By Michael H. Crawford, MD, Editor
SYNOPSIS: A small, invasive study of coronary microvascular disease patients has shown that those with a coronary flow reserve < 2.5 may benefit from anti-ischemic therapy.
SOURCE: Sinha A, Rahman H, Douiri A, et al. ChaMP-CMD: A phenotype-blinded, randomized controlled, cross-over trial. Circulation 2023; Oct 31. doi: 10.1161/CIRCULATIONAHA.123.066680. [Online ahead of print].
It is unclear whether the efficacy of anti-ischemic therapy is related to reduced coronary artery flow reserve (CFR) in angina patients with nonobstructive coronary arteries (ANOCA). Thus, the Characterising disease Mechanisms in Patients with Coronary Microvascular Disease to Stratify Therapy (ChaMP-CMD) trial was designed to assess whether a diminished CFR relates to the effects of anti-ischemic therapy on exercise time in patients with ANOCA. This trial was a phenotype-blinded, randomized, crossover study. Phenotype was determined by invasive coronary artery studies in patients with angina, normal left ventricular ejection fraction, and unobstructed coronary arteries without demonstrable vasospasm. Unobstructed coronary arteries were defined as no lesions with a fractional flow reserve < 0.80. Such patients were considered to have coronary microvascular disease (CMD) if, after intravenous adenosine, CFR was < 2.5. Those with CFR > 2.5 were the reference group without CMD.
The CMD patients were further characterized as functional if minimal microvascular resistance (mMR) was < 2.5 mmHg·cm-1·s-1 or structural if mMR was ≥ 2.5 mmHg·cm-1·s-1. Between 2020 and 2023, 486 ANOCA patients were identified. After various exclusion criteria were applied, 100 patients with CMD were selected for the study and 87 patients were randomized to amlodipine or ranolazine titrated to maximally tolerated doses for four weeks and then crossed over to the alternate drug for another four weeks after a one-week washout period. Their mean age was 61 years and 62% were women. CMD was identified in 57 patients at baseline (35 functional; 22 structural) and 30 were in the reference group.
Amlodipine could not be tolerated in 13 patients, and ranolazine was not tolerated in 11 patients, resulting in 74 patients who completed the amlodipine part of the study and 76 patients who completed the ranolazine portion. The primary outcome was the change in Bruce protocol treadmill exercise time (ET) from baseline to the end of each treatment period. The secondary outcome was the change in the Seattle Angina Questionnaire (SAQ) score. Baseline exercise time and SAQ summary scores were similar between the two groups.
The CMD group had a greater increment in ET than the reference group in response to both amlodipine (82 seconds, P < 0.001) and ranolazine (68 seconds, P = 0.005). The CMD patients had a greater increment in SAQ score than the reference group in response to ranolazine (7 points, P = 0.048), but not to amlodipine (2 points, P = 0.549). ET increased with both drugs in the functional and structural groups of CMD patients. Patients with structural CMD had a greater increment in ET in response to amlodipine than ranolazine (mean difference 46 seconds, P = 0.056). Patients with functional CMD had a similar increment in ET in response to ranolazine and amlodipine (mean difference 3 seconds, P = 0.859). The authors concluded that in phenotypically similar patients with ANOCA without demonstrable vasospasm, only those with CMD derive benefit from anti-ischemic therapy.
COMMENTARY
It is uncommon today, in the era of big data, to see small, focused, mechanistic pathophysiology studies in humans. ChaMP-CMD is such a study, and it helps direct therapy for ANOCA patients. ANOCA is a heterogeneous group of patients with three main subgroups: coronary vasospasm, CMD, and non-cardiac chest pain. In patients with angina pectoris and positive stress tests for myocardial ischemia, the diagnosis can be made by coronary angiography, using either computed tomography (CT) or invasive approaches. The invasive strategy has the added advantage of being able to induce vasospasm and to quantitate coronary microvascular flow characteristics, although CT angiography is making strides in the latter area.
In ChaMP-CMD, ANOCA patients without vasospasm or any flow-limiting coronary lesions by fractional flow reserve were categorized by their response to intravenous adenosine as having CMD (CFR < 2.5) or not (the reference group). The CMD group was divided further by measuring minimal microvascular resistance into a functional group and a smaller structural group. All the CMD and reference group patients were randomized to a crossover study of titrated doses of amlodipine or ranolazine for four-week periods, with the change in treadmill ET as the primary endpoint and the SAQ as the secondary endpoint. Only the CMD patients had a significant change in ET with both drugs. Thus, the authors concluded that invasively diagnosed CMD identifies those ANOCA patients who may benefit from antianginal therapy. Also, both the functional and structural subtypes of CMD responded to therapy. There were some differences in the quantitative responses to amlodipine and ranolazine, but the clinical significance of these nuances is unclear.
The strengths of this study include the detailed physiologic characterization of the patients and the well-designed crossover protocol, which included washout periods with repeated exercise tests to eliminate any training effects of multiple tests. Weaknesses include the small, highly select group of patients (18% of those screened) and a dropout rate of about 25% of those enrolled. The study was open-label, but the investigators were blinded to the physiologic phenotype. Also, invasive coronary physiology studies were not repeated. In addition, only two drugs were studied.
Although ChaMP-CMD makes a strong case for invasive coronary physiology studies to select therapy for ANOCA patients, one might ask, why not just try empiric treatment? If you were to start with a calcium channel blocker, that potentially would treat vasospasm as well as CMD. If the patient failed a calcium channel blocker, you then could try ranolazine. Failure of both drugs would suggest you are dealing with non-cardiac chest pain. Hopefully, in the future, CT angiography or some other less invasive approach to picking the best therapy for each patient will be perfected, as I suspect the invasive approach will meet with resistance from patients, payers, and some physicians.
