Antianginal Drugs

Introduction

• Angina is substernal chest pain caused by decreased blood flow to the heart, usually lasting less than 10 minutes. It is typically triggered by emotional stress or physical activity.^1-4
• Atypical angina, more commonly seen in elderly patients and women, may present as jaw pain or shortness of breath.²
• CMD causes angina in cases of ANOCA and is also associated with persistent angina after coronary revascularization.^4,5
• Antianginal medication dosages are typically increased as needed to control symptoms while maintaining stable heart rate and blood pressure levels, but persistent symptoms despite 2 weeks of pharmacotherapy may indicate the need for cardiac catheterization.²
• Optimal medical therapy aims to reduce the lifetime risk of cardiovascular events while alleviating angina symptoms by maintaining strict blood pressure control in patients with hypertension, managing lipids with high-intensity statins, optimizing blood sugar levels in patients with diabetes, quitting smoking to lower vasospastic triggers, and managing weight to improve exercise tolerance.^2,4

Mechanisms of Action, Systemic Effects, and Pharmacokinetics

• Antianginal drugs relieve ischemic chest pain by (1) lowering myocardial oxygen consumption or (2) increasing oxygen delivery to ischemic myocardial tissue.¹
• Beta-blockers or CCBs are the first-line therapy for patients without contraindications.^1,5
• In patients with angina refractory to monotherapy, adding adjunctive antianginal medications such as nitrates, ranolazine, ivabradine, and trimetazidine may be effective.^1,5
• Beta-blockers, non-dihydropyridine CCBs, and ivabradine lower cardiac oxygen consumption by reducing chronotropy and inotropy.³
• Dihydropyridine CCBs and nitrates promote vasodilation, increased coronary perfusion, and thus greater oxygen availability to myocardial tissue.¹

First Line Antianginal Therapies

The 2024 European Society of Cardiology and the 2023 American Heart Association/American College of Cardiology (AHA/ACC) guidelines recommend either beta-blockers or CCBs as first-line therapy for patients without contraindications.^1,5

Beta-Blockers

Mechanism

• Beta-blockers competitively bind G-protein-coupled beta receptors, blocking the physiologic effects of epinephrine and norepinephrine.³

Systemic Effects

• Beta-1 receptor blockade decreases contractility, heart rate, renin release, and atrioventricular nodal conduction, thereby reducing myocardial oxygen demand and prolonging diastolic filling and coronary blood flow.³
• The elimination half-life of beta-blockers varies widely, from 2-5 hours for metoprolol to 5-15 hours for sotalol.³
• More lipid-soluble beta-blockers (carvedilol, labetalol, and propranolol) have shorter half-lives and are metabolized by the liver.³
• In contrast, more water-soluble beta-blockers (atenolol and sotalol) have longer half-lives and are renally excreted.³

Dosing

• AHA/ACC guidelines recommend titrating beta-blocker doses to keep a resting heart rate between 55 and 60 beats per minute (bpm), or 50 bpm in patients with recalcitrant angina.
• In patients with heart failure with reduced ejection fraction (HFrEF), beta-blockers should be titrated to the maximally tolerated dose.⁴
• In patients without HF, titrating beta-blockers or adding another medication is recommended to achieve heart rate targets and improve symptom relief.⁴

Clinical Uses

• Beta-blockers have proven effective in decreasing nitroglycerin use and reducing anginal episodes and exercise-induced angina.¹
• Third-generation beta-blockers offer extra benefits for patients with concurrent hypertension. Nonselective beta-blockers with alpha-1-blocking and antioxidant properties, like carvedilol, can lower peripheral vascular resistance and may improve insulin sensitivity.⁴ Nebivolol, a highly selective beta-1 blocker, leads to nitric oxide-mediated vasodilation and enhances endothelial function.⁴

Side Effects

• Adverse effects include fatigue, depression, bronchospasm, peripheral vasoconstriction (due to inhibitory effects on beta-2 receptors), and masked hypoglycemia.²
• The hemodynamic effects of beta-blockers can cause bradycardia, heart block, and hypotension. Therefore, these drugs are contraindicated in patients with bradycardia, impaired heart conduction, cardiogenic shock, or decompensated heart failure.^2,4
• Beta-blockers are relatively contraindicated in obstructive lung disease because they inhibit the bronchodilatory effects of beta-2 receptors.²
• Careful monitoring is needed when beta-blockers are combined with non-dihydropyridine CCBs or agents that affect sinus node activity or AV conduction, as these combinations can have synergistic effects.^2,3
• Please see the OA summary on beta blockers for more details. Link

CCBs

Mechanism

• CCBs inhibit calcium entry through L-type calcium channels.³
• They are metabolized by the hepatic cytochrome P450 system, which can lead to potential drug interactions due to high first-pass metabolism.³

Systemic Effects

• Nondihydropyridine CCBs (including verapamil and diltiazem) decrease myocardial oxygen demand through negative chronotropic and inotropic effects, promote coronary vasodilation, increasing myocardial oxygen supply, and reduce afterload by lowering blood pressure. The half-life is 4-6 hours.³
• Dihydropyridine CCBs (e.g., amlodipine and nifedipine) promote smooth muscle relaxation, arterial vasodilation, and decreased coronary vascular resistance, thereby increasing coronary blood flow. They are more effective at inducing coronary vasodilation and lowering blood pressure but lack the inotropic and chronotropic effects of non-DHPs. The half-life is 2-5 hours for nifedipine and 25-50 hours for amlodipine.³

Dosing

• 10 mg of amlodipine daily maximizes antianginal effectiveness; 60-90 mg of nifedipine demonstrates high efficacy.⁴

Clinical Uses

• CCBs have demonstrated effectiveness and outcomes similar to those of beta-blockers, providing significant angina relief, increased exercise tolerance, and reduced nitroglycerin use.¹ However, CCBs decrease left ventricular (LV) contractility and are not recommended for patients with severe LV dysfunction.¹
• In patients with angina unresponsive to monotherapy, long-acting nitrates can be combined with a beta-blocker or a nondihydropyridine CCB (which helps reduce the reflex sympathetic response), leading to decreased anginal frequency, fewer short-acting nitrates, and improved exercise tolerance.^1,3
• Caution is advised when using nondihydropyridine CCBs with beta-blockers due to their synergistic effects on lowering contractility and heart rate, which can lead to bradycardia and heart failure.¹

Side Effects

• Nondihydropyridine CCBs, similar to beta-blockers, cause bradycardia with reduced ejection fraction and are therefore contraindicated in cardiogenic shock or severe aortic stenosis.2,3 Additional side effects include constipation and gingival hyperplasia.²
• Vasodilatory effects of dihydropyridine CCBs cause side effects such as peripheral edema, flushing, reflex tachycardia, and headache.2 These agents are contraindicated in cardiac rhythm disorders or bradycardia, hypotension, or congestive heart failure.²
• Please see the OA summary on CCBs for more details. Link

Adjunctive Antianginal Agents

Patient comorbidities and insufficient symptom relief may necessitate adding adjunctive antianginal medications such as nitrates, ranolazine, ivabradine, and trimetazidine.¹

Nitrates

Mechanism

• Organic nitrates generate nitric oxide (NO) in the endothelial cells of blood vessels through enzymatic denitrification. NO induces relaxation of smooth muscle by increasing cyclic guanosine monophosphate (cGMP) via stimulation of guanylyl cyclase and by decreasing calcium entry into the muscle cells.³
• Nitrates also dilate epicardial arteries, lower blood pressure, and may inhibit platelet aggregation, all of which further enhance their anti-ischemic effects.⁴

Systemic Effects

• Peripheral venous dilation decreases preload, thereby reducing myocardial wall tension and oxygen demand.^3,4
• Nitrates include short-acting nitroglycerin (1–3-minute onset and 10-30-minute duration) and long-acting isosorbide dinitrate (30-60-minute onset and 6-8-hour duration).³

Dosing

• Sublingual or spray short-acting nitrates are used at the start of an anginal episode compared to once-daily, long-acting isosorbide dinitrate.¹

Clinical Uses

• Short-acting nitrates effectively provide quick relief from angina. Nitroglycerin spray may be more effective than sublingual nitroglycerin.¹
• Long-acting nitrates, in contrast, improve exercise capacity while decreasing anginal symptoms.¹

Side Effects

• Both long- and short-acting nitrates are associated with adverse effects attributed to vasodilation, including reflex tachycardia, hypotension, flushing, and headache, as well as methemoglobinemia.²
• Nitrates are contraindicated in hypertrophic obstructive cardiomyopathy because they decrease left ventricular preload.²
• Nitrates can cause life-threatening hypotension when combined with phosphodiesterase-5 inhibitors, such as sildenafil.²

Ranolazine

Mechanism

• Ranolazine inhibits late inward sodium current in ischemic myocytes, thereby reducing calcium overload by facilitating calcium outflow through the sodium-calcium exchanger.^2,4
• This reduces LV diastolic tension and improves coronary blood flow.^2,4

Systemic Effects

• Ranolazine alleviates myocardial ischemia and enhances myocardial relaxation by decreasing ventricular diastolic stress without changing heart rate or blood pressure.^2,4

Dosing

• Started at 500 mg twice daily, titrated up to 1000 mg twice daily.⁴

Clinical Uses

• Ranolazine has been shown to improve anginal relief and exercise capacity, with or without concurrent standard antianginal therapy, and to decrease anginal frequency and nitroglycerin requirements.
• However, some data indicate that ranolazine does not significantly decrease hospitalizations for ischemia or the need for subsequent revascularization.²
• Because of ranolazine’s lack of hemodynamic effects, this agent may be used as a first-line therapy for patients with hypotension or bradycardia.²

Side Effects

• Ranolazine has dose-dependent adverse effects, including dizziness (5% of patients), constipation (2%), and nausea (2%).
• Although ranolazine increases the QT interval, there is no evidence of increased significant arrhythmias; caution is advised when used with other QT-prolonging agents.²
• Ranolazine is contraindicated in liver cirrhosis.³

Ivabradine

Mechanism

• Ivabradine is a selective heart rate-lowering agent that acts on the sinoatrial (SA) node by inhibiting the I(f) “funny” current, decreasing myocardial oxygen demand without affecting atrioventricular (AV) conduction.²

Systemic Effects

• While beta-blockers and non-DHP CCBs act on both the AV and SA nodes, ivabradine selectively inhibits the I(f) current in the SA node without affecting AV conduction.⁴
• Ivabradine selectively lowers heart rate without inotropic effects, thus decreasing myocardial oxygen demand.²

Dosing

• Started at 5 mg twice daily, titrated up to 7.5 mg twice daily.4

Clinical Uses

• Ivabradine is indicated for patients with HFrEF who have a resting heart rate of more than 70 beats per minute despite receiving maximally tolerated guideline-directed medical therapy.^1,2,4
• Ivabradine may yield benefits for angina and exercise tolerance similar to those of amlodipine and atenolol, and comparable results might be achieved with the addition of ivabradine to atenolol.¹
• A randomized controlled trial involving patients with stable coronary artery disease without heart failure with a resting heart rate of 70 beats per minute demonstrated elevated rates of death and myocardial infarction in patients receiving ivabradine compared to those receiving placebo; therefore, ivabradine is not recommended for angina without heart failure.^1,2

Side Effects

• Due to its mechanism of action, ivabradine can cause bradycardia and atrioventricular block and is contraindicated in patients with low heart rate, severe liver disease, and concurrent nondihydropyridine CCBs.³
• Ivabradine can cause visual disturbances, dizziness, headache, atrial fibrillation, and QT interval prolongation.³

Trimetazidine

Mechanism

• Offers a unique mechanism of action, shifting myocardial metabolism from fatty acid to glucose oxidation, thereby providing benefits without affecting hemodynamics.⁴

Systemic Effects

• Trimetazidine is primarily used as an adjunct therapy for patients with stable angina who remain symptomatic despite optimal treatment with standard medications, especially those who cannot tolerate the hemodynamic side effects of other traditional antianginal drugs.⁴ Although it has been used in Europe as a second-line agent for over 40 years, it remains unapproved by the Food and Drug Administration (FDA) for use in the USA, partly due to safety concerns and a lack of observed benefit in some trials.⁴

Perioperative Care

• Perioperative cardiovascular events occur in about 3% of patients hospitalized for noncardiac surgical procedures in the United States.⁶
• Perioperative cardiovascular risk is usually evaluated through a detailed history and physical exam, assessment of daily functional capacity, and cardiovascular tests, such as stress testing, in patients with poor functional capacity or those undergoing high-risk surgery, to detect signs of ischemic heart disease.⁶
• Patients are advised to continue taking chronic beta-blockers and CCBs on the day of surgery, as abrupt discontinuation of these medications may cause ischemia or arrhythmia.⁷
• Please see the OA summary on Continuing vs. Stopping Cardiovascular medications for more details. Link
• Perioperative beta-blockade initiation may be associated with reduced mortality in patients with higher revised cardiac index scores.⁸
• Perioperative beta-blocker therapy is most effective when started one week to one month prior to surgery to allow for dosage adjustment and tolerability. Starting beta-blockers immediately before surgery should be avoided. Taking high-dose beta-blockers 2 to 4 hours before surgery is associated with increased risk of stroke and mortality.⁶
• It is recommended to avoid perioperative beta-blockers in conditions that impact heart rate, such as hypovolemia, significant anemia, infection, and clinical signs of instability.⁸
• Intraoperatively, beta-blockers can also be continued to reduce oxygen demand by lowering heart rate and myocardial contractility, and to prevent the stress response and catecholamine release, with monitoring for bradycardia or hypotension.⁹
• Further research is necessary to evaluate the risks and benefits of continuing, initiating, or stopping CCBs perioperatively.10 Trials investigating the initiation of CCBs have not shown significant reductions in perioperative mortality or myocardial infarction, although some studies have reported bradycardia and hypotension.10 CCBs should be used cautiously during the perioperative period, particularly in patients with left ventricular dysfunction.¹⁰
• In patients with stable hemodynamic status, beta-blockers and nitrates may be used perioperatively to relieve anginal symptoms.¹⁰
• Postoperatively, anginal medications can be resumed once oral intake is feasible and tolerated, with close monitoring for hemodynamic or cardiac instability.10 Ultimately, perioperative antianginal therapy must be determined based on patient comorbidities and hemodynamic status. Further study of the optimal timing and dosing of perioperative antianginal therapy is warranted.