ChaMP-CMD: A Phenotype-Blinded, Randomized Controlled, Cross-Over Trial

Angina with nonobstructive coronary arteries is a common condition for which no effective treatment has been established. We hypothesized that the measurement of coronary flow reserve (CFR) allows identification of patients with angina with nonobstructive coronary arteries who would benefit from anti-ischemic therapy.

Patients with angina with nonobstructive coronary arteries underwent blinded invasive CFR measurement and were randomly assigned to receive 4 weeks of amlodipine or ranolazine. After a 1-week washout, they crossed over to the other drug for 4 weeks; final assessment was after the cessation of study medication for another 4 weeks. The primary outcome was change in treadmill exercise time, and the secondary outcome was change in Seattle Angina Questionnaire summary score in response to anti-ischemic therapy. Analysis was on a per protocol basis according to the following classification: coronary microvascular disease (CMD group) if CFR<2.5 and reference group if CFR≥2.5. The study protocol was registered before the first patient was enrolled (International Standard Randomised Controlled Trial Number: ISRCTN94728379).

Eighty-seven patients (61±8 years of age; 62% women) underwent random assignment (57 CMD group and 30 reference group). Baseline exercise time and Seattle Angina Questionnaire summary scores were similar between groups. The CMD group had a greater increment (delta) in exercise time than the reference group in response to both amlodipine (difference in delta, 82 s [95% CI, 37-126 s]; P<0.001) and ranolazine (difference in delta, 68 s [95% CI, 21-115 s]; P=0.005). The CMD group reported a greater increment (delta) in Seattle Angina Questionnaire summary score than the reference group in response to ranolazine (difference in delta, 7 points [95% CI, 0-15]; P=0.048), but not to amlodipine (difference in delta, 2 points [95% CI, -5 to 8]; P=0.549).

Among phenotypically similar patients with angina with nonobstructive coronary arteries, only those with an impaired CFR derive benefit from anti-ischemic therapy. These findings support measurement of CFR to diagnose and guide management of this otherwise heterogeneous patient group.