Isosorbide Hydralazine Research Articles

Hydralazine and Isosorbide Dinitrate in Heart Failure

Until the 1970s, treatment options for heart failure were limited to digitalis and diuretics.1 Although effective for symptoms, there was no evidence of mortality benefit with this combination, and it was an inadequate option for many patients with advanced symptoms. The search for more effective options led to strategies that modulated hemodynamics.1 Numerous physiological studies showed the dependence of ventricular function on vascular resistance, and drugs that reduced systemic vascular resistance improved cardiac performance.2,–,5 A pivotal study by Franciosa et al6 showed that sodium nitroprusside in patients with heart failure in the setting of acute myocardial infarction reduced left ventricular filling pressures from 22.7±2.0 to 11.3±1.6 mm Hg and led to a modest increase in cardiac output. A subsequent study revealed more striking improvements in patients with refractory heart failure, in whom nitroprusside reduced systemic vascular resistance by 50%, increased cardiac output by 56%, and reduced left ventricular filling pressure by 47%.7 These hemodynamic benefits with nitroprusside led to studies with oral agents, including hydralazine, isosorbide dinitrate (ISDN), prazosin, phentolamine, and minoxidil. Although these drugs did affect hemodynamics, none was as effective as nitroprusside individually.8,–,12 In 1977, Massie et al13 studied the combination of 2 oral agents, hydralazine and ISDN (H-ISDN) in class III to IV heart failure patients, proposing that simultaneously reducing preload with ISDN and afterload with hydralazine would result in a better response than with either drug individually. They found that H-ISDN reduced left ventricular filling pressure by 36%, increased cardiac index by 58%, and reduced systemic vascular resistance by 34%. Later, Pierpont et al14 compared H-ISDN with nitroprusside and showed that the 2 therapies had similar effects on wedge pressure reduction and cardiac index increase. Considering these hemodynamic benefits with …

Adherence to Guideline-Recommended Adjunctive Heart Failure Therapies Among Outpatient Cardiology Practices (Findings from IMPROVE HF)

Although previous studies have documented adherence with certain established heart failure (HF) quality metrics in outpatient cardiology practices, the extent to which there is conformity with other evidence-based, guideline-driven quality metrics in outpatients with HF is unknown. IMPROVE HF is a prospective cohort study designed to characterize the current management of patients with chronic HF and left ventricular ejection fraction <or=35% in outpatient cardiology practices. We evaluated baseline data for conformity with adjunctive HF therapies including pneumococcal vaccinization, hydralazine/isosorbide dinitrate (HYD/ISDN) for Black patients, statin therapy, antiplatelet therapy, smoking-cessation counseling, low-density lipoprotein cholesterol levels (<100 mg/dl), and systolic blood pressure decrease (all patients <140 mm Hg or [optimal] <130 mm Hg). Baseline data were available for 15,381 patients attending 167 cardiology practices. Patient characteristics included a median age 70 years, 71.0% men, 9.1% Black patients, 65.2% with ischemic HF cause, and 61.7% with a history of hypertension. Mean adherences or documentations of adherence were only 7.3% for HYD/ISDN and 1.0% for pneumococcal vaccination. Adherence to other adjunctive therapies ranged from 27.4% to 82.0% but none of the adjunctive treatment interventions were associated with high levels of adherence. Conformity with guideline-recommended, adjunctive HF therapies is deficient in the management of outpatients with HF. Critical gaps in documentation or delivery of care exist, especially for the use of pneumococcal vaccination and HYD/ISDN. In conclusion, improved processes of care, better documentation, and/or increased measures to promote adherence to all primary and adjunctive therapies for HF are needed.

Effectiveness of hydralazine/isosorbide dinitrate in racial/ethnic subgroups with heart failure

Background: The addition of hydralazine/isosorbide dinitrate (H-ISDN) to a standard heart failure treatment regimen in the African-American Heart Failure Trial was associated with a 43% reduction in mortality. However, the effectiveness of H-ISDN in a community sample of African-American patients and other racial/ethnic groups is unknown. Objective: The aim of this study was to assess the associations between treatment with H-ISDN and mortality or hospitalization for heart failure in veterans with the disease. Methods: For this retrospective cohort study, electronic data on outpatient prescriptions, comorbidity, and other heart failure risk factors were analyzed in veterans with heart failure. Patients were classified based on whether they were prescribed H-ISDN and subclassified based on race/ethnicity (African American, Hispanic, or white). Patients who were prescribed H-ISDN were subclassified based on time of initiation of H-ISDN treatment (0–121, 122–365, or >365 days after diagnosis). Data were analyzed using propensity-adjusted Cox regression analyses, with exposure to H-ISDN modeled as a time-varying covariate. Results: Data from 76,828 veterans were analyzed (98% men, 2% women). H-ISDN prescription was not associated with the risk of death in 5 of the 9 subgroups predefined by race/ethnicity or time of initiation of H-ISDN; however, H-ISDN was associated with an increased risk of death in the 4 subgroups with longer times to initiation. H-ISDN was associated with a significantly increased risk of heart failure hospitalization in all but 1 of the 9 subgroups. The risk of both mortality and hospitalization associated with H-ISDN was significantly lower in African-American patients than in those who were Hispanic or white. Concurrent prescription of other, evidence-based heart failure therapies (eg, angiotensin-converting enzyme inhibitors, β-blockers, and combinations) had strong, statistically significant associations with reduced mortality. Conclusions: In this population of veterans with heart failure, H-ISDN prescription was not associated with significant reductions in mortality or hospitalization in any of the subgroups defined by race/ethnicity and time of initiation of H-ISDN analyzed compared with the group that did not receive H-ISDN. It is possible, or even likely, that unmeasured differences in important risk factors—particularly heart failure severity and left ventricular dysfunction—between the group that received H-ISDN and the one that did not masked a beneficial effect of H-ISDN. Therefore, our conclusions must be regarded as hypothesis generating and need to be tested in subsequent randomized trial(s).

Isosorbide dinitrate-hydralazine improves outcomes in African Americans with heart failure.

The African American Heart Failure Trial (A-HeFT) found that African American patients with advanced heart failure fared better if the fixed-dose combination of isosorbide dinitrate and hydralazine was added to their regimen, which for most of them already included an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB), a beta-blocker, and a diuretic (N Engl J Med 2004; 351:2049-2057). This placebo-controlled trial was the first to evaluate a therapy in a specific racial group, and it points the way to a more individualized approach to heart failure therapy.

Fixed combination isosorbide dinitrate–hydralazine for nitric-oxide-enhancing therapy in heart failure

The major advances in our understanding and management of heart failure (HF) in recent decades have not fully benefited all segments of our population. HF still represents a growing epidemic, especially for African-Americans, in whom the burden of HF is even greater. The recently reported beneficial effects of the fixed combination of isosorbide dinitrate and hydralazine (ISDN+HYD) in the African-American Heart Failure Trial (A-HeFT), has led to both the FDA approval of this agent and its endorsement by the latest HF guidelines. The properties of ISDN+HYD are well known as its components are mature agents, readily available in generic formulations that have been used for decades in other indications. However, fixed-dose ISDN+HYD represents the first drug to undergo targeted clinical development and to be approved for use in a specific ethnic group. As such, A-HeFT and the approval of ISDN+HYD represent landmark events that merit further scrutiny.

Results of the Extension to A-HeFT [X-A-HeFT] Support the Continued Safety and Tolerability of Fixed-Dose Isosorbide Dinitrate/Hydralazine (ISDN/HYD)

Introduction: A-HeFT established the benefit of ISDN/HYD as adjunctive therapy for HF when added to evidence-based agents in AA patients with NYHA class III/IV HF. Objective: X-A-HeFT tested the continued safety and tolerability of ISDN/HYD. Methods: A total of 198 AA A-HeFT patients were treated with ISDN/HYD in addition to standard therapy for HF. Patient characteristics (mean +/− SD): age- 57.4 +/− 12.7 yrs; gender M:F (%) 58:42; wgt- 97.6 +/− 27.4 kg. Medical history: HTN 93.9%, duration 12.6 +/− 11.7 yrs; DM- 40.9%; CRI- 13.6%; Prior MI- 29.3%.

Mode of Death in African American (AA) Heart Failure (HF) Population

Introduction: Limited data exists on mode of death in AA HF patients. A-HeFT is the only prospective study in this unique patient population. Methods: The mode of death was explored in A-HeFT, a randomized double-blind placebo-controlled study in 1,050 AA patients that showed a 43% reduction in mortality in patients receiving a fixed-dose combination of isosorbide dinitrate/hydralazine (ISDN/HYD) added to standard therapy. The cause of death was adjudicated by an Independent Central Adjudication Committee.

Section 14: Managing Patients With Hypertension and Heart Failure

Section 14: Managing Patients With Hypertension and Heart Failure

Section 13: Evaluation and Therapy for Heart Failure in the Setting of Ischemic Heart Disease

Section 13: Evaluation and Therapy for Heart Failure in the Setting of Ischemic Heart Disease

Section 15: Management of Heart Failure in Special Populations

Section 15: Management of Heart Failure in Special Populations

Cost-effectiveness of fixed-dose combination of isosorbide dinitrate and hydralazine therapy for blacks with heart failure.

Fixed-dose combination of isosorbide dinitrate/hydralazine (ISDN/HYD) improved clinical outcomes in the African-American Heart Failure Trial (A-HeFT). We assessed the resource use, costs of care, and cost-effectiveness of ISDN/HYD therapy in the A-HeFT trial population. We obtained resource use data from A-HeFT, assigning costs through the use of US federal sources. Excluding indirect costs, we summarized the within-trial experience and modeled cost-effectiveness over extended time horizons, including a US societal lifetime reference case. During the mean trial follow-up of 12.8 months, the ISDN/HYD group incurred fewer heart failure-related hospitalizations (0.33 versus 0.47 per subject; P=0.002) and shorter mean hospital stays (6.7 versus 7.9 days; P=0.006). When study drug costs were excluded, both heart failure-related and total healthcare costs were lower in the ISDN/HYD group (mean per-subject heart failure-related costs, 5997 dollars versus 9144 dollars; P=0.04; mean per-subject total healthcare costs, 15,384 dollars versus 19,728 dollars; P=0.03). With an average daily drug cost of 6.38 dollars, ISDN/HYD therapy was dominant (reduced costs and improved outcomes) over the trial duration. Assuming that no additional benefits accrue beyond the trial, we project the cost-effectiveness of ISDN/HYD therapy using heart failure-related costs to be 16,600 dollars/life-year at 2 years after enrollment, 37,100 dollars/life-year at 5 years, and 41,800 dollars/life-year over lifetime (reference case). ISDN/HYD therapy, previously shown to improve clinical outcomes, also reduced resource use and costs in A-HeFT, primarily because of a large reduction in hospitalizations. Long-term use of ISDN/HYD therapy should be associated with a favorable cost-effectiveness profile in this population.

The African American Heart Failure Trial: A Clinical Trial Update

Progressive vascular and myocardial remodeling in heart failure is effectively slowed by therapy with neurohormonal antagonists, including angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, aldosterone antagonists, and adrenergic-receptor blockers. These therapies, along with the correction of hemodynamic abnormalities, have dramatically reduced morbidity and mortality in patients with heart failure. Endothelial dysfunction, increased oxidative stress, and decreased bioavailability of nitric oxide (NO) also occur in heart failure. Data suggest that endothelial dysfunction and reduced NO bioavailability may be more prevalent in populations who self-identify as African Americans. Thus, differences observed in the African American population with respect to prevalence of heart failure, etiology, outcomes, and response to medication may in part be explained by differences in the relative contributions of neurohormonal activation and diminished NO bioavailability to the progression of heart failure. The African American Heart Failure Trial (A-HeFT) was designed to assess the benefit of fixed-dose combination isosorbide dinitrate-hydralazine (ISDN-HYD) in an African American population with advanced heart failure. The A-HeFT enrolled 1,050 African American patients with New York Heart Association (NYHA) class III-IV heart failure with dilated ventricles and low ejection fractions. Patients were randomized to receive either a fixed-dose combination of ISDN-HYD or placebo added to standard neurohormonal blockade. The primary end point was a composite score in which mortality, hospitalization, and quality of life were weighted. On July 19, 2004, the independent Data Safety Monitoring Committee recommended early termination of the trial because of a significant mortality benefit in the cohort receiving fixed-dose ISDN-HYD. The A-HeFT confirms the benefit of fixed-dose ISDN-HYD, which may enhance NO bioavailability in African American patients with NYHA class III-IV heart failure and suggests that NO-enhancing therapy is an effective new treatment strategy for heart failure. In addition, the A-HeFT affirms the critical importance of the inclusion of population subgroups in clinical trials both as a way to probe for pathophysiologic mechanisms of disease and to devise optimal treatment strategies. The rich and unique A-HeFT database will provide new opportunities to understand the pathophysiology and management of heart failure.

International Society for Heart and Lung Transplantation: Practice guidelines for management of heart failure in children

Heart failure (HF) in the United States is well recognized as a major public health problem, with over 900,000 hospital admissions annually in the United States, and greater than 250,000 deaths per year. The great majority of heart failure occurs in adults. In children, the scope of the problem is less well defined, but recent data from the Pediatric Cardiomyopathy Registry suggest an annual incidence of 1.13 cases of cardiomyopathy per 100,000 children. 1 While some of this represents asymptomatic disease, the burden of disease overall is nonetheless quite high. In the Pediatric Cardiomyopathy Registry, the majority of children with cardiomyopathy also had HF, with mortality rates of 13.6% at 2 years in dilated forms of cardiomyopathy. The etiology of heart failure differs greatly between children and adults. Children in the Pediatric Cardiomyopathy Registry had a recognizable syndrome or genetic diagnosis in 27% of cases, with an additional 5% of cases due to myocarditis. Furthermore, a large percentage of children with end-stage HF (between 25% and 75%, depending upon the age group) have an underlying diagnosis of congenital heart disease. 2 In contrast to adult patients, ischemic heart disease is rare in children. There is a large, and rapidly growing literature addressing HF treatment for adult patients, with a much smaller literature concerning HF therapy in children. Excellent guidelines for adult patients have recently been published, but given the significant differences between adult and pediatric patients with HF, there is little reason to believe that these guidelines are directly applicable to children. 3 Accordingly, in this document we have attempted to summarize the relevant literature and synthesize management guidelines for children with HF. The document that follows has been prepared in a consensus fashion, with input from pediatric cardiologists at multiple sites throughout the United States and Canada.

Felodipine improves left ventricular emptying in patients with chronic heart failure: V-HeFT III echocardiographic substudy of multicenter reproducibility and detecting functional change

The echocardiographic substudy of the Vasodilator-Heart Failure Trial III (V-HeFT III) aimed to determine if felodipine treatment in patients with heart failure who were taking an angiotensin-converting enzyme inhibitor had a favorable effect on left ventricular (LV) structure and function. Earlier V-HeFT trials showed that hydralazine-isosorbide dinitrate improved ejection fraction (EF) and survival, whereas enalapril achieved greater survival with smaller increases in EF. Would the combination of a potent vasodilator and enalapril produce greater improvements in function and survival? Doppler-echocardiographic data were collected from 260 males with heart failure who were randomized to felodipine or a placebo. Mean intrasubject differences between baseline, at 3 months, and at 12 months were compared. Intersite and intrareader reproducibilities were measured from duplicate recordings and readings. At 3 months, no changes in ultrasound variables from baseline occurred in either group. At 12 months, felodipine patients achieved greater increases in EF, shortening of LV end-systolic length, and increases in stroke volume index. Reproducibility coefficients of variation were 7.4% (EF), 6.0% (end-diastolic length), and 13.0% (stroke volume index). The echocardiographic substudy showed that felodipine, added to heart failure therapy, increased EF, shortened end-systolic length, and increased stroke volume index. The changes were small and confirmed that reproducibility from multiple laboratories can be coordinated into a useful research tool.

Vasodilator therapy of hypertensive acute left ventricular failure: Comparison of captopril-prazosin with Hydralazine-isosorbide dinitrate

A prospective study to evaluate and compare the cardiorespiratory effects and clinical efficacy of the Neurohormonal inhibitors (Captopril 50 mg+prazosin 1 mg only) and direct arteriolar and venular dilators (Intravenous hydralazine 30 mg+oral isosorbide dinitrate 30 mg) used as vasodilator therapy, was undertaken in a randomized, single blind study in 17 Nigerian patients with hypertensive acute left ventricular failure. Both vasodilator regimes separately and significantly reduced the systolic and diastolic blood pressures ( P<0.001 ANOVA), heart rate ( P<0.001 ANOVA), and the respiratory rate ( P<0.05 ANOVA), the double product, but increased the peak expiratory flow rate ( P<0.05 ANOVA). However, the neurohormonal antagonists, captopril and prazosin ( n=9) caused a statistically significantly greater reduction in heart rate ( P<0.05 ANOVA) respiratory rate ( P<0.05 ANOVA) and induced a significantly greater increase in the self-paced exercise capacity, 24 h after initiation of treatment, ( P<0.02) compared to the hydralazine and isosorbide dinitrate combination ( n=8). Five of the nine patients on the neurohormonal antagonist therapy were ambulant at 24 h, compared to none of the eight patients receiving conventional venular and arteriolar dilators hydralazine and isosorbide dinitrate ( X 2=5.84 dfi P<0.05). There was a significant inverse correlation between the systolic blood pressure heart rate product, and the distance covered during symptom limited self paced exercise capacity ( r=−0.58, P=0.0146 ANOVA). One of eight patients in the hydralazine+isosorbide nitrate combination died, but there was no mortality in the captopril+prazosin group. These findings collectively suggest that captopril+prazosin combination may be a superior vasodilator therapy compared to hydralazine-isosorbide dinitrate, in hypertensive acute pulmonary oedema.

Hydralazine-Induced Prevention of Nitrate Tolerance: Experimental and Clinical Evidence and Potential Mechanisms

The clinical use of hydralazine in combination with organic nitrates has resulted in a beneficial effect on survival, cardiac function, and exercise tolerance. More recently, hydralazine has been shown to prevent development of nitrate tolerance and early attenuation of nitrate-mediated hemodynamic effects in both experimental animals as well as patients with severe heart failure due to depression of left ventricular systolic function. Recent in vitro animal results have shown that prolonged nitroglycerin treatment results in increased production of endogenous vascular superoxide (ċO 2) production due to a specific NADH-dependent membrane-associated oxidase and that this is at least in part responsible for the development of nitrate tolerance. Further studies demonstrated that concomitant administration of hydralazine normalized endogenous rates of vascular ċO 2 production and prevented the development of nitrate tolerance. The ability of hydralazine to inhibit vascular ċO 2 anion production and to prevent the development of nitrate tolerance may provide further explanations for the benefits demonstrated in the V-HeFT studies with the hydralazine–isosorbide dinitrate combination in the treatment of patients with chronic CHF.

Improvement of Alveolar–Capillary Membrane Diffusing Capacity With Enalapril in Chronic Heart Failure and Counteracting Effect of Aspirin

KII ACE, the enzyme that converts angiotensin I and inactivates bradykinin, is highly concentrated in the lungs; its blockade reduces exposure to angiotensin II and enhances exposure to prostaglandins generated by local kinin hyperconcentration. Our hypothesis is that ACE inhibitors improve pulmonary function in chronic heart failure (CHF) by readjusting lung vessel tone and permeability or alveolar-capillary membrane diffusion. In 16 CHF patients and 16 normal volunteers or mild untreated hypertensives, pulmonary function and exercise tests with respiratory gas analysis were assessed on placebo, enalapril (10 mg BID), enalapril plus aspirin (325 mg/d), or aspirin, in random order and double blind, for 15 days each. In CHF, enalapril increased pulmonary carbon monoxide diffusion (DLCO), oxygen consumption (VO2), and exercise tolerance and reduced the ratio of dead space to tidal volume (VD/VT) and the ventilatory equivalent for carbon dioxide production (VE/VCO2). On enalapril, VO2 (r = .80, P < .0001) and VD/VT (r = -.69, P = .003) changes from placebo correlated with those in DLCO. These effects were inhibited by aspirin and were absent in control subjects. In 8 additional patients, hydralazine-isosorbide dinitrate, as an alternative treatment for reducing pulmonary capillary wedge pressure (PCWP) and increasing exercise capacity, were more effective than enalapril for the PCWP but did not affect DLCO and VE/VCO2; amelioration in VO2 and VD/VT was unrelated to DLCO and was not modified by aspirin. ACE inhibition improved pulmonary diffusion in CHF. Hydralazine-isosorbide dinitrate failed to provide this result. Counteraction by aspirin, a prostaglandin inhibitor, bespeaks prostaglandin participation while on enalapril that might readjust capillary permeability or alveolar-capillary membrane diffusion.

Rationale and design of the third Vasodilator-Heart Failure Trial (V-HeFT III): Felodipine as adjunctive therapy to enalapril and loop diuretics with or without digoxin in chronic congestive heart failure

Therapy with angiotensin-converting enzyme inhibitors and nonselective vasodilators (hydralazine and isosorbide dinitrate) has become accepted treatment in patients with symptomatic, chronic congestive heart failure (CHF), and has been demonstrated in large clinical trials to ameliorate symptoms, improve exercise performance, and reduce cardiac mortality. Nevertheless, the management of patients with CHF remains a therapeutic challenge. The second Vasodilator-Heart Failure Trial (V-HeFT II) showed that the average 2-year mortality with enalapril (18%) was significantly lower than that with hydralazine-isosorbide dinitrate (25%) but, somewhat surprisingly, the nonspecific vasodilators produced significantly more improvement in exercise performance and left ventricular function. Such data suggest that improvement in symptoms, hemodynamics, and survival may not be afforded by the use of a single class of vasodilator therapy, but might be optimized by the combined use of different agents. This report describes the rationale and design of V-HeFT III, a multicenter, prospective, randomized, double-blind, placebo-controlled trial comparing the effects of chronic oral extended-release felodipine (felodipine ER) 2.5 to 5 mg twice daily, when added to a stable regimen of enalapril and loop diuretics, with or without digoxin, on exercise performance, morbidity, and mortality in patients with New York Heart Association functional class II to III CHF followed for a minimum of 12 weeks. Felodipine is a second-generation dihydropyridine calcium antagonist with a high degree of vascular selectivity which, in the doses used in this study, exerts its systemic arterial effect by decreasing peripheral vascular resistance without producing negative inotropic effects. The results of V-HeFT III may shed important light on the role of additive vasodilator therapy in the management of patients with CHF.

Pharmacologic treatment of congestive heart failure

Congestive heart failure is a clinical syndrome producing symptomatic deterioration, functional impairment, and shortened life span. The syndrome is complex in that it includes both peripheral and cardiac effects which contribute to the progression of heart failure. In the periphery, elevations in the sympathetic nervous system and renin-angiotensin system increase afterload and contribute to further salt and water retention. The central cardiac abnormalities include remodeling of the heart and downregulation of beta receptors. Traditional heart failure therapy has included treatment of fluid retention with diuretics, although their effect on mortality has never been addressed. The most proven therapy in heart failure is treatment with vasodilators, particularly angiotensin-converting enzyme (ACE) inhibitors. Improved survival with ACE-inhibitor therapy has been demonstrated in patients with severe heart failure (CONSENSUS), mild to moderate heart failure (SOLVD), and in comparison with vasodilator therapy with hydralazine isosorbide dinitrate (VHeFT II). Improved survival has also been noted in postmyocardial infarction when the ejection fraction is decreased (SAVE). The ACE inhibitors have now become standard therapy for heart failure regardless of severity. Additive vasodilator therapy with calcium-channel antagonists is under investigation. Inotropic therapy is controversial at present because of disappointing mortality results. The clinical mainstay digitalis remains without convincing mortality reduction data. Other inotropic agents, particularly phosphodiesterase inhibitors, have shown uniformly negative survival results. However, the new mixed action agents vesnarinone and pimobenden have shown favorable data, with vesnarinone demonstrating a mortality reduction effect. Beta-blocker therapy in heart failure has also found renewed interest, particularly with the new agents carvedolol and bucindolol which also have vasodilating properties.

Role of Vasodilator Therapy in Congestive Heart Failure: Effects on Mortality

Congestive heart failure is associated with a considerable reduction in survival with only about 50% of patients alive within 5 years of its diagnosis. Recent trials have demonstrated that vasodilator therapy can improve survival in this condition. Agents that have been shown to be effective in well-designed double-blind clinical trials include the combination of hydralazine-isosorbide dinitrate (in V-HeFT) and the angiotensin converting enzyme inhibitors (in SOLVD, SAVE, and CONSENSUS).