Fixed-Dose Versus Off-Label Combination of Isosorbide Dinitrate Plus Hydralazine Hydrochloride: Retrospective Propensity-Matched Analysis in Black Medicare Patients with Heart Failure.

Introduction: Based upon the findings of the African-American Heart Failure Trial, the US Food and Drug Administration approved the fixed-dose combination of isosorbide dinitrate (ISDN) and hydralazine hydrochloride (HYD) (FDC-ISDN/HYD) as a new drug for treatment of heart failure (HF) in self-identified African Americans. According to the FDA, FDC-ISDN/HYD has no therapeutic equivalent. However, off-label combinations of the separate generic drugs ISDN and HYD (OLC-ISDN+HYD) or isosorbide mononitrate (ISMN) and HYD (OLC-ISMN+HYD) are routinely substituted without any supporting outcome data. We conducted an exploratory retrospective propensity-matched cohort study using Medicare data to determine whether a survival difference exists between these treatments in medication-adherent patients.

Methods: Black Medicare beneficiaries with HF were matched with Medicare Part D data to identify patients with prescriptions to FDC-ISDN/HYD or the off-label combinations. Only patients with 1-year adherence levels ≥80% were included in the analysis. Propensity-matched scoring created two sets of matched cohort pairs on a 1:1 basis, each set comparing FDC-ISDN/HYD with one of the off-label combinations. Kaplan-Meier (KM) survival curves with the log-rank test were then calculated for each pair for the year of medication adherence.

Results: The analysis population was relatively older (77 years) and mainly female (66.7%), with a high burden of comorbid disease. The KM estimates of 1-year survival were 87.9% (95% CI 85.6-89.9%) and 83.0% (95% CI 80.3-85.3%) (log rank p = 0.0024), respectively, for the matched cohorts FDC-ISDN/HYD and OLC-ISDN+HYD (n = 886 in each group) and 88.2% (95% CI 85.9-90.2%) and 84.8% (95% CI 82.2-87.0%) (log rank p = 0.0320), respectively, for the matched cohorts FDC-ISDN/HYD and OLC-ISMN+HYD (n = 868 in each group).

Conclusion: The 1-year survival advantage for FDC-ISDN/HYD compared with off-label combinations in adherent black Medicare beneficiaries with HF suggests a genuine difference between these medications and warrants prospective investigation.