Abstract

Background

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.

Methods

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).

Results

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).

Conclusions

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.

Angina with nonobstructive coronary arteries (ANOCA) is a common clinical condition, although this umbrella term covers several distinct pathophysiological entities. These include coronary microvascular disease (CMD), defined as an inability of the coronary vasculature to increase coronary blood flow in response to heightened myocardial oxygen demand despite the absence of epicardial coronary artery disease. CMD leads to impaired quality of life and a heightened risk of adverse cardiovascular outcomes. A diagnosis of CMD is traditionally made by invasive assessment in the cardiac catheter laboratory to delineate the hallmark of CMD, a diminished coronary flow reserve (CFR), representing the ratio of maximal achievable flow to resting flow. CFR<2.5 is associated with impaired coronary perfusion efficiency during exercise and myocardial ischemia on noninvasive assessment. It has recently been demonstrated that CMD itself may be a heterogeneous condition comprising 2 distinct endotypes termed functional and structural CMD, distinguished by elevated minimal microvascular resistance in the latter. Although the 2 endotypes are phenotypically similar, the underlying pathobiology is distinct.

Although the CorMicA study (Coronary Microvascular Angina) has previously demonstrated the value of coronary physiology-stratified therapy in enhancing angina-specific quality of life in patients with ANOCA (including patients with CMD, vasospastic angina, and noncardiac chest pain), uptake by physicians has been low; this is partly because of skepticism about the mechanistic link between coronary physiology parameters and response to therapy. Furthermore, it is not known whether physiology-stratified therapy leads to an improvement in exercise capacity, which is the reference standard for efficacy of anti-ischemic therapies.

The ChaMP-CMD trial (Characterising Mechanisms in Patients with Coronary Microvascular Disease to Stratify Therapy) aims to assess whether a diminished CFR relates to the effects of anti-ischemic therapy on exercise time in patients with ANOCA and, if it does, whether further endotyping, on the basis of minimal microvascular resistance, allows even more granular stratification of therapy.