from Cox proportional hazard models. CI = confidence interval; CRNMBE = clinically relevant nonmajor bleeding event; DE = dabigatran etexilate; DTE = death or thromboembolic event; HR = hazard ratio; ISTH = International Society on Thrombosis and Haemostasis; MBE = major bleeding event.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 5Kaplan-Meier analysis for (A) time to first adjudicated ISTH MBE or CRNMBE and (B) DTE or unplanned revascularization (intent to treat period) by age group: dabigatran 150 mg dual therapy.*For the comparison with dabigatran 150 mg dual therapy, elderly patients outside the United States aged ≥ 80 years (≥ 70 years in Japan) are excluded. CRNMBE = clinically relevant nonmajor bleeding event; DE = dabigatran etexilate; DTE = death or thromboembolic event; ISTH = International Society on Thrombosis and Haemostasis; MBE = major bleeding event.View Large Image Figure ViewerDownload Hi-res image Download (PPT) For the thromboembolic end point, there was a trend of a higher risk with dabigatran 110 mg dual therapy in older patients compared with warfarin triple therapy (HR 1.54; 95% CI 1.07 to 2.22), whereas the risk was similar to warfarin triple therapy in younger patients (HR 0.90; 95% CI 0.66 to 1.23; Figures 2 and 3). Thus, older patients seem to be less protected for thromboembolic events by the dabigatran 110 mg dose than younger patients, as is suggested by the significant interaction p value (0.029; Figure 2). For dabigatran 150 mg dual therapy, the thromboembolic risk versus warfarin triple therapy was similar in older (HR 1.34; 95% CI 0.73 to 2.44) and younger patients (HR 0.79; 95% CI 0.57 to 1.09; interaction p value: 0.129; Figures 4 and 5). A reliable conclusion is however difficult, because the number of older patients with dabigatran 150 mg dual therapy is low. The interaction plots displaying the HRs and 95% CIs in the comparison of dabigatran 110 mg dual therapy versus warfarin triple therapy and dabigatran 150 mg dual therapy versus warfarin triple therapy are shown in Figure 6, Figure 7. They mainly support the results as obtained from the subgroup analysis. However, in contrast to the subgroup analysis with age as a categorical variable, the interaction p value from the model considering age as a continuous variable was statistically not significant (0.219) when comparing the efficacy between dabigatran 110 mg dual therapy and warfarin triple therapy.Figure 7DTE and unplanned revascularization—interaction plot for varying values of age as a continuous variable: (A) dabigatran 110 mg dual therapy; (B) dabigatran 150 mg dual therapy.HRs (solid lines) and Wald 95% CIs from Cox proportional hazard model including treatment, age, and interaction between treatment and age. For the comparison with dabigatran 150 mg dual therapy, elderly patients outside the United States aged ≥ 80 years (≥ 70 years in Japan) are excluded. CI = confidence interval; DTE = death or thromboembolic event; HR = hazard ratio.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Because older patients have an increased risk both for bleeding and for thromboembolic events compared with younger patients, we analyzed whether the observed reduction of bleeding and similar thromboembolic risk with the use of dabigatran dual therapy compared with warfarin triple therapy observed in RE-DUAL PCI was the same in older (≥ 75 years of age) and in younger (< 75) patients. The most important findings of this analysis were: (1) both older and younger patients had a lower risk of bleeding with dabigatran 110 mg dual therapy than with warfarin triple therapy; (2) in younger patients treated with dabigatran 110 mg dual therapy, the risk of the thromboembolic end point was similar to that of patients treated with warfarin triple therapy, whereas in older patients, the risk tended to be higher for patients treated with dabigatran dual therapy; (3) the benefit of dabigatran 150 mg dual therapy with regard to bleeding risk was observed only in younger patients, whereas the results suggest no benefit in older patients; (4) the risk of the thromboembolic end point with dabigatran 150 mg dual versus warfarin triple therapy was similar in older and younger patients; (5) a reliable conclusion for older patients treated with dabigatran 150 mg dual versus warfarin triple therapy is difficult because of the low numbers. There is a paucity of published data to guide anticoagulation regimens in older patients with AF who underwent PCI. Neither the WOEST, PIONEER-PCI, nor AUGUSTUS trials reported comparative outcomes in different age groups.4Dewilde WJ Oirbans T Verheugt FW Kelder JC De Smet BJ Herrman JP Adriaenssens T Vrolix M Heestermans AA Vis MM Tijsen JG van 't Hof AW ten Berg JM WOEST Study InvestigatorsUse 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: 1107-1115Abstract Full Text Full Text PDF PubMed Scopus (1199) Google Scholar, 5Gibson 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: 2423-2434Crossref PubMed Scopus (860) Google Scholar, 6Lopes RD Heizer G Aronson R Vora AN Massaro T Mehran R Goodman SG Windecker S Darius H Li J Averkov O Bahit MC Berwanger O Budaj A Hijazi Z Parkhomenko A Sinnaeve P Storey RF Thiele H Vinereanu D Granger CB Alexander JH Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation.N Engl J Med. 2019; 380: 1509-1524Crossref PubMed Scopus (406) Google Scholar Subgroup analysis of the RE-LY trial based on age category showed that dabigatran at 110 and 150 mg twice daily doses was associated with lower risks of intracranial and extracranial bleeding compared with warfarin in younger patients (age <75 years), whereas older patients had a lower risk of intracranial bleeding and a similar or higher risk of extracranial bleeding with dabigatran than warfarin, the latter potentially attributable to a combination of age-related factors such as decreased renal excretion and increased prevalence of gastrointestinal pathology and pharmacokinetic interactions.7Eikelboom JW Wallentin L Connolly SJ Ezekowitz M Healey JS Oldgren J Yang S Alings M Kaatz S Hohnloser SH Diener HC Franzosi MG Huber K Reilly P Varrone J Yusuf S Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial.Circulation. 2011; 123: 2363-2372Crossref PubMed Scopus (929) Google Scholar Our analysis also shows different outcomes in elderly patients compared with younger patients. For the 110-mg dabigatran dose (when combined with clopidogrel or ticagrelor), the results suggest that it is less effective in preventing thromboembolism in older patients compared with younger patients. For the 150-mg dabigatran dose (combined with clopidogrel or ticagrelor), the results suggest that there is no reduced bleeding risk in older patients compared with warfarin triple therapy which was observed in younger patients. The same factors observed in the RE-LY trial explaining the different effects of dabigatran in elderly patients may apply to this analysis. A limitation of our current analysis is that, as a subgroup analysis of the RE-DUAL PCI trial, it was not powered for formal statistical analysis. The moderate size of the RE-DUAL PCI patient cohort, and the fact that outcomes data were prospectively collected and adjudicated, alleviate this limitation to an extent, but for the low number of older patients treated with dabigatran 150 mg dual therapy, a reliable conclusion is difficult. In conclusion, dabigatran 110 mg dual therapy provided a consistent reduction in bleeding risk compared with warfarin triple therapy in both older and younger patients. The risk for the thromboembolic end point appeared to be higher in older patients with dabigatran 110 mg dual therapy versus warfarin triple therapy but the risk was similar in younger patients. Dabigatran 150 mg dual therapy lowered bleeding risk compared with warfarin triple therapy in younger patients, whereas the benefit for risk of bleeding in older patients could not be observed. For the thromboembolic end point, the results suggest similar risks with dabigatran 150 mg dual therapy as for warfarin triple therapy in both older and younger patients. In conclusion, the benefits of dabigatran dual therapy differed in the 2 age groups, which may help dose selection when using dabigatran dual therapy. Jurrien M. ten Berg reports advisory/consulting/speakers’ fees from Accumetrics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, The Medicines Company, and Pfizer, and research grants from AstraZeneca and ZonMw. Philippe Gabriel Steg reports research grants from Bayer, and or fees from AstraZeneca, Boehringer Ingelheim, Lilly, Pfizer, Bhatt the of Society of Data for for the trial, by for the trial, by of the trial, by Daiichi of and for RE-DUAL PCI trial by Boehringer by in trial including for the trial, by in of of the of the and by Society of Steering and AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, Pfizer, The Medicines A to of Hohnloser reports fees from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, and reports fees from and Boehringer Nordaby is an of Boehringer International is an of Kimura reports grants from Boehringer Lip has as a for Bristol-Myers Boehringer Ingelheim, and Daiichi has been a for Bayer, Bristol-Myers Boehringer Ingelheim, and Daiichi fees are Oldgren reports fees to from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, and reports research grants from Bristol-Myers Squibb, Daiichi Sankyo, fees from Boehringer Ingelheim, Bristol-Myers Pfizer, JM ten PG DL SH A T GYH J and CP and M and C Data and to and was provided by at with from Boehringer of study Boehringer grants all to all relevant including study and relevant as by to and as the Furthermore, study study study and statistical analysis and study data are to be after of the primary in a and are and other the Boehringer on and of Study to be and the data be to the data of study and and to respect the of the of the study Study and be via this such be by a and medical may to study data with the and of the and by a Data data are in a for a of 1 which may be use to to study has not been published and is not for is approved by all the