An Arrhythmia Risk Stratification and Genetic Trial

NCT01209494 | Completed DMC

• 1 other identifier: HEALTH-F2-2009-241526
• Study Type: observational
• Target: 672
• Locations: 4 countries
• Sites: 4

Brief Summary

The prospective EUTrigTreat multi-center study is an observational, advanced diagnostics and genetic risk stratification trial in patients with standard indications for ICD treatment, with and without myocardial infarction in their history. Its aims are fourfold: 1) To accurately risk stratify a large cohort of implantable cardioverter-defibrillator (ICD) patients for ICD shock risk and mortality using traditional risk markers as well as genetic markers 2) To find a link between repolarization biomarkers and genetic markers of calcium metabolism. 3) To compare invasive and noninvasive electrophysiologic (EP) testing systematically 4) To assess temporal changes of typical noninvasive risk stratifiers and their prognostic implication. In five European academic clinical centers, 700 ICD patients are prospectively enrolled (optionally the number of enrolled patients may be expanded to 1000 patients). Comprehensive non-invasive risk stratifying ECG diagnostics including beat-to-beat variability of repolarization (BVR) are applied, and candidate genes associated with malignant arrhythmias are analyzed. Programmed electrical stimulation is performed to test for inducibility of malignant ventricular arrhythmias and BVR. In a subset of patients, electrophysiologic studies include recording of monophasic action potentials (MAP) from the right ventricle for assessment of restitution properties. Non-invasive risk stratifying ECG methods are repeated annually. Outcome (mortality, ICD shocks) will be assessed until September 2014.

Conditions

Cardiomyopathies, Primary; Arrhythmia; Sudden Cardiac Death; Calcium Metabolism Disorders

Keywords

sudden cardiac death; implantable cardioverter defibrillator; ventricular arrhythmias; genetic syndromes; calcium metabolism; ventricular repolarization; ECG; T wave; programmed electrical stimulation; alternans; late potentials; risk stratification

Outcome Measures

Primary Outcomes (1)

• Total Mortality

  2010-2014

Secondary Outcomes (3)

• Sudden Cardiac, Cardiac and Non-Cardiac Mortality

  2010-2014

• Appropriate and Inappropriate Shocks

  2010-2014

• Secondary Composite Endpoints

  2010-2014

Study Arms (2)

Invasive EP Study Group

200 patients are studied before clinically indicated (according to AHA/ACC/ESC guidelines) first ICD implantation or ICD exchange. Invasive EP study is performed to test inducibility of malignant arrhythmia. In addition MAP recordings are performed for measurements of restitution properties. Pacing is done for 12-lead ECG and MAP recordings for analysis of BVR and TWA, if applicable.

Noninvasive EP Study Group

The assignment of patients to the invasive and noninvasive EP groups does not occur by randomization or for intervention. In the noninvasive EP study group, 500 patients with chronically implanted ICD (\>3 month after implantation) are investigated using non-invasive EP study via ICD programmer. Programmed electrical stimulation is performed to test for inducibility of malignant arrhythmia. In addition pacing is done for measurements of BVR from the 12-lead ECG.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients with standard indications for ICD treatment according to ACC/AHA/ESC guidelines with and without myocardial infarction in their history are eligible for the study

You may qualify if:

• Standard indication for ICD treatment according to ACC/AHA/ESC guidelines for primary or secondary prevention of SCD
• Age ≥ 18 years
• Nonischemic cardiomyopathies: DCM, HCM/HOCM, ARVC or
• Channelopathies: Brugada, LQT, CPVT or
• Idiopathic VT/VF or
• Diffuse coronary artery disease, without transmural myocardial infarction in history (ACS and NSTEMI with CK maximum of 400 U/l allowed)

You may not qualify if:

• Unstable cardiac disease
• PCI or CABG \< 3 months ago
• Implantation of a CRT device \< 6 months ago
• ICD unable to deliver programmed ventricular stimulation via programmer (only in the noninvasive EP study group)
• Women of childbearing potential in case of positive pregnancy test at the time of enrollment

Sponsors & Collaborators

• University Medical Center Goettingen: lead
• UMC Utrecht: collaborator
• KU Leuven: collaborator
• University of Athens: collaborator

Study Sites (4)

Katholieke Universiteit Leuven, Dept. of Cardiology

Leuven, 3000, Belgium

Location

University Medical Center Goettingen, Dept. of Cardiology and Pneumology

Göttingen, 37075, Germany

Location

Attikon Hospital University of Athens, BRFAA, Dept. of Cardiology

Athens, 17151, Greece

Location

Universitair Medisch Centrum Utrecht, Depts. of Cardiology and Physiology

Utrecht, 3584 CM, Netherlands

Location

Related Publications (14)

• Koller MT, Schaer B, Wolbers M, Sticherling C, Bucher HC, Osswald S. Death without prior appropriate implantable cardioverter-defibrillator therapy: a competing risk study. Circulation. 2008 Apr 15;117(15):1918-26. doi: 10.1161/CIRCULATIONAHA.107.742155. Epub 2008 Apr 7.

  PMID: 18391108 BACKGROUND

• Poole JE, Johnson GW, Hellkamp AS, Anderson J, Callans DJ, Raitt MH, Reddy RK, Marchlinski FE, Yee R, Guarnieri T, Talajic M, Wilber DJ, Fishbein DP, Packer DL, Mark DB, Lee KL, Bardy GH. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med. 2008 Sep 4;359(10):1009-17. doi: 10.1056/NEJMoa071098.

  PMID: 18768944 BACKGROUND

• Vollmann D, Luthje L, Vonhof S, Unterberg C. Inappropriate therapy and fatal proarrhythmia by an implantable cardioverter-defibrillator. Heart Rhythm. 2005 Mar;2(3):307-9. doi: 10.1016/j.hrthm.2004.11.019. No abstract available.

  PMID: 15851324 BACKGROUND

• Zabel M, Malik M, Hnatkova K, Papademetriou V, Pittaras A, Fletcher RD, Franz MR. Analysis of T-wave morphology from the 12-lead electrocardiogram for prediction of long-term prognosis in male US veterans. Circulation. 2002 Mar 5;105(9):1066-70. doi: 10.1161/hc0902.104598.

  PMID: 11877356 BACKGROUND

• Zabel M, Acar B, Klingenheben T, Franz MR, Hohnloser SH, Malik M. Analysis of 12-lead T-wave morphology for risk stratification after myocardial infarction. Circulation. 2000 Sep 12;102(11):1252-7. doi: 10.1161/01.cir.102.11.1252.

  PMID: 10982539 BACKGROUND

• Bloomfield DM, Hohnloser SH, Cohen RJ. Interpretation and classification of microvolt T wave alternans tests. J Cardiovasc Electrophysiol. 2002 May;13(5):502-12. doi: 10.1046/j.1540-8167.2002.00502.x.

  PMID: 12030535 BACKGROUND

• Schmidt G, Malik M, Barthel P, Schneider R, Ulm K, Rolnitzky L, Camm AJ, Bigger JT Jr, Schomig A. Heart-rate turbulence after ventricular premature beats as a predictor of mortality after acute myocardial infarction. Lancet. 1999 Apr 24;353(9162):1390-6. doi: 10.1016/S0140-6736(98)08428-1.

  PMID: 10227219 BACKGROUND

• Franz MR, Chin MC, Sharkey HR, Griffin JC, Scheinman MM. A new single catheter technique for simultaneous measurement of action potential duration and refractory period in vivo. J Am Coll Cardiol. 1990 Oct;16(4):878-86. doi: 10.1016/s0735-1097(10)80336-5.

  PMID: 2212368 BACKGROUND

• Hummel JD, Strickberger SA, Daoud E, Niebauer M, Bakr O, Man KC, Williamson BD, Morady F. Results and efficiency of programmed ventricular stimulation with four extrastimuli compared with one, two, and three extrastimuli. Circulation. 1994 Dec;90(6):2827-32. doi: 10.1161/01.cir.90.6.2827.

  PMID: 7994827 BACKGROUND

• Thomsen MB, Volders PG, Beekman JD, Matz J, Vos MA. Beat-to-Beat variability of repolarization determines proarrhythmic outcome in dogs susceptible to drug-induced torsades de pointes. J Am Coll Cardiol. 2006 Sep 19;48(6):1268-76. doi: 10.1016/j.jacc.2006.05.048. Epub 2006 Aug 28.

  PMID: 16979017 BACKGROUND

• Narayan SM, Franz MR, Lalani G, Kim J, Sastry A. T-wave alternans, restitution of human action potential duration, and outcome. J Am Coll Cardiol. 2007 Dec 18;50(25):2385-92. doi: 10.1016/j.jacc.2007.10.011.

  PMID: 18154963 BACKGROUND

• Arvanitis DA, Sanoudou D, Kolokathis F, Vafiadaki E, Papalouka V, Kontrogianni-Konstantopoulos A, Theodorakis GN, Paraskevaidis IA, Adamopoulos S, Dorn GW 2nd, Kremastinos DT, Kranias EG. The Ser96Ala variant in histidine-rich calcium-binding protein is associated with life-threatening ventricular arrhythmias in idiopathic dilated cardiomyopathy. Eur Heart J. 2008 Oct;29(20):2514-25. doi: 10.1093/eurheartj/ehn328. Epub 2008 Jul 9.

  PMID: 18617481 BACKGROUND

• Lehnart SE, Lederer WJ. An antidote for calcium leak: targeting molecular arrhythmia mechanisms. J Mol Cell Cardiol. 2010 Feb;48(2):279-82. doi: 10.1016/j.yjmcc.2009.11.005. Epub 2009 Nov 26. No abstract available.

  PMID: 19931542 BACKGROUND

• Seegers J, Vos MA, Flevari P, Willems R, Sohns C, Vollmann D, Luthje L, Kremastinos DT, Flore V, Meine M, Tuinenburg A, Myles RC, Simon D, Brockmoller J, Friede T, Hasenfuss G, Lehnart SE, Zabel M; EUTrigTreat Clinical Study Investigators. Rationale, objectives, and design of the EUTrigTreat clinical study: a prospective observational study for arrhythmia risk stratification and assessment of interrelationships among repolarization markers and genotype. Europace. 2012 Mar;14(3):416-22. doi: 10.1093/europace/eur352. Epub 2011 Nov 23.

  PMID: 22117037 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Whole blood specimens for genetic analyses

MeSH Terms

Conditions

Cardiomyopathies; Arrhythmias, Cardiac; Death, Sudden, Cardiac; Calcium Metabolism Disorders; Genetic Diseases, Inborn

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Heart Arrest; Death, Sudden; Death; Metabolic Diseases; Nutritional and Metabolic Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Markus Zabel, M.D.

  University Medical Center Goettingen

  STUDY DIRECTOR

• Marc A. Vos, Ph.D.

  UMC Utrecht

  PRINCIPAL INVESTIGATOR

• Panagotia Flevari, M.D.

  University of Athens

  PRINCIPAL INVESTIGATOR

• Rik Willems, M.D.

  KU Leuven

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor, Head of Clinical Electrophysiology

Study Record Dates

• First Submitted: September 24, 2010
• First Posted: September 27, 2010
• Study Start: January 1, 2010
• Primary Completion: February 1, 2014
• Study Completion: September 1, 2014
• Last Updated: December 2, 2015

Record last verified: 2015-12

Locations

BE (1); NL (1); GR (1); DE (1)