Clinical Effectiveness of Hydralazine-Isosorbide Dinitrate in African American Heart Failure Patients

Abstract

Objectives

To evaluate the effectiveness of hydralazine and isosorbide dinitrate (H-ISDN) in African Americans (AA) with heart failure (HF) with reduced ejection fraction (HFrEF)

Background

Among AA patients with HFrEF, H-ISDN was found to improve quality of life, lower HF hospitalization and mortality rates in the A-HEFT trial. Few studies have evaluated the effectiveness in clinical practice.

Methods

VA patients with a HF admission between 2007 to 2013 were screened. Inclusion criteria included AA race, left ventricular ejection fraction (LVEF) <40%, and receipt of VA medications. Exclusions were documented contraindications to H-ISDN, creatinine > 2.0, or intolerance to ACE inhibitors or ARB. Adjusted hazard ratios (HR) were calculated for patients who received H-ISDN 6-months prior to admission compared to those that did not receive H-ISDN using inverse probability weighting of propensity scores and a time to death analysis for 18 months of follow-up. Propensity scores were generated using patient characteristics, LVEF, lab values, and hospital characteristics.

Results

The final cohort included 5,168 AA HF patients (mean age 65.2) with 15.2% treated with H-ISDN prior to index admission. After 18 months, there were 1,275 reported deaths (24.7%). The adjusted mortality rate at 18 months was 22.1% for H-ISDN treatment and 25.2% for untreated (p=0.009); adjusted HR 0.85 (95% CI: 0.73–1.00, p=0.057).

Conclusions

H-ISDN remains underutilized in AA patients with HFrEF. In this cohort, we find H-ISDN use was associated with lower mortality in AA HFrEF patients when controlling for patient selection using an inverse probability weighting of propensity scores.

Introduction

The efficacy of hydralazine-isosorbide dinitrate (H-ISDN) therapy for heart failure (HF) was established in the first Vasodilator-Heart Failure Trial (V-HeFT I), regarded as the first major randomized controlled in cardiovascular medicine (1, 2). Subsequent trials established angiotensin converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), and angiotensin receptor-neprilysin inhibitors (ARNI) as preferred agents in heart failure with reduced ejection fraction (HFrEF) patients, though post hoc analyses suggested that African American patients may particularly benefit from H-ISDN (3–6). In the African-American Heart Failure Trial (A-HeFT), the addition of a combination pill of H-ISDN to optimal medical therapy was found to further improve quality of life, reduce HF hospitalizations, and mortality (7). This earned H-ISDN a Class 1 guideline recommendation in 2009 and the only Food and Drug Administration race specific therapy approved for African Americans with HFrEF (8, 9). H-ISDN has a class IIA recommendation for all other ethnicities with HFrEF, if they do not tolerate an ACEI, ARB, or ARNI.

Clinical usage rates of H-ISDN have been low among outpatients and inpatients eligible for treatment (10, 11). Furthermore, real-world clinical effectiveness of H-ISDN prescription has not been previously demonstrated (12). The Veterans Health Administration (VHA) is the largest integrated health system in the United States serving 8.76 million veterans (13). We used national data from the VHA to determine if an observable mortality benefit may be identified in a large cohort of African Americans with HFrEF eligible for treatment with H-ISDN.

Methods

Data Sources

Data for this analysis was extracted from the VHA standard electronic health record system through the External Peer Review Program linked to patient level data from the electronic health record included demographics, medical history, laboratory values, and prescription drug usage (14). The External Peer Review Program generates a national chart abstraction database containing performance data for all VA hospitals on over 90 metrics including quality of care. These data were used to determine the left ventricular ejection fraction and physician documentation of contraindications or intolerance to medications. Charts are abstracted by the West Virginia Medical Institute using explicit rules and auditing. Health records were linked to the VHA death files. The study was approved by the institutional review board at Stanford University.

Study Cohort

VA patients with a primary HF admission between January 1, 2007 to December 31, 2013 were screened for inclusion in the observational cohort. Inclusion criteria included age greater than 18, African American race, left ventricular ejection fraction less than or equal to 40%, and regular VA pharmacy benefit utilization. A primary HF hospitalization was defined by ICD-9 codes (402.01, 402.11, 402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.93, 428), as previously described (15). Patients were excluded from the cohort if they had contraindications to receiving H-ISDN, renal insufficiency (creatinine greater than 2.0), documented intolerance to ACE inhibitors or ARBs, or received hospice services.

Treatment

Exposure was defined as a filled prescription for hydralazine nitrate combinations (i.e. fixed dose combinations of H-ISDN, H-ISDN, or hydralazine and isosorbide mononitrate) in the 6 months prior to index admission. The lack of H-ISDN filled prescription was defined non-exposure.

Outcome

The primary outcome measure was all-cause mortality in a time to event analysis. Health records were linked to VHA death files to identify the primary outcome. Patients were followed for 18 months after index admission to assess mortality. The period of observation mirrors that from A-HeFT (7).

Covariates

Clinical data included the dates of admission and discharge, age, race, gender, comorbidities, LVEF, prescription drug usage, laboratory values (white blood cell count, hemoglobin, sodium, blood urea nitrogen, serum creatinine, and B-type natriuretic peptide), and date of death. Hospital characteristics (from the American Hospital Association) included: region (Northeast, Midwest, South, West) teaching status, academic affiliation, and Accreditation Council for Graduate Medical Education approved training status.

Statistical Analysis

Patient characteristics are described with averages and prevalence rates for relevant factors among exposed and non-exposed HF patients. The medication possession ratio for H-ISDN and other medications were estimated prior to hospitalization. The risk of mortality was modeled as a time to event analysis after the index admission. Missing covariate data (rare) were imputed using the mean for continuous variables and the most common category for categorical variables. An inverse probability of treatment weighting (IPTW) propensity score model adjusted for the patient and hospital characteristics in a Cox proportional hazards model to control for potential selection bias or confounding related to H-ISDN prescription use (16, 17). Patient factors used to risk adjust were based on available known predictors of mortality for VHA HF patients (18). The propensity score model utilized patient and hospital characteristics to generate individual patient weights. Comparisons of propensity scoring methods report negligible bias with correctly specified IPTW models (19). The model used general estimating equations (GEE) to account for clustering of patients within hospitals. Cumulative incidence plots were made to display survival curves. An additional analysis of the factors associated with receipt of H-ISDN at baseline was performed. We report 95% confidence intervals and used α=0.05 to establish the statistical significance of tests. Analyses were performed in SAS 9.4 (SAS Institute, Inc, Cary, NC) and STATA 11.1 (StataCorp, College Station, TX).

Results

The final observational cohort included a sample of 5,168 African Americans with HFrEF from 105 VHA medical centers (Figure 1). Mean number of patients per hospital were 49 (range: 1–257 subjects). In 2011, an estimated 48% of VHA medical centers had clinics devoted to HF. The exposure cohort consisting of those treated with H-ISDN prior to the index admission represented 15.2% of the total cohort (Table 1). Patients treated with H-ISDN prior to admission were slightly younger at 63.6 years (SD=11.8) compared to 65.5 years (SD=12.2) for the non-treated cohort. Female representation was less than 3% in both cohorts. The distribution of LVEF was similar between treated and non-treated cohorts. Rates of ACE inhibitor or ARB use was greater than 90% in both cohorts. Beta-blocker use was higher in the treated H-ISDN cohort in comparison to the non-treated cohort. Medication possession ratios for hydralazine and nitrates were 54.3% and 59.3% respectively prior to the index admission. Good adherence is typically categorized as greater than 80% (20, 21). With respect to comorbidities, the prevalence of chronic kidney disease, diabetes mellitus, ischemic heart disease, hypertension, cerebrovascular disease, and acute myocardial infarction were higher among the treated cohort. The non-exposed cohort had slightly more chronic obstructive pulmonary disease and prior history of malignancy. Laboratory values were generally similar between cohorts. There was evidence for slightly worse renal function on average with higher serum blood urea nitrogen and creatinine in the treated cohort. C-reactive protein levels were also slightly higher in the treated cohort.

Figure 1.

Observational cohort selection between 2007 and 2013 to VHA.

Table 1.

Baseline characteristics based on treatment exposure with hydralazine-isosorbide dinatrate.

	Taking H-ISDN	No H-ISDN	p-value
N (%)	786 (15.2%)	4,382 (84.8%)
Age	63.6 (SD 11.8)	65.5 (SD 12.2)	<.0001
Female	2.54%	2.21%	0.5657
Admission Year			<.0001
2007	23.0%	19.2%
2008	13.4%	13.1%
2009	14.6%	14.9%
2010	16.5%	15.4%
2011	13.2%	14.3%
2012	7.3%	14.6%
2013	12.0%	8.6%
LVEF			0.7918
Mean	23.6 (SD 11.80)	23.3 (SD 8.10)
<20%	24.2%	24.8%
20–29%	44.9%	45.4%
30–35%	30.9%	29.7%
Medications
ACE or ARB	96.1%	93.8%	0.01
ACE Inhibitor	83.0%	83.8%	0.5767
ARB	19.0%	13.7%	<.0001
BB	96.3%	88.5%	<.0001
Medication Possession Ratio
Hydralazine	54.3% (SD 31.4)
Nitrates	59.3% (SD 32.0)
ACE	73.4% (SD 29.6)	74.7% (SD 29.1)	0.31
ARB	66.1% (SD 33.4)	68.9% (SD 32.2)	0.30
BB	78.2% (SD 26.0)	78.4% (SD 26.7)	0.81
NYHA Class			0.0057
1	3.82%	3.86%
2	20.74%	23.19%
3	29.77%	24.26%
4	5.98%	4.77%
Missing	39.69%	43.93%
Comorbidities
Chronic Kidney Disease	39.19%	25.38%	<.0001
Diabetes Mellitus	53.69%	45.98%	<.0001
Ischemic Heart Disease	66.54%	57.05%	<.0001
Hypertension	95.17%	90.71%	<.0001
COPD	33.08%	34.66%	0.3889
Cerebrovascular Disease	19.72%	15.15%	0.0012
Acute Myocardial Infarction	22.52%	17.32%	0.0005
Malignancy (past 2 years)	11.70%	13.81%	0.1122
Laboratory Values
Hemoglobin (mg/dl)	12.37 (SD 1.92)	12.73 (SD 1.86)	0.27
White blood cells (/mcL)	6.83 (SD 3.14)	6.82 (SD 6.22)	0.97
Sodium (mmol/L)	138.62 (SD 3.20)	138.48 (SD 3.28)	0.27
BUN (mg/dl)	23.67 (SD 10.52)	21.65 (SD 10.16)	<0.0001
Serum Creatinine (mg/dl)	1.35 (SD 0.31)	1.25 (SD 0.29)	<0.0001
CRP (mg/L)	14.71 (SD 27.65)	12.46 (SD 26.20)	0.63
Region			<.0001
Midwest	22.77%	19.86%
Northeast	8.27%	11.96%
South	61.45%	56.77%
West	7.51%	11.41%
Hospital Characteristics
Member of Council on Teaching Hospitals	59.61%	59.03%	0.7628
Accreditation Council for Graduate Medical Education	97.16%	94.14%	0.0006
Academic Affiliation	97.81%	96.30%	0.0347

Values are percentages unless noted otherwise

^*LVEF = Left Ventricular Ejection Fraction, ACE = ACE inhibitor, ARB = angiotensin receptor blocker, BB = beta blocker, NYHA = New York Heart Association, COPD = chronic obstructive pulmonary disease, BUN = blood urea nitrogen, CRP = c-reactive protein

Treatment with H-ISDN was more common in Midwest and South compared to other regions. More exposed patients were treated at hospitals with training programs approved by the Accreditation Council for Graduate Medical Education compared to those in the non-treated cohort. After 18 months of follow-up from index admission, there were 1,275 (24.67%) reported deaths. The unadjusted mortality rate was lower in the treated cohort (22.39%) compared to the non-treated cohort (25.08%).

Unadjusted cumulative incidence survival plots show the separation and lower mortality among those treated with H-ISDN compared to the non-treated cohort (Figure 2). The unadjusted HR for mortality at 18 months with H-ISDN treatment is 0.878 (95% CI: 0.75–1.03, p=0.110). The partially adjusted model using IPTW without cluster adjustment estimates a HR of 0.853 (95% CI: 0.76–0.96, p=0.006) After risk adjustment, the mortality rate at 18 months was 22.1% for H-ISDN treatment and 25.2% for untreated (p=0.009). The fully adjusted model using IPTW and GEE to account for clustering estimates a HR of 0.85 (95% CI:0.73–1.00, p=0.057) for H-ISDN exposure (Table 2).

Figure 2. Unadjusted cumulative incidence survival plots.

Cumulative mortality rates over days since discharge for patients treated and not-treated with hydralazine and isosorbide dinitrate.

Table 2.

Proportional Cox model comparison for H-ISDN benefit on mortality.

	HR	95% CI	p-value
Unadjusted Model	0.88	0.75–1.03	0.110
Adjusting for patient characteristics only	0.83	0.70–0.98	0.024
IPTW without cluster adjustment	0.85	0.76–0.96	0.006
Fully adjusted (IPTW and GEE)	0.85	0.73–1.00	0.057

Values are unadjusted and adjusted hazard ratios (HR), 95% confidence intervals (CI) are provided and associated p-values.

Patient characteristics controlled for include: age, gender, year of admission, LVEF category, medications (ACE/ARB, beta-blocker), NYHA Class, comorbidities (chronic kidney disease, diabetes mellitus, ischemic heart disease, hypertension, COPD, cerebrovascular disease, acute myocardial infarction, malignancy), laboratory values (hemoglobin, sodium, BUN, creatinine, BNP), region, hospital characteristics (teaching status, ACGME, academic affiliation).

^*IPTW = inverse propensity of treatment weighting (patient selection adjustment), GEE = generalized estimating equations (cluster adjustment)

A few patient and hospital factors were associated with an increased odds of receiving H-ISDN at baseline (Table 3). Patients that were younger in age, on a ARB or beta-blocker, had a history of ischemic heart disease, hypertension, cerebrovascular disease, lower hemoglobin levels, treated in the South and Midwest were more likely to receive H-ISDN at baseline.

Table 3.

Factors associated with H-ISDN receipt.

	OR	95% CI	p-value
Age	0.98	0.97–0.98	<0.001
Female	1.12	0.67–1.88	0.674
Admission Year			<0.0001
2007	ref.
2008	0.82	0.63–1.08
2009	0.83	0.63–1.08
2010	0.90	0.69–1.16
2011	0.80	0.60–1.05
2012	0.44	0.32–0.62
2013	1.17	0.88–1.57
LVEF			0.92
30–35%	ref.
<20%	0.96	0.77–1.19
20–29%	0.99	0.82–1.19
Medications
ACE Inhibitor	1.02	0.76–1.37	0.896
ARB	1.34	1.00–1.78	0.047
BB	2.41	1.62–3.58	<0.001
Comorbidities
Diabetes Mellitus	1.16	0.98–1.36	0.081
Ischemic Heart Disease	1.34	1.12–1.61	0.002
Hypertension	1.66	1.16–2.37	0.005
COPD	0.91	0.77–1.08	0.269
Cerebrovascular Disease	1.24	1.01–1.53	0.040
Acute Myocardial Infarction	1.08	0.88–1.33	0.476
Malignancy (past 2 years)	0.84	0.66–1.08	0.175
Laboratory Values
Hemoglobin (mg/dl)	0.91	0.87–0.95	<0.001
Sodium (mmol/L)	1.02	1.00–1.05	0.081
Creatinine			<0.0001
<1.0 mg/dl	ref.
1.0–1.5 mg/dl	1.13	0.86–1.49
1.5–2.0 mg/dl	2.09	1.54–2.85
missing	1.52	1.05–2.19
BUN			0.27
<15 mg/ml	ref.
15–25 mg/ml	1.17	0.92–1.48
25–35 mg/ml	1.01	0.76–1.35
35–45 mg/ml	1.21	0.83–1.76
>45 mg/ml	1.58	1.001.68
missing	1.10	0.72–1.68
BNP
<100 pg/ml	ref.		0.65
100–500 pg/ml	1.37	0.74–2.54
500–750 pg/ml	1.15	0.61–2.18
750–1,000 pg/ml	1.40	0.73–2.66
1,000–5,000 pg/ml	1.36	0.75–2.47
>5,000 pg/ml	1.46	0.67–3.19
missing	1.50	0.83–2.72
Region			0.003
West	ref.
Northeast	0.89	0.6–1.32
South	1.43	1.05–1.93
Midwest	1.43	1.01–1.98
Hospital Characteristics
Member of Council on Teaching Hospitals	1.02	0.86–1.21	0.811
Accreditation Council for Graduate Medical Education	1.59	0.94–2.68	0.081
Academic Affiliation	1.26	0.70–2.27	0.447

^*OR = adjusted odds ratio, CI = confidence interval, LVEF = Left Ventricular Ejection Fraction, ACE = ACE inhibitor, ARB = angiotensin receptor blocker, BB = beta blocker, NYHA = New York Heart Association, COPD = chronic obstructive pulmonary disease, BUN = blood urea nitrogen, CRP = c-reactive protein

Discussion

This observational study of real-world clinical practice suggests a benefit of H-ISDN use for African Americans with HFrEF. The use of H-ISDN was associated with a 15% lower mortality hazard during 18 months of observation post-hospitalization. In the fully adjusted model, the statistical significance was marginal but still suggestive of benefit. A larger cohort or less clustering may have strengthened the observed statistical significance in the fully adjusted model.

A-HeFT reported a 43% reduction in mortality and was terminated early for benefit. The lower benefit observed in this study may reflect differences in medication adherence between clinical practice and randomized controlled trials. The medication possession ratio for H-ISDN in our study (54.9%) was below research standards for good adherence. In A-HeFT, adherence was high at 84.6% (22). Medications that require three times a day administration are expected to have lower adherence in comparison to a once a day medication (23). In this VHA study, over 95% of the H-ISDN prescribed was as a generic formulation. Given the evidence for H-ISDN usage, the pharmaceutical industry should prioritize the development of a once daily, long-acting formulation of H-ISDN to improve real-world patient adherence. Concerns have been described regarding the differences in bioavailability of H-ISDN formulations used in the prior randomized trials. All three prior randomized controlled trials of H-ISDN used different formulations of H-ISDN with varied bioavailabilities, which may explain differential results between the trials (2). The branded combination pill of H-ISDN utilized in A-HeFT has the greatest measured serum concentration when compared to other H-ISDN formulations (2). Whether the lower bioavailability of the generic formulations of H-ISDN influences patient outcomes is unknown.

A prior study from the Get With The Guidelines-HF Registry linked to Medicare data did not find an observed benefit on all-cause mortality or readmissions for African Americans treated with H-ISDN (12). The sample size in that study was limited to 1,392 African American HF patients with a mean age of 75 years. This VHA study observed a larger population and featured a younger cohort of HFrEF patients, which may explain the beneficial response to treatment. Older patients with more comorbid conditions may not derive the same degree of benefit as observed in the A-HeFT trial where the average age of enrolled patients was 57. Generally, patients treated with H-ISDN had more comorbidities and mildly worse renal function. Despite the greater burden of comorbid conditions, unadjusted mortality rates were observed to be lower for patients treated with H-ISDN.

Despite the guideline recommendations to prescribe H-ISDN for African American patients with HFrEF, the observed prescription rates in this cohort are low (8, 24). In our study, only 15% of African Americans with HFrEF, determined as eligible, received H-ISDN. Since regions with larger African American populations had higher observed rates of H-ISDN usage, provider familiarity with the management of African American HFrEF patients is likely a factor in better guideline adherence. Given the high risk of mortality and readmission for hospitalized patients, efforts to improve the receipt of guideline directed medical therapy are desperately needed, especially for African American patients (25). While ivabradine and valsartan/sacubitril are new evidence based therapies for all HFrEF patients, representation of African American patients in these trials were low (26, 27). Strong consideration for the prescription of H-ISDN is encouraged given the level of evidence.

Outpatient networks providing care for HFrEF patients require greater implementation efforts to assess the prescription of evidenced based therapies for all patients, especially African Americans who benefit from the additional therapeutic class. The development of performance metrics and provider feedback would be beneficial in improving the prescription rates of H-ISDN for indicated patients, as was seen with quality improvement efforts for beta-blocker and ACE inhibitor/ARB usage. African Americans with newly diagnosed HFrEF should be educated on all their therapeutic options. Partnering with community stakeholders in areas with high HF prevalence to improve education and adherence through multifaceted interventions are recommended (28). The known efficacy and effectiveness of H-ISDN should be communicated to patients regarding improved life expectancy, decreased hospitalization burden, and higher quality of life. Careful attention should be paid by providers in dosing H-ISDN and monitoring for adherence to therapy.

Limitations

For this study, a hospital cohort was identified and followed for events retrospectively. Of further interest would be the clinical effectiveness among outpatient African Americans with HFrEF. Unfortunately, the left ventricular ejection fraction data were only available for inpatients. Approximately 15% of VA patients may readmitted to non-VA hospitals, therefore we did not attempt to identify additional outcomes beyond death that were not reliably captured.

Given the nature of observational data, confounding related to patient selection and exposure status is a concern. We did not have vital measurements for systolic blood pressure or heart rate reliably captured and are unable to comment on differences in hemodynamic parameters during hospitalization. H-ISDN is frequently prescribed to HF patients with renal insufficiency, hyperkalemia, or intolerant to ACE inhibitors or ARBs. Patients on H-ISDN may be more likely to have greater comorbidities and at risk for more adverse events and mortality. This cohort excluded patients with renal insufficiency and documented ACE inhibitor and ARB intolerance to minimize treatment selection biases. We found that after adjustment for patient characteristics the benefit of H-ISDN increased. While most risk factors predicative of HF mortality were included in the IPTW model, if complete risk adjustment were possible the benefit of H-ISDN may have been greater (29). If H-ISDN usages correlates with other guideline directed medical therapies not included in the model such as implantable cardioverter-defibrillator placement, then H-ISDN exposure may be positively biased (11).

The IPTW model attempts to adjust for possible confounding related to patient selection. The IPTW model may not perform well if factors that increase the risk of death are not included in the model and are differentially distributed based on H-ISDN exposure. Blood pressure and heart rate at admission were not available. However, the VHA dataset includes detailed patient comorbidities, and laboratory values that permit appropriate risk adjustment of HF patients (18). If hospitals with higher or lower prescription rates of H-ISDN for HFrEF exhibit characteristics not controlled for in the model and that influence mortality rates, then the model without clustering adjustments may be biased. Our study included males primarily and our findings may not be generalizable to women; however, H-ISDN has similar benefit for men and women in A-HEFT (27).

Conclusion

The goal of this analysis was to evaluate the clinical effectiveness of H-ISDN on mortality among African American HFrEF patients. These findings suggest a modest benefit associated with the use of H-ISDN among African Americans with HFrEF. The mortality benefits observed were not as robust as those observed in the A-HeFT trial. This may be related to the observational nature of the VHA study, the lower rates of medication adherence, or differences in bioavailability of H-ISDN formulations. H-ISDN remains an underutilized medication for HF despite guideline endorsement. Efforts to improve medication adherence to H-ISDN therapy may further improve outcomes. African Americans with HF have a high mortality risk, especially after an acute HF hospitalization. Efforts to improve the receipt of guideline directed medical therapy are likely to reduce morbidity and mortality. H-ISDN therapy should be considered for all African American HF patients without contraindication based on prior research and the current findings presented.

Clinical Perspectives.

Competency in Medical Knowledge

The combination of H-ISDN in African American HFrEF patients is observed to lower the risk of mortality in clinical practice.

Competency in Patient Care

African American HFrEF patients should be offered H-ISDN as an additional therapy to further lower their risk for mortality, hospitalization, and improve their quality of life per guideline recommendations.

Translational Outlook

Further research is needed to encourage improved guideline adherence to H-ISDN therapy. Identifying strategies to improve patient medication adherence are also needed.

Abbreviations

A-HeFT

African-American Heart Failure Trial

ACEI

angiotensin converting enzyme inhibitor

ARB

angiotensin II receptor blockers

ARNI

angiotensin receptor-neprilysin inhibitors (ARNI)

GEE

generalized estimating equations

H-ISDN

hydralazine-isosorbide dinitrate

HF

heart failure

HFrEF

heart failure with reduced ejection fraction

HR

hazard ratio

IPWT

inverse probability of treatment weighting

V-HeFT I

First Vasodilator-Heart Failure Trial

VHA

Veterans Health Administration