An Arrhythmia Risk Stratification and Genetic Trial

Arrhythmia Clinical Trial

— EUTrigTreat  

Official title:

The EU TrigTreat Clinical Study: An Advanced Diagnostics and Observational Trial for Arrhythmia Risk Stratification and Correlation With Genotype

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01209494
• Other study ID #: HEALTH-F2-2009-241526
• Status: Completed
• Phase: N/A
• First received: September 24, 2010
• Last updated: December 1, 2015
• Start date: January 2010
• Est. completion date: September 2014

Study information

• Verified date: December 2015
• Source: University Medical Center Goettingen
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Ethics CommissionGreece: Ethics CommitteeBelgium: Ethics CommitteeNetherlands: Medical Ethics Review Committee (METC)
• Study type: Observational

Clinical Trial 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.

Description:

An increasing number of patients receive implantable cardioverter-defibrillators for primary and secondary prevention of sudden cardiac death. Within this group, it is difficult to differentiate between patients at high risk with need for additional treatment and, on the other hand, patients at low risk without benefit from implantable cardioverter-defibrillator therapy. Risk stratification techniques have been studied extensively over the last decades, but no conclusive recommendations can be found in the current guidelines for prevention of SCD. Furthermore, new genetic markers associated with sudden cardiac death were discovered recently, however, have not been implemented in concurrent risk analysis. Last, time dependent changes of risk stratification assessment are unknown.

The prospective EUTrigTreat multi-center study is an observational, advanced diagnostics and genetic risk stratification trial in patients with standard indications for ICD treatment 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 four European academic clinical centers, 700 ICD patients are prospectively enrolled. Optionally, the number of patients may be expanded to 1000. 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 672
• Est. completion date: September 2014
• Est. primary completion date: February 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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)

Exclusion Criteria:

• 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

Study Design

Observational Model: Cohort, Time Perspective: Prospective

Related Conditions & MeSH terms

• Arrhythmia
• Calcium Metabolism Disorders
• Cardiomyopathies
• Cardiomyopathies, Primary
• Death, Sudden, Cardiac
• Metabolic Diseases
• Sudden Cardiac Death

Locations

Country	Name	City	State
Belgium	Katholieke Universiteit Leuven, Dept. of Cardiology	Leuven
Germany	University Medical Center Goettingen, Dept. of Cardiology and Pneumology	Goettingen
Greece	Attikon Hospital University of Athens, BRFAA, Dept. of Cardiology	Athens
Netherlands	Universitair Medisch Centrum Utrecht, Depts. of Cardiology and Physiology	Utrecht

Sponsors (4)

Lead Sponsor	Collaborator
University Medical Center Goettingen	Katholieke Universiteit Leuven, UMC Utrecht, University of Athens

Countries where clinical trial is conducted

Belgium,  Germany,  Greece,  Netherlands, 

References & Publications (13)

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. — View Citation

Bloomfield DM, Hohnloser SH, Cohen RJ. Interpretation and classification of microvolt T wave alternans tests. J Cardiovasc Electrophysiol. 2002 May;13(5):502-12. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Schmidt G, Malik M, Barthel P, Schneider R, Ulm K, Rolnitzky L, Camm AJ, Bigger JT Jr, Schömig 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. — View Citation

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. Epub 2006 Aug 28. — View Citation

Vollmann D, Lüthje L, Vonhof S, Unterberg C. Inappropriate therapy and fatal proarrhythmia by an implantable cardioverter-defibrillator. Heart Rhythm. 2005 Mar;2(3):307-9. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Total Mortality		2010-2014	No
Secondary	Sudden Cardiac, Cardiac and Non-Cardiac Mortality	The standard definition of SCD applied. A cardiac death is defined as any death presumed to have occurred from a cardiac cause other than SCD. Non-cardiac deaths are all other deaths.	2010-2014	No
Secondary	Appropriate and Inappropriate Shocks	Appropriate shock is a secondary endpoint. ICD shock is classified as appropriate if delivered for a true ventricular tachyarrhythmia in the VT or VF zone. Appropriate ICD shock is classified as 1 primarily delivered in the VF zone, 2 secondarily delivered as a backup to failed ATP in the VT zone or 3 secondarily delivered after acceleration of failed ATP to VF zone.; Inappropriate shock is a secondary endpoint. Inappropriate shock is an ICD shock caused by oversensing of cardiac or non-cardiac electrical signals as VT or VF, or by inappropriate interpretation of SVT as VT/VF by the device.	2010-2014	No
Secondary	Secondary Composite Endpoints	A secondary composite endpoint of total mortality and appropriate ICD shocks is defined. Another secondary composite endpoint is defined as the sum of appropriate and inappropriate ICD shocks, i.e. all ICD shocks.	2010-2014	No