Double-blind efficacy and safety study of a novel anti-ischemic agent, ranolazine, versus placebo in patients with chronic stable angina pectoris. Ranolazine Study Group.

Thadani, Udho; Ezekowitz, M. D.; Fenney, L.; Chiang, Yu-Kun

doi:10.1161/01.cir.90.2.726

Cited by 69 publications

(54 citation statements)

References 4 publications

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“…The therapeutic concentration needed to reduce calcium overload is similar to that at which an increase in glucose oxidation was observed. Regardless of the main mechanism of action, ranolazine has been shown to exert an antianginal action, with conflicting results when the immediate-release formulation was used 62 . Reduction of chronic stable angina occurs without affecting heart rate, blood pressure, or myocardial perfusion.…”

Section: Ranolazinementioning

confidence: 99%

A 'diamond' approach to personalized treatment of angina

et al. 2017

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Chronic stable angina pectoris is the most prevalent symptomatic manifestation of ischaemic heart disease, and its management is a priority (BOX 1). Current clinical guidelines recommend antianginal therapy to control symptoms, before considering coronary artery revasculariza tion [1][2][3][4] . However, revascularization by either percutaneous coronary angioplasty or CABG surgery is indicated in patients who have significant artery steno sis (50% left main narrowing or proximal three-vessel disease) to reduce myocardial ischaemia and its adverse clinical manifestation. Antianginal agents are approved by documenting that they improve total exercise duration, together with a reduction in daily frequency of chronic stable angina compared with placebo and/or equivalence to an active comparator. Cardiovascular outcomes, although highly advocated, are not a pre requisite for regulatory approval. None of the antianginal drugs has been proved to reduce cardiovascular mortality or the rate of myocardial infarction. When patients are optimally treated, mortality for chronic stable angina is low, which might explain why all trials designed to improve prognosis have been negative. Guidelines recom mend a first-choice and a second-choice approach, based more on tradition and expert opinion, rather than evidence. This categorical approach has been questioned in the past couple of years 5-8 . Newer antianginal drugs, which are classified as second choice, have more evidence-based clinical data that are more contemporary to support their use than is available for the traditional first-choice drugs. Equally, the often-needed combin ation of double or triple therapy is based on expert opinion and not related to the underlying pathophysio logy. What constitutes optimal antianginal treatment, therefore, varies considerably between countries, and the majority of doctors treat their patients according to their own preconceptions.A group of experts with experience and interest in chronic stable angina met at the University of Ferrara, Italy, to discuss an individualized approach to medical treatment of chronic stable angina, on the basis E X P E RT C O N S E N S U S D O C U M E N TA 'diamond' approach to personalized treatment of angina Abstract | In clinical guidelines, drugs for symptomatic angina are classified as being first choice (β-blockers, calcium-channel blockers, short-acting nitrates) or second choice (ivabradine, nicorandil, ranolazine, trimetazidine), with the recommendation to reserve second-choice medications for patients who have contraindications to first-choice agents, do not tolerate them, or remain symptomatic. No direct comparisons between first-choice and second-choice treatments have demonstrated the superiority of one group of drugs over the other. Meta-analyses show that all antianginal drugs have similar efficacy in reducing symptoms, but provide no evidence for improvement in survival. The newer, second-choice drugs have more evidence-based clinical data that are more contemporary than is available for tr...

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Section: Ranolazinementioning

confidence: 99%

A 'diamond' approach to personalized treatment of angina

et al. 2017

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“…The first Phase 2 clinical trials with this agent were conducted in the early 1990s with favourable results. 166,167 Ranolazine was approved by the Food and Drug Administration as an anti-anginal medication in 2006 following the outcome of the MARISA, 168 CARISA, 169 and ERICA 170 clinical trials. In these trials, ranolazine in monotherapy or in combination with other drugs increased exercise duration, lengthened exercise time until angina or until significant ST-depression, and reduced the number of angina episodes as well as nitroglycerin consumption.…”

Section: Clinical Studiesmentioning

confidence: 99%

The late sodium current in heart failure: pathophysiology and clinical relevance

Horváth

Bers

2014

ESC Heart Failure

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Large and growing body of data suggest that an increased late sodium current (I Na,late ) can have a significant pathophysiological role in heart failure and other heart diseases. The first goal of this article is to describe how I Na,late functions under physiological circumstances. The second goal is to show the wide range of cellular mechanisms that can increase I Na,late in cardiac disease, and also to describe how the up-regulated I Na,late contributes to the pathophysiology of heart failure. The final section of the article discusses the possible use of I Na,late -modifying drugs in heart failure, on the basis of experimental and preclinical data.

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“…Ranolazine is known to be an effective antianginal agent in humans (Jain et al, 1990;Thadani et al, 1994;Rousseau et al, 2005;Pepine and Wolffe, 1999;Chaitman et al, 2004a,b). Although an early theory held that ranolazine functioned by partially inhibiting fatty acid oxidation, new research provides evidence that the cardioprotective actions of ranolazine (at least at the doses currently being used) are not related to inhibition of fatty acid oxidation but are instead related to its effect of inhibiting the late sodium current (I Na ) in cardiac cells Belardinelli et al, 2004;Song et al, 2004).…”

mentioning

confidence: 99%

Improved Left Ventricular Function and Reduced Necrosis after Myocardial Ischemia/Reperfusion in Rabbits Treated with Ranolazine, an Inhibitor of the Late Sodium Channel

Hale

Leeka²,

Kloner³

2006

J Pharmacol Exp Ther

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Ranolazine is an inhibitor of the late sodium current and, via this mechanism, decreases sodium-dependent intracellular calcium overload during ischemia and reperfusion. Ranolazine reduces angina, but there is little information on its effects in acute myocardial infarction. The aim of this study was to test the effects of ranolazine on left ventricular (LV) function and myocardial infarct size after ischemia/reperfusion in rabbits. Ten minutes before coronary artery occlusion (CAO), anesthetized rabbits were assigned to vehicle (n ϭ 15) or ranolazine (2 mg/kg i.v. bolus plus 60 g/kg/min i.v. infusion; n ϭ 15). Hearts received 60 min of CAO and 3 h of reperfusion. CAO caused LV dysfunction associated with necrosis. However, at the end of reperfusion, rabbits treated with ranolazine had better global LV ejection fraction (0.42 Ϯ 0.02 versus 0.33 Ϯ 0.02; p Ͻ 0.007) and stroke volume (1.05 Ϯ 0.08 versus 0.78 Ϯ 0.07 ml; p Ͻ 0.01) compared with vehicle. The fraction of the LV wall that was akinetic or dyskinetic was significantly less in the ranolazine group at 0.23 Ϯ 0.03 versus 0.34 Ϯ 0.03 in vehicle-treated group; p Ͻ 0.02. The ischemic risk region was similar in both groups; however, infarct size was significantly smaller in the treated group (44 Ϯ 5 versus 57 Ϯ 4% vehicle; p Ͻ 0.04). There were no significant differences among groups in heart rate, arterial pressure, LV end-diastolic pressure, or maximum-positive or -negative first time derivative of LV pressure (dP/dt). In conclusion, the results of this study show that ranolazine provides protection during acute myocardial infarction in this rabbit model of ischemia/reperfusion. Ranolazine treatment led to better ejection fraction, stroke volume and less wall motion abnormality after reperfusion, and less myocardial necrosis.

show abstract

Double-blind efficacy and safety study of a novel anti-ischemic agent, ranolazine, versus placebo in patients with chronic stable angina pectoris. Ranolazine Study Group.

Cited by 69 publications

References 4 publications

A 'diamond' approach to personalized treatment of angina

A 'diamond' approach to personalized treatment of angina

The late sodium current in heart failure: pathophysiology and clinical relevance

Improved Left Ventricular Function and Reduced Necrosis after Myocardial Ischemia/Reperfusion in Rabbits Treated with Ranolazine, an Inhibitor of the Late Sodium Channel

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