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Table 4 Studies without synchronization of eligibility, treatment assignment, and follow-up

From: Risk of bias in observational studies using routinely collected data of comparative effectiveness research: a meta-research study

Author, year Patients (n) Intervention Comparator Outcomes Time points of eligibility Times points of treatment assignment Start of follow-up Situations of failure of emulating a target trial Type of bias might arise Solution described by authors
Converse 2019 [19] 111 Angiotensin II inhibitors after continuous-flow left ventricular assist devices implant Usual care Gastrointestinal bleeding 30 days after operation to implant continuous-flow left ventricular assist devices Within 30 days since operation 30 days after operation b. Follow-up starts at eligibility but after treatment initiation. Prevalent user bias, selection bias due to post-treatment eligibility No solution described.
Skriver 2019 [20] 29,136 Low-dose aspirin Usual care Prostate cancer mortality 1 year after prostate cancer diagnosis Within 1 year since diagnosis 1 year after prostate cancer diagnosis b. Follow-up starts at eligibility but after treatment initiation. Prevalent user bias, selection bias due to post-treatment eligibility No solution described.
Friberg 2019 [21] 47,492 Oral anticoagulant No treatment Diagnosis of dementia, ischemic stroke, intracranial bleeding At the time of diagnosis of atrial fibrillation 6 months before the start of follow-up 30 days after the diagnosis of atrial fibrillation b. Follow-up starts at eligibility but after treatment initiation. Prevalent user bias, selection bias due to post-treatment eligibility No solution described.
Brauer 2019 [23] 424,996 Trazodone Other antidepressants Diagnosis of dementia At the second prescription of antidepressant At the first prescription of antidepressant At the first prescription of antidepressant c. Follow-up starts at treatment initiation but before eligibility. Immortal time bias and selection bias due to post-treatment eligibility No solution described.
Xie 2019 [24] 214,467 Proton pump inhibitors H2 blockers All-cause mortality 180 days after treatment group assignment At the first prescription of either PPI or H2 blocker At the first prescription of either PPI or H2 blocker c. Follow-up starts at treatment initiation but before eligibility. Selection bias due to post-treatment eligibility No solution described.
Brown 2019 [25] 1555 Immunomodulatory disease-modifying therapies No treatment Disease progression 6 months after treatment commencement Date of treatment commencement Date of treatment commencement c. Follow-up starts at treatment initiation but before eligibility. Immortal time bias and selection bias due to post-treatment eligibility Exposure was considered as time-dependent variable in all analysis to adjust for immortal time bias, but no solution described for selection bias due to post-treatment eligibility.
Kim 2019 [26] 1.0705 Statin Statin + fenofibrate Cardiovascular events 3 months after fenofibrate initiation Date of fenofibrate initiation Date of fenofibrate initiation c. Follow-up starts at treatment initiation but before eligibility. Immortal time bias and selection bias due to post-treatment eligibility No solution described.
Axtell 2019 [30] 3276 Surgery Medical therapy All-cause mortality The first echocardiographic diagnosis Time of surgery The first echocardiographic diagnosis d. Follow-up start at eligibility, but treatment is assigned later. Immortal time bias and misclassification of treatment Time-dependent propensity score matching and allocate time before surgery to the control group.
Gharbi 2019 [31] 157,264 Antibiotic No treatment Bloodstream infection, hospital admission, and all-cause mortality Date of urinary tract infection diagnosis Within 7 days since diagnosis Date of urinary tract infection diagnosis d. Follow-up start at eligibility, but treatment is assigned later. Immortal time bias and misclassification of treatment No solution described.
Gray 2019 [32] 9653 Chemotherapy Usual care All-cause mortality and breast cancer mortality Date of diagnosis Date of chemotherapy commencement not reported but likely to be after the date of diagnosis Date of diagnosis d. Follow-up start at eligibility, but treatment is assigned later. Immortal time bias and misclassification of treatment No solution described.
van Rein 2019 [33] 272,315 Antithrombotic therapy No treatment Major bleeding The date of their atrial fibrillation diagnosis Treatment starts at any time after diagnosis The date of their atrial fibrillation diagnosis d. Follow-up start at eligibility, but treatment is assigned later. Immortal time bias and misclassification of treatment Exposure was treated as time-dependent variable in Cox regression.
Mahévas 2020 [34] 173 Hydroxychloroquine Usual care Survival without transfer to ICU Admission to hospital Within 48 h since admission Admission to hospital d. Follow-up start at eligibility, but treatment is assigned later. Immortal time bias and misclassification of treatment Patients from the control group who reached the primary outcome during the grace period were randomly assigned to one of the two groups, given that their observational data were compatible with both groups at the time of the event.
Rosenberg 2020 [35] 1438 Hydroxychloroquine with or without azithromycin Usual care In-hospital mortality At admission to hospital Start treatment at any time during hospitalization 24 h after admission d. Follow-up start at eligibility, but treatment is assigned later. Immortal time bias and misclassification of treatment No solution described.
Geleris 2020 [38] 1446 Hydroxychloroquine Usual care Composite of intubation and death 24 h after arrival at the emergency department Start treatment before or any time after hospitalization 24 h after arrival at the emergency department b. Follow-up starts at eligibility but after treatment initiation for prevalent user group.
d. Follow-up start at eligibility, but treatment is assigned later for new user group.
Prevalent user bias and immortal time bias No solution described.
Jorge 2019 [36] 9659 Renal transplant Usual care All-cause mortality The initial date of entry into the waitlist Surgery at any time after being the waitlist The initial date of entry onto the waitlist d. Follow-up start at eligibility, but treatment is assigned later. Immortal time bias and misclassification of treatment Exposure was considered as time-dependent variable in all analysis.
Rea 2018 [28] 44,534 Two drug therapy antihypertension Monotherapy antihypertension Cardiovascular events 1 year after the dispensing of treatment The first day of drug dispensing The first day of drug dispensing c. Follow-up starts at treatment initiation but before eligibility. Immortal time bias and selection bias due to post-treatment eligibility No solution described.
Lin 2018 [27] 6558 Low-dose of rivaroxaban Standard dose of rivaroxaban Major bleeding events Patients refilled prescription more than once since the start of rivaroxaban The first prescription of rivaroxaban The first prescription of rivaroxaban c. Follow-up starts at treatment initiation but before eligibility. Immortal time bias and selection bias due to post-treatment eligibility A sensitivity analysis was performed to include patients who did not refill their prescription after the first one.
Siontis 2018 [22] 25,523 Apixaban or switching from warfarin to apixaban Warfarin Ischemic stroke, major bleeding events, and death Diagnosis of atrial fibrillation The date of the initial anticoagulation prescription or the date of apixaban prescription if patient switched from warfarin to apixaban The date of the initial anticoagulation prescription or the date of apixaban prescription if patient switched from warfarin to apixaban b. Follow-up starts at eligibility but after treatment initiation. Selection bias due to post-treatment eligibility No solution described.
Ramos 2018 [29] 46864 Statin No treatment Incidences of atherosclerotic cardiovascular diseases and all-cause mortality The second invoice of statin The first invoice of statin The first invoice of statin c. Follow-up starts at treatment initiation but before eligibility. Immortal time bias and selection bias due to post-treatment eligibility No solution described.