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

Abstract

IntroductionBased 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.MethodsBlack 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.ResultsThe 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).ConclusionThe 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.

Underuse of hydralazine and isosorbide dinitrate for heart failure in patients of African ancestry: a cross‐European survey

“…This estimation is conservatively based on a 40% reduction in mortality with H-ISDN from 10 to 6%, while real-world data indicate that annual mortality rates in AA HF patients might be considerably higher, 18,21,22,26 in particular when the fixed combination is not used. This estimation is conservatively based on a 40% reduction in mortality with H-ISDN from 10 to 6%, while real-world data indicate that annual mortality rates in AA HF patients might be considerably higher, 18,21,22,26 in particular when the fixed combination is not used.…”

“…[1][2][3]5,7,18,20 In the absence of European data, the age-adjusted population prevalence in AA is estimated to be 4% based on US data. [1][2][3]5,7,18,20 In the absence of European data, the age-adjusted population prevalence in AA is estimated to be 4% based on US data.…”

“…Data from the Duke Databank of Cardiovascular Disease 26 indicated adjusted mortality rates for HF in AA of 12% at 1 year and 49% at 5 years. 2,5,7,8,[10][11][12][13][14][15]18,22,23 After H + ISDN treatment in Vasodilator-Heart Failure Trial I (only AA men), the annual mortality rate of HFrEF was 9.7 vs. 17.3% without receiving this therapy, 10 and in A-HeFT (AA men and women) using fixed combination H-ISDN, this was respectively 6.2 vs. 10.2%. 22 HF is a heterogeneous clinical entity, with a prominent distinction between patients with reduced ejection fraction (HFrEF, broadly corresponding to systolic HF) with usually a dilated left ventricular cavity size, occurring in around half of all HF patients, or preserved (HFpEF) left ventricular ejection fraction with usually a normal left ventricular cavity and concentric hypertrophy.…”

“…The health status of patients is put at risk if they are not receiving their prescribed medicines in a timely manner. 18 Thus, the use of the combination therapy should be properly registered, and the fixed combination H-ISDN and/or its components should become available across Europe for use for HF in AA patients. While throughout Europe there is no harmonized definition of 'drug shortages', the HMA has identified what types of drug shortages are most critical, and the definition includes pharmaceutical for which there is a medical need but that are not authorized or not marketed in a Member State.…”

“…13 Real-world data indicate that mortality after 1 year of adherence is 41% higher with H + ISDN (17.0%), compared with fixeddose H-ISDN (12.1%), a difference partly attributed to consistent simultaneous intake of both drugs and better bioavailability with the fixed combination. 18…”