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Randomized Controlled Trial
. 2016 May 14;37(19):1504-13.
doi: 10.1093/eurheartj/ehv647. Epub 2015 Nov 27.

A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve

C Noel Bairey Merz  1 , Eileen M Handberg  2 , Chrisandra L Shufelt  3 , Puja K Mehta  3 , Margo B Minissian  3 , Janet Wei  3 , Louise E J Thomson  4 , Daniel S Berman  4 , Leslee J Shaw  5 , John W Petersen  2 , Garrett H Brown  2 , R David Anderson  2 , Jonathan J Shuster  6 , Galen Cook-Wiens  7 , André Rogatko  7 , Carl J Pepine  2
Affiliations
Randomized Controlled Trial

A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve

C Noel Bairey Merz et al. Eur Heart J. .

Abstract

Aims: The mechanistic basis of the symptoms and signs of myocardial ischaemia in patients without obstructive coronary artery disease (CAD) and evidence of coronary microvascular dysfunction (CMD) is unclear. The aim of this study was to mechanistically test short-term late sodium current inhibition (ranolazine) in such subjects on angina, myocardial perfusion reserve index, and diastolic filling.

Materials and results: Randomized, double-blind, placebo-controlled, crossover, mechanistic trial in subjects with evidence of CMD [invasive coronary reactivity testing or non-invasive cardiac magnetic resonance imaging myocardial perfusion reserve index (MPRI)]. Short-term oral ranolazine 500-1000 mg twice daily for 2 weeks vs. placebo. Angina measured by Seattle Angina Questionnaire (SAQ) and SAQ-7 (co-primaries), diary angina (secondary), stress MPRI, diastolic filling, quality of life (QoL). Of 128 (96% women) subjects, no treatment differences in the outcomes were observed. Peak heart rate was lower during pharmacological stress during ranolazine (-3.55 b.p.m., P < 0.001). The change in SAQ-7 directly correlated with the change in MPRI (correlation 0.25, P = 0.005). The change in MPRI predicted the change in SAQ QoL, adjusted for body mass index (BMI), prior myocardial infarction, and site (P = 0.0032). 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).

Conclusions: In this mechanistic trial among symptomatic subjects, no obstructive CAD, short-term late sodium current inhibition was not generally effective for SAQ angina. Angina and myocardial perfusion reserve changes were related, supporting the notion that strategies to improve ischaemia should be tested in these subjects.

Trial registration: clinicaltrials.gov Identifier: NCT01342029.

Keywords: Angina; Coronary microvascular dysfunction.

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Figures

Figure 1
Figure 1
Study subject enrolment, screening, randomization and completion flow diagram. Treatment period 1 and 2: randomized to sequence of ranolazine first followed by crossover to placebo, or vice-versa.
Figure 2
Figure 2
Mid-ventricular and mid-ventricular sub-endocardial myocardial perfusion reserve index change vs. Seattle Angina Questionnaire quality of life change (ranolazine vs. placebo) model. The observed change in mid-ventricular myocardial perfusion reserve index (A) and mid-ventricular sub-endocardial myocardial perfusion reserve index (B) are plotted against the observed differences in treatment change for Seattle Angina Questionnaire quality of life with a line depicting a simple linear regression. The Pearson correlation and standard error (r, SEE) for this association are shown with the P-value for the test against zero correlation. The multiple regression described in the results showed that as myocardial perfusion reserve index–mid-ventricular change increased, Seattle Angina Questionnaire quality of life change increased, adjusted for body mass index, prior myocardial infarction and site (P = 0.005) with a similar model results for myocardial perfusion reserve index–mid-sub-endocardial change and Seattle Angina Questionnaire quality of life change (P = 0.005). Other variables tested that were not selected by the model include: pharmacological stress heart rate change, age, body mass index, site, history of hypertension, history of diabetes, prior ranolazine use, gender, left ventricular mass, end-diastolic volume, quality of life depressed change, had menopausal symptoms, baseline Seattle Angina Questionnaire angina frequency, Seattle Angina Questionnaire change (each of the five subdomains), adenosine vs. regadenson, and ranolazine dose level.
Figure 3
Figure 3
Myocardial perfusion reserve index change according to qualifying coronary flow reserve in the subset of subjects with invasive coronary reactivity testing. Among subjects with qualifying coronary reactivity testing available coronary flow reserve and both period myocardial perfusion reserve index (n = 78), lower coronary flow reserve had significantly greater mid-ventricular myocardial perfusion reserve index change on ranolazine vs. placebo (P = 0.014). A higher myocardial perfusion reserve index number indicates better myocardial perfusion reserve.
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References

    1. Pepine CJ, Ferdinand KC, Shaw L, Light-McGroary KA, Shah R, Gulati M, Duvernoy C, Walsh MN, Bairey Merz CN. Emergence of non-obstructive coronary artery disease: a woman's problem and need for change in definition on angiography. J Am Coll Cardiol 2015;66:1918–1933. - PMC - PubMed
    1. Jespersen L, Abildstrom SZ, Hvelplund A, Galatius S, Madsen JK, Pedersen F, Hojberg S, Prescott E. Symptoms of angina pectoris increase the probability of disability pension and premature exit from the workforce even in the absence of obstructive coronary artery disease. Eur Heart J 2013;34:3294–3303. - PubMed
    1. Shaw LJ, Merz CN, Pepine CJ, Reis SE, Bittner V, Kip KE, Kelsey SF, Olson M, Johnson BD, Mankad S, Sharaf BL, Rogers WJ, Pohost GM, Sopko G, Women's Ischemia Syndrome Evaluation I. The economic burden of angina in women with suspected ischemic heart disease: results from the National Institutes of Health—National Heart, Lung, and Blood Institute—sponsored Women's Ischemia Syndrome Evaluation. Circulation 2006;114:894–904. - PubMed
    1. Johnson BD, Shaw LJ, Buchthal SD, Bairey Merz CN, Kim HW, Scott KN, Doyle M, Olson MB, Pepine CJ, den Hollander J, Sharaf B, Rogers WJ, Mankad S, Forder JR, Kelsey SF, Pohost GM. Prognosis in women with myocardial ischemia in the absence of obstructive coronary disease: results from the National Institutes of Health-National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE). Circulation 2004;109:2993–2999. - PubMed
    1. Pepine CJ. Ischemic heart disease in women. J Am Coll Cardiol 2006;47(3 Suppl):S1–S3. - PubMed

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