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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Clinical implications of inhibition of the late sodium current: ranolazine

Jean-Pierre Bassand*

Department of Cardiology, University Hospital Jean Minjoz, Boulevard Fleming, 25000 Besançon, France

* Corresponding author. Tel: +33 381 668 539; fax: +33 381 668 582. E-mail address: jean-pierre.bassand{at}ufc-chu.univ-fcomte.fr


   Abstract
Top
 Abstract
Introduction
 Current treatment of chronic...
 Clinical evidence of anti...
 Safety profile of ranolazine
 Latest developments
 Conclusion
 References
 
Ranolazine is a unique anti-ischaemic drug that does not significantly affect haemodynamic parameters such as heart rate and blood pressure. Ranolazine has been shown in clinical trials to significantly prolong exercise duration and time to angina, as monotherapy or when administered with conventional anti-anginal therapy. It also reduces angina attacks and consumption of nitroglycerin and is well tolerated at therapeutic doses.

Key Words: Chronic stable angina • Ranolazine • Anti-ischemic agents • Exercise stress testing


   Introduction
Top
 Abstract
 Introduction
Current treatment of chronic...
 Clinical evidence of anti...
 Safety profile of ranolazine
 Latest developments
 Conclusion
 References
 
Chronic stable angina is a common condition that is thought to affect as many as 6.8 million people in the USA alone.1 In Europe, the figures are more difficult to assess, as there is a lack of reliable epidemiological data covering the whole continent. Nonetheless, national registries give some indication of the frequency of the disease in some European countries. In addition, the European Society of Cardiology has launched a series of Europe-wide surveys in several conditions, including stable angina, which give some idea if not about the epidemiology of the disease, at least about how frequent it is when compared with other coronary artery disease (CAD) conditions. The surveys also provide comprehensive information about management, diagnosis, and treatment. In addition, clinicians tend to think that due to more frequent revascularization, either by percutaneous coronary intervention (PCI) or by coronary artery bypass graft (CABG) surgery, chronic stable angina is becoming less common. Actually, it would appear that even after revascularization, this condition persists and is observed in as many as 25–30% of patients 1 year after PCI or CABG.2–4

In this context, the management of chronic stable angina is well categorized and has been described in many reports, including clinical practice guidelines from the ACC–AHA and from the ESC.5,6 A new set of guidelines on the management of chronic angina pectoris is due to be released by the ESC in 2006. Current guidelines describe the diagnostic methods and management of chronic stable angina, including drug therapy, use of invasive and non-invasive diagnostic methods, and revascularization strategies.

Ranolazine is a unique anti-ischaemic drug that was initially thought to act purely through metabolic mechanisms. However, it has recently been shown to be capable of inhibiting the late sodium current, thereby maintaining sodium and calcium homeostasis and preventing ischaemia-induced diastolic dysfunction. In chronic stable angina, ischaemia is due to increased oxygen demand, which is marked by increased heart rate, blood pressure, loading conditions of the heart, or contractility. Ischaemia leads to an increase in late sodium current and, eventually, calcium overload. The consequences are electrical instability and myocardial dysfunction, both systolic and diastolic, because of increased diastolic stiffness. This latter condition results in compression of nutritive blood vessels, leading to a decreased oxygen supply and worsening of the ischaemia.7–14

In this situation, conventional anti-ischaemic drugs, such as beta-blockers, nitrates, and calcium channel inhibitors, all work on the factors leading to increased oxygen demand (i.e. heart rate, loading conditions, and contractility). Ranolazine has a unique mechanism: by decreasing the late sodium current, it decreases calcium overload and thereby diastolic stiffness. This in turn improves myocardial perfusion. The anti-ischaemic properties of ranolazine have been shown to be exerted without significant modifications in heart rate, blood pressure, and inotropic state.15–19


   Current treatment of chronic stable angina
Top
 Abstract
 Introduction
 Current treatment of chronic...
Clinical evidence of anti...
 Safety profile of ranolazine
 Latest developments
 Conclusion
 References
 
Current therapeutic approaches to chronic stable angina are based on both drug therapy and revascularization.

Drug therapy
Several pharmacological classes are used in the treatment of chronic stable angina, for their anti-ischaemic properties and/or for their capacity to improve outcome.

Aspirin is currently recommended in any form of atherosclerosis, including CAD, and has been shown in randomized clinical trials to reduce risk, at doses ranging from 75 to 325 mg. Similar improvements are seen with the lower doses as with the higher doses, but with a reduced risk of bleeding.20 Nitrates, immediate or sustained release, are effective at relieving symptoms, but have never been shown to improve outcome. Beta-blockers are very effective at reducing the frequency of anginal attacks in chronic stable angina, but have been shown to improve prognosis only in the post-infarction setting.21 Statins reduce the risk of major adverse cardiac events, including death at 5 years, in a broad range of patients with atherosclerotic disease, particularly CAD. Statins have become the standard therapy, irrespective of the initial low-density lipoprotein and total cholesterol levels.22

In two large clinical trials that included a broad spectrum of CAD patients (EUROPA) or patients at high risk of developing cardiovascular events (HOPE), angiotensin-converting enzyme (ACE) inhibitors (ramipril and perindopril) reduced the risk of death, myocardial infarction (MI), stroke, or cardiac arrest.23,24 In both trials, the significant risk reduction in major adverse cardiovascular events was deemed to be independent of the anti-hypertensive properties of the drugs and of cardiac remodelling. However, in these trials, it was unclear whether patients with stable angina actually benefit from this risk reduction. Calcium channel inhibitors have potent anti-ischaemic effects, but have had no impact on long-term outcome, either alone or in combination with beta-blockers.25,26 In the ACTION study, long-acting nifedipine was shown to be unable to modify prognosis.27 The only positive outcome in this study was a significant reduction in the need for revascularization. A potassium channel opener, nicorandil, was shown in at least one trial (IONA) to be able to both reduce anginal attacks and improve long-term prognosis.28 However, nicorandil, although proved to be efficacious in this trial, is less frequently prescribed than beta-blockers and/or calcium channel blockers. Trimetazidine is a pure metabolic agent that has been shown to be capable of reducing ischaemia during exercise stress tests. So far, however, no improvement in outcome has been demonstrated with this drug.29,30

Revascularization
CABG surgery has the capacity to improve long-term survival in a wide spectrum of patients with CAD, including chronic stable angina. Patients at higher risk are more likely to benefit from mortality reduction than lower risk patients. In particular, patients with main stem, or double or triple vessel, disease involving the first segment of the left anterior descending (LAD) artery and patients with reduced ventricular ejection fraction have an improved outcome after surgery when compared with medical therapy. PCI, with or without stent implantation, improves the symptoms of myocardial ischaemia. Several trials comparing PCI and CABG have shown CABG to be superior to PCI in improving outcome in moderate-to-high-risk patients, especially those with double-vessel disease with involvement of the proximal LAD artery.31 PCI offers better outcome in patients at low risk when compared with surgery.31 CABG was shown to be superior to PCI in diabetic patients in the BARI trial.2 More recent comparisons of CABG vs. PCI involving stents, particularly drug-eluting stents, do not show any clear superiority of CABG over PCI.32 Ongoing trials in the setting of multi-vessel disease, CAD, and diabetes may provide further evidence in the future.

Current management of CAD: lessons from the Euro Heart Survey
The Euro Heart Survey on chronic stable angina included 3779 patients throughout Europe.33 Patients with prior revascularization or recent MI were excluded. Patient's data were collected at the time of consultation or at admission to hospital for symptoms of angina. Data were collected on diagnostic procedures and on drug therapy at entry and at discharge from hospital or consultation. It appears that at entry into the survey, patients with proven or suspected CAD with chronic stable angina had suboptimal treatment. Only 50% had aspirin or anti-platelet agents, one-third had beta-blockers or nitrates, one-sixth had calcium antagonists, and 25% had statins and ACE inhibitors. The rates of prescription of nicorandil and metabolic agents were extremely low.

Most of the patients in the survey were male; 18% had diabetes, 62% had hypertension, 58% had documented hyperlipidaemia, 42% had a family history of CAD, and 23% were current smokers. Canadian Cardiovascular Society (CCS) classes I and II angina was most frequently observed in 42 and 46% of patients, respectively. CCS class III angina was observed in only 12% of patients, but elderly patients tended to have class II or III angina symptoms more often than class I.

At hospital discharge, a significant improvement in drug therapy was noted, as 78% of patients received aspirin or anti-platelet agents, 67% beta-blockers, and 48% statins. The reasons for non-prescription of drugs were contraindication in 22% and no indication in 45% (investigator's judgement); other reasons were invoked in the remaining 33%, without further clarification. This indicates that a significant number of patients are inappropriately treated and that some of them are denied therapy for reasons that are probably not well founded.


   Clinical evidence of anti-ischaemic properties of ranolazine
Top
 Abstract
 Introduction
 Current treatment of chronic...
 Clinical evidence of anti...
Safety profile of ranolazine
 Latest developments
 Conclusion
 References
 
Immediate-release ranolazine was tested in patients with chronic stable angina in the setting of exercise testing. Ranolazine was administered at a dose of 400 mg t.i.d. for a week, vs. atenolol or placebo, after washout from therapy. Exercise stress tests were performed at the end of each treatment period. Time to 1 mm ST-segment depression and exercise duration were both improved by ranolazine when compared with placebo. In addition, exercise duration was significantly longer with ranolazine than with either placebo or atenolol (Figure 1). Haemodynamic measurements during the exercise tests did not differ significantly between ranolazine and placebo, except for a modest increase in systolic blood pressure at peak exercise with ranolazine.34 These results confirmed previous studies with the same compound in patients with angina pectoris previously conventionally treated with beta-blockers and/or calcium channel inhibitors.35,36


Figure 0921
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  		Figure 1 Therapeutic effects of placebo (n=142), ranolazine (n=142), and atenolol (n=142) on exercise tolerance and ischaemia markers. (IR, immediate release; q.d., daily; t.i.d., three times a day.) Adapted from Rousseau et al.34 with permission from the publisher.

 
The MARISA (Monotherapy Assessment of Ranolazine In Stable Angina) trial aimed to establish the dose–response relationship of sustained-release ranolazine in a population of 191 high-risk patients with angina/limited exercise capacity, washed out from previous therapy.37 Exercise stress tests were carried out at 4 and 12 h after administration of 500, 1000, or 1500 mg sustained-release ranolazine b.i.d. (peak and trough levels). Improvements in exercise duration and efficacy parameters were observed at all doses of the drugs, but the improvement was greater at higher doses (Figure 2). This improvement was obtained without significant differences in heart rate and blood pressure at rest and during exercise between the three doses of ranolazine and placebo. Minor blood pressure depression was observed with 1000 and 1500 mg of ranolazine, in particular during exercise, but it is fair to say that the anti-ischaemic effect was obtained without any major modification of heart rate or blood pressure. In summary, sustained-release ranolazine administered twice daily significantly improves exercise performance and delays occurrence of symptoms and signs of ischaemia, at doses from 500 to 1500 mg, without significant haemodynamic effects.37


Figure 0922
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  		Figure 2 Improvement in exercise capacity with sustained-release ranolazine vs. placebo, at trough and peak exercise. A significant improvement in exercise duration, time to angina, and time to 1 mm ST-segment depression was observed in a dose-ranging manner, at both trough and peak exercise. (n=175, all/near completers population; LS means ±SE; **P<0.01 vs. placebo; ***P<0.001 vs. placebo.) Adapted from Chaitman et al.37 with permission from the publisher.

 
In the CARISA (Combination Assessment of Ranolazine in Stable Angina) trial, two doses of sustained-release ranolazine (750 or 1000 mg b.i.d.) were used in combination with diltiazem, amlodipine, or atenolol in patients with chronic stable angina.38 The cohort was quite large, with more than 800 patients included. Treadmill exercise was carried out at 12 h after administration and at 2, 6, and 12 weeks treatment in three parallel groups, according to a double-blind, placebo-controlled design. Again, all three efficacy parameters (exercise duration, time to angina, and time to 1 mm ST-depression) were improved, but without clear dose-related changes. During the 12-week duration of the trial, the frequency of anginal attacks and consumption of nitroglycerin were significantly reduced in ranolazine-treated patients (Figure 3). From this trial, it is clear that sustained-release ranolazine offers additional anti-anginal effect and anti-ischaemic efficacy in patients receiving standard doses of anti-ischaemic agents such as atenolol, amlodipine, or diltiazem, without significant haemodynamic changes at rest or during exercise. It is worth mentioning that in this trial, 480 patients received open-label ranolazine for 1 year, whereas 173 patients received the drug for 2 years. There were no significant safety concerns in this trial.38


Figure 0923
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  		Figure 3 Angina frequency and nitroglycerin consumption in the intent-to-treat population. Data are presented as mean values (SE). P-values are for comparisons of each ranolazine group vs. placebo. Adapted from Chaitman et al.38 with permission from the publisher.

 
On the basis of these trials, as well as safety data (discussed subsequently), the 1000 mg b.i.d. dose was selected as being as efficient as a higher dose, but better tolerated in terms of side effects.


   Safety profile of ranolazine
Top
 Abstract
 Introduction
 Current treatment of chronic...
 Clinical evidence of anti...
 Safety profile of ranolazine
Latest developments
 Conclusion
 References
 
The safety profile of ranolazine seems to be extremely favourable. More than 3000 patients have been exposed to either immediate- or sustained-release ranolazine. In controlled trials, minor side effects such as dizziness, constipation, nausea, asthenia, headache, and dyspepsia were observed at a frequency of <10%. However, the frequency of these side effects with doses >1000 mg b.i.d. led to the cessation of the 1500 mg b.i.d. dose.

Again, no effect on blood pressure and heart rate at rest, and a slight decrease in blood pressure and heart rate during exercise, has been observed at higher doses. The drug has been shown to be well tolerated in congestive heart failure patients, but was not tested in the New York Heart Association class IV heart failure.

A minor prolongation of QTc was observed with sustained-release ranolazine in MARISA and CARISA, at plasma concentrations of up to 10 000 ng/mL of ranolazine. It remained linear at 2.4 ms/1000 ng/mL. The total increase is 2–5 ms within the therapeutic range and <20 ms at the maximum recommended dose during maximal CYP3A4 inhibition. The prolongation ranged from 5 to 14 ms with doses from 500 to 1500 mg b.i.d. However, no evidence of QT dispersion and no documentation of torsade de pointes have ever been reported (unpublished results). It has to be stressed that the cellular electrophysiological mechanism underlying the QTc effect of ranolazine is fundamentally different from that of drugs known to cause torsade de pointes.15 Five syncopes were observed in CARISA, but without documentation of ventricular arrhythmias.38 These syncopes may have been related to orthostatic hypotension, as four patients had concomitant therapy with diltiazem, and all five received ACE-inhibitors. No injury was observed, and recovery was spontaneous in all five cases. It is known that diltiazem can increase plasma levels of ranolazine through competitive metabolism by CYP2C4 enzyme.35

Diabetes
It has been shown that ranolazine leads to a dose-related reduction in HbA1c in diabetic patients. The absolute reduction was 0.48% with 750 mg b.i.d. and 0.7% with 1000 mg b.i.d. This effect, if confirmed, could result in a potential favourable effect of ranolazine on glycaemic control in diabetic patients.39


   Latest developments
Top
 Abstract
 Introduction
 Current treatment of chronic...
 Clinical evidence of anti...
 Safety profile of ranolazine
 Latest developments
Conclusion
 References
 
Evaluation of Ranolazine In Chronic Angina (ERICA) was a clinical randomized trial in patients with continuing anginal attacks (more than three attacks per week) already treated with amlodipine at a dose of 10 mg daily, with or without long-acting nitrates. Ranolazine was administered at a dose of 500 mg b.i.d. vs. placebo for a week, then titrated to 1000 mg b.i.d. for 6 weeks. The primary endpoint was angina frequency during the last 6 weeks, and the secondary endpoints were safety, tolerability, nitroglycerin consumption, and quality of life, according to the Seattle Angina questionnaire. Of 567 patients randomized, 25% were female, 40% were elderly, and 45% were on long-acting nitrates. The results of this study showed a significant reduction in anginal attacks, with excellent tolerability, without syncope or torsade de pointes.

This development led to the conception of a phase III trial, MERLIN TIMI 36 (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST segment elevation acute coronary syndromes). This trial, currently under way, aims to include at least 5500 patients in a double-blind, event-driven design. The trial needs to record 730 events (death, MI, or severe recurrent ischaemia). The average follow-up will be 8–12 months. Additional endpoints will be exercise stress test performance, left ventricular function, and efficacy on arrhythmias during the first 7 days of the acute phase.


   Conclusion
Top
 Abstract
 Introduction
 Current treatment of chronic...
 Clinical evidence of anti...
 Safety profile of ranolazine
 Latest developments
 Conclusion
References
 
In conclusion, chronic stable angina is a common disease, with unmet therapeutic needs. Surveys and reports have shown that current treatment is suboptimal for various reasons, such as contraindications or poor tolerance. Even after revascularization, up to 25% of patients remain symptomatic after 1 year. In this context, ranolazine has consistently demonstrated its anti-ischaemic properties and has been shown to prolong exercise duration, and time to occurrence of ischaemia, without significantly affecting haemodynamic parameters such as heart rate or blood pressure. Ranolazine is well tolerated in the short- and long-term, with only minor QTc prolongation, the mechanism of which is fundamentally different from the QTc prolongation linked to torsade de pointes. Ranolazine has an excellent safety profile at all the currently tested doses, and more than 3000 patients have been successfully treated so far. Further studies are necessary to confirm the full potential of ranolazine in the treatment of chronic stable angina and other CAD conditions.

Conflict of interest: none declared.


   References
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 Abstract
 Introduction
 Current treatment of chronic...
 Clinical evidence of anti...
 Safety profile of ranolazine
 Latest developments
 Conclusion
 References
 

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