Ranolazine in Coronary Microvascular Dysfunction - Ranolazine in CMD

Description:

The goal of the trial was to assess the safety and efficacy of short-term ranolazine in improving anginal symptoms in patients with objective evidence of coronary microvascular dysfunction (CMD).

Contribution to the Literature: The Ranolazine in Microvascular Dysfunction trial showed that short-term ranolazine is not superior to placebo for reducing anginal symptoms, myocardial perfusion, or diastolic filling in patients with documented CMD and no significant epicardial stenosis.

Study Design

Patients with coronary ischemic symptoms and presence of objectively documented CMD without significant epicardial stenoses were randomized in a 2 x 2 cross-over fashion to either ranolazine 500-1000 mg or placebo for 2 weeks (n = 128).

  • Total number of enrollees: 128
  • Duration of follow-up: 2 weeks
  • Mean patient age: 55.2 years
  • Percentage female: 96%

Other salient features/characteristics:

  • Diabetes: 18%
  • Post-menopausal: 81.3%
  • Typical stable anginal symptoms: 31.3%
  • Beta-blockers: 42.2%, calcium channel blockers: 22.7%, nitrates: 39.1%

Inclusion criteria:

  • Patients with chronic angina or its equivalent
  • Coronary angiogram revealing CMD with no obstructive coronary artery disease (CAD) (epicardial coronary stenosis <50% luminal diameter stenosis)
  • Left ventricular ejection fraction ≥45%
  • Objective evidence of ischemia by noninvasive methods such as exercise stress test, stress echo, cardiac magnetic resonance perfusion imaging (CMRI), or single-photon emission tomography (SPECT)
  • Patients with CMD defined as an invasive measured coronary flow reserve <2.5 or acetylcholine (ACH) response of no dilation or constriction, determined by local site read, or a CMRI-derived myocardial perfusion reserve index ≤2.0
  • Patients must have withdrawn from ranolazine at least 2 weeks prior to study entry

Exclusion criteria:

  • Acute coronary syndrome (defined by World Health Organization [WHO]), cardiogenic shock, or requiring inotropic or intra-aortic balloon support
  • Planned percutaneous coronary intervention (PCI) or coronary bypass surgery or established obstructive CAD with ischemia eligible for revascularization
  • Acute myocardial infarction
  • Prior noncardiac illness with estimated life expectancy <4 years
  • Allergy or contraindication to CMRI testing
  • Surgically uncorrected significant congenital or valvular heart disease and other disease likely to be fatal or require frequent hospitalization within the next 6 months
  • Documented obstructive hypertrophic cardiomyopathy
  • Aortic stenosis (valve area <1.5 cm)
  • History of significant cocaine or amphetamine abuse
  • Taking potent CYP3A4 inhibitors (ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir)

Principal Findings:

Primary endpoint:

  • Seattle Angina Questionnaire overall scores for ranolazine vs. placebo: 62.5 vs. 61.0, p > 0.05
  • Individual components:
  • Anginal frequency: 63.9 vs. 62.7, p = 0.97
  • Anginal stability: 58.4 vs. 51.2, p = 0.24
  • Quality of life: 56.1 vs. 54.2, p = 0.59

Secondary outcomes:

  • Anginal episodes for ranolazine vs. placebo: 4.8 vs. 4.9, p = 0.81
  • Depressed (on HIS-GWB Mental Health Battery scale): 4.4 vs. 4.3, p = 0.0009
  • Stress and diastolic filling parameters similar between the two arms

Interpretation:

The results of this trial indicate that short-term ranolazine is not superior to placebo in improving anginal symptoms, myocardial perfusion, or diastolic filling in patients with documented CMD and no significant epicardial stenoses (96% women). In a subgroup analysis, patients with CMD based on CFR <2.5 (38%) had some improvements in myocardial perfusion reserve index on CMR, suggesting a possible role for this therapy in this patient subset (with severe CMD). These findings are hypothesis generating and deserve further attention given the lack of major evidence-based treatment options for patients with CMD.

Ranolazine has been studied before in patients with angina without PCI in the CARISA, MARISA, and TERISA trials, with a significant benefit in anginal symptoms among diabetic patients in the latter trial. More recently, ranolazine did not show a benefit in patients with unrevascularized disease post-PCI. This trial provides complementary information among patients with CMD.

References:

Bairey Merz CN, Handberg EM, Shufelt CL, et al. A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve. Eur Heart J 2015;Oct 27:[Epub ahead of print].

Clinical Topics: Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Stable Ischemic Heart Disease, Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Computed Tomography, Echocardiography/Ultrasound, Nuclear Imaging, Chronic Angina

Keywords: Acetylcholine, Angina Pectoris, Angina, Stable, Coronary Angiography, Coronary Artery Disease, Coronary Stenosis, Echocardiography, Stress, Magnetic Resonance Spectroscopy, Myocardial Ischemia, Perfusion Imaging, Quality of Life, Tomography, Emission-Computed, Single-Photon


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