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Abstract

Intravenous nitrates are widely used in the management of acute heart failure syndrome (AHFS) yet with lack of robust evidence to support their use. We therefore sought to analyze all randomized studies that evaluated the effects of nitrates on clinical outcomes in patients with AHFS. In total, 15 relevant trials comparing nitrates and alternative interventions in 1824 patients were identified. All but 3 were conducted before 1998. No trials demonstrated a beneficial effect on mortality, apart from 1 trial reporting a reduction in mortality, which was related to the time of treatment. Retrospective review suggests that there is a lack of data to draw any firm conclusions concerning the use of nitrates in patients with AHFS. More studies are needed to evaluate the safety and efficacy of these agents in the modern era of guideline-directed use of heart failure therapy.

Keywords

acute heart failure syndrome nitrates vasodilator therapy morbidity mortality

Introduction

Heart failure continues to represent a major and growing burden on public health worldwide both in terms of its prevalence and poor prognosis. This is, at least in part, because the contemporary medications that are received by patients with heart failure are often insufficient to fully prevent hospitalizations.¹ Also, there has been little research into the management of acute heart failure syndrome (AHFS), with many treatment strategies being based on clinical experience rather than on evidence from high-quality studies. Nitrates are widely used in patients with heart failure, yet evidence supporting their use is apparently scarce.

Historical drug treatments for heart failure syndromes included only diuretics and digitalis, mainly for the relief of symptoms of congestion rather than for a mortality benefit or morbidity reduction.² This prompted further search for other agents as potential treatments, especially in patients with advanced heart failure. In the early 1970s, initial vasodilator studies in heart failure showed some added hemodynamic benefits with the use of nitrates, mainly through reduction in preload.^3,4 Observational studies suggested that the addition of the nitric oxide (NO) donor isosorbide dinitrate (ISDN) in acute decompensated heart failure (ADHF) was associated with lower all-cause mortality and favorable long-term clinical outcomes but without reduction in rehospitalization rate.^5,6 Interest in nitrate therapy has increased further as a result of the widespread use of intravenous nitrates in the emergency management of AHFS.

Standard guideline-directed therapy for heart failure has changed dramatically over the last 25 years.⁷ The beneficial effects of nitrates may or may not have been masked by newer heart failure treatments. Moreover, it is unclear whether nitrates can significantly improve symptoms of heart failure, although it is widely believed that they do. It is also uncertain whether the effect of these agents confers a different effect on different heart failure phenotypes (for example, heart failure with preserved systolic function, heart failure with reduced systolic function, ischemic heart disease [IHD], valve disease, etc). Previous reviews that studied nitrates in acute heart failure have been small and included only a few studies.^8,9 Perhaps this is due, in part, to the fact that most prior studies are considered dated, with inaccurate methodology, which might have shaped final results. Recently, a study of home monitoring using a pulmonary artery pressure monitoring device demonstrated a substantial reduction in rehospitalization rate, but not mortality, in patients with symptomatic heart failure.¹⁰ Apart from diuretics, nitrates were the main agents used to reduce pulmonary pressure, which appeared to be the main mechanism by which the benefit was achieved. In order to examine the evidence for the use of nitrates in heart failure, we sought to analyze studies that evaluated the effects of nitrates on clinical outcomes.

Methods

The study was designed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement.¹¹ Inclusion criteria were as follows: randomized controlled trials assessing nitrates versus placebo, or no therapy, or an active comparator, whether parallel or multiple arms (ie, other arms with different class, route, and dosage), were included. Participants were patients who received nitrates for the management of ADHF. Observational studies, registries, and studies conducted in chronic heart failure were excluded.

The PubMed/MEDLINE, Embase, Scopus, and Cochrane Central Register of Controlled Trials databases were searched up to August 2015. All studies assessing the effects of nitrates in acute heart failure and reporting the effect on clinical end points were included, with no language restrictions. Eligible studies were identified with the following headings: nitrates, nitroglycerine, nicorandil, isosorbide mononitrate (ISMN), isosorbide dinitrate, glyceryltrinitrate, sodium nitroprusside, heart failure, cardiac failure, ventricular failure, randomly, random, and randomised controlled trial. Reference lists of the retrieved articles were searched to identify other eligible studies. Furthermore, online oral presentations and expert slide presentations were examined.

The study investigators independently reviewed all titles or titles and abstracts from the search results to identify articles according to the fulfillment of the inclusion criteria. Selected trials were compared, and discrepancies were resolved by team discussion. 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 team 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 patient characteristics, heart failure phenotype, presence of IHD, New York Heart Association functional classification, background heart failure therapy, study interventions, and clinical outcomes at baseline and end of follow-up.

Of 4415 articles identified by the initial search, 75 were retrieved for more detailed evaluation (Figure 1). Thirty-three studies were excluded from the review because they assessed the effects in chronic heart failure (Supplementary Appendix^{1

–33}). Twenty-seven studies primarily addressed tolerance issues (eg, clinical pharmacological trials; Supplementary Appendix^34–60), and 15 studies assessed the effects on clinical outcomes in AHFS (Table 1).

Figure 1.

Flow chart of review.

Table 1.

Randomized Trials That Evaluated the Use of Nitrates in AHFS.

Study	Design	Treatment	Control	Patients (n)	Age (Mean)	Men, %	Follow-Up	Background Therapy	SR, %	LVSD, %	IHD, %	NYHA III/IV, %	Symptoms	PAWP Reduction	Cardiac Index Improvement	Mortality Benefit
Cohn, 1982¹⁵	Parallel	Sodium nitroprusside (94.4 μg/min) IV	Placebo	812	59	100	13 weeks	D, L	NR	100%	100%	100%	NR	NR	NR	Related to time of treatment^a
Nelson, 1983¹⁶	Parallel	ISDN 30.5 mg IV	Hydralazine 11.7 mg IV	20	56	100	3 hours	L (used after randomization)	100	100%	100%	100%	Favored ISDN	No difference	Favored hydralazine	None
Nelson, 1983¹⁷	Parallel	ISDN 13.2 mg IV	Furosemide 80 mg IV	28	56	100	90 minutes	None	100	100%	100%	100%	Favored ISDN	No difference	Favored ISDN	None
Nelson, 1983¹⁸	Parallel	ISDN (50-200 μg/kg/h) IV	Hydralazine (0.15 mg/kg) IV	20	58	100	90 minutes	L (used before randomization)	100	100%	100%	100%	Favored ISDN	No difference	Favored hydralazine	None
Dubourg, 1984¹⁹	Parallel	ISDN 40 mg PO	Placebo	20	60	85	8 hours	None	100	100%	100%	100%	NR	Favored ISDN	No difference	None
Nelson, 1984²⁰	Parallel	ISDN 14.3 mg IV	Hydralazine 12.3 mg IV	20	51	100	4.30 hours	Furosemide 82 mg IV and B1 agonist, positive inotropic (prenalterol) 12 mg IV (used at randomization)	100	100	100	100	No difference	No difference	No difference	No difference
Nelson, 1984²¹	Parallel	ISDN 24.1 mg IV	Hydralazine 11.9 mg IV	12	59	100	90 minutes	None	100	100	100	100	Favored ISDN	Favored ISDN	Favored hydralazine	None
Verma, 1987²²	Parallel	ISDN 11.8 mg IV	Hydralazine 12.8 mg IV, furosemide 84 mg IV, prenalterol 10.8 mg IV	48	58	100	90 minutes	None	NR	100	100	100	Favored ISDN	No difference	Favored hydralazine and prenalterol	No difference
Kieler-Jensen, 1995²³	Cross- over	Sodium nitroprusside (0.8 ± 0.2 μg/kg/min) IV	Prostacyclin (13.5 ± 4.7 ng/kg/min) IV	10	64	70	<1 week	None	NR	100	100	100	NR	Favored sodium nitroprusside	Favored prostacyclin	NR
Cotter, 1998²⁴	Parallel	ISDN^b (3 mg bolus) IV every 5 minutes, plus furosemide 40 mg IV	Furosemide (80 mg bolus) IV every 15 minutes plus ISDN 1 mg/h increased to 10 mg/h every 10 minutes	104	74	52	24 hours	L, oral nitrates	100	NR	64	100	Favored high-dose ISDN	NR	NR	No difference
Beltrame, 1998²⁵	Parallel	Nitroglycerine (2.5 μg/min) plus N-acetylcysteine IV	Furosemide 80 mg IV plus morphine 3 mg IV	69	77	45	24 hours	D, L, ACEI, oral nitrates	NR	NR	38	100	No difference	NR	NR	No difference
VMAC, 2002²⁶	Parallel	Nitroglycerine (titrated up to 56 ± 64 μg/min) IV	Nesiritide^c (2 μg/kg bolus then 0.01 μg/kg/min for 3 hours) IV, placebo	489	62	69	48 hours	BB, D, L, ACEI, oral nitrates	65	85	49	100	Favored nitroglycerine and nesiritide	Favored nesiritide	No difference	No difference
Shirakabe, 2010²⁷	Parallel	Nicorandil^d 100 μg/kg bolus, then continuous infusion for 5 days (60-100 μg/kg) IV	No therapy	31	70	71	1 week	BB, D, L, MRA, ACEI	NR	100	45	100	No difference	NR	No difference	NR
Shigekiyo, 2011²⁸ ^, ^e	Parallel	Nicorandil (0.2 mg/kg bolus, followed by 0.2 mg/kg/h) IV plus low-dose carperitide^f	Low-dose carperitide	118	75	31	24 hours	BB, L, ACEI	81	40	11	95	Favored nicorandil	NR	NR	NR

Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; AHFS, acute heart failure syndrome; ANP, atrial natriuretic peptide; BB, β-blocker; BNP, brain natriuretic peptide; D, digitalis; IHD, ischemic heart disease; ISDN, isosorbide dinitrate; IV, intravenous; L, loop diuretic; LVSD, left ventricular systolic dysfunction; MRA, mineralocorticoid receptor antagonist; NR, not reported; NT-pro-B, N-terminal pro–B-type natriuretic peptide; NYHA, New York Heart Association functional classification; PAWP, pulmonary artery wedge pressure; PO, orally; SR, sinus rhythm.

Drug doses are presented by average or mean ± SD.

^aThe drug had deleterious effect in patients whose infusions were started within 9 hours of onset of pain and had beneficial effect in those whom infusions were started later.

^bHigh-dose isosorbide dinitrate, given as repeated intravenous boluses after low-dose intravenous furosemide, significantly reduced the need for mechanical ventilation and frequency of myocardial infarction.

^cNesiritide is a recombinant form of BNP.

^dNicorandil significantly reduced cardiac stress markers (BNP, NT-pro-B) compared to no therapy.

^eCarperitide is a recombinant form of ANP.

^fStudy presented but not published.

Results

Mechanism of Action

Many nitrates (eg, nitroglycerine, ISMN, and ISDN) exert their effects in the human body by being converted to NO. Nitric oxide is recognized as the most important cellular signaling molecule involved in many physiological and pathological cardiovascular processes.¹² There has been a growing body of evidence to suggest that NO production, as a potent natural vasodilator and a major biological regulator of cardiovascular function, is impaired in patients with heart failure, thus indicating a potential significant beneficial effect of NO enhancing therapy with nitrates.^13,14

Evidence for Use in AHFS

Fifteen randomized studies including a total of 1824 patients with AHFS and reporting clinical outcomes were identified. Two small studies including 35 patients with a mean age of 51 ± 8 years studied the combination therapy of nitrates and hydralazine. Of these, one study compared the combination to either drug as monotherapy, and the other study compared the combination to captopril and prazosin. For nitrates alone, 14 studies were identified, of which 13 studies included 1714 patients comparing nitrates to alternative interventions, and one study compared a high-dose nitrate to a low-dose nitrate (Table 1). The mean age of the participants was 62 ± 8 years, and 17% were women. The majority of studies assessed the effects in men with ADHF due predominantly to left ventricular systolic dysfunction. The etiology of heart failure was IHD in about 76% of patients among all studies (Table 1).

In a study by Nelson et al,²¹ when ISDN and hydralazine combination (H-ISDN) was used, by intravenous administration (the average dose of H was 11.6 mg and of ISDN was 13.4 mg over 90 minutes) in 18 men in sinus rhythm with ADHF secondary to IHD, it resulted in a composite hemodynamic profile, which was superior to either drug used alone. There was a significant reduction in left ventricular filling pressures, systolic and diastolic blood pressures, and systemic vascular resistance, accompanied by a significant increase in stroke volume, cardiac output, and heart rate, compared to either drug used alone. Given that combination therapy resulted in powerful preload and afterload reduction, it was concluded that combination therapy may be of greater benefit as long as the fall in mean arterial pressure does not compromise peripheral perfusion, as it appears that the large fall in mean arterial blood pressure was not fully compensated by the reflex increase in heart rate and cardiac output. In another study by Adigun et al,²⁹ 17 Nigerian patients with hypertensive ADHF (35% were women and all patients were in sinus rhythm) were given H-ISDN combination therapy (intravenous H 30 mg and oral ISDN 30 mg), as compared to captopril 50 mg and prazosin 1 mg given orally in a single-blind parallel group fashion on a background therapy of standard treatments of acute pulmonary edema including a furosemide diuretic. The neurohormonal inhibitors captopril and prazosin exerted the same hemodynamic effects of combination therapy (ie, reduced left ventricular filling pressures, systolic and diastolic blood pressures, and systemic vascular resistance) over 24 hours, yet without causing tachycardia, suggesting that there may be a favorable hemodynamic profile associated with these agents in ADHF.

In comparison with furosemide, ISDN showed no effect on pulmonary artery pressures, suggesting no real major hemodynamic differences between the 2 agents when given over 90 minutes, mainly in men with ADHF secondary to IHD.^17,22 In a landmark study, Cotter et al reported that high-dose ISDN given as repeated intravenous boluses after low-dose intravenous furosemide was beneficial in controlling severe pulmonary edema in 104 patients with a mean age of 74 ± 9 years (48% were women), compared to low-dose ISDN given after high-dose intravenous furosemide.²⁴ The high-dose ISDN significantly decreased the need for mechanical ventilation and the frequency of myocardial infarction. In that study, all patients were in sinus rhythm, and the etiology of heart failure was IHD in 64% of the patients. The mean dose of ISDN administered during treatment was 11.4 ± 6.8 mg in the high-dose group and 1.4 ± 0.6 mg in the low-dose group. The mean furosemide doses were 56 ± 28 mg and 200 ± 65 mg, respectively. Although the study by Cotter et al has positively influenced clinical practice to date, it is debatable that the results are difficult to interpret because nitrates were used in both arms of the study.⁹

The Vasodilation in the Management of Acute Congestive Heart Failure study compared nitroglycerine infusion, nesiritide infusion, and placebo in 489 patients with ADHF.²⁶ Nitroglycerine and nesiritide significantly reduced symptoms of heart failure, but only nesiritide significantly reduced pulmonary artery pressures compared to placebo. In another study, Cohn et al reported that short-term (48 hours) sodium nitroprusside infusion may cause a decrease in mortality if only used more than 9 hours after establishment of left ventricular failure following acute myocardial infarction.¹⁵ Interestingly, this study from 1982 is considered the only randomized study to show any reduction in mortality with nitrate use in the setting of heart failure. In comparison with hydralazine, ISDN reduced filling pressures and improved symptoms of heart failure.^16,18,21,22 However, ISDN was inferior to hydralazine in optimizing cardiac output.^16,18,21,22

Nitrate Tolerance

Organic nitrates have been commonly prescribed to patients with heart failure mainly for the relief of concomitant angina symptoms, with excellent clinical results. However, their long-term use has been partly limited by tolerance in those patients. For some time, it has been known that the early development of nitrate tolerance with frequent administration of oral preparations or continuous administration of intravenous preparations or long-acting topical preparations leads to significant attenuation of the drug effects.³⁰ The mechanisms underlying this phenomenon are still poorly understood. Since the increasing awareness of this problem, extensive research has been conducted to understand the underlying mechanisms in order to prevent nitrate tolerance. Consequently, few approaches have been introduced into clinical practice, including the application of a nitrate-free interval or the administration of concomitant drugs that have been suggested to reduce or prevent nitrate tolerance. Only a few randomized studies assessed nitrate tolerance with respect to the hemodynamic and anti-ischemic effects in heart failure. Some of these studies reported conflicting results. There is some evidence to suggest that long-term oral administration of ISDN and ISMN is associated with sustained hemodynamic effects in patients with congestive heart failure.^31,32 N-acetylcysteine was suggested to be associated with the potentiation of the hemodynamic effects of ISDN in patients with stable heart failure.³³ The concomitant use of oral hydralazine with intravenous nitroglycerine was found to prevent the early development of nitrate tolerance.³⁰ However, with respect to glyceryltrinitrate therapy,^34,35 or sodium nitroprusside,³⁵ no benefit of adding hydralazine was observed. Wada et al suggested that angiotensin-converting enzyme inhibitor or angiotensin receptor blockers may prevent the development of nitrate tolerance.³⁶ Intravenous nicorandil remained hemodynamically effective during the first 24-hour infusion in patients with congestive heart failure,^37,38 partly due to its action as a potassium channel opener.³⁷ It was suggested that this could represent a clinical advantage of nicorandil in the short-term treatment of patients with ADHF. However, more studies are needed to support this hypothesis.³⁹

Discussion

The review including available randomized studies suggests that nitrates do not confer a mortality benefit in the management of ADHF. Current evidence suggests that nitrates may have some benefit, as an add-on therapy, to relieve symptoms of heart failure. The reduction in heart failure symptoms with nitrates may in part relate to reduction in left ventricular filling pressure, consistent with the lowering of pulmonary artery pressure seen with the same agents in the CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients) trial.¹⁰ The benefit was mostly observed in male patients predominantly in sinus rhythm and having ADHF secondary to IHD (Table 1). This is not surprising given the fact that in a recent UK survey, IHD was responsible for almost 50% of all cases hospitalized with a diagnosis of heart failure.¹ There is insufficient data concerning the use of nitrates in female patients, patients with AHFS who have atrial fibrillation, patients with preserved left ventricular systolic function, or patients with nonischemic etiology of heart failure.

Patients with AHFS are generally classified into 2 major categories: those who present with heart failure for the first time and those who have an acute exacerbation of chronic heart failure. In fact, all physicians are trained to be familiar with the initial management of acute heart failure, which includes oxygen, morphine, diuretics, and nitrates, as described in standard textbooks⁴⁰ and guidelines.⁴¹ Nitrates are probably most useful in patients with hypertension. It is surprising that, to date, there are only a few randomized studies to validate the optimal management of AHFS. Indeed, it may well be that developing AHFS management has been neglected, with no new agents approved for use, for almost a quarter century.

The hemodynamic hallmark of AHFS includes an elevated left ventricular filling pressure, raised vascular resistance, and a normal or diminished cardiac output. The main goal of initial management used to be hemodynamic stabilization and symptom improvement. Contemporary management continues to focus on improving hemodynamics and relief of symptoms by relieving congestion, which may be considered an appropriate strategy to a certain extent.⁴² Conventional treatment with acute diuretic therapy (ie, intravenous furosemide, the most commonly used loop diuretic in clinical practice) may have the disadvantage of causing a large fall in cardiac output leading temporarily to acute pump dysfunction in occasional patients with left ventricular failure.^43,44 This has led to the search for newer agents with effects not only to improve hemodynamics and symptoms but also to improve clinical outcomes, with reduction in mortality and hospitalization. Vasodilator therapy with nitrates, particularly with ISDN, nitroglycerine, and nesiritide, has provided some promising results in clinical practice, as suggested by large observational studies.^45,46 A post hoc analysis of the ALARM-HF registry suggested better benefits of patients with AHFS receiving a vasodilator in combination with a diuretic than a diuretic alone.⁴⁷ Propensity-based matching (n = 1007 matched pairs) confirmed the lower in-hospital mortality of patients with AHFS receiving diuretics plus vasodilators: 7.8% versus 11.0% (P = .016). However, loop diuretics have remained the mainstay of AHFS management. This is mainly because the decision to use vasodilators is sometimes complex. Vasodilators should probably be avoided in patients presenting with ADHF associated with hypotension or severe mitral or aortic stenosis for fear of increased mortality.⁴¹

Available studies have been limited by the small number of patients and the different dosing regimens and clinical outcomes. None of the included studies have reported any cost-effectiveness analysis. Further high-quality studies are needed to improve our understanding in the growing acute heart failure patient population. There is little evidence to support the use of nitrates in AHFS, other than for possible hemodynamic benefit, and certainly no hard data to support a reduction in mortality or morbidity with these agents. Further large, randomized trials are needed to evaluate the safety and efficacy of these agents in the modern era of guideline-directed heart failure therapy.

Footnotes

Author Contributions

Mohamed Farag is the first author, conceived idea, collected data and wrote the draft. Ahmad Shoaib is the co-first author, collected data, wrote draft and critically review the paper. Diana A. Gorog contributed to the critically review writing.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Supplemental Material

The online supplemental appendices are available at .

References

Cleland

McDonagh

Rigby

. The national heart failure audit for England and Wales 2008-2009. Heart. 2011;97(11):876–886.

Taylor

Storstein

. Diuretics and digitalis in the treatment of chronic heart failure. Eur Heart J. 1983;4(suppl A):153–59.

Guiha

Cohn

Mikulic

Franciosa

Limas

. Treatment of refractory heart failure with infusion of nitroprusside. N Engl J Med. 1974;291(12):587–592.

Massie

Chatterjee

Werner

Greenberg

Hart

Parmley

. Hemodynamic advantage of combined administration of hydralazine orally and nitrates nonparenterally in the vasodilator therapy of chronic heart failure. Am J Cardiol. 1977;40(5):794–801.

Mullens

Abrahams

Francis

. Sodium nitroprusside for advanced low-output heart failure. J Am Coll Cardiol. 2008;52(3):200–207.

Mullens

Abrahams

Francis

. Usefulness of Isosorbide Dinitrate and Hydralazine as add-on therapy in patients discharged for advanced decompensated heart failure. Am J Cardiol. 2009;103(8):1113–1119.

Jhund

Macintyre

Simpson

. 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. 2009;119(4):515–523.

Donlan

Quattromani

Pang

Gheorghiade

. Therapy for acute heart failure syndromes. Curr Cardiol Rep. 2009;11(3):192–201.

Wakai

McCabe

Kidney

. Nitrates for acute heart failure syndromes. Cochrane Database Syst Rev. 2013;8:CD005151.

10.

Abraham

Adamson

Bourge

. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet. 2011;377(9766):658–666.

11.

Moher

Liberati

Tetzlaff

Altman

; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement. Open Med. 2009;3(3):e123–e130.

12.

Hou

Janczuk

Wang

. Current trends in the development of nitric oxide donors. Curr Pharm Des. 1999;5(6):417–441.

13.

Macdonald

Schyvens

Winlaw

. The role of nitric oxide in heart failure. Potential for pharmacological intervention. Drugs Aging. 1996;8(6):452–428.

14.

Dixon

Morgan

Hughes

. Functional consequences of endothelial nitric oxide synthase uncoupling in congestive cardiac failure. Circulation. 2003;107(13):1725–1728.

15.

Cohn

Franciosa

Francis

. Effect of short-term infusion of sodium nitroprusside on mortality rate in acute myocardial infarction complicated by left ventricular failure: results of a Veterans Administration cooperative study. N Engl J Med. 1982;306(19):1129–1135.

16.

Nelson

Silke

Forsyth

Verma

Hussain

Taylor

. Hemodynamic comparison of primary venous or arteriolar dilatation and the subsequent effect of furosemide in left ventricular failure after acute myocardial infarction. Am J Cardiol. 1983;52(8):1036–1040.

17.

Nelson

Silke

Ahuja

Hussain

Taylor

. Management of acute heart failure following myocardial infarction: hemodynamic advantages of isosorbide dinitrate over frusemide. Z Kardiol. 1983;72 Suppl 3:141–146.

18.

Nelson

Ahuja

Silke

Hussain

Taylor

. Arteriolar or venous dilatation in left ventricular failure following acute myocardial infarction: a haemodynamic trial of hydralazine and isosorbide dinitrate. J Cardiovasc Pharmacol. 1983;5(4):574–579.

19.

Dubourg

Gueret

Ferrier

. Controlled, eight-hour haemodynamic study of a sustained-release formulation of isosorbide dinitrate in moderate left ventricular failure. Eur J Clin Pharmacol. 1984;27(3):259–263.

20.

Nelson

Silke

Ahuja

. Hemodynamic trial of sequential treatment with diuretic, vasodilator, and positive inotropic drugs in left ventricular failure following acute myocardial infarction. Am Heart J. 1984;107(6):1202–1209.

21.

Nelson

Verma

Hussain

. A randomised study of the haemodynamic changes induced by venodilatation and arteriolar dilatation singly and together in left ventricular failure complicating acute myocardial infarction. J Cardiovasc Pharmacol. 1984;6(2):331–338.

22.

Verma

Silke

Hussain

. First-line treatment of left ventricular failure complicating acute myocardial infarction: a randomised evaluation of immediate effects of diuretic, venodilator, arteriodilator, and positive inotropic drugs on left ventricular function. J Cardiovasc Pharmacol. 1987;10(1):38–46.

23.

Kieler-Jensen

Houltz

Ricksten

. A comparison of prostacyclin and sodium nitroprusside for the treatment of heart failure after cardiac surgery. J Cardiothorac Vasc Anesth. 1995;9(6):641–646.

24.

Cotter

Metzkor

Kaluski

. Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. Lancet. 1998;351(9100):389–393.

25.

Beltrame

Zeitz

Unger

. Nitrate therapy is an alternative to furosemide/morphine therapy in the management of acute cardiogenic pulmonary edema. J Card Fail. 1998;4(4):271–279.

26.

Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF). Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA. 2002;287(12):1531–1540.

27.

Shirakabe

Hata

Yokoyama

. Efficacy and safety of nicorandil therapy in patients with acute heart failure. J Cardiol. 2010;56(3):339–347.

28.

Shigekiyo

Harada

Okada

. Intravenous nicorandil improves symptoms and left ventricular diastolic function immediately in patients with acute heart failure: a randomized, controlled trial. European Heart Journal. 2011;32:963.

29.

Adigun

Ajayi

Sofowora

Ajayi

. Vasodilator therapy of hypertensive acute left ventricular failure: comparison of captopril-prazosin with hydralazine-isosorbide dinitrate. Int J Cardiol. 1998;67(1):81–86.

30.

Gogia

Mehra

Parikh

. Prevention of tolerance to hemodynamic effects of nitrates with concomitant use of hydralazine in patients with chronic heart failure. J Am Coll Cardiol. 1995;26(7):1575–1580.

31.

Franciosa

Cohn

. Sustained hemodynamic effects without tolerance during long-term isosorbide dinitrate treatment of chronic left ventricular failure. Am J Cardiol. 1980;45(3):648–654.

32.

Rabinowitz

Hod

Chouraqui

Rath

Agranat

Neufeld

. Hemodynamic effects of oral isosorbide-5-mononitrate and dinitrate in ischemic heart failure. Clin Cardiol. 1987;10(10):603–608.

33.

Mehra

Shotan

Ostrzega

Hsueh

Vasquez-Johnson

Elkayam

. Potentiation of isosorbide dinitrate effects with N-acetylcysteine in patients with chronic heart failure. Circulation. 1994;89(6):2595–2600.

34.

Parker

Farrell

Parker

. The effect of hydralazine on the development of tolerance to continuous nitroglycerin. J Pharmacol Exp Ther. 1997;280(2):866–875.

35.

Chirkov

De Sciscio

Sverdlov

Leslie

Sage

Horowitz

. Hydralazine does not ameliorate nitric oxide resistance in chronic heart failure. Cardiovasc Drugs Ther. 2010;24(2):131–137.

36.

Wada

Ueda

Masumori-Maemoto

Kuji

Sugimoto

Umemura

. Angiotensin II attenuates the vasodilating effect of a nitric oxide donor, glyceryl trinitrate: roles of superoxide and angiotensin II type 1 receptors. Clin Pharmacol Ther. 2002;71(6):440–447.

37.

Tsutamoto

Kinoshita

Nakae

. Absence of hemodynamic tolerance to nicorandil in patients with severe congestive heart failure. Am Heart J. 1994;127(4 Pt 1):866–873.

38.

Larsen

Gøransson

Aarsland

Tamby

Dickstein

. Comparison of the degree of hemodynamic tolerance during intravenous infusion of nitroglycerin versus nicorandil in patients with congestive heart failure. Am Heart J. 1997;134(3):435–441.

39.

Tanaka

Kato

Takano

. Acute effects of intravenous nicorandil on hemodynamics in patients hospitalized with acute decompensated heart failure. J Cardiol. 2010;56(3):291–299.

40.

Longmore

Wilkinson

Baldwin

Wallin

. Oxford Handbook of Clinical Medicine. Chapter 3. 8th ed. Oxford, United Kingdom: Oxford University Press; 2014.

41.

McMurray

Adamopoulos

Anker

. 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. 2012;33(14):1787–1847.

42.

Gheorghiade

Zannad

Sopko

. Acute heart failure syndromes: current state and framework for future research. Circulation. 2005;112(25):3958–3968.

43.

Kiely

Kelly

Taylor

Pitt

. The role of furosemide in the treatment of left ventricular dysfunction associated with acute myocardial infarction. Circulation. 1973;48(3):581–587.

44.

Francis

Siegel

Goldsmith

Olivari

Levine

Cohn

. Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure. Activation of the neurohumoral axis. Ann Intern Med. 1985;103(1):1–6.

45.

Yancy

Lopatin

Stevenson

De Marco

Fonarow

, Investigators ASACa. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) Database. J Am Coll Cardiol. 2006;47(1):76–84.

46.

Peacock

Fonarow

Emerman

. Impact of early initiation of intravenous therapy for acute decompensated heart failure on outcomes in ADHERE. Cardiology. 2007;107(1):44–51.

47.

Mebazaa

Parissis

Porcher

. Short-term survival by treatment among patients hospitalized with acute heart failure: the global ALARM-HF registry using propensity scoring methods. Intensive Care Med. 2011;37(2):290–301.

Nitrates for the Management of Acute Heart Failure Syndromes,A Systematic Review

Abstract

Keywords

Introduction

Methods

Results

Mechanism of Action

Evidence for Use in AHFS

Nitrate Tolerance

Discussion

Footnotes

Author Contributions

Declaration of Conflicting Interests

Funding

Supplemental Material

References