Risk of stroke/systemic embolism, major bleeding and associated costs in non-valvular atrial fibrillation patients who initiated apixaban, dabigatran or rivaroxaban compared with warfarin in the United States Medicare population

Figures & data

Figure 1. Patient selection flow chart. Abbreviations. AF, atrial fibrillation; OAC, oral anticoagulant; ICD-9-CM; International Classification of Disease, 9th Revision, Clinical Modification; VTE, venous thromboembolism.

Table 1. Baseline characteristics and follow-up time in propensity score matched cohorts.

	Warfarin Cohort (N = 16,731)		Dabigatran Cohort (N = 16,731)			Warfarin Cohort (N = 52,476)		Rivaroxaban Cohort (N = 52,476)			Warfarin Cohort (N = 20,803)		Apixaban Cohort (N = 20,803)
	N/Mean	%/SD	N/Mean	%/SD	STD*	N/Mean	%/SD	N/Mean	%/SD	STD*	N/Mean	%/SD	N/Mean	%/SD	STD*
Age	77.1	7.3	77.2	7.0	1.2	77.8	7.2	77.7	7.2	0.6	78.1	7.5	78.4	7.4	3.5
65–74	6,977	41.7	6,777	40.5	2.4	19,932	38.0	19,840	37.8	0.4	7,506	36.1	7,214	34.7	2.9
75–84	6,911	41.3	7,062	42.2	1.8	22,264	42.4	22,286	42.5	0.1	8,660	41.6	8,830	42.4	1.7
≥85	2,843	17.0	2,892	17.3	0.8	10,280	19.6	10,350	19.7	0.3	4,637	22.3	4,759	22.9	1.4
Sex
Male	8,540	51.0	8,462	50.6	0.9	25,226	48.1	25,341	48.3	0.4	9,971	47.9	9,919	47.7	0.5
Female	8,191	49.0	8,269	49.4	0.9	27,250	51.9	27,135	51.7	0.4	10,832	52.1	10,884	52.3	0.5
US Geographic Region
Northeast	2,980	17.8	3,414	20.4	6.6	9,726	18.5	9,193	17.5	2.6	3,918	18.8	3,596	17.3	4.0
North Central	4,854	29.0	3,856	23.0	13.6	15,817	30.1	11,773	22.4	17.6	6,079	29.2	4,220	20.3	20.8
South	5,947	35.5	6,299	37.6	4.4	18,024	34.3	22,181	42.3	16.3	7,300	35.1	9,377	45.1	20.5
West	2,936	17.5	3,135	18.7	3.1	8,859	16.9	9,231	17.6	1.9	3,491	16.8	3,595	17.3	1.3
Other	14	0.1	27	0.2	2.2	50	0.1	98	0.2	2.4	15	0.1	15	0.1	0.0
Baseline Comorbidity
Deyo-Charlson Comorbidity Index Score	2.6	2.5	2.5	2.4	3.2	2.7	2.5	2.7	2.5	0.2	2.9	2.6	2.8	2.6	5.2
CHADS2 Score	2.7	1.4	2.6	1.4	2.2	2.7	1.4	2.7	1.4	0.5	2.8	1.4	2.8	1.4	2.4
0 = Low Risk	682	4.1	686	4.1	0.1	2,028	3.9	1,981	3.8	0.5	575	2.8	625	3.0	1.4
1 = Moderate Risk	2,939	17.6	2,994	17.9	0.9	9,079	17.3	9,147	17.4	0.3	3,378	16.2	3,411	16.4	0.4
2 = High Risk	4,880	29.2	5,027	30.0	1.9	15,402	29.4	15,398	29.3	0.0	5,817	28.0	6,042	29.0	2.4
>2 = High Risk	8,230	49.2	8,024	48.0	2.5	25,967	49.5	25,950	49.5	0.1	11,033	53.0	10,725	51.6	3.0
CHADS2-VASc Score	4.5	1.7	4.4	1.7	2.6	4.5	1.7	4.5	1.7	0.5	4.7	1.7	4.6	1.7	2.9
0 = Low Risk	0	0.0	0	0.0	0.0	0	0.0	0	0.0	0.0	0	0.0	0	0.0	0.0
1 = Moderate Risk	371	2.2	371	2.2	0.0	1,019	1.9	1,034	2.0	0.2	264	1.3	318	1.5	2.2
2 = High Risk	1,706	10.2	1,721	10.3	0.3	5,038	9.6	5,014	9.6	0.2	1,791	8.6	1,787	8.6	0.1
>2 = High Risk	14,654	87.6	14,639	87.5	0.3	46,419	88.5	46,428	88.5	0.1	18,748	90.1	18,698	89.9	0.8
HAS-BLED Score	3.2	1.2	3.1	1.2	4.2	3.2	1.2	3.2	1.2	0.0	3.3	1.2	3.3	1.2	4.8
0 = Low Risk	0	0.0	0	0.0	0.0	0	0.0	0	0.0	0.0	0	0.0	0	0.0	0.0
1–2 = Moderate Risk	5,478	32.7	5,793	34.6	4.0	16,024	30.5	15,983	30.5	0.2	5,521	26.5	5,963	28.7	4.8
>2 = High Risk	11,253	67.3	10,938	65.4	4.0	36,452	69.5	36,493	69.5	0.2	15,282	73.5	14,840	71.3	4.8
Prior Bleed	3,344	20.0	3,264	19.5	1.2	11,910	22.7	11,831	22.5	0.4	4,731	22.7	4,548	21.9	2.1
Prior Stroke	2,043	12.2	1,974	11.8	1.3	6,392	12.2	6,331	12.1	0.4	2,872	13.8	2,686	12.9	2.6
Congestive Heart Failure	4,909	29.3	4,784	28.6	1.6	15,328	29.2	15,239	29.0	0.4	6,698	32.2	6,388	30.7	3.2
Diabetes	6,291	37.6	6,214	37.1	1.0	19,122	36.4	18,989	36.2	0.5	7,467	35.9	7,341	35.3	1.3
Hypertension	14,870	88.9	14,743	88.1	2.4	46,616	88.8	46,544	88.7	0.4	18,980	91.2	18,782	90.3	3.3
Renal Disease	3,333	19.9	3,198	19.1	2.0	11,072	21.1	11,078	21.1	0.0	5,312	25.5	4,977	23.9	3.7
Myocardial Infarction	1,918	11.5	1,810	10.8	2.1	6,369	12.1	6,416	12.2	0.3	2,844	13.7	2,659	12.8	2.6
Dyspepsia or Stomach Discomfort	3,584	21.4	3,365	20.1	3.2	11,580	22.1	11,510	21.9	0.3	4,815	23.1	4,640	22.3	2.0
Peripheral Vascular Disease	9,238	55.2	8,915	53.3	3.9	29,417	56.1	29,369	56.0	0.2	12,617	60.6	12,286	59.1	3.2
Transient Ischemic Attack	1,308	7.8	1,231	7.4	1.7	4,132	7.9	4,077	7.8	0.4	1,842	8.9	1,769	8.5	1.2
Coronary Artery Disease	7,940	47.5	7,692	46.0	3.0	25,385	48.4	25,304	48.2	0.3	11,086	53.3	10,758	51.7	3.2
Baseline Medication Use
Angiotensin Converting Enzyme   Inhibitors	6,490	38.8	6,409	38.3	1.0	18,981	36.2	19,048	36.3	0.3	7,452	35.8	7,420	35.7	0.3
Amiodarone	1,469	8.8	1,431	8.6	0.8	4,179	8.0	4,205	8.0	0.2	2,158	10.4	2,171	10.4	0.2
Angiotensin Receptor Blockers	4,231	25.3	4,171	24.9	0.8	13,076	24.9	13,145	25.0	0.3	5,660	27.2	5,558	26.7	1.1
Beta Blockers	9,186	54.9	9,008	53.8	2.1	28,409	54.1	28,415	54.1	0.0	12,273	59.0	11,880	57.1	3.8
H2-Receptor Antagonists	1,152	6.9	1,090	6.5	1.5	3,495	6.7	3,553	6.8	0.4	1,546	7.4	1,446	7.0	1.9
Proton Pump Inhibitors	5,157	30.8	4,958	29.6	2.6	16,742	31.9	16,604	31.6	0.6	7,104	34.1	6,907	33.2	2.0
Anti-platelets	2,606	15.6	2,520	15.1	1.4	8,820	16.8	8,863	16.9	0.2	4,196	20.2	4,100	19.7	1.2
Statins	9,783	58.5	9,611	57.4	2.1	30,265	57.7	30,180	57.5	0.3	13,075	62.9	12,791	61.5	2.8
Baseline Healthcare Utilization
Inpatient Admission	6,872	41.07	6,646	39.72	2.75	24,297	46.30	24,105	45.94	0.73	8,553	41.11	8,143	39.14	4.02
Follow-up Time (in days)
Mean	199.3	185.2	196.1	192.3	1.7	197.1	185.2	203.8	192.4	3.5	196.2	184.1	171.2	153.4	14.8
Minimum	1		1			1		1			1		1
Quartile 1	53		30			50		33			52		43
Median	126		113			120		130			122		115
Quartile 3	307		307			301		328			299		261
Maximum	730		730			730		730			730		702

Abbreviations. SD, standard deviation; STD, standardized difference.

Figure 2. Hazard ratio of stroke/SE for propensity score matched patients. Abbreviations. HR, hazard ratio; CI, confidence interval; SE: systemic embolism.

Figure 3. Hazard ratio of major bleeding for propensity score matched patients. Abbreviations. HR, hazard ratio; CI, confidence interval; GI, Gastrointestinal; ICH, Intracranial hemorrhage.

Figure 4. Stroke-related medical costs PPPM for propensity score matched patients. *p = .064; **p = .002; ***p < .001. Abbreviations. PPPM, per patient per month; CI, confidence interval; SE, systemic embolism.

Figure 5. Major-bleeding-related medical costs PPPM for propensity score matched patients. *p = .036; **p = .177; ***p < .001. Abbreviations. PPPM, per patient per month; CI, confidence interval.

Table 2. Dose sensitivity analysis for propensity score matched patients.

	Dabigatran vs. Warfarin	p value*	Rivaroxaban vs. Warfarin	p value*	Apixaban vs. Warfarin	p value*
Stroke/SE
Reduced Dose	1.41 (0.86, 2.30)	0.075	0.78 (0.63, 0.96)†	0.576	0.60 (0.38, 0.96)†	0.046
Standard Dose	0.84 (0.63, 1.12)		0.69 (0.58, 0.83)‡		0.34 (0.24, 0.47)‡
Major Bleeding
Reduced Dose	0.96 (0.74, 1.25)	0.121	1.14 (1.03, 1.27)†	0.387	0.48 (0.38, 0.60)‡	0.407
Standard Dose	0.75 (0.64, 0.89)‡		1.21 (1.11, 1.33)‡		0.54 (0.46, 0.64)‡

* p-value in the table is for interaction.

† p < .05, ‡p < .001.

Table 3. Hazard ratio of stroke/SE and major bleeding for propensity score matched patients in the sensitivity analyses.

	Dabigatran vs. Warfarin	Rivaroxaban vs. Warfarin	Apixaban vs. Warfarin
≥30 days Follow-up
Stroke/SE	0.91 (0.71, 1.18)	0.72 (0.63, 0.83)*	0.40 (0.31, 0.53)*
Major bleeding	0.80 (0.69, 0.92)†	1.19 (1.11, 1.28)*	0.52 (0.45, 0.59)*
Censoring at 6 months
Stroke/SE	0.98 (0.74, 1.30)	0.71 (0.61, 0.84)*	0.42 (0.31, 0.56)*
Major bleeding	0.79 (0.67, 0.93)†	1.19 (1.10, 1.29)*	0.52 (0.45, 0.61)*

*p < .001, †p < .01.