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

Abstract

Background

A principle of cohort studies is that cohort membership is defined by current rather than future exposure information. Pharmacoepidemiologic studies using existing databases are vulnerable to violation of this principle. We evaluated the impact of using data on future redemption of prescriptions to determine cohort membership, motivated by a published example seeking to emulate a “per-protocol” association between continuous versus never use of low-dose acetylsalicylic acid (ASA) and major bleeding (e.g., cerebral hemorrhage or gastrointestinal bleeding).

Materials and methods

Danish medical registry data from 2004 to 2011 were used to construct two analytic cohorts. In Cohort 1, we used information about future redemption of low-dose ASA prescriptions to identify cohorts of continuous and never-ASA users. In Cohort 2, we identified ASA initiators and non-initiators using only contemporaneous data and censored follow-up for changes in use over time. We implemented propensity score-matched Poisson regression to evaluate associations between ASA use and major bleeding and estimated adjusted incidence rate differences (IRDs) per 1,000 person-years and ratios (IRRs) overall and stratified by time since initiation.

Results

Among >6 million eligible Danish adults, we identified 403,693 low-dose ASA initiators (Cohort 2), of whom 189,150 were defined as continuous users (Cohort 1). Overall, IRDs and IRRs were similar across cohorts. However, the IRD for major bleeding in the first 90 days was substantially larger in Cohort 1 (IRD=25 per 1,000 person-years) compared with Cohort 2 (IRD=10 per 1,000 person-years).

Conclusion

Using future medication redemption data to define baseline cohorts violates basic epidemiologic principles. Compared with an approach using only contemporaneous data to define cohorts, the approach based on future redemption data generated a substantially higher short-term association between low-dose ASA use and major bleeding on the absolute, but not the relative, scale possibly due to selection and immortal time biases.

Keywords:

• pharmacoepidemiology
• cohort studies
• immortal time bias
• selection bias

Supplementary materials

International Classification of Diseases, Tenth Revision (ICD-10) and Anatomical Therapeutic Chemical (ATC) codes used in analysis

Exposure

Low-dose acetylsalicylic acid (ASA) ≤300 mg (ATC code): B01AC06

Outcome

Hospitalization for upper gastrointestinal bleeding

Bleeding from gastritis (K29.0)

Bleeding from ulcers in the stomach (K25.0, K25.2, K25.4, K25.6)

Bleeding from ulcers in the duodenum (K26.0, K26.2, K26.4, K26.6)

Bleeding from gastro-duodenal ulcers (K27.0, K27.2, K27.4, K27.6)

Bleeding from anastomotic ulcers, i.e. gastrojejunal ulcers (K28.0, K28.2, K28.4, K28.6)

Haematemesis (K92.0)

Melaena (K92.1)

Gastrointestinal hemorrhage without specification (K92.2)

Cerebral hemorrhage

ICD-10 codes I60–I62

Covariates

Previous inpatient and outpatient diagnoses for

Alcoholism (not included in Charlson) (F10, G312, G621, G721, I426, R780, T51, Z714, Z721)

Non-bleeding ulcer diagnosis (K25.1, K25.3, K25.5, K25.7, K25.9, K26.1, K26.3, K26.5, K26.7, K26.9, K27.1, K27.3, K27.5, K27.7, K27.9, K28.1, K28.3, K28.5, K28.7, K28.9)

Non-bleeding conditions from esophagitis, gastritis, duodenitis or Mallory–Weiss lesions (K20.9, K21, K22, K23, K29.1–K29.9)

Diabetes (E10–E14, O24, H360)

Modified Charlson Comorbidity Index (Hospitalization or outpatient hospital visit)

• Myocardial infarction, I21–I23

• Congestive heart failure, I50, I11.0, I13.0, I13.2

• Peripheral vascular disease, I70–I74, I77

• Dementia, F00–F03, F05.1, G30

• Chronic pulmonary disease, J40–J47, J60–J67, J68.4, J70.1, J70.3, J84.1, J92.0, J96.1, J98.2, J98.3

• Connective tissue disease, M05, M06, M08, M09, M30–M36, D86

• Ulcer disease, K22.1, K25–K28

• Mild liver disease, B18, K70.0–K70.3, K70.9, K71, K73, K74, K76.0

• Moderate to severe renal disease, I12, I13, N00–N05, N07, N11, N14, N17–N19, Q61

• Non-metastatic solid tumor, C00–C75

• Leukemia, C91–C95

• Lymphoma, C81–C85, C88, C90, C96

• Moderate to severe liver disease, B15.0, B16.0, B16.2, B19.0, K70.4, K72, K76.6, I85;

• Metastatic solid tumor, C76–C80

• AIDS, B21–B24

Co-medications (defined during the 1 year prior to the index date)

• Oral anticoagulants (B01AA03, B01AA04)

• High dose ASA (N02BA01, N02BA51)

• Nonselective non-steroidal anti-inflammatory drugs (NSAIDs) (M01AH02, M01AH01)

• Glucocorticoids (H02AB)

• Selective serotonin reuptake inhibitors (SSRIs) (N06AB)

• Proton pump inhibitors (PPIs) (A02BC05, A02BC03, A02BC01, A02BC02, A02BC04)

• Nitrates (C01D)

• Calcium antagonists (C08)

• Statins (C10AA0, B04AB0)

• H2 antagonists (A02BA01, A02BA03, A02BA04, A02BA02, A02BA07)

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

Acknowledgments

We would like to thank Dr Mark Weaver for his thoughtful comments on an earlier version of the manuscript. This study was funded by the Program for Clinical Research Infrastructure (PROCRIN) established by the Lundbeck Foundation and the Novo Nordisk Foundation and administered by the Danish Regions.

Disclosure

Dr Lund received research funding from the National Cancer Institute K12CA120780 and her spouse is a full-time paid employee of GlaxoSmithKline. Dr Stürmer has research funding (R01/56 AG023178, R01 CA174453, R01 HL118255, R21-HD080214) from the National Institutes of Health. He receives salary support as Director of the Comparative Effectiveness Research Strategic Initiative, Translational Science Award (UL1TR001111), and as Director of the Center for Pharmacoepidemiology and research support from pharmaceutical companies (Amgen, AstraZeneca) to the Department of Epidemiology at UNC. He owns stock in Novartis, Roche, BASF, AstraZeneca, and Novo Nordisk. Dr Sørensen did not report receiving fees, honoraria, grants, or consultancies. Department of Clinical Epidemiology is, however, involved in studies with funding from various companies as research grants to (and administered by) Aarhus University. None of these studies have relation to the present study. All other authors report no conflicts of interest in this work.