Clinical trial NCT01822808: Bi Treatment With Hydralazine/Nitrates Versus Placebo in Africans Admitted With Acute Heart Failure
Official title: A Prospective, Placebo-controlled, Double-blind, Randomized Study to Compare Hydralazine-isosorbide-dinitrate(HYIS) Versus Placebo on Top of Std Care in African Patients With Acute Heart Failure (AHF) and Left Ventricular Dysfunction
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Acute Heart Failure
Left Ventricular Dysfunction
Keywords: acute heart failure
left ventricular dysfunction
hydralazine
isosorbide dinitrate
Lead sponsor: University of Cape Town
Sponsor class: OTHER
Collaborators: name: Momentum Research, Inc.
First posted: 2013-04-02
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To investigate the effect of hydralazine isosorbide dinitrate on clinical outcomes, symptoms, cardiac parameters and functional status of African patients hospitalized with AHF and left ventricular dysfunction during 24 weeks of therapy.

Administration of hydralazine/nitrates will be superior to placebo administration in reducing HF readmission or death, improving dyspnoea, reducing blood pressure and brain natriuretic peptide (BNP) in African patients admitted with AHF and left ventricular dysfunction.

Detailed description: Heart failure (HF) is a pathophysiologic condition and is a final common pathway of most forms of cardiovascular disease. Patients with HF experience poor quality of life, recurrent emergency hospitalizations and premature mortality.

Recent publications highlight the multiple challenges of dealing with an increasing burden of heart disease within an urban African community. The predominance of women and novel underlying causes contrast with the demographic of HF in high income countries. More than 50% of 5328 de novo cases of heart disease captured at a tertiary clinic in Soweto presented with some form of heart failure, mainly due to poorly treated hypertension, idiopathic dilated cardiomyopathy, peripartum cardiomyopathy and HIV-related cardiomyopathy. The most prevalent form of heart disease was hypertensive heart failure (\> 1100 cases).

Programs have been developed in high income countries that cost-effectively prevent progressive cardiac dysfunction in high risk individuals and apply evidence-based treatments to optimize the overall management of HF. There is, however, a paucity of data describing the etiology and underlying cardiac structure and function, as well as contemporary management of HF in low to middle income countries.

In 2005 a number of leading clinicians from Africa and the US published a "call for action" highlighting the need for an African study documenting the aetiology of acute heart failure and the management practices applied to these patients. As a result, The Sub-Saharan Africa Survey of Heart Failure (THESUS HF) study, was initiated in 9 countries in Africa to determine aetiology, treatment, morbidity and mortality of acute heart failure (HF) in the African sub-continent. The data reported in this study are unique as they are the first larger outcome study in acute heart failure from this continent. This first multinational study of over 1000 patients with acute decompensated heart failure conducted in all regions of sub-Saharan Africa shows, for the first time, that the treatment of heart failure is sub-optimal in the region, with relatively low proven medical treatments (such as beta-blockers, hydralazine and nitrates) and inappropriately high use of aspirin in a cohort of patients with non-ischaemic heart failure. This study also had the clear purpose of enhancing research capacity in Africa via collaborative research as outlined in our publication.

The use of Ace inhibitors (ACEi) and hydralazine/nitrates has never been examined in patients admitted with acute heart failure. All studies demonstrating the beneficial effects of these drugs were performed in patients with chronic heart failure. Previous studies have shown that the administration of ACEi in African Americans with chronic heart failure is less effective and not superior to combined treatment with hydralazine/isosorbide dinitrate. The African American Heart Failure Trial (A-HeFT) established the benefit of adjunctive administration of isosorbide dinitrate/hydralazine (ISDN/HYD) in addition to standard therapy for African American patients with symptomatic heart failure. The risk of death was reduced by 33% and markers of quality of life were improved.

The THESUS registry has shown a high prevalence of hypertension with left ventricular systolic dysfunction (hypertensive heart failure) and dilated cardiomyopathy as a cause of acute heart failure in all participating African countries. Patients in Africa are rarely treated with this combination therapy as the fixed combination (Bidil) is unavailable in Africa. There is uncertainty if the combination of hydralazine and isosorbide dinitrate, available as generic agents, is beneficial in Africans and many physicians in Africa are not aware of the outcome of those studies published in high impact factor journals, often not available to local doctors.

Performing a multicentre study in Africa could confirm data obtained in African Americans, create awareness for this promising combination treatment and extend the use of the medication to patients with acute heart failure.

This BAHEF protocol has an approved 'Amendment # 1' dated 29 April 2013. Amendments were changes to the Eligibility criteria and have been changed on this site.

To date, 22 Sept 2014, the BAHEF study has enrolled 110 study subjects. To date, 13 Aug 2015, the BAHEF study has enrolled 145 eligible subjects.

Eligibility criteria: Inclusion Criteria:

1. \> 18 years of age
2. Hospital admission for acute heart failure as defined by the presence of acute dyspnea and the presence of clinical signs of heart failure on physical examination.
3. Where available, NT-proBNP \>900 pg/ml, \>1800 pg/ml if the patient has atrial fibrillation at screening or \>450 pg/ml if BMI \> 35 kg/m2, LVEF \<45% assessed by echocardiography or other method within the previous 12 months
4. Background therapy with at least ACE-inhibitor or angiotensin receptor blocker (ARB) and beta-blocker (unless beta-blocker is contraindicated due to severe volume overload, low output heart failure, or cardiogenic shock)
5. Available for regular follow up

Exclusion Criteria:

1. Currently being treated with Hydralazine and/or nitrates or a history of intolerance to oral therapy with either hydralazine or nitrates.
2. . Any intravenous treatment for heart failure, except IV furosemide (eg. IV inotropes, pressors, nitrates or nesiritide) at the time of screening.
3. Systolic blood pressure \<100 mmHg
4. Plan for revascularization
5. Greater than 96 hours after admission
6. Reversible etiology of acute heart failure such as myocarditis, acute myocardial infarction, arrhythmia. Acute MI is defined as symptoms and major electrocardiogram (ECG) changes(i.e., ST segment elevations), and arrhythmia includes unstable heart rates above 120/min or below 50/min.
7. Hypertrophic obstructive cardiomyopathy, constrictive cardiomyopathy, endomyocardial fibroelastosis
8. Known severe congenital heart disease (such as uncorrected tetralogy of fallot or transposition of the aorta)
9. Severe aortic or mitral stenosis or severe rheumatic mitral regurgitation.
10. Renal impairment (defined by creatinine \>3 mg/dL) at screening or on any type of dialysis.
11. Known hepatic impairment (total bilirubin \>3mg/dl) or increased ammonia levels at screening.
12. History of systemic lupus erythematous.
13. Stroke or TIA within 2 weeks from screening.
14. Women who are pregnant or lactating.
15. Allergy to organic nitrates.
16. History or presence of any other diseases (ie. Including malignancies or AIDS) with a life expectancy of \< 12 months

Primary outcomes:
measure: Time to death or HF re-admission
timeFrame: through to day 180
Secondary outcomes:
measure: Change in symptoms of heart failure
timeFrame: within 7 days post randomization
measure: Change in systolic blood pressure
timeFrame: within 7 days post randomization
measure: Functional status
timeFrame: 7 days post randomization
measure: Changes in serum creatinine
timeFrame: up to 8 weeks post randomization
measure: Change in left ventricular dimensions
timeFrame: up to 24 weeks post randomization
Other outcomes:
Locations:
city: Cape Town
country: South Africa
facility: Hatter Institute for Cardiovascular Research in Africa
state: Western Cape
Study officials:
affiliation: Hatter Institute for Cardiovascular Research In Africa (HICRA), University of Cape Town
name: Karen Sliwa, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Momentum Research, Inc.
name: Gad Cotter, MD
role: STUDY_DIRECTOR
References:
citation: Sani MU, Damasceno A, Davison BA, Cotter G, Mayosi BM, Edwards C, Azibani F, Adam T, Arif G, Jessen N, Sliwa K. N-terminal pro BNP and galectin-3 are prognostic biomarkers of acute heart failure in sub-Saharan Africa: lessons from the BAHEF trial. ESC Heart Fail. 2021 Feb;8(1):74-84. doi: 10.1002/ehf2.13032. Epub 2020 Nov 28.
citation: Sliwa K, Damasceno A, Davison BA, Mayosi BM, Sani MU, Ogah O, Mondo C, Ojji D, Dzudie A, Kouam CK, Yonga G, Ba SA, Ogola E, Edwards C, Milo O, Cotter G. Bi treatment with hydralazine/nitrates vs. placebo in Africans admitted with acute HEart Failure (BA-HEF). Eur J Heart Fail. 2016 Oct;18(10):1248-1258. doi: 10.1002/ejhf.581. Epub 2016 May 20.