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Estimating dose-response for time to remission with instrumental variable adjustment: the obscuring effects of drug titration in Genome Based Therapeutic Drugs for Depression Trial (GENDEP): clinical trial data.

ABSTRACT: BACKGROUND:Threshold regression, in which time to remission is modelled as a stochastic drift towards a boundary, is an alternative to the proportional hazards survival model and has a clear conceptual mechanism for examining the effects of drug dose. However, for both threshold regression and proportional hazard models, when dose titration occurs during treatment, the estimated causal effect of dose can be biased by confounding. An instrumental variable analysis can be used to minimise such bias. METHOD:Weekly antidepressant dose was measured in 380 men and women with major depression treated with escitalopram or nortriptyline for 12 weeks as part of the Genome Based Therapeutic Drugs for Depression (GENDEP) study. The averaged dose relative to maximum prescribing dose was calculated from the 12 trial weeks and tested for association with time to depression remission. We combined the instrumental variable approach, utilising randomised treatment as an instrument, with threshold regression and proportional hazard survival models. RESULTS:The threshold model was constructed with two linear predictors. In the naïve models, averaged daily dose was not associated with reduced time to remission. By contrast, the instrumental variable analyses showed a clear and significant relationship between increased dose and faster time to remission, threshold regression (velocity estimate: 0.878, 95% confidence interval [CI]: 0.152-1.603) and proportional hazards (log hazards ratio: 3.012, 95% CI: 0.086-5.938). CONCLUSIONS:We demonstrate, using the GENDEP trial, the benefits of these analyses to estimate causal parameters rather than those that estimate associations. The results for the trial dataset show the link between antidepressant dose and time to depression remission. The threshold regression model more clearly distinguishes the factors associated with initial severity from those influencing treatment effect. Additionally, applying the instrumental variable estimator provides a more plausible causal estimate of drug dose on treatment effect. This validity of these results is subject to meeting the assumptions of instrumental variable analyses. TRIAL REGISTRATION:EudraCT, 2004-001723-38; ISRCTN, 03693000. Registered on 27 September 2007.

SUBMITTER: Hellier J

PROVIDER: S-EPMC6942263 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Estimating dose-response for time to remission with instrumental variable adjustment: the obscuring effects of drug titration in Genome Based Therapeutic Drugs for Depression Trial (GENDEP): clinical trial data.

Hellier Jennifer J Emsley Richard R Pickles Andrew A

Trials 20200103 1

<h4>Background</h4>Threshold regression, in which time to remission is modelled as a stochastic drift towards a boundary, is an alternative to the proportional hazards survival model and has a clear conceptual mechanism for examining the effects of drug dose. However, for both threshold regression and proportional hazard models, when dose titration occurs during treatment, the estimated causal effect of dose can be biased by confounding. An instrumental variable analysis can be used to minimise ...[more]

PMID: 31900198

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Project description:OBJECTIVES:To assess the incremental effects of adding extra antihypertensive drugs from a new class to a patient's regimen. DESIGN:Instrumental variable analysis of data from SPRINT (Systolic Blood Pressure Intervention Trial). To account for confounding by indication-when treatments seem less effective if they are administered to sicker patients-randomization status was used as the instrumental variable. Patients' randomization status was either intensive (systolic blood pressure target <120 mm Hg) or standard (systolic blood pressure target <140 mm Hg) treatment. Results from instrumental variable models were compared with those from standard multivariable models. SETTING:Secondary data analysis of a randomized clinical trial conducted at 102 sites in 2010-15. PARTICIPANTS:9092 SPRINT participants with hypertension and increased cardiovascular risk but no history of diabetes or stroke. MAIN OUTCOMES MEASURES:Systolic blood pressure, major cardiovascular events, and serious adverse events. RESULTS:In standard multivariable models not adjusted for confounding by indication, addition of an antihypertensive drug from a new class was associated with modestly lower systolic blood pressure (-1.3 mm Hg, 95% confidence interval -1.6 to -1.0) and no change in major cardiovascular events (absolute risk of events per 1000 patient years, 0.5, 95% confidence interval -1.5 to 2.3). In instrumental variable models, the addition of an antihypertensive drug from a new class led to clinically important reductions in systolic blood pressure (-14.4 mm Hg, -15.6 to -13.3) and fewer major cardiovascular events (absolute risk -6.2, -10.9 to -1.3). Incremental reductions in systolic blood pressure remained large and similar in magnitude for patients already taking drugs from zero, one, two, or three or more drug classes. This finding was consistent across all subgroups of patients. The addition of another antihypertensive drug class was not associated with adverse events in either standard or instrumental variable models. CONCLUSIONS:After adjustment for confounding by indication, the addition of a new antihypertensive drug class led to large reductions in systolic blood pressure and major cardiovascular events among patients at high risk for cardiovascular events but without diabetes. Effects on systolic blood pressure persisted across all levels of baseline drug use and all subgroups of patients.

Project description:Diabetes patients are usually started on a low dose of insulin and their dose is adjusted or "titrated" according to their blood glucose levels. Insulin titration administered through face-to-face visits with a clinician can be time consuming and logistically burdensome for patients, especially those of low socioeconomic status (SES). Given the wide use of mobile phones among this population, there is the potential to use short message service (SMS) text messaging and phone calls to perform insulin titration remotely.The goals of this pilot study were to (1) evaluate if our Mobile Insulin Titration Intervention (MITI) intervention using text messaging and phone calls was effective in helping patients reach their optimal insulin glargine dose within 12 weeks, (2) assess the feasibility of the intervention within our clinic setting and patient population, (3) collect data on the cost savings associated with the intervention, and (4) measure patient satisfaction with the intervention.This was a pilot study evaluating an intervention for patients requiring insulin glargine titration in the outpatient medical clinic of Bellevue Hospital Center in New York City. Patients in the intervention arm received weekday SMS text messages from a health management platform requesting their fasting blood glucose values. The clinic's diabetes nurse educator monitored the texted responses on the platform website each weekday for alarm values. Once a week, the nurse reviewed the glucose values, consulted the MITI titration algorithm, and called patients to adjust their insulin dose. Patients in the usual care arm continued to receive their standard clinic care for insulin titration. The primary outcome was whether a patient reached his/her optimal insulin glargine dose within 12 weeks.A total of 61 patients consented and were randomized into the study. A significantly greater proportion of patients in the intervention arm reached their optimal insulin glargine dose than patients in the usual care arm (88%, 29/33 vs 37%, 10/27; P<.001). Patients responded to 84.3% (420/498) of the SMS text messages requesting their blood glucose values. The nurse reached patients within 2 attempts or by voicemail 91% of the time (90/99 assigned calls). When patients traveled to the clinic, they spent a median of 45 minutes (IQR 30-60) on travel and 39 minutes (IQR 30-64) waiting prior to appointments. A total of 61% (37/61) of patients had appointment copays. After participating in the study, patients in the intervention arm reported higher treatment satisfaction than those in the usual care arm.MITI is an effective way to help low-SES patients reach their optimal insulin glargine dose using basic SMS text messaging and phone calls. The intervention was feasible and patients were highly satisfied with their treatment. The intervention was cost saving in terms of time for patients, who were able to have their insulin titrated without multiple clinic appointments. Similar interventions should be explored to improve care for low-SES patients managing chronic disease.Clinicaltrials.gov NCT01879579; https://clinicaltrials.gov/ct2/show/NCT01879579 (Archived by WebCite at http://www.webcitation.org/6YZik33L3).

Dataset Information

Estimating dose-response for time to remission with instrumental variable adjustment: the obscuring effects of drug titration in Genome Based Therapeutic Drugs for Depression Trial (GENDEP): clinical trial data.

Publications

Estimating dose-response for time to remission with instrumental variable adjustment: the obscuring effects of drug titration in Genome Based Therapeutic Drugs for Depression Trial (GENDEP): clinical trial data.

Similar Datasets

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