Exercise Therapy for Women With ANOCA

Overview

Angina is a feeling of chest pain or discomfort which can happen if there is reduced blood flow to the heart. Patients can experience angina with no obstructive coronary arteries (ANOCA) which is a difficult condition to treat (ie relieve angina) since few randomised, controlled therapy trials have been undertaken for ANOCA. Until now, angina has been mainly studied in men even though women are at least two-fold more likely than men to experience ANOCA. In 2023, a Scientific Statement from the American Heart Association affirmed that resistance exercise training can improve or maintain muscle mass and strength and confer favourable physiological and clinical effects on cardiovascular disease and risk factors. Resistance exercise has not been assessed in ANOCA and it offers an important opportunity to study non drug alternatives to treatment for women. This study will use a resistance based exercise programme to investigate if symptoms of ANOCA can be improved in women. It will recruit at least 76 patients (maximum 152 patients) across 13 hospitals in the UK and the Netherlands. The study will use a randomised wait list control design. This means all participants will be offered the intervention, but the randomisation will decide when they undergo it. It is part of a platform of trials for women with ANOCA. We are also setting up a drug study called ANOCA Therapy and a cohort study called ANOCA- Diagnosis.

There is a gap in knowledge on evidence-based therapy for ANOCA. Stratified medicine is a population-level diagnostic approach for identifying endotypes in a heterogenous population of all-comers. An endotype is defined as a subtype of a condition, which must be characterised by a distinct functional or pathophysiological mechanism. Use of quantitative noninvasive and invasive diagnostic methods, such as magnetic resonance imaging and coronary function tests involving acetylcholine testing, enables more accurate identification and discrimination of causal endotypes of ANOCA. This is especially relevant for women with ANOCA who have historically been under-recognised. Quantitative diagnostic methods should bring an end to empirical therapy, therapeutic nihilism and sex disparities in ANOCA. Precision medicine is different. Precision medicine targets the individual (and their endotype) with a mechanism informed therapy. Accordingly, in this Wellcome Leap Visible project, we will employ a stratified medicine diagnostic approach in women with suspected ANOCA undergoing invasive CFTs in multiple hospitals and then employ a precision medicine strategy by offering each woman an endotype-informed therapy option. Resistance exercise has not been previously investigated in ANOCA and it therefore represents a novel therapeutic option. This lifestyle intervention will increase the range of trial options, maximize patient choice for participation, and facilitate timely delivery of this project. The beneficial effects of resistance exercise on cardiovascular function have recently been endorsed in a Scientific Statement from the American Heart Association and further supported by a systematic review and favourable experience in our recent randomized trial in Long COVID. In 2023, a Scientific Statement from the American Heart Association affirmed that resistance exercise training can improve or maintain muscle mass and strength and confer favourable physiological and clinical effects on cardiovascular disease and risk factors. In 19 men with coronary artery disease and endothelial dysfunction, indicated by abnormal acetylcholine-induced coronary vasoconstriction, a randomized controlled trial of aerobic exercise training demonstrated improvements in endothelium-dependent vasodilatation both in epicardial coronary vessels and in resistance vessels. The intervention involved an exercise program six times per day for at least 10 minutes. These results were promising but came with major limitations: no women were included in the study and the exercise program is both burdensome and impractical. Resistance exercise has not been assessed in ANOCA. Inclusion of a non-CTIMP (lifestyle intervention) brings strategic advantages to our ANOCA platform. A non-medicinal intervention provides an accessible therapy option for women of child-bearing age and for those who may prefer not to participate in an investigational drug trial. This non-CTIMP may also become an option for women who withdraw from a CTIMP, or who complete a CTIMP and are willing to continue into a second trial. The basket trial of resistance exercise may include participants who have completed a precision medicine CTIMP who then wish to participate in the resistance exercise trial or vice versa.