Isosorbide

What it is

These are two closely related organic nitrate drugs built on the sugar alcohol isosorbide. Isosorbide dinitrate carries two nitrate groups; isosorbide mononitrate carries one and is in fact the main active metabolite of the dinitrate, which is why the label states most of the dinitrate's clinical activity is attributable to the mononitrate. The practical difference is pharmacokinetic: the dinitrate is heavily metabolised on first pass through the liver so its bioavailability is highly variable (10 to 90 percent, averaging about 25 percent) with a serum half-life of about an hour, whereas the mononitrate escapes first-pass metabolism, has bioavailability close to 100 percent and a half-life of about 5 hours. Food does not meaningfully change mononitrate absorption.

What the research says

Both are vasodilators: they release nitric oxide, which relaxes the smooth muscle in blood vessels, mainly veins, so less blood returns to the heart and the heart has less work to do. Isosorbide mononitrate is approved for preventing and treating angina and the trial evidence there is about exercise tolerance, not about survival: in a 313-patient placebo-controlled trial extended-release mononitrate added roughly 30 to 60 seconds of treadmill time 4 and 12 hours after dosing, with no difference from placebo at 24 hours. In the one large mortality trial, ISIS-4 in 58,050 people with suspected heart attack, oral mononitrate did not reduce 5-week death (7.34 percent versus 7.54 percent on placebo). Isosorbide dinitrate's survival evidence is only in combination with hydralazine: the A-HeFT trial in 1,050 self-identified Black patients with class III-IV heart failure was stopped early because mortality was 6.2 percent on the combination versus 10.2 percent on placebo, an absolute reduction of 4 percentage points. The defining problem of both drugs is tolerance: continuous dosing stops working within 24 hours, so a daily nitrate-free gap is built into the dosing schedule. The most dangerous interaction is with PDE5 inhibitors such as sildenafil, which is an absolute contraindication.

Evidence grade: Well established.

How it works

Drug class: Organic nitrate vasodilator (nitric oxide donor)

Both drugs release nitric oxide in the blood-vessel wall. Nitric oxide switches on an enzyme called guanylyl cyclase, which relaxes the muscle in the vessel wall. Veins relax more than arteries, so blood pools in the periphery and less returns to the heart, lowering the pressure the heart has to pump against from the filling side (preload). Arteries relax too, which lowers the resistance the heart pumps into (afterload), and the coronary arteries widen. The labels state that how much of the antianginal benefit comes from each of these three effects remains undefined. (Source 1)

What it is used for

• Approved use for the mononitrate. The benefit measured in trials is exercise tolerance, not survival. In 313 patients, extended-release mononitrate 120 or 240 mg once daily added about 50 to 60 seconds of exercise time 4 hours after dosing and 30 to 35 seconds at 12 hours, with no difference from placebo at 24 hours. The label's own trial data show the effect shrinks to 60 to 70 percent of day-one size by day 21. Evidence: established. (Source 2)
• Approved for prevention only, not for aborting an attack. The dinitrate's own label is unusually candid: most controlled trials of twice-daily or more frequent dosing showed statistically significant antianginal effect for only 2 hours after a dose, and one 8-patient study found total effectiveness of about 6 hours in a 24-hour day. Evidence: limited. (Source 3)
• Approved as the fixed-dose combination. A-HeFT, in 1,050 self-identified Black patients with class III-IV heart failure already on standard therapy, was stopped early for a mortality difference: 6.2 percent versus 10.2 percent on placebo, and first heart-failure hospitalisation 16.4 percent versus 24.4 percent. The label notes it has never been tested whether the nitrate, the hydralazine, or both produce the benefit. Evidence: established. (Source 4)
• Tested and failed. In NEAT-HFpEF, 110 patients crossed over between mononitrate and placebo; patients on mononitrate were measurably less active, not more, and had no better quality of life, 6-minute walk distance or NT-proBNP. Evidence: not-supported. (Source 5)
• Tested in the largest nitrate trial ever run and failed. In ISIS-4, 58,050 patients, one month of oral controlled-release mononitrate gave no reduction in 5-week mortality overall or in any subgroup, and increased hypotension by 15 per 1,000. The mononitrate label states the benefit in acute myocardial infarction has not been established. Evidence: not-supported. (Source 6)
• Not approved in the US and the long-term follow-up is actively unfavourable. In 118 cirrhotic patients followed up to 7 years, mononitrate was no better than propranolol at preventing a first bleed but was an independent predictor of death, with 72 percent versus 48 percent mortality at 6 years in patients over 50. Evidence: not-supported. (Source 7)
• Promising but not established. LACI-2 was a feasibility trial in 363 patients, open-label, in which mononitrate did not reduce the composite outcome but did reduce recurrent stroke and cognitive impairment on secondary analysis. The investigators' own conclusion is that it should now be tested in large phase 3 trials, not that it works. Evidence: limited. (Source 8)
• One small pilot. In a 22-patient double-blind crossover study, dinitrate spray applied to the feet reduced overall pain and burning but changed no other sensory symptom, and only half the patients wanted to continue it. The authors themselves call it a pilot study. Evidence: limited. (Source 9)

Interactions

• PDE5 inhibitors for erectile dysfunction and pulmonary hypertension (sildenafil, tadalafil, vardenafil, avanafil) (clinical trial): This is the one absolutely forbidden combination. Both drugs raise the same signalling molecule inside blood vessels, so taken together they can drop blood pressure catastrophically, causing fainting or starving the heart muscle of blood. Both isosorbide labels list it as a contraindication, not a caution. In a controlled crossover study, sildenafil produced a fourfold greater fall in systolic pressure after a sublingual nitrate. (Source 10)
• Sildenafil and isosorbide mononitrate, each measured on its own in the same study (clinical trial): In men with coronary disease, a single 40 mg dose of isosorbide mononitrate lowered mean arterial pressure by 22 mm Hg at 2 hours while sildenafil 100 mg lowered it by 10 mm Hg. The two were given to separate groups of men and were never taken together in this study, so it shows how large each drug's blood-pressure effect is, not what happens when they are combined. The ban on combining them rests on the labels, which contraindicate it, and on the crossover study in which sildenafil roughly quadrupled the fall in systolic pressure after a nitrate. (Source 11)
• Riociguat (a soluble guanylate cyclase stimulator for pulmonary hypertension) (label): Also contraindicated with both isosorbide forms and with the dinitrate-hydralazine combination, for the same reason: it acts on the same pathway and the combination can cause hypotension. (Source 12)
• Alcohol (label): Alcohol is itself a vasodilator and the labels state its effects add to the nitrate's. The practical consequence named in the patient information is light-headedness on standing, which is more frequent in people who have also been drinking. (Source 13)
• Alcohol (dinitrate, orthostatic symptoms) (label): The dinitrate patient information makes the same point from the symptom side: feeling light-headed on standing up is more likely in people who have also consumed alcohol. (Source 14)
• Calcium channel blockers (for example amlodipine, nifedipine, diltiazem) (case reports): Marked symptomatic orthostatic hypotension, meaning a significant drop in blood pressure on standing, has been reported when a calcium channel blocker and an organic nitrate are taken together. The label says the dose of either class may need adjusting. (Source 13)
• Food (pharmacokinetic study): Food is one of the few things that does not matter here: it does not significantly change how much isosorbide mononitrate is absorbed or its bioavailability, which is already close to 100 percent. Metoprolol taken alongside did not change mononitrate pharmacokinetics either. (Source 15)
• Vitamin C (ascorbate) (clinical trial): Not an interaction to avoid, but a documented one. In healthy volunteers given mononitrate 120 mg daily for a week, infusing vitamin C into the artery completely restored the blunted blood-vessel response, which the authors read as evidence that oxygen free radicals drive nitrate-induced blood-vessel dysfunction. This was an intra-arterial infusion in a mechanistic study, not oral supplementation, and it says nothing about whether taking vitamin C tablets would help. (Source 16)
• Aspirin or paracetamol (acetaminophen) for nitrate headache (label): Documented as safe to combine for this purpose: the labels say aspirin and/or acetaminophen often relieve the headache nitrates cause without blunting the antianginal effect. The same sections warn against the alternative of shifting dose times to dodge the headache, because losing the headache may mean losing the benefit. (Source 17)

Stopping it

• Stopping is unusual here in that a daily gap is built into treatment on purpose. Because continuous 24-hour nitrate levels cause refractory tolerance, the mononitrate immediate-release schedule puts the two doses only seven hours apart, leaving a 17-hour nitrate-free interval each day. (Source 18)
• For the mononitrate specifically, that asymmetric twice-daily schedule was shown to avoid significant rebound or withdrawal effects, though the label notes such effects depend heavily on the schedule used. (Source 19)
• For organic nitrates generally, rebound during the drug-free interval is documented: in some nitroglycerin trials angina attacks were more easily provoked than before treatment and patients showed haemodynamic rebound and reduced exercise tolerance. The dinitrate label says the relevance of this to ordinary oral dinitrate use is not known. (Source 20)
• True physical dependence on organic nitrates is documented, but in industrial workers exposed long-term to presumably very high doses, among whom chest pain, heart attack and sudden death occurred during temporary withdrawal. Both isosorbide labels record this and both say its relevance to routine clinical use is unknown. (Source 21)
• Few trials of organic nitrates were even designed to look for rebound or withdrawal, and for isosorbide dinitrate specifically the incidence, size and clinical significance of such effects have not been studied. (Source 22)
• One stopping behaviour is specifically discouraged: changing the dosing schedule to avoid the headache. The labels treat the headache as a marker of the drug working and warn that losing it may mean losing the antianginal effect. (Source 17)

What goes wrong

In 19 healthy volunteers, 7 days of isosorbide-5-mononitrate 120 mg once daily blunted the forearm blood-vessel response to acetylcholine, a laboratory measure of blood-vessel lining function rather than a clinical outcome, and infusing vitamin C into the artery restored it. (Source 16)

• Randomized trial, Low certainty.
• Size: 19 healthy volunteers.
• Who: 19 healthy volunteers, not patients, randomised double-blind to mononitrate 120 mg once daily or placebo.
• How long: 7 days.
• Result: Peak forearm blood flow response to acetylcholine: placebo 127 +/- 31% versus mononitrate 52 +/- 24%. Response to L-NMMA: placebo 41 +/- 5% versus mononitrate 22 +/- 8%. Intra-arterial vitamin C restored the acetylcholine response (vitamin C 180 +/- 33% versus saline 107 +/- 17%)
• Funding: not stated.

Limit of this finding: This is a mechanism experiment, not a clinical result. Nineteen healthy volunteers took the drug for a week and what was measured was how much blood flow in the forearm increased in response to infused acetylcholine. Nobody was followed for heart attacks, angina or death, so the finding says the drug blunts a laboratory marker of blood-vessel function, not that it causes harm a patient would notice. The vitamin C that reversed it was infused directly into the artery, which tells you nothing about vitamin C tablets.

As compared with placebo, IS-5-MN caused significant blunting of the responses to both Ach (peak responses: placebo 127 +/- 31%; IS-5-MN 52 +/- 24%) and L-NMMA (peak responses: placebo 41 +/- 5%; IS-5-MN 22 +/- 8%).

In the A-HeFT safety data, 21 percent of patients stopped isosorbide dinitrate plus hydralazine for adverse reactions versus 12 percent on placebo, with headache the commonest reason for stopping. (Source 23)

• Randomized trial, Moderate certainty.
• Size: 517 heart-failure patients exposed in A-HeFT (317 for at least 6 months, 220 for at least 12 months); 527 placebo.
• Who: self-identified Black patients with NYHA class III-IV heart failure.
• How long: up to 18 months.
• Result: Discontinuation for adverse reactions 21% on the combination versus 12% on placebo, an absolute excess of 9 percentage points (about 11 patients treated per extra discontinuation). Headache was the commonest reason for stopping, at 7%.
• Funding: industry-funded (manufacturer label reporting the sponsor's trial)

In A-HeFT, 21% of the patients discontinued BiDil for adverse reactions compared to 12% who discontinued placebo.

In the mononitrate label's pooled placebo-controlled trials, headache caused 2 percent of all dropouts and was the most frequent side effect, decreasing after the first few days. (Source 24)

• Official position, Low certainty.
• Size: 6 placebo-controlled studies; 160 placebo, 54 on 5 mg, 52 on 10 mg, 159 on 20 mg.
• Who: subjects in the mononitrate placebo-controlled trial programme in the United States and abroad.
• How long: not stated.
• Result: Headache was the most frequent side effect and caused 2% of all dropouts. The label's own table, across 6 placebo-controlled studies, gives headache as 6% on placebo, 17% on 5 mg, 13% on 10 mg and 35% on 20 mg, with 5% of the 20 mg group discontinuing for it; the rate is therefore not a smooth rise with dose.
• Funding: industry-funded (manufacturer label)

Limit of this finding: The quotation stops where the label's dose-by-dose adverse-reaction table begins. In the electronic label that table is flattened into a single run of numbers with no column headings, so quoting it would leave a reader unable to tell which percentage belongs to which dose; the figures are given in this finding's effect field instead. On the label's own numbers headache does not rise steadily with dose: it is 17 percent at 5 mg, 13 percent at 10 mg and 35 percent at 20 mg.

Headache is the most frequent side effect and was the cause of 2% of all dropouts from controlled-clinical trials. Headache decreased in incidence after the first few days of therapy.

In ISIS-4 the only significant side effect of the mononitrate regimen was hypotension, increased by 15 per 1,000 patients treated for one month. (Source 6)

• Randomized trial, High certainty.
• Size: about 29,000 allocated mononitrate versus about 29,000 placebo.
• Who: patients with suspected acute myocardial infarction.
• How long: 1 month of treatment.
• Result: An increase of 15 (SD 2) per 1,000 in hypotension, a number needed to harm of about 67. Patients allocated active treatment had somewhat fewer deaths on days 0-1.
• Funding: not stated.

Limit of this finding: Two things about the source text. The abstract is cut off by the indexing service at 400 words, and the marker '(ABSTRACT TRUNCATED AT 400 WORDS)' is part of what we quote, so do not read it as the paper's full account. It also contains the typo 'reassuring a bout the safety', which is in the record and which we have not corrected. Neither affects the mononitrate result quoted here, which is complete within the truncation.

The only significant side-effect of the mononitrate regimen studied was an increase of 15 (SD 2) per 1000 in hypotension.

In cirrhosis, isosorbide-5-mononitrate was no better than propranolol at preventing a first variceal bleed but was an independent predictor of death, with 72 percent versus 48 percent mortality at 6 years in patients over 50. (Source 7)

• Randomized trial, Moderate certainty.
• Size: 118 patients (57 mononitrate, 61 propranolol)
• Who: patients with cirrhosis in a randomised trial of first-bleeding prophylaxis, followed up to 7 years (range 2-91 months)
• How long: up to 7 years of follow-up.
• Result: 30 first bleeding episodes, 16 in the mononitrate group; actuarial probability of bleeding not different. Of 52 deaths, 28 in the mononitrate group. Likelihood of death greater on mononitrate but only in patients older than 50 years: 72% versus 48% at 6 years (P = 0.006), an absolute excess of 24 percentage points. Likelihood of death without bleeding also higher (P = 0.05)
• Funding: not stated.

Limit of this finding: Three things to hold in mind. The mortality excess applied only to patients older than 50; it was not seen across the whole group. These 118 patients were followed up from an earlier randomised trial rather than randomised afresh for this analysis, so the long-term survival comparison is extended observational follow-up. And the paper's own description of the follow-up, 'up to 7 years (range, 2-91 months)', is inconsistent with itself, because 91 months is more than seven and a half years.

The likelihood of death was greater among patients assigned to Is-5-Mn than to Pro, but only in patients older than 50 years (72% vs. 48% at 6 years; P = 0.006).

In LACI-2, isosorbide mononitrate significantly increased headache after lacunar stroke (adjusted odds ratio 1.89) although serious adverse events were rare. (Source 25)

• Randomized trial, Low certainty.
• Size: 363 recruited, 358 retained at 12 months.
• Who: patients with clinical lacunar ischaemic stroke, median age 64, 69.1% men, in 26 UK stroke centres.
• How long: 12 months of open-label mononitrate 40-60 mg/day.
• Result: Headache increased with mononitrate (adjusted odds ratio 1.89, 95% CI 1.23 to 2.92; P = .004). Only 2 serious adverse events were judged likely attributable to the study drugs, one each to mononitrate and cilostazol.
• Funding: investigator-initiated (UK National Institute for Health Research infrastructure)

Headache increased with ISMN (aOR, 1.89 [95% CI, 1.23 to 2.92]; P = .004)

Nitrate tolerance is not simply the body getting used to the drug: a narrative review attributes it to increased vascular superoxide production and heightened sensitivity to vasoconstrictors, on top of early neurohormonal counter-regulation. (Source 26)

• Expert review, not systematic, Low certainty.
• Size: not applicable (mechanistic review, largely of nitroglycerin)
• Who: laboratory and human studies of organic nitrates.
• How long: not applicable.
• Result: No effect sizes; mechanisms described are pseudotolerance from neurohormonal vasoconstrictor activation and volume expansion, then vascular tolerance from superoxide production and tonic protein kinase C activation.
• Funding: not stated.

Neurohormonal activation of vasoconstrictor signals and intravascular volume expansion constitute early counter-regulatory responses (pseudotolerance), whereas long-term treatment induces intrinsic vascular changes, eg, a loss of nitrovasodilator-responsiveness (vascular tolerance).

Sildenafil potentiated the blood-pressure-lowering effect of an organic nitrate in a double-blind crossover study, producing a fourfold greater fall in systolic pressure, which is the basis of the absolute contraindication. (Source 27)

• Randomized trial, Moderate certainty.
• Size: healthy male subjects in a double-blind, placebo-controlled crossover study (exact n not stated in the abstract)
• Who: healthy male subjects given sildenafil 25 mg three times daily for 4 days or placebo, then challenged with intravenous and sublingual glyceryl trinitrate.
• How long: 5 days.
• Result: Subjects were significantly less tolerant of intravenous glyceryl trinitrate on sildenafil, judged by a fall in blood pressure greater than 25 mm Hg or symptomatic hypotension (p <0.01). After sublingual glyceryl trinitrate, a 4-fold greater decrease in systolic blood pressure on sildenafil than on placebo. Heart rate changes negligible.
• Funding: industry-funded (sildenafil interaction studies conducted by the manufacturer)

When a sublingual glyceryl trinitrate tablet was administered on day 5, a 4-fold greater decrease in systolic blood pressure was observed for the subjects during the sildenafil treatment period than during the placebo treatment period.

Measured separately in the same single-dose study, isosorbide mononitrate 40 mg lowered mean arterial pressure more than twice as much as sildenafil 100 mg (-22 versus -10 mm Hg at 2 hours); the two drugs were given to different men and were never combined, so the study says nothing about taking them together. (Source 11)

• Randomized trial, Very low certainty.
• Size: 31 men in three parallel single-dose arms (sildenafil 100 mg n = 10, isosorbide mononitrate 40 mg n = 11, placebo n = 10)
• Who: men aged 35 or older with angiographic coronary artery disease and erectile dysfunction.
• How long: one single dose, with haemodynamics measured at baseline and 1, 2, 4 and 6 hours; the drugs were never co-administered.
• Result: Mononitrate reduced mean arterial pressure by 22 mm Hg at 2 hours versus 10 mm Hg for sildenafil. Mononitrate reduced stroke volume index by 5.8 mL/m2 at 1 hour and cardiac index by 0.14 L/min/m2; heart rate rose 7 beats/minute on mononitrate versus 4 on sildenafil. No serious adverse events were reported in the 10 men given sildenafil alone.
• Funding: industry-funded (sildenafil manufacturer's study programme)

Limit of this finding: This study never gave anyone both drugs. It was a single dose, with 31 men split into three separate groups - 10 given sildenafil, 11 given isosorbide mononitrate and 10 given placebo - so it measured what each drug does on its own and compared the two sets of measurements. Its sentence 'There were no serious adverse events in the sildenafil group' therefore describes 10 men who took sildenafil without a nitrate, after one dose. It is not evidence that the two are safe together. Taking a nitrate with a PDE5 inhibitor such as sildenafil is contraindicated on both isosorbide labels because the combination can cause severe hypotension, fainting or starvation of the heart muscle of blood.

ISMN reduced mean arterial pressure more than sildenafil did (-22 vs. -10 mm Hg at 2 hours, respectively).

Both labels record true physical dependence on organic nitrates in industrially exposed workers, with chest pain, myocardial infarction and sudden death during temporary withdrawal. (Source 21)

• Official position, Very low certainty.
• Size: not quantified (industrial workers with long-term exposure to unknown, presumably high, doses)
• Who: industrial workers exposed long-term to organic nitrates.
• How long: long-term exposure with temporary withdrawal.
• Result: No rates given; chest pain, acute myocardial infarction and sudden death during temporary withdrawal. The labels state the relevance to ordinary clinical use of oral isosorbide is not known.
• Funding: industry-funded (manufacturer labels)

Chest pain, acute myocardial infarction, and even sudden death have occurred during temporary withdrawal of nitrates from these workers, demonstrating the existence of true physical dependence.

Methemoglobinemia is a documented but extremely rare nitrate effect; at ordinary doses measured methemoglobin was 0.2 percent, no different from placebo. (Source 28)

• Official position, Low certainty.
• Size: 36 patients in the cited continuous-nitroglycerin study.
• Who: patients receiving 2-4 weeks of continuous nitroglycerin at a nitrate-ion dose equivalent to 7.8-11.1 mg of isosorbide mononitrate per hour.
• How long: 2 to 4 weeks.
• Result: Average methemoglobin level 0.2%, comparable to parallel patients on placebo. About 2 mg/kg of mononitrate would be needed before clinically significant (10% or more) methemoglobinemia in a patient with no cytochrome b5 reductase activity at all.
• Funding: industry-funded (manufacturer label)

the average methemoglobin level measured was 0.2%; this was comparable to that observed in parallel patients who received placebo.

The hydralazine component of the fixed dinitrate combination brings its own distinct harms: a drug-induced lupus syndrome and peripheral neuritis. (Source 29)

• Official position, Low certainty.
• Size: not quantified.
• Who: patients taking hydralazine-containing products.
• How long: not stated.
• Result: No rates; signs and symptoms usually regress when hydralazine is discontinued.
• Funding: industry-funded (manufacturer label)

Hydralazine hydrochloride has been reported to cause a drug-induced systemic lupus erythematosus (SLE) syndrome.

What the evidence supports

Isosorbide dinitrate plus hydralazine added to standard heart-failure therapy cut all-cause mortality from 10.2 percent to 6.2 percent in 1,050 self-identified Black patients, an absolute reduction of 4 percentage points over a mean 12 months. (Source 4)

• Randomized trial, Moderate certainty.
• Size: 1,050 self-identified Black patients (518 combination, 532 placebo)
• Who: self-identified Black patients with NYHA class III or IV heart failure and dilated ventricles, on standard therapy including diuretics (94%), beta-blockers (87%) and an ACE inhibitor or ARB (93%)
• How long: treated for up to 18 months; trial stopped early at a mean follow-up of 12 months.
• Result: All-cause mortality 6.2% vs 10.2% (hazard ratio 0.57; P=0.01 in the abstract, P=0.012 in the BiDil label), an absolute risk reduction of 4.0 percentage points, implying about 25 patients treated for a year to prevent one death. First hospitalization for heart failure: the abstract records a 33 percent relative reduction with rates of 16.4 percent vs 22.4 percent, but those two rates are a 27 percent reduction, not 33 percent; the BiDil label reports a 39 percent reduction in first heart-failure hospitalization (p<0.001)
• Funding: industry-funded (the fixed-dose combination was developed commercially as BiDil; the trial sponsor was NitroMed)

Limit of this finding: The abstract record we quote contradicts itself on heart-failure hospitalisations. It says the reduction was 33 percent, then gives the rates as 16.4 percent against 22.4 percent, which is a reduction of about 27 percent, not 33 percent. The figure that fits a 33 percent reduction is 24.4 percent, and that is what the trial summaries and the BiDil label's 39 percent hospitalisation reduction are consistent with. The 22.4 figure is in the US National Library of Medicine's own abstract record, which Europe PMC mirrors, so it is the source's error and we have not altered the quotation. Read the hospitalisation percentages as unreliable as printed; the mortality figures, 10.2 percent on placebo against 6.2 percent on the combination, are not affected.

The study was terminated early owing to a significantly higher mortality rate in the placebo group than in the group given isosorbide dinitrate plus hydralazine (10.2 percent vs. 6.2 percent, P=0.02).

In a 313-patient placebo-controlled trial, extended-release isosorbide mononitrate increased treadmill exercise time by about 30 to 60 seconds at 4 and 12 hours after dosing, but was no different from placebo at 24 hours. (Source 2)

• Randomized trial, Moderate certainty.
• Size: 313 patients.
• Who: patients with stable effort-induced angina pectoris.
• How long: 42 days; serial Bruce protocol exercise testing on days 1, 7, 14, 28 and 42.
• Result: After initial dosing, all active groups gained about 30 to 50 seconds of total exercise time versus placebo at 4 and 12 hours (p < 0.01). On day 42, the 120 mg and 240 mg groups exceeded placebo by about 50 to 60 seconds at 4 hours (p < 0.01) and 30 to 35 seconds at 12 hours (p < or = 0.05). No significant difference from placebo at 24 hours.
• Funding: not stated.

On day 42, mean changes from baseline in total exercise time of patients who received 120 or 240 mg of extended-release isosorbide mononitrate exceeded placebo by approximately 50 to 60 seconds 4 hours after dosing (p < 0.01), and by 30 to 35 seconds 12 hours after dosing (p < or = 0.05).

What the evidence does not support

In V-HeFT I, hydralazine plus isosorbide dinitrate showed no overall significant mortality difference from placebo, and survival in white patients was similar on both; the apparent benefit in Black patients came from a retrospective subgroup analysis. (Source 30)

• Randomized trial, Low certainty.
• Size: V-HeFT I: 186 on hydralazine plus isosorbide dinitrate, 273 on placebo (128 Black patients, 324 white patients)
• Who: men with impaired cardiac function and reduced exercise tolerance, primarily NYHA class II and III, on digitalis and diuretics.
• How long: not stated in this label section.
• Result: No overall significant difference in mortality; a trend favouring the combination that on retrospective analysis was attributable to an effect in Black patients; survival in white patients similar on placebo and combination.
• Funding: industry-funded (manufacturer label reporting the trial)

There was no overall significant difference in mortality between the two treatment groups. There was, however, a trend favoring hydralazine and isosorbide dinitrate, which on retrospective analysis, was attributable to an effect in blacks (n=128).

In V-HeFT II, hydralazine plus isosorbide dinitrate was inferior to enalapril: two-year mortality was 25 percent on the combination versus 18 percent on enalapril. (Source 31)

• Randomized trial, Moderate certainty.
• Size: 804 men.
• Who: men with impaired cardiac function and reduced exercise tolerance (NYHA class II and III) on digoxin and diuretics.
• How long: two years of follow-up.
• Result: Two-year mortality 18% enalapril vs 25% hydralazine-isosorbide dinitrate (P = 0.016; relative reduction in mortality 28.0%), an absolute difference of 7 percentage points favouring enalapril. Peak exercise oxygen consumption was increased only by hydralazine-isosorbide dinitrate.
• Funding: not stated.

Limit of this finding: Two cautions. First, this trial compared the hydralazine-isosorbide dinitrate combination against enalapril, not against placebo, so it says enalapril did better, not that the nitrate combination did nothing. Second, everyone in it was male, so it does not tell you how the comparison would come out in women. The misplaced comma before '(34 percent)' is in the published abstract.

and in the present trial (25 percent), as compared with that in the placebo arm in the previous trial, (34 percent) and the further survival benefit with enalapril in the present trial (18 percent)

In ISIS-4, one month of oral controlled-release isosorbide mononitrate in 58,050 patients with suspected myocardial infarction produced no reduction in 5-week mortality: 7.34 percent versus 7.54 percent on placebo. (Source 6)

• Randomized trial, High certainty.
• Size: 58,050 patients randomised in a 2 x 2 x 2 factorial design, about 29,000 per comparison arm.
• Who: patients entering 1,086 hospitals up to 24 hours (median 8 hours) after onset of suspected acute myocardial infarction, without cardiogenic shock or persistent severe hypotension.
• How long: 1 month of oral controlled-release mononitrate 30 mg titrated to 60 mg once daily; mortality at 5 weeks with longer follow-up.
• Result: 2,129 (7.34%) mononitrate deaths vs 2,190 (7.54%) placebo at 5 weeks, an absolute difference of 0.2 percentage points and not significant; no benefit in any subgroup; no later survival advantage; the only significant side effect was an increase of 15 (SD 2) per 1,000 in hypotension (number needed to harm about 67)
• Funding: not stated.

Limit of this finding: Two things about the source text. The abstract is cut off by the indexing service at 400 words, and the marker '(ABSTRACT TRUNCATED AT 400 WORDS)' is part of what we quote, so do not read it as the paper's full account. It also contains the typo 'reassuring a bout the safety', which is in the record and which we have not corrected. Neither affects the mononitrate result quoted here, which is complete within the truncation.

Mononitrate There was no significant reduction in 5-week mortality, either overall (2129 [7.34%] mononitrate-allocated deaths vs 2190 [7.54%] placebo) or in any subgroup examined (including those receiving short-term non-study intravenous or oral nitrates at entry).

In NEAT-HFpEF, patients with heart failure and preserved ejection fraction who took isosorbide mononitrate were significantly less active than on placebo, with no improvement in quality of life, 6-minute walk distance or NT-proBNP. (Source 5)

• Randomized trial, Moderate certainty.
• Size: 110 patients in a double-blind crossover design.
• Who: patients with heart failure and a preserved ejection fraction.
• How long: 6 weeks of dose escalation from 30 mg to 60 mg to 120 mg once daily, then 6 weeks crossover.
• Result: At 120 mg, daily activity -381 accelerometer units (95% CI -780 to 17; P=0.06) and hours of activity per day -0.30 hours (95% CI -0.55 to -0.05; P=0.02). Across all doses, activity -439 accelerometer units (95% CI -792 to -86; P=0.02). No significant difference in 6-minute walk distance, quality-of-life scores or NT-proBNP.
• Funding: independent (funded by the US National Heart, Lung, and Blood Institute)

During all dose regimens, activity in the isosorbide mononitrate group was lower than that in the placebo group (-439 accelerometer units; 95% CI, -792 to -86; P=0.02).

Continuous nitrate dosing stops working: in the large majority of well-controlled exercise trials, nitrates given round the clock were indistinguishable from placebo after 24 hours or less, and raising the dose does not fix it. (Source 32)

• Official position, Moderate certainty.
• Size: not quantified (the label refers to several well-controlled clinical trials)
• Who: patients with angina in exercise-testing trials of continuously delivered nitrates.
• How long: 24 hours or less of continuous therapy.
• Result: Active agents indistinguishable from placebo after 24 hours or less; dose escalation even far in excess of acutely effective doses has consistently failed; efficacy returns only after nitrates have been absent from the body for several hours.
• Funding: industry-funded (manufacturer label)

In the large majority of these trials, active agents were indistinguishable from placebo after 24 hours (or less) of continuous therapy. Attempts to overcome tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed.

Isosorbide dinitrate's own label reports that most multiple-dose trials showed statistically significant antianginal efficacy for only 2 hours after a dose, and that later doses work less well and for less time than the first. (Source 33)

• Official position, Moderate certainty.
• Size: not quantified (most controlled trials of multiple-dose oral isosorbide dinitrate)
• Who: patients with angina pectoris.
• How long: several weeks of dosing every 12 hours or more frequently.
• Result: Statistically significant antianginal efficacy for only 2 hours after dosing; effects of second and later doses smaller and shorter-lasting than the first.
• Funding: industry-funded (manufacturer label)

Most controlled trials of multiple-dose oral isosorbide dinitrate taken every 12 hours (or more frequently) for several weeks have shown statistically significant anti-anginal efficacy for only 2 hours after dosing.

No isosorbide dinitrate dosing regimen has ever been shown to deliver the roughly 12 hours of daily antianginal effect believed achievable; in one 8-patient study total effectiveness was about 6 hours in a 24-hour day. (Source 34)

• Official position, Low certainty.
• Size: 8 patients in the cited study.
• Who: patients given a pretitrated average 27.5 mg dose of immediate-release isosorbide dinitrate at 0800, 1300 and 1800 hours.
• How long: 2 weeks.
• Result: Significant antianginal effectiveness was discontinuous and totalled about 6 hours in a 24-hour period.
• Funding: industry-funded (manufacturer label)

No dosing regimen for isosorbide dinitrate, however, has ever actually been shown to achieve this duration of effect.

Where the evidence is mixed

The A-HeFT result has never been separated into the contribution of the isosorbide dinitrate and the contribution of the hydralazine, and neither drug alone is indicated for heart failure. (Source 35)

• Official position, Moderate certainty.
• Size: 1,050 patients in A-HeFT.
• Who: self-identified Black patients with heart failure.
• How long: mean 12 months.
• Result: Blood pressure on the combination averaged 3/3 mmHg lower than placebo, and the label states the contribution of that difference to the outcome is unknown.
• Funding: industry-funded (manufacturer label)

Whether both hydralazine and isosorbide dinitrate contribute to the overall outcome difference has not been studied in outcome trials. Isosorbide dinitrate and hydralazine have not been systematically studied for the treatment of heart failure as separate agents, and neither drug is indicated for heart failure.

The mononitrate label's own trial data show the antianginal effect shrinks with repeated dosing: by day 21 the effect two hours after the first dose was only 60 to 70 percent of what it had been on day one. (Source 36)

• Official position, Low certainty.
• Size: 214 patients enrolled (54 placebo, 106 on 10 or 20 mg twice daily seven hours apart)
• Who: patients with angina pectoris in a multicentre placebo-controlled trial.
• How long: acute and chronic (3 weeks) treatment.
• Result: Single 20 mg dose increased exercise capacity by 42.7% at one hour, 29.6% at 6 hours and 25% at eight hours versus placebo. By day 14 the increase 14 hours after the first dose was still significant but about half of that seen 2 hours after the first dose of day one; on day 21 the effect was 60 to 70% of day one.
• Funding: industry-funded (manufacturer label)

Limit of this finding: The label's own arithmetic does not add up here: it says 214 patients were enrolled, then that 54 went to placebo and 106 to isosorbide mononitrate, which is 160. The missing 54 are unaccounted for in the label text. Treat the enrolment figure as unreliable. Separately, the 42.7 percent gain in exercise capacity after one hour comes from a single 20 mg dose given to 21 patients, not from a course of treatment, so it is not a general measure of how well the drug works.

On day 21, two hours after the first dose the effect of isosorbide mononitrate was 60 to 70% of that seen on day one.

In LACI-2, mononitrate alone did not reduce the trial's composite outcome; the reductions in recurrent stroke and cognitive impairment came from secondary analyses in an open-label feasibility trial. (Source 8)

• Randomized trial, Low certainty.
• Size: 363 recruited; composite outcome analysed in 297.
• Who: patients with lacunar ischaemic stroke, recruited a median 79 days after stroke.
• How long: 12 months.
• Result: Composite outcome adjusted hazard ratio for mononitrate 0.80 (95% CI 0.59 to 1.09; P = .16), not significant. Recurrent stroke adjusted odds ratio 0.23 (95% CI 0.07 to 0.74; P = .01) in 353 patients; cognitive impairment adjusted odds ratio 0.55 (95% CI 0.36 to 0.86; P = .008) in 308 patients.
• Funding: investigator-initiated.

Compared with those participants not receiving that particular drug, neither ISMN (adjusted hazard ratio [aHR], 0.80 [95% CI, 0.59 to 1.09]; P = .16) nor cilostazol (aHR, 0.77 [95% CI, 0.57 to 1.05]; P = .10) alone reduced the composite outcome in 297 patients.

Isosorbide dinitrate spray reduced overall neuropathic pain and burning in a 22-patient crossover pilot, but changed no other sensory symptom and only half the patients wanted to continue it. (Source 9)

• Randomized trial, Very low certainty.
• Size: 22 diabetic patients (13 men, 20 with type 2 diabetes), mean age 63.7 +/- 1.8 years.
• Who: people with chronic painful diabetic peripheral neuropathy of mean duration 2.6 +/- 0.4 years.
• How long: 4 weeks per arm with a 2-week washout, after a 2-week run-in; spray applied to both feet before bedtime.
• Result: Overall neuropathic pain reduced (P = 0.02) and burning sensation reduced (P = 0.006); no difference in hot/cold sensation, tingling, numbness, hyperesthesia or jabbing. At completion 11 patients (50%) reported benefit and wished to continue, 4 (18%) preferred placebo, 7 (32%) were undecided.
• Funding: not stated.

ISDN spray reduced overall neuropathic pain (P = 0.02) and burning sensation (P = 0.006). No treatment difference was observed with other sensory modalities (hot/cold sensation, tingling, numbness, hyperesthesia, and jabbing-like sensation).

Where the research disagrees

Whether the A-HeFT mortality benefit belongs to isosorbide dinitrate, to hydralazine, or only to the two together, and whether a race-defined indication follows from it

• Taylor and colleagues, New England Journal of Medicine 2004 (A-HeFT), rct: The addition of a fixed dose of isosorbide dinitrate plus hydralazine to standard therapy for heart failure including neurohormonal blockers is efficacious and increases survival among black patients with advanced heart failure. (Source 37)
• BiDil US prescribing information (SPL published 22 January 2026), position: Whether both hydralazine and isosorbide dinitrate contribute to the overall outcome difference has not been studied in outcome trials. Isosorbide dinitrate and hydralazine have not been systematically studied for the treatment of heart failure as separate agents, and neither drug is indicated for heart failure. (Source 35)
• The V-HeFT I and V-HeFT II results as summarised in the same label, rct: The combination of hydralazine and isosorbide dinitrate was inferior to enalapril overall, but retrospective analysis showed that the difference was observed in the white population (n=574); there was essentially no difference in the black population (n=215). (Source 30)

Whether long-term nitrate therapy is harmless beyond losing potency, or actively damages blood vessels

• The isosorbide mononitrate label, which frames the problem as tolerance alone and solves it with a dosing gap, position: The asymmetric twice-daily regimen of isosorbide mononitrate tablets successfully avoided significant rebound/withdrawal effects. (Source 19)
• Thomas and colleagues, Journal of the American College of Cardiology 2007, rct: We document for the first time that IS-5-MN impairs endothelial function in humans in vivo. Suggesting a role of oxygen free radicals, nitrate-induced abnormalities in endothelium-dependent vasomotor responses were reversed by the antioxidant vitamin C. (Source 38)
• Munzel and colleagues, Circulation Research 2005, narrative-review: This is caused by increased vascular superoxide production and a supersensitivity to vasoconstrictors secondary to a tonic activation of protein kinase C. (Source 26)

How much

• Reference intake: There is no reference intake for a drug. Dose is set by the prescriber. As positions: the isosorbide mononitrate immediate-release label states 20 mg twice daily with the doses seven hours apart (ANI Pharmaceuticals label, SPL effective 27 March 2026); the BiDil fixed combination label states one tablet of 20 mg isosorbide dinitrate with 37.5 mg hydralazine three times a day, titrated to a maximum of two tablets three times daily if tolerated (Azurity label, SPL effective 30 November 2025). (Source 18)
• Upper limit: No tolerable upper intake level exists for a drug. The limits set by the labels are contraindications rather than dose ceilings: both isosorbide labels forbid use with PDE5 inhibitors such as sildenafil, tadalafil or vardenafil, and with the soluble guanylate cyclase stimulator riociguat, in each case because of severe hypotension, syncope or myocardial ischaemia (SPLs effective 27 March 2026 and 31 July 2026). (Source 10)
• Studied: Extended-release isosorbide mononitrate 30, 60, 120 or 240 mg once daily in the morning versus placebo in 313 patients with stable effort angina. (Source 39)
• Studied: Isosorbide mononitrate escalated from 30 mg to 60 mg to 120 mg once daily versus placebo in 110 patients with heart failure and preserved ejection fraction (NEAT-HFpEF). (Source 40)
• Studied: Oral controlled-release isosorbide mononitrate 30 mg titrated to 60 mg once daily for 1 month versus placebo in 58,050 patients with suspected acute myocardial infarction (ISIS-4). (Source 6)
• Studied: Isosorbide dinitrate 20 mg with hydralazine 37.5 mg three times daily, titrated to a target of 40 mg/75 mg three times daily or the maximum tolerated dose, in 1,050 patients in A-HeFT. (Source 41)
• Studied: Hydralazine 300 mg plus isosorbide dinitrate 160 mg daily versus enalapril 20 mg daily in 804 men in V-HeFT II. (Source 42)
• Studied: Isosorbide mononitrate 40 to 60 mg per day, open-label for 12 months, in 363 patients after lacunar ischaemic stroke (LACI-2). (Source 43)
• Studied: Isosorbide-5-mononitrate 20 mg three times daily versus propranolol in 118 patients with cirrhosis. (Source 44)
• Studied: Single doses of isosorbide mononitrate 40 mg, sildenafil 100 mg or placebo given to separate groups of 31 men with coronary artery disease and erectile dysfunction (mononitrate arm n = 11); the two drugs were never given together. (Source 45)
• Studied: Isosorbide-5-mononitrate 120 mg once daily for 7 days versus placebo in 19 healthy volunteers, with forearm blood flow as the measured outcome. (Source 46)

A common belief, and what the research shows

The belief: Isosorbide is a heart medicine, so like a statin or an ACE inhibitor it must help you live longer, and taking it steadily round the clock gives steady protection.

What the research shows: Both halves are wrong for the mononitrate. On survival, the largest nitrate trial ever run found nothing: in ISIS-4, "Mononitrate There was no significant reduction in 5-week mortality, either overall (2129 [7.34%] mononitrate-allocated deaths vs 2190 [7.54%] placebo) or in any subgroup examined (including those receiving short-term non-study intravenous or oral nitrates at entry)." On round-the-clock dosing, the label itself says "In the large majority of these trials, active agents were indistinguishable from placebo after 24 hours (or less) of continuous therapy. Attempts to overcome tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed." The survival evidence for isosorbide belongs to the dinitrate, and only in fixed combination with hydralazine, in the A-HeFT population: "The study was terminated early owing to a significantly higher mortality rate in the placebo group than in the group given isosorbide dinitrate plus hydralazine (10.2 percent vs. 6.2 percent, P=0.02)."

Questions and answers

What is it?

Isosorbide mononitrate and isosorbide dinitrate are two related nitrate drugs built on isosorbide, a sugar alcohol. The dinitrate carries two nitrate groups, the mononitrate one. They are not independent drugs so much as parent and child: the mononitrate is the main active breakdown product of the dinitrate, and most of what the dinitrate does in the body is actually done by the mononitrate. Both come as tablets, including extended-release forms; the dinitrate also comes combined with hydralazine in one tablet. (Source 1)

What does it do in the body?

Both release nitric oxide, which relaxes the muscle in blood-vessel walls. Veins relax more than arteries, so blood pools in the limbs and less returns to the heart, which reduces the pressure inside the heart before each beat. Arteries relax too, lowering the resistance the heart pumps against, and the coronary arteries widen. For angina the practical result in trials is more exercise before chest pain, not a longer life. (Source 1)

Is it good or bad for you?

It depends which drug, which condition and for how long. The dinitrate-hydralazine combination clearly saved lives in the A-HeFT heart-failure population, cutting death from 10.2 to 6.2 percent. The mononitrate reliably improves exercise tolerance in angina but did not reduce death in 58,050 heart-attack patients in ISIS-4, made people with preserved-ejection-fraction heart failure less active rather than more in NEAT-HFpEF, and was linked to higher long-term mortality than propranolol in cirrhosis. The headache rate is high and dose-related, the effect fades within days unless a daily nitrate-free gap is kept, and combining it with a PDE5 inhibitor such as sildenafil can be fatal. (Source 47)

How do you get more of it?

Does not apply in the nutrient sense; these are manufactured prescription drugs and no food or behaviour increases them. Absorption differs between the two forms, which matters practically: the mononitrate avoids first-pass metabolism in the liver and has bioavailability close to 100 percent, and food does not meaningfully change it, so it can be taken with or without a meal. The dinitrate's bioavailability is highly variable, between 10 and 90 percent. (Source 15)

If it is harmful, what reduces it?

The drug clears on its own within hours, which is why the dosing schedule relies on a daily nitrate-free gap rather than on anything being given to remove it. In overdose there is no antidote: because the problem is dilated veins and too little circulating volume, treatment is directed at raising central fluid volume, starting with simply elevating the legs and adding intravenous saline if needed. The label warns that adrenaline and other artery-constricting drugs are likely to do more harm than good. (Source 48)

Why might someone be low in it or missing it?

Does not apply: nobody can be deficient in a nitrate drug. What does happen is that it stops working, which is a different problem. Taking nitrates continuously for 24 hours or less produces tolerance, at which point the drug becomes indistinguishable from placebo, and raising the dose does not recover the effect. Only a drug-free interval of several hours restores it. Some people also cannot take it at all: it is contraindicated with PDE5 inhibitors or riociguat, in allergy, and the labels warn against it when someone is volume depleted or already hypotensive. (Source 32)

Which whole foods contain it or feed it?

No whole food contains isosorbide mononitrate or dinitrate; they are synthetic drugs. Food is relevant only in that it does not interfere: it does not significantly change mononitrate absorption or bioavailability. The dietary item that does matter is alcohol, whose vasodilating effect adds to the nitrate's and makes light-headedness on standing more likely. (Source 15)

What happens if you do not have it?

Nothing is lost physiologically, since these are not body substances. What a person forgoes depends on the condition. For stable angina, the placebo arms of the mononitrate trials show the loss is exercise capacity: a single 20 mg dose increased it by 42.7 percent at one hour compared with placebo, in a 21-patient study. For the A-HeFT heart-failure population, the placebo arm shows the stake is survival, with 10.2 percent dying over a mean 12 months against 6.2 percent on the combination. For acute heart attack, ISIS-4 shows that going without mononitrate costs nothing measurable. (Source 36)

How can you test for it?

There is no useful blood test for these drugs. The label states plainly that laboratory measurement of isosorbide mononitrate and its metabolites is not widely available and has no established role even in managing overdose. What is monitored instead is the clinical effect and its side effects: blood pressure, including standing blood pressure because severe postural hypotension can occur at small doses, and the symptoms themselves. Methemoglobin levels can be measured if methemoglobinemia is suspected, and that test is available from most clinical laboratories. (Source 48)

References

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