Electronic medical records can be used to emulate target trials of sustained treatment strategies

Abstract

Objective: To emulate three target trials: single treatment vs. no treatment, joint treatment vs. no treatment, and head-to-head comparison of two treatments, we explain how to estimate the observational analogs of intention-to-treat and per-protocol effects, using hazard ratios and survival curves. For per-protocol effects, we describe two methods for adherence adjustment via inverse-probability weighting.

Study design and setting: Prospective observational study using electronic medical records of individuals aged 55-84 with coronary heart disease from >500 practices in the United Kingdom between 2000 and 2010.

Results: The intention-to-treat mortality hazard ratio (95% confidence interval) was 0.90 (0.84, 0.97) for statins vs. no treatment, 0.88 (0.73, 1.06) for statins plus antihypertensives vs. no treatment, and 0.91 (0.77, 1.06) for atorvastatin vs. simvastatin. When censoring nonadherent person-times, the per-protocol mortality hazard ratio was 0.74 (0.64, 0.85) for statins vs. no treatment, 0.55 (0.35, 0.87) for statins plus antihypertensives vs. no treatment, and 1.13 (0.88, 1.45) for atorvastatin vs. simvastatin. We estimated per-protocol hazard ratios for a 5-year treatment using different dose-response marginal structural models and standardized survival curves for each target trial using intention-to-treat and per-protocol analyses.

Conclusion: When randomized trials are not available or feasible, observational analyses can emulate a variety of target trials.

Keywords: Comparative effectiveness; Confounding; Electronic health records; Medication adherence; Secondary prevention; Survival analysis.

Figure 1

Selection process for participants, The Health Improvement Network 2000–2010 (A) statins; (B) statins and antihypertensives; (C) atorvastatin versus simvastatin. Numbers in parentheses indicate unique individuals. ^aMajor chronic disease was defined as cancer, chronic kidney disease, liver failure, congestive heart failure, dementia, schizophrenia or organ transplant.

Figure 1

Selection process for participants, The Health Improvement Network 2000–2010 (A) statins; (B) statins and antihypertensives; (C) atorvastatin versus simvastatin. Numbers in parentheses indicate unique individuals. ^aMajor chronic disease was defined as cancer, chronic kidney disease, liver failure, congestive heart failure, dementia, schizophrenia or organ transplant.

Figure 1

Selection process for participants, The Health Improvement Network 2000–2010 (A) statins; (B) statins and antihypertensives; (C) atorvastatin versus simvastatin. Numbers in parentheses indicate unique individuals. ^aMajor chronic disease was defined as cancer, chronic kidney disease, liver failure, congestive heart failure, dementia, schizophrenia or organ transplant.

Figure 2

Estimated survival curves after initiation and no initiation of statins, The Health Improvement Network 2000–2010. (A) intention-to-treat effect, (B) per-protocol effect via censoring non-adherent person-times, (C) per-protocol effect via dose-response model

Figure 2

Estimated survival curves after initiation and no initiation of statins, The Health Improvement Network 2000–2010. (A) intention-to-treat effect, (B) per-protocol effect via censoring non-adherent person-times, (C) per-protocol effect via dose-response model

Figure 3

Adherence to treatment in the eligible population when emulating three target trials, The Health Improvement Network 2000–2010. (A) statins vs. no statins, (B) statins and antihypertensives versus neither, and (C) atorvastatin versus simvastatin

Figure 3

Adherence to treatment in the eligible population when emulating three target trials, The Health Improvement Network 2000–2010. (A) statins vs. no statins, (B) statins and antihypertensives versus neither, and (C) atorvastatin versus simvastatin

Figure 4

Estimated survival curves after initiation and no initiation of statins plus antihypertensives, The Health Improvement Network 2000–2010. (A) intention-to-treat effect, (B) per-protocol effect via censoring non-adherent person-times, (C) per-protocol effect via dose-response model

Figure 4

Estimated survival curves after initiation and no initiation of statins plus antihypertensives, The Health Improvement Network 2000–2010. (A) intention-to-treat effect, (B) per-protocol effect via censoring non-adherent person-times, (C) per-protocol effect via dose-response model

Figure 5

Estimated survival curves after initiation of atorvastatin and initiation of simvastatin, The Health Improvement Network 2000–2010. (A) intention-to-treat effect, (B) per-protocol effect via censoring non-adherent person-times, (C) per-protocol effect via dose-response model

Figure 5

Estimated survival curves after initiation of atorvastatin and initiation of simvastatin, The Health Improvement Network 2000–2010. (A) intention-to-treat effect, (B) per-protocol effect via censoring non-adherent person-times, (C) per-protocol effect via dose-response model