Ranolazine following percutaneous coronary intervention: For whom? For what?

Ranolazine is a late sodium current blocker that reduces intracellular calcium overload during ischemia [1]. It also influences cardiac metabolism by switching from fatty acid to glucose metabolism which is more efficient in terms of oxygen expenditure [2]. Ranolazine has no negative inotropic, chronotropic, or dromotropic effects and was shown to be safe and effective at reducing angina severity in patients with stable ischemic heart disease (IHD). It therefore emerged as a promising new treatment strategy for patients across the IHD spectrum [3–5]. This enthusiasm has been curbed now that two large-scale, multicenter, randomized controlled trials have failed to show superiority of ranolazine over placebo in regard to clinical outcomes for patients with acute coronary syndromes [6] or stable coronary artery disease (CAD) [7]. Furthermore, ranolazine’s lack of effect on angina scores or quality of life (QoL) in the recent Ranolazine in Patients With Incomplete Revascularization After Percutaneous Coronary Intervention (RIVER-PCI) trial sheds doubt on ranolazine’s place among evidence-based treatment alternatives for IHD [8]. Similarly, a smaller trial detected no effect of ranolazine treatment on angina scores in patients with coronary microvascular dysfunction in the absence of obstructive coronary artery disease [9]. However, a closer look at the large-scale trials and other available data on ranolazine draws attention to the heterogeneity among patients with CAD and raises interesting questions about differential effects of treatment across subsets of patients.

Herein, we address some of these questions, with emphasis on (i) the interpretation of the available data on ranolazine’s anti-ischemic effects in light of between-study heterogeneities, (ii) ranolazine’s effect on glycemic control and its potential as an antianginal treatment for patients with diabetes mellitus, (iii) ranolazine’s antiarrhythmic effects and (iv) ranolazine’s well established safety profile. In discussing the first topic we touch on two important issues related to clinical trials, namely the interpretation of post hoc subgroup analyses, and the difficulty in balancing between statistical power and widespread external validity on the one hand and appropriate patient selection on the other when conducting clinical trials.

The Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndromes (MERLIN) trial randomized 6560 patients to ranolazine or placebo. Although the trial was neutral in regard to its primary clinical end point, it confirmed the results of earlier smaller-scale studies that showed that ranolazine improved angina status [6]. A subgroup analysis of MERLIN data implied that ranolazine reduced the risk of adverse clinical events in patients with chronic angina.

This led to RIVER-PCI, a trial that randomized 2651 patients with stable CAD who had incomplete revascularization to ranolazine or placebo [10]. Similar to MERLIN, RIVER-PCI was neutral in regard to its primary clinical end point, a composite of time to first occurrence of ischemia-driven revascularization or ischemia-driven hospitalization without revascularization. Contrary to MERLIN, the results from RIVER-PCI did not imply that ranolazine improves angina status [7]. The interpretation of the results from RIVER-PCI is complicated by the fact that one fourth of the patients discontinued the study drug within the first 12 months (28% in the ranolazine arm and 23% in the placebo arm) [10]. This led to loss of statistical power and an increased risk of committing a type II statistical error (concluding that the drug has no effect when in fact it does). The higher proportion of drug discontinuations in the ranolazine arm points to a need for improving the tolerability of ranolazine. The high proportion of drug discontinuations in the placebo arm is perhaps more concerning as it implies that similar studies in this patient population would need to enroll additional patients to avoid being underpowered for their end point of interest.

We believe that two lessons can be learned when considering the MERLIN and RIVER-PCI trials in conjunction. First, treatment benefits observed in post hoc subgroup analyses should be interpreted with caution. In fact, RIVER-PCI is only the most recent of many neutral trials that failed to confirm a treatment effect that was observed in a post hoc subgroup analysis of an earlier trial [11]. Second, the effectiveness of ranolazine or any other antianginal drug likely depends on the clinical context and angiographic status of the patient. In RIVER-PCI, less than half of the patients were incompletely revascularized because medical therapy was believed by the operator to be an acceptable approach and for 25% of the patients complete revascularization with PCI was considered too difficult or impossible [7]. An alternative interpretation of the RIVER-PCI trial is that medical therapy is unlikely to be sufficient for many of these patients and/or that complete revascularization is necessary in most patients with ongoing angina. This notion is supported by several other studies that have shown benefits with complete revascularization [12,13]. The lack of improvement in angina status in RIVER-PCI, therefore, does not refute the results of the earlier studies but rather points to the difficulty in systematically applying a treatment strategy across a heterogeneous population.

Interestingly, a post hoc analysis from the MERLIN trial showed that ranolazine improved glycemic control for patients with diabetes and CAD [14]. This finding may be related to ranolazines metabolic effects [2] and was later confirmed by the 949 patient Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina (TERISA) trial [15]. The TERISA trial also demonstrated improvement in angina with ranolazine treatment for patients with diabetes and CAD; however, as discussed above, subgroup analyses are difficult to interpret and neither MERLIN nor RIVER-PCI subgroup analyses revealed an interaction between diabetes and treatment effect in regard to clinical outcomes [6,7]. Hence, the observation that ranolazine may be beneficial in patients with diabetes is hypothesis generating and needs to be confirmed in prospective studies. That being said, the reduction in the risk of adverse clinical events associated with better glycemic control is not immediately observed; therefore, the current follow-up in MERLIN and RIVER-PCI may be too short for improvement in glycemic control to translate to a reduction in clinical events.

Another post hoc analysis from the MERLIN trial revealed a lower incidence of both intra- and supraventricular arrhythmia for patients treated with ranolazine [16]. This implies that ranolazine has antiarrhythmic effects and is consistent with preclinical data [17,18]. Another recent report from the MERLIN trial which demonstrated lower long-term risk of atrial fibrillation for patients in the ranolazine arm lends further support for ranolazine’s antiarrhythmic effect [19]. In light of these data, several multicenter, randomized controlled trials to prospectively assess ranolazine’s antiarrhythmic effects have started or are being planned [20].

Contrary to other antianginal drugs, ranolazine does not reduce heart rate, inotropy, or blood pressure. This is an important advantage with ranolazine as many patients cannot use the other drugs because of hypotension (beta blockers, calcium channel antagonists, nitrates) and/or bradycardia (beta blockers, calcium channel antagonists, ivabradine). Lastly, in RIVER-PCI adverse events and drug discontinuations were disproportionally high in older patients (>75 years) who were treated with ranolazine. This observation is consistent with a smaller study that noted a higher risk of adverse events for patients aged ≥75 years who were treated with ranolazine. For patients aged <75 years neither RIVER-PCI nor MERLIN nor any of the smaller studies identified any serious safety concerns associated with ranolazine. Hence, ranolazine appears to be safe for patients <75 years of age.

In conclusion, given the neutral outcomes in regard to clinical events in the MERLIN and RIVER-PCI trials, ranolazine should not be seen as a first-line antianginal therapy for patients with IHD; however, ranolazine could be of value for patients who have been incompletely revascularized and are already treated with optimal doses of the other antianginal drugs or cannot tolerate these drugs. Given its possible beneficial effects on glycemic control and pending more prospective confirmatory data, ranolazine might be an interesting option for patients with diabetes and stable CAD. Similarly, ongoing trials may confirm a role for ranolazine in atrial fibrillation management, representing an attractive alternative for patients with concomitant stable CAD and atrial fibrillation.

Financial and competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Notes on contributors

Björn Redfors

Philippe Généreux