Author + information
- Received May 21, 2017
- Revision received July 14, 2017
- Accepted July 25, 2017
- Published online September 18, 2017.
- Miney Paquette, MSca,b,∗ (, )
- Lionel Riou França, PhDc,
- Christine Teutsch, MDd,
- Hans-Christoph Diener, MD, PhDe,
- Shihai Lu, PhDf,
- Sergio J. Dubner, MDg,
- Chang Sheng Ma, MDh,
- Kenneth J. Rothman, DrPHi,
- Kristina Zint, PhDc,
- Jonathan L. Halperin, MDj,
- Menno V. Huisman, MD, PhDk,
- Gregory Y.H. Lip, MDl,m and
- Robby Nieuwlaat, PhDa
- aDepartment of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
- bDepartment of Medicine, Boehringer Ingelheim Ltd., Burlington, Ontario, Canada
- cDepartment of Epidemiology, Boehringer Ingelheim GmbH, Ingelheim am Rhein, Germany
- dDepartment of Medicine, Boehringer Ingelheim GmbH, Ingelheim am Rhein, Germany
- eDepartment of Neurology, University Hospital Essen, Essen, Germany
- fDepartment of Biostatistics and Data Sciences, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut
- gDepartment of Cardiology, Clínica y Maternidad Suizo Argentina, Buenos Aires, Argentina
- hDepartment of Cardiology, Atrial Fibrillation Center, Beijing Anzhen Hospital, Beijing, China
- iRTI Health Solutions, Research Triangle Park, Durham, North Carolina
- jIcahn School of Medicine at Mount Sinai, Mount Sinai School of Medicine, New York, New York
- kDepartment of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands
- lInstitute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom
- mAalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
- ↵∗Address for correspondence:
Ms. Miney Paquette, Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.
Background Guidelines recommend long-term oral anticoagulation therapy for stroke prevention in patients with atrial fibrillation (AF). Treatment discontinuation rates in vitamin K antagonist (VKA)-treated patients are high but may be lower with non-VKA oral anticoagulant agents.
Objectives The goal of this study was to describe and explore predictors of dabigatran etexilate persistence in patients with newly diagnosed AF over 2 years of follow-up.
Methods Consecutive patients newly diagnosed with AF and ≥1 stroke risk factor were followed up for 2 years. Dabigatran nonpersistence was defined as discontinuation of dabigatran for >30 days. A multivariable Cox regression model included region as well as patient clinical and sociodemographic characteristics to explore predictors of nonpersistence.
Results Eligible patients (N = 2,932) took ≥1 dabigatran dose; their mean age was 70.3 ± 10.2 years, and 55.3% were male. The 2-year probability of dabigatran persistence was 69.2%. Approximately 7% switched to a factor Xa inhibitor and 6% to a VKA. Approximately one-third of dabigatran discontinuations were primarily due to serious or nonserious adverse events. Patients from North America had the highest discontinuation risk, and Latin America had the lowest. Minimally symptomatic or asymptomatic AF and permanent AF were associated with a lower risk for dabigatran nonpersistence. Previous proton pump inhibitor use was associated with a higher risk for dabigatran nonpersistence.
Conclusions Probability of treatment persistence with dabigatran after 2 years was approximately 70%. Nearly one-half of the patients who stopped dabigatran switched to another oral anticoagulant agent. Patients from North America, and those with paroxysmal, persistent, or symptomatic AF, may be at a higher risk for discontinuing dabigatran.
Atrial fibrillation (AF) is the most common cardiac arrhythmia. It is a well-documented independent factor for ischemic stroke (1) that is associated with considerable mortality and morbidity (2–4). Current guidelines recommend long-term oral anticoagulant (OAC) therapy for stroke prevention in patients with AF who are at risk for stroke (5). Until 2010, when dabigatran etexilate, the first non–vitamin K oral anticoagulant (NOAC) became available, vitamin K antagonists (VKAs) were the standard anticoagulation therapy for patients with AF. Although VKAs are effective in preventing strokes, treatment discontinuation rates are pronounced, with only 39% to 60% remaining on VKA treatment after 1 year (6–8).
Several factors contribute to suboptimal treatment adherence with VKAs. These factors include narrow therapeutic windows that require frequent laboratory monitoring, a variable dose–response relationship, and interactions with food and medications for comorbid conditions. These problems are diminished with NOACs, which have been endorsed as a Class Ia recommendation in the most recent guidelines for managing patients with AF from the European Society of Cardiology (5), as well as the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society (9).
Medication adherence is defined as the accurate intake of medications based on the dose, frequency, and schedule prescribed (10). A closely related concept, and the main target of the present investigation, is medication persistence, defined as “the duration of time from the initiation to discontinuation of therapy” (11). The evidence evaluating the persistence of VKA and NOAC therapies shows highly variable reports of both persistence and medication adherence, with generally better rates of adherence and persistence with NOACs versus VKAs (12).
Adherence and, particularly, persistence are expected to be affected by various factors, including the incidence of adverse events (AEs). Nonetheless, the reasons for treatment nonpersistence (used interchangeably with treatment discontinuation) in patients taking OACs for stroke prevention have not been extensively described, especially in large prospective patient cohorts.
We therefore sought to describe and assess reasons for nonpersistence with treatment, including those related to AEs. The present global, prospective cohort study aimed to describe dabigatran nonpersistence, with or without subsequent treatment with another OAC, in patients receiving dabigatran and enrolled in the GLORIA-AF (Global Registry on Long-term Oral Anti-thrombotic Treatment in Patients with Atrial Fibrillation) registry program between 2011 and 2014.
The GLORIA-AF registry program enrolled consecutive adult patients with AF seen in routine clinical practice in 44 countries in 5 regions. Sources used to identify a broad range of potential sites and physicians included professional directories, referrals from selected investigators and national coordinators, and sites that had previously worked with the study sponsor that funded the registry. Sites were selected only on the basis of confirmation that they diagnosed and followed up patients with AF; previous research experience was not a prerequisite. Patients were managed according to routine standard practice and were not required to be prescribed any specific OAC or any OAC at all.
Once dabigatran was approved for the indication of stroke prevention in a respective country, countries were immediately approached to start phase II. The time to initiate the study in the countries varied and depended on site identification, regulatory review timelines, and ethical committee reviews at participating sites. Additional details on the design of the GLORIA-AF program have been published previously (13), and baseline characteristics of all eligible patients enrolled in the phase II program have been described elsewhere (14). In phase II of this study, follow-up included only dabigatran-treated patients who were recruited from various outpatient settings, including university and community hospitals as well as specialist and general practice offices. Patients with newly diagnosed documented AF within 3 months of the baseline visit and at least 1 risk factor for stroke according to CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke/transient ischemic attack [TIA], vascular disease, age 65 to 74 years, sex category) criteria (15) were eligible for inclusion into the registry program. Patients with previous VKA therapy for >60 days, AF due to generally reversible causes, and patients with mechanical heart valves were excluded.
Patients who had important protocol violations (e.g., lack of appropriate informed consent, participation in a clinical trial or international registry) or data insufficiently cleaned (i.e., >2 open manual queries) were excluded from analysis. Only patients taking at least 1 dose of dabigatran and who had follow-up data available were included.
Standard electronic case report forms were used to record baseline characteristics, including stroke and bleeding risk factors that constitute the CHA2DS2-VASc (15) and HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly [age ≥65 years], drugs/alcohol concomitantly) scores (16), respectively. Other characteristics included were AF type (paroxysmal, persistent, or permanent), AF-related symptoms based on the European Heart Rhythm Association classification of symptomatic, minimally symptomatic, or asymptomatic (17), antithrombotic treatment, medical history, concomitant medications, and reimbursement status of prescribed OAC. Start and stop dates of antithrombotic therapies and concomitant medications were recorded by the treating physician based on information included in the patient source data records.
Index therapy was the treatment prescribed for long-term anticoagulation therapy after the diagnosis of AF and recorded at the baseline visit. At follow-up intervals (approximately 3, 6, 12, and 24 months after baseline), changes to medical conditions, antithrombotic treatment changes, and all serious adverse events (SAEs), interventions, and adverse drug reactions, including major and life-threatening bleeding events, were recorded. The primary and mutually exclusive reasons for discontinuing index dabigatran treatment were also captured. Physicians could choose 1 reason from a pre-specified list that included bleeding events, alcohol intake, dementia, AEs, dyspepsia, hypersensitivity, drug interactions, cost, or “other” if the former options did not apply.
Therapy nonpersistence was defined in 2 ways to characterize the probability of discontinuing the index dabigatran therapy: 1) dabigatran nonpersistence—patients who stop index dabigatran treatment (for >30 days) during the follow-up period or switch to another OAC within 30 days; or 2) dabigatran nonpersistence without switching—subgroup of patients from the first group who stop index dabigatran treatment (for >30 days) and do not start another OAC within 30 days of dabigatran discontinuation.
All data were analyzed using SAS version 9.4 (SAS Institute, Inc., Cary, North Carolina). Baseline data were summarized descriptively overall, according to region, and for factors related to treatment nonpersistence. Continuous variables were reported as mean ± SD, and categorical variables were reported as absolute frequencies and percentages. In addition, reasons for discontinuation of dabigatran treatment at 2 years were summarized descriptively.
Probabilities of dabigatran persistence were evaluated by using a Kaplan-Meier time-to-event analysis. Dose changes (e.g., lowering dose from 150 mg twice daily to 110 mg twice daily) were not considered as switched treatment because dose adjustments represented part of the antithrombotic therapy management process.
Variables included in the Cox regression models to evaluate risk factors associated with dabigatran discontinuation included region, reimbursement status of medication, and patient clinical and sociodemographic characteristics. Patients were followed up until study withdrawal, death, end of study, or occurrence of dabigatran nonpersistence, whichever came first.
To evaluate whether reclassification of patients who switched treatments after a longer period after dabigatran discontinuation (i.e., >30 days) would change the results, an additional sensitivity analysis was conducted, reclassifying the 28 patients who switched to another OAC following the 30-day period after dabigatran discontinuation.
A total of 3,002 patients were enrolled; 65 were ineligible (2.2%), including 45 who did not meet inclusion criteria or who met exclusion criteria, and 20 who did not meet data cleaning requirements. The main reason for not meeting inclusion criteria was absence of a new AF diagnosis (n = 35). The remainder (n = 10) had AF with a reversible cause, >60 days of warfarin treatment, or exclusionary valve disease. Five patients (0.5%) were prescribed dabigatran but were not treated, producing a total of 2,932 patients eligible for analysis who were prescribed dabigatran and took at least 1 dose. Most patients were enrolled in Europe (51.2%), followed by North America (27.9%); these were the regions in which NOACs were first approved. In regions with later NOAC approvals, fewer dabigatran-treated patients were enrolled: Asia (12.4%), Latin America (6.6%), and Africa and the Middle East (1.8%) (Figure 1).
Patients’ mean age was 70.3 ± 10.2 years, and slightly more than one-half of patients were male. Approximately one-half had paroxysmal AF (n = 1,481; 50.5%), 1,063 (36.3%) had persistent AF, and a minority had permanent AF at the time of enrollment (n = 388; 13.2%). Approximately one-quarter of the patient group had symptomatic AF (26.5%), 46.5% reported minimally symptomatic AF, and 27.0% reported asymptomatic AF.
About one-third of patients were ≥75 years of age, and most were considered at high risk for stroke (CHA2DS2-VASc score ≥2 in 88.2% of patients). The majority of patients were considered at low risk for bleeding (HAS-BLED score <3 in 83.5% of patients), and only 5.0% had a previous bleeding event. The majority of patients had a history of hypertension, and 1 in 5 had coronary artery disease. The baseline characteristics of patients according to region and other risk factors for discontinuation are shown in Tables 1 and 2.
Overall treatment persistence
The probability of dabigatran treatment persistence was 76.6% at 1 year and 69.2% at 2 years. This finding was even higher when considering those who remained on dabigatran or discontinued dabigatran to start another OAC within 30 days (i.e., 87.7% at 1 year and 84.1% at 2 years) (Central Illustration).
At the end of follow-up, 828 patients had discontinued dabigatran. Of the total 2,932 dabigatran-treated patients, 1,859 remained on dabigatran (63.4%) until study termination, 438 (14.9%) discontinued treatment without switching to another OAC, and 390 (13.3%) switched to another OAC. Baseline characteristics of the patients who remained on dabigatran, discontinued with switching to another OAC, or discontinued without switching are shown in Online Table 1. There were 214 patients (7.3%) who switched to a factor Xa inhibitor, and 176 patients (6.0%) who switched to a VKA; 128 patients (4.4%) were lost to follow-up, and 117 (4.0%) died before the end of follow-up.
Reasons for nonpersistence at 2 years
Primary reasons given for discontinuing dabigatran treatment are presented in Table 3. Among patients discontinuing dabigatran (n = 828), 66 (8.0%) stopped primarily due to dyspepsia and approximately 25% stopped primarily due to other AEs (64 [7.7%] SAEs; 62 [7.5%] nonserious AEs; 58 [7.0%] bleeding events; 22 [2.7%] hypersensitivity to agent; 2 [0.2%] bruising; and 2 [0.2%] due to concomitant medication interactions). The majority of respondents (59.8%) cited “other” (reason not otherwise specified) as the primary reason for discontinuation of dabigatran. Upon further investigation of the proportion of patients who discontinued treatment citing AEs as the primary reason (including bleeding, bruising, dyspepsia, hypersensitivity or interactions with the agent, or other AEs or SAEs), more than one-half of these discontinuations (58.3%) occurred in the first 6 months. Most individual AEs were reported in the first 6 months, including the following: bleeding events or bruising, 65.0%; dyspepsia, 57.8%; hypersensitivity to agents, 72.7%; and general adverse drug reactions, 62.9%. For SAEs that were not necessarily related to dabigatran, 43.8% were reported in the first 6 months.
Overall, primary discontinuation due to cost of treatment was reported relatively infrequently, with <3% of all primary reasons for discontinuation cited due to cost (Table 3). When evaluating the main reasons for discontinuation in North America compared with Europe, for example, where we might expect higher rates of reimbursement, the proportion of primary reasons for discontinuation due to cost were not markedly different (North America, 1.0%; Asia, 4.0%; Europe, 3.1%; and Latin America, 0.0%).
Upon further investigation of patients who discontinued treatment with a primary reason documented as “other,” only a small proportion of the patients overall (8.1%) had adverse drug reactions or serious AEs that were reported within 30 days before discontinuation (not necessarily related to treatment discontinuation). Furthermore, there were no thromboembolic events observed within 30 days before discontinuation in this group of patients.
Predictors of treatment persistence
Factors associated with dabigatran nonpersistence were region, type of AF, type of site, categorization of AF, physician specialty, and previous proton pump inhibitor use (Table 4). In particular, patients in North America were at higher risk of dabigatran discontinuation (hazard ratio [HR]: 1.66; 95% confidence interval [CI]: 1.35 to 2.04) compared with those in Europe, and patients in Latin America were at lower risk (HR: 0.61; 95% CI: 0.40 to 0.90). Patients with asymptomatic or minimally symptomatic AF were more likely to be persistent compared with symptomatic patients. Those with permanent AF were similarly less at risk for nonpersistence versus those with paroxysmal or persistent AF, as were patients followed up by a primary care physician compared with those followed up at a community hospital. Previous proton pump inhibitor use was predictive of dabigatran nonpersistence (HR: 1.26; 95% CI: 1.04 to 1.51).
Patients who were enrolled at a specialist’s office had a similar risk for discontinuation compared with those at a community hospital (HR: 0.99; 95% CI: 0.80 to 1.23); however, patients enrolled at a university hospital did not seem to be markedly at higher risk of discontinuation (Table 4). Other factors included in the model are shown in Online Table 2.
Patients without switch to another OAC
Region was the strongest predictor of nonpersistence without switch, with North America having the greatest risk of dabigatran nonpersistence. In this subgroup analysis, patients in Asia had similar rates of discontinuation as Europe but were at higher risk of discontinuing without switching (HR: 1.64; 95% CI: 1.20 to 2.21) (Table 4). Latin America and the Middle East (including South Africa) had the lowest risk of dabigatran nonpersistence in this subgroup versus Europe. The main clinical variables associated with a lower risk of dabigatran nonpersistence without switch in the Cox model were previous stroke or TIA and permanent AF versus paroxysmal or persistent AF. Previous myocardial infarction was associated with a higher risk of nonpersistence, as was treatment at a university hospital compared with a community hospital. Other factors included in the model are shown in Online Table 2.
The sensitivity analysis considering patients as switchers if they had started another OAC after remaining untreated for >30 days (28 patients identified) yielded similar results.
In this prospective assessment of clinical practice data from a global registry program, overall dabigatran persistence in an incident AF population was high, with the probability of remaining on dabigatran treatment after 1 year at approximately 75% and approximately 70% after 2 years. Of clinical importance, about one-half of those patients who discontinued treatment during follow-up did not start another OAC within 30 days, leaving patients at risk for stroke at least in the early period after initial discontinuation. To our knowledge, this trial was the first global, prospective study cohort describing regional differences in persistence patterns, specifically with an NOAC (dabigatran).
Published studies of OAC persistence
Previous evaluations of persistence have consistently shown relatively poor persistence with warfarin treatment, with 1-year discontinuation rates ranging from approximately 25% (18,19) to >60% (7). Some studies defined discontinuation as a treatment gap of 45 to 60 days, a definition less stringent than the one used here (30 days). Comparing persistence across studies is difficult, because even those focused on the same OAC may differ with respect to the patient populations, study designs, and definitions of nonpersistence.
In XANTUS (Xarelto for Prevention of Stroke in Patients with Atrial Fibrillation), another prospective registry of patients treated with the NOAC rivaroxaban, persistence over a 1-year period was high, with discontinuation rates of approximately 20% (20). A database study by Jackevicius et al. (21), which evaluated NOAC treatment persistence, defined nonpersistence as >14-day gaps between prescriptions. Persistence was described at 6-month follow-up, and approximately one-third of patients were nonpersistent to dabigatran and rivaroxaban. This population was considerably older, had a higher prevalence of comorbidity, and did not represent an incident AF population, with just over one-half of the population having a history of warfarin use. Importantly, in this study, the risk of stroke, TIA, or death was significantly higher in those nonpersistent to dabigatran or rivaroxaban compared with those who were persistent.
Better persistence with NOACs may stem from better overall acceptance of NOAC therapies, resulting from a lower burden of monitoring and fewer food and drug interactions compared with VKAs. Conversely, it also could be posited that persistence with NOACs could be less favorable due to fewer overall visits with health care providers, resulting in fewer opportunities to have the importance of treatment persistence emphasized.
It has been shown that risk of discontinuation is highest in the early period after treatment initiation (6 months to 1 year), after which discontinuation rates level off or decline more gradually (18,19,22). Therefore, studies evaluating treatment persistence for only limited periods after treatment initiation might not accurately predict the discontinuation rates over the long term. Persistence should thus be measured directly for at least a period of 1 year or longer where possible.
Reasons for discontinuation
The data from this analysis suggest that the reasons for discontinuation of treatment are complex and might not be fully explained solely by examining adverse drug reactions such as bleeding or other AEs. Approximately one-third of all reasons for primary dabigatran discontinuation were cited as due to an AE or SAE. The majority of primary reasons cited for treatment discontinuation or switch were “other”; that is, not related to AEs or SAEs or to AEs associated with OAC treatment, such as bleeding or dyspepsia. A separate analysis in this group of patients found only a small number of AEs reported within 30 days before discontinuation, confirming that the responses indicated under the other reasons for discontinuation did not seem to include adverse events.
There might be an influence of patient or physician preference, potentially a higher perceived risk for outcomes that prompted changes in treatment, or other factors that were not directly explored. Indeed, in a review of adherence to NOACs, the importance of the patient’s perspective was emphasized for making decisions around anticoagulant choice (23), and these preferences could also have strong implications for treatment persistence or switching to an alternative OAC.
Predictors of treatment discontinuation
In the present study, clinical factors predicted which patients were most likely to discontinue dabigatran treatment, with or without switching to an alternative OAC. The multivariable analyses showed that factors such as region (North America) and previous proton pump inhibitor use might be associated with dabigatran nonpersistence. Measures that might be markers of disease severity, such as permanent AF, were associated with persistence.
This pattern was also seen in predictors of the subgroup that discontinued dabigatran but did not switch to another OAC within 30 days. In this group, which better reflects those who are at risk of complications stemming from lack of prophylaxis, the factors associated with a lower risk of nonpersistence included permanent AF (vs. paroxysmal or persistent AF) and previous stroke or TIA. Previous myocardial infarction was also associated with a higher risk of nonpersistence. Patients from Asia and North America had a higher risk of nonpersistence with dabigatran compared with patients from Europe.
Treatment-related AEs, such as dyspepsia or hypersensitivity reactions, were a more prevalent reason for switching than for discontinuing treatment. In cases of discontinuation without switching, SAEs and bleeding events were more often cited compared with those who switched, suggesting that patients who have more serious OAC-related side effects would more often remain untreated.
Clinical factors such as permanent AF, previous stroke, and low symptom burden, all associated with treatment persistence, might be important clinical surrogates for disease severity. Physicians might provide more vigorous reminders or directives regarding the importance of OACs in stroke prevention for patients with these markers, or patients themselves could be more committed to remaining on treatment after experiencing a previous stroke or TIA or experiencing more longstanding episodes of AF. Longer episodes of AF duration could, indeed, relate to the perception that a higher AF burden increases stroke risk and, thus, influence patients to remain on OAC therapy.
To our knowledge, this study was the first prospective study to describe regional differences in persistence patterns. These regional differences might be secondary to differences in clinical standards, patient preferences, or patient management. Of note, the predictors of increased risk for treatment nonpersistence seemed to relate to factors associated with lower disease severity and to geographic differences.
Our study had several limitations that should be noted. Patients consented to participate in the study, and physicians were aware that persistence to treatment would be recorded, potentially modifying behaviors (i.e., the Hawthorne effect) (24). There could be increased attention from the treating physician, influencing patients to remain on treatment. Also, patients more likely to have good adherence might agree to participate in a registry, resulting in higher overall rates of treatment persistence.
Patients were not followed up in the VKA group in this phase of the registry, which limited our ability to make comparisons. Another limitation was that only 1 primary reason was ascertained for treatment discontinuation. Furthermore, for a large proportion of patients, no specific information on the reason for discontinuation was available, as the “other” category of reason for discontinuation was chosen without an option for additional free field text. Finally, phase II started later in certain regions (Latin America, Africa and the Middle East), which are therefore less well represented in the data.
In this analysis of patients newly diagnosed with AF, we found evidence for long-term persistence with dabigatran, with an approximately 30% probability of discontinuing index dabigatran treatment after 2 years. About one-half of those who discontinued dabigatran received another OAC within 30 days. Most of the primary reasons noted for treatment discontinuation did not directly relate to AEs, which implies that other factors, such as perceived thromboembolic and bleeding risks or patient preferences, might play an important role in decisions to persist with treatment. Surrogate markers of AF severity, such as permanent AF, were associated with a lower risk of treatment discontinuation, suggesting that patients without these characteristics might be an important group to target to increase treatment persistence.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Persistence with OAC therapy in patients with AF is a barrier to achieving optimum clinical outcomes. Long-term persistence with dabigatran was high, with approximately 70% remaining on treatment after 2 years. Factors associated with discontinuation of dabigatran included region (North America and Asia with the highest risk compared with Europe), high AF symptom burden, paroxysmal or persistent rather than permanent AF, previous use of proton pump inhibitor inhibitors, and absence of previous stroke or TIA.
TRANSLATIONAL OUTLOOK: Future studies should evaluate reasons for discontinuing OAC therapy over time in patients with AF to develop interventions that improve treatment persistence.
Programming support was provided by Paul Allison and Ralph Minkenberg. Editorial support was provided by PAREXEL with funding from Boehringer Ingelheim.
For supplemental tables, please see the online version of this article.
This study was funded by Boehringer Ingelheim GmbH. Ms. Paquette and Drs. Riou França, Teutsch, Lu, and Zint are employees of Boehringer Ingelheim and contributed to the design and conduct of the study, interpretation of the data, and writing of results. Dr. Lu conducted the analysis. Professor Diener, Dr. Dubner, Professor Ma, Dr. Rothman, Dr. Halperin, Dr. Huisman, and Professor Lip contributed to the design of the study, interpretation of the data, and writing of the manuscript. Dr. Nieuwlaat contributed to the interpretation of the data and writing of the manuscript. Dr. Huisman has received honoraria for research grants, consultation, and presentations from Actelion, Bayer HealthCare, Boehringer Ingelheim, GlaxoSmithKline, and Pfizer. Prof. Lip has served as a consultant for Bayer/Janssen, Bristol-Myers Squibb/Pfizer, Biotronik, Medtronic, Boehringer Ingelheim, Microlife, and Daiichi-Sankyo; and is a speaker for Bayer, Bristol-Myers Squibb/Pfizer, Medtronic, Boehringer Ingelheim, Microlife, Roche, and Daiichi-Sankyo. Professor Diener has received honoraria for participation in clinical trials, contribution to advisory boards, or oral presentations from Abbott, Allergan, AstraZeneca, Bayer Vital, Bristol-Myers Squibb, Boehringer Ingelheim, CoAxia, Corimmun, Covidien, Daiichi-Sankyo, D-Pharm, Fresenius, GlaxoSmithKline, Janssen-Cilag, Johnson & Johnson, Knoll, Lilly, Merck Sharp & Dohme, Medtronic, MindFrame, Neurobiological Technologies, Novartis, Novo Nordisk, Paion, Parke-Davis, Pfizer, Sanofi, Schering-Plough, Servier, Solvay, St. Jude, Syngis, Talecris, Thrombogenics, WebMD Global, Wyeth, and Yamanouchi; has received financial support for research projects from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Lundbeck, Novartis, Janssen-Cilag, Sanofi, Syngis, and Talecris; and his institution, the Department of Neurology at the University Duisburg–Essen, has received research grants from the German Research Council, German Ministry of Education and Research, European Union, the National Institutes of Health, Bertelsmann Foundation, and Heinz-Nixdorf Foundation. Dr. Dubner has received consultancy fees for serving as a steering committee member for Boehringer Ingelheim; and holds research grants from St. Jude Medical. Professor Ma has received consultancy fees/honoraria from Bayer Healthcare Pharmaceuticals, Bristol-Myers Squibb, Boehringer Ingelheim, Johnson & Johnson, and Pfizer. Dr. Rothman is an employee of RTI Health Solutions, an independent, nonprofit research organization that does work for government agencies and pharmaceutical companies. Dr. Halperin has received consulting fees/honoraria or research support from Bayer HealthCare, Boehringer Ingelheim, Daiichi-Sankyo Pharma, Janssen Pharmaceuticals, Johnson & Johnson, Sanofi, Boston Scientific, Medtronic, and Pfizer. Dr. Nieuwlaat has reported that he has no relationships relevant to the contents of this paper to disclose. Drs. Huisman and Lip are co-chairs of the GLORIA-AF registry, and Dr Nieuwlaat is principal supervisor of this analysis; all 3 are joint senior authors. Peter R. Kowey, MD, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- adverse event
- atrial fibrillation
- confidence interval
- hazard ratio
- non–vitamin K oral anticoagulant
- oral anticoagulant
- serious adverse event
- transient ischemic attack
- vitamin K antagonist
- Received May 21, 2017.
- Revision received July 14, 2017.
- Accepted July 25, 2017.
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