Cost-effectiveness and Safety of the CADScorSystem in Patients With Symptoms Suggestive of Stable Coronary Artery Disease. (FILTER-SCAD)

A Prospective, Randomized, Controlled, Parallel-group, Multicentre Trial to Examine the Cost-effectiveness and Safety of Adding the CADScorSystem as a Rule-out Test in Patients Referred With Symptoms Suggestive of Stable Coronary Artery Disease.

This study evaluates the addition of the CADScorSystem to a standard Diamond-Forrester score guided rule-out strategy in ambulatory patients referred with symptoms suggestive of stable coronary artery disease. Half of the patients will undergo stratification using a Diamond-Forrester score only, while the other half will undergo stratification using a Diamond-Forrester score and a CAD-score. The study hypothesis is that the addition of a CAD-score will reduce unnecessary testing without compromising patient safety.

Study Overview

• Status: Completed
• Conditions: Angina, Stable
• Intervention / Treatment: Device: CADScor®System

Detailed Description

Purpose and Rationale for the Study:

The declining incidence of obstructive CAD and a good prognosis for patients with stable angina challenges the resource demanding approach recommended in current guidelines. The CADScor®System may be an efficient, fast and low-cost diagnostic tool with a high rule-out efficiency. The current study aims to investigate if the CADScor®System can be added as a rule-out test in patients referred with suspected stable CAD to reduce unnecessary testing

Study Hypothesis:

A Diamond-Forrester score plus CAD-score guided rule-out strategy is superior to a Diamond-Forrester score guided strategy alone in reducing diagnostic procedures and non-inferior in terms of safety outcomes in patients with symptoms suggestive of stable coronary artery disease.

Study Setting:

This study will enrol patients without known CAD who are referred with symptoms suggestive for stable CAD for outpatient evaluation at the participating sites. All patients will be symptomatic and require evaluation for suspected CAD. Thus, whether or not the patient chooses to participate in the study, the patient will undergo evaluation for suspected CAD. All the standard NIT modalities and ICA in the study are clinically well established and performed routinely and safely. Experimental testing involves the CADScor®System, for ruling out CAD before any NIT in the intervention group.

End of Study:

The study will end when all the following have occurred: (1) at least 2000 patients have been randomized, and (2) 12±1 months (1 year) have elapsed since the last patient was randomized.

Extended Follow-up after Study Termination:

Follow-up might be performed for up to 10 years after randomization. Follow-up information will be extracted from national registers, including information on cardiovascular events and treatments, hospitalizations and ambulatory visits due to cardiovascular events, and causes of death.

Statistical methods:

A detailed description of the planned statistical analyses will be documented in a separate statistical report and analysis plan (SAP), which will be completed before data base lock.

Sample size considerations:

A reduction of 15% or more in the primary endpoint is regarded as clinically significant. Assuming an alpha significance level of 0.05, a statistical power of 80% and an expected number of NIT/ICA of 0.94 per patient in the standard care group, a sample size of 314 patients in each arm is needed to ascertain superiority of the intervention.

A sample size of 1914 provides 90% power for testing non-inferiority in terms of MACE between the two testing strategies, at an alpha significance level of 0.05.

We choose to include 2000 patients, i.e. 1000 patients in each group, allowing for a 4% loss to follow-up and drop out and providing power for the primary endpoint and the secondary MACE non-inferiority endpoint.

Statistical analysis:

The full analysis set (FAS) will include all randomized patients in whom written informed consent was obtained and in accordance with the intention-to-treat principle all patients will be analysed according to the allocated treatment group.

The per-protocol set (PPS) will include only those patients from the FAS who did not have one of the following major protocol violations: inclusion criteria not met, exclusion criteria met, no DF-score calculation, or no CAD-score measurement (intervention group only). Patients who did not receive the randomly allocated CAD-score measurement will be included and analysed in the control group (per protocol analysis).

• Study Type: Interventional
• Enrollment (Actual): 2016
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen S, Denmark, 2300
    • Amager Hospital
  • Herlev, Denmark, 2730
    • University Hospital Herlev and Gentofte
  • Hillerød, Denmark, 3400
    • University Hospital Nordsjaelland
  • Hvidovre, Denmark, 2650
    • University Hospital Hvidovre
  • København NV, Denmark, 2400
    • University Hospital Bispebjerg and Frederiksberg
• Sweden
  • Lund, Sweden, 222 42
    • Skåne University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Have signed the informed consent form.
2. Males and females, aged 30 years or above.
3. Be able and willing to comply with the clinical investigational plan.
4. Symptoms suggestive of stable coronary artery disease.
5. No history of coronary artery disease (prior myocardial infarction, percutaneous coronary intervention or coronary artery bypass graft).

Exclusion Criteria:

1. Diamond-Forrester score >85%.
2. Prior non-invasive testing for stable CAD or invasive coronary angiography within 6 months of randomization.
3. Implanted donor heart, mechanical heart, mechanical heart pump.
4. Pacemaker or Cardioverter Defibrillator (ICD).
5. Implanted electronic equipment in the area above and around the heart.
6. Significant operation scars, abnormal body shape, fragile or compromised skin in the fourth left intercostal space recording area.
7. Receiving same day treatment with nitro-glycerine on the day of randomization.
8. Pregnancy.

The exclusion criteria '1. Diamond-Forrester score >85%' was removed after updating the study according to the 2019 ESC guidelines on chronic coronary syndrome. According to these current guidelines, no patients should be referred to invasive diagnostic test based on their PTP alone, and therefore is this exclusion criteria is no longer relevant.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control group; The control group will receive standard-of-care treatment recommended by current ESC guidelines for patients with low to intermediate likelihood of stable CAD using the Diamond-Forrester (DF) score only: Rule-out if DF-score <15%; NIT if DF-score 15-85%. As per January 2020 the protocol was updated according to the 2019 ESC Guidelines on Chronic Coronary Syndrome: The control group will receive standard-of-care treatment recommended by current ESC guidelines based on the patients likelihood of stable CAD using the Pre-test Probability score (PTP): Rule-out if PTP≤5%, NIT may be considered if PTP 6-15%, NIT if PTP>15%
Experimental: Intervention group; The intervention group will undergo a modified diagnostic pathway where a CAD-score <30 rules out stable CAD in the group of patients having a DF-score <15% and a CAD-score ≤20 rules out stable CAD in the group of patients having a DF-score in the range 15-85%, and thus not tested with NIT. Otherwise NIT is performed. As per January 2020 the protocol was updated according to the 2019 ESC Guidelines on Chronic Coronary Syndrome: The intervention group will undergo a modified diagnostic pathway where a CAD-score ≤20 rules out stable CAD. If CAD-score >20 NIT is performed.	Device: CADScor®System; The CADScor®System is a low cost, low resource-demanding, non-invasive, radiation-free device using highly advanced analysis of sounds originating from blood flow turbulence in the coronary circulation and myocardial motion. Heart sound recordings are obtained transcutaneously during a 3 minutes recording period with a microphone mounted at the IC4. A CAD-score on a scale from 0 to 99 is estimated immediately after the recording with a fully automated algorithm. The algorithm measures eight acoustic properties and the resulting acoustic score is combined with the clinical risk factors gender, age, and hypertension. The entire procedure lasts approximately 10 minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative number of non-invasive and invasive diagnostic procedures	Difference between the two treatment groups in cumulative number of non-invasive and invasive diagnostic procedures. Non-invasive procedures include exercise electrocardiogram (ECG), cardiac computed tomography angiography (CCTA), Rubidium cardiac PET (Rb-PET), myocardial perfusion imaging (MPI), cardiac magnetic resonance imaging (CMRi) and stress echocardiography. Invasive procedures include invasive coronary angiography (ICA) only.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Major adverse cardiac events (MACE)	Difference between the two treatment groups in proportion of major adverse cardiac events. Major adverse cardiac events (MACE) are a composite of all-cause death, non-fatal myocardial infarction, unstable angina pectoris, heart failure, and ischaemic stroke.	1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in chest pain	Change in chest pain from baseline as assessed by the Seattle Angina Questionnaire (SAQ).	3 months and 1 year
Change in quality of life	Change in quality of life from baseline as assessed by the EuroQoL-5D.	3 months and 1 year
First non-invasive tests	Difference between the two treatment groups in the number of first non-invasive testings.	1 year
Downstream tests	Difference between the two treatment groups in the number of downstream tests. Downstream tests are defined as all NITs and ICAs to detect CAD performed after a) DF-score and first standard non-invasive testing and b) DF-score, CAD-score and first non-invasive testing, respectively, in the two groups.	1 year
Invasive coronary angiographies (ICA)	Difference between the two treatment groups in the number of invasive coronary angiographies.	1 year
Negative invasive coronary angiographies	Difference between the two treatment groups in the number of negative invasive coronary angiographies.	1 year
Repeat referrals	Difference between the two treatment groups in the number of repeat referrals.	1 year
Time to rule-out CAD	Difference between the two treatment groups in time to rule-out CAD. Time to rule-out is assessed as the period from randomisation until the first test that rules out stable CAD.	1 year
Time to diagnosis of CAD	Difference between the two treatment groups in time to diagnosis of CAD. Time to diagnosis is assessed as the period from randomisation until the first test that leads to the final diagnosis.	1 year
Change in lifestyle measures	Change in lifestyle measures from baseline as assessed by the HeartDiet questionnaire.	3 months and 1 year
Optimal medical treatment	Difference between the two treatment groups in the proportion of patients initiating and adhering to optimal medical treatment (event prevention, antianginal therapy).	1 year
Incidence of individual components of MACE	Difference between the two treatment groups in the proportion of each of the individual components of major adverse cardiac events (all-cause death, myocardial infarction, unstable angina pectoris, heart failure, ischaemic stroke).	1 year
Cumulative contrast dose	Difference between the two treatment groups in the cumulative contrast dose.	1 year
Cumulative radiation dose	Difference between the two treatment groups in the cumulative radiation dose.	1 year
Bleedings requiring hospitalization	Difference between the two treatment groups in the proportion of bleedings requiring hospitalization.	1 year
Adverse events	Difference between the two treatment groups in the proportion adverse events related to the CADScor®System.	1 year

Collaborators and Investigators

• Sponsor: Bispebjerg Hospital
• Collaborators: Larix A/S; Region Hovedstadens Apotek; Acarix; Kai Hansen Foundation; Kai Houmann Nielsens Fond
• Investigators: Principal Investigator: Eva Prescott, DMSc., Bispebjerg og Frederiksberg Hospitaler; Principal Investigator: Søren Galatius, DMSc., Bispebjerg og Frederiksberg Hospitaler

Publications and helpful links

General Publications

• Bjerking LH, Hansen KW, Biering-Sorensen T, Bronnum-Schou J, Engblom H, Erlinge D, Haahr-Pedersen SA, Heitmann M, Hove JD, Jensen MT, Kruse M, Rader S, Strange S, Galatius S, Prescott EIB. Cost-effectiveness of adding a non-invasive acoustic rule-out test in the evaluation of patients with symptoms suggestive of coronary artery disease: rationale and design of the prospective, randomised, controlled, parallel-group multicenter FILTER-SCAD trial. BMJ Open. 2021 Aug 23;11(8):e049380. doi: 10.1136/bmjopen-2021-049380.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2019
• Primary Completion (Actual): September 15, 2023
• Study Completion (Actual): September 15, 2023

Study Registration Dates

• First Submitted: October 9, 2019
• First Submitted That Met QC Criteria: October 9, 2019
• First Posted (Actual): October 10, 2019

Study Record Updates

• Last Update Posted (Actual): October 5, 2023
• Last Update Submitted That Met QC Criteria: October 3, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: coronary artery disease; diagnostic strategies
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Pain; Neurologic Manifestations; Chest Pain; Angina Pectoris; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Angina, Stable
• Other Study ID Numbers: FILTER-SCAD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No