The three conventional antianginal drug classes, namely nitrates, beta-blockers, and calcium channel blockers, reduce myocardial ischemia primarily through hemodynamic mechanisms: reducing heart rate, preload, afterload, or contractility. Despite maximally tolerated combination therapy, a substantial proportion of patients with stable angina continue to experience symptoms.3·4 This therapeutic gap has driven the development of agents that operate through non-hemodynamic or hemodynamically selective mechanisms, offering additive anti-ischemic benefit without compounding bradycardia or hypotension.
Ranolazine and ivabradine are the two agents from this group with robust evidence and regulatory approval in the United States.3·4 Nicorandil and trimetazidine have meaningful evidence bases and are used widely outside the US. This module covers the pharmacology, clinical evidence, indications, and limitations of each agent, and frames their role within the broader antianginal treatment algorithm.
Ranolazine's anti-ischemic mechanism is mechanistically distinct from all conventional antianginal agents. It does not reduce heart rate, blood pressure, or contractility at therapeutic doses.1·2 Its primary target is the late inward sodium current (late INa) in cardiac myocytes.10 Under normal conditions, the voltage-gated cardiac sodium channel (Nav1.5) opens briefly during depolarization (peak INa in phase 0) and rapidly inactivates within milliseconds. A small residual "late" sodium current (late INa) persists through the action potential plateau (phase 2-3), normally trivial in magnitude.10 During myocardial ischemia, this changes dramatically: late INa increases substantially (5-10 fold above baseline) during ischemia, hypoxia, oxidative stress, and in heart failure.10 This excessive late INa drives persistent Na+ influx during the action potential plateau. Elevated intracellular Na+ inhibits the Na+/Ca2+ exchanger (NCX), which normally extrudes Ca2+ in exchange for Na+ entry. NCX reversal or inhibition leads to intracellular Ca2+ accumulation, calcium overload, diastolic dysfunction, increased wall stiffness, elevated left ventricular end-diastolic pressure (LVEDP), and worsening subendocardial ischemia. Calcium overload also contributes to early afterdepolarizations (EADs) and triggered arrhythmias.10 The resulting ischemic paradox, in which ischemia leads to late INa increase leads to Ca2+ overload leads to worsened ischemia, is the self-amplifying cycle that ranolazine targets.10
Ranolazine selectively inhibits late INa without significantly blocking peak INa,10 breaking the ischemia-Na+-Ca2+ overload cycle, reducing intracellular Ca2+ during ischemia, improving diastolic relaxation, and reducing myocardial oxygen consumption (MVO2) per unit of mechanical work. There is NO significant effect on heart rate, blood pressure, contractility, or AV conduction at therapeutic doses.1·2 A secondary mechanism is weak hERG channel blockade: ranolazine also weakly inhibits IKr (hERG channel), producing mild QTc prolongation (~6 ms at therapeutic doses; up to 15 ms at maximum dose).1·2 This is the primary adverse effect of clinical significance.
Formulation: extended-release tablets only (500 mg, 1000 mg). Bioavailability: ~76% (food does not significantly affect absorption). Half-life: ~7 hours (extended-release provides 12-hour dosing intervals). Dosing: 500 mg twice daily (starting dose); titrate to 1000 mg twice daily based on tolerability and response. Metabolism: CYP3A4 (cytochrome P450 3A4) (primary) and CYP2D6 (cytochrome P450 2D6) (minor). Protein binding: ~62%. Excretion: hepatic; dose adjustment required in hepatic impairment. Renal adjustment not routinely required unless severe CKD (metabolites accumulate).1·2
The CARISA trial (Chaitman et al., 2004) enrolled 823 patients with chronic angina on background atenolol, amlodipine, or diltiazem. Ranolazine 750 mg or 1000 mg twice daily vs. placebo significantly increased exercise duration, time to ST depression, and time to angina onset, and reduced anginal episodes and sublingual nitroglycerin (SL-NTG) use. There was no difference in HR or BP between groups, confirming the hemodynamically neutral mechanism.1 The ERICA trial (Stone et al., 2006) enrolled 565 patients on maximum-dose amlodipine 10 mg. Ranolazine 1000 mg twice daily vs. placebo produced significant reduction in weekly anginal episodes and SL-NTG use, demonstrating efficacy specifically as add-on to maximal dihydropyridine calcium channel blocker (DHP-CCB) therapy.2 The MERLIN-TIMI 36 trial (Morrow et al., 2007) enrolled 6,560 patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) on standard ACS therapy. The primary endpoint (CV death, MI, recurrent ischemia) was not significantly reduced overall. Key findings included reduced recurrent ischemia; fewer new-onset AF episodes in the ranolazine arm; reduced ventricular arrhythmias in patients with prior MI and diabetes; and no increase in mortality. This trial established safety in a high-risk CAD population.3
The FDA-approved indication is chronic stable angina as add-on therapy in patients who remain symptomatic on adequate doses of beta-blockers, CCBs, or nitrates.3·4 The optimal patient profile for ranolazine includes: stable angina inadequately controlled on conventional dual therapy (BB + CCB or BB + nitrate) who cannot tolerate a third hemodynamic agent due to bradycardia or hypotension;3·4 diabetes with stable angina (ranolazine has a mild HbA1c-lowering effect of approximately 0.5% at 1000 mg twice daily, as it inhibits late INa in pancreatic beta cells, reducing glucotoxic intracellular Ca2+ overload and improving insulin secretion,3 with no hypoglycemia risk); angina with ventricular arrhythmias (MERLIN data);3 and angina where additional negative inotropy from higher beta-blocker doses or non-dihydropyridine CCB is undesirable. Ranolazine is NOT indicated for acute angina relief (extended-release only; too slow onset); for vasospastic angina (insufficient evidence); or as monotherapy (approved only as add-on).3·4
QTc prolongation is the most clinically important adverse effect.1·2 Average prolongation is ~6 ms at 500 mg BID and ~9-14 ms at 1000 mg BID. The risk of torsades de pointes (TdP) is low but increased with baseline QTc >500 ms, concurrent QT-prolonging agents (antipsychotics, certain antibiotics, amiodarone, sotalol), hypokalemia, hypomagnesemia, and hepatic impairment. Baseline ECG and QTc measurement are required. Ranolazine is CONTRAINDICATED if QTc >500 ms at baseline or with significant hepatic impairment (Child-Pugh B or C).1·2 CYP3A4 drug interactions:1·2 strong CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir) increase ranolazine levels 3.5-4.5 fold and are CONTRAINDICATED; moderate CYP3A4 inhibitors (diltiazem, verapamil, erythromycin, fluconazole) increase levels 1.5-2.5 fold; limit ranolazine to 500 mg twice daily and monitor QTc; strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin, St. John's Wort) cause levels to fall dramatically; combination not recommended. CYP2D6 (cytochrome P450 2D6) inhibition: ranolazine inhibits CYP2D6, increasing levels of metoprolol, tricyclics, and certain antipsychotics; monitor for metoprolol-related bradycardia.1·2 Digoxin levels increase ~1.5 fold via P-glycoprotein inhibition; monitor levels and reduce digoxin dose.1·2 Simvastatin levels increase ~2 fold (CYP3A4); limit simvastatin to 20 mg/day or consider an alternative statin.1·2 Common dose-related adverse effects include dizziness and lightheadedness (~6-10%), nausea (~5%), constipation (~5%), and headache (~4%); generally mild and often resolve with time or dose reduction from 1000 mg to 500 mg BID.1·2
Ivabradine is a pure heart rate-reducing agent with a distinct mechanism from beta-blockers and non-dihydropyridine CCBs.6·7·8 The funny current (If) is a mixed Na+/K+ inward current that activates on hyperpolarization, conducted by HCN (hyperpolarization-activated cyclic nucleotide-gated) channels in SA node pacemaker cells.11 It is responsible for the slow spontaneous depolarization during phase 4 of the SA node action potential (the pacemaker potential). If magnitude directly determines the rate of spontaneous depolarization and therefore heart rate. It is also upregulated by catecholamines via cAMP, explaining the tachycardic response to adrenergic stimulation.11 Ivabradine acts as a selective open-channel blocker of HCN channels in SA node cells, slowing the rate of spontaneous SA node depolarization and reducing heart rate.6·11 HR reduction is dose-dependent (graded, predictable); rate-dependent (greater effect at higher baseline HR, an intrinsic safety mechanism against excessive bradycardia); and preserved during exercise (reduces resting and peak exercise HR proportionately). There is NO effect on contractility (inotropy fully preserved), AV conduction, blood pressure, ventricular repolarization (no QTc effect), or atrial or ventricular myocardial function.6 This preserved contractility is the principal clinical advantage over beta-blockers for pure HR reduction, particularly relevant in patients with impaired LV function.6
Formulation: immediate-release tablets (2.5 mg, 5 mg, 7.5 mg). Bioavailability: ~40% due to first-pass metabolism; food increases absorption; take with meals. Half-life: ~11 hours. Dosing:5 mg twice daily (starting dose); titrate to 7.5 mg twice daily based on resting HR (target 55-60 bpm); reduce to 2.5 mg twice daily if bradycardia occurs. Metabolism: CYP3A4 (extensive); active metabolite S18982 (~40% of parent activity). Dose adjustment required with moderate-to-strong CYP3A4 inhibitors.6
The BEAUTIFUL trial (Fox et al., 2008) enrolled 10,917 patients with stable CAD, LV dysfunction (EF <40%), and resting HR ≥70 bpm; all on standard therapy including beta-blockers. The primary endpoint (CV death + hospital admission for MI or HF) was NOT significantly reduced overall. However, in the prespecified subgroup of patients with HR ≥70 bpm and angina, there was a significant reduction in hospital admission for MI and coronary revascularization, establishing proof of concept for HR-driven anti-ischemic benefit.5 The SIGNIFY trial (Fox et al., 2014) enrolled 19,102 patients with stable CAD WITHOUT HF and resting HR ≥70 bpm. The primary endpoint (CV death + nonfatal MI) was NOT significantly reduced overall; in the angina subgroup receiving the higher dose of 7.5 mg BID, there was a significantly increased incidence of primary endpoint events.6 The regulatory consequence was that the ivabradine dose for angina is now limited to 5 mg BID maximum (not 7.5 mg) in stable CAD without HF in most regulatory frameworks.6 The SHIFT trial (Swedberg et al., 2010) enrolled 6,558 patients with heart failure with reduced ejection fraction (HFrEF) (EF ≤35%), sinus rhythm, and resting HR ≥70 bpm despite maximally tolerated beta-blocker. The primary endpoint (CV death + hospital admission for worsening HF) was significantly reduced by 18%.7 This trial is the basis for the HFrEF FDA indication. In HFrEF patients with concurrent angina, one drug addresses both conditions.7
FDA-approved indications: stable angina, in patients in sinus rhythm with resting HR ≥70 bpm who are on maximally tolerated beta-blocker doses or in whom beta-blockers are contraindicated or not tolerated.3·4 Post-SIGNIFY constraint: start at 5 mg twice daily; do not exceed 5 mg twice daily for stable angina without HF.6 Monitor resting HR; if <50 bpm, reduce dose or discontinue. Heart failure with reduced EF (HFrEF): EF ≤35%, sinus rhythm, resting HR ≥70 bpm despite maximally tolerated beta-blocker.7 In HFrEF patients with concurrent angina, one drug addresses both indications.7 The optimal patient profile for ivabradine in angina includes: stable angina on maximally tolerated beta-blocker with resting HR still ≥70 bpm; stable angina with beta-blocker intolerance (asthma, severe COPD, peripheral arterial disease (PAD)) where HR reduction is still needed; HFrEF (EF ≤35%) with concurrent stable angina; and angina where additional negative inotropy is undesirable.
Absolute contraindications include:6·7 resting HR <60 bpm before initiation; sick sinus syndrome or sinoatrial block; 3rd degree AV block without pacemaker; acute decompensated HF; severe hepatic impairment (Child-Pugh C); atrial fibrillation or flutter (the If channel is specific to the sinus node and ivabradine has NO rate-slowing effect in AF; must confirm sinus rhythm on ECG before prescribing and at each follow-up; concurrent use of strong CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir, which increase levels 7-8 fold); pacemaker-dependent rhythm (100% paced); and pregnancy and breastfeeding. Relative contraindications/caution include:6 diltiazem or verapamil (moderate CYP3A4 (cytochrome P450 3A4) inhibition plus additive HR reduction; avoid if possible; if used, limit ivabradine dose and monitor HR closely); hypotension; and moderate hepatic impairment.
Visual symptoms (phosphenes) are the most distinctive and class-specific adverse effect.6·7 Incidence is ~14-18% (substantially higher than placebo ~5%). The mechanism is that HCN channels are also expressed in retinal cells; ivabradine blocks these channels, causing transient luminous visual phenomena (bright flashes, halos, colored patterns) triggered by sudden changes in light intensity such as entering a dark room or encountering oncoming headlights while driving. These usually occur in the first 2 months and diminish over time. They are completely reversible on dose reduction or discontinuation. All patients must be counseled before initiation because unexpected visual phenomena at night cause alarm and frequently lead to abrupt self-discontinuation. Bradycardia is dose-dependent, occurs in ~10% of patients, and is usually asymptomatic at resting HR 50-55 bpm; symptomatic bradycardia requires dose reduction to 2.5 mg BID or discontinuation.6 AF has a higher incidence in ivabradine-treated patients in SIGNIFY and SHIFT (~5% vs ~3.8% in placebo).6·7 Monitor for AF: irregular pulse, palpitations; ECG if suspected. If AF develops: discontinue ivabradine (no efficacy in AF; continued use is inappropriate).6
Nicorandil is a dual-mechanism antianginal agent.9 Its first mechanism is ATP-sensitive potassium (KATP) channel opening in vascular smooth muscle: K+ efflux leads to membrane hyperpolarization, voltage-gated Ca2+ channels close, reduced intracellular Ca2+ produces vasodilation. It dilates both coronary arteries and peripheral arterioles, reducing preload and afterload. It also opens mitochondrial KATP channels, producing a cardioprotective preconditioning effect that mimics ischemic preconditioning and reduces infarct size in experimental models.9 Its second mechanism is a nitrate-like component: nicorandil also releases NO (similar to organic nitrates), producing venodilation via the cGMP pathway and preload reduction.9 Cross-tolerance with organic nitrates may occur (though less prominent than with pure nitrates). The combined result is balanced preload and afterload reduction, coronary vasodilation, and cardioprotective preconditioning, representing a hemodynamically comprehensive profile distinct from any individual conventional antianginal class.9 Pharmacokinetics: half-life ~1 hour (twice-daily dosing); bioavailability ~75-80%; no significant CYP interactions. Dosing: 10-30 mg twice daily (start 10 mg BID; titrate).
The IONA trial (IONA Study Group, 2002) enrolled 5,126 patients with stable angina and randomized them to nicorandil 10-20 mg twice daily vs. placebo on top of standard antianginal therapy. The primary endpoint (CHD death, nonfatal MI, or unplanned hospital admission for chest pain) was significantly reduced by 17%.9 This was the first and only antianginal trial (other than beta-blockers post-MI) to show a significant reduction in hard cardiovascular endpoints in stable angina, though primary endpoint heterogeneity has generated some debate.9
Nicorandil is NOT approved by the FDA and is not available in the United States. It is available in the UK, Japan, France, Germany, Australia, Canada, and most of Europe and Asia.9 ESC 2019 guidelines give it a Class IIb recommendation as second-line add-on therapy for stable angina.3 Adverse effects include headache (most common; NO-mediated cerebrovascular dilation, the same mechanism as nitrate headache), hypotension (combined vasodilatory mechanisms), and mucocutaneous ulceration, a distinctive and serious adverse effect in which nicorandil can cause mucocutaneous ulcers affecting the mouth, gastrointestinal tract (esophagus, small bowel, colon), perianal region, and skin; these can be large, painful, and slow to heal; the mechanism is poorly understood; nicorandil must be discontinued and ulcers typically heal after cessation.9
Trimetazidine operates at the cellular metabolic level, protecting myocytes from ischemic metabolic damage without altering hemodynamics.8 Under normal aerobic conditions, the myocardium preferentially metabolizes fatty acids (~60-70% of ATP generation) over glucose (~30-40%). During ischemia, fatty acid oxidation becomes inefficient: more O2 is consumed per ATP generated, more H+ ions are generated (worsening intracellular acidosis), and incomplete oxidation yields toxic lipid intermediates.8 Trimetazidine inhibits mitochondrial long-chain 3-ketoacyl-CoA thiolase (3-KAT), the final enzyme in beta-oxidation of long-chain fatty acids. Partial inhibition produces a metabolic shift toward glucose oxidation, generating more ATP per O2 consumed (oxygen-efficient metabolism) and reducing intracellular acidosis and lactate production during ischemia. There are no hemodynamic effects: HR, BP, and contractility remain unchanged.8
Multiple small-to-medium RCTs demonstrated improved exercise tolerance, reduced anginal episodes, and reduced ST changes on exercise testing with trimetazidine as add-on therapy. A Cochrane systematic review (Ciapponi et al., 2005/updated 2017) confirmed significant improvements in exercise duration and time to 1 mm ST depression.8 Studies in combination with beta-blockers, CCBs, and nitrates consistently show additive anti-ischemic benefit.8 No large RCT has demonstrated mortality benefit.
Trimetazidine is NOT available in the United States (never received FDA approval). It is available in Europe, Asia, and Latin America.8 The European Medicines Agency (EMA) restricted its indications in 2012 due to neurological adverse effects.8 ESC 2019 gives it a Class IIb recommendation as second-line add-on for stable angina.3 It is on the World Anti-Doping Agency (WADA) Prohibited List (in-competition, for specified sports); athletes must be informed.8 Adverse effects include Parkinson-like symptoms (tremor, rigidity, bradykinesia, gait disturbance) with chronic use, possibly due to dopaminergic interference; this prompted EMA restriction in 2012 to exclude patients with movement disorders; these effects are generally reversible on discontinuation. Dizziness and headache are less common. There are no significant drug interactions, and the drug is otherwise generally well tolerated.8
A fundamental distinction in antianginal pharmacology is between hemodynamic agents (which reduce MVO2 by altering HR, preload, afterload, or contractility (nitrates, beta-blockers, CCBs, and ivabradine [HR only]) and non-hemodynamic/metabolic agents (which reduce ischemic injury without altering cardiovascular hemodynamics: ranolazine via late INa inhibition and trimetazidine via metabolic shift).3·4 Nicorandil is partially hemodynamic (KATP + nitrate). The clinical value of the non-hemodynamic agents is precisely their ability to add anti-ischemic benefit without compounding bradycardia, hypotension, or negative inotropy, the common dose-limiting factors of conventional agents.1·2·8
Step 1: First-line monotherapy:3·4 beta-blocker (preferred) OR long-acting CCB (if BB contraindicated) + SL-NTG PRN for all patients. Step 2: Dual therapy:3·4 beta-blocker + DHP-CCB (amlodipine, preferred dual); alternative: BB + long-acting nitrate (with nitrate-free interval (NFI)); if BB not tolerated: DHP-CCB + long-acting nitrate, or non-dihydropyridine CCB as monotherapy. Step 3: Triple conventional therapy:3·4 BB + DHP-CCB + long-acting nitrate (Canadian Cardiovascular Society (CCS) III-IV; monitor for hypotension); ranolazine 500-1000 mg BID may substitute for nitrate if hemodynamic tolerance is a concern. Step 4: Add-on novel agents:3·4 ranolazine 500 mg BID titrated to 1000 mg BID (add to any regimen; check QTc and drug interactions first; limit to 500 mg BID if on diltiazem or verapamil); ivabradine 5 mg BID (if sinus rhythm confirmed; HR ≥70 bpm on maximally tolerated beta-blocker; do not exceed 5 mg BID in stable CAD without HF, per the SIGNIFY signal).6 Step 5: Refractory angina: reassess revascularization candidacy; specialist referral; EECP; spinal cord stimulation in selected cases; nicorandil or trimetazidine (outside US); reassess diagnosis to exclude vasospastic or microvascular angina.3·4
The choice between ranolazine and ivabradine as add-on antianginal therapy is determined by the patient's comorbidity profile, heart rhythm, resting HR, and concurrent drug interactions rather than by drug efficacy differences in symptom control alone. The following framework provides a structured decision approach for the most common clinical scenarios.3·4·6·7
Diabetes mellitus with stable angina: ranolazine is the preferred add-on agent. Beyond its anti-ischemic mechanism, ranolazine produces a clinically relevant reduction in hemoglobin A1c of approximately 0.5% at 1000 mg twice daily in diabetic patients with stable angina, an effect mediated by late INa inhibition in pancreatic beta cells, reducing glucotoxic intracellular calcium overload and improving insulin secretion kinetics.3 There is no associated hypoglycemia risk. Ivabradine has no metabolic benefit and adds nothing beyond HR reduction. If sinus rhythm and HR criteria are also met, both agents can be combined.3
Heart failure with reduced ejection fraction (ejection fraction below 40%) combined with stable angina: ivabradine is preferred for its dual indication addressing both conditions simultaneously, provided the patient is in sinus rhythm with a resting HR at or above 70 beats per minute despite maximally tolerated beta-blocker therapy (SHIFT trial criteria).7 Ranolazine does not worsen ejection fraction and can be safely added as an additional anti-ischemic agent; it has no mortality benefit in heart failure with reduced ejection fraction but adds symptom control. Non-dihydropyridine CCBs should be avoided entirely in this population due to negative inotropy.3
Atrial fibrillation with stable angina: ivabradine is CONTRAINDICATED because it blocks the sinus node If current and has no effect on AV nodal rate in atrial fibrillation.6 Rate control in atrial fibrillation requires AV nodal agents (beta-blockers, diltiazem, digoxin). Ranolazine is the appropriate add-on anti-ischemic agent. Secondary evidence from MERLIN-TIMI 36 suggests ranolazine may reduce atrial fibrillation burden and new-onset atrial fibrillation, though this has not driven a formal indication.3 The combination of diltiazem for rate control and ranolazine for anti-ischemic benefit requires ranolazine dose limitation to 500 mg twice daily due to the CYP3A4 interaction.3
COPD or asthma with stable angina where beta-blocker is not tolerated: ivabradine provides pure sinus rate reduction without any effect on bronchomotor tone; it is the only pure HR-reducing agent without beta-2 receptor activity and is therefore the preferred agent for rate reduction in this population.3·4 Ranolazine adds non-hemodynamic anti-ischemic benefit without any pulmonary adverse effects. The combination of ivabradine plus ranolazine plus a dihydropyridine CCB (amlodipine) in a patient unable to tolerate beta-blockers provides three complementary mechanisms without bronchospasm risk.3
Baseline QTc prolongation (QTc above 450 ms but below 500 ms): ranolazine requires baseline and follow-up QTc measurement; it is contraindicated when QTc exceeds 500 ms.1·2 In patients with QTc in the borderline elevated range (450-480 ms), ranolazine can be initiated at 500 mg twice daily with QTc monitoring after one to two weeks before uptitrating. Ivabradine has no effect on ventricular repolarization (no QTc effect) and is the preferred HR-reducing add-on when QTc elevation limits other options.6
Concurrent non-dihydropyridine CCB therapy (diltiazem or verapamil): the ranolazine dose ceiling is 500 mg twice daily due to moderate CYP3A4 (cytochrome P450 3A4) inhibition raising ranolazine levels.3 Ivabradine dose must also be reduced when combined with diltiazem or verapamil because both the pharmacodynamic (additive HR reduction) and pharmacokinetic (CYP3A4 inhibition raising ivabradine levels) effects are present. If either drug produces excessive bradycardia (HR below 55 bpm), consider whether the non-dihydropyridine CCB can be replaced with amlodipine to allow full dosing of add-on agents.3
Post-myocardial infarction with residual angina: ranolazine has the strongest safety evidence in this population from MERLIN-TIMI 36, which enrolled over 6,500 high-risk ACS patients and demonstrated no increase in mortality, reduced recurrent ischemia, and reduced ventricular arrhythmia burden in the ranolazine group.3 Ivabradine can be added if sinus rhythm and HR criteria are met, but the BEAUTIFUL trial showed no overall mortality benefit in stable CAD with LV dysfunction; the HR reduction benefit in this population is primarily symptomatic and ischemia-driven rather than mortality-directed.5
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(3):309-316
doi:10.1001/jama.291.3.309Stone PH, Gratsiansky NA, Blokhin A, et al. Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA trial. J Am Coll Cardiol. 2006;48(3):566-575
doi:10.1016/j.jacc.2006.05.044Knuuti J, Wijns W, Saraste A, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020;41(3):407-477
doi:10.1093/eurheartj/ehz425Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA Guideline for the diagnosis and management of patients with stable ischemic heart disease. J Am Coll Cardiol. 2012;60(24):e44-e164
doi:10.1016/j.jacc.2012.07.013Fox K, Ford I, Steg PG, et al. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL). Lancet. 2008;372(9641):807-816
doi:10.1016/S0140-6736(08)61170-8Fox K, Ford I, Steg PG, et al. Ivabradine in stable coronary artery disease without clinical heart failure (SIGNIFY). N Engl J Med. 2014;371(12):1091-1099
doi:10.1056/NEJMoa1406430Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376(9744):875-885
doi:10.1016/S0140-6736(10)61198-1Ciapponi A, Pizarro R, Harrison J. Trimetazidine for stable angina. Cochrane Database Syst Rev. 2005;(4):CD003614
doi:10.1002/14651858.CD003614.pub2IONA 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(9314):1269-1275
doi:10.1016/S0140-6736(02)08265-XBelardinelli L, Shryock JC, Fraser H. Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine. Heart. 2006;92(Suppl 4):iv6-iv14
doi:10.1136/hrt.2005.078790DiFrancesco D. The role of the funny current in pacemaker activity. Circ Res. 2010;106(3):434-446
doi:10.1161/CIRCRESAHA.109.208041Morrow 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(16):1775-1783
doi:10.1001/jama.297.16.1775