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European Journal of Heart Failure 2005 7(6):1027-1032; doi:10.1016/j.ejheart.2005.05.006
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© 2005 European Society of Cardiology

Outcome in patients with an ICD incorporating cardiac resynchronisation therapy: Differences between primary and secondary prophylaxis

Dominic A.M.J. Theuns*, Andrew S. Thornton, A. Peter J. Klootwijk, Marcoen F. Scholten, Pascal J.M.J. Vantrimpont, Aggie H.M.M. Balk and Luc J. Jordaens

Department of Cardiology Erasmus MC, Rotterdam, The Netherlands

* Corresponding author. Department of Electrophysiology, Bd416 P.O. Box 2040 3000 CA Rotterdam, The Netherlands. Tel.: +31 10 463 3991; fax: +31 10 463 4420. E-mail address: d.theuns{at}erasmusmc.nl


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations of the...
 6. Conclusion
 References
 
Background: The incidence of ventricular tachyarrhythmias in ICD patients with cardiac resynchronisation therapy (CRT-D) is not well studied.

Aim: To analyse event free survival in CRT-D patients with a primary or a secondary prophylactic ICD indication.

Methods: Prospective, single centre. Eighty-six patients, 44% with a primary prophylactic indication. Actuarial event-free rates for mortality and arrhythmias were calculated.

Results: Baseline clinical characteristics were not significantly different between primary and secondary prophylaxis. Primary prophylaxis patients were more likely to be in NYHA class III. Over 21 months, 724 ventricular events with therapy occurred in 36 patients (42%). The actuarial event-free rates, at 1 and 3 years, from appropriate ICD therapy were higher (P<0.001) for primary (79.0% and 67.8%) than for secondary prophylaxis (45.6% and 27.0%). Appropriate ICD therapy occurred more in NYHA class II compared to class III (P=0.016). Underlying disease (ischemic versus non-ischemic) and functional class did not play a role in multivariate analysis.

Conclusion: Important arrhythmic events in patients with heart failure, and CRT-D occur at a very high rate when the indication is secondary prophylaxis. Patients with primary prophylaxis have an annual event rate of 10%, even though they tend to have a worse heart failure class.

Key Words: Cardiac resynchronisation therapy • Heart failure • Defibrillation • ICD • Ventricular tachycardia

Received September 15, 2004; Revised February 6, 2005; Accepted May 10, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Limitations of the...
 6. Conclusion
 References
 
Heart failure (HF) is reported to occur in 1% to 5% of the European population. [1] The long-term prognosis still remains poor. [2] Mortality is high, due to deterioration of left ventricular function and sudden death. [3] Arrhythmic sudden death is diverse and includes ventricular tachycardia (VT), ventricular fibrillation (VF), and bradycardic events, including some unrecognized hemodynamic situations leading to electromechanic dissociation or asystole. The prevention of life-threatening ventricular arrhythmias as such, is a major goal in the management of patients with HF. In multiple randomised studies, the implantable cardioverter-defibrillator (ICD) has been shown to be effective for life-threatening ventricular arrhythmias and to prevent sudden cardiac death in patients with reduced left ventricular function. [4–10] Although ICD treatment prolongs life in patients at risk, it does not improve quality of life or symptoms of HF. Recent data has demonstrated that cardiac resynchronisation therapy (CRT) has the potential to improve hemodynamic parameters and symptoms in heart failure patients, thereby potentially preventing disease progression and prolonging life. [11–13] The latter however, has never been proven in randomised trials. Recent trials have demonstrated that HF patients have a mortality benefit with ICD therapy [10,14]. This benefit can be achieved with conventional, single chamber ICDs, whereas patients with a profile suitable for resynchronisation have lower morbidity after receiving a combined device with CRT as well.

The aim of this study was to analyse the outcome and incidence of ventricular tachyarrhythmias in patients with heart failure, treated with a cardiac resynchronisation ICD (CRT-D).


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Limitations of the...
 6. Conclusion
 References
 
2.1. Patient population
The study population consisted of patients who received a CRT-D in combination with a transvenous approach. Indications for ICD therapy were a history of symptomatic sustained ventricular tachyarrhythmia or aborted sudden death without reversible cause (secondary prophylaxis). The primary prophylaxis group included patients with ischemic and nonischemic heart diseases, who were being considered for cardiac transplantation, and patients who fulfilled the criteria as described in the first Multicenter Automatic Defibrillator Implantation Trial or MADIT I [LVEF<30%, nonsustained ventricular tachycardia (NSVT), inducible, but without rechallenge after drugs] [4]. All patients met CRT criteria: symptomatic CHF, inter-or intraventricular conduction delay (QRS duration≥120 ms), LVEF≤35%, and left ventricular end-diastolic diameter of more than 55 mm. Nonischemic dilated cardiomyopathy was diagnosed after exclusion of coronary artery disease by the absence of a Q wave myocardial infarction, and/or exclusion of significant luminal stenosis in one or more coronary arteries. The clinical characteristics of the patients are summarised in Table 1.


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  		Table 1 Clinical characteristics of the patients

 
2.2. Implantation procedure and programming
Implantations were performed preferably with a single left pectoral incision, a left cephalic vein cutdown and a left subclavian puncture. Defibrillation leads were positioned in the right ventricular apex. The LV pacing lead was placed in a tributary of the coronary sinus. A postero-lateral branch was used in 39 patients (45%), an anterior branch in 20%, and a lateral branch in 10% of patients. The lowest effective defibrillation energy was less than 15 J in 49/56 tested patients. The selected devices were InSync 7272 and 7279 (Medtronic Inc., Minneapolis, MN, USA), Contak CD, Renewal I, and Renewal II (Guidant Inc., St. Paul, MN, USA), and Epic HF (St Jude Medical, Sylmar, CA, USA). ICD programming was intended to avoid inappropriate therapy and tailored according to the clinical presentation. The mean ventricular tachycardia detection rate was 383±40 ms, the mean fibrillation detection interval was 290±22 ms. Biventricular pacing was monitored by 12-lead surface ECG during threshold testing. At the 3-month visit, the mean programmed AV delay was 106 ms and the ventricular output to ensure biventricular capture was programmed at 3.6 V. The maximum ventricular output was programmed in only 9 patients (10%) at this interval.

2.3. Data collection and tachyarrhythmia classification
Follow-up started at the time of ICD implantation. All patients were followed at 3-monthly intervals and were advised to contact our out-patient clinic as soon as possible after a symptomatic event. At each visit, arrhythmic events were retrieved from the device's memory. The stored electrograms (EGMs) were visually analysed by 2 investigators to assess the type of the recurrent arrhythmia. In case of disagreement between the 2 reviewers about the stored EGMs, a third reviewer was consulted to reach a final agreement. The stored arrhythmias were classified as (1) ventricular tachyarrhythmia or (2) atrial tachyarrhythmia without a coexistent ventricular arrhythmia. As the atrial electrogram was present, the presence of atrioventricular dissociation was used to diagnose ventricular tachycardia. Otherwise, a ventricular tachyarrhythmia was defined as an event with a sudden increase in rate combined with a change in electrogram morphology from the baseline rhythm. Ventricular arrhythmias were classified as "sustained" or "nonsustained". A "sustained ventricular tachyarrhythmia" was defined as a ventricular event lasting long enough to allow delivery of device therapy. "Nonsustained" events were defined as events, not long enough for triggering device therapy, and were excluded from analysis.

2.4. Statistical analysis
Continuous variables are expressed as mean±SD if normally distributed, or otherwise by median. Continuous variables were analysed with Student's t-test. Categorical data are summarised as frequency (percentage). Chi-square test was used for analysis of categorical variables. Estimated survival and the actuarial event-free rates were calculated according to the Kaplan–Meier method and were compared by use of the log-rank test. Survival time was defined as the date from ICD implantation to the date of death or last follow-up. Patients undergoing cardiac transplantation were censored from the moment of transplantation. The actuarial event-free rates from ventricular tachyarrhythmias triggering ICD therapy were measured from the date of ICD implantation to the date of the first ventricular tachyarrhythmia triggering ICD therapy or last follow-up; deaths and cardiac transplantation were treated as censored observations. Covariates previously identified to be independently associated with the occurrence of appropriate ICD therapy were used in a Cox proportional–hazards model. A P value<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Limitations of the...
 6. Conclusion
 References
 
3.1. Patient population
A total of 86 patients received a CRT-D. Clinical characteristics and demographic data are listed in Table 1. The underlying cardiac disease was coronary artery disease (CAD) in 50 patients (58%). Mean QRS duration was 174±31 ms. The ICD was indicated as secondary prophylaxis for 48 patients (56%), and as primary prophylaxis in 38 patients (44%). Twenty-one patients were formally listed for cardiac transplantation, 8 in the secondary prophylaxis and 13 in the primary prophylaxis group.

The mean follow-up duration was 21 months, with a cumulative follow-up of 1772 months. During this follow-up, a total of 11 deaths were reported. Of these deaths, 5 (45%) were attributed to progressive heart failure, 2 (18%) were arrhythmic, and 2 (18%) were non-cardiac. Operative mortality, defined as death from any cause within 30 days of the implant procedure, was documented in 1 (9%) patient. The cause of death was unknown in 1 patient. Eight patients underwent successful heart transplantation. The actuarial mortality was 6.7% and 21.9%, at 1 and 4 years, respectively (Fig. 1).


Figure 1
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  		Fig. 1 Actuarial event-free curves from all-cause mortality (dashed line) and from ventricular tachyarrhythmias triggering ICD therapy (solid line).

 
3.2. Spontaneous ventricular tachyarrhythmias
During the follow-up period, 869 episodes of ventricular tachyarrhythmias were recorded in 40 patients (46.5%). Of the 869 episodes, 145 episodes of nonsustained ventricular tachyarrhythmias were excluded from analysis. Thus 724 episodes were eligible for analysis in 36 patients (range 1 to 92 episodes per patient). The first appropriate therapy occurred at a median interval of 63 days after ICD implantation. The actuarial event-free rates from appropriate ICD intervention were 59.4% and 38.8% at 1 and 4 years, respectively (Fig. 1). Seventy episodes (10%) were treated with shock therapy (18 patients, range 1 to 12 episodes per patient). Anti-tachycardia pacing therapy was delivered in 654 episodes (90%) occurring in 23 patients (range 1 to 91 episodes per patient).

Clinical characteristics of patients with and without ventricular tachyarrhythmias during follow-up are summarised in Table 2. Ventricular tachyarrhythmias occurred in only 7 out-of-38 patients with a primary prophylactic indication compared with 29 out-of-48 patients with a secondary prophylactic indication (P<0.001). In a univariate model, male sex, lower NYHA class, and a secondary prophylactic indication correlated with a higher recurrence rate for ventricular tachyarrhythmias. To evaluate clinical predictors of appropriate device therapy, univariate covariates with P value≤0.10 were entered in a Cox proportional hazards model adjusted for difference in follow-up time. This multivariate model with "appropriate device therapy" as the dependent variable revealed the prophylactic indication as the only independent predictor (P=0.009).


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  		Table 2 Clinical characteristics of patients with and without ventricular tachyarrhythmias triggering appropriate device therapy

 
3.3. Primary and secondary prophylaxis
Of the 86 patients, a total of 38 patients had a primary prophylactic indication and 48 patients a secondary prophylactic indication for ICD implantation. Demographic and clinical variables for both groups are listed in Table 1. Underlying cardiac disease was not different between the 2 groups. Proportionally, patients with NYHA Class III were significantly higher in the primary prophylactic group. Amiodarone as antiarrhythmic drug treatment was significantly higher for patients with secondary prophylaxis. The Kaplan–Meier curves illustrating time to first appropriate ICD intervention for patients in both groups are shown in Fig. 2. The actuarial event-free rates from appropriate ICD intervention were lower in the secondary prophylaxis group (79.0% and 67.8% for primary versus 45.6% and 27.0% for secondary prophylaxis, at 1 and 3 years, respectively; P=0.001).


Figure 2
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  		Fig. 2 Actuarial event-free rates from first appropriate ICD intervention for patients with primary prophylaxis and patients with secondary prophylaxis.

 
Twelve patients (14%) experienced ventricular tachyarrhythmias with cycle length (CL)≤250 ms, and 19 patients (22%) had ventricular tachyarrhythmias with CL>350 ms. For the primary prophylactic group, 75% of ventricular tachyarrhythmias had CL≤350 ms, for the secondary prophylactic group it was 52%.

3.4. Inappropriate therapy
Inappropriate tachyarrhythmia detection was observed in 17 patients (20%). The first inappropriate therapy occurred at a median interval of 194 days after ICD implantation. Six patients experienced inappropriate device therapy for atrial fibrillation or atrial flutter, and 12 patients received inappropriate therapy for sinus or atrial tachycardia. Inappropriate detection was not significantly different between the primary and secondary prophylaxis group.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Limitations of the...
 6. Conclusion
 References
 
The present study addresses the incidence of appropriate ICD interventions in HF patients with either a primary or secondary prophylactic indication for ICD therapy using a CRT-D. The major finding of this study is that recurrent ventricular tachyarrhythmias triggering device therapy are more common in patients with a secondary prophylactic indication, than in patients with a primary prophylactic indication for ICD implantation. However, the annual event rate in the primary prophylactic group was 10%, which is a generally accepted criterion for defining very high risk. The interpretation is difficult as it was suggested that patients with a MADIT I profile would have the same recurrence rate as secondary prophylaxis patients. On the other hand, the more advanced HF patients in the primary prophylactic group (as suggested by their NYHA classification) are expected to die from heart failure rather than from arrhythmias.

4.1. Heart failure and secondary prophylaxis for arrhythmias
ICD therapy reduces sudden cardiac death in high-risk patients. [6–8] Meta-analysis of secondary prophylactic trials demonstrated a significant benefit from ICD therapy for patients with LVEF≤35% as compared to those with LVEF>35%. [15] The ICD can be regarded as the treatment of choice in heart failure patients with life-threatening ventricular tachyarrhythmias. In the present study, we observed a very high incidence of ventricular tachyarrhythmias triggering device therapy in HF patients with a secondary prophylactic indication. Almost all patients had a recurrence after 2 years. The benefit of ICD therapy was observed in patients with ischemic heart disease as well in patients with nonischemic heart disease. These findings reconfirm the guideline to implant an ICD in patients who have already experienced a life-threatening ventricular arrhythmia, and demonstrate the frightening high recurrence rate of ventricular tachyarrhythmias.

4.2. Heart failure and primary prophylaxis for arrhythmias
The first primary prophylactic trials showed that patients with ischemic heart disease, poor left ventricular function, NSVT, and inducible sustained ventricular tachyarrhythmias benefit from prophylactic ICD implantation. [4,5] In contrast, the benefit from prophylactic ICD implantation was not proven in patients with nonischemic heart disease. [16,17] The presence of NSVT is common in patients with HF and does not always predict sudden cardiac death. [18] The presence of NSVT in functional class III patients is rather a marker of worse prognosis related to poor left ventricular function than an indication for sudden cardiac death. The MADIT II trial reported a 31% reduction in all-cause mortality for post-myocardial infarction patients with LVEF≤30%, even without NSVT, an effect that was enhanced as a function of QRS duration. [9] This was confirmed by data from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), showing that a simple back-up ICD reduced overall mortality by 23%. [10] Adding CRT will improve quality of life, and the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial confirmed again the superiority of CRT-D over pacing alone in patients with a primary indication. [14] Wilkoff et al. recently reviewed the difference in tachyarrhythmia detection between primary and secondary prophylaxis in patients with resynchronization therapy. [19] Patients with a primary prophylaxis were much less likely to develop ventricular tachyarrhythmias; and when they did, it was at significantly faster cycle lengths compared to patients with secondary prophylaxis. These findings were confirmed in our study. We observed an annual recurrence rate of 10%, which is very high, given the prophylactic indication. The majority of ventricular tachyarrhythmias in the primary prophylactic group had a cycle length≤350 ms.

It has always been thought that sudden cardiac death comes early in the course of cardiac disease, while non-sudden cardiac death comes later, i.e., in stages of more advanced heart failure. [20] This finding is supported by the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF), in which sudden death was more common in patients with NYHA class II. [21] This is also in accordance with our data, as appropriate device therapy occurred more frequently in patients with NYHA class II. These patients more often had a secondary prophylactic indication. It should be noted that the rate of interventions in the primary prophylaxis group remained high in spite of resynchronisation therapy.


   5. Limitations of the study
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations of the...
6. Conclusion
 References
 
The present study was a retrospective analysis in a highly selected group of patients with HF. However, both groups were followed prospectively on a regular basis at the out-patient clinic. We selected primary prophylactic patients with ischemic heart disease who fulfilled MADIT I criteria or who were being considered for cardiac transplantation, as was also the case for nonischemic patients. In spite of the small numbers of patients in the subgroups, our data support the policy of adding an ICD component to CRT in the primary prophylaxis group.


   6. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations of the...
 6. Conclusion
References
 
Ventricular tachyarrhythmias triggering device therapy appear extremely frequent in patients with HF who received an ICD after a first symptomatic arrhythmia in spite of CRT, which was well delivered in our study. Further, patients selected for a primary prophylactic indication, using MADIT I criteria, or when waiting for cardiac transplantation face a high recurrence rate.

The decision to implant an ICD in HF patients for primary prophylaxis of sudden cardiac death now becomes a clinical decision based on low LVEF plus heart failure. This will probably result in a lower recurrence rate (SCD-HeFT). The option of adding cardiac resynchronisation remains uncertain: SCD-HeFT improved survival without CRT. COMPANION had no arm without CRT and yet a simple ICD. Until these questions are answered, our policy to combine both ICD and CRT for primary prophylaxis remains an option, which is open for discussion.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Limitations of the...
 6. Conclusion
 References
 

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  16. Strickberger S.A., Hummel J.D., Bartlett T.G., et al. Amiodarone versus implantable cardioverter-defibrillator: randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic nonsustained ventricular tachycardia-AMIOVIRT. J Am Coll Cardiol (2003) 41:1707–1712.[Abstract/Free Full Text]
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