Hydralazine and nitrates alone or combined for the management of chronic heart failure: A systematic review

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Abstract

Background

Hydralazine (H) and nitrates (Ns), when combined, reduced morbidity and mortality in some trials of chronic heart failure (CHF). It is unclear whether either agent used alone provides similar benefits. We aimed to evaluate the effects of H and/or N in patients with CHF.

Methods

A systematic review of randomised trials assessing the effects of H and N in CHF. For meta-analysis, only the endpoints of all-cause mortality and cardiovascular mortality were considered.

Results

In seven trials evaluating H&N in 2626 patients, combination therapy reduced all-cause mortality (OR 0.72; 95% CI 0.55–0.95; p = 0.02), and cardiovascular mortality (OR 0.75; 95% CI 0.57–0.99; p = 0.04) compared to placebo. However, when compared to angiotensin converting enzyme inhibitors (ACEIs), combination therapy was associated with higher all-cause mortality (OR 1.35; 95% CI 1.03–1.76; p = 0.03), and cardiovascular mortality (OR 1.37; 95% CI 1.04–1.81; p = 0.03). For N alone, ten trials including 375 patients reported all-cause mortality and showed a trend to harm (13 deaths in those assigned to nitrates and 7 to placebo; OR 2.13; 95% CI 0.88–5.13; p = 0.09). For H alone, three trials showed no difference in all-cause mortality compared to placebo (OR 0.96; 95% CI 0.37–2.47; p = 0.93), and two trials suggested inferiority to ACEI (OR 2.28; 95% CI 1.03–5.04; p = 0.04).

Conclusions

Compared to placebo, H&N reduces mortality in patients with CHF. Whether race or background therapy influences benefit is uncertain, but on direct comparison H&N appears inferior to ACEI. There is little evidence to support the use of either drug alone in CHF.

Section snippets

Background

The therapy of chronic heart failure (CHF) has advanced dramatically over the last 20–30 years [1]. Good medical treatment with angiotensin converting enzyme inhibitors (ACEIs), beta adrenoceptor antagonists (BB) and mineralocorticoid receptor antagonists (MRAs), now approximately doubles life expectancy [2]. However, mortality rates remain high, particularly in the first year after a hospitalisation for heart failure [3]. ACEIs were initially thought to mediate their benefit, at least in part,

Methods

The study was designed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) Statement [7]. Inclusion criteria were as follows: randomised controlled trial comparing H or N, or a combination, versus placebo, or no therapy, or an active comparator, whether parallel or multiple arms (i.e. other arms with different class, route, and dosage) were used. The studies included were all for patients with CHF. Observational studies, studies in acute heart failure,

Hydralazine and nitrate combination

Seven studies of H&N combination were identified including 2626 patients [Table 1]. Four studies compared the combination to placebo, one study compared the combination to either placebo or captopril, and two studies compared the combination to enalapril. The majority of patients were men (58% AAOS) and had left ventricular systolic dysfunction (LVSD). The aetiology of heart failure was IHD in about 37% of patients. Common adverse effects reported in these trials are shown in Table 2.

Discussion

This is the first comprehensive systematic review and meta-analysis appraising the use of H or N, alone and in combination, for patients with CHF. It highlights the surprising lack of data on the effects of nitrates alone in heart failure despite their widespread use in clinical practice. The paucity of data on hydralazine is less surprising since this agent is rarely used. There is a substantial body of evidence to support the use of the combination of H+ISDN as an alternative to ACEI in the

Conclusions

H&N in combination confer a survival benefit in patients with CHF when compared to placebo, particularly in men, patients of AAOS, and with advanced heart failure due to LVSD. It is unclear whether background therapy has an important influence on observed benefit. Combination therapy may have a favourable effect on symptoms, exercise tolerance, ventricular function, and hospitalisation rate. There is little evidence to support the use of either H or N alone in CHF, although nitrates are

Statement of authorship

The authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

Contributors

MF and TM did the literature search. All the authors analysed the data, interpreted the findings, drafted the manuscript, and approved the manuscript submitted.

Authors' disclosures

None.

Funding

None.

Conflict of interest

None.

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