Title: Effect of antianginals on patient-reported outcomes and tests of ischaemia in stable coronary artery disease
Funder: Department of Health and Social Care

Abstract: Background The diagnosis of stable angina is made by ischaemic tests, either noninvasively for example with dobutamine stress echo (DSE) or invasively with coronary physiology. By the time patients undergo these tests they have often already been started on antianginals. The original research on these antianginals used exercise as the stressor and ECG as the marker of ischaemia. We do not know the impact of these medications on present day diagnostic ischaemia indices which tend to use pharmacological stress. Therefore, we do not know if the tests are inaccurate when patients are taking antianginals. This might mean we are inappropriately exposing patients to unnecessary procedures, or equally undesirable, denying them definitive treatment and further investigation. Aims This Fellowship will tackle our lack of understanding of how the antianginal medications doctors prescribe for patients affect the tests' accuracy and second, the relatively poor image resolution which can make interpretation difficult. It will also collect pilot patient-reported outcome data on the different antianginals. Design Double-blinded randomised-controlled study of 50 patients Primary outcome measures DSE score using traditional echo, FFR (fractional flow reserve), iFR (instantaneous wave-free ratio) Secondary outcome measures DSE score using ultrafast echo, exercise time, blood pressure trend (finapres), heart rate, symptom score (mobile phone application/ Rose angina questionnaire/ Seattle Angina Questionnaire), quality of life, side effects, change in GLS and cardiac output MethodsPatients awaiting angioplasty for severe coronary artery disease will be enrolled. They will receive each of the following medications for a week: Bisoprolol (beta blocker) Nifedipine (calcium channel blocker) Isosorbide mononitrate (long-acting nitrate) Enalapril (ACE-inhibitor) - active control No antianginals -h; inactive controlThe sequence of medications will be randomised, and patients and staff will be blinded to the medication allocation. Blinding will be achieved by the use of matched placebos. At the end of each week, patients will undergo a DSE, an exercise treadmill test and questionnaires. DSE images will be acquired using traditional echo and ultrafast echo using the same probe. Ultrafast echo is a new tool that captures images at a massively increased frame rate and trades the increase in frame rate for an increase in resolution. At the end of the final week, patients will have a coronary angiogram with an invasive pressure wire to measure FFR and iFR prior to their scheduled angioplasty. Patients will complete a symptom app daily throughout the study. Conclusion This study will reveal the mechanisms of angina relief from antianginals and provide an evidence base for handling noninvasive and invasive tests of ischaemia for patients who are taking them. This will inform guidelines for test interpretation. More accurate interpretation will reduce healthcare costs incurred by unnecessary appointments and procedures and will improve the patient experience. This study will demonstrate feasibility of ultrafast echo. A larger scale study will be planned to validate this tool for clinical practice. Finally, the patient-reported outcome data will be used to inform the design of a larger trial that will identify predictors of angina relief by specific antianginals or combinations of antianginals.

Lay abstract: Angina is chest pain during physical activity caused by narrowing of the coronary arteries. This can cause a reduction in the blood supply to the heart (known as ischaemia) as the heart rate increases during exercise. One test for ischaemia is a dobutamine stress echo (DSE). In this test we compare images of the heart before and after increasing the heart rate with a medication called dobutamine to simulate what happens during exercise and see if the blood supply to the heart is reduced at that time. We can also directly observe the narrowings using a coronary angiogram and measure the pressure loss across them (FFR - fractional flow reserve and iFR -h; instantaneous wave-free ratio). These measurements represent the change in blood flow caused by the narrowing. Patients with angina are usually given medications to relieve angina. We expect that these medications act by improving the blood supply to the heart. Patients are also frequently tested using DSE and invasive pressure measurements like FFR and iFR. We do not know the effect of antianginal medications on the test results. Sometimes the results of these tests are unexpected and this may be due to the effect of antianginal medications. Given that these results are used to decide on key future management steps including whether to open up the narrowing with a stent, understanding the effect of these medications could be very important for improving patient care. This research will measure the effect of three common types of medications on DSE, FFR and iFR. Participants will take each medication for one week. The three medications (bisoprolol, nifedipine and isosorbide mononitrate) are licensed for treatment of stable angina and are commonly prescribed. At the end of each week, a DSE, a treadmill test and questionnaires will be performed. FFR and iFR will be measured during an angiogram at the end of the final week. Patients will report their symptoms daily via a smartphone application. As part of DSE testing, I will also collect images of the heart using a new technique named ultrafast echo to assess whether this improves the accuracy of DSE. While DSE is a useful test for assessing the blood supply to the heart, as the heart beats faster with the medication given during the DSE, the quality of the images goes down. This affects the accuracy of the final report. I am working with engineers who have developed a way of making the images more precise using ultrafast echo. This tool is expected to provide clearer pictures of the moving heart muscle allowing us to more clearly define the effects of the antianginal medications on DSE. To eliminate the bias that may come from staff and patients knowing which medication they are taking that week, staff and patients will not have knowledge of this. There will be 24-hour study team helpline which can reveal the week's medication if urgently needed, for example for safety or because a patient wants to withdraw from the study. Each patient enrolling in the study will be assessed by a doctor to ensure it is safe for them to take the medications and will be carefully monitored for safety and side effects for the duration of their participation in the study. No long-term adverse effects are anticipated as a result of participation in the study. This will study will help us to understand the results of ischaemic tests better and the effect of common antianginal medications on these tests. This will help ensure optimal management and investigation for patients with angina.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR