Conditioning on future exposure to define study cohorts can induce bias: the case of low-dose acetylsalicylic acid and risk of major bleeding

Figures & data

Figure 1 Acetylsalicylic acid (ASA) exposure and major bleeding outcome information for five hypothetical individuals eligible for Cohorts 1 and 2. The circles denote the first and last prescriptions and the “X”s denote the outcome events, used to define Cohort 1. The dashed lines represent unexposed person-time and the solid lines represent exposed person-time.

Figure 2 Cohort construction for Cohort 1 (A) using future acetylsalicylic acid (ASA) information and Cohort 2 (B) using contemporary ASA information only.

Abbreviation: ASA, acetylsalicylic acid.

Table 1 Patient characteristics of Cohort 1 (replication cohort)

Patient characteristics	Full cohort				PS-matched cohort
	Continuous users		Never-users		Continuous users		Never-users
	N=189,150	%	N=2,938,044	%	N=166,983	%	N=166,983	%
Age groups (years)
<50	12,745	7	1,534,688	52	11,493	7	10,204	6
50–59	31,214	17	631,015	22	27,434	16	27,126	16
60–69	56,453	30	466,101	16	50,070	30	50,261	30
70–79	49,651	26	206,731	7	43,533	26	44,255	27
≥80	39,087	21	99,509	3	34,453	21	35,137	21
Gender
Female	88,974	47	1,523,641	52	80,657	48	81,436	49
Male	100,176	53	1,414,403	48	86,326	52	85,547	51
Comorbid conditions
Alcoholism	3,739	2	27,062	1	3,180	2	3,389	2
Non-bleeding ulcer diagnosis	1,734	1	9,202	0	1,422	1	1,514	1
Non-bleeding conditions from esophagus	5,315	3	38,898	1	4,482	3	4,671	3
Diabetes	29,801	16	85,944	3	24,916	15	28,576	17
Myocardial infarction	19,920	11	3,957	0	7,440	5	3,957	2
Congestive heart failure	10,339	6	11,186	0	7,015	4	6,813	4
Peripheral vascular disease	10,640	6	11,832	0	7,772	5	7,452	5
Cerebrovascular disease	24,671	13	23,312	1	19,035	11	18,993	11
Dementia	3,896	2	7,477	0	3,308	2	3,440	2
Chronic pulmonary disease	12,902	7	59,267	2	10,483	6	10,866	7
Connective tissue disease	4,386	2	26,996	1	3,710	2	3,854	2
Ulcer disease	53	0	305	0	42	0	47	0
Mild liver disease	1,012	1	11,409	0	885	1	962	1
Hemiplegia	330	0	2,315	0	279	0	301	0
Moderate to severe renal disease	3,231	2	9,492	0	2,515	2	2,477	2
Any tumor	11,858	6	74,633	3	10,457	6	10,803	7
Leukemia	442	0	2,433	0	388	0	371	0
Lymphoma	922	1	5,241	0	790	1	835	1
Moderate to severe liver disease	218	0	2,030	0	199	0	208	0
Metastatic solid tumor	1,343	1	7,779	0	1,184	1	1,178	1
AIDS	103	0	1,957	0	81	0	74	0
Concomitant medication use
Oral anticoagulants	10,707	6	36,310	1	9,351	6	10,799	7
High-dose ASA	26,246	14	18,261	1	18,191	11	16,120	10
NSAIDs	631	0	3,431	0	528	0	544	0
Glucocorticoids	15,251	8	109,747	4	13,046	8	13,597	8
SSRIs	20,247	11	169,328	6	17,306	10	18,353	11
PPIs	31,722	17	217,590	7	26,854	16	29,214	18
Nitrates	14,024	7	11,813	0	9,787	6	8,723	5
Calcium antagonists	41,555	22	145,513	5	35,429	21	39,582	24
Statins	56,548	30	173,160	6	47,003	28	53,147	32
H2 antagonists	3,180	2	21,316	1	2,719	2	2,785	2

Abbreviations: PS, propensity score; ASA, acetylsalicylic acid; SSRIs, selective serotonin reuptake inhibitors; PPIs, proton-pump inhibitors; NSAIDs, nonsteroidal anti-inflammatory drugs.

Table 2 Patient characteristics of Cohort 2 (reconstructed cohort)

Patient characteristics	Full cohort				Propensity-score-matched Cohort
	Low-dose ASA initiators		Non-initiators		Low-dose ASA initiators		Non-initiators
	N=403,693	%	N=3,195,091	%	N=367,326	%	N=367,326	%
Age groups (years)
<50	36,701	9	1,565,801	49	34,298	9	30,124	8
50–59	73,674	18	683,695	21	66,717	18	65,087	18
60–69	120,820	30	541,482	17	110,120	30	110,012	30
70–79	101,049	25	265,918	8	91,126	25	94,192	26
≥80	71,449	18	138,195	4	65,065	18	67,911	19
Gender
Female	191,444	47	1,646,653	52	177,264	48	178,754	49
Male	212,249	53	1,548,438	49	190,062	52	188,572	51
Comorbid conditions
Alcoholism	7,611	2	31,268	1	6,530	2	7,015	2
Non-bleeding ulcer diagnosis	3,573	1	11,828	0	3,090	1	3,219	1
Non-bleeding conditions from esophagus	11,553	3	46,505	2	10,067	3	10,600	3
Diabetes	57,814	14	113,453	4	49,798	14	56,664	15
Myocardial infarction	34,253	9	9,105	0	16,776	5	9,104	3
Congestive heart failure	18,872	5	18,054	1	14,094	4	13,448	4
Peripheral vascular disease	20,825	5	19,997	1	15,936	4	15,129	4
Cerebrovascular disease	48,002	12	38,802	1	37,329	10	35,886	10
Dementia	6,184	2	9,815	0	5,323	1	5,544	2
Chronic pulmonary disease	25,434	6	71,478	2	21,475	6	22,673	6
Connective tissue disease	9,048	2	31,832	1	7,842	2	8,161	2
Ulcer disease	111	0	392	0	91	0	111	0
Mild liver disease	2,266	1	12,871	0	2,036	1	2,169	1
Hemiplegia	645	0	2,612	0	545	0	584	0
Moderate to severe renal disease	6,192	2	12,327	0	4,998	1	4,994	1
Any tumor	23,555	6	86,392	3	21,200	6	22,482	6
Leukemia	865	0	2,893	0	769	0	797	0
Lymphoma	1,933	1	6,137	0	1,731	1	1,836	1
Moderate to severe liver disease	457	0	2,368	0	419	0	450	0
Metastatic solid tumor	2,499	1	8,741	0	2,233	1	2,341	1
AIDS	233	0	2,105	0	188	0	201	0
Concomitant medication use
Oral anticoagulants	21,500	5	50,212	2	19,213	5	21,989	6
High-dose ASA	61,067	15	47,223	2	46,312	13	43,752	12
NSAIDs	1,273	0	4,417	0	1,127	0	1,137	0
Glucocorticoids	31,071	8	126,701	4	27,351	7	29,017	8
SSRIs	39,845	10	191,574	6	34,934	10	37,814	10
PPIs	66,641	17	253,070	8	58,304	16	63,874	17
Nitrates	27,905	7	22,767	1	20,979	6	18,934	5
Calcium antagonists	82,788	21	185,278	6	72,051	20	79,474	22
Statins	115,557	29	226,428	7	99,031	27	109,607	30
H2 antagonists	7,090	2	26,467	1	6,215	2	6,413	2

Abbreviations: ASA, acetylsalicylic acid; SSRIs, selective serotonin reuptake inhibitors; PPIs, proton-pump inhibitors; NSAIDs, nonsteroidal anti-inflammatory drugs.

Table 3 Association between low-dose ASA use and major bleeding (composite endpoint), cerebral hemorrhage, and gastrointestinal bleeding by cohort before and after propensity-score matching

Outcome	Full cohort						Propensity-score-matched cohort
	ASA use	Number of persons	Number of events	IR/1,000 PYRs (95% CI)	Unadjusted IRD (95% CI)	Unadjusted IRR (95% CI)	Number of persons	Number of events	IR/1,000 PYRs (95% CI)	Adjusted IRD (95% CI)	Adjusted IRR (95% CI)
Cohort 1
Major bleeding (composite endpoint)	Continuous	189,150	6,758	11.03 (10.77, 11.29)	9.54 (9.28, 9.81)	7.40 (7.19, 7.62)	166,983	5,768	10.69 (10.42, 10.97)	5.12 (4.78, 5.46)	1.92 (1.84, 2.01)
	Never	2,938,044	16,032	1.49 (1.47, 1.51)	0.00	1.00	166,983	2,937	5.57 (5.37, 5.77)	0.00	1.00
Cerebral hemorrhage	Continuous	189,150	1,565	2.55 (2.43, 2.68)	2.05 (1.92, 2.18)	5.06 (4.79, 5.36)	166,983	1,358	2.52 (2.38, 2.65)	0.97 (0.80, 1.14)	1.63 (1.49, 1.77)
	Never	2,938,044	5,427	0.50 (0.49, 0.52)	0.00	1.00	166,983	816	1.55 (1.44, 1.65)	0.00	1.00
Gastrointestinal bleeding	Continuous	189,150	5,193	8.48 (8.25, 8.71)	7.49 (7.26, 7.72)	8.60 (8.32, 8.89)	166,983	4,410	8.18 (7.94, 8.42)	4.15 (3.86, 4.45)	2.03 (1.93, 2.14)
	Never	2,938,044	10,605	0.99 (0.97, 1.00)	0.00	1.00	166,983	2,121	4.02 (3.85, 4.19)	0.00	1.00
Cohort 2
Major bleeding (composite endpoint)	Initiators	403,693	7,236	10.05 (9.81, 10.28)	8.41 (8.18, 8.64)	6.14 (5.98, 6.31)	367,326	6,346	9.77 (9.53, 10.01)	4.87 (4.59, 5.14)	1.99 (1.92, 2.06)
	Non-initiators	3,195,091	19,055	1.64 (1.61, 1.66)	0.00	1.00	367,326	5,370	4.91 (4.78, 5.04)	0.00	1.00
Cerebral hemorrhage	Initiators	403,693	1,672	2.32 (2.21, 2.43)	1.76 (1.65, 1.87)	4.14 (3.92, 4.37)	367,326	1,490	2.29 (2.18, 2.41)	0.86 (0.72, 0.99)	1.60 (1.49, 1.71)
	Non-initiators	3,195,091	6,535	0.56 (0.55, 0.57)	0.00	1.00	367,326	1,573	1.44 (1.37, 1.51)	0.00	1.00
Gastrointestinal bleeding	Initiators	403,693	5,564	7.72 (7.52, 7.93)	6.65 (6.45, 6.85)	7.19 (6.96, 7.42)	367,326	4,856	7.48 (7.27, 7.69)	4.01 (3.77, 4.25)	2.15 (2.07, 2.25)
	Non-Initiators	3,195,091	12,520	1.07 (1.06, 1.09)	0.00	1.00	367,326	3,797	3.47 (3.36, 3.58)	0.00	1.00

Abbreviations: ASA, acetylsalicylic acid; IR, incidence rate; PYRs, person-years; IRD, incidence rate difference; IRR, incidence rate ratio; 95% CI, 95% confidence interval.

Figure 3 (A–D) Time-stratified measures of association between low-dose acetylsalicylic acid (ASA) use and major bleeding in Cohorts 1 and 2. Cohort 1 incidence rate differences (IRDs per 1,000 person-years) and incidence rate ratios at 0–89 days, 90–179 days, 180 days to <1 year, 1 to <2 years, and 2–7 years are presented in (A) and (C), respectively. Cohort 2 IRDs and IRRs for the same time periods are presented in (B) and (D), respectively.

Table S1 Results of sensitivity analyses using a 60-day and 120-day grace period in the Cohort 2

60-day grace period
Outcome	ASA use	No. of persons	No. of endpoint	Sum of person-years	Incidence rate/1, 000 PYRs (95% CI)	Adjusted IRD (95% CI)	Adjusted IRR (95% CI)
Major bleeding	No	367,326	5,370	1,093,950	4.91 (4.78, 5.04)	–	–
Major bleeding	Yes	367,326	5,428	543,420	9.99 (9.72, 10.25)	5.08 (4.78, 5.38)	2.03 (1.96, 2.11)
Cerebral hemorrhage	No	367,326	1,573	1,093,950	1.44 (1.37, 1.51)	–	–
Cerebral hemorrhage	Yes	367,326	1,256	543,420	2.31 (2.18, 2.44)	0.87 (0.73, 1.02)	1.61 (1.49, 1.73)
Gastrointestinal bleeding	No	367,326	3,797	1,093,950	3.47 (3.36, 3.58)	–	–
Gastrointestinal bleeding	Yes	367,326	4,172	543,420	7.68 (7.44, 7.91)	4.21 (3.95, 4.46)	2.21 (2.12, 2.31)
120-day grace period
Outcome	ASA use	No. of persons	No. of endpoint	Sum of person-years	Incidence rate/1,000 PYRs (95% CI)	Adjusted IRD (95% CI)	Adjusted IRR (95% CI)
Major bleeding	No	367,326	5,370	1,093,950	4.91 (4.78, 5.04)	–	–
Major bleeding	Yes	367,326	7,064	748,210	9.44 (9.22, 9.66)	4.53 (4.28, 4.79)	1.92 (1.86, 1.99)
Cerebral hemorrhage	No	367,326	1,573	1,093,950	1.44 (1.37, 1.51)	–	–
Cerebral hemorrhage	Yes	367,326	1,683	748,210	2.25 (2.14, 2.36)	0.81 (0.68, 0.94)	1.56 (1.46, 1.68)
Gastrointestinal bleeding	No	367,326	3,797	1,093,950	3.47 (3.36, 3.58)	–	–
Gastrointestinal bleeding	Yes	367,326	5,381	748,210	7.19 (7.00, 7.38)	3.72 (3.50, 3.94)	2.07 (1.99, 2.16)

Abbreviations: ASA, acetylsalicylic acid; PYRs, person-years; IRD, incidence rate difference; IRR, incidence rate ratio; 95% CI, 95% confidence interval.