Management of myocardial ischemia. Is ranolazine needed? For all or some patients with myocardial ischemia?

Abstract

This editorial refers to ‘Should ranolazine be used for all patients with ischemic heart disease or only for symptomatic patients with stable angina or for those with refractory angina pectoris? A critical appraisal' by U Thadani also published in this issue.

Keywords::

• angina pectoris
• cardiology
• myocardial ischemia
• ranolazine

1. Introduction

Given the prevalence, high morbidity, mortality and impaired quality of life, ischemic heart disease (IHD) is a major medical challenge. The use of myocardial revascularization techniques and of antianginal and cardioprotective drugs had an outstanding positive therapeutic impact. However, under anatomic circumstances in some patients a complete revascularization may be impossible, for example, after previous interventions or in the presence of peripheral pathology. In some patients conventional antianginal drugs, such as β-blockers, calcium-channel blockers, nicorandil (a nitrate and K⁺- and ATP-channel agonist), molsidomine and ivabradine either exert reduce symptoms to an insufficient extent or the therapy induces limiting side effects. Last, up to 10% of all patients with angina pectoris (mostly women) have symptoms and cardiac ischemia in the absence of significant coronary artery disease, supposedly because of microcoronary dysfunction.

Ranolazine [1] and trimetazidine [2] are effective antianginal drugs without reducing heart rate and blood pressure, and therefore with a pharmacologic mechanism of action which is completely different from those of conventional agents. Ranolazine may be a good choice for some patients with IHD who are not appropriately treatable with other therapies.

2. Mechanism of action

Ranolazine's antianginal mechanism of action is yet undetermined [3]. At therapeutic levels ranolazine inhibits the cardiac late Na⁺-current (INa⁺) thus reducing Ca²⁺-overload, ameliorating cross-bridge kinetics of the cardiomyocytes, and reducing diastolic myofilament activation [3-5]. This effect is useful to treat diastolic dysfunction, but its impact as an antianginal mechanism is speculative, even if some believe that net result is reduced oxygen consumption and reduced wall tension thereby improving microvascular blood flow. Ranolazine also inhibits the IKr-current [5] and this effect explains its electrophysiological effects, but it is does not explain its anti-ischemic and antianginal effect.

3. Clinical studies

Ranolazine's first clinical studies [7-14] were performed with a normal release formulation. In 1993, ranolazine was sold to another pharmaceutical company and the project was changed and extended. The new approach led to the extended-release formulation and to the definition of the required dosage. At present, ranolazine is only used with an extended-release formulation [15,16].

4. Therapeutic indications

Thadani [17] reviews the managements of IHD with ranolazine. Based on the available data, and the US-FDA approved indications [15,16] he explains that, i) ranolazine's use is indicated for symptomatic patients with angina pectoris, but not for all patients with stable IHD; ii) ranolazine can be safely added to a β-blocker and/or calcium channel blocker, or without a background of long-acting organic nitrates in patients who remain symptomatic despite treatment with these agents; and iii) ranolazine can be used as initial antianginal therapy instead of treatment with a β-blocker, or a calcium-channel blocker, or a nitrate preparation, especially when an absolute or a relative contraindication to treatment with these agents is present and if there is a concern with low blood pressure or low heart rate.

Thadani appropriately discusses the electrophysiological effects of ranolazine. It should be outlined that ranolazine prolongs the QTc-interval, but that it shortens the repolarization in type-3 long-QT-syndrome [18].

Thadani also states that ranolazine is not indicated to treat patients with cardiac arrhythmias or for lowering hemoglobin A1C in diabetic patients and underlines that, compared to conventional antianginal agents, ranolazine is not cheap.

On the other hand, some clinicians use ranolazine to treat atrial fibrillation and other arrhythmias [19-24]. Other clinicians use ranolazine to treat IHD patients with diabetes or metabolic syndrome [25-27]. Finally, other clinicians use ranolazine to treat symptomatic IHD patients with left ventricular dysfunction [1,28-30], an interesting approach because conventional anti-ischemic drugs may be disappointing in the therapy of this condition.

5. Gender effects

Ranolazine seems to exert different antianginal effect in males and females, but there are discording opinions. In a meta-analysis [31] ranolazine's antianginal effect was better in males, and in other studies [1,32] it was better in females. In my experience ranolazine's antianginal effect is better in females than in males.

Furthermore, ranolazine is particularly effective useful in treating female patients with angina pectoris and myocardial ischemia without significant coronary artery disease [33]. Generally, these patients do not respond or poorly tolerate conventional antianginal drugs.

6. Interactions and safety issues

Thadani describes also many possible pharmacologic interactions with ranolazine [17]. The list of interactions should not, however, be considered complete or final, for example, ranolazine interacts with tacrolimus [34] and the use might be problematic in patients with tacrolimus eluting coronary stents or in patients receiving tacrolimus after organ transplantation. Thadani does not mention the important interaction between ranolazine and colchicine [35-37]. Both drugs inhibit the P-glycoprotein (P-gp) and their co-administration may significantly increase the serum concentrations of colchicine by enhanced absorption as well as reduced excretion of colchicine due to inhibition of P-gp efflux transporter in the intestine, renal proximal tubule, and liver [38]. I have observed two patients who were treated with colchicine for recurring pericardial effusion and who received ranolazine for chest pain. They developed nausea, gastrointestinal symptoms with diarrhea, severe myalgia; increased CK values up eight times the upper range, and it was found that serum colchicine concentrations had increased by an approximately fourfold in comparison to the baseline values. This combination should be possibly avoided. Last, there is patent for the combined therapy with ranolazine and digoxin has been patented [39] and it is claimed that ranolazine may be safely added to low-dosed digoxin, and that ranolazine may reduce dizziness and some of the gastrointestinal side effects of glycosides. However, I would recommend being cautious, because ranolazine may increase digoxin's serum concentration [40].

One should also consider that we lack experience with long-term use of ranolazine. Unknown side effects could appear, for example, ranolazine has been shown to reduce A1C by improving β-cell survival. However, the effect of long-term stimulation of these cells is unknown, and at least in mice ranolazine promotes the development of intestinal tumors [41].

7. Conclusions

What conclusions can be drawn from the review by Thadani? The author should be congratulated for the excellent review on ranolazine which does not raise any doubts on its value in IHD. Ranolazine's use is likely to be extended to other aspects of the cardiovascular system, for example, in the therapy of symptomatic patients with angina pectoris and myocardial ischemia IHD without coronary artery disease; in symptomatic patients with IHD and diabetes mellitus and/or some arrhythmias, and finally, in symptomatic patients with IHD and diastolic dysfunction, but further studies are needed before these indications may be generally accepted.

Declaration of interest

The author states no conflict of interest and has received no payment in preparation of this manuscript.