What is the comparative efficacy and safety of isosorbide mononitrate versus isosorbide dinitrate in patients with congestive heart failure (compensated or decompensated)?

Comment by InpharmD Researcher

While isosorbide mononitrate (ISMN) is well-acknowledged for its prolonged effects, minimal data exist comparing the clinical efficacy and safety of ISMN with isosorbide dinitrate (ISDN) in patients with heart failure in general. A dated randomized crossover study reported similar hemodynamic effects of both agents in patients with pump failure of ischemic etiology; however, clinically meaningful differences between the two formulations remain uncertain.

Background

Per the 2022 American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Failure Society of America (HFSA) guidelines, a combination of hydralazine and isosorbide dinitrate is recommended to improve symptoms and reduce morbidity and mortality patients self-identified as African American with New York Heart Association (NYHA) class III-IV heart failure with reduced ejection fraction (HFrEF) who are receiving optimal medical therapy. Alternatively, in patients with current or previous symptomatic HFrEF who cannot be given first-line agents because of drug intolerance or renal insufficiency, a combination of hydralazine and isosorbide dinitrate might be considered to reduce morbidity and mortality. The guidelines provide no preference for one agent over the other with or without combination with hydralazine. [1]

A 1984 review comparing isosorbide mononitrate and dinitrate (ISMN and ISDN) formulations discussed that oral ISMN might provide a more predictable blood concentration compared to ISDN due to the less variability in first-pass metabolism or absorption. The majority of the clinical studies, dated back to the 1980s, compared the two agents for angina with no detailed information on heart failure status. Results from a 1981 German study involving 13 patients with chronic heart failure reported similar hemodynamic effects of 60 mg ISMN and 60 mg slow-release ISDN but slightly more reductions in right atrial mean pressure and pulmonary artery diastolic pressure associated with ISMN. Given the study was only available in Germany, detailed information cannot be further confirmed. [2], [3]

A 2018 retrospective study evaluated the comparative clinical outcomes of chronic systolic HF patients (N= 362) receiving hydralazine-isosorbide dinitrate (H-ISDN; n= 145) versus hydralazine-isosorbide mononitrate (H-ISMN; n= 217). The use of HF medications was similar between the two groups. However, there was a significantly greater number of patients with coronary artery disease in H-ISMN group than H-ISDN group (51.2% vs. 41.4%; p= 0.04) and more African American patients in the H-ISMN group than the H-ISDN group (55.9% vs. 43.4%; p= 0.01). The combined primary end-point of death or hospitalization comparing H-ISMN to H-ISDN revealed a significantly different outcome (odds ratio 0.577, 95% confidence interval 0.337 to 0.987; p= 0.04). However, the outcome of death alone was not significantly different between the two groups. Of note, this study was merely published as a poster presentation abstract. Results may be considered preliminary, and further studies confirming the results are warranted. [4]

References:

[1] Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022;79(17):e263-e421. doi:10.1016/j.jacc.2021.12.012
[2] Ltd BPG. Is isosorbide mononitrate better than the dinitrate? Drug and Therapeutics Bulletin. 1984;22(2):7-8.
[3] Bödigheimer K, Nowak FG, Delius W. Vergleichende invasive Untersuchung über die Wirking von Isosorbid-5-Mononitrat und Isosorbiddinitrat bei chronischer Herzinsuffizienz [Comparative invasive examination of the effect of isosorbide-5-mononitrate and isosorbide dinitrate in chronic coronary insufficiency]. Med Welt. 1981;32(14A):543-547.
[4] Peltzer B, Nag T, Kim Y, et al. FEWER DEATHS OR HOSPITALIZATIONS FOR HEART FAILURE USING HYDRALAZINE-ISOSORBIDE MONONITRATE COMPARED TO HYDRALAZINE-ISOSORBIDE DINITRATE IN PATIENTS WITH SYSTOLIC HEART FAILURE. Journal of the American College of Cardiology. 2018;71(11):A867. doi:10.1016/s0735-1097(18)31408-6
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What is the comparative efficacy and safety of isosorbide mononitrate versus isosorbide dinitrate in patients with congestive heart failure (compensated or decompensated)?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Table 1 for your response.

 

Hemodynamic Effects of Oral Isosorbide-5-Mononitrate and Dinitrate in Ischemic Heart Failure

Design

Single-blind, randomized, crossover study

N= 20

Objective

To compare the hemodynamic effects of oral isosorbide-5-mononitrate and dinitrate (ISMN and ISDN), administered in equal doses in a randomized, crossover fashion, in patients with pump failure of ischemic etiology

Study Groups

Isosorbide-5-mononitrate followed by isosorbide dinitrate (n= 10)

Isosorbide dinitrate followed by isosorbide-5-mononitrate (n= 10)

Inclusion Criteria

 Evidence of ischemic heart disease and clinical pump failure, pulmonary capillary wedge pressure (PCW) ≥ 20 mmHg, systolic arterial pressure (AP) ≥ 90 mmHg

Exclusion Criteria

Patients in shock

Methods

Patients were randomized to receive either a single oral dose of isosorbide-5-mononitrate 40 mg followed by isosorbide dinitrate 40 mg when their hemodynamic parameters reversed to baseline or vice versa. Patients whose hemodynamic parameters did not return to baseline 24 hours after administration of the first drug were not given the second drug and excluded, leaving 20 patients included in the analysis. Hemodynamic parameters were obtained from a triple-lumen, balloon-tipped Swan-Ganz thermodilution catheter introduced through an antecubital vein and passed into the pulmonary artery. Diuretics and other nitrates were held during the study, but patients would continue use of digitalis, anticoagulants, antibiotics, and lidocaine.

Ten patients were studied during the first week of an acute myocardial infarction complicated with left heart failure, while the other 10 patients had coronary artery disease, old infarctions, and chronic (predominantly left) heart failure. Clinical left heart failure was diagnosed by physical signs of moist rales on lung auscultation and radiologic evidence of congestion. 

No statistical trend was seen with respect to the order of medication administration, and thus statistical analysis did not take into account the order of administration.

Duration

Follow-up: 6 hours post-medication

Outcome Measures

Hemodynamic parameters including pulmonary arterial (PA) pressure, PCW, right atrial (RA) pressure, cardiac output (CO), and systemic vascular resistance (SVR)

Baseline Characteristics

  

All patients (N= 20) 

Mean age, years (range)

 64 (43 to 75)

Female

20%

Statistical analysis showed no significant differences in major patient characteristics and hemodynamic results. As such, the following endpoint for each parameter refers to the whole group of 20 patients with ischemic pump failure. 

Results

Endpoint

All patients (N= 20)

Pulmonary capillary wedge pressure, mmHg

Baseline

ISMN Maximal hemodynamic effect

ISDN Maximal hemodynamic effect

 

25.5

20

19.5

Cardiac output, L/min

Baseline

ISMN Maximal hemodynamic effect

ISDN Maximal hemodynamic effect

 

4.1

4.3

4.5

Heart rate, beats/min

Baseline

ISMN Maximal hemodynamic effect

ISDN Maximal hemodynamic effect

 

96

94

90

Mean arterial pressure, mmHg

Baseline

ISMN Maximal hemodynamic effect

ISDN Maximal hemodynamic effect

 

95

92

90

Systemic vascular resistance, dyn*s*cm5

Baseline

ISMN Maximal hemodynamic effect

ISDN Maximal hemodynamic effect

 

1,900

1,600

1,700

From almost equal baseline pressures, each drug reduced the systolic and diastolic pulmonary arterial pressures by approximately equal degrees, with the change attaining statistical significance 30 minutes after drug administration. Both medications were also equipotent in decreasing pulmonary capillary wedge pressures and right atrial pressures in patients. The effect on pulmonary arterial pressure, pulmonary capillary wedge pressure, and right atrial pressure were maintained for a significantly longer duration (up to 4 hours) in patients when they received isosorbide-5-mononitrate compared to isosorbide dinitrate (60 to 120 minutes). 

statistically significantly different from baseline

Adverse Events

Not disclosed

Study Author Conclusions

The results appear to demonstrate that both isosorbide dinitrate and isosorbide-5-mononitrate administered in a single identical dose in a randomized, crossover fashion in patients with pump failure are equally effective hemodynamically at their peak effect. However, they have different time courses of action, with isosorbide-5-mononitrate consistently showing a more prolonged effect. The predominant effect observed with both medications was a decrease in filling pressures.

InpharmD Researcher Critique

The study analyzed hemodynamic parameters, which are surrogate markers for heart failure assessment, and did not directly compare the overall efficacy and safety of the interventions for heart failure management in patients. The study was only powered to assess differences in mean pulmonary arterial and pulmonary capillary wedge pressures, and statistical significance calculations for other parameters were made based on explorative data analysis.



References:

Rabinowitz B, Hod H, Chouraqui P, Rath S, Agranat O, Neufeld HN. Hemodynamic effects of oral isosorbide-5-mononitrate and dinitrate in ischemic heart failure. Clin Cardiol. 1987;10(10):603-608. doi:10.1002/clc.4960101019