Cardiac Resynchronization Therapy with or without an Implantable Defibrillator: Only Indicated When Everything Else has Failed?

Cardiac resynchronization therapy (CRT) is potentially an important new treatment for patients with heart failure due to left ventricular systolic dysfunction and cardiac dyssynchrony. There is growing evidence that CRT can improve symptoms although it is possible that similar benefits could be obtained by skillful manipulation of pharmacological therapy. There is also preliminary but inconclusive evidence to suggest that CRT alone or in synergy with an implantable cardiac defibrillator (ICD) may reduce morbidity and mortality. However, fashion is in danger of overtaking facts and it is important to ensure that benefits are not only statistically proven but clinically meaningful and cost-effective. Optimal timing of intervention and patient selection will be essential to ensure that treatment is deployed efficiently.If CRT with or without ICD becomes part of mainstream therapy for heart failure this will have far-reaching consequences for heart failure management. Implantation is a skilled and often time-consuming procedure. Long-term management of both CRT and ICD is likely to provide challenges in terms of lead technology, pacing thresholds and device management. Heart failure physicians will have to learn new skills and collaborate more closely with electrophysiologists. Such developments, in addition to the need for complex pharmacological interventions will accelerate the move away from general practice and towards specialist care for this most common of malignant diseases.If CRT does reduce mortality, it will graduate from an adjunctive therapy which could be used to an essential one that should be used as part of routine therapy for appropriate patients. Currently, CRT is a symptomatic therapy for patients with severe heart failure resistant to intensive pharmacological therapy delivered by a heart failure specialist.     

Is implantable defibrillator indicated in all patients on cardiac resynchronization therapy?

Implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy (CRT) have been introduced during the recent years to improve survival, decrease hospital readmissions and mortality, and to improve functional status and quality of life for patients with heart failure and left ventricular systolic dysfunction (LVSD). Studies which evaluated the use of CRT or ICD alone or compared CRT with CRT-ICD in patients with heart failure and LVSD are listed in this article. The results obtained are already influencing clinical practice in the US, where it has been estimated that 90% of patients receiving a CRT device now are being implanted with an ICD component. However, it is still today debated whether patients with LVSD and heart failure should be routinely offered a CRT-ICD. In fact, there are some issues that still should be solved before to establish indication for CRT-D in all heart failure patients with an indication for CRT: 1) a non complete agreement among the different societies which wrote recommendations for guidelines (a comparative table is reported); 2) a better identification of implantable patients and an amelioration of utilized devices; 3) economic and ethical ramifications of this therapy. Anyway still now the crucial question is: 'Can resynchronization be done in isolation or must be accompanied by an ICD device?'. To answer to this question we can only express which is, in our opinion, the actual position of many physicians who work in the field of pacing and electrophysiology: 'The lesson to be learned is that we still can not predict surely which patient will die of sudden death. Until a method of identifying the high risk patients can be developed, the safest strategy should be to advise a combined ICD-CRT device for patients with indication for CRT'.     

Benefit of combined resynchronization and defibrillator therapy in heart failure patients with and without ventricular arrhythmias.

OBJECTIVES: We attempted to assess the efficacy of combined cardiac resynchronization therapy-implantable cardioverter-defibrillator (CRT-ICD) in heart failure patients with and without ventricular arrhythmias. BACKGROUND: Because CRT and ICDs both lower all-cause mortality in patients with advanced heart failure, combination of both therapies in a single device is challenging. METHODS: A total of 191 consecutive patients with advanced heart failure, left ventricular ejection fraction <35%, and a QRS duration >120 ms received CRT-ICD. Seventy-one patients had a history of ventricular arrhythmias (secondary prevention); 120 patients did not have prior ventricular arrhythmias (primary prevention). During follow-up, ICD therapy rate, clinical improvement after 6 months, and mortality rate were evaluated. RESULTS: During follow-up (18 +/- 4 months), primary prevention patients experienced less appropriate ICD therapies than secondary prevention patients (21% vs. 35%, p < 0.05). Multivariate analysis revealed, however, no predictors of ICD therapy. Furthermore, a similar, significant, improvement in clinical parameters was observed at 6 months in both groups. Also, the mortality rate in the primary prevention group was lower than in the secondary prevention group (3% vs. 18%, p < 0.05). CONCLUSIONS: As 21% of the primary prevention patients and 35% of the secondary prevention patients experienced appropriate ICD therapy within 2 years after implant, and no predictors of ICD therapy could be identified, implantation of a CRT-ICD device should be considered in all patients eligible for CRT.     

Implantable device therapy

Sudden cardiac death (SCD) accounts for two-thirds of fatal events related to heart disease. Coronary heart disease and non-ischemic cardiomyopathy are the most common causes of SCD. Data from major randomized trials have consistently shown that therapy with an implantable cardioverter defibrillator (ICD) results in a significant and meaningful effect on survival through a reduction in the risk of SCD in these population. These data have resulted in a marked increase in the application of implantable device therapy in the past 2 decades from secondary prevention with an implantable cardioverter/defibrillator (ICD) in survivors of a cardiac arrest to primary prevention of SCD in asymptomatic patients with ischemic and non-ischemic left ventricular dysfunction, and prevention of symptomatic heart failure progression and death with cardiac resynchronization therapy (CRT), and devices that combine CRT and ICD therapies (CRT-D). However, there are still areas of uncertainty regarding device therapy that include inconsistent benefit in risk-subgroups of patients with low ejection fraction; increased risk of heart failure after life-prolonging ICD therapy, and a considerable rate of device malfunction despite increasing sophistication. In the present review we focus on current data regarding the clinical indications as well as the safety and efficacy of implantable device therapy, including ICD, CRT, and CRT-D.     

Current role of device therapy to reduce sudden cardiac death in heart failure

Sudden cardiac death (SCD) continues to be a major contributor to mortality in patients with heart failure (HF) despite recent advances in medical therapy. Device therapy, including the implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy (CRT), serves as an adjunct in reducing HF mortality. Several clinical trials support the prophylactic use of the ICD in reducing mortality in certain HF populations and have established the clinical benefits of CRT in advanced HF. More recently, the Comparison of Medical Therapy Pacing and Defibrillation in Heart Failure trial was the first study to demonstrate a survival benefit of CRT alone or in conjunction with an ICD. This article reviews the most pertinent data regarding the role of device therapy in reducing SCD in HF and addresses future challenges faced by device manufacturers and clinicians.     

Kardiale Resynchronisationstherapie

Cardiac resynchronization therapy (CRT) is a new concept in the treatment of patients with drug-refractory heart failure (HI). Candidates for CRT are HI patients with NYHA class III-IV, left bundle branch block and QRS width ≥0.12 s. CRT leads to improvements in hemodynamics both acutely and during long-term follow-up, resulting in better cardiopulmonary exercise tolerance. In addition, patients receiving CRT have a better survival rate with or without implantable cardiac defibrillator (ICD) back-up. CRT is possible in patients with atrial fibrillation. CRT with ICD back-up is indicated in patients with HI, low left ventricular function (EF), indication for CRT and coronary artery disease, whereas this question is not fully resolved in patients with dilated cardiomyopathy. CRT patients must be followed up; home monitoring is a very promising approach for quick and safe surveillance of these patients.     

Cardiac Resynchronization Therapy in Asymptomatic or Mildly Symptomatic Heart Failure Patients

Heart failure is a constantly progressing disease involving patients with ischemic and nonischemic cardiac disease. Cardiac resynchronization therapy (CRT) has been used successfully in patients with severe heart failure symptoms, poor left ventricular (LV) function, and a prolonged QRS duration. Large trials in patients with New York Heart Association (NYHA) class III/IV heart failure have demonstrated that heart failure symptoms can be reduced and exercise capacity improved, overall mortality decreased, and ventricular function increased. How long these beneficial effects of CRT will last in patients with an already advanced stage of heart failure, particularly in NYHA IV, is still unknown. Therefore, it is more reasonable to initiate CRT in appropriate patients who have structural heart disease but have not yet developed severe heart failure symptoms. Slowing heart failure progression seems to be the most important target. Medical treatment alone has not demonstrated that this can be achieved in patients with poor ventricular function and prolonged QRS (>120 ms). The recently published results of MADIT-CRT, as well as the extended follow-up of the REVERSE substudy of the European patient cohort, have shown that prevention of heart failure progression can be well accomplished with CRT and implantable cardioverter–defibrillator (ICD) backup (CRT-D). Heart failure events and death occurred significantly less often in patients with CRT-D than in those with an ICD only. A clinically important reversal of ventricular remodeling with reduced ventricular volumes and increased LV ejection fraction was found in the CRT-D–treated patients. The benefit was seen in patients with ischemic and nonischemic cardiomyopathy and in those with NYHA class I or II heart failure; the most benefit was demonstrated in patients showing a “classic” left bundle branch block electrocardiogram pattern (about 70% of the enrolled patients) and in female patients. Results from both trials support the view that future efforts regarding heart failure treatment should concentrate more on prevention of heart failure progression in mildly symptomatic or even asymptomatic candidates for CRT-D. It is time to change the guidelines for heart failure treatment.     

Kardiale Resynchronisationstherapie

Chronic postinfarction patients with an ejection fraction ≤ 30% and heart failure patients in NYHA classes II and III with an ejection fraction ≤ 35% due to ischemic or dilated cardiomyopathy meet current indications for ICD therapy. There is significant overlap with patients in NYHA class III also exhibiting a wide QRS complex (>120 ms), who commonly benefit from resynchronization therapy. Although a combination of ICD and CRT seems reasonable in many patients, one should be aware of subtle distinctions regarding selection criteria for either therapy. There is no clear ICD indication for heart failure patients in NYHA class IV or even III, taking subclass analysis of SCD-HeFT [4] into account. Uncertainty still exists for the subacute postinfarction phase (4 weeks to 6 months), whereas the early postinfarction phase should clearly not be considered for ICD evaluation. No randomized data exist for heart failure due to other etiologies. CRT, on the other hand, is not only helpful regarding symptom relief and quality of life, but also with respect to life expectancy. The additive value of adjunctive ICD therapy has not yet been proven in a randomized comparison. Finally, particularly in elderly patients, quality of life might seem more desirable than prevention of sudden cardiac death. Thus, combination of ICD and CRT is not always a “must”. Instead, ICD guidelines still leave room for a patient specific decision, with “stand-alone” CRT still providing a very helpful, prognostically significant therapy.     

Roles and indications for use of implantable defibrillator and resynchronization therapy in the prevention of sudden cardiac death in heart failure

Implantable devices are indicated in the primary and secondary prevention of potentially life-threatening ventricular tachyarrhythmias in patients with heart failure. Early studies, including the landmark MADIT trials, showed that implantable cardioverter–defibrillator (ICD) and cardiac resynchronization therapy (CRT) devices can play a significant role in aborting and preventing ventricular arrhythmias, respectively, that can cause sudden cardiac death. To this day, there have been a number of randomized controlled trials, with respective substudy analyses, that have attempted to better understand the indications for these interventions in patient care. Here, we summarize the major results of these studies, and we discuss the role of ICD therapy for both ischemic and non-ischemic cardiomyopathy, emerging evidence in support of wearable defibrillators, and the impact of modified ICD programming strategies on patient outcomes. Regarding CRT therapy, the phenomenon of ventricular reverse remodeling is an important prognostic indicator in preventing future ventricular tachyarrhythmia episodes. In summation, we provide an overview of the possible selection criteria that can be used in identifying appropriate patients for ICD and/or CRT therapy, as supported by the data.     

Clinical trials update and cumulative meta-analyses from the American College of Cardiology: WATCH, SCD-HeFT, DINAMIT, CASINO, INSPIRE, STRATUS-US, RIO-Lipids and cardiac resynchronisation therapy in heart failure

This article continues a series of reports on recent research developments in the field of heart failure. Key presentations made at the American College of Cardiology meeting, held in New Orleans, Louisiana, USA in March 2004 are reported. These new data have been added to existing data in cumulative meta-analyses. The WATCH study randomised 1587 patients with heart failure and left ventricular systolic dysfunction to warfarin, aspirin or clopidogrel. The study showed no difference between the effects of these agents on mortality or myocardial infarction, but hospitalisations for heart failure were higher on aspirin (22.2%) compared to warfarin (16.1%). The SCD-HeFT study showed that ICD therapy reduced all-cause mortality at 5 years by 23% in patients with predominantly NYHA class II heart failure and left ventricular systolic dysfunction, but amiodarone was ineffective. The DINAMIT study showed that ICD therapy was not beneficial in patients with left ventricular dysfunction after a recent MI, even in those with risk factors for arrhythmic death. In CASINO, levosimendan improved survival compared with dobutamine or placebo in patients with decompensated heart failure. INSPIRE showed that SPECT imaging can be used to assess risk early after acute MI safely and accurately. Rimonabant was shown to be safe and effective in treating the combined cardiovascular risk factors of smoking and obesity. An overview of new developments in cardiac resynchronisation therapy (CRT) in heart failure is also reported.     

Influence of cardiac-resynchronization therapy on heart rate and blood pressure variability: 1-year follow-up

BACKGROUND: Several studies have shown that cardiac-resynchronization therapy (CRT) improves haemodynamic function, cardiac symptoms, and heart rate variability (HRV) and reduces the risk of mortality and sudden death in subjects with chronic heart failure (CHF). In subjects with CHF, power spectral values for the low-frequency (LF) component of RR variability < or =13 ms2, are associated with an increased risk of sudden death. AIMS AND METHODS: To assess whether spectral indexes obtained by power spectral analysis of HRV and systolic blood pressure (SBP) variability could predict malignant ventricular arrhythmias in patients with severe CHF treated with an implantable cardioverter-defibrillator (ICD) alone or with ICD+CRT. In addition, changes in non-invasive spectral indices using short-term power spectral analysis of HRV and SBP variability during controlled breathing in 15 patients with CHF treated with an ICD alone and 16 patients receiving ICD+CRT, were assessed pre-treatment and at 1 year. RESULTS: Arrhythmias necessitating an appropriate ICD shock were more frequent in subjects who had low LF power. CRT improved all spectral components, including LF power. CONCLUSIONS: Low LF power values predict an increased risk of malignant ventricular arrhythmias; after 1 year of CRT most non-spectral and spectral data, including LF power, improved. Whether these improvements lead to better long-term survival in patients with CHF remains unclear.     

Cardiac resynchronization therapy in heart failure.

Cardiac resynchronization therapy (CRT) is a new therapeutic approach for a selected group of patients with symptomatic heart failure (NYHA functional class III-IV) despite optimal medical therapy, due to dilated cardiomyopathy of any etiology (left ventricular ejection fraction < or = 35% and left ventricular end-diastolic diameter > or = 55 mm), who present with electromechanical dyssynchrony (QRS > or = 130 ms). Safety and effectiveness of CRT have been demonstrated by several clinical trials, with patients achieving significant improvement in both clinical symptoms as well as functional status and exercise capacity. Furthermore, CRT has reduced morbidity of heart failure patients, while its impact in improving survival still remains to be clarified. Whether or not heart failure patients candidate to CRT should receive a defibrillator back-up remains debatable, although growing evidence is pointing to extensive use of a defibrillator in such a population.     

Cardiac resynchronization therapy and tools to identify responders

Heart failure is a major epidemic. Many people with heart failure struggle with refractory symptoms despite optimal medical therapy. Those with severe left ventricular dysfunction and ventricular conduction delay are at significant risk from either dying suddenly or dying from progression of their heart failure. Cardiac resynchronization therapy (CRT) improves hemodynamics and symptoms of heart failure and has recently been shown to improve survival. One problem facing the use of CRT is that 30% of patients fail to respond. The dominant theory is that QRS duration (electrical dyssynchrony) does not accurately reflect mechanical dyssynchrony. Echocardiographic tools have recently been developed that enable clinicians to assess the degree of mechanical dyssynchrony in patients being considered for CRT. These tools are able to predict with a significant amount of accuracy whether a patient will respond to CRT. This allows for a more refined approach to evaluating patients for CRT and optimizing the treatment of congestive heart failure.     

Implantable cardioverter defibrillators and cardiac resynchronization therapy in patients with left ventricular dysfunction: randomized trial evidence through 2004

Although many studies have shown that implantable cardioverter defibrillator (ICD) therapy improves the survival of patients with significant left ventricular dysfunction, the magnitude of effectiveness of ICD therapy in clinically defined subgroups remains uncertain. Similarly, although studies have shown an improvement in patients' hemodynamics and quality of life with cardiac resynchronization therapy (CRT), there is a continuing uncertainty about the effect of CRT on patients' survival and the magnitude of improvement in quality of life with this therapy. On August 24, 2004, an ad hoc group of experts representing clinical cardiovascular medicine, biostatistics, economics, and health policy were joined by representatives of the Food and Drug Administration, Centers for Medicare and Medicaid Services (Baltimore, Md), Agency for Healthcare Research and Quality (Rockville, Md), and the device industry for a 1-day round table to review the available clinical trial evidence on the effect of ICD therapy in the primary prevention of sudden cardiac death and the effect of CRT in patients with congestive heart failure. The meeting was organized by the Duke Clinical Research Institute, Durham, NC, and funded in part by the Agency for Healthcare Research and Quality. This document summarizes the evidence reviewed at that meeting and the discussions of that evidence.     

Arrhythmias in heart failure

Opinion statement  

The current role of cardiac resynchronization therapy in reducing mortality and hospitalization in heart failure patients: a meta-analysis from clinical trials

Many diagnostic and therapeutic advances have been reached for congestive heart failure (HF). However, despite clinical improvement and longer survival conferred by new pharmacological options, this syndrome is associated with high morbidity and mortality. Atrial-synchronized biventricular pacing (cardiac resynchronization therapy, CRT) has proven to be effective treatment in symptomatic patients with reduced left ventricular ejection fraction and electromechanical dyssynchrony. To date, many papers have been published on the role of CRT in improving quality of life, functional and neurohormonal parameters and reducing mortality and hospitalization. Eligible studies were randomized controlled trials of CRT for the treatment of chronic, symptomatic left ventricular dysfunction. Our search began dating back to 1994 and was updated to October 2006. Pooled data from the 6 selected studies showed that CRT reduced all-cause mortality by 28% (hazard ration [HR] = 0.72; 95% confidence interval [CI]: 0.60-0.86) and new hospitalizations for worsening HF by 37% (HR = 0.63; 95% CI: 0.44-0.91). This meta-analysis showed that patients with implantable cardiac defibrillators (ICDs) alone and ICD+CRT had a significant reduction of worsening HF hospitalization rate compared to no CRT-no ICD patients. Among patients with ICDs, CRT showed a slight effect on all-cause mortality reduction but no clear impact on worsening HF rehospitalization.     

Cardiac resynchronization therapy: a practical guide for device optimization, part I

This is the first part of a two-part series on strategies for optimizing the delivery of cardiac resynchronization therapy (CRT), focusing on device-related aspects. There is overwhelming evidence from prospective randomized controlled trials providing consistent and concordant support for CRT in patients with symptomatic heart failure and ventricular dyssynchrony. CRT has consistently improved quality of life, cardiac structure and function, and survival in the majority of patients enrolled in these trials. No longer a consideration for select individuals with heart failure, the 2005 American College of Cardiology/American Heart Association Guidelines for Managing Adults with Chronic Heart Failure now consider CRT a class IA recommendation for stage C patients (QRS duration > or = 120 milliseconds, left ventricular ejection fraction < or = 35%) who remain symptomatic despite optimal medical therapy. However, not everyone experiences clinical improvement from CRT. This article discusses measures that should be considered to ensure proper functioning of a CRT device. A subsequent article will present strategies to optimize patients' responses to CRT.     

Electrical devices for left ventricular dysfunction and heart failure: do we need revised guidelines?

Three recent trials have demonstrated the benefit of cardiac resynchronization therapy (CRT) in the New York Heart Association (NYHA) class II patients with heart failure (HF) with ischemic or nonischemic cardiomyopathy as well as in NYHA class I (asymptomatic) patients mostly with ischemic cardiomyopathy. Earlier intervention with CRT in asymptomatic or minimally symptomatic patients improves survival and reduces HF hospitalizations. The reduction or the prevention of HF hospitalizations is of paramount importance because the HF episodes seem to alter the natural history of disease and are associated with deterioration of left ventricular (LV) function and a marked increase in mortality. The CRT benefit is greatest in patients with a QRS ≥ 150 ms. At this time, it would seem prudent to consider CRT-D (D = ICD) therapy for class I NYHA patients with a QRS ≥ 150 ms and an LV ejection fraction ≤ 30% regardless of etiology. Although the data for NYHA class I patients with nonischemic cardiomyopathy are scanty, the recommendation for class I patients is justified because CRT achieves a much greater degree of LV reverse remodeling in nonischemic compared to ischemic patients. With regard to lone ICDs, there is no evidence that they prevent sudden cardiac death more efficiently in symptomatic than in asymptomatic patients. Cardiomyopathy should be the primary target for device therapy regardless of symptoms for both CRT and lone ICD therapy. New guidelines are needed to address the role of CRT in hospitalized NYHA class IV HF patients or those who depend on inotropic therapy or an LV assist device because randomized CRT trials have not included these patients. CRT in these patients remains controversial. The mortality of such patients even with CRT is very high despite the occasional positive response. The role of CRT in patients waiting for cardiac transplantation also needs guidelines. With the expansion of CRT indications to minimally symptomatic or asymptomatic patients, the benefit of device therapy must be carefully weighed against the potential risk of lifelong device complications.     

Cardiac Resynchronization Therapy is an Important Advance in the Management of Congestive Heart Failure

Cardiac resynchronization therapy (CRT) is an emerging therapy that improves symptoms and exercise tolerance in patients with advanced heart failure, left ventricular systolic dysfunction, and intraventricular conduction delay. By correcting the AV, interventricular, and intraventricular dyssynchrony induced by conduction disorders, controlled studies have shown that CRT improved functional status, decreased heart failure hospitalization rate, and might have a positive effect on left ventricular remodeling. Recent and preliminary data from the COMPANION trial suggest that CRT alone or in association with defibrillator capacity significantly reduced total mortality and hospitalization and that total mortality was significantly reduced only in the CRT plus implantable cardioverter defibrillator (ICD) group. Many questions remain unanswered, particularly the selection of responder patients. (J Cardiovasc Electrophysiol, Vol. 14, pp. S27-S29, September 2003, Suppl.)     

Successful treatment of heart failure with devices requires collaboration

Implanted biventricular pacemakers (cardiac resynchronisation therapy, CRT) with or without implantable cardioverter defibrillators (ICD) improve survival and morbidity in some patients with chronic heart failure (CHF) who are optimally treated with pharmacologic agents according to current guidelines. Correspondingly, ICDs improve survival. However, there is only limited evidence for device treatment in certain patient subgroups, such as the impact of ICD on outcomes in patients with reduced ejection fraction in New York Heart Association (NYHA) Class I or IV heart failure. Similarly, limited evidence exists for CRT in patients with only modest QRS prolongation or only modestly reduced ejection fraction. Despite evidence for a beneficial effect of device therapy in CHF, only a minority of eligible patients are currently offered these options. Multiple reasons contribute to the underuse of these potentially life‐saving therapies. A lack of adherence to guidelines by health care professionals is an important barrier. Clearly, efforts should be made to improve the standard of care and to familiarise all physicians involved in managing CHF patients with the indications and potential efficacy of these devices. Increased collaboration between structured heart failure care and pacemaker clinics as well as between electrophysiologists, heart failure clinicians, and primary care physicians is required. Such team collaborations should lead to improved care with reduced mortality and morbidity and increased cost effectiveness. Treatment strategy should be based on a structured approach tailored to local practice and national priorities.