Skip Navigation

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Disclaimer
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Hohnloser, S. H.
Right arrow Articles by Prystowsky, E. N.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Hohnloser, S. H.
Right arrow Articles by Prystowsky, E. N.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

CRT-D use in heart failure: too little or too much?

Stefan H. Hohnloser1,* and Eric N. Prystowsky2

1 Division of Clinical Electrophysiology, Department of Cardiology, JW Goethe University, Theodor Stern Kai 7, 60590 Frankfurt, Germany
2 The Care Group, St Vincent Hospital and Health Center Program, Indianapolis, IN, USA

* Corresponding author. Tel: +49 69 6301 7404; fax: +49 69 6301 7017. E-mail address: hohnloser{at}em.uni-frankfurt.de


   Abstract
Top
 Abstract
Introduction
 Implantable cardioverter...
 Cardiac resynchronization...
 Discussion
 Conclusion
 References
 
Cardiac resynchronization therapy (CRT) is a new therapy for patients with symptomatic heart failure (HF) resulting from systolic dysfunction. Numerous clinical investigations have demonstrated that in selected patients with ventricular dyssynchrony, CRT improved left ventricular function, functional status, and left ventricular ejection fraction (LVEF). Randomized clinical trials showed that in patients already on optimal medical therapy, CRT reduced morbidity and all-cause mortality. On the basis of the inclusion criteria and the results of these CRT trials, CRT is currently recommended, both in Europe and in the USA, for patients with NYHA functional Class III or IV heart failure, a LVEF ≤35%, and a QRS duration ≥160 ms (or ≥120 ms with other evidence of ventricular dyssynchrony) who are receiving chronic optimal medical therapy. However, several issues still remain unresolved: in particular, the benefit of CRT therapy has not been established in patients with mild HF (NYHA Class I or II), atrial fibrillation, minor conduction abnormality, or pacemaker dependence. In addition, ~20–30% of patients do not respond to CRT. Considering that CRT is an invasive and costly procedure, identification of patients most likely to benefit from CRT is clearly a research priority.

Key Words: Heart failure • Cardiac resynchronization therapy • Implantable cardioverter-defibrillator


   Introduction
Top
 Abstract
 Introduction
Implantable cardioverter...
 Cardiac resynchronization...
 Discussion
 Conclusion
 References
 
Heart failure (HF) remains a major and growing public health concern in developed countries, in terms of morbidity, mortality, and cost to society.1,2 Between 1 and 2% of the population have HF.2 Despite the additive benefit of several pharmacological interventions, the incidence of HF is still increasing due, at least in part, to better and earlier management of patients with acute myocardial infarction (MI) and to the increasing age of the population. In addition, HF is a deadly condition, most patients dying from worsening HF or suddenly.1,2 About 30–40% of patients will die within 1 year of diagnosis, and 60–70% within 5 years.2 The goals of treatment of patients with HF are to relieve symptoms, to avoid hospital admission, and to prolong life.

Pharmacological agents such as angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, angiotensin receptor blockers (ARB), and aldosterone antagonists are the mainstay of treatment, based on the demonstration of impressive reductions in morbidity and mortality.2 However, symptomatic HF still carries an unacceptably poor prognosis and novel therapeutic approaches are needed.


   Implantable cardioverter-defibrillators
Top
 Abstract
 Introduction
 Implantable cardioverter...
Cardiac resynchronization...
 Discussion
 Conclusion
 References
 
About half of all patients with HF die suddenly, most likely due to ventricular arrhythmias.1,2 Patients with current or prior symptoms of HF and reduced left ventricular ejection fraction (LVEF), a history of previous cardiac arrest or documented sustained ventricular arrhythmias, are at high risk of recurrence. Based on a large body of evidence, placement of an implantable cardioverter-defibrillator (ICD) was recommended as secondary prevention in these patients in both European (ESC) and US (ACC/AHA) guidelines issued in 2005 (Class I recommendation, level of evidence A),2,3 and is similarly recommended in the joint ESC/ACC/AHA guidelines published in 2006.4

In patients with HF and low ejection fraction, and no history of cardiac arrest or spontaneous or inducible ventricular arrhythmia, several studies have shown that antiarrhythmic drugs not only fail to improve survival, but may even increase mortality in post-MI patients.5–9 The role of ICD implantation in the primary prevention of sudden death in such patients has been addressed in several trials which, overall, showed survival benefit.10–14 The 2005 ESC and ACC/AHA recommendations2,3 concerning the use of ICD for primary prevention in these patients differed somewhat, particularly with respect to patients with an LVEF between 30 and 35%, a population not specifically studied in any clinical trial to date.4 Both guidelines recommended the use of ICD in patients with LV dysfunction due to prior MI, NYHA Class II or III, and an LVEF of 30% or less (Class I recommendation, level of evidence A3 and B2, respectively). In the ESC guidelines3, the same recommendation extended to patients with an LVEF of 30–35%, whereas in the ACC/AHA guidelines2, ICD placement in these patients was only a Class IIa recommendation (level of evidence B). The main reason for the inconsistencies between the different guidelines with respect to this patient population was the heterogeneity of the relevant clinical trial data which were derived from studies varying in their enrolment criteria and actual mean patient values with respect to LVEF.4 The recommendations of the 2006 ACC/AHA/ESC guidelines, therefore apply to patients with an LVEF less than or equal to a range of values, rather than within a specified range, the class of recommendation being based on all trials that recruited patients with an LVEF equal to or less than the stated range. These guidelines recommend placement of ICD for primary prevention, to diminish total mortality by reducing sudden cardiac death (SCD), in the following contexts:

  • patients with LV dysfunction due to prior MI who are at least 40 days post-MI, have an LVEF less than or equal to 30–40%, are NYHA functional Class II or III, are receiving chronic optimal medical therapy, and have a reasonable expectation of survival with a good functional status for more than 1 year (Class I recommendation, level of evidence A);
  • patients with non-ischaemic dilated cardiomyopathy who have an LVEF less than or equal to 30–35%, are NYHA functional Class II or III, are receiving chronic optimal medical therapy, and have a reasonable expectation of survival with a good functional status for more than 1 year (Class I recommendation, level of evidence B).


   Cardiac resynchronization therapy
Top
 Abstract
 Introduction
 Implantable cardioverter...
 Cardiac resynchronization...
Discussion
 Conclusion
 References
 
About one-third of patients with low EF and NYHA functional Class III to IV HF have abnormal electrical activation of the left ventricle (defined by a QRS duration greater than 120 ms).1,2,15 This leads to dyssynchronous contraction of the walls of the left ventricle, resulting in suboptimal ventricular filling, decrease in stroke volume, facilitation of mitral regurgitation, increased wall stress, and delayed relaxation.1,2,15,16 Ventricular dyssynchrony has also been associated with increased morbidity and mortality in HF patients.2,15 Cardiac resynchronization therapy (CRT) is achieved by simultaneously pacing both the left and right ventricles in a synchronized manner. Numerous clinical investigations have demonstrated that in selected patients with ventricular dyssynchrony, CRT provided acute haemodynamic benefits while reducing myocardial energy consumption.1,2,14,31

To date, more than 4000 HF patients with ventricular dyssynchrony have been evaluated in randomized controlled cross-over17–23 and parallel-group24–28 trials of optimal medical therapy alone vs. optimal medical therapy plus CRT with22,25,27 or without an ICD. The inclusion criteria for these trials are summarized in Table 1. CRT has been shown to improve functional status as assessed by quality of life, NYHA functional class, exercise capacity, exercise distance during a 6 min walk test, and LVEF.17–28 In addition, these improvements were accompanied by reverse remodelling.29 In the two most recent trials, morbidity and mortality benefits were demonstrated.27,28 In the COMPANION study,27 CRT reduced the composite of all-cause mortality and all-cause hospital admission by ~20%. CRT alone reduced the risk of death from any cause by 24% (P = 0.059). When CRT was combined with an ICD, all-cause mortality was significantly reduced by 36% (P = 0.003).27 In the CARE-HF study,28 it was demonstrated that CRT reduced by 37% the risk of the primary outcome of death from any cause or unplanned hospital admission for a major cardiovascular event. CRT reduced by 52% the risk of hospitalization for heart failure. More importantly, CARE-HF demonstrated for the first time that CRT alone (without a defibrillator) reduced by 36% the risk of death from any cause.28 The beneficial effect of CRT on mortality evidenced in a meta-analysis of CRT trials (nine trials, 3216 patients) appeared to be largely driven by reductions in progressive heart failure, became apparent by three months after implantation and was similar in patients with and without ICDs.30 In the most recent systematic review (eight trials, including the CARE-HF trial, 3380 patients), CRT reduced all-cause mortality by 28% (Figure 1) and hospitalization for worsening HF by 45% (Figure 2).31


View this table:
[in this window]
[in a new window]

  		Table 1 Inclusion criteria and main characteristics of CRT trials

 

Figure 1
View larger version (8K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 1 Effects of CRT on all-cause mortality. Reproduced from Freemantle et al.31 with permission from Elsevier. CI denotes confidence intervals. Breslow–Day test for heterogeneity = 5.3 (df = 8) P = 0.73.

 

Figure 2
View larger version (8K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 2 Effects of CRT on hospitalization for heart failure. Reproduced from Freemantle et al.31 with permission from Elsevier. CI denotes confidence intervals. Breslow–Day test for heterogeneity = 11.2 (df = 6) P = 0.08.

 
On the basis of the inclusion criteria and the results of the CRT trials,17–28 CRT was recommended in the ACC/AHA 2005 guidelines in patients presenting either ischaemic or non-ischaemic cardiomyopathy with LVEF less than or equal to 35%, sinus rhythm, and NYHA functional Class III or ambulatory Class IV symptoms, despite recommended optimal medical therapy, accompanied by cardiac dyssynchrony, currently defined as a QRS duration greater than 120 ms (Class I recommendation, level of evidence A).2 Similarly, although not specifying a cut-off value for LVEF, the ESC 2005 guidelines recommended that CRT using biventricular pacing be considered in patients with reduced ejection fraction and ventricular dyssynchrony (QRS width >120 ms), who remain symptomatic in NYHA functional Class III–IV despite optimal medical therapy to improve symptoms (Class I recommendation, level of evidence A), and to reduce hospitalizations (Class I, level A) and mortality (Class I, level B).3

The most recent guidelines issued jointly by the ACC/AHA and the ESC in 20064, include somewhat weaker recommendations for the use of biventricular pacing:

  • in conjunction with ICD therapy for primary prevention to diminish total mortality by reducing SCD in patients with NYHA functional Class III or IV HF, who are receiving optimal medical therapy, and who are in sinus rhythm with a QRS complex ≥120 ms (Class IIa, level of evidence B);
  • in the absence of ICD therapy for the prevention of SCD in patients with NYHA functional Class III or IV HF, LVEF ≤35% and a QRS complex ≥160 ms (or ≥120 ms in the presence of other evidence of ventricular dyssynchrony) who are receiving chronic optimal medical therapy (Class IIa, level of evidence B).
However, several issues still remain unresolved: the beneficial effect of CRT, if any, has not been established in patients with mild HF (NYHA functional Class I or II), atrial fibrillation (AF), minor conduction abnormality or pacemaker dependence, or in patients in whom medical therapy has proved inadequate.


   Discussion
Top
 Abstract
 Introduction
 Implantable cardioverter...
 Cardiac resynchronization...
 Discussion
Conclusion
 References
 
There are four main questions relating to the use of CRT in HF patients that deserve careful consideration at the present time.

Should patients with NYHA functional Class II HF, LVEF ≤35%, and evidence of LV dyssynchrony receive a CRT-D to prevent worsening HF?
The objectives of electrical therapy in HF patients are to resynchronize the heart to improve its mechanical performance, and to prevent the risk of SCD by automatic defibrillation. These two objectives can be achieved separately with dedicated devices, using a specific pacemaker for CRT (CRT-P) or an ICD, or at the same time using a combined device, the CRT by biventricular defibrillation (CRT-D) device. The question is therefore: should these patients receive CRT in addition to ICD?

Most CRT trials included patients with NYHA functional Class III or IV symptoms (Table 1).17–28 Data supporting the use of CRT in patients with milder HF are therefore limited. In the MIRACLE ICD study II in patients with NYHA functional Class II symptoms despite medical therapy, a depressed LVEF, a wide QRS duration, and an indication for ICD therapy,26 CRT reduced LV volumes and increased LVEF. It is noteworthy that the clinical composite of mortality, serious morbidity, and symptoms (a secondary endpoint) was significantly improved, indicating less disease progression. However, the study failed to show a significant improvement in exercise capacity (the primary endpoint) or in quality of life. In the CONTAK-CD trial, significant reverse remodelling was also observed after 6 months of CRT, although the benefits were less pronounced than in the much larger group of NYHA III–IV patients.22

These observations suggest that CRT might have a benefit in patients with less advanced HF and ventricular dyssynchrony. However, this benefit remains uncertain. More definitive evidence of efficacy of CRT in this less symptomatic population is therefore needed. Currently, three prospective, randomized, parallel-group, controlled trials evaluating CRT in Class I–II HF patients are ongoing. The REVERSE study will establish whether CRT combined with optimal medical treatment can attenuate HF disease progression compared with optimal medical treatment alone in patients with asymptomatic left ventricular dysfunction and with NYHA Class I or NYHA Class II HF, QRS duration ≤120 ms, LVEF ≤40%, and left ventricular end-diastolic diameter ≥55 mm.32 The primary endpoint is the HF clinical composite response (combining changes in NYHA class and global assessment with information provided from the occurrence of major clinical events) and left ventricular end-systolic volume index is the first-order secondary endpoint. Approximately 500 patients from 100 centres in North America and Europe will be randomized to CRT vs. no CRT. The follow-up period is 5 years with the primary and first-order secondary endpoints reported at 12 months. The MADIT-CRT trial will determine whether CRT-D can reduce the risk of mortality and HF events by ~25% in subjects with ischaemic (NYHA Class I–II) and non-ischaemic (NYHA Class II) cardiomyopathy, left ventricular dysfunction (LVEF ≤ 30%), and prolonged intraventricular conduction (QRS duration ≥130 ms).33 The primary endpoint is the time to all-cause mortality or first HF event. This study will include 1820 subjects with an estimated follow-up of 24 months. The RAFT study is designed to determine whether the addition of CRT to ICD (indicated for primary or secondary prevention) and optimal medical therapy reduces the combined endpoint of all-cause mortality and CHF hospitalization in patients with left ventricular dysfunction (LVEF ≤ 30%), QRS duration ≥120 ms, NYHA Class II HF symptoms, and normal sinus rhythm or chronic persistent AF. The trial will include ~2000 patients followed-up for 5 years.

The main goals of treatment for patients in NYHA functional Classes I–II are very different from those set for patients in Class III–IV, consisting primarily of preventing disease and HF progression besides lowering the risk of SCD. In this respect, available data showing reversal of cardiac remodelling22,26 suggest that CRT may prevent disease progression from Class II to Class III HF. In the CRT trials, the non-response rate to CRT among Class III–IV HF patients was 25–30%. In a recent observational study in 143 patients scheduled to receive CRT, independent predictors of lack of response to CRT (20% of patients) were ischaemic heart disease, severe mitral regurgitation, and left ventricular end-diastolic diameter >75 mm.34 Patients with these three predictors had a probability of response of 27%. Waiting for more advanced disease in these patients may therefore lead to starting CRT too late, with an increased risk of non-response. Another important issue is the difficulty in practice of distinguishing Class II from Class III HF patients, a classification that depends not only on patient perception and thus reporting of symptoms, but also on the subjective perception of the treating physician. In addition, it may be argued that patients who present with NYHA functional class II HF, but have been hospitalized for HF within the preceding year, should be considered rather as Class III HF patients.

On the other hand, while CRT might be beneficial in NYHA Class II HF patients with left ventricular dyssynchrony, this is not currently supported by solid scientific evidence. Indeed, the former routine practice of treating post-MI patients with antiarrhythmic drugs, mainly based on physician beliefs about benefits, was severely contradicted by the unexpected results of the CAST study showing increased mortality with antiarrhythmics in this setting.5 In addition, considering that CRT trials17–28 showed that 8–10% of patients could not be technically implanted, 25–30% of implanted patients were non-responders to CRT, the response rate in the control group was about 30% (placebo effect), and the acute complication rate was 8–10%, a net benefit in no more than 40% of patients could be expected.

Are patients with NYHA Class III heart failure, LVEF ≤35%, and QRS duration ≥120 ms, without mechanical LV dyssynchrony, CRT-D candidates?
The rationale behind this question is based on the assumption that left ventricular dyssynchrony is a major predictor of response to CRT. Thus, a method that could identify patients with such dyssynchrony would allow the selection of suitable recipients for CRT. In most CRT trials published to date, dyssynchronous ventricular contraction was defined on the basis of prolongation of the QRS complex duration, usually a left bundle-branch block and a QRS duration of more than 120 ms.17–28 However, the non-response rate to CRT observed in these studies ranged between 20–30%. This observation suggests that a QRS duration longer than 120 ms is not an optimal marker to select patients for CRT. Advanced echocardiographic techniques (in particular tissue Doppler imaging) have consequently been developed to identify mechanical dyssynchrony.35,36 Several studies showed that electrical dyssynchrony was not always synonymous with mechanical dyssynchrony. Some patients with a wide QRS complex do not exhibit mechanical LV dyssynchrony. For instance, an absence of mechanical LV dyssynchrony has been shown in 48% of patients with an intermediate (120–150 ms) QRS complex and in 28% of patients with a wide (>150 ms) QRS complex,37 which may explain, at least in part, the high rate of non-response observed in the randomized trials. Conversely, some patients with a narrow QRS complex demonstrate mechanical dyssynchrony38,39 and seem to benefit from CRT.40,41

Although the use of methods for detecting mechanical dyssynchrony to select appropriate candidates for CRT appears logical and has tended to be implemented in routine practice, the accuracy and validity of such methods have not been adequately demonstrated. In addition, there are concerns about inter-observer and intra-observer variability of available techniques. Thus, the idea that mechanical rather than electrical measures of dyssynchrony provide better patient selection criteria for CRT remains to be proved in adequate prospective trials. In the CARE-HF study, patients with a QRS interval of 120–149 ms were required to meet two out of three additional echocardiographic criteria for dyssynchrony; however, only 10% of patients were included on the basis of these criteria. Thus no definite conclusion can be drawn regarding the ability of echocardiographic measures to predict response to CRT, emphasizing the need for adequately powered studies. In this respect, a variety of conventional echocardiographic and tissue Doppler imaging parameters will be prospectively and individually tested against measures of clinical response in the ongoing prospective, multicentre, non-randomized PROSPECT study.42

In the large trials assessing the efficacy of CRT, patients with a QRS duration over 120 ms could be entered; however, the average QRS duration in the patients eventually included was considerably longer, on average in the range of 160–170 ms.17–28 Patients with moderate QRS complex prolongation may not benefit from CRT to the same extent as those with more marked prolongation. For instance, when the population of the COMPANION study was analysed according to the duration of the QRS complex, patients with a QRS duration of 147 ms or less did not demonstrate any benefit from CRT.27 Similarly, in the PATH-CHF II study, the benefit of CRT was more pronounced in patients with a QRS duration >150 ms when compared with those with a QRS duration of 120–150 ms.23 In the CARE-HF study, where echocardiographic mechanistic parameters were stipulated in the inclusion criteria for patients with a QRS duration of 120–149 ms, the favourable effects of CRT seemed to show less dependence on QRS duration.28

There are several other reasons for non-response to CRT, including suboptimal left ventricular lead placement, HF disease progression, and a variety of other factors (above all, the presence of myocardial scars or perfusion defects that cannot be resynchronized in patients with ischaemic cardiomyopathy). In a recently published observational study in 197 patients scheduled to undergo CRT, ischaemic heart disease was one of the three independent predictors of lack of response to CRT identified.34 It was postulated that CRT may be more effective when the contraction abnormality is due to a conduction delay, as in idiopathic cardiomyopathy, but less effective in patients with poor cardiac contractility due to extensive scarring. Nevertheless, the definition of non-response remains elusive and reliable predictors of lack of response to CRT are urgently needed.

Is it reasonable to implant CRT-P without defibrillation back-up devices initially to patients with appropriate criteria who have NICM and LVEF 0.30–0.34, to see if the LVEF rises above 35% ?
The rationale for this question is based on the assumption that the response to CRT should be greater in non-ischaemic cardiomyopathy (NICM), where LV asynchrony is often associated with an intraventricular conduction defect, than in ischaemic patients, in whom dyssynchrony may be related to segmental wall motion abnormalities due to the presence of myocardial scars or perfusion defects that cannot be resynchronized. Ischaemic cardiomyopathy was identified as an independent predictor of lower response to CRT in a recently published observational study.34 Thus, in NICM patients, CRT alone (CRT-P) may improve LVEF to a value above 35%, so there is no longer a need for ICD implantation according to the LVEF criteria.2,3 Indeed, although the benefit of ICD in preventing SCD has been proved in patients with low EF, frequent shocks, whether appropriate or inappropriate, reduce patients’ quality of life.2

The measurement of LVEF is very imprecise, with poor reproducibility and predictive value in patients with NICM, and the cut-off value of 35% should be interpreted in the context of better understanding of the overall clinical picture of the patient. For instance, in a patient with an LVEF of 33%, but no apparent additional risk criteria for arrhythmia (based on ECG, Holter monitoring or family history), it may be reasonable to wait for 2 or 3 months and to see whether EF improves so that ICD implantation can be avoided. Conversely, in a patient with an LVEF of 38%, the presence of risk criteria for arrhythmias may reasonably prompt the decision to implant an ICD.

The major drawback of implanting CRT-P instead of CRT-D is that, in the event of non-response to CRT-P (20–30% of cases), the patient would need to be re-operated a few months later. Thus, implanting CRT-P instead of CRT-D could be envisaged only if a reliable predictor of response (at least with 85–90% accuracy) was available. New CRT devices with capabilities to deliver a limited number of shocks (for instance up to 20) may also have value.

Are patients with NYHA functional Class III HF, LVEF ≤35%, QRS duration >150 ms and permanent AF, CRT-D candidates?
Permanent AF affects 10–30% of patients with permanent HF, its prevalence increasing in parallel with disease severity. However, the majority of CRT trials excluded patients with AF (Table 1).17–28 The reason for this may be that in one of the early studies, the single-blind, randomized, controlled, cross-over MUSTIC-AF study, only a modest benefit of biventricular pacing compared with classic right ventricular pacing was observed in patients with effective therapy (i.e. CRT for ≥85% of time), in terms of NYHA functional class, 6-min walking distance, quality-of-life score, reverse remodelling, and hospitalization rate.18 It has been postulated that AF may interfere with certain programming functions that limit optimal delivery of CRT. Data supporting the use of CRT in patients with permanent AF, otherwise eligible, are therefore limited, and current recommendations specify that CRT candidates should be in sinus rhythm.2,3

Data from the literature indicate that CRT may provide a functional benefit to AF patients. First, the benefits of CRT observed in the MUSTIC-AF study were maintained over a 12-month follow-up and reinforced in the AF group, although in general, the results for patients with AF were less impressive.43 In two prospective non-randomized studies, the long-term benefit of CRT in patients with AF was compared with that in patients who had sinus rhythm.44,45 Overall the benefit was comparable in both groups. In a post-hoc analysis of CARE-HF, the effect of CRT on the incidence of AF and the outcome of patients with new-onset AF was evaluated.46 By the end of follow-up (29.4 months), CRT did not affect the incidence of AF (16.1% in the CRT group vs. 14.4% in the medical treatment group). In addition, new onset of AF did not diminish the beneficial effects of CRT: in patients with new-onset AF, CRT significantly reduced the risk for all-cause mortality and all other predefined end points, and improved LVEF and symptoms (no interaction between AF and CRT; P = 0.2 for all comparisons). Importantly, in patients with new-onset AF, the median cumulative percentage of ventricular pacing was similar before development of AF (at 3 months, 99.4%) compared with the first visit after new-onset AF (97.6%; P = 0.28). These findings are in agreement with those found in the observational study by Diaz-Infante et al.,34 in 197 patients scheduled to undergo CRT, where the presence of AF did not appear to be an independent predictor of a lower probability of response. Nevertheless, larger studies are needed to confirm the beneficial effect of CRT in patients with permanent AF. In this respect, it may be noted that patients with long-standing persistent AF are being enrolled in the ongoing RAFT study evaluating CRT in patients with NYHA Class II or III HF (but not in the REVERSE and MADIT-CRT trials).

There is also an ongoing debate as to whether CRT in permanent AF patients should be accompanied by atrioventricular (AV) nodal ablation, as it is critical that rapid intrinsic AV nodal conduction should not inhibit resynchronization therapy. It may be proposed that the percentage of biventricular pacing should initially be monitored after a period of 3–6 months under beta-blockers, and that AV nodal ablation should not be performed if this percentage is ≥85%. Indeed, a theoretical argument against AV nodal ablation is the hypothesis that the reverse remodelling induced by CRT, with reduction of mitral regurgitation, might induce a spontaneous restoration of sinus rhythm over time. However, in the post-hoc analysis of CARE-HF, CRT did not reduce the incidence of AF over a 29.4-month follow-up period.46 In addition, in a recently published prospective cohort study by Gasparini et al.,47 the efficacy of CRT up to 4 years was compared between three groups: 48 patients with permanent AF in whom ventricular rate was controlled by drugs, thus resulting in apparently adequate delivery of biventricular pacing (≥85% of pacing time), 114 permanent AF patients, who had undergone AV ablation (100% of resynchronization therapy delivery), and 511 sinus rhythm patients. Within the AF group, only patients who underwent ablation showed significant benefits in terms of increased ejection fraction (P < 0.001), reverse remodelling effect (P < 0.001), and improved exercise tolerance (P < 0.001); no improvements were observed in AF patients who did not undergo ablation. However, at present, no data from controlled, randomized studies are available to support the importance of AV nodal ablation in CRT-treated AF patients.


   Conclusion
Top
 Abstract
 Introduction
 Implantable cardioverter...
 Cardiac resynchronization...
 Discussion
 Conclusion
References
 
CRT represents a major advance in the management of patients with symptomatic HF resulting from systolic dysfunction, with proved dramatic reductions in morbidity and mortality. However, several issues are still unresolved regarding its use in some situations that are routine in clinical practice, due to the paucity or sometimes even complete lack of data. One of these issues concerns the benefit of implanting CRT devices in patients, otherwise eligible, without mechanical dyssynchrony or with AF. Likewise, the value of initially implanting CRT-P instead of CRT-D in patients with appropriate criteria who have NICM to see if the EF rises above 0.35 remains debatable. Importantly, the clinical value of CRT in patients with NYHA Class II HF is currently being evaluated in three large randomized trials.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Implantable cardioverter...
 Cardiac resynchronization...
 Discussion
 Conclusion
 References
 

  1. McMurray JJV, Pfeffer MA. Heart failure. Lancet (2005) 365:1877–1889.[CrossRef][Web of Science][Medline]
  2. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Warner Stevenson L, Yancy CW, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Hunt SA, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing committee to update the 2001 guidelines for the evaluation and management of heart failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation (2005) 112:e154–e235.[Free Full Text]
  3. Swedberg K, Cleland J, Dargie H, Drexler H, Follath F, Komajda M, Tavazzi L, Smiseth OA, Gavazzi A, Haverich A, Hoes A, Jaarsma T, Korewicki J, Lévy S, Linde C, Lopez-Sendon J-L, Nieminen MS, Piérard L, Remme WJ. Task force for the diagnosis and treatment of chronic heart failure of the European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005). Eur Heart J (2005) 26:1115–1140.[Free Full Text]
  4. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, Gregoratos G, Klein G, Moss AJ, Myerburg RJ, Priori SG, Quinones MA, Roden DM, Silka MJ, Tracy C, Smith SC Jr, Jacobs AK, Adams CD, Antman EM, Anderson JL, Hunt SA, Halperin JL, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc J-J, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL. ACC/AHA/ESC 2006 Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College 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) 48:247–346.[CrossRef]
  5. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med (1989) 321:406–412.[Abstract]
  6. The Cardiac Arrhythmia Suppression Trial II Investigators. Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. N Engl J Med (1992) 327:227–233.[Abstract]
  7. Coplen SE, Antman EM, Berlin JA, Hewitt P, Chalmers TC. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion: a meta-analysis of randomized controlled trials. Circulation (1990) 82:1106–1116. [Published erratum appears in Circulation 1991;83:714].[Abstract/Free Full Text]
  8. Waldo AL, Camm AJ, deRuyter H, Friedman PL, MacNeil DJ, Pauls JF, Pitt B, Pratt CM, Schwartz PJ, Veltri EP. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction: the SWORD Investigators. Survival With Oral d-Sotalol. Lancet (1996) 348:7–12. [Published erratum appears in Lancet 1996;348:416].[CrossRef][Web of Science][Medline]
  9. Pratt CM, Camm AJ, Cooper W, Friedman PL, MacNeil DJ, Moulton KM, Pitt B, Schwartz PJ, Veltri EP, Waldo AL. Mortality in the Survival With ORal D-sotalol (SWORD) trial: why did patients die? Am J Cardiol (1998) 81:869–876.[CrossRef][Web of Science][Medline]
  10. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, Troutman C, Anderson J, Johnson G, McNulty SE, Clapp-Channing N, Davidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip JH. Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med (2005) 352:225–237.[Abstract/Free Full Text]
  11. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML. Multicentre Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med (2002) 346:877–883.[Abstract/Free Full Text]
  12. Hohnloser SH, Kuck KH, Dorian P, Roberts RS, Hampton JR, Hatala R, Fain E, Gent M, Connolly SJ. DINAMIT Investigators. Prophylactic use of an implantable cardioverter–defibrillator after acute myocardial infarction. N Engl J Med (2004) 351:2481–2488.[Abstract/Free Full Text]
  13. Kadish A, Dyer A, Daubert JP, Quigg R, Estes NA, Anderson KP, Calkins H, Hoch D, Goldberger J, Shalaby A, Sanders WE, Schaechter A, Levine JH. Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) Investigators. Prophylactic defibrillator implantation in patients with nonischaemic dilated cardiomyopathy. N Engl J Med (2004) 350:2151–2158.[Abstract/Free Full Text]
  14. Soejima K, Suzuki M, Maisel WH, Brunckhorst CB, Delacretaz E, Blier L, Tung S, Khan H, Stevenson WG. Catheter ablation in patients with multiple and unstable ventricular tachycardias after myocardial infarction: short ablation lines guided by reentry circuit isthmuses and sinus rhythm mapping. Circulation (2001) 104:664–669.[Abstract/Free Full Text]
  15. Abraham WT. Cardiac resynchronization therapy. Prog Cardiovasc Dis (2006) 48:232–238.[CrossRef][Web of Science][Medline]
  16. Strickberger SA, Conti J, Daoud EG, Havranek E, Mehra MR, Piña IL, Young J. Council on Clinical Cardiology Subcommittee on Electrocardiography and Arrhythmias and the Quality of Care and Outcomes Research Interdisciplinary Working Group; Heart Rhythm Society. Patient selection for cardiac resynchronization therapy. Circulation (2005) 111:2146–2150.[Abstract/Free Full Text]
  17. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, Garrigue S, Kappenberger L, Haywood GA, Santini M, Bailleul C, Daubert JC. Multisite Stimulation in Cardiomyopathies (MUSTIC) Study Investigators. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med (2001) 344:873–880.[Abstract/Free Full Text]
  18. Leclercq C, Walker S, Linde C, Clementy J, Marshall AJ, Ritter P, Djiane P, Mabo P, Levy T, Gadler F, Bailleul C, Daubert JC. Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with chronic atrial fibrillation. Eur Heart J (2002) 23:1780–1787.[Abstract/Free Full Text]
  19. Auricchio A, Stellbrink C, Sack S, Block M, Vogt J, Bakker P, Huth C, Schöndube F, Wolfhard U, Böcker D, Krahnefeld O, Kirkels H. Pacing Therapies in Congestive Heart Failure (PATH-CHF) Study Group. Long-term clinical effect of haemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay. J Am Coll Cardiol (2002) 39:2026–2033.[Abstract/Free Full Text]
  20. Garrigue S, Bordachar P, Reuter S, Jaïs P, Kobeissi A, Gaggini G, Haïssaguerre M, Clementy J. Comparison of permanent left ventricular and biventricular pacing in patients with heart failure and chronic atrial fibrillation: prospective haemodynamic study. Heart (2002) 87:529–534.[Abstract/Free Full Text]
  21. Leclercq C, Cazeau S, Lellouche D, Fossati F, Anselme F, Szekely L, Mollo L, Daubert C. Upgrading from right-ventricular pacing to biventricular pacing in previously paced patients with advanced heart failure: a randomized controlled study (abstract). Presented at the European Society of Cardiology Congress, 30 8–3 9 2003: Vienna, Austria.
  22. Higgins SL, Hummel JD, Niazi IK, Giudici MC, Worley SJ, Saxon LA, Boehmer JP, Higginbotham MB, De Marco T, Foster E, Yong PG. Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias. J Am Coll Cardiol (2003) 42:1454–1459.[Abstract/Free Full Text]
  23. Auricchio A, Stellbrink C, Butter C, Sack S, Vogt J, Misier AR, Böcker D, Block M, Kirkels JH, Kramer A, Huvelle E. Pacing Therapies in Congestive Heart Failure (PATH-CHF) II Study Group; Guidant Heart Failure Research Group. Clinical efficacy of cardiac resynchronization therapy using left ventricular pacing in heart failure patients stratified by severity of ventricular conduction delay. J Am Coll Cardiol (2003) 42:2109–2116.[Abstract/Free Full Text]
  24. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ, Underwood J, Pickering F, Truex C, McAtee P, Messenger J. MIRACLE Study Group. Multicentre InSync Randomized Clinical Evaluation. Cardiac resynchronization in chronic heart failure. N Engl J Med (2002) 346:1845–1853.[Abstract/Free Full Text]
  25. Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff B, Canby RC, Schroeder JS, Liem LB, Hall S, Wheelan K. Multicentre InSync ICD Randomized Clinical Evaluation (MIRACLE ICD) Trial Investigators. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA (2003) 289:2685–2694.[Abstract/Free Full Text]
  26. Abraham WT, Young JB, León AR, Adler S, Bank AJ, Hall SA, Lieberman R, Liem LB, O'Connell JB, Schroeder JS, Wheelan KR, on behalf of the Multicenter InSync ICD II Study Group. Effects of cardiac resynchronization on disease progression in patients with left ventricular systolic dysfunction, an indication for an implantable cardioverter-defibrillator, and mildly symptomatic chronic heart failure. Circulation (2004) 110:2864–2868.[Abstract/Free Full Text]
  27. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM. Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med (2004) 350:2140–2150.[Abstract/Free Full Text]
  28. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L. Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med (2005) 352:1539–1549.[Abstract/Free Full Text]
  29. Donal E, Leclercq C, Linde C, Daubert JC. Effects of cardiac resynchronization therapy on disease progression in chronic heart failure. Eur Heart J (2006) 27:1018–1025.[Abstract/Free Full Text]
  30. McAlister FA, Ezekowitz JA, Wiebe N, Rowe B, Spooner C, Crumley E, Hartling L, Klassen T, Abraham W. Systematic review: cardiac resynchronization in patients with symptomatic heart failure. Ann Intern Med (2004) 141:381–390.[Abstract/Free Full Text]
  31. Freemantle N, Tharmanathan P, Calvert MJ, Abraham WT, Ghosh J, Cleland JGF. Cardiac resynchronisation for patients with heart failure due to left ventricular systolic dysfunction. A systematic review and meta-analysis. Eur J Heart Failure (2006) 8:433–440.[Abstract/Free Full Text]
  32. Linde C, Gold M, Abraham WT, Daubert JC, for the REVERSE Study Group. Rationale and design of a randomized controlled trial to assess the safety and efficacy of cardiac resynchronization therapy in patients with asymptomatic left ventricular dysfunction with previous symptoms or mild heart failure. The REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) study. Am Heart J (2006) 151:288–294.[CrossRef][Web of Science][Medline]
  33. Moss AJ, Brown MW, Cannom DS, Daubert JP, Estes M, Foster E, Greenberg HM, Hall WJ, Higgins SL, Klein H, Pfeffer M, Wilber D, Zareba W. Multicentre automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT): design and clinical protocol. Ann Noninvasive Electrocardiol (2005) 10(Suppl. 4):34–43.[CrossRef][Web of Science][Medline]
  34. Díaz-Infante E, Mont L, Leal J, García-Bolao I, Fernández-Lozano I, Hernández-Madrid A, Pérez-Castellano N, Sitges M, Pavón-Jiménez R, Barba J, Cavero MA, Moya JL, Pérez-Isla L, Brugada J. SCARS Investigators. Predictors of lack of response to resynchronization therapy. Am J Cardiol (2005) 95:1436–1440.[CrossRef][Web of Science][Medline]
  35. Bax JJ, Ansalone G, Breithardt OA, Derumeaux G, Leclercq C, Schalij MJ, Sogaard P, St. John Sutton M, Nihoyannopoulos P. Echocardiographic evaluation of cardiac resynchronization therapy: ready for routine clinical use? A critical appraisal. J Am Coll Cardiol (2004) 44:1–9.[Abstract/Free Full Text]
  36. Bax JJ, Abraham T, Barold SS, Breithardt OA, Fung JW, Garrigue S, Gorcsan J, Hayes DL, Kass DA, Knuuti J, Leclercq C, Linde C, Mark DB, Monaghan MJ, Nihoyannopoulos P, Schalij MJ, Stellbrink C, Yu CM. Cardiac resynchronization therapy. Part 1 - issues before device implantation. J Am Coll Cardiol (2005) 46:2153–2167.[Abstract/Free Full Text]
  37. Ghio S, Constantin C, Klersy C, Serio A, Fontana A, Campana C, Tavazzi L. Interventricular and intraventricular dyssynchrony are common in heart failure patients, regardless of QRS duration. Eur Heart J (2004) 25:571–578.[Abstract/Free Full Text]
  38. Yu CM, Lin H, Zhang Q, Sanderson JE. High prevalence of left ventricular systolic and diastolic asynchrony in patients with congestive heart failure and normal QRS duration. Heart (2003) 89:54–60.[Abstract/Free Full Text]
  39. Bleeker GB, Schalij MJ, Molhoek SG, Verwey HF, Holman ER, Boersma E, Steendijk P, Van Der Wall EE, Bax JJ. Relationship between QRS duration and left ventricular dyssynchrony in patients with end-stage heart failure. J Cardiovasc Electrophysiol (2004) 15:544–549.[Web of Science][Medline]
  40. Achilli A, Sassara M, Ficili S, Pontillo D, Achilli P, Alessi C, De Spirito S, Guerra R, Patruno N, Serra F. Long-term effectiveness of cardiac resynchronization therapy in patients with refractory heart failure and ‘narrow’ QRS. J Am Coll Cardiol (2003) 42:2117–2124.[Abstract/Free Full Text]
  41. Turner MS, Bleasdale RA, Vinereanu D, Mumford CE, Paul V, Fraser AG, Frenneaux MP. Electrical and mechanical components of dyssynchrony in heart failure patients with normal QRS duration and left bundle-branch block: impact of left and biventricular pacing. Circulation (2004) 109:2544–2549.[Abstract/Free Full Text]
  42. Yu CM, Abraham WT, Bax J, Chung E, Fedewa M, Ghio S, Leclercq C, León AR, Merlino J, Nihoyannopoulos P, Notabartolo D, Sun JP, Tavazzi L. PROSPECT Investigators. Predictors of response to cardiac resynchronization therapy (PROSPECT) - study design. Am Heart J (2005) 149:600–605.[CrossRef][Web of Science][Medline]
  43. Linde C, Leclercq C, Rex S, Garrigue S, Lavergne T, Cazeau S, McKenna W, Fitzgerald M, Deharo JC, Alonso C, Walker S, Braunschweig F, Bailleul C, Daubert JC. Long-term benefits of biventricular pacing in congestive heart failure: results from the MUltisite STimulation in cardiomyopathy (MUSTIC) study. J Am Coll Cardiol (2002) 40:111–118.[Abstract/Free Full Text]
  44. Leclercq C, Victor F, Alonso C, Pavin D, Revault d'Allones G, Bansard JY, Mabo P, Daubert C. Comparative effects of permanent biventricular pacing for refractory heart failure in patients with stable sinus rhythm or chronic atrial fibrillation. Am J Cardiol (2000) 85:1154–1156.[CrossRef][Web of Science][Medline]
  45. Molhoek SG, Bax JJ, Bleeker GB, Boersma E, van Erven L, Steendijk P, van der Wall EE, Schalij MJ. Comparison of response to cardiac resynchronization therapy in patients with sinus rhythm versus chronic atrial fibrillation. Am J Cardiol (2004) 94:1506–1509.[CrossRef][Web of Science][Medline]
  46. Hoppe UC, Casares JM, Eiskjaer H, Hagemann A, Cleland JG, Freemantle N, Erdmann E. Effect of cardiac resynchronization on the incidence of atrial fibrillation in patients with severe heart failure. Circulation (2006) 114:18–25.[Abstract/Free Full Text]
  47. Gasparini M, Auricchio A, Regoli F, Fantoni C, Kawabata M, Galimberti P, Pini D, Ceriotti C, Gronda E, Klersy C, Fratini S, Klein HH. Four-year efficacy of cardiac resynchronization therapy on exercise tolerance and disease progression: the importance of performing atrioventricular junction ablation in patients with atrial fibrillation. J Am Coll Cardiol (2006) 48:734–743.[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Disclaimer
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Hohnloser, S. H.
Right arrow Articles by Prystowsky, E. N.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Hohnloser, S. H.
Right arrow Articles by Prystowsky, E. N.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?