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Hydralazine and nitrates alone or combined for the management of chronic heart failure: A systematic review
International Journal of Cardiology 196 (2015) 61–69
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Hydralazine and nitrates alone or combined for the management of chronic heart failure: A systematic review Mohamed Farag a,⁎, Thato Mabote a, Ahmad Shoaib a, Jufen Zhang a, Ashraf F. Nabhan c, Andrew L. Clark a, John G. Cleland b a b c
Department of Cardiology, Castle Hill Hospital, Hull York Medical School (at University of Hull), Kingston upon Hull HU16 5JQ, UK National Heart & Lung Institute, Imperial College, London, UK Postgraduate Medical School, Ain Shams University, Cairo, Egypt
a r t i c l e
i n f o
Article history: Received 3 April 2015 Accepted 27 May 2015 Available online 3 June 2015 Keywords: Chronic heart failure Systematic review Hydralazine Nitrate Morbidity Mortality
a b s t r a c t 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. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. 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, through their action as vasodilators, and other vasodilators have also
Abbreviations: AAOS, African-American origin or similar; ACEIs, angiotensin converting enzyme inhibitors; ARNIs, angiotensin receptor neprilysin inhibitors; ARBs, angiotensin receptor blockers; BB, beta adrenoceptor antagonists; CHF, chronic heart failure; H, hydralazine; IHD, ischaemic heart disease; ISDN, isosorbide dinitrate; ISMN, isosorbide mononitrate; LVSD, left ventricular systolic dysfunction; MRAs, mineralocorticoid receptor antagonists; Ns, nitrates; NYHA, New York Heart Association. ⁎ Corresponding author. E-mail address: [email protected] (M. Farag).
http://dx.doi.org/10.1016/j.ijcard.2015.05.160 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
been tried. In particular, the combination of hydralazine (H) and nitrates (Ns) was shown to be beneficial in the V-HeFT-I trial [4]. Nitrates are prescribed to patients with CHF although often for the relief of angina rather than for their effects on the symptoms of heart failure, venous capacity, or vascular resistance. Hydralazine is used in some countries, but is either not available, or rarely used in many others. A series of trials has suggested that the H&N combination may reduce morbidity and mortality, and that this combination may be almost as effective as ACEIs [4–6]. Evidence is most compelling amongst patients of African-American origin or similar (AAOS), but it is unclear whether racial origin is an important determinant of benefit [6]. There are many other uncertainties related to the use of these agents. For instance, it is not known whether they need to be used in combination, or whether one component of the combination delivers all or most of the benefit. Indeed, it is possible that the combination could be less effective than either agent used alone. Moreover, the effects of H and/or N may or may not have been altered by the changes in background heart failure therapy. It is unclear whether H and/or N improve symptoms, although it is widely believed that they do. It is also uncertain whether H and/or N
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M. Farag et al. / International Journal of Cardiology 196 (2015) 61–69
Table 1 Trials evaluating the use of H and N combination in chronic heart failure. Study/design Treatment
Control
Treatment Control Age Women Race (n) (n) (yrs) (%) (%)
Follow-up Background SR therapy (%)
IHD NYHA LVSD HR SBP DBP (%) III/IV (%) (mean) (mean) (mean) (%)
Franciosa [8], parallel Unverferth [9], parallel V-HeFT I [4], parallel
Combination (H 100 mg + ISDN 40 mg) PO Combination (H 225 mg + ISDN 160 mg) PO Combination (H 300 mg + ISDN 160 mg) PO
Placebo
11
11
54
NR
NR
90 min
D, L
NR
54% 91%
100% 84
113
NR
Placebo
7
11
57
24%
NR
12 weeks
D, L
NR
0% 94%
100% NR
NR
NR
Placebo
186
273
58
0%
D, L
NR
44% NYHA 100% 83 II/IV 100%
119
76
60
68
0%
60% 2.3 years white 40% black NR 1 year
Lin [10], parallel
Combination (H 200 mg +
Enalapril 20 mg PO
60
D, L
NR
30% NYHA 100% NR II/IV 100%
130
80
Enalapril 20 mg PO
401
403
61
0%
D, L
86
53% 43%
100% 78
126
78
Placebo, captopril 100 mg PO Placebo
50
51, 52
41
43%
D, L
NR
52%
100% NR
NR
NR
532
57
40%
D, L, ACEI/ARB, BB, MRA
83% 23% 99.9%
100% NR
126
77
Sorbitrate 80 mg) PO V-HeFT II [5], Combination (H parallel 300 mg + ISDN 160 mg) PO Ghose [11], parallel
Combination (H 100 mg + ISDN 60 mg) PO
A-HeFT [6], parallel
Combination (H 225 mg + ISDN 120 mg) PO
518
63% 2.5 years white 37% black NR 1 year
100% black
3 years
ACEI: angiotensin converting enzyme inhibitor, ARB: angiotensin receptor blocker, BB: beta adrenoceptor antagonists, DBP: diastolic blood pressure, D: digitalis, H: hydralazine, HR: heart rate, IHD: ischaemic heart disease, ISDN: isosorbide dinitrate, L: loop diuretic, LVSD: left ventricular systolic dysfunction, MRA: mineralocorticoid receptor antagonist, NR: not reported, NYHA: New York Heart Association, SR: sinus rhythm, SBP: systolic blood pressure.
confer a different effect on different heart failure phenotypes (for example, heart failure with normal ejection fraction, heart failure with reduced ejection fraction, ischaemic heart disease, and valve disease).
We therefore sought to analyse all clinical trials that had used H or N, either alone or in combination, in patients with CHF in order to describe the characteristics of patients recruited to these trials, to describe
Table 2 Adverse effects reported with the use of H and N combination in chronic heart failure. Study
Treatment
Control
Combination adverse effects (% of patients)
Control adverse effects (% of patients)
Franciosa [8] Unverferth [9] V-HeFT I [4]
Combination (H 100 mg + ISDN 40 mg) PO Combination (H 225 mg + ISDN 160 mg) PO Combination (H 300 mg + ISDN 160 mg) PO
Placebo Placebo Placebo
None Headache (several patients) Headache 12.4%⁎ Dizziness 6.5%⁎
None Headache (several patients) Headache 0.4% Dizziness 1.8% Gastrointestinal 1.8% Nervous system 0.4% Rash 0% Arthralgia 0% Possible lupus 0.7% Headache 0% Dizziness 6.7% Gastrointestinal 1.7% Presyncope 1.7% Facial flushing 0% Palpitation 0% Cough 10%⁎
Lin [10]
V-HeFT II [5]
Combination (H 200 mg + Sorbitrate 80 mg) PO
Combination (H 300 mg + ISDN 160 mg) PO
Enalapril 20 mg PO
Gastrointestinal 3.8% Nervous system 3.8% Rash 1.6% Arthralgia 1.6% Possible lupus 1.6% Headache 8.6%⁎
Enalapril 20 mg PO
Dizziness 5.2% Gastrointestinal 1.7% Presyncope 1.7% Facial flushing 1.7% Palpitation 5.2% Cough 0% Headache 73%⁎
Ghose [11]
Combination (H 100 mg + ISDN 60 mg) PO
Placebo, captopril 100 mg PO
A-HeFT [6]
Combination (H 225 mg + ISDN 120 mg) PO
Placebo
H: hydralazine, ISDN: isosorbide dinitrate. ⁎ This value was significantly higher than the corresponding value for the other treatment (p b 0.05).
Rash 31% Arthralgia 63% Palpitation 51% Nausea 44% Fatigue 76% Symptomatic hypotension 20% Taste disturbance 28% Nasal congestion 63% Cough 29% Hypotension Mild renal dysfunction Headache 47.5%⁎ Dizziness 29.3%⁎
Headache 54% Rash 33% Arthralgia 65% Palpitation 46% Nausea 52% Fatigue 79% Symptomatic hypotension 28%⁎ Taste disturbance 28% Nasal congestion 63% Cough 37%⁎ Hypotension Mild renal dysfunction Headache 19.2% Dizziness 12.3%
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Fig. 1. Mortality with nitrates and hydralazine combination vs. placebo. (A) All-cause mortality, and (B) cardiovascular mortality.
background medical therapy, and to assess the effect of H and/or N on mortality. 2. 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, studies that primarily addressed dosing and tolerance issues
(e.g. clinical pharmacological trials), or reported no clinical outcomes were excluded. The PubMed/Medline, Embase, Scopus and Cochrane Central Register of Controlled Trials databases were searched until December 2014. All studies reporting the effect of H and/or N on clinical endpoints in patients with CHF were included, with no language restrictions. Eligible studies were identified with the following headings: nitrates, nitroglycerine, nicorandil, isosorbide mononitrate, ISMN, isosorbide dinitrate, ISDN, glyceryltrinitrate, GTN, sodium nitroprusside, hydralazine, heart failure, cardiac failure, ventricular failure, randomly, random and randomised controlled trial. We also searched reference lists of the retrieved articles to identify other eligible studies, and we sought information from colleagues to identify more recently published articles.
Fig. 2. Mortality with nitrates and hydralazine combination vs. ACEI. (A) All-cause mortality, and (B) cardiovascular mortality.
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Table 3 Trials evaluating the use of nitrates alone in chronic heart failure. Treatment
Control
Franciosa [17], cross-over Mikulic [18], cross-over Franciosa [19], cross-over Franciosa [20], parallel Wilson [21], parallel Hermanovich [22], parallel
ISDN 20 mg PO
Placebo
12
54
0%
b24 h
D
NR
58% 100%
NR
ISDN 10 mg chewable, nitroglycerin 0.6 mg sublingual ISDN 160 mg PO
Placebo
8
55
13%
b24 h
D
NR
25% 100%
NR
Placebo
14
55
7%
22 weeks
D, L
NR
75% 100%
NR
ISDN 160 mg PO
Placebo
16
58
NR
12 weeks
D, L
NR
69%
ISDN 10 mg chewable
Placebo
13
57
NR
48 h
D, L
NR
69% 100%
Sodium nitroprusside 33
Captopril 100 mg PO
11
62
18%
48 h
D, L
NR
100% 100%
Placebo
30
49
17%
12 weeks
D, L
83%
23% 100%
ISDN 160 mg PO
Placebo
17
57
25%
12 weeks
D, L
NR
ISDN 40 mg PO
Captopril 25
18
68
44%
48 h
D, L
NR
56% 100%
mg PO Placebo
18
67
17%
4 weeks
56%
44%
50%
NR
72%
11%
mcg/min IV Leier [23], parallel ISDN 160 mg PO
Unverferth [9], parallel Packer [24], cross-over Lindvall [25], cross-over Wilkes [26], parallel Elkayam [27], cross-over Vogt [28], parallel Wieshammer [29], parallel Keck [30], parallel NICE [31], Parallel Elkayam [32], cross-over Wieshammer [33], withdrawal Tingberg [34], parallel
Nitroglycerin 15 mg transdermal patch OD ISDN 50 mg PO
Patients Age Women Follow-up Background SR (n) (yrs) (%) therapy (%)
IHD (%)
0%
NYHA LVSD Symptoms III/IV (%) (%)
75%
94%
21
62
NR
12 weeks
20
55
8%
8 weeks
D, L
NR
32%
71%
ISDN 1.25 mg buccal spray, ISDN 2.5 mg buccal spray ISDN 80 mg PO
Captopril 100 mg PO Nifedipine 80 mg PO Placebo
BB, D, L, MRA D, L
30
56
3%
20 min
D, L, ACEI
NR
60%
93%
Placebo
54
57
8%
16 weeks
D, L, ACEI
NR
100%
57%
ISMN 50 mg PO ISMN 50 mg PO
Placebo Placebo
21 136
52 57
0% 6%
4 weeks 24 weeks
D, L, ACEI L, ACEI
NR NR
100% 100%
43% 20%
Nitroglycerin 57 ± 5 mg transdermal patch OD ISDN 80 mg PO
Placebo
29
48
17%
12 weeks
D, L, ACEI
NR
24%
59%
Placebo
29
55
0%
22 weeks
D, L, ACEI
100% 100%
41%
ISMNb 60 mg PO
Placebo
92
64
25%
11
BB, D, L, ACEI
NR
35%
ISDNa 160 mg PO
months
100%
Exercise tolerance
PAWP
Ventricular function
Mortality
NR
NR
NR
Favoured ISDN
None
NR
NR
NR
Favoured ISDN
None
No difference
NR
No difference
Favoured ISDN 100% No difference 100% NR
Favoured ISDN
Favoured ISDN
No difference
No difference None
Favoured ISDN
Favoured ISDN
Favoured ISDN
NR
100% NR
NR
NR
Favoured sodium nitro-prusside
NR
NR
Favoured ISDN
Favoured ISDN
No difference
NR
Favoured ISDN
No difference
NR
Favoured ISDN
Favoured ISDN
No difference No difference NR
100% No difference 100% Favoured captopril 100% Favoured ISDN 93% NR
No difference
NR
No difference
NR
No difference
NR
No difference
NR
Favoured ISDN
NR
No difference
NR
NR
100% No difference 100% NR 100% No difference 100% No difference 100% NR
No difference
Favoured ISDN (both doses) NR
No difference NR
NR
NR
Favoured ISMN NR
No difference No difference
NR
Favoured Nitro-glycerin Favoured ISDN during exercise
None No difference No difference NR
Favoured ISDN 100% Favoured ISDN 100% NR
100% No difference
NR Favoured ISMN in severe HF Favoured nitro-glycerin NR
No difference
NR
No difference
Favoured ISMN in severe HF
No difference
ACEI: angiotensin converting enzyme inhibitor, BB: beta adrenoceptor antagonists, D: digitalis, HF: heart failure, IHD: ischaemic heart disease, ISDN: isosorbide dinitrate, ISMN: isosorbide mononitrate, LVSD: left ventricular systolic dysfunction, L: loop diuretic, MRA: mineralocorticoid receptor antagonist, NYHA: New York Heart Association, NR: not reported, PAWP: pulmonary artery wedge pressure, SR: sinus rhythm. Drug doses are presented by average or mean ± SD. a ISDN alone significantly reduced hospitalisation compared with nifedipine. b ISMN resulted in lower plasma concentrations of atrial natriuretic peptide (ANP).
M. Farag et al. / International Journal of Cardiology 196 (2015) 61–69
Study/design
M. Farag et al. / International Journal of Cardiology 196 (2015) 61–69
Online oral presentations and expert slide presentations were also examined. Two investigators independently reviewed all titles, or titles and abstracts from the search results to identify articles meeting the inclusion criteria. Disagreement was resolved by team discussion and consensus. If any of the eligibility criteria were not met, the article was excluded. Data extraction was carried out independently and in duplicate by the study investigators. Results of data extraction were then compared, and any discrepancies were resolved by discussion. If results were incomplete or unclear, the study authors were contacted. Articles finally selected for the review were checked to avoid inclusion of data published in duplicate. Relevant data were collected on baseline characteristics, presence of ischaemic heart disease (IHD), New York Heart Association (NYHA) functional classification, background heart failure therapy, study interventions, clinical observations, and clinical outcomes at baseline and end follow-up. We considered only the endpoints of all-cause mortality and cardiovascular mortality for statistical analysis, but provide a narrative report for other measures. Cardiovascular mortality was defined as sudden death, death due to heart failure, or other cardiovascular deaths. Of 1254 articles identified by the initial search, 74 were retrieved for more detailed evaluation. 26 studies were excluded because they primarily addressed dosing and tolerance issues, rather than focusing on clinical outcomes, and 15 studies were also excluded because they assessed the effects of the drugs in acute heart failure [Supplementary appendix]. Finally, 33 randomised studies were included in the review [Supplemental Fig. 1]. Statistical analysis was carried out using the Review Manager software (RevMan version 5.3). Aggregate data were used. Mortality outcomes are presented as odds ratios with 95% confidence intervals (CI). P values are also shown, and were considered statistically significant if less than 0.05. Heterogeneity was assessed using chi-squared tests as well as I-squared tests. Forest plots are used to represent the metaanalysis graphically. We show pooled odds ratios and the degree of heterogeneity between studies. We used a Mantel–Haenszel fixed effects model as substantial heterogeneity was less than 40%. The quality of the studies analysed was evaluated using the risk-of-bias tool of the Review Manager software, based on the authors' judgements about each methodological quality item, including selection bias, performance bias, detection bias, attrition bias, reporting bias and other sources of bias [Supplementary appendix]. The result was expressed as a low, high or unclear risk of each type of bias. Publication bias was minimized by comprehensive literature searching. In addition, a graphical display (funnel plot) of the size of the treatment effect against the precision of the trial (1/standard error) was used to investigate publication bias. However, the funnel plot approach was not used where the number of included studies was small.
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3. Results 3.1. 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. Isosorbide dinitrate (ISDN) was the most commonly studied nitrate formulation. 3.1.1. H&N combination versus placebo Compared to placebo, the combination of hydralazine and isosorbide dinitrate (H+ISDN) improved NYHA functional class by at least one functional class [9,11]. The V-HeFT I study [4], which was the first large randomised study to evaluate the role of vasodilator drugs in heart failure, suggested that the addition of H+ISDN combination to a background regimen of diuretics and digitalis in patients with CHF has a favourable effect on left ventricular ejection fraction and mortality at two years, as compared to placebo. Subsequent sub-group analysis suggested that the benefit was most marked in patients with AAOS [12]. There was a trend for fewer hospitalisations with the use of the combination. The A-HeFT study [6] enrolled patients of AAOS who were randomised to receive H+ISDN or placebo on a background of standard heart failure medications (90% received diuretics, 60% digitalis, 70% ACEI, 17% ARB, 74% BB and 39% MRA). It was terminated early owing to a significant survival benefit for the actively-treated group (H+ISDN) compared to the placebo group. Days to first hospitalisation for heart failure were significantly delayed by H+ISDN. In addition, a large proportion of patients reported substantial improvement in the quality of life, as measured by a specific heart failure questionnaire. H+ISDN was cost-effective because of the large reduction in hospitalisations [13]. The X-A-HeFT study [14], which was an extension of the original A-HeFT study, showed that the symptomatic benefits persist. Our meta-analysis suggested that H+ISDN reduced all-cause (OR 0.72; 95% confidence intervals [CI] 0.55–0.95; p = 0.02) [Fig. 1-A], and cardiovascular mortality (OR 0.75; 95% CI 0.57–0.99; p = 0.04) [Fig. 1-B] [15] compared to placebo. 3.1.2. H&N combination versus ACEI In the V-HeFT II study [5], patients were randomised to H+ISDN or enalapril. Although H+ISDN exerted greater benefit on symptoms of heart failure, the time to first hospitalisation for heart failure was similar between H+ISDN combination and enalapril, and patients assigned to
Fig. 3. All-cause mortality with nitrates vs. placebo.
54% 68% D, L, ISDN 8 months 14% 52 104 147 mg PO 164 mg PO
Hy-C [42], parallel
BB beta adrenoceptor antagonists, D: digitalis, IHD: ischaemic heart disease, ISDN: isosorbide dinitrate, LVSD: left ventricular systolic dysfunction, L: loop diuretic, MRA: mineralocorticoid receptor antagonist, NYHA: New York Heart Association, NR: not reported, PAWP: pulmonary artery wedge pressure, SR: sinus rhythm. Drug doses are presented by average or mean ± SD. ⁎ Survival was improved with captopril as a result of lower rate of sudden death (p b 0.01).
100%
100% NR
NR
No difference
NR
Favoured captopril ⁎
No difference Favoured captopril NR Favoured captopril 100% Favoured captopril 100% 86% 80% D, L, MRA, nitrates 12 weeks 10% 56 50
mg PO Captopril 206 ±
Schofield [41], parallel
58 mg PO Hydralazine 410 ±
NR Favoured hydralazine NR 100% NR 100% 78% NR None b1 week 0% 58
Elkayam [39], cross-over
mg IV mg PO Hydralazine 12.5 mg Nisoldipine 4 IV mcg/kg IV Hydralazine 166 ± Captopril 53 ± 24
18
9
3.6 mg PO Nifedipine 34 ± 20 0.9 mg IV Hydralazine 14 ± 8
Elkayam [38], cross-over
Haitas [40], cross-over
mg PO Nifedipine 26.4 ±
Elkayam [37], cross-over
None
None Favoured hydralazine 100% 28% NR D b1 week 28%
Nifedipine 34 ± 22
mg IV Hydralazine 11.1 ±
54
62 Placebo
11 mg PO Hydralazine 10 ± 5
15
20
Unverferth [9], parallel Conradson [36], parallel
Placebo
9
50
54
20%
11%
b1 week
b1 week
D
D, L
NR
NR
40%
22%
100%
100%
100% NR
100% NR
NR
NR
Favoured hydralazine
NR
NR
NR Favoured hydralazine NR 100% NR
NR Favoured Hydralazine Favoured Hydralazine NR 100% 73% NR D, L, BB, MRA 1 year 29% 64
NR 100% No difference 94% 0% NR D, L 12 weeks 25% 57
None
None
No difference
No difference No difference
Favoured hydralazine NR
No difference NR No difference 100% No difference 100% 33% NR D, L 26 weeks 33% Hydralazine 188 ±
Franciosa [35], parallel
Control Treatment
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 rare instances where these agents are contra-indicated (angioneurotic oedema), or not tolerated due to renal dysfunction. There is also evidence that H+ISDN improves outcome when added to contemporary neuroendocrine therapy in AAOS patients; this effect needs to be explored in other racial groups. In CHF, activation of the renin–angiotensin–aldosterone and adrenergic systems causes an increase in vascular tone and salt and water retention resulting in an increase in cardiac afterload and preload, further compromising the failing heart. Treatments that interfere with these systems improve the prognosis of patients with heart failure. For ACEIs and angiotensin receptor blockers (ARBs), it remains unclear how much of their benefit is mediated by improvements in vascular tone and haemodynamics or by other mechanisms; the rather similar benefits of ACEI and H+ISDN in head-to-head comparisons suggests that vasodilatation might be a common mechanism of benefit. However, the additive benefit observed in A-HeFT suggests that mechanisms of benefit might differ, although it is possible that H+ISDN simply delivers more vasodilatation. ACEI and ARB can cause a fall in glomerular filtration rate by reducing arterial perfusion pressure and relaxation of
Table 4 Trials evaluating the use of hydralazine alone in chronic heart failure.
4. Discussion
Patients Age (n) (yrs)
Women Follow-up Background (%) therapy
SR (%)
IHD (%)
NYHA III/IV (%)
A summary of randomised trials evaluating the use of hydralazine (H) alone in CHF is shown in Table 4. We identified nine studies including 319 patients. Three studies compared H to placebo, two compared H to captopril, and four studies compared H to calcium channel blockers. Most patients were men and had severe CHF due predominantly to LVSD. The aetiology of heart failure was IHD in about 56% of patients. The studies that compared H to calcium channel blockers suggested that H exerted greater improvement in left ventricular ejection fraction [37–40]. However, the short duration and the small sample size of the studies make the results difficult to generalize. For the studies that reported mortality, the meta-analysis showed that H alone had no effect on all-cause mortality (OR 0.96; 95% CI 0.37–2.47; p = 0.93) compared to placebo [Fig. 4-A], but higher with H (OR 2.28; 95% CI 1.03–5.04; p = 0.04) compared to captopril [Fig. 4-B].
58
3.3. Hydralazine alone
32
LVSD Symptoms (%)
Exercise tolerance
PAWP
A summary of randomised trials evaluating nitrates (Ns) alone in CHF is shown in Table 3. There were 19 studies with 589 patients. Ten studies including 375 patients compared N to placebo, and nine compared N to alternative interventions. Most patients were men and had moderate to severe CHF due predominantly to LVSD. The aetiology of heart failure was IHD in about 77% of patients. For the studies which reported mortality and compared N to placebo, the meta-analysis showed that N alone had no effect on all-cause mortality. However, there were few events in these studies and the trend was towards harm (13 deaths in those assigned to N and 7 to placebo; OR 2.12; 95% CI 0.88–5.12; p = 0.09) [Fig. 3]. In the studies of N compared with alternative interventions, eight did not report mortality and the final study showed no difference between N and nifedipine.
Placebo
Ventricular function
3.2. Nitrates alone
47 mg PO Hydralazine 225 mg PO Hydralazine 149 ±
Mortality
enalapril had a lower mortality [16]. In the meta-analysis, compared to ACEI, the combination of H+ISDN was associated with a higher allcause (OR 1.35; 95% CI 1.03–1.76; p = 0.03) [Fig. 2-A], and cardiovascular mortality (OR 1.37; 95% CI 1.04–1.81; p = 0.03) [Fig. 2-B].
No difference
M. Farag et al. / International Journal of Cardiology 196 (2015) 61–69
Study/design
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M. Farag et al. / International Journal of Cardiology 196 (2015) 61–69
efferent glomerular arterioles, whereas H&N combination only cause a fall in arterial perfusion pressure, the effect of which may be attenuated by a fall in renal venous pressure, which maintains the net renal perfusion pressure [43]. However, this theoretical advantage over ACEI is supported only by clinical opinion and anecdote rather than solid experimental evidence. A combination of a more robust evidence-base, fewer side effects, less frequent dosing, guideline recommendations and stronger marketing, rather than greater efficacy, may account for the dominant use of ACEIs in current clinical practice. H or N, alone or in combination, are unlikely to displace ACEIs, but might provide additional benefit as suggested in the A-HeFT trial; this possibility should be explored in other racial groups. The advent of angiotensin receptor neprilysin inhibitors (ARNIs) may change the therapeutic approach to the management of heart failure [44]. It is not clear whether addition of H&N combination to an ACEI would prove equally effective, or whether addition of H&N combination to an ARNI would be effective. Hydralazine and nitrates may work synergistically in patients with CHF [45]. Nitrates exert their effects by being converted to nitric oxide (NO). NO is a potent endogenous vasodilator and a major biological regulator of cardiovascular function, and its metabolism is impaired in patients with heart failure. Nitrate therapy thus appears intuitively likely to be beneficial [46,47]. Hydralazine is a potent vasodilator that has some antioxidant effects that help prevent NO degradation [48]. Although the precise cardiovascular properties of hydralazine are not fully understood, it reduces peripheral vascular resistance directly by relaxing vascular smooth muscle cells [49]. Hydralazine is also thought to inhibit activation of a membrane-associated oxidase responsible for the increased superoxide production that causes nitrate tolerance [50]. AAOS have a lesser response in terms of NO-mediated cardiovascular effects than whites [51,52], and so it is possible that the NO-mediated effects of the H&N combination could be responsible for a differential benefit in AAOS. The reduction in heart failure hospitalisations and the improvement in NYHA functional classification with H&N combination may in part relate to reductions in left ventricular filling pressures, consistent with the lowering of pulmonary artery pressure seen with the same agents in the CHAMPION trial [53]. As nitrates reduce preload and hydralazine reduces afterload, the combination might provide optimal haemodynamic benefit to CHF patients. We only found a survival benefit when both agents were used in combination. However, when either agent is used alone, there was a divergence between haemodynamic and survival benefits.
67
H&N combination do seem to confer a survival benefit, particularly in AAOS men with advanced LVSD, but there is little evidence to support the use of either drug alone. 4.1. Study limitations The study has several limitations. Firstly, as is the case for any metaanalysis, data were combined from different studies, each of which had its own protocol, follow-up period, and definitions. Secondly, some trials of H and/or N studied patients irrespective of the type, aetiology or severity of heart failure, and therefore, a favourable drug effect in certain subgroups of patients might have been missed (for example, those with more severe congestion, higher blood pressure or with normal ejection fraction). Thirdly, studies assessing H or N as single agents were small and had very few events, which weakens the conclusions about the ineffectiveness of single agents in CHF. Fourthly, the quality of some studies was poor, with poor methods and soft clinical outcome measures, making the assessment of hard clinical endpoints such as hospitalisation rate, improvement in NHYA functional classification, and the haemodynamic effects (for example, blood pressure and pulmonary artery pressure measurements) difficult. Furthermore, the study participants were predominantly men. Importantly, the V-HeFT trials included only men [4,5]. In A-HeFT, nearly 40% of the study were women, but with no significant treatment interaction by gender was found [6,54]. Additionally, one of the largest trials was conducted only in patients of AAOS, so it is not known whether the results can be extrapolated to other racial groups, especially Caucasian women. Lastly, most of the eligible studies were conducted in developed Western countries. Consequently, the findings may not be generalisable to other healthcare settings. 5. 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 commonly prescribed in clinical practice. Large randomised trials are needed to evaluate the safety and efficacy of adding H and N, alone or in combination, to contemporary medical therapy.
Fig. 4. All-cause mortality with hydralazine. (A) vs. placebo, and (B) vs. ACEI.
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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. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2015.05.160. References [1] P.S. Jhund, K. Macintyre, C.R. Simpson, et al., Long-term trends in first hospitalization for heart failure and subsequent survival between 1986 and 2003: a population study of 5.1 million people, Circulation 119 (2009) 515–523. [2] J.J. McMurray, S. Adamopoulos, S.D. Anker, et al., ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC, Eur. Heart J. 33 (2012) 1787–1847. [3] J.G. Cleland, T. McDonagh, A.S. Rigby, et al., The national heart failure audit for England and Wales 2008–2009, Heart 97 (2011) 876–886. [4] J.N. Cohn, D.G. Archibald, S. Ziesche, et al., Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study, N. Engl. J. Med. 314 (1986) 1547–1552. [5] J.N. Cohn, G. Johnson, S. Ziesche, et al., A comparison of enalapril with hydralazineisosorbide dinitrate in the treatment of chronic congestive heart failure, N. Engl. J. Med. 325 (1991) 303–310. [6] A.L. Taylor, S. Ziesche, C. Yancy, et al., Combination of isosorbide dinitrate and hydralazine in blacks with heart failure, N. Engl. J. Med. 351 (2004) 2049–2057. [7] D. Moher, A. Liberati, J. Tetzlaff, D.G. Altman, P. Group, Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement, Open Med. 3 (2009) e123–e130. [8] J.A. Franciosa, J.N. Cohn, Immediate effects of hydralazine–isosorbide dinitrate combination on exercise capacity and exercise hemodynamics in patients with left ventricular failure, Circulation 59 (1979) 1085–1091. [9] D.V. Unverferth, J.P. Mehegan, R.D. Magorien, B.J. Unverferth, C.V. Leier, Regression of myocardial cellular hypertrophy with vasodilator therapy in chronic congestive heart failure associated with idiopathic dilated cardiomyopathy, Am. J. Cardiol. 51 (1983) 1392–1398. [10] M. Lin, H.T. Chiang, C.Y. Chen, B.N. Chiang, Comparison of enalapril and conventional vasodilator therapy in patients with chronic congestive heart failure, J. Formos. Med. Assoc. 90 (1991) 452–459. [11] J.C. Ghose, S. Chakraborty, M. Mondal, B. Bhandari, Effect of vasodilator therapy on mortality in chronic congestive heart failure, J. Assoc. Physicians India 41 (1993) 269–271. [12] P. Carson, S. Ziesche, G. Johnson, J.N. Cohn, Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group, J. Card. Fail. 5 (1999) 178–187. [13] D.C. Angus, W.T. Linde-Zwirble, S.W. Tam, et al., Cost-effectiveness of fixed-dose combination of isosorbide dinitrate and hydralazine therapy for blacks with heart failure, Circulation 112 (2005) 3745–3753. [14] C.W. Yancy, J.K. Ghali, V.M. Braman, et al., Evidence for the continued safety and tolerability of fixed-dose isosorbide dinitrate/hydralazine in patients with chronic heart failure (the extension to African-American Heart Failure Trial), Am. J. Cardiol. 100 (2007) 684–689.
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Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Hydralazine and nitrates alone or combined for the management of chronic heart failure: A systematic review Mohamed Farag a,⁎, Thato Mabote a, Ahmad Shoaib a, Jufen Zhang a, Ashraf F. Nabhan c, Andrew L. Clark a, John G. Cleland b a b c
Department of Cardiology, Castle Hill Hospital, Hull York Medical School (at University of Hull), Kingston upon Hull HU16 5JQ, UK National Heart & Lung Institute, Imperial College, London, UK Postgraduate Medical School, Ain Shams University, Cairo, Egypt
a r t i c l e
i n f o
Article history: Received 3 April 2015 Accepted 27 May 2015 Available online 3 June 2015 Keywords: Chronic heart failure Systematic review Hydralazine Nitrate Morbidity Mortality
a b s t r a c t 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. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. 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, through their action as vasodilators, and other vasodilators have also
Abbreviations: AAOS, African-American origin or similar; ACEIs, angiotensin converting enzyme inhibitors; ARNIs, angiotensin receptor neprilysin inhibitors; ARBs, angiotensin receptor blockers; BB, beta adrenoceptor antagonists; CHF, chronic heart failure; H, hydralazine; IHD, ischaemic heart disease; ISDN, isosorbide dinitrate; ISMN, isosorbide mononitrate; LVSD, left ventricular systolic dysfunction; MRAs, mineralocorticoid receptor antagonists; Ns, nitrates; NYHA, New York Heart Association. ⁎ Corresponding author. E-mail address: [email protected] (M. Farag).
http://dx.doi.org/10.1016/j.ijcard.2015.05.160 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
been tried. In particular, the combination of hydralazine (H) and nitrates (Ns) was shown to be beneficial in the V-HeFT-I trial [4]. Nitrates are prescribed to patients with CHF although often for the relief of angina rather than for their effects on the symptoms of heart failure, venous capacity, or vascular resistance. Hydralazine is used in some countries, but is either not available, or rarely used in many others. A series of trials has suggested that the H&N combination may reduce morbidity and mortality, and that this combination may be almost as effective as ACEIs [4–6]. Evidence is most compelling amongst patients of African-American origin or similar (AAOS), but it is unclear whether racial origin is an important determinant of benefit [6]. There are many other uncertainties related to the use of these agents. For instance, it is not known whether they need to be used in combination, or whether one component of the combination delivers all or most of the benefit. Indeed, it is possible that the combination could be less effective than either agent used alone. Moreover, the effects of H and/or N may or may not have been altered by the changes in background heart failure therapy. It is unclear whether H and/or N improve symptoms, although it is widely believed that they do. It is also uncertain whether H and/or N
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M. Farag et al. / International Journal of Cardiology 196 (2015) 61–69
Table 1 Trials evaluating the use of H and N combination in chronic heart failure. Study/design Treatment
Control
Treatment Control Age Women Race (n) (n) (yrs) (%) (%)
Follow-up Background SR therapy (%)
IHD NYHA LVSD HR SBP DBP (%) III/IV (%) (mean) (mean) (mean) (%)
Franciosa [8], parallel Unverferth [9], parallel V-HeFT I [4], parallel
Combination (H 100 mg + ISDN 40 mg) PO Combination (H 225 mg + ISDN 160 mg) PO Combination (H 300 mg + ISDN 160 mg) PO
Placebo
11
11
54
NR
NR
90 min
D, L
NR
54% 91%
100% 84
113
NR
Placebo
7
11
57
24%
NR
12 weeks
D, L
NR
0% 94%
100% NR
NR
NR
Placebo
186
273
58
0%
D, L
NR
44% NYHA 100% 83 II/IV 100%
119
76
60
68
0%
60% 2.3 years white 40% black NR 1 year
Lin [10], parallel
Combination (H 200 mg +
Enalapril 20 mg PO
60
D, L
NR
30% NYHA 100% NR II/IV 100%
130
80
Enalapril 20 mg PO
401
403
61
0%
D, L
86
53% 43%
100% 78
126
78
Placebo, captopril 100 mg PO Placebo
50
51, 52
41
43%
D, L
NR
52%
100% NR
NR
NR
532
57
40%
D, L, ACEI/ARB, BB, MRA
83% 23% 99.9%
100% NR
126
77
Sorbitrate 80 mg) PO V-HeFT II [5], Combination (H parallel 300 mg + ISDN 160 mg) PO Ghose [11], parallel
Combination (H 100 mg + ISDN 60 mg) PO
A-HeFT [6], parallel
Combination (H 225 mg + ISDN 120 mg) PO
518
63% 2.5 years white 37% black NR 1 year
100% black
3 years
ACEI: angiotensin converting enzyme inhibitor, ARB: angiotensin receptor blocker, BB: beta adrenoceptor antagonists, DBP: diastolic blood pressure, D: digitalis, H: hydralazine, HR: heart rate, IHD: ischaemic heart disease, ISDN: isosorbide dinitrate, L: loop diuretic, LVSD: left ventricular systolic dysfunction, MRA: mineralocorticoid receptor antagonist, NR: not reported, NYHA: New York Heart Association, SR: sinus rhythm, SBP: systolic blood pressure.
confer a different effect on different heart failure phenotypes (for example, heart failure with normal ejection fraction, heart failure with reduced ejection fraction, ischaemic heart disease, and valve disease).
We therefore sought to analyse all clinical trials that had used H or N, either alone or in combination, in patients with CHF in order to describe the characteristics of patients recruited to these trials, to describe
Table 2 Adverse effects reported with the use of H and N combination in chronic heart failure. Study
Treatment
Control
Combination adverse effects (% of patients)
Control adverse effects (% of patients)
Franciosa [8] Unverferth [9] V-HeFT I [4]
Combination (H 100 mg + ISDN 40 mg) PO Combination (H 225 mg + ISDN 160 mg) PO Combination (H 300 mg + ISDN 160 mg) PO
Placebo Placebo Placebo
None Headache (several patients) Headache 12.4%⁎ Dizziness 6.5%⁎
None Headache (several patients) Headache 0.4% Dizziness 1.8% Gastrointestinal 1.8% Nervous system 0.4% Rash 0% Arthralgia 0% Possible lupus 0.7% Headache 0% Dizziness 6.7% Gastrointestinal 1.7% Presyncope 1.7% Facial flushing 0% Palpitation 0% Cough 10%⁎
Lin [10]
V-HeFT II [5]
Combination (H 200 mg + Sorbitrate 80 mg) PO
Combination (H 300 mg + ISDN 160 mg) PO
Enalapril 20 mg PO
Gastrointestinal 3.8% Nervous system 3.8% Rash 1.6% Arthralgia 1.6% Possible lupus 1.6% Headache 8.6%⁎
Enalapril 20 mg PO
Dizziness 5.2% Gastrointestinal 1.7% Presyncope 1.7% Facial flushing 1.7% Palpitation 5.2% Cough 0% Headache 73%⁎
Ghose [11]
Combination (H 100 mg + ISDN 60 mg) PO
Placebo, captopril 100 mg PO
A-HeFT [6]
Combination (H 225 mg + ISDN 120 mg) PO
Placebo
H: hydralazine, ISDN: isosorbide dinitrate. ⁎ This value was significantly higher than the corresponding value for the other treatment (p b 0.05).
Rash 31% Arthralgia 63% Palpitation 51% Nausea 44% Fatigue 76% Symptomatic hypotension 20% Taste disturbance 28% Nasal congestion 63% Cough 29% Hypotension Mild renal dysfunction Headache 47.5%⁎ Dizziness 29.3%⁎
Headache 54% Rash 33% Arthralgia 65% Palpitation 46% Nausea 52% Fatigue 79% Symptomatic hypotension 28%⁎ Taste disturbance 28% Nasal congestion 63% Cough 37%⁎ Hypotension Mild renal dysfunction Headache 19.2% Dizziness 12.3%
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Fig. 1. Mortality with nitrates and hydralazine combination vs. placebo. (A) All-cause mortality, and (B) cardiovascular mortality.
background medical therapy, and to assess the effect of H and/or N on mortality. 2. 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, studies that primarily addressed dosing and tolerance issues
(e.g. clinical pharmacological trials), or reported no clinical outcomes were excluded. The PubMed/Medline, Embase, Scopus and Cochrane Central Register of Controlled Trials databases were searched until December 2014. All studies reporting the effect of H and/or N on clinical endpoints in patients with CHF were included, with no language restrictions. Eligible studies were identified with the following headings: nitrates, nitroglycerine, nicorandil, isosorbide mononitrate, ISMN, isosorbide dinitrate, ISDN, glyceryltrinitrate, GTN, sodium nitroprusside, hydralazine, heart failure, cardiac failure, ventricular failure, randomly, random and randomised controlled trial. We also searched reference lists of the retrieved articles to identify other eligible studies, and we sought information from colleagues to identify more recently published articles.
Fig. 2. Mortality with nitrates and hydralazine combination vs. ACEI. (A) All-cause mortality, and (B) cardiovascular mortality.
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Table 3 Trials evaluating the use of nitrates alone in chronic heart failure. Treatment
Control
Franciosa [17], cross-over Mikulic [18], cross-over Franciosa [19], cross-over Franciosa [20], parallel Wilson [21], parallel Hermanovich [22], parallel
ISDN 20 mg PO
Placebo
12
54
0%
b24 h
D
NR
58% 100%
NR
ISDN 10 mg chewable, nitroglycerin 0.6 mg sublingual ISDN 160 mg PO
Placebo
8
55
13%
b24 h
D
NR
25% 100%
NR
Placebo
14
55
7%
22 weeks
D, L
NR
75% 100%
NR
ISDN 160 mg PO
Placebo
16
58
NR
12 weeks
D, L
NR
69%
ISDN 10 mg chewable
Placebo
13
57
NR
48 h
D, L
NR
69% 100%
Sodium nitroprusside 33
Captopril 100 mg PO
11
62
18%
48 h
D, L
NR
100% 100%
Placebo
30
49
17%
12 weeks
D, L
83%
23% 100%
ISDN 160 mg PO
Placebo
17
57
25%
12 weeks
D, L
NR
ISDN 40 mg PO
Captopril 25
18
68
44%
48 h
D, L
NR
56% 100%
mg PO Placebo
18
67
17%
4 weeks
56%
44%
50%
NR
72%
11%
mcg/min IV Leier [23], parallel ISDN 160 mg PO
Unverferth [9], parallel Packer [24], cross-over Lindvall [25], cross-over Wilkes [26], parallel Elkayam [27], cross-over Vogt [28], parallel Wieshammer [29], parallel Keck [30], parallel NICE [31], Parallel Elkayam [32], cross-over Wieshammer [33], withdrawal Tingberg [34], parallel
Nitroglycerin 15 mg transdermal patch OD ISDN 50 mg PO
Patients Age Women Follow-up Background SR (n) (yrs) (%) therapy (%)
IHD (%)
0%
NYHA LVSD Symptoms III/IV (%) (%)
75%
94%
21
62
NR
12 weeks
20
55
8%
8 weeks
D, L
NR
32%
71%
ISDN 1.25 mg buccal spray, ISDN 2.5 mg buccal spray ISDN 80 mg PO
Captopril 100 mg PO Nifedipine 80 mg PO Placebo
BB, D, L, MRA D, L
30
56
3%
20 min
D, L, ACEI
NR
60%
93%
Placebo
54
57
8%
16 weeks
D, L, ACEI
NR
100%
57%
ISMN 50 mg PO ISMN 50 mg PO
Placebo Placebo
21 136
52 57
0% 6%
4 weeks 24 weeks
D, L, ACEI L, ACEI
NR NR
100% 100%
43% 20%
Nitroglycerin 57 ± 5 mg transdermal patch OD ISDN 80 mg PO
Placebo
29
48
17%
12 weeks
D, L, ACEI
NR
24%
59%
Placebo
29
55
0%
22 weeks
D, L, ACEI
100% 100%
41%
ISMNb 60 mg PO
Placebo
92
64
25%
11
BB, D, L, ACEI
NR
35%
ISDNa 160 mg PO
months
100%
Exercise tolerance
PAWP
Ventricular function
Mortality
NR
NR
NR
Favoured ISDN
None
NR
NR
NR
Favoured ISDN
None
No difference
NR
No difference
Favoured ISDN 100% No difference 100% NR
Favoured ISDN
Favoured ISDN
No difference
No difference None
Favoured ISDN
Favoured ISDN
Favoured ISDN
NR
100% NR
NR
NR
Favoured sodium nitro-prusside
NR
NR
Favoured ISDN
Favoured ISDN
No difference
NR
Favoured ISDN
No difference
NR
Favoured ISDN
Favoured ISDN
No difference No difference NR
100% No difference 100% Favoured captopril 100% Favoured ISDN 93% NR
No difference
NR
No difference
NR
No difference
NR
No difference
NR
Favoured ISDN
NR
No difference
NR
NR
100% No difference 100% NR 100% No difference 100% No difference 100% NR
No difference
Favoured ISDN (both doses) NR
No difference NR
NR
NR
Favoured ISMN NR
No difference No difference
NR
Favoured Nitro-glycerin Favoured ISDN during exercise
None No difference No difference NR
Favoured ISDN 100% Favoured ISDN 100% NR
100% No difference
NR Favoured ISMN in severe HF Favoured nitro-glycerin NR
No difference
NR
No difference
Favoured ISMN in severe HF
No difference
ACEI: angiotensin converting enzyme inhibitor, BB: beta adrenoceptor antagonists, D: digitalis, HF: heart failure, IHD: ischaemic heart disease, ISDN: isosorbide dinitrate, ISMN: isosorbide mononitrate, LVSD: left ventricular systolic dysfunction, L: loop diuretic, MRA: mineralocorticoid receptor antagonist, NYHA: New York Heart Association, NR: not reported, PAWP: pulmonary artery wedge pressure, SR: sinus rhythm. Drug doses are presented by average or mean ± SD. a ISDN alone significantly reduced hospitalisation compared with nifedipine. b ISMN resulted in lower plasma concentrations of atrial natriuretic peptide (ANP).
M. Farag et al. / International Journal of Cardiology 196 (2015) 61–69
Study/design
M. Farag et al. / International Journal of Cardiology 196 (2015) 61–69
Online oral presentations and expert slide presentations were also examined. Two investigators independently reviewed all titles, or titles and abstracts from the search results to identify articles meeting the inclusion criteria. Disagreement was resolved by team discussion and consensus. If any of the eligibility criteria were not met, the article was excluded. Data extraction was carried out independently and in duplicate by the study investigators. Results of data extraction were then compared, and any discrepancies were resolved by discussion. If results were incomplete or unclear, the study authors were contacted. Articles finally selected for the review were checked to avoid inclusion of data published in duplicate. Relevant data were collected on baseline characteristics, presence of ischaemic heart disease (IHD), New York Heart Association (NYHA) functional classification, background heart failure therapy, study interventions, clinical observations, and clinical outcomes at baseline and end follow-up. We considered only the endpoints of all-cause mortality and cardiovascular mortality for statistical analysis, but provide a narrative report for other measures. Cardiovascular mortality was defined as sudden death, death due to heart failure, or other cardiovascular deaths. Of 1254 articles identified by the initial search, 74 were retrieved for more detailed evaluation. 26 studies were excluded because they primarily addressed dosing and tolerance issues, rather than focusing on clinical outcomes, and 15 studies were also excluded because they assessed the effects of the drugs in acute heart failure [Supplementary appendix]. Finally, 33 randomised studies were included in the review [Supplemental Fig. 1]. Statistical analysis was carried out using the Review Manager software (RevMan version 5.3). Aggregate data were used. Mortality outcomes are presented as odds ratios with 95% confidence intervals (CI). P values are also shown, and were considered statistically significant if less than 0.05. Heterogeneity was assessed using chi-squared tests as well as I-squared tests. Forest plots are used to represent the metaanalysis graphically. We show pooled odds ratios and the degree of heterogeneity between studies. We used a Mantel–Haenszel fixed effects model as substantial heterogeneity was less than 40%. The quality of the studies analysed was evaluated using the risk-of-bias tool of the Review Manager software, based on the authors' judgements about each methodological quality item, including selection bias, performance bias, detection bias, attrition bias, reporting bias and other sources of bias [Supplementary appendix]. The result was expressed as a low, high or unclear risk of each type of bias. Publication bias was minimized by comprehensive literature searching. In addition, a graphical display (funnel plot) of the size of the treatment effect against the precision of the trial (1/standard error) was used to investigate publication bias. However, the funnel plot approach was not used where the number of included studies was small.
65
3. Results 3.1. 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. Isosorbide dinitrate (ISDN) was the most commonly studied nitrate formulation. 3.1.1. H&N combination versus placebo Compared to placebo, the combination of hydralazine and isosorbide dinitrate (H+ISDN) improved NYHA functional class by at least one functional class [9,11]. The V-HeFT I study [4], which was the first large randomised study to evaluate the role of vasodilator drugs in heart failure, suggested that the addition of H+ISDN combination to a background regimen of diuretics and digitalis in patients with CHF has a favourable effect on left ventricular ejection fraction and mortality at two years, as compared to placebo. Subsequent sub-group analysis suggested that the benefit was most marked in patients with AAOS [12]. There was a trend for fewer hospitalisations with the use of the combination. The A-HeFT study [6] enrolled patients of AAOS who were randomised to receive H+ISDN or placebo on a background of standard heart failure medications (90% received diuretics, 60% digitalis, 70% ACEI, 17% ARB, 74% BB and 39% MRA). It was terminated early owing to a significant survival benefit for the actively-treated group (H+ISDN) compared to the placebo group. Days to first hospitalisation for heart failure were significantly delayed by H+ISDN. In addition, a large proportion of patients reported substantial improvement in the quality of life, as measured by a specific heart failure questionnaire. H+ISDN was cost-effective because of the large reduction in hospitalisations [13]. The X-A-HeFT study [14], which was an extension of the original A-HeFT study, showed that the symptomatic benefits persist. Our meta-analysis suggested that H+ISDN reduced all-cause (OR 0.72; 95% confidence intervals [CI] 0.55–0.95; p = 0.02) [Fig. 1-A], and cardiovascular mortality (OR 0.75; 95% CI 0.57–0.99; p = 0.04) [Fig. 1-B] [15] compared to placebo. 3.1.2. H&N combination versus ACEI In the V-HeFT II study [5], patients were randomised to H+ISDN or enalapril. Although H+ISDN exerted greater benefit on symptoms of heart failure, the time to first hospitalisation for heart failure was similar between H+ISDN combination and enalapril, and patients assigned to
Fig. 3. All-cause mortality with nitrates vs. placebo.
54% 68% D, L, ISDN 8 months 14% 52 104 147 mg PO 164 mg PO
Hy-C [42], parallel
BB beta adrenoceptor antagonists, D: digitalis, IHD: ischaemic heart disease, ISDN: isosorbide dinitrate, LVSD: left ventricular systolic dysfunction, L: loop diuretic, MRA: mineralocorticoid receptor antagonist, NYHA: New York Heart Association, NR: not reported, PAWP: pulmonary artery wedge pressure, SR: sinus rhythm. Drug doses are presented by average or mean ± SD. ⁎ Survival was improved with captopril as a result of lower rate of sudden death (p b 0.01).
100%
100% NR
NR
No difference
NR
Favoured captopril ⁎
No difference Favoured captopril NR Favoured captopril 100% Favoured captopril 100% 86% 80% D, L, MRA, nitrates 12 weeks 10% 56 50
mg PO Captopril 206 ±
Schofield [41], parallel
58 mg PO Hydralazine 410 ±
NR Favoured hydralazine NR 100% NR 100% 78% NR None b1 week 0% 58
Elkayam [39], cross-over
mg IV mg PO Hydralazine 12.5 mg Nisoldipine 4 IV mcg/kg IV Hydralazine 166 ± Captopril 53 ± 24
18
9
3.6 mg PO Nifedipine 34 ± 20 0.9 mg IV Hydralazine 14 ± 8
Elkayam [38], cross-over
Haitas [40], cross-over
mg PO Nifedipine 26.4 ±
Elkayam [37], cross-over
None
None Favoured hydralazine 100% 28% NR D b1 week 28%
Nifedipine 34 ± 22
mg IV Hydralazine 11.1 ±
54
62 Placebo
11 mg PO Hydralazine 10 ± 5
15
20
Unverferth [9], parallel Conradson [36], parallel
Placebo
9
50
54
20%
11%
b1 week
b1 week
D
D, L
NR
NR
40%
22%
100%
100%
100% NR
100% NR
NR
NR
Favoured hydralazine
NR
NR
NR Favoured hydralazine NR 100% NR
NR Favoured Hydralazine Favoured Hydralazine NR 100% 73% NR D, L, BB, MRA 1 year 29% 64
NR 100% No difference 94% 0% NR D, L 12 weeks 25% 57
None
None
No difference
No difference No difference
Favoured hydralazine NR
No difference NR No difference 100% No difference 100% 33% NR D, L 26 weeks 33% Hydralazine 188 ±
Franciosa [35], parallel
Control Treatment
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 rare instances where these agents are contra-indicated (angioneurotic oedema), or not tolerated due to renal dysfunction. There is also evidence that H+ISDN improves outcome when added to contemporary neuroendocrine therapy in AAOS patients; this effect needs to be explored in other racial groups. In CHF, activation of the renin–angiotensin–aldosterone and adrenergic systems causes an increase in vascular tone and salt and water retention resulting in an increase in cardiac afterload and preload, further compromising the failing heart. Treatments that interfere with these systems improve the prognosis of patients with heart failure. For ACEIs and angiotensin receptor blockers (ARBs), it remains unclear how much of their benefit is mediated by improvements in vascular tone and haemodynamics or by other mechanisms; the rather similar benefits of ACEI and H+ISDN in head-to-head comparisons suggests that vasodilatation might be a common mechanism of benefit. However, the additive benefit observed in A-HeFT suggests that mechanisms of benefit might differ, although it is possible that H+ISDN simply delivers more vasodilatation. ACEI and ARB can cause a fall in glomerular filtration rate by reducing arterial perfusion pressure and relaxation of
Table 4 Trials evaluating the use of hydralazine alone in chronic heart failure.
4. Discussion
Patients Age (n) (yrs)
Women Follow-up Background (%) therapy
SR (%)
IHD (%)
NYHA III/IV (%)
A summary of randomised trials evaluating the use of hydralazine (H) alone in CHF is shown in Table 4. We identified nine studies including 319 patients. Three studies compared H to placebo, two compared H to captopril, and four studies compared H to calcium channel blockers. Most patients were men and had severe CHF due predominantly to LVSD. The aetiology of heart failure was IHD in about 56% of patients. The studies that compared H to calcium channel blockers suggested that H exerted greater improvement in left ventricular ejection fraction [37–40]. However, the short duration and the small sample size of the studies make the results difficult to generalize. For the studies that reported mortality, the meta-analysis showed that H alone had no effect on all-cause mortality (OR 0.96; 95% CI 0.37–2.47; p = 0.93) compared to placebo [Fig. 4-A], but higher with H (OR 2.28; 95% CI 1.03–5.04; p = 0.04) compared to captopril [Fig. 4-B].
58
3.3. Hydralazine alone
32
LVSD Symptoms (%)
Exercise tolerance
PAWP
A summary of randomised trials evaluating nitrates (Ns) alone in CHF is shown in Table 3. There were 19 studies with 589 patients. Ten studies including 375 patients compared N to placebo, and nine compared N to alternative interventions. Most patients were men and had moderate to severe CHF due predominantly to LVSD. The aetiology of heart failure was IHD in about 77% of patients. For the studies which reported mortality and compared N to placebo, the meta-analysis showed that N alone had no effect on all-cause mortality. However, there were few events in these studies and the trend was towards harm (13 deaths in those assigned to N and 7 to placebo; OR 2.12; 95% CI 0.88–5.12; p = 0.09) [Fig. 3]. In the studies of N compared with alternative interventions, eight did not report mortality and the final study showed no difference between N and nifedipine.
Placebo
Ventricular function
3.2. Nitrates alone
47 mg PO Hydralazine 225 mg PO Hydralazine 149 ±
Mortality
enalapril had a lower mortality [16]. In the meta-analysis, compared to ACEI, the combination of H+ISDN was associated with a higher allcause (OR 1.35; 95% CI 1.03–1.76; p = 0.03) [Fig. 2-A], and cardiovascular mortality (OR 1.37; 95% CI 1.04–1.81; p = 0.03) [Fig. 2-B].
No difference
M. Farag et al. / International Journal of Cardiology 196 (2015) 61–69
Study/design
66
M. Farag et al. / International Journal of Cardiology 196 (2015) 61–69
efferent glomerular arterioles, whereas H&N combination only cause a fall in arterial perfusion pressure, the effect of which may be attenuated by a fall in renal venous pressure, which maintains the net renal perfusion pressure [43]. However, this theoretical advantage over ACEI is supported only by clinical opinion and anecdote rather than solid experimental evidence. A combination of a more robust evidence-base, fewer side effects, less frequent dosing, guideline recommendations and stronger marketing, rather than greater efficacy, may account for the dominant use of ACEIs in current clinical practice. H or N, alone or in combination, are unlikely to displace ACEIs, but might provide additional benefit as suggested in the A-HeFT trial; this possibility should be explored in other racial groups. The advent of angiotensin receptor neprilysin inhibitors (ARNIs) may change the therapeutic approach to the management of heart failure [44]. It is not clear whether addition of H&N combination to an ACEI would prove equally effective, or whether addition of H&N combination to an ARNI would be effective. Hydralazine and nitrates may work synergistically in patients with CHF [45]. Nitrates exert their effects by being converted to nitric oxide (NO). NO is a potent endogenous vasodilator and a major biological regulator of cardiovascular function, and its metabolism is impaired in patients with heart failure. Nitrate therapy thus appears intuitively likely to be beneficial [46,47]. Hydralazine is a potent vasodilator that has some antioxidant effects that help prevent NO degradation [48]. Although the precise cardiovascular properties of hydralazine are not fully understood, it reduces peripheral vascular resistance directly by relaxing vascular smooth muscle cells [49]. Hydralazine is also thought to inhibit activation of a membrane-associated oxidase responsible for the increased superoxide production that causes nitrate tolerance [50]. AAOS have a lesser response in terms of NO-mediated cardiovascular effects than whites [51,52], and so it is possible that the NO-mediated effects of the H&N combination could be responsible for a differential benefit in AAOS. The reduction in heart failure hospitalisations and the improvement in NYHA functional classification with H&N combination may in part relate to reductions in left ventricular filling pressures, consistent with the lowering of pulmonary artery pressure seen with the same agents in the CHAMPION trial [53]. As nitrates reduce preload and hydralazine reduces afterload, the combination might provide optimal haemodynamic benefit to CHF patients. We only found a survival benefit when both agents were used in combination. However, when either agent is used alone, there was a divergence between haemodynamic and survival benefits.
67
H&N combination do seem to confer a survival benefit, particularly in AAOS men with advanced LVSD, but there is little evidence to support the use of either drug alone. 4.1. Study limitations The study has several limitations. Firstly, as is the case for any metaanalysis, data were combined from different studies, each of which had its own protocol, follow-up period, and definitions. Secondly, some trials of H and/or N studied patients irrespective of the type, aetiology or severity of heart failure, and therefore, a favourable drug effect in certain subgroups of patients might have been missed (for example, those with more severe congestion, higher blood pressure or with normal ejection fraction). Thirdly, studies assessing H or N as single agents were small and had very few events, which weakens the conclusions about the ineffectiveness of single agents in CHF. Fourthly, the quality of some studies was poor, with poor methods and soft clinical outcome measures, making the assessment of hard clinical endpoints such as hospitalisation rate, improvement in NHYA functional classification, and the haemodynamic effects (for example, blood pressure and pulmonary artery pressure measurements) difficult. Furthermore, the study participants were predominantly men. Importantly, the V-HeFT trials included only men [4,5]. In A-HeFT, nearly 40% of the study were women, but with no significant treatment interaction by gender was found [6,54]. Additionally, one of the largest trials was conducted only in patients of AAOS, so it is not known whether the results can be extrapolated to other racial groups, especially Caucasian women. Lastly, most of the eligible studies were conducted in developed Western countries. Consequently, the findings may not be generalisable to other healthcare settings. 5. 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 commonly prescribed in clinical practice. Large randomised trials are needed to evaluate the safety and efficacy of adding H and N, alone or in combination, to contemporary medical therapy.
Fig. 4. All-cause mortality with hydralazine. (A) vs. placebo, and (B) vs. ACEI.
68
M. Farag et al. / International Journal of Cardiology 196 (2015) 61–69
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