Chronic Coronary Syndrome in Swedish Primary Care

Study Overview
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Brief Summary
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The goal of this clinical trial is to learn about a new procedure for investigation of possible coronary heart disease and to see if it is faster, cheaper or more expensive, promotes healthier behavior, mental well-being, adherence to drugs for heart protection and the risk for cardiac events like acute myocardial infarction over years to come. The novelty in the procedure is that a myocardial perfusion scan to assess blood flow to areas of the heart muscle, echocardiography i.e., heart ultrasound and heart CT scan comes as a package investigation performed on the same day. According to existing routines, standard investigation an exercise stress bicycle test is done, as well as an echocardiography and if needed the work up is completed by a myocardial perfusion scan. The main questions the trial aims to answer are: are the results from the procedure given to the patient faster with package investigation as compared to standard investigation? does the cost differ between the package and standard investigation group? does self-reported physical activity, physical fitness, dietary habits and mental well-being differ between the package and standard investigation group at start and after one, three and five years? does prescription of drugs taken for heart protection and adherence to the prescribed drugs differ between the package and standard investigation group after two and five years? does the risk for heart events like acute heart infarction differ between package and standard investigation after two and five years? Primary health care centers in Region Östergötland are randomly assigned to use either the new or existing procedure for investigation of possible coronary heart disease a so called cluster randomization. Patients who consult a physician at any of these primary health care centers are potential participants in the trial and are informed about the trial by written information, as they get their appointment for the medical investigation at either of two hospitals in the Region Östergötland. When the patient comes to the hospital for the investigations, he or she is asked to give written consent to the research i.e., to answer questionnaires now after one, three and five years, to let the researchers take part of the medical records, investigational results and data from medical registries over time.

Detailed Description
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In primary health care patients with chest symptoms are common. In many cases the cause is benign but chronic coronary artery disease (CAD) must often be considered. In the clinical work, evaluation of symptoms and risk factors are fundamental for a plausible working diagnosis and to judge if any further investigation is needed. The probability of CAD for a person of a certain age, sex and character of chest symptoms, scored from 0-3, i.e. pretest probability (PTP) for CAD, is substantially lower now than it was a decade ago in western countries. Consequently, recent European guidelines recommend that further investigation to rule out CAD may be omitted if the risk for CAD is judged to be low (PTP<15 %) and there are no further cardiovascular risk factors. If further investigation is needed in the low-risk group, computed tomography angiography (CTA) is preferable. When the risk for CAD is judged to be intermediate (PTP> 15 %) an imaging investigation is advocated instead of the well-established exercise stress bicycle test. A much-used imaging test is myocardial perfusion scan in which an exercise stress bicycle test is performed, with the addition of an intravenous injection of a small amount of radioactive tracer, whereafter the myocardial blood flow is demonstrated by imaging. Sensitivity for myocardial perfusion scan to detect significant CAD is 87 % (95 % CI 83-90) in comparison with exercise stress bicycle test where it is only 58 % (95 % CI 46-69). Specificity is 70 % (95 % CI 63-76) and 62 (95 % CI 54-69) respectively. However, the exercise stress bicycle test reveals indirect signs of myocardial ischemia and is reasonable in price, easy to perform and available in many clinics and hospitals. It is since long the first-line method for referral from the primary care setting. If the result from the exercise stress bicycle test is inconclusive, the work-up should be continued, e.g. with myocardial perfusion scan. An echocardiogram is often performed as well to evaluate the condition of the myocardium, heart valves and left ventricular ejection fraction. This stepwise or sequential clinical work-up strategy is well known and reasonable in general practice where patients in general have a low prevalence of serious diseases compared to organ specialist clinics. Since June 2021 in Region Östergötland (471 912 inhabitants 2022) CTA is recommended if further investigation is deemed necessary in patients with a low risk of CAD (PTP< 15 %) in primary care. For patients with intermediate risk of CAD (PTP> 15 %) exercise stress bicycle test is still the first-line choice. There may be advantages if myocardial perfusion scan and echocardiogram is performed on a single visit. In addition, a CT scan of the heart to determine coronary artery calcification (CAC) score is easy to perform on the same visit, gives only a small amount of radiation and adds useful information. The CAC-score has been shown to be an independent predictor of future cardiovascular events and is useful for reclassification of cardiovascular risk based on traditional risk factors like age, cholesterol levels and smoking habits. Furthermore, a clear and coherent answer on all three investigations, to the referring GP can provide a more secure basis for clinical decision making. For the individual patient it is probably an advantage to get a thorough investigation done at one single visit and possibly a faster and more valid statement from the investigations by the GP. On the other hand, if many advanced investigations are done unnecessarily, expenses and exposure to radiation will increase unjustifiably. Possibly there is also a risk of medicalization and to create worries for future cardiovascular events communicating the CAC-score to people that has not asked for the information. In order to get a faster and more complete basis for the evaluation of CAD in primary care patients with an intermediate (PTP> 15 %) risk the investigators created a package investigation comprised of myocardial perfusion scan, echocardiogram and CT scan of the heart on a single visit. The results from myocardial perfusion scan will be written according to national guidelines and communicated to the referring GP together with results from echocardiogram and CAC-scoring as a coherent answer. Moreover, registration of heart sounds followed by risk calculation by a technical device Cadscore® will be performed but only for scientific analyzes and not be given as a clinical answer. In this study the investigators aim to compare the standard routine sequential investigation for detecting CAD with a single-visit package investigation.

Official Title
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Chronic Coronary Syndrome in Swedish Primary Care

Conditions
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Coronary Artery Disease

Intervention / Treatment
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* Diagnostic Test: Package investigation
* Device: Sound registration with Cadscore® and added risk calculation
* Diagnostic Test: Standard investigation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • People who seek primary care for symptoms judged to be compatible with a medium probability (PTP> 15) for symptomatic chronic coronary artery disease. Exclusion Criteria: Suspicion of acute coronary syndrome when care is sought. Previously diagnosed acute myocardial infarction Revascularization with PCI/CABG Proven reversible ischemia according to myocardial scintigraphy. Left Bundle Branch Block (LBBB). Ventricular pacemaker People whose meaning due to illness, mental disorder, weakened state of health or any other similar condition cannot be obtained, to be included in a research project. Insufficient understanding of spoken and written Swedish language.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Cluster randomised trial. All of 47 primary health care centres in Region Östergötland are invited to take part. After acceptance the actual number of primary health care centres will be randomly allocated to to either package or standard investigation group. The aim is to include about 20 primary health care centers in the study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Package investigation<br>Resting ECG, Evaluation of risk according to PTP-table. Echocardiography, Exercise stress bicycle test (secondarily drug provocation) with injection of isotope for myocardial scintigraphy, Scanning for myocardial perfusion CAC-scoring with CT | Diagnostic Test: Package investigation<br>* Investigations performed on a single visit, according to arm description<br>Device: Sound registration with Cadscore® and added risk calculation<br>* Recording of cardiac diastolic sounds enabling the calculation of a risk score.<br>|
| Active Comparator: Standard investigation<br>Resting ECG Evaluation of risk according to PTP-table. Echocardiography. Exercise stress bicycle test. If judged to be needed according to clinical indication sequentially completed by: Echocardiography, Exercise stress bicycle test (secondarily drug provocation) with injection of isotope for myocardial scintigraphy and/or Coronary CTA. In addition, cardiac examinations done with other modalities chosen on clinical grounds will be examined in the study. , | Diagnostic Test: Standard investigation<br>* Sequential investigations according to arm description<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of days till completed assessment of myocardial ischemia | waiting time (days) after the results of package investigation or exercise stress bicycle test (standard investigation) are available at the primary health care center till invasive coronary angiography is done or results from completed non-invasive myocardial ischemia investigation is communicated to the participant (patient). | From the day of inclusion up to one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Swedish crowns or other currency | Costs for medical investigations, consultations and costs generated by participants loss of production and travel costs. Data will be gathered by review of the participants computerized medical records one year after the day of inclusion. Medical investigations will be sought in local medical registries.The participant will be asked if being a professional worker or not on the day of inclusion. | From the day of inclusion and one year thereafter | 
| Health related quality of life | Health related quality of life will be measured by EQ-5D-5L Swedish version (Devlin NJ et al., 2017) | Up to five years | 
| Radiation per patient | millisievert (mSv) | One year | 
| Physical activity | Physical activity will be measured by two categorical questions asking for level of physical activity (Olsson SJ et al., 2016) | Up to five years | 
| Dietary habits | Dietary habits will be measured by five categorical questions about consumption of fruit, vegetables, snacks and soft drinks during the last week. (Henriksson H et al., 2020) | Up to five years | 
| Health and life quality | Health and life quality will be measured by the Swedish RAND-36 A 36-item scale. (Ohlsson-Nevo E et al., 2021) | Up to five years | 
| Heart focused anxiety | Heart focused anxiety will be measured by the Cardiac Anxiety Questionnaire - CAQ An 18-item scale (Eifert et al., 2000) | Up to five years | 
| Generalized anxiety | Generalized anxiety will be measured by the Brief Measure for Assessing Generalized Anxiety Disorder - GAD-7 A seven item scale. (Spitzer et al., 2006) | Up to five years | 
| Depression symptoms | Depression symptoms will be measured by the Patient Health Questionnaire - PHQ-9 Maximum score 27 (Hansson et al., 2009) | Up to five years | 
| Sleep quality | Sleep quality will be measured by The Pittsburgh Sleep Quality Index - PSQI A 19-item scale which assesses sleep quality and disturbances over a 1-month time interval. (Buysse et al., 1989) | Up to five years | 
| Physical fitnes | Physical fitness will be measured by The International Fitness Scale - IFIS A 5-item scale (Ortega FB et al., 2011) | Up to five years | 
| MACE | Major adverse cardiovascular event - MACE Data will be gathered from national Swedish registries i.e. SWEDEHEART, the National Patient Register and Dödsorsaksregistret (The Cause of Death Register) | Up to five years | 
| Compliance to cardioprotective drugs | Data on prescribed and purchased drugs will be gathered from the National Prescribed Drug Register . | Two years before and up to five years after inclusion. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Primary Health Care, Diagnostic Imaging, Myocardial Perfusion Imaging