Abstract
Aims
The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial allowed patients who completed the trial receiving their assigned dabigatran 150 mg (D150) or 110 mg (D110) twice a day to continue into the Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) trial. This permitted assessment of outcomes over a median of 4.6 and a maximum of 6.7 years, respectively.
Methods and results
The analysed population included only those patients who completed RE-LY on dabigatran and continued into RELY-ABLE without interruption of assigned dabigatran. Cumulative risk was expressed as Kaplan–Meier plots. Outcomes were compared using Cox proportional hazard modelling. Stroke or systemic embolization rates were 1.25 and 1.54% per year (D150 and D110, respectively); hazard ratio (HR) 0.81 [95% confidence interval (CI): 0.68–0.96] (P = 0.02). Ischaemic stroke was 1.03 (D150) and 1.29%/year (D110); HR 0.79 (95% CI: 0.66–0.95) (P = 0.01). Haemorrhagic stroke rates were 0.11 (D150) and 0.13%/year (D110); HR 0.91 (95% CI: 0.51–1.62) (P = 0.75). Rates of major haemorrhage were 3.34 (D150) and 2.76%/year (D110); HR 1.22 (95% CI: 1.08–1.37) (P = 0.0008). Intracranial haemorrhage rates were 0.32 (D150) and 0.23%/year (D110); HR 1.37 (95% CI: 0.93–2.01) (P = 0.11). Mortality was 3.43 (D150) and 3.55%/year (D110); HR 0.97 (95% CI: 0.87–1.08) (P = 0.54).
Conclusion
Annualized rates of all outcomes were constant with better efficacy of D150, less major bleeding with D110, and low intracerebral haemorrhage rates for both doses. There were no additional safety concerns. This is the longest continuous randomized experience of a novel anticoagulant.
Keywords: Atrial fibrillation, Stroke, Dabigatran etexilate, Long-term outcome
What's new?
This report describes the longest continuous randomized experience of any target-specific oral anticoagulant.
The annualized rates for all outcomes were constant over a mean of 4.6 years and a maximum of 6.7 years.
Compared to warfarin, dabigatran 150mg BID had better efficacy and dabigatran 110mg BID had less major extracranial bleeding. Intracerebral hemorrhage rates on both dabigatran doses were low.
Introduction
Atrial fibrillation (AF) increases the risk of ischaemic stroke, systemic embolization (SE), and death.1,2 Thus, life-long oral anticoagulant therapy is usually indicated to reduce stroke risk.1,2 Recently, several new oral anticoagulants have been approved because of either greater efficacy or safety and for convenience compared with vitamin K antagonists (VKAs) for stroke prevention in AF.3–6 The longest follow-up for these trials has been a median of 2.8 years.7
Dabigatran etexilate is a direct thrombin inhibitor. It is a prodrug which is rapidly converted by serum esterases to its active metabolite dabigatran. The half-life is ∼12–17 h. Renal clearance accounts for 80% of total elimination.8 The Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial allocated 18 113 patients with AF to receive either of two blinded fixed doses of dabigatran 110 mg (D110) or 150 mg (D150) twice a day (bid) or unblinded, adjusted-dose warfarin.3,9 Dabigatran 150 mg bid was superior (by 35%) to warfarin for prevention of stroke or SE with a similar rate of major bleeding and D110 mg bid was non-inferior to warfarin with a lower rate of bleeding.3,10 The mean duration of observation in RE-LY was 2.0 years with a maximum duration of 3 years.3 Patients completing the RE-LY trial on dabigatran were allowed into the Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) study, which provided additional follow-up data on both doses of dabigatran (double blind).10 Both RE-LY and RELY-ABLE results have been published separately.3,7 We are reporting a pre-planned analysis consisting only of patients who were randomized into RELY and completed RE-LY on their assigned dose of dabigatran and entered RELY-ABLE without interruption of their dabigatran. This provided a median and maximum follow-up of 4.6 and 6.7 years, respectively.
Methods
Analysed population
The analysed population therefore began with patients (n = 12 091) who were randomized to dabigatran in the RE-LY trial, then observed for a maximum of 3 years and completed (n = 9011) RE-LY, and then transitioned to RELY-ABLE without any interruption of assigned dabigatran (n = 5851) (Figure 1). The reduction from 9011 patients completing RE-LY to 5851 entering RELY-ABLE is due to the fact that some eligible patients were administratively excluded because of non-participation in RELY-ABLE by their respective countries (35 of 44 RE-LY countries participated in RELY-ABLE; non-participating countries were Turkey, Ukraine, Spain, Argentina, Mexico, Peru, Colombia, Japan, and South Africa), or by non-participation in RELY-ABLE by certain sites (571 of 951 RE-LY sites participated in RELY-ABLE), or because some individual patients opted not to participate in RELY-ABLE (898 patients did not participate). In addition, the RELY-ABLE protocol allowed interruption of dabigatran treatment for up to 8 weeks after the final RE-LY study visit, during which time patients could be treated at the discretion of the local investigator. This period of interruption was not included in the analysed population (Figure 1).
Figure 1.
Patient disposition over time. The maximum observation period was 6.7 years; the median, 4.6 years.
Thirty-two patients from two sites that were closed prematurely for non-compliance and eight patients who entered RELY-ABLE but did not receive treatment were excluded. Thus, for this analysis, a total of 3160 patients who completed RE-LY on dabigatran were excluded. The inclusion and exclusion criteria for RE-LY and RELY-ABLE have been described.8,11 Patients provided written informed consent for both RE-LY and RELY-ABLE. Patients randomized to warfarin in RE-LY were not eligible for RELY-ABLE.
Patient follow-up
Patients were enrolled in RE-LY from December 2005 to December 2007. The final RE-LY study visits occurred between December 2008 and March 2009. Patients continued into RELY-ABLE beginning at their final RE-LY visit. The RELY-ABLE trial opened on 16 December 2008. RELY-ABLE visits occurred at 4, 8, 13, 18, and 23 months. The final visit was scheduled at 28 months after study enrolment in RELY-ABLE, with the last patient last visit scheduled for 12 December 2012.7 However, in some countries, dabigatran was not approved for stroke prevention in AF at the time of the 28-month visit. The period of observation was extended for these patients (n = 2188). These data were included in this analysis, allowing a maximum of 6.7 years of continuous evaluation.
Definition of outcome events
All efficacy and safety endpoints were documented. For the RE-LY time period, these endpoints were adjudicated. During RELY-ABLE, these data were documented by the local investigators. The efficacy and safety outcomes in the long-term analysis, RE-LY, and RELY-ABLE were identical. Efficacy outcomes were stroke (ischaemic, haemorrhagic, or unspecified), systemic embolism, myocardial infarction, hospitalization, vascular mortality, and total mortality. Safety outcomes were major, life-threatening, gastrointestinal (GI), intracranial, extra-cranial, minor, and fatal bleeding. Major bleeding was defined as bleeding associated with a reduction in haemoglobin of at least 20 g/L or leading to a transfusion of at least two units of blood or packed cells or symptomatic bleeding into a critical area or organ. Major bleeds were classified as life-threatening if they met any of the following: fatal, symptomatic, intracranial, haemoglobin reduction ≥50 g/L, transfusion ≥4 units, associated with hypotension requiring intravenous inotropic agents, or necessitating surgical intervention. Minor bleeds were any other clinical bleeds that did not meet the criteria for major bleeds. Unlike RE-LY, there was no adjudication of outcome events in RELY-ABLE.
Statistical analysis
The annual rates of efficacy and safety endpoints were assessed in patients receiving the blinded dose of D150 or D110 mg in the analysed population. Cumulative risk is represented over the entire period of observation by Kaplan–Meier plots. Patients who had experienced an outcome event during RE-LY or RELY-ABLE and then returned to their assigned therapy were included in the time-to first-event analyses for other outcome events. All patients in the RELY-ABLE phase who permanently discontinued study medication were censored at the time of permanent discontinuation. RELY-ABLE patients on treatment were censored at their normal termination date, defined by the date that dabigatran became commercially available. Cox proportional hazard modelling was used to compare the outcomes of patients receiving D150 or D110. The characteristics of patients completing RELY on drug were compared with those who then continued into RELY-ABLE, to evaluate a potential selection effect of patients who contributed with additional years to the analysis period.
Study conduct
The RE-LY and RELY-ABLE studies were sponsored by Boehringer Ingelheim GmbH & Co. KG and were coordinated at the Population Health Research Institute at McMaster University in Hamilton, Ontario, which independently managed the database and performed the primary data analysis. An operations committee was responsible for the design, conduct, and reporting of the studies. The studies were approved by all appropriate national regulatory authorities and ethics committees of the participating centres and all subjects gave written informed consent. All authors had complete access to the primary clinical trial data and had final responsibility for the decision to submit for publication. Both trials were registered at clinicaltrials.gov (RE-LY: NCT00262600; RELY-ABLE: NCT00808067).
Results
Efficacy outcomes
The annual rate of stroke or systemic embolism in RELY-ABLE was consistent with RE-LY (Table 1 and Figure 2) and was lower on D150 bid compared with D110 bid, 1.25 and 1.54%/year respectively [HR 0.81, 95% confidence interval (CI): 0.68–0.96] (P = 0.01). The rates of all stroke were lower on D150 compared with D110, 1.12 and 1.41%/year, respectively (HR 0.79, 95% CI: 0.66–0.95) (P = 0.01). Specifically, ischaemic stroke rates, 1.03 and 1.29%/year, were lower on D150 (HR 0.79, 95% CI: 0.66–0.95) (P = 0.01). Haemorrhagic stroke (Figure 3) rates were low and similar on either dose of dabigatran, 0.11 and 0.13%/year on D150 and D110, respectively (HR 0.91, 95% CI: 0.51–1.62) (P = 0.75). The rates of myocardial infarction were similar on D150 and D110, 0.69 and 0.72%/year (HR 0.96, 95% CI: 0.76–1.22) (P = 0.75). The rates of vascular mortality were also similar on either dose, 2.05 and 2.12%/year (HR 0.97, 95% CI: 0.84–1.11) (P = 0.63). The rates of all-cause mortality (Figure 4) were similar by dose and represented the highest major event rate, 3.43 and 3.55%/year on D150 and D110, respectively (HR 0.97, 95% CI: 0.87–1.08) (P = 0.54).
Table 1.
Long-term annualized efficacy and safety outcomes
| Dabigatran 150 mg, n (%/year) | Dabigatran 110 mg, n (%/year) | Hazard ratio (D150 vs. D110) | 95% CI | P-Value | |
|---|---|---|---|---|---|
| Efficacy outcomes | |||||
| Stroke or systemic embolism | 243 (1.25) | 296 (1.54) | 0.81 | 0.68–0.96 | 0.01 |
| All stroke | 217 (1.12) | 270 (1.41) | 0.79 | 0.66–0.95 | 0.01 |
| Ischaemic or type uncertain | 199 (1.03) | 248 (1.29) | 0.79 | 0.66–0.95 | 0.01 |
| Myocardial infarction | 134 (0.69) | 138 (0.72) | 0.96 | 0.76–1.22 | 0.75 |
| Cardiovascular hospitalization | 1484 (7.66) | 1401 (7.30) | 1.06 | 0.99–1.14 | 0.09 |
| Any hospitalization | 3133 (16.18) | 3045 (15.87) | 1.05 | 1.00–1.10 | 0.06 |
| Total mortality | 665 (3.43) | 681 (3.55) | 0.97 | 0.87–1.08 | 0.54 |
| Vascular mortality | 397 (2.05) | 407 (2.12) | 0.97 | 0.84–1.11 | 0.63 |
| Safety outcomes | |||||
| Haemorrhagic stroke | 22 (0.11) | 24 (0.13) | 0.91 | 0.51–1.62 | 0.75 |
| Major bleeding | 646 (3.34) | 529 (2.76) | 1.22 | 1.08–1.37 | 0.00081 |
| Life-threatening | 300 (1.55) | 261 (1.36) | 1.14 | 0.97–1.35 | 0.12 |
| Gastrointestinal | 291 (1.50) | 242 (1.26) | 1.19 | 1.01–1.42 | 0.05 |
| Intracranial | 62 (0.32) | 45 (0.23) | 1.37 | 0.93–2.01 | 0.11 |
| Extra-cranial | 589 (3.04) | 495 (2.58) | 1.18 | 1.05–1.33 | 0.00554 |
| Fatal | 45 (0.23) | 42 (0.22) | 1.06 | 0.70–1.62 | 0.78 |
| Minor bleeding | 2127 (10.98) | 1884 (9.82) | 1.15 | 1.08–1.22 | <0.00001 |
Figure 2.
Cumulative risk of stroke or systemic embolism over time.
Figure 3.
Cumulative risk of haemorrhagic stroke over time.
Figure 4.
All-cause total mortality over time.
Safety outcomes
The rate of major bleeding (Table 1 and Figure 5) was higher on D150 compared with D110, 3.34 and 2.76%/year (HR 1.22, 95% CI: 1.08–1.37) (P = 0.0008). The rates of intracranial bleeding were similar for both doses, 0.32 and 0.23%/year on D150 and D110, respectively (HR 1.37, 95% CI: 0.93–2.01) (P = 0.11). Most major bleeding was extra-cranial and higher on D150. The rates of extra-cranial bleeding were 3.04 and 2.48%/year on D150 and D110, respectively (HR 1.18, 95% CI: 1.05–1.33) (P = 0.01). Gastrointestinal bleeding (Figure 6) was higher on D150 compared with D110, 1.50 and 1.26%/year (HR 1.19, 95% CI: 1.01–1.42) (P = 0.05). Life-threatening bleeding was higher on D150 but did not reach significance, 1.55 compared with 1.36%/year on D110 (HR 1.14, 95% CI: 0.97–1.35) (P = 0.12). The rates of fatal bleeding were very low and similar by dose, 0.23 and 0.22%/year on D150 and D110, respectively (HR 1.06, 95% CI: 0.70–1.62) (P = 0.78). The total mortality rate was 3.43 (D150) and 3.55%/year (D110), HR 0.97 (95% CI: 0.87–1.08, P = 0.54).
Figure 5.
Cumulative risk of major bleeding over time.
Figure 6.
Cumulative risk of major GI bleeding over time.
Dyspepsia
During the total 6.7-year follow-up period, dyspepsia symptoms were reported in 602 (10.0%) and 569 (9.4%) of patients on D110 and D150, respectively. During RELY-ABLE, a questionnaire was administered designed to describe methods used to relieve dyspepsia symptoms (Table 2). The most commonly used methods were the use of a proton pump inhibitor or taking dabigatran with meals, with symptomatic improvement in more than 85% of patients.
Table 2.
Measures used to relieve dyspepsia symptoms in RELY-ABLE patients
| Measures taken to alleviate dyspepsia | Dabigatran 110 mg |
Dabigatran 150 mg |
||||
|---|---|---|---|---|---|---|
| Number of patients | Symptoms improved, n (%) | Symptoms not improved, n (%) | Number of patients | Symptoms improved, n (%) | Symptoms not improved, n (%) | |
| Proton pump inhibitor | 272 | 248 (91.2) | 23 (8.5) | 240 | 213 (88.8) | 27 (11.3) |
| H2 blocker | 43 | 40 (93.0) | 3 (7.0) | 61 | 50 (82.0) | 11 (18.0) |
| Non-prescription Antacids | 68 | 67 (98.5) | 1 (1.5) | 56 | 50 (89.3) | 6 (10.7) |
| Discontinuation of NSAIDS | 1 | 0 | 1 (100.0) | 1 | 1 (100.0) | 0 |
| Discontinuation of ASA | 1 | 1 (100.0) | 0 | 6 | 4 (66.7) | 2 (33.3) |
| Taking dabigatran with meals | 106 | 93 (87.7) | 13 (12.3) | 107 | 95 (88.8) | 12 (11.2) |
| Discontinuation of dabigatran | 6 | 4 (66.7) | 2 (33.3) | 8 | 6 (75.0) | 2 (25.0) |
| No measure taken | 84 | 23 (27.4) | 7 (8.3) | 90 | 25 (27.8) | 5 (5.6) |
| Other | 82 | 71 (86.6) | 9 (11.0) | 65 | 62 (95.4) | 3 (4.6) |
ASA, acetylsalicylic acid; NSAIDS, non-steroidal anti-inflammatory drugs.
Discussion
This long-term pre-planned analysis of AF patients followed without permanent discontinuation of dabigatran for a median of 4.6 and a maximum of 6.7 years reinforces the previously published data of the efficacy and safety of dabigatran evaluated over a shorter duration.3
During RE-LY, most patients who discontinued dabigatran permanently remained in the study. All contributed to the ‘analysed population’. In the RELY-ABLE phase, patients who permanently discontinued assigned therapy for any reason stopped follow-up and were censored. Patients who temporarily stopped and then restarted study medication were not censored. During RELY-ABLE, dabigatran became commercially available in certain countries; patients could start marketed dabigatran at which point their inclusion in this analysis was terminated. The dose prescribed depended on the country label and their physician preferences. The patients entering RELY-ABLE on assigned drug treatment were not substantially different from those who completed RE-LY (see Supplementary material online, Table S1). The Kaplan–Meier plots demonstrate that the relative benefit of D150 over D110 continued for up to 6.7 years for ischaemic stroke. Major and minor bleeding but not life-threatening or fatal bleeding were higher with D150, and all-cause and vascular mortality were not different between the doses, reflecting event rates during RE-LY. An important outcome was the low incidence of stroke and systemic embolism for a patient population with a mean CHADs score of 2.1. Intracerebral bleeds were uncommon. The most frequent event in the analysed population was death. It is important to note that warfarin reduces all-cause mortality by ∼25% compared with placebo and that D150 and D110 reduces mortality by 12 and 9%, respectively, compared with warfarin.10,11
Apart from bleeding, the only notable adverse event observed with dabigatran was dyspepsia. We observed very similar rates of dyspepsia on the two dabigatran doses. It has been previously reported that dyspepsia occurring during RE-LY was mostly mild or moderate and that the most common dyspeptic symptom reported was gastroesophageal reflux disease.12 A questionnaire was administered during the RELY-ABLE phase to determine which treatments were used to manage symptoms of dyspepsia. Proton pump inhibitors were effective. The analysis was limited, as it was administered late in RELY-ABLE.
This is the longest continuous experience of any novel oral anticoagulant and documents no additional safety concerns as well as constant annualized event rates over the entire time period of observation.
Supplementary material
Funding
Financial support for research projects was provided by AstraZeneca, GSK, Boehringer Ingelheim, Lundbeck, Novartis, Janssen-Cilag, Sanofi-Aventis, Syngis, and Talecris. The Department of Neurology at the University Duisburg-Essen received research grants from the German Research Council (DFG), German Ministry of Education and Research (BMBF), European Union, NIH, Bertelsmann Foundation, and Heinz-Nixdorf Foundation.
Conflict of interest: M.D.E. has served as a consultant for AstraZeneca, Eisai, Pozen Inc., Boehringer Ingelheim, ARYx Therapeutics, Pfizer, Sanofi, Bristol-Myers Squibb, Portola, Daiichi Sankyo, Medtronic, Merck, Johnson & Johnson, Gilead, Janssen Scientific Affairs, and Armetheon. He has received research grant support from Boehringer Ingelheim, Bayer, Daiichi Sankyo, Pfizer, and Bristol-Myers Squibb. J.E. has received consulting fees and/or honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myer Squibb, Daiichi Sankyo, Eli-Lilly, GlaxoSmithKline, Pfizer, Janssen, and Sanofi-Aventis. He has received grants and/or in-kind support from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myer Squibb, GlaxoSmithKline, Pfizer, Janssen, and Sanofi-Aventis. J.O. reports receiving consulting and lecture fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer. P.A.R., M.B., and H.N. are employees of Boehringer Ingelheim. A.C. was employee of Boehringer Ingelheim. H.-C.D. received honoraria for participation in clinical trials, contribution to advisory boards or oral presentations from: Abbott, Allergan, AstraZeneca, Bayer Vital, BMS, Boehringer Ingelheim, CoAxia, Corimmun, Covidien, Daiichi Sankyo, D-Pharm, Fresenius, GlaxoSmithKline, Janssen-Cilag, Johnson & Johnson, Knoll, Lilly, MSD, Medtronic, MindFrame, Neurobiological Technologies, Novartis, Novo-Nordisk, Paion, Parke-Davis, Pfizer, Sanofi-Aventis, Schering-Plough, Servier, Solvay, St Jude, Syngis, Talecris, Thrombogenics, WebMD Global, Wyeth, and Yamanouchi.
Supplementary Material
Acknowledgements
Christine Duffy, MSHS, contributed to data collection for this study.
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