Results
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 (Figure 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 http://content.onlinejacc.org/data/Journals/JAC/930377/03039_mmc1.docx. 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 (Figure 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 Figure 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 Figure 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.
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Figure 3.
Risk of Outcomes
Risk of thromboembolism (A), serious bleeding (B), heart failure hospitalization (C), and myocardial infarction (D) according to AF status and antithrombotic therapy. Rates are events per 100 person-years with 95% CI. Adjusted for age, sex, inclusion year, heart failure severity group and CHA2DS2-VASc (congestive heart failure, hypertension, older than 75 years of age, diabetes, stroke/thromboembolism, vascular disease, 65 to 74 years or age, female sex) (for thromboembolism), HAS-BLED (hypertension, abnormal liver/renal function, stroke, bleeding, labile international normalized ratio, elderly, drugs) (for serious bleeding), evidence-based pharmacotherapy (for heart failure hospitalization) and coronary risk factors/medication (myocardial infarction). Single AP denotes either aspirin or clopidogrel. All p values denote tests for difference. AF = atrial fibrillation; AP = antiplatelet; CI = confidence interval; HR = hazard ratio; VKA = vitamin K antagonists.
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 (Figure 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) (Figure 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 http://content.onlinejacc.org/data/Journals/JAC/930377/03039_mmc1.docx).