Nitrates For Acute Heart Failure Syndromes

Cochrane Database of Systematic Reviews
Nitrates for acute heart failure syndromes (Review)
Wakai A, McCabe A, Kidney R, Brooks SC, Seupaul RA, Diercks DB, Salter N, Fermann GJ, Pospisil C
Wakai A, McCabe A, Kidney R, Brooks SC, Seupaul RA, Diercks DB, Salter N, Fermann GJ, Pospisil C.
Nitrates for acute heart failure syndromes.
Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD005151.
DOI: 10.1002/14651858.CD005151.pub2.
www.cochranelibrary.com
Nitrates for acute heart failure syndromes (Review)

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Analysis 1.1. Comparison 1 Changes in systolic blood pressure, Outcome 1 Change in SBP after 90 mins (nitrates vs
frusemide). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Analysis 2.1. Comparison 2 Changes in diastolic blood pressure after 90 minutes, Outcome 1 Change in DBP (nitrates vs
frusemide). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Analysis 3.1. Comparison 3 Changes in heart rate, Outcome 1 Change in heart rate at 90 minutes (nitrates vs frusemide). 28
Analysis 4.1. Comparison 4 Changes in cardiac output, Outcome 1 Change in cardiac index at 90 minutes (nitrates vs
frusemide). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Analysis 5.1. Comparison 5 Changes in pulmonary artery occlusion pressure, Outcome 1 Change in pulmonary artery
occlusion pressure at 90 minutes (nitrates vs frusemide). . . . . . . . . . . . . . . . . . . . 30
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 37
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Nitrates for acute heart failure syndromes (Review) i

[Intervention Review]
Nitrates for acute heart failure syndromes
Abel Wakai1 , Aileen McCabe1 , Rachel Kidney2 , Steven C Brooks3 , Rawle A Seupaul4 , Deborah B Diercks5 , Nigel Salter6 , Gregory J
Fermann7 , Caroline Pospisil8
1
Emergency Care Research Unit (ECRU), Division of Population Health Sciences (PHS), Royal College of Surgeons in Ireland, Dublin
2, Ireland. 2 Department of Pharmacology and Therapeutics, Trinity Centre for Health Sciences, St. James Hospital, Dublin, Ireland.
3 Department of Emergency Medicine, Queen’s University, Kingston, Canada. 4 Emergency Medicine, UAMS, Little Rock, AR, USA.
5 Department of Emergency Medicine, University of California, Davis Medical Centre, Sacramento, USA. 6 Department of Emergency
Medicine, Limerick Regional Hospital, Limerick, Ireland. 7 Department of Emergency Medicine, University of Cincinnati, Cincinnati,
Ohio, USA. 8 Sunnybrook Health Sciences Centre, Division of Emergency Medicine, Toronto, Canada
Contact address: Abel Wakai, Emergency Care Research Unit (ECRU), Division of Population Health Sciences (PHS), Royal College
of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2, Ireland. awakai@rcsi.ie. abelwakai@gmail.com.
Editorial group: Cochrane Heart Group.

Publication status and date: New, published in Issue 8, 2013.
Review content assessed as up-to-date: 20 January 2012.
Citation: Wakai A, McCabe A, Kidney R, Brooks SC, Seupaul RA, Diercks DB, Salter N, Fermann GJ, Pospisil C. Ni-
trates for acute heart failure syndromes. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD005151. DOI:
10.1002/14651858.CD005151.pub2.
ABSTRACT
Background
Current drug therapy for acute heart failure syndromes (AHFS) consists mainly of diuretics supplemented by vasodilators or inotropes.
Nitrates have been used as vasodilators in AHFS for many years and have been shown to improve some aspects of AHFS in some small
studies. The aim of this review was to determine the clinical efficacy and safety of nitrate vasodilators in AHFS.
Objectives
To quantify the effect of different nitrate preparations (isosorbide dinitrate and nitroglycerin) and the effect of route of administration
of nitrates on clinical outcome, and to evaluate the safety and tolerability of nitrates in the management of AHFS.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3), MEDLINE (1950
to July week 2 2011) and EMBASE (1980 to week 28 2011). We searched the Current Controlled Trials MetaRegister of Clinical
Trials (compiled by Current Science) (July 2011). We checked the reference lists of trials and contacted trial authors. We imposed no
language restriction.
Selection criteria
Randomised controlled trials comparing nitrates (isosorbide dinitrate and nitroglycerin) with alternative interventions (frusemide and
morphine, frusemide alone, hydralazine, prenalterol, intravenous nesiritide and placebo) in the management of AHFS in adults aged
18 and over.
Data collection and analysis
Two authors independently performed data extraction. Two authors performed trial quality assessment. We used mean difference
(MD), odds ratio (OR) and 95% confidence intervals (CI) to measure effect sizes. Two authors independently assessed and rated the
methodological quality of each trial using the Cochrane Collaboration tool for assessing risk of bias.
Nitrates for acute heart failure syndromes (Review) 1
Main results
Four studies (634 participants) met the inclusion criteria. Two of the included studies included only patients with AHFS following
acute myocardial infarction (AMI); one study excluded patients with overt AMI; and one study included participants with AHFS with
and without acute coronary syndromes.
Based on a single study, there was no significant difference in the rapidity of symptom relief between intravenous nitroglycerin/N-
acetylcysteine and intravenous frusemide/morphine after 30 minutes (fixed-effect MD -0.30, 95% CI -0.65 to 0.05), 60 minutes (fixed-
effect MD -0.20, 95% CI -0.65 to 0.25), three hours (fixed-effect MD 0.20, 95% CI -0.27 to 0.67) and 24 hours (fixed-effect MD
0.00, 95% CI -0.31 to 0.31). There is no evidence to support a difference in AHFS patients receiving intravenous nitrate vasodilator
therapy or alternative interventions with regard to the following outcome measures: requirement for mechanical ventilation, systolic
blood pressure (SBP) change after three hours and 24 hours, diastolic blood pressure (DBP) change after 30, 60 and 90 minutes, heart
rate change at 30 minutes, 60 minutes, three hours and 24 hours, pulmonary artery occlusion pressure (PAOP) change after three
hours and 18 hours, cardiac output (CO) change at 90 minutes and three hours and progression to myocardial infarction. There is a
significantly higher incidence of adverse events after three hours with nitroglycerin compared with placebo (odds ratio 2.29, 95% CI
1.26 to 4.16) based on a single study. There was no consistent evidence to support a difference in AHFS patients receiving intravenous
nitrate vasodilator therapy or alternative interventions with regard to the following secondary outcome measures: SBP change after
30 and 60 minutes, heart rate change after 90 minutes, and PAOP change after 90 minutes. None of the included studies reported
healthcare costs as an outcome measure. There were no data reported by any of the studies relating to the acceptability of the treatment
to the patients (patient satisfaction scores).
Overall there was a paucity of relevant quality data in the included studies. Assessment of overall risk of bias in these studies was limited
as three of the studies did not give sufficient detail to allow assessment of potential risk of bias.
Authors’ conclusions
There appears to be no significant difference between nitrate vasodilator therapy and alternative interventions in the treatment of
AHFS, with regard to symptom relief and haemodynamic variables. Nitrates may be associated with a lower incidence of adverse effects
after three hours compared with placebo. However, there is a lack of data to draw any firm conclusions concerning the use of nitrates
in AHFS because current evidence is based on few low-quality studies.
PLAIN LANGUAGE SUMMARY

Nitrates for acute heart failure syndromes
Heart failure occurs when the lower muscular heart chamber is unable to fill or eject blood normally due to heart disease of any origin.
Acute heart failure syndromes (AHFS) are defined as gradual or rapid (over a period of less than 48 hours) deterioration in heart failure
signs and symptoms resulting in a need for urgent therapy. There are many types of drugs and non-drug based interventions used for
the treatment of AHFS. The aim of this review has been to determine the effectiveness and safety of nitrates (one drug group used for
the treatment of AHFS) compared with alternative interventions in the treatment of patients with AHFS.
The four studies in this review included 634 patients with AHFS and employed two types of nitrates (isosorbide dinitrate and
nitroglycerin). The studies compared nitrates with frusemide and morphine, frusemide alone, hydralazine, prenalterol, intravenous
nesiritide and placebo. The study population in the trials was predominantly male (469/634 or 74% of all the patients included in
the studies were male). The findings of this review indicate that there is no significant difference between nitrates and alternative
treatment interventions for patients with AHFS in terms of healthcare outcomes. Nitrates appeared to be well tolerated in all four
studies. Headaches is the most common side effect reported by patients. Headaches occurred more frequently when compared with
nesiritide. There appeared to be no significant difference in the occurrence of symptomatic hypotension, pain, nausea and angina
between patients administered nitroglycerin and nesiritide. The included studies did not report healthcare costs as an outcome measure.
The limitations of the review include the following: there were few studies eligible for inclusion (only four); the quality of the studies
were relatively poor; the study participants were predominantly male; and all the eligible studies were conducted in developed Western
countries. Consequently, the findings may not be generalisable to other healthcare settings and to females. The review also found no
consistent evidence to support a difference in AHFS patients receiving nitrates or alternative interventions with regard to many of the
healthcare outcome measures studied. Due to these limitations, the results of the review preclude definitive conclusions regarding the
effectiveness and safety of nitrates compared with alternative interventions in the treatment of patients with AHFS.
BACKGROUND lar compartment to the lung interstitium and alveoli; ultimately
the syndrome of acute cardiogenic pulmonary oedema may result
(Kaluski 2003).
Description of the condition The International Working Group on Acute Heart Failure Syn-
dromes determined that AHFS encompassed at least three clinical
Heart failure is a syndrome in which the patients should have the
distinct entities (Gheorghiade 2005):
following features: symptoms of heart failure, typically shortness
1. worsening chronic heart failure associated with reduced or
of breath at rest or during exertion, or fatigue (or both); signs of
preserved left ventricular ejection fraction (LVEF) (70% of all
fluid retention such as pulmonary congestion or ankle swelling;
admissions);
and objective evidence of an abnormality of the structure or func-
2. de novo heart failure (e.g. after a large myocardial
tion of the heart at rest (McMurray 2012). Acute heart failure
infarction; sudden increase in blood pressure superimposed on a
syndromes (AHFS) are defined as gradual or rapid deterioration
noncompliant left ventricle) (25% of all admissions); and
in heart failure signs and symptoms resulting in a need for urgent
3. advanced heart failure (i.e. refractory to therapy) with
therapy (Gheorghiade 2005; McMurray 2012). AHFS are com-
severe left ventricle systolic dysfunction, associated with a
plex and can result from any structural or functional cardiac dis-
continually worsening low output state (5% of all admissions).
order that impairs the ability of the ventricle to fill with or eject
The two fundamental haemodynamic parameters relate to the
blood (Hunt 2001). For patients with pre-existing chronic heart
presence or absence of elevated filling pressures (wet or dry) and
failure the following may be responsible for the acute phase of
perfusion that is adequate or critically limited (warm or cold).
decompensation (episodes of AHFS) of the underlying condition:
Over 90% of patients presenting with acute decompensated heart
myocardial ischaemia, lack of compliance to diet or medication
failure have clinical congestion (classified as being wet) and, if
regimen, uncontrolled hypertension, cardiac arrhythmia, systemic
right heart catheterisation were performed, would show elevated
infection or anaemia (DiGuili 2001; Fonarow 2008; McMurray
pulmonary capillary wedge pressure (Nohria 2002). These pa-
2012; Weintraub 2010; Whellan 2013).
tients may have adequate or reduced perfusion, with the majority
Despite the fact that AHFS are one of the most common syn-
showing elevation in systemic vascular resistance. Identification of
dromes in emergency medicine, the exact pathogenesis has re-
congestion (elevated filling pressures) in acute decompensation of
mained largely unknown. This is because the availability of haemo-
chronic heart failure relies heavily on the symptoms of dyspnoea
dynamic data on which to base rational therapy in AHFS is limited
and orthopnoea. Meanwhile, the most assessable indicator of per-
by the difficulty in performing ethical clinical trials. However, the
fusion is blood pressure and pulse pressure (Nohria 2002). The
use of implantable device diagnostics is leading to a better under-
use of this haemodynamic classification system allows for more
standing of the pathogenesis of AHFS (Adamson 2011; Whellan
appropriate targeting therapy in patients presenting with acute
2013; Zile 2011). For example, using an implantable haemody-
heart failure. A minority (less than 1%) of patients present with
namic monitor (HIM), it has recently been demonstrated that the
cardiogenic shock (Cleland 2003). This is caused by a severe re-
product of the level to which estimated pulmonary artery dias-
duction in cardiac output which is not met by an adequate increase
tolic (ePAD) pressure (P) is increased and the length of time (T)
in peripheral vascular resistance leading to a significant decrease
over which that pressure is increased (PxT) is the pressure-based
in blood pressure and end organ perfusion. Consequently, the
haemodynamic factor most closely associated with transition to
management of cardiogenic shock is directed at improving cardiac
AHFS in heart failure patients (Zile 2011). In the meantime, the
performance (by optimising filling pressure, intra-aortic balloon
fulminant presentation of AHFS, and rapid resolution with some
pump and emergent revascularisation) (Cotter 2000; Hochman
traditional pharmacological agents, creates ethical barriers to jus-
1999). The other AHFS (pulmonary oedema, hypertensive crisis
tification of the need for clinical trials with new treatment modal-
and exacerbated heart failure) are caused by a combination of pro-
ities or ’non-treatment’. Nevertheless, several studies have aimed
gressive excessive vasoconstriction superimposed on reduced left
to better characterise the pathogenesis of AHFS. These studies
ventricular functional reserve (Cotter 2003). The impaired car-
demonstrate that AHFS results from a rapidly deteriorating cycle
diac power and extreme vasoconstriction induces a vicious cycle
of events in which patients with reduced baseline systolic and di-
of afterload mismatch resulting in a dramatic reduction of cardiac
astolic reserve are faced with an acute increase in systemic vascular
output and elevated left ventricular end diastolic pressure, which
resistance and, hence, afterload (Cotter 2003; Sharon 2000). This
is transferred backwards to the pulmonary capillaries yielding pul-
causes an acute decompensated state, leading to decreased periph-
monary oedema (Cotter 2003). Therefore, the emergency man-
eral perfusion, neurohormonal activation, decreasing left ventric-
agement of these AHFS should be based on the administration of
ular function and increasing vascular resistance (Kaluski 2003).
potent, rapidly acting intravenous vasodilators.
The result of this vicious cycle is an increase in left ventricular
Heart failure complicating myocardial infarction is associated with
end-diastolic pressure that is transmitted backwards to the pul-
a three to four-fold increase in hospital mortality (Hellermann
monary vasculature, causing an acute increase in pulmonary cap-
2002; Spencer 1999; Spencer 2002; Steg 2004; Wu 2002). De-
illary pressure and the transudation of fluid from the intravascu-

pending on study design, the incidence of heart failure after my- Why it is important to do this review
ocardial infarction varies greatly from 3% to 53% (Ambrosioni
The use of nitrates for AHFS is a clinically valid topic for a
1995; Bueno 1995; Hellermann 2002). Meanwhile, because of
Cochrane systematic review for many reasons.
their haemodynamically beneficial effects, nitrates are recom-
Firstly, AHFS are very common. With a prevalence of 5,700,000
mended in heart failure (Hunt 2001) and acute coronary syn-
(2.4% of the entire populace) in 2008, and an estimated yearly
dromes (Peacock 2004), respectively. Intravenous nitrate vasodila-
incidence of 670,000, the burden of heart failure in the United
tors are well tolerated in acute myocardial infarction with clini-
States is tremendous (Roger 2011).
cally significant hypotension occurring in less than 4% of patients
Secondly, AHFS are associated with significant morbidity, health-
(GISSI-3 1994), but this responds to dose reduction and fluid re-
care costs and societal economic burden. In the United States, the
placement. However, two mega-trials have failed to demonstrate
mortality rate stood at 56,565 in 2007 and 990,000 hospital dis-
any mortality reduction attributable to nitrate use in acute coro-
charges pertained to heart failure admissions (Roger 2011). The
nary syndromes (GISSI-3 1994; ISIS-4 1995). The primary rea-
EuroHeart Failure survey programme, one of the largest surveys of
son for the use of nitrates in acute coronary syndromes is for a
how patients hospitalised for heart failure are managed, reported
beneficial haemodynamic effect and to decrease the pain of my-
13% mortality during and after first hospitalisation for heart fail-
ocardial ischaemia (Peacock 2004).
ure (Cleland 2003).
AHFS are presently the leading cause of hospitalisation in per-
sons over 60 years of age in developed countries (Cleland 2001;
Cowie 1997; Hunt 2001; Khand 1999; Stewart 2001). Patients
Description of the intervention with acute heart failure face a median six-day duration of hospital-
Nitrates (for example, nitroglycerin, isosorbide dinitrate and isation and a rehospitalisation rate over the next six months as high
sodium nitroprusside) are established intravenous vasodilators in as 50% (AHA 2001; Fonarow 2003; Hunt 2001). It is estimated
clinical practice and are recommended for moderate to severe vol- that AHFS account for almost 2% of National Health Service
ume overload in acute decompensated heart failure (DiDomenico (NHS) expenditure in the United Kingdom, with the predomi-
2004). At low doses they induce only venodilatation, but as the nant cost component being hospitalisation (Berry 2001; Stewart
dose is gradually increased they cause the arteries, including the 2002). These findings are consistent with those of several other
coronary arteries, to dilate (Imhof 1980). They therefore cause countries (Doughty 1995; Eriksson 1991; Ghali 1990; Reitsma
balanced vasodilatation of the venous and arterial sides of the cir- 1996; Rodriguez 1997).
culation, thereby reducing elevated left ventricular filling pressures Emergency department visits and subsequent hospitalisations for
and elevated systemic vascular resistance, without impairing tissue acute heart failure constitute a major public health problem. In
perfusion. 2006, there were nearly 658,000 annual emergency department
Nitrates can be administered sublingually, orally, transcutaneously encounters primarily for acute heart failure in the United States
and intravenously. (Schappert 2008).
Ageing populations and improved post-infarction survival lead to a
high number of older patients with heart failure in more developed
countries (Cleland 2001). A British study predicts that the annual
number of male and female hospital admissions associated with
How the intervention might work a principal diagnosis of heart failure will increase by 34% (from
The main principles in the management of acute heart failure 5500 to 7500) and by 12% (from 7800 to 8500), respectively, by
are symptom relief, reversal of acute haemodynamic abnormalities 2020 (Stewart 2003)
and a search for underlying precipitants of heart failure decom- Thirdly, despite the demonstrable beneficial effects of intravenous
pensation. Acute reduction in high left ventricular filling pressure nitrate vasodilators as first-line agents in the management of pa-
with intravenous vasodilators corresponds most closely with symp- tients with acute heart failure, the most common therapy admin-
tomatic relief of dyspnoea at rest (Fonarow 2001; Stevenson 1999) istered to these patients is intravenous loop diuretics, particularly
and is the only significant haemodynamic predictor of subsequent frusemide (Nelson 1983; Verma 1987). In a United Kingdom
mortality (Campana 1993; Lucas 2000). Thus using intravenous emergency department study, the majority of patients with acute
vasodilators to reverse acute heart failure decompensation is more heart failure received frusemide, with less than 70% receiving ni-
physiologically rational in that it primarily targets elevated ven- trates (Crane 2002). Among patients in the Acute Decompensated
tricular filling pressures and elevated systemic vascular resistance Heart Failure National Registry (ADHERE 2003) in the United
(Fonarow 2001). In addition, intravenous vasodilators reduce my- States, 64% of acute heart failure patients received intravenous
ocardial oxygen consumption and are not associated with wors- diuretic therapy alone and only 27% of all admitted patients re-
ening of myocardial ischaemia or precipitation of ventricular ar- ceived intravenous vasoactive therapy (Fonarow 2003). A properly
rhythmias (Fonarow 2002; Nohria 2002). conducted quantitative systematic review may provide an objec-

tive evidence base for the role of nitrates in the management of Types of interventions
patients with acute heart failure. The target intervention was administration of a nitrate (for ex-
Fourthly, concerning the use of nitrates for AHFS, it is important ample nitroglycerin or isosorbide dinitrate) compared with an al-
to document any incidence of adverse effects, cost of treatment ternative intervention (pharmacological agent like frusemide, hy-
and acceptability to the patient in a systematic and scientifically dralazine, prenalterol and nesiritide or non-pharmacological in-
valid way. tervention such as non-invasive positive pressure ventilation) for
Furthermore, a Cochrane systematic review that is continuously acute heart failure.
updated as new evidence is published may lead to clinical practice
guidelines which may improve the efficiency and quality of patient
care. To date there has been no systematic review on this topic. Types of outcome measures
This Cochrane review aims to synthesise current best evidence and
will be continuously updated as relevant new trials regarding the
role of nitrates in the management of AHFS are published. Primary outcomes
Rapidity with which symptoms (for example dyspnoea, fatigue,
self reported patient satisfaction score, global clinical status) are
relieved.
OBJECTIVES Secondary outcomes

1. Requirement for mechanical ventilation.
1. To quantify the effect of different nitrate preparations on 2. Changes in haemodynamic variables (systolic blood
clinical outcome in AHFS in adults. pressure, diastolic blood pressure, heart rate, pulmonary artery
occlusion pressure, cardiac output).
2. To determine the effect of route of administration of 3. Progression to myocardial infarction.
nitrates on clinical outcome in AHFS in adults. 4. Immediate adverse events.
5. Adverse events during hospitalisation.
3. To evaluate the safety and tolerability of nitrates in AHFS 6. Duration of hospitalisation.
in adults. 7. Cost.
8. All-cause mortality.
METHODS
Search methods for identification of studies
Criteria for considering studies for this review Electronic searches

We made a computer-assisted search for RCTs of nitrate ther-
apy in patients with AHFS without language restriction in the
Cochrane Central Register of Controlled Trials (CENTRAL)
Types of studies on The Cochrane Library (2011, Issue 3), MEDLINE (1950 to
Randomised controlled trials (RCTs) in all languages were eligible July week 2 2011), EMBASE (1980 to week 28 2011) and the
for inclusion in the review, with a randomised controlled trial HERDIN database (Appendix 1). We used the Cochrane sensitiv-
defined as a study in which patients were allocated to treatment ity-maximising RCT filter (Lefebvre 2011). We searched the Cur-
groups on the basis of a random or quasi-random method (for rent Controlled Trials MetaRegister of Clinical Trials (compiled
example, using random number tables, hospital number, date of by Current Science) (July 2011).
birth). We applied no language restrictions.
Searching other resources

Types of participants
We also searched reference lists of review articles, relevant trials,
Adult patients aged 18 and older with AHFS (sudden impairment relevant textbooks and abstracts of scientific meetings without lan-
of the ability of the ventricle to fill with or eject blood resulting guage restriction to identify further RCTs. We reviewed the titles
from any structural or functional cardiac disorder) of any severity. and abstracts to identify all potential RCTs. We obtained full-text

versions of these articles. We also made additional efforts to lo- and other sources of bias (Higgins 2011). Two review authors
cate potential RCTs relevant to the topic from the following data assessed the risk of bias in eligible trials.
sources: We evaluated each study and assessed them separately for these
1. ’grey literature’ (theses, internal reports, non-peer reviewed domains. We judged each explicitly as follows:
journals) databases (Open Grey - System for Information on • low risk of bias;
Grey Literature in Europe); • high risk of bias; and
2. references (and references of references, etc.) cited in • unclear risk (lack of information or uncertainty over the
primary sources; potential for bias).
3. other unpublished sources known to experts in the specialty
We resolved any disagreement by discussion.
(sought by personal communication); and
4. raw data from published trials (sought by personal
communication). Dealing with missing data
No simple solution exists for the problem of missing data. We
handled this problem by contacting the investigators, whenever
Data collection and analysis possible, to ensure that no data were missing for the studies. In
addition, we planned to be explicit about the assumptions of what-
ever method we used to cope with missing data.
Selection of studies
Two authors (RK and SB) independently decided on inclusion of Assessment of heterogeneity
studies, having read the methods section of each review and applied We evaluated clinical heterogeneity (differences between studies in
the stated criteria. We assessed trial outcomes for comparability. key characteristics of the participants, interventions, or outcome
Two authors (RS and DBD) independently entered data into the measures). In the absence of clinical heterogeneity, we used the I2
Review Manager software (RevMan 5.2) for statistical analysis. We statistic to describe the percentage of total variation across studies
resolved any disagreements by discussion. There was no occasion that was due to heterogeneity rather than chance (Higgins 2003).
where uncertainty remained after this discussion. An I2 > 50% may represent substantial or considerable statistical
heterogeneity (Higgins 2011). The importance we placed on the
observed value of I2 depended on (i) the magnitude and direction
Data extraction and management
of effects and (ii) the strength of evidence for heterogeneity (P
We used a revised data extraction form to incorporate the new value from the Chi2 test and confidence interval for I2 ).
additions on quality assessment from the Cochrane Handbook for We used visual inspection of the graphic representation of studies
Systematic Reviews of Interventions (Higgins 2011). We extracted with their 95% CIs to assess heterogeneity. We generated tables
relevant data regarding inclusion criteria (study design, partici- and graphs using the analysis module included in RevMan 5.2.
pants, interventions and outcomes), risk of bias (sequence genera- We represented pooled odds ratios pictorially as a ’forest plot’ to
tion, allocation concealment, blinding, incomplete outcome data, permit visual examination of the degree of heterogeneity between
selective outcome reporting and other sources of bias) and results. studies.
In cases where insufficient data were reported (for example, com-
pleteness of outcome data) we contacted the study authors for fur-
ther information. Two review authors carried out data extraction. Statistical and data analysis
Excluded studies and reasons for exclusion are detailed in the table The results concentrated on the objectives and comparisons speci-
Characteristics of excluded studies. Where necessary, we contacted fied in the protocol for the review. We identified post hoc analyses
the authors of included studies for missing information. as such.
We minimised publication bias by comprehensive literature We considered the appropriateness of meta-analysis in the presence
searching (Glasziou 2001). In addition, we planned to use a graph- of significant clinical or statistical heterogeneity. We performed
ical display (funnel plot) of the size of the treatment effect against meta-analyses using RevMan software (RevMan 5.2). We calcu-
the precision of the trial (one/standard error) to investigate publi- lated summary estimates of treatment effect with 95% confidence
cation bias. intervals (CIs) for each comparison.
For dichotomous (or binary) data, we described the results both
as a relative measure (odds ratio (OR), risk ratio (RR) and relative
Assessment of risk of bias in included studies risk reduction) and an absolute measure (risk difference (RD)).
We assessed risk of bias in terms of sequence generation, allocation Relative measures (odds ratios and risk ratios) can be used to com-
concealment, blinding (of participants, personnel and outcome bine studies but absolute measures can be more informative than
assessors), incomplete outcome data, selective outcome reporting relative measures because they reflect the baseline risk as well as the

change in risk with the intervention. Relative measures are used to quality studies. We defined a good-quality study as one which ful-
combine studies but absolute measures (such as the risk difference) fils all of the following criteria: adequate allocation concealment,
are particularly useful when considering trade-offs between likely blinding of outcome assessment and data analysis performed ac-
benefits and likely harms of an intervention (Deeks 2011). cording to the intention-to-treat principle. We defined a poor-
For continuous data, we used the mean difference (MD) whenever quality study as one which lacked one or more of these key do-
outcomes were measured in a standard way across studies. This mains.
has the advantage of summarising results in natural units that
are easily understood. When it was desirable to summarise results
Glossary
across studies with outcomes that are conceptually the same but
measured in different ways (for example, different pain scores), we Please see http://www.cochrane.org/glossary for a glossary of
planned to use the standardised mean difference (SMD). terms.
Subgroup analysis and investigation of heterogeneity

RESULTS
The effect of nitrates on heart failure complicating acute myocar-
dial infarction is poorly defined. We performed subgroup analysis
for the effects of nitrates on the subset of patients with AHFS
Description of studies
complicating acute myocardial infarction.
Results of the search

Sensitivity analysis
The electronic database search yielded a total of 622 publications.
We planned to perform sensitivity analyses to test how sensitive the After reviewing titles and abstracts we retrieved six full-text ver-
results were to reasonable changes in the assumptions that we made sions of the trials for possible inclusion. After examining the full-
in the protocol for combining the data (Lau 1998). We planned text versions, we excluded two papers and included four studies.
to perform sensitivity analysis for randomised versus quasi-ran- The study selection process is summarised in the PRISMA flow
domised studies and eventually good-quality studies versus poor- diagram shown in Figure 1.

Figure 1. Study flow diagram.

Two studies recruited only male participants (Nelson 1983; Verma
Included studies
1987), while two studies recruited both male and female partic-
ipants (Beltrame 1998; VMAC 2002). Only one study detailed
We included four trials (634 participants) comparing nitrates with
the ethnicity of the participants (VMAC 2002).
alternative interventions in AHFS. Two of the studies had two
Only one study (VMAC 2002) reported the primary outcome
comparison arms (Beltrame 1998; Nelson 1983), one of the studies
measure of the review: rapidity with which symptoms are relieved.
had three comparison arms (VMAC 2002) and one of the studies
One of the primary outcome measures of VMAC 2002 was the
had four comparison arms (Verma 1987).
patient’s self evaluation of dyspnoea (all patients) from baseline to
Two studies each enrolled trial participants in a single coronary
three hours after the start of the study drug.
care unit (Nelson 1983; Verma 1987). One study enrolled and ran-
Only two of the included studies (Nelson 1983; Verma 1987) were
domised trial participants in one emergency department (Beltrame
used for pooling data because they were the only included studies
1998). One multi-centre trial included patients with AHFS severe
employing the same comparator arms (intravenous frusemide 1
enough to require hospitalisation and intravenous therapy, but the
mg/kg versus intravenous isosorbide dinitrate 50 to 200 µg/kg/h)
authors did not specify the specific hospital setting where the trial
in the same trial setting (coronary care unit).
participants were enrolled (VMAC 2002).
Details of the included studies are shown in Characteristics of
The specific intravenous nitrate drug employed was isosorbide
included studies and Figure 1.
dinitrate in two studies (Nelson 1983; Verma 1987) and nitro-
glycerin in two studies (Beltrame 1998; VMAC 2002). One of
the studies which employed nitroglycerin also employed N-acetyl- Excluded studies
cysteine to potentiate the pharmacological effects of nitroglycerin Two trials were ultimately excluded (Cotter 1998; Elkayam 2004).
(Beltrame 1998). One of the trials (Elkayam 2004) was excluded because it was a
Two studies were UK-based (Nelson 1983; Verma 1987), one was subgroup analysis of an included study (VMAC 2002). One of
based in Australia (Beltrame 1998) and one was based in the US the trials was excluded because both intervention arms of the trial
(VMAC 2002). The studies reported outcomes ranging from 24 included a nitrate (Cotter 1998). Details of the excluded studies
hours to six months (Nelson 1983 48 hours; Verma 1987 five days; are shown in Characteristics of excluded studies and Figure 1.
Beltrame 1998 24 hours; VMAC 2002 six months).
Two studies included only patients with AHFS following acute
myocardial infarction (Nelson 1983; Verma 1987). One trial ex-
Risk of bias in included studies
cluded patients with overt acute myocardial infarction as evi- The methodological quality graph (Figure 2) presents the review
denced by ST segment elevation or severe anginal pain neces- authors’ judgements about each methodological quality item pre-
sitating treatment with intravenous nitrates, morphine or both sented as percentages across all included studies. Given the small
(Beltrame 1998). One trial included participants with AHFS with number of included studies we were unable to assess publication
and without acute coronary syndromes (VMAC 2002). bias using a funnel plot approach (Higgins 2011).

Figure 2. ’Risk of bias’ graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.
In terms of random sequence generation and allocation conceal-

ment, three of the studies did not give sufficient detail to assess
their potential risk of bias (Figure 3). Only one study reported
sufficient detail concerning random sequence generation and allo-
cation concealment to determine the potential risk of bias was low
for these domains (VMAC 2002). Blinding of participants and
personnel had a low potential risk of bias in all studies except one
which had a high potential risk of bias for that domain (Beltrame
1998). Only one study had a low potential risk of bias in all do-
mains (VMAC 2002).

Figure 3. ’Risk of bias’ summary: review authors’ judgements about each risk of bias item for each included
study.
Effects of interventions and reported in different ways in the two studies. Beltrame 1998
reported no significant difference in the dyspnoea score (0 to 3) be-
Primary outcome tween intravenous nitroglycerin/N-acetylcysteine and intravenous
frusemide/morphine at 30 minutes (fixed-effect mean difference
(MD) -0.30, 95% confidence interval (CI) -0.65 to 0.05), 60 min-
Rapidity of symptom relief utes (fixed-effect MD -0.20, 95% CI -0.65 to 0.25), three hours
Two studies reported the rapidity of symptom relief, the primary (fixed-effect MD 0.20, 95% CI -0.27 to 0.67) and 24 hours (fixed-
outcome measure of this review. It was not possible to pool the effect MD 0.00, 95% CI -0.31 to 0.31). VMAC 2002 reported
results of these two trials because the comparator interventions the patient’s self evaluation of dyspnoea (all patients) and global
were different and the rapidity of symptom relief was measured clinical status at three, six and 24 hours, respectively, after the start

of the study drug. Global clinical status was rated by the patient Change in heart rate
on a five-category scale (markedly better, better, no change, worse
or markedly worse). Dyspnoea was rated by the patient on a three-
category scale (improved, no change or worse). However, the re-
sults were reported graphically and sufficient detail about the exact
Change in heart rate after 90 minutes
scores for these end points was not published (VMAC 2002).
Two trials involving 52 participants (Nelson 1983; Verma 1987)
comparing isosorbide dinitrate with frusemide reported no signif-
Secondary outcomes icant difference in heart rate change at 90 minutes between the
two interventions (fixed-effect MD 2.00, 95% CI -0.57 to 4.57;
Analysis 3.1).
1. Requirement for mechanical ventilation
One study reported the need for mechanical ventilation (Beltrame
1998). The study reported that only seven patients required respi-
Change in pulmonary artery occlusion pressure (PAOP)
ratory assistance (continuous positive airway pressure in four pa-
tients and intubation with ventilation in three patients), with no
difference between the study groups (nitroglycerin/N-acetylcys-
teine and frusemide/morphine). However, the study did not pro-
vide sufficient detail regarding the exact number of participants Change in PAOP after 90 minutes
who needed mechanical ventilation in each comparator group Two trials involving 52 participants (Nelson 1983; Verma 1987),
(Beltrame 1998). comparing isosorbide dinitrate with frusemide, reported no sig-
nificant difference in PAOP change at 90 minutes between the
2. Changes in haemodynamic variables (systolic blood two interventions (fixed-effect MD -2.00, 95% CI -2.80 to -1.20;
pressure, diastolic blood pressure, heart rate, pulmonary Analysis 5.1).
artery occlusion pressure, cardiac output)
The changes in many haemodynamic outcome measures at specific
time points after drug initiation may be imprecise because they Change in cardiac output
were reported by only one trial (Table 1).
Change in systolic blood pressure (SBP)

Change in cardiac output after 90 minutes
Two trials involving 52 participants (Nelson 1983; Verma 1987),
comparing isosorbide dinitrate with frusemide, reported no signif-
Change in SBP after 90 minutes icant difference in cardiac output change at 90 minutes between
Two of the included trials (52 participants) comparing isosorbide the two interventions (fixed-effect MD 0.15 L/min/m2 , 95% CI
dinitrate with frusemide reported change in systolic blood pressure 0.07 to 0.22; Analysis 4.1).
after 90 minutes (Nelson 1983; Verma 1987). The pooled analysis
for two trials revealed a significantly greater SBP reduction with
isosorbide dinitrate compared with frusemide (fixed-effect MD - 3. Progression to myocardial infarction
8.97 mmHg, 95% CI -13.00 to -4.94; Analysis 1.1).
One trial involving 69 participants (Beltrame 1998), comparing
nitroglycerin/N-acetylcysteine with frusemide/morphine (F/M),
Change in diastolic blood pressure (DBP) reported that acute myocardial infarction occurred in 10 patients
(14%), of whom four (12%) were treated with F/M and six (16%)
were treated with nitroglycerin/N-acetylcysteine (Beltrame 1998).
No further data is given regarding these patients.
Change in DBP after 90 minutes
There were no significant differences reported in one trial in the
Two trials (52 participants) reported DBP as an outcome measure frequency or severity of ischaemic events between nitroglycerin
(Nelson 1983; Verma 1987). In the pooled analysis of the two trials and nesiritide groups in the first 24 hours (VMAC 2002). In the
regarding DBP change after 90 minutes, there was no significant same study, through 30 days, there were three myocardial infarc-
difference between isosorbide dinitrate and frusemide (fixed-effect tions reported in nitroglycerin patients and two in nesiritide pa-
MD -2.08, 95% CI -3.71 to -0.45; Analysis 2.1). tients.

4. Immediate adverse events 2002). The investigators reported that readmission for acutely de-
Two studies reported that no untoward adverse events occurred in compensated congested heart failure (CHF) occurred in 27 (13%)
any patient during the studies (Nelson 1983; Verma 1987). nitroglycerin and 20 (7%) nesiritide patients (VMAC 2002).
In one trial with three comparison arms, during the initial three-
hour placebo-controlled period, any adverse event occurred in 39
(27%) nitroglycerin, 36 (18%) nesiritide and 20 (14%) placebo 7. Cost
patients (Fisher exact test, P = 0.02) (VMAC 2002). Specifically,
None of the included studies reported healthcare costs as an out-
headache occurred in 17 (12%) patients administered nitroglyc-
come measure or made any reference to the cost of treatment.
erin, 11 (5%) administered nesiritide and three (2%) placebo pa-
tients (P = 0.003). Abdominal pain occurred in four (3%) nitro-
glycerin patients only (P = 0.01) (VMAC 2002).
In one trial involving 69 participants, no adverse events (other 8. Mortality
than requirement for assisted ventilation and acute myocardial
Two trials reported no mortality associated with use of nitrates
infarction discussed above) were documented (Beltrame 1998).
(Nelson 1983; Verma 1987).
One trial reported that there were three in-hospital deaths dur-
5. Adverse events during hospitalisation
ing the study but the authors did not attribute the deaths to
acute cardiogenic pulmonary oedema (Beltrame 1998). In one
Two studies reported that no untoward adverse events occurred trial comparing nitroglycerin with nesiritide in 347 patients, re-
to any patient during the studies (Nelson 1983; Verma 1987). ported through seven days, deaths occurred in one (0.5%) nitro-
In the trial involving 69 participants, no adverse events (other glycerin and four (1.5%) nesiritide patients (VMAC 2002). None
than requirement for assisted ventilation and acute myocardial of these deaths was believed to be due to either study drug. The
infarction discussed above) were documented (Beltrame 1998). trial further demonstrated that there was no significant difference
In one trial with three comparison arms, during the first 24 hours in six-month mortality for nitroglycerin 20.8% (95% CI 15.5%
of treatment with nesiritide, headache (8%) occurred significantly to 26.5%) versus nesiritide patients 25.1% (95% CI 20.0% to
less frequently than with nitroglycerin (Fisher exact test, P = 0.001) 30.5%; P = 0.32) (VMAC 2002).
(VMAC 2002). One trial involving 489 participants (VMAC 2002), comparing
nitroglycerin with nesiritide, reported no significant difference be-
tween the two interventions in 30-day mortality rate (odds ratio
Adverse events after three hours
1.91, 95% CI 0.32 to 11.52).
One trial involving 285 participants (VMAC 2002), comparing The trials reporting mortality as an outcome measure could not
nitroglycerin with placebo, reported a significantly lower incidence be pooled because the comparator interventions employed were
of adverse events after three hours with placebo (odds ratio 2.29, different.
95% CI 1.26 to 4.16). One trial involving 347 participants (
VMAC 2002), comparing nitroglycerin with nesiritide, reported a
lower incidence of adverse events after three hours with nesiritide
(odds ratio 1.75, 95% CI 1.05 to 2.93). Subgroup analysis
There were no significant differences in the frequency or sever- Two trials reported the effects of nitrates on the subset of patients
ity of asymptomatic or symptomatic hypotension or arrhythmias with acute heart failure syndromes (AHFS) complicating acute
between nitroglycerin and nesiritide groups in the first 24 hours myocardial infarction (Nelson 1983; Verma 1987). The pooled
(VMAC 2002). analysis for the two trials revealed a significantly greater SBP re-
duction with isosorbide dinitrate compared with frusemide af-
ter 90 minutes (fixed-effect MD -8.97 mmHg, 95% CI -13.00
6. Duration of hospitalisation to -4.94; Analysis 1.1). In the pooled analysis of the two trials,
Two of the studies did not report any data regarding duration of there was no significant difference in terms of change in haemo-
hospitalisation (Nelson 1983; Verma 1987). dynamic parameters after 90 minutes between isosorbide dinitrate
One of the studies reported no variation in duration of hospital- and frusemide (Analysis 2.1 to Analysis 4.1). In terms of immedi-
isation (overall mean 5.6 + 3.0 days) between treatment groups ate adverse events and adverse events during hospitalisation, both
(Beltrame 1998). trials reported that no untoward event occurred to any patient
In one trial with three comparison arms involving 489 partici- during the studies. Both trials reported no mortality associated
pants, through 30 days, 48 (23%) of patients administered nitro- with the use of nitrates. However, neither trial reported the pri-
glycerin and 50 (20%) administered nesiritide were readmitted to mary outcome measure of this review, rapidity of symptom relief,
the hospital for any cause (Fisher exact test, P = 0.36) (VMAC or cost as outcome measures.

DISCUSSION Verma 1987); these studies therefore had a different, and narrower,
focus than that of this review. Three of the four included stud-
This review assessed the randomised controlled trial (RCT) evi-
ies in this review enrolled inpatients with AHFS, bypassing the
dence comparing the outcomes of nitrate vasodilator therapy and
emergency department phase of management. Depending on the
alternative interventions in the management of acute heart failure
drug’s pharmacodynamic properties, it is possible that a therapeu-
syndromes (AHFS).
tic window exists beyond which apparent efficacy is diminished
Our review found no evidence to support a difference in the pri- (Weintraub 2010). This may be particularly true for relief of dys-
mary outcome measure, rapidity of symptom relief, between intra- pnoea, one of the key end points in AHFS management (Mebazaa
venous nitrate vasodilator therapy and alternative interventions. 2010; Pang 2008; Weintraub 2010). Furthermore, there is cur-
Specifically, only two studies reported the rapidity of symptom rently no consensus on reasonable end points in relation to AHFS
relief as an outcome measure. The two trials involved 69 and management (Weintraub 2010). These factors may contribute to
285 participants, respectively. Both studies recruited both male the inconsistent evidence found by this review regarding many of
and female participants (Beltrame 1998; VMAC 2002), but only the outcomes studied.
one study detailed the ethnicity of the trial participants (VMAC
2002). Only the trial involving 69 patients presented numerical The eligible RCTs for this review do not have comparisons which
measures of rapidity of symptom relief; sufficient detail regarding permit us to address two of the a priori objectives of this review.
this outcome measure was not provided by the study involving First, based on the eligible RCTs for this review, it is not possible
285 patients because the results were presented graphically. It was to determine the effect of route of administration of nitrates on
not possible to pool the results of these two trials because the com- clinical outcome in AHFS in adults, because all the studies which
parator interventions were different and the rapidity of symptom met the a priori inclusion criteria only employed the intravenous
relief was measured and reported in different ways in the respective route for nitrate administration. Second, it also not possible to
studies, and it was not possible to obtain the individual patient quantify validly the effect of different nitrate preparations on clin-
data from the trialists. The estimates yielded by the trial which ical outcome in AHFS in adults based on the eligible RCTs for
reported numerical measures of rapidity of symptom relief may be this review.
imprecise due to the relatively small sample size. We were unable to perform a valid sensitivity analysis as planned
This review found no evidence to support a difference in AHFS a priori because all the included RCTs in this review were ran-
patients receiving intravenous nitrate vasodilator therapy or alter- domised (there were no included quasi-randomised trials eligible
native interventions with regard to the following outcome mea- for inclusion) and none of the included RCTs met the criteria of a
sures: requirement for mechanical ventilation, systolic blood pres- good-quality study (one which meets all of the following criteria:
sure (SBP) change after three hours and 24 hours, diastolic blood adequate allocation concealment, blinding of outcome assessment
pressure (DBP) change after 30, 60 and 90 minutes, heart rate and data analysis performed according to the intention-to-treat
change at 30 minutes, 60 minutes, three hours and 24 hours, principle).
pulmonary artery occlusion pressure (PAOP) change after three Regarding the a priori subgroup analysis, this review found that
hours and 18 hours, cardiac output change at 90 minutes and nitrates (isosorbide dinitrate) cause a significantly greater SBP re-
three hours, and progression to myocardial infarction. Regarding duction after 90 minutes compared with frusemide in patients
adverse events after three hours, our review found a higher in- with AHFS complicating acute myocardial infarction. However, it
cidence of adverse events with intravenous nitrate therapy com- found no significant difference between nitrates (isosorbide dini-
pared with placebo and compared with nesiritide; however, both trate) and frusemide in terms of other haemodynamic parameters
of these findings were based on one trial respectively, therefore the (DBP, heart rate, PAOP and cardiac output). The findings of the
estimates yielded may be imprecise. subgroup analysis are limited and imprecise because it is based on
This review found no consistent evidence to support a difference two small RCTs which did not report the primary outcome mea-
in AHFS patients receiving intravenous nitrate vasodilator ther- sure of this review and employed only one comparison (isosorbide
apy or alternative interventions with regard to the following sec- dinitrate versus frusemide).
ondary outcome measures: SBP change after 30 and 60 minutes,
There is no previous non-Cochrane systematic review based on
heart rate change after 90 minutes, PAOP change after 90 min-
RCT evidence comparing outcomes of nitrate vasodilator therapy
utes. The inconsistency in the evidence is due to the existence of
and alternative interventions in the management of AHFS. It is
RCT evidence both for and against a difference in AHFS patients
therefore not possible to contextualise the findings of this review
receiving intravenous nitrate vasodilator therapy or alternative in-
in relation to evidence from an existing systematic review. Mean-
terventions.
while, like all systematic reviews, the findings of our review are
Two of the four included studies in this review recruited only pa- limited by the quality of existing studies (Khan 1996): the small
tients with AHFS following myocardial infarction (Nelson 1983; number of studies, the relatively small sample sizes in the respec-

tive studies and the different comparator interventions employed. in males; the evidence may not be generalisable in other healthcare
Only two included studies in this review shared the same compara- settings or females.
tor interventions. Additionally, three of the four included studies
had a high or unclear risk of bias. In terms of observable statistical Implications for research
heterogeneity in the five pooled analysis on haemodynamic pa-
More adequately powered studies of high methodological quality
rameters, considerable heterogeneity is present in one haemody-
are required to determine whether there is any difference in clin-
namic parameter and moderate heterogeneity may be present in
ical outcomes between nitrate vasodilator therapy and alternative
another haemodynamic parameter. Due to these limitations, the
interventions in patients with AHFS. Due to the diverse patho-
estimates yielded by the review are imprecise and firm conclusions
physiological processes seen in AHFS, future research should focus
cannot be drawn regarding the effects of the interventions.
on conducting studies in relatively homogeneous AHFS patient
The relatively low methodological quality of existing RCT evi- subgroups to limit phenotypic variability.
dence is probably due to the diverse pathophysiological precipi- Patients enrolled in inpatient acute heart failure studies are often
tants (for example, acute coronary syndromes, arrhythmias, infec- enrolled after they have reached the inpatient unit some 12 to 24
tion, poor compliance with drug therapy or dietary requirements) hours after presentation. As most patients have symptom relief
of AHFS and the heterogenous patient population presenting with with either diuretic or nitroglycerin given in the emergency setting,
AHFS. Small studies, but in multiple, tightly controlled, relatively enrolling patients in trials after they have received acute therapy is
homogeneous AHFS patient subgroups (to limit phenotypic vari- likely to be significantly confounded. Testing of new therapies for
ability), may have better internal and external validity (Pang 2010). AHFS should include collaboration among emergency physicians
and cardiologists to enrol participants early in the course of their
exacerbation.
AUTHORS’ CONCLUSIONS Currently, there are a lack of validated measures in the manage-
ment of AHFS that assess long-term outcomes. It is therefore clear
Implications for practice that future studies should employ appropriate end points that are
based on the mechanism of action and the principles of AHFS
Our review found no evidence to support a difference in the ra- management.
pidity of symptom relief between intravenous nitrate vasodilator
therapy and alternative interventions in patients with acute heart
failure syndromes (AHFS). However, randomised controlled trial
(RCT) evidence comparing clinical outcomes of nitrate vasodila-
ACKNOWLEDGEMENTS
tor therapy and alternative interventions in the management of
AHFS is limited and of relatively low methodological quality. The We would like to thank the Cochrane Heart Group for their help
risk of bias in existing RCT evidence is therefore difficult to ascer- and editorial advice during the preparation of this systematic re-
tain. The existing RCT evidence is derived from trials conducted view. We would also like to thank Dr. Geraldine McMahon for
in Western developed countries and they were mainly conducted her help in developing the protocol for this review.
REFERENCES
References to studies included in this review Verma 1987 {published data only}
Verma SP, Silke B, Hussain M, Nelson G, Reynolds
GW, Richmond A, et al. First-line treatment of left
Beltrame 1998 {published data only} ventricular failure complicating acute myocardial infarction:
Beltrame J, Zeitz C, Unger S, Brennan R, Moran J, a randomised evaluation of immediate effects of diuretic,
Horowitz J. Nitrate therapy is an alternative to furosemide/ venodilator, arteriodilator, and positive inotropic drugs
morphine therapy in the management of acute cardiogenic on left ventricular function. Journal of Cardiovascular
pulmonary oedema. Journal of Cardiac Failure 1998;4(4): Pharmacology 1987;10:38–46. [PUBMED: 2441152]
271–9. [PUBMED: 9924848]
Nelson 1983 {published data only} VMAC 2002 {published data only}
Nelson GIC, Silke B, Ahuja RC, Hussain M, Taylor SH. Publication committee for the VMAC Investigators.
Haemodynamic advantages of isosorbide dinitrate over Intravenous nesiritide vs nitroglycerin for treatment of
frusemide in acute heart failure following myocardial decompensated congestive heart failure. JAMA 2002;287
infarction. Lancet 1983;321:730–3. [PUBMED: 6132082] (12):1531–40. [PUBMED: 11911755]
References to studies excluded from this review programme - a survey of the quality of care among patients
with heart failure in Europe. Part 1: Patient characteristics
Cotter 1998 {published data only} and diagnosis. European Heart Journal 2003;24:442–63.
Cotter G, Metzkor E, Kaluski E, Faigenberg Z. Randomised
Cotter 2000
trial of high-dose isosorbide dinitrate plus low-dose
Cotter G, Kaluski E, Blatt A, Milovanov O, Moshkovitz Y,
furosemide versus high-dose furosemide plus low-dose
Zaidenstein R, et al. L-NMMA (a nitric oxide synthase
isosorbide dinitrate in severe pulmonary oedema. Lancet
inhibitor) is effective in the treatment of cardiogenic shock.
1998;351:389–93. [PUBMED: 9482291]
Circulation 2000;101:1358–61.
Elkayam 2004 {published data only}
Cotter 2003
Elkayam U, Akhter MW, Singh H, Khan S, Usman A.
Cotter G, Moshkovitz Y, Kaluski E, Milo O, Nobikov Y,
Comparison of effects on left ventricular filling pressure
Schneeweiss A, et al. The role of cardiac power and systemic
of intravenous nesiritide and high-dose nitroglycerin in
vascular resistance in the pathophysiology and diagnosis
patients with decompensated heart failure. American Journal
of patients with acute congestive heart failure. European
of Cardiology 2004;93:237–40. [PUBMED: 14715359]
Journal of Heart Failure 2003;5:443–51.
Additional references Cowie 1997
Cowie MR, Mosterd A, Wood DA, Deckers JW, Poole-
Adamson 2011 Wilson PA, Suresh V, et al. The epidemiology of heart
Adamson PB, Zile MR, Cho YK, Bennett TD, Bourge failure. European Heart Journal 1997;18:208–25.
RC, Aaron MF, et al. Hemodynamic factors associated
Crane 2002
with acute decompensated heart failure: part 2 - use in
Crane SD. Epidemiology, treatment and outcome of
automated detection. Journal of Cardiac Failure 2011;17
acidotic, acute, cardiogenic pulmonary oedema presenting
(5):366–73. [PUBMED: 21549292]
to an emergency department. European Journal of Emergency
ADHERE 2003 Medicine 2002;9:320–4.
The ADHERE Registry. First Quarter 2003 National
Deeks 2011
Benchmark Report. The ADHERE Registry 2003.
Deeks JJ, Higgins JPT, Altman DG. Chapter 9: Analysing
AHA 2001 data and undertaking meta-analyses . Cochrane Handbook
Heart and stroke statistical update. American Heart for Systematic Reviews of Interventions Version 5.1.0 [updated
Association 2001. March 2011].. The Cochrane Collaboration, 2011.
Ambrosioni 1995 DiDomenico 2004
Ambrosioni E, Borghi C, Magnani B (The Survival of DiDomenico RJ, Park HY, Southworth MR, Eyrich
Myocardial Infarction Long-Term Evaluation (SMILE) HM, Lewis RK, Finley JM, et al. Guidelines for
Study Investigators). The effect of the angiotensin- acute decompensated heart failure treatment. Annals of
converting enzyme inhibitor zofenopril on mortality and Pharmacotherapy 2004;38:646–60.
morbidity after myocardial infarction. New England Journal
DiGuili 2001
of Medicine 1995;332:80–5.
DiGuili F, Anand I. Current issues in heart failure. Acute
Berry 2001 Heart Failure 2001.
Berry C, Murdoch DR, McMurray JJ. Economics of chronic Doughty 1995
heart failure. European Journal of Heart Failure 2001;3: Doughty R, Yee T, Sharpe N, MacMahon S. Hospital
283–91. admissions and deaths due to congestive heart failure in
Bueno 1995 New Zealand, 1981-1991. New Zealand Medical Journal
Bueno H, Vidan MT, Almazan A, Lopez-Sendon JL, Delcan 1995;108:473–5.
JL. Influence of sex on the short-term outcome of elderly Eriksson 1991
patients with a first acute myocardial infarction. Circulation Eriksson H, Wilhelmsen L, Caidahl K, Svardsudd K.
1995;92:1133–40. Epidemiology and prognosis of heart failure. Zeitschrift fur
Campana 1993 Kardiologie 1991;80:1–6.
Campana C, Gavazii A, Berzuini C, Larizza C, Marioni Fonarow 2001
R, D’Armini A, et al. Predictors of prognosis in patients Fonarow GC. The treatment targets in acute decompensated
awaiting heart transplantation. Journal of Heart and Lung heart failure. Reviews in Cardiovascular Medicine 2001;2:
Transplantation 1993;12:756–65. S7–S12.
Cleland 2001 Fonarow 2002
Cleland JGF, Khand A, Clark A. The heart failure epidemic: Fonarow GC. Pharmacologic therapies for acutely
exactly how big is it?. European Heart Journal 2001;22: decompensated heart failure. Reviews in Cardiovascular
623–6. Medicine 2002;3:S18–S27.
Cleland 2003 Fonarow 2003
Cleland JG, Swedberg K, Follath F, Komajda M, Cohen- Fonarow GC (ADHERE Scientific Advisory Committee).
Solal A, Aguilar JC, et al. The EuroHeart Failure survey The Acute Decompensated Heart Failure National Registry
(ADHERE): opportunities to improve care of patients Imhof 1980
hospitalized with acute decompensated heart failure. Imhof PR, Ott B, Frankhauser P, Chu LC, Hodler J.
Reviews in Cardiovascular Medicine 2003;4:S21–S30. Difference in nitroglycerin dose response in the venous and
Fonarow 2008 arterial beds. European Journal of Clinical Pharmacology
Fonarow GC, Abraham WT, Albert NM, Stough WG, 1980;18:455–60.
Gheorghiade M, Greenberg BH, et al. Factors identified ISIS-4 1995
as precipitating hospital admissions for heart failure and Anonymous. ISIS-4: a randomised factorial trial assessing
clinical outcomes: findings from OPTIMIZE-HF. Archives early oral captopril, oral mononitrate, and intravenous
of Internal Medicine 2008;168:847–54. [PUBMED: magnesium sulphate in 58 050 patients with suspected
18443260] acute myocardial infarction. ISIS-4 (Fourth International
Ghali 1990 Study of Infarct Survival) Collaborative Group. Lancet
Ghali JK, Cooper R, Ford E. Trends in hospitalisation rates 1995;345:669–85.
for heart failure in the United States 1973-1986: evidence Kaluski 2003
for screening population prevalence. Archives of Internal Kaluski E, Kobrin I, Zimlichman R, Marmov A, Krakov
Medicine 1992;150:769–73. O, Milo O, et al. RITZ-5: Randomized intravenous
Gheorghiade 2005 tezosentan (an endothelin-A/B antagonist) for the treatment
Gheorghiade M, Zannad F, Sopko G, Klein L, Piña IL, of pulmonary edema. A prospective, multicenter, double-
Konstam MA, et al. Acute heart failure syndromes: current blind, placebo-controlled study. Journal of the American
state and framework for future research. Circulation 2005; College of Cardiology 2003;41:204–10.
20(112(25)):3958–68. Khan 1996
GISSI-3 1994 Khan KS, Daya S, Jadad A. The importance of quality of
GISSI-3. Effects of lisinopril and transdermal glyceryl primary studies in producing unbiased systematic reviews.
trinitrate singly and together on 6-week mortality and Archives of Internal Medicine 1996;156:661–6. [PUBMED:
ventricular function after acute myocardial infarction. 8629879]
Lancet 1994;343:1115–23. Khand 1999
Glasziou 2001 Khand A, Gemmel I, Clark AL, Cleland JGF. Is the
Glasziou P, Irwig L, Bain C, Colditz G. Systematic Reviews prognosis of heart failure improving?. European Journal of
in Health Care: a Practical Guide. Cambridge: Cambridge Heart Failure 1999;1:229–41.
University Press, 2001. Lau 1998
Hellermann 2002 Lau J, Ioannidis JPA, Schmid CH. Quantitative synthesis
Hellermann JP, Jacobsen SJ, Gersh BJ, Rodeheffer RJ, in systematic reviews. In: Mulrow C, Cook D editor(s).
Reeder GS, Roger VL. Heart failure after myocardial Systematic Reviews: Synthesis of Best Evidence for Health Care
infarction: a review. American Journal of Medicine 2002; Decisions. 1st Edition. Philadelphia: American College of
113:324–30. Physicians, 1998:91–101.
Higgins 2003 Lefebvre 2011
Higgins JPT, Thompson SG, Deeks JD, Altman G. Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching
Measuring inconsistency in meta-analysis. BMJ 2003;327: for studies. Using the Cochrane sensitivity-maximising
557–60. [MEDLINE: 12958120] RCT filter. In: Higgins JPT, Green S (editors). Cochrane
Higgins 2011 Handbook for Systematic Reviews of Interventions Version
Higgins JPT, Green S (editors). Cochrane Handbook 5.1.0 [updated March 2011]. The Cochrane Collaboration,
for Systematic Reviews of Interventions Version 5.1.0 2011. Available from www.cochrane-handbook.org.
[updated March 2011]. The Cochrane Collaboration, Lucas 2000
2011. Available from www.cochrane-handbook.org. Lucas C, Johnson W, Hamilton MA, Fonarow GC, Woo
Hochman 1999 MA, Flavell CM, et al. Freedom from congestion predicts
Hochman JS, Sleeper LA, Webb JG, Sanborn TA, White good survival despite previous class IV symptoms of heart
HD, Talley JD, et al. Early revascularization in acute failure. American Heart Journal 2000;140:840–7.
myocardial infarction complicated by cardiogenic shock. McMurray 2012
SHOCK Investigators. Should we emergently revascularize McMurray JJ, Adamopoulos S, Anker SD, Auricchio A,
occluded coronaries for cardiogenic shock. New England Bohm M, Dickstein K, et al. ESC guidelines for the
Journal of Medicine 1999;341:625–34. diagnosis and treatment of acute and chronic heart failure
Hunt 2001 2012: The Task Force for the Diagnosis and Treatment of
Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman Acute and Chronic Heart Failure 2012 of the European
AM, Francis GS, et al. ACC/AHA guidelines for the Society of Cardiology. Developed in collaboration with
evaluation and management of chronic heart failure in the the Heart Failure Association (HFA) of the ESC. European
adult. Journal of the American College of Cardiology 2001; Journal of Heart Failure 2012;14(8):803–69. [PUBMED:
38:2101–13. 22828712]
Mebazaa 2010 Spencer 1999
Mebazaa A, Pang PS, Tavares M, Collins SP, Storrow Spencer FA, Meyer TE, Goldberg RJ, Yarzebski J, Hatton
AB, Laribi S, et al. The impact of early standard therapy M, Lessard D, et al. Twenty year trends (1975-1995) in the
on dyspnoea in patients with acute heart failure: the incidence, in-hospital and long-term death rates associated
URGENT- dyspnoea study. European Heart Journal 2010; with heart failure complicating acute myocardial infarction:
31(7):832–41. [PUBMED: 19906690] a community-wide perspective. Journal of the American
Nohria 2002 College of Cardiology 1999;34:1378–87.
Nohria A, Lewis E, Stevenson LW. Medical management of Spencer 2002
advanced heart failure. JAMA 2002;287:628–40. Spencer FA, Meyer TE, Gore JM, Goldberg RJ.
Pang 2008 Heterogeneity in the management and outcomes of patients
Pang PS, Cleland JG, Teerlink JR, Collins SP, Lindsell with acute myocardial infarction complicated by heart
CJ, Sopko G, et al. A proposal to standardize dyspnoea failure: the National Registry of Myocardial Infarction.
measurement in clinical trials of acute heart failure Circulation 2002;105:2605–10. [MEDLINE: 12045165]
syndromes: the need for a uniform approach. European Steg 2004
Heart Journal 2008;29(6):816–24. [PUBMED: 18310669] Steg PG, Dabbous OH, Feldman LJ, Cohen-Solal A,
Pang 2010 Aumont MC, Lopez-Sendon J, et al. Determinants and
Pang PS, Komajda M, Gheorghiade M. The current and prognostic impact of heart failure complicating acute
future management of acute heart failure syndromes. coronary syndromes: observations from the Global Registry
European Heart Journal 2010;31(7):784–93. [PUBMED: of Acute Coronary Events (GRACE). Circulation 2004;109:
20207624] 494–9.
Peacock 2004 Stevenson 1999
Peacock WF, Emerman CL, Young J. Nesiritide in Stevenson LW. Tailored therapy to hemodynamic goals for
congestive heart failure associated with acute coronary advanced heart failure. European Journal of Heart Failure
syndromes: a pilot study of safety and efficacy. Journal of 1999;1:251–7.
Cardiac Failure 2004;10:120–5. Stewart 2001
Reitsma 1996 Stewart S, MacIntyre K, Hole DJ. More ’malignant’ than
Reitsma JB, Mosterd A, de Craen AJ, Koster RW, van cancer? 5-year survival following a first admission with heart
Capelle FJ, Grobbee DE, et al. Increase in hospital failure. European Journal of Heart Failure 2001;3:315–22.
admission rates for heart failure in the Netherlands, 1980- Stewart 2002
1993. Heart 1996;76:388–92. Stewart S, Jenkins A, Buchan A, McGuire A, Capewell
RevMan 5.2 [Computer program] S, McMurray JJ. The current cost of heart failure to the
The Nordic Centre, The Cochrane Collaboration. Review National Health Service in the UK. European Journal of
Manager (RevMan). Version 5.2. Copenhagen: The Heart Failure 2001;3:361–71.
Nordic Centre, The Cochrane Collaboration, 2012. Stewart 2003
Rodriguez 1997 Stewart S, MacIntyre K, Capewell S, McMurray JJV. Heart
Rodriguez-Artalejo F, Guallar-Castillon P, Banegas Banegas failure and the aging population: an increasing burden in
JR, del Rey Calero J. Trends in hospitalization and mortality the 21st century?. Heart 2003;89(1):49–53.
for heart failure in Spain, 1980-1993. European Heart Weintraub 2010
Journal 1997;18:388–92. Weintraub NL, Collins SP, Pang PS, Levy PD, Anderson
Roger 2011 AS, Arslanian-Engoren C, et al. Acute heart failure
Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, syndromes: emergency department presentation, treatment
Brown TM, et al. Heart disease and stroke statistics--2011 and disposition: current approaches and future aims: a
update: a report from the American Heart Association.. scientific statement from the American Heart Association.
Circulation 2011;1(123(4)):e18–e209. Circulation 2010;122(19):1975–96.
Schappert 2008 Whellan 2013
Schappert SM, Rechtsteiner EA. Ambulatory medical care Whellan DJ, Sarkar S, Koehler J, Small RS, Boyle A,
utilization estimates for 2006. National Health Statistics Warman EN, et al. Development of a method to risk
Reports 2008;6(8):1–29. stratify patients with heart failure for 30-day readmission
Sharon 2000 using implantable device diagnostics. American Journal of
Sharon A, Shpirer I, Kalunski E, Moshkovitz Y, Milovanov Cardiology 2013;111(1):79–84. [PUBMED: 23040596]
O, Polak R, et al. High-dose intravenous isosorbide- Wu 2002
dinitrate is safer and better than Bi-PAP ventilation Wu AH, Parsons L, Every NR, Bates ER. Hospital
combined with conventional treatment for severe pulmonary outcomes in patients presenting with congestive heart
edema. Journal of the American College of Cardiology 2000; failure complicating acute myocardial infarction: a report
36:832–7. from the Second National Registry of Myocardial Infarction

(NRMI-2). Journal of the American College of Cardiology
2002;40:1389–94.
Zile 2011
Zile MR, Adamson PB, Cho YK, Bennett TD, Bourge RC,
Aaron MF, et al. Hemodynamic factors associated with
acute decompensated heart failure: part 1 - insights into
pathophysiology. Journal of Cardiac Failure 2011;17(4):
282–91. [PUBMED: 21440865]
∗
Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Beltrame 1998
Methods Randomised, open-label trial
Participants 87 consecutive patients with acute pulmonary oedema presenting to an ED of a Univer-

sity teaching hospital in Adelaide, Australia
69 patients enrolled (32 frusemide/morphine, 37 nitroglycerin/N-acetylcysteine) pre-
senting with:
1) Acute onset of dyspnoea within the preceding 6 hours
2) Clinical findings consistent with pulmonary oedema including tachypnoea, signs of
increased respiratory work, gallop rhythm, widespread crepitations in the absence of a
history of chest infection or aspiration
3) Radiological evidence of pulmonary oedema
Interventions Intervention 1: Frusemide/morphine therapy: morphine by slow IV injection (1 to 2

mg/5 minutes) to a maximum dose of 10 mg + frusemide 40 mg IV bolus (or twice the
patient’s daily maintenance dose if appropriate) with a second bolus at 60 minutes if
there was an inadequate response
Intervention 2: Nitroglycerin/N-acetylcysteine: N-acetylcysteine 6.6 µg/minute as a
continuous IV infusion over 24 hours + nitroglycerin 2.5 µg/minute as a continuous
simultaneous infusion over 24 hours; if clinical response was considered inadequate and
systolic BP was stable, the dose of the nitroglycerin infusion could be increased to 5 µg/
minute after 15 minutes and/or 10 µg/minute after 60 minutes
Outcomes Primary end point: change in the PaO2/FiO2 ratio over the first hour of therapy
Secondary end points:
Clinical status assessment by measuring: respiratory rate, pulse rate, blood pressure,
Flammang dyspnoea score, pulmonary crepitation score, sweating score
Rate of mechanical ventilatory assistance
Duration of hospital admission
Notes Clinical parameters improved significantly after 60 minutes of medical therapy although
the PaO2/FiO2 ratio did not improve significantly until 3 hours
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection Unclear risk Quote: “On arrival...patients were...if suitable, ran-
bias) domised to F/M or NTG/NAC therapy. Trial therapy
was then instituted...”
Comment: method of randomisation is not described
Allocation concealment (selection bias) Unclear risk Quote: “On arrival...patients were...if suitable, ran-
domised to F/M or NTG/NAC therapy. Trial therapy
was then instituted...”

Beltrame 1998 (Continued)
Comment: likely to have been done as baseline char-

acteristics, including age, sex, history of heart disease,
cardiovascular risk factors and drug therapy, are similar
between both groups; however, there is no description of
the randomisation process, with potential for selection
bias
Blinding (performance bias and detection High risk Comment: conducted as an open-label study, with dif-
bias) ferent administration protocols between the 2 types of
drugs used
Incomplete outcome data (attrition bias) Low risk Quote: “Of the 69 patients enrolled, 4 were subse-
All outcomes quently shown not to have acute pulmonary oedema.
..However, all were included in the intention to treat
analysis”
Selective reporting (reporting bias) Low risk Comment: likely, with data being analysed on an inten-
tion-to-treat basis
Other bias Unclear risk Comment: as this was an open-label study with no de-
scription of the randomisation process there is a poten-
tial for selection bias
Nelson 1983
Methods Prospective, randomised, between-group study
Participants Men aged between 35 and 65 years who fulfilled the study criteria were evaluated in
a coronary care unit between 5 and 14 hours of the onset of symptoms of myocardial
infarction
Interventions Group I: intravenous bolus of frusemide (1 mg/kg)

Group II: isosorbide dinitrate by intravenous infusion, commencing at 50 µg/kg and
doubled every 30 minutes to a maximum of 200 µg/kg/h or until the mean systemic
arterial pressure has been reduced by approximately 10 mmHg; the infusion was then
continued at this dose
Outcomes Systemic arterial pressure, pulmonary artery occluded pressure, heart rate, cardiac output,
stroke volume and systemic vascular resistance
Notes
Risk of bias
Random sequence generation (selection Unclear risk Quote: “Patients in the two randomised
bias) groups were well matched for age, site of in-
farct, plasma level of cardiac enzymes, and

Nelson 1983 (Continued)
radiological evidence of left ventricular fail-

ure.”
Comment: method of randomisation is not
described
Allocation concealment (selection bias) Unclear risk Quote: “Patients in the two randomised
groups were well matched for age, site of in-
farct, plasma level of cardiac enzymes, and
radiological evidence of left ventricular fail-
ure.”
Comment: baseline characteristics, includ-
ing age, site of infarct, plasma level of
cardiac enzymes are similar between both
groups; however, there is no description of
the randomisation process or concealment
Blinding (performance bias and detection Low risk Quote: “The study was designed as a single-
bias) blind between-group comparison.”
Incomplete outcome data (attrition bias) Low risk Quote: “No untoward incident occurred in
All outcomes any patient.”
Comment: no missing data from any treat-
ment groups
Selective reporting (reporting bias) Low risk Comment: all of the study’s pre-specified
outcomes that are of interest in the review
have been reported in the pre-specified way
Other bias Low risk Comment: the study appears to be free of

other sources of bias
Verma 1987
Methods Randomised, single-blind, parallel trial
Participants Men aged 35 to 68 years were studied in a coronary care unit within 18 hours of the
onset of symptoms of acute myocardial infarction
Interventions Patients received 1 of 4 drugs:

1. Frusemide (1 mg/kg IV bolus)
2. Isosorbide dinitrate. Isosorbide infusion was commenced at 50 µg/kg/h and the
dose doubled at 30-minute intervals until the infusion rate was 200 µg/kg/h
3. Hydralazine (0.15 mg/kg IV over 5 minutes)
4. Prenalterol. The prenalterol infusion was commenced at 50 µg/kg/h and the dose
doubled at 30-minute intervals until the infusion rate was 200 µg/kg/h
Outcomes Systemic arterial pressure, pulmonary artery occluded pressure, heart rate, cardiac index,
stroke volume, systemic vascular resistance index and stroke work index

Verma 1987 (Continued)
Notes
Risk of bias
Random sequence generation (selection Unclear risk Quote: “The 48 patients were equally allo-
bias) cated, 12 to each of the four treatment groups
according to predetermined randomisation.”
Comment: method of randomisation is not
described
Allocation concealment (selection bias) Unclear risk Quote: “The 48 patients were equally allo-
cated, 12 to each of the four treatment groups
according to predetermined randomisation”
Comment: Method of concealment is not de-
scribed.
Blinding (performance bias and detection Low risk Quote: “The study was a randomised single-
bias) blind parallel-group comparison of ...”
Incomplete outcome data (attrition bias) Low risk Quote: “The study was accomplished without
All outcomes any untoward incident in any patient”
Comment: no missing data from any treat-
ment groups
Selective reporting (reporting bias) Low risk Comment: all of the study’s pre-specified out-
comes that are of interest to this review have
been reported in the pre-specified way
Other bias Low risk Comment: the study appears to be free of

other sources of bias
VMAC 2002
Methods Prospective, multi-centre trial
Participants Patients were randomised, of which 489 were treated with study drug (143 nitroglyc-
erin, 204 nesiritide and 142 placebo) at 55 centres. All patients had dyspnoea at rest
(or New York Heart Association class IV symptoms) at study entry, 84% had chronic
decompensated CHF that was classified as class III or class IV prior to decompensation,
and most had clinical evidence of fluid overload)
Interventions Intravenous nesiritide (n = 204), intravenous nitroglycerin (n = 143) or placebo (n =

142) added to standard medications for 3 hours, followed by nesiritide (n = 278) or
nitroglycerin (n = 216) added to standard medication for 24 hours

VMAC 2002 (Continued)
Outcomes Primary outcome measure: change in pulmonary capillary wedge pressure (PCWP)
among catheterised patients and patient self evaluation of dyspnoea at 3 hours after ini-
tiation of study drug among all patients
Secondary outcomes included comparisons of haemodynamic and clinical effects be-

tween nesiritide and nitroglycerin at 24 hours
Notes
Risk of bias
Random sequence generation (selection Low risk Quote: ”Randomization occurred after patients were
bias) confirmed to meet all inclusion and exclusion criteria
and informed consent was obtained. ... Non catheter-
ized patients were randomly assigned to receive either
placebo, nitroglycerin… Catheterized patients were
randomly assigned to these same 3 treatment groups
or to the adjustable-dose nesiritide group. For placebo
patients in both strata, the randomization included a
crossover to double blind treatment with either titrat-
able dose or to fixed-dose nesiritide at 3 hours…”
Allocation concealment (selection bias) Low risk Quote: “Randomization was performed using random
permuted blocks within strata (catherized or non-
catherized), with a block size of 8 for the catheter-
ized strata and of 6 for the noncathereterized strata.
Non catheterized patients were randomly assigned to
receive either placebo, nitroglycerin… Catheterized pa-
tients were randomly assigned to these same 3 treatment
groups or to the adjustable-dose nesiritide group. For
placebo patients in both strata, the randomization in-
cluded a crossover to double blind treatment with either
titratable dose or to fixed-dose nesiritide at 3 hours…”
Blinding (performance bias and detection Low risk Quote: ”The study used a double-blind, double-
bias) dummy study drug administration design in which each
patient received simultaneous infusions of nitroglyc-
erin/placebo and nesiritide/placebo.”
Incomplete outcome data (attrition bias) Low risk Comment: small numbers 2 to 4 (per group) did not
All outcomes receive the study drug as assigned
Selective reporting (reporting bias) Low risk The study protocol is available and all of the study’s pre-
specified (primary and secondary) outcomes that are of
interest in the review have been reported in the pre-
specified way

VMAC 2002 (Continued)
Other bias Low risk The study appears to be free of other major sources of
bias
BP: blood pressure

CHF: congestive heart failure
ED: emergency department
IV: intravenous
NAC: N-acetylcysteine
NTG: nitroglycerin
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Cotter 1998 Both arms of the study contain nitrates
Elkayam 2004 This is a subgroup analysis of another study (VMAC 2002)

DATA AND ANALYSES
Comparison 1. Changes in systolic blood pressure
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Change in SBP after 90 mins 2 52 Mean Difference (IV, Fixed, 95% CI) -8.97 [-11.00, -4.94]
(nitrates vs frusemide)
Comparison 2. Changes in diastolic blood pressure after 90 minutes
No. of No. of
1 Change in DBP (nitrates vs 2 52 Mean Difference (IV, Fixed, 95% CI) -2.08 [-3.71, -0.45]
frusemide)
Comparison 3. Changes in heart rate
No. of No. of
1 Change in heart rate at 90 2 52 Mean Difference (IV, Fixed, 95% CI) 2.0 [-0.57, 4.57]
minutes (nitrates vs frusemide)
Comparison 4. Changes in cardiac output
No. of No. of
1 Change in cardiac index at 90 2 52 Mean Difference (IV, Fixed, 95% CI) 0.15 [0.07, 0.22]

Comparison 5. Changes in pulmonary artery occlusion pressure
No. of No. of
1 Change in pulmonary artery 2 52 Mean Difference (IV, Fixed, 95% CI) -2.0 [-2.80, -1.20]
occlusion pressure at 90
Analysis 1.1. Comparison 1 Changes in systolic blood pressure, Outcome 1 Change in SBP after 90 mins
(nitrates vs frusemide).
Review: Nitrates for acute heart failure syndromes
Comparison: 1 Changes in systolic blood pressure
Outcome: 1 Change in SBP after 90 mins (nitrates vs frusemide)
Mean Mean
Study or subgroup ISDN Frusemide Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
Nelson 1983 14 -12 (6) 14 -3 (5) 97.0 % -9.00 [ -13.09, -4.91 ]
Verma 1987 12 -13 (36) 12 -5 (20) 3.0 % -8.00 [ -31.30, 15.30 ]
Total (95% CI) 26 26 100.0 % -8.97 [ -13.00, -4.94 ]

Heterogeneity: Chi2 = 0.01, df = 1 (P = 0.93); I2 =0.0%
Test for overall effect: Z = 4.36 (P = 0.000013)
Test for subgroup differences: Not applicable
-100 -50 0 50 100

Favours ISDN Favours frusemide

Analysis 2.1. Comparison 2 Changes in diastolic blood pressure after 90 minutes, Outcome 1 Change in
DBP (nitrates vs frusemide).
Comparison: 2 Changes in diastolic blood pressure after 90 minutes
Outcome: 1 Change in DBP (nitrates vs frusemide)
Mean Mean
Study or subgroup ISDN Frusemide Difference Weight Difference
Nelson 1983 14 -5 (3) 14 -2 (3) 53.8 % -3.00 [ -5.22, -0.78 ]
Verma 1987 12 -4 (3) 12 -3 (3) 46.2 % -1.00 [ -3.40, 1.40 ]
Total (95% CI) 26 26 100.0 % -2.08 [ -3.71, -0.45 ]

Heterogeneity: Chi2 = 1.44, df = 1 (P = 0.23); I2 =30%
-100 -50 0 50 100

Favours ISDN Favours frusemide
Analysis 3.1. Comparison 3 Changes in heart rate, Outcome 1 Change in heart rate at 90 minutes (nitrates
vs frusemide).
Comparison: 3 Changes in heart rate
Outcome: 1 Change in heart rate at 90 minutes (nitrates vs frusemide)
Mean Mean
Study or subgroup nitroglycerin alternative therapy Difference Weight Difference
Nelson 1983 14 4 (5) 14 2 (4) 58.7 % 2.00 [ -1.35, 5.35 ]
Verma 1987 12 4 (5) 12 2 (5) 41.3 % 2.00 [ -2.00, 6.00 ]
Total (95% CI) 26 26 100.0 % 2.00 [ -0.57, 4.57 ]

Heterogeneity: Chi2 = 0.0, df = 1 (P = 1.00); I2 =0.0%
-100 -50 0 50 100

Favours experimental Favours control

Analysis 4.1. Comparison 4 Changes in cardiac output, Outcome 1 Change in cardiac index at 90 minutes
(nitrates vs frusemide).
Comparison: 4 Changes in cardiac output
Outcome: 1 Change in cardiac index at 90 minutes (nitrates vs frusemide)
Mean Mean
Study or subgroup Nitrates Frusemide Difference Weight Difference
Nelson 1983 14 0.1 (0.2) 14 -0.2 (0.2) 22.6 % 0.30 [ 0.15, 0.45 ]
Verma 1987 12 0.1 (0.1) 12 0 (0.1) 77.4 % 0.10 [ 0.02, 0.18 ]
Total (95% CI) 26 26 100.0 % 0.15 [ 0.07, 0.22 ]

Heterogeneity: Chi2 = 5.42, df = 1 (P = 0.02); I2 =82%
-100 -50 0 50 100


Analysis 5.1. Comparison 5 Changes in pulmonary artery occlusion pressure, Outcome 1 Change in
pulmonary artery occlusion pressure at 90 minutes (nitrates vs frusemide).
Comparison: 5 Changes in pulmonary artery occlusion pressure
Outcome: 1 Change in pulmonary artery occlusion pressure at 90 minutes (nitrates vs frusemide)
Mean Mean
Study or subgroup Nitrates Frusemide Difference Weight Difference
Nelson 1983 14 -8 (1) 14 -4 (0) Not estimable
Verma 1987 12 -6 (1) 12 -4 (1) 100.0 % -2.00 [ -2.80, -1.20 ]
Total (95% CI) 26 26 100.0 % -2.00 [ -2.80, -1.20 ]

Heterogeneity: not applicable
Test for overall effect: Z = 4.90 (P < 0.00001)
-100 -50 0 50 100

ADDITIONAL TABLES
Table 1. Haemodynamic outcome measures for comparator interventions reported by only one trial
Change in SBP after 30 minutes
Study ID Number of participants Comparator interventions Measure of effects
Nelson 1983 28 ISDN versus frusemide Fixed-effect MD -6.00 mmHg,

95% CI -10.51 to -1.49
Beltrame 1998 69 NTG/NAC versus frusemide/ Fixed-effect MD -2.00 mmHg,

morphine 95% CI -21.49 to 17.49
Change in SBP after 60 minutes

95% CI -12.62 to -7.38

morphine 95% CI -23.75 to 15.75

Table 1. Haemodynamic outcome measures for comparator interventions reported by only one trial (Continued)
Change in SBP after 3 hours
VMAC 2002 285 NTG versus placebo Fixed-effect MD -3.20 mmHg,

95% CI -6.19 to -0.21
VMAC 2002 347 NTG versus nesiritide Fixed-effect MD -3.05 mmHg,

95% CI -3.05 to 2.85

morphine 95% CI -21.32 to 17.32
Change in SBP after 24 hours

morphine 95% CI -21.94 to 15.94

95% CI -5.22 to -0.78

95% CI -7.22 to -2.78
Change in HR after 30 minutes
Nelson 1983 28 ISDN versus frusemide Fixed-effect MD 0.00 bpm, 95%

CI -3.35 to 3.35
Beltrame 1998 69 NTG/NAC versus frusemide/ No significant difference reported

morphine
Change in HR after 60 minutes

Nelson 1983 28 ISDN versus frusemide Fixed-effect MD 1.00 bpm, 95%

CI -2.35 to 4.35
Beltrame 1998 69 NTG/NAC versus frusemide/ No significant difference reported

morphine
Change in HR after 3 hours
Beltrame 1998 69 NTG/NAC versus frusemide/ Fixed-effect MD -2.00 bpm, 95%

morphine CI -15.54 to 11.54
Change in HR after 24 hours
Beltrame 1998 69 NTG/NAC versus frusemide/ Fixed-effect MD 10.00 bpm, 95%

morphine CI -2.78 to 22.78
Change in PAOP after 3 hours
VMAC 2002 122 NTG versus placebo Fixed-effect MD -1.80 mmHg,

95% CI -3.50 to -0.10
VMAC 2002 184 NTG versus nesiritide Fixed-effect MD 2.00 mmHg,

95% CI 0.24 to -3.76
Verma 1987 24 ISDN versus frusemide Fixed-effect MD 2.00 mmHg,

95% CI -3.34 to 7.34
VMAC 2002 246 NTG versus nesiritide Mean reduction in PAOP was sig-
nificantly greater with nesiritide (-
8.2 mmHg) than with NTG (-6.
3; P = 0.04)
Change in CO after 3 hours

VMAC 2002 184 NTG versus placebo Fixed-effect MD 0.20 L/min/m2 ,

95% CI 0.00 to 0.40
VMAC 2002 184 NTG versus nesiritide Fixed-effect MD 0.10 L/min/m2 ,

95% CI -0.05 to -0.25
bpm: beats per minute
CI: confidence interval
CO: cardiac output
HR: heart rate
ISDN: isosorbide dinitrate
MD: mean difference
NAC: N-acetylcysteine
NTG: nitroglycerin
PAOP: pulmonary artery occlusion pressure
SBP: systolic blood pressure
APPENDICES
Appendix 1. Search strategies 2011
CENTRAL
#1 MeSH descriptor Heart Failure explode all trees
#2 heart next failure
#3 cardiac next failure
#4 (#1 OR #2 OR #3)
#5 MeSH descriptor Nitroglycerin, this term only
#6 MeSH descriptor Nitrates explode all trees
#7 nitrat*
#8 nitroglycerin*
#9 trinitrate*
#10 dinitrate*
#11 mononitrate*
#12 nitroprusside*
#13 trinitrin
#14 glyceryltrinitrate*
#15 isosorbide
#16 gtn
#17 MeSH descriptor Isosorbide Dinitrate, this term only
#18 MeSH descriptor Nitroprusside, this term only
#19 (#5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11)
#20 (#12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18)
#21 (#19 OR #20)
#22 (#4 AND #21)
MEDLINE
1. exp Heart Failure/
2. heart failure.tw.
3. cardiac failure.tw.
4. or/1-3
5. Nitroglycerin/
6. exp Nitrates/
7. Isosorbide Dinitrate/
8. Nitroprusside/
9. nitrate*.tw.
10. nitroglycerin*.tw.
11. trinitrate*.tw.
12. dinitrate*.tw.
13. mononitrate*.tw.
14. nitroprusside*.tw.
15. trinitrin.tw.
16. glyceryltrinitrate*.tw.
17. isosorbide.tw.
18. gtn.tw.
19. or/5-18
20. 4 and 19
21. randomized controlled trial.pt.
22. controlled clinical trial.pt.
23. randomized.ab.
24. placebo.ab.
25. clinical trials as topic.sh.
26. randomly.ab.
27. trial.ti.
28. 21 or 22 or 23 or 24 or 25 or 26 or 27
29. exp animals/ not humans.sh.
30. 28 not 29
31. 20 and 30
EMBASE 2011
1. exp heart failure/
2. heart failure.tw.
3. cardiac failure.tw.
4. or/1-3
5. glyceryl trinitrate/
6. nitrate/
7. exp nitric acid derivative/
8. nitroprusside sodium/
9. nitrate*.tw.
10. nitroglycerin*.tw.
11. trinitrate*.tw.
12. dinitrate*.tw.
13. mononitrate*.tw.
14. nitroprusside*.tw.
15. trinitrin.tw.
16. glyceryltrinitrate*.tw.
17. isosorbide.tw.
18. gtn.tw.
19. or/5-18
20. 4 and 19
21. random$.tw.
22. factorial$.tw.
23. crossover$.tw.
24. cross over$.tw.
25. cross-over$.tw.
26. placebo$.tw.
27. (doubl$ adj blind$).tw.
28. (singl$ adj blind$).tw.
29. assign$.tw.
30. allocat$.tw.
31. volunteer$.tw.
32. crossover procedure/
33. double blind procedure/
34. randomized controlled trial/
35. single blind procedure/
36. 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35
37. (animal/ or nonhuman/) not human/
38. 36 not 37
39. 20 and 38
40. (200807* or 200808* or 200809* or 20081* or 2009* or 2010* or 2011*).dd.
41. 39 and 40
WHAT’S NEW
Last assessed as up-to-date: 20 January 2012.
Date Event Description
29 March 2014 Amended The following statement in the Discussion section of the review (paragraph 3) has been amended:
“Regarding adverse events after three hours, our review found a lower incidence of adverse events with
intravenous nitrate therapy compared with placebo, but a higher incidence of adverse events compared
with nesiritide; however, both of these findings were based on one trial respectively, therefore the
estimates yielded may be imprecise.” The statement has been amended to read as follows: “Regarding
adverse events after three hours, our review found a higher incidence of adverse events with intravenous
nitrate therapy compared with placebo and compared with nesiritide; however, both of these findings
were based on one trial respectively, therefore the estimates yielded may be imprecise.”

HISTORY
Protocol first published: Issue 1, 2005
Review first published: Issue 8, 2013
Date Event Description
27 June 2013 Amended Since the publication of the protocol for this review, the term ’acute heart failure syndromes’ has emerged,
by international consensus, as the encompassing term for the disease entities of interest in this review.
The title of this review has therefore been changed from ’acute heart failure’ to ’acute heart failure
syndromes’, to be consistent with the new international consensus terminology
CONTRIBUTIONS OF AUTHORS
Conceiving the review: Abel Wakai (AW)
Co-ordinating the review: AW
Undertaking manual searches: AW
Screening search results: Rachel Kidney (RK), Caroline Pospisil (CP)
Organising retrieval of papers: AW
Screening retrieved papers against inclusion criteria: AW and Gregory J Fermann (GJF)
Appraising quality of papers: Aileen McCabe (AM) and Nigel Salter (NS)
Abstracting data from papers: Steven C Brooks (SCB) and RK
Writing to authors of papers for additional information: AW
Providing additional data about papers: AW and NS
Obtaining and screening data on unpublished studies: AW
Data management for the review: AW
Entering data into Review Manager (RevMan 5.2): Rawle A Seupal (RAS) and Deborah B Diercks (DBD)
RevMan statistical data: AW
Other statistical analysis not using RevMan: N/A
Double entry of data: (data entered by person one: RAS; data entered by person two: DBD)
Interpretation of data: AW
Statistical inferences: AW
Writing the review: AW
Securing funding for the review: N/A
Performing previous work that was the foundation of the present study: AW and Dr. Geraldine McMahon
Guarantor for the review (one author): AW
Person responsible for reading and checking review before submission: AW
DECLARATIONS OF INTEREST
None known.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

Since the publication of the protocol for this review, the term ’acute heart failure syndromes’ has emerged, by international consensus,
as the encompassing term for the disease entities of interest in this review. The title of this review has therefore been changed from
’acute heart failure’ to ’acute heart failure syndromes’, to be consistent with the new international consensus terminology.
INDEX TERMS
Medical Subject Headings (MeSH)
Acute Disease; Heart Failure [∗ drug therapy]; Isosorbide Dinitrate [therapeutic use]; Nitrates [∗ therapeutic use]; Nitroglycerin [thera-
peutic use]; Randomized Controlled Trials as Topic; Syndrome; Vasodilator Agents [∗ therapeutic use]
MeSH check words

Adult; Humans


Nitrates For Acute Heart Failure Syndromes

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Nitrates For Acute Heart Failure Syndromes

Uploaded by

Copyright:

Available Formats

Cochrane Database of Systematic Reviews

Nitrates for acute heart failure syndromes (Review)

Nitrates for acute heart failure syndromes (Review)

Nitrates for acute heart failure syndromes (Review) i

Nitrates for acute heart failure syndromes

Editorial group: Cochrane Heart Group.

PLAIN LANGUAGE SUMMARY

Nitrates for acute heart failure syndromes (Review) 3

Nitrates for acute heart failure syndromes (Review) 4

OBJECTIVES Secondary outcomes

Criteria for considering studies for this review Electronic searches

Searching other resources

Nitrates for acute heart failure syndromes (Review) 5

Nitrates for acute heart failure syndromes (Review) 6

Subgroup analysis and investigation of heterogeneity

Results of the search

Nitrates for acute heart failure syndromes (Review) 7

Nitrates for acute heart failure syndromes (Review) 8

Nitrates for acute heart failure syndromes (Review) 9

In terms of random sequence generation and allocation conceal-

Nitrates for acute heart failure syndromes (Review) 10

Nitrates for acute heart failure syndromes (Review) 11

Change in systolic blood pressure (SBP)

Nitrates for acute heart failure syndromes (Review) 12

Nitrates for acute heart failure syndromes (Review) 13

Nitrates for acute heart failure syndromes (Review) 14

Nitrates for acute heart failure syndromes (Review) 18

Nitrates for acute heart failure syndromes (Review) 19

Characteristics of included studies [ordered by study ID]

Methods Randomised, open-label trial

Participants 87 consecutive patients with acute pulmonary oedema presenting to an ED of a Univer-

Interventions Intervention 1: Frusemide/morphine therapy: morphine by slow IV injection (1 to 2

Bias Authors’ judgement Support for judgement

Nitrates for acute heart failure syndromes (Review) 20

Comment: likely to have been done as baseline char-

Methods Prospective, randomised, between-group study

Interventions Group I: intravenous bolus of frusemide (1 mg/kg)

Bias Authors’ judgement Support for judgement

Nitrates for acute heart failure syndromes (Review) 21

radiological evidence of left ventricular fail-

Other bias Low risk Comment: the study appears to be free of

Methods Randomised, single-blind, parallel trial

Interventions Patients received 1 of 4 drugs:

Nitrates for acute heart failure syndromes (Review) 22

Bias Authors’ judgement Support for judgement

Other bias Low risk Comment: the study appears to be free of

Methods Prospective, multi-centre trial

Interventions Intravenous nesiritide (n = 204), intravenous nitroglycerin (n = 143) or placebo (n =

Nitrates for acute heart failure syndromes (Review) 23

Secondary outcomes included comparisons of haemodynamic and clinical effects be-

Bias Authors’ judgement Support for judgement

Nitrates for acute heart failure syndromes (Review) 24

BP: blood pressure

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Cotter 1998 Both arms of the study contain nitrates

Elkayam 2004 This is a subgroup analysis of another study (VMAC 2002)

Nitrates for acute heart failure syndromes (Review) 25

Comparison 1. Changes in systolic blood pressure

Comparison 2. Changes in diastolic blood pressure after 90 minutes

Comparison 3. Changes in heart rate

Comparison 4. Changes in cardiac output

Nitrates for acute heart failure syndromes (Review) 26