Library › Pharmacology › Antianginal drugs

Antianginal drugs: nitrates, ranolazine, and others

The pharmacology, dosing, interactions, evidence, and sequencing of nitrates, ranolazine, and the antianginal agents used outside the United States, with first-line drugs summarized.

Myocardial oxygen supply and demand as targets of antianginal drugs

Angina is the symptom of an imbalance between myocardial oxygen demand and coronary oxygen delivery. Because the myocardium extracts about 70% to 80% of arterial oxygen at rest, it cannot meet higher demand by extracting more; additional delivery requires additional coronary flow. A flow-limiting epicardial stenosis, diffuse atherosclerosis, microvascular dysfunction, or vasospasm caps that flow, and ischemia follows once demand exceeds the ceiling.

Determinants of demand. Myocardial oxygen consumption rises with heart rate, contractility, and systolic wall stress. Wall stress, by the Laplace relation, is proportional to cavity pressure and radius and inversely proportional to wall thickness, so both afterload (systolic pressure) and preload (ventricular volume) raise it. The rate-pressure product, heart rate multiplied by systolic blood pressure, is the bedside index of demand. Patients with exertional angina tend to develop symptoms at a reproducible rate-pressure product, so drugs that lower heart rate or blood pressure raise the exercise threshold for angina.

Determinants of supply. Left ventricular subendocardial perfusion occurs almost entirely in diastole, because systolic compression closes the intramural vessels. Subendocardial flow therefore depends on the duration of diastole and on the gradient between aortic diastolic pressure and left ventricular diastolic pressure. Tachycardia shortens diastole disproportionately, and a rise in left ventricular diastolic pressure during ischemia narrows the perfusion gradient further. The subendocardium is ischemic first, which is why exercise-induced ischemia produces ST depression.

Action of each antianginal class on supply and demand. Antianginal classes act on one or more of these determinants. Beta-blockers and the non-dihydropyridine calcium channel blockers lower heart rate and contractility and lengthen diastole. Dihydropyridine calcium channel blockers lower afterload and relax epicardial and arteriolar smooth muscle. Nitrates lower preload through venodilation, dilate epicardial arteries and collaterals, and relieve spasm. Ranolazine reduces sodium-dependent calcium overload of ischemic myocytes and the diastolic wall tension that compresses the subendocardial microcirculation, without changing heart rate or blood pressure. Metabolic agents such as trimetazidine and perhexiline shift substrate use from fatty acids toward glucose, which yields more adenosine triphosphate (ATP) per molecule of oxygen. Ivabradine slows the sinus node alone.

Hemodynamic profiles of antianginal drugs. Arrows show the usual direction of effect at therapeutic doses; reflex tachycardia with dihydropyridines and nitrates is blunted by concomitant beta-blockade.

Symptom relief versus event reduction with antianginal drugs

The clinical justification for antianginal drugs is fewer angina episodes, less sublingual nitroglycerin use, longer exercise duration, and better health status. With the exception of beta-blockade after myocardial infarction and in reduced ejection fraction, no antianginal drug has reduced death or myocardial infarction in a randomized trial of chronic coronary disease. The 2024 European Society of Cardiology (ESC) guideline states that direct comparisons provide no robust evidence that one antianginal drug relieves symptoms better than another. It also states that no antianginal medication improves long-term cardiovascular outcomes except beta-blockers given within 1 year of myocardial infarction.

The large trials support that conclusion for each class:

• Nitrates after myocardial infarction. ISIS-4 randomized 58,050 patients with suspected acute infarction to controlled-release isosorbide mononitrate (30 mg titrated to 60 mg daily for 1 month) or placebo; 5-week mortality was 7.34% versus 7.54%, with no benefit in any subgroup. GISSI-3 (19,394 patients) found no independent effect of intravenous then transdermal nitroglycerin on 6-week mortality (odds ratio 0.94). Nitrates in acute coronary syndromes are therefore used for ischemic pain, hypertension, or pulmonary congestion, not for prognosis.
• Ranolazine. MERLIN-TIMI 36 (6,560 patients with non-ST-elevation acute coronary syndrome) did not reduce cardiovascular death, myocardial infarction, or recurrent ischemia (21.8% versus 23.5%; hazard ratio 0.92; P = .11), although recurrent ischemia alone fell (13.9% versus 16.1%). RIVER-PCI (2,651 patients with incomplete revascularization after percutaneous coronary intervention [PCI]) did not reduce ischemia-driven revascularization or hospitalization (26% versus 28%; hazard ratio 0.95).
• Trimetazidine. ATPCI (6,007 patients after PCI) found no difference in its composite of cardiac death, cardiac hospitalization, and recurrent or persistent angina (23.3% versus 23.7%; hazard ratio 0.98) over a median of 47.5 months.
• Ivabradine. SIGNIFY (19,102 patients with stable coronary disease, no clinical heart failure, and heart rate of 70 beats/min or more) did not reduce cardiovascular death or nonfatal infarction, and in the subgroup with activity-limiting angina the primary outcome increased.
• Nicorandil. IONA is the only antianginal trial with a positive outcome result: in 5,126 patients with stable angina, nicorandil reduced the composite of coronary death, nonfatal infarction, or unplanned admission for cardiac chest pain (13.1% versus 15.5%; hazard ratio 0.83). The secondary end point of coronary death or nonfatal infarction was not significantly reduced (4.2% versus 5.2%; P = .068), so the result rests largely on admissions for chest pain.

Event prevention in chronic coronary disease comes from antiplatelet therapy, lipid lowering, blood pressure control, renin-angiotensin system inhibition, sodium-glucose cotransporter 2 (SGLT2) inhibitors or glucagon-like peptide-1 (GLP-1) receptor agonists where indicated, colchicine in selected patients, and lifestyle change. That framework and the place of revascularization after ISCHEMIA and ORBITA-2 are covered in the chronic coronary disease hub. Because antianginal drugs act on symptoms, their dose and number are titrated to the patient's angina burden and tolerance, and an asymptomatic patient without another indication does not need one.

Guideline recommendations for antianginal therapy: 2023 AHA/ACC and 2024 ESC

The 2023 American Heart Association/American College of Cardiology (AHA/ACC) multisociety guideline for chronic coronary disease (CCD) and the 2024 ESC guideline for chronic coronary syndromes (CCS) agree that drug choice follows heart rate, blood pressure, ventricular function, comorbidities, and drug interactions. They differ in ranking. The US guideline places long-acting nitrates alongside beta-blockers and calcium channel blockers as initial options and gives ranolazine a Class 1 recommendation for persistent symptoms. The ESC guideline recommends a beta-blocker and/or a calcium channel blocker for most patients and places long-acting nitrates and ranolazine at Class IIa as add-on or selected initial therapy. It gives nicorandil and trimetazidine Class IIb; neither is available in the United States.

Antianginal recommendations in the 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA chronic coronary disease guideline (with its 2023 corrections) and the 2024 ESC chronic coronary syndromes guideline (Recommendation Tables 16 and 31, with its 2025 correction, which did not alter these recommendations). The ESC footnote lists ivabradine, nicorandil, long-acting nitrates, ranolazine, or trimetazidine as initial therapy when beta-blockers and calcium channel blockers are not tolerated or are contraindicated. It lists ranolazine and trimetazidine for microvascular angina and nicorandil or nitrates for coronary spasm.

The ESC task force describes its approach as a departure from the historical hierarchy of first-line and second-line drugs. Initial therapy is chosen for the individual hemodynamic profile and the presumed mechanism of ischemia (obstructive, vasospastic, or microvascular), and other agents can be added to, or used instead of, a beta-blocker or calcium channel blocker. Both guidelines expect the response to be reassessed and the regimen adapted when angina is not controlled. The ESC document notes that a combination of two or more antianginal drugs can be established over about 6 weeks before refractory symptoms lead to invasive angiography.

Beta-blockers and calcium channel blockers in the antianginal sequence

Beta-blockers and calcium channel blockers have their own hubs, which cover agents, doses, outcome evidence, and adverse effects: beta-blockers and calcium channel blockers.

A beta-blocker is the natural first choice when the resting heart rate is high, after recent myocardial infarction, with LVEF of 40% or less (where it also reduces major adverse cardiovascular events, Class 1), with tachyarrhythmias, or with hypertension. Beta-blockade is avoided in sinus node dysfunction and high-grade atrioventricular block without pacing, is used cautiously with bronchospasm and severe peripheral artery disease, and is not used as monotherapy in vasospastic angina, where unopposed alpha-adrenergic tone can provoke spasm. Abrupt withdrawal can produce rebound ischemia. A target resting heart rate of about 55 to 60 beats/min is commonly used.

A dihydropyridine calcium channel blocker (amlodipine, felodipine, or long-acting nifedipine) is preferred with vasospasm, with bradycardia or conduction disease that limits rate-slowing drugs, and with hypertension, and it combines well with a beta-blocker, which blunts its reflex tachycardia. Short-acting nifedipine is avoided. Verapamil and diltiazem lower heart rate and contractility and are alternatives when a beta-blocker cannot be used. They are harmful in heart failure with reduced ejection fraction (Class 3: Harm, 2022 AHA/ACC/HFSA) and carry a risk of bradycardia and atrioventricular block when combined with a beta-blocker. As moderate CYP3A inhibitors, they limit ranolazine to 500 mg twice daily and raise the levels of simvastatin, lovastatin, digoxin, and ivabradine.

Organic nitrates: bioactivation, cGMP signaling, and hemodynamic effects

Organic nitrates (nitroglycerin, also called glyceryl trinitrate; isosorbide dinitrate; and isosorbide-5-mononitrate) are prodrugs. They release nitric oxide or a related nitrogen species that binds the reduced heme of soluble guanylate cyclase (sGC) in vascular smooth muscle. Activated sGC converts guanosine triphosphate (GTP) to cGMP, which activates protein kinase G. Protein kinase G lowers intracellular calcium and activates myosin light-chain phosphatase, and the smooth muscle relaxes. PDE5 terminates the signal by hydrolyzing cGMP. Every drug interaction that matters for nitrates follows from this pathway.

Bioactivation. At therapeutic concentrations, nitroglycerin is bioactivated mainly by mitochondrial aldehyde dehydrogenase 2 (ALDH2), the high-affinity pathway identified in 2002; cytochrome P450 enzymes and other systems contribute at higher concentrations. Isosorbide mononitrate and isosorbide dinitrate depend less on ALDH2. The common East Asian ALDH2 variant (Glu504Lys, the ALDH2*2 allele carried by roughly 30% to 50% of East Asian people) nearly abolishes enzyme activity. In Chinese patients, carriers had a much weaker response to sublingual nitroglycerin, and the catalytic efficiency of the variant enzyme for nitroglycerin was about one-tenth that of the wild type. A patient who reports that sublingual nitroglycerin never helps, particularly one of East Asian ancestry, may have this variant instead of a nonischemic cause of pain.

Hemodynamic effects. At low doses, nitrates dilate capacitance veins more than arteries, so preload, ventricular volume, and diastolic wall stress fall; this is the main antianginal effect in exertional angina. The fall in left ventricular diastolic pressure also improves the subendocardial perfusion gradient. Nitrates dilate epicardial coronary arteries, including stenotic segments with residual compliant wall, and collateral vessels, and they reverse and prevent vasospasm. At higher doses, arteriolar dilation lowers systolic pressure and afterload. Reflex tachycardia offsets part of the benefit and is blunted by a beta-blocker. Nitrates act mainly on veins and larger conductance arteries and have comparatively little effect on the small resistance arterioles, which helps explain their limited and inconsistent effect in microvascular angina.

Pharmacokinetics. Nitroglycerin has a plasma half-life of 2 to 3 minutes, and its clearance exceeds hepatic blood flow; its 1,2- and 1,3-dinitro metabolites have half-lives of about 30 to 40 minutes and contribute to the duration of effect. Swallowed nitroglycerin is almost entirely removed by first-pass metabolism, which is why it is given sublingually, buccally, by spray, transdermally, or intravenously. Isosorbide dinitrate has variable oral bioavailability (10% to 90%, average about 25%) because of first-pass metabolism. Its serum half-life is about 1 hour, and it has two active metabolites, of which the 5-mononitrate has a half-life of about 5 hours. Isosorbide mononitrate is not subject to first-pass metabolism, has an absolute bioavailability of about 100% and a half-life of about 5 hours, and needs no adjustment for renal or hepatic impairment.

Short-acting nitroglycerin for acute angina and prophylaxis

Every patient with chronic coronary disease and angina is prescribed sublingual nitroglycerin or nitroglycerin spray for immediate relief (Class 1, 2023 AHA/ACC). The sublingual tablets come in 0.3, 0.4, and 0.6 mg strengths; the lingual spray delivers 0.4 mg per metered dose.

Administration. One tablet is placed under the tongue or in the buccal pouch at the first sign of an attack and allowed to dissolve without swallowing; the spray is given as one or two metered doses onto or under the tongue. A dose may be repeated every 5 minutes, up to three tablets or three sprays within 15 minutes. If pain persists after three doses, or differs from the usual pattern, prompt medical attention is sought. The drug is taken at rest, preferably sitting, because postural hypotension and syncope occur. For patients with a dry mouth, a sip of water before the tablet helps it dissolve. Vasodilation begins 1 to 3 minutes after a sublingual dose, peaks by about 5 minutes, and lasts at least 25 minutes.

Prophylaxis. Sublingual nitroglycerin or spray taken 5 to 10 minutes before an activity that predictably provokes angina (climbing a hill, sexual activity in a patient not taking a PDE5 inhibitor, exertion in the cold) prevents the attack. For a patient whose angina is confined to one predictable situation, prophylactic use can make a daily drug unnecessary.

What frequent use indicates. Rising use of sublingual nitroglycerin is a sign of worsening angina and is evaluated as such. Angina at rest, angina of increasing frequency or severity, or pain that does not respond to the usual dose is managed as a possible acute coronary syndrome. The labels note that excessive use produces tolerance and that only the smallest dose needed for relief is used.

Long-acting nitrates: preparations, dosing, and the nitrate-free interval

Long-acting nitrates prevent angina for part of each day. Their defining problem is tolerance: when nitrate levels are maintained continuously, antianginal efficacy is lost, usually within 24 hours, and dose escalation does not restore it. Every chronic regimen therefore builds in a daily nitrate-free (or low-nitrate) interval, timed for the part of the day when the patient is least likely to need protection, usually overnight. The ESC gives the nitrate-free or low-nitrate interval a Class IIa recommendation.

Nitrate preparations used for angina in the United States, from US prescribing information. Transdermal release rates were formerly labeled per 24 hours (0.1 mg/h = 2.5 mg/24 h). Isosorbide dinitrate combined with hydralazine is used in heart failure with reduced ejection fraction and is covered in that hub.

Preparation choice and titration of extended-release isosorbide mononitrate. Extended-release isosorbide mononitrate once daily is the most widely used long-acting nitrate in the United States because its single morning dose provides daytime coverage with a built-in trough overnight, and its bioavailability is predictable. In the labeling trial of the extended-release product, the 30 and 60 mg doses improved treadmill time at 4 and 12 hours early in treatment but were no longer distinguishable from placebo by day 42. The 120 and 240 mg doses retained a significant effect at 4 and 12 hours. The dose is therefore titrated to response, to 120 mg once daily and rarely 240 mg. Isosorbide dinitrate is cheaper but requires two or three doses a day timed eccentrically (for example, 8 a.m., 1 p.m., and no evening dose). Patches are convenient but must be removed for 10 to 12 hours each day; a patch worn continuously provides no benefit after about 24 hours. Ointment is used mainly in the hospital.

Rebound during the nitrate-free interval. During the nitrate-free interval, some patients have more angina than before treatment and reduced exercise tolerance compared with placebo. In one controlled trial, patients receiving intermittent nitroglycerin had lower exercise tolerance at the end of the daily drug-free interval than the parallel placebo group. For patients with nocturnal or early-morning angina, the free interval is moved to a different part of the day, or a drug without tolerance (a beta-blocker, calcium channel blocker, or ranolazine) covers that period. The extreme form of withdrawal was described in munitions and explosives workers with heavy industrial nitrate exposure, who developed angina, myocardial infarction, and sudden death on weekends or holidays away from exposure. The headache and tolerance pattern on return to work was called "Monday disease." The labels for long-acting nitrates cite this experience as a reason not to stop high-dose nitrate therapy abruptly.

Headache as a marker. Daily headache is the most common adverse effect and usually wanes within the first weeks. The ointment label notes that headache is a marker of drug activity and that patients who change their schedule to avoid it are likely to lose antianginal effect as well. Starting at a low dose and titrating, with acetaminophen as needed, improves tolerability.

Nitrate tolerance and nitrate-induced endothelial dysfunction

Nitrate tolerance is the loss of hemodynamic and antianginal effect during sustained exposure. It has two broad components. Pseudotolerance comes from counterregulation outside the vessel wall: venodilation activates the sympathetic nervous system and the renin-angiotensin-aldosterone system, and plasma volume expands, which restores preload. True vascular tolerance is a reduced response of the vessel itself to the same nitrate concentration and is explained mainly by oxidative stress.

Mechanisms of nitrate tolerance. The oxidative-stress mechanisms are best characterized for nitroglycerin.

Endothelial dysfunction. Sustained nitroglycerin exposure impairs endothelium-dependent vasodilation in humans, and the impairment can persist after the drug is stopped. Because the same oxidative mechanisms reduce the bioavailability of endogenously produced nitric oxide, continuous nitrate therapy can worsen the endothelial function that the drug was meant to support. This is the basis for concern that chronic continuous nitrate exposure may be harmful beyond the loss of effect, although outcome trials have not shown excess events with intermittent regimens.

Prevention. The only established strategy is the daily nitrate-free interval: 10 to 12 hours is sufficient for nitroglycerin patches, and at least 14 hours is advised for immediate-release isosorbide dinitrate. Several co-therapies attenuate tolerance experimentally or in small human studies:

• Hydralazine. In rabbits, hydralazine prevented nitroglycerin tolerance by inhibiting a membrane-bound NADH oxidase and normalizing vascular superoxide production. In 28 patients with heart failure and reduced ejection fraction receiving a 24-hour nitroglycerin infusion, oral hydralazine 75 mg four times daily prevented the attenuation of the fall in pulmonary artery and wedge pressures seen with nitroglycerin alone. This antioxidant effect is one rationale for the hydralazine-isosorbide dinitrate combination in heart failure.
• Renin-angiotensin system inhibition and carvedilol. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers counter the neurohormonal component; carvedilol has antioxidant properties. Their effect on clinical tolerance has not been established in trials.
• Antioxidants and other approaches. N-acetylcysteine, vitamin C, and folic acid attenuated tolerance in small studies. None is part of routine practice.

Isosorbide mononitrate is less dependent on ALDH2 than nitroglycerin but is still subject to tolerance and to the counterregulatory mechanisms, which is why the once-daily extended-release regimen, with its overnight trough, is the standard. Pentaerythritol tetranitrate, used in Europe, was reported to cause less oxidative stress than nitroglycerin; it is not available in the United States.

Nitrates with PDE5 inhibitors, riociguat, and vericiguat

PDE5 inhibitors (sildenafil, vardenafil, tadalafil, and avanafil, used for erectile dysfunction, and sildenafil and tadalafil for pulmonary arterial hypertension) block the breakdown of cGMP. Added to a nitrate, which increases cGMP production, they cause profound, sometimes refractory hypotension, syncope, and myocardial ischemia. Riociguat stimulates sGC independently of nitric oxide and has the same interaction. Concomitant use is contraindicated in the labels of every US nitroglycerin product and in the labels of the PDE5 inhibitors and riociguat, whether the nitrate is taken regularly or intermittently. The 2023 AHA/ACC chronic coronary disease guideline classifies concomitant use of PDE5 inhibitors and nitrates as Class 3: Harm (B-NR), and the ESC gives nitrates with PDE5 inhibitors a Class III recommendation.

Interactions between nitrates and drugs that act on the cGMP pathway. Half-lives are from US prescribing information and the nitrate pharmacology literature. Nicorandil, which contains a nitrate moiety, is also contraindicated with PDE5 inhibitors and sGC stimulators.

Vericiguat. The prescribing information for vericiguat reports no clinically significant difference in seated blood pressure when vericiguat 10 mg was given with nitroglycerin spray or modified-release isosorbide mononitrate 60 mg in patients with coronary disease. It also notes that short-acting nitrates were well tolerated in the heart failure trial and that experience with long-acting nitrates is limited. The current nitroglycerin labels, by contrast, list soluble guanylate cyclase stimulators as a class among their contraindications and name riociguat as the example. Combined use of a long-acting nitrate with vericiguat therefore lies outside what the labels support. Vericiguat is covered in the adjunctive heart failure drugs hub.

Patients with coronary disease who use PDE5 inhibitors. Erectile dysfunction is common in men with coronary disease, and many such patients use PDE5 inhibitors. Each patient with angina is asked about these drugs, and each patient who uses them is told not to take nitroglycerin within the intervals in the preceding table and to report chest pain after a PDE5 inhibitor to emergency staff. When angina occurs in that situation, the patient is evaluated without a nitrate; ischemia is treated with other agents (beta-blockade if hemodynamics allow, analgesia, and revascularization when indicated). In a Swedish registry of 55,777 men with prior infarction or revascularization treated with nitrates, the 5,710 who also filled PDE5 inhibitor prescriptions had higher risks of all-cause mortality (hazard ratio 1.39), myocardial infarction (1.72), and heart failure (1.67). The design was observational and cannot separate drug interaction from confounding, but it argues against prescribing both drugs to the same patient. For a patient who needs both, the long-acting nitrate is usually the drug to replace, since ranolazine, a beta-blocker, or a calcium channel blocker can provide antianginal effect without the interaction.

Treatment of nitrate–PDE5 hypotension. The patient is placed supine with legs raised, intravenous fluid is given, and an alpha-adrenergic agonist (phenylephrine or norepinephrine) is used for refractory hypotension, with invasive monitoring when needed. Agents that further reduce preload are avoided.

Adverse effects, contraindications, and hemodynamic hazards of nitrates

Adverse effects and restrictions for organic nitrates, from US prescribing information and the 2024 ESC guideline.

Nitrates in heart failure with preserved ejection fraction. Patients with heart failure with preserved ejection fraction and angina or exertional dyspnea are often prescribed nitrates. In NEAT-HFpEF (110 patients, crossover design), isosorbide mononitrate titrated to 120 mg daily reduced daily activity measured by accelerometer and did not improve quality of life, 6-minute walk distance, or N-terminal pro-B-type natriuretic peptide (NT-proBNP). Long-acting nitrates are therefore not used to improve exercise tolerance in heart failure with preserved ejection fraction; when such a patient has angina, the nitrate is prescribed for angina and its effect on activity is reassessed. The heart failure with preserved ejection fraction hub covers the condition.

Nitrates in heart failure with reduced ejection fraction. Isosorbide dinitrate with hydralazine reduces mortality in self-identified Black patients with symptomatic heart failure with reduced ejection fraction on optimized therapy, and it is used in other patients who cannot take renin-angiotensin system inhibitors; that indication is covered in the heart failure with reduced ejection fraction hub. A nitrate prescribed for angina in such a patient follows the same nitrate-free principle, although the fixed hydralazine-isosorbide dinitrate regimen is given three times daily.

Ranolazine: late sodium current inhibition and anti-ischemic mechanism

Ranolazine is a piperazine derivative approved in the United States in 2006 for chronic angina. Its current label indication is the treatment of chronic angina, alone or with beta-blockers, nitrates, calcium channel blockers, antiplatelet therapy, lipid-lowering therapy, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers. The label states that the mechanism of its antianginal effect has not been determined; the accepted explanation is inhibition of the late inward sodium current.

Late sodium current and calcium overload. The cardiac sodium channel (Nav1.5) opens briefly at the upstroke of the action potential and then inactivates. A small fraction of current persists through the plateau, the late sodium current. Ischemia, oxidative stress, and heart failure increase it. Sodium entering through this current raises intracellular sodium, which drives the sodium-calcium exchanger in reverse and loads the cell with calcium. Calcium overload impairs diastolic relaxation and raises diastolic wall tension, which compresses the subendocardial microcirculation and increases oxygen demand, so ischemia perpetuates itself. Ranolazine inhibits the late sodium current at therapeutic concentrations with little effect on the peak current, interrupting this cycle. The first trials attributed its effect to partial inhibition of fatty acid oxidation; later work identified late sodium current inhibition as the principal action.

Hemodynamic neutrality. In controlled angina trials, ranolazine changed mean heart rate by less than 2 beats/min and systolic blood pressure by less than 3 mm Hg, including in patients with heart failure, diabetes, reactive airway disease, and older age. This is its main clinical advantage: it adds antianginal effect when bradycardia, conduction disease, or low blood pressure limits beta-blockers, calcium channel blockers, and nitrates.

Electrophysiologic effects. Ranolazine also blocks the rapid delayed rectifier potassium current (I_Kr), which prolongs the corrected QT (QTc) interval in a dose- and concentration-related manner. Because inhibition of the late sodium current shortens action potential duration and suppresses early afterdepolarizations, the net effect is a modest QTc increase without the proarrhythmic signal of pure I_Kr blockers. The same mechanism underlies its antiarrhythmic effects in atrial and ventricular tissue, discussed below. It reduces T-wave amplitude and occasionally produces notched T waves.

Ranolazine trials: MARISA, CARISA, ERICA, TERISA, MERLIN-TIMI 36, and RIVER-PCI

The antianginal efficacy of ranolazine was established in four placebo-controlled trials and its outcome effect tested in two large event-driven trials.

Principal randomized trials of ranolazine. HR, hazard ratio. ERICA values are from the published trial; the label reports means of 3.3 versus 4.3 episodes/week and 2.7 versus 3.6 nitroglycerin doses/week.

The benefit is modest in absolute terms, about one fewer angina episode per week, but it adds to background beta-blockers, calcium channel blockers, and nitrates. In CARISA, tolerance did not develop over 12 weeks, and rebound was not observed after abrupt withdrawal. Effects were smaller in women. The label reports that the improvement in exercise duration in CARISA among women was about one-third of that among men at 1,000 mg twice daily. In ERICA, the mean reduction in weekly angina was 0.3 episodes in women and 1.3 in men. Patients with more frequent angina at baseline derived more benefit, as did those with higher glycated hemoglobin in TERISA and RIVER-PCI. MERLIN-TIMI 36 is the main safety reassurance for long-term use in high-risk coronary patients: total mortality and symptomatic arrhythmias were no higher with ranolazine. The label carries a section titled lack of benefit in acute coronary syndrome, and ranolazine is not used to improve outcomes after an acute coronary syndrome.

Ranolazine dosing, pharmacokinetics, and organ impairment

Dose. Ranolazine extended-release tablets are started at 500 mg twice daily and increased to 1,000 mg twice daily as needed for symptoms; 1,000 mg twice daily is the maximum. Doses above 1,000 mg twice daily are poorly tolerated. Tablets are swallowed whole, not crushed, broken, or chewed, with or without food. A missed dose is not doubled. Ranolazine does not relieve an acute attack, and patients continue to carry sublingual nitroglycerin.

Pharmacokinetics. Peak concentrations occur 2 to 5 hours after a dose, the apparent terminal half-life is 7 hours, and steady state is reached within 3 days of twice-daily dosing. Bioavailability of the tablet relative to an oral solution is 76%, and exposure is highly variable: at 1,000 mg twice daily the mean steady-state peak concentration was 2,600 ng/mL with 95% confidence limits of 400 to 6,100 ng/mL. Between 500 and 1,000 mg twice daily, peak concentration and exposure rise slightly more than proportionally (2.2-fold and 2.4-fold). Ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6, is a substrate of P-glycoprotein, and is about 62% protein bound; less than 5% is excreted unchanged. Age, sex, food, and heart failure do not alter its pharmacokinetics.

Kidney disease. Peak concentrations are 40% to 50% higher with mild, moderate, or severe renal impairment, independent of its degree. In a pharmacokinetic study in severe renal impairment (creatinine clearance below 30 mL/min), 2 of 4 participants developed acute renal failure after 5 days of 500 mg twice daily followed by 1,000 mg twice daily, and one required hemodialysis; the study was stopped. The label therefore warns of acute renal failure with creatinine clearance below 30 mL/min. It calls for monitoring of renal function after initiation, and periodically when creatinine clearance is below 60 mL/min. Ranolazine is stopped if acute renal failure develops (a marked rise in creatinine with a rise in blood urea nitrogen or potassium). Separately, ranolazine raises serum creatinine by about 0.1 mg/dL in all patients by inhibiting tubular secretion of creatinine; this rise is rapid, nonprogressive, reversible, unaccompanied by a change in blood urea nitrogen, and unrelated to any fall in glomerular filtration rate. Its pharmacokinetics in dialysis have not been studied.

Liver disease. Ranolazine is contraindicated in liver cirrhosis. Peak concentration was 30% higher in mild (Child-Pugh A) and 80% higher in moderate (Child-Pugh B) cirrhosis, and the slope of the relation between ranolazine concentration and QTc was much steeper in cirrhosis, producing about three times the QT prolongation.

Older adults. Patients aged 75 years and older had more adverse events, serious adverse events, and discontinuations than placebo-treated patients of the same age. Dosing starts at the low end, with attention to renal function and interacting drugs.

Pregnancy and lactation. There are no human data in pregnancy; animal studies at exposures up to 4 times the maximum human dose showed no fetal harm. Ranolazine is present in rat milk, and human data are absent. It is not a standard antianginal in pregnancy; the cardiovascular drugs in pregnancy and lactation hub covers the choice.

Heart failure and diabetes. No dose adjustment is required for heart failure (New York Heart Association class I to IV) or diabetes.

Ranolazine drug interactions, QT prolongation, and adverse effects

The safety of ranolazine depends mainly on its interactions. It is a CYP3A and P-glycoprotein substrate, so inhibitors raise its levels and inducers abolish its effect. It is also a weak CYP3A inhibitor, a moderate CYP2D6 and P-glycoprotein inhibitor, and an inhibitor of the organic cation transporter OCT2, so it raises the levels of several common cardiovascular and metabolic drugs.

Drug interactions of ranolazine, from US prescribing information (revised October 2019). Paroxetine increased ranolazine concentrations by 20% and requires no adjustment; simvastatin 20 mg and cimetidine, weak CYP3A inhibitors, did not increase ranolazine exposure.

QT prolongation. At the time of peak concentration on 1,000 mg twice daily, mean QTc increases by about 6 ms; in the 5% of patients with the highest concentrations, the increase is at least 15 ms. The QTc-concentration relation is linear (about 2.6 ms per 1,000 ng/mL) through exposures several times the maximum dose and is not altered by age, sex, heart rate, heart failure, diabetes, or renal impairment, but it is much steeper in hepatic impairment. The label notes little experience at doses above 1,000 mg twice daily, with other QT-prolonging drugs, in congenital long QT syndrome or a family history of it, and in acquired QT prolongation. In MERLIN-TIMI 36, QTc prolongation required a dose reduction of the intravenous drug in 0.9% of ranolazine-treated patients versus 0.3% on placebo, with no excess of symptomatic arrhythmias or death. A modest QTc increase on ranolazine is therefore reviewed for its cause (interacting CYP3A inhibitors, hypokalemia, hypomagnesemia, other QT-prolonging drugs, renal or hepatic impairment) before the drug is stopped. The general approach to drug-induced QT prolongation is in the long QT syndrome and QT prolongation hub.

Adverse effects. In controlled angina trials, the adverse reactions that occurred in more than 4% of patients and more often than with placebo were dizziness (6.2%), headache (5.5%), constipation (4.5%), and nausea (4.4%); dizziness may be dose related. About 6% of patients stopped ranolazine for an adverse event, compared with about 3% on placebo. Less common effects include bradycardia, palpitations, tinnitus, vertigo, blurred vision, abdominal pain, dry mouth, vomiting, asthenia, peripheral edema, vasovagal syncope, and confusion. Renal failure, angioedema, tremor, and paresthesia occurred in fewer than 0.5% of patients in controlled trials. Postmarketing reports include abnormal coordination, myoclonus, paresthesia, tremor, and other neurologic effects, often after a dose increase; hypoglycemia in patients with diabetes taking antidiabetic drugs; hallucinations; urinary retention; and angioedema. Overdose causes hypotension, QT prolongation, bradycardia, myoclonus, severe tremor, ataxia, and hallucinations; ranolazine is about 62% protein bound, so hemodialysis is unlikely to remove it.

Ranolazine in diabetes, atrial fibrillation, and ventricular arrhythmia

Glycemic effect. Ranolazine produces small reductions in glycated hemoglobin (HbA_1c) in patients with diabetes; the label states that the clinical significance is unknown and that ranolazine is not a treatment for diabetes. In a secondary analysis of RIVER-PCI, ranolazine lowered HbA_1c by 0.42% at 6 months and 0.44% at 12 months compared with placebo in the 961 patients with diabetes, and by about 0.2% in those without diabetes. The angina benefit at 6 months was numerically greater when baseline HbA_1c was 7.5% or more. Together with TERISA, these data support ranolazine as an add-on for patients with diabetes and persistent angina, provided that the metformin dose is kept at or below 1,700 mg daily when ranolazine is taken at 1,000 mg twice daily.

Atrial fibrillation. Late sodium current inhibition prolongs atrial refractoriness more than ventricular refractoriness, particularly at fast rates. In the 7-day Holter substudy of MERLIN-TIMI 36 (6,351 patients), ranolazine reduced ventricular tachycardia lasting 8 beats or more (5.3% versus 8.3%), supraventricular tachycardia (44.7% versus 55.0%), pauses of 3 seconds or more (3.1% versus 4.3%), and, nonsignificantly, new atrial fibrillation (1.7% versus 2.4%; P = .08). In HARMONY (134 patients with paroxysmal atrial fibrillation and pacemakers), ranolazine 750 mg twice daily with dronedarone 225 mg twice daily reduced atrial fibrillation burden by 59% versus placebo, whereas either drug alone did not. Ranolazine is not approved for atrial fibrillation in the United States, and HARMONY, which did not enroll patients for angina, does not support a stand-alone indication; in a patient who takes ranolazine for angina and also has paroxysmal atrial fibrillation, any effect on atrial fibrillation is incidental. Management of atrial fibrillation is in the atrial fibrillation hub.

Ventricular arrhythmia and heart failure. The label notes that the lower arrhythmia incidence in MERLIN-TIMI 36 did not translate into fewer deaths, arrhythmia hospitalizations, or arrhythmia symptoms. Ranolazine has been studied as an adjunct for ventricular arrhythmias and in heart failure with preserved ejection fraction, without an established indication in either.

Nicorandil: nitrate and potassium channel opener

Nicorandil is a nicotinamide ester with two actions. Its nitrate moiety increases cGMP and dilates veins, lowering preload, and its opening of ATP-sensitive potassium channels hyperpolarizes arterial smooth muscle, dilating epicardial and resistance coronary arteries and lowering afterload. Potassium channel opening also mimics ischemic preconditioning. Nicorandil is used in Europe, Japan, and elsewhere; it is not available in the United States.

Evidence from IONA. In IONA, 5,126 patients with stable angina and additional risk factors received nicorandil 20 mg twice daily or placebo added to standard therapy (mean follow-up 1.6 years). The primary composite of coronary death, nonfatal myocardial infarction, or unplanned admission for cardiac chest pain fell from 15.5% to 13.1% (hazard ratio 0.83; P = .014), and acute coronary syndromes fell from 7.6% to 6.1%.

Indication and dosing. The UK summary of product characteristics restricts nicorandil to stable angina in adults who are inadequately controlled by, or have a contraindication to or intolerance of, first-line drugs such as beta-blockers or calcium channel blockers. The usual starting dose is 10 mg twice daily (5 mg twice daily in patients prone to headache), the usual range is 10 to 20 mg twice daily, and the dose can be increased to 40 mg twice daily. The 2024 ESC guideline gives nicorandil Class IIb as add-on therapy and lists it, with nitrates, as an option for coronary spasm.

Adverse effects and contraindications. Headache is the most common reason for stopping, especially early in treatment. Nicorandil causes ulceration of the mouth, gastrointestinal tract (including anal and perianal ulcers, fistulas, and perforation, particularly with diverticular disease or concomitant corticosteroids), skin, mucosa, and eye (conjunctival and corneal ulcers). Ulcers may appear soon after starting or years later, are often refractory to standard treatment, and usually require withdrawal of the drug. Severe hyperkalemia has been reported rarely, especially with renal impairment and other potassium-raising drugs. Nicorandil is contraindicated with PDE5 inhibitors and sGC stimulators and in shock, severe hypotension, hypovolemia, acute pulmonary edema, and left ventricular dysfunction with low filling pressures.

Trimetazidine: a metabolic antianginal agent

Trimetazidine inhibits mitochondrial long-chain 3-ketoacyl-CoA thiolase, the last enzyme of fatty acid beta-oxidation, and shifts myocardial energy production toward glucose oxidation. Glucose oxidation produces more ATP per molecule of oxygen consumed than fatty acid oxidation, and the shift reduces lactate and proton accumulation during ischemia. Trimetazidine has no effect on heart rate or blood pressure. It is widely used in Europe, Asia, and Latin America and is not approved in the United States.

Regulatory restriction, contraindications, and dosing. After a review completed in 2012, the European Medicines Agency restricted trimetazidine to add-on treatment of stable angina in patients inadequately controlled by or intolerant of first-line antianginal therapies, and removed its indications for tinnitus, vertigo, and visual disturbance. It is contraindicated in Parkinson disease, parkinsonian symptoms, tremor, restless legs syndrome, and other related movement disorders, and in severe renal impairment; it is used with caution, and at a reduced dose, in moderate renal impairment and in older adults. It is stopped permanently in a patient who develops a movement disorder, and a neurologic opinion is sought if parkinsonian symptoms persist more than 4 months after withdrawal. The modified-release dose is 35 mg twice daily with meals, and 35 mg once daily in the morning with creatinine clearance of 30 to 60 mL/min, including in older adults. Trimetazidine has also been misused as a performance-enhancing drug and is on the World Anti-Doping Agency prohibited list.

Evidence from ATPCI and smaller trials. Smaller trials tested trimetazidine against, or in addition to, beta-blockers and calcium channel blockers. ATPCI, the only large outcome trial, enrolled 6,007 patients within 30 days of elective or urgent PCI. It found no reduction in cardiac death, cardiac hospitalization, or recurrent or persistent angina requiring a change in therapy or angiography (23.3% versus 23.7%) over a median of 47.5 months. The 2024 ESC guideline gives trimetazidine Class IIb as add-on therapy and lists it, with ranolazine, as an option for microvascular angina and for patients with low heart rate or blood pressure.

Ivabradine, perhexiline, allopurinol, and other antianginal agents

Ivabradine. Ivabradine inhibits the I_f current of the sinus node and lowers heart rate without affecting contractility, conduction, or blood pressure. It is approved in the United States for heart failure with reduced ejection fraction in sinus rhythm with a resting heart rate of 70 beats/min or more, not for angina. The 2023 AHA/ACC guideline classifies its addition to standard antianginal therapy in patients with normal left ventricular function as potentially harmful (Class 3: Harm), on the basis of SIGNIFY. The 2024 ESC guideline gives it Class IIa as add-on antianginal therapy when LVEF is below 40% and Class III when LVEF is above 40% without clinical heart failure. Ivabradine is not combined with diltiazem, verapamil, or strong CYP3A4 inhibitors. Its pharmacology and heart failure evidence are in the adjunctive heart failure drugs hub.

Perhexiline. Perhexiline inhibits carnitine palmitoyltransferase, reducing mitochondrial uptake of long-chain fatty acids and shifting metabolism toward carbohydrate. It is effective for refractory angina but has a narrow therapeutic range and is metabolized by CYP2D6; poor metabolizers accumulate the drug and develop hepatotoxicity and peripheral neuropathy. With plasma level monitoring and dose adjustment it remains in use in Australia and New Zealand for refractory angina. It is not available in the United States.

Allopurinol. Xanthine oxidase inhibition lowers the oxygen cost of contraction in experimental models. In a crossover trial of 65 patients with stable angina, allopurinol 600 mg daily for 6 weeks increased median time to ST depression (by 43 seconds compared with placebo), total exercise time (58 seconds), and time to chest pain. ALL-HEART (5,721 patients aged 60 years or more with ischemic heart disease and no gout) found no reduction in nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death with allopurinol up to 600 mg daily (hazard ratio 1.04). Allopurinol is not an antianginal drug in any guideline.

Cilostazol in vasospastic angina. In a Korean trial of 50 patients with vasospastic angina and at least one weekly episode despite amlodipine 5 mg, cilostazol up to 200 mg daily reduced the weekly incidence of chest pain (−66.5% versus −17.6%) and more patients became pain free (76.0% versus 33.3%); headache was the most common adverse effect. Cilostazol is contraindicated in heart failure of any severity in its US labeling.

Molsidomine and fasudil. Molsidomine, a nitric oxide donor that does not require ALDH2 bioactivation, is used for angina in some European countries. The Rho-kinase inhibitor fasudil, approved in Japan for cerebral vasospasm after subarachnoid hemorrhage, has been studied in coronary spasm. Neither has substantial outcome evidence, and neither is available in the United States.

Sequencing antianginal drugs by heart rate, blood pressure, and comorbidity

No head-to-head trial shows one antianginal class to be superior for symptom relief, so selection rests on mechanism, hemodynamics, comorbidity, interactions, and tolerability. The numbered sequence below follows the guidelines.

1. Every patient has sublingual nitroglycerin or spray, with instructions for acute and prophylactic use and an explicit warning about PDE5 inhibitors.
2. First daily drug. A beta-blocker or a calcium channel blocker for most patients; a long-acting nitrate is an alternative initial option under the US guideline. The choice follows heart rate and blood pressure: a beta-blocker when the heart rate is high, after recent infarction, or with LVEF of 40% or less; a dihydropyridine calcium channel blocker when the heart rate is low, with conduction disease, with vasospasm, or with hypertension that needs more treatment.
3. Second drug from a different class when angina persists (Class 1, 2023 AHA/ACC). A beta-blocker with a dihydropyridine calcium channel blocker is the pairing the 2024 ESC guideline recommends (Class IIa). A long-acting nitrate or ranolazine is added to either.
4. Ranolazine when angina persists despite beta-blockers, calcium channel blockers, or long-acting nitrates (Class 1), and earlier when bradycardia, conduction disease, low blood pressure, or a PDE5 inhibitor limits the other classes.
5. Reassessment. Adherence, doses, and the nitrate schedule are reviewed. Anemia, thyroid disease, uncontrolled hypertension, tachyarrhythmias, and anginal triggers (cold, large meals, sympathomimetics, cocaine) are addressed. Persistent lifestyle-limiting angina on two or three drugs leads to evaluation for revascularization, covered in the chronic coronary disease hub, or to invasive coronary function testing when angiography shows no obstructive disease.

Combinations to avoid. A beta-blocker with verapamil or diltiazem risks bradycardia, atrioventricular block, and depressed contractility and is used only with close monitoring, if at all. Ivabradine is not combined with verapamil or diltiazem. Nitrates are not combined with PDE5 inhibitors or riociguat. Ranolazine is limited to 500 mg twice daily with diltiazem or verapamil and is not used with strong CYP3A inhibitors or inducers. Two drugs from the same mechanistic group (for example, two dihydropyridines, or a nitrate with nicorandil) add adverse effects without adding mechanism.

Antianginal selection by comorbidity, from the 2023 AHA/ACC and 2024 ESC guidelines and US prescribing information. Nicorandil, trimetazidine, and perhexiline are not available in the United States.

The selector classifies each US antianginal class as favored, suitable, used with caution, or avoided for a given patient profile and gives the reason.

Selection rules from the 2023 AHA/ACC chronic coronary disease guideline, the 2024 ESC chronic coronary syndromes guideline, the 2022 AHA/ACC/HFSA heart failure guideline, and US prescribing information for nitrates and ranolazine. Every patient also carries short-acting nitroglycerin unless a PDE5 inhibitor or riociguat is in use. CCB, calcium channel blocker.

Antianginal therapy in microvascular and vasospastic angina

Angina with nonobstructive coronary arteries (ANOCA) and ischemia with nonobstructive coronary arteries (INOCA) are covered in the ANOCA, INOCA, vasospastic angina, and MINOCA hub, including invasive coronary function testing and the endotypes it defines. Antianginal drugs are chosen by endotype; when the endotype is unknown, the response to an empirical drug is often the first clue.

Vasospastic angina. Calcium channel blockers are first-line therapy (Class I, level A, 2024 ESC): they control symptoms and prevent ischemia and its potentially fatal complications. Doses are often high and timed in the evening because attacks cluster at night and in the early morning; dihydropyridines and non-dihydropyridines are both effective and are combined in refractory cases. Long-acting nitrates are added to prevent recurrent episodes (Class IIa), with the nitrate-free interval placed at a time of day when attacks are infrequent, and sublingual nitroglycerin terminates attacks. Nicorandil is an alternative outside the United States, and cilostazol reduced attacks in a small trial. Nonselective beta-blockers are avoided, and beta-blocker monotherapy can provoke spasm. Smoking, cocaine and other stimulants, triptans, and ergot derivatives are removed as triggers.

Microvascular angina. For microvascular angina with reduced coronary flow reserve or increased microvascular resistance, the 2024 ESC guideline gives Class IIa (B) to antianginal drugs that prevent demand ischemia, principally beta-blockers, for symptom control, and Class IIa to an ACE inhibitor for endothelial dysfunction. Calcium channel blockers are used for microvascular spasm. Ranolazine and trimetazidine are listed by the ESC as options for microvascular angina. The largest randomized trial of ranolazine in coronary microvascular dysfunction (128 participants, 96% women, 2-week crossover) found no overall improvement in Seattle Angina Questionnaire scores or myocardial perfusion reserve; participants with coronary flow reserve below 2.5 improved perfusion reserve and angina frequency. Nitrates are less reliable in microvascular angina than in epicardial disease. In CorMicA, stratifying therapy by the endotype identified at invasive testing improved angina and quality of life compared with standard care.

Refractory angina: options after optimized drug therapy

The 2024 ESC guideline defines refractory angina as symptoms lasting more than 3 months due to established reversible ischemia that cannot be controlled by escalating medical therapy, bypass grafting, or PCI (including recanalization of chronic total occlusions). The definition also covers symptoms due to ANOCA/INOCA once the endotype has been defined and treated. Before that label is applied, the regimen is assessed for reversible limitations. These include doses below target, a missing class (many patients have never received ranolazine or a long-acting nitrate), a nitrate schedule without a free interval or with the free interval at the time of symptoms, interacting drugs that limit ranolazine, and untreated anemia, tachyarrhythmia, hypertension, or thyroid disease. Microvascular dysfunction and vasospasm are evaluated, because they persist after revascularization and respond to targeted drugs; for refractory angina with documented or suspected ANOCA/INOCA, the ESC recommends invasive coronary function testing (Class I).

Options for refractory angina after drug therapy and revascularization have been exhausted. Chronic total occlusion PCI for symptoms is covered in the chronic coronary disease hub.

Antianginal drugs in older adults, kidney and liver disease, pregnancy, and surgery

Older adults. Orthostatic hypotension, falls, bradycardia, polypharmacy, and reduced renal function shape the regimen. Nitrates cause more postural hypotension in older adults, and the transdermal labels note greater susceptibility to hypotension and falls. Ranolazine produced more adverse events and discontinuations at age 75 and older. Short-acting nitroglycerin is taken sitting. The cardiovascular disease in older adults hub covers deprescribing and fall risk.

Chronic kidney disease. Isosorbide mononitrate and nitroglycerin need no renal dose adjustment. Ranolazine levels rise 40% to 50% with any degree of renal impairment, acute renal failure has occurred with creatinine clearance below 30 mL/min, and renal function is monitored when clearance is below 60 mL/min; the small fixed rise in creatinine from blocked tubular secretion is distinguished from true renal injury by an unchanged blood urea nitrogen. Atenolol and other renally cleared beta-blockers are dose-adjusted. Trimetazidine is contraindicated in severe renal impairment. The chronic kidney disease and the heart hub covers coronary disease in kidney failure.

Liver disease. Ranolazine is contraindicated in cirrhosis. Isosorbide dinitrate exposure varies with first-pass metabolism; isosorbide mononitrate does not undergo first-pass metabolism and is unaffected by cirrhosis. Calcium channel blockers and lipophilic beta-blockers are started at low doses.

Pregnancy and lactation. Coronary disease in pregnancy is uncommon and usually presents as spontaneous coronary artery dissection, atherosclerotic infarction, or vasospasm. Nitroglycerin is used for ischemia and hypertension in pregnancy when indicated; the labels report insufficient human data to determine a risk of birth defects. Beta-blockers (labetalol, metoprolol) and nifedipine have the most experience. Choices in pregnancy are covered in the cardiovascular drugs in pregnancy and lactation hub.

Noncardiac surgery. Chronic beta-blockers are continued through surgery, and abrupt withdrawal is avoided. Prophylactic intravenous nitroglycerin does not reduce myocardial ischemia in patients undergoing noncardiac surgery (Class III: No Benefit, 2014 ACC/AHA perioperative guideline); intravenous nitroglycerin is used to treat perioperative hypertension, raised filling pressures, or suspected coronary spasm. Patients who use PDE5 inhibitors are asked about the timing of their last dose so that nitrates are not given within the contraindicated interval. Ranolazine is continued when oral intake allows; it cannot be crushed for tube administration. Preoperative assessment is in the perioperative cardiovascular evaluation hub.

Common errors in antianginal prescribing

• A long-acting nitrate dosed symmetrically (isosorbide dinitrate every 8 hours, a patch left on for 24 hours, or extended-release isosorbide mononitrate twice daily): tolerance develops within a day, and the drug stops working.
• No sublingual nitroglycerin prescription, or no instruction on prophylactic use before exertion.
• No question about PDE5 inhibitors before a nitrate is prescribed, and no warning to a patient who uses both. The interval is at least 24 hours for sildenafil and vardenafil and 48 hours for tadalafil.
• Ranolazine at 1,000 mg twice daily in a patient taking diltiazem or verapamil; the maximum is 500 mg twice daily.
• Ranolazine prescribed with clarithromycin, an azole antifungal, ritonavir-boosted therapy, rifampin, carbamazepine, phenytoin, or St. John's wort.
• Metformin left above 1,700 mg daily, or simvastatin above 20 mg daily, after ranolazine is started.
• A 0.1 mg/dL rise in creatinine after ranolazine is read as kidney injury, or a true rise in creatinine and blood urea nitrogen in a patient with creatinine clearance below 30 mL/min is missed.
• A beta-blocker combined with verapamil or diltiazem in a patient with bradycardia, conduction disease, or reduced ejection fraction.
• Verapamil or diltiazem used for angina with LVEF of 40% or less.
• Ivabradine added for angina in a patient with preserved ejection fraction and no heart failure, against the SIGNIFY result and the US Class 3: Harm recommendation.
• Nitrates given to a patient with right ventricular infarction, severe aortic stenosis, or obstructive hypertrophic cardiomyopathy.
• A nitrate added to improve exercise tolerance in heart failure with preserved ejection fraction.
• Beta-blocker monotherapy for suspected vasospastic angina.
• Antianginal drugs presented as protection against infarction or death, and event-preventing therapy (antiplatelet, statin, blood pressure control) neglected because angina is controlled.
• Refractory angina diagnosed before ranolazine, a long-acting nitrate with a proper schedule, and testing for microvascular dysfunction and vasospasm have been tried.

References

1. 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: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2023;148:e9–e119. doi:10.1161/CIR.0000000000001168
2. Corrections to: 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA guideline for the management of patients with chronic coronary disease. Circulation. 2023;148:e148 and e186. doi:10.1161/CIR.0000000000001183; doi:10.1161/CIR.0000000000001195
3. Vrints C, Andreotti F, Koskinas KC, et al. 2024 ESC guidelines for the management of chronic coronary syndromes. Eur Heart J. 2024;45:3415–3537. doi:10.1093/eurheartj/ehae177
4. 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. Circulation. 2022;145:e895–e1032. doi:10.1161/CIR.0000000000001063
5. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non–ST-elevation acute coronary syndromes. Circulation. 2014;130:e344–e426. doi:10.1161/CIR.0000000000000134
6. Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery. Circulation. 2014;130:e278–e333. doi:10.1161/CIR.0000000000000106
7. RANEXA (ranolazine) extended-release tablets: US prescribing information. Gilead Sciences; revised October 2019 (last labeling revision for NDA 021526; generic ranolazine labeling follows this text). accessdata.fda.gov
8. NITROSTAT (nitroglycerin sublingual tablets): US prescribing information. Viatris Specialty; 2023. DailyMed
9. NITROLINGUAL PUMPSPRAY (nitroglycerin lingual spray): US prescribing information. 2024. DailyMed
10. Isosorbide mononitrate extended-release tablets: US prescribing information. 2026. DailyMed
11. Isosorbide dinitrate tablets: US prescribing information. Par Health; 2026. DailyMed
12. NITRO-DUR (nitroglycerin transdermal system): US prescribing information. 2023. DailyMed
13. VERQUVO (vericiguat) tablets: US prescribing information. Merck Sharp & Dohme; 2026. DailyMed
14. ADEMPAS (riociguat) tablets: US prescribing information. Bayer HealthCare; 2026. DailyMed
15. Münzel T, Daiber A, Gori T. Nitrate therapy: new aspects concerning molecular action and tolerance. Circulation. 2011;123:2132–2144. doi:10.1161/CIRCULATIONAHA.110.981407
16. Li Y, Zhang D, Jin W, et al. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin. J Clin Invest. 2006;116:506–511. doi:10.1172/JCI26564
17. Münzel T, Kurz S, Rajagopalan S, et al. Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membrane-bound NADH oxidase: a new action for an old drug. J Clin Invest. 1996;98:1465–1470. doi:10.1172/JCI118935
18. Gogia H, Mehra A, Parikh S, et al. Prevention of tolerance to hemodynamic effects of nitrates with concomitant use of hydralazine in patients with chronic heart failure. J Am Coll Cardiol. 1995;26:1575–1580. doi:10.1016/0735-1097(95)00368-1
19. Kloner RA, Hutter AM, Emmick JT, et al. Time course of the interaction between tadalafil and nitrates. J Am Coll Cardiol. 2003;42:1855–1860. doi:10.1016/j.jacc.2003.09.023
20. Trolle Lagerros Y, Grotta A, Freyland S, et al. Risk of death in patients with coronary artery disease taking nitrates and phosphodiesterase-5 inhibitors. J Am Coll Cardiol. 2024;83:417–426. doi:10.1016/j.jacc.2023.10.041
21. ISIS-4 Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet. 1995;345:669–685.
22. Gruppo Italiano per lo Studio della Sopravvivenza nell'infarto Miocardico. GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet. 1994;343:1115–1122.
23. Redfield MM, Anstrom KJ, Levine JA, et al. Isosorbide mononitrate in heart failure with preserved ejection fraction (NEAT-HFpEF). N Engl J Med. 2015;373:2314–2324. doi:10.1056/NEJMoa1510774
24. Chaitman BR, Skettino SL, Parker JO, et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina (MARISA). J Am Coll Cardiol. 2004;43:1375–1382. doi:10.1016/j.jacc.2003.11.045
25. Chaitman BR, Pepine CJ, Parker JO, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial (CARISA). JAMA. 2004;291:309–316. doi:10.1001/jama.291.3.309
26. Stone PH, Gratsiansky NA, Blokhin A, et al. Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial. J Am Coll Cardiol. 2006;48:566–575. doi:10.1016/j.jacc.2006.05.044
27. Kosiborod M, Arnold SV, Spertus JA, et al. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial. J Am Coll Cardiol. 2013;61:2038–2045. doi:10.1016/j.jacc.2013.02.011
28. Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, et al. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA. 2007;297:1775–1783. doi:10.1001/jama.297.16.1775
29. Scirica BM, Morrow DA, Hod H, et al. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non-ST-segment elevation acute coronary syndrome: results from the MERLIN-TIMI 36 randomized controlled trial. Circulation. 2007;116:1647–1652. doi:10.1161/CIRCULATIONAHA.107.724880
30. Weisz G, Généreux P, Iñiguez A, et al. Ranolazine in patients with incomplete revascularisation after percutaneous coronary intervention (RIVER-PCI): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2016;387:136–145. doi:10.1016/S0140-6736(15)00459-6
31. Fanaroff AC, James SK, Weisz G, et al. Ranolazine after incomplete percutaneous coronary revascularization in patients with versus without diabetes mellitus: RIVER-PCI trial. J Am Coll Cardiol. 2017;69:2304–2313. doi:10.1016/j.jacc.2017.02.056
32. Reiffel JA, Camm AJ, Belardinelli L, et al. The HARMONY trial: combined ranolazine and dronedarone in the management of paroxysmal atrial fibrillation: mechanistic and therapeutic synergism. Circ Arrhythm Electrophysiol. 2015;8:1048–1056. doi:10.1161/CIRCEP.115.002856
33. Bairey Merz CN, Handberg EM, Shufelt CL, et al. A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve. Eur Heart J. 2016;37:1504–1513. doi:10.1093/eurheartj/ehv647
34. IONA Study Group. Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial. Lancet. 2002;359:1269–1275. doi:10.1016/S0140-6736(02)08265-X
35. Nicorandil 10 mg tablets: summary of product characteristics. electronic Medicines Compendium (UK)
36. European Medicines Agency. European Medicines Agency recommends restricting use of trimetazidine-containing medicines (EMA/CHMP/417861/2012). 2012. ema.europa.eu
37. Ferrari R, Ford I, Fox K, et al. Efficacy and safety of trimetazidine after percutaneous coronary intervention (ATPCI): a randomised, double-blind, placebo-controlled trial. Lancet. 2020;396:830–838. doi:10.1016/S0140-6736(20)31790-6
38. Fox K, Ford I, Steg PG, et al. Ivabradine in stable coronary artery disease without clinical heart failure (SIGNIFY). N Engl J Med. 2014;371:1091–1099. doi:10.1056/NEJMoa1406430
39. Ashrafian H, Horowitz JD, Frenneaux MP. Perhexiline. Cardiovasc Drug Rev. 2007;25:76–97. doi:10.1111/j.1527-3466.2007.00006.x
40. Noman A, Ang DS, Ogston S, et al. Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial. Lancet. 2010;375:2161–2167. doi:10.1016/S0140-6736(10)60391-1
41. Mackenzie IS, Hawkey CJ, Ford I, et al. Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial. Lancet. 2022;400:1195–1205. doi:10.1016/S0140-6736(22)01657-9
42. Shin ES, Lee JH, Yoo SY, et al. A randomised, multicentre, double blind, placebo controlled trial to evaluate the efficacy and safety of cilostazol in patients with vasospastic angina. Heart. 2014;100:1531–1536. doi:10.1136/heartjnl-2014-305986
43. Arora RR, Chou TM, Jain D, et al. The multicenter study of enhanced external counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes. J Am Coll Cardiol. 1999;33:1833–1840. doi:10.1016/S0735-1097(99)00140-0
44. Verheye S, Jolicœur EM, Behan MW, et al. Efficacy of a device to narrow the coronary sinus in refractory angina (COSIRA). N Engl J Med. 2015;372:519–527. doi:10.1056/NEJMoa1402556
45. Foley MJ, Rajkumar CA, Ahmed-Jushuf F, et al. Coronary sinus reducer for the treatment of refractory angina (ORBITA-COSMIC): a randomised, placebo-controlled trial. Lancet. 2024;403:1543–1553. doi:10.1016/S0140-6736(24)00256-3