Available online 9 December 2023

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The vast majority of antianginal drugs decrease heart rate and or blood pressure levels or the inotropic status of the left ventricle to decrease MVO2 and thus anginal symptoms. Ranolazine presents a completely different mechanism of action, which reduces the sodium-dependent calcium overload inhibiting the late sodium current. Current ESC guidelines for the management of angina in patients with chronic coronary symptoms recommend the use of several drugs such as ranolazine, b-blockers, calcium channel blockers, long-acting nitrates, ivabradine, nicorandil and trimetazidine for angina relief. However, ranolazine, in addition to symptom relief properties, is an antianginal drug showing favorable effects in decreasing the arrhythmic burden and in ameliorating the glycemic profile of these patients. In this review, we summarize the available data regarding the antianginal and pleiotropic effects of this drug.

Section snippetsINTRODUCTION

Cardiovascular disease (CVD), and especially coronary heart disease (CAD) and stroke, represent the leading cause of death and a major contributor to disability worldwide.1 Stable angina is by far the most common presentation of CAD in the general population in Western countries while the incidence and prevalence of patients with angina is anticipated to increase in the coming decade.1

Stable angina represents a chronic debilitating condition that affects ordinary daily activities and quality of

Mechanism of action

Although the vast majority of antianginal drugs decrease heart rate and or blood pressure levels or the inotropic status of the left ventricle to decrease myocardial oxygen consumption and thus anginal symptoms, ranolazine presents a completely different mechanism of action. The mechanism of action of ranolazine mainly relies on the inhibition of the late phase of the inward sodium current (late INa) following cardiac depolarization.7 Different clinical conditions such as myocardial ischemia

Clinical Research in Angina with ranolazine

Several randomized controlled studies have shown that ranolazine as a standalone therapy or on top of other antianginal drugs, decreases angina attacks, increases exercise tolerance, and hence, reduces the frequency of nitroglycerin consumption, compared to comparator arms.

In the Monotherapy Assessment of Ranolazine in Stable Angina (MARISA) study, a double‐blind randomized controlled study that enrolled patients with stable angina, 191 patients received ranolazine at several doses (500, 1000,

Ranolazine and incomplete Revascularization after Percutaneous Coronary Intervention

The use of ranolazine in post percutaneous coronary intervention (PCI) patients was evaluated in the RIVER-PCI trial.23 This was a randomized, double-blind trial including 2651 patients with a history of stable angina and incomplete revascularization. The primary endpoint was the time to first occurrence of ischemic driven revascularization or hospitalization without revascularization. There was no difference between ranolazine and placebo (26% vs 28%, p=0.48). However, there are several

Ranolazine in acute coronary syndrome

In the MERLIN-TIMI 36 trial,24 ranolazine treatment was evaluated in patients with non-ST-elevation acute coronary syndrome. In this randomized, double-blind, placebo-controlled study, 6560 patients within 48 hours of ischemic symptoms were enrolled. Ranolazine was administrated in 3279 patients (intravenously followed by oral ranolazine 1000 mg b.i.d) while 3281 matched patients received placebo. The primary endpoint was a composite of death, myocardial infarction, or recurrent ischemia. There

Clinical Research in microvascular angina with ranolazine

In a randomized, double-blind cross-over study, 81 patients with microvascular angina were randomized to receive ranolazine or placebo.25 Left ventricular volume and myocardial perfusion reserve index (MPRI) were assessed by magnetic resonance imaging (MRI). In this study, ranolazine proved effective to reduce angina and ameliorate myocardial perfusion in symptomatic patients with coronary flow reserve (CFR) <2.5 and no obstructive epicardial coronary heart disease. In a metanalysis that

Diabetes

Patients with angina symptoms present several comorbidities and a significant proportion of these patients suffer from DM.29,30 In the National Health and Nutrition Examination Survey (NHANES) cohort, an analysis of 1957 adults with CAD, 48,9% of the patients with DM had also angina symptoms.30 Thus, the use of an antianginal drug that ameliorates the glycemic profile in these patients is preferred.

In the CARISA trial, ranolazine's efficacy and safety were assessed in 189 patients with type 2

Approach of a patient with stable angina

Current ESC guidelines for the management of stable angina in patients with chronic coronary syndrome recommend a four-step approach to medical treatment.6 Although this recommendation takes into consideration the hemodynamic profile and the presence or not of left ventricle dysfunction, the majority of patients with stable angina present frequently also other comorbidities and risk factors such as DM and atrial fibrillation. Moreover, the recommendation of step-by–by-step approach lacks of

CONCLUSIONS

Ranolazine is an anti-ischemic drug with a neutral hemodynamic profile and significant pleiotropic effects. Individualizing treatment in patients with stable angina using a drug with pleiotropic effects may improve not only angina symptoms but also other conditions such as the glycemic profile and arrhythmic burden.

AUTHORS’ CONTRIBUTIONS

AM has conceived this review. KM, PL and TC drafted the manuscript. AM, MK, PL and TC critically revised the manuscript.

Declaration of Competing Interest

None

FUNDING

None

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© 2023 Published by Elsevier Inc. on behalf of Southern Society for Clinical Investigation.