As an electrophysiologist, I am referred large numbers of patients with, or at risk of, arrhythmias as part of the heart failure complex. In this review I will concentrate on the role of pacemakers and defibrillators in heart failure, because these are my areas of greatest experience. Left ventricular assist devices and implantable hemodynamic monitors will not be reviewed. The first controversy for discussion is how to assess patients for suitability to receive these devices. Patients with heart failure are frequently fitted into a New York Heart Association (NYHA) class. The NYHA class is, however, a blunt instrument for decision-making that is based on a physician's or nurse's impression of how patients express their symptoms. Two patients with similar levels of symptomatology but with different responses to their symptoms may therefore receive different NYHA classifications and be candidates for different management approaches. Guidelines such as those from the European Society of Cardiology (ESC) offer valuable guidance on the use of cardiac resynchronization therapy (CRT).12 There are, however, issues in the use of CRT which the guidelines do not consider. Controversies that relate particularly to CRT include the identification of which patients benefit most from this technique and the characterization of its role in atrial fibrillation, in patients with bradycardia, and in non-responders. CRT has been available for approximately 10 years. An early meta-analysis of randomized controlled trials of CRT, including CONTAK-CD, InSync ICD, MIRACLE, and MUSTIC, showed that CRT reduced death from progressive heart failure by 51%, reduced heart failure hospitalization by 29%, and showed a trend to reduced all-cause mortality2 (Figures 12–3). Some of these trials included a defibrillator component, which made characterization of the effects of CRT alone problematic. Subsequent to these trials, the CARE-HF study was performed. CARE-HF observed that CRT produced a 37% reduction in all-cause mortality or unplanned hospitalization compared to medical therapy over 4 years (P < 0.0001)5 (Figure 4). All-cause mortality alone was reduced 36% by CRT when compared to optimal medical therapy (P = 0.0019). CARE-HT was the first major trial to demonstrate a definite improvement in all-cause mortality from CRT pacing. The COMPANION study included patients at higher risk than those in CARE-HF and investigated three treatment limbs – optimal pharmacological therapy, biventricular pacing, and biventricular defibrillation.3 COMPANION was not powered to detect a difference in outcome between the two types of biventricular device, but did appear to show that biventricular defibrillation was superior to medical therapy based on the secondary endpoint of all-cause mortality at 12 months (Figure 5). On the basis of these trials, the ESC guidelines recommend that “CRT using biventricular pacemakers can be considered [my italics] in patients with reduced ejection fraction and ventricular asynchrony (QRS width ≥120 ms) who remain symptomatic despite optimal medical therapy (NYHA III/IV) to improve symptoms, hospitalizations, and mortality”.12 From my viewpoint, this statement may require to be updated in the revised ESC guidelines and CRT should be performed much more commonly than presently. National guidelines from the Scottish Intercollegiate Guidelines Network (SIGN), which have been more produced recently (2007) than those from the ESC (2005), make a similar statement – namely, that CRT “should be considered” in patients with characteristics similar to those described in the ESC guidelines. The English National Institute for Clinical Excellence (NICE) Health Technology Appraisal of the place of CRT in heart failure (2007) states that: “CRT with a pacing device (CRT-P) is recommended as a treatment option for patients with heart failure who fulfill the following criteria. They are currently experiencing or have recently experienced NYHA class III-IV symptoms. They are in sinus rhythm either with a QRS duration 150 ms or longer … or with a QRS duration of 120–149 ms and mechanical dyssynchrony. They have a LVEF of 35% or less. They are receiving optimal pharmacological therapy.” The NICE guidelines therefore strongly recommend CRT for a precisely defined group of patients. The NICE guidelines also offer guidance on the use of CRT with a defibrillator (CRT-D). “CRT-D may be considered for people who fulfill the criteria for implantation of a CRT-P device and who separately fulfill the criteria for use of an ICD as recommended in NICE Technology Appraisal Guidance 95.” The latter criteria include wide QRS and poor LV function post-myocardial infarction. There is controversy over whether mechanical dyssynchrony is also required for the selection of patients for CRT. Considerable heterogeneity exists in the echocardiographic criteria adopted to define dyssynchrony, but a few small observational studies suggest that echocardiographic measurement of mechanical dyssynchrony may best identify patients who are likely to benefit from CRT.7 Further work is required in this area. What are the cost implications of using CRT-P and CRT-D? Based on data from the CARE-group using data from COMPANION, the incremental cost-effectiveness of CRT-P versus medical therapy was €7538 per quality-adjusted life-year (QALY), and the incremental cost-effectiveness of CRT-D versus CRT-P was €47 909.13 CRT-P was concluded to be relatively inexpensive, while CRT-D was of borderline cost-effectiveness. The patient's age comes into consideration in deciding who, among eligible patients, should receive CRT-D. In younger patients, CRT-D may be considered affordable in order to keep patients alive for as long as possible. In patients aged above 70 years, by contrast, other factors are more likely to cause death and the cost of CRT-D compared to CRT-P becomes prohibitive. The use of CRT in patients with atrial fibrillation (AF) is a contentious issue. The ESC guidelines do not specify a rhythm, but most other guidelines do specify the presence of sinus rhythm (SR) in their recommendations. Most trials have included only patients in SR, although the MUSTIC study included approximately equal numbers of patients in SR and AF. In MUSTIC, patients in SR improved significantly, whereas those in AF did not.4,8 For patients in SR, activation of the pacemaker was associated with an improvement in 6-min walking distance, which worsened when the device was inactivated. However, it is notable that only 37 of 64 patients in AF completed both limbs of the study. A long-term follow-up of patients in MUSTIC at 9 and 12 months found that all SR patients and 88% of AF patients were programmed to biventricular pacing.9 The two groups experienced similar magnitudes of improvement in walking distance, peak VO2, quality of life, NYHA class, and ejection fraction (Figure 6). Therefore, for every factor measured, AF patients appeared to do as well as SR patients in the long term. MUSTIC and some smaller studies represent the only trial evidence on which to base treatment in patients with AF. This raises the question of whether the potential benefits of CRT should be denied to AF patients in the absence of large-scale randomized studies. Opinions obtained from members of the Heart Rhythm UK suggest that most large centers are implanting CRT devices in a proportion of AF patients. There are two schools of thought on the type of AF patient who may benefit from CRT. In one school, CRT should be offered to the relatively small numbers of patients in whom rigorous rate control can be achieved by medical therapy and, if necessary, ablation of atrioventricular conduction to ensure biventricular pacing all of the time. According to the results of MUSTIC, this group may improve. This is called the “rate control” group. In the second school of thought, patients should be selected in whom stringent efforts will be made to restore and maintain SR. CRT may help by increasing the ejection fraction, lowering mitral regurgitation, and lowering left ventricular pressure. Cardioversion will be easier, and amiodarone and atrial catheter ablation may be added. This is called the “rhythm control” group. It is clear that the rate control group and the rhythm control groups encompass almost all patients with AF who fit CRT criteria. In other words, there is little agreement on which patients not to implant. Another controversial area is that, in every trial, there are patients classified as “non-responders”, who represent approximately 40% of the study population. In a proportion of these cases, however, the CRT device is stabilizing the patient who would otherwise deteriorate. Although the patient may complain of not feeling better, the device may actually be preventing deterioration or death. This situation illustrates the difficulty in measuring response. Other indices may need to be assessed, such brain natriuretic peptide levels, echocardiography/magnetic resonance imaging, and evidence of dyssynchrony, in order to identify patients who will benefit from CRT. CRT-D is an option in younger patients, especially those considered for future transplantation, while CRT-P may be provided in older patients to improve symptoms and reduce hospitalization. CRT-D may be considered in the presence of risk factors for sudden death, such as non-sustained ventricular tachycardia (VT) or T-wave alternans. The role of CRT-D in Class IV heart failure and AF requires clarification. Controversies that relate particularly to the use of implantable cardioverters-defibrillators (ICDs) include the identification of which patients will benefit from an ICD or from a CRT plus an ICD, whether the trial evidence for coronary artery disease can be extrapolated to dilated cardiomyopathy (DCM), and issues of deactivation at end of life. The ESC guidelines state that: “Implantation of an ICD in combination with biventricular pacing can be considered (my italics) in patients who remain symptomatic with severe heart failure (NYHA class III/IV) with LVEF [left ventricular ejection fraction] ≤35% and QRS duration >120 ms to improve morbidity or mortality”. “ICD therapy is recommended (my italics) to improve survival in patients who have survived cardiac arrest or who have sustained VT, which is either poorly tolerated or associated with reduced systolic LV function.” “ICD implantation is reasonable (my italics) in selected symptomatic patients with LVEF <30–35%, not within 40 days of a myocardial infarction, on optimal background therapy … to reduce sudden death.” The largest trial that has provided evidence to substantiate these statements is SCD-HeFT.1 SCD-HeFT randomized 2500 patients with symptomatic heart failure (NYHA II/III) and LVEF <35% to no antiarrhythmic therapy, amiodarone, or ICD with a 5-year follow-up. One half of the patients had an ischaemic etiology and one half had idiopathic DCM. Patients were relatively young (mean 60 years) and a proportion were overweight (mean 85 kg). Background medication use with an ACE inhibitor or angiotensin receptor blocker and beta-blocker was good, with rates approaching 90% and 80%, respectively, and use of spironolactone (31% at last follow-up) was reasonable. Loop diuretics were prescribed in the majority. Annual mortality over 5 years was 7.2% in the placebo group. Amiodarone had no influence on morality (hazard ratio [HR] 1.06. P = 0.529 vs placebo), but ICD significantly reduced the mortality rate (HR 0.77, P = 0.007 vs placebo) (Figure 7). Analysis of subgroups showed that the HR of mortality for ICD versus placebo was 0.54 in patients with NYHA II and 1.16 in those with NYHA class III, indicating that patients with Class II heart failure benefited while those with Class III tended to fare worse. Patients with an ischaemic or non-ischaemic etiology had HRs of 0.79 and 0.73, respectively, suggesting equal benefit from ICD. Further subgroup analyses indicated that patients with a low EF (≤30%) had the most to gain (HR 0.73, vs 1.08 for those with an EF >30%), as did those on beta-blocker therapy (HR 0.68, vs 0.92 for those not on beta-blocker therapy), which emphasizes that ICD therapy is not a substitute for good medical therapy. There have been problems in interpreting the outcomes of studies such as SCD-HeFT and MADIT-II.10 The reliance on subgroup analyses in these trials has reduced the power of these studies. Inaccuracies in measurement utilizing LVEF cutoff values and NYHA class has further hampered interpretation, and the relationship between the severity of the condition and the magnitude of improvement requires clarification. No “evidence base” exists on which to guide practice at end of life. Discussing these issues with the patient and relatives is difficult, but needs to be done openly and with sensitivity if any crisis or deterioration develops. Booklets and websites are a valuable source of information that patients can choose to look at, and base decisions on, at their own pace. In the UK, information for patients on websites is available from the British Heart Foundation (www.bhf.org) and the Arrhythmia Alliance (www.arrhythmiaalliance.org.uk). Primary prevention ICDs may be considered in stable heart failure patients who are already receiving optimal medical therapy. ICD should not be considered as a substitute for medical therapy. Ischaemic and non-ischaemic patients benefit equally from ICD, and the worse the LV function, the greater is the benefit. ICD may be considered as a bridge to transplant or, alternatively, as a means to keep the patient away from transplant.
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