Editorial Cardiology 2014;128:251–258 DOI: 10.1159/000358871
Received: January 13, 2014 Accepted after revision: January 19, 2014 Published online: May 16, 2014
Use of Ranolazine in Patients with Stable Angina Pectoris Sahil Khera Dhaval Kolte Wilbert S. Aronow
Key Words Stable angina pectoris · Ranolazine · Late sodium current inhibition · Coronary artery disease
Abstract The current American Heart Association/American College of Cardiology guidelines for patients with stable angina pectoris recommend β-blockers as the initial drug therapy for prevention of angina pectoris (class I B indication). Long-acting nitrates or calcium channel blockers should be prescribed for prevention of angina when β-blockers are contraindicated or not tolerated secondary to side effects (class I B indication). Long-acting nitrates or calcium channel blockers in combination with β-blockers should be prescribed for angina prevention when initial treatment with β-blockers is unsuccessful (class I B indication). Only sublingual nitroglycerin or nitroglycerin spray should be used for immediate relief of angina pectoris (class I B indication). Ranolazine with β-blockers can be used for prevention of angina when initial treatment with β-blockers is not successful (class IIa A indication). If angina persists despite treatment with β-blockers, long-acting nitrates and calcium channel blockers, we recommend the addition of ranolazine for prevention of stable angina pectoris. This editorial discusses the contemporary role of ranolazine in the management of patients with stable angina pectoris. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 0008–6312/14/1283–0251$39.50/0 E-Mail [email protected] www.karger.com/crd
The current American Heart Association/American College of Cardiology guidelines for patients with stable angina pectoris [1] recommend β-blockers as the initial drug therapy for prevention of angina pectoris (class I B indication). Long-acting nitrates or calcium channel blockers should be prescribed for prevention of angina when β-blockers are contraindicated or not tolerated secondary to side effects (class I B indication). Long-acting nitrates or calcium channel blockers in combination with β-blockers should be prescribed for angina prevention when initial treatment with β-blockers is unsuccessful (class I B indication). Only sublingual nitroglycerin or nitroglycerin spray should be used for immediate relief of angina pectoris (class I B indication). Ranolazine with β-blockers can be used for prevention of angina when initial treatment with β-blockers is not successful (class IIa A indication). If angina persists despite treatment with β-blockers, long-acting nitrates and calcium channel blockers, we recommend the addition of ranolazine for prevention of stable angina pectoris. This editorial discusses the contemporary role of ranolazine in the management of patients with stable angina pectoris. Ranolazine [Ranexa, Gilead Sciences, Foster City, Calif., USA; N-(2,6-dimethylphenyl)-4(2-hydroxy-3-[2methoxyphenoxy]-propyl)-1-piperazine acetamide dihydrochloride], a sustained-release, hemodynamically neuProf. Wilbert S. Aronow, MD, FACC, FAHA Division of Cardiology New York Medical College Macy Pavilion, Room 138, Valhalla, NY 10595 (USA) E-Mail wsaronow @ aol.com
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Division of Cardiology, Department of Medicine, New York Medical College, Valhalla, N.Y., USA
Mechanism of Action and Pharmacokinetics
Initial reports suggested that the mechanism of action of ranolazine involved partial inhibition of fatty acid β-oxidation and stimulation of glucose oxidation leading to better energy dynamics (increased adenosine triphosphate production per mole of oxygen consumption) in ischemic states and decreased concentration of hydrogen ions and fatty acyl intermediates [5, 8]. However, the plasma concentrations effective for stable angina pectoris are in the usual range of 2–6 μmol/l [9], whereas the partial fatty acid oxidation is inhibited by only 12% at concentrations of 100 μmol/l [10]. Hence, partial inhibition of fatty acid oxidation does not conclusively explain the mechanism of action of ranolazine as an anti-anginal therapy. Recent evidence suggests that ranolazine exerts its anti-anginal effects via the voltage-, frequency- and concentration-dependent inhibition of the late sodium current (INa) in the ischemic myocyte [11–13]. This is selective inhibition of the late INa and does not affect the fast depolarizing INa responsible for the rapid initial upstroke of the action potential at usual therapeutic concentrations [14, 15]. Normally, the late INa makes up only 1% of the total Na+ influx, but its augmentation during ischemic states leads to increased intracellular Na+, which induces calcium (Ca2+) overload by the Na+/Ca2+ counter exchanger. Increased intracellular calcium leads to electrical disharmony and worsened diastolic tension [6]. Elevated diastolic tension can further compromise the coronary blood flow. By inhibiting the augmented late Na+ influx in ischemic myocytes, ranolazine decreases intracellular calcium and diastolic tension [16]. Decreased diastolic tension improves the diastolic coronary blood flow and improves anginal symptoms (fig. 1). This unique mechanism places ranolazine in a cyto-protective class of anti-anginal drugs [17, 18]. 252
Cardiology 2014;128:251–258 DOI: 10.1159/000358871
Ranolazine is a racemic mixture of S-ranolazine and R-ranolazine enantiomeric forms and is available as 500and 1,000-mg sustained-release tablets. The oral bioavailability is 30–55% and is unaffected by meals. Ranolazine protein binding ranges from 61 to 64% in the therapeutic concentration range. Ranolazine is an inhibitor of P-glycoprotein. Verapamil (≥360 mg per day), an inhibitor of P-glycoprotein itself, can lead to a 2.3-fold increase in plasma levels of ranolazine. Digoxin concentration is also increased 1.5 times in patients on ranolazine secondary to competition for renal and intestinal P-glycoprotein [6]. Ranolazine is metabolized mainly by the cytochrome P450 3A4 (CYP 3A4) pathway in the liver [4]. A minimal amount of the drug is metabolized via cytochrome P450 2D6 and glucuronidation. Less than 5% is excreted by the kidneys and unchanged in the feces. Ranolazine increases serum creatinine by 0.1 mg/dl irrespective of the baseline renal function; this is likely due to the inhibition of tubular secretion of creatinine. Jerling and Abdallah [19] reported that the area under the concentration curve between 0 and 12 h after ranolazine dosing doubles in patients with severe renal impairment versus healthy subjects at steady state (geometric mean ratio 1.97; 90% CI 1.23–3.16). The current Ranexa prescribing information [20] suggests periodic monitoring of renal function in patients with moderate-to-severe renal impairment (estimated glomerular filtration rate 500 mg twice a day. No dosage adjustment is required in patients with heart failure (NYHA I–IV) and diabetes mellitus.
Clinical Evidence of Efficacy and Safety – Randomized Controlled Trials
Three landmark trials – Monotherapy Assessment of Ranolazine in Stable Angina (MARISA) [9], Combination Assessment of Ranolazine in Stable Angina (CARISA) [21] and Efficacy of Ranolazine in Chronic Angina (ERICA) [22] – established the role of ranolazine in the management of chronic stable angina. A recently published, first randomized controlled trial studying the efficacy and safety of ranolazine in patients with type 2 diaKhera/Kolte/Aronow
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tral anti-anginal piperazine derivative, was approved by the US Food and Drug Administration in 2006. Ranolazine has no major effects on heart rate, blood pressure or rate-pressure product during rest or exercise [2], and is a beneficial adjunct therapy to the other anti-anginal medications, the tolerability of which may be limited by bradycardia and hypotension [3] when used in combination or at higher therapeutic doses. The half-life of the drug is 7 h during a steady state (usually reached after 3 days of twice-daily dosing) with peak plasma concentrations seen 6 h after administration [4–7].
Color version available online
Ischemia and pathological states linked to imbalances of O2 supply and demand
D Late INa
Ranolazine D [Na]i
NCX
Ca2+ overload
Electrical instability
Mechanical dysfunction Abnormal contraction and relaxation D Diastolic tension
betes mellitus and stable angina pectoris – Type 2 Diabetes Evaluation of Ranolazine in Subjects with Chronic Stable Angina (TERISA) [23] – is also discussed in this editorial. Table 1 outlines the study designs of the four trials. The MARISA trial [9] was the first to study the effects of monotherapy with ranolazine in patients with effort angina. Patients with coronary artery disease and at least a 3-month history of angina on effort minimized by β-blockers, long-acting nitrates and/or calcium channel blockers were included. All anti-anginal medications were discontinued during the study period (except shortacting sublingual nitrate as needed). Eligible patients entered the single-blind placebo-treatment phase in which they underwent two exercise treadmill tests, 7 days apart. The study subjects (average age 64 years, predominantly male and Caucasian) were included in the double-blind phase if they reported angina during exercise with a ≥1mm horizontal or down-sloping ST-segment depression between 3 and 9 min during each exercise treadmill test, and the difference in exercise duration between the two tests did not exceed 20% of the longer test or 1 min. It was
designed as a 4-group, double-blind, crossover, placebocontrolled study of three ranolazine dose regimens (500, 1,000 and 1,500 mg twice a day for a total of 1 week) in 191 patients. The primary endpoint was the exercise duration on the treadmill at trough (i.e. immediately before the next scheduled dose). Exercise duration increased incrementally with increasing dose, and no clinically important hemodynamic changes were observed. The subgroup analysis revealed no difference in outcomes in diabetics, age ≥65 years or heart failure (NYHA I or II). Fifteen patients (7.9%) discontinued the medication secondary to adverse events (most commonly dose-related dizziness, nausea, asthenia and constipation). Minor corrected QT (QTc) prolongation was observed (mean difference in QTc interval compared to placebo: 6.7 and 11 ms at trough with 500-, 1,000- and 1,500-mg dosing, respectively) but no adverse effects were associated with this change. The CARISA [21] trial was a randomized, doubleblind, 3-group, placebo-controlled trial that enrolled 823 patients with chronic stable angina on once-daily atenolol (50 mg), once-daily diltiazem (180 mg) or once-daily am-
Use of Ranolazine in Patients with Stable Angina Pectoris
Cardiology 2014;128:251–258 DOI: 10.1159/000358871
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Fig. 1. Mechanism of action of ranolazine. Increased activation of the late INa during ischemic states leads to increased intracellular Na+ concentration ([Na]i), which induces calcium (Ca2+) overload via the Na+/ Ca2+ counter exchanger (NCX). Increased intracellular Ca2+ leads to myocardial electrical disharmony, contractile dysfunction and increased diastolic tension. By inhibiting the augmented late Na+ influx in ischemic myocytes, ranolazine decreases intracellular Ca2+ and diastolic tension, thereby improving diastolic coronary blood flow and anginal symptoms. Ranolazine does not alter the function of the normal heart, in which late INa is a small current. Thus, the action of ranolazine may be classified as cytoprotective. Adapted and modified with permission from [17].
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Cardiology 2014;128:251–258 DOI: 10.1159/000358871 12 weeks
Placebo twice daily
Follow-up 1 week
Placebo twice daily
Control
8 weeks
Ranolazine SR 500 mg twice daily for 1 week → 1,000 mg twice daily
Ranolazine SR 500 mg twice daily for 1 week → 1,000 mg twice daily for 6 weeks 6 weeks
Placebo twice daily
Placebo twice daily
Inclusion criteria – ≥18 years of age – Type 2 diabetes mellitus – Coronary artery disease – Chronic stable angina ≥3 months – Treated with 1 or 2 anti-anginal therapies (β-blockers, CCBs, LANs) at a stable dose for at least 2 weeks prior to study entry Exclusion criteria – NYHA class III or IV heart failure – Acute coronary syndrome within the prior 2 months – Planned coronary artery revascularization during the study period – Stroke or TIA within 6 months prior to screening – Uncontrolled HTN – Clinically significant hepatic impairment – Dialysis – Prior treatment with or without hypersensitivity/intolerance to ranolazine – QTc >500 ms – Current treatment with trimetazidine, ivabradine or nicorandil, CYP3A inhibitors, inducers or substrates, Pgp inducers, class I or III antiarrhythmics, simvastatin >20 mg/day, metformin >1,000 mg/day Inclusion criteria – ≥18 years of age – Coronary artery disease – Chronic stable angina ≥3 months – ≥3 episodes of angina per week during a 2-week qualification period despite treatment with 10 mg/day amlodipine (patients were required to have begun 10 mg/day amlodipine at least 2 weeks before entering the 2-week qualification period) – Off anti-anginal medications (except LANs, SL NTG and amlodipine) ≥4 weeks before initiation of the study drug and throughout the study period Exclusion criteria – NYHA class IV heart failure – UA or MI within the prior 2 months – Active acute myocarditis, pericarditis, hypertrophic cardiomyopathy or uncontrolled HTN – History of torsades de pointes, QTc >500 ms or any medication known to prolong QTc interval – Receiving inhibitors of CYP450 3A4 or with clinically significant hepatic disease, creatinine clearance ≤30 ml/min or chronic illness likely to interfere with protocol compliance – Patients taking any digitalis preparation, perhexiline, trimetazidine, β-blockers or CCBs (except amlodipine)
Inclusion criteria – Coronary artery disease – Minimum 3-month history of exertional angina – Reproducible angina, ischemic ST-segment depression of at least 1 mm and limited exercise capacity on treadmill testing (3–9 min on a modified Bruce protocol) – On background anti-anginal treatment (atenolol 50 mg, amlodipine 5 mg or diltiazem 180 mg once daily) Exclusion criteria – Factors precluding satisfactory interpretation of ECG – NYHA class III or IV heart failure – Acute coronary syndrome or coronary revascularization procedure within the prior 2 months
Ranolazine SR 750 or 1,000 mg twice daily
Inclusion criteria – ≥21 years of age – Coronary artery disease – Minimum 3-month history of effort angina responding to β-blockers, CCBs, and/or LANs – Two modified Bruce ETTs 1 week apart with exercise-limiting angina and ≥1-mm ST-segment depression between 3 and 9 min during each ETT with the difference between the two tests not exceeding 20% of the longer test or 1 min – Off anti-anginal medications (except SL NTG) 48 h prior to enrollment and throughout the study period Exclusion criteria – Conditions that might compromise ECG or ETT interpretation – NYHA class III or IV heart failure – UA, MI or coronary revascularization procedure within 2 months of enrollment – QTc >500 ms or any medication known to prolong QTc interval – Requirement for medication or food known to affect metabolism by CYP450 3A4
Patient selection
Randomized, double-blind, placebo-controlled trial (n = 949)
TERISA
Randomized, double-blind, parallel-group, 3-phase, placebo-controlled trial (n = 564)
ERICA
Randomized, 3-group parallel, double-blind, placebo-controlled trial (n = 823)
CARISA
Treatment Ranolazine SR 500, 1,000 or 1,500 mg twice daily
Randomized, double-blind, 4-period crossover, placebo-controlled trial (n = 191)
Design
MARISA
Table 1. Overview of four major randomized controlled trials of ranolazine in stable angina pectoris
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Khera/Kolte/Aronow
Use of Ranolazine in Patients with Stable Angina Pectoris
Cardiology 2014;128:251–258 DOI: 10.1159/000358871
22.2% in placebo versus 26.8% in ranolazine group
Weekly angina frequency significantly lower with ranolazine versus placebo [3.8 (95% CI 3.6–4.1) vs. 4.3 (95% CI 4–4.5); p < 0.008]. SL NTG use significantly reduced Higher proportion of patients achieving ≥50% reduction in weekly angina frequency Change in SF-36 Physical Component Score greater in the ranolazine than placebo group No difference in change in SF-36 Mental Component or PGIC Scores
Weekly angina frequency significantly lower with ranolazine versus placebo (2.88 ± 0.19 vs. 3.31 ± 0.22; p = 0.028) SL NTG consumption significantly reduced SAQ angina frequency assessment significantly improved Other SAQ dimensions not significantly changed
Exercise duration at trough increased by 23.7 s (750-mg dose) and 24.0 s (1,000-mg dose) relative to placebo (p < 0.03 and p < 0.029, respectively) Significant increases in exercise duration, time to angina onset and time to 1-mm ST-segment depression at peak, and in time to angina onset at trough. Significant reduction in average weekly angina frequency and SL NTG consumption
35.3% in placebo versus 39.9% in ranolazine group
Primary – Average weekly number of angina episodes from weeks 2 to 8 of treatment Secondary – Average weekly frequency of SL NTG use – Number of angina-free days – Proportion of subjects with 50% reduction in average weekly angina frequency – Health-related quality of life, as assessed by the Medical Outcomes Short Form-36
Primary – Average weekly frequency of self-reported angina episodes Secondary – Average weekly SL NTG consumption rate – Change from baseline of the 5 dimensions of the SAQ
Primary – ETT exercise duration at trough ranolazine levels Secondary – ETT exercise duration at peak ranolazine levels – Time to onset of angina at peak and trough levels – Time to 1-mm ST-segment depression at peak and trough levels – SL NTG use – Number of angina attacks
26.4% in placebo versus 31.2% in 750-mg and 32.7% in 1,000-mg groups
TERISA
ERICA
CARISA
CCBs = Calcium channel blockers; LANs = long-acting nitrates; ETT = exercise treadmill test; SL NTG = sublingual nitroglycerin; ECG = electrocardiogram; UA = unstable angina; MI = myocardial infarction; HTN = hypertension; TIA = transient ischemic attack; CYP450 = cytochrome P450; SR = sustained release; PGIC = Patient’s Global Impression of Change.
15.6% in placebo versus 21.7% in 500-mg, 27.7% in 1,000-mg and 34.2% in 1,500-mg groups
Exercise duration at trough increased in a dose-dependent fashion relative to placebo (23.8, 33.7 and 45.9 s for 500, 1,000 and 1,500 mg doses, respectively; p < 0.005) Significant, dose-related increases in exercise duration at peak and in time to angina onset and time to 1-mm ST-segment depression at peak and trough
Results
Adverse events
Primary – ETT exercise duration at trough ranolazine levels Secondary – ETT exercise duration at peak ranolazine levels – Time to onset of angina at peak and trough levels – Time to 1-mm ST-segment depression at peak and trough levels
Outcome measures
MARISA
Table 1 (continued)
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Cardiology 2014;128:251–258 DOI: 10.1159/000358871
nitroglycerin consumption was lower in those on ranolazine (trimmed mean 2.03 ± 0.20) versus placebo (trimmed mean 2.68 ± 0.22; p = 0.014). None of the SAQ dimensions except angina frequency were significantly different between the two groups (SAQ angina frequency dimension: 22.5 ± 19.0 in ranolazine vs. 18.5 ± 18.8 in placebo; p = 0.008). There were no significant differences in hemodynamic parameters (heart rate and blood pressure) in patients on ranolazine versus placebo. Mild-to-moderate adverse events occurred in 35.3% of patients on placebo and 39.9% on ranolazine. The most commonly reported side effect was constipation, followed by peripheral edema, dizziness, nausea and headache. The ERICA trial established the safety and efficacy of ranolazine in patients with stable angina pectoris who were symptomatic on maximal daily doses of amlodipine. The TERISA [23] trial studied patients with type II diabetes mellitus with chronic stable angina pectoris (minimum 3 months duration) on treatment with 1–2 conventional anti-anginal drugs (β-blockers, long-acting nitrates or calcium-channel blockers) for at least 2 weeks. After a 4-week single-blind placebo run-in period, 949 patients were randomized to either twice-daily placebo or ranolazine for 8 weeks. The reported weekly anginal episodes in the ranolazine group at week 2–8 after randomization averaged 3.8 episodes versus 4.1 episodes in the placebo group (p = 0.008). Weekly sublingual nitrate use was also lower in the treatment group (1.7 doses vs. 2.1 doses in the placebo group; p = 0.003). In subgroup and exploratory analysis, the beneficial effects of ranolazine were seen in all subgroups (baseline weekly anginal episodes, number of concomitant anti-anginal agents, age, sex and those with a history of revascularization). Of note, the anti-anginal effect (reduction in weekly anginal frequency) was more marked in patients with higher hemoglobin A1C (HbA1C) values (pinteraction = 0.027). This was the first trial to demonstrate the safety and efficacy of sustained release ranolazine in type II diabetics with stable angina pectoris.
Ranolazine and HbA1C
There is also evidence of a lowering of HbA1C with use of ranolazine in diabetic patients. Thus, in a post hoc analysis of CARISA [26], ranolazine reduced HbA1C levels (vs. placebo) in diabetics (0.48 ± 0.18%, p = 0.008 in the 750-mg twice-daily group; 0.70 ± 0.18%, p = 0.0002 in the 1,000-mg twice-daily group). This was not associated with any weight gain during the 3-month double-blind Khera/Kolte/Aronow
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lodipine (5 mg). Patients were randomly assigned to receive twice-daily placebo, 750 mg of ranolazine or 1,000 mg of ranolazine. The primary goal was to assess the effect of ranolazine (vs. placebo) on treadmill exercise duration at trough. At the time of enrollment, 43% of patients were on atenolol, 31% on amlodipine and 25.9% on diltiazem. Exercise duration increased by 26% more with ranolazine than placebo (p = 0.01). The increase in exercise duration persisted throughout the 12 weeks of study. Ranolazinetreated patients had no changes in end-exercise or standing heart rates or blood pressures. Commonly reported adverse events were constipation, asthenia, dizziness and nausea. Mean QTc prolongation above placebo was 6.1 ms in the 750-mg twice-daily group and 9.2 ms for the 1,000-mg twice-daily group. None of the patients developed torsades de pointes. The Ranolazine Open Label Experience (ROLE) program [24] enrolled patients after completion of the CARISA and MARISA trials to assess the safety and tolerability of long-term use of ranolazine in patients with severe functional limitations secondary to angina (mean Duke treadmill score: –14.4). A total of 746 patients were followed for an average of 2.82 years. After the 2-year followup, 76.7% remained on therapy; 9.7% discontinued ranolazine due to adverse reactions. There were 68 deaths during the 2,372 patient-years of follow-up, translating into a 2.8% annual mortality. Since a Duke treadmill score of –14.4, as recorded in the patients of the ROLE cohort, predicts an annual mortality of >5%, the results of ROLE suggest that the drug does not reduce survival and, indeed, despite the very modest mean QTc prolongation of 2.4 ms (p < 0.001), none of the patients discontinued the medication secondary to QTc prolongation or developed torsades de pointes. Moreover, despite increasing QTc minimally, ranolazine does not induce early afterdepolarizations or increase spatial dispersion of repolarization [11] and, hence, should not lead to torsades de pointes. The ERICA trial [22] studied the effects of ranolazine versus placebo in patients ≥18 years of age with chronic stable angina pectoris of ≥3 months duration and ≥3 anginal episodes/week on 10 mg of amlodipine daily. This trial randomized 565 patients, 281 to ranolazine and 284 to placebo. The primary efficacy endpoint was the weekly anginal attack frequency during the 6-week period (dosing treatment phase 1,000 mg twice daily). Nitroglycerin consumption per week and the Seattle Angina Questionnaire (SAQ) were used as the secondary efficacy endpoints [25]. Ranolazine reduced the weekly frequency of anginal episodes compared to placebo (2.88 ± 0.19 on ranolazine vs. 3.31 ± 0.22 on placebo; p = 0.028). Weekly
period and it did not affect the fasting glucose levels in the treatment phase (12 weeks). Chisholm et al. [27] analyzed the data from the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes (MERLIN)-TIMI 36 trial, and reported an absolute reduction in HbA1C of 0.28% (95% CI –0.38 to –0.19) in the ranolazine-treated patients with a baseline HbA1C of 6 to 8–10%. The decrease (placebo corrected) in HbA1C with ranolazine was 0.28 and 0.59% in the 6–8 and >8–10 mg/dl groups, respectively. The meta-analysis conducted by Savarese et al. [28] looked at the cumulative data from the CARISA and the MERLIN-TIMI 36 trials and reported an HbA1C decrease of 0.43% (95% CI –0.748 to –0.109; p = 0.009) in the ranolazine-treated groups. Although the exact mechanism of action is unclear, there is evidence from animal models that ranolazine has B cell preservation properties and causes glucose-dependent insulin secretion [29].
Conclusions
There is a paucity of data on the use of ranolazine in treating African Americans, Asians and Hispanics with stable angina pectoris. Future research should also focus on understanding the effects of ranolazine in diabetics and the better efficacy of ranolazine in patients with poorer glycemic control. On the basis of the available data, the authors conclude that ranolazine is an acceptably safe and efficacious anti-anginal therapy in treating patients with persistent stable angina pectoris despite maximum tolerable doses of β-blockers, long-acting nitrates and calcium channel blockers. Ranolazine increases exercise duration, decreases weekly anginal frequency, decreases nitroglycerin use and improves time to angina. It is hemodynamically inert and has a favorable metabolic profile in diabetics. We believe its use should be regularly considered by clinicians caring for patients with angina pectoris due to coronary artery disease.
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Use of Ranolazine in Patients with Stable Angina Pectoris
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27 Chisholm JW, Goldfine AB, Dhalla AK, Braunwald E, Morrow DA, KarwatowskaProkopczuk E, Belardinelli L: Effect of ranolazine on A1C and glucose levels in hyperglycemic patients with non-ST elevation acute coronary syndrome. Diabetes Care 2010; 33: 1163–1168. 28 Savarese G, Rosano G, D’Amore C, Musella F, Ratta Della GL, Pellegrino AM, Formisano T, Vitagliano A, Cirillo A, Cice G, Fimiani L, del Guercio L, Trimarco B, Perrone-Filardi P: Effects of ranolazine in symptomatic patients with stable coronary artery disease: a systematic review and meta-analysis. Int J Cardiol 2013;169:262–270. 29 Ning Y, Zhen W, Fu Z, Jiang J, Liu D, Belardinelli L, Dhalla AK: Ranolazine increases β-cell survival and improves glucose homeostasis in low-dose streptozotocin-induced diabetes in mice. J Pharmacol Exp Ther 2011; 337:50–58.
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20 Gilead Sciences: Ranexa prescribing information. http://www.gilead.com/∼/media/Files/ pdfs/medicines/cardiovascular/ranexa/ ranexa_pi.ashx (accessed January 2014). 21 Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, Wang W, Skettino SL, Wolff AA, CARISA Investigators: Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA 2004;291:309–316. 22 Stone PH, Gratsiansky NA, Blokhin A, Huang I-Z, Meng L, ERICA Investigators: 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. 23 Kosiborod M, Arnold SV, Spertus JA, McGuire DK, Li Y, Yue P, Ben-Yehuda O, Katz A, Jones PG, Olmsted A, Belardinelli L, Chaitman
Received: January 13, 2014 Accepted after revision: January 19, 2014 Published online: May 16, 2014
Use of Ranolazine in Patients with Stable Angina Pectoris Sahil Khera Dhaval Kolte Wilbert S. Aronow
Key Words Stable angina pectoris · Ranolazine · Late sodium current inhibition · Coronary artery disease
Abstract The current American Heart Association/American College of Cardiology guidelines for patients with stable angina pectoris recommend β-blockers as the initial drug therapy for prevention of angina pectoris (class I B indication). Long-acting nitrates or calcium channel blockers should be prescribed for prevention of angina when β-blockers are contraindicated or not tolerated secondary to side effects (class I B indication). Long-acting nitrates or calcium channel blockers in combination with β-blockers should be prescribed for angina prevention when initial treatment with β-blockers is unsuccessful (class I B indication). Only sublingual nitroglycerin or nitroglycerin spray should be used for immediate relief of angina pectoris (class I B indication). Ranolazine with β-blockers can be used for prevention of angina when initial treatment with β-blockers is not successful (class IIa A indication). If angina persists despite treatment with β-blockers, long-acting nitrates and calcium channel blockers, we recommend the addition of ranolazine for prevention of stable angina pectoris. This editorial discusses the contemporary role of ranolazine in the management of patients with stable angina pectoris. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 0008–6312/14/1283–0251$39.50/0 E-Mail [email protected] www.karger.com/crd
The current American Heart Association/American College of Cardiology guidelines for patients with stable angina pectoris [1] recommend β-blockers as the initial drug therapy for prevention of angina pectoris (class I B indication). Long-acting nitrates or calcium channel blockers should be prescribed for prevention of angina when β-blockers are contraindicated or not tolerated secondary to side effects (class I B indication). Long-acting nitrates or calcium channel blockers in combination with β-blockers should be prescribed for angina prevention when initial treatment with β-blockers is unsuccessful (class I B indication). Only sublingual nitroglycerin or nitroglycerin spray should be used for immediate relief of angina pectoris (class I B indication). Ranolazine with β-blockers can be used for prevention of angina when initial treatment with β-blockers is not successful (class IIa A indication). If angina persists despite treatment with β-blockers, long-acting nitrates and calcium channel blockers, we recommend the addition of ranolazine for prevention of stable angina pectoris. This editorial discusses the contemporary role of ranolazine in the management of patients with stable angina pectoris. Ranolazine [Ranexa, Gilead Sciences, Foster City, Calif., USA; N-(2,6-dimethylphenyl)-4(2-hydroxy-3-[2methoxyphenoxy]-propyl)-1-piperazine acetamide dihydrochloride], a sustained-release, hemodynamically neuProf. Wilbert S. Aronow, MD, FACC, FAHA Division of Cardiology New York Medical College Macy Pavilion, Room 138, Valhalla, NY 10595 (USA) E-Mail wsaronow @ aol.com
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Division of Cardiology, Department of Medicine, New York Medical College, Valhalla, N.Y., USA
Mechanism of Action and Pharmacokinetics
Initial reports suggested that the mechanism of action of ranolazine involved partial inhibition of fatty acid β-oxidation and stimulation of glucose oxidation leading to better energy dynamics (increased adenosine triphosphate production per mole of oxygen consumption) in ischemic states and decreased concentration of hydrogen ions and fatty acyl intermediates [5, 8]. However, the plasma concentrations effective for stable angina pectoris are in the usual range of 2–6 μmol/l [9], whereas the partial fatty acid oxidation is inhibited by only 12% at concentrations of 100 μmol/l [10]. Hence, partial inhibition of fatty acid oxidation does not conclusively explain the mechanism of action of ranolazine as an anti-anginal therapy. Recent evidence suggests that ranolazine exerts its anti-anginal effects via the voltage-, frequency- and concentration-dependent inhibition of the late sodium current (INa) in the ischemic myocyte [11–13]. This is selective inhibition of the late INa and does not affect the fast depolarizing INa responsible for the rapid initial upstroke of the action potential at usual therapeutic concentrations [14, 15]. Normally, the late INa makes up only 1% of the total Na+ influx, but its augmentation during ischemic states leads to increased intracellular Na+, which induces calcium (Ca2+) overload by the Na+/Ca2+ counter exchanger. Increased intracellular calcium leads to electrical disharmony and worsened diastolic tension [6]. Elevated diastolic tension can further compromise the coronary blood flow. By inhibiting the augmented late Na+ influx in ischemic myocytes, ranolazine decreases intracellular calcium and diastolic tension [16]. Decreased diastolic tension improves the diastolic coronary blood flow and improves anginal symptoms (fig. 1). This unique mechanism places ranolazine in a cyto-protective class of anti-anginal drugs [17, 18]. 252
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Ranolazine is a racemic mixture of S-ranolazine and R-ranolazine enantiomeric forms and is available as 500and 1,000-mg sustained-release tablets. The oral bioavailability is 30–55% and is unaffected by meals. Ranolazine protein binding ranges from 61 to 64% in the therapeutic concentration range. Ranolazine is an inhibitor of P-glycoprotein. Verapamil (≥360 mg per day), an inhibitor of P-glycoprotein itself, can lead to a 2.3-fold increase in plasma levels of ranolazine. Digoxin concentration is also increased 1.5 times in patients on ranolazine secondary to competition for renal and intestinal P-glycoprotein [6]. Ranolazine is metabolized mainly by the cytochrome P450 3A4 (CYP 3A4) pathway in the liver [4]. A minimal amount of the drug is metabolized via cytochrome P450 2D6 and glucuronidation. Less than 5% is excreted by the kidneys and unchanged in the feces. Ranolazine increases serum creatinine by 0.1 mg/dl irrespective of the baseline renal function; this is likely due to the inhibition of tubular secretion of creatinine. Jerling and Abdallah [19] reported that the area under the concentration curve between 0 and 12 h after ranolazine dosing doubles in patients with severe renal impairment versus healthy subjects at steady state (geometric mean ratio 1.97; 90% CI 1.23–3.16). The current Ranexa prescribing information [20] suggests periodic monitoring of renal function in patients with moderate-to-severe renal impairment (estimated glomerular filtration rate 500 mg twice a day. No dosage adjustment is required in patients with heart failure (NYHA I–IV) and diabetes mellitus.
Clinical Evidence of Efficacy and Safety – Randomized Controlled Trials
Three landmark trials – Monotherapy Assessment of Ranolazine in Stable Angina (MARISA) [9], Combination Assessment of Ranolazine in Stable Angina (CARISA) [21] and Efficacy of Ranolazine in Chronic Angina (ERICA) [22] – established the role of ranolazine in the management of chronic stable angina. A recently published, first randomized controlled trial studying the efficacy and safety of ranolazine in patients with type 2 diaKhera/Kolte/Aronow
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tral anti-anginal piperazine derivative, was approved by the US Food and Drug Administration in 2006. Ranolazine has no major effects on heart rate, blood pressure or rate-pressure product during rest or exercise [2], and is a beneficial adjunct therapy to the other anti-anginal medications, the tolerability of which may be limited by bradycardia and hypotension [3] when used in combination or at higher therapeutic doses. The half-life of the drug is 7 h during a steady state (usually reached after 3 days of twice-daily dosing) with peak plasma concentrations seen 6 h after administration [4–7].
Color version available online
Ischemia and pathological states linked to imbalances of O2 supply and demand
D Late INa
Ranolazine D [Na]i
NCX
Ca2+ overload
Electrical instability
Mechanical dysfunction Abnormal contraction and relaxation D Diastolic tension
betes mellitus and stable angina pectoris – Type 2 Diabetes Evaluation of Ranolazine in Subjects with Chronic Stable Angina (TERISA) [23] – is also discussed in this editorial. Table 1 outlines the study designs of the four trials. The MARISA trial [9] was the first to study the effects of monotherapy with ranolazine in patients with effort angina. Patients with coronary artery disease and at least a 3-month history of angina on effort minimized by β-blockers, long-acting nitrates and/or calcium channel blockers were included. All anti-anginal medications were discontinued during the study period (except shortacting sublingual nitrate as needed). Eligible patients entered the single-blind placebo-treatment phase in which they underwent two exercise treadmill tests, 7 days apart. The study subjects (average age 64 years, predominantly male and Caucasian) were included in the double-blind phase if they reported angina during exercise with a ≥1mm horizontal or down-sloping ST-segment depression between 3 and 9 min during each exercise treadmill test, and the difference in exercise duration between the two tests did not exceed 20% of the longer test or 1 min. It was
designed as a 4-group, double-blind, crossover, placebocontrolled study of three ranolazine dose regimens (500, 1,000 and 1,500 mg twice a day for a total of 1 week) in 191 patients. The primary endpoint was the exercise duration on the treadmill at trough (i.e. immediately before the next scheduled dose). Exercise duration increased incrementally with increasing dose, and no clinically important hemodynamic changes were observed. The subgroup analysis revealed no difference in outcomes in diabetics, age ≥65 years or heart failure (NYHA I or II). Fifteen patients (7.9%) discontinued the medication secondary to adverse events (most commonly dose-related dizziness, nausea, asthenia and constipation). Minor corrected QT (QTc) prolongation was observed (mean difference in QTc interval compared to placebo: 6.7 and 11 ms at trough with 500-, 1,000- and 1,500-mg dosing, respectively) but no adverse effects were associated with this change. The CARISA [21] trial was a randomized, doubleblind, 3-group, placebo-controlled trial that enrolled 823 patients with chronic stable angina on once-daily atenolol (50 mg), once-daily diltiazem (180 mg) or once-daily am-
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Fig. 1. Mechanism of action of ranolazine. Increased activation of the late INa during ischemic states leads to increased intracellular Na+ concentration ([Na]i), which induces calcium (Ca2+) overload via the Na+/ Ca2+ counter exchanger (NCX). Increased intracellular Ca2+ leads to myocardial electrical disharmony, contractile dysfunction and increased diastolic tension. By inhibiting the augmented late Na+ influx in ischemic myocytes, ranolazine decreases intracellular Ca2+ and diastolic tension, thereby improving diastolic coronary blood flow and anginal symptoms. Ranolazine does not alter the function of the normal heart, in which late INa is a small current. Thus, the action of ranolazine may be classified as cytoprotective. Adapted and modified with permission from [17].
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Cardiology 2014;128:251–258 DOI: 10.1159/000358871 12 weeks
Placebo twice daily
Follow-up 1 week
Placebo twice daily
Control
8 weeks
Ranolazine SR 500 mg twice daily for 1 week → 1,000 mg twice daily
Ranolazine SR 500 mg twice daily for 1 week → 1,000 mg twice daily for 6 weeks 6 weeks
Placebo twice daily
Placebo twice daily
Inclusion criteria – ≥18 years of age – Type 2 diabetes mellitus – Coronary artery disease – Chronic stable angina ≥3 months – Treated with 1 or 2 anti-anginal therapies (β-blockers, CCBs, LANs) at a stable dose for at least 2 weeks prior to study entry Exclusion criteria – NYHA class III or IV heart failure – Acute coronary syndrome within the prior 2 months – Planned coronary artery revascularization during the study period – Stroke or TIA within 6 months prior to screening – Uncontrolled HTN – Clinically significant hepatic impairment – Dialysis – Prior treatment with or without hypersensitivity/intolerance to ranolazine – QTc >500 ms – Current treatment with trimetazidine, ivabradine or nicorandil, CYP3A inhibitors, inducers or substrates, Pgp inducers, class I or III antiarrhythmics, simvastatin >20 mg/day, metformin >1,000 mg/day Inclusion criteria – ≥18 years of age – Coronary artery disease – Chronic stable angina ≥3 months – ≥3 episodes of angina per week during a 2-week qualification period despite treatment with 10 mg/day amlodipine (patients were required to have begun 10 mg/day amlodipine at least 2 weeks before entering the 2-week qualification period) – Off anti-anginal medications (except LANs, SL NTG and amlodipine) ≥4 weeks before initiation of the study drug and throughout the study period Exclusion criteria – NYHA class IV heart failure – UA or MI within the prior 2 months – Active acute myocarditis, pericarditis, hypertrophic cardiomyopathy or uncontrolled HTN – History of torsades de pointes, QTc >500 ms or any medication known to prolong QTc interval – Receiving inhibitors of CYP450 3A4 or with clinically significant hepatic disease, creatinine clearance ≤30 ml/min or chronic illness likely to interfere with protocol compliance – Patients taking any digitalis preparation, perhexiline, trimetazidine, β-blockers or CCBs (except amlodipine)
Inclusion criteria – Coronary artery disease – Minimum 3-month history of exertional angina – Reproducible angina, ischemic ST-segment depression of at least 1 mm and limited exercise capacity on treadmill testing (3–9 min on a modified Bruce protocol) – On background anti-anginal treatment (atenolol 50 mg, amlodipine 5 mg or diltiazem 180 mg once daily) Exclusion criteria – Factors precluding satisfactory interpretation of ECG – NYHA class III or IV heart failure – Acute coronary syndrome or coronary revascularization procedure within the prior 2 months
Ranolazine SR 750 or 1,000 mg twice daily
Inclusion criteria – ≥21 years of age – Coronary artery disease – Minimum 3-month history of effort angina responding to β-blockers, CCBs, and/or LANs – Two modified Bruce ETTs 1 week apart with exercise-limiting angina and ≥1-mm ST-segment depression between 3 and 9 min during each ETT with the difference between the two tests not exceeding 20% of the longer test or 1 min – Off anti-anginal medications (except SL NTG) 48 h prior to enrollment and throughout the study period Exclusion criteria – Conditions that might compromise ECG or ETT interpretation – NYHA class III or IV heart failure – UA, MI or coronary revascularization procedure within 2 months of enrollment – QTc >500 ms or any medication known to prolong QTc interval – Requirement for medication or food known to affect metabolism by CYP450 3A4
Patient selection
Randomized, double-blind, placebo-controlled trial (n = 949)
TERISA
Randomized, double-blind, parallel-group, 3-phase, placebo-controlled trial (n = 564)
ERICA
Randomized, 3-group parallel, double-blind, placebo-controlled trial (n = 823)
CARISA
Treatment Ranolazine SR 500, 1,000 or 1,500 mg twice daily
Randomized, double-blind, 4-period crossover, placebo-controlled trial (n = 191)
Design
MARISA
Table 1. Overview of four major randomized controlled trials of ranolazine in stable angina pectoris
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22.2% in placebo versus 26.8% in ranolazine group
Weekly angina frequency significantly lower with ranolazine versus placebo [3.8 (95% CI 3.6–4.1) vs. 4.3 (95% CI 4–4.5); p < 0.008]. SL NTG use significantly reduced Higher proportion of patients achieving ≥50% reduction in weekly angina frequency Change in SF-36 Physical Component Score greater in the ranolazine than placebo group No difference in change in SF-36 Mental Component or PGIC Scores
Weekly angina frequency significantly lower with ranolazine versus placebo (2.88 ± 0.19 vs. 3.31 ± 0.22; p = 0.028) SL NTG consumption significantly reduced SAQ angina frequency assessment significantly improved Other SAQ dimensions not significantly changed
Exercise duration at trough increased by 23.7 s (750-mg dose) and 24.0 s (1,000-mg dose) relative to placebo (p < 0.03 and p < 0.029, respectively) Significant increases in exercise duration, time to angina onset and time to 1-mm ST-segment depression at peak, and in time to angina onset at trough. Significant reduction in average weekly angina frequency and SL NTG consumption
35.3% in placebo versus 39.9% in ranolazine group
Primary – Average weekly number of angina episodes from weeks 2 to 8 of treatment Secondary – Average weekly frequency of SL NTG use – Number of angina-free days – Proportion of subjects with 50% reduction in average weekly angina frequency – Health-related quality of life, as assessed by the Medical Outcomes Short Form-36
Primary – Average weekly frequency of self-reported angina episodes Secondary – Average weekly SL NTG consumption rate – Change from baseline of the 5 dimensions of the SAQ
Primary – ETT exercise duration at trough ranolazine levels Secondary – ETT exercise duration at peak ranolazine levels – Time to onset of angina at peak and trough levels – Time to 1-mm ST-segment depression at peak and trough levels – SL NTG use – Number of angina attacks
26.4% in placebo versus 31.2% in 750-mg and 32.7% in 1,000-mg groups
TERISA
ERICA
CARISA
CCBs = Calcium channel blockers; LANs = long-acting nitrates; ETT = exercise treadmill test; SL NTG = sublingual nitroglycerin; ECG = electrocardiogram; UA = unstable angina; MI = myocardial infarction; HTN = hypertension; TIA = transient ischemic attack; CYP450 = cytochrome P450; SR = sustained release; PGIC = Patient’s Global Impression of Change.
15.6% in placebo versus 21.7% in 500-mg, 27.7% in 1,000-mg and 34.2% in 1,500-mg groups
Exercise duration at trough increased in a dose-dependent fashion relative to placebo (23.8, 33.7 and 45.9 s for 500, 1,000 and 1,500 mg doses, respectively; p < 0.005) Significant, dose-related increases in exercise duration at peak and in time to angina onset and time to 1-mm ST-segment depression at peak and trough
Results
Adverse events
Primary – ETT exercise duration at trough ranolazine levels Secondary – ETT exercise duration at peak ranolazine levels – Time to onset of angina at peak and trough levels – Time to 1-mm ST-segment depression at peak and trough levels
Outcome measures
MARISA
Table 1 (continued)
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nitroglycerin consumption was lower in those on ranolazine (trimmed mean 2.03 ± 0.20) versus placebo (trimmed mean 2.68 ± 0.22; p = 0.014). None of the SAQ dimensions except angina frequency were significantly different between the two groups (SAQ angina frequency dimension: 22.5 ± 19.0 in ranolazine vs. 18.5 ± 18.8 in placebo; p = 0.008). There were no significant differences in hemodynamic parameters (heart rate and blood pressure) in patients on ranolazine versus placebo. Mild-to-moderate adverse events occurred in 35.3% of patients on placebo and 39.9% on ranolazine. The most commonly reported side effect was constipation, followed by peripheral edema, dizziness, nausea and headache. The ERICA trial established the safety and efficacy of ranolazine in patients with stable angina pectoris who were symptomatic on maximal daily doses of amlodipine. The TERISA [23] trial studied patients with type II diabetes mellitus with chronic stable angina pectoris (minimum 3 months duration) on treatment with 1–2 conventional anti-anginal drugs (β-blockers, long-acting nitrates or calcium-channel blockers) for at least 2 weeks. After a 4-week single-blind placebo run-in period, 949 patients were randomized to either twice-daily placebo or ranolazine for 8 weeks. The reported weekly anginal episodes in the ranolazine group at week 2–8 after randomization averaged 3.8 episodes versus 4.1 episodes in the placebo group (p = 0.008). Weekly sublingual nitrate use was also lower in the treatment group (1.7 doses vs. 2.1 doses in the placebo group; p = 0.003). In subgroup and exploratory analysis, the beneficial effects of ranolazine were seen in all subgroups (baseline weekly anginal episodes, number of concomitant anti-anginal agents, age, sex and those with a history of revascularization). Of note, the anti-anginal effect (reduction in weekly anginal frequency) was more marked in patients with higher hemoglobin A1C (HbA1C) values (pinteraction = 0.027). This was the first trial to demonstrate the safety and efficacy of sustained release ranolazine in type II diabetics with stable angina pectoris.
Ranolazine and HbA1C
There is also evidence of a lowering of HbA1C with use of ranolazine in diabetic patients. Thus, in a post hoc analysis of CARISA [26], ranolazine reduced HbA1C levels (vs. placebo) in diabetics (0.48 ± 0.18%, p = 0.008 in the 750-mg twice-daily group; 0.70 ± 0.18%, p = 0.0002 in the 1,000-mg twice-daily group). This was not associated with any weight gain during the 3-month double-blind Khera/Kolte/Aronow
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lodipine (5 mg). Patients were randomly assigned to receive twice-daily placebo, 750 mg of ranolazine or 1,000 mg of ranolazine. The primary goal was to assess the effect of ranolazine (vs. placebo) on treadmill exercise duration at trough. At the time of enrollment, 43% of patients were on atenolol, 31% on amlodipine and 25.9% on diltiazem. Exercise duration increased by 26% more with ranolazine than placebo (p = 0.01). The increase in exercise duration persisted throughout the 12 weeks of study. Ranolazinetreated patients had no changes in end-exercise or standing heart rates or blood pressures. Commonly reported adverse events were constipation, asthenia, dizziness and nausea. Mean QTc prolongation above placebo was 6.1 ms in the 750-mg twice-daily group and 9.2 ms for the 1,000-mg twice-daily group. None of the patients developed torsades de pointes. The Ranolazine Open Label Experience (ROLE) program [24] enrolled patients after completion of the CARISA and MARISA trials to assess the safety and tolerability of long-term use of ranolazine in patients with severe functional limitations secondary to angina (mean Duke treadmill score: –14.4). A total of 746 patients were followed for an average of 2.82 years. After the 2-year followup, 76.7% remained on therapy; 9.7% discontinued ranolazine due to adverse reactions. There were 68 deaths during the 2,372 patient-years of follow-up, translating into a 2.8% annual mortality. Since a Duke treadmill score of –14.4, as recorded in the patients of the ROLE cohort, predicts an annual mortality of >5%, the results of ROLE suggest that the drug does not reduce survival and, indeed, despite the very modest mean QTc prolongation of 2.4 ms (p < 0.001), none of the patients discontinued the medication secondary to QTc prolongation or developed torsades de pointes. Moreover, despite increasing QTc minimally, ranolazine does not induce early afterdepolarizations or increase spatial dispersion of repolarization [11] and, hence, should not lead to torsades de pointes. The ERICA trial [22] studied the effects of ranolazine versus placebo in patients ≥18 years of age with chronic stable angina pectoris of ≥3 months duration and ≥3 anginal episodes/week on 10 mg of amlodipine daily. This trial randomized 565 patients, 281 to ranolazine and 284 to placebo. The primary efficacy endpoint was the weekly anginal attack frequency during the 6-week period (dosing treatment phase 1,000 mg twice daily). Nitroglycerin consumption per week and the Seattle Angina Questionnaire (SAQ) were used as the secondary efficacy endpoints [25]. Ranolazine reduced the weekly frequency of anginal episodes compared to placebo (2.88 ± 0.19 on ranolazine vs. 3.31 ± 0.22 on placebo; p = 0.028). Weekly
period and it did not affect the fasting glucose levels in the treatment phase (12 weeks). Chisholm et al. [27] analyzed the data from the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes (MERLIN)-TIMI 36 trial, and reported an absolute reduction in HbA1C of 0.28% (95% CI –0.38 to –0.19) in the ranolazine-treated patients with a baseline HbA1C of 6 to 8–10%. The decrease (placebo corrected) in HbA1C with ranolazine was 0.28 and 0.59% in the 6–8 and >8–10 mg/dl groups, respectively. The meta-analysis conducted by Savarese et al. [28] looked at the cumulative data from the CARISA and the MERLIN-TIMI 36 trials and reported an HbA1C decrease of 0.43% (95% CI –0.748 to –0.109; p = 0.009) in the ranolazine-treated groups. Although the exact mechanism of action is unclear, there is evidence from animal models that ranolazine has B cell preservation properties and causes glucose-dependent insulin secretion [29].
Conclusions
There is a paucity of data on the use of ranolazine in treating African Americans, Asians and Hispanics with stable angina pectoris. Future research should also focus on understanding the effects of ranolazine in diabetics and the better efficacy of ranolazine in patients with poorer glycemic control. On the basis of the available data, the authors conclude that ranolazine is an acceptably safe and efficacious anti-anginal therapy in treating patients with persistent stable angina pectoris despite maximum tolerable doses of β-blockers, long-acting nitrates and calcium channel blockers. Ranolazine increases exercise duration, decreases weekly anginal frequency, decreases nitroglycerin use and improves time to angina. It is hemodynamically inert and has a favorable metabolic profile in diabetics. We believe its use should be regularly considered by clinicians caring for patients with angina pectoris due to coronary artery disease.
References
Use of Ranolazine in Patients with Stable Angina Pectoris
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