Clinical trial NCT01838148: Biochemical and Electrocardiographic Signatures in the Detection of Exercise-induced Myocardial Ischemia
Official title: BASEL VIII Trial - Biochemical and Electrocardiographic Signatures in the Detection of Exercise-induced Myocardial Ischemia
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Coronary Artery Disease
Angina, Stable
Exercise Test
Biological Markers
SPECT
Keywords: coronary artery disease
angina, stable
exercise test
biological Markers
SPECT
Lead sponsor: University Hospital, Basel, Switzerland
Sponsor class: OTHER
First posted: 2013-04-23
Enrollment: 4000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Consecutive patients presenting with suspected exercise-induced myocardial ischemia referred for rest/ergometry myocardial perfusion SPECT.

Brief summary: The primary aim is to perform the largest study worldwide to evaluate novel biochemical and electrocardiographic signatures alone as well as in combination with the standard 12-lead exercise ECG in the detection of exercise-induced myocardial ischemia (diagnostic endpoint). The secondary aim is to evaluate these innovative tools in the risk prediction for the occurrence of cardiovascular death and acute myocardial infarction during long-term follow-up.

Detailed description: Background: The detection of coronary artery disease (CAD) is one of the most important tasks in medicine. Exercise-induced myocardial ischemia is the pathophysiological hallmark of stable CAD. Currently, sophisticated imaging techniques including coronary angiography, rest/stress myocardial perfusion single-photon emission computed tomography (SPECT), and coronary CT-scanning are required to accurately detect CAD. Unfortunately, these techniques are associated with inherent risks due to substantial radiation exposure, intraarterial or intravenous application of iodinated contrast media, mechanical complications, require referral to a specialist, and are very costly. In addition, most of them provide anatomical but not functional information. For clinical practice, functional information that differentiates lesions that cause exercise-induced myocardial ischemia from functionally irrelevant lesions is critical. Exercise electrocardiography (ECG) is a widely used simple and non-invasive functional test, which however has imperfect sensitivity and specificity (both below 75%) in the detection of CAD. Novel cardiac biomarkers as well as novel computer-based quantitative approaches to analyse the ECG signal recorded during exercise offered by advances in information technology and signal processing may provide incremental value to the exercise ECG and thereby improve clinical care.

Aim: The primary aim is to perform the largest study worldwide to evaluate novel biochemical and electrocardiographic signatures alone as well as in combination with the standard 12-lead exercise ECG in the detection of exercise-induced myocardial ischemia (diagnostic endpoint). The secondary aim is to evaluate these innovative tools in the risk prediction for the occurrence of cardiovascular death and acute myocardial infarction during long-term follow-up.

Methodology: We will enroll approximately 4200 consecutive patients with suspected exercise induced myocardial ischemia referred for rest/ergometry myocardial perfusion SPECT. SPECT findings (complemented by coronary angiography and fractional flow reserve \[FFR, if availabe\] findings in patients who obtain both investigations) are used to adjudicate and quantify the presence of myocardial ischemia (the primary diagnostic end point). Clinical long-term follow-up will be obtained at 1 year, 2 years, 5 years and 8 years to record death, cardiovascular death, and acute myocardial infarction as well as coronary revascularisation.

Investigational tests: Venous blood samples will be collected before exercise stress testing for the determination of biochemical signatures possibly associated with myocardial ischemia including high-sensitivity cardiac troponin I, high-sensitivity cardiac troponin T, B-type natriuretic peptide, IL-6, and cardiac microRNA. In addition, continuous ECG signals are recorded using 12 leads (16 leads in a subset of patients) and 24-bit amplitude resolution with 8000 Hz sampling frequency before, during and after the stress test. Novel methods of computer-based ECG signal-processing technology will be used to decipher electronic markers of myocardial ischemia and to develop improved software algorithms for automated ECG interpretation. All investigational tests will be performed in a blinded fashion.

Potential Significance: We hypothesize that biochemical and electrocardiographic signals of myocardial ischemia will significantly improve the non-invasive detection of exercise-induced myocardial ischemia. This would markedly improve the initiation of treatment in affected patients and thus advance medical management of patients with suspected CAD. In addition, this approach would help to simplify (exercise ECG versus myocardial SPECT) the non-invasive detection of exercise-induced myocardial ischemia and help to avoid the inherent health hazards associated current radiologic imaging procedures.

Eligibility criteria: Inclusion Criteria:

* Patients presenting with suspected exercise-induced myocardial ischemia referred for rest/ergometry myocardial perfusion SPECT

Exclusion Criteria:

* Age \< 18 years
* Pregnancy
* Unable or unwilling to give informed consent
* Symptoms at rest or minor exertion

Primary outcomes:
measure: Diagnostic utility of novel biochemical and electrocardiographic signatures
timeFrame: baseline
Secondary outcomes:
measure: One year event-free survival
timeFrame: 360 days
measure: Two year event-free survival
timeFrame: 2 years
measure: Five year event-free survival
timeFrame: 5 years
measure: Eight year event-free survival
timeFrame: 8 years
Other outcomes:
Locations:
city: Basel
country: Switzerland
facility: University Hospital Basel
Study officials:
affiliation: University Hospital, Basel, Switzerland
name: Christian Mueller, Prof. Dr. MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Amrein M, Li XS, Walter J, Wang Z, Zimmermann T, Strebel I, Honegger U, Leu K, Schafer I, Twerenbold R, Puelacher C, Glarner N, Nestelberger T, Koechlin L, Ceresa B, Haaf P, Bakula A, Zellweger M, Hazen SL, Mueller C. Gut microbiota-dependent metabolite trimethylamine N-oxide (TMAO) and cardiovascular risk in patients with suspected functionally relevant coronary artery disease (fCAD). Clin Res Cardiol. 2022 Jun;111(6):692-704. doi: 10.1007/s00392-022-01992-6. Epub 2022 Feb 26.
citation: Walter JE, Amrein MLF, Schafer I, Zimmermann T, Lopez-Ayala P, Boeddinghaus J, Twerenbold R, Puelacher C, Nestelberger T, Wussler D, Honegger U, Badertscher P, Eugen-Olsen J, Koechlin L, Fahrni G, Jeger R, Kaiser C, Zellweger M, Mueller C. Soluble urokinase plasminogen activator receptor and functionally relevant coronary artery disease: a prospective cohort study. Biomarkers. 2022 May;27(3):278-285. doi: 10.1080/1354750X.2022.2038269. Epub 2022 Feb 15.
citation: Walter J, du Fay de Lavallaz J, Koechlin L, Zimmermann T, Boeddinghaus J, Honegger U, Strebel I, Twerenbold R, Amrein M, Nestelberger T, Wussler D, Puelacher C, Badertscher P, Zellweger M, Fahrni G, Jeger R, Kaiser C, Reichlin T, Mueller C. Using High-Sensitivity Cardiac Troponin for the Exclusion of Inducible Myocardial Ischemia in Symptomatic Patients: A Cohort Study. Ann Intern Med. 2020 Feb 4;172(3):175-185. doi: 10.7326/M19-0080. Epub 2020 Jan 7.
citation: Badertscher P, Strebel I, Honegger U, Schaerli N, Mueller D, Puelacher C, Wagener M, Abacherli R, Walter J, Sabti Z, Sazgary L, Marbot S, du Fay de Lavallaz J, Twerenbold R, Boeddinghaus J, Nestelberger T, Kozhuharov N, Breidthardt T, Shrestha S, Flores D, Schumacher C, Wild D, Osswald S, Zellweger MJ, Mueller C, Reichlin T. Automatically computed ECG algorithm for the quantification of myocardial scar and the prediction of mortality. Clin Res Cardiol. 2018 Sep;107(9):824-835. doi: 10.1007/s00392-018-1253-z. Epub 2018 Apr 17.
citation: Puelacher C, Wagener M, Honegger U, Assadian M, Schaerli N, Mueller D, Strebel I, Twerenbold R, Boeddinghaus J, Nestelberger T, Wildi K, Sabti Z, Sazgary L, Badertscher P, du Fay de Lavallaz J, Marbot S, Kaiser C, Wild D, Zellweger MJ, Reichlin T, Mueller C. Combining high-sensitivity cardiac troponin and B-type natriuretic peptide in the detection of inducible myocardial ischemia. Clin Biochem. 2018 Feb;52:33-40. doi: 10.1016/j.clinbiochem.2017.10.014. Epub 2017 Nov 8.
citation: Sou SM, Puelacher C, Twerenbold R, Wagener M, Honegger U, Reichlin T, Schaerli N, Pretre G, Abacherli R, Jaeger C, Rubini Gimenez M, Wild D, Rentsch KM, Zellweger MJ, Mueller C. Direct comparison of cardiac troponin I and cardiac troponin T in the detection of exercise-induced myocardial ischemia. Clin Biochem. 2016 Apr;49(6):421-432. doi: 10.1016/j.clinbiochem.2015.12.005. Epub 2015 Dec 17.