International Journal of Cardiology 181 (2015) 376–381
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Review
Ranolazine: Drug overview and possible role in primary microvascular angina management☆ Mattia Cattaneo a,⁎, Alessandra Pia Porretta a, Augusto Gallino a,b a b
Cardiovascular Medicine Department, Ospedale Regionale di Bellinzona e Valli-San Giovanni, Bellinzona, Switzerland University of Zürich, Zürich, Switzerland
a r t i c l e
i n f o
Article history: Received 26 November 2014 Accepted 21 December 2014 Available online 23 December 2014 Keywords: Ranolazine Microvascular dysfunction Primary microvascular angina Cardiac X syndrome
a b s t r a c t Ranolazine is a novel well-tolerated anti-ischemic drug, which selectively inhibits late sodium current and exerts metabolic properties without any hemodynamic effect. Ranolazine has been approved as a second-line medical treatment for symptomatic stable coronary artery disease. Primary microvascular angina (MVA) is suspected when angina symptoms occur in patients with demonstrated myocardial ischemia, absence of myocardial disease and normal coronary artery angiography. Recent clinical data suggest that MVA represents a complex entity, which has been increasingly recognized as a significant cause of morbidity. High variability and low response to traditional anti-anginal treatment characterize primary MVA. Despite the fact that clinical and preclinical evidence provides information regarding ranolazine usefulness in primary MVA management, only three recent small randomized trials have investigated this issue. By selecting peer-reviewed literature in Pubmed and Cochrane Library, this review provides an overview on ranolazine pharmacology and efficacy, focusing on recent evidence suggesting its usefulness in management of primary MVA. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Ranolazine is a novel well-tolerated anti-ischemic drug, which selectively inhibits late sodium current, it has metabolic properties and does not exert any hemodynamic effect. Ranolazine has been approved as a second-line medical treatment for symptomatic stable CAD. The annual incidence of chronic stable angina in the USA increases with age and varies with both sex, and ethnic origin, and is much more prevalent than acute myocardial infarction [1]. Microvascular angina (MVA) is a complex entity, which has been increasingly recognized as a significant cause of morbidity, especially in middle-aged post-menopausal women [2,3]. Primary MVA is usually diagnosed when angina symptoms occur in patients with demonstrated myocardial ischemia, absence of heart disease and normal coronary artery angiography [4]. Epidemiological data on microvascular (MVA) angina are missing. Nonetheless, recent clinical data suggest that MVA and vasospastic angina account for up to two-thirds of patients symptomatic for stable angina but without significant coronary stenosis on angiography. MVA prevalence is higher in women [2]. High variability as well as low response to traditional anti-anginal treatment characterize
☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Cardiovascular Medicine Department — Ospedale Regionale di Bellinzona e Valli, San Giovanni (EOC), Via Soleggio, 6500 Bellinzona, Switzerland. E-mail address: [email protected] (M. Cattaneo).
http://dx.doi.org/10.1016/j.ijcard.2014.12.055 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
primary MVA [4,5]. Hence, the quest for further anti-anginal drugs that may be used in addition to standard therapy, either in patients intolerant to first-line agents or in patients with persistent and refractory angina, still represents an open issue. This review provides an overview on ranolazine pharmacology and efficacy focusing on recent evidence regarding its possible usefulness in management of primary MVA. 2. Study selection Relevant peer-reviewed literature was selected in Pubmed and Cochrane Library using terms ‘ranolazine’, ‘microvascular angina’, ‘cardiac syndrome X’, and ‘stable coronary artery disease’. The search was limited to English language publications, without date limitation. Furthermore, European Medicines Agency (EMA) product information papers were included [6]. 3. Clinical pharmacology 3.1. Mechanisms of ischemia Myocardial ischemia is characterized by impaired energy supply to various proteins relevant to the contraction–relaxation cycle of the cardiac myocyte. It results in disruption of intracellular sodium and calcium homoeostasis (Fig. 1). Fast inward sodium current may be altered during ischemia, which enhances late opening of the sodium channel following depolarisation. This is known as late sodium current
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Fig. 1. Disrupted intracellular sodium and calcium homoeostasis during ischemia and suggested ranolazine anti-ischemic action. Energy impairment during ischemia, results in disruption of intracellular sodium and calcium homoeostasis. Enhanced late sodium current (late Ina) which represents a major source for increased intracellular sodium during ischemia by reversing the direction of the Na+–Ca2+ transporter efflux. Consequently, calcium-activate contractile proteins during diastole lead to mechanical dysfunction, augmented energy consumption and increased micro-circulatory resistance, which contribute to energy imbalance in the ischemic myocardium. Ranolazine prevents calcium overload inhibiting late Ina in ischemic cardiac myocytes during cardiac repolarization. As a consequence, ranolazine is thought to exert anti-ischemic and antianginal action by improving the mechanical dysfunction and coronary blood flow without exerting any hemodynamic effect. + means promotion; − means inhibition.
(late Ina) which represents a major source for increased intracellular sodium during ischemia [7]. Similarly, intracellular calcium overload during myocardial ischemia, results from energy lack for active calcium efflux via Na+–Ca2 + exchange. These two mechanisms result in increased intracellular sodium reversing the direction of the Na+–Ca2+ transporter. Consequently, elevated diastolic calcium levels activate contractile proteins even during diastole. Such mechanical dysfunction leads to increased myocardial diastolic tone, augmented energy consumption and increased micro-circulatory resistance, which contribute to further energy balance disruption of the ischemic myocardium [8]. 3.2. Pharmacodynamics Ranolazine is N-(2,6-dimethylphenyl)-4(2-hydroxy-3-[2-methoxyphenoxy]-propyl)-1-piperazine acetamide dihydrochloride. Ranolazine exerts anti-anginal and anti-ischemic effects without consequence on heart rate or blood pressure, but its specific mechanism of action has not yet been fully elucidated (Fig. 1). According to preclinical data, ranolazine inhibits the late phase of the inward sodium channel (late INa) in ischemic cardiac myocytes during cardiac repolarization. It exerts a concentration, voltage and frequency-dependent inhibition of late INa [9]. Reduced intracellular sodium concentration prevents intracellular calcium overload, possibly improving mechanical dysfunction and coronary blood flow [10,11]. In other words, ranolazine is thought to reduce ischemia and subsequent angina symptoms by improving the diastolic function [12], through prevention of intracellular sodium and calcium imbalance. At higher concentrations, ranolazine inhibits the rapid delayed rectifier potassium current (IKr), thus prolonging the QT interval [9]. Furthermore, ranolazine improves glycometabolic homeostasis. Despite the lack of clear evidence, ranolazine has been shown to improve endothelial function in rats enhancing insulin function [13]. Those preclinical data seem to be confirmed by a sub-analysis of the MERLIN-TIMI 36 trial [14] and CARISA trial [15], which demonstrated a significant reduction in HbA1c and recurrent ischemia in patients with diabetes mellitus as well as a reduced progression toward diabetes. Last but not least, recent findings suggest that ranolazine may have
some additional anti-inflammatory or antioxidant effects [16], possibly providing additional explanations to endothelial function improvement in patients with type two diabetes [17] or stable CAD [18]. 3.3. Pharmacokinetics Ranolazine pharmacokinetics is detailed in Table 1. Nonetheless, a few aspects deserve particular attention. Immediate-release (IR) ranolazine was firstly investigated but the short half-life and highly variable interindividual absorption of this formulation led to the development of the currently approved extended-release formulation (ER) [6]. Ranolazine undergoes an extensive hepatic metabolism by the cytochrome P450 (CYP) [6,19]. Age and gender do not influence ranolazine pharmacokinetics, but it should be used with caution in patients ≥75 years of age, related mainly to impaired renal function [6]. 3.4. Tolerability and precautions Data on both short-term [20,21] and long-term [22–24] tolerability demonstrated that ER ranolazine is a well-tolerated drug. Most of the adverse events ranged from mild to moderate severity [6,25]. The most frequent dose-related adverse events (mainly with dose beyond Table 1 Pharmacokinetics characteristics of ranolazine [6,19]. Parameters
Value
Bioavailability
35%–55% Interindividual variability for IR 2–6 h (oral dose) About 3 days About 7 h 6–22 h metabolites with undefined activity P-glycoprotein substrate Extensive hepatic (CYP3A4 ≫ CYP2D6) About 62% Urine (75%) Feces (about 20%) 5–7% as unchanged drug
Peak plasma concentration Steady state Half-life at steady state Metabolism Protein bound Excreted
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1000 mg twice daily and in the elderly) experienced with short-term ranolazine treatment were dizziness, headache, peripheral oedema, constipation, and nausea [20,21,25]. Additional dose-related adverse events experienced with open-label long-term ranolazine treatment account for hypertension, cough and syncope [23]. Ranolazine was also well-tolerated also in NSTEMI acute setting [24]. Few disease concerns exist. Despite being well-tolerated by patients with moderate hepatic or renal impairment, ranolazine plasma levels increase up to 50%–60% in these subgroups [6,25]. For this reason, the drug should be used with caution in patients with renal or hepatic dysfunction and is contraindicated in patients with ≤30 ml/min creatinine clearance or dialyzed and cirrhotic patients (it has not been evaluated in the latter conditions) [6]. 3.5. Arrhythmias As inhibitor of outward repolarizing current, ranolazine contributes to the protraction of the plateau phase, prolonging action potential duration and QT interval by 2–5 ms [9,20]. Nonetheless, ranolazine does not influence further mechanisms increasing the risk of Torsade de pointes [9] as supported by several trials [20–24]. Conversely, latest evidence suggests that ranolazine might reduce ventricular arrhythmias [26] and provide a specific benefit in the management of atrial fibrillation [27].
Ranolazine is a substrate of the P-glycoprotein and undergoes extensive hepatic metabolism by CYP3A4 and to a lesser extent by CYP2D6. Therefore, several interactions exist with cardiovascular drugs, antibiotics, herbal and nutritional products that represent inducers, inhibitors and substrates of the same proteins [6,28] (Table 2). 3.7. Label approval According to the above-mentioned evidence, ranolazine ER has been approved by the European Medicines Agency (EMA) in three different dosages (375–500–750 mg) [6] and by the Food and Drug Administration (FDA) in two different dosages (500–1000 mg) [29], administered independently from meals. Drug administration should comply with the indications displayed in Table 3. The EMA approved ranolazine in 2009 as a potential second-line add-on treatment in stable angina for patients either intolerant to first-line agents or ineffectively controlled by optimal medical therapy with first-line drugs [6,25], irrespective of previous scheduling for percutaneous coronary intervention and according to patient's heart rate, blood pressure and tolerance [25]. On the other hand, ranolazine Table 2 Potential and known ranolazine ER drug interactions [6,28]. Effect on plasma levels of Ranolazine Antifungal agents Aripiprazole Atorvastatin Calcium channel blockers (nondihydropyridine) CYP3A4 inducers CYP2D6 substrates Digoxin Lovastatin Metformin Rifampin Simvastatin Tacrolimus Grapefruit juice
4. Ranolazine efficacy in stable CAD Despite a detailed information on ranolazine ER use in stable CAD is beyond the aim of this review, it is mandatory to provide some key proofs of efficacy and current critical evidence supporting conceivable usefulness of ranolazine in MVA management. Four double-blinded randomized trials (RCT) [20–22,30] and an open-label extension have been published on ranolazine ER in patients with stable angina and one in non-ST-segment elevation myocardial infarction (NSTEMI) [24]. An ongoing angina registry is investigating ranolazine in treating refractory angina [31]. Overall, these studies demonstrated that ranolazine is a well-tolerated agent that reduced angina occurrence, ST-segment changes and increased exercise capacity. Ranolazine improved hard endpoints neither in chronic stable angina nor in acute setting, MERLIN-TIMI 36 RCT [24]. However, double-blind, placebo-controlled studies are still necessary to evaluate the usefulness of ranolazine (ER) in treating patients symptomatic despite optimal doses of triple first-line anti-anginal medications. 5. Ranolazine in primary microvascular angina (cardiac X syndrome) 5.1. Diagnosis of MVA
3.6. Interactions
Interacting drugs
ER is currently not approved for the treatment of different conditions comprising MVA.
Interacting drug
▲ ▲ ▲ ▲ ▼ ▲ ▲ ▲ ▲ ▼ ▲ ▲ ▲
▲ = increased serum concentration; ▼ = decreased serum concentration.
According to a recent classification [32], primary MVA (cardiac syndrome X) is diagnosed by exclusion, when angina occurs in patient with demonstrated myocardial ischemia, in the absence of myocardial disease and significant coronary artery obstruction on angiography. This definition comprises uncomplicated hypertension, diabetes mellitus and hypercholesterolemia of which coronary microvascular dysfunction (CMVD) may represent the microvascular manifestation [4,32]. CMVD has been suggested to be implicated in the pathogenesis of primary MVA and represents a complex entity that can be classified on the basis of the clinical setting in which it is diagnosed [32]. 5.2. Prognosis and management Long-term prognosis of patients with stable primary MVA has been demonstrated to be similar to the general population [33,34]. Nonetheless, patients often present with persistent or worsening angina symptoms (20% to 30% of patients), which significantly impair quality of life (QoL). No evidence based guidelines exist for the treatment of primary MVA, but the empiric approach may be implemented [4,5], taking into account the high variability in patient relief [25]. First-line treatment relies on standard anti-anginal drugs but symptom control is often scarce. Several second-line drugs have been suggested and among them ranolazine. 5.3. Ranolazine and CMVD-related ischemia Pathophysiological mechanisms of primary MVA are likely to be multiple, accounting for the great heterogeneity of MVA patients. This subsequently encompasses different clinical implications and individualized diagnostic and therapeutic approaches. In several previous studies, heterogeneous inclusion criteria may have represented an important bias, leading to conflicting results on management of MVA [4,35]. Despite high variability in primary MVA patients' responses to treatment, clinical and preclinical evidence provides information regarding ranolazine possible usefulness in primary MVA management (Table 4). Among causal mechanisms implied in MVA, CMVD seems to play a pivotal role [2]. The relation between CMVD and myocardial ischemia remains controversial since several studies failed to demonstrate
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Table 3 FDA and EMA approval for ranolazine administration.
EMA [6] FDA [29]
Starting dose
Up-titration
Maximum dose
Down titration-titration
375 mg Twice daily 500 mg Twice daily
Every 2–4 weeks
750 mg Twice daily 1000 mg Twice daily
Treatment-related adverse events
No time schedule
myocardial ischemia in patients with MVA. However, a potential explanation may be represented by CMVD patchy distribution in the myocardium [36]. Moreover, several studies demonstrated CMVD in patients with stable primary MVA, as the result of different functional alterations in coronary microcirculation [4,5]. Importantly, recent findings suggest that ranolazine may have some additional anti-inflammatory or antioxidant effects [16] that may improve endothelial function in different clinical settings [17,18]. Besides, other studies reported increased insulin resistance as a potential cause of CMVD, prompting endothelial dysfunction [37] and ranolazine improves glycometabolic homeostasis [14,15]. Moreover, ranolazine might diminish mechanical compression of microcirculation by improving mechanical dysfunction resulting in reduced micro-circulatory resistance [10,11]. Primary MVA affects mostly middle-aged and post-menopausal women. Despite the fact that ranolazine was thought to have reduced efficacy in female patients, a review of the three main trials on ranolazine, found no difference in angina symptoms and exercise stress test (EST) ECG changes between male and female patients [38].
5.4. Ranolazine in primary MVA: current evidence Ranolazine did not improve hard endpoint in CAD, but none of the first-line anti-anginal agents has been proved so, and patients with stable primary MVA have excellent long-term prognosis despite impaired QoL due to frequent persistent or worsening symptoms [34]. Thus, the main aim of the therapy is to reduce symptoms. Only three recent studies specifically investigated ranolazine in primary stable MVA setting, applying different inclusion criteria and protocols (Table 5). The study by Mehta et al. [39] was a pilot randomized, placebocontrolled, crossover trial. Inclusion criteria were satisfied in the case of angina symptoms, absence of angiographic obstructive CAD and ≥10 percentage ischemic myocardium on adenosine stress cardiac magnetic resonance (CMR) imaging. Twenty women were assigned to ranolazine (500 mg orally twice daily for 2 weeks and further increased to 1000 mg twice daily as tolerated) or placebo groups for 4 weeks. The study assessed both clinical and imaging endpoints at the end of each 4-week period. All participants underwent two validated selfadministered health history questionnaires: the Seattle Angina Questionnaire (SAQ) [40] and the Duke Activity Status Index (DASI) [41] evaluating respectively angina changes and functional capacity. Additionally, CMR-derived myocardial perfusion reserve index (MPRI) [39] was semi-quantitatively and quantitatively measured. Patients assigned to ranolazine had significantly higher (three of five) SAQ, including physical functioning (p 0.046), angina stability (p 0.008) and quality of life (p 0.021). No significant difference in DASI questionnaire and only a trend toward a higher mid-ventricular MPRI were found in Table 4 Possible role of ranolazine in the management of primary MVA. MVA pathogenetic factor
Action of ranolazine
Conceivably an ischemic disease Microvascular dysfunction Endothelial dysfunction
Anti-ischemic drug [20–22,24,30] Reduce mechanical dysfunction [10–12] Anti-inflammatory or antioxidant effects [16] May improve endothelial function [17,18] Improve glycometabolic control [14,15]
Glucose intolerance
=
ranolazine group. Nonetheless, among women treated with ranolazine and undergoing clinically indicated invasive coronary reactivity testing (CRT) (n 13), the subgroup with lower coronary flow reserve (CFR) presented a significant MPRI improvement compared to women with higher CFR values (Δ in MPRI placebo/ranolazine: 0.48 vs. − 0.82, p 0.04). Certainly, it has to be considered that cross-over design may have produced carry-over effects, reducing anyway the impact of different usual therapies on which ranolazine was added. The second study by Villano et al. [42] was a randomized, doubleblind trial. Patients with stable primary MVA according to previous criteria [4,32] and suboptimal angina control on first-line anti-anginal drugs were enrolled. Patients were randomized to receive ivabradine 5 mg twice daily, or ranolazine 375 mg twice daily, or placebo twice daily for a 4-week period. Participants underwent two validated selfadministered health history questionnaires to evaluate primary clinical endpoints: the SAQ and the EuroQoL, a visual analogic scale assessing QoL [43]. Also functional endpoints were evaluated including: change in maximal symptom/sign-limited EST; non-invasively assessed change in coronary blood flow response to different vasoconstrictors; noninvasively assessed change in peripheral flow-mediated and nitratemediated vasodilation. Both drugs improved SAQ items and EuroQoL scale compared with placebo (p b 0.01) and ranolazine group showed higher results for 4 of 5 SAQ items and for the EuroQoL (p b 0.01) compared to ivabradine even after correction for basal values. EST functional results did not differ among groups. Nevertheless, ECG differences in ST-segment depression were found, with ranolazine showing the best results. No significant differences in endothelial function were present despite a trend toward improvement in flow-mediated dilation. The last study by Tagliamonte et al. [44] is a randomized, placebocontrolled trial. Patients with symptomatic for angina pectoris with myocardial ischemia demonstrated by Tc-99m MIBI myocardial perfusion imaging in the absence of obstructive CAD were enrolled in the study. Patients were randomized to ranolazine 350 mg orally twice a day for 4 weeks with up-titration to 500 mg twice a day for an additional 4 weeks. Coronary flow reserve (CFR), as a marker of microvascular dysfunction, was non-invasively measured using the spectral Doppler signals in the left anterior descending coronary artery (LAD) using dipyridamole test. CFR was assessed before treatment period and at the end of it. Also clinical endpoint was assessed by SAQ. Patients assigned to ranolazine had significantly higher (4 of 5) SAQ results (p b 0.01) and significant improvement in baseline diastolic flow velocity, hyperemic diastolic flow velocity and coronary flow reserve (p b 0.01). Certainly, two aspects represent a certain bias. CFR was assessed only in the LAD territory and some patients with left ventricle hypertrophy were included in the study, thus not completely fulfilling primary MVA diagnostic criteria. In conclusion, although small sample size and short follow-up periods may represent a limitation and bias, these studies suggest ranolazine efficacy, safety and tolerability in primary MVA.
5.5. Ranolazine in primary MVA: perspectives Despite small sample size and short follow-up period, clinical evidence seems to support findings from preclinical studies and provides a first scientific bearing to ranolazine usefulness in primary MVA management. So far, a few single-center randomized trials are ongoing [45].
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Table 5 Study investigating ranolazine ER in stable primary MVA (Cardiac syndrome X). N
Ranolazine dosage
Study design
Inclusion criteria
Anti-anginal Follow-up drugs
• Suboptimal angina control • ≥10% ischemic myocardium on adenosine CMR imaging
Not withdrawn
Mehta et al. [39]
20 500 mg, 1000 mg twice daily
Double-blind Placebo-controlled Crossover
Villano et al. [42]
46 375 mg twice daily
Double-blind • Suboptimal angina Placebo and ivabradine control 5 mg twice daily — • Objective evidence of controlled induced ischemia
Not withdrawn
• Suboptimal angina control • Objective evidence of induced ischemia Tc-99 m MIBI
Not withdrawn
Tagliamonte 58 Ranolazine 350 mg [44]a twice daily
Double-blind Placebo-controlled
Clinical endpoints
Functional endpoint
Change in SAQ • Semiquantitative and quantitative measured week-periods, and DASI questionnaires MPRI on CMR imaging 2-week score • Change in MPRI on CMR washout imaging according to CRT score 4 weeks Change in SAQ • Change in symptom and/or and EuroQoL sign-limited EST questionnaires • CBF response to adenosine score and cold pressor test • Peripheral FMD and NM dilation 8 weeks Change in SAQ Changes in transthoracic Doppler-derived CFR 4
Dropout for side effects None
None
None
CBF = coronary blood flow; EST = exercise stress test; FMD = flow-mediated dilation; NM = nitrate-mediated dilation. a Some patients do not fulfill primary MVA criteria (left ventricle hypertrophy).
New multicentre randomized controlled trials should be implemented in order to further endorse the efficacy of ranolazine among patients affected by primary MVA. 6. Conclusions Ranolazine is a novel anti-anginal drug not affecting hemodynamic parameters, approved as a second-line treatment for stable angina. Indeed, it has been demonstrated to be a safe, well-tolerated agent able to reduce angina occurrence as well as ST-segment changes and increase exercise capacity. Primary MVA is a disorder affecting mainly woman, possibly related to MVCD, which may result from different pathogenetic mechanisms including endothelial dysfunction and impaired glucose homeostasis. Despite high variability in primary MVA patients' response to treatment, small sample size and short follow-up period, clinical and preclinical evidence provided a first scientific bearing to ranolazine possible usefulness in primary MVA management. However, new randomized controlled trials should be implemented in order to further endorse the efficacy of ranolazine among patients affected by primary MVA. Conflict of interest No authors' conflicts of interest and relationship with industry exist for the work under consideration for publication. Acknowledgments None. References [1] A.S. Go, D. Mozaffarian, V.L. Roger, E.J. Benjamin, J.D. Berry, M.J. Blaha, et al., Heart disease and stroke statistics—2014 update: a report from the American Heart Association, Circulation 129 (2014) e28–e292. [2] S.E. Reis, R. Holubkov, A.J. Conrad Smith, S.F. Kelsey, B.L. Sharaf, N. Reichek, et al., Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study, Am. Heart J. 141 (2001) 735–741. [3] H.M. Arthur, P. Campbell, P.J. Harvey, M. McGillion, P. Oh, E. Woodburn, et al., Women, cardiac syndrome X, and microvascular heart disease, Can. J. Cardiol. 28 (2 Suppl.) (2012) S42–S49. [4] G.A. Lanza, F. Crea, Primary coronary microvascular dysfunction: clinical presentation, pathophysiology, and management, Circulation 121 (2010) 2317–2325. [5] G.A. Lanza, R. Parrinello, S. Figliozzi, Management of microvascular angina pectoris, Am. J. Cardiovasc. Drugs 14 (2014) 31–40.
[6] European Medicines Agency, Ranexa (Ranolazine): EU Summary of Product CharacteristicsAvailable at: http://www.ema.europa.eu/ema/index.jsp?curl= pages/medicines/human/medicines/000805/human_med_001009.jsp&mid= WC0b01ac058001d124July 2014. [7] Y.K. Ju, D.A. Saint, P.W. Gage, Hypoxia increases persistent sodium current in rat ventricular myocytes, J. Physiol. 497 (Pt 2) (1996) 337–347. [8] M. Meyer, B. Keweloh, K. Guth, J.W. Holmes, B. Pieske, S.E. Lehnart, et al., Frequencydependence of myocardial energetics in failing human myocardium as quantified by a new method for the measurement of oxygen consumption in muscle strip preparations, J. Mol. Cell. Cardiol. 30 (1998) 1459–1470. [9] C. Antzelevitch, L. Belardinelli, A.C. Zygmunt, A. Burashnikov, J.M. Di Diego, J.M. Fish, et al., Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties, Circulation 110 (2004) 904–910. [10] H. Fraser, L. Belardinelli, L. Wang, P.E. Light, J.J. McVeigh, A.S. Clanachan, Ranolazine decreases diastolic calcium accumulation caused by ATX-II or ischemia in rat hearts, J. Mol. Cell. Cardiol. 41 (2006) 1031–1038. [11] R. Venkataraman, L. Belardinelli, B. Blackburn, J. Heo, A.E. Iskandrian, A study of the effects of ranolazine using automated quantitative analysis of serial myocardial perfusion images, JACC Cardiovasc. Imaging 2 (2009) 1301–1309. [12] W. Hayashida, C. van Eyll, M.F. Rousseau, H. Pouleur, Effects of ranolazine on left ventricular regional diastolic function in patients with ischemic heart disease, Cardiovasc. Drugs Ther. 8 (1994) 741–747. [13] Z. Fu, L. Zhao, W. Chai, Z. Dong, W. Cao, Z. Liu, Ranolazine recruits muscle microvasculature and enhances insulin action in rats, J. Physiol. 591 (2013) 5235–5249. [14] D.A. Morrow, B.M. Scirica, B.R. Chaitman, D.K. McGuire, S.A. Murphy, E. Karwatowska-Prokopczuk, et al., Evaluation of the glycometabolic effects of ranolazine in patients with and without diabetes mellitus in the MERLIN-TIMI 36 randomized controlled trial, Circulation 119 (2009) 2032–2039. [15] A.D. Timmis, B.R. Chaitman, M. Crager, Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes, Eur. Heart J. 27 (2006) 42–48. [16] M. Aldakkak, A.K. Camara, J.S. Heisner, M. Yang, D.F. Stowe, Anolazine reduces Ca2+ overload and oxidative stress and improves mitochondrial integrity to protect against ischemia reperfusion injury in isolated hearts, Pharmacol. Res. 64 (2011) 381–392. [17] P. Lamendola, R. Nerla, D. Pitocco, A. Villano, G. Scavone, A. Stazi, et al., Effect of ranolazine on arterial endothelial function in patients with type 2 diabetes mellitus, Atherosclerosis 226 (2013) 157–160. [18] S.H. Deshmukh, S.R. Patel, E. Pinassi, C. Mindrescu, E.V. Hermance, M.N. Infantino, et al., Ranolazine improves endothelial function in patients with stable coronary artery disease, Coron. Artery Dis. 20 (2009) 343–347. [19] M. Jerling, Clinical pharmacokinetics of ranolazine, Clin. Pharmacokinet. 45 (2006) 469–491. [20] B.R. Chaitman, C.J. Pepine, J.O. Parker, J. Skopal, G. Chumakova, J. Kuch, 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, JAMA 291 (2004) 309–316. [21] P.H. Stone, N.A. Gratsiansky, A. Blokhin, I.Z. Huang, L. Meng, Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial, J. Am. Coll. Cardiol. 48 (2006) 566–575. [22] B.R. Chaitman, S.L. Skettino, J.O. Parker, P. Hanley, J. Meluzin, J. Kuch, et al., Antiischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina, J. Am. Coll. Cardiol. 43 (2004) 1375–1382. [23] M.J. Koren, M.R. Crager, M. Sweeney, Long-term safety of a novel antianginal agent in patients with severe chronic stable angina: the Ranolazine Open Label Experience (ROLE), J. Am. Coll. Cardiol. 9 (2007) 1027–1034.
M. Cattaneo et al. / International Journal of Cardiology 181 (2015) 376–381 [24] D.A. Morrow, B.M. Scirica, E. Karwatowska-Prokopczuk, S.A. Murphy, A. Budaj, S. Varshavsky, 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 297 (2007) 1775–1783. [25] G. Montalescot, U. Sechtem, S. Achenbach, F. Andreotti, C. Arden, A. Budaj, et al., 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology, Eur. Heart J. 34 (2013) 2949–3003. [26] B.M. Scirica, D.A. Morrow, H. Hod, S.A. Murphy, L. Belardinelli, C.M. Hedgepeth, et al., Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the Metabolic Efficiency With Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial, Circulation 116 (2007) 1647–1652. [27] S. Sossalla, L.S. Maier, Role of ranolazine in angina, heart failure, arrhythmias, and diabetes, Pharmacol. Ther. 133 (2012) 311–323. [28] M. Jerling, B.L. Huan, K. Leung, N. Chu, H. Abdallah, Z. Hussein, Studies to investigate the pharmacokinetic interactions between ranolazine and ketoconazole, diltiazem, or simvastatin during combined administration in healthy subjects, J. Clin. Pharmacol. 45 (2005) 422–433. [29] Food and Drug Administration, FDA Approved Drug Products: Ranexa (Ranolazine), December 2013Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ index.cfm?fuseaction=Search.DrugDetailsOctober 2014. [30] M.F. Rousseau, H. Pouleur, G. Cocco, A.A. Wolff, Comparative efficacy of ranolazine versus atenolol for chronic angina pectoris, Am. J. Cardiol. 95 (2005) 311–316. [31] N.M. Bennett, T.L. Arndt, V. Iyer, R.F. Garberich, J.H. Traverse, K. Johnson Randall, et al., Ranolazine refractory angina registry trial: 1-year results, J. Am. Coll. Cardiol. 57 (14s1) (2011) E1050. [32] P.G. Camici, F. Crea, Coronary microvascular dysfunction, N. Engl. J. Med. 356 (2007) 830–840. [33] J.C. Kaski, G.M. Rosano, P. Collins, P. Nihoyannopoulos, A. Maseri, P.A. Poole-Wilson, Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study, J. Am. Coll. Cardiol. 25 (1995) 807–814.
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[34] P. Lamendola, G.A. Lanza, A. Spinelli, G.A. Sgueglia, A. Di Monaco, L. Barone, et al., Long-term prognosis of patients with cardiac syndrome X, Int. J. Cardiol. 140 (2010) 197–199. [35] R.O. Cannon, P.G. Camici III, S.E. Epstein, Pathophysiological dilemma of syndrome X, Circulation 85 (1992) 883–892. [36] A. Maseri, F. Crea, J.C. Kaski, T. Crake, Mechanisms of angina pectoris in syndrome X, J. Am. Coll. Cardiol. 17 (1991) 499–506. [37] H.E. Botker, N. Moller, P. Ovesen, A. Mengel, O. Schmitz, H. Orskov, et al., Insulin resistance in microvascular angina (syndrome X), Lancet 342 (1993) 136–140. [38] N.K. Wenger, B. Chaitman, G.W. Vetrovec, Gender comparison of efficacy and safety of ranolazine for chronic angina pectoris in four randomized clinical trials, Am. J. Cardiol. 99 (2007) 11–18. [39] P.K. Mehta, P. Goykhman, L.E. Thomson, C. Shufelt, J. Wei, Y. Yang, et al., Ranolazine improves angina in women with evidence of myocardial ischemia but no obstructive coronary artery disease, JACC Cardiovasc. Imaging 4 (2011) 514–522. [40] J.A. Spertus, J.A. Winder, T.A. Dewhurst, R.A. Deyo, J. Prodzinski, M. McDonell, et al., Development and evaluation of the Seattle Angina Questionnaire: a new functional status measure for coronary artery disease, J. Am. Coll. Cardiol. 25 (1995) 333–341. [41] M.A. Hlatky, R.E. Boineau, M.B. Higginbotham, K.L. Lee, D.B. Mark, R.M. Califf, et al., A brief self-administered questionnaire to determine functional capacity (the Duke Activity Status Index), Am. J. Cardiol. 64 (1989) 651–654. [42] A. Villano, A. Di Franco, R. Nerla, A. Sestito, P. Tarzia, P. Lamendola, et al., Effects of ivabradine and ranolazine in patients with microvascular angina pectoris, Am. J. Cardiol. 112 (2013) 8–13. [43] EuroQol—a new facility for the measurement of health-related quality of life, Health Policy 16 (1990) 199–208. [44] E. Tagliamonte, F. Rigo, T. Cirillo, C. Astarita, G. Quaranta, U. Marinelli, et al., Effects of ranolazine on noninvasive coronary flow reserve in patients with myocardial ischemia but without obstructive coronary artery disease, Echocardiography (2014). http://dx.doi.org/10.1111/echo.12674 (Epub ahead of print). [45] ClinicalTrials.gov: Registered TrialsAvailable at: https://clinicaltrials.gov/ct2/ results?term=microvascular+angina&recr=Open&rslt=&type=&cond=&intr= ranolazine&titles=&outc=&spons=&lead=&id=&state1=&cntry1=&state2= &cntry2=&state3=&cntry3=&locn=&gndr=&rcv_s=&rcv_e=&lup_s=&lup_e= November 2014.
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Review
Ranolazine: Drug overview and possible role in primary microvascular angina management☆ Mattia Cattaneo a,⁎, Alessandra Pia Porretta a, Augusto Gallino a,b a b
Cardiovascular Medicine Department, Ospedale Regionale di Bellinzona e Valli-San Giovanni, Bellinzona, Switzerland University of Zürich, Zürich, Switzerland
a r t i c l e
i n f o
Article history: Received 26 November 2014 Accepted 21 December 2014 Available online 23 December 2014 Keywords: Ranolazine Microvascular dysfunction Primary microvascular angina Cardiac X syndrome
a b s t r a c t Ranolazine is a novel well-tolerated anti-ischemic drug, which selectively inhibits late sodium current and exerts metabolic properties without any hemodynamic effect. Ranolazine has been approved as a second-line medical treatment for symptomatic stable coronary artery disease. Primary microvascular angina (MVA) is suspected when angina symptoms occur in patients with demonstrated myocardial ischemia, absence of myocardial disease and normal coronary artery angiography. Recent clinical data suggest that MVA represents a complex entity, which has been increasingly recognized as a significant cause of morbidity. High variability and low response to traditional anti-anginal treatment characterize primary MVA. Despite the fact that clinical and preclinical evidence provides information regarding ranolazine usefulness in primary MVA management, only three recent small randomized trials have investigated this issue. By selecting peer-reviewed literature in Pubmed and Cochrane Library, this review provides an overview on ranolazine pharmacology and efficacy, focusing on recent evidence suggesting its usefulness in management of primary MVA. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Ranolazine is a novel well-tolerated anti-ischemic drug, which selectively inhibits late sodium current, it has metabolic properties and does not exert any hemodynamic effect. Ranolazine has been approved as a second-line medical treatment for symptomatic stable CAD. The annual incidence of chronic stable angina in the USA increases with age and varies with both sex, and ethnic origin, and is much more prevalent than acute myocardial infarction [1]. Microvascular angina (MVA) is a complex entity, which has been increasingly recognized as a significant cause of morbidity, especially in middle-aged post-menopausal women [2,3]. Primary MVA is usually diagnosed when angina symptoms occur in patients with demonstrated myocardial ischemia, absence of heart disease and normal coronary artery angiography [4]. Epidemiological data on microvascular (MVA) angina are missing. Nonetheless, recent clinical data suggest that MVA and vasospastic angina account for up to two-thirds of patients symptomatic for stable angina but without significant coronary stenosis on angiography. MVA prevalence is higher in women [2]. High variability as well as low response to traditional anti-anginal treatment characterize
☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Cardiovascular Medicine Department — Ospedale Regionale di Bellinzona e Valli, San Giovanni (EOC), Via Soleggio, 6500 Bellinzona, Switzerland. E-mail address: [email protected] (M. Cattaneo).
http://dx.doi.org/10.1016/j.ijcard.2014.12.055 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
primary MVA [4,5]. Hence, the quest for further anti-anginal drugs that may be used in addition to standard therapy, either in patients intolerant to first-line agents or in patients with persistent and refractory angina, still represents an open issue. This review provides an overview on ranolazine pharmacology and efficacy focusing on recent evidence regarding its possible usefulness in management of primary MVA. 2. Study selection Relevant peer-reviewed literature was selected in Pubmed and Cochrane Library using terms ‘ranolazine’, ‘microvascular angina’, ‘cardiac syndrome X’, and ‘stable coronary artery disease’. The search was limited to English language publications, without date limitation. Furthermore, European Medicines Agency (EMA) product information papers were included [6]. 3. Clinical pharmacology 3.1. Mechanisms of ischemia Myocardial ischemia is characterized by impaired energy supply to various proteins relevant to the contraction–relaxation cycle of the cardiac myocyte. It results in disruption of intracellular sodium and calcium homoeostasis (Fig. 1). Fast inward sodium current may be altered during ischemia, which enhances late opening of the sodium channel following depolarisation. This is known as late sodium current
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Fig. 1. Disrupted intracellular sodium and calcium homoeostasis during ischemia and suggested ranolazine anti-ischemic action. Energy impairment during ischemia, results in disruption of intracellular sodium and calcium homoeostasis. Enhanced late sodium current (late Ina) which represents a major source for increased intracellular sodium during ischemia by reversing the direction of the Na+–Ca2+ transporter efflux. Consequently, calcium-activate contractile proteins during diastole lead to mechanical dysfunction, augmented energy consumption and increased micro-circulatory resistance, which contribute to energy imbalance in the ischemic myocardium. Ranolazine prevents calcium overload inhibiting late Ina in ischemic cardiac myocytes during cardiac repolarization. As a consequence, ranolazine is thought to exert anti-ischemic and antianginal action by improving the mechanical dysfunction and coronary blood flow without exerting any hemodynamic effect. + means promotion; − means inhibition.
(late Ina) which represents a major source for increased intracellular sodium during ischemia [7]. Similarly, intracellular calcium overload during myocardial ischemia, results from energy lack for active calcium efflux via Na+–Ca2 + exchange. These two mechanisms result in increased intracellular sodium reversing the direction of the Na+–Ca2+ transporter. Consequently, elevated diastolic calcium levels activate contractile proteins even during diastole. Such mechanical dysfunction leads to increased myocardial diastolic tone, augmented energy consumption and increased micro-circulatory resistance, which contribute to further energy balance disruption of the ischemic myocardium [8]. 3.2. Pharmacodynamics Ranolazine is N-(2,6-dimethylphenyl)-4(2-hydroxy-3-[2-methoxyphenoxy]-propyl)-1-piperazine acetamide dihydrochloride. Ranolazine exerts anti-anginal and anti-ischemic effects without consequence on heart rate or blood pressure, but its specific mechanism of action has not yet been fully elucidated (Fig. 1). According to preclinical data, ranolazine inhibits the late phase of the inward sodium channel (late INa) in ischemic cardiac myocytes during cardiac repolarization. It exerts a concentration, voltage and frequency-dependent inhibition of late INa [9]. Reduced intracellular sodium concentration prevents intracellular calcium overload, possibly improving mechanical dysfunction and coronary blood flow [10,11]. In other words, ranolazine is thought to reduce ischemia and subsequent angina symptoms by improving the diastolic function [12], through prevention of intracellular sodium and calcium imbalance. At higher concentrations, ranolazine inhibits the rapid delayed rectifier potassium current (IKr), thus prolonging the QT interval [9]. Furthermore, ranolazine improves glycometabolic homeostasis. Despite the lack of clear evidence, ranolazine has been shown to improve endothelial function in rats enhancing insulin function [13]. Those preclinical data seem to be confirmed by a sub-analysis of the MERLIN-TIMI 36 trial [14] and CARISA trial [15], which demonstrated a significant reduction in HbA1c and recurrent ischemia in patients with diabetes mellitus as well as a reduced progression toward diabetes. Last but not least, recent findings suggest that ranolazine may have
some additional anti-inflammatory or antioxidant effects [16], possibly providing additional explanations to endothelial function improvement in patients with type two diabetes [17] or stable CAD [18]. 3.3. Pharmacokinetics Ranolazine pharmacokinetics is detailed in Table 1. Nonetheless, a few aspects deserve particular attention. Immediate-release (IR) ranolazine was firstly investigated but the short half-life and highly variable interindividual absorption of this formulation led to the development of the currently approved extended-release formulation (ER) [6]. Ranolazine undergoes an extensive hepatic metabolism by the cytochrome P450 (CYP) [6,19]. Age and gender do not influence ranolazine pharmacokinetics, but it should be used with caution in patients ≥75 years of age, related mainly to impaired renal function [6]. 3.4. Tolerability and precautions Data on both short-term [20,21] and long-term [22–24] tolerability demonstrated that ER ranolazine is a well-tolerated drug. Most of the adverse events ranged from mild to moderate severity [6,25]. The most frequent dose-related adverse events (mainly with dose beyond Table 1 Pharmacokinetics characteristics of ranolazine [6,19]. Parameters
Value
Bioavailability
35%–55% Interindividual variability for IR 2–6 h (oral dose) About 3 days About 7 h 6–22 h metabolites with undefined activity P-glycoprotein substrate Extensive hepatic (CYP3A4 ≫ CYP2D6) About 62% Urine (75%) Feces (about 20%) 5–7% as unchanged drug
Peak plasma concentration Steady state Half-life at steady state Metabolism Protein bound Excreted
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1000 mg twice daily and in the elderly) experienced with short-term ranolazine treatment were dizziness, headache, peripheral oedema, constipation, and nausea [20,21,25]. Additional dose-related adverse events experienced with open-label long-term ranolazine treatment account for hypertension, cough and syncope [23]. Ranolazine was also well-tolerated also in NSTEMI acute setting [24]. Few disease concerns exist. Despite being well-tolerated by patients with moderate hepatic or renal impairment, ranolazine plasma levels increase up to 50%–60% in these subgroups [6,25]. For this reason, the drug should be used with caution in patients with renal or hepatic dysfunction and is contraindicated in patients with ≤30 ml/min creatinine clearance or dialyzed and cirrhotic patients (it has not been evaluated in the latter conditions) [6]. 3.5. Arrhythmias As inhibitor of outward repolarizing current, ranolazine contributes to the protraction of the plateau phase, prolonging action potential duration and QT interval by 2–5 ms [9,20]. Nonetheless, ranolazine does not influence further mechanisms increasing the risk of Torsade de pointes [9] as supported by several trials [20–24]. Conversely, latest evidence suggests that ranolazine might reduce ventricular arrhythmias [26] and provide a specific benefit in the management of atrial fibrillation [27].
Ranolazine is a substrate of the P-glycoprotein and undergoes extensive hepatic metabolism by CYP3A4 and to a lesser extent by CYP2D6. Therefore, several interactions exist with cardiovascular drugs, antibiotics, herbal and nutritional products that represent inducers, inhibitors and substrates of the same proteins [6,28] (Table 2). 3.7. Label approval According to the above-mentioned evidence, ranolazine ER has been approved by the European Medicines Agency (EMA) in three different dosages (375–500–750 mg) [6] and by the Food and Drug Administration (FDA) in two different dosages (500–1000 mg) [29], administered independently from meals. Drug administration should comply with the indications displayed in Table 3. The EMA approved ranolazine in 2009 as a potential second-line add-on treatment in stable angina for patients either intolerant to first-line agents or ineffectively controlled by optimal medical therapy with first-line drugs [6,25], irrespective of previous scheduling for percutaneous coronary intervention and according to patient's heart rate, blood pressure and tolerance [25]. On the other hand, ranolazine Table 2 Potential and known ranolazine ER drug interactions [6,28]. Effect on plasma levels of Ranolazine Antifungal agents Aripiprazole Atorvastatin Calcium channel blockers (nondihydropyridine) CYP3A4 inducers CYP2D6 substrates Digoxin Lovastatin Metformin Rifampin Simvastatin Tacrolimus Grapefruit juice
4. Ranolazine efficacy in stable CAD Despite a detailed information on ranolazine ER use in stable CAD is beyond the aim of this review, it is mandatory to provide some key proofs of efficacy and current critical evidence supporting conceivable usefulness of ranolazine in MVA management. Four double-blinded randomized trials (RCT) [20–22,30] and an open-label extension have been published on ranolazine ER in patients with stable angina and one in non-ST-segment elevation myocardial infarction (NSTEMI) [24]. An ongoing angina registry is investigating ranolazine in treating refractory angina [31]. Overall, these studies demonstrated that ranolazine is a well-tolerated agent that reduced angina occurrence, ST-segment changes and increased exercise capacity. Ranolazine improved hard endpoints neither in chronic stable angina nor in acute setting, MERLIN-TIMI 36 RCT [24]. However, double-blind, placebo-controlled studies are still necessary to evaluate the usefulness of ranolazine (ER) in treating patients symptomatic despite optimal doses of triple first-line anti-anginal medications. 5. Ranolazine in primary microvascular angina (cardiac X syndrome) 5.1. Diagnosis of MVA
3.6. Interactions
Interacting drugs
ER is currently not approved for the treatment of different conditions comprising MVA.
Interacting drug
▲ ▲ ▲ ▲ ▼ ▲ ▲ ▲ ▲ ▼ ▲ ▲ ▲
▲ = increased serum concentration; ▼ = decreased serum concentration.
According to a recent classification [32], primary MVA (cardiac syndrome X) is diagnosed by exclusion, when angina occurs in patient with demonstrated myocardial ischemia, in the absence of myocardial disease and significant coronary artery obstruction on angiography. This definition comprises uncomplicated hypertension, diabetes mellitus and hypercholesterolemia of which coronary microvascular dysfunction (CMVD) may represent the microvascular manifestation [4,32]. CMVD has been suggested to be implicated in the pathogenesis of primary MVA and represents a complex entity that can be classified on the basis of the clinical setting in which it is diagnosed [32]. 5.2. Prognosis and management Long-term prognosis of patients with stable primary MVA has been demonstrated to be similar to the general population [33,34]. Nonetheless, patients often present with persistent or worsening angina symptoms (20% to 30% of patients), which significantly impair quality of life (QoL). No evidence based guidelines exist for the treatment of primary MVA, but the empiric approach may be implemented [4,5], taking into account the high variability in patient relief [25]. First-line treatment relies on standard anti-anginal drugs but symptom control is often scarce. Several second-line drugs have been suggested and among them ranolazine. 5.3. Ranolazine and CMVD-related ischemia Pathophysiological mechanisms of primary MVA are likely to be multiple, accounting for the great heterogeneity of MVA patients. This subsequently encompasses different clinical implications and individualized diagnostic and therapeutic approaches. In several previous studies, heterogeneous inclusion criteria may have represented an important bias, leading to conflicting results on management of MVA [4,35]. Despite high variability in primary MVA patients' responses to treatment, clinical and preclinical evidence provides information regarding ranolazine possible usefulness in primary MVA management (Table 4). Among causal mechanisms implied in MVA, CMVD seems to play a pivotal role [2]. The relation between CMVD and myocardial ischemia remains controversial since several studies failed to demonstrate
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Table 3 FDA and EMA approval for ranolazine administration.
EMA [6] FDA [29]
Starting dose
Up-titration
Maximum dose
Down titration-titration
375 mg Twice daily 500 mg Twice daily
Every 2–4 weeks
750 mg Twice daily 1000 mg Twice daily
Treatment-related adverse events
No time schedule
myocardial ischemia in patients with MVA. However, a potential explanation may be represented by CMVD patchy distribution in the myocardium [36]. Moreover, several studies demonstrated CMVD in patients with stable primary MVA, as the result of different functional alterations in coronary microcirculation [4,5]. Importantly, recent findings suggest that ranolazine may have some additional anti-inflammatory or antioxidant effects [16] that may improve endothelial function in different clinical settings [17,18]. Besides, other studies reported increased insulin resistance as a potential cause of CMVD, prompting endothelial dysfunction [37] and ranolazine improves glycometabolic homeostasis [14,15]. Moreover, ranolazine might diminish mechanical compression of microcirculation by improving mechanical dysfunction resulting in reduced micro-circulatory resistance [10,11]. Primary MVA affects mostly middle-aged and post-menopausal women. Despite the fact that ranolazine was thought to have reduced efficacy in female patients, a review of the three main trials on ranolazine, found no difference in angina symptoms and exercise stress test (EST) ECG changes between male and female patients [38].
5.4. Ranolazine in primary MVA: current evidence Ranolazine did not improve hard endpoint in CAD, but none of the first-line anti-anginal agents has been proved so, and patients with stable primary MVA have excellent long-term prognosis despite impaired QoL due to frequent persistent or worsening symptoms [34]. Thus, the main aim of the therapy is to reduce symptoms. Only three recent studies specifically investigated ranolazine in primary stable MVA setting, applying different inclusion criteria and protocols (Table 5). The study by Mehta et al. [39] was a pilot randomized, placebocontrolled, crossover trial. Inclusion criteria were satisfied in the case of angina symptoms, absence of angiographic obstructive CAD and ≥10 percentage ischemic myocardium on adenosine stress cardiac magnetic resonance (CMR) imaging. Twenty women were assigned to ranolazine (500 mg orally twice daily for 2 weeks and further increased to 1000 mg twice daily as tolerated) or placebo groups for 4 weeks. The study assessed both clinical and imaging endpoints at the end of each 4-week period. All participants underwent two validated selfadministered health history questionnaires: the Seattle Angina Questionnaire (SAQ) [40] and the Duke Activity Status Index (DASI) [41] evaluating respectively angina changes and functional capacity. Additionally, CMR-derived myocardial perfusion reserve index (MPRI) [39] was semi-quantitatively and quantitatively measured. Patients assigned to ranolazine had significantly higher (three of five) SAQ, including physical functioning (p 0.046), angina stability (p 0.008) and quality of life (p 0.021). No significant difference in DASI questionnaire and only a trend toward a higher mid-ventricular MPRI were found in Table 4 Possible role of ranolazine in the management of primary MVA. MVA pathogenetic factor
Action of ranolazine
Conceivably an ischemic disease Microvascular dysfunction Endothelial dysfunction
Anti-ischemic drug [20–22,24,30] Reduce mechanical dysfunction [10–12] Anti-inflammatory or antioxidant effects [16] May improve endothelial function [17,18] Improve glycometabolic control [14,15]
Glucose intolerance
=
ranolazine group. Nonetheless, among women treated with ranolazine and undergoing clinically indicated invasive coronary reactivity testing (CRT) (n 13), the subgroup with lower coronary flow reserve (CFR) presented a significant MPRI improvement compared to women with higher CFR values (Δ in MPRI placebo/ranolazine: 0.48 vs. − 0.82, p 0.04). Certainly, it has to be considered that cross-over design may have produced carry-over effects, reducing anyway the impact of different usual therapies on which ranolazine was added. The second study by Villano et al. [42] was a randomized, doubleblind trial. Patients with stable primary MVA according to previous criteria [4,32] and suboptimal angina control on first-line anti-anginal drugs were enrolled. Patients were randomized to receive ivabradine 5 mg twice daily, or ranolazine 375 mg twice daily, or placebo twice daily for a 4-week period. Participants underwent two validated selfadministered health history questionnaires to evaluate primary clinical endpoints: the SAQ and the EuroQoL, a visual analogic scale assessing QoL [43]. Also functional endpoints were evaluated including: change in maximal symptom/sign-limited EST; non-invasively assessed change in coronary blood flow response to different vasoconstrictors; noninvasively assessed change in peripheral flow-mediated and nitratemediated vasodilation. Both drugs improved SAQ items and EuroQoL scale compared with placebo (p b 0.01) and ranolazine group showed higher results for 4 of 5 SAQ items and for the EuroQoL (p b 0.01) compared to ivabradine even after correction for basal values. EST functional results did not differ among groups. Nevertheless, ECG differences in ST-segment depression were found, with ranolazine showing the best results. No significant differences in endothelial function were present despite a trend toward improvement in flow-mediated dilation. The last study by Tagliamonte et al. [44] is a randomized, placebocontrolled trial. Patients with symptomatic for angina pectoris with myocardial ischemia demonstrated by Tc-99m MIBI myocardial perfusion imaging in the absence of obstructive CAD were enrolled in the study. Patients were randomized to ranolazine 350 mg orally twice a day for 4 weeks with up-titration to 500 mg twice a day for an additional 4 weeks. Coronary flow reserve (CFR), as a marker of microvascular dysfunction, was non-invasively measured using the spectral Doppler signals in the left anterior descending coronary artery (LAD) using dipyridamole test. CFR was assessed before treatment period and at the end of it. Also clinical endpoint was assessed by SAQ. Patients assigned to ranolazine had significantly higher (4 of 5) SAQ results (p b 0.01) and significant improvement in baseline diastolic flow velocity, hyperemic diastolic flow velocity and coronary flow reserve (p b 0.01). Certainly, two aspects represent a certain bias. CFR was assessed only in the LAD territory and some patients with left ventricle hypertrophy were included in the study, thus not completely fulfilling primary MVA diagnostic criteria. In conclusion, although small sample size and short follow-up periods may represent a limitation and bias, these studies suggest ranolazine efficacy, safety and tolerability in primary MVA.
5.5. Ranolazine in primary MVA: perspectives Despite small sample size and short follow-up period, clinical evidence seems to support findings from preclinical studies and provides a first scientific bearing to ranolazine usefulness in primary MVA management. So far, a few single-center randomized trials are ongoing [45].
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Table 5 Study investigating ranolazine ER in stable primary MVA (Cardiac syndrome X). N
Ranolazine dosage
Study design
Inclusion criteria
Anti-anginal Follow-up drugs
• Suboptimal angina control • ≥10% ischemic myocardium on adenosine CMR imaging
Not withdrawn
Mehta et al. [39]
20 500 mg, 1000 mg twice daily
Double-blind Placebo-controlled Crossover
Villano et al. [42]
46 375 mg twice daily
Double-blind • Suboptimal angina Placebo and ivabradine control 5 mg twice daily — • Objective evidence of controlled induced ischemia
Not withdrawn
• Suboptimal angina control • Objective evidence of induced ischemia Tc-99 m MIBI
Not withdrawn
Tagliamonte 58 Ranolazine 350 mg [44]a twice daily
Double-blind Placebo-controlled
Clinical endpoints
Functional endpoint
Change in SAQ • Semiquantitative and quantitative measured week-periods, and DASI questionnaires MPRI on CMR imaging 2-week score • Change in MPRI on CMR washout imaging according to CRT score 4 weeks Change in SAQ • Change in symptom and/or and EuroQoL sign-limited EST questionnaires • CBF response to adenosine score and cold pressor test • Peripheral FMD and NM dilation 8 weeks Change in SAQ Changes in transthoracic Doppler-derived CFR 4
Dropout for side effects None
None
None
CBF = coronary blood flow; EST = exercise stress test; FMD = flow-mediated dilation; NM = nitrate-mediated dilation. a Some patients do not fulfill primary MVA criteria (left ventricle hypertrophy).
New multicentre randomized controlled trials should be implemented in order to further endorse the efficacy of ranolazine among patients affected by primary MVA. 6. Conclusions Ranolazine is a novel anti-anginal drug not affecting hemodynamic parameters, approved as a second-line treatment for stable angina. Indeed, it has been demonstrated to be a safe, well-tolerated agent able to reduce angina occurrence as well as ST-segment changes and increase exercise capacity. Primary MVA is a disorder affecting mainly woman, possibly related to MVCD, which may result from different pathogenetic mechanisms including endothelial dysfunction and impaired glucose homeostasis. Despite high variability in primary MVA patients' response to treatment, small sample size and short follow-up period, clinical and preclinical evidence provided a first scientific bearing to ranolazine possible usefulness in primary MVA management. However, new randomized controlled trials should be implemented in order to further endorse the efficacy of ranolazine among patients affected by primary MVA. Conflict of interest No authors' conflicts of interest and relationship with industry exist for the work under consideration for publication. Acknowledgments None. References [1] A.S. Go, D. Mozaffarian, V.L. Roger, E.J. Benjamin, J.D. Berry, M.J. Blaha, et al., Heart disease and stroke statistics—2014 update: a report from the American Heart Association, Circulation 129 (2014) e28–e292. [2] S.E. Reis, R. Holubkov, A.J. Conrad Smith, S.F. Kelsey, B.L. Sharaf, N. Reichek, et al., Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study, Am. Heart J. 141 (2001) 735–741. [3] H.M. Arthur, P. Campbell, P.J. Harvey, M. McGillion, P. Oh, E. Woodburn, et al., Women, cardiac syndrome X, and microvascular heart disease, Can. J. Cardiol. 28 (2 Suppl.) (2012) S42–S49. [4] G.A. Lanza, F. Crea, Primary coronary microvascular dysfunction: clinical presentation, pathophysiology, and management, Circulation 121 (2010) 2317–2325. [5] G.A. Lanza, R. Parrinello, S. Figliozzi, Management of microvascular angina pectoris, Am. J. Cardiovasc. Drugs 14 (2014) 31–40.
[6] European Medicines Agency, Ranexa (Ranolazine): EU Summary of Product CharacteristicsAvailable at: http://www.ema.europa.eu/ema/index.jsp?curl= pages/medicines/human/medicines/000805/human_med_001009.jsp&mid= WC0b01ac058001d124July 2014. [7] Y.K. Ju, D.A. Saint, P.W. Gage, Hypoxia increases persistent sodium current in rat ventricular myocytes, J. Physiol. 497 (Pt 2) (1996) 337–347. [8] M. Meyer, B. Keweloh, K. Guth, J.W. Holmes, B. Pieske, S.E. Lehnart, et al., Frequencydependence of myocardial energetics in failing human myocardium as quantified by a new method for the measurement of oxygen consumption in muscle strip preparations, J. Mol. Cell. Cardiol. 30 (1998) 1459–1470. [9] C. Antzelevitch, L. Belardinelli, A.C. Zygmunt, A. Burashnikov, J.M. Di Diego, J.M. Fish, et al., Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties, Circulation 110 (2004) 904–910. [10] H. Fraser, L. Belardinelli, L. Wang, P.E. Light, J.J. McVeigh, A.S. Clanachan, Ranolazine decreases diastolic calcium accumulation caused by ATX-II or ischemia in rat hearts, J. Mol. Cell. Cardiol. 41 (2006) 1031–1038. [11] R. Venkataraman, L. Belardinelli, B. Blackburn, J. Heo, A.E. Iskandrian, A study of the effects of ranolazine using automated quantitative analysis of serial myocardial perfusion images, JACC Cardiovasc. Imaging 2 (2009) 1301–1309. [12] W. Hayashida, C. van Eyll, M.F. Rousseau, H. Pouleur, Effects of ranolazine on left ventricular regional diastolic function in patients with ischemic heart disease, Cardiovasc. Drugs Ther. 8 (1994) 741–747. [13] Z. Fu, L. Zhao, W. Chai, Z. Dong, W. Cao, Z. Liu, Ranolazine recruits muscle microvasculature and enhances insulin action in rats, J. Physiol. 591 (2013) 5235–5249. [14] D.A. Morrow, B.M. Scirica, B.R. Chaitman, D.K. McGuire, S.A. Murphy, E. Karwatowska-Prokopczuk, et al., Evaluation of the glycometabolic effects of ranolazine in patients with and without diabetes mellitus in the MERLIN-TIMI 36 randomized controlled trial, Circulation 119 (2009) 2032–2039. [15] A.D. Timmis, B.R. Chaitman, M. Crager, Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes, Eur. Heart J. 27 (2006) 42–48. [16] M. Aldakkak, A.K. Camara, J.S. Heisner, M. Yang, D.F. Stowe, Anolazine reduces Ca2+ overload and oxidative stress and improves mitochondrial integrity to protect against ischemia reperfusion injury in isolated hearts, Pharmacol. Res. 64 (2011) 381–392. [17] P. Lamendola, R. Nerla, D. Pitocco, A. Villano, G. Scavone, A. Stazi, et al., Effect of ranolazine on arterial endothelial function in patients with type 2 diabetes mellitus, Atherosclerosis 226 (2013) 157–160. [18] S.H. Deshmukh, S.R. Patel, E. Pinassi, C. Mindrescu, E.V. Hermance, M.N. Infantino, et al., Ranolazine improves endothelial function in patients with stable coronary artery disease, Coron. Artery Dis. 20 (2009) 343–347. [19] M. Jerling, Clinical pharmacokinetics of ranolazine, Clin. Pharmacokinet. 45 (2006) 469–491. [20] B.R. Chaitman, C.J. Pepine, J.O. Parker, J. Skopal, G. Chumakova, J. Kuch, 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, JAMA 291 (2004) 309–316. [21] P.H. Stone, N.A. Gratsiansky, A. Blokhin, I.Z. Huang, L. Meng, Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial, J. Am. Coll. Cardiol. 48 (2006) 566–575. [22] B.R. Chaitman, S.L. Skettino, J.O. Parker, P. Hanley, J. Meluzin, J. Kuch, et al., Antiischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina, J. Am. Coll. Cardiol. 43 (2004) 1375–1382. [23] M.J. Koren, M.R. Crager, M. Sweeney, Long-term safety of a novel antianginal agent in patients with severe chronic stable angina: the Ranolazine Open Label Experience (ROLE), J. Am. Coll. Cardiol. 9 (2007) 1027–1034.
M. Cattaneo et al. / International Journal of Cardiology 181 (2015) 376–381 [24] D.A. Morrow, B.M. Scirica, E. Karwatowska-Prokopczuk, S.A. Murphy, A. Budaj, S. Varshavsky, 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 297 (2007) 1775–1783. [25] G. Montalescot, U. Sechtem, S. Achenbach, F. Andreotti, C. Arden, A. Budaj, et al., 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology, Eur. Heart J. 34 (2013) 2949–3003. [26] B.M. Scirica, D.A. Morrow, H. Hod, S.A. Murphy, L. Belardinelli, C.M. Hedgepeth, et al., Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the Metabolic Efficiency With Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial, Circulation 116 (2007) 1647–1652. [27] S. Sossalla, L.S. Maier, Role of ranolazine in angina, heart failure, arrhythmias, and diabetes, Pharmacol. Ther. 133 (2012) 311–323. [28] M. Jerling, B.L. Huan, K. Leung, N. Chu, H. Abdallah, Z. Hussein, Studies to investigate the pharmacokinetic interactions between ranolazine and ketoconazole, diltiazem, or simvastatin during combined administration in healthy subjects, J. Clin. Pharmacol. 45 (2005) 422–433. [29] Food and Drug Administration, FDA Approved Drug Products: Ranexa (Ranolazine), December 2013Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ index.cfm?fuseaction=Search.DrugDetailsOctober 2014. [30] M.F. Rousseau, H. Pouleur, G. Cocco, A.A. Wolff, Comparative efficacy of ranolazine versus atenolol for chronic angina pectoris, Am. J. Cardiol. 95 (2005) 311–316. [31] N.M. Bennett, T.L. Arndt, V. Iyer, R.F. Garberich, J.H. Traverse, K. Johnson Randall, et al., Ranolazine refractory angina registry trial: 1-year results, J. Am. Coll. Cardiol. 57 (14s1) (2011) E1050. [32] P.G. Camici, F. Crea, Coronary microvascular dysfunction, N. Engl. J. Med. 356 (2007) 830–840. [33] J.C. Kaski, G.M. Rosano, P. Collins, P. Nihoyannopoulos, A. Maseri, P.A. Poole-Wilson, Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study, J. Am. Coll. Cardiol. 25 (1995) 807–814.
381
[34] P. Lamendola, G.A. Lanza, A. Spinelli, G.A. Sgueglia, A. Di Monaco, L. Barone, et al., Long-term prognosis of patients with cardiac syndrome X, Int. J. Cardiol. 140 (2010) 197–199. [35] R.O. Cannon, P.G. Camici III, S.E. Epstein, Pathophysiological dilemma of syndrome X, Circulation 85 (1992) 883–892. [36] A. Maseri, F. Crea, J.C. Kaski, T. Crake, Mechanisms of angina pectoris in syndrome X, J. Am. Coll. Cardiol. 17 (1991) 499–506. [37] H.E. Botker, N. Moller, P. Ovesen, A. Mengel, O. Schmitz, H. Orskov, et al., Insulin resistance in microvascular angina (syndrome X), Lancet 342 (1993) 136–140. [38] N.K. Wenger, B. Chaitman, G.W. Vetrovec, Gender comparison of efficacy and safety of ranolazine for chronic angina pectoris in four randomized clinical trials, Am. J. Cardiol. 99 (2007) 11–18. [39] P.K. Mehta, P. Goykhman, L.E. Thomson, C. Shufelt, J. Wei, Y. Yang, et al., Ranolazine improves angina in women with evidence of myocardial ischemia but no obstructive coronary artery disease, JACC Cardiovasc. Imaging 4 (2011) 514–522. [40] J.A. Spertus, J.A. Winder, T.A. Dewhurst, R.A. Deyo, J. Prodzinski, M. McDonell, et al., Development and evaluation of the Seattle Angina Questionnaire: a new functional status measure for coronary artery disease, J. Am. Coll. Cardiol. 25 (1995) 333–341. [41] M.A. Hlatky, R.E. Boineau, M.B. Higginbotham, K.L. Lee, D.B. Mark, R.M. Califf, et al., A brief self-administered questionnaire to determine functional capacity (the Duke Activity Status Index), Am. J. Cardiol. 64 (1989) 651–654. [42] A. Villano, A. Di Franco, R. Nerla, A. Sestito, P. Tarzia, P. Lamendola, et al., Effects of ivabradine and ranolazine in patients with microvascular angina pectoris, Am. J. Cardiol. 112 (2013) 8–13. [43] EuroQol—a new facility for the measurement of health-related quality of life, Health Policy 16 (1990) 199–208. [44] E. Tagliamonte, F. Rigo, T. Cirillo, C. Astarita, G. Quaranta, U. Marinelli, et al., Effects of ranolazine on noninvasive coronary flow reserve in patients with myocardial ischemia but without obstructive coronary artery disease, Echocardiography (2014). http://dx.doi.org/10.1111/echo.12674 (Epub ahead of print). [45] ClinicalTrials.gov: Registered TrialsAvailable at: https://clinicaltrials.gov/ct2/ results?term=microvascular+angina&recr=Open&rslt=&type=&cond=&intr= ranolazine&titles=&outc=&spons=&lead=&id=&state1=&cntry1=&state2= &cntry2=&state3=&cntry3=&locn=&gndr=&rcv_s=&rcv_e=&lup_s=&lup_e= November 2014.
