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Canadian Journal of Cardiology

Canadian Cardiovascular Society Guidelines on the Use of Cardiac Resynchronization Therapy: Evidence and Patient Selection

      Abstract

      Recent landmark trials provided the impetus to update the recommendations for cardiac resynchronization therapy (CRT). This article provides guidance on the prescription of CRT within the confines of published data. A future article will explore the implementation of these guidelines. These guidelines are intended to serve as a framework for the prescription of CRT within the Canadian health care system and beyond. They were developed through a critical evaluation of the existing literature, and expert consensus. The panel unanimously adopted each recommendation. The 8 recommendations relate to ensuring the adequacy of medical therapy before the initiation of CRT, the use of symptom severity to select candidates for CRT, differing recommendations based on the presence or absence of sinus rhythm, the presence of left bundle branch block vs other conduction patterns, and QRS duration. The use of CRT in the setting of chronic right ventricular pacing, left ventricular lead placement, and the routine assessment of dyssynchrony to guide the prescription of CRT are also included. The strength of evidence was weighed, taking full consideration of any risks of bias, as well as any imprecision, inconsistency, and indirectness of the available data. The strength of each recommendation and the quality of evidence were adjudicated. Trade-offs between desirable and undesirable consequences of alternative management strategies were considered, as were values, preferences, and resource availability. These guidelines were externally reviewed by experts, modified based on those reviews, and will be updated as new knowledge is acquired.

      Résumé

      Des essais novateurs récents ont stimulé la mise à jour des recommandations sur le traitement de resynchronisation cardiaque (TRC). Cet article fournit des lignes directrices sur la prescription de TRC dans les limites des données publiées. Un futur article explorera la mise en œuvre de ces lignes directrices. Ces lignes directrices sont destinées à servir de cadre à la prescription de TRC dans le système de soins de santé canadien et au-delà. Elles ont été développées par une évaluation critique de la littérature existante et le consensus des experts. Le panel a adopté unanimement chacune des recommandations. Les 8 recommandations visent à assurer l'adéquation du traitement médical avant le début du TRC, l'utilisation de la gravité des symptômes pour sélectionner les candidats au TRC, les diverses recommandations basées sur la présence ou l'absence de rythme sinusal, la présence de bloc de branche gauche par rapport à d'autres modèles de conduction et la durée du complexe QRS. L'utilisation du TRC dans le cadre de stimulation ventriculaire droite chronique, la pose de sonde ventriculaire gauche et l'évaluation systématique de la dyssynchronie pour orienter la prescription de TRC sont aussi incluses. La force des preuves a été pondérée, en tenant pleinement compte de tout risque de partialité, ainsi que de toute imprécision, toute incohérence et toute divergence des données disponibles. La force de chacune des recommandations et la qualité des preuves ont été soupesées. Les compromis entre les conséquences désirables et indésirables des autres stratégies de prise en charge ont été considérés, comme l'on été les valeurs, les préférences et la disponibilité des ressources. Ces lignes directrices ont été examinées à l'externe par des experts, modifiées selon ces revues, et seront mises à jour dès l'acquisition de nouvelles connaissances.

      Introduction

      Rationale for cardiac resynchronization therapy

      Heart failure affects more than 485,000 Canadians and results in significant morbidity and mortality.
      Public Health Agency of Canada
      Tracking Heart Disease and Stroke in Canada.
      Despite advances in medical therapy, patients with heart failure remain at high risk for death and hospitalization.
      Public Health Agency of Canada
      Tracking Heart Disease and Stroke in Canada.
      Dyssynchronous ventricular contraction affects 1 in 4 patients with systolic heart failure.
      • Ghio S.
      • Constantin C.
      • Klersy C.
      • et al.
      Interventricular and intraventricular dyssynchrony are common in heart failure patients, regardless of QRS duration.
      Cardiac resynchronization therapy (CRT) is designed to synchronize the mechanical activity of the ventricles, and the timing of the atria and ventricles among those in sinus rhythm. QRS duration, along with functional class and left ventricular ejection fraction (LVEF), are used to select candidates for CRT. Among selected patients, CRT has been shown to improve left ventricular (LV) function (reverse remodelling), reduce mitral regurgitation, enhance cardiac output, and reduce heart failure symptoms without increasing myocardial energy consumption.
      • Nelson G.S.
      • Berger R.D.
      • Fetics B.J.
      • et al.
      Left ventricular or biventricular pacing improves cardiac function at diminished energy cost in patients with dilated cardiomyopathy and left bundle-branch block [erratum in 2001;103:476].
      • Linde C.
      • Abraham W.T.
      • Gold M.R.
      • Daubert C.
      REVERSE Study Group
      Cardiac resynchronization therapy in asymptomatic or mildly symptomatic heart failure patients in relation to etiology: results from the REVERSE (REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction) study.
      Improved cardiac mechanical synchrony is thought to be central to the benefit of CRT.
      • Auricchio A.
      • Stellbrink C.
      • Sack S.
      • et al.
      Long-term clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay.
      • Salukhe T.V.
      • Francis D.P.
      • Morgan M.
      • et al.
      Mechanism of cardiac output gain from cardiac resynchronization therapy in patients with coronary artery disease or idiopathic dilated cardiomyopathy.
      Improved survival and reduced morbidity have been demonstrated among selected patients with systolic heart failure enrolled in large randomized trials of CRT.
      • Wells G.
      • Parkash R.
      • Healey J.S.
      • et al.
      Cardiac resynchronization therapy: a meta-analysis of randomized controlled trials.

      Updated guidelines

      The completion of several landmark trials provided the impetus to update the Canadian CRT recommendations.
      • Arnold J.M.
      • Liu P.
      • Demers C.
      • et al.
      Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: diagnosis and management.
      • Malcom J.
      • Arnold O.
      • Howlett J.G.
      • et al.
      Canadian Cardiovascular Society Consensus Conference guidelines on heart failure–2008 update: best practices for the transition of care of heart failure patients, and the recognition, investigation and treatment of cardiomyopathies.
      This document provides guidance on the prescription of CRT within the confines of published data. A subsequent publication will further explore the implementation of these guidelines. These guidelines are intended to serve as a framework for the prescription of CRT within the Canadian healthcare system and beyond. The intended audience for these documents includes specialist and generalist physicians and surgeons, allied professionals, and administrators involved in the care of patients with heart failure. These guidelines were developed through a critical evaluation of the existing literature, expert consensus, and use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system.
      • Guyatt G.
      • Oxman A.D.
      • Akl E.A.
      • et al.
      GRADE guidelines: 1 Introduction-GRADE evidence profiles and summary of findings tables.
      The strength of evidence was weighed, taking full consideration of any risks of bias, including publication bias, and any imprecision, inconsistency, and indirectness of the available data. The strength of each recommendation was categorized as “Strong” or “Weak (conditional),” and the quality of this evidence as “High,” “Moderate,” “Low,” or “Very Low.” The trade-off between desirable and undesirable consequences of alternative management strategies was considered, as were values, preferences, and resource availability. Valid systematic methods were used when possible, based on published evidence similar to previous guidelines.
      • Gillis A.M.
      • Skanes A.C.
      CCS Atrial Fibrillation Guidelines Committee
      Canadian Cardiovascular Society atrial fibrillation guidelines 2010: implementing GRADE and achieving consensus.
      These guidelines were externally reviewed by experts and modified, based on those reviews. The literature supporting each recommendation is discussed in the following sections. The committee's 8 recommendations are contained within the following sections and are summarized in Supplemental Table S1. The panel unanimously adopted each recommendation.

      Clinical Selection Criteria

      Clinical trials evaluating a new intervention for patients with heart failure typically require that it be assessed on a background of appropriate pharmacologic therapy. Thus, CRT is adjunct to, not a replacement of medical therapy. The prescription of CRT should typically only be considered in the setting of adequate background medical therapy for heart failure.
      • McKelvie R.S.
      • Moe G.W.
      • Cheung A.
      • et al.
      The 2011 Canadian Cardiovascular Society heart failure management guidelines update: focus on sleep apnea, renal dysfunction, mechanical circulatory support, and palliative care.
      All of the landmark trials of CRT required that patients receive adequate medical therapy before enrollment. Further, because New York Heart Association (NYHA) functional class, QRS duration, and LVEF are each central in deciding on the appropriateness of CRT, these data need to be based on objective assessment methods.

      Appropriate medical therapy

      Heart failure medications should be optimized to enhance the probability that CRT will be successful. For patients with NYHA II-IV functional class, this should include guideline-specified doses of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, β-blockers, and mineralocorticoid receptor antagonists for patients with class III-IV symptoms and those with NYHA II symptoms and high-risk features.
      • McKelvie R.S.
      • Moe G.W.
      • Cheung A.
      • et al.
      The 2011 Canadian Cardiovascular Society heart failure management guidelines update: focus on sleep apnea, renal dysfunction, mechanical circulatory support, and palliative care.
      A summary of medication use in selected trials is presented in Table 1.
      Table 1Baseline medication use in the major CRT trials (shown as percentages)
      Study (year)ACEi/ARBβ-BlockerMRADiuretic
      MedCRTCRT-DMedCRTCRT-DMedCRTCRT-DMedCRTCRT-D
      COMPANION (2004)
      • Bristow M.R.
      • Saxon L.A.
      • Boehmer J.
      • et al.
      Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.
      89899066559
      68357
      MedCRTMedCRTMedCRTMedCRT
      CARE-HF (2005)
      • Cleland J.G.
      • Daubert J.C.
      • Erdmann E.
      • et al.
      The effect of cardiac resynchronization on morbidity and mortality in heart failure.
      9595747059544443
      ICDCRT-DICDCRT-DICDCRT-DICDCRT-D
      MADIT-CRT (2009)
      • Moss A.J.
      • Hall W.J.
      • Cannom D.S.
      • et al.
      Cardiac-resynchronization therapy for the prevention of heart-failure events.
      9798939331327376
      ICDCRT-DICDCRT-DICDCRT-DICDCRT-D
      RAFT (2010)
      • Tang A.S.
      • Wells G.A.
      • Talajic M.
      • et al.
      Cardiac-resynchronization therapy for mild-to-moderate heart failure.
      9796899042428485
      ACEi/ARB, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker; CARE-HF, Cardiac Resynchronization in Heart Failure; COMPANION, Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure; CRT, cardiac resynchronization therapy; CRT-D, CRT plus implantable cardioverter-defibrillator; ICD, implantable cardioverter-defibrillator; MADIT-CRT, Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy; Med, medical therapy alone; MRA, mineralocorticoid receptor antagonist; RAFT, Resynchronization/Defibrillation for Ambulatory Heart Failure Trial.
      • 1
        It is recommended that adequate medical therapy be implemented before the initiation of CRT, that each patient's suitability for CRT be thoroughly assessed, and the details of that assessment be recorded in their medical record (Strong Recommendation, Low-Quality Evidence).
      Values and preferences. This recommendation places greater value on the landmark CRT trials; all of which required patients to receive optimal medical therapy at the time of enrollment.

      Practical tip

      Reasons for nonuse of recommended heart failure medications or the prescription of lower than the recommended doses of these medications should be recorded. Each patient's functional capacity should be assessed. Although measures of functional status other than the NYHA system have been proposed, the landmark trials solely used this as an inclusion criterion.
      • Wells G.
      • Parkash R.
      • Healey J.S.
      • et al.
      Cardiac resynchronization therapy: a meta-analysis of randomized controlled trials.
      Thus, at a minimum, assessment of functional class should include the patient's NYHA class. Six-minute hall walk distance, disease-specific health-related quality of life, and cardiopulmonary testing should also be considered. In addition, the QRS duration should be measured from a standard 12-lead electrocardiograph and the LVEF quantified using a validated assessment method. The results of these assessments should be recorded in the patient's medical record.

      Efficacy of CRT

      Assessing benefit

      Though CRT is efficacious on average, not all patients clearly benefit from this intervention. One challenge in assessing benefit from CRT is the lack of a common definition of response to CRT. Clinical response scores, LV remodelling, functional class, and clinical outcomes have all been used. Yet, there is poor correlation between these measures.
      • Fornwalt B.K.
      • Sprague W.W.
      • BeDell P.
      • et al.
      Agreement is poor among current criteria used to define response to cardiac resynchronization therapy.
      Further, lack of response to CRT by a given patient might relate to an absence of mechanical dyssynchrony, a failure to achieve adequate resynchronization, disease which has advanced too far, changes in a patient's underlying condition, other factors, or a combination of these elements.
      • Exner D.V.
      • Auricchio A.
      • Singh J.P.
      Contemporary and future trends in cardiac resynchronization therapy to enhance response.

      Randomized trial data

      Wells and colleagues performed a detailed systematic review and meta-analysis of CRT.
      • Wells G.
      • Parkash R.
      • Healey J.S.
      • et al.
      Cardiac resynchronization therapy: a meta-analysis of randomized controlled trials.
      This included 7539 patients enrolled in 12 trials, 4244 of whom were randomized to a CRT pacemaker (CRT-P) or CRT defibrillator (CRT-D) in addition to medical therapy, and 3295 patients assigned to medical therapy alone or in addition to an implantable cardioverter-defibrillator (ICD). These studies are summarized in Table 2. The length of follow up in these trials ranged from 3 to 40 months.
      • Wells G.
      • Parkash R.
      • Healey J.S.
      • et al.
      Cardiac resynchronization therapy: a meta-analysis of randomized controlled trials.
      Most (63%-89%) patients were male, their mean age ranged from 62 to 66 years, and a sizable percentage (38%-70%) had ischemic cardiomyopathy. The mean LVEF ranged from 21%-25%. Nearly all studies required patients to be in sinus rhythm and limited enrollment to patients with QRS durations ≥ 130 ms. Mean QRS durations of enrolled subjects were similar, ranging from 153-176 ms. Of the studies that reported conduction patterns, most patients had left bundle branch block (LBBB). Right bundle branch block (RBBB) was present in only 10%-16% of subjects (see Patient Selection section). Patients with severe pulmonary, renal, or liver disease, or an estimated survival less than 6-12 months were uniformly excluded. Thus, some patients are too ill, too frail, or have extensive comorbidities that preclude consideration of CRT. An in-depth discussion of these issues will be dealt with in a future publication related to implementation of these guidelines.
      Table 2Characteristics of the major CRT trials
      Study (year)Intervention/control Design Intervention (n)/control (n)QRS duration (msec); LVEF (%) at inclusionMean follow-up (mo)NYHA I-II (%) III-IV (%)Primary end point
      Lozano (2000)
      • Lozano I.
      • Bocchiardo M.
      • Achtelik M.
      • et al.
      Impact of biventricular pacing on mortality in a randomized crossover study of patients with heart failure and ventricular arrhythmias.
      CRT-D/ICD

      Crossover

      109/113
      >120; ≤35335

      65
      Mortality
      MUSTIC-SR (2001)
      • Cazeau S.
      • Leclercq C.
      • Lavergne T.
      • et al.
      Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay.
      CRT-P/Med

      Crossover

      29/29
      >150; <356100

      0
      Walk distance
      MIRACLE (2002)
      • Abraham W.T.
      • Fisher W.G.
      • Smith A.L.
      • et al.
      Cardiac resynchronization in chronic heart failure.
      CRT-P/Med

      Parallel

      228/225
      ≥130; ≤3560

      100
      NYHA, QOL, walk distance
      MIRACLE ICD (2003)
      • Young J.B.
      • Abraham W.T.
      • Smith A.L.
      • et al.
      Combined Cardiac Resynchronization and Implantable Cardioversion Defibrillation in Advanced Chronic Heart Failure: The MIRACLE ICD Trial.
      CRT-D/ICD

      Parallel

      187/182
      ≥130; ≤3560

      100
      QOL, NYHA, walk distance
      MIRACLE ICD II (2004)
      • Abraham W.T.
      • Young J.B.
      • León A.R.
      • et al.
      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.
      CRT-D/ICD

      Parallel

      85/101
      ≥130; ≤356100

      0
      Peak VO2
      COMPANION (2004)
      • Bristow M.R.
      • Saxon L.A.
      • Boehmer J.
      • et al.
      Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.
      CRT-D/CRT-P/ICD

      Parallel

      617/595/308
      ≥120; ≤3514.8-16.50

      100
      Mortality or all-cause hospitalization
      CARE-HF (2005)
      • Cleland J.G.
      • Daubert J.C.
      • Erdmann E.
      • et al.
      The effect of cardiac resynchronization on morbidity and mortality in heart failure.
      CRT-P/Med

      Parallel

      409/404
      ≥120 (120-149, dyssynchrony); ≤3529.40

      100
      Mortality or cardiovascular hospitalization
      REVERSE (2008)
      • Linde C.
      • Abraham W.T.
      • Gold M.R.
      • et al.
      Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms.
      CRT-D/ICD

      Parallel

      419/191
      ≥130; ≤4012100

      0
      Heart failure clinical composite
      RHYTHM-ICD
      US Food and Drug Administration
      Summary of Safety and Effectiveness Data. Dual Chamber Implantable Cardioverter Defibrillator (ICD) with Cardiac Resynchronization Therapy. St. Jude Medical Epic HF System including the Epic HF Model V-338 cardiac resynchronization therapy defibrillator, the Aescula LV model 1055K lead, the QuickSite LV model 1056K lead, and the model 3307, v4.5m programmer software.
      CRT-D/ICD

      Parallel

      119/59
      ≥150; ≤3512.18

      92
      LV lead/system complications; VF detection; peak VO2
      VECTOR
      US Food and Drug Administration
      Summary of Safety and Effectiveness Data. Cardiac Resynchronization Therapy - Pacemaker (CRT-P)System. St. Jude Medical Frontier model 5508L and Frontier II model 5586 cardiac resynchronization therapy pacemakers (CRT-P) supported on the model 3510 programmer platforms with the model 3307, v4.8m programmer software.
      CRT-P/Med

      Parallel

      59/47
      ≥140; ≤3519.929

      71
      Safety, rate of successful LV lead implant
      MADIT-CRT (2009)
      • Moss A.J.
      • Hall W.J.
      • Cannom D.S.
      • et al.
      Cardiac-resynchronization therapy for the prevention of heart-failure events.
      CRT-D/ICD

      Parallel

      1089/731
      ≥130; ≤3028.8100

      0
      Death or nonfatal heart failure event
      RAFT (2010)
      • Tang A.S.
      • Wells G.A.
      • Talajic M.
      • et al.
      Cardiac-resynchronization therapy for mild-to-moderate heart failure.
      CRT-D/ICD

      Parallel

      894/904
      ≥120 or paced ≥200; ≤304080

      20
      Death or heart failure hospitalization
      CARE-HF, Cardiac Resynchronization in Heart Failure; COMPANION, Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure; CRT, cardiac resynchronization therapy; CRT-D, CRT plus implantable cardioverter-defibrillator; CRT-P, CRT pacemaker; ICD, implantable cardioverter-defibrillator; LV, left ventricular; LVEF, LV ejection fraction; MADIT-CRT, Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy; Med, medical therapy alone; MIRACLE, Multicenter InSync ICD Randomized Clinical Evaluation; MUSTIC-SR, Multisite Stimulation in Cardiomyopathies Sinus Rhythm; NYHA, New York Heart Association; QOL, health-related quality of life; RAFT, Resynchronization/Defibrillation for Ambulatory Heart Failure Trial; REVERSE, Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction; RHYTHM-ICD, Resynchronization for Hemodynamic Treatment for Heart Failure Management - ICD; VO2, peak oxygen consumption; VECTOR, Ventricular Resynchronization Therapy Randomized Trial; VF, ventricular fibrillation.
      Very few patients who were asymptomatic at the time of enrollment (ie, NYHA class I) or with chronic, nonambulatory NYHA class IV symptoms (ie, end-stage heart failure requiring intravenous diuretic therapy, inotropic therapy, or intraaortic balloon-pump support) were included in the randomized CRT trials. Most studies also excluded patients with previous pacing therapy or permanent atrial fibrillation (AF). These latter 2 subgroups are discussed in the Patient Selection section. The primary end points of the CRT trials encompassed safety, functional status, 6-minute hall walk distance, health-related quality of life, peak oxygen consumption (VO2), along with hospitalizations and death.
      • Wells G.
      • Parkash R.
      • Healey J.S.
      • et al.
      Cardiac resynchronization therapy: a meta-analysis of randomized controlled trials.

      Sources of bias

      Biases were taken into account in assessing the quality of the evidence, in that studies with less bias were considered to represent a higher quality of evidence. Studies were examined using the Cochrane risk of bias tool.
      • Higgins J.P.
      • Altman D.G.
      • Gøtzsche P.C.
      • et al.
      The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.
      Most studies were double blind, with the exception of Cardiac Resynchronization in Heart Failure (CARE-HF),
      • Cleland J.G.
      • Daubert J.C.
      • Erdmann E.
      • et al.
      The effect of cardiac resynchronization on morbidity and mortality in heart failure.
      Comparison of Medical Therapy, Pacing and Defibrillation in Chronic Heart Failure (COMPANION),
      • Bristow M.R.
      • Saxon L.A.
      • Boehmer J.
      • et al.
      Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.
      Lozano et al.,
      • Lozano I.
      • Bocchiardo M.
      • Achtelik M.
      • et al.
      Impact of biventricular pacing on mortality in a randomized crossover study of patients with heart failure and ventricular arrhythmias.
      and Multisite Stimulation in Cardiomyopathies Sinus Rhythm (MUSTIC-SR).
      • Cazeau S.
      • Leclercq C.
      • Lavergne T.
      • et al.
      Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay.
      The 3 former studies, although not blinded, had end point evaluation performed by a blinded committee, and MUSTIC-SR was single-blinded. An important source of bias that is unique to CRT trials is that 8 trials randomized patients after the device was successfully implanted,
      • Lozano I.
      • Bocchiardo M.
      • Achtelik M.
      • et al.
      Impact of biventricular pacing on mortality in a randomized crossover study of patients with heart failure and ventricular arrhythmias.
      • Cazeau S.
      • Leclercq C.
      • Lavergne T.
      • et al.
      Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay.
      • Abraham W.T.
      • Fisher W.G.
      • Smith A.L.
      • et al.
      Cardiac resynchronization in chronic heart failure.
      • Young J.B.
      • Abraham W.T.
      • Smith A.L.
      • et al.
      Combined Cardiac Resynchronization and Implantable Cardioversion Defibrillation in Advanced Chronic Heart Failure: The MIRACLE ICD Trial.
      • Abraham W.T.
      • Young J.B.
      • León A.R.
      • et al.
      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.
      • Linde C.
      • Abraham W.T.
      • Gold M.R.
      • et al.
      Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms.
      US Food and Drug Administration
      Summary of Safety and Effectiveness Data. Dual Chamber Implantable Cardioverter Defibrillator (ICD) with Cardiac Resynchronization Therapy. St. Jude Medical Epic HF System including the Epic HF Model V-338 cardiac resynchronization therapy defibrillator, the Aescula LV model 1055K lead, the QuickSite LV model 1056K lead, and the model 3307, v4.5m programmer software.
      US Food and Drug Administration
      Summary of Safety and Effectiveness Data. Cardiac Resynchronization Therapy - Pacemaker (CRT-P)System. St. Jude Medical Frontier model 5508L and Frontier II model 5586 cardiac resynchronization therapy pacemakers (CRT-P) supported on the model 3510 programmer platforms with the model 3307, v4.8m programmer software.
      thereby introducing a systematic bias. Follow-up in several studies was less than 12 months,
      • Wells G.
      • Parkash R.
      • Healey J.S.
      • et al.
      Cardiac resynchronization therapy: a meta-analysis of randomized controlled trials.
      limiting conclusions with respect to the effect of CRT on mortality. This is of particular importance, as the 2 studies that demonstrated a mortality benefit with CRT, CARE-HF and ICD Resynchronization/Defibrillation for Ambulatory Heart Failure Trial (RAFT) noted a separation of survival curves beyond 1 year of follow-up. Finally, RAFT
      • Tang A.S.
      • Wells G.A.
      • Talajic M.
      • et al.
      Cardiac-resynchronization therapy for mild-to-moderate heart failure.
      and MUSTIC-SR
      • Cazeau S.
      • Leclercq C.
      • Lavergne T.
      • et al.
      Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay.
      were primarily funded by peer-reviewed granting agencies; the others were funded by industry.

      CRT pacemaker

      Data on the efficacy of CRT-P is available from 5 studies.
      • Bristow M.R.
      • Saxon L.A.
      • Boehmer J.
      • et al.
      Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.
      • Cleland J.G.
      • Daubert J.C.
      • Erdmann E.
      • et al.
      The effect of cardiac resynchronization on morbidity and mortality in heart failure.
      • Cazeau S.
      • Leclercq C.
      • Lavergne T.
      • et al.
      Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay.
      • Abraham W.T.
      • Fisher W.G.
      • Smith A.L.
      • et al.
      Cardiac resynchronization in chronic heart failure.
      US Food and Drug Administration
      Summary of Safety and Effectiveness Data. Dual Chamber Implantable Cardioverter Defibrillator (ICD) with Cardiac Resynchronization Therapy. St. Jude Medical Epic HF System including the Epic HF Model V-338 cardiac resynchronization therapy defibrillator, the Aescula LV model 1055K lead, the QuickSite LV model 1056K lead, and the model 3307, v4.5m programmer software.
      These trials were limited to symptomatic patients; those with NYHA class II, NYHA class III, or ambulatory NYHA class IV symptoms. Wells et al. noted a 27% significant relative risk reduction (RRR) in all-cause mortality when the studies were combined (P < 0.0001; RR, 0.73; 95% confidence interval [CI], 0.62-0.85) (Figure 1).
      • Wells G.
      • Parkash R.
      • Healey J.S.
      • et al.
      Cardiac resynchronization therapy: a meta-analysis of randomized controlled trials.
      CARE-HF and COMPANION provide the bulk of evidence in this group. These 2 larger studies, along with 3 smaller studies, uniformly found a significant reduction in heart failure hospitalizations, along with improvements in hall walk distance and health-related quality of life with CRT-P. Collectively, these studies provide high quality evidence for CRT-P in addition to medical therapy for patients with symptomatic heart failure, QRS durations ≥ 130 ms, and LVEF values ≤ 35%.
      Figure thumbnail gr1
      Figure 1Random effects model for overall mortality in patients treated with cardiac resynchronization therapy (CRT) plus medical therapy or CRT plus an implantable cardioverter-defibrillator (ICD) vs their comparators. Random effects meta-analysis of overall mortality among patients with mildly symptomatic (New York Heart Association I-II) and advanced (III-IV) heart failure treated with CRT added to medical therapy or with CRT added to ICD. Values less than 1.0 indicate decreased risk of mortality with CRT. CARE-HF, Cardiac Resynchronization in Heart Failure; COMPANION, Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure; MADIT-CRT, Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy; MIRACLE, Multicenter InSync ICD Randomized Clinical Evaluation; MUSTIC-SR, Multisite Stimulation in Cardiomyopathies Sinus Rhythm; RAFT, Resynchronization/Defibrillation for Ambulatory Heart Failure Trial; REVERSE, Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction; RHYTHM, Resynchronization for Hemodynamic Treatment for Heart Failure Management; VECTOR, Ventricular Resynchronization Therapy Randomized Trial.
      Adapted from Wells et al.
      • Wells G.
      • Parkash R.
      • Healey J.S.
      • et al.
      Cardiac resynchronization therapy: a meta-analysis of randomized controlled trials.

      CRT defibrillator

      The addition of CRT to ICD was evaluated in 7 studies.
      • Moss A.J.
      • Hall W.J.
      • Cannom D.S.
      • et al.
      Cardiac-resynchronization therapy for the prevention of heart-failure events.
      • Tang A.S.
      • Wells G.A.
      • Talajic M.
      • et al.
      Cardiac-resynchronization therapy for mild-to-moderate heart failure.
      • Lozano I.
      • Bocchiardo M.
      • Achtelik M.
      • et al.
      Impact of biventricular pacing on mortality in a randomized crossover study of patients with heart failure and ventricular arrhythmias.
      • Young J.B.
      • Abraham W.T.
      • Smith A.L.
      • et al.
      Combined Cardiac Resynchronization and Implantable Cardioversion Defibrillation in Advanced Chronic Heart Failure: The MIRACLE ICD Trial.
      • Abraham W.T.
      • Young J.B.
      • León A.R.
      • et al.
      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.
      US Food and Drug Administration
      Summary of Safety and Effectiveness Data. Dual Chamber Implantable Cardioverter Defibrillator (ICD) with Cardiac Resynchronization Therapy. St. Jude Medical Epic HF System including the Epic HF Model V-338 cardiac resynchronization therapy defibrillator, the Aescula LV model 1055K lead, the QuickSite LV model 1056K lead, and the model 3307, v4.5m programmer software.
      • Linde C.
      Cardiac resynchronization therapy in mild heart failure.
      These trials included a spectrum of heart failure severity, ranging from NYHA class I to IV. Wells et al. found a significant RR of 17% in mortality (P = 0.01; RRR, 0.83; 95% CI, 0.72-0.96) when these data were combined (Figure 2).
      • Wells G.
      • Parkash R.
      • Healey J.S.
      • et al.
      Cardiac resynchronization therapy: a meta-analysis of randomized controlled trials.
      Three trials considered less symptomatic patients, with NYHA class I/II limitation,
      • Moss A.J.
      • Hall W.J.
      • Cannom D.S.
      • et al.
      Cardiac-resynchronization therapy for the prevention of heart-failure events.
      • Abraham W.T.
      • Young J.B.
      • León A.R.
      • et al.
      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.
      • Linde C.
      Cardiac resynchronization therapy in mild heart failure.
      and 3 evaluated patients with more advanced symptoms, NYHA class III/IV.
      • Lozano I.
      • Bocchiardo M.
      • Achtelik M.
      • et al.
      Impact of biventricular pacing on mortality in a randomized crossover study of patients with heart failure and ventricular arrhythmias.
      • Young J.B.
      • Abraham W.T.
      • Smith A.L.
      • et al.
      Combined Cardiac Resynchronization and Implantable Cardioversion Defibrillation in Advanced Chronic Heart Failure: The MIRACLE ICD Trial.
      US Food and Drug Administration
      Summary of Safety and Effectiveness Data. Dual Chamber Implantable Cardioverter Defibrillator (ICD) with Cardiac Resynchronization Therapy. St. Jude Medical Epic HF System including the Epic HF Model V-338 cardiac resynchronization therapy defibrillator, the Aescula LV model 1055K lead, the QuickSite LV model 1056K lead, and the model 3307, v4.5m programmer software.
      RAFT spanned these groups.
      • Tang A.S.
      • Wells G.A.
      • Talajic M.
      • et al.
      Cardiac-resynchronization therapy for mild-to-moderate heart failure.
      In the 4 studies that evaluated the addition of CRT to ICD in patients with NYHA class I/II symptoms a 20% reduction in the risk of death was found (P = 0.02; RRR, 0.80; 95% CI, 0.67-0.96).
      • Moss A.J.
      • Hall W.J.
      • Cannom D.S.
      • et al.
      Cardiac-resynchronization therapy for the prevention of heart-failure events.
      • Tang A.S.
      • Wells G.A.
      • Talajic M.
      • et al.
      Cardiac-resynchronization therapy for mild-to-moderate heart failure.
      • Abraham W.T.
      • Young J.B.
      • León A.R.
      • et al.
      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.
      • Linde C.
      Cardiac resynchronization therapy in mild heart failure.
      Figure thumbnail gr2
      Figure 2Random-effects model for overall mortality in those treated with CRT-D vs an ICD alone, stratified by NYHA class. Random-effects meta-analysis of overall mortality with mildly symptomatic (NYHA I-II) and advanced (III-IV) heart failure treated with CRT-D vs an ICD. Values less than 1.0 indicate decreased risk of mortality with CRT. CRT, cardiac resynchronization therapy; CRT-D, CRT plus implantable cardioverter-defibrillator; ICD, implantable cardioverter-defibrillator; MADIT-CRT, Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy; MIRACLE, Multicenter InSync ICD Randomized Clinical Evaluation; NYHA, New York Heart Association; RAFT, Resynchronization/Defibrillation for Ambulatory Heart Failure Trial; REVERSE, Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction; RHYTHM, Resynchronization for Hemodynamic Treatment for Heart Failure Management.
      Adapted from Wells et al.
      • Wells G.
      • Parkash R.
      • Healey J.S.
      • et al.
      Cardiac resynchronization therapy: a meta-analysis of randomized controlled trials.
      Of the 2 most recent CRT trials, Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) was the smallest. It demonstrated improvements in the clinical composite response (19% vs 34%; P = 0.01) and LV remodelling.
      • Linde C.
      • Abraham W.T.
      • Gold M.R.
      • Daubert C.
      REVERSE Study Group
      Cardiac resynchronization therapy in asymptomatic or mildly symptomatic heart failure patients in relation to etiology: results from the REVERSE (REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction) study.
      The 2 larger recent studies, Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy (MADIT-CRT) and RAFT, were powered to evaluate clinical outcomes. They provide the most conclusive evidence for CRT in a less symptomatic population. Both demonstrated significant reductions in their primary end points. The primary outcome in MADIT-CRT was worsening heart failure, defined as nonfatal heart failure events that were responsive to outpatient intravenous diuretic therapy or heart failure medication adjustment during hospital stay.
      • Moss A.J.
      • Hall W.J.
      • Cannom D.S.
      • et al.
      Cardiac-resynchronization therapy for the prevention of heart-failure events.
      Patients assigned to CRT-D had a significantly lower (13.9%) risk of this outcome vs those randomized to an ICD alone (22.8%; P < 0.001). MADIT-CRT was stopped early, with an average follow-up of 29 months. The primary outcome in RAFT was all-cause death or hospitalization for heart failure. All-cause death was a secondary outcome.
      • Tang A.S.
      • Wells G.A.
      • Talajic M.
      • et al.
      Cardiac-resynchronization therapy for mild-to-moderate heart failure.
      The average follow-up in RAFT was 40 months. A lower risk of death or hospitalization for heart failure was observed in the group assigned to CRT-D (33%) vs an ICD alone (40%; P = 0.0002). The risk of death from any cause was also lower with CRT-D (34%) vs an ICD alone (45%) in RAFT (P = 0.003).

      No heart failure symptoms

      Adabag and colleagues performed a systematic review and meta-analysis of CRT in patients with asymptomatic and mildly symptomatic heart failure.
      • Adabag S.
      • Roukoz H.
      • Anand I.S.
      • Moss A.J.
      Cardiac resynchronization therapy in patients with minimal heart failure a systematic review and meta-analysis.
      Among patients who were free of symptoms at the time of enrollment (ie, NYHA class I) a nonsignificant 15% reduction in the risk of death and a 43% reduction (95% CI, 3%-66%) in the risk of death or hospitalization for heart failure was identified.
      • Adabag S.
      • Roukoz H.
      • Anand I.S.
      • Moss A.J.
      Cardiac resynchronization therapy in patients with minimal heart failure a systematic review and meta-analysis.
      Considering the present lack of clear evidence, there is not sufficient evidence to recommend CRT for patients without heart failure symptoms (NYHA class I).

      Minimally symptomatic heart failure

      In patients with mild symptoms, NYHA class II, Adabag et al. found a 22% reduction (95% CI, 4%-35%) in the risk of death and a 33% reduction (95% CI, 21%-43%) in the risk of hospitalization for heart failure.
      • Adabag S.
      • Roukoz H.
      • Anand I.S.
      • Moss A.J.
      Cardiac resynchronization therapy in patients with minimal heart failure a systematic review and meta-analysis.
      In absolute terms, 28 patients with NYHA class II limitation would need to be treated with CRT to prevent 1 death and 2 admissions for heart failure during a period of 28 months.

      Symptomatic heart failure

      Four studies assessed the efficacy of CRT-D vs ICD on mortality in highly symptomatic patients (NYHA class III or ambulatory NYHA class IV).
      • Tang A.S.
      • Wells G.A.
      • Talajic M.
      • et al.
      Cardiac-resynchronization therapy for mild-to-moderate heart failure.
      • Lozano I.
      • Bocchiardo M.
      • Achtelik M.
      • et al.
      Impact of biventricular pacing on mortality in a randomized crossover study of patients with heart failure and ventricular arrhythmias.
      • Young J.B.
      • Abraham W.T.
      • Smith A.L.
      • et al.
      Combined Cardiac Resynchronization and Implantable Cardioversion Defibrillation in Advanced Chronic Heart Failure: The MIRACLE ICD Trial.
      US Food and Drug Administration
      Summary of Safety and Effectiveness Data. Dual Chamber Implantable Cardioverter Defibrillator (ICD) with Cardiac Resynchronization Therapy. St. Jude Medical Epic HF System including the Epic HF Model V-338 cardiac resynchronization therapy defibrillator, the Aescula LV model 1055K lead, the QuickSite LV model 1056K lead, and the model 3307, v4.5m programmer software.
      In this group, Wells et al. demonstrated a nonsignificant reduction of 14% in the risk of death (P = 0.17).
      • Wells G.
      • Parkash R.
      • Healey J.S.
      • et al.
      Cardiac resynchronization therapy: a meta-analysis of randomized controlled trials.
      This result, in conjunction with the evidence of benefit with CRT-P provides support for the use of CRT in this population. Considering these marginal results with CRT-D, its use in this group needs to be viewed in terms of the likelihood of benefit vs risk. There is not sufficient evidence to recommend CRT-D for patients with chronic, nonambulatory NYHA class IV symptoms considering the lack of data.

      Risk vs benefit

      Cardiac rhythm devices carry risk at the time of their implantation and over the long-term. The population evaluated for CRT therapy and the complexity of a CRT implant both need to be considered. This is particularly relevant when considering the potential added complexity of upgrading a patient with an existing cardiac rhythm device to CRT.
      Adabag et al. summarized the risks associated with mostly de novo CRT implants and identified a 30-day adverse event rate of over 18% with CRT vs 4% with an ICD alone.
      • Adabag S.
      • Roukoz H.
      • Anand I.S.
      • Moss A.J.
      Cardiac resynchronization therapy in patients with minimal heart failure a systematic review and meta-analysis.
      Most of these excess adverse events were related to LV lead dislodgment (5.1%) and implant failure (6.6%). In addition, the risks of repeated intervention might be significant in CRT recipients. For example, a large registry reported that complications related to pulse generator replacements, with or without lead revision, were significantly higher with CRT vs non-CRT procedures.
      • Poole J.E.
      • Gleva M.J.
      • Mela T.
      • et al.
      Complication rates associated with pacemaker or implantable cardioverter-defibrillator generator replacements and upgrade procedures: results from the REPLACE registry.
      Though the noted advantages of CRT vs its comparators accounts for these risks in the near term, there is a lack of data on long-term outcomes. Hence, the application of CRT requires a thoughtful weighing of risks vs benefits in an individual patient.
      Clinical risk scores have been promoted as a means of identifying patients less likely to benefit from arrhythmia device therapy, notably the very elderly, patients with very advanced symptoms of heart failure, and those with chronic renal failure.
      • Barsheshet A.
      • Moss A.J.
      • Huang D.T.
      • McNitt S.
      • Zareba W.
      • Goldenberg I.
      Applicability of a risk score for prediction of the long-term (8-year) benefit of the implantable cardioverter-defibrillator.
      • Kramer D.B.
      • Friedman P.A.
      • Kallinen L.M.
      • et al.
      Development and validation of a risk score to predict early mortality in recipients of implantable cardioverter-defibrillators.
      • van Rees J.B.
      • Borleffs C.J.
      • van Welsenes G.H.
      • et al.
      Clinical prediction model for death prior to appropriate therapy in primary prevention implantable cardioverter defibrillator patients with ischaemic heart disease: the FADES risk score.
      • Sheldon R.
      • Connolly S.
      • Krahn A.
      • Roberts R.
      • Gent M.
      • Gardner M.
      Identification of patients most likely to benefit from implantable cardioverter-defibrillator therapy: the Canadian Implantable Defibrillator Study.
      • Exner D.V.
      • Sheldon R.S.
      • Pinski S.L.
      • Kron J.
      • Hallstrom A.
      Do baseline characteristics accurately discriminate between patients likely versus unlikely to benefit from implantable defibrillator therapy? Evaluation of the Canadian implantable defibrillator study implantable cardioverter defibrillatory efficacy score in the antiarrhythmics versus implantable defibrillators trial.
      • Moss A.J.
      • Fadl Y.
      • Zareba W.
      • Cannom D.S.
      • Hall W.J.
      Defibrillator Implantation Trial Research Group
      Survival benefit with an implanted defibrillator in relation to mortality risk in chronic coronary heart disease.
      However, none of these risk scores have been independently validated and there are no randomized data to guide clinical decision-making. Further, patients with advanced heart failure symptoms who undergo CRT might have a significant improvement in their heart failure symptoms and this might alter their long-term prognosis and perspective related to preventing sudden death.
      • 2
        CRT is recommended for patients in sinus rhythm with NYHA class II, NYHA class III, or ambulatory NYHA class IV heart failure symptoms, a LVEF ≤ 35%, and QRS duration ≥ 130 ms because of LBBB (Strong Recommendation, High-Quality Evidence).
      Values and preferences. This recommendation places great value on the inclusion criteria of the landmark CRT trials, the characteristics of the patients enrolled in these trials, and the derived benefit of CRT in patient groups identified in subsequent analyses of these landmark trials.

      Practical tip

      There is insufficient evidence to recommend CRT in patients with NYHA class I limitation or for nonambulatory class IV NYHA symptoms because these patients were largely not included in the major CRT studies. For this same reason, there is insufficient data to recommend CRT in patients with QRS durations < 130 ms. Patients with LBBB and QRS duration ≥ 150 ms appear more likely to benefit from CRT than patients with non-LBBB conduction and/or less QRS prolongation (see the Patient Selection section).

      Delivery of CRT

      CRT-P vs CRT-D

      Significant geographic variation in CRT-P vs CRT-D prescription exists, with CRT-D accounting for > 70% of CRT systems.
      • Bogale N.
      • Priori S.
      • Gitt A.
      • et al.
      The European cardiac resynchronization therapy survey: patient selection and implantation practice vary according to centre volume.
      This is likely because of the fact that most patients who qualify for CRT meet the criteria for a primary prevention ICD.
      • McKelvie R.S.
      • Moe G.W.
      • Cheung A.
      • et al.
      The 2011 Canadian Cardiovascular Society heart failure management guidelines update: focus on sleep apnea, renal dysfunction, mechanical circulatory support, and palliative care.
      Only sparse data on the relative benefit of the 2 CRT platforms exist.
      • Dickstein K.
      • Vardas P.E.
      • Auricchio A.
      • et al.
      2010 Focused Update of ESC Guidelines on device therapy in heart failure: an update of the 2008 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC guidelines for cardiac and resynchronization therapy Developed with the special contribution of the Heart Failure Association and the European Heart Rhythm Association.
      COMPANION evaluated the efficacy of CRT-P and CRT-D.
      • Bristow M.R.
      • Saxon L.A.
      • Boehmer J.
      • et al.
      Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.
      The primary end point was all-cause death or hospitalization. The secondary end point was mortality. CRT-P and CRT-D similarly reduced the primary end point (CRT-P hazard ratio [HR], 0.81; P = 0.014; and CRT-D HR, 0.80; P = 0.01) and the risk of death or hospitalization for heart failure (CRT-P HR, 0.66; P < 0.002; and CRT-D HR, 0.60; P < 0.001). In contrast, CRT-D reduced the risk of death significantly (HR, 0.64; P = 0.003), and only a trend toward a reduction was observed with CRT-P (HR, 0.76; P = 0.059). CARE-HF included only CRT-P.
      • Cleland J.G.
      • Daubert J.C.
      • Erdmann E.
      • et al.
      The effect of cardiac resynchronization on morbidity and mortality in heart failure.
      After a mean follow-up of 29.4 months, the primary end point (all-cause death or hospitalization for heart failure) was significantly reduced with CRT-P (HR, 0.73; P < 0.001), as was the secondary outcome of all-cause death (HR, 0.74; P < 0.002). These reductions are comparable with those observed in COMPANION. However, 7% of the patients randomized to CRT-P in CARE-HF died suddenly. It is unclear whether some of these deaths would have been prevented by CRT-D. MADIT-CRT and RAFT only included patients treated with an ICD.
      Cost effectiveness should also be considered. CRT-P is generally considered to be more cost effective than CRT-D. Based on present exchange rates, 1 analysis found that the incremental cost effectiveness ratio for CRT-P was CAD$13,900 (11,200 €) per quality-adjusted life year (QALY) vs CAD$38,400 (30,900 €) per QALY for CRT-D.
      • Neyt M.
      • Stroobandt S.
      • Obyn C.
      • et al.
      Cost-effectiveness of cardiac resynchronisation therapy for patients with moderate-to-severe heart failure: a lifetime Markov model.
      In another analysis the incremental cost effectiveness for CRT-D over CRT-P was CAD$59,500 (47,900 €) per QALY.
      • Owen A.
      Cost-effectiveness of cardiac resynchronization therapy: results from the CARE-HF trial.
      • Yao G.
      • Freemantle N.
      • Calvert M.J.
      • Bryan S.
      • Daubert J.C.
      • Cleland J.G.
      The long-term cost-effectiveness of cardiac resynchronization therapy with or without an implantable cardioverter-defibrillator.
      A factual and comprehensive discussion with the patient as to the choice of CRT-P vs CRT-D is necessary.
      • Exner D.V.
      • Auricchio A.
      • Singh J.P.
      Contemporary and future trends in cardiac resynchronization therapy to enhance response.
      This should take into consideration the patient's estimated life expectancy, comorbidities, expectations, beliefs regarding quality vs quantity of life, and the differential risks of CRT-D vs CRT-P over the long-term. CRT-P has been shown to improve survival, reduce morbidity, and enhance quality of life in patients with symptomatic heart failure. In fact, much of the data on the effect of CRT in these patients is based on CRT-P, rather than CRT-D.
      • 3
        A CRT-P is recommended for patients who are suitable for resynchronization therapy, but not for an ICD (Strong Recommendation, Moderate-Quality Evidence).
      Values and preferences. This recommendation places a greater value on quality of life and improvement of heart failure symptoms, rather than prevention of sudden death.

      Practical tip

      CRT-P has been shown to reduce morbidity and mortality in patients with NYHA class III and ambulatory class IV heart failure symptoms. Therapy should be individualized in accordance with the overall goals of care.

      Lead placement

      Most studies have delivered CRT via biventricular pacing.
      • Bristow M.R.
      • Saxon L.A.
      • Boehmer J.
      • et al.
      Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.
      • Cleland J.G.
      • Daubert J.C.
      • Erdmann E.
      • et al.
      The effect of cardiac resynchronization on morbidity and mortality in heart failure.
      • Moss A.J.
      • Hall W.J.
      • Cannom D.S.
      • et al.
      Cardiac-resynchronization therapy for the prevention of heart-failure events.
      • Tang A.S.
      • Wells G.A.
      • Talajic M.
      • et al.
      Cardiac-resynchronization therapy for mild-to-moderate heart failure.
      • Abraham W.T.
      • Fisher W.G.
      • Smith A.L.
      • et al.
      Cardiac resynchronization in chronic heart failure.
      There are no reliable published data regarding the optimal right ventricular (RV) lead position.
      • Riedlbauchová L.
      • Cihák R.
      • Bytesník J.
      • et al.
      Optimization of right ventricular lead position in cardiac resynchronisation therapy.
      • Bulava A.
      • Lukl J.
      Similar long-term benefits conferred by apical versus mid-septal implantation of the right ventricular lead in recipients of cardiac resynchronization therapy systems.
      • Haghjoo M.
      • Bonakdar H.R.
      • Jorat M.V.
      • et al.
      Effect of right ventricular lead location on response to cardiac resynchronization therapy in patients with end-stage heart failure.
      • Khan F.Z.
      • Salahshouri P.
      • Duehmke R.
      • et al.
      The impact of the right ventricular lead position on response to cardiac resynchronization therapy.
      • Stockinger J.
      • Staier K.
      • Schiebeling-Römer J.
      • Keyl C.
      Acute hemodynamic effects of right and left ventricular lead positions during the implantation of cardiac resynchronization therapy defibrillators.
      • Kristiansen H.M.
      • Vollan G.
      • Hovstad T.
      • Keilegavlen H.
      • Faerestrand S.
      A randomized study of haemodynamic effects and left ventricular dyssynchrony in right ventricular apical vs. high posterior septal pacing in cardiac resynchronization therapy.
      • Thébault C.
      • Donal E.
      • Meunier C.
      • et al.
      Sites of left and right ventricular lead implantation and response to cardiac resynchronization therapy observations from the REVERSE trial.
      Rather, its position is based on other considerations such as lead performance (pacing, sensing, and defibrillation), potential interaction with existing leads, and future removal.
      There is significant variability in what defines an optimal LV lead position.
      • Stockinger J.
      • Staier K.
      • Schiebeling-Römer J.
      • Keyl C.
      Acute hemodynamic effects of right and left ventricular lead positions during the implantation of cardiac resynchronization therapy defibrillators.
      • Derval N.
      • Steendijk P.
      • Gula L.J.
      • et al.
      Optimizing hemodynamics in heart failure patients by systematic screening of left ventricular pacing sites: the lateral left ventricular wall and the coronary sinus are rarely the best sites.
      Various methods have been proposed to identify the optimal site for LV pacing, but no approach has been proven most effective.
      • Bedi M.
      • Suffoletro M.
      • Tanabe M.
      • Gorcsan J.
      • Saba S.
      Effect of concordance between sites of left ventricular pacing and dyssynchrony on acute electrocardiographic and echocardiographic parameters in patients with heart failure undergoing cardiac resynchronization therapy.
      • Merchant F.M.
      • Heist E.K.
      • McCarty D.
      • et al.
      Impact of segmental left ventricle lead position on cardiac resynchronization therapy outcomes.
      • Becker M.
      • Kramann R.
      • Franke A.
      • et al.
      Impact of left ventricular lead position in cardiac resynchronization therapy on left ventricular remodelling A circumferential strain analysis based on 2D echocardiography.
      • Ypenburg C.
      • van Bommel R.J.
      • Delgado V.
      • et al.
      Optimal left ventricular lead position predicts reverse remodeling and survival after cardiac resynchronization therapy.
      • Becker M.
      • Altiok E.
      • Ocklenburg C.
      • et al.
      Analysis of LV lead position in cardiac resynchronization therapy using different imaging modalities.
      • Nakamae H.
      • Tsumura K.
      • Hino M.
      • Hayashi T.
      • Tatsumi N.
      QT dispersion as a predictor of acute heart failure after high-dose cyclophosphamide.
      Analysis of LV lead position in MADIT-CRT found no difference in clinical outcome based on lead position, apart from poorer outcomes in patients with LV leads placed in an apical region. Thus, pacing the LV from a nonapical LV epicardial region should be considered.
      • Thébault C.
      • Donal E.
      • Meunier C.
      • et al.
      Sites of left and right ventricular lead implantation and response to cardiac resynchronization therapy observations from the REVERSE trial.
      • Singh J.P.
      • Klein H.U.
      • Huang D.T.
      • et al.
      Left ventricular lead position and clinical outcome in the multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT) trial.
      It is recognized that coronary venous anatomy, pacing thresholds, and phrenic nerve stimulation might limit LV lead placement in a specific region and that correlation between various imaging methods and standard radiography is imperfect.
      • Kumar P.
      • Blendea D.
      • Nandigam V.
      • Moore S.A.
      • Heist E.K.
      • Singh J.P.
      Assessment of the post-implant final left ventricular lead position: a comparative study between radiographic and angiographic modalities.
      • Rickard J.
      • Ingelmo C.
      • Sraow D.
      • et al.
      Chest radiography is a poor predictor of left ventricular lead position in patients undergoing cardiac resynchronization therapy: comparison with multidetector computed tomography.
      One smaller randomized study found that LV pacing at a site of late mechanical activation resulted in greater LV remodelling vs placing an LV lead at a standard position.
      • Khan F.Z.
      • Virdee M.S.
      • Palmer C.R.
      • et al.
      Targeted left ventricular lead placement to guide cardiac resynchronization therapy: the TARGET study: a randomized, controlled trial.
      Though targeted LV lead placement, where feasible, might be of benefit, additional data are required to support this notion.
      • 4
        In patients treated with CRT, pacing from a nonapical LV epicardial region might be considered (Weak Recommendation, Low-Quality Evidence).
      Values and preferences. This recommendation places great value on the quality of the evidence.

      Patient Selection

      Sex

      Data from multicentre studies evaluating the effects of sex on CRT benefit have been contradictory. COMPANION and CARE-HF found similar benefit in women and men,
      • Cleland J.G.
      • Daubert J.C.
      • Erdmann E.
      • et al.
      The effect of cardiac resynchronization on morbidity and mortality in heart failure.
      • Saxon L.A.
      • Bristow M.R.
      • Boehmer J.
      • et al.
      Predictors of sudden cardiac death and appropriate shock in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Trial.
      and REVERSE, RAFT, and MADIT-CRT suggested greater benefit in women than in men.
      • Linde C.
      • Abraham W.T.
      • Gold M.R.
      • Daubert C.
      REVERSE Study Group
      Cardiac resynchronization therapy in asymptomatic or mildly symptomatic heart failure patients in relation to etiology: results from the REVERSE (REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction) study.
      • Moss A.J.
      • Hall W.J.
      • Cannom D.S.
      • et al.
      Cardiac-resynchronization therapy for the prevention of heart-failure events.
      • Tang A.S.
      • Wells G.A.
      • Talajic M.
      • et al.
      Cardiac-resynchronization therapy for mild-to-moderate heart failure.
      In most studies female patients were more likely to have nonischemic cardiomyopathy and LBBB, which might explain these differences. However, additional explanations have been proposed, including that QRS duration is, on average, 10 ms shorter in women vs men. Thus, for a given QRS duration, women might have more conduction disturbance and greater cardiac dyssynchrony vs men.
      • Arshad A.
      • Moss A.J.
      • Foster E.
      • et al.
      Cardiac resynchronization therapy is more effective in women than in men: the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy) trial.

      QRS duration

      Sipahi et al. performed a systematic review and meta-analysis of data from 5 randomized trials, totaling 5813 patients.
      • Sipahi I.
      • Carrigan T.P.
      • Rowland D.Y.
      • Stambler B.S.
      • Fang J.C.
      Impact of QRS duration on clinical event reduction with cardiac resynchronization therapy: meta-analysis of randomized controlled trials.
      Patients were dichotomized to those with moderately vs severely prolonged QRS durations. This analysis was hampered by a lack of standardization between studies. For example, the QRS duration used to subdivide the patients in RAFT was 150 ms,
      • Tang A.S.
      • Wells G.A.
      • Talajic M.
      • et al.
      Cardiac-resynchronization therapy for mild-to-moderate heart failure.
      while it was 160 ms in CARE-HF.
      • Cleland J.G.
      • Daubert J.C.
      • Erdmann E.
      • et al.
      The effect of cardiac resynchronization on morbidity and mortality in heart failure.
      Nonetheless, consistency across the trials was identified, with a 40% reduction in clinical events with CRT among those with more prolonged QRS durations (P < 0.001). A consistent, differential response across NYHA classes was also observed. Because patient level data were not used, the interaction between QRS morphology and duration could not be assessed. These data indicate that patients with LBBB and a QRS duration ≥ 150 ms appear more likely to benefit from CRT.

      AF

      Approximately 15% of patients with heart failure who receive an ICD have a history of AF.
      • Bardy G.H.
      • Lee K.L.
      • Mark D.B.
      • et al.
      Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure [erratum in 2005;352:2146].
      These patients have reduced survival and more advanced symptoms of heart failure as compared with patients without AF.
      • Dries D.L.
      • Exner D.V.
      • Gersh B.J.
      • Domanski M.J.
      • Waclawiw M.A.
      • Stevenson L.W.
      Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials Studies of Left Ventricular Dysfunction.
      • Pozzoli M.
      • Cioffi G.
      • Traversi E.
      • Pinna G.D.
      • Cobelli F.
      • Tavazzi L.
      Predictors of primary atrial fibrillation and concomitant clinical and hemodynamic changes in patients with chronic heart failure: a prospective study in 344 patients with baseline sinus rhythm.
      • Crijns H.J.
      • Tjeerdsma G.
      • de Kam P.J.
      • et al.
      Prognostic value of the presence and development of atrial fibrillation in patients with advanced chronic heart failure.
      Further, approximately 25% of patients who undergo CRT have a history of AF.
      • Bogale N.
      • Priori S.
      • Gitt A.
      • et al.
      The European cardiac resynchronization therapy survey: patient selection and implantation practice vary according to centre volume.
      Yet, fewer than 5% of the patients enrolled in the aforementioned randomized trials of CRT had permanent AF.
      • Wells G.
      • Parkash R.
      • Healey J.S.
      • et al.
      Cardiac resynchronization therapy: a meta-analysis of randomized controlled trials.
      In fact, only 2 of the trials included patients with chronic AF.
      • Tang A.S.
      • Wells G.A.
      • Talajic M.
      • et al.
      Cardiac-resynchronization therapy for mild-to-moderate heart failure.
      • Leclercq C.
      • Walker S.
      • Linde C.
      • et al.
      Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with chronic atrial fibrillation.
      Thus, the efficacy of CRT in patients with permanent AF is less certain.
      It is unclear if patients without regular, organized atrial activity derive the same benefit from CRT, as atrioventricular (AV) timing appears important for the response to CRT.
      • Mullens W.
      • Grimm R.A.
      • Verga T.
      • et al.
      Insights from a cardiac resynchronization optimization clinic as part of a heart failure disease management program.
      • Ritter P.
      • Padeletti L.
      • Gillio-Meina L.
      • Gaggini G.
      Determination of the optimal atrioventricular delay in DDD pacing Comparison between echo and peak endocardial acceleration measurements.
      Moreover, even moderately rapid ventricular rates during AF might lead to a significant reduction in biventricular pacing, further reducing the potential benefit of CRT.
      • Hayes D.L.
      • Boehmer J.P.
      • Day J.D.
      • et al.
      Cardiac resynchronization therapy and the relationship of percent biventricular pacing to symptoms and survival.
      Observational studies suggest that the benefits of CRT are reduced among patients with a history of AF vs those without such a history.
      • Wilton S.B.
      • Leung A.A.
      • Ghali W.A.
      • Faris P.
      • Exner D.V.
      Outcomes of cardiac resynchronization therapy in patients with versus those without atrial fibrillation: a systematic review and meta-analysis.
      Moreover, the benefits of CRT appear greatest in patients with ≥95% biventricular pacing.
      • Gasparini M.
      • Auricchio A.
      • Metra M.
      • et al.
      Long-term survival in patients undergoing cardiac resynchronization therapy: the importance of performing atrio-ventricular junction ablation in patients with permanent atrial fibrillation.
      AV junctional ablation might be necessary to achieve this. Importantly, though device counters are often used to estimate the percent of biventricular pacing, these data might be unreliable in patients with permanent AF.
      • Kamath G.S.
      • Cotiga D.
      • Koneru J.N.
      • et al.
      The utility of 12-lead Holter monitoring in patients with permanent atrial fibrillation for the identification of nonresponders after cardiac resynchronization therapy.
      RAFT, the largest randomized evaluation of CRT in patients with permanent AF, failed to show a significant improvement in clinical outcomes, quality of life, or hall walk distance with CRT-D vs an ICD alone in these patients.
      • Healey J.S.
      • Hohnloser S.H.
      • Exner D.V.
      • et al.
      Cardiac resynchronization therapy in patients with permanent atrial fibrillation: results from the Resynchronization for Ambulatory Heart Failure Trial (RAFT).
      However, only one-third of patients with AF assigned to CRT-D in RAFT received ≥ 95% ventricular pacing and only 1 patient underwent an AV junctional ablation. A pooled analysis of 3 observational studies found a 60% reduction in the rate of nonresponse to CRT in CRT-treated patients who did vs did not undergo of AV junctional ablation.
      • Wilton S.B.
      • Leung A.A.
      • Ghali W.A.
      • Faris P.
      • Exner D.V.
      Outcomes of cardiac resynchronization therapy in patients with versus those without atrial fibrillation: a systematic review and meta-analysis.
      Moreover, an observational study of CRT-treated patients with permanent AF reported lower annual mortality rate among CRT-treated patients with permanent AF who did (4.3%) vs did not (15.2%) undergo AV junctional ablation (P < 0.001).
      • Gasparini M.
      • Auricchio A.
      • Metra M.
      • et al.
      Long-term survival in patients undergoing cardiac resynchronization therapy: the importance of performing atrio-ventricular junction ablation in patients with permanent atrial fibrillation.
      At present, randomized trial evidence supporting the use of CRT in patients with permanent AF is not conclusive. Additional trials are needed to determine the efficacy of CRT among these patients and how best to deliver CRT in this population. Until such data are available, CRT might be considered for patients in permanent AF who are otherwise suitable for this therapy. If CRT is undertaken in these patients it is important to ensure that a very high percentage of biventricular pacing is achieved.
      • 5
        CRT may be considered for patients in permanent AF who are otherwise suitable for this therapy (Weak Recommendation, Low-Quality Evidence).
      Values and preferences. This recommendation places great value on the inclusion criteria of the landmark trials, the characteristics of the patients enrolled, the derived benefit of CRT in patients with permanent AF, and the quality of the evidence.

      Practical tip

      The amount of biventricular pacing needs to be evaluated. Arrhythmia device counters alone might not accurately reflect the true percent of biventricular pacing. It is important to ensure a very high percentage of biventricular pacing. AV junctional ablation might be necessary to achieve sufficient biventricular pacing.

      Electrocardiographic morphology

      A sizable proportion of patients being treated with CRT have RBBB, a nonspecific intraventricular conduction delay, or only a moderate prolongation in QRS duration (ie, QRS width < 140 ms).
      • Bilchick K.C.
      • Kamath S.
      • DiMarco J.P.
      • Stukenborg G.J.
      Bundle-branch block morphology and other predictors of outcome after cardiac resynchronization therapy in Medicare patients.
      • Bogale N.
      • Priori S.
      • Cleland J.G.
      • et al.
      The European CRT Survey: 1 year (9-15 months) follow-up results.
      A better understanding of how QRS features can be used to better predict who is likely vs unlikely to benefit from CRT is necessary. This would best be achieved via a patient level meta-analysis of the major clinical trials. Until such data are available, summary data from trials can be used to guide clinical decision-making.

      LBBB

      Multiple studies have consistently found that a LBBB pattern is a strong predictor of benefit from CRT.
      • Sipahi I.
      • Carrigan T.P.
      • Rowland D.Y.
      • Stambler B.S.
      • Fang J.C.
      Impact of QRS duration on clinical event reduction with cardiac resynchronization therapy: meta-analysis of randomized controlled trials.
      • Gervais R.
      • Leclercq C.
      • Shankar A.
      • et al.
      Surface electrocardiogram to predict outcome in candidates for cardiac resynchronization therapy: a sub-analysis of the CARE-HF trial.
      • Nery P.B.
      • Ha A.C.
      • Keren A.
      • Birnie D.H.
      Cardiac resynchronization therapy in patients with left ventricular systolic dysfunction and right bundle branch block: a systematic review.
      • Zareba W.
      • Klein H.
      • Cygankiewicz I.
      • et al.
      Effectiveness of cardiac resynchronization therapy by QRS morphology in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT).
      • Gold M.R.
      • Thébault C.
      • Linde C.
      • et al.
      Effect of QRS duration and morphology on cardiac resynchronization therapy outcomes in mild heart failure: results from the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) Study.
      Overall, patients with a classic LBBB are much more likely to have favourable LV remodelling and are approximately twice as likely to derive clinical benefit from CRT vs those with other conduction patterns. Thus, these guidelines include separate recommendations for patients with LBBB vs other forms of conduction impairment.

      RBBB

      There are pathophysiologic reasons why CRT efficacy might differ among patients with heart failure and RBBB vs LBBB.
      • Haghjoo M.
      • Bagherzadeh A.
      • Farahani M.M.
      • Haghighi Z.O.
      • Sadr-Ameli M.A.
      Significance of QRS morphology in determining the prevalence of mechanical dyssynchrony in heart failure patients eligible for cardiac resynchronization: particular focus on patients with right bundle branch block with and without coexistent left-sided conduction defects.
      • Fantoni C.
      • Kawabata M.
      • Massaro R.
      • et al.
      Right and left ventricular activation sequence in patients with heart failure and right bundle branch block: a detailed analysis using three-dimensional non-fluoroscopic electroanatomic mapping system.
      Nery et al. performed a systematic review and meta-analysis of the data from 5 randomized trials in which outcomes among patients with vs without RBBB were reported.
      • Nery P.B.
      • Ha A.C.
      • Keren A.
      • Birnie D.H.
      Cardiac resynchronization therapy in patients with left ventricular systolic dysfunction and right bundle branch block: a systematic review.
      They found no significant improvement in objective variables such as peak VO2, LVEF, hall walk distance, or norepinephrine levels among patients with RBBB who received CRT. In fact, the presence of RBBB was an independent predictor of adverse outcomes in CARE-HF, with 2-fold higher risk of death or cardiovascular hospitalization.
      • Lewinter C.
      • Torp-Pedersen C.
      • Cleland J.G.
      • Køber L.
      Right and left bundle branch block as predictors of long-term mortality following myocardial infarction.
      Further, Bilchick et al. assessed the relationship between conduction pattern and outcomes in 14,946 Medicare registry patients who received CRT-D and were followed a median of 40 months.
      • Bilchick K.C.
      • Kamath S.
      • DiMarco J.P.
      • Stukenborg G.J.
      Bundle-branch block morphology and other predictors of outcome after cardiac resynchronization therapy in Medicare patients.
      In that analysis the presence of RBBB was independently associated with an increased risk of death despite being treated with CRT. Finally, though patients with non-LBBB conduction appear less likely to benefit from CRT, wider baseline QRS durations appear to be important determinants of favourable LV reverse ventricular remodelling and improved clinical outcomes among patients with non-LBBB conduction who receive CRT.
      • Rickard J.
      • Bassiouny M.
      • Cronin E.M.
      • et al.
      Predictors of response to cardiac resynchronization therapy in patients with a non-left bundle branch block morphology.
      Thus, the present guidelines provide differing recommendation among patients with LBBB vs RBBB conduction patterns.

      Nonspecific intraventricular conduction delay

      There are few data on patients with nonspecific intraventricular conduction delay undergoing CRT. In the aforementioned analysis by Bilchick and colleagues
      • Bilchick K.C.
      • Kamath S.
      • DiMarco J.P.
      • Stukenborg G.J.
      Bundle-branch block morphology and other predictors of outcome after cardiac resynchronization therapy in Medicare patients.
      the 20% of CRT recipients categorized as having nonspecific intraventricular conduction delay had outcomes intermediate to patients with LBBB and RBBB.
      • 6
        CRT may be considered for patients in sinus rhythm with NYHA class II, NYHA class III, or ambulatory NYHA class IV heart failure, a LVEF ≤ 35%, and QRS duration ≥ 150 msec not because of LBBB conduction (Weak Recommendation, Low-Quality Evidence).
      Values and preferences. This recommendation places great value on the inclusion criteria of the landmark trials, the characteristics of the patients enrolled, and the quality of this evidence. This recommendation also places greater weight on QRS duration as a determinant of CRT response.

      Practical tip

      There is no clear evidence of benefit with CRT among patients with QRS durations < 150 ms because of non-LBBB conduction.

      Chronically paced or high likelihood of RV pacing

      There is uncertainty in predicting which patients with an indication for permanent cardiac pacing will require a high percentage of chronic RV pacing long-term.
      • Gillis A.M.
      • Pürerfellner H.
      • Israel C.W.
      • et al.
      Reducing unnecessary right ventricular pacing with the managed ventricular pacing mode in patients with sinus node disease and AV block.
      • Milasinovic G.
      • Sperzel J.
      • Smith T.W.
      • et al.
      Reduction of RV pacing by continuous optimization of the AV interval.
      Further, it is uncertain whether pacing-induced dyssynchrony is equivalent to an intrinsic LBBB.
      • Dilaveris P.
      • Pantazis A.
      • Giannopoulos G.
      • Synetos A.
      • Gialafos J.
      • Stefanadis C.
      Upgrade to biventricular pacing in patients with pacing-induced heart failure: can resynchronization do the trick?.
      Of the randomized CRT trials discussed, only RAFT included patients who had been previously chronically RV-paced.
      • Tang A.S.
      • Wells G.A.
      • Talajic M.
      • et al.
      Cardiac-resynchronization therapy for mild-to-moderate heart failure.
      All of the randomized trials excluded patients who had previously received an ICD. Yet, in clinical practice some pacemaker or ICD patients develop symptomatic LV systolic dysfunction. In fact, nearly 30% of present CRT implants in Europe involve upgrading of an existing pacemaker or ICD to a CRT system.
      • Bogale N.
      • Priori S.
      • Gitt A.
      • et al.
      The European cardiac resynchronization therapy survey: patient selection and implantation practice vary according to centre volume.
      Observational studies have reported improvements in functional class, favourable LV remodelling, fewer atrial and ventricular arrhythmias, and improved clinical outcomes after CRT upgrade.
      • Ermis C.
      • Seutter R.
      • Zhu A.X.
      • et al.
      Impact of upgrade to cardiac resynchronization therapy on ventricular arrhythmia frequency in patients with implantable cardioverter-defibrillators.
      • Eldadah Z.A.
      • Rosen B.
      • Hay I.
      • et al.
      The benefit of upgrading chronically right ventricle-paced heart failure patients to resynchronization therapy demonstrated by strain rate imaging.
      • Yannopoulos D.
      • Lurie K.G.
      • Sakaguchi S.
      • et al.
      Reduced atrial tachyarrhythmia susceptibility after upgrade of conventional implanted pulse generator to cardiac resynchronization therapy in patients with heart failure.
      • Leon A.R.
      • Greenberg J.M.
      • Kanuru N.
      • et al.
      Cardiac resynchronization in patients with congestive heart failure and chronic atrial fibrillation: effect of upgrading to biventricular pacing after chronic right ventricular pacing.
      Yet, as discussed, these procedures carry the potential for significant risk.
      • Adabag S.
      • Roukoz H.
      • Anand I.S.
      • Moss A.J.
      Cardiac resynchronization therapy in patients with minimal heart failure a systematic review and meta-analysis.
      • Poole J.E.
      • Gleva M.J.
      • Mela T.
      • et al.
      Complication rates associated with pacemaker or implantable cardioverter-defibrillator generator replacements and upgrade procedures: results from the REPLACE registry.
      Moreover, it is unclear if patients with LBBB vs non-LBBB conduction before chronic RV pacing derive similar benefit with CRT upgrade.
      • Wokhlu A.
      • Rea R.F.
      • Asirvatham S.J.
      • et al.
      Upgrade and de novo cardiac resynchronization therapy: impact of paced or intrinsic QRS morphology on outcomes and survival.
      • Adelstein E.C.
      • Saba S.
      Usefulness of baseline electrocardiographic QRS complex pattern to predict response to cardiac resynchronization.
      • Witte K.K.
      • Pipes R.R.
      • Nanthakumar K.
      • Parker J.D.
      Biventricular pacemaker upgrade in previously paced heart failure patients–improvements in ventricular dyssynchrony.
      • Fröhlich G.
      • Steffel J.
      • Hürlimann D.
      • et al.
      Upgrading to resynchronization therapy after chronic right ventricular pacing improves left ventricular remodelling.
      Thus, based on the likelihood of benefit vs risk, CRT might be considered for patients who are chronically RV-paced or are likely to be chronically paced, have signs and/or symptoms of heart failure, and a LVEF ≤ 35%.
      At present there is no clinical evidence to support the use of CRT in patients with preserved LV function and without heart failure. However, chronic RV pacing is known to increase the risk of heart failure among ICD recipients
      • Wilkoff B.L.
      • Cook J.R.
      • Epstein A.E.
      • et al.
      Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial.
      and there are data to indicate that biventricular pacing is less detrimental than RV pacing among patients requiring chronic ventricular pacing.
      • Doshi R.N.
      • Daoud E.G.
      • Fellows C.
      • et al.
      Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study).
      • Yu C.M.
      • Chan J.Y.
      • Zhang Q.
      • et al.
      Biventricular pacing in patients with bradycardia and normal ejection fraction.
      Hence, patients undergoing AV junctional ablation with moderate LV dysfunction might benefit from CRT. Strategies to minimize RV pacing should be implemented before CRT upgrade. The Biventricular versus Right Ventricular Pacing in Patients with Left Ventricular Dysfunction and Atrioventricular Block (BLOCK HF) study randomized 691 patients with LV dysfunction and heart block requiring a pacemaker or ICD to CRT vs RV pacing.
      • Curtis A.B.
      • Adamson P.B.
      • Chung E.
      • Sutton M.S.
      • Tang F.
      • Worley S.
      Biventricular versus right ventricular pacing in patients with AV block (BLOCK HF): clinical study design and rationale.
      These results have been recently presented, but are not yet published.
      • Curtis A.B.
      Biventricular versus Right Ventricular Pacing in Patients with Left Ventricular Dysfunction and Atrioventricular Block (BLOCK HF Study).
      The reported average LVEF of these patients was 40%, 84% had NYHA class II or III limitation, and average follow-up was 37 months. A 25% (95% CI, 0.60-0.90) RRR in the primary outcome, a composite of death, need for intravenous heart failure therapy, or a 15% or larger reduction in LV end systolic volume index, was found with CRT vs RV pacing.
      • Curtis A.B.
      Biventricular versus Right Ventricular Pacing in Patients with Left Ventricular Dysfunction and Atrioventricular Block (BLOCK HF Study).
      A 30% (95% CI, 0.52-0.93) RRR in the secondary outcome of hospitalization for heart failure was also found, but no significant alteration in mortality was identified (HR, 0.83; 95% CI, 0.61-1.14).
      • 7
        CRT may be considered for patients with chronic RV pacing or who are likely to be chronically paced, have signs and/or symptoms of heart failure, and a LVEF value ≤ 35% (Weak Recommendation, Low-Quality Evidence).
      Values and preferences. This recommendation places great value on the inclusion criteria of the landmark trials and the characteristics of the patients enrolled.

      Practical tip

      Attempts to minimize RV pacing, when implemented, should be undertaken before consideration of CRT upgrade. There is less evidence for the utility of CRT in patients who do not have a pre-existing LBBB and are chronically RV-paced. The risks of CRT upgrade need to be considered and balanced with the potential benefits of CRT upgrade. Patients undergoing AV junctional ablation with moderate LV dysfunction might benefit from CRT, as may those who have an indication for chronic pacing and characteristics similar to patients randomized in BLOCK HF. It is often difficult to predict reliably which patients will be chronically RV paced at the time of initiation of pacemaker therapy.

      Role of imaging

      Nearly half of the patients with LV systolic dysfunction and QRS durations > 120 ms lack evidence of mechanical dyssynchrony,
      • Bax J.J.
      • Molhoek S.G.
      • van Erven L.
      • et al.
      Usefulness of myocardial tissue Doppler echocardiography to evaluate left ventricular dyssynchrony before and after biventricular pacing in patients with idiopathic dilated cardiomyopathy.
      and a similar proportion with QRS durations < 120 ms have evidence of mechanical dyssynchrony.
      • Yu C.M.
      • Yang H.
      • Lau C.P.
      • et al.
      Regional left ventricle mechanical asynchrony in patients with heart disease and normal QRS duration: implication for biventricular pacing therapy.
      Thus, identifying and quantifying the degree of mechanical dyssynchrony in a given patient to target those most likely to derive benefit from CRT and tailor CRT to enhance clinical benefit are important, unresolved needs.
      Echocardiography (echo) is the most widely available technique for imaging of cardiac dyssynchrony. This includes visual identification of dyssynchrony,
      • Szulik M.
      • Tillekaerts M.
      • Vangeel V.
      • et al.
      Assessment of apical rocking: a new, integrative approach for selection of candidates for cardiac resynchronization therapy.
      assessment of mechanical timing,
      • Achilli A.
      • Peraldo C.
      • Sassara M.
      • et al.
      Prediction of response to cardiac resynchronization therapy: the selection of candidates for CRT (SCART) study.
      and detailed tissue Doppler imaging assessment.
      • Yu C.M.
      • Fung J.W.
      • Zhang Q.
      • et al.
      Tissue Doppler imaging is superior to strain rate imaging and postsystolic shortening on the prediction of reverse remodeling in both ischemic and nonischemic heart failure after cardiac resynchronization therapy.
      The capacity of echo and tissue Doppler imaging to identify patients with vs without dyssynchrony was assessed in a prospective observation study of 429 patients.
      • Chung E.S.
      • Leon A.R.
      • Tavazzi L.
      • et al.
      Results of the Predictors of Response to CRT (PROSPECT) trial.
      When assessed in a blinded manner, none of the 12 echo parameters evaluated reliably predicted clinical response or favourable LV remodelling. Thus, the routine assessment of dyssynchrony with the standard echo techniques is not recommended to guide prescription of CRT.
      A variety of other imaging techniques have been advocated to identify patients more likely to respond to CRT. Speckle tracking
      • Tanaka H.
      • Nesser H.J.
      • Buck T.
      • et al.
      Dyssynchrony by speckle-tracking echocardiography and response to cardiac resynchronization therapy: results of the Speckle Tracking and Resynchronization (STAR) study.
      and 3-D echo techniques
      • Marsan N.A.
      • Henneman M.M.
      • Chen J.
      • et al.
      Left ventricular dyssynchrony assessed by two three-dimensional imaging modalities: phase analysis of gated myocardial perfusion SPECT and tri-plane tissue Doppler imaging.
      have been developed, but their utility is uncertain. Cardiac magnetic resonance has excellent spatial and temporal resolution, and can be used to assess myocardial scar burden and/or location
      • White J.A.
      • Yee R.
      • Yuan X.
      • et al.
      Delayed enhancement magnetic resonance imaging predicts response to cardiac resynchronization therapy in patients with intraventricular dyssynchrony.
      • Bleeker G.B.
      • Kaandorp T.A.
      • Lamb H.J.
      • et al.
      Effect of posterolateral scar tissue on clinical and echocardiographic improvement after cardiac resynchronization therapy.
      • Chalil S.
      • Foley P.W.
      • Muyhaldeen S.A.
      • et al.
      Late gadolinium enhancement-cardiovascular magnetic resonance as a predictor of response to cardiac resynchronization therapy in patients with ischaemic cardiomyopathy.
      and dyssynchrony.
      • Westenberg J.J.
      • Lamb H.J.
      • van der Geest R.J.
      • et al.
      Assessment of left ventricular dyssynchrony in patients with conduction delay and idiopathic dilated cardiomyopathy: head-to-head comparison between tissue doppler imaging and velocity-encoded magnetic resonance imaging.
      • Reichek N.
      MRI myocardial tagging.
      • Bilchick K.C.
      • Dimaano V.
      • Wu K.C.
      • et al.
      Cardiac magnetic resonance assessment of dyssynchrony and myocardial scar predicts function class improvement following cardiac resynchronization therapy.
      Yet, most CRT systems are not magnetic resonance-compatible. Radionuclide imaging is widely available, but has poorer spatial resolution and entails radiation. Nonetheless, it can be used to estimate scar burden
      • Sciagrà R.
      • Giaccardi M.
      • Porciani M.C.
      • et al.
      Myocardial perfusion imaging using gated SPECT in heart failure patients undergoing cardiac resynchronization therapy.
      and regional systolic function.
      • Henneman M.M.
      • Chen J.
      • Dibbets-Schneider P.
      • et al.
      Can LV dyssynchrony as assessed with phase analysis on gated myocardial perfusion SPECT predict response to CRT?.
      Computed tomography has excellent spatial resolution and has been shown to be useful in guiding for LV lead placement.
      • Girsky M.J.
      • Shinbane J.S.
      • Ahmadi N.
      • Mao S.
      • Flores F.
      • Budoff M.J.
      Prospective randomized trial of venous cardiac computed tomographic angiography for facilitation of cardiac resynchronization therapy.
      While these and other imaging techniques hold promise, larger studies are needed to better understand their respective roles in CRT recipients.
      • 8
        Routine assessment of dyssynchrony with present echo techniques is not recommended to guide the prescription of CRT (Strong Recommendation, Low-Quality Evidence).
      Values and preferences. This recommendation takes into account the quality of the evidence and the results of larger, multicentre studies.

      Practical tip

      Issues of reproducibility and inter- and intrarater assessment identified in the larger studies limit the routine role of echo to guide the prescription of CRT. Ongoing imaging research (eg, scar, viability) is presently under investigation.

      Summary

      These updated guidelines are intended to provide guidance on the prescription of CRT in Canada. A future article will provide direction on the implementation of these guidelines. As additional studies are completed these guidelines will be updated accordingly.

      Acknowledgements

      Dr Exner is a Clinical Scholar of Alberta Innovates Health Solutions and Canada Research Chair in Cardiovascular Clinical Trials.

      Supplementary material

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