Effect of Cancer on Clinical Outcomes in Elderly Patients With Non-Valvular Atrial Fibrillation　― Substudy of the ANAFIE Registry ―

Takanori Ikeda; Takeshi Yamashita; Masaharu Akao; Hirotsugu Atarashi; Yukihiro Koretsune; Ken Okumura; Wataru Shimizu; Hiroyuki Tsutsui; Kazunori Toyoda; Atsushi Hirayama; Masahiro Yasaka; Takenori Yamaguchi; Satoshi Teramukai; Tetsuya Kimura; Jumpei Kaburagi; Atsushi Takita; Hiroshi Inoue

doi:10.1253/circj.CJ-21-0631

Abstract

Background: Data on outcomes for patients with atrial fibrillation (AF) and active cancer are scarce. The effect of active cancer on thrombosis and bleeding risks in elderly (≥75 years) patients with non-valvular AF (NVAF) enrolled in the All Nippon AF In the Elderly (ANAFIE) Registry were prospectively analyzed.

Methods and Results: In this subanalysis of the ANAFIE Registry, a prospective, multicenter, observational study conducted in Japan, we compared the incidence rates of clinical outcomes between active cancer and non-cancer groups. Relationships between primary outcomes and anticoagulation status were evaluated. Of the 32,725 patients enrolled in the Registry, 3,569 had active cancer at baseline; 92.0% of active cancer patients received anticoagulants (23.7%, warfarin; 68.2%, direct oral anticoagulants [DOACs]). Two-year probabilities of stroke/systemic embolic events (SEE) were similar in the cancer (3.33%) and non-cancer (3.16%) groups. Patients with cancer had greater incidences of major bleeding (2.86% vs. 2.04%), all-cause death (10.95% vs. 6.77%), and net clinical outcomes (14.63% vs. 10.00%) than those without cancer. In patients without cancer, DOACs were associated with a decreased risk of stroke/SEE, major bleeding, all-cause death, and net clinical outcome compared with warfarin. No between-treatment differences were observed in patients with active cancer.

Conclusions: Active cancer had no effect on stroke/SEE incidence in elderly NVAF patients, but those with cancer had higher incidences of major bleeding events and all-cause death than those without cancer.

Atrial fibrillation (AF) is the most common cardiac arrhythmia,¹ and the incidence and prevalence of AF increases sharply with age.²^,³ Cancer is one of the leading causes of death,⁴ and increases in incidence and prevalence according to advancing age.⁵ With the growth of aging populations, AF- and cancer-related complications are also expected to increase in the coming years.

Editorial p 211

Aside from aging, hypertension, obesity, diabetes, and smoking are independent predictors of AF.⁶ It has also been reported that patients with all major cancer subtypes, including prostate, colon, lung, hematological, and breast cancer, are at higher risk for developing AF compared with individuals without cancer.⁷ The risk of AF in cancer patients is also exacerbated by surgery or chemotherapy.⁸^,⁹ Although the underlying mechanisms are not completely understood, systemic inflammation, cancer-specific treatment, and autonomic dysregulation, are thought to be involved.⁸^,¹⁰ Therefore, elderly cancer patients are at high risk of developing AF.

Both AF and cancer are risk factors for stroke and death.⁷^,¹¹^,¹² Cancer is associated with a hypercoagulable state, which results in an increased risk of venous thromboembolism (VTE).¹³ Although death of cancer patients who experience a thromboembolic event may be directly caused by thrombosis, increased mortality that is not directly attributable to thrombotic events is also seen in cancer patients who develop VTE.¹⁴

To prevent stroke, systemic embolic events (SEE), and death among non-valvular AF (NVAF) patients at high risk of complications, current treatment guidelines¹⁵^,¹⁶ recommend oral anticoagulation with vitamin K antagonists or direct oral anticoagulants (DOACs); however, treating patients with AF and active cancer is especially challenging. In particular, the risk of bleeding in patients who are receiving anticoagulation is considerably higher in patients with cancer.¹⁷^,¹⁸ However, studies verifying the risk of thrombosis and bleeding in NVAF patients with cancer are scarce. Some reports, typically subanalyses of larger trials, have examined anticoagulation for patients with concomitant cancer and AF.¹⁹^,²⁰ A recent meta-analysis of oral anticoagulant use in patients with cancer and AF reported that DOACs were associated with a lower incidence of bleeding, thromboembolic complications, and all-cause death than warfarin.²¹ Overall, however, although the benefits of anticoagulation therapy for patients with AF have been reported,²²^–²⁵ data on the effects of DOACs on thrombosis and bleeding risk among AF patients with cancer remain limited.²⁶

The All Nippon AF In the Elderly (ANAFIE) Registry was a prospective, multicenter, observational study that enrolled >30,000 Japanese patients aged ≥75 years with NVAF.²⁷ The objective of this subanalysis was to evaluate the effect of active cancer on outcomes in elderly patients with NVAF using real-world data of patients enrolled in the ANAFIE Registry.

Methods

Study Design

Full details of the study design have been published previously.²⁸ In brief, the ANAFIE Registry was a multicenter, prospective registration, cohort study conducted in Japan between October 2016 and January 2020 (the registration period ended in January 2018). Follow-up data were collected at 12 and 24 months.²⁷ As it was an observational study, no treatments were mandated; instead, the treating physician selected antithrombotic therapy and the type of medication, dosage, and duration of treatment.

The ANAFIE Registry was approved by the ethics committees of the participating centers. The study was conducted in accordance with the Declaration of Helsinki and all applicable local and national requirements for clinical studies. All participants provided written informed consent, and patients were able to withdraw from participation at any time. The ANAFIE Registry was registered in the University hospital Medical Information Network Clinical Trials Registry (study identifier: UMIN000024006).

Patients

The study population consisted of ambulatory patients aged ≥75 years, with NVAF diagnosed by electrocardiogram, recruited from 1,273 medical institutions in Japan. Patients needed to be able to attend specified hospital visits.²⁸ Patients were excluded from enrollment if they were participating in or planning to participate in other interventional studies; they had a definitive diagnosis of mitral stenosis, mechanical or tissue heart valve prosthesis/prostheses, a recent history of significant cardiovascular events, or a life expectancy of <1 year; or their inclusion was otherwise deemed inappropriate by investigators.

Patients were classified into cancer and non-cancer groups for between-group comparisons. The cancer group consisted of elderly patients with NVAF and active cancer (primary cancer-bearing), defined as patients diagnosed with primary gastric, colorectal, lung, breast, uterine, ovarian, pancreatic, or other cancers, who were either treatment naïve, planned to undergo or undergoing cancer treatment, including chemotherapy, radiotherapy, or surgery for cancer resection,²⁹ and who had a life expectancy of ≥1 year at the time of providing informed consent. Additionally, as gastrointestinal (GI) bleeding has been reported as a complication of anticoagulant therapy, not only in patients with and without cancer but also among patients with GI cancers,³⁰ the data of patients with GI cancer were extracted to evaluate their anticoagulant therapy status.

Measures

The primary outcomes of interest were stroke/SEE, major bleeding, specifically including intracranial hemorrhage, all-cause death, and the net clinical outcome of stroke/SEE, major bleeding, and all-cause death. The relationships between the primary outcomes and anticoagulation status were evaluated, including the presence or absence of anticoagulants; the type of anticoagulants (DOACs vs. warfarin); and anticoagulant dosage. All endpoint events were adjudicated by event evaluation committees.

The DOAC dose categories were defined for each DOAC medication, taking into account serum creatinine, creatinine clearance, and/or other patient characteristics, as follows: (1) standard dose (per the approved label); (2) overdose (a dosage greater than those approved for use by the regulatory authorities); (3) reduced dose (dose reduction recommended in the approved labeling for special populations or to reduce toxicity); (4) underdose (on-label reduced dose that does not meet the approved dose-reduction criteria); and (5) off-label underdose (dosages less than the underdose level).

Statistical Methods

The present study analysis was performed using the full analysis set, which included all enrolled patients, but excluded patients with protocol violations (i.e., not meeting all of the inclusion criteria or meeting any of the exclusion criteria), lack of follow-up visits after obtaining informed consent, and other reasons. Data are shown as the number (%) of patients or mean±standard deviation (SD). Kaplan-Meier methodology was used to estimate the 2-year probabilities of stroke/SEE, major bleeding, and all-cause death by cancer presence or absence. Incidence rates per 100 person-years with 95% confidence intervals (CIs) were also estimated.

Univariate and multivariate analyses were performed by using the Cox proportional hazards model for each event. Hazard ratios (HR), 95% CIs, and P values were calculated for the presence or absence of cancer. Statistical analyses were undertaken using SAS version 9.4 or higher (SAS Institute Japan Ltd., Tokyo, Japan).

Results

Patient Disposition and Characteristics

Of the 32,725 patients enrolled in the ANAFIE Registry, 3,569 had an active cancer diagnosis at baseline. Among patients with active cancer, 1,416 had GI cancer (Figure 1). Characteristics of patients in the cancer and non-cancer groups are summarized in Table 1. Characteristics of the patients in the GI cancer group are shown in Supplementary Table 1. Baseline characteristics were similar between the 2 groups, except for the cancer group having a higher frequency of male patients, prior major bleeding, and GI diseases.

Figure 1.

Patient disposition. GI, gastrointestinal.

Table 1. Patient Characteristics

Characteristics	Non-cancer group (n=28,706)	Cancer group (n=3,569)	P value***
Male	15,930 (55.5)	2,552 (71.5)	<0.001
Age, years	81.5±4.8	81.4±4.5	0.149
≥85	7,546 (26.3)	873 (24.5)	<0.001
BMI, kg/m²	23.4±3.6	23.1±3.6	<0.001
SBP, mmHg	127.5±16.9	126.6±17.7	0.005
DBP, mmHg	70.7±11.6	70.2±11.8	0.017
Creatinine clearance, mL/min	48.4±18.4	48.0±17.1	0.217
CHADS₂ score	2.8±1.2	3.0±1.2	<0.001
CHA₂DS₂-VASc score	4.5±1.4	4.5±1.5	0.458
HAS-BLED score	1.8±0.8	2.1±0.9	<0.001
Antithrombotic drugs
OACs	26,535 (92.4)	3,283 (92.0)	0.531
Warfarin	7,387 (25.7)	846 (23.7)	0.012
Time in therapeutic range*, %	75.8±29.6	72.4±31.4	0.004
Dabigatran	2,089 (7.3)	258 (7.2)	0.975
Rivaroxaban	5,742 (20.0)	661 (18.5)	0.047
Apixaban	7,073 (24.6)	972 (27.2)	<0.001
Edoxaban	4,244 (14.8)	546 (15.3)	0.351
Antiplatelets	5,611 (19.5)	640 (17.9)	0.538
Combined use of the OACs and antiplatelets	4,290 (14.9)	574 (16.1)	<0.001
History of major bleeding	1,194 (4.2)	245 (6.9)	<0.001
Type of AF			0.365
Paroxysmal	12,052 (42.0)	1,534 (43.0)
Persistent	4,781 (16.7)	555 (15.6)
Long-term persistent/permanent	11,873 (41.4)	1,480 (41.5)
History of non-pharmacological therapy for AF	4,982 (17.4)	695 (19.5)	0.002
Catheter ablation	2,598 (9.1)	372 (10.4)	0.008
Comorbidities
Hypertension	21,656 (75.4)	2,656 (74.4)	0.182
Diabetes mellitus	7,597 (26.5)	1,136 (31.8)	<0.001
Chronic kidney disease	5,905 (20.6)	800 (22.4)	0.010
Myocardial infarction	1,576 (5.5)	275 (7.7)	<0.001
Heart failure**	10,709 (37.3)	1,407 (39.4)	0.014
History of cerebrovascular disease	6,402 (22.3)	901 (25.2)	<0.001
GI diseases	7,945 (27.7)	1,522 (42.6)	<0.001
Dementia	2,264 (7.9)	248 (6.9)	0.049
Falls within 1 year	2,070 (7.2)	277 (7.8)	0.050

Data are presented as n (%) or mean±standard deviation. *Target international normalized ratio of prothrombin time was between 1.6 and 2.6. **Including non-congestive or controlled heart failure. ***Non-cancer group vs. cancer group. AF, atrial fibrillation; BMI, body mass index; DBP, diastolic blood pressure; GI, gastrointestinal; OAC, oral anticoagulant; SBP, systolic blood pressure.

Anticoagulant Use in Patients With Cancer

The distributions of oral anticoagulant use are shown in Table 1. Warfarin was used by 25.7% of patients in the non-cancer group, compared with 23.7% in the cancer group (P=0.012). Warfarin treatment was considered to be well managed in the cancer group, with a time in the therapeutic range of 72.4%. The remaining 66.7% and 68.3% of patients in the non-cancer and cancer groups, respectively, were taking DOACs. Similar proportions of patients using warfarin and DOACs were observed in the GI cancer groups.

Supplementary Table 2 shows the distributions of DOACs by dose category in the non-cancer and cancer groups and by cancer type. Of note, 43.2–44.4% of patients were receiving a reduced DOAC dose. Roughly similar proportions of patients (16.6–18.3%) were receiving a standard dose or an underdose of DOACs in the non-cancer and cancer groups, as well as the GI cancer groups. The proportions of patients receiving an overdose or an off-label underdose were low in the GI cancer groups, ranging from 3.0% to 3.7%. Overall, the distributions of DOACs were similar in the non-cancer and cancer groups.

Outcomes

The probability of each event in the presence and absence of cancer is shown as a Kaplan-Meier curve in Figure 2. The 2-year probabilities in the cancer vs. non-cancer groups for stroke/SEE (3.33% vs. 3.16%), intracranial hemorrhage (ICH) (1.79% vs. 1.45%), and cardiovascular death (1.99% vs. 2.20%) were similar. However, higher 2-year probabilities were observed for major bleeding (2.86% vs. 2.04%), all-cause death (10.95% vs. 6.77%), and net clinical outcomes (14.63% vs. 10.00%) in the cancer group compared with the non-cancer group.

Figure 2.

Kaplan-Meier curves for the probability of stroke/SEE, major bleeding, ICH, all-cause death, cardiovascular death, and net clinical outcome occurrence by presence or absence of cancer. Percentages show 2-year probabilities. *Net clinical outcome: stroke/SEE, major bleeding, and all-cause mortality. ICH, intracranial hemorrhage; SEE, systemic embolic events.

The incidence (assessed per 100 person-years) of stroke/SEE was similar between the cancer group (1.71 [95% CI: 1.39, 2.03]) and the non-cancer group (1.61 [95% CI: 1.51, 1.72]; (HR: 1.00; 95% CI: 0.82, 1.22; P=0.999, Table 2). Except for cardiovascular death, the incidences of all bleeding events, major bleeding, ICH, GI bleeding, all-cause death, and the net clinical outcome were higher in the cancer group compared with the non-cancer group.

Table 2. Event Breakdown by Non-Cancer and Cancer Groups, and Incidence of Events

Event	Non-cancer group (n=28,706)			Cancer group (n=3,569)			HR (95% CI)	P value
Event	Patient- years	Events, n	Incidence, per 100 patient- years (95% CI)	Patient- years	Events, n	Incidence, per 100 patient- years (95% CI)	HR (95% CI)	P value
Stroke/SE	53,251	860	1.61 (1.51, 1.72)	6,446	110	1.71 (1.39, 2.03)	1.00 (0.82, 1.22)	0.999
Stroke	53,271	838	1.57 (1.47, 1.68)	6,449	107	1.66 (1.34, 1.97)	1.00 (0.81, 1.22)	0.963
Ischemic stroke	53,376	664	1.24 (1.15, 1.34)	6,468	79	1.22 (0.95, 1.49)	0.95 (0,75, 1.20)	0.656
Hemorrhagic stroke	53,777	173	0.32 (0.27, 0.37)	6,508	28	0.43 (0.27, 0.59)	1.17 (0.78, 1.77)	0.439
SE	53,856	25	0.05 (0.03, 0.06)	6,524	3	0.05 (−0.01, 0.10)	0.96 (0.28, 3.28)	0.954
All bleeding*	51,949	2,177	4.19 (4.01, 4.37)	6,176	380	6.15 (5.53, 6.77)	1.32 (1.18, 1.48)	<0.001
Major bleeding	53,511	549	1.03 (0.94, 1.11)	6,463	96	1.49 (1.19, 1.78)	1.34 (1.08, 1.68)	0.009
Intracranial hemorrhage	53,625	256	0.73 (0.66, 0.81)	6,486	60	0.93 (0.69, 1.16)	1.19 (0.90, 1.57)	0.222
GI bleeding	52,955	978	1.85 (1.73, 1.96)	6,377	161	2.52 (2.13, 2.91)	1.17 (0.99, 1.39)	0.065
All deaths	53,879	1,866	3.46 (3.31, 3.62)	6,527	376	5.76 (5.18, 6.34)	1.54 (1.38, 1.73)	<0.001
Cardiovascular death	53,879	589	1.09 (1.00, 1.18)	6,527	66	1.01 (0.77, 1.26)	0.86 (0.67, 1.12)	0.266
Net clinical outcome**	52,999	2,768	5.22 (5.03, 5.42)	6,401	505	7.89 (7.20, 8.58)	1.41 (1.28, 1.55)	<0.001

*Includes major, clinically significant, and minor bleeds. **A composite of stroke, SE, major bleeding, and all deaths. CI, confidence interval; GI, gastrointestinal; HR, hazard ratio; SE, systemic embolism.

The effect of DOACs vs. warfarin on outcomes in cancer and non-cancer groups is shown in Table 3. In the non-cancer group, DOAC use (n=19,148) was associated with a decreased risk of stroke/SEE, stroke, ischemic stroke, all bleeding, major bleeding, ICH, all-cause death, cardiovascular death, and the net clinical outcome as compared with warfarin use (n=7,387). However, in the cancer group, no differences were observed between warfarin (n=846) and DOAC use (n=2,437) for any outcomes. The 2-year probabilities of each event in the cancer vs. non-cancer groups treated with DOACs vs. warfarin are shown in the Supplementary Figure. In the cancer group, the 2-year probabilities among patients using DOACs vs. warfarin were similar for stroke/SEE (3.24% vs. 3.42%), major bleeding (2.82% vs. 2.68%), and ICH (1.82% vs 1.79%); however, numerically lower 2-year probabilities were observed for all-cause death (10.23% vs. 11.97%), cardiovascular death (1.76% vs. 2.57%), and net clinical outcomes (13.84% vs. 15.52%) among patients with cancer treated with DOACs vs. warfarin. In the non-cancer group, DOAC use was associated with a lower 2-year probability of all events compared with warfarin use.

Table 3. Effect of Anticoagulants (DOACs vs. Warfarin) on Incidence of Primary Outcomes

Event	Anticoagulant	Non-cancer group					Cancer group
		Event, n (%)	Univariate		Multivariate		Event, n (%)	Univariate		Multivariate
		Event, n (%)	HR (95% CI)	P value	HR (95% CI)	P value	Event, n (%)	HR (95% CI)	P value	HR (95% CI)	P value
Stroke/SE	Warfarin	272 (3.68)	–	–	–	–	26 (3.07)	–	–	–	–
Stroke/SE	DOAC	510 (2.66)	0.71 (0.61, 0.82)	<0.001	0.78 (0.67, 0.91)	0.002	74 (3.04)	0.97 (0.62, 1.51)	0.876	1.07 (0.67, 1.70)	0.777
Stroke	Warfarin	262 (3.55)	–	–	–	–	25 (2.96)	–	–	–	–
Stroke	DOAC	499 (2.61)	0.72 (0.62, 0.84)	<0.001	0.79 (0.68, 0.92)	0.003	73 (3.00)	0.99 (0.63, 1.56)	0.970	1.09 (0.68, 1.75)	0.720
Ischemic stroke	Warfarin	207 (2.80)	–	–	–	–	20 (2.36)	–	–	–	–
Ischemic stroke	DOAC	388 (2.03)	0.71 (0.60, 0.84)	<0.001	0.79 (0.67, 0.94)	0.009	51 (2.09)	0.86 (0.51, 1.45)	0.573	0.95 (0.55, 1.63)	0.855
Hemorrhagic stroke	Warfarin	55 (0.74)	–	–	–	–	5 (0.59)	–	–	–	–
Hemorrhagic stroke	DOAC	109 (0.57)	0.75 (0.54, 1.04)	0.086	0.79 (0.56, 1.10)	0.157	22 (0.90)	1.50 (0.57, 3.95)	0.416	1.52 (0.55, 4.22)	0.423
SE	Warfarin	12 (0.16)	–	–	–	–	1 (0.12)	–	–	–	–
SE	DOAC	12 (0.06)	0.38 (0.17, 0.85)	0.018	0.48 (0.21, 1.11)	0.087	1 (0.04)	0.34 (0.02, 5.41)	0.444	0.41 (0.00, –)	1.000
All bleeding*	Warfarin	664 (8.99)	–	–	–	–	85 (10.05)	–	–	–	–
All bleeding*	DOAC	1,424 (7.44)	0.81 (0.74, 0.89)	<0.001	0.88 (0.80, 0.97)	0.011	266 (10.92)	1.07 (0.84, 1.36)	0.607	1.19 (0.93, 1.54)	0.170
Major bleeding	Warfarin	195 (2.64)	–	–	–	–	21 (2.48)	–	–	–	–
Major bleeding	DOAC	324 (1.69)	0.63 (0.53, 0.75)	<0.001	0.69 (0.57, 0.83)	<0.001	65 (2.67)	1.05 (0.64, 1.72)	0.846	1.08 (0.64, 1.80)	0.779
Intracranial hemorrhage	Warfarin	142 (1.92)	–	–	–	–	14 (1.65)	–	–	–	–
Intracranial hemorrhage	DOAC	228 (1.19)	0.61 (0.49, 0.75)	<0.001	0.64 (0.51, 0.79)	<0.001	42 (1.72)	1.02 (0.56, 1.87)	0.949	1.07 (0.57, 2.04)	0.827
GI bleeding	Warfarin	283 (3.83)	–	–	–	–	33 (3.90)	–	–	–	–
GI bleeding	DOAC	648 (3.38)	0.87 (0.76, 1.00)	0.049	0.96 (0.83, 1.11)	0.597	115 (4.72)	1.18 (0.80, 1.74)	0.394	1.29 (0.86, 1.93)	0.223
All-cause death	Warfarin	631 (8.54)	–	–	–	–	97 (11.47)	–	–	–	–
All-cause death	DOAC	1,038 (5.42)	0.62 (0.56, 0.69)	<0.001	0.81 (0.73, 0.90)	<0.001	240 (9.85)	0.83 (0.66, 1.06)	0.134	1.04 (0.81, 1.33)	0.746
Cardiovascular death	Warfarin	211 (2.86)	–	–	–	–	20 (2.36)	–	–	–	–
Cardiovascular death	DOAC	311 (1.62)	0.56 (0.47, 0.66)	<0.001	0.79 (0.66, 0.95)	0.010	40 (1.64)	0.68 (0.39, 1.16)	0.152	0.83 (0.47, 1.44)	0.505
Net clinical outcome**	Warfarin	908 (12.29)	–	–	–	–	126 (14.89)	–	–	–	–
Net clinical outcome**	DOAC	1,598 (8.35)	0.66 (0.61, 0.72)	<0.001	0.81 (0.74, 0.88)	<0.001	327 (13.42)	0.88 (0.71, 1.08)	0.212	1.06 (0.85, 1.31)	0.622

*Includes major, clinically significant, and minor bleeds. **A composite of stroke, SE, major bleeding, and all-cause deaths. The multivariate analysis model included the following explanatory variables: sex, age (<85 years/≥85 years), BMI, history of major bleeding, AF type, hypertension, severe hepatic dysfunction, diabetes, hyperuricemia, heart disease (heart failure, left ventricular systolic dysfunction), heart disease (myocardial infarction), cerebrovascular disorder, thrombosis/embolism-related disease, dementia, fall within 1 year, catheter ablation, arrhythmia drug, anti-platelet drugs, proton pump inhibitors, P-glycoprotein inhibitors, dyslipidemia, creatinine clearance, GI disorders, and polypharmacy (≥5 drugs). DOAC, direct oral anticoagulant. Other abbreviations as in Tables 1,2.

In the GI-cancer group, the risk of GI bleeding did not significantly increase in the OAC group compared with the no-OAC group (1.63 [95% CI: 0.46, 5.77], P=0.446, Supplementary Table 3). Further, there was no significant difference in GI bleeding between the DOAC (n=958) and warfarin (n=343) groups (1.56 [95% CI: 0.71, 3.45], P=0.269, Supplementary Table 3).

Discussion

In this subanalysis of the ANAFIE Registry population, we evaluated, for the first time, the real-world status of anticoagulation therapy and the effect of active cancer on outcome events in patients with AF in the era of DOAC therapy. Major findings of the present study are as follows. First, the 2-year probability of stroke in the cancer group was 3.33%, which was similar to that in the non-cancer group at 3.16%; however, patients with cancer did have greater incidence rates of major bleeding, ICH, all-cause death, and net outcomes. Second, a slightly higher proportion of patients in the cancer group (68.2%) received DOACs than in the non-cancer group (66.7%). Third, in the non-cancer group, DOAC use was associated with decreased risks of stroke/SEE, major bleeding, all-cause death, and net clinical outcome compared with warfarin use; no difference was observed between warfarin and DOAC use among patients with cancer.

Events in Patients With AF and Cancer

A recent retrospective, single-center study on a small group of patients (n=224) with active cancer and AF in Japan reported similar incidences of thromboembolic events (3.8%/year) and major bleeding (4.9%/year)³¹ to the present study results. These rates, as well as our own, are higher than those reported in another large-scale AF registry study for stroke/SEE and major bleeding, the Fushimi Registry (2.3%/year and 1.8%/year, respectively),³² but were similar to those reported in the SAKURA AF Registry (4.1% and 3.8%, respectively).³³ However, neither of these registries focused on outcomes of patients with NVAF and active cancer, so direct comparisons are not possible. An analysis of patients with active malignancies in the ENGAGE AF-TIMI 48 trial concluded that patients with malignancy and AF were at a higher risk of death and major bleeding, but not of stroke/SEE,¹⁹ a finding consistent with the present study.

Safety and Efficacy of DOACs vs. Warfarin in Patients With AF and Cancer

In the present subanalysis, the effect of anticoagulants on outcomes between cancer and non-cancer groups differs somewhat from previous observations. The ENGAGE AF-TIMI 48 trial showed the relative frequencies of stroke/SEE and major bleeding were not different between warfarin and edoxaban regardless of presence or absence of malignancy; however, edoxaban had greater efficacy than warfarin in reducing the composite ischemic endpoint of ischemic stroke/SEE/myocardial infarction in patients with malignancy compared with patients without malignancy.¹⁹ The ARISTOTLE trial concluded that apixaban consistently demonstrated superior safety and efficacy compared with warfarin in patients with and without a history of cancer.²⁰ By contrast, a recent, small, single-center, retrospective cohort study of Japanese patients with cancer and AF (n=224, mean age 72.7 years) who were followed up for 12 months reported different results; the incidence of stroke/SEE (2.8%/year vs. 5.4%/year) or major bleeding (4.0%/year vs. 6.5%/year) did not differ between patients treated with DOACs and warfarin.³¹ Thus, our results were consistent with those of a previous Japanese study,³¹ but not with those of the ENGAGE AF-TIMI 48 trial and ARISTOTLE trial.³⁴^,³⁵

The differences in results between the present subanalysis and global, randomized controlled trials, that is, ENGAGE AF-TIMI 48 and ARISTOTLE, might be attributable to differences in the DOACs used and their doses, as well as in the target prothrombin time-international standard ratio (PT-INR) of warfarin. As the target PT-INR of warfarin was lower in the ANAFIE Registry (1.6–2.6) due to patients’ ages, the incidence rate of major bleeding caused by warfarin was lower than that found in global trials. The low incidence of major bleeding caused by warfarin may be one of the reasons for the lack of benefit of DOACs compared with warfarin in the cancer group of the ANAFIE Registry. Although we expected to observe differences in the rates of stroke/SEE, the present study results indicate that DOACs might offer similar benefits with warfarin in terms of reducing the risk of stroke/SEE for elderly Japanese patients with active cancer. In addition, patients with cancer and AF have overlapping risk factors for age-related cardiovascular disease.³⁶ In our study, ANAFIE patients with and without cancer had a similar cardiovascular mortality. However, in those with cancer, the all-cause mortality was 5.7-fold higher than the cardiovascular mortality, compared with 3.2-fold higher in those without cancer. The overall mortality among patients with cancer was also high. These results may also have confounded our ability to observe between-group differences in the effects of DOACs.

It is also possible that drug–drug interactions may have affected the present outcomes, specifically for major bleeding events and all-cause death. It is known that some DOACs are substrates of CYP3A4,³⁷ so there may be potential for CYP3A4-mediated drug interactions with anticancer drugs. However, concomitant administration of warfarin with anticancer drugs can also be subject to drug–drug interactions, resulting in increased anticoagulant effects of warfarin.³⁸ These interactions may be even more marked with warfarin than with DOACs.

Effect of DOAC Dosages on Outcome Events

The rates of on-label and off-label use of DOACs were similar between patients with and without active cancer. It has been previously reported that GI bleeding is more common with DOAC usage than with warfarin,³⁹^–⁴¹ but in the present study, we did not observe an association between DOAC use and GI bleeding, even in the GI cancer group. This result may reflect the use of reduced doses of DOACs (approximately 65% in the present study, including reduced, underdose, and off-label underdose).

Study Limitations

In common with all analyses from the ANAFIE Registry, the study limitations are mainly related to the observational, registry-based design.²⁷^,²⁸ Because this subanalysis was based on existing registry data, all-cause deaths include deaths due to cancer, which may bias the assessment of the incidence of mortality compared with the assessment of mortality in the total registry population. As participation in the Registry was restricted to Japanese patients, the generalizability of the data to patient populations of other ethnicities may also be limited. The effects of GI site, cancer stage, and treatment received (e.g., surgery or radiation) were not considered in this analysis. Further, the design of the questionnaire may have resulted in the inclusion of patients with a history of cancer, and not only those with active cancer. Finally, the effects on outcomes of different anticancer drugs were not individually assessed and compared, restricting the inferences that can be drawn from the data.

Conclusions

In this subanalysis of patients aged ≥75 years with NVAF, a large proportion of patients in the cancer group were receiving anticoagulant therapy, and >65% were receiving DOACs. No difference was seen in the incidence rate of stroke/SEE between elderly NVAF patients with active cancer and those without cancer. However, those with cancer had a higher incidence of major bleeding events and all-cause death than those without cancer. DOAC use was associated with a lower risk for outcome events when compared with warfarin use among NVAF patients without cancer. In cancer patients, however, there was no observable difference in the efficacy and safety of DOACs vs. warfarin.

Acknowledgments

This study was supported by Daiichi Sankyo Co., Ltd., Tokyo, Japan. The authors thank all individuals (physicians, nurses, institutional staff, and patients) involved in the ANAFIE Registry. They also thank IQVIA Services Japan K.K. and EP-CRSU for their partial support in the conduct of this Registry, and Matt Glasgow and Keyra Martinez Dunn, MD, of Edanz (www.edanz.com) for providing medical writing support, which was funded by Daiichi Sankyo Co., Ltd., Tokyo, Japan, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). In addition, the authors thank Daisuke Chiba, of Daiichi Sankyo Co., Ltd., for support during the preparation of this manuscript.

Contributor Statements

T.I., T. Yamashita, M.A., H.A., Y.K., K.O., W.S., H.T., K.T., A.H., M.Y., T. Yamaguchi, H.I. designed and conducted the study; T.I. interpreted the data analysis; S.T. carried out statistical analyses. T.I., T.K., J.K., A.T. wrote and reviewed the manuscript; all authors revised and commented on the manuscript, and approved the final version.

Disclosures

T.I. has received research grants from Daiichi Sankyo, Medtronic Japan, and Japan Lifeline and honoraria from Ono Pharma, Bayer Yakuhin, Daiichi Sankyo, Bristol-Myers Squibb, and Pfizer. Additionally, T.I. was a member of the advisory board for Bayer Yakuhin, Bristol-Myers Squibb, and Daiichi Sankyo. T. Yamashita 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, Bayer, Pfizer Japan, Bristol-Myers Squibb, and Ono Pharmaceutical. 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. Y.K. received remuneration from Daiichi Sankyo, Bayer, 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 patent royalties/licensing fees from Daiichi Sankyo, Pfizer Japan, Bristol-Myers Squibb, Bayer, and Nippon Boehringer Ingelheim. H.T. received research funding from Daiichi Sankyo, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, and IQVA services Japan, remuneration from Daiichi Sankyo, Bayer, Nippon Boehringer Ingelheim, Pfizer Japan, Otsuka Pharmaceutical, and Mitsubishi Tanabe Pharma, scholarship funding from Daiichi Sankyo, Mitsubishi Tanabe Pharma, and Teijin Pharma, and consultancy fees from Novartis Pharma, Pfizer Japan, Bayer, Nippon Boehringer Ingelheim, and Ono Pharmaceutical. K.T. received remuneration from Daiichi Sankyo, Bayer, Bristol-Myers Squibb, Takeda, and Nippon Boehringer Ingelheim. A.H. participated in a course endowed by Boston Scientific Japan, and has received research funding from Daiichi Sankyo and Bayer, and remuneration from Bayer, Daiichi Sankyo, Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Sanofi, Astellas Pharma, Sumitomo Dainippon Pharma, Amgen Astellas BioPharma, and AstraZeneca, and patent royalties/licensing fees from Toa Eiyo. M.Y. received research funding from Nippon Boehringer Ingelheim, and remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Bayer, Bristol-Myers Squibb, Pfizer Japan, and CSL Behring. T. Yamaguchi acted as an advisory board member of Daiichi Sankyo, and received remuneration from Daiichi Sankyo and Bristol-Myers Squibb. S.T. received research grants from Nippon Boehringer Ingelheim and remuneration from Daiichi Sankyo, Sanofi, Takeda, Chugai Pharmaceutical, Solasia Pharma, and Bayer. T.K. has stock and is an employee of Daiichi Sankyo. J.K., A.T. are employees of Daiichi Sankyo. H.I. received remuneration from Daiichi Sankyo, Bayer, and Bristol-Myers Squibb.

T. Yamashita, W.S., H.T. are members of Circulation Journal’s Editorial Team.

IRB Information

Ethical approvals were 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 the principal ethics committee was The Ethics Committee of The Cardiovascular Institute (Tokyo, Japan) and the number was 299.

Data Availability

1. Will the individual deidentified participant data (including data dictionaries) be shared?

→ Yes

2. What data in particular will be shared?

→ Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).

3. Will any additional, related documents be available? If so, what is it? (e.g., study protocol, statistical analysis plan, etc.)

→ Study Protocol

4. When will the data become available and for how long?

→ Ending 36 months following article publication.

5. By what access criteria will the data be shared (including with whom)?

→ Researchers who provide a methodologically sound proposal. But the proposal may be reviewed by a committee led by Daiichi-Sankyo.

6. For what types of analyses, and by what mechanism will the data be available?

→ Any purpose, Proposals should be directed to yamt-tky@cvi.or.jp

To gain access, data requestors will need to sign a data access agreement.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-21-0631

References

1. Martinez C, Katholing A, Wallenhorst C, Granziera S, Cohen AT, Freedman SB. Increasing incidence of non-valvular atrial fibrillation in the UK from 2001 to 2013. Heart 2015; 101: 1748–1754.
2. Inoue H, Fujiki A, Origasa H, Ogawa S, Okumura K, Kubota I, et al. Prevalence of atrial fibrillation in the general population of Japan: An analysis based on periodic health examination. Int J Cardiol 2009; 137: 102–107.
3. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery, Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, et al. Guidelines for the management of atrial fibrillation: The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31: 2369–2429.
4. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [published correction appears in CA Cancer J Clin 2020; 70: 313]. CA Cancer J Clin 2018; 129: 837–847.
5. White MC, Holman DM, Boehm JE, Peipins LA, Grossman M, Henley SJ. Age and cancer risk: A potentially modifiable relationship. Am J Prev Med 2014; 46(3 Suppl 1): S7–S15.
6. Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ, et al. Worldwide epidemiology of atrial fibrillation: A global burden of disease 2010 study. Circulation 2014; 129: 837–847.
7. Jakobsen CB, Lamberts M, Carlson N, Lock-Hansen M, Torp-Pedersen C, Gislason GH, et al. Incidence of atrial fibrillation in different major cancer subtypes: A nationwide population-based 12 year follow up study. BMC Cancer 2019; 19: 1105.
8. Fitzpatrick T, Carrier M, Le Gal G. Cancer, atrial fibrillation, and stroke. Thromb Res 2017; 155: 101–105.
9. Vinter N, Christesen AMS, Fenger-Grøn M, Tjønneland A, Frost L. Atrial fibrillation and risk of cancer: A Danish population-based cohort study. J Am Heart Assoc 2018; 7: e009543.
10. Chu G, Versteeg HH, Verschoor AJ, Trines SA, Hemels MEW, Ay C, et al. Atrial fibrillation and cancer: An unexplored field in cardiovascular oncology. Blood Rev 2019; 35: 59–67.
11. Ruigomez A, Johansson S, Wallander MA, Edvardsson N, Garcia Rodriguez LA. Risk of cardiovascular and cerebrovascular events after atrial fibrillation diagnosis. Int J Cardiol 2009; 136: 186–192.
12. Zaorsky NG, Zhang Y, Tchelebi LT, Mackley HB, Chinchilli VM, Zacharia BE. Stroke among cancer patients. Nat Commun 2019; 10: 5172.
13. Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood 2013; 122: 1712–1723.
14. Khorana AA. Venous thromboembolism and prognosis in cancer. Thromb Res 2010; 125: 490–493.
15. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64: e1–e76.
16. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016; 37: 2893–2962.
17. Nishimoto Y, Yamashita Y, Kim K, Morimoto T, Saga S, Amano H, et al. Risk factors for major bleeding during anticoagulation therapy in cancer-associated venous thromboembolism: From the COMMAND VTE registry. Circ J 2020; 84: 2006–2014.
18. Farmakis D, Parissis J, Filippatos G. Insights into onco-cardiology: Atrial fibrillation in cancer. J Am Coll Cardiol 2014; 63: 945–953.
19. Fanola CL, Ruff CT, Murphy SA, Murphy SA, Jin J, Duggal A, et al. Efficacy and safety of edoxaban in patients with active malignancy and atrial fibrillation: Analysis of the ENGAGE AF-TIMI 48 trial. J Am Heart Assoc 2018; 7: e008987.
20. Melloni C, Dunning A, Granger CB, Thomas L, Khouri MG, Garcia DA, et al. Efficacy and safety of apixaban versus warfarin in patients with atrial fibrillation and a history of cancer: Insights from the ARISTOTLE trial. Am J Med 2017; 130: 1440–1448.e1.
21. Yang P, Zhu D, Xu X, Shen W, Wang C, Jiang Y, et al. Efficacy and safety of oral anticoagulants in atrial fibrillation patients with cancer: A network meta-analysis. Heart Fail Rev 2020; 25: 823–831.
22. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation [published correction appears in N Engl J Med 2010; 363: 1877]. N Engl J Med 2009; 361: 1139–1151.
23. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883–891.
24. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981–992.
25. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369: 2093–2104.
26. Shah S, Norby FL, Datta YH, Lutsey PL, MacLehose RF, Chen LY, et al. Comparative effectiveness of direct oral anticoagulants and warfarin in patients with cancer and atrial fibrillation. Blood Adv 2018; 2: 200–209.
27. Koretsune Y, Yamashita T, Akao M, Atarashi H, Ikeda T, Okumura K, et al. Baseline demographics and clinical characteristics in the All Nippon AF in the Elderly (ANAFIE) registry [published correction appears in Circ J 2020; 84: 360]. Circ J 2019; 83: 1538–1545.
28. Inoue H, Yamashita T, Akao M, Atarashi H, Ikeda T, Okumura K, et al. Prospective observational study in elderly patients with non-valvular atrial fibrillation: Rationale and design of the All Nippon AF In the Elderly (ANAFIE) Registry. J Cardiol 2018; 72: 300–306.
29. Sakamoto J, Yamashita Y, Morimoto T, Amano H, Takase T, Hiramori S, et al. Cancer-associated venous thromboembolism in the real world: From the COMMAND VTE Registry. Circ J 2019; 83: 2271–2281.
30. Kraaijpoel N, Di Nisio M, Mulder FI, van Es N, Beyer-Westendorf J, Carrier M, et al. Clinical impact of bleeding in cancer-associated venous thromboembolism: Results from the Hokusai VTE Cancer study. Thromb Haemost 2018; 118: 1439–1449.
31. Yasui T, Shioyama W, Oboshi M, Oka T, Fujita M. Oral anticoagulants in Japanese patients with atrial fibrillation and active cancer. Intern Med 2019; 58: 1845–1849.
32. Yamashita Y, Uozumi R, Hamatani Y, Esato M, Chun YH, Tsuji H, et al. Current status and outcomes of direct oral anticoagulant use in real-world atrial fibrillation patients: Fushimi AF registry. Circ J 2017; 81: 1278–1285.
33. Okumura Y, Yokoyama K, Matsumoto N, Tachibana E, Kuronuma K, Oiwa K, et al. Three-year clinical outcomes associated with warfarin vs. direct oral anticoagulant use among Japanese patients with atrial fibrillation: Findings from the SAKURA AF registry. Circ J 2018; 82: 2500–2509.
34. Avezum A, Lopes RD, Schulte PJ, Lanas F, Gersh BJ, Hanna M, et al. Apixaban in comparison with warfarin in patients with atrial fibrillation and valvular heart disease: Findings from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Circulation 2015; 132: 624–632.
35. Kato ET, Giugliano RP, Ruff CT, Koretsune Y, Yamashita T, Kiss RG, et al. Efficacy and safety of edoxaban in elderly patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial. J Am Heart Assoc 2016; 5: e003432.
36. O’Neal WT, Lakoski SG, Qureshi W, Judd SE, Howard G, Howard VJ, et al. Relation between cancer and atrial fibrillation (from the REasons for Geographic And Racial Differences in Stroke Study). Am J Cardiol 2015; 115: 1090–1094.
37. Hanigan S, Das J, Pogue K, Barnes GD, Dorsch MP. The real world use of combined P-glycoprotein and moderate CYP3A4 inhibitors with rivaroxaban or apixaban increases bleeding. J Thromb Thrombolysis 2020; 49: 636–643.
38. Akbulut M, Urun Y. Onco-cardiology: Drug-drug interactions of antineoplastic and cardiovascular drugs. Crit Rev Oncol Hematol 2020; 145: 102822.
39. Mazurek M, Lip GYH. Gastrointestinal bleeding and direct oral anticoagulants amongst patients with atrial fibrillation in the “real world”. Gastroenterology 2017; 152: 932–934.
40. Laine L. Bleeding with direct oral anticoagulants: The gastrointestinal tract and beyond. Clin Gastroenterol Hepatol 2017; 15: 1665–1667.
41. Miller CS, Dorreen A, Martel M, Huynh T, Barkun AN. Risk of gastrointestinal bleeding in patients taking non-vitamin K antagonist oral anticoagulants: A systematic review and meta-analysis. Clin Gastroenterol Hepatol 2017; 15: 1674–1683.e3.

Corresponding author

Register with J-STAGE for free!