ICD THERAPIES: are they harmful or just high risk markers? Konstantinos P. Letsas, MD, PhD, FESC LAB OF CARDIAC ELECTROPHYSIOLOGY EVANGELISMOS GENERAL HOSPITAL ATHENS
ICD therapies are common In a meta-analysis of 7 major ICD trials, appropriate ICD therapy (including both ATP and shock) occurred in up to 64% and inappropriate therapies occurred in up to 24% during 20 to 45 months of follow-up. Among the 194 000 patients included in the ALTITUDE survival study, appropriate and inappropriate shock rates at 5 years were 23% and 17%, respectively. In MADIT-RIT, in conventional therapy arm, the incidence of appropriate and inappropriate therapies was 22% and 20%, respectively. Am J Cardiol. 2006;97:1255-1261 Circulation. 2010;122:2359-2367 N Engl J Med 2012;367:2275-83.
Are ICD shocks simply a marker of risk or the shocks themselves cause harm???
Shock-induced damage of the myocardium Experimental studies have shown that the occurrence of biophysical injury with electrical shocks leads to electroporation of cellular membrane and cellular necrosis (Pakhomov et al. Arch Biochem Biophys 2007;465:109-18. Lee et al. Ann Rev Biomed Eng 2000;2:477-509). Shocks after ventricular arrhythmia can contribute to intracellular calcium overload, maintaining a vicious cycle of arrhythmia promotion and electrical storm (Tsuji Y, et al. Circulation 2011;123:2192-203). ICD shocks >9 J delivered during sinus rhythm or VF result in a 10-15% reduction in the cardiac index and increase the risk of HF (J Cardiovasc Electrophys 1998;9:791 797).
Shock-induced impact on mortality
A Systematic Review and Meta-analysis of the Association Between Implantable Cardioverter- Defibrillator Shocks and Long-term Mortality In this pooled analysis, a significant association was detected between ICD shocks and mortality. Although the association is significant for both appropriate and inappropriate shocks, the level of association is stronger for appropriate shocks. Proietti et al. Canadian Journal of Cardiology 2015; 31: 270 277
Predictors of Mortality in Patients With an Implantable Cardiac Defibrillator: A Systematic Review and Meta-analysis Any type of shock (appropriate and inappropriate) was an independent predictor. The comparison of different types of shocks showed that the mortality risk associated with appropriate shocks (HR, 1.84) was not significantly different from the mortality risk associated with inappropriate shocks (HR, 1.55), electrical storm (HR, 2.4), or appropriate and inappropriate shocks (HR, 2.34). The ATP therapies during follow-up were not associated with increased mortality (high to moderate confidence). LAB OF CARDIAC Alba et ELECTROPHYSIOLOGY al. Canadian Journal, EVANGELISMOS of Cardiology GENERAL 29;2013:1729-1740 HOSPITAL, ATHENS
Effect of appropriate ICD Therapies on mortality: the OMNI Trial For patients who experienced only appropriate therapy compared with patients experiencing no episodes, after adjusting for baseline predictors HR was 1.46 (p = 0.023) in the ATP-treated group; 2.11 (p < 0.001) for SSE patients; 2.55 (p = 0.002) for MSE patients (>1 shock). Thus, all groups receiving appropriate therapy had significantly increased mortality compared to those with no episodes. J Cardiovasc Electrophysiol. 2016;27:192-9.
Effect of inappropriate therapies on mortality: the OMNI Trial The HR for mortality for patients who experienced only inappropriate therapy compared with patients experiencing no episodes, after adjusting for baseline predictors, was 0.99 (p= 0.984) for the inappropriate ATP group; 1.52 (p = 0.052) for the inappropriate SSE group; 1.15 (p= 0.734) for the inappropriate MSE group. None of the groups receiving inappropriate therapy had a significant increase in mortality compared with those with no episodes. J Cardiovasc Electrophysiol. 2016;27:192-9.
The shock burden ICD shocks are associated with increased mortality risk, and the burden of shocks plays a role in this association Patients with 1 5 shock days did not have a significantly increased risk of death (HR 1.30), while those with 6 10 shock days (HR 2.22) and 10 shock days (HR 3.66) had increasingly higher risk. Likewise, patients who received one to five total shocks did not have an increased risk of death (HR 1.08), while those receiving 6 10 shocks (HR 2.07), or >10 shocks (HR 2.31) had a greater than twofold increased risk of death as compared with patients who received no shocks. Heart Rhythm 2011;8:1881 1886
Data from the MADIT-RIT trial Circ Arrhythm Electrophysiol. 2014;7:785-792
Data from the MADIT-RIT trial: are ATP therapies harmful?
Data from the MADIT-RIT trial: are ATP therapies harmful? The significant reduction in appropriate and inappropriate ATP in the high rate and delayedtherapy groups may have contributed to the observed mortality reduction of 44 to 55% seen in this study, and the findings raise questions about the need for and safety of empirical ATP. Are ATP therapies pro-arrhythmic (AF, VT, VF)? N Engl J Med 2012;367:2275-83.
All types of ICD therapies have been associated with increased mortality Appropriate and inappropriate shocks Appropriate and inappropriate ATP therapies
Can we uncouple the effect of arrhythmia from the effect of therapy?
Can we uncouple the effect of arrhythmia from the effect of therapy? Each VT, FVT and VF episode increased risk by 4%, 2% and 15%, respectively. Each episode of VT treated with ATP was associated with an approximately 3% increased risk of death, whereas shocked FVT increased risk by 31% and shocked VF by 16%. Patients who died had 5-6 times more VAs (VT,FVT,VF) than survivors. Patients with more VA episodes and more shocks have higher mortality than patients with less of both; Inappropriate shocked episodes were not associated with increased mortality risk. Sweeney MO et al. Heart Rhythm 2010;7:353 360.
Can we uncouple the effect of arrhythmia from the effect of therapy? Sweeney MO et al. Heart Rhythm 2010;7:353 360.
Risk of death by VA type and therapy ATP-terminated VT was not associated with an increased mortality, whereas shocks for similar arrhythmias were associated with a worse outcome. This possibly indicates a direct detrimental effect of ICD shocks on mortality. Sweeney MO et al. Heart Rhythm 2010;7:353 360.
Does ICD therapies reduction decrease mortality? The answer should be YES
Impact of Programming Strategies Aimed at Reducing Nonessential ICD Therapies on Mortality: A Systematic Review and Meta-Analysis Therapy reduction programming was associated with a significant 30% lower risk of death versus with conventional programming. Similar reductions in mortality were observed when only the 4 RT were included (26% relative reduction). Circ Arrhythm Electrophysiol. 2014;7:164-170
Implantable cardioverter-defibrillator shock prevention does not reduce mortality: A systemic review The 17 trials included in this meta-analysis enrolled a total of 5875 patients. 9 antiarrhythmic medications studies included 2428 patients 3 catheter ablation studies enrolled 256 patients 5 ICD programming studies enrolled 3191 patients. Heart Rhythm 2012;9:2068 2074
Effect of interventions on ICD shocks Antiarrhythmic medications and catheter ablation of VT significantly reduced the number of patients receiving shocks by 41% (OR 0.59) and 65% (OR 0.35), respectively. Of the ICD programming trials, only the PAINFREE-II (Pacing Fast Ventricular Tachycardia Reduces Shock Therapies) trial demonstrated a significant reduction in shocks (OR 0.38). Heart Rhythm 2012;9:2068 2074
NO effect of intervention on all-cause mortality!!! None of the individual studies demonstrated a reduction in mortality, nor did the pooled estimate of treatment effect for any of the antiarrhythmic medication) or the catheter ablation of VT trials. Of note, the 2 studies that included an amiodarone group (ALPHEE and OPTIC) showed higher mortality in the amiodarone group compared with the control, which was statistically significant in ALPHEE (17.0% vs 5.5%) but not in OPTIC trial (4.3% vs 1.4%). The only ICD programming trial to show a reduction in shocks, the PAINFREE-II trial, did not demonstrate any reduction on mortality (OR 1.41).
ICD shocks are simply an adverse prognostic marker: limitations of the studies The lack of survival benefit observed with these therapies could suggest that ICD shocks are simply an adverse prognostic marker and that they do not contribute to the increased risk of death among patients experiencing shocks. Most of the trials included in this review had a mean follow-up of only 1 to 2 years. This may be too short to observe a reduction in mortality, particularly for interventions such as catheter ablation, which have early,periprocedural risks. Overtime, repeated ICD shocks can produce cumulative myocardial injury; thus,the mortality benefits of preventing ICD shocks could be more manifest as time passes. Another possible explanation for the lack of survival benefit in these trials is the relatively modest reduction in ICD shocks that was achieved.
ICD shock is the innocent bystander in the equation and not the guilty suspect Inappropriate shocks associated with AF or atrial flutter increase mortality, whereas inappropriate shocks associated with sinus tachycardia, artifacts, or noises were not associated with increased mortality (J Am Coll Cardiol 2013;62:1674-9). ICD shocks delivered after noninvasive electrophysiological study were not associated with an increase in mortality compared with shocks occurred after spontaneous VT/VF (Heart Rhythm 2010;7:755-60). This evidence supports the concept that it is the condition underlying the myocardium and not the shock that causes damage.
The occurrence of appropriate or inappropriate shocks may be a marker of HF progression: Data from the SCD-HeFT and MADIT II trials Thirty percent of deaths occurred within 24 h of an appropriate shock, a sign of impending death. The most common cause of death during follow-up among shock recipients was progressive HF. The risk of first and recurrent HF hospitalization increased by 90% and 74%, respectively, after appropriate shocks. Triggers for ventricular arrhythmias include myocardial ischemia, catecholamines, electrolyte abnormalities, and ventricular remodeling. These arrhythmogenic factors can be precipitated by the onset of HF decompensation. The same factors can cause AF either causing or worsening HF. N Engl J Med 2008;359:1009 1017. Circulation 2006;113:2810 2817.
Anxiety and stress following ICD shocks Patients with ICD shocks have increased levels of psychological distress, anxiety, anger, post-traumatic stress disorder, and depression as compared with patients who do not receive shocks, and these psychological sequelae may be a contributing factor to the increased mortality seen in patients who receive ICD shocks. Int J Cardiol 2011; 147:420 423
ICD THERAPIES: are they harmful or just high risk markers? Both answers are possibly correct. ICD therapies themselves are likely to only be partially responsible for the increased mortality associated with their use, and that therapies themselves are often a marker for more severe cardiac disease.
EHRA Young EP Group European Society of Cardiology The Young Electrophysiologists Committee has been formed by EHRA to facilitate, enhance and accelerate the development of early career electrophysiologists. Electrophysiologists until the age of 40 or those older than 40 but no more than 3 years out of training are directly targeted by this new EHRA initiative. Apply for EHRA young EP Group at : https://www.formstack.com/forms/escardioehra_young_ep_data
Networking and education among Young EPs across all countries We are planning to promote networking and education among Young EPs across all member countries. Requirements in your country to have a Young EP come for a 1-2 week observership in a particular centre. Potential centres that would have a Young EP contact and would be willing to accept other members of the Young EP community for a 1-2 week observership. Strengths/skills of each centre. If there are particular extra requirements for a particular centre, the Young EP contact there should specify it.
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