Isosorbide Dinitrate
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Acute treatment and prevention of angina pectoris due to coronary artery disease — sublingual tablets | Adults with CAD | Used 15 minutes before triggering activity (prophylaxis) or for an acute anginal episode | FDA Approved |
| Prevention of angina pectoris due to coronary artery disease — oral immediate-release tablets | Adults with CAD | Chronic prophylaxis; not for aborting acute episodes | FDA Approved |
| Prevention of angina pectoris due to coronary artery disease — oral extended/sustained-release formulations | Adults with CAD | Chronic once- or twice-daily prophylaxis with built-in nitrate-free interval | FDA Approved |
Isosorbide dinitrate is an organic nitrate used primarily to prevent and relieve angina by reducing myocardial oxygen demand (preload reduction with secondary afterload effect) and modestly improving coronary perfusion. The 2023 ACC/AHA chronic coronary disease guideline includes long-acting nitrates as an antianginal option in patients with persistent angina despite optimized first-line therapy (typically beta-blockers or calcium channel blockers); short-acting sublingual nitrates remain a Class 1 recommendation for acute angina relief. ISDN’s clinical limitation is rapid development of pharmacologic tolerance with continuous exposure, which mandates a daily nitrate-free interval in every regimen.
HFrEF — combination with hydralazine (H-ISDN): The fixed-dose combination of ISDN with hydralazine carries a Class 1 recommendation in the 2022 AHA/ACC/HFSA HF guideline for self-identified African-American patients with NYHA class III–IV HFrEF on optimal GDMT (based on the A-HeFT trial), and Class 2a for patients of any race/ethnicity with current or prior symptomatic HFrEF intolerant to ACEi/ARB/ARNI. Evidence quality: high (within the African-American HFrEF population).
Esophageal spasm and achalasia (symptom relief): Sublingual ISDN can relieve smooth-muscle spasm and lower esophageal sphincter pressure; used as bridging therapy or for symptom-driven management. Evidence quality: low — small case series and physiologic studies.
Acute decompensated heart failure with hypertension: Sublingual or IV nitrate therapy is sometimes used for rapid preload reduction in pulmonary edema; nitroglycerin is generally preferred over ISDN in this acute setting. Evidence quality: moderate (for nitrates as a class).
Dosing
ISDN dosing is structured by clinical scenario and is dominated by one principle: every chronic regimen must include a daily nitrate-free interval. Without it, pharmacologic tolerance develops within 24 hours and the drug becomes no more effective than placebo.
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Acute anginal episode (sublingual) | 2.5–5 mg SL at onset of pain | May repeat every 5–10 minutes for up to 3 doses in 15 minutes if pain persists | 3 doses; if no relief, evaluate for ACS | Patient should sit before dosing; SL onset slower than nitroglycerin SL (use NTG-SL when available for true acute relief) Call emergency services if pain unrelieved after first dose with prolonged or atypical features |
| Pre-activity angina prophylaxis (sublingual) | 2.5–5 mg SL ~15 minutes before activity expected to provoke angina | — | — | Effect lasts approximately 1–2 hours Useful before exertion, sex, or cold exposure for stable angina patients |
| Chronic angina prophylaxis (oral immediate-release) | 5–20 mg PO 2–3 times daily | 10–40 mg PO 2–3 times daily | Total daily doses up to 480 mg have been studied; use the lowest effective dose | Asymmetric schedule (e.g., 7 AM, 12 PM, 5 PM) preserves a ~14-hour nitrate-free interval overnight Avoid every-12-hour or every-8-hour schedules — these produce continuous coverage and tolerance |
| Chronic angina prophylaxis (oral extended-release) | 40 mg PO once daily in the morning | 40–80 mg PO once daily; up to 160 mg/day in divided doses | 160 mg/day (4 capsules) | Once-daily dosing aims to provide a daily nitrate-free interval >18 hours Swallow whole; do not crush or chew |
| HFrEF — adjunctive (with hydralazine, per A-HeFT / fixed-dose BiDil) | ISDN 20 mg + hydralazine 37.5 mg PO three times daily | Titrate to ISDN 40 mg + hydralazine 75 mg PO three times daily | ISDN 120 mg/day total + hydralazine 225 mg/day total at the maintenance dose | Standard three-times-daily dosing for HFrEF still leaves a nitrate-free overnight interval Continue background ARNI/ACEi/ARB plus beta-blocker plus MRA plus SGLT2i unless contraindicated |
| HFrEF — patient intolerant to ACEi/ARB/ARNI (Class 2a, any race) | ISDN 20 mg + hydralazine 25–50 mg PO three times daily | Titrate to ISDN 40 mg + hydralazine 75 mg PO three times daily as tolerated | ISDN 120 mg/day + hydralazine 225 mg/day | Lower individual-component doses are reasonable when titrating outside of the fixed-dose combination Watch for orthostatic hypotension during titration |
| Missed dose (oral chronic regimen) | Take as soon as remembered if reasonably close to the scheduled time | — | — | If close to the next scheduled dose, skip and resume normal schedule Never double up |
Population-Specific Adjustments
| Population | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Hepatic impairment (cirrhosis) | Lower starting dose | Individualize | Lowest effective dose | Plasma concentrations are elevated in cirrhosis; cautious use is advised |
| Renal impairment | Standard initiation | Standard | Standard | No specific adjustment recommended; supplemental dose after intermittent hemodialysis is not required |
| Older adults (≥65 y) | Start at the low end of the range | Titrate slowly | As tolerated | Higher risk of orthostatic hypotension and falls; check standing BP |
| Pediatric | Not approved — safety and efficacy not established | — | ||
Continuous 24-hour nitrate exposure produces complete tolerance within days; doubling the dose does not restore efficacy — only a drug-free window does. For immediate-release ISDN, schedule three doses asymmetrically (e.g., 7 AM, 12 PM, 5 PM) so that 14+ hours pass before the next morning dose. For extended-release products, dose once daily in the morning so that the overnight period is nitrate-free. If a patient has predominantly nocturnal angina, schedule the regimen so that the nitrate-free window falls during the day instead — and warn the patient about possible rebound angina during the unprotected window.
The A-HeFT trial used a three-times-daily schedule for the fixed-dose H-ISDN combination (typically morning, midday, and early evening), which still leaves a nitrate-free overnight interval. Although the formal nitrate-tolerance literature comes from antianginal regimens, the same biologic principle applies: continuous nitrate exposure compromises efficacy. Maintain the asymmetric three-times-daily pattern in HFrEF rather than spreading doses every 8 hours.
Pharmacology
Mechanism of Action
Isosorbide dinitrate is a prodrug that releases nitric oxide (NO) within vascular smooth muscle through enzymatic and non-enzymatic biotransformation, principally by mitochondrial aldehyde dehydrogenase (ALDH2). Released NO activates soluble guanylate cyclase (sGC), increasing intracellular cGMP, which in turn drives smooth muscle relaxation. The hemodynamic profile is dominated by venodilation, with secondary effects on coronary and systemic arterial beds. Venodilation reduces venous return and ventricular preload, lowering myocardial wall stress and oxygen demand — the dominant antianginal mechanism. Coronary vasodilation, redistribution of subendocardial blood flow, and a modest reduction in afterload contribute additionally.
Tolerance to nitrates develops with continuous exposure and is multifactorial: depletion of intracellular sulfhydryl groups, ALDH2 inactivation, increased oxidative stress, neurohormonal counter-regulation, and plasma volume expansion all contribute. The clinical correlate is loss of antianginal effect within 24 hours of continuous dosing, recoverable only by an extended drug-free interval. Hydralazine appears to attenuate this tolerance, which is part of the rationale for the H-ISDN combination in HFrEF in addition to the complementary preload + afterload reduction profile.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Sublingual: rapid, bypasses first-pass metabolism (onset ~5 min). Oral: nearly complete absorption but extensive hepatic first-pass; oral Tmax ~1 h; bioavailability highly variable (10–90%) and ~25% on average; bioavailability increases progressively during chronic therapy | SL formulation is preferred for acute angina; oral IR/ER for chronic prophylaxis; expect interpatient variability and titrate to clinical effect |
| Distribution | Volume of distribution ~2–4 L/kg; crosses placenta; excretion in human milk not characterized | Wide tissue distribution; pregnancy and lactation considerations apply but data are limited |
| Metabolism | Hepatic — denitrated to two pharmacologically active metabolites: isosorbide-2-mononitrate (~half-life 2 h) and isosorbide-5-mononitrate (5-MN; ~half-life 5 h, the principal active species and itself a separately marketed agent) | The active metabolites — particularly 5-MN — drive most of the sustained effect after oral dosing; CYP3A4 inducers can lower exposure |
| Elimination | Parent drug half-life ~1 h; clearance 2–4 L/min (approaching hepatic blood flow); excretion of metabolites in urine and feces | Short parent half-life, but downstream metabolites extend pharmacodynamic effect; tolerance dictates schedule rather than half-life |
Side Effects
The adverse effect profile of ISDN is dominated by predictable consequences of nitric oxide-mediated vasodilation: headache, hypotension, dizziness, and reflex tachycardia. Headache is so consistent that the FDA prescribing information explicitly notes it as a marker of pharmacologic activity. The PI also states that systematic frequency data have not been collected for most adverse reactions, so the categorization below combines PI listings with published clinical observations.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Headache | Very common precise rate not characterized in PI; dose-related | Often termed “nitrate headache”; throbbing, frontotemporal. The FDA PI explicitly notes that headache is a marker of drug activity — patients should not skip doses to avoid it. Acetaminophen or aspirin usually relieves headache without compromising antianginal efficacy. |
| Lightheadedness / dizziness on standing | Very common | Reflects orthostatic blood pressure drop; counsel on slow positional changes and seated administration |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Hypotension (including orthostatic) | Common | Can occur with even small doses, especially in volume-depleted patients; may be accompanied by paradoxical bradycardia and worsening angina per FDA PI |
| Reflex tachycardia / palpitations | Common | Baroreceptor-mediated; usually mild. May worsen angina in patients with fixed coronary stenoses if not paired with a beta-blocker |
| Flushing | Common | Cutaneous vasodilation; usually self-limited and well-tolerated |
| Nausea, vomiting | Common | Generally mild; may improve with dose reduction or food |
| Tolerance with continuous exposure | Universal if no nitrate-free interval is provided | Loss of anti-anginal efficacy within ~24 hours of continuous dosing; restored only by a daily drug-free window. Not reversible by dose escalation. |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Severe hypotension / syncope (especially with PDE-5 inhibitors) | Uncommon overall; high risk with PDE-5 co-exposure | Minutes to hours after dosing | Position supine with legs elevated; IV fluids; per FDA PI, vasoconstrictors (e.g., epinephrine) are likely to do more harm than good in this setting and should be avoided |
| Crescendo angina or rebound ischemia during nitrate-free interval | Uncommon | During the daily drug-free window | Bridge with a beta-blocker, calcium channel blocker, or ranolazine to cover the nitrate-free interval; reassess overall antianginal regimen |
| Methemoglobinemia | Very rare at therapeutic doses; risk increases with overdose | Minutes to hours; may follow large or repeated doses | Stop nitrate; supplemental oxygen; methylene blue 1–2 mg/kg IV for symptomatic methemoglobinemia (caution in G6PD deficiency) |
| Hemolysis in G6PD deficiency | Rare | Hours to days after exposure | Discontinue; supportive care; document G6PD status before re-exposure |
| Hypersensitivity reactions (rash, urticaria, anaphylaxis) | Rare | Any time | Discontinue permanently; standard hypersensitivity management; document allergy |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Persistent headache despite analgesics and dose reduction | Common reason | Often improves over the first 1–2 weeks; if intractable, switch to alternative antianginal (calcium channel blocker, ranolazine, beta-blocker) |
| Symptomatic hypotension | Uncommon | Re-assess volume status, concurrent antihypertensives, and dose schedule before stopping |
| Loss of anti-anginal effect | Common if scheduled improperly | Almost always due to inadequate nitrate-free interval rather than true treatment failure; correct the schedule first |
| Hemodynamic intolerance during titration | Uncommon | Especially with concurrent ARNI or aggressive diuresis |
“Nitrate headache” is the single most common cause of regimen non-adherence on ISDN. Counsel proactively at the first visit: warn that headache is expected, occurs especially in the first 1–2 weeks, and is a marker of drug activity rather than a danger sign. Recommend acetaminophen or aspirin (which do not reduce antianginal efficacy) at the same time as the dose for the first 7–14 days; most patients tolerate the medication after this period of induction. Patients who skip doses to avoid headache lose protection against angina and may also lose the gradual desensitization that allows the headache to fade.
Drug Interactions
The most clinically important ISDN interactions are absolute pharmacodynamic contraindications with two drug classes that converge on the NO–cGMP axis: phosphodiesterase-5 (PDE-5) inhibitors and soluble guanylate cyclase (sGC) stimulators. Beyond these, most relevant interactions are additive hypotensive or pharmacodynamic. CYP3A4 inducers can reduce ISDN exposure but this is a less common clinical issue.
Monitoring
Monitoring on ISDN is mostly symptom-driven and clinical. Routine laboratory surveillance is light; the key parameters are blood pressure, anginal pattern, and the integrity of the nitrate-free interval.
-
Blood Pressure & Heart Rate
At initiation; with each titration step; periodically during chronic therapy
Routine Check seated and standing BP. Watch for symptomatic orthostasis. Reflex tachycardia >90 bpm in CAD patients without a beta-blocker should prompt regimen review. -
Anginal Frequency & Pattern
Each visit
Routine Document anginal episodes per week, exertion threshold, and timing relative to dosing. Increasing frequency or change in character warrants ACS evaluation, not dose escalation. -
Tolerance Audit
Each visit on chronic therapy
Routine Confirm an adequate daily nitrate-free interval. If the patient reports gradual loss of effect, audit dose timing first; tolerance from improper scheduling is the most common reason for “treatment failure.” -
Headache Severity & Frequency
First 2–4 weeks; then as needed
Routine Headache typically attenuates after 1–2 weeks of consistent therapy. Persistent disabling headache may require dose reduction or switching to an alternative antianginal class. -
Methemoglobin Level
Not routine
Trigger-based Order if cyanosis develops disproportionate to hypoxia, after suspected overdose, or with altered mental status; methemoglobinemia is rare at therapeutic doses. -
G6PD Status
Trigger-based
Trigger-based Consider testing in patients with relevant ancestry (Mediterranean, Middle Eastern, African, South-East Asian) before high-dose or chronic exposure if hemolysis develops. -
PDE-5 Inhibitor / sGC Stimulator Use
Each visit
Routine Specifically ask about ED medication use (including “as-needed” pills, samples from another physician, or pills shared by others); confirm no co-prescription with riociguat or vericiguat.
Contraindications & Cautions
Concomitant use of isosorbide dinitrate with PDE-5 inhibitors (sildenafil, tadalafil, vardenafil, avanafil) is contraindicated; the combination can cause severe, sometimes refractory hypotension, syncope, and myocardial ischemia. Concomitant use with the soluble guanylate cyclase stimulators riociguat and vericiguat is also contraindicated for the same convergent mechanism.
This warning extends to “as-needed” PDE-5 inhibitor use for erectile dysfunction. In a patient who has taken a recent PDE-5 inhibitor and develops chest pain, hold nitrates: wait at least 24 hours after the last sildenafil or vardenafil dose, and at least 48 hours after the last tadalafil dose, before administering any nitrate. Treat acute coronary ischemia in the interim with oxygen, antiplatelet therapy, and other non-nitrate options.
Absolute Contraindications
- Concurrent use of PDE-5 inhibitors (sildenafil, tadalafil, vardenafil, avanafil) — risk of severe hypotension and ischemia
- Concurrent use of soluble guanylate cyclase stimulators (riociguat, vericiguat) — convergent mechanism, severe hypotension
- Hypersensitivity to isosorbide dinitrate, other organic nitrates, or any tablet/capsule excipient
Relative Contraindications (Specialist Input Recommended)
- Hypertrophic cardiomyopathy with significant LV outflow tract obstruction — preload reduction worsens dynamic obstruction and may trigger syncope
- Severe aortic or mitral stenosis — preload reduction can compromise stroke volume and produce profound hypotension
- Constrictive pericarditis or cardiac tamponade — preload-dependent states; nitrates can precipitate hemodynamic collapse
- Right ventricular MI — preload-dependent right ventricle; nitrates can cause profound hypotension
- Severe anemia — methemoglobin formation reduces oxygen-carrying capacity further; FDA injection labels for nitrates list this as a contraindication for IV nitroglycerin
- Increased intracranial pressure or recent head trauma — vasodilation may further raise ICP
- Closed-angle glaucoma — theoretical concern with vasodilation raising intraocular pressure (nitrate-class precaution)
- Baseline severe hypotension or hypovolemia — initiate only after volume status is corrected
Use with Caution
- Older adults — higher risk of orthostatic hypotension and falls; titrate slowly and check standing BP
- Cirrhosis / hepatic impairment — plasma concentrations are elevated; cautious use is advised
- G6PD deficiency — risk of nitrate-induced oxidative hemolysis
- Concurrent use with other vasodilators or antihypertensives — additive hypotension; common and often intentional in HFrEF
- Pregnancy — limited human data; only if benefit clearly outweighs risk. Alternatives such as labetalol or extended-release nifedipine are preferred for chronic BP management in pregnancy
- Lactation — excretion in human milk is not characterized; observe the infant for sedation or feeding difficulty
- Nocturnal angina patients — standard daytime dosing may leave them unprotected at the time of usual symptoms; consider a different schedule or alternative agent
Animal studies of isosorbide dinitrate have shown a dose-related increase in embryotoxicity in rabbits at very high exposures (35–150× the maximum recommended human dose); rat data have not shown teratogenicity. Human data are limited to case reports of nitrate use for cardiac ischemia in pregnancy; safety has not been established. For chronic antianginal therapy in pregnancy, alternative agents (e.g., cardioselective beta-blockers) are generally preferred. Excretion of ISDN into human milk is not characterized; if used during breastfeeding, observe the infant for unusual sedation, feeding difficulty, or hypotension.
Patient Counselling
Purpose of Therapy
Frame ISDN according to the patient’s indication. For patients with stable angina, explain that ISDN is taken regularly to prevent chest pain and to help with episodes when they occur, by relaxing the blood vessels and reducing the workload on the heart. For patients with heart failure, explain that ISDN is one part of a combination (with hydralazine) that helps the heart work more easily and reduces the chance of being readmitted to hospital. ISDN does not cure the underlying problem; it controls symptoms and, in heart failure, improves outcomes when taken consistently.
How to Take
Different forms of ISDN are taken differently, and patients often confuse them. The under-the-tongue (sublingual) tablets dissolve quickly and are used either at the start of an angina attack or about 15 minutes before an activity that usually triggers chest pain. The swallowed tablets and capsules are taken on a regular schedule to prevent chest pain and do not work fast enough to relieve an attack already underway. Whatever the schedule, the most important rule is to take the medicine exactly as prescribed — there is a specific reason behind the timing of doses (the body needs a daily medicine-free period or the drug stops working). Most early side effects, especially headache, settle within 1–2 weeks of consistent use.
Sources
- U.S. Food and Drug Administration. Isordil Titradose (isosorbide dinitrate) tablets — full prescribing information. accessdata.fda.gov/drugsatfda_docs/label/2015/012093s052lbl.pdf Authoritative U.S. label for immediate-release oral ISDN with detailed clinical pharmacology, tolerance discussion, and the PDE-5 inhibitor contraindication.
- U.S. Food and Drug Administration. Dilatrate-SR (isosorbide dinitrate) sustained-release capsules — prescribing information. accessdata.fda.gov/drugsatfda_docs/label/2014/019790s011lbl.pdf Sustained-release product label specifying once-daily dosing up to 160 mg/day and the >18-hour nitrate-free interval recommendation.
- U.S. Food and Drug Administration. BiDil (isosorbide dinitrate / hydralazine hydrochloride) — prescribing information. NDA 020727 (approval 2005). accessdata.fda.gov — NDA 020727 FDA approval record for the fixed-dose H-ISDN combination indicated for HFrEF in self-identified African-American patients, with maintenance dosing of 37.5 mg/20 mg three times daily titrated to 75 mg/40 mg three times daily.
- Taylor AL, Ziesche S, Yancy C, et al; African-American Heart Failure Trial Investigators. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351(20):2049–2057. doi.org/10.1056/NEJMoa042934 A-HeFT — pivotal trial showing a mortality and hospitalization benefit of fixed-dose H-ISDN added to standard therapy in self-identified African-American patients with HFrEF.
- Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study. N Engl J Med. 1986;314(24):1547–1552. doi.org/10.1056/NEJM198606123142404 V-HeFT I — first trial demonstrating a survival benefit of H-ISDN over placebo in chronic heart failure.
- Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991;325(5):303–310. doi.org/10.1056/NEJM199108013250502 V-HeFT II — found enalapril superior to H-ISDN in overall survival but with similar mortality in self-identified Black participants, foundation for the racial subgroup hypothesis.
- Parker JD, Parker JO. Nitrate therapy for stable angina pectoris. N Engl J Med. 1998;338(8):520–531. doi.org/10.1056/NEJM199802193380807 Authoritative review of nitrate pharmacology and the clinical management of nitrate tolerance, with a focus on the asymmetric dosing schedule that preserves antianginal efficacy.
- Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. Circulation. 2022;145(18):e895–e1032. doi.org/10.1161/CIR.0000000000001063 Class 1 recommendation for fixed-dose H-ISDN in self-identified African-American patients with NYHA III–IV HFrEF on optimal GDMT; Class 2a recommendation in any race intolerant to ACEi/ARB/ARNI.
- Virani SS, Newby LK, Arnold SV, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease. J Am Coll Cardiol. 2023;82(9):833–955. doi.org/10.1016/j.jacc.2023.04.003 Current U.S. chronic coronary disease guideline; supports short-acting sublingual nitrates for acute angina (Class 1) and long-acting nitrates as add-on antianginal therapy when first-line agents are insufficient.
- Münzel T, Daiber A, Mülsch A. Explaining the phenomenon of nitrate tolerance. Circ Res. 2005;97(7):618–628. doi.org/10.1161/01.RES.0000184694.03262.6d Comprehensive mechanistic review of nitrate tolerance covering ALDH2 inactivation, oxidative stress, sulfhydryl depletion, and neurohormonal counter-regulation.
- Cole RT, Kalogeropoulos AP, Georgiopoulou VV, et al. Hydralazine and isosorbide dinitrate in heart failure: historical perspective, mechanisms, and future directions. Circulation. 2011;123(21):2414–2422. doi.org/10.1161/CIRCULATIONAHA.110.012781 Mechanistic and historical review covering preload/afterload complementarity, attenuation of nitrate tolerance by hydralazine, and racial differences in response.
- Thadani U, Rodgers T. Side effects of using nitrates to treat angina. Expert Opin Drug Saf. 2006;5(5):667–674. doi.org/10.1517/14740338.5.5.667 Practical review of nitrate side effects including headache, hypotension, methemoglobinemia, and tolerance, with management strategies.
- Abrams J. The role of nitrates in coronary heart disease. Arch Intern Med. 1995;155(4):357–364. doi.org/10.1001/archinte.1995.00430040027004 Foundational clinical review on the role of organic nitrates in CAD, including isosorbide dinitrate pharmacokinetics and the dosing implications of its active metabolites.
- Cheitlin MD, Hutter AM Jr, Brindis RG, et al. ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. J Am Coll Cardiol. 1999;33(1):273–282. doi.org/10.1016/s0735-1097(98)00656-1 Consensus document establishing the nitrate–PDE-5 inhibitor contraindication and the recommended washout intervals (24 h for sildenafil/vardenafil; longer for tadalafil based on its extended half-life).