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Archives of cardiovascular diseases
Volume 109, n° 8-9
pages 449-456 (août 2016)
Doi : 10.1016/j.acvd.2016.01.014
Received : 24 September 2015 ;  accepted : 26 January 2016
Temporal trends in nitrate utilization for acute heart failure in elderly emergency patients: A single-centre observational study
Évolution temporelle de l’utilisation des dérivés chez les patients de plus de 75ans admis aux urgences pour insuffisance cardiaque aiguë

Najla Lemachatti a, Anne-Laure Philippon a, b, Benjamin Bloom c, Pierre Hausfater a, b, Bruno Riou a, b, Patrick Ray b, d, Yonathan Freund a, b,
a Emergency Department, Hôpital Pitié-Salpêtrière, AP–HP, 75013 Paris, France 
b Paris Sorbonne Université, UPMC Université Paris 6, UMRS Inserm 1166, IHU ICAN, 75013 Paris, France 
c Queen Mary University, London, UK 
d Emergency Department, Hôpital Tenon, AP–HP, 75020 Paris, France 

Corresponding author at: Service d’Accueil des Urgences, Groupe Hospitalier Pitié-Salpêtrière, 47–83, boulevard de l’Hôpital, 75013 Paris, France.

We previously conducted a pilot study that reported the safety of isosorbide dinitrate boluses for elderly emergency patients with acute heart failure syndrome.


To assess the temporal trend in the rate of elderly patients treated with isosorbide dinitrate, and to evaluate subsequent outcome differences.


This was a single-centre study. We compared patients aged>75 years who attended the emergency department with a primary diagnosis of acute pulmonary oedema in the years 2007 and 2014. The primary endpoint was the rate of patients who received isosorbide dinitrate boluses in the emergency department. Secondary endpoints included in-hospital mortality, need for intensive care and length of stay.


We analysed 368 charts, 232 from patients included in 2014 (63%) and 136 in 2007 (37%). The mean age was 85±6 years in both groups. There was a significant rise in the rate of patients treated with isosorbide dinitrate between 2007 and 2014: 97 patients (42%) in 2014 vs. 24 patients (18%) in 2007 (P <0.01). Comparing the two periods, we report similar in-hospital mortality rates (8% vs. 11%; P =0.5), rates of admission to the intensive care unit (13% vs. 17%; P =0.3) and lengths of stay (10 days in both groups).


We observed a significant rise in the rate of elderly patients treated with isosorbide dinitrate boluses for acute heart failure. However, we did not observe any significant improvement in outcomes.

The full text of this article is available in PDF format.

Nous avons publié précédemment une étude rapportant la sécurité d’utilisation du dinitrate d’isosorbide (ISDN) chez les patients de plus de 75ans aux urgences.


Évaluer l’évolution temporelle du taux de patients âgés traités par ISDN aux urgences pour œdème aigu pulmonaire (OAP), et l’impact en terme de pronostic.


Étude monocentrique rétrospective. Nous avons comparé les patients de plus de 75ans admis aux urgences pour OAP sur les années 2007 et 2014. Le critère de jugement principal était le traitement par bolus intraveineux d’ISDN. Les critères secondaires incluaient la mortalité hospitalière, l’admission en soins intensifs, et la durée d’hospitalisation.


Nous avons analysé 368 dossiers – 232 en 2014 (63 %) et 136 en 2007 (37 %). L’âge moyen était de 85ans (écart-type 6) dans les deux groupes. Il y avait une augmentation significative du taux de patients traités par ISDN en 2014 : 97 patients (42 %) vs 24 (18 %) en 2007. La mortalité hospitalière, l’admission en soins intensifs et la durée d’hospitalisation étaient inchangées entre les deux périodes.


Le taux de patients traités par ISDN a bien augmenté avec le temps, sans que nous n’ayons pu en montrer un impact pronostique.

The full text of this article is available in PDF format.

Keywords : Heart failure, Isosorbide dinitrate, Nitrates, Elderly, Emergency

Mots clés : Nitrés, Dinitrate d’isosorbide, Insuffisance cardiaque aiguë, Urgences, Gériatrie

Abbreviations : AHF, APE, ED, ESC, ICD10, ICU, ISDN, IQR


Acute heart failure (AHF) syndrome represents 5% of all emergency hospitalizations [1], and is reported to be the most common discharge diagnosis from the emergency department (ED) in elderly patients [2, 3, 4, 5]. Rates of rehospitalization and/or death at 60 days range from 30% to 50% [1]. Acute pulmonary oedema (APE) is characterized by an increase in capillary pulmonary pressures and tissue congestion, and its pharmacological therapy usually includes loop diuretics and nitrates. The value of these treatments lies in their potential to reduce congestion, through either vasodilatation or diuresis, which subsequently helps to decrease systemic vascular resistances and capillary pulmonary pressures. Since the pivotal studies by Cotter et al. [6, 7], nitrates are recommended for the treatment of APE. The American Heart Association and the European Society of Cardiology (ESC) include the use of nitrates in their guidelines [8, 9] for patients with systolic blood pressure>110mmHg [8]. Recently, this treatment has been confirmed as first-line therapy by the ESC and the European Society of Emergency Medicine [10].

Although recommended by the ESC (grade IIA), nitrates are still insufficiently prescribed, as described in several studies [11, 12, 13]. A very low rate of elderly patients treated with nitrates was also seen in our previous retrospective study conducted in 2007 [14]. Of note, this study reported that isosorbide dinitrate (ISDN) as an intravenous bolus was safe in patients aged>75 years presenting to the ED with APE.

Since the publication of our 2007 study, we have repeatedly highlighted the need for and safety of use of ISDN boluses for the treatment of elderly patients who present with APE in our ED; this was done by regular training sessions. The principal objective of this study was, therefore, to determine the effect of these training sessions on the use of nitrates by emergency physicians, by establishing the change in the rate of patients treated with ISDN in bolus form between 2007 and 2014. The secondary objective was to describe the evolution of patient status between 2007 and 2014.


This was a single-centre study. We retrospectively included all patients who presented to our ED with a diagnosis of APE in the year 2007 (the “before” cohort, from our previously published study [14]) and 2014 (the “after” cohort). Our institution is an academic, urban, 1800-bed hospital, with an ED attendance of approximately 70,000 visits each year. As the study was observational and retrospective, our Institutional Review Board (Comité de Protection des Personnes-Paris Île-de-France VI) waived the need for approval. We followed the recommendations by Kaji et al. [15] for chart abstractions, including training of the abstractors, explicit definition of the inclusion criteria (International Classification of Diseases, Tenth Revision [ICD10] of APE or AHF syndrome) and endpoint (provision of intravenous nitrates), definition of variables, standardized abstraction forms, regular meetings with the principal investigators and abstractors or experts, and chart abstractions only performed by two abstractors who were not blinded to each other's work, and who were aware of the study hypothesis.

Selection of participants and outcomes

We included patients aged75 with cardiogenic APE in the ED with an indication for treatment using nitrates. These patients correspond to clinical scenarios 1 and 2 of the practical recommendations for early in-hospital management of patients with AHF syndrome [10]: patients with a systolic blood pressure>110mmHg, signs of pulmonary oedema, no sign of shock and no predominant signs of hypoperfusion. To select these patients, we first electronically retrieved all the files for patients who visited the ED with a primary discharge diagnosis (using ICD10) of “pulmonary oedema” or “acute heart failure” and an age>74 years. Two abstractors reviewed all charts pertaining to the patients’ ED visit, to select those with a presentation of clinical scenario 1 or 2. Patients with another primary diagnosis and those with incomplete records were excluded, as were patients with a primary diagnosis of AHF and no APE, and patients with hypotension or pulmonary oedema from a cause other than AHF. We also excluded patients with a contraindication for ISDN (e.g. aortic stenosis).

Our primary endpoint was the administration of ISDN in bolus form in the ED. Secondary endpoints include receipt of other treatments within the ED, in-hospital mortality, intensive care unit (ICU) admission and length of hospital stay.

Baseline characteristics, treatment and disposition were collected through our electronic system for medical charts and prescriptions (UrQual; McKesson, San Francisco, CA, USA). Data regarding outcomes were collected in the department or the institution where the patients were admitted or transferred to, through examination of the medical charts or the administrative system, if necessary.


After 2007 and the results of our pilot study, we emphasized the need for and safety of ISDN use for elderly patients with APE. We presented the results at a national scientific assembly, and at other faculty courses on emergency and geriatrics.

Every 6 months, our trainees underwent a 30-minute course on APE and its recommended treatment, with particular emphasis on ISDN boluses. Senior emergency physicians repeatedly insisted on this treatment during morning rounds, and our standard of protocols set after 2007 included the use of ISDN in bolus form for patients with APE who presented to our institution: all patients with evidence of cardiogenic pulmonary oedema should be treated with boluses of 3mg intravenous ISDN, every 5minutes, as long as their systolic blood pressure remains>90–100mmHg.

Statistical analysis

Continuous variables are expressed as means±standard deviations when normally distributed, and as medians (interquartile ranges [IQRs]) when not. Normality was tested with the Kolgomorov-Smirnov test. Categorical variables are expressed as numbers (percentages). We compared means and medians using Student's t -test and the Mann-Whitney U test, respectively, and percentages using the Chi2 test or Fisher's exact test, when appropriate. The numbers of patients with missing data are reported for each analysed category. A sensitivity analysis was prespecified to include only patients in whom the diagnosis of APE was confirmed during the hospitalization.

To assess the effect of the period, we ran a multivariable logistic regression with prespecified variables that we found clinically relevant and without missing data, namely period, age, history of chronic obstructive pulmonary disorder, history of diabetes, history of hypertension, chronic use of nitrates, chronic use of diuretics, heart rate on arrival, systolic blood pressure and clinical signs of respiratory distress.

A P level of 0.05 was required to rule out the null hypothesis, and all comparisons were two-tailed. Statistical analysis was carried out with NCSS 2007 software (Statistical Solutions Ltd., Cork, Ireland).


In the 2007 cohort, we included 136 patients with APE (from an annual census of 50,497 ED visits). In 2014, 13% of patients were aged>75 years. From these, 256 files were extracted and 24 patients were excluded (12 with incorrect main diagnosis, five incomplete files and seven patients aged<75 years), leaving 232 patients in total (from an annual census of 59,507 ED visits).

Baseline characteristics of the population are shown in Table 1. The mean age of included patients was 85±6 years. Patients included in 2014 had a higher prevalence of co-morbidities and cardiovascular risk factors. Chronic obstructive pulmonary disease (28% vs. 8%; P <0.01), AHF (69% vs. 40%; P <0.01) and ischaemic heart disease (38% vs. 28%; P =0.05) were more prevalent in the 2014 cohort compared with the 2007 cohort. Similarly, diuretics, angiotensin-converting enzyme inhibitors and beta-blockers were more commonly prescribed in 2014 compared with 2007. Physiological variables on admission were similar in both groups, except for the more frequent presence of signs of acute respiratory distress – paradoxical respiration, intercostal indrawing or use of accessory inspiratory muscle (23% in 2014 vs. 13% in 2007; P =0.02).

In total, 122 patients (33%) received ISDN in bolus form in the ED. There was a significantly higher rate of patients treated with ISDN boluses in 2014 compared with in 2007 (42% vs. 18%; P <0.01). These patients received a higher median prescribed dosage of ISDN: 5mg (IQR 4–9mg) vs. 3mg (IQR 3–4mg) (P <0.01). The rates of patients treated with diuretics in the ED were similar in both cohorts: 88% in 2007 vs. 83% in 2014 (P =0.2); median dose, 40mg (P =0.8) (Table 2). Logistic regression confirmed the effect of the period, with an odds ratio of 3.94 (95% confidence interval 2.22–7.01) as shown in Table 3, along with the influence of systolic blood pressure, chronic intake of nitrates and signs of respiratory distress.

After admission to the ED, 92% of patients in 2014 and 90% in 2007 were admitted to hospital (P =0.5). The median length of stay was 10 days in both cohorts (IQR 5–15; P =0.9). There were no significant differences in outcomes, with similar rates of ICU admission (17% vs. 13%; P =0.3) and in-hospital death (11% vs. 8%; P =0.5) (Table 4).

After excluding patients in whom the diagnosis of APE had subsequently been excluded during hospitalization (n =27), we found similar results and trends, with a higher rate of ISDN bolus utilization in 2014, and no significant changes in outcomes.

Of note, we confirmed our previous results regarding the safety of ISDN in boluses, with similar rates of hypotension after treatment in both groups: five (4%) in the bolus group vs. 14 (6%).


Our study compared the prescription of nitrates in an ED in 2007 and 2014, for the treatment of APE in patients aged>75 years. After our intervention, we saw a significant increase in the rate of elderly patients treated with ISDN boluses: 42% vs. 18% (P <0.01). Our pilot study published in 2009 [14] did not report any hypotension under 90mmHg in these treated patients, which may have reassured emergency physicians about this prescription. Bertini et al. [16] reported an approach seeking to familiarize emergency physicians with the use of nitrates for the prehospital care of APE, with the implementation of guidelines including boluses of nitroglycerin despite equipoise. The authors reported a subsequent significant increase in patients treated with boluses of nitroglycerin (67% vs. 34%).

Although being part of the recommended medical treatment strategy for AHF, nitrates remain underused. Several studies have reported insufficient prescription rates. In the ESC Heart Failure Long-Term Registry [12], Maggioni et al. reported that only 20% of patients received intravenous nitrates in accordance with European guidelines. Similarly, a single-centre study carried out by Mohan et al. in Scotland [17] showed that among the 49% of patients with AHF and eligible for treatment with nitrates, only 12% actually received them. Finally, in a Canadian study carried out in six EDs, only 29% of AHF patients received nitrates [18]. These studies emphasize the need for intervention to improve these rates, such as we report on in the present study.

Our two cohorts were not similar in terms of co-morbidities. Compared with 2007, the elderly patients with APE in 2014 presented more often with chronic obstructive pulmonary disease, heart failure and dementia. A high rate of co-morbidities has also been reported recently in the European studies of Maggioni et al. [12] and Zannad et al. [19], where similar rates of heart failure, ischaemic heart disease and other co-morbidities are described. However, the reasons why this has changed from 2007 to 2014 is not clear. It is possible that elderly patients are followed more closely and hence diagnosed earlier with these co-morbidities; this may occur as a result of the provision of more intensive primary care to an elderly population.

Interestingly, we did not see a subsequent improvement in outcomes, with similar in-hospital mortality rates (8% and 11%), rates of admission to ICU (13% and 17%) and lengths of stay (10 days in both groups) in 2014 and 2007. These data are in line with reported outcomes from recent European studies on heart failure [4, 20]. Other studies showed significant differences concerning patients’ outcomes when treated with nitrates. Kwiatkowski et al. [21] conducted a retrospective study in the USA, where treatment with a high-dose of nitroglycerin was associated with a significantly lower rate of ICU admission in patients with acute, hypertensive heart failure, compared with other nitrate administration strategies.

The issue of whether the use of ISDN improves outcomes of AHF remains controversial. After pivotal studies by Cotter et al. [6, 7], nitrate treatment was given a Class I recommendation [1, 22]. In 2012, this recommendation was downgraded to Class IIa [8, 10], as the scientific basis supporting its utilization seemed limited, with very few patients enrolled in randomized controlled trials evaluating nitrates in AHF [6, 7]. Furthermore, some studies reported an absence of benefit in patients treated with nitrates [23, 24], whereas others reported a significant improvement in terms of mortality and severe outcome after nitrate utilization [16, 25]. A systematic review concluded that prescription of nitrates is based more on a clinical dogma than on high-quality trials, and reliable data on survival benefit are lacking [26]. Despite the absence of many high-quality, generalizable, randomized trials, evidence of benefit of a treatment strategy including nitrates in AHF has still been reported (in the ALARM-HF study), with the use of a powerful statistical tool to match patients [25].

We did not find any changes in outcomes between 2007 and 2014 in our study, which may be caused by a lack of power to detect significant benefits, or because our two cohorts did not have similar baseline characteristics at presentation to the ED, as highlighted above. Multiple confounding factors prevented us from studying the effect of nitrate treatment on outcomes, as populations could not be matched. Unadjusted comparisons would not result in a satisfactory result, and our sample was too small to consider other adjusting methods, such as logistic regression or propensity score.

Study limitations

This study has some limitations. First, this was a single-centre study, which means that the results are not generalizable. Second, the principal limitation is that we cannot associate the trends in outcomes with the trends in treatment. Many factors may have changed between 2007 and 2014 (e.g. different physicians, easier access to investigations and different patient profiles). These factors do not allow us to assert that the rise in patients treated with ISDN did not translate into better outcomes. The impact of the “before/after” methodology can be influenced by other variations. This chosen methodology can only inform on the evolution of practices in the unit. Assessment of the impact of ISDN would require matched patients or a randomized intervention. The difference in the size of the two samples may be explained by the continuous rise in the ED census: almost 20% between the two periods analysed. Moreover, with a small sample of analysed patients, we may have been underpowered to detect a difference. It would have been interesting to analyse separately patients with clinical scenarios 1 or 2 (i.e. systolic blood pressure higher or lower than 140mmHg).

Another source of inclusion bias lies in the fact that our endpoint was treatment with nitrates as boluses – not an intravenous drip. This reflects our daily practice, as our standard of protocol includes boluses of 3mg intravenous nitrates every 5minutes, which may not be the standard of care in another setting. Finally, the study suffers from the retrospective design, which resulted in poor quality of collected data, and potential bias regarding inclusion and classification.


We report a significant rise in the rate of elderly patients treated with ISDN boluses for APE, from 18% in 2007 to 42% in 2014 (P <0.01). We do not report any subsequent change in terms of outcomes.

Disclosure of interest

The authors declare that they have no competing interest.


This study was presented in part at the 2015 Scientific Assembly of the French Society of Emergency Medicine, Paris, France. This work has not been published previously, and is not under consideration for publication elsewhere. Y. F. and P. R. conceived the study. Y. F. and N. L. collected the data. A. L. P. and P. H. provided chart expertise. Y. F. ran the statistical analysis. Y. F., N. L. and B. R. interpreted the data. N. L. drafted the manuscript. Y. F., B. B. and B. R. provided substantial revisions. All authors read and approved the manuscript.Sources of funding : none.


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