research article persistence of primary giuseppe stabile, … · 2016. 10. 12. · stabile g,...

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Journal of Cardiology & Clinical Research

Cite this article: Stabile G, D’Onofrio A, Capucci A, Amellone C, De Simone A, et al. (2016) Persistence of Primary Prevention Indication to Implantable Car-dioverter Defibrillators at One Year from Implantation. J Cardiol Clin Res 4(5): 1075.

*Corresponding author

Giuseppe Stabile, Laboratorio di Elettrofisiologia, Clinica Mediterranea, Via Orazio 2, 80100 Napoli, Italy, Tel: +390817259641; Fax: +390817259777; Email:

Submitted: 16 July 2016

Accepted: 01 September 2016

Published: 02 September 2016

Copyright© 2016 Stabile et al.

OPEN ACCESS

Keywords• Cardioverter defibrillators• Ventricular tachycardia• Cardiomyopathy

Research Article

Persistence of Primary Prevention Indication to Implantable Cardioverter Defibrillators at One Year from ImplantationGiuseppe Stabile1*, Antonio D’Onofrio2, Alessandro Capucci3, Claudia Amellone4, Antonio De Simone5, Loira Leoni6, Ernesto Ammendola7, Raffaele Sangiuolo8, Assunta Iuliano1, Valeria Calvi9, Catia Checchinatol, Gabriele Zanotto10, Umberto Giordano11, Giovanni Morani12, Monica Campari13, and Gianfranco Buja61Clinica Mediterranea, Naples, Italy 2Ospedale Monaldi, Naples, Italy3Università Politecnica delle Marche, Ancona, Italy 4Ospedale di Ciriè - ASL TO 4, Ciriè (TO), Italy5Clinica San Michele, Maddaloni (CE), Italy6Policlinico Universitario, Padua, Italy7Ospedale Monaldi SUN, Naples, Italy8Ospedale Buon Consiglio Fatebenefratelli, Naples, Italy 9A.O.U.P. “Vittorio Emanuele”, Ospedale Ferrarotto, Italy 10Ospedale Santa Croce di Moncalieri, Moncalieri (TO), Italy11Ospedale di Legnago, Legnago, Italy 12Ospedale Civico Di Cristina Benfratelli, Palermo, Italy 13Ospedale Civile Maggiore di Borgo Trento, Verona, Italy

Abstract

Aims: Current criteria for the appropriate implantation of an implantable cardioverter-defibrillator (ICD) for primary prevention of sudden cardiac death (SCD) are based on left ventricular ejection fraction (LVEF) assessment. It is unknown whether patients continue to meet criteria over the follow-up. We sought to determine the persistence of ICD indication for SCD primary prevention in patients with both ischemic and non-ischemic cardiomyopathy at one year after ICD implantation.

Methods: The EFFECT study was a multicenter clinical trial aimed at measuring and comparing the outcome of ICD patients conventionally followed-up by means of in-clinic visits or by remote monitoring. We assessed the LVEF at one-year follow-up in 292 patients who underwent single- or dual-chamber ICD implantation for primary prevention of SCD due to an LVEF ≤35%.

Results: At the 12-month echocardiographic evaluation, 94 (32%) patients showed an increase in LVEF >5% and 53 (18%) patients an increase >10%, 76 (26%) patients had an LVEF >35%. The proportion of patients with ischemic heart disease was lower in the group with improved LVEF (59% versus 73%, p=0.023). The number of patients who experienced appropriately treated ventricular fibrillation events during the first 12 months after implantation was comparable between groups (11% versus 8%, p=0.476), and the rate of events was non-significantly different (0.49 versus 0.32 events per year, p=0.054).

Conclusion: Approximately 25% of patients who received ICDs for SCD primary prevention did not maintain indication at one year after implantation. LVEF increased above 35% mainly among patients with non-ischemic heart disease.

Clinical Trial Registration: URL: http://clinicaltrials.gov/ Identifier: NCT01723865


Stabile et al. (2016)Email:

2/5J Cardiol Clin Res 4(5): 1075 (2016)

INTRODUCTIONPrimary prevention of sudden cardiac death (SCD) refers

to the use of implantable cardioverter-defibrillators (ICDs) in individuals who are at risk for but have not yet had an episode of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), or resuscitated cardiac arrest. Left ventricle ejection fraction (LVEF) plays a pivotal role among criteria for the appropriate implantation of ICD for primary prevention of SCD. Although the accuracy of LVEF assessment ranges from approximately ± 2% to ± 6% for radionuclide angiography [1] and is in excess of ±10% for both visual estimation and calculation by Simpson’s rule with echocardiography [2], reduced LVEF has been the most consistently reported risk factor for overall mortality and SCD in heart failure. Previous studies have reported that 25% to 40% of patients, implanted for primary SCD prevention improve their LVEF to >35% after ICD implantation [3,4]. However these experiences refer to patients enrolled more than 10 years ago (they were younger, did not have remote monitoring, and currently recommended heart failure drugs as ivabradine) and include only patients with non-ischemic cardiomyopathy.

We sought to determine the persistence of ICD indication for primary prevention of SCD, based on LVEF evaluation, in patients with both ischemic and non-ischemic cardiomyopathy at one year after ICD implantation.

METHODSStudy protocol and data collection

We performed a retrospective analysis of all patients who underwent single- and dual-chamber ICD implantation for primary prevention of SCD according to current guidelines [5], and were enrolled in the EFFECT study (Clinical Trial Registration: URL: http://clinicaltrials.gov/Identifier: NCT01723865) [6]. We included in analysis all patients with LVEF ≤35% at implantation, and who were alive and underwent the echocardiographic assessment of LVEF one year after implantation. Patients implanted with a cardiac resynchronization ICD were excluded. The investigation conforms with the principles outlined in the Declaration of Helsinki. The Institutional Review Boards at the participating centers approved the study and all patients gave written informed consent to participate in the study.

Data collection included patient characteristics such as age, initial indication for ICD implantation, presence or absence of comorbid conditions. Comorbid conditions included: chronic kidney disease (stage III or greater), atrial fibrillation, hypertension, diabetes and chronic obstructive pulmonary disease. Echocardiographic findings and pertinent medication usage (diuretics, beta blockers, ace-inhibitors, antiarrhythmic drugs) at baseline and after one year was reviewed. Data about delivery of appropriate therapies for ventricular arrhythmia were also collected from device interrogation records.

Statistical analysis

Descriptive statistics were reported as means ± SD. Categorical data were expressed by percentages. Differences between mean data were compared by a t-test for Gaussian variables, and by Mann-Whitney or Wilcoxon nonparametric test for non-Gaussian variables, respectively, for independent or paired samples. Differences in proportions were compared

by a chi-square analysis. The rates of events were analyzed by using the Comparison of Incidence Rates (Large Sample) Test. Univariate and multivariate binary logistic regression analyses were utilized to identify baseline variables associated with the persistence of primary prevention indication to ICD (i.e. LVEF ≤35% at 12 months or occurrence of appropriately treated ventricular fibrillation events during the first 12 months after implantation). A p value




At the 12-month echocardiographic evaluation, 94 (32%) patients showed an increase in LVEF >5% and 53 (18%) patients an increase >10%, 76 (26%) patients had an LVEF >35%. The comparison of basal clinical and echocardiographic characteristics of patients with LVEF >35% and ≤35% after one year of follow-up is reported in Table (2). The proportion of patients with ischemic heart disease was lower in the group with improved LVEF. These patients were also more frequently on diuretics.

The number of patients who experienced appropriately treated VF (ventricular arrhythmias faster than 200 bpm) events during the first 12 months after implantation was comparable between groups: 8 (11%) patients with LVEF >35% and 17 (8%) patients with LVEF ≤35% (p=0.476). Nonetheless, we observed a trend toward a higher rate of events among patients with LVEF ≤35% (63 versus 34; 0.49 versus 0.32 events per year; p=0.054).

We therefore measured the persistence of primary prevention indication to ICD (i.e. LVEF ≤35% at 12 months or appropriately treated events of VF during the first 12 months after implantation) in 224 (76%) patients. At binary logistic regression analysis, the only independent predictor among baseline variables was ischemic etiology (Odds Ratio: 2.03; 95% confidence interval: 1.16 – 3.57; p=0.015).

DISCUSSIONThe relevant finding of our study was that the ICD indication

for primary prevention of SCD did not persist at one year after implantation in about a quarter of patients who received single-

or dual-chamber ICDs, in the setting of heart failure of ischemic or non-ischemic etiology with reduced LVEF. In particular, LVEF increased above 35% mainly among patients with non-ischemic heart disease. Nonetheless, the incidence of arrhythmic events was roughly independent of the LVEF value at one year.

The use of ICD has reduced the incidence of SCD and total mortality in a variety of clinical scenarios, in both primary and secondary prevention settings [7]. A debate is currently ongoing regarding the selection of patients for ICD therapy for primary prevention of SCD [8-11]. At the moment, the indication to ICD implantation for primary prevention of SCD is mainly based on LVEF value at the time of patient assessment [5,12]. A previous study showed that at least a quarter of patients with non-ischemic cardiomyopathy, implanted for primary prevention of SCD, improved their LVEF to more than 35% after ICD implantation [3]. We confirmed this data in a population with both ischemic and non-ischemic cardiomyopathy. Moreover, our data were obtained in patients enrolled almost ten years after the previous study, and thus who had undergone current guideline-directed medical and revascularization therapies.

Mechanism of LVEF improvement during the follow-up

Many reasons may explain the increase of LVEF and decrease of LV volumes observed in our population. According to current guidelines (12), in order to determine ICD eligibility, repeat evaluation of LVEF is required after an appropriate duration of time following recovery from myocardial infarction or revascularization, or following guideline-directed medical

Table 2: Comparison between groups (persistence versus no-persistence of LVEF ≤35% at 12 months).Parameter Baseline p-value 12 months p-value

LVEF >35% (n=76)

LVEF ≤35% (n=216)

LVEF >35% (n=76)

LVEF ≤35% (n=216)

Male gender, n (%) 65 (86) 176 (81) 0.424Age, years 65 ± 13 65 ± 11 0.294Ischemic etiology, n (%) 45 (59) 158 (73) 0.023History of atrial fibrillation, n (%) 21 (28) 50 (23) 0.433Hypertension, n (%) 38 (50) 127 (59) 0.183Diabetes, n (%) 21 (28) 66 (31) 0.631COPD, n (%) 8 (11) 36 (17) 0.198Chronic kidney disease, n (%) 15 (20) 38 (18) 0.676Single-chamber ICD, n (%) 27 (36) 82 (38) 0.706Remote patient monitoring, n (%) 38 (50) 90 (42) 0.208QRS duration, ms 103 ± 21 105 ± 23 0.551 107 ± 29 105 ± 26 0.616NYHA class I-II, n (%) 44 (58) 138 (64) 0.353 63 (83) 168 (78) 0.345LV ejection fraction, % 29 ± 5 28 ± 5 0.384 41 ± 6 29 ± 5




therapy in the setting of a new diagnosis of heart failure or cardiomyopathy. Indeed, substantial improvement in LVEF with treatment of ischemia, with improvement in loading conditions, or after administration of neurohormonal blocking agents may not be immediate and often becomes apparent only over time. Therefore, we might suppose that in some of our patients this waiting period was not fully expired.

Second, an echocardiographic core lab was not used for this study and some degree of variability among different operators could explain our results. Indeed, although the labs performing LVEF assessment should have quality assurance measures in place to ensure accuracy, it is recognized that there may be variability in the measurement of LVEF. Previous studies on device therapy found pronounced differences between the echocardiographic assessment of LVEF at local sites and at central core laboratory [13,14]. In particular, the authors noticed an under estimation of LVEF at the time of patient selection, and ascribed it to the non-blinded reading, influenced by the patient’s condition and affected by an inclusion bias.

The pattern of longitudinal change in LVEF has been recently described in a community cohort of incident heart failure patients [15]. In patients with reduced LVEF, the LVEF increased with greater improvements in women, younger patients, those without coronary artery disease, and those treated with evidence-based medications. In our population the only difference between patients with and without increase in LVEF was the higher prevalence of non-ischemic heart disease in the first group. Interestingly, in that study the trend over time of LVEF was opposite among patients with preserved LVEF at baseline, as they showed LVEF decline during follow-up. Although this may be explained with an actual progressive contractile dysfunction, it is also plausible that regression to the mean may have been in play, indicating a reduction that was an artifact of the patient stratification criterion regarding LVEF. The same could have been occurred in our series and in previous studies that, without a control group, showed an improvement of systolic function in patients who received an ICD based on LVEF value at the time of baseline assessment.

Lastly, the observed positive outcome may have been a result of trial participation, with the increase in LVEF due to good care and adherence to the therapy as a result of close follow-up (i.e., the Hawthorne effect) [16], or use of remote monitoring system, which in our series was adopted by about 50% of patients and which was associated with improved clinical outcomes [6,17]. Indeed, one year after implantation more patients were on β-blockers and the symptoms of heart failure declined, confirming the positive clinical outcome measured by echocardiographic indexes.

In summary, although our data suggested that the arrhythmic risk is independent of the LVEF value at one year, a correct assessment of LVEF remains particularly important for patients undergoing prophylactic ICD implantation, especially in the setting of an initial LVEF of 30-35%. Indeed, in a previous study this group was shown to benefit less from a primary prevention ICD implantation [18], and thus the treatment appropriateness should be carefully considered also in view of possible LVEF improvement.

Clinical implications

Our findings have 3 major clinical implications. First, they emphasize the need of a more accurate assessment of LVEF at pre-implantation screening, also including other imaging techniques like magnetic resonance [19,20]. This will permit to better identify good ICD candidates and avoid exposing patients to unnecessary procedural risk if not indicated.

Second, these findings reinforce the recommendation of current guidelines [12] of considering ICD implantation only after an appropriate waiting time following recovery from acute events and medical therapy initiation. Indeed, many patients who at first appear to be candidates for ICD based on presence of low LVEF may well show improvement with appropriate treatment and timing.

Third, the modification of LVEF, as well as LV volumes is the most used parameters to assess the degree of LV remodeling after CRT. Many studies [21] have used an increase of 5% in LVEF as criteria to define the response to CRT. In our population 32% of patients showed an increase of 5% in LVEF without CRT. This may at least partially explain the great variability of response to CRT. Thus, the use of reliable response scores should be promoted for heart failure therapies [22], as well as the adoption of controlled study designs for the assessment of therapy response.

LIMITATIONSOur study has some important limitations. We used the

echocardiography to assess the LVEF. Because of the superior reproducibility and accuracy of cardiac magnetic resonance imaging [14,15], this imaging technique is increasingly used in clinical practice and is often considered to be the gold standard for LVEF assessment. Although it is reasonable to assume that cardiac magnetic resonance will become a prevailing method for eligibility assessment in primary prevention ICD implantation, till now the echocardiography is the widest method to assess the LVEF before ICD implantation. Second, an echocardiographic core lab was not used for this study and some degree of variability among different operators could explain our results. However the LV function was evaluated in each patient by the same operator, at baseline and during the follow-up. In this setting, this observational retrospective study may provide a representative image of the real-life scenario in the use of echocardiography for selecting patients for SCD primary prevention.Third, the follow-up length was only one year. This period was adequate to assess the change in LVEF but is too short to accurately evaluate the incidence of arrhythmias in the two study groups.

CONCLUSIONSIn about a quarter of patients, who received a single- or

dual-chamber ICD, for primary prevention of SCD, the ICD indication, based on echocardiographic evaluation of the LVEF, did not persist at one year after implantation. In particular, LVEF increased above 35% mainly among patients with non-ischemic heart disease.

DISCLOSURESMonica Campari is an employee of Boston Scientific Italia.




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Stabile G, D’Onofrio A, Capucci A, Amellone C, De Simone A, et al. (2016) Persistence of Primary Prevention Indication to Implantable Cardioverter Defibrillators at One Year from Implantation. J Cardiol Clin Res 4(5): 1075.

Cite this article

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Persistence of Primary Prevention Indication to Implantable Cardioverter Defibrillators at One Year AbstractIntroductionMethodsStudy protocol and data collectionStatistical analysis

ResultsPatients characteristics One year follow-up

DiscussionMechanism of LVEF improvement during the follow-upClinical implications

LimitationsConclusionsDisclosuresReferencesTable 1Table 2

research article persistence of primary giuseppe stabile, … · 2016. 10. 12. · stabile g,...

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