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ORAL PRESENTATION

<i>Circulation: Arrhythmia and Electrophysiology</i> Editors’ Picks

Managing atrial fibrillation in the CRT patient: Controversy or consensus?

Can we predict, prevent, and minimize defibrillator shocks? Lessons learned from “remote monitoring”

More than 4000 patients have been evaluated in randomized controlled trials of cardiac resynchronization therapy (CRT). These studies have demonstrated that CRT with or without an implantable cardioverter-defibrillator (ICD) consistently improves quality of life, functional status, exercise capacity, and cardiac structure and function and reduces morbidity and mortality in heart failure patients with ventricular dyssynchrony. The magnitude of benefit seen with CRT is comparable to or exceeds that seen with evidence-based drug therapies for heart failure but occurs in patients who are already receiving such medications. Thus, CRT has been added to the list of evidence-based therapies that make heart failure patients feel better and live longer (the Table). Consequently, a strong ethical mandate exists for the use of CRT in heart failure. This mandate is reflected in our current practice guidelines for the management of chronic heart failure, which state that all eligible patients should receive CRT unless contraindicated.1,2 End of debate! CRT should be a routine part of any evidence-based treatment regimen for heart failure. View this table: Major Benefits of Evidence-Based Heart Failure Therapies Of course, things are never quite so simple, so let us take a look at the evidence supporting this clinical mandate for CRT and address patient selection, some of the limitations of CRT, and some of the unanswered questions about the use of CRT in heart failure. None of this discussion will lessen the role of CRT in the treatment of heart failure; rather, it will guide the selection of appropriate patients and speculate on the future application of CRT to an even broader group of heart failure patients. Response by Greenberg and Mehra p 2698 Approximately one third of patients with systolic heart failure exhibit ventricular dyssynchrony, defined as a QRS duration >120 ms on the surface ECG.3,4 Ventricular dyssynchrony produces suboptimal ventricular …

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.

Sex differences have the potential to impact diagnostic and therapeutic interventions in a wide variety of medical conditions, and cardiac arrhythmias are no exception.1 Studies evaluating pathophysiology, disease course, and therapeutic options for cardiac arrhythmias have been performed predominantly in male patients. However, catheter and device-based therapies coupled with landmark clinical trials have contributed to an improved understanding of this important aspect. The objective of this review is to present the current state of knowledge on sex differences in cardiac arrhythmias with a focus on clinical management, while highlighting gaps in knowledge that would benefit from future investigation. ### Atrial Fibrillation and Atrial Flutter #### Disease Burden Atrial fibrillation (AF) and atrial flutter (AFL) are the most commonly encountered tachyarrhythmias in clinical practice, with significant implications for public health and healthcare costs. Stroke, hospitalization, and loss of productivity are the major consequences of AF.2 The incidence of AF (per 1000 person-years) is reported to be between 1.6 and 2.7 in women and between 3.8 and 4.7 in men.2 The age-adjusted incidence and prevalence of AF is lower in women compared with that in men, and accordingly, the lifetime risk of AF from the Framingham Heart Study at 40 years of age was higher in men (26.0% for men versus 23.0% for women).3 Another analysis from the Framingham Heart Study demonstrated no significant sex differences in the risk of developing AFL.4 The prevalence of AF continues to rise among both men and women. In a study investigating the global burden of disease from 1980 to 2010, there was not only an increase in overall burden, incidence, and prevalence of AF, but most importantly an increase in AF-associated mortality in both men and women (Figure 1).5 The age-adjusted mortality for women was consistently higher compared with that for men from 1990 to 2010 (Figure …

Developed in Collaboration With the American Association for Thoracic Surgery, Heart Failure Society of America, and Society of Thoracic Surgeons

In This Issue: March.

Contemporary and future trends in cardiac resynchronization therapy to enhance response

▪ Abstract Atrial fibrillation is frequently disabling and resistant to antiarrhythmic drugs. Curative treatment by catheter-based ablation has been shown to be feasible either by achieving long linear lesions, mainly in the left atrium, or by targeting the initiating focus, most frequently in the pulmonary veins. This paper reviews the different ablation approaches, their results, potential complications, and relative merits.

Background: Cardiac resynchronization therapy (CRT) is known to improve left ventricular (LV) systolic function and symptoms of systolic heart failure. The effect of CRT on atrial fibrillation (AF) burden is less clarified. Methods: 18 patients mean age of 77 ± 11 (72% male) underwent CRT implantations. There were no changes to concomitant anti-arrhythmic medication and permanent AF patients were excluded. Echocardiograms were obtained six month before and after device implantation. LV ejection fraction (LVEF), LV end diastolic dimension (LVEDd), left atrial (LA) dimension, and magnitude of mitral regurgitation (MR) were measured by echocardiogram before and after CRT. The burden of AF was evaluated by 24-hour Holter monitoring before and by device arrhythmic log after implantation. There were no concomitant medication changes. The results were later divided into presence (Group I) and absence (Group II) of paroxysmal or persistent AF. No patient was in permanent AF at the time of CRT implantation. Results: LVEF improved after CRT in both groups. Patients with AF showed the most beneficial effects of LVEF with average improvement of 41% (P-value=0.004) in comparison to 13% improvement in patients without AF (P-value=0.044). The LVEDd was improved by 11.9% in patients with AF (P-value=0.01) while it was improved by only 5.6% in patients without AF (P-value=0.08). LA Dimension was decreased by 4.4% in patients with AF (P-value=0.038). MR was reduced on average from moderate to mild for both groups. The number of AF episodes and duration of the AF were also decreased in all of our AF patients. The pre and post effect of CRT in patients with and without AF is shown in the table below: Conclusions: The AF burden in patients who received CRT was significantly reduced. There were excellent correlations between improvement of LVEF, LVEDd, LA dimension, and AF burden. This may be due to LV and LA remodeling. Further studies need to elaborate the mechanisms of this finding.

His-bundle pacing is the best approach to physiological pacing.

A heat-treatment process for conditioning waxy crude oils, developed by Burmah Oil Co. and British Petroleum Co. Ltd., is used in the new 1.25 million ton Moran facility by Oil India Ltd. to make Assam crude pumpable during Indian winters. In the batch process used at the new facility, crude oil is initially heated in a vertical tube heater to 203/sup 0/-208/sup 0/F and then passed through a heat exchanger where it warms the incoming oil. After the crude oil cools to 149/sup 0/F, it passes into 14 conditioning vessels (treaters) where it is cooled under static conditions to about 64/sup 0/F at about 0.5/sup 0/-25/sup 0/F/min. The unit cost about $4 million to build and will cost about $0.15-$0.20/ton of crude oil to operate. Both capital and operating costs could be reduced by converting from batch to continuous operation, but pilot plant testing of the continuous process is still required.

In this issue, Al-Majed and colleagues report a systematic review of 25 trials that suggests that CRT benefits patients with reduced left ventricular ejection fraction, symptoms, and prolonged QRS ...