Coronary flow reserve predicts response to anti-ischaemic therapy in patients with angina with non-obstructive coronary arteries
Authors: Sinha A , Rahman H , Dutta U , Demir O , De Silva K , Clapp B , Webb I , Gulati A , Pinho P , Ellis H , Chiribiri A , Shah A , Marber M , Webb A , Perera D 
Published: November 2023

Abstract

Background
Half of all patients with angina have non-obstructive coronary arteries (ANOCA) and therapy is often empirical. The CorMicA trial showed improved symptom scores with a physiology-guided approach but the mechanistic relationship between physiological classification and outcome remains unclear.

Purpose
To assess if invasively assessed coronary flow reserve (CFR) can predict change in exercise time (ET) and angina-specific quality of life (QOL) in response to anti-ischaemic therapy in patients with ANOCA.

Methods
Prospective, randomised, crossover trial of consecutively evaluated patients with ANOCA. Inclusion criteria: (i) typical and limiting angina; (ii) non-obstructive coronary arteries (fractional flow reserve &gt;0.80); (iii) normal left ventricular systolic function. Coronary physiological assessment was performed using a pressure and Doppler dual sensor-tipped wire in the left anterior descending artery and microvascular dysfunction defined a priori as CFR&lt;2.5 in response to intravenous Adenosine. Patients, clinicians, and researchers were blinded to coronary physiology data. All patients were then sequentially treated with Amlodipine and Ranolazine (in a randomised order), in 4 week blocks with 1 week washout (Figure 1). The outcome measures are 1) Primary (objective): change in ET on exercise stress testing and 2) Secondary (subjective): change in angina-specific QOL on Seattle Angina Questionnaire (SAQ). Data are presented as mean±SD or median (IQR).

Results
Sixty-six patients with ANOCA were enrolled into the study [62±8 years, 64% females, CCS 3 (2, 3)]; eight patients were excluded. Forty patients had an impaired CFR (2.0±0.3), whilst 18 patients had normal CFR (3.1±0.6), with similar baseline ET (324±133 vs 321±136 seconds, respectively; p=0.94). Patients with an impaired CFR improved their exercise capacity with Ranolazine (ΔET 70±108 seconds; p&lt;0.01) and Amlodipine (ΔET 70±82 seconds; p&lt;0.01). However, there was no such improvement in patients with normal CFR, with either Ranolazine (ΔET 16±88 seconds; p=0.49) or Amlodipine (ΔET 21±59 seconds; p=0.18) (Figure 2). There was no evidence of a training effect (ΔET between visit 1 and visit 4 was 15±112 seconds; p=0.57). Angina-specific QOL improved in patients with impaired CFR [Ranolazine ΔSAQ 12±18 (p&lt;0.01) and Amlodipine ΔSAQ 8±13 (p&lt;0.01)]; the change in SAQ was less marked in patients with normal CFR [Ranolazine ΔSAQ 7±14 (p=0.07) and Amlodipine ΔSAQ 6±10 (p=0.03)].

Conclusion
Patients with impaired CFR demonstrated an improved exercise capacity, whereas patients with normal CFR did not. CFR-guided management of ANOCA is likely to be superior to an empirical strategy. This type of physiology-blinded study design could act as a template for future therapy trials in patients with stable angina.Study design for therapeutic trialResponse to anti-ischaemic therapy