Background

Clinical trials demonstrating the efficacy of implantable cardioverter defibrillators (ICDs) for the primary and secondary prevention of sudden cardiac death have involved induction of ventricular fibrillation (VF) at the time of initial implantation to demonstrate effective arrhythmia termination. Until recently, routine defibrillation testing at the time of initial ICD insertion has been considered the "standard of care." In addition, the instructions for usage of ICDs in the United States include labeling by the Food and Drug Administration (FDA) for use with defibrillation testing.

Marked advancements in technology have occurred since initial approval of ICD systems in the 1980s and the value of defibrillation testing (DT) has been questioned. Higher defibrillation thresholds were seen with older ICDs implanted using an epicardial approach with abdominal pulse generators and monophasic waveforms. Current pectoral systems now utilize biphasic waveforms, active can technology, and deliver higher output shocks, resulting in more effective defibrillation. Therefore, the risk of failing defibrillation at the time of implantation is now much lower.

However, patients receiving contemporary ICDs may also have multiple comorbidities, as well as more severe heart failure, increasing the risk of failed shocks. Testing at the time of initial implantation provides an opportunity for system revision in the event that a high defibrillation threshold is identified. System modifications at the time of implantation may include repositioning of the lead, capping the proximal coil, changing polarity, altering the biphasic waveform, or adding an additional lead to improve defibrillation efficacy.

Nonetheless, DT at the time of implantation has never been proven to improve long-term outcome in prospective randomized trials. In fact, DT can be associated with serious complications, and its performance in the vulnerable populations undergoing ICD implantation could potentially result in significant morbidity or even mortality. In addition, DT adds to the cost of the procedure with separately billable physician fees, in addition to potential added costs of adverse events which may be the direct result of testing.

Fortunately, prospective randomized trials comparing outcomes in patients who undergo DT to those who do not undergo testing are now available.^1-4 In addition, a recent consensus document also outlines current recommendations related to testing at the time of ICD implantation.⁵ The current analysis will summarize available literature related to outcomes of studies evaluating DT, as well as current trends in testing.

Definition and How to Measure Defibrillation Threshold

"Defibrillation threshold" is a quantitative estimate of the ability of the heart to defibrillate, and can be defined as the minimum shock strength that defibrillates.⁶ It can be measured by systematically decreasing the stored voltages in subsequent VF inductions until the first shock is unable to defibrillate. However, there is a probabilistic nature of defibrillation, and the clinical measurement of the "defibrillation threshold" is not always reproducible, and represents an estimate of a point on a patient's defibrillation probability of success curve. Several methods have been used to determine a "defibrillation threshold," including step-down or step-up approaches. However, recent practice has instead utilized "safety margin" testing as a criterion for device implantation to minimize the number of VF inductions at the time of implantation.⁷ For example, an adequate safety margin for defibrillation may be defined as successful shock therapy at 10 joules below the maximum device output.

Patients Who Have Been Routinely Excluded from Defibrillation Testing

Even prior to availability of prospective randomized data related to testing, DT was not recommended in certain patients who were felt to be at high risk for complications.^7,18 Testing was considered "contraindicated" or "not recommended" in patients with left atrial (LA) or left ventricle (LV) thrombus, atrial fibrillation in the absence of therapeutic anticoagulation (unless transesophageal echocardiography was performed to exclude LA thrombus), severe aortic stenosis, severe proximal three-vessel or left main coronary artery disease without revascularization, hemodynamic instability, or recent stroke. In addition, known inadequate external defibrillation and respiratory issues that preclude adequate sedation or absence of anesthesia support for DT are also reasons to avoid testing during initial implantation. In some of these situations, the patient would be reconsidered for testing at a later date once issues resolved.

Frequency of High Defibrillation Thresholds and Results of System Modifications

Previous studies have shown that a high DT is obtained in 2-12% of patients.^2,8-18 A high DT was defined as a less than 10 joule safety margin in many of these studies,^{8-10,12-15,17} less than or equal to 25 joules in one study² or less than or equal to 30 joules in another study.¹¹ The study with the greatest need for system revision (12%) included only cardiac resynchronization therapy (CRT) patients.¹⁰ The sickest patients appear to have the highest energy requirements for effective defibrillation and greater need for system revision to meet implantation criteria. With system modifications performed at the time of implantation, 67-100% of patients will meet implantation criteria for defibrillation after system revisions.^{2,8-10,12,14-17}

Non-randomized Study Results

Some retrospective studies suggested no difference in mortality in patients who underwent DT versus those who did not, but studies were often small with relatively short follow-up and few treated clinical events.^19,20 In a prospective observational study, there was also no difference in mortality of patients who underwent DT versus those who did not, although large variations in practice between centers was identified and selection bias could not be excluded.²¹ In a post-hoc analysis of the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), there was no difference in all-cause mortality for patients with "high" or "low" defibrillation thresholds.¹¹ However, "high" threshold was arbitrarily defined as >10 joules and "low" as ≤10 joules, and all subjects had effective defibrillation at ≤30 joules in this trial. In fact, only 16 patients had a less than 10 joule safety margin. It should also be noted that "sicker" patients requiring CRT were not included in SCD-HeFT.

In contrast, one small retrospective study demonstrated lower survival in the no DT group, but after adjusting for differences in baseline characteristics, multivariate analysis found only a trend toward an increased risk of death in patients who did not undergo testing.²² Another retrospective study by Pires et al. demonstrated similar findings, with a lower long-term survival in the no-testing group; in this study, multivariate analysis confirmed that absence of DT was an independent predictor of mortality.²³ Examination of a much larger number (64,227) of initial implantation procedures in the ACC NCDR Registry® revealed that patients who did not undergo testing had a higher in-hospital mortality than those who did undergo testing, even after adjusting for baseline differences, although long-term mortality was not available.²⁴ However, selection bias makes it difficult to interpret results of these studies as DT is typically excluded in the sickest patients, and unrecognized confounders may contribute to outcomes in non-randomized studies. Therefore, differences in outcome of patients who undergo testing compared to those who do not can only be answered by randomized clinical trials.

Randomized Trial Results

Randomized clinical trial data are now available regarding outcome of patients who undergo DT compared to those in whom DT is not performed at the time of initial implantation.^1-4 There are currently four randomized trials evaluating defibrillation testing, including (a) the Shockless IMPLant Evaluation (SIMPLE), (b) substudy of the Resynchronization for Ambulatory Heart Failure Trial (RAFT), (c) pilot Test-No Test (TNT) study, and (d) NO Regular Defibrillation testing In Cardioverter Defibrillator Implantation (NORDIC ICD) study. Table 1 summaries enrollment numbers, follow-up duration, and differences in exclusion criteria.

Table 1: Randomized Clinical Trials of Defibrillation Testing and Exclusions

			Exclusions:
Study	N=	FU, mos	R-sided	Amio	HCM	RVCM	CRF
SIMPLE1	2500	37.2	Yes	No	No	No	No
RAFT2	145	24.2	Yes	No	No	No	No
TNT3	72	26.8	Yes	Yes	No	No	No
NORDIC4	1077	22.8	Yes	No	Yes	Yes	Yes

SIMPLE is the landmark trial evaluating DT at the time of initial ICD implantation. This was a single-blind, randomized, non-inferiority trial of DT at 85 hospitals in 18 countries (including Canada, Europe, Israel and Asia Pacific) randomizing DT to no DT at the time of ICD implantation using Boston Scientific devices.¹ The primary efficacy endpoint was non-inferiority of no-testing versus testing using a composite outcome of arrhythmic death or failed appropriate shock for spontaneous ventricular tachycardia (VT) or ventricular fibrillation (VF). After a mean follow-up of 3.1 years, the primary endpoint occurred in fewer patients in the no-testing group (7% per year) than in the testing group (8% per year), with a HR of 0.86, 95% CI 0.65-1.14, p_{non-inferiority} <0.0001. The safety outcomes were not significantly different between groups; however, a pre-specified safety composite outcome, which included only events most likely to be directly caused by DT, occurred in 3.2% of patients in the no-testing group and 4.5% of patients in the testing group (p=0.08). The authors concluded that routine DT at the time of initial ICD implantation is generally well-tolerated, but did not improve shock efficacy or reduce arrhythmic death at follow-up.

A randomized, controlled pilot study comparing ICD implantation with and without DT was performed as a substudy of the Resynchronization for Ambulatory Heart Failure Trial (RAFT).² A total of 145 subjects were enrolled in this substudy, with 75 randomized to DT and 70 to no DT. No patients experienced serious peri-operative adverse events (stroke, MI, heart failure, intubation or unexpected ICU stay), and length of stay was not prolonged in the DT group. One patient in the DT group had a failed appropriate shock, but no patient suffered arrhythmic death during follow-up. There was a non-significant increase in risk of death or HF hospitalization in the no DT group (10% in the no DT versus 19% in the DT groups, HR 0.53, 95% CI 0.21-1.31, p=0.14).

The TNT ICD pilot study was the only one of the four trials that enrolled subjects in the U.S.³ As devices are "labeled" with instructions for usage with defibrillation testing in the U.S., an Investigational Device Exemption (IDE) was required. A total of 72 patients with devices were randomized in this study. The primary outcome of this study was a composite of total mortality and operative complications in patients who undergo DT compared to those who do not undergo testing at the time of initial ICD implantation. Secondary outcomes included 1st shock efficacy for clinical occurrence of spontaneous VT/VF and implant complications at 90-days post-implant. There was no difference in outcomes or procedural complications, although this pilot study was not powered to detect these differences.

The NORDIC ICD trial randomized 1,077 patients with devices to DT versus no DT at the time of initial ICD implantation.⁴ The primary endpoint was first shock efficacy for VT/VF events during follow-up, and secondary endpoints included serious adverse events and mortality. During a median follow-up of 22.8 months, first shock efficacy was non-inferior in patients who did not undergo DT compared to those who did undergo testing. Procedure-related serious adverse events within 30 days occurred in 17.6% of patients in the DT group compared to 13.9% of patients in the no testing group (p=0.095).

Practice Trends

There has been a trend toward omission of DT at the time of ICD implantation.^24-26 Previous studies examining testing in patients from 1996 to 2009 report that 39-100% of patients underwent testing at implantation, and at least part of this trend toward reduction in testing is related to the year of publication. The use of DT in clinical practice also appears to vary by geographic location, country, hospital, and physician training.^24,25,27-29 Analysis of 64,227 initial ICD implantation procedures in the NCDR Registry® from 2010 revealed the DT was not performed in 29% of patients, with marked variation noted between centers, suggesting implanting physician preference.²⁴ These studies were performed prior to availability of prospective randomized trials, with variations in practice that were likely related to gaps in evidence at that time. Based on recent randomized trial results, it is anticipated that a further reduction in DT will be identified in future studies or in registry data.

Consensus Statement Recommendations

A multi-national Consensus Statement on Optimal ICD Programming and Testing has been recently published.⁵ This document recommends the following:

1. Defibrillation efficacy testing is recommended in patients undergoing a subcutaneous ICD implantation. (Class I recommendation)
2. It is reasonable to omit defibrillation efficacy testing in patients undergoing initial left pectoral transvenous ICD implantation procedures where appropriate sensing, pacing, and impedance values are obtained with fluoroscopically well-positioned RV leads. (Class IIa recommendation)
3. Defibrillation efficacy testing is reasonable in patients undergoing a right pectoral transvenous ICD implantation or ICD pulse generator changes. (Class IIa recommendation)
4. Defibrillation efficacy testing at the time of implantation of a transvenous ICD should not be performed on patients with a documented non-chronic cardiac thrombus, atrial fibrillation or atrial flutter without adequate systemic anticoagulation, critical aortic stenosis, unstable CAD, recent stroke or TIA, hemodynamic instability, or other known morbidities associated with poor outcomes. (Class III – Harm)

Gaps in evidence still exist in right-sided implants, generator replacements, and the totally subcutaneous ICD. There are currently no prospective trials comparing outcomes of patients who do or do not undergo DT with the totally subcutaneous ICD. Right-sided implants were excluded from all four randomized DT trials, and results cannot necessarily be extrapolated to this subgroup. Observational data suggest that patients undergoing ICD generator replacement may be an increased risk for an inadequate defibrillation safety margin.¹³ Testing may also sometimes yield important results for leads on advisory. At the time of generator replacement, certain lead failure problems may only be identified with testing of the high voltage system,^30-32 although a high voltage shock may be delivered in sinus rhythm without induction of VF to identify "concealed" lead abnormalities or fracture. Furthermore, patients with separately implanted devices, such as a transvenous pacemaker and totally subcutaneous ICD, should have testing to exclude over-sensing or under-sensing. For example, over-sensing of pacemaker output may result in inappropriate ICD therapy, while undersensing of VF related to detection of pacemaker spikes during VF and failure to deliver therapy may be a life-threatening problem.

Conclusion

The role of DT at the time of ICD implantation has been highly debated, with wide differences in opinion related to this topic. These differences in opinion have stemmed from previously limited data and paucity of randomized clinical trials evaluating outcomes of patients who undergo testing versus those who do not. Many of these "gaps" in evidence have now been filled with availability of data related to outcomes of patients in recently published randomized clinical trials discussed in this summary.

However, gaps in evidence still exist related to right-sided implants, generator replacements, and the totally subcutaneous ICD. In addition, adverse device-device interactions may occur in patients with separately implanted devices. Therefore, DT may still be considered in patients with (a) totally subcutaneous ICDs, (b) right-sided implants, (c) known ineffective clinical shock therapy or known high defibrillation energy requirements in patients requiring addition of a drug that may further increase defibrillation requirements, and (d) separately implanted devices (e.g., ICD and separately implanted permanent pacemaker) to assess potential device-device interactions. Testing should be individualized, weighing risks and benefits in certain subgroups where prospective randomized data are not currently available. Future prospective randomized studies, in addition to registry data, may help to address some of these remaining gaps in evidence related to DT in unique patient subgroups.

References

1. Healey JS, Hohnloser SH, Glikson M, et al. Cardioverter defibrillator implantation without induction of ventricular fibrillation: a single-blind, non-inferiority, randomised controlled trial (SIMPLE). Lancet 2015;385:785-91.
2. Healey JS, Gula LJ, Birnie DH, et al. A randomized-controlled pilot study comparing ICD implantation with and without intraoperative defibrillation testing in patients with heart failure and severe left ventricular dysfunction: a substudy of the RAFT trial. J Cardiovasc Electrophysiol 2012;23:1313-6.
3. Russo AM, Andriulli J, Ortman M, et al. Outcome Following ICD Implantation With Versus Without Defibrillation Testing: Preliminary Results of The Prospective Randomized Test-No Test (TNT) Pilot Study. J Am Coll Cardiol 2014;63:A451 (abstract).
4. Bänsch D, Bonnemeier H, Brandt J, et al. Intra-operative defibrillation testing and clinical shock efficacy in patients with implantable cardioverter-defibrillators: the NORDIC ICD randomized clinical trial. Eur Heart J 2015;36:2500-7.
5. Wilkoff BL, Fauchier L, Stiles MK, et al. 2015 HRS/EHRA/APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing. Heart Rhythm 2016;13:e50-86.
6. Rattes MF, Jones DL, Sharma AD, Klein GJ. Defibrillation threshold: A simple and quantitative estimate of the ability to defibrillate. Pacing Clin Electrophysiol 1987;10:70-7.
7. Swerdlow CD, Russo AM, Degroot PJ. The dilemma of ICD implant testing. Pacing Clin Electrophysiol 2007;30:675-700.
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9. Leong-Sit P, Gula LJ, Diamantouros P, et al. Effect of defibrillation testing on management during implantable cardioverter-defibrillator implantation. Am Heart J 2006;152:1104-8.
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12. Day JD, Olshansky B, Moore S, et al. High defibrillation energy requirements are encountered rarely with modern dual-chamber implantable cardioverter-defibrillator systems. Europace 2008;10:347-50.
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16. Keyser A, Hilker MK, Schmidt S, et al. Shock or no shock - a question of philosophy or should intraoperative implantable cardioverter defibrillator testing be recommended? Interact Cardiovasc Thorac Surg 2013;16:321-5.
17. Vischer AS, Sticherling C, Kühne MS, Osswald S, Schaer BA. Role of defibrillation threshold testing in the contemporary defibrillator patient population. J Cardiovasc Electrophysiol 2013;24:437-41.
18. Russo AM, Chung MK. Is defibrillation testing necessary for implantable transvenous defibrillators?: defibrillation testing is necessary at the time of implantable cardioverter defibrillator implantation. Circ Arrhythm Electrophysiol 2014;7:337-46.
19. Codner P, Nevzorov R, Kusniec J, Haim M, Zabarski R, Strasberg B. Implantable cardioverter defibrillator with and without defibrillation threshold testing. Isr Med Assoc J 2012;14:343-6.
20. Michowitz Y, Lellouche N, Contractor T, et al. Defibrillation threshold testing fails to show clinical benefit during long-term follow-up of patients undergoing cardiac resynchronization therapy defibrillator implantation. Europace 2011;13:683-8.
21. Brignole M, Occhetta E, Bongiorni MG, et al. Clinical evaluation of defibrillation testing in an unselected population of 2,120 consecutive patients undergoing first implantable cardioverter-defibrillator implant. J Am Coll Cardiol 2012;60:981-7.
22. Hall B, Jeevanantham V, Levine E, et al. Comparison of outcomes in patients undergoing defibrillation threshold testing at the time of implantable cardioverter-defibrillator implantation versus no defibrillation threshold testing. Cardiol J 2007;14:463-9.
23. Pires LA, Johnson KM. Intraoperative testing of the implantable cardioverter-defibrillator: how much is enough? J Cardiovasc Electrophysiol 2006;17:140-5.
24. Russo A, Wang Y, Curtis J, Al-Khatib, S, Lampert R. Patient, physician, and procedural factors influencing the use of defibrillation testing during initial implantable cardioverter insertion: findings from the NCDR®. Pacing Clin Electrophysiol 2013;36:1522-31.
25. Healey JS, Brambatti M. Is defibrillation testing necessary for implantable transvenous defibrillators?: defibrillation testing should not be routinely performed at the time of implantable cardioverter defibrillator implantation. Circ Arrhythm Electrophysiol 2014;7:347-51.
26. Russo AM, Gerstenfeld EP, Dixit S, et al. Changing patterns of defibrillation testing at the time of implantable cardioverter defibrillator insertion over the past 8 Years. J Am Coll Cardiol 2009;53(suppl):A134.
27. Bianchi S, Ricci RP, Biscione F, et al. Primary prevention implantation of cardioverter defibrillator without defibrillation threshold testing: 2-year follow-up. Pacing Clin Electrophysiol 2009;32:573-8.
28. Stefano B, Pietro RR, Maurizio G, et al. Defibrillation testing during implantable cardioverter-defibrillator implantation in Italian current practice: the Assessment of Long-term Induction clinical ValuE (ALIVE) project. Am Heart J 2011;162:390-7.
29. Brignole M, Raciti G, Bongiorni MG, et al. Defibrillation testing at the time of implantation of cardioverter defibrillator in the clinical practice: a nation-wide survey. Europace 2007;9:540-3.
30. Bun SS, Duytschaever M, Tavernier R. Defibrillation testing can reveal 'concealed' lead fracture. Europace 2013;15:54.
31. Doshi R, Ceballos S, Mendez F. Is high-voltage lead integrity measurement adequate during defibrillator generator replacement? Journal of Innovations in Cardiac Rhythm Management 2012;3:1016-9.
32. Shah P, Singh G, Chandra S, Schuger CD. Failure to deliver therapy by a Riata Lead with internal wire externalization and normal electrical parameters during routine interrogation. J Cardiovasc Electrophysiol 2013;24:94-6.

Keywords: Anesthesia, Aortic Valve Stenosis, Atrial Fibrillation, Atrial Flutter, Cardiac Resynchronization Therapy, Comorbidity, Coronary Artery Disease, Death, Sudden, Cardiac, Defibrillators, Implantable, Drug Repositioning, Echocardiography, Transesophageal, Electric Countershock, Electric Impedance, Heart Failure, Heart Ventricles, Hemodynamics, Hospital Mortality, Intensive Care Units, Intubation, Multivariate Analysis, Pacemaker, Artificial, Probability, Prospective Studies, Randomized Controlled Trials as Topic, Registries, Retrospective Studies, Risk Assessment, Secondary Prevention, Selection Bias, Single-Blind Method, Standard of Care, Stroke, Tachycardia, Ventricular, Thrombosis, Ventricular Fibrillation, Vulnerable Populations

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