Healthcare costs of stroke and major bleeding in patients with atrial fibrillation treated with non-vitamin K antagonist oral anticoagulants

Figures & data

Table 1. Baseline demographics and clinical characteristics of the stroke/no stroke and major bleeding/no major bleeding matched cohorts.

Characteristics	Matched cohorts^a			Matched cohorts^b
	NOAC users with stroke/SE	NOAC users without stroke/SE	SD (%)	NOAC users with MB	NOAC users without MB	SD (%)
	(n = 1,340)	(n = 1,340)		(n = 3,774)	(n = 3,774)
Observation period,^c days, mean [median] (SD)	343.4 [206] (380.8)	326.8 [215] (328.7)	4.7	387.3 [263] (390.1)	355.3 [246] (342.3)	8.7
Demographics^d
Age, years, mean [median] (SD)	77.3 [79] (9.4)	77.3 [79] (8.7)	0.2	77.5 [79] (8.7)	77.5 [78] (8.3)	0.9
Gender, female, n (%)	699 (52.2)	727 (54.3)	4.2	1,916 (50.8)	1,905 (50.5)	0.6
Region, n (%)
South	521 (38.9)	548 (40.9)	4.1	1,516 (40.2)	1,494 (39.6)	1.2
West	243 (18.1)	231 (17.2)	2.3	731 (19.4)	744 (19.7)	0.9
Midwest	295 (22.0)	282 (21.0)	2.4	867 (23.0)	830 (22.0)	2.3
Northeast	278 (20.7)	275 (20.5)	0.6	646 (17.1)	694 (18.4)	3.3
Unknown	3 (0.2)	4 (0.3)	1.5	14 (0.4)	12 (0.3)	0.9
Insurance plan type,^d n (%)
Medicare	1,062 (79.3)	1,068 (79.7)	1.1	3,122 (82.7)	3,148 (83.4)	1.8
Commercial insurance	278 (20.7)	272 (20.3)	1.1	652 (17.3)	626 (16.6)	1.8
POS	160 (11.9)	145 (10.8)	3.5	329 (8.7)	298 (7.9)	3.0
HMO	23 (1.7)	21 (1.6)	1.2	44 (1.2)	56 (1.5)	2.8
PPO	10 (0.7)	15 (1.1)	3.9	32 (0.8)	37 (1.0)	1.4
EPO	24 (1.8)	31 (2.3)	3.7	60 (1.6)	71 (1.9)	2.2
IND	61 (4.6)	60 (4.5)	0.4	187 (5.0)	165 (4.4)	2.8
Other insurance	0 (0.0)	0 (0.0)	0.0	0 (0.0)	0 (0.0)	0.0
Medicaid	0 (0.0)	0 (0.0)	0.0	0 (0.0)	0 (0.0)	0.0
Year of index date,^d n (%)
2010	0 (0.0)	1 (0.1)	3.9	1 (0.0)	1 (0.0)	0.0
2011	33 (2.5)	36 (2.7)	1.4	129 (3.4)	101 (2.7)	4.3
2012	109 (8.1)	83 (6.2)	7.5	278 (7.4)	274 (7.3)	0.4
2013	186 (13.9)	179 (13.4)	1.5	521 (13.8)	507 (13.4)	1.1
2014	244 (18.2)	251 (18.7)	1.3	702 (18.6)	691 (18.3)	0.8
2015	352 (26.3)	358 (26.7)	1.0	941 (24.9)	941 (24.9)	0.0
2016	416 (31.0)	432 (32.2)	2.6	1,202 (31.8)	1,259 (33.4)	3.2
Index NOAC agent,^d n (%)
Apixaban	336 (25.1)	380 (28.4)	7.4	833 (22.1)	859 (22.8)	1.7
Dabigatran	426 (31.8)	405 (30.2)	3.4	1,090 (28.9)	1,142 (30.3)	3.0
Edoxaban	2 (0.1)	3 (0.2)	1.7	4 (0.1)	7 (0.2)	2.1
Rivaroxaban	576 (43.0)	552 (41.2)	3.6	1,847 (48.9)	1,766 (46.8)	4.3
Comorbidity index scores,^e mean [median] (SD)
Quan-Charlson comorbidity index	3.4 [3] (2.5)	3.4 [3] (2.5)	0.8	3.8 [3] (2.6)	3.7 [3] (2.6)	3.0
CHA2DS2-VASc score	4.8 [5] (1.7)	4.8 [5] (1.7)	1.9	5.1 [5] (1.7)	5.1 [5] (1.8)	1.0
HAS-BLED score	2.4 [2] (0.9)	2.4 [2] (0.9)	0.5	2.7 [3] (0.9)	2.6 [3] (0.9)	1.4
Time from initiation of NOAC to the index date^f
Months, mean [median] (SD)	457.3 [351] (422.4)	432.4 [362] (368.6)	6.3	403.8 [295] (399.1)	397.0 [311] (364.6)	1.8
Baseline healthcare resource utilization,^e mean [median] (SD)
Hospitalizations	0.8 [0] (1.2)	0.8 [0] (1.2)	1.0	0.9 [0] (1.2)	0.8 [0] (1.2)	6.8
Skilled nursing and long-term care facilities	1.0 [0] (5.2)	1.3 [0] (5.8)	5.8	1.2 [0] (6.0)	1.5 [0] (5.8)	4.7
ER visits	1.3 [0] (3.3)	1.2 [0] (2.6)	5.1	1.4 [1] (2.4)	1.3 [0] (2.8)	2.6
Outpatient visits	24.8 [19] (22.5)	25.2 [20] (23.7)	1.7	26.4 [21] (24.6)	26.9 [21] (24.1)	1.9
Other visits	3.8 [0] (8.5)	3.8 [0] (8.4)	0.1	4.5 [1] (9.4)	4.1 [0] (10.4)	3.5
Baseline healthcare cost,^e $US 2016, mean (SD)
Total healthcare cost	$41,676 (50,966)	$41,551 (50,788)	0.2	$48,404 (61,215)	$44,514 (55,639)	6.6
Hospitalizations	$13,179 (26,108)	$14,434 (29,814)	4.5	$17,490 (37,005)	$15,275 (31,789)	6.4
Skilled nursing and long-term care facilities	$2,368 (10,820)	$2,678 (9,783)	3.0	$2,781 (10,193)	$2,968 (10,060)	1.8
ER visits	$4,261 (12,172)	$3,375 (7,729)	8.7	$4,752 (13,493)	$4,493 (12,799)	2.0
Outpatient visits	$14,257 (28,873)	$13,562 (24,472)	2.6	$15,307 (33,873)	$13,951 (28,471)	4.3
Other visits	$1,052 (2,915)	$838 (2,045)	8.5	$1,200 (4,085)	$1,125 (3,871)	1.9
Pharmacy	$6,559 (7,155)	$6,664 (7,467)	1.4	$6,875 (9,734)	$6,704 (8,918)	1.8
Specific comorbid conditions,^e n (%)
Diverticulosis	122 (9.1)	118 (8.8)	1.0	442 (11.7)	410 (10.9)	2.7
Percutaneous coronary intervention	41 (3.1)	38 (2.8)	1.3	160 (4.2)	83 (2.2)	11.6
Helicobacter pylori infection	3 (0.2)	7 (0.5)	4.9	21 (0.6)	17 (0.5)	1.5
Risk factors^e for bleeding and stroke, n (%)
Hypertension	1,198 (89.4)	1,193 (89.0)	1.2	3,439 (91.1)	3,456 (91.6)	1.6
Hyperlipidemia	991 (74.0)	1,001 (74.7)	1.7	2,846 (75.4)	2,836 (75.1)	0.6
Congestive heart failure	621 (46.3)	657 (49.0)	5.4	1,950 (51.7)	1,874 (49.7)	4.0
Diabetes	565 (42.2)	572 (42.7)	1.1	1,522 (40.3)	1,546 (41.0)	1.3
Renal disease	541 (40.4)	547 (40.8)	0.9	1,698 (45.0)	1,632 (43.2)	3.5

^aStroke patients were matched 1:1 with non-stroke patients using propensity score calipers of 10%. Variables used in the propensity score calculation included the following: age, gender, region, insurance type, year of index date, index NOAC, time from initiation of NOAC to the index date, baseline medication, baseline risk factors for stroke and/or bleeding (with a prevalence ≥5%), Quan-Charlson comorbidity index, CHA₂DS₂-VASc score, HAS-BLED score, and healthcare resource utilization.

^bMajor bleeding patients were matched 1:1 with non-major bleeding patients using propensity score calipers of 10%. Variables used in the propensity score calculation included the following: age, gender, region, insurance type, year of index date, index NOAC, time from initiation of NOAC to the index date, baseline medication, history of stroke or systemic embolism, baseline risk factors for stroke and/or bleeding (with a prevalence ≥5%), Quan-Charlson comorbidity index, CHA₂DS₂-VASc score, HAS-BLED score, and healthcare resource utilization.

^cThe observation (follow-up) period spanned from the index date up to end of data availability, death, switch to warfarin, or end of insurance coverage.

^dEvaluated at the index date.

^eEvaluated during the 12-month baseline period.

^fEvaluated from the start of the eligibility period to the index date.

Abbreviations. EPO, Exclusive provider organization; ER, Emergency room; HMO, Health maintenance organization; IND, Indemnity; MB, Major bleeding; NOAC, Non vitamin-k oral anticoagulant; POS, Point-of-service; PPO, Preferred provider organization; SD, Standard difference; SE, Systemic embolism.

Figure 1. All-cause healthcare cost comparison PPPY over the entire follow-up period—patients with non-valvular atrial fibrillation using NOACs.

^aStatistical differences between cohorts (95% CI) were obtained using non-parametric bootstrap procedure methods with 999 replications. Abbreviations. NOAC, non-vitamin K antagonist oral anticoagulant; PPPY, per patient per year; SE, systemic embolism; CI, confidence interval.

Table 2. All-cause healthcare costs—matched ischemic stroke/systemic embolism cohorts and matched major bleeding cohorts.

All-cause healthcare cost, $US 2016 (per patient per year)	NOAC users with event	NOAC users without event	Mean cost difference (95% CI)		p-value^a
Matched ischemic stroke/SE cohorts
No. of patients	1,340	1,340
Hospitalizations	$48,697	$10,539	$38,158	(33,069–43,555)	<0.001
Skilled nursing and LTC facilities	$9,242	$1,986	$7,256	(6,140–8,382)	<0.001
ER visits	$4,576	$2,736	$1,840	(925–2,831)	<0.001
Outpatient visits	$10,811	$10,188	$623	(−929–2,095)	0.412
Other visits	$1,164	$668	$496	(291–704)	<0.001
Home healthcare	$782	$328	$454	(304–616)	<0.001
Other/Unclassified	$382	$340	$42	(−87–177)	0.555
Pharmacy costs	$6,925	$6,491	$434	(−499–1,413)	0.386
Matched major bleeding cohorts
No. of patients	3,774	3,774
Hospitalizations	$32,516	$10,834	$21,682	(19,248–23,765)	<0.001
Skilled nursing and LTC facilities	$5,756	$2,460	$3,296	(2,662–3,888)	<0.001
ER visits	$3,707	$3,286	$421	(−75–945)	0.112
Outpatient visits	$14,287	$11,188	$3,100	(1,669–4,681)	<0.001
Other visits	$1,086	$918	$168	(−2–331)	0.058
Home healthcare	$726	$526	$201	(53–338)	0.012
Other/Unclassified	$359	$392	−$33	(−123–53)	0.477
Pharmacy costs	$6,552	$6,921	−$369	(−1,002–276)	0.282

^aStatistical difference between cohorts (95% CI and p-value) were obtained using non-parametric bootstrap procedure methods with 999 replications.

Abbreviations. CI, Confidence interval; ER, Emergency room; LTC, Long-term care; MB, Major bleeding; NOAC, Non-vitamin K antagonist oral anticoagulant; SE, Systemic embolism.

Table 3. Long-term all-cause healthcare costs by stroke/systemic embolism events and major bleeding events.

All-cause healthcare cost, $US 2016 (Lin’s method)	Matched cohorts^a				Matched cohorts^b
	NOAC users with stroke/SE (n = 1,340)	NOAC users without stroke/SE (n = 1,340)	Mean cost difference^c (95% CI)		NOAC users with MB (n = 3,774)	NOAC users without MB (n = 3,774)	Mean cost difference^c (95% CI)
At 1 year
No. of patients^d	455	466			1,497	1,413
Total costs, mean	$82,779	$32,904	$49,876*	(43,175–56,104)	$68,500	$37,208	$31,292*	(27,749–35,447)
Hospitalizations	$48,236	$10,201	$38,034*	(32,958–42,540)	$35,336	$11,768	$23,568*	(21,248–26,281)
Skilled nursing and LTC facilities	$10,009	$1,993	$8,016*	(6,735–9,256)	$6,401	$2,529	$3,873*	(3,146–4,664)
ER visits	$4,702	$3,096	$1,605*	(465–2,662)	$3,869	$3,210	$660*	(62–1,242)
Outpatient visits	$11,476	$10,360	$1,116	(−739–2,821)	$15,336	$11,850	$3,486*	(1,533–5,206)
Other visits^e	$1,366	$674	$692*	(403–956)	$1,155	$937	$218*	(31–412)
Pharmacy	$6,992	$6,580	$412	(−918–1,498)	$6,402	$6,914	–$513	(−1,157–106)
At 2 years
No. of patients^d	202	169			658	522
Total costs, mean	$111,800	$60,174	$51,627*	(39,885–64,697)	$100,439	$64,781	$35,658*	(30,169–41,473)
Hospitalizations	$57,250	$19,459	$37,791*	(29,094–47,835)	$45,839	$18,731	$27,108*	(23,758–30,911)
Skilled nursing and LTC facilities	$11,668	$3,186	$8,482*	(6,834–10,089)	$8,658	$4,580	$4,079*	(3,027–5,206)
ER visits	$8,514	$5,069	$3,445*	(754–5,645)	$6,828	$6,007	$821	(−224–1,840)
Outpatient visits	$19,077	$18,785	$291	(−3,141–3,909)	$24,896	$20,524	$4,372*	(1,440–6,881)
Other visits^e	$2,019	$1,293	$726*	(260–1,126)	$1,910	$1,689	$222	(−103–561)
Pharmacy	$13,273	$12,382	$892	(−1,248–2,902)	$12,307	$13,251	–$944	(−2,305–437)
At 3 years
No. of patients^d	73	42			249	167
Total costs, mean	$141,579	$83,758	$57,822*	(41,506–75,010)	$130,226	$86,157	$44,069*	(35,690–52,172)
Hospitalizations	$68,435	$26,667	$41,768*	(31,174–53,996)	$54,808	$22,895	$31,913*	(27,118–36,936)
Skilled nursing and LTC facilities	$14,723	$4,636	$10,086*	(6,965–13,132)	$11,054	$5,578	$5,476*	(4,170–6,951)
ER visits	$11,274	$7,760	$3,515*	(389–6,852)	$8,919	$8,477	$442	(−938–1,767)
Outpatient visits	$26,084	$25,041	$1,043	(−3,396–5,812)	$35,054	$27,865	$7,189*	(2,715–11,404)
Other visits^e	$2,555	$1,839	$716*	(112–1,289)	$2,753	$2,433	$320	(−330–1,055)
Pharmacy	$18,508	$17,815	$693	(−2,254–3,658)	$17,638	$18,909	–$1,272	(−3,564–963)
At 4 years
No. of patients^d	27	13			77	44
Total costs, mean	$165,210	$104,519	$60,691*	(36,478–84,462)	$155,534	$108,512	$47,022*	(35,014–59,119)
Hospitalizations	$77,950	$34,978	$42,973*	(26,752–59,565)	$60,726	$29,443	$31,282*	(24,124–39,958)
Skilled nursing and LTC facilities	$15,634	$4,666	$10,968*	(7,759–14,126)	$12,845	$6,242	$6,604*	(4,769–8,585)
ER visits	$13,845	$8,168	$5,677*	(2,001–9,652)	$11,669	$10,681	$988	(−1,099–3,295)
Outpatient visits	$31,978	$32,519	–$541	(−9,745–9,318)	$43,804	$34,991	$8,813*	(2,915–14,619)
Other visits^e	$3,003	$2,286	$717	−165–1,682)	$3,389	$3,304	$85	(−805–1,127)
Pharmacy	$22,800	$21,903	$897	(−2,840–4,626)	$23,101	$23,851	–$750	(−4,171–2,612)

^aStroke patients were matched 1:1 with non-stroke patients using propensity score calipers of 10%. Variables used in the propensity score calculation included the following: age, gender, region, insurance type, year of index date, index NOAC, time from initiation of NOAC to the index date, baseline medication, baseline risk factors for stroke and/or bleeding (with a prevalence ≥ 5%), Quan-Charlson comorbidity index, CHA₂DS₂-VASc score, HAS-BLED score, and healthcare resource utilization.

^bMajor bleeding patients were matched 1:1 with non-major bleeding patients using propensity score calipers of 10%. Variables used in the propensity score calculation included the following: age, gender, region, insurance type, year of index date, index NOAC, time from initiation of NOAC to the index date, baseline medication, history of stroke or systemic embolism, baseline risk factors for stroke and/or bleeding (with a prevalence ≥5%), Quan-Charlson comorbidity index, CHA₂DS₂-VASc score, HAS-BLED score, and healthcare resource utilization.

^cStatistical difference between cohorts (95% CI) were obtained using non-parametric bootstrap procedure methods with 999 replications.

^dNumber of patients still observed at the specific point in time.

^eIncluding patient home, and other unlisted facilities.

*Statistical significance (p-value < 0.05).

Abbreviations. CI, Confidence interval; ER, Emergency room; LTC, Long-term care; MB, Major bleeding; NOAC, Non-vitamin K antagonist oral anticoagulant.

Table 4. All-cause healthcare resource utilization—matched ischemic stroke/systemic embolism cohorts and matched major bleeding cohorts.

All-cause healthcare resource utilization, mean (per patient per year)	NOAC users with event	NOAC users without event	Mean HRU difference (95% CI)	p-value^a
Matched ischemic stroke/SE cohorts
No. of patients	1,340	1,340
Hospitalizations and other inpatient stays	1.9	0.5	1.4 (1.2–1.5)	<0.001
Skilled nursing facility/Long-term care facility	2.2	1.0	1.2 (0.8–1.7)	<0.001
ER visits	1.3	0.8	0.5 (0.3–0.8)	<0.001
Outpatient visits	26.0	20.1	5.9 (4.1–7.8)	<0.001
Other visits	4.7	2.9	1.8 (1.2–2.5)	<0.001
Home healthcare	3.7	1.9	1.8 (1.1–2.4)	<0.001
Other/unclassified	1.0	0.9	0.1 (−0.3–0.4)	0.711
Matched major bleeding cohorts
No. of patients	3,774	3,774
Hospitalizations and other inpatient stays	2.4	0.8	1.6 (1.5–1.7)	<0.001
Skilled nursing facility/Long-term care facility	1.7	1.3	0.4 (0.1–0.7)	0.008
ER visits	1.1	1.0	0.1 (0.0–0.3)	0.048
Outpatient visits	25.6	21.7	3.9 (2.5–5.2)	<0.001
Other visits	4.6	3.2	1.4 (0.9–1.9)	<0.001
Home healthcare	3.7	2.4	1.3 (0.8–1.7)	<0.001
Other/unclassified	0.9	0.8	0.2 (0.0–0.3)	0.048

^aStatistical difference between cohorts (95% CI and p-value) were obtained using non-parametric bootstrap procedure methods with 999 replications.

Abbreviations. CI, Confidence interval; ER, Emergency room; HRU, Healthcare resource utilization; NOAC, Non-vitamin K antagonist oral anticoagulant.

Data availability statement

The data that support the findings of this study are available from Optum (a division of UnitedHealth Group), but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Any researchers interested in obtaining the data used in this study can access the database through Optum, under a license agreement, including the payment of an appropriate license fee.