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Evaluating the causal effect of medication adherence on adverse clinical outcomes in the target trial framework
Avik Ray1, Julie C Lauffenburger1, Rishi J Desai1
1Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02120, United States.
Insights
Optimal adherence to Sacubitril/Valsartan (SAC/VAL) significantly reduces adverse clinical outcomes like heart failure hospitalization or death in patients with heart failure with reduced ejection fraction. This study highlights the importance of medication adherence for better patient prognosis.
Area of Science:
- Cardiology
- Pharmacology
- Health Services Research
Background:
- Heart failure with reduced ejection fraction (HFrEF) is a major cause of morbidity and mortality.
- Sacubitril/Valsartan (SAC/VAL) is a key therapy for HFrEF, but its effectiveness can be influenced by patient adherence.
- Previous studies may have been limited by biases in evaluating the causal impact of SAC/VAL adherence.
Purpose of the Study:
- To determine the causal effect of adherence to Sacubitril/Valsartan (SAC/VAL) on adverse clinical outcomes in patients with HFrEF.
- To employ advanced statistical methods, including a target trial emulation and bias calibration, to minimize confounding and bias.
Main Methods:
- Utilized Medicare Fee-For-Service claims data to emulate a target trial comparing continued adherence (proportion of days covered ≥80%) versus non-adherence (<80%) to SAC/VAL.
- Employed marginal structural models with inverse probability treatment weighting to adjust for baseline and time-varying confounders.
- Conducted a bias calibration analysis using osteoporotic fractures as a negative control outcome to assess residual confounding.
Main Results:
- The study included 42,915 patients in the continued adherence group and 19,782 in the continued non-adherence group.
- After adjustment, continued adherence to SAC/VAL was associated with a reduced hazard ratio (HR) of 0.59 (95% CI, 0.56-0.62) for HF hospitalization or all-cause mortality.
- The bias-calibrated HR was 0.77 (95% CI, 0.71-0.84), suggesting that while residual confounding exists, adherence still confers a significant benefit.
Conclusions:
- Optimal adherence to Sacubitril/Valsartan (SAC/VAL) is associated with a substantially lower risk of heart failure hospitalization or all-cause death in Medicare beneficiaries with HFrEF.
- The target trial framework offers a robust methodology for assessing the causal relationship between medication adherence and clinical outcomes, effectively mitigating common biases.
Objectives:
We sought to evaluate the causal effect of adherence to Sacubitril/Valsartan (SAC/VAL) on adverse clinical outcomes in patients with heart failure (HF) with reduced ejection fraction, employing methods designed to minimize biases observed in earlier studies.
Methods:
Medicare Fee-For-Service claims data was utilized to emulate a target trial comparing two strategies of adherence to SAC/VAL: (a) continued adherence, (b) continued non-adherence. Patients with proportion of days covered ≥80% during an adherence assessment period of 60 days post-initiation were categorized as the continued adherence group, while those with a proportion of days covered <80% were categorized as the continued non-adherence group. Adherence was measured monthly, and patients were censored upon deviating from their strategy. HF hospitalization or all-cause mortality over 1 year was assessed. Marginal structural models with inverse probability treatment weighting to estimate hazard ratios (HRs), while accounting for both baseline and time-varying confounders were employed. A bias calibration analysis using osteoporotic fractures as a negative control outcome accounted for residual bias.
Key Findings:
A total of 42 915 individuals were identified in the continued adherence group and 19 782 in the continued non-adherence group. The unadjusted HR for continued adherence vs. continued non-adherence for the composite outcome was 0.52(95% CI, 0.50-0.55). After adjusting for baseline and time-varying covariates, the HR was 0.59(95% CI, 0.56-0.62). The bias-calibrated HR was 0.77(95% CI, 0.71-0.84), indicating the effect is not fully explained by residual confounding.
Conclusions:
Among Medicare beneficiaries with HF newly initiated on SAC/VAL, optimal medication adherence was associated with a substantially lower risk of HF hospitalization or all-cause death. For assessing the causal relationship between medication adherence and clinical outcomes, the target trial framework provides a principled approach to avoid common biases.
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