Problem of immortal time bias in cohort studies: example using statins for preventing progression of diabetes

Lévesque, Linda E.; Hanley, James A.; Kezouh, Abbas; Suissa, Samy

doi:10.1136/bmj.b5087

Cited by 897 publications

(811 citation statements)

References 32 publications

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“…Other sensitivity analyses not reported below (Tables available on request) include: (5) addressing immortal time bias by dropping all episodes that began before patients were transferred into CPRD or follow‐up began or including only the last treatment episode (no change in results) 48; and testing that the direction and magnitude of IRR between buprenorphine and methadone were robust to changing the minimum gap between episodes (e.g. moving from fewer than 28 days to 7 days) (they were).…”

Section: Methodsmentioning

confidence: 99%

The impact of buprenorphine and methadone on mortality: a primary care cohort study in the United Kingdom

et al. 2018

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AimsTo estimate whether opioid substitution treatment (OST) with buprenorphine or methadone is associated with a greater reduction in the risk of all‐cause mortality (ACM) and opioid drug‐related poisoning (DRP) mortality.DesignCohort study with linkage between clinical records from Clinical Practice Research Datalink and mortality register.SettingUK primary care.ParticipantsA total of 11 033 opioid‐dependent patients who received OST from 1998 to 2014, followed‐up for 30 410 person‐years.MeasurementsExposure to methadone (17 373, 61%) OST episodes or buprenorphine (9173, 39%) OST episodes. ACM was available for all patients; information on cause of death and DRP was available for 5935 patients (54%) followed‐up for 16 363 person‐years. Poisson regression modelled mortality by treatment period with an interaction between OST type and treatment period (first 4 weeks on OST, rest of time off OST, first 4 weeks off OST, rest of time out of OST censored at 12 months) to test whether ACM or DRP differed between methadone and buprenorphine. Inverse probability weights were included to adjust for confounding and balance characteristics of patients prescribed methadone or buprenorphine.FindingsACM and DRP rates were 1.93 and 0.53 per 100 person‐years, respectively. DRP was elevated during the first 4 weeks of OST [incidence rate ratio (IRR) = 1.93 95% confidence interval (CI) = 0.97–3.82], the first 4 weeks off OST (IRR = 8.15, 95% CI = 5.45–12.19) and the rest of time out of OST (IRR = 2.13, 95% CI = 1.47–3.09) compared with mortality risk from 4 weeks to end of treatment. Patients on buprenorphine compared with methadone had lower ACM rates in each treatment period. After adjustment, there was evidence of a lower DRP risk for patients on buprenorphine compared with methadone at treatment initiation (IRR = 0.08, 95% CI = 0.01–0.48) and rest of time on treatment (IRR = 0.37, 95% CI = 0.17–0.79). Treatment duration (mean and median) was shorter on buprenorphine than methadone (173 and 40 versus 363 and 111, respectively). Model estimates suggest that there was a low probability that methadone or buprenorphine reduced the number of DRP in the population: 28 and 21%, respectively.ConclusionsIn UK general medical practice, opioid substitution treatment with buprenorphine is associated with a lower risk of all‐cause and drug‐related poisoning mortality than methadone. In the population, buprenorphine is unlikely to give greater overall protection because of the relatively shorter duration of treatment.

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Section: Methodsmentioning

confidence: 99%

The impact of buprenorphine and methadone on mortality: a primary care cohort study in the United Kingdom

et al. 2018

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“…Immortal time is the follow‐up period during which the outcome cannot happen 22. This bias can be introduced when either the treatment status or the follow‐up time is inappropriately assigned.…”

Section: Discussionmentioning

confidence: 99%

“…The immortal time from diabetes mellitus diagnosis to the start of antidiabetic drugs and in those with a short follow‐up period of <180 days was not included in the person‐years calculation in the study. It is worth mentioning that the immortal time during the waiting period between drug prescription and dispense when patients are discharged from the hospital (as pointed out by Lévesque et al22) would not happen in Taiwan because the patients can get all discharge medications directly from the hospital when they are discharged.…”

Section: Discussionmentioning

confidence: 99%

Metformin and Risk of Hypertension in Taiwanese Patients With Type 2 Diabetes Mellitus

Tseng

2018

JAHA

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BackgroundWhether metformin use may reduce hypertension risk has not been studied. This study investigated such possibility in patients with type 2 diabetes mellitus.Methods and ResultsNewly diagnosed patients with type 2 diabetes mellitus during 1999–2005 were enrolled from the reimbursement database of the Taiwan's National Health Insurance and followed to December 31, 2011. Hypertension was defined either by a diagnosis or by a diagnosis plus the use of angiotensin converting enzyme inhibitors/angiotensin receptor blockers and/or calcium channel blockers. Analyses were conducted in a propensity score matched‐pair cohort of 4810 ever users and 4810 never users. Cox proportional hazards regression model was used to estimate the hazard ratios. Results showed that when hypertension was defined by a diagnosis, 2261 never users and 1908 ever users developed hypertension. The overall hazard ratio was 0.724 (0.681–0.769) and the hazard ratios for the first (<2.0 months), second (2.0–13.0 months) and third (>13.0 months) tertiles of cumulative duration were 0.820 (0.745–0.903), 0.692 (0.634–0.756), and 0.687 (0.630–0.749), respectively. When cumulative duration of metformin therapy was treated as a continuous variable, the hazard ratio was 0.991 (0.989–0.994) for every 1‐month increment of metformin use. When hypertension was defined by a diagnosis plus the use of antihypertensive drugs, the overall hazard ratio was 0.831 (0.771–0.895), the hazard ratios for the respective tertiles were 0.868 (0.769–0.980), 0.852 (0.767–0.946), and 0.787 (0.709–0.874), and the hazard ratio was 0.994 (0.991–0.997) for every 1‐month increment of metformin use.ConclusionsA reduced risk of hypertension is observed in metformin users in a dose‐response pattern.

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“…Because filter placement varied from early to late during the index admission, analysis of the effect of IVC filter placement on early mortality is subject to immortal time bias [35][36][37]. Patients in the filter group had to be alive at time of insertion, whereas some in the NO filter group might have died before having the opportunity for IVC filter placement.…”

Section: Immortal Time Biasmentioning

confidence: 99%

Inferior vena cava filters in patients with cancer and venous thromboembolism (VTE): patterns of use and outcomes

Brunson¹,

Ho²,

White

et al. 2016

Thrombosis Research

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Problem of immortal time bias in cohort studies: example using statins for preventing progression of diabetes

Abstract: Immortal time in observational studies can bias the results in favour of the treatment group, but it is not difficult to identify and avoid

Cited by 897 publications

References 32 publications

The impact of buprenorphine and methadone on mortality: a primary care cohort study in the United Kingdom

The impact of buprenorphine and methadone on mortality: a primary care cohort study in the United Kingdom

Metformin and Risk of Hypertension in Taiwanese Patients With Type 2 Diabetes Mellitus

Inferior vena cava filters in patients with cancer and venous thromboembolism (VTE): patterns of use and outcomes

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