Renal Function and Outcomes With
Dabigatran Dual Antithrombotic Therapy
in Atrial Fibrillation Patients After PCI
Stefan H. Hohnloser, MD,aPhilippe Gabriel Steg, MD,b,c,d,eJonas Oldgren, MD, P
HD,fGeorg Nickenig, MD,g Robert G. Kiss, MD, PHD,hZeki Ongen, MD,iJose L. Navarro Estrada, MD,jTon Oude Ophuis, MD, PHD,k Gregory Y.H. Lip, MD,l,mMatias Nordaby, MD,nEva Kleine, MS
C,nJurrien M. ten Berg, MD,o Deepak L. Bhatt, MD, MPH,pChristopher P. Cannon, MD,p
on behalf of the RE-DUAL PCI Steering Committee and Investigators
ABSTRACT
OBJECTIVESThe study sought to evaluate the effect of dabigatran dual therapy versus warfarin triple therapy across categories of renal function in the RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial.
BACKGROUNDThe RE-DUAL PCI (NCT02164864) trial of patients with atrialfibrillation undergoing percutaneous coronary intervention reported that dabigatran dual therapy (110 or 150 mg twice daily, plus clopidogrel or ticagrelor) reduced the primary endpoint of major bleeding events (MBE) or clinically relevant nonmajor bleeding events (CRNMBE) compared with warfarin triple therapy, with noninferiority in overall thromboembolic events.
METHODSRisk of afirst MBE or CRNMBE and the composite of death or thromboembolic event (DTE) or unplanned revascularization were evaluated in 2,725 patients according to baseline creatinine clearance (CrCl) categories: 30 to<50, 50 to <80, and $80 ml/min.
RESULTSCompared with warfarin, dabigatran 110 mg dual therapy reduced risk of MBE or CRNMBE across all cate-gories of CrCl (p for interaction¼ 0.19). Dabigatran 150 mg dual therapy reduced risk of MBE or CRNMBE regardless of the CrCl category (p for interaction¼ 0.31). Risk of DTE or unplanned revascularization was similar to warfarin triple therapy for dabigatran 110 mg dual therapy across all CrCl categories. Dabigatran 150 mg dual therapy versus warfarin triple therapy had similar risk for DTE or unplanned revascularization in patients with CrCl 30 to<80 ml/min and lower risk at CrCl$80 ml/min (p for interaction ¼ 0.02).
CONCLUSIONSIn the RE-DUAL PCI trial, dabigatran dual therapy reduced bleeding events versus warfarin triple therapy irrespective of renal function, with overall similar risks of thromboembolic events but lower risks with dabigatran 150 mg in patients with normal CrCl. (J Am Coll Cardiol Intv 2019;12:1553–61) © 2019 Published by Elsevier on behalf of the American College of Cardiology Foundation.
ISSN 1936-8798/$36.00 https://doi.org/10.1016/j.jcin.2019.05.050
From the aDepartment of Cardiology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany;bDépartement
Hospitalo-Universitaire, French Alliance for Cardiovascular Trials (FACT), Hôpital Bichat, Paris, France;cUniversité Paris Diderot,
Paris, France;dINSERM U_1148, Paris, France;eHôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France;fUppsala
Clinical Research Center and Department of Medical Sciences, Uppsala, Sweden;gMedizinische Klinik und Poliklinik II, University
of Bonn, Bonn, Germany;hMedical Centre, Hungarian Defence Forces, Budapest, Hungary;iDepartment of Cardiology, Istanbul
University Cerrahpasa, Istanbul, Turkey;jDepartment of Cardiology, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; kDepartment of Cardiology, Canisius-Wilhelmina Hospital, Nijmegen, the Netherlands;lLiverpool Centre for Cardiovascular
Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom;mAalborg Thrombosis Research
Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark;nBoehringer Ingelheim International GmbH,
Ingelheim, Germany;oDepartment of Cardiology, St. Antonius Ziekenhuis, Nieuwegein, the Netherlands; and thepBrigham and
Women’s Hospital Heart and Vascular Center, and Harvard Medical School, Boston, Massachusetts. This work was supported by Boehringer Ingelheim International GmbH, Ingelheim, Germany. Dr. Hohnloser has received personal fees from Bayer Health-care, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Medtronic, Pfizer, St. Jude Medical, and Zoll. Dr. Steg has received research grants from Bayer HealthCare, Merck, Sanofi, and Servier; has received 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. Dr. Oldgren has received fees to his institution from AstraZeneca, Boehringer Ingelheim, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Pfizer, Portola, Roche Diagnostics, and Sanofi. Dr. Nickenig has received personal
A
substantial fraction of patients with atrialfibrillation (AF), ranging from 18% to 60%, have concurrent mild-to-moderate renal dysfunction (1–6).Patients with chronic kidney disease
(CKD) are at high risk for cardiovascular and bleeding events, especially when tak-ing antithrombotic agents. Non–vitamin K oral anticoagulants (NOACs) are partially cleared renally (7–10), so there is a concern about the risk of bleeding in patients with CKD. As dabigatran has the highest rate of renal clearance of all available NOACs, the safety of this NOAC in CKD patients is of major interest. In the past, anticoagulation has often been withheld from patients with AF and renal impairment, despite the need for stroke prevention, because of safety concerns (11–13).
Dabigatran is a direct thrombin inhibitor approved worldwide at doses of 110 mg (excluding the United States) or 150 mg twice daily for the prevention of stroke in AF (14). The RE-DUAL PCI (Randomized
Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy with Warfarin in
Patients with Nonvalvular Atrial Fibrillation
Undergoing Percutaneous Coronary Intervention;
NCT02164864) trial assessed the safety and efficacy of dabigatran dual therapy at doses of 110 mg or 150 mg twice daily (combined with a P2Y12inhibitor) versus warfarin triple therapy (with a P2Y12 inhibitor and acetylsalicylic acid [ASA]) in patients with AF who underwent percutaneous coronary intervention (PCI)
(15). Both doses of dabigatran dual therapy were shown to be noninferior to warfarin triple therapy with regard to International Society on Thrombosis and Haemostasis (ISTH) major bleeding events (MBE) or clinically relevant nonmajor bleeding events (CRNMBE) (p< 0.001 for noninferiority). Both doses combined were also noninferior to warfarin triple therapy with regard to the secondary composite endpoint of death or thromboembolic event (DTE) (myocardial infarction, stroke, or systemic embolism) or unplanned revascularization (p< 0.001 for non-inferiority). In addition, there were significantly fewer ISTH MBE or CRNMBE with dabigatran 110 mg dual therapy versus warfarin (p< 0.001 for superi-ority)(15).
SEE PAGE 1562 A B B R E V I A T I O N S
A N D A C R O N Y M S AF= atrialfibrillation ASA= acetylsalicylic acid CI= confidence interval CKD= chronic kidney disease CrCl= creatinine clearance CRNMBE= clinically relevant nonmajor bleeding event DTE= death or thromboembolic event HR= hazard ratio
ISTH= International Society on Thrombosis and Haemostasis MBE= major bleeding event NOAC= non–vitamin K oral anticoagulant
PCI= percutaneous coronary intervention
fees and grants from Abbott, Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Edwards, Medtronic, Mitratech, Novartis, Pfizer, Sanofi, and Zoll. Dr. Kiss has received honoraria as a speaker from Bayer, Boehringer Ingelheim, Merck Sharp and Dohme, and Pfizer. Dr. Ongen has received advisory-speaker fees from Bayer, Boehringer Ingelheim, and Daiichi-Sankyo. Dr. Navarro Estrada has received advisory-speaker fees from AstraZeneca, Boehringer Ingelheim, and Sanofi. Dr. Oude Ophuis has received advisory, consulting, and speaker fees from Amgen, AstraZeneca, Bristol-Myers Squibb, and Medtronic. Dr. Lip has served as a consultant for Bayer/Janssen, Bristol-Myers Squibb/Pfizer, Medtronic, Boehringer Ingelheim, Novartis, Ver-seon, and Daiichi-Sankyo; and has been a speaker for Bayer, Bristol-Myers Squibb/Pfizer, Medtronic, Boehringer Ingelheim, and Daiichi-Sankyo. Dr. Nordaby and Ms. Kleine are employees of Boehringer Ingelheim International GmbH. Dr. ten Berg has received advisory, consulting, and speaker fees from Accumetrics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Ferrer, The Medicines Company, and Pfizer; and has received research grants from AstraZeneca and ZonMw. Dr. Bhatt has served on the Advisory Board for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, and Regado Biosciences; has served on the Board of Directors for Boston VA Research Institute, Society of Cardio-vascular Patient Care, and TobeSoft; has served as the Chair of the American Heart Association Quality Oversight Committee, NCDR-ACTION Registry Steering Committee, and VA CART Research and Publications Committee; has served on the Data Monitoring Committees for the Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), and Pop-ulation Health Research Institute; has received honoraria from the 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), Medtelligence/ReachMD (CME steering committees), Population Health Research Institute (COMPASS clinical trial steering committee funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Car-diovascular Patient Care (Secretary/Treasurer), WebMD (CME Steering Committees); has served as the Deputy Editor for Clinical Cardiology; has received research funding from 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; has received royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); has served as a site co-investigator for Biotronik, Boston Scientific, St. Jude Medical (now Abbott), and Svelte; has served as a trustee for the American College of Cardiology; and has conducted un-funded research for FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, and Takeda. Dr. Cannon has received research grants from Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Janssen, and Merck; and consulting fees from Alnylam, Amarin, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Janssen, Kowa, Merck, Pfizer, Regeneron, and Sanofi. Manuscript received January 28, 2019; revised manuscript received April 17, 2019, accepted May 21, 2019.
This pre-specified analysis of the RE-DUAL PCI trial evaluated the effect of dabigatran dual therapy versus warfarin triple therapy on outcomes in pa-tients categorized by renal function.
METHODS
TRIAL DESIGN AND TREATMENT. The design and
results of the RE-DUAL PCI trial have been reported previously (15,16). In brief, the trial randomly assigned 2,725 patients to receive dual therapy comprising dabigatran 110 mg or 150 mg twice daily plus either clopidogrel or ticagrelor, or receive triple therapy with warfarin (adjusted to achieve an inter-national normalized ratio of 2.0 to 3.0) plus ASA (#100 mg daily) and either clopidogrel or ticagrelor. Outside the United States, patients$80 years of age ($70 years of age in Japan) were randomized only to the 110-mg dabigatran dose versus warfarin. All pa-tients were to receive clopidogrel (75 mg daily) or ticagrelor (90 mg twice daily) for $12 months after randomization. In the warfarin triple therapy group, ASA was discontinued after 1 month in patients implanted with a bare-metal stent and after 3 months in patients with a drug-eluting stent.
PATIENTS. Men and women $18 years of age with nonvalvular AF who underwent PCI with a bare-metal or drug-eluting stent within the previous 120 h were eligible for study inclusion. The indications for PCI could be either acute coronary syndrome or stable coronary artery disease. Patients with bioprosthetic or mechanical heart values, severe renal insufficiency (creatinine clearance [CrCl]<30 ml/min at screening, calculated by the Cockcroft–Gault equation), or other major coexisting conditions were excluded. For pa-tients randomized to dabigatran treatment whose renal function declined between screening and baseline to<30 ml/min, or who were enrolled into the study despite having CrCl <30 ml/min, either CrCl increased to a value$30 ml/min after enrollment or study medication was discontinued.
ASSESSMENTS. Risk of afirst ISTH MBE or CRNMBE during follow-up (median 12.7 [interquartile range: 9 to 18] months) was evaluated according to the CrCl categories: 30 to<50, 50 to <80, and $80 ml/min, based on analysis of central laboratory samples at the time of randomization. Risk of the composite endpoint of DTE (myocardial infarction, stroke, or systemic embolism) or unplanned revascularization (first event) was also evaluated according to baseline CrCl category.
STATISTICAL ANALYSIS. Clinical characteristics of patients were summarized by baseline CrCl cate-gories. For the comparison of dabigatran 110 mg dual
therapy versus warfarin triple therapy within baseline CrCl categories, stratified Cox proportional hazards regression models were applied, which included age as a stratifying factor (nonelderly vs. elderly [<70 years of age vs. $70 years of age in Japan and <80 years of age vs. $80 years of age elsewhere]) and treatment arm. For the dabigatran 150 mg dual ther-apy versus warfarin triple therther-apy comparison within baseline CrCl categories, corresponding unstratified Cox proportional hazards regression models were applied (excluding patients $80 years of age [$70 years of age in Japan] outside the United States). Exploratory treatment by subgroup interaction p values resulting from Cox proportional hazards regression models were provided. Additionally, for both endpoints, a multivariable Cox proportional hazards regression model including treatment, base-line CrCl, and the interaction between treatment and baseline CrCl was applied to investigate baseline CrCl as a continuous variable. For the comparison of dabigatran 110 mg versus warfarin triple therapy, the model was stratified by age. This analysis was visu-alized with interaction plots displaying the hazard ratios and 95% confidence intervals (CIs) comparing dabigatran 110 or 150 mg versus warfarin for varying values of CrCl.
RESULTS
PATIENT CHARACTERISTICS. In the 2,725 patients randomized in the RE-DUAL PCI trial, the overall mean baseline CrCl was 78.0 29.8 ml/min (Table 1). Baseline CrCl categories of 30 to <50, 50 to <80, and $80 ml/min were recorded in 347 (12.7%), 1,114 (40.9%), and 1,013 (37.2%) patients, respectively. Pa-tient characteristics for these 2,474 paPa-tients are shown in Table 2 according to baseline CrCl and in
Online Table 1 additionally according to treatment group. The majority of patients were men, although the proportion of women tended to increase with the degree of renal impairment. As expected, the mean age at baseline was higher in the more severe cate-gories of renal impairment. Patients with more severe renal impairment were also more likely to have experienced a previous stroke. CrCl data were missing in 232 (8.5%) patients and 19 (0.7%) patients had renal function<30 ml/min at baseline. The baseline char-acteristics for these patients, who were excluded from the current analysis, are shown inOnline Table 2. BLEEDING EVENTS. The risk of MBE or CRNMBE was reduced by dabigatran 110 mg dual therapy compared with warfarin triple therapy in all categories of CrCl evaluated (Figure 1), with an exploratory treatment-by-CrCl subgroup interaction p value of 0.19. For
dabigatran 150 mg dual therapy versus warfarin triple therapy, the exploratory treatment-by-CrCl subgroup interaction p value was 0.31, indicating a consistent treatment effect across all evaluated CrCl categories. The minor variations in bleeding events across CrCl categories may be attributed to unbalanced numbers of patients. Considering CrCl as a continuous variable led to similar results. For varying values of CrCl
ranging from 30 to 200 ml/min, the hazard ratios (HRs) and their 95% CIs were always below the reference line of 1.0 when comparing dabigatran 110 mg dual therapy versus warfarin triple therapy (Central Illustration) (interaction p value¼ 0.20). For dabigatran 150 mg dual therapy (Central Illustration), HRs and their 95% CIs were below the reference line for CrCl values>60 ml/min, whereas the upper con-fidence limits exceeded 1.0 for CrCl values #60 ml/min (interaction p value¼ 0.14).
THROMBOEMBOLIC EVENTS. The risk of the
com-posite endpoint of DTE or unplanned revasculariza-tion was similar between dabigatran 110 mg dual therapy and warfarin triple therapy across CrCl cate-gories (Figure 2) (p for interaction ¼ 0.30). Risk of thromboembolic events was similar between dabiga-tran 150 mg dual therapy and warfarin triple therapy in CrCl level categories 30 to<50 ml/min (HR: 1.55; 95% CI: 0.63 to 3.79) and 50 to<80 ml/min (HR: 1.31; 95% CI: 0.83 to 2.07), and was lower for dabigatran 150 mg dual therapy in the CrCl$80 ml/min category (HR: 0.56; 95% CI: 0.36 to 0.88), yielding a treatment interaction p value of 0.02 (Figure 2). A similar trend was also observed in the interaction plot for the comparison of dabigatran 150 mg dual therapy versus warfarin triple therapy (Central Illustration). The HRs were below the reference line for high CrCl values and above for lower CrCl values, with some wider CIs for the extreme low and high CrCl values (interaction p value ¼ 0.07). For dabigatran 110 mg dual therapy, this trend was less pronounced (Central Illustration) (interaction p value¼ 0.46).
The p values for interaction for individual bleeding events (MBE alone or CRNMBE alone) (Figure 3) or individual thromboembolic outcomes (including DTE, unplanned revascularization, stent thrombosis, TABLE 2 Patient Characteristics According to Baseline CrCl
Baseline CrCl 30 to<50 ml/min (n¼ 347) 50 to<80 ml/min (n¼ 1,114) $80 ml/min (n¼ 1,013)
Baseline CrCl value, ml/min 42.0 5.3 65.0 8.2 105.7 25.5
Male 203 (58.5) 819 (73.5) 870 (85.9) Age, yrs 78.3 6.1 73.4 6.7 65.2 7.8 Age group Elderly* 161 (46.4) 225 (20.2) 25 (2.5) Nonelderly† 186 (53.6) 889 (79.8) 988 (97.5) Diabetes mellitus 134 (38.6) 388 (34.8) 375 (37.0) Previous MI 90 (25.9) 288 (25.9) 259 (25.6) Previous CAD 238 (68.6) 752 (67.5) 659 (65.1) Previous PCI 117 (33.7) 389 (34.9) 324 (32.0) Baseline AF Paroxysmal 148 (42.7) 577 (51.8) 512 (50.5) Persistent 69 (19.9) 189 (17.0) 181 (17.9) Permanent 130 (37.5) 348 (31.2) 319 (31.5) Previous stroke 38 (11.0) 103 (9.2) 65 (6.4)
Modified HAS-BLED score 3.0 0.6 2.8 0.6 2.4 0.7
CHA2DS2-VASc score 4.6 1.3 3.9 1.5 3.0 1.5
Values are mean SD or n (%). *Elderly: $70 years of age for Japanese and $80 yrs of age for non-Japanese patients.†Nonelderly: <70 years of age for Japanese and <80 years of age for non-Japanese patients.
AF¼ atrial fibrillation; CAD ¼ coronary artery disease; CHA2DS2-VASc¼ congestive heart failure, hypertension, age$75 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age 65–74 years, sex category; CrCl ¼ creatinine clearance; HAS-BLED ¼ hypertension, abnormal renal or liver function, stroke, bleeding, labile international normalized ratio, elderly, drugs or alcohol; MI¼ myocardial infarction; PCI¼ percutaneous coronary intervention.
TABLE 1 Baseline CrCl According to Treatment Group
Dabigatran 110 mg Dual Therapy (n¼ 981) Warfarin Triple Therapy (n¼ 981) Dabigatran 150 mg Dual Therapy (n¼ 763) Warfarin Triple Therapy (n¼ 764)* Total (N¼ 2,725) Baseline CrCl value n 890 901 702 701 2,493 Mean SD, ml/min 76.3 28.9 75.4 29.1 83.7 31.0 81.3 29.6 78.0 29.8
Median (range), ml/min 71.9 (20–198) 69.8 (21–294) 79.3 (28–249) 76.2 (24–294) 73.0 (20–294) Baseline CrCl categories <30 ml/min† 11 (1.1) 6 (0.6) 2 (0.3) 3 (0.4) 19 (0.7) 30 to<50 ml/min 139 (14.2) 137 (14.0) 71 (9.3) 69 (9.0) 347 (12.7) 50 to<80 ml/min 393 (40.1) 435 (44.3) 286 (37.5) 315 (41.2) 1,114 (40.9) $80 ml/min 347 (35.4) 323 (32.9) 343 (45.0) 314 (41.1) 1,013 (37.2) Missing 91 (9.3) 80 (8.2) 61 (8.0) 63 (8.2) 232 (8.5)
Values are n (%), unless otherwise indicated. *For the comparison with dabigatran 150 mg dual therapy, patients$80 years of age ($70 yrs of age in Japan) outside the United States were excluded.†Patients whose renal function declined between screening and baseline or who were enrolled although meeting respective exclusion criterion.
stroke, and myocardial infarction) (Online Figure 1) were all statistically nonsignificant. Outcomes in pa-tients with CrCl<30 ml/min are shown inOnline Table 3. DISCUSSION
The main finding of the present prospectively
designed subanalysis of the RE-DUAL PCI trial is that dual therapy with dabigatran 110 mg and a P2Y12 in-hibitor reduced the risk of ISTH MBE or CRNMBE compared with warfarin triple therapy consistently across all categories of renal impairment (defined as CrCl of 30 to<50, 50 to <80, and $80 ml/min). A similar beneficial effect on the risk of MBE or CRNMBE was observed for dabigatran 150 mg dual therapy compared with warfarin triple therapy, with slight variations in the single categories.
Renal function is often impaired in patients with AF and coronary disease and the incidence of impaired kidney function increases with age. From prior studies, it is well known that impaired kidney function is associated with an increased incidence of cardiovascular events, including stroke, mortality, and severe bleeding(6,17). For instance, Olesen et al.
(17)reported a significant increase in the risk of stroke or systemic embolic events (HR: 1.49; 95% CI: 1.38 to 1.59), bleeding events (HR: 2.24; 95% CI: 2.10 to 2.38), and death (HR: 2.37; 95% CI: 2.30 to 2.44) in a large
cohort of AF patients with concurrent non–end-stage renal disease compared with those without renal impairment. As all NOACs are excreted via the kid-neys—with dabigatran having the highest renal excretion rate of all 4 compounds(7–10)—it is partic-ularly relevant to evaluate the association of out-comes of anticoagulation regimens in AF patients undergoing coronary interventions. In the RE-DUAL PCI trial, dual therapy with dabigatran and a P2Y12 antagonist significantly reduced the risk of bleeding (ISTH-defined MBE or CRNMBE) compared with warfarin triple therapy, with noninferiority for over-all thromboembolic events (15). The present
sub-analysis confirmed this safety profile by
demonstrating consistentfindings across all levels of impaired kidney function. The safety of
dabigatran-based dual antithrombotic therapy is further
enhanced by the availability of a specific reversal agent for this anticoagulant(18).
In accordance with the main trial results, there was no relevant difference in the risk of thromboembolic events between dabigatran 110 mg dual therapy versus warfarin triple therapy across the different degrees of renal function (interaction p value> 0.05). However, we acknowledge the potential for a type II error for this finding. Interestingly, there was an interaction p value of 0.02 for dabigatran 150 mg dual therapy versus warfarin triple therapy, with a FIGURE 1 Risk of ISTH MBE or CRNMBE by Treatment Group and Baseline CrCl Category
Hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox proportional hazards model; stratified by age (elderly vs. nonelderly) for 110-mg dabigatran dual therapy versus warfarin triple therapy; unstratified for 150-110-mg dabigatran dual therapy versus warfarin triple therapy. *For the comparison with 150-mg dabigatran dual therapy, elderly patients outside the United States$80 years of age ($70 years of age in Japan) were excluded. CrCl¼ creatinine clearance; CRNMBE ¼ clinically relevant nonmajor bleeding event; ISTH ¼ International Society on Thrombosis and Haemostasis; MBE¼ major bleeding event.
numerically lower risk of thromboembolic events in patients with CrCl$80 ml/min.
Our findings from the RE-DUAL PCI trial are
consistent with data described in previous dabigatran studies in patients with AF and mild or moderate
renal impairment (19,20). The pivotal RE-LY
(Randomized Evaluation of Long-term
Anti-coagulation Therapy) trial demonstrated that patients with CKD were at higher risk of stroke or systemic embolism, major bleeding, and all-cause mortality as renal function decreased, irrespective of treatment. When compared with warfarin, the rates of stroke or
CENTRAL ILLUSTRATION Interaction Plots for Comparison of Dabigatran 110 mg and 150 mg Dual Therapy Versus Warfarin Triple Therapy for Varying Values of CrCl
1.5 1.0 0.5 0.0 1.5 1.0 0.5 0.0 40 60 80 100 120 140 160 180 200 40 60 80 100 120 140 160 180 200 Hazard R a tio Hazard R a tio
Dabigatran 110 mg Dual Therapy
Versus Warfarin Triple Therapy
3.0 2.0 2.5 1.0 0.5 1.5 0.0 Hazard R a tio
Dabigatran 110 mg Dual Therapy
Versus Warfarin Triple Therapy
C
A
D
B
3.0 2.0 2.5 1.0 0.5 1.5 0.0 Hazard R a tioDabigatran 150 mg Dual Therapy
Versus Warfarin Triple Therapy
Dabigatran 150 mg Dual Therapy
Versus Warfarin Triple Therapy
CrCl (mL/min) 40 60 80 100 120 140 160 180 200 CrCl (mL/min) 40 60 80 100 120 140 160 180 200 CrCl (mL/min) CrCl (mL/min)
Adjudicated ISTH MBE or CRNMBE
Adjudicated DTE/Unplanned Revascularization
Hohnloser, S.H. et al. J Am Coll Cardiol Intv. 2019;12(16):1553–61.
Hazard ratios and Wald confidence limits from Cox proportional hazard model including treatment, CrCl, and interaction between treatment and CrCl. For the comparison with dabigatran 110 mg dual therapy, the model is stratified by age: nonelderly versus elderly (<70 or $70 years in Japan and <80 or $80 years elsewhere). For the comparison with dabigatran 150 mg dual therapy, elderly patients outside the US are excluded. Patients with missing CrCl or CrCl<30 ml/min are excluded from the analyses. Patients with CrCl>200 ml/min are included in the model calculation but not displayed. CrCl ¼ creatinine clearance; CRNMBE ¼ clinically relevant nonmajor bleeding event; DTE¼ death or thromboembolic event; ISTH ¼ International Society on Thrombosis and Haemostasis; MBE ¼ major bleeding event.
FIGURE 2 Risk of Death or Thromboembolic Event or Unplanned Revascularization by Treatment Group and Baseline CrCl Category
HRs and 95% CIs from Cox proportional hazards model; stratified by age (elderly vs. nonelderly) for 110-mg dabigatran dual therapy versus warfarin triple therapy; unstratified for 150-mg dabigatran dual therapy versus warfarin triple therapy. Thromboembolic events included myocardial infarction, stroke, and systemic embolism.*For the comparison with 150-mg dabigatran dual therapy, elderly patients outside the United States$80 years of age ($70 years of age in Japan) were excluded. Abbreviations as inFigure 1.
FIGURE 3 Individual Bleeding Events by Baseline CrCl Category
HRs and 95% CIs from Cox proportional hazards model; stratified by age (elderly vs. nonelderly) for 110-mg dabigatran dual therapy versus warfarin triple therapy; unstratified for 150-mg dabigatran dual therapy versus warfarin triple therapy. *For the comparison with 150-mg dabigatran dual therapy, elderly patients outside the United States$80 years of age ($70 years of age in Japan) were excluded. Abbrevi-ations as inFigure 1.
systemic embolism were similar for dabigatran 110 mg and were lower for dabigatran 150 mg, without sta-tistically significant heterogeneity in subgroups of renal function (20). More recently, practice-based data confirmed these findings; the risk of MBE was lower in subjects treated with dabigatran 110 mg and was similar for dabigatran at 150 mg when compared with warfarin patients with AF and concurrent mild-to-moderate renal function (GFR 30 to 89 ml/min)—a benefit for dabigatran over warfarin was suggested, although there was heterogeneity of treatment effects by baseline renal function(19).
As recently stated in a North American consensus document, NOACs should be dosed according to the dosages used in the trials of patients with AF under-going PCI(21). Based on the RE-DUAL PCI main study
(15)and the present subgroup analysis, it appears to be reasonable to use dabigatran 150 mg dual therapy in patients considered to be at higher thrombotic risk. By contrast, the 110-mg regimen may be preferred in patients deemed to be at higher bleeding risk. This seems to apply for all ranges of renal function eval-uated in this analysis.
There is accumulating evidence supporting the use of dual rather than triple therapy in patients with AF undergoing PCI, supported by data from the WOEST (What is the Optimal antiplatElet & Anticoagulant Therapy in Patients With Oral Anti-coagulation and Coronary StenTing) and PIONEER AF-PCI (A Study Exploring Two Strategies of Rivar-oxaban [JNJ39039039; BAY-59-7939] and One of Oral Vitamin K Antagonist in Patients With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention) studies (22–24). In the WOEST trial, dual therapy (oral anticoagulant plus clopidogrel)
significantly reduced bleeding complications
compared with triple therapy (oral anticoagulant, clopidogrel, and ASA), with no increase in the rate of thrombotic events (22). In the PIONEER AF-PCI
trial, rivaroxaban dual therapy significantly
reduced bleeding events and had similar efficacy when compared with warfarin triple therapy (23). However, neither of these studies provided data stemming from patients with impaired renal func-tion. Analyses by renal function of these trials, and of the recently completed AUGUSTUS (A Study of Apixaban in Patients With Atrial Fibrillation, Not Caused by a Heart Valve Problem, Who Are at Risk for Thrombosis [Blood Clots] Due to Having Had a Recent Coronary Event, Such as a Heart Attack or a Procedure to Open the Vessels of the Heart)(25)and the ongoing ENTRUST-AF-PCI (Edoxaban Treatment
Versus Vitamin K Antagonist in Patients With Atrial
Fibrillation Undergoing Percutaneous Coronary
Intervention; NCT02866175) studies, will help to further define optimal antithrombotic therapy in AF patients undergoing coronary interventions.
STUDY LIMITATIONS. This is a prospectively
designed substudy of the RE-DUAL PCI trial. As such, our observations should be considered hypothesis generating rather than definitive. Nevertheless, this is the largest analysis of the association between impaired kidney function and clinical outcomes in AF patients undergoing coronary interventions. The interaction p values can only be regarded as explor-atory (i.e., the RE-DUAL trial was not powered for this analysis). Additionally, the sample size across the CrCl categories was not balanced. In particular, the group of patients with moderate renal impairment was very small, as there were only 347 patients with a CrCl of 30 to<50 ml/min. This limitation, however, is shared in common with other subgroup analyses of similar studies, such as the PIONEER study (23). A much larger study would have been necessary to demonstrate noninferiority or superiority within subgroups. Clearly, such a large study was deemed not to be feasible.
CONCLUSIONS
This pre-specified subgroup analysis from the RE-DUAL PCI trial shows that dabigatran dual therapy at both 110- and 150-mg doses reduced bleeding events compared with warfarin triple therapy across all ranges of renal function, with overall similar risks of thromboembolic events but lower risks with dabi-gatran 150 mg in patients with normal CrCl.
ACKNOWLEDGMENTSEditorial assistance with
formatting and figure preparation was provided by Bill Wolvey at Parexel, with funding from Boehringer Ingelheim International GmbH. Assistance with sta-tistical analyses was provided by Corinna Miede, an employee of HMS Analytical Software contracted by Boehringer Ingelheim International GmbH. Assis-tance with programming was provided by Clemens
Tilke from Boehringer Ingelheim International
GmbH.
ADDRESS FOR CORRESPONDENCE: Dr. Stefan H.
Hohnloser, Department of Cardiology, Johann Wolf-gang Goethe University, Theodor Stern Kai 7, Building 23A, 60590 Frankfurt am Main, Germany. E-mail:
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KEY WORDS atrialfibrillation, dabigatran dual therapy, percutaneous coronary intervention, renal function, warfarin triple therapy
APPENDIX For supplemental tables and a figure, please see the online version of this paper.
PERSPECTIVES
WHAT IS KNOWN?Dabigatran dual therapy (110 or 150 mg twice daily) was shown to reduce risk of bleeding events compared with warfarin triple therapy in the RE-DUAL PCI trial of atrialfibrillation patients who under-went percutaneous coronary intervention, with similar risk of thromboembolic events.
WHAT IS NEW?This subanalysis of the RE-DUAL PCI trial assessed bleeding and thromboembolic events in patients according to baseline CrCl categories: 30 to<50, 50 to<80, and $80 ml/min. We found that dabigatran
dual therapy reduced bleeding events versus warfarin triple therapy irrespective of renal function, with overall similar risks of thromboembolic events, consistent with the main RE-DUAL PCI trial.
WHAT IS NEXT?From these results, it appears reasonable to use dabigatran 150 mg dual therapy in patients considered to be at higher thrombotic risk; by contrast, the 110-mg regimen may be preferred in pa-tients deemed to be at higher bleeding risk.
