What is the mechanism of action of the Coronary Sinus Reducer in refractory angina? A randomised placebo-controlled study

Background

With an ageing population and improved survival from heart attacks, a growing number of people are living with coronary artery disease. One of the main treatment aims in coronary artery disease is the prevention of angina, which is chest pain that comes on with exertion. Conventional therapies for angina include medications, coronary stents (coronary angioplasty) and coronary artery bypass surgery. Despite these interventions, approximately 10% of patients with coronary artery disease have ongoing chest pain (refractory angina). Until recently, these patients have had no available treatment options. Refractory angina is an extremely debilitating condition and patients are often confined to their homes due to severe exertional chest pain, leading to a poor quality of life for the majority. Patients with refractory angina frequently visit their general practitioner and emergency departments with chest pain. They often have repeated invasive coronary angiograms without treatment and until recently physicians have not been equipped with an effective therapy to offer to these patients.

A novel device for treatment of refractory angina was developed in response to this unmet clinical need - the Coronary Sinus Reducer (CSR). It is an hourglass shaped, stainless steel mesh which is implanted in the coronary sinus (the vessel which drains blood from the heart muscle). This is a simple procedure performed under local anaesthetic, which takes approximately 30 minutes. It is thought to improve the flow of blood to the heart muscle. In a randomised trial with a placebo control arm, CSR improved angina compared to placebo (Coronary Sinus Reducer for treatment of Refractory Angina Trial - COSIRA).

Objectives

The mechanism through which the CSR exerts its effect is unknown and this fellowship is designed to discover it. In small animal studies, a surgical stitch used to narrow the coronary sinus caused redistribution of blood in the heart muscle, favouring the areas which were most in need. This is thought to be how the CSR acts, but this has never been demonstrated in humans. As we do not know how it works, we cannot identify patients who are most likely to benefit from the device. In this fellowship I will study the how the CSR works in patients with refractory angina.

Methods

This study will enrol 40 patients with refractory angina. I will use cardiac imaging with MRI scans to assess blood flow in the heart muscle and will use ultrasound to measure blood flow in the coronary arteries. We will assess patients' symptoms, using questionnaires, exercise time and a symptom smartphone application, into which patients can input their symptoms daily throughout the study.

This study will utilise a placebo control, so that we can understand the true effects of the device. Patients will be randomly assigned 1:1 to the treatment arm, where they will receive a CSR in the normal fashion, or the control arm, where they will have a placebo procedure. Participants and researchers will be blinded to treatment arm. At the end of a 6 month follow up period, the baseline tests will be repeated. The study has been designed in collaboration with the NHLI ORBITA focus group of patients with lived experience of stable angina.

I will discover whether the CSR causes improved blood flow to the heart muscle on MRI and I will correlate changes in symptoms and exercise time, with the baseline tests of blood flow, to better understand who would benefit from the device. This fellowship will define the effect that the CSR has on patients with refractory angina, improve our understanding of its mechanism and advance our ability to target therapy in this undertreated group of patients.

Background:

The coronary sinus reducer (CSR) is a novel device for the treatment of angina which is refractory to all conventional therapies and has shown placebo-controlled angina relief in a randomised trial. It has been used in humans for many years, with an excellent safety profile and is now in the European Society of Cardiology guidelines. Use of the CSR remains very limited and the mechanism of action is poorly understood.

Aims:

1. To discover the mechanism of action of the CSR in refractory angina
2. To identify patients who are most likely to receive benefit from the CSR

Methods:

I will conduct a randomised, double-blinded, placebo-controlled study. I will enrol 40 patients with refractory angina. They will undergo baseline assessment with angina and quality of life questionnaires and exercise time. A smart phone symptom app will be completed daily throughout the study. Participants will also undergo quantitative, Kellman sequence cardiac perfusion MRI scans and non-invasive coronary flow measurement with pulsed-wave spectral doppler.

In the catheterisation laboratory, after establishing auditory isolation with headphones and a deep level of conscious sedation, participants will be randomised 1:1 to the CSR or placebo. The follow-up will be six months, at which point, participants will repeat their baseline assessments and be unblinded.

Outcomes:

The primary endpoint will be the difference in myocardial perfusion reserve (MPR) increment on MRI, between the CSR group and the placebo group. A secondary endpoint will be the correlation between baseline MPR and exercise time increment.

Opportunities:

This fellowship will demonstrate the true placebo subtracted effects of the CSR on the ischaemic myocardium, defining the mechanism of action. It will advance the use of placebo control in mechanistic studies and stimulate new research in the role of the cardiac venous system in ischaemia.

1. Patients

The principal beneficiaries of this fellowship will be patients. There is a large and growing number of patients with refractory angina who cannot access therapy and have a very poor quality of life. This group will benefit hugely from the discoveries of this fellowship, which will potentially provide a clear mechanistic explanation for the benefits seen with the CSR. Defining this mechanism will inspire new confidence with the device and increase referral of appropriate patients. This fellowship will also identify predictors of good clinical response to the CSR, meaning for the first time, appropriate patients can be confidently selected.

2. Academic beneficiaries

The mechanism and significance of angina and ischaemia, despite significant research in the field, is uncertain, particularly in the light the ORBITA and ISCHEMIA trials. This mechanistic study of the coronary sinus reducer is the first of its kind. It is the only placebo-controlled study to evaluate the physiological changes caused by coronary sinus intervention. The results will therefore have a significant impact in the field, with the potential to re-define our current ischaemic model to incorporate the cardiac venous circulation.

This study will have a global impact. By utilising a placebo-controlled design and mechanistic focus, it will demonstrate the value of a robust methodology in generating reliable results, reiterating the MRC's commitment to scientific excellence.

3. Health policy

The CSR is currently in the European Society Guidelines with a class IIb recommendation. It is not currently recommended by NICE. The CSR does have placebo-controlled evidence of efficacy in ischaemic heart disease. However, these results are un-replicated and crucially, are not married to a well described mechanism. If an investigator-led, MRC funded study which is independent of industry, demonstrates this mechanism for the first time, it will have profound implications for both national and international guidelines.

4. Delivery of highly trained researchers

I intend to use this dedicated period of training to become a leader in cardiovascular research, ready to enter higher speciality training already highly skilled in cardiac imaging, coronary physiology and a novel interventional cardiology technique. Through the training delivered by world class supervisors, this fellowship, at this institution will deliver me as highly skilled academic cardiologist. Through the skills and experience gained during this MRC funded fellowship, I will be well placed to deliver high quality, patient centred research throughout my career in cardiology.


5. Advancing placebo-controlled mechanistic studies

The use of a placebo-control in drug trials is widely accepted as necessary but has not been widely utilised for interventional procedures. Moreover, placebo-control and double blinding are not well established in trials to discover the mechanism of action of a device or procedure. This fellowship will deliver results which physicians and patients can be confident in, as the methodology will ensure the removal of placebo, nocebo and bias. On publishing these results, we will make the case for widespread use of a placebo group in mechanistic studies as well as for efficacy trials of interventional procedures. The success of this fellowship will emphasise the feasibility of this methodology and inspire confidence in other researchers who aspire to reliable results.