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

Joachim Seegers, Marc A Vos, Panagiota Flevari, Rik Willems, Christian Sohns, Dirk Vollmann, Lars Lüthje, Dimitrios T Kremastinos, Vincent Floré, Mathias Meine, Anton Tuinenburg, Rachel C Myles, Dirk Simon, Jürgen Brockmöller, Tim Friede, Gerd Hasenfuß, Stephan E Lehnart, Markus Zabel, EUTrigTreat Clinical Study Investigators, Joachim Seegers, Marc A Vos, Panagiota Flevari, Rik Willems, Christian Sohns, Dirk Vollmann, Lars Lüthje, Dimitrios T Kremastinos, Vincent Floré, Mathias Meine, Anton Tuinenburg, Rachel C Myles, Dirk Simon, Jürgen Brockmöller, Tim Friede, Gerd Hasenfuß, Stephan E Lehnart, Markus Zabel, EUTrigTreat Clinical Study Investigators

Abstract

Aims: The EUTrigTreat clinical study has been designed as a prospective multicentre observational study and aims to (i) risk stratify patients with an implantable cardioverter defibrillator (ICD) for mortality and shock risk using multiple novel and established risk markers, (ii) explore a link between repolarization biomarkers and genetics of ion (Ca(2+), Na(+), K(+)) metabolism, (iii) compare the results of invasive and non-invasive electrophysiological (EP) testing, (iv) assess changes of non-invasive risk stratification tests over time, and (v) associate arrythmogenomic risk through 19 candidate genes.

Methods and results: Patients with clinical ICD indication are eligible for the trial. Upon inclusion, patients will undergo non-invasive risk stratification, including beat-to-beat variability of repolarization (BVR), T-wave alternans, T-wave morphology variables, ambient arrhythmias from Holter, heart rate variability, and heart rate turbulence. Non-invasive or invasive programmed electrical stimulation will assess inducibility of ventricular arrhythmias, with the latter including recordings of monophasic action potentials and assessment of restitution properties. Established candidate genes are screened for variants. The primary endpoint is all-cause mortality, while one of the secondary endpoints is ICD shock risk. A mean follow-up of 3.3 years is anticipated. Non-invasive testing will be repeated annually during follow-up. It has been calculated that 700 patients are required to identify risk predictors of the primary endpoint, with a possible increase to 1000 patients based on interim risk analysis.

Conclusion: The EUTrigTreat clinical study aims to overcome current shortcomings in sudden cardiac death risk stratification and to answer several related research questions. The initial patient recruitment is expected to be completed in July 2012, and follow-up is expected to end in September 2014. Clinicaltrials.gov identifier: NCT01209494.

Figures

Figure 1
Figure 1
Study work flow. APD, action potential duration; BVR, beat-to-beat variability of repolarization [non-invasive part: 12-lead ECG (electrocardiogram), invasive part: 12-lead ECG and MAP (monophasic action potential)]; EP, electrophysiological; HRT, heart-rate turbulence; HRV, heart-rate variability; LVEF, left ventricular ejection fraction; ICD, implantable cardioverter defibrillator; SAECG, signal-averaged ECG; TWA, T-wave alternans; TWM, T-wave morphology.

References

    1. Pratt CM, Greenway PS, Schoenfeld MH, Hibben ML, Reiffel JA. Exploration of the precision of classifying sudden cardiac death. Implications for the interpretation of clinical trials. Circulation. 1996;93:519–24.
    1. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J Am Coll Cardiol. 2006;48:e247–346.
    1. Goldberger JJ, Cain ME, Hohnloser SH, Kadish AH, Knight BP, Lauer MS, et al. American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society scientific statement on noninvasive risk stratification techniques for identifying patients at risk for sudden cardiac death. A scientific statement from the American Heart Association Council on Clinical Cardiology Committee on Electrocardiography and Arrhythmias and Council on Epidemiology and Prevention. J Am Coll Cardiol. 2008;52:1179–99.
    1. Myerburg RJ, Kessler KM, Castellanos A. Sudden cardiac death: epidemiology, transient risk, and intervention assessment. Ann Intern Med. 1993;119:1187–97.
    1. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352:225–37.
    1. Poole JE, Johnson GW, Hellkamp AS, Anderson J, Callans DJ, Raitt MH, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med. 2008;359:1009–17.
    1. 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;117:1918–26.
    1. Daubert JP, Zareba W, Cannom DS, McNitt S, Rosero SZ, Wang P, et al. Inappropriate implantable cardioverter-defibrillator shocks in MADIT II: frequency, mechanisms, predictors, and survival impact. J Am Coll Cardiol. 2008;51:1357–65.
    1. Sweeney MO, Wathen MS, Volosin K, Abdalla I, DeGroot PJ, Otterness MF, et al. Appropriate and inappropriate ventricular therapies, quality of life, and mortality among primary and secondary prevention implantable cardioverter defibrillator patients: results from the Pacing Fast VT REduces Shock ThErapies (PainFREE Rx II) trial. Circulation. 2005;111:2898–905.
    1. Vollmann D, Lüthje L, Vonhof S, Unterberg C. Inappropriate therapy and fatal proarrhythmia by an implantable cardioverter-defibrillator. Heart Rhythm. 2005;2:307–9.
    1. Spragg DD, Berger RD. How to avoid inappropriate shocks. Heart Rhythm. 2008;5:762–5.
    1. EMEA: The European Agency for the Evalu ation of Medicinal Products. Guideline for Good Clinical Practice: ICH Harmonised Tripartite Guideline. Step 5 Consolidated Guideline 1/5/96. London: 2002.
    1. Zabel M, Malik M, Hnatkova K, Papademetriou V, Pittaras A, Fletcher RD, et al. Analysis of T-wave morphology from the 12-lead electrocardiogram for prediction of long-term prognosis in male US veterans. Circulation. 2002;105:1066–70.
    1. Berbari EJ, Lazzara R. An introduction to high-resolution ECG recordings of cardiac late potentials. Arch Intern Med. 1988;148:1859–63.
    1. Bloomfield DM, Hohnloser SH, Cohen RJ. Interpretation and classification of microvolt T wave alternans tests. J Cardiovasc Electrophysiol. 2002;13:502–12.
    1. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Eur Heart J. 1996;17:354–81.
    1. Schmidt G, Malik M, Barthel P, Schneider R, Ulm K, Rolnitzky L, et al. Heart-rate turbulence after ventricular premature beats as a predictor of mortality after acute myocardial infarction. Lancet. 1999;353:1390–6.
    1. 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;16:878–86.
    1. Hummel JD, Strickberger SA, Daoud E, Niebauer M, Bakr O, Man KC, et al. Results and efficiency of programmed ventricular stimulation with four extrastimuli compared with one, two, and three extrastimuli. Circulation. 1994;90:2827–32.
    1. Thomsen MB, Volders PGA, Beekman JDM, 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;48:1268–76.
    1. Ehrlich JR, Wegener FT, Anneken L, Duray G, Israel CW, Hohnloser SH. Biventricular pacing does not affect microvolt T-wave alternans in heart failure patients. Heart Rhythm. 2008;5:348–52.
    1. 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;50:2385–92.
    1. Koller BS, Karasik PE, Solomon AJ, Franz MR. Relation between repolarization and refractoriness during programmed electrical stimulation in the human right ventricle. Implications for ventricular tachycardia induction. Circulation. 1995;91:2378–84.
    1. Bennett PB, Yazawa K, Makita N, George AL. Molecular mechanism for an inherited cardiac arrhythmia. Nature. 1995;376:683–5.
    1. Birinyi P, Tóth A, Jóna I, Acsai K, Almássy J, Nagy N, et al. The Na+/Ca2+exchange blocker SEA0400 fails to enhance cytosolic Ca2+transient and contractility in canine ventricular cardiomyocytes. Cardiovasc Res. 2008;78:476–484.
    1. Arvanitis DA, Sanoudou D, Kolokathis F, Vafiadaki E, Papalouka V, Kontrogianni-Konstantopoulos A, et al. The Ser96Ala variant in histidine-rich calcium-binding protein is associated with life-threatening ventricular arrhythmias in idiopathic dilated cardiomyopathy. Eur Heart J. 2008;29:2514–25.
    1. Lehnart SE, Lederer WJ. An antidote for calcium leak: targeting molecular arrhythmia mechanisms. J Mol Cell Cardiol. 2010;48:279–82.
    1. Fiset C, Giles WR. Cardiac troponin T mutations promote life-threatening arrhythmias. J Clin Invest. 2008;118:3845–7.
    1. Li Y, Vinckenbosch N, Tian G, Huerta-Sanchez E, Jiang T, Jiang H, et al. Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants. Nat Genet. 2010;42:969–72.
    1. The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med. 1997;337:1576–83.
    1. Kadish A, Dyer A, Daubert JP, Quigg R, Estes NAM, Anderson KP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med. 2004;350:2151–8.
    1. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346:877–83.
    1. Friede T, Kieser M. Sample size recalculation in internal pilot study designs: a review. Biom J. 2006;48:537–55.
    1. Gurka MJ, Coffey CS, Gurka KK. Internal pilots for observational studies. Biom J. 2010;52:590–603.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다