Abstract
Aims
Atrial fibrillation (AF) and heart failure (HF) often coexist. Older age is strongly associated with stroke, HF, and mortality. The association between coexistence of HF and a risk of clinical outcomes and the effectiveness of anticoagulation therapy including direct oral anticoagulants (DOACs) in elderly patients with AF and HF have not been investigated. We aimed to evaluate 2 years of outcomes and to elucidate the efficacy of DOACs or warfarin in elderly AF patients in the All Nippon AF In the Elderly (ANAFIE) Registry with and without a history of HF.
Methods and results
The ANAFIE Registry is a multicentre, prospective observational study following elderly non‐valvular AF patients aged ≥75 years for 2 years. Hazard ratios (HRs) were calculated based on the presence or absence of an HF diagnosis and DOAC or warfarin use at enrolment. Among 32 275 eligible patients, 12 116 (37.5%) had been diagnosed with HF. Patients with HF had significantly higher rates of HF hospitalization or cardiovascular death (HR 1.94, P < 0.001), cardiovascular events (HR 1.59, P < 0.001), cardiovascular death (HR 1.49, P < 0.001), all‐cause death (HR 1.32, P < 0.001), and net clinical outcome including stroke/systemic embolism, major bleeding, and all‐cause death (HR 1.23, P < 0.001), compared with those without HF; however, HRs for stroke/systemic embolism (HR 0.96, P = 0.56) and major bleeding (HR 1.14, P = 0.13) were similar. DOAC use was associated with a low risk of stroke/systemic embolism (HR 0.86, P = 0.19 in HF; HR 0.79, P = 0.016 in non‐HF; P for interaction = 0.56), major bleeding (HR 0.71, P = 0.008 in HF; HR 0.75, P = 0.016 in non‐HF; P for interaction = 0.74), HF hospitalization or cardiovascular death (HR 0.81, P < 0.001 in HF; HR 0.78, P < 0.001 in non‐HF; P for interaction = 0.26), cardiovascular events (HR 0.83, P < 0.001 in HF; HR 0.82, P = 0.001 in non‐HF; P for interaction = 0.65), cardiovascular death (HR 0.84, P = 0.12 in HF; HR 0.75, P = 0.035 in non‐HF; P for interaction = 0.18), all‐cause death (HR 0.89, P = 0.082 in HF; HR 0.80, P = 0.001 in non‐HF; P for interaction = 0.091), and net clinical outcome (HR 0.88, P = 0.019 in HF; HR 0.81, P < 0.001 in non‐HF; P for interaction = 0.21) compared with warfarin, irrespective of the presence or absence of HF. Analysis using the propensity score matching method showed similar associations.
Conclusions
Non‐valvular AF patients aged ≥75 years with a history of HF had higher risks of cardiovascular events and mortality. DOACs were favourable to warfarin regardless of the coexistence of HF. These results might encourage the use of DOACs in elderly patients with non‐valvular AF with or without HF.
Keywords: Heart failure, Atrial fibrillation, Elderly patients, Direct oral anticoagulant, Warfarin, Anticoagulation
Introduction
Atrial fibrillation (AF) and heart failure (HF) are common in the elderly population and often exist concomitantly. 1 Coexistence of HF with AF can affect the prognosis of patients with AF. 2 , 3 , 4 , 5 However, the association between the coexistence of HF and the risk of clinical events may be indirect or attenuated because elderly AF patients may have more comorbidities and heart damage, and older age itself is strongly associated with stroke, HF, and mortality. 1 , 6 , 7
Direct oral anticoagulants (DOACs) have been reported to be better for the prevention of stroke and systemic embolism than vitamin K antagonists (warfarin). 8 A meta‐analysis using published data from four phase 3 trials (RE‐LY, ROCKET AF, ARISTOTLE, and ENGAGE AF‐TIMI 48) showed no interaction in the efficacy and safety of DOACs between patients with AF with and without HF. 2 , 3 , 4 , 5 , 9 However, both old age and HF are associated with impaired renal function, higher rates of persistent or permanent AF, and concomitant antiplatelet drug use. 4 , 10 , 11 , 12 These factors possibly affect the risk of clinical outcomes in AF patients; thus, further data are needed to evaluate the real‐world effectiveness of DOACs in elderly AF patients with HF.
The All Nippon AF In the Elderly (ANAFIE) Registry (UMIN000024006) is a multicentre, prospective, observational study that included >30 000 patients with non‐valvular AF aged ≥75 years and followed them for 2 years. 13 The aim of this subanalysis was to compare 2 years of outcomes between elderly non‐valvular AF patients with and without HF and to investigate the effectiveness of DOACs compared with warfarin for clinical events according to the presence or absence of HF.
Methods
Patients
The design and results of the ANAFIE Registry have been reported in detail. 13 , 14 Briefly, all patients were aged ≥75 years and diagnosed with non‐valvular AF and were able to visit outpatient clinics. Patients with cardiovascular events including stroke and myocardial infarction, cardiac intervention, HF requiring hospitalization, or any bleeding leading to hospitalization within 1 month prior to enrolment were excluded. Patients with life expectancy of <1 year were also excluded. The ANAFIE Registry complied with the Declaration of Helsinki; local requirements for registries and ethical guidelines for clinical studies in Japan were met. Ethical approval was obtained from all relevant institutional review boards, and all patients provided written informed consent and were free to withdraw from the registry at any time. The name of principal ethics committee was The Ethics Committees of The Cardiovascular Institute (Tokyo, Japan) and the number was 299.
HF was diagnosed by each clinician based on the HF guidelines of the Japanese Circulation Society/Japanese Heart Failure Society in association with those of the European Society of Cardiology and American College of Cardiology/American Heart Association. 15 , 16 , 17 Coexistence of left ventricular systolic dysfunction was separately reported. Types of anticoagulation (DOAC or warfarin) were based on the prescription at baseline.
Outcomes
The clinical outcomes analysed in this study were stroke/systemic embolism, major bleeding, HF hospitalization or cardiovascular death, cardiovascular events, cardiovascular death, all‐cause death, and net clinical outcome. Event definitions were prespecified and identical to previous reports of the ANAFIE Registry. 13 Cardiovascular events included non‐fatal stroke, non‐fatal myocardial infarction, cardiac intervention for ischaemic heart diseases other than myocardial infarction, HF requiring hospitalization, and cardiovascular death. Net clinical outcome was defined as the composite of stroke/systemic embolism, major bleeding, and all‐cause death. All events were adjudicated by event evaluation committees blinded to anticoagulation treatment.
Statistical analysis
Analysis was performed using the full analysis set, which included all enrolled patients but excluded patients with protocol violations (i.e. not meeting all inclusion criteria or meeting any of the exclusion criteria), lack of follow‐up visits after obtaining informed consent, and other reasons. Continuous variables were expressed as mean ± standard deviation and analysed using the t‐test or one‐way analysis of variance. Categorical variables were expressed as raw numbers and percentages and compared using the χ 2 test. Outcomes were assessed at 2 years after obtaining informed consent, and the effect of oral anticoagulation (OAC) therapy on outcomes was analysed by the history of HF and type of OAC at enrolment.
The occurrence of primary and secondary endpoints was analysed with Kaplan–Meier curves and also described as rate per 100 person‐years with 95% confidence intervals (CIs). For the comparison of the risk of clinical events between DOAC use and warfarin use, the Cox proportional hazards model was used, with hazard ratios (HRs) and 95% CIs calculated using the warfarin group as a reference. In this analysis, patients who did not receive anticoagulation therapy at baseline were excluded because of the aim of the study. The multivariate Cox proportional hazards model included age, sex, body mass index, history of major bleeding, type of AF, hypertension, severe hepatic disease, diabetes, hyperuricaemia, dyslipidaemia, history of myocardial infarction, cerebrovascular disease, thrombo‐embolic disease, active cancer, dementia, fall within 1 year, type of OAC therapy, history of catheter ablation, creatinine clearance, digestive diseases, polypharmacy, and use of antiarrhythmic drugs, antiplatelet drugs, proton pump inhibitors, and P‐glycoprotein inhibitors as covariables. As a sensitivity analysis, one‐to‐one matching in each group stratified by patients with and without HF using the nearest neighbour match on the logit of the propensity score for DOAC use with the calliper width set to 0.20 times the standard deviation of the logit of the propensity score was performed to compare the risks for events between DOAC and warfarin use. The propensity score was calculated using the same covariables as those used in the Cox proportional hazards model. A two‐sided P value < 0.05 indicated statistical significance. All statistical analyses were performed using SAS Version 9.4 (SAS Institute, Tokyo, Japan).
Results
Patient characteristics
A total of 33 062 patients were enrolled in the ANAFIE Registry. After excluding patients for protocol violations, lack of visits, or other reasons, 32 275 patients were analysed in this study. Of these, 12 116 (37.5%) had a history of HF (the HF group) and 20 159 (62.5%) did not (the non‐HF group) (Table 1 ). In patients with HF, 521 patients (4.3% of 12 116 patients with HF) were reported to have left ventricular systolic dysfunction. Mean age was higher in the HF group. Systolic/diastolic blood pressure and creatinine clearance were lower in the HF group. CHADS2, CHA2DS2‐VASc, and HAS‐BLED scores were higher in the HF group. Persistent, long‐standing persistent, and permanent AF were more frequently observed in the HF group, while paroxysmal AF was more frequently observed in the non‐HF group. Patients in the HF group more frequently had comorbidities. Over 90% of patients in both groups received OAC therapy, whereas the proportion of DOAC use was significantly higher in the non‐HF group compared with the HF group (68.5% in the non‐HF group vs. 64.2% in the HF group, P < 0.001).
Table 1.
Patient characteristics according to history of heart failure
| Total (N = 32 275) | HF group (N = 12 116) | Non‐HF group (N = 20 159) | P value | |
|---|---|---|---|---|
| Male | 18 482 (57.3) | 6476 (53.4) | 12 006 (59.6) | <0.001 |
| Age, years | 81.5 ± 4.8 | 82.4 ± 5.1 | 80.9 ± 4.6 | <0.001 |
| BMI, kg/m2 | 23.3 ± 3.6 | 23.2 ± 3.8 | 23.4 ± 3.4 | <0.001 |
| SBP, mmHg | 127.4 ± 17.0 | 124.8 ± 17.5 | 128.9 ± 16.5 | <0.001 |
| DBP, mmHg | 70.6 ± 11.6 | 69.3 ± 11.8 | 71.4 ± 11.5 | <0.001 |
| CCr, mL/min | 48.4 ± 18.2 | 43.3 ± 17.3 | 51.6 ± 18.1 | <0.001 |
| CHADS2 score | 2.9 ± 1.2 | 3.6 ± 1.1 | 2.4 ± 1.0 | <0.001 |
| CHA2DS2‐VASc score | 4.5 ± 1.4 | 5.3 ± 1.3 | 4.0 ± 1.2 | <0.001 |
| HAS‐BLED score | 1.9 ± 0.9 | 2.0 ± 0.9 | 1.8 ± 0.8 | <0.001 |
| History of major bleeding | 1439 (4.5) | 620 (5.1) | 819 (4.1) | <0.001 |
| LV systolic dysfunction | 682 (2.1) | 521 (4.3) | 161 (0.8) | <0.001 |
| AF type | ||||
| Paroxysmal AF | 13 586 (42.1) | 3664 (30.2) | 9922 (49.2) | |
| Persistent AF | 5336 (16.5) | 2172 (17.9) | 3164 (15.7) | <0.001 |
| Long‐standing persistent AF | 4365 (13.5) | 1998 (16.5) | 2367 (11.7) | |
| Permanent AF | 8988 (27.8) | 4282 (35.3) | 4706 (23.3) | |
| History of non‐pharmacological therapy for AF | ||||
| Catheter ablation | 2970 (9.2) | 851 (7.0) | 2119 (10.5) | <0.001 |
| Electrical defibrillation | 715 (2.2) | 324 (2.7) | 391 (1.9) | <0.001 |
| ICD | 151 (0.5) | 79 (0.7) | 72 (0.4) | <0.001 |
| Pacemaker | 2358 (7.3) | 1106 (9.1) | 1252 (6.2) | <0.001 |
| Other | 112 (0.3) | 51 (0.4) | 61 (0.3) | 0.08 |
| Comorbidities | ||||
| Hypertension | 24 312 (75.3) | 9290 (76.7) | 15 022 (74.5) | <0.001 |
| Diabetes mellitus | 8733 (27.1) | 3876 (32.0) | 4857 (24.1) | <0.001 |
| Chronic kidney disease | 6705 (20.8) | 3368 (27.8) | 3337 (16.6) | <0.001 |
| History of cerebrovascular disease | 7303 (22.6) | 2906 (24.0) | 4397 (21.8) | <0.001 |
| Gastrointestinal disease | 9467 (29.3) | 4326 (35.7) | 5141 (25.5) | <0.001 |
| Active cancer | 3569 (11.1) | 1407 (11.6) | 2162 (10.7) | 0.014 |
| Dementia | 2512 (7.8) | 1228 (10.1) | 1284 (6.4) | <0.001 |
| Fall within 1 year | 2347 (7.3) | 1032 (8.5) | 1315 (6.5) | <0.001 |
| Medication | ||||
| OAC | 29 830 (92.4) | 11 374 (93.9) | 18 456 (91.6) | <0.001 |
| Warfarin | 8233 (25.5) | 3592 (29.6) | 4641 (23.0) | <0.001 |
| DOAC | 21 585 (66.9) | 7780 (64.2) | 13 805 (68.5) | <0.001 |
| Antiplatelet | 5704 (18.6) | 2261 (19.4) | 3443 (18.1) | 0.007 |
AF, atrial fibrillation; BMI, body mass index; CCr, creatinine clearance; DBP, diastolic blood pressure; DOAC, direct oral anticoagulant; HF, heart failure; ICD, implantable cardioverter defibrillator; LV, left ventricular; OAC, oral anticoagulation; SBP, systolic blood pressure.
Values are mean ± standard deviation or n (%).
Outcomes by the presence or absence of heart failure
The incidence of stroke/systemic embolism, major bleeding, HF hospitalization or cardiovascular death, cardiovascular events, cardiovascular death, all‐cause death, and net clinical outcome was significantly higher in the HF group (Table 2 and Figure 1 ). After adjustment, history of HF was significantly associated with HF hospitalization or cardiovascular death, cardiovascular events, cardiovascular death, all‐cause death, and net clinical outcome, but not with stroke/systemic embolism or major bleeding (Figure 2 ).
Table 2.
Incidence rates of clinical events
| HF group (n = 12 116) | Non‐HF group (n = 20 159) | |
|---|---|---|
| Incidence rate | Incidence rate | |
| 100 person‐years (95% CI) | 100 person‐years (95% CI) | |
| Stroke/SE | 1.80 (1.63–1.98) | 1.52 (1.40–1.65) |
| Major bleeding | 1.29 (1.14–1.44) | 0.95 (0.85–1.05) |
| HF hospitalization or CV death | 7.45 (7.09–7.82) | 2.46 (2.30–2.62) |
| CV events | 9.23 (8.82–9.64) | 4.05 (3.84–4.25) |
| CV death | 1.74 (1.56–1.91) | 0.70 (0.62–0.78) |
| All‐cause death | 5.34 (5.04–5.64) | 2.76 (2.59–2.92) |
| Net clinical outcome | 7.39 (7.03–7.75) | 4.41 (4.20–4.63) |
CI, confidence interval; CV, cardiovascular; HF, heart failure; SE, systemic embolism.
Figure 1.
Cumulative incidence of clinical outcomes stratified by the presence or absence of heart failure (HF). CV, cardiovascular; SE, systemic embolism.
Figure 2.
Adjusted hazard ratios (HRs) of coexistence of heart failure (HF) for clinical outcomes. Adjusted by age, sex, body mass index, history of major bleeding, type of atrial fibrillation, hypertension, severe hepatic disease, diabetes, hyperuricaemia, dyslipidaemia, history of myocardial infarction, cerebrovascular disease, thrombo‐embolic disease, active cancer, dementia, fall within 1 year, type of oral anticoagulation therapy, history of catheter ablation, creatinine clearance, digestive diseases, polypharmacy, and use of antiarrhythmic drugs, antiplatelet drugs, proton pump inhibitors, and P‐glycoprotein inhibitors. CI, confidence interval; CV, cardiovascular; SE, systemic embolism.
Patient characteristics according to the history of heart failure and anticoagulation therapy
Both the HF and non‐HF groups were divided according to the type of anticoagulation therapy (DOAC, warfarin, or no OAC) (Table 3 ). Mean age was lowest in the DOAC subgroup and highest in the no OAC subgroup in both the HF and non‐HF groups. Creatinine clearance was lowest in the no OAC subgroup in the HF group, whereas it was lowest in the warfarin subgroup in the non‐HF group. CHADS2 and CHA2DS2‐VASc scores were lowest in the no OAC subgroup in the patients without HF, whereas they were comparable among the three subgroups in the HF group. HAS‐BLED score was highest in the no OAC subgroup in the HF group. Paroxysmal AF was the most frequently observed AF type in the no OAC subgroup in both the HF and non‐HF groups (51.9% and 78.4%, respectively). Chronic kidney disease was more common in the warfarin subgroup in both the HF and non‐HF groups. Patients receiving antiplatelet drugs were the most frequent in the no OAC subgroup in both the HF and non‐HF groups.
Table 3.
Patient characteristics classified by history of heart failure and oral anticoagulation
| HF group | Non‐HF group | |||||||
|---|---|---|---|---|---|---|---|---|
| DOAC (N = 7780) | Warfarin (N = 3592) | No OAC (N = 742) | P value | DOAC (N = 13 805) | Warfarin (N = 4641) | No OAC (N = 1703) | P value | |
| Male | 4068 (52.3) | 2048 (57.0) | 358 (48.2) | <0.001 | 8023 (58.1) | 3061 (66.0) | 915 (53.7) | <0.001 |
| Age, years | 82.1 ± 4.9 | 82.7 ± 5.1 | 84.3 ± 5.9 | <0.001 | 80.7 ± 4.5 | 81.2 ± 4.6 | 81.5 ± 5.0 | <0.001 |
| BMI, kg/m2 | 23.3 ± 3.8 | 23.3 ± 3.8 | 22.5 ± 3.7 | <0.001 | 23.5 ± 3.4 | 23.4 ± 3.4 | 22.8 ± 3.4 | <0.001 |
| SBP, mmHg | 125.1 ± 17.3 | 123.8 ± 17.7 | 127.6 ± 19.0 | <0.001 | 129.1 ± 16.5 | 127.4 ± 16.4 | 131.1 ± 16.7 | <0.001 |
| DBP, mmHg | 69.7 ± 11.7 | 68.7 ± 11.9 | 68.7 ± 12.1 | <0.001 | 71.7 ± 11.5 | 70.8 ± 11.5 | 71.2 ± 11.2 | <0.001 |
| CCr, mL/min | 45.3 ± 16.8 | 39.9 ± 17.3 | 38.6 ± 18.8 | <0.001 | 52.9 ± 18.0 | 48.6 ± 18.1 | 49.0 ± 16.9 | <0.001 |
| CHADS2 score | 3.6 ± 1.1 | 3.6 ± 1.1 | 3.6 ± 1.1 | 0.78 | 2.4 ± 1.0 | 2.5 ± 1.1 | 2.2 ± 0.9 | <0.001 |
| CHA2DS2‐VASc score | 5.3 ± 1.3 | 5.3 ± 1.3 | 5.4 ± 1.3 | 0.11 | 4.0 ± 1.2 | 4.0 ± 1.2 | 3.8 ± 1.1 | <0.001 |
| HAS‐BLED score | 1.9 ± 0.9 | 2.0 ± 0.9 | 2.2 ± 1.0 | <0.001 | 1.8 ± 0.8 | 1.9 ± 0.9 | 1.8 ± 0.8 | <0.001 |
| History of major bleeding | 350 (4.5) | 191 (5.3) | 79 (10.6) | <0.001 | 531 (3.8) | 196 (4.2) | 91 (5.3) | 0.010 |
| LV systolic dysfunction | 299 (3.8) | 185 (5.2) | 36 (4.9) | 0.0045 | 102 (0.7) | 49 (1.1) | 10 (0.6) | 0.065 |
| AF type | ||||||||
| Paroxysmal AF | 2498 (32.1) | 780 (21.7) | 385 (51.9) | 6928 (50.2) | 1651 (35.6) | 1335 (78.4) | ||
| Persistent AF | 1478 (19.0) | 587 (16.3) | 106 (14.3) | <0.001 | 2323 (16.8) | 692 (14.9) | 149 (8.7) | <0.001 |
| Long‐standing persistent AF | 1239 (15.9) | 662 (18.4) | 97 (13.1) | 1537 (11.1) | 745 (16.1) | 83 (4.9) | ||
| Permanent AF | 2565 (33.0) | 1563 (43.5) | 154 (20.8) | 3017 (21.9) | 1553 (33.5) | 136 (8.0) | ||
| History of non‐pharmacological therapy for AF | 1392 (17.9) | 586 (16.3) | 167 (22.5) | <0.001 | 2362 (17.1) | 756 (16.3) | 413 (24.3) | <0.001 |
| Catheter ablation | 613 (7.9) | 162 (4.5) | 76 (10.2) | <0.001 | 1481 (10.7) | 338 (7.3) | 300 (17.6) | <0.001 |
| Electrical defibrillation | 222 (2.9) | 89 (2.5) | 13 (1.8) | 0.14 | 267 (1.9) | 97 (2.1) | 27 (1.6) | 0.43 |
| ICD | 40 (0.5) | 32 (0.9) | 7 (0.9) | 0.040 | 40 (0.3) | 22 (0.5) | 10 (0.6) | 0.048 |
| Pacemaker | 666 (8.6) | 353 (9.8) | 87 (11.7) | 0.004 | 790 (5.7) | 360 (7.8) | 102 (6.0) | <0.001 |
| Other | 26 (0.3) | 21 (0.6) | 4 (0.5) | 0.14 | 33 (0.2) | 18 (0.4) | 9 (0.5) | 0.052 |
| Comorbidities | ||||||||
| Hypertension | 5968 (76.7) | 2747 (76.5) | 574 (77.4) | 0.87 | 10 355 (75.0) | 3412 (73.5) | 1247 (73.2) | 0.058 |
| Diabetes mellitus | 2453 (31.5) | 1184 (33.0) | 238 (32.1) | 0.31 | 342 (20.1) | 1232 (26.5) | 3281 (23.8) | <0.001 |
| Chronic kidney disease | 1984 (25.5) | 1174 (32.7) | 209 (28.2) | <0.001 | 2127 (15.4) | 976 (21.0) | 232 (13.6) | <0.001 |
| History of cerebrovascular disease | 1893 (24.3) | 821 (22.9) | 191 (25.7) | 0.12 | 3067 (22.2) | 1052 (22.7) | 277 (16.3) | <0.001 |
| Gastrointestinal disease | 2783 (35.8) | 1246 (34.7) | 297 (40.0) | 0.022 | 3542 (25.7) | 1090 (23.5) | 508 (29.8) | <0.001 |
| Active cancer | 911 (11.7) | 395 (11.0) | 100 (13.5) | 0.14 | 1526 (11.1) | 451 (9.7) | 184 (10.8) | 0.039 |
| Dementia | 800 (10.3) | 312 (8.7) | 116 (15.6) | <0.001 | 890 (6.4) | 262 (5.6) | 132 (7.8) | 0.008 |
| Fall within 1 year | 640 (8.2) | 324 (9.0) | 68 (9.2) | 0.36 | 878 (6.4) | 336 (7.2) | 99 (5.8) | 0.048 |
| Medication | ||||||||
| Antiplatelet | 1209 (16.1) | 774 (22.2) | 277 (40.9) | <0.001 | 1954 (15.0) | 924 (21.0) | 563 (36.3) | <0.001 |
AF, atrial fibrillation; BMI, body mass index; CCr, creatinine clearance; DBP, diastolic blood pressure; DOAC, direct oral anticoagulant; HF, heart failure; ICD, implantable cardioverter defibrillator; LV, left ventricular; OAC, oral anticoagulation; SBP, systolic blood pressure.
Values are mean ± standard deviation or n (%).
Risks for clinical events with direct oral anticoagulant use compared with warfarin use
The incidence rate of clinical events in each OAC subgroup in the HF and non‐HF groups is provided in Supporting Information, Table S1 . Figure 3 shows the results of the multivariate Cox regression analysis for each clinical event comparing DOAC use and warfarin use. No significant interaction between the coexistence of HF and DOAC/warfarin use was observed for risks for any event, and DOAC use was similarly associated with a low risk of all events compared with warfarin use, irrespective of presence or absence of the history of HF.
Figure 3.
Adjusted hazard ratios (HRs) of direct oral anticoagulant (DOAC) use vs. warfarin use for clinical outcomes stratified by heart failure (HF) status. Adjusted by age, sex, body mass index, history of major bleeding, type of atrial fibrillation, hypertension, severe hepatic disease, diabetes, hyperuricaemia, dyslipidaemia, history of myocardial infarction, cerebrovascular disease, thrombo‐embolic disease, active cancer, dementia, fall within 1 year, history of catheter ablation, creatinine clearance, digestive diseases, polypharmacy, and use of antiarrhythmic drugs, antiplatelet drugs, proton pump inhibitors, and P‐glycoprotein inhibitors. CI, confidence interval; CV, cardiovascular; SE, systemic embolism.
The propensity score matching method was performed as a sensitivity analysis. Patient characteristics before and after matching are provided in Supporting Information, Tables S2 and S3 . Similar to the analysis using Cox proportional hazards models, no interaction was observed between the coexistence of HF and DOAC/warfarin use. DOAC use was associated with lower risks for stroke/systemic embolism, major bleeding, HF hospitalization or cardiovascular death, cardiovascular events, all‐cause death, and net clinical outcome compared with warfarin use (Table 4 ).
Table 4.
Hazard ratios for clinical events in propensity‐score‐matched patients
| HF group | Non‐HF group | Overall | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | P value | HR | 95% CI | P value | P value for interaction | HR | 95% CI | P value | ||
| Stroke/SE | Warfarin | ||||||||||
| DOAC | 0.82 | 0.63–1.06 | 0.13 | 0.83 | 0.66–1.04 | 0.10 | 0.86 | 0.82 | 0.69–0.98 | 0.026 | |
| Major bleeding | Warfarin | ||||||||||
| DOAC | 0.66 | 0.49–0.90 | 0.007 | 0.71 | 0.53–0.95 | 0.023 | 0.75 | 0.69 | 0.56–0.85 | <0.001 | |
| HF hospitalization or CV death | Warfarin | ||||||||||
| DOAC | 0.81 | 0.72–0.92 | 0.001 | 0.73 | 0.61–0.87 | <0.001 | 0.41 | 0.78 | 0.71–0.87 | <0.001 | |
| CV events | Warfarin | ||||||||||
| DOAC | 0.82 | 0.73–0.92 | 0.001 | 0.82 | 0.71–0.94 | 0.005 | 0.88 | 0.82 | 0.75–0.90 | <0.001 | |
| CV death | Warfarin | ||||||||||
| DOAC | 0.87 | 0.68–1.12 | 0.28 | 0.76 | 0.56–1.04 | 0.085 | 0.61 | 0.83 | 0.68–1.00 | 0.053 | |
| All‐cause death | Warfarin | ||||||||||
| DOAC | 0.91 | 0.79–1.05 | 0.20 | 0.79 | 0.67–0.93 | 0.005 | 0.34 | 0.85 | 0.77–0.95 | 0.004 | |
| Net clinical outcome | Warfarin | ||||||||||
| DOAC | 0.87 | 0.77–0.98 | 0.027 | 0.81 | 0.71–0.92 | 0.002 | 0.62 | 0.84 | 0.76–0.92 | <0.001 | |
CI, confidence interval; CV, cardiovascular; DOAC, direct oral anticoagulant; HF, heart failure; HR, hazard ratio; SE, systemic embolism.
Additional exploratory analyses based on creatinine clearance, AF type, and antiplatelet drug usage were performed in the HF group (Supporting Information, Tables S4 – S6 ). No significant interaction between creatinine clearance (≥50, 30–50, and <30 mL/min) and DOAC/warfarin use for any event was observed. Regarding AF type, DOAC use was significantly favourable for all‐cause death (HR 0.66, 95% CI 0.51–0.87, P = 0.003) and net clinical outcome (HR 0.71, 95% CI 0.56–0.89, P = 0.003) compared with warfarin only in patients with paroxysmal AF (P for interaction = 0.009 and 0.028, respectively). Regarding antiplatelet drug use, no interaction between antiplatelet drugs and DOAC/warfarin use for any event was observed.
Discussion
This subanalysis of the ANAFIE Registry firstly showed an association between the coexistence of HF with AF in elderly patients aged ≥75 years and the risk of clinical events such as HF hospitalization or cardiovascular events. This study secondly showed that DOAC usage was consistently associated with a lower risk for stroke/systemic embolism, major bleeding, HF hospitalization or cardiovascular death, cardiovascular events, cardiovascular death, all‐cause death, and net clinical outcome including stroke/systemic embolism, major bleeding, and all‐cause death, compared with warfarin usage regardless of the presence or absence of HF in elderly patients with non‐valvular AF. In this HF substudy, left ventricular systolic dysfunction was reported in only 4.3% of patients with HF. Thus, most patients with HF in this study were likely to have had HF with preserved ejection fraction (HFpEF). These results correspond with previous reports suggesting that AF is more prevalent in patients with HFpEF and that AF precedes HFpEF more frequently than HF with reduced ejection fraction (HFrEF). 18 , 19
The ANAFIE Registry included only elderly patients aged ≥75 years with non‐valvular AF, who are commonly seen in real‐world clinical practice. Subanalyses of pivotal phase 3 trials (median age 70–73 years) have reported an association between the coexistence of HF and a higher risk of cardiovascular events or mortality. 2 , 3 , 4 , 5 While it is difficult to compare our study directly with these previous studies, the incidence of stroke/systemic embolism and all‐cause/cardiovascular mortality in patients with or without HF in the ANAFIE Registry seems to be comparable with these previous studies. 2 , 3 , 4 , 5 After adjustment for potential confounders, HF was associated with a higher risk of HF hospitalization or cardiovascular death, cardiovascular events, cardiovascular death, all‐cause death, and net clinical outcomes. Thus, the coexistence of HF may still predict future cardiovascular morbidity or mortality in elderly non‐valvular AF patients, even though older age itself is strongly associated with stroke, HF, and mortality. 1 , 6 , 7
This study also investigated the effects of a history of HF on the association between DOAC/warfarin use and the risks of clinical outcomes. We assumed that impaired kidney function, high prevalence of persistent or permanent AF, and high rates of antiplatelet drug use, which have been reported to be associated with aging and with the coexistence of HF, might attenuate the beneficial effects of DOACs. 20 , 21 , 22 , 23 In fact, the characteristics of patients receiving DOACs or warfarin differed on some points (Table 3 ): Creatinine clearance was lower, left ventricular systolic dysfunction was frequently observed, paroxysmal AF was less frequently observed, permanent AF was frequently observed, and antiplatelet drugs were frequently prescribed in patients receiving warfarin compared with those receiving DOACs, with or without HF. These different patient characteristics might affect prognosis. 24 , 25 , 26 , 27 However, the multivariate Cox proportional hazards model revealed that a history of HF did not affect the effectiveness of anticoagulation therapy with DOACs compared with warfarin. Furthermore, we adjusted patients' background between those receiving DOACs and those receiving warfarin in the HF/non‐HF groups using the propensity score matching method. The results were quite similar to those of the Cox regression analysis, and the association between DOACs and a low risk for clinical events, regardless of the coexistence of HF, was robust. In addition, our subgroup analysis based on creatinine clearance, AF type, and antiplatelet drug use revealed that these factors only marginally affected the benefit of DOACs compared with warfarin. Therefore, DOAC use seemed to be approximately equally beneficial compared with warfarin in patients with and without HF, even if elderly patients with concomitant HF had impaired kidney function and persistent/permanent AF or used antiplatelet drugs.
Interestingly, DOAC use was associated with lower rates of HF hospitalization or cardiovascular death and cardiovascular events than warfarin, irrespective of the presence or absence of HF. The favourable association of DOACs for HF hospitalization or cardiovascular death was partially driven by the lower rate of cardiovascular death; however, the difference in HF hospitalization or cardiovascular death incidence between DOACs and warfarin was much larger than that of cardiovascular death. Thus, there might be a favourable effect of DOACs for HF itself. There are several potential reasons that may underly this association. One might be the lower incidence of bleeding with DOACs than with warfarin. 28 The potential benefits of DOACs for the prevention of atherosclerosis, atherothrombosis, and cardiac remodelling—which have been observed in animal studies—might be another possible explanation. 29 , 30 , 31 , 32 The association between DOAC use and HF prognosis, and the mechanism responsible for this association, should be addressed in further basic and clinical research. The subanalysis of ARISTOTLE showed that apixaban was not associated with a decrease in HF hospitalization. 2 The findings of our study were inconsistent with this, but the reason for this difference is difficult to determine. It is possible that the duration of taking DOACs might be involved: All patients started and continued to take apixaban for 2 years in ARISTOTLE, whereas the duration might have been longer in the ANAFIE Registry.
There are some potential limitations that should be acknowledged in this study. First, this analysis was post hoc, not prespecified. Nevertheless, it is of clinical importance to investigate the effects of this association on the outcomes and efficacy of anticoagulation in elderly patients using large‐scale registry data. Second, HF diagnosis was based on each investigator, and detailed data such as echocardiography, plasma B‐type natriuretic peptide levels, or the severity and clinical course of HF were not available. However, the previous report of the ANAFIE echocardiographic subcohort study, which included 1494 participants receiving a detailed echocardiographic test, has shown that left ventricular ejection fraction was 59.7 ± 12.3% in patients with HF (n = 611). 33 Thus, although detailed echocardiographic data were not available in this subanalysis, most patients with HF in this study may have HFpEF or HF with mildly reduced ejection fraction (HFmrEF). A previous meta‐analysis including 10 studies showed that DOAC use was associated with lower risks for stroke or systemic embolism and major bleeding in patients with AF and HFpEF or HFmrEF. 34 Our subanalysis presents similar results to this meta‐analysis in elderly patients; however, further study may be required to elucidate the effectiveness of DOAC use in older patients with AF and HFrEF. Third, recently emerging drugs such as angiotensin receptor‐neprilysin inhibitor (ARNI) and sodium‐glucose cotransporter‐2 (SGLT‐2) inhibitors were not used when the ANAFIE Registry was performed, 35 , 36 although apparent interaction has not been reported between SGLT‐2 inhibitors or ARNI and OAC therapy. Finally, this study was performed using an active‐comparator design, and most patients received OAC therapy at registration, which was prevalent use. Thus, although we investigated the association between DOAC use and the prevention of cardiovascular events or HF hospitalization, this does not prove a cause–effect relationship.
Conclusions
A history of HF was associated with a higher risk of cardiovascular events, cardiovascular death, all‐cause death, and net clinical outcome in elderly patients with non‐valvular AF commonly seen in routine clinical practice. DOACs were more favourable for stroke/systemic embolism, major bleeding, HF hospitalization or cardiovascular death, cardiovascular events, cardiovascular death, all‐cause death, and net clinical outcome than warfarin in these patients, regardless of the presence or absence of HF. These analyses might encourage the use of DOACs in elderly patients with non‐valvular AF, even those with a history of HF.
Conflict of interest
K.H. received remuneration from Daiichi Sankyo, Nippon Boehringer Ingelheim, Pfizer, Bristol‐Myers Squibb, Bayer, and Otsuka Pharmaceutical. H.I. received remuneration from Daiichi Sankyo, Bayer, and Bristol‐Myers Squibb and consultancy fee from Daiichi Sankyo. T.Yamas. received research funding from Bristol‐Myers Squibb, Bayer, and Daiichi Sankyo, manuscript fees from Daiichi Sankyo and Bristol‐Myers Squibb, and remuneration from Daiichi Sankyo, Bristol‐Myers Squibb, Bayer, Ono Pharmaceutical, Novartis, Otsuka Pharmaceutical, and Toa Eiyo. M.A. received research funding from Bayer and Daiichi Sankyo and remuneration from Bristol‐Myers Squibb, Nippon Boehringer Ingelheim, Bayer, and Daiichi Sankyo. H.A. received remuneration from Daiichi Sankyo. T.I. received research funding from Daiichi Sankyo and Bayer and remuneration from Daiichi Sankyo, Bayer, Nippon Boehringer Ingelheim, and Bristol‐Myers Squibb. Y.K. received remuneration from Daiichi Sankyo, Bristol‐Myers Squibb, and Nippon Boehringer Ingelheim. K.O. received remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, and Medtronic. W.S. received research funding from Bristol‐Myers Squibb, Daiichi Sankyo, and Nippon Boehringer Ingelheim and remuneration from Daiichi Sankyo, Pfizer Japan, Bristol‐Myers Squibb, Bayer, and Nippon Boehringer Ingelheim. S.S. received remuneration from Bristol‐Myers Squibb and Daiichi Sankyo. K.T. received remuneration from Daiichi Sankyo, Bayer, Bristol‐Myers Squibb, Otsuka, Novartis, and Abbott Medical. A.H. participated in a course endowed by Boston Scientific Japan and received research funding from Daiichi Sankyo and Bayer and remuneration from Bayer, Daiichi Sankyo, Bristol‐Myers Squibb, and Nippon Boehringer Ingelheim. M.Y. received remuneration from Nippon Boehringer Ingelheim and Daiichi Sankyo. T.Yamag. acted as an advisory board member of Daiichi Sankyo and received remuneration from Daiichi Sankyo and Bristol‐Myers Squibb. S.T. received research funding from Nippon Boehringer Ingelheim and remuneration from Daiichi Sankyo, Sanofi, Takeda, Chugai Pharmaceutical, Solasia Pharma, Bayer, Sysmex, Nipro, NapaJen Pharma, Gunze, and Atworking. T.K., Y.M., and A.T. are employees of Daiichi Sankyo. H.T. received remuneration from Otsuka Pharmaceutical, Takeda Pharmaceutical, Mitsubishi‐Tanabe Pharma, Daiichi Sankyo, Nippon Boehringer Ingelheim, Bayer, Pfizer, Novartis Pharma, MSD, Teijin Pharma, Bristol‐Myers Squibb, Kowa Pharmaceutical, and Astellas Pharma; research funding from Nippon Boehringer Ingelheim, Mitsubishi‐Tanabe Pharma, Japan Tobacco, Daiichi Sankyo, IQVIA Services Japan, Acterion Pharmaceuticals Japan, and Omron Healthcare; donations from Astellas Pharma, Novartis Pharma, Daiichi Sankyo, Takeda Pharmaceutical, Mitsubishi‐Tanabe Pharma, Teijin Pharma, and MSD; and consultancy from Nippon Boehringer Ingelheim, Bayer, Novartis Pharma, and Ono Pharmaceutical. S.I. declares no conflict of interest.
Funding
This work was supported by Daiichi Sankyo Co., Ltd.
Supporting information
Table S1. Incidence of events classified by heart failure and anticoagulation.
Table S2. Demographic and baseline characteristics of pre‐ and post‐propensity score matching in patients with HF, stratified by DOAC use or warfarin use.
Table S3. Demographic and baseline characteristics of pre‐ and post‐propensity score matching in patients without HF, stratified by DOAC or warfarin use.
Table S4. Standardized association between direct oral anticoagulant and clinical outcomes stratified by creatinine clearance in patients with heart failure.
Table S5. Standardized association between direct oral anticoagulant and clinical outcomes stratified by the type of atrial fibrillation in patients with heart failure.
Table S6. Standardized association between direct oral anticoagulant use and clinical outcomes stratified by use of antiplatelet drugs in patients with heart failure.
Acknowledgements
We thank the physicians, nurses, institutional staff, and patients involved in the ANAFIE Registry. We also thank IQVIA Services Japan and EP‐CRSU for their partial support in the conduct and the data analysis of this registry, which was funded by Daiichi Sankyo. The authors would also like to thank Helen Roberton of Edanz (www.edanz.com) for providing editing services, which were funded by Daiichi Sankyo, in accordance with Good Publication Practice (GPP 2022) guidelines (https://www.ismpp.org/gpp‐2022).
Ikeda, S. , Hiasa, K. , Inoue, H. , Yamashita, T. , Akao, M. , Atarashi, H. , Koretsune, Y. , Okumura, K. , Shimizu, W. , Suzuki, S. , Ikeda, T. , Toyoda, K. , Hirayama, A. , Yasaka, M. , Yamaguchi, T. , Teramukai, S. , Kimura, T. , Morishima, Y. , Takita, A. , and Tsutsui, H. (2024) Clinical outcomes and anticoagulation therapy in elderly non‐valvular atrial fibrillation and heart failure patients. ESC Heart Failure, 11: 902–913. 10.1002/ehf2.14550.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1. Incidence of events classified by heart failure and anticoagulation.
Table S2. Demographic and baseline characteristics of pre‐ and post‐propensity score matching in patients with HF, stratified by DOAC use or warfarin use.
Table S3. Demographic and baseline characteristics of pre‐ and post‐propensity score matching in patients without HF, stratified by DOAC or warfarin use.
Table S4. Standardized association between direct oral anticoagulant and clinical outcomes stratified by creatinine clearance in patients with heart failure.
Table S5. Standardized association between direct oral anticoagulant and clinical outcomes stratified by the type of atrial fibrillation in patients with heart failure.
Table S6. Standardized association between direct oral anticoagulant use and clinical outcomes stratified by use of antiplatelet drugs in patients with heart failure.