Chest pain - what now?

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Dorthy Reeves
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1 Chest pain - what now? A new device for patients with chest pain Phonocardiographic (acoustic) exclusion of coronary artery disease CAD Fast, radiation-free, non-invasive Summary The CADScor System is a new, precise and efficient method for the exclusion of CAD. Patients without CAD, who do not need to undergo more complex diagnostics, are identified by a low CAD-score. The performance of a CADScor System relies on a simple, fast and completely non-invasive test, without the use of contrast media or radiation. Patients do not have to ride a bicycle or "lie in the tube" but lay back and rest. The measurement takes less than 10 minutes in which patients hold their breath for several seconds. The CADScor test is based on innovative phonocardiography technology, state-of-the-art electronics and mathematical algorithms. No other primary care procedure is as reliable for the exclusion of coronary artery disease. The CADSscor System story 1 Stable coronary artery disease 2 CADScor System: a new decision aid 3 CADScor System principle: from nature to Medtech 3 Exclusion of CAD within 10 minutes 3 Overview of the study situation 4 Health economics 5 Fundamental heart information 5 Heart sounds for the diagnosis of CAD 5 Risk factors for CAD 6 Diagnosis & therapy of CAD 6 Coronary Artery Disease CAD 6 Contact 6 The CADSscor System story In 2003 two young scientists from Aalborg University in Denmark developed the idea of acoustically detecting constrictions in the coronary arteries instead of using an invasive cardiac catheter. Samuel Schmidt and Claus Graff both professors in their fields in the meantime integrate various disciplines, mathematics, physics and medicine into their discourse on the detectability of coronary vessel constrictions caused by changes in blood flow. Heart murmurs have been evaluated acoustically for the last 200 years. The world's first stethoscope, developed in 1818 by René Laennec, and today's binaural stethoscope, which is based on developments from the 1850s, can only perceive "loud" heart murmurs, such as heart valves and flow noises between the heart chambers. But there are also flow noises in the arteries supplying blood to the heart when the blood flow is disturbed. Presstext from acarix.com August

2 The fact that stenosed vessels cause turbulence in the blood flow, which in turn generates corresponding noise that can be detected in the diastole, has been described for the past 50 years 1. Early attempts to systematically record these and make them diagnostically useful failed due to the technological requirements. The vision of the two young Danish researchers was to combine state-of-the-art Danish acoustic technologies in the form of ultra-sensitive microphones with mathematical algorithms in order to systematically record the flow noises of the coronary vessels for the first time. The interdisciplinary research group started its work in 2004 and received the 'MedicoPrisen' award from Medicoindustrien (Danish Medtech Trade Association) in In the same year, a research and development cooperation between Aalborg University and the medical device company Coloplast A / S was founded. The group received public support from the Danish National Advanced Technology Foundation in A prototype was successfully developed, and in 2015 the final device, the CADScor System, was approved in Europe for the diagnosis of CAD, this marketed in Germany for the first time in The basic idea of this system is to offer the symptomatic patient a diagnosis without invasive or radiation exposure: a tool which allows the rapid exclusion of significant coronary artery disease (CAD). Acarix was founded in 2009 as a spin-out of Coloplast A / S, and since 2010 investors of SEED Capital (DK) and Sunstone Life Science Ventures (DK) have been supporting the market launch. Acarix was listed on the Nasdaq First North Premier in Stable coronary artery disease Stable coronary artery disease is one of the most widespread diseases among the general population. In Germany, almost one million heart catheter examinations are performed every year. A large proportion of these examinations do not detect any abnormalities or do not lead to any further therapeutic consequences. According to the guidelines on the diagnosis of CAD published in October 2017, it would be desirable to reduce the number of invasive diagnoses while maintaining diagnostic reliability 2. The guideline states that only 8-11% of patients with chest pain at the primary care level have stable coronary heart disease, whereas this figure at the cardiological care level is 20-25% of patients. The probability of the presence of CAD is determined without the use of large equipment on the basis of so-called "scores 3 ", which contain patient data and information on the course of the disease. These scores can be a good decision aid for patients with a very low or very high risk. However, many patients are in the medium risk range in which further non-invasive diagnostics are recommended before cardiac catheterisation needs to be carried out. The methods currently used are cardiac CT, stress echocardiography, myocardial perfusion SPECT or stress MRI. Exercise ECG (mostly bicycle ergometry), which is still practised very frequently, does not offer sufficient diagnostic certainty for a decision to be taken regarding a cardiac catheter examination. The innovative, side-effect-free technology of the Acarix CADScor System has been available since July As with cardio CT or cardio MRI, cardiac catheters can therefore be avoided in patients without 1 Dock W, Zoneraich S: A diastolic murmur arising in a stenosed coronary artery, Am J Med Apr;42:617-9 & Sangster JF, Oakley CM, Diastolic murmur of coronary artery stenosis, Br Heart J Aug; 35(8): Albus C, Barkhausen J, Fleck E, Haasenritter J, Lindner O, Silber S, on behalf of the German National Disease Management Guideline Chronic CAD development group: Clinical practice guideline: The diagnosis of chronic coronary heart disease. Dtsch Arztebl Int 2017; 114: DOI: /arztebl The Marburg score at the general practitioner level, the pre-test probability for cardiology specialists Presstext from acarix.com August

3 coronary heart disease and the costs reduced to a much greater extent than with CT and MRI. The cost of an examination, for example, is currently only around 80 euros. If the examination does not reliably exclude coronary heart disease (e.g. CAD-score over 20), a cardio MRI or cardio CT might be appropriate. CADScor System: a new decision aid Fast, cost-efficient test for the non-invasive exclusion of CAD In patients suffering from chest pain or unclear heart problems, the CADScor System can exclude coronary artery disease as the cause of the complaints with 97% accuracy. It is no larger than a smartphone and is placed on the chest like a stethoscope. There, it converts the flow noises caused by blood passing through the heart vessels into frequency images and compares them with those of healthy frequency images. Sizeable atherosclerotic plaques cause relevant vascular constriction with audible turbulence of the blood in the vessel and can be detected acoustically. In this way it is possible to detect narrowing of the coronary arteries without a diagnostic heart catheter or other expensive methods. With the CADScor System it is possible to carry out a fast, complication-free outpatient diagnosis. It is superior to other methods of assessing the risk of CAD in terms of diagnostic certainty and therapeutic validity and makes a significant contribution towards preventing further complex diagnostic examinations. CADScor System combines state-of-the-art electronics and innovative mathematics to form a new, revolutionary method: ultrasensitive phonocardiography. According to the German Heart Report, over 900,000 diagnostic invasive heart catheters were performed in Germany in % of patients suffer an incident, with 0.19% dying during the intervention. With almost one million interventions, this means approximately 1800 patients (German Heart Report 2015). Since a large proportion of the patients with a diagnostic catheter do not yield any significant findings, the question arises of how to improve the selection of patients who actually need a heart catheter and an intervention, e.g. vascular support. CADScor System principle: from nature to Medtech It has long been known that turbulent currents generate sound, not only in flowing rivers and water pipes, but also in the bloodstream. Vortex movements in the blood circulation caused by a partial obstruction (stenoses) in the coronary arteries cause very weak sounds, usually described as "coronary murmurs", typically in a frequency range below 1000 Hz. It is difficult to detect this sound because its amplitude is very weak. The detection and recording of this coronary sound requires not only a highly-sophisticated sensor, but also suitable attachment to the skin above the heart in order to optimise the recorded signal and avoid external interference. The Acarix CADScor System was developed to provide a simple and highly accurate method of excluding CAD. The fast, non-invasive procedure provides an immediate result. The examination takes less than 10 minutes, including preparation of the patient plus recording, analysis and display of the CAD-score. Any trained employee of a medical practice can carry out the examination. Exclusion of CAD within 10 minutes The core of the CADScor System consists of efficient high-performance microphones. The CADScor procedure is performed in the supine position and starts with a 5-minute rest phase for the patient. Presstext from acarix.com August

4 The CADScor System device is then fixed to the patient's chest using a special patch by placing the recording head in the 4th intercostal space on the left. Three recordings are carried out within 8 seconds each. After the recording, the CAD-score is calculated and shown on the display of the CADScor sensor within 2 minutes so that further decisions can be taken immediately. The total duration of the measurement is approximately 10 minutes. The result is a score between 0 and 99, the level of which correlates with the probability of coronary stenosis. Overview of the study situation After the successful completion of various technical studies for the general investigation into the procedure carried out on over 750 patients 4, the first major clinical study was conducted in Denmark with 228 participants in This resulted in the granting of the CE mark in August The CADScor System is therefore approved in Europe as diagnostic aid for symptomatic patients with suspected CAD and has been available for purchase and use since The participants in the registration study were patients who due to clinical symptoms had been referred to a cardiology centre for further diagnosis (coronary CT or invasive coronary angiography (ICA)) in order to rule out CAD. Before further diagnoses were carried out, a CAD-score was determined for all participants using the CADScor System. Although these results of the study were sufficient for approval due to the negative prediction value of 87%, the system was not yet made available, as first of all the aim was to achieve a further improvement and carry out a check of the test accuracy. The goal was to obtain a high negative predictive value in order to optimise the CADScor System as an exclusion diagnostic method. A patient with a negative test result should not have CAD with a high degree of certainty. 6 A further technical study was conducted, which confirmed the results of the marketing authorisation study. Then a larger clinical study, Dan-NICAD, was conducted using an old and new algorithm at two cardiology centres in Denmark. 7 A total of 1,675 patients who had been referred for the exclusion of CAD took part in this study. A CAD-score was obtained from 1,437 patients and further diagnostics carried out according to a defined protocol up to coronary CT or ICA. After the diagnostic procedure had been completed, 78% of patients were found to have no CAD, while 12% had non-obstructive CAD (insignificant stenosis of < 50% of vessel diameter) and 10% obstructive CAD (stenosis > 50% of vessel diameter). At the pre-determined threshold value for the CAD-score of 20, the negative prediction value was 96%. These results were presented at two major cardiological congresses. 89 An extensive publication was recently made available. 10 As a result, the algorithm used in the device was further improved. The negative predictive value for the total population of 2260 patients and healthy controls from the clinical database used in the algorithm is 97%. The CADScor System was subsequently launched on the market in July Schmidt SE, Holst-Hansen C, Hansen J, Toft E, Struijk JJ: Acoustic Features for the Identification of Coronary Artery Disease, Transactions on Biomedical Engineering 2015: 62: Winther S, Schmidt SE, Holm NR, Toft E, Struijk JJ, Bøtker HE, Bøttcher M: Diagnosing coronary artery disease by sound analysis from coronary stenosis induced turbulent blood flow: diagnostic performance in patients with stable angina pectoris, Int J Cardiovasc Imaging, DOI /s Thomas JL, Winther S, Wilson RF, Bøttcher M: A novel approach to diagnosing coronary artery disease: acoustic detection of coronary turbulence. Int J Cardiovasc Imaging 2016: DOI /s Nissen L, Winther S, Isaksen C, et al., Danish study of Non-Invasive testing in Coronary Artery Disease (Dan-NICAD): study protocol for a randomised controlled trial. Trials May 26;17(1):262 8 Bøttcher M; Vortrag, American College of Cardiology Bøttcher M; Vortrag V1511, DGK 2017: Exclusion of CAD through detection of diastolic murmurs: data overview, BMJ Heart, 2017, heartjnl Winter S, Nissen L, Schmidt SE, et al, Diagnostic performance of an acoustic-based system for coronary artery disease risk stratification, BMJ Heart J, doi: /heartjnl Presstext from acarix.com August

5 A further major study was launched in The first patients were included in the Dan-NICAD 2 study in February Dan-NICAD 2 fundamentally resembles the previous Dan-NICAD study, but with respect to the endpoints is especially tailored to the question of cost and procedure reduction: Can the cost of current patient evaluation using non-invasive, invasive and high-radiation diagnostics be avoided with the CADScor System? Health economics The economic effects on healthcare have already been demonstrated for the marketing authorisation study for the Danish system. 11 The financial savings were primarily achieved not through a reduction in invasive coronary angiographies, but from the reduction in the number of cardio CTs and magnetic resonance diagnostics performed. With the results of the Dan-NICAD study, a cost model for the German statutory health insurance has already been developed, although this has not yet been published. Fundamental heart information The basic function of the heart is to pump fresh, oxygenated blood into all organs of the body. The beating heart also relies on fresh blood, as the heart muscle is always moving. The heart muscle is supplied by a network of small arteries (coronary arteries), which are located around the heart muscle. The human heart is a strong muscle that reaches a weight of approximately 300 g when fully grown. The heart is located in the thorax behind a cage consisting of ribs and sternum that provides adequate protection against injury. When the heart beats, the flow of blood through the heart produces sound known as lub and dub which can be easily heard through the human ear, either directly above the chest or indirectly by means of a stethoscope. At rest, an adult's heart pumps around 70 ml of blood per beat at a frequency of approximately 60 to 70 beats per minute. Per minute this more or less corresponds to the body's blood volume of approx. 4,900 ml of blood, which is also referred to as the "cardiac output" in ml/min. In order to achieve a higher cardiac output, e.g. during increased activity or movement, the heart muscle itself also needs an increased blood supply. If the heart muscle is not supplied with sufficient oxygen-rich blood due to a narrowed coronary artery, patients often feel discomfort or pain in their chest. Often this is also the first sign of coronary heart disease. Heart sounds for the diagnosis of CAD When coronary arteries narrow due to coronary artery disease (CAD), turbulence can occur in the blood stream as soon as the blood passes through the constriction. Such sound due to turbulence can be an important indicator of CAD. The resulting sounds cannot be heard by the human ear or through a stethoscope, as they are up to 1000 times quieter than the normal heartbeat. The innovative Acarix CADScor System has been specially developed for the highly sensitive recording and evaluation of these sounds, which can be ascribed to CAD. Using state-of-the-art algorithms, the recorded heart sounds are analysed in order to identify abnormal sound patterns. The more anomalies that are detected during the sound recording of the heart, the higher the risk that the patient is suffering from coronary heart disease. The CADScor test divides patients up into three risk groups (low, medium or high risk). If a patient is placed in the low risk group, the doctor can directly exclude CAD with a very high degree of certainty and instead continue with the evaluation of other symptoms such as back or shoulder pain, stomach complaints or stress-related problems. For patients who are classified as medium or high-risk patients, the doctor will probably explain the further steps taken to investigate CAD. If the probability of coronary heart disease is sufficiently high, 11 Winther S, Bøttcher M, Wahler S, Bolin K, Cost Model for a New Acoustic Diagnostic AID to Rule Out Coronary Artery Disease, Value in Health, 2017(20) 9:A405 Presstext from acarix.com August

6 further examinations are often necessary for the final diagnosis. Typical examinations include treadmill/cycling stress tests and stress echocardiography, both of which are functional tests, and CT scanning, that provides an image of the coronary calcification, or coronary angiography, which shows the narrowing of the coronary artery (stenosis). Functional tests or the degree of calcification or stenosis can be used to offer various treatments, ranging from the prescription of beta-blockers to the invasive vascular dilatation of narrowed arteries. Risk factors for CAD Medical research in recent years has shown a close link between coronary artery disease and certain risk factors, some of which depend on our lifestyle. The most important risk factors are smoking, raised cholesterol levels in the blood, being overweight and having high blood pressure. Diabetes can also have adverse effects. Some studies suggest that a lack of exercise and continual stress play a significant role in the progression of CAD. Two risk factors are unavoidable: advancing age and gender. The risk of CAD increases with age and is higher in men than in women. The presence of risk factors is an important component in the evaluation of a patient's risk for CAD. Diagnosis & therapy of CAD Symptoms of CAD can be classic symptoms such as chest pain or difficulty breathing. However, some patients do not suffer from classic symptoms and do not display any unusual symptoms either. For this reason alone, you should consult your doctor if you suspect or notice the symptoms of coronary heart disease. Your family doctor or cardiologist can determine the risk of coronary heart disease based on your symptoms, family and medical history and the presence of one or more risk factors. Today, two rating systems are widely used; the Framingham Risk Score and the EU Score take into account factors such as smoking habits, cholesterol levels, blood pressure, age and gender. If the likelihood of coronary heart disease is high, further examinations are often required for a final diagnosis. Typical examinations include treadmill/cycling stress tests and stress echocardiography both functional tests as well as CT scanning, which provides an image of coronary calcification, or coronary angiography, the latter showing stenosis of the coronary artery. Functional tests or the degree of calcification or stenosis can be used to offer various treatments, ranging from the prescription of beta-blockers to the invasive vascular dilatation of narrowed arteries. Both CT scanning and coronary angiography are complex procedures that require clinical facilities. Many patients undergo these procedures due to symptoms that indicate CAD. However, it is often found that their symptoms are not associated with CAD. Coronary Artery Disease CAD Coronary artery disease results from the accumulation of fat, cholesterol and calcium in plaque layers on the walls of the coronary arteries, which supply the heart muscle with oxygen and nutrients. Arteriosclerosis (deposits) is largely irreversible, although worsening of the condition can be inhibited. The degree of arteriosclerosis can influence the severity of the symptoms, but since CAD develops over a long period of time, the disease can remain unnoticed until symptoms suddenly appear. One in four deaths from CAD occurs suddenly and asymptomatically and therefore without warning. Signs of deposits can already be observed in adolescents, confirming the need for a healthy lifestyle from early childhood on. More than 50% of all heart disease worldwide is CAD, which accounts for 20% of all deaths. Contact Acarix can be contacted for general questions or information by at info@acarix.com CEO Christian Lindholm. Presstext from acarix.com August

The CADScor System Frequently asked questions

1 The CADScor System Frequently asked questions Clinical Usage...2 How can I use the CADScor System?... 2 Contra-indications for use... 2 What is the performance of the CADScor System?... 2 Table: Performance