Author + information
- Received October 14, 2013
- Revision received February 22, 2014
- Accepted March 4, 2014
- Published online June 24, 2014.
- Morten Lamberts, MD, PhD∗∗ (, )
- Gregory Y.H. Lip, MD†,
- Martin H. Ruwald, MD, PhD∗,
- Morten Lock Hansen, MD, PhD∗,
- Cengiz Özcan, MD∗,
- Søren L. Kristensen, MD∗,
- Lars Køber, MD, DMSc‡,
- Christian Torp-Pedersen, MD, DMSc§ and
- Gunnar H. Gislason, MD, PhD∗,‖
- ∗Department of Cardiology, Gentofte University Hospital, Hellerup, Copenhagen, Denmark
- †University of Birmingham, Centre for Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom
- ‡The Heart Centre, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark
- §Institute of Health, Science and Technology, Aalborg University, Aalborg, Denmark
- ‖National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark
- ↵∗Reprint requests and correspondence:
Dr. Morten Lamberts, Department of Cardiology, Gentofte University Hospital, Post 635, Niels Andersens Vej 65, 2900 Hellerup, DK, Denmark.
Objectives The aim of this study was to investigate the impact of atrial fibrillation (AF) and antithrombotic treatment on the prognosis in patients with heart failure (HF) as well as vascular disease.
Background HF, vascular disease, and AF are pathophysiologically related, and understanding antithrombotic treatment for these conditions is crucial.
Methods In hospitalized patients with HF and coexisting vascular disease (coronary artery disease or peripheral arterial disease) followed from 1997 to 2009, AF status was categorized as prevalent AF, incident AF, or no AF. Risk of thromboembolism (TE), myocardial infarction (MI), and serious bleeding was assessed by Cox regression models (hazard ratio [HR] with 95% confidence interval [CI]) with antithrombotic therapy and AF as time-dependent variables.
Results A total of 37,464 patients were included (age, 74.5 ± 10.7 years; 36.3% females) with a mean follow-up of 3 years during which 20.7% were categorized as prevalent AF and 17.2% as incident AF. Compared with vitamin K antagonist (VKA) in prevalent AF, VKA plus antiplatelet was not associated with a decreased risk of TE (HR: 0.91; 95% CI: 0.73 to 1.12) or MI (HR: 1.11; 95% CI: 0.96 to 1.28), whereas bleeding risk was significantly increased (HR: 1.31; 95% CI: 1.09 to 1.57). Corresponding estimates for incident AF were HRs of 0.77 (95% CI: 0.56 to 1.06), 1.07 (95% CI: 0.89 to 1.28), and 2.71 (95% CI: 1.33 to 2.21) for TE, MI, and bleeding, respectively. In no AF patients, no statistical differences were seen between antithrombotic therapies in TE or MI risk, whereas bleeding risk was significantly increased for VKA with and without single-antiplatelet therapy.
Conclusions In AF patients with coexisting HF and vascular disease, adding single-antiplatelet therapy to VKA therapy is not associated with additional benefit in thromboembolic or coronary risk, but notably increased bleeding risk.
Although systolic heart failure (HF) is associated with increased risk of thromboembolism (TE) and death, no firm evidence exists of the benefit of antithrombotic treatment in uncomplicated HF in sinus rhythm (1–3). For example, a recent Cochrane review found no convincing evidence that oral anticoagulant therapy modified mortality or vascular events in patients with HF in sinus rhythm (4).
Two conditions commonly related to HF are vascular disease and atrial fibrillation (AF), with both frequently requiring the use of antithrombotic therapy with antiplatelet drugs and oral anticoagulation, respectively. In patients with coronary or peripheral artery disease, antiplatelet therapy is recommended (5–7), although the benefits of antiplatelet therapy in patients with concomitant HF are less well defined in relation to mortality and vascular events (4). In HF patients with AF, oral anticoagulation is clearly indicated (8,9).
The use of antithrombotic therapy has to balance a reduction in TE against the potential increase in risk of bleeding (10). Bleeding while on antithrombotic therapy may have implications for subsequent adverse outcomes (11–15). Patients with HF may also be predisposed to more bleeding due to difficulties with warfarin and liver congestion (16), and in the recent WARCEF (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction) trial conducted in HF patients in sinus rhythm, the beneficial effects of reducing ischemic stroke were offset by an increase in major bleeding with warfarin therapy (17).
If patients with HF have both vascular disease and AF, a common practice is to concomitantly prescribe oral anticoagulation and antiplatelet therapy because such patients are considered high risk. Indeed, incident and prevalent AF may confer different risks. In general population studies, there is little evidence of a beneficial effect of such combination antithrombotic therapy on TE, given the increase in serious bleeding (11,12). Limited data are available for HF patients who have both vascular disease and AF.
In a real-life cohort of HF patients with vascular disease, our objective was to assess the relationship of incident or prevalent AF to TE and serious bleeding. Second, we also assessed the effectiveness and safety of ongoing antithrombotic treatment in such patients.
We linked information on the individual level from several nationwide databases. The National Patient Registry classifies all hospital contacts according to the International Classification of Diseases (ICD) since 1977 (with the eighth revision until 1994 and then the 10th revision.). Coding is performed for the primary diagnosis of contact, and, if appropriate, ≥1 secondary diagnoses, and when identifying diagnoses in the registries was allowed (18). Procedures performed are also coded according to Nordic Medical Statistics Committee of Surgical Procedures. From the national prescription registry, we collected information on the dose, number of tablets, and date of dispensing for each individual according to the Anatomical Therapeutic Chemical Classification system endorsed by the World Health Organization (19). Vital status and cause of death according to the ICD 10th revision were obtained from the Danish Personal Registration System and the National Causes of Death register, respectively (20). Using a unique number, we retrospectively linked this information for each individual. All ICD and Anatomical Therapeutic Chemical Classification system codes used are available in the Online Table 1.
All Danish residents with a first-time HF hospitalization between January 1, 1997 and December 31, 2009 were identified. We included patients with a previous diagnosis of myocardial infarction (MI), aortic plaque, and peripheral artery disease and having undergone procedures on coronary arteries (coronary artery bypass and coronary intervention) as markers of vascular disease. The date of study inclusion of patients with HF was the date of discharge. The presence of no AF included patients without an AF diagnosis (since 1977) before HF hospitalization, whereas prevalent AF patients had a diagnosis of AF before hospitalization for HF. During the study period, no AF patients were continuously screened for an AF diagnosis and categorized as incident AF at the date of a first-time AF admission. Hence, the study population initially comprised patients with a HF hospitalization and coexisting vascular disease with status of prevalent (known) AF or no AF. During follow-up, the status of no AF patients could subsequently change to incident AF (Fig. 1). Categorizing AF patients was predefined as the occurrence of AF (either prevalent or incident) from a first-time HF hospitalization might pose different risks (e.g., duration of AF disease burden, influencing antithrombotic treatment strategy, progression of HF).
The administrative discharge coding for HF classified HF as hypertensive (ICD-10 DI11.0), cardiomyopathy (ICD-10 DI42, including dilated, alcoholic, and obstructive cardiomyopathy), acute pulmonary edema (ICD-10 DJ81.9), and unspecified HF (ICD-10 DI50 including decompensated HF [ICD-10 I50.9]). To assess the severity of HF, we calculated the daily dose of loop diuretics before and after HF hospitalization: group 1 (0 to 39 mg), group 2 (40 mg to 79 mg), group 3 (80 mg to 159 mg), and group 4 (≥160 mg), as previously done (21).
For each individual, all prescriptions of aspirin, clopidogrel, and vitamin K antagonists (VKA) (i.e., warfarin and phenprocoumon) were identified, and the following commonly used treatment regimens were classified: single-antiplatelet therapy (aspirin or clopidogrel), VKA, and VKA plus single-antiplatelet therapy. In no AF patients, dual-antiplatelet therapy (aspirin and clopidogrel) was also assessed for the primary outcomes. Ongoing antithrombotic treatment was determined from claimed prescriptions as previously done (11,22). Briefly, from the number of tablets dispensed and the strength of tablets, the average daily dose was defined. Patients were allowed to change group but could only be exposed to 1 treatment group at any given time and were only considered at risk when having tablets available for consumption. Subsequent antithrombotic treatment at baseline was defined as any claimed prescriptions of VKA, antiplatelet drugs, or both up to 30 days after HF discharge (11).
TE was defined as hospitalization or death caused by ischemic stroke, transient ischemic attack, and arterial embolism. Serious bleeding was defined as hospitalization or death caused by intracranial, gastrointestinal, respiratory, and urogenital bleeding and anemia caused by bleeding. As secondary outcomes, recurrent HF hospitalization and MI including hospitalization and coronary death were used. Due to study design of continuous inclusion of incident AF, death was included as an outcome for prevalent AF and no AF patients only. The outcome definitions were previously used (22–24). For overall thrombosis risk, an outcome including both TE and MI was also defined.
Other pharmacotherapy and comorbidity
Any prescriptions 180 days before inclusion of the following drugs defined other pharmacotherapy: renin-angiotensin inhibitors, beta-blockers, spironolactone, thiazides, loop diuretics, nonsteroidal anti-inflammatory drugs, and statins. For risk factors for TE and bleeding, we calculated scores of CHA2DS2-VASc (congestive HF, hypertension, age older than 75 years, diabetes, stroke/TE, vascular disease, 65 to 74 years of age, female sex) and HAS-BLED (hypertension, abnormal liver/renal function, stroke, bleeding, labile international normalized ratio [INR], elderly, drugs [non-steroidal anti-inflammatory drugs]) from recorded comorbidities and pharmacotherapy as previously used and validated (23,25). All patients were scored at least 2 for CHA2DS2-VASc according to HF and vascular disease status. INR values were not available in the registries, and use of aspirin was not incorporated in the (modified) HAS-BLED score, as this was an explanatory variable. For incident AF patients, all characteristics were determined at the date of the first-time AF diagnosis.
Continuous variables are presented as mean ± SD, and categorical variables as number (percentage). All rates are crude incidence rates calculated as events per 100 person-years with 95% confidence intervals (CIs). Hazard ratio (HR) estimates with 95% CIs for outcomes were calculated in a Cox proportional hazard model with antithrombotic treatment and AF status as time-varying variables. These models were adjusted for age, sex, inclusion year, HF severity group (daily dose of loop diuretics at inclusion), and CHA2DS2-VASc score for events of TE and HAS-BLED for events of serious bleeding. For the secondary outcomes, adjustment included evidence-based HF medication (beta-blockers, renin-angiotensin receptor inhibitors, and spironolactone) for HF hospitalization, and coronary risk factors/medication (beta-blockers, renin-angiotensin receptor inhibitors, statins, diabetes, hypertension, and renal failure) for events of MI. In models not assessing antithrombotic treatment, ongoing antithrombotic treatment was also used for adjustment. As mentioned previously, characteristics were updated in patients changing from no AF to incident AF status. To illustrate the overall prognosis in the population, we calculated Kaplan-Meier survival estimates for patients with prevalent AF and no AF at inclusion (the no AF group comprised subsequently incident AF patients) (Fig. 2). For sensitivity and the potential reduction of unmeasured confounders, we performed matching analyses using a propensity score model. We defined controls as no AF patients and cases as the presence of AF (whether prevalent and incident) and used risk set matching by date of potential AF. This allowed a patient without AF to be defined as a control and subsequently as a case if an AF hospitalization occurred. Propensity score was calculated by a Cox regression model conditional on baseline variables of age, inclusion year, and risk factors included in the CHA2DS2-VASc and HAS-BLED scores. Matching was performed using the Greedy matching macro. Patients were followed to death or the end of the study period (December 31, 2009). For model control, assumptions were not violated (linearity of continuous variables, proportional hazard assumptions, and lack of clinical relevant interaction). Statistical software packages SAS version 9.2 (SAS Institute, Inc., Cary, North Carolina) and Stata version 11.0 (StataCorp, College Station, Texas) were used.
The study was approved by the Danish Data Protection agency (ref 2007-41-1667), and data were made available to us so no individuals could be identified. As a retrospective registry-based study, Danish law does not require ethical approval.
A total of 37,464 patients with HF and vascular disease were included (age, 74.5 ± 10.7 years; 36.3% females). Of these 7,804 (20.7%) had prevalent AF, whereas in another 6,432 (17.2%) incident AF developed (Fig. 1). The characteristics of the study population according to AF status (no, prevalent, or incident AF) are shown in Table 1. In patients with no AF, potential indications for antithrombotic therapy are provided in Online Table 2. The mean time between the date of the first hospitalization for vascular disease and inclusion (with HF) was 6.5 ± 6.5 years, with a median of 4.5 years (interquartile range: 0.8 to 10.5 years). The mean CHA2DS2-VASc and HAS-BLED scores were 5.0 ± 1.5 and 2.1 ± 1.0, respectively. During a mean follow-up of 3 years (median, 3.3 years; interquartile range: 0.9 to 7.9 years), 23,154 (61.8%) patients died. Prevalent AF patients were more likely to die compared with no AF patients (Fig. 2). A total of 4,272 (11.4%), 4,383 (11.7%), 17,889 (47.7%), and 13,003 (34.7%) events of TE, serious bleeding, recurrent HF hospitalization and MI, respectively, occurred.
Relationship of AF status to outcomes
The total number of person-years accumulated for prevalent AF was 20,691 and 15,758 person-years for incident AF. The no AF group accumulated 77,317 person-years. The mean time to incident AF was 473 ± 787 days with a median 56 days (interquartile range, 0 to 632 days). Crude rates of TE (events per 100 person-years were 5.8 [95% CI: 5.5 to 6.2], 4.6 [95% CI: 4.2 to 5.0], and 4.1 [95% CI: 3.9 to 4.2]) for prevalent, incident, and no AF, respectively. For serious bleeding, the corresponding crude rates were 5.6 (95% CI: 5.3 to 6.0), 4.6 (95% CI: 4.3 to 5.0), and 3.7 (95% CI: 3.5 to 3.8). Figures 3A and 3B show that incident and prevalent AF had similar HRs of TE and serious bleeding, and the risk was higher than in patients without AF. For the secondary outcomes of HF hospitalization and MI, crude rates and HRs are shown in Figures 3C and 3D. Among patients with either prevalent or incident AF, no marked difference was apparent for the risk of recurrent HF hospitalization. With regard to the risk of MI, an increased risk was seen for incident AF compared with no AF or prevalent AF. No clinically relevant effect modification was present for the use of evidence-based HF medication (beta-blockers, renin-angiotensin receptor inhibitors, and spironolactone) among AF patients compared with no AF patients. In the propensity score–matched model, the risk of TE (HR: 1.29; 95% CI: 1.20 to 1.38) and bleeding (HR 1.48; 95% CI: 1.38 to 1.60) among patients with AF compared with patients without AF resembled the main analyses.
Relationship to antithrombotic therapy according to AF status on the risk of TE and serious bleeding
Among HF patients with coexisting vascular disease and prevalent AF, TE rates were highest among those on single-antiplatelet therapy and lowest for VKA plus single-antiplatelet therapy (Fig. 3A). No statistical difference in the risk of TE was found for VKA plus single-antiplatelet therapy compared with VKA (HR: 0.91; 95% CI: 0.73 to 1.12). Bleeding risk was significantly increased for VKA plus single-antiplatelet therapy compared with VKA alone (HR: 1.31; 95% CI: 1.09 to 1.57) (Fig. 3B). In HF patients with incident AF, TE rates were higher among those on antiplatelet therapy and lowest in those with combined VKA and antiplatelet therapy. Bleeding risk was greater in patients with VKA plus single-antiplatelet therapy compared with those on VKA-only therapy. Among HF patients with no AF, the risk of TE was similar between single-antiplatelet therapy, VKA, and VKA plus single-antiplatelet therapy. Bleeding risk was lowest in single-antiplatelet therapy and highest in VKA plus single-antiplatelet therapy. For fatal bleedings only, no differences were seen between the antithrombotic therapies (data not shown), although increased crude rates for prevalent (0.8 events per 100 person-years) and incident (0.7 events per 100 person-years) AF were seen compared with no AF patients (0.4 events per 100 person-years). Dual-antiplatelet therapy (aspirin and clopidogrel) was frequently used in no AF patients (4,608 person-years accumulated), and crude rates were 3.5 (95% CI: 3.0 to 4.1) and 5.5 events per 100 person-years (95% CI: 4.8 to 6.2) of TE and bleeding, respectively. Regarding single-antiplatelet therapy, the risk of TE was significantly reduced (HR: 0.82; 95% CI: 0.69 to 0.97), whereas the risk of bleeding was significantly increased (HR: 1.53; 95% CI: 1.33 to 1.76) when on dual-antiplatelet therapy.
Relationship to antithrombotic therapy according to AF status on secondary outcomes
In patients without AF, VKA and VKA plus single-antiplatelet therapy were associated with an increased risk of HF hospitalization compared with single-antiplatelet therapy. No difference was found between VKA plus single-antiplatelet therapy and VKA-only therapy (Fig. 3C). Among AF patients, no significant differences were found between antithrombotic treatment regimens, although adding a single antiplatelet to VKA was associated with an HR of 1.11 (95% CI: 1.00 to 1.23) for risk of HF hospitalization in prevalent AF patients. Regardless of AF status, no statistically significant difference was found between VKA plus single-antiplatelet therapy and VKA-only therapy regarding the risk of MI (Fig. 3D). Among AF patients, single-antiplatelet therapy was associated with increased risk of MI. For the combined outcome of TE and MI, no statistical difference was found for VKA plus single-antiplatelet therapy compared with VKA-therapy for prevalent (HR: 1.00; 95% CI: 0.89 to 1.14) or incident AF (HR: 0.97; 95% CI: 0.82 to 1.14) (Online Table 3).
In this study, we show that among patients with HF and vascular disease, the presence of incident and prevalent AF conferred similar HRs of TE, which was greater than those with no AF. However, the risk of serious bleeding for incident and prevalent AF was particularly high when a single antiplatelet was added to VKA therapy. Second, we show that among patients with no AF, there was no difference between antiplatelet therapy and VKA therapy for TE, but serious bleeding increased with VKA therapy.
AF contributes to a high risk of stroke and TEs in HF, and our data support previous studies (26,27). For either prevalent or incident AF, we found similar risks of TE, serious bleeding, and HF hospitalization, suggesting that regardless of the first appearance of AF, the prognosis is worsened for these specific outcomes. Incident AF was associated with an increased risk of coronary events, whereas prevalent AF was not compared with no AF. It has been suggested that AF could be a marker of disease progression, and our findings support previous studies that found that new-onset AF was independently associated with cardiovascular events and death in both healthy individuals and HF patients (28,29). HF, whether due to reduced ejection fraction or preserved ejection fraction, has been associated with TE, especially when AF is present. Indeed, the C in the CHA2DS2-VASc score refers to recent acute decompensated HF or the presence of moderate to severe left ventricular dysfunction (30). Nonetheless, reliance on diagnostic coding of any HF may be less reliable because only ∼50% of such patients actually have confirmed HF in the primary care setting (8,31). Although a considerable higher predictive value of HF has been found in hospitalized patients, the risk and mechanisms of thrombosis related to the type and degree of HF are still unresolved (32). Unsurprisingly, any HF did not emerge as an independent stroke risk factor in the large Swedish AF cohort study (33), but has been associated with TE in other AF populations (23). AF carries a particularly poor prognosis in HF patients, with mortality being significantly greater with AF compared with no AF, as shown in our nationwide cohort study. Importantly, we show a beneficial impact of VKA therapy in these patients with regard to TE protection compared with single-antiplatelet therapy, and even in the historical trials, VKA therapy significantly reduced all-cause mortality by 26% (34).
The use of antithrombotic therapy has to balance the reduction in TE with an increase in bleeding risk. Our data show that among HF patients with no AF, there is no difference between antiplatelet therapy and VKA therapy for TE, but serious bleeding is significantly less. These findings are supportive of the recent European Society of Cardiology guidelines on HF, which give a class III recommendation on the use of VKA therapy in HF patients without AF with regard to thrombosis protection (8). This is also consistent with observations in WARCEF, which showed a significant reduction in ischemic stroke with VKA therapy but at the cost of greater major bleeding risk (17). As expected, the combination of VKA and antiplatelet therapy is associated with an even higher bleeding risk. In the presence of AF (whether prevalent or incident), VKA-treated patients with HF had lower TE compared with antiplatelet therapy, with a higher bleeding risk. When the analysis was confined to fatal bleeds only, the difference between VKA therapy and single-antiplatelet therapy was nonsignificant. Patients with previous vascular disease are at increased risk of a coronary event, and we also assessed whether combination therapy of VKA and a single antiplatelet agent might provide further protection from MI. In both AF and no AF patients, we did not find statistical difference between VKA with or without a single antiplatelet agent, suggesting adequate coronary prophylaxis with VKA-only therapy. Our data support findings from a previous controlled trial of the favorable efficacy of VKA (against aspirin and VKA plus aspirin) during 26 months of follow-up post-MI (35). A meta-analysis of trials before year 2000 concluded that oral anticoagulant therapy (moderate- or high-intensity therapy) with or without aspirin was beneficial for secondary coronary artery disease protection, whereas the degree of bleeding hazard was uncertain (36). Both studies allowed for effects at different INR levels but were limited because of a small sample size and did not specifically include HF patients or investigate contemporary real-life patients with currently used treatment regimens.
The endpoint of HF admissions and death is commonly the primary outcome in HF trials. In our analysis, we chose a secondary outcome of HF hospitalization (without death) as prescribed antithrombotic medication would likely be withdrawn in terminally ill patients. We found that this outcome was increased in those with AF (whether prevalent or incident) compared with those with no AF. With regard to different antithrombotic strategies in AF patients, we did not find significant differences in the risk of HF hospitalization. Regarding single-antiplatelet therapy in no AF patients, we surprisingly found an increased risk of HF hospitalization with VKA therapy with or without single-antiplatelet therapy. This contradicts findings of the WARCEF trial, which found a nonsignificant increase in a secondary outcome of HF hospitalization with aspirin therapy compared with warfarin therapy in HF patients in sinus rhythm. However, these findings are readily explained by the fact that no information was available of the specific indication for therapy, and patients receiving VKA therapy could be considered having a greater disease burden (e.g., potential nonregistered AF burden). Of note, use of renin-angiotensin system inhibitors and other HF evidence-based medication did not influence antithrombotic treatment effect in the present population.
This study is limited by its dependence on retrospective registry data, and inherent in the observational design, causal interpretation of treatment effects is not possible. The diagnoses of AF, HF, MI, and ischemic stroke have been validated in the registries with positive predictive values of 97%, 81%, 93%, and 97%, respectively (32,37–39). INR measurements were not available in the registries. Although actual ongoing VKA exposure was continuously updated and these data demonstrated everyday antithrombotic treatment strategies, we had no information on the specific degree of anticoagulation therapy selected by the prescribing physicians. As efficacy and hazard have been shown to be influenced by target INR levels in especially controlled settings, this limitation should be acknowledged when interpreting the results (36). Selection bias could be present in the no AF group because we did not have data on silent AF before patients' initial presentation with their arrhythmia diagnosis. Thus, the no AF patients may have included a number of such asymptomatic AF patients who have an equally poor prognosis as symptomatic patients (40,41). This is also implied by the high risk of HF hospitalizations in this group and the many patients treated with VKA therapy despite no registered indication (Online Table 2). Nonetheless, we clearly show a mortality difference between prevalent AF compared with no AF patients. The availability of prolonged electrocardiographic monitoring may enable greater detection of AF episodes. We may also not have accounted for patients with an outpatient diagnosis of HF who have not been hospitalized. Confounding by indication may be present (i.e., patients perceived at higher risk of thrombosis are treated with more intense antithrombotic therapy). We did not have information on the specific indication for antithrombotic therapy, and unmeasured confounders could affect the outcomes under investigation, although we controlled for a wide range of known risk factors and prophylactic medication for the specific outcomes. It should be noted that for the outcome of MI, all patients were included as having an indication for antiplatelet therapy but with a wide range and timing of previous conditions of vascular disease, which could have affected the antithrombotic treatment prescribed. Consequently, our findings do not support any recommendation after an acute ischemic event or after percutaneous coronary intervention. Finally, compared with other large stroke prevention trials, our outcomes differentiate strokes into ischemic and hemorrhagic for better discrimination of the effectiveness and safety of antithrombotic treatment.
The presence of AF (prevalent or incident) is an adverse feature in HF patients with vascular disease, and arrhythmia has an effect on TE/bleeding and HF hospitalizations. No further beneficial effect on TE or coronary risk was apparent when adding a single antiplatelet agent to VKA therapy in patients with AF (but with an increase in bleeding risk), whereas antiplatelet therapy only is inadequate.
For supplemental tables, please see the online version of this article.
Dr. Gislason is supported by an independent research scholarship from the Novo Nordisk Foundation. Dr. Lip has served as a consultant for Bayer, Astellas, Merck, Sanofi-Aventis, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Biotronik, Medtronic, Portola, and Boehringer Ingelheim; and has been on the Speakers' Bureau of Bayer, Bristol-Myers Squibb/Pfizer. Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, and Sanofi Aventis. Dr. Torp-Pederson is a consultant for Cardiome, Merck, Sanofi-Aventis, and Daiichi Sankyo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Lip and Gislason contributed equally to this paper.
- Abbreviations and Acronyms
- atrial fibrillation
- congestive heart failure, hypertension, older than 75 years of age, diabetes, stroke/thromboembolism, vascular disease, 65 to 74 years or age, female sex
- confidence interval
- hypertension, abnormal liver/renal function, stroke, bleeding, labile international normalized ratio, elderly, drugs
- heart failure
- hazard ratio
- International Classification of Diseases
- international normalized ratio
- vitamin K antagonist
- Received October 14, 2013.
- Revision received February 22, 2014.
- Accepted March 4, 2014.
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