Prof Juan Carlos Kaski, St George's, University of London, UK

Myocardial ischaemia in patients without obstructive coronary artery disease (NOCAD) is often caused by coronary microvascular dysfunction (CMD). Treatment of these patients is not straightforward and new therapies are needed to improve symptoms and signs of myocardial ischaemia in subjects presenting with angina despite NOCAD. Ranolazine is a promising pharmacological option for the treatment of this condition given its mechanism of action. Small studies have shown a beneficial effect of ranolazine in patients with coronary MVD (1,2). Ranolazine blocks the late sodium current in the heart and thus reduces the compressive effect of heart muscle stiffness during ischaemia, a mechanism often responsible for coronary microvascular dysfunction. Bairey Merz et al (3) carried out a study aimed at testing the effects of short-term late sodium current inhibition with ranolazine, in subjects with angina, NOCAD, and myocardial perfusion reserve index abnormalities. This was a randomised, double-blind, placebo-controlled, crossover, trial in 128 patients with documented CMD. Ranolazine -500-1000 mg twice daily- was administered for 2 weeks vs. placebo. Primary outcome variables assessed were angina measured by Seattle Angina Questionnaire (SAQ) and SAQ-7. Secondary objectives were: diary angina, stress myocardial perfusion MRI, diastolic filling and quality of life (QoL). The vast majority of patients (96%) were women. The main study results were that no treatment differences in the outcomes were observed. The change in SAQ-7 directly correlated with the change in MPRI (correlation 0.25, P = 0.005) and predicted the change in SAQ QoL, adjusted for body mass index, prior myocardial infarction, and site (P = 0.0032). Of importance, low coronary flow reserve (CFR <2.5) subjects improved MPRI (P < 0.0137), SAQ angina frequency (P = 0.027), and SAQ-7 (P = 0.041) with ranolazine treatment.

The authors (3) concluded that this study, in symptomatic subjects with NOCAD, “showed that short-term late sodium current inhibition was not generally effective for SAQ angina”. Angina and myocardial perfusion reserve changes were related, and this should represent a stimulus to develop strategies to improve ischaemia. Despite the neutral effect observed in the Bairey-Merz study, in the population as a whole, the use of ranolazine in subgroups of patients with low CFR may still be beneficial.


  1. Ranolazine improves angina in women with evidence of myocardial ischemia but no obstructive coronary artery disease. Mehta PK, et al. JACC Cardiovasc Imaging. 2011; 4:514-22
  2. Effects of ivabradine and ranolazine in patients with microvascular angina pectoris. Villano A, et al. Am J Cardiol. 2013 Jul 1;112(1):8-13. doi: 10.1016/j.amjcard.2013.02.045. Epub 2013 Apr 1.
  1. A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve. Bairey Merz CN et al. Eur Heart J 2016; 14;37:1504-13
Cardio Debate Expert Comments

The authors have to be congratulated for this excellent work. The main strengths of the study include its double-blind randomized design and the large number of enrolled patients (much larger than in previous similar trials), which allow to draw reliable conclusions. The data unequivocally demonstrate that ranolazine does not improve symptoms or objective signs of myocardial ischemia in an unselected population of patients with microvascular angina (MVA).

A major limitation of the study is the inclusion of a non-selected and heterogeneous population of patients with a diagnosis of MVA. Thus, the benefit of ranolazine, that subgroup post-hoc analyses revealed in the patient subset with low coronary flow reserve (CFR), was probably diluted by the lack of efficacy in the remaining patients. Indeed, in the current study, 31% only of patients had typical angina. Furthermore, among the entire cohort, slightly more than half underwent clinically indicated invasive coronary reactivity tests, and 38% only had low CFR <2.5.

Taken together, the results of previous studies and of post-hoc analyses of the current trial show that, among patients with MVA, those with reduced CFR and evidence of exercise-induced myocardial ischemia may have appreciable benefits from ranolazine administration. In contrast, ranolazine is unlikely to be beneficial in patients with MVA caused by increased susceptibility to constrictor stimuli, who represent a sizeable proportion, or in those whose chest pain is predominantly caused by a hypersensitive heart syndrome. The prevalence of the latter is still uncertain, but it might contribute to modulate the severity of symptoms in several patients with MVA.

Some small studies reported beneficial effects of ranolazine in patients with microvascular angina (MVA) (1). Bairey Merz et al. recently challenged these findings showing no effects of ranolazine on symptoms and myocardial perfusion abnormalities in such patients (2). Patients included in this study, however, were quite heterogeneous. Most had atypical chest pain (CP), and coronary microvascular dysfunction (CMD) was diagnosed using different methods and criteria. This probably led to inclusion of patients with different mechanisms of CMD (e.g., impaired vasodilation vs. increased vasoconstriction) and, possibly, also of some with no CMD-related CP (e.g., enhanced cardiac pain sensitivity), thus precluding the possibility to demonstrate significant effects of the drug. Ranolazine, indeed, can reasonably be expected to be effective in patients with typical stress-induced MVA, but not in other kinds of patients. Accordingly, in Bairey Merz study, the subgroup of patients with reduced coronary flow reserve showed some significant benefits from ranolazine administration (2), in agreement with data of the earlier studies (1).

Thus, waiting for larger trials, at present data suggest that ranolazine may be helpful in patients with primary exercise-induced MVA. In the future, homogeneous patients should be included in clinical trials of MVA to avoid inconclusive results; although this is a general rule in medicine, it particularly applies to the complex world of CMD and MVA.


  1. Treatment of microvascular angina: the need for precision medicine. Crea F, Lanza Eur Heart J. 2016;37:1514-6.
  2. A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve. Bairey Merz CN et al. Eur Heart J. 2016;37:1504-13.