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Canadian Journal of Cardiology

Canadian Cardiovascular Society Guidelines on the Use of Cardiac Resynchronization Therapy: Implementation

      Abstract

      Recent studies have provided the impetus to update the recommendations for cardiac resynchronization therapy (CRT). This article provides guidance on the implementation of CRT and is intended to serve as a framework for the implementation of CRT within the Canadian health care system and beyond. These guidelines were developed through a critical evaluation of the existing literature, and expert consensus. The panel unanimously adopted each recommendation. The 9 recommendations relate to patient selection in the presence of comorbidities, delivery and optimization of CRT, and resources required to deliver this therapy. The strength of evidence was weighed, taking full consideration of any risk of bias, and 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 études récentes ont incité à mettre à jour les recommandations sur la thérapie de resynchronisation cardiaque (TRC). Cet article fournit des lignes directrices sur la mise en application de la TRC et est destiné à servir de cadre à la mise en application de la TRC dans le système de soins de santé canadien et au-delà. Ces lignes directrices 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 9 recommandations concernent la sélection des patients en présence de comorbidités, l’offre et l’optimisation de la TRC, et les ressources requises pour offrir ce traitement. 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.
      The 9 recommendations in this document are based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) assessment method and expert consensus.
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      This document was developed to directly address the practical use of cardiac resynchronization therapy (CRT), beyond clinical trial inclusion/exclusion criteria, in a real-world population. The consensus panel consisted of experts in cardiac electrophysiology, heart failure (HF), cardiac surgery, cardiac imaging, general cardiology, internal medicine, knowledge translation, and health services. Competing interests of panel members are provided on the Canadian Cardiovascular Society (CCS) Web site (www.ccs.ca). These guidelines are intended for internists, nurse clinicians in heart function and device clinics, general cardiologists, HF experts, cardiac electrophysiologists, policy makers, and trainees. This document is meant to provide guidance for patient selection, platform selection, and appropriate preoperative, operative, and postoperative patient management to reduce risk, and optimize CRT delivery. The economics and accessibility of CRT are also addressed, including the timely application of this therapy.

      Preimplant Assessment and Procedural Preparation

      Patient selection

      Functional assessment

      New York Heart Association (NYHA) Functional Classification is the most commonly used measure of HF clinical severity and is one of the central criteria in deciding on the appropriateness of CRT. Categorizing patients into a NYHA class is a subjective process. Nevertheless, it is relatively straightforward to identify patients with NYHA class I (asymptomatic) or nonambulatory NYHA class IV (ie, severe HF requiring intravenous diuretics, inotropic therapy, or intra-aortic balloon pump support), for whom CRT is not currently recommended because of a lack of evidence.
      • Lindenfeld J.
      • Albert N.M.
      • Boehmer J.P.
      • et al.
      HFSA 2010 Comprehensive Heart Failure Practice Guideline.
      Yet, it might be difficult to determine if symptoms are attributable to HF or comorbidities such as musculoskeletal, pulmonary, or other chronic diseases, aging, frailty, or physical deconditioning. Therefore, an objective assessment of functional capacity should be considered in patients with confirmed HF and multiple comorbidities, or if there is disparity between reported symptoms and the clinical assessment.
      • Lindenfeld J.
      • Albert N.M.
      • Boehmer J.P.
      • et al.
      HFSA 2010 Comprehensive Heart Failure Practice Guideline.
      The 6-minute walk test and cardiopulmonary exercise test
      • Arena R.
      • Myers J.
      • Williams M.A.
      • et al.
      Assessment of functional capacity in clinical and research settings: a scientific statement from the American Heart Association Committee on Exercise, Rehabilitation, and Prevention of the Council on Clinical Cardiology and the Council on Cardiovascular Nursing.
      were included in earlier CRT trials as objective measures of changes in functional capacity in response to treatment.
      • Cazeau S.
      • Bordachar P.
      • Jauvert G.
      • et al.
      Echocardiographic modeling of cardiac dyssynchrony before and during multisite stimulation: a prospective study.
      • 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.
      • 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.
      The use of more reproducible and reliable measures of functional capacity than NYHA class, such as the Specific Activity Scale, should also be considered.
      Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Australia/New Zealand Heart Failure Research Collaborative Group.
      Finally, it is important to emphasize that serial determinations of functional capacity provide benchmarks for disease severity, response to CRT, and progression of HF.
      • Olsson L.G.
      • Swedberg K.
      • Clark A.L.
      • Witte K.K.
      • Cleland J.G.
      Six minute corridor walk test as an outcome measure for the assessment of treatment in randomized, blinded intervention trials of chronic heart failure: a systematic review.

      Practical tip

      Objective evaluation of the pre-CRT implantation functional capacity and symptoms is important, particularly in patients in whom there is disparity between the reported symptoms and the clinical assessment, or to distinguish the non-HF related causes of functional limitation.

      Patient factors and comorbidities

      As with most clinical trial populations, patients included in the major CRT trials differ from those in a general HF patient population.
      • McAlister F.A.
      • Tu J.V.
      • Newman A.
      • et al.
      How many patients with heart failure are eligible for cardiac resynchronization? Insights from two prospective cohorts.
      As noted in part 1 of the 2013 CRT Guidelines, sex, the presence of atrial fibrillation (AF) and type of intraventricular conduction delay (left bundle branch block [LBBB] vs right bundle vs nonspecific) help to identify potential benefit from CRT.
      • Exner D.V.
      • Birnie D.H.
      • Moe G.
      • et al.
      Canadian Cardiovascular Society guidelines on the use of cardiac resynchronization therapy: evidence and patient selection.
      Other factors affecting patients who would benefit most are discussed in this section. Table 1 presents the overall considerations before CRT implantation.
      Table 1Factors to consider before CRT implantation
      Factors to considerRecommendedFor consideration
      Patient selectionNYHA II, III, or ambulatory IV, HF, LVEF ≤ 35%, QRS ≥ 130 ms if LBBB; sinus rhythm, and the absence of severe CKD (creatinine < 200 mmol/L or GFR > 30 mL/min/m2)QRS > 150 ms if non-LBBB; presence of AF; elderly age; evidence of frailty; chronic RV pacing with LVEF ≤ 45%
      ImagingEvaluation of LVEF: echocardiogram, nuclear imaging, cardiac magnetic resonanceImaging for assistance in LV lead placement
      AnticoagulationContinue warfarin if high risk for thromboembolismNovel oral anticoagulants will need to be considered on an individual basis (see text)
      Renal insufficiencyAdequate hydration; hold or decrease diuretics
      AF, atrial fibrillation; CKD, chronic kidney disease; CRT, cardiac resynchronization therapy; GFR, glomerular filtration rate; HF, heart failure; LBBB, left bundle branch block; LV, left ventricular; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; RV, right ventricular.

      Age

      In CRT trials, the mean age among patients ranged from 62 to 66 years.
      • Wells G.
      • Parkash R.
      • Healey J.S.
      • et al.
      Cardiac resynchronization therapy: a meta-analysis of randomized controlled trials.
      The evidence to support the use of CRT in elderly patients, who otherwise qualify, is presently limited. However, a cohort study found similar outcomes with CRT in patients aged ≥ 80 years to those < 80 and both groups had similar device-related complication rates.
      • Achilli A.
      • Turreni F.
      • Gasparini M.
      • et al.
      Efficacy of cardiac resynchronization therapy in very old patients: the Insync/Insync ICD Italian Registry.
      Hence, elderly patients with comorbidities, but a good life expectancy (> 1 year) who otherwise fulfil criteria, might derive functional improvements with CRT and should be considered for referral.

      Renal function

      Significant concomitant chronic kidney disease (CKD) might be present in up to a third of HF patients and is associated with a poor prognosis.
      • McAlister F.A.
      • Ezekowitz J.
      • Tonelli M.
      • Armstrong P.W.
      Renal insufficiency and heart failure: prognostic and therapeutic implications from a prospective cohort study.
      The large clinical trials of CRT excluded patients with CKD so there is limited evidence to guide clinical decision-making in this population.
      • Cannizzaro L.A.
      • Piccini J.P.
      • Patel U.D.
      • Hernandez A.F.
      Device therapy in heart failure patients with chronic kidney disease.
      The mortality benefit achieved with adding CRT to an implantable cardioverter defibrillator (ICD) appears attenuated in those with more advanced CKD (glomerular filtration rate [GFR], < 30 mL/min/1.73 m2).
      • Adelstein E.C.
      • Shalaby A.
      • Saba S.
      Response to cardiac resynchronization therapy in patients with heart failure and renal insufficiency.
      Adelstein et al
      • Adelstein E.C.
      • Shalaby A.
      • Saba S.
      Response to cardiac resynchronization therapy in patients with heart failure and renal insufficiency.
      analyzed 787 patients with a CRT plus an ICD (CRT-D) and correlated survival, changes in left ventricular (LV) ejection fraction (LVEF) and LV end-systolic diameter and GFR with a control group in whom LV lead implant was unsuccessful. Survival improved for each 10 mL/min/1.73m2 in GFR with a hazard ratio of 1.21 (95% confidence interval [CI], 1.13-1.30; P < 0.0001). Those with a GFR < 30 mL/min/1.73m2 had no echocardiographic benefit. Those with moderate renal insufficiency (GFR, 30-59) had significantly better survival than control subjects (hazard ratio, 2.23; 95% CI, 1.34-1.70; P = 0.002), and improved renal and cardiac function. Other studies have also demonstrated improvements in renal function with CRT that have correlated with greater favourable LV remodelling and reduced mortality.
      • Boerrigter G.
      • Costello-Boerrigter L.C.
      • Abraham W.T.
      • et al.
      Cardiac resynchronization therapy improves renal function in human heart failure with reduced glomerular filtration rate.
      Considering the increased procedural risks of device implantation in patients with advanced CKD (see the section on Avoidance of Complications), the risk vs benefit of CRT and the selection of a CRT pacemaker (CRT-P) vs CRT-D need to be carefully considered.
      • Aggarwal A.
      • Wang Y.
      • Rumsfeld J.S.
      • Curtis J.P.
      • Heidenreich P.A.
      Clinical characteristics and in-hospital outcome of patients with end-stage renal disease on dialysis referred for implantable cardioverter-defibrillator implantation.

      Etiology of LV dysfunction

      The mortality benefit with CRT is similar in patients with an ischemic vs a nonischemic etiology and should not be a factor in the decision to prescribe CRT.
      • 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.
      The degree of favourable LV remodelling is less with an ischemic vs nonischemic cause of LV dysfunction.
      • Ghio S.
      • Freemantle N.
      • Scelsi L.
      • et al.
      Long-term left ventricular reverse remodelling with cardiac resynchronization therapy: results from the CARE-HF trial.
      This might relate to the extent of the scar, a differential effect of CRT on diastolic function, or other factors.

      Frailty

      The concept of frailty is not always considered in the chronic care of patients with cardiac disease. Yet, considering our aging population it should be considered. Clarke et al. have demonstrated that overall mortality and nonsudden death (53% because of HF) was associated with an increase in the Charlson Comorbidity Index (P < 0.0001), with a Charlson Index > 4 resulting in a 49% risk of nonsudden death in a competing risk model.
      • Clarke B.
      • Howlett J.G.
      • Parkash R.
      A risk score predicting non sudden cardiac death in congestive heart failure.
      The most widely used definition of frailty includes subjective and objective measures of weight loss, weakness, a sense of exhaustion, slowed walking speed, and low physical activity.
      • Rockwood K.
      • Fox R.A.
      • Stolee P.
      • Robertson D.
      • Beattie B.L.
      Frailty in elderly people: an evolving concept.
      Those displaying 1 or 2 of these characteristics are considered “pre-frail,” and those with 3 or more are categorized as “frail.” Quantification of frailty and comorbidity can be accomplished through use of validated instruments such as the Charlson Comorbidity Index and the Clinical Frailty Scale (see Supplemental Tables S1 and S2).
      • Clarke B.
      • Howlett J.G.
      • Parkash R.
      A risk score predicting non sudden cardiac death in congestive heart failure.
      • Rockwood K.
      • Song X.
      • MacKnight C.
      • et al.
      A global clinical measure of fitness and frailty in elderly people.
      • Charlson M.E.
      • Pompei P.
      • Ales K.L.
      • Mackenzie C.R.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      Familiarity with these scales might be helpful in determining the degree of frailty. Frail patients might be unable to withstand device implantation, which might reduce the overall benefit of CRT. However, many of the factors that contribute to frailty might be reversible with CRT, including weakness and low physical activity. Assessment by a clinician familiar with frailty (eg, a geriatrician) might be helpful when the likelihood of benefit from CRT is less certain.
      Recommendation
      • 1.
        We recommend that the prescription of CRT and the choice of platform (CRT-P vs CRT-D) should take into account clinical factors that would affect the overall goals of care (Strong Recommendation, Moderate-Quality Evidence).
      Values and preferences. This recommendation places great value on the benefit of CRT in appropriately selected patients with HF, and minimization of risk.
      Practical tip. Comorbid conditions and clinical factors (eg, age, renal function, frailty) should be considered together, and 1 alone should not preclude a patient from CRT implantation. Therapy should be individualized in accordance with the overall goals of care and patient preference.

      De novo onset of pacemaker dependence

      Evidence has emerged regarding new-onset atrioventricular (AV) block requiring ventricular pacing. The Biventricular vs Right Ventricular Pacing in Patients With Left Ventricular Dysfunction and AV Block (BLOCK HF) trial randomized 691 patients with LVEF ≤ 50%, high-degree AV block requiring pacing, and NYHA class I/II/III limitation requiring a pacemaker or ICD to CRT vs right ventricular (RV) -only pacing.
      • Curtis A.B.
      • Worley S.J.
      • Adamson P.B.
      • et al.
      Biventricular pacing for atrioventricular block and systolic dysfunction.
      The mean LVEF of participants was 40 ± 8.3% (pacemaker, 43% and ICD, 33%). A 26% relative risk reduction (95% CI, 10%-40%) in the primary end point of all cause mortality, urgent care visit for HF, or an increase in the LV end systolic volume index of ≥ 15% was found with CRT vs standard RV apical pacing.
      Recommendation
      • 2.
        We suggest that CRT might be considered for patients with new-onset high-degree AV block requiring chronic RV pacing, signs and/or symptoms of HF, and LVEF ≤ 45% (Conditional Recommendation, Moderate-Quality Evidence).
      Values and preferences. This recommendation places value on the knowledge that CRT might provide more benefit than RV apical pacing, even though the strength of evidence is moderate and the available data result in a conditional rating.
      Practical tip. Most patients in BLOCK HF had reduced LV systolic function (LVEF ≤ 45%) and symptomatic (NYHA class II/III) HF. Further, BLOCK HF enrolled patients with de novo implants and the same considerations might not apply in patients who are chronically RV-paced. (See Supplemental Tables S3 for further details.) There are limited randomized clinical trial (RCT) data with respect to CRT upgrade and potential benefits must be balanced with the significantly higher risk with CRT vs generator replacement alone.

      Consideration for upgrade to CRT

      Patients with HF who are undergoing a system revision of a previous cardiac implantable electronic device (CIED) should be evaluated for CRT indication considering the expanded indications for CRT (Fig. 1). Although there are no RCT data in this population, 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.
      The risk of intervention in a patient not requiring system revision for another reason (eg, generator change or lead revision) needs to be balanced by potential benefits of CRT.
      • 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.
      Recommendation
      • 3.
        We recommend that all patients with HF who are planned to receive a CIED system revision should be considered for their eligibility for upgrade to CRT (Strong Recommendation, Low-Quality Evidence).
      Values and preferences. Careful evaluation of the risks and benefits of upgrades in patients with existing CIED systems who are eligible for CRT should be considered.
      Figure thumbnail gr1
      Figure 1Evaluation of patients with a CIED and HF. CHF, congestive heart failure; CIED, cardiovascular implantable electronic device; CRT, cardiac resynchronization therapy; ECG, electrocardiogram; EF, ejection fraction; LV, left ventricular; NYHA, New York Heart Association; RV, right ventricular.
      Practical tip. Considering the expanding indications for CRT and the changes over time that might occur in a patient's condition, the need for CRT should be considered at the time of CIED change, because risk/benefit of adding an LV lead when a procedure is being performed might be favourable. For further details, refer to Figure 1.

      Patients undergoing open heart surgery

      There are data that support the utility of epicardial LV lead placement to facilitate CRT delivery.
      • Mair H.
      • Sachweh J.
      • Meuris B.
      • et al.
      Surgical epicardial left ventricular lead versus coronary sinus lead placement in biventricular pacing.
      However, there are a paucity of data with respect to indications and outcomes for prophylactic placement of an LV epicardial lead at the time of open heart surgery. A single retrospective study identified that 2.3% of patients undergoing cardiac surgery could benefit from CRT.
      • Mellert F.
      • Schneider C.
      • Esmailzadeh B.
      • et al.
      Implantation of left ventricular epicardial leads in cardiosurgical patients with impaired cardiac function–a worthwhile procedure in concomitant surgical interventions?.
      However, the precise characteristics of patients that would benefit from prophylactic LV lead placement are unknown. Patients likely to benefit from the cardiac surgical procedure and less likely to later require CRT include those with severe aortic stenosis or extensive coronary artery disease with demonstrated viability. In contrast, those with a pre-existing LBBB, HF, and previous sustained ventricular tachycardia or a cardiac arrest represent a group more likely to require CRT in the future. The ideal location for epicardial LV lead placement likely varies in a given patient. In general, placement of the LV epicardial lead in a posterobasal position between the ramus intermedius and the obtuse marginal arteries when that region is free of scar is generally preferred.
      • Edgerton J.R.
      • Edgerton Z.J.
      • Mack M.J.
      • Hoffman S.
      • Dewey T.M.
      • Herbert M.A.
      Ventricular epicardial lead placement for resynchronization by determination of paced depolarization intervals: technique and rationale.
      The incremental intraoperative risk is low and the ease of LV lead placement at the ideal location on the epicardium makes this an important consideration for those who fit the criteria. Transvenous implantation for LV leads is the usual method but is limited by venous anatomy, lead stability, pacing threshold, and potential for diaphragmatic capture. These considerations do not pose challenges in epicardial placement. Preoperative consultation between the cardiac surgeon and the cardiac electrophysiologist is important in identifying patients most likely to benefit from intraoperative LV lead placement and the appropriate location for the LV lead.
      Recommendation
      • 4.
        We suggest that placement of an LV lead at the time of open heart surgery, for the purpose of facilitating future CRT, might be considered in patients for whom CRT is recommended and the need for device therapy is unlikely to be changed by the surgical procedure (Conditional Recommendation, Low-Quality Evidence).
      Values and preferences. This recommendation places value on practical considerations and multidisciplinary discussion in the absence of substantial data.
      Practical tip. Patients who have severe structural abnormalities that can be easily corrected with cardiac surgery are the least likely to benefit from LV lead placement. The risk and costs of placing hardware that might be unnecessary needs to be balanced with the feasibility and risk of placing/testing an LV lead at the time of surgery in an eligible patient. As discussed in part 1 of the 2013 Guidelines, an apical LV lead position should be avoided.
      • Abraham W.T.
      • Fisher W.G.
      • Smith A.L.
      • et al.
      Cardiac resynchronization in chronic heart failure.

      Use of antithrombotic agents periprocedurally

      There is now definitive evidence that CRT implantation can be performed safely without interruption of warfarin or vitamin K-dependent antagonist treatment in patients at high risk for thromboembolism. Examples of high-risk patients include those with mechanical mitral valve or nonvalvular AF and Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack (CHADS2) score ≥ 3.
      • Birnie D.H.
      • Healey J.S.
      • Wells G.A.
      • et al.
      Pacemaker or defibrillator surgery without interruption of anticoagulation.
      In the Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial (BRUISE CONTROL) trial, 668 patients with a high risk of thromboembolism undergoing a CIED procedure were randomized to bridging, per-operative use of low molecular weight heparin, vs continued warfarin. The primary outcome was the development of a clinically significant pocket hematoma. The trial was terminated early because continuation of warfarin resulted in an 81% relative risk reduction in the primary outcome (95% CI, 64%-90%; P < 0.001). A meta-analysis of 8 studies enrolling 2321 patients confirmed that uninterrupted warfarin therapy was associated with a significantly lower risk of postoperative bleeding than heparin-based bridging therapy (odds ratio, 0.30; 95% CI, 0.18-0.50; P < 0.01), shorter hospital admission (mean difference, 2.4 days), and no difference in thromboembolic events.
      • Ghanbari H.
      • Phard W.S.
      • Al-Ameri H.
      • et al.
      Meta-analysis of safety and efficacy of uninterrupted warfarin compared to heparin-based bridging therapy during implantation of cardiac rhythm devices.
      There are no safety data on an uninterrupted use of the new oral anticoagulation agents (Factor Xa and direct thrombin inhibitors) during CIED surgery. Temporary cessation of oral anticoagulation (OAC) before a procedure is typically preferred in patients with lower thromboembolic risk (CHADS2 ≤ 2).
      • Douketis J.D.
      • Spyropoulos A.C.
      • Spencer F.A.
      • et al.
      Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      Recommendation
      • 5.
        We recommend that in patients taking warfarin for whom perioperative anticoagulation is deemed necessary, continued warfarin is recommended over the use of heparin-based bridging (Strong Recommendation, Moderate-Quality Evidence).
      Values and preferences. This recommendation places great value on safely preventing perioperative bleeding and the quality of the evidence.
      Practical tip. Perioperative OAC is usually deemed necessary in patients at high risk of thromboembolism (CHADS2 ≥ 3 or > 5% annual risk, refer to Use of Antithrombotic Agents Periprocedurally section for details). No data are presently available on the use of novel oral anticoagulants in this population; interruption of these agents should be of short duration in patients at high risk of thromboembolism, but renal function, procedural risk, and complexity of the procedure might need to be considered in these situations. The rapidity of onset and offset make these more facile to control periprocedurally. Discontinuation of OAC in patients at lower risk of thromboembolism should be considered to minimize the risk of bleeding.

      Operative Issues

      General principles

      Patients undergoing CRT implantation typically have substantial LV dysfunction and symptomatic HF and are high-risk surgical candidates.
      • Goldman L.
      • Caldera D.L.
      • Nussbaum S.R.
      • et al.
      Multifactorial index of cardiac risk in noncardiac surgical procedures.
      Hence, the procedure should be performed in an environment with careful hemodynamic monitoring and the capacity to provide appropriate hemodynamic support. Infection prevention is central to all CIED procedures. Preoperative antibiotics that provide adequate coverage against skin flora are the standard of care. They must be administered before skin incision to provide appropriate protection. Appropriate attention to sterile technique, minimal handling of the implanted components, and adequate air flow are also essential proven infection prevention control strategies.
      • Williams M.
      Infection control and prevention in perioperative practice.
      Recommendation
      • 6.
        We recommend that CRT implantation be performed only in facilities that have strict infection prevention control standards (Strong Recommendation, Low-Quality Evidence).
      Values and preferences. This recommendation takes into account that infection prevention is a key aspect to CRT implantation and system revision.

      Radiation safety

      The amount of ionizing radiation to which CRT recipients and operators are exposed during a complex CRT procedures is significant (might exceed 60 minutes of fluoroscopy). Deterministic effects including cataracts and stochastic effects such as cancer are of primary concern. For every 60 minutes of fluoroscopy, the mean total lifetime risk of fatal malignancy is estimated to increase by 0.03%-0.065%.
      • Kovoor P.
      • Ricciardello M.
      • Collins L.
      • Uther J.B.
      • Ross D.L.
      Risk to patients from radiation associated with radiofrequency ablation for supraventricular tachycardia.
      If appropriate radiation shielding is not in place the operator is subject to scatter radiation. Scatter radiation is greatly increased when: (1) the distance between the image intensifier and the patient increases; (2) steep lateral or oblique positions are used; and (3) when body mass or other factors require increased fluoroscopic output (kv).
      • Calkins H.
      • Brugada J.
      • Packer D.L.
      • et al.
      HRS/EHRA/ECAS expert Consensus Statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. A report of the Heart Rhythm Society (HRS) Task Force on catheter and surgical ablation of atrial fibrillation.
      Major exposure-reduction techniques include: (1) exposure time reduction by using short bursts of “on-time”; (2) field limitation (“coning” and avoidance of magnification); and (3) lower frame rates (pulsed mode; 10-15 frames per second reduces the radiation dose by more than 50% vs nonpulsed modes), and shielding. Typical forms of shielding include the use of a protective (lead) apron, thyroid collar, and eyeglasses. These interventions are used by most electrophysiologists.
      • Marinskis G.
      • Bongiorni M.G.
      • Dagres N.
      • Lewalter T.
      • Pison L.
      • Blomstrom-Lundqvist C.
      X-ray exposure hazards for physicians performing ablation procedures and device implantation: results of the European Heart Rhythm Association survey.
      However, nonprotected areas (eg, cranium, arms, hands) receive large doses of radiation. Radiation shields above and below the operating table, protective cabins and suspended vests, and sterile radiation-absorbing drapes provide additional protection, but do not protect some areas (eg, hands).
      • Dragusin O.
      • Weerasooriya R.
      • Jais P.
      • et al.
      Evaluation of a radiation protection cabin for invasive electrophysiological procedures.
      • Brambilla M.
      • Occhetta E.
      • Ronconi M.
      • Plebani L.
      • Carriero A.
      • Marino P.
      Reducing operator radiation exposure during cardiac resynchronization therapy.
      Although desirable, the As Low as Reasonably Achievable (ALARA) principle has to be balanced with sufficient image quality to safely perform these complex procedures without unnecessary radiation exposure.
      • Rogers D.P.
      • England F.
      • Lozhkin K.
      • Lowe M.D.
      • Lambiase P.D.
      • Chow A.W.
      Improving safety in the electrophysiology laboratory using a simple radiation dose reduction strategy: a study of 1007 radiofrequency ablation procedures.
      Further information on radiation issues is discussed in the CCS Position Statement on Radiation Exposure from Cardiac Imaging and Interventional Procedures.
      • Natarajan M.K.
      • Paul N.
      • Mercuri M.
      • et al.
      Canadian Cardiovascular Society Position Statement on radiation exposure from cardiac imaging and interventional procedures.
      Recommendation
      • 7.
        We recommend that appropriate fluoroscopic equipment, radiation shielding, and radiation reduction imaging methods be used to minimize radiation exposure to the operator, patient, and other staff (Strong Recommendation, Low-Quality Evidence).
      Values and preferences. This recommendation takes into account that fluoroscopic exposure poses risk to patients, staff, and operators, and must be minimized using all available means.

      Avoidance of complications

      CRT implantation is a surgical procedure and should only be performed by highly trained physicians. As with many surgical procedures, the outcome and complication rate is directly related to the implant volume performed by the operator and implanting centre.
      • Freeman J.V.
      • Wang Y.
      • Curtis J.P.
      • Heidenreich P.A.
      • Hlatky M.A.
      Physician procedure volume and complications of cardioverter-defibrillator implantation.
      Methods to prevent and avoid complications are listed in Table 2.
      • 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.
      • Birnie D.H.
      • Healey J.S.
      • Wells G.A.
      • et al.
      Pacemaker or defibrillator surgery without interruption of anticoagulation.
      • Cowburn P.J.
      • Patel H.
      • Pipes R.R.
      • Parker J.D.
      Contrast nephropathy post cardiac resynchronization therapy: an under-recognized complication with important morbidity.
      • Sharma G.
      • Senguttuvan N.B.
      • Thachil A.
      • et al.
      A comparison of lead placement through the subclavian vein technique with fluoroscopy-guided axillary vein technique for permanent pacemaker insertion.
      • Greenspon A.J.
      • Rhim E.S.
      • Mark G.
      • Desimone J.
      • Ho R.T.
      Lead-associated endocarditis: the important role of methicillin-resistant Staphylococcus aureus.
      • Darouiche R.O.
      • Wall Jr., M.J.
      • Itani K.M.
      • et al.
      Chlorhexidine-alcohol versus povidone-iodine for surgical-site antisepsis.
      Table 2Complications with CRT implantation
      ComplicationIncidenceSuggested methods to prevent
      Contrast-induced nephropathy7%-43%Prehydration; lower dose of diuretics; lower dose of contrast, dilution of contrast
      • Cowburn P.J.
      • Patel H.
      • Pipes R.R.
      • Parker J.D.
      Contrast nephropathy post cardiac resynchronization therapy: an under-recognized complication with important morbidity.
      Pneumothorax0.6%-1.0%Extrathoracic puncture, echo-guided or contrast-guided venous puncture, axillary is preferred to subclavian; use of cephalic vein
      • Sharma G.
      • Senguttuvan N.B.
      • Thachil A.
      • et al.
      A comparison of lead placement through the subclavian vein technique with fluoroscopy-guided axillary vein technique for permanent pacemaker insertion.
      Pericardial effusion1.5%Use of soft-tip guides and access tools
      Hematoma3%-6%Avoid low molecular weight heparin periprocedurally
      • Birnie D.H.
      • Healey J.S.
      • Wells G.A.
      • et al.
      Pacemaker or defibrillator surgery without interruption of anticoagulation.
      Phrenic nerve stimulationUp to 13%Conscious sedation; no paralytic agents; identify all available coronary vein branches; use of multipolar leads (additional electrodes)
      Lead-related complications3.5%-18.7%
      • 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.
      Appropriate training and adequate procedural volumes
      Device infection1.3%-2.6%Appropriate antibiotic prophylaxis before skin incision
      • Greenspon A.J.
      • Rhim E.S.
      • Mark G.
      • Desimone J.
      • Ho R.T.
      Lead-associated endocarditis: the important role of methicillin-resistant Staphylococcus aureus.
      ; chlorhexidine skin preparation
      • Darouiche R.O.
      • Wall Jr., M.J.
      • Itani K.M.
      • et al.
      Chlorhexidine-alcohol versus povidone-iodine for surgical-site antisepsis.
      ; limited shaving
      In-hospital mortality0.3%Careful preoperative assessment; intraoperative monitoring; appropriate postoperative care
      CRT, cardiac resynchronization therapy.

      Operative considerations related to CRT upgrade

      Performing an upgrade to CRT in the setting of existing hardware can be challenging because of partial or total venous occlusion, resistance along the LV lead course from the existing leads, the presence of scar tissue, and other factors. Venoplasty or lead extraction in the setting of venous occlusion or abandoned hardware might be required to facilitate transvenous LV lead placement.
      • Worley S.J.
      Implant venoplasty: dilation of subclavian and coronary veins to facilitate device implantation: indications, frequency, methods, and complications.
      • Maytin M.
      • Epstein L.M.
      • Henrikson C.A.
      Lead extraction is preferred for lead revisions and system upgrades: when less is more.
      Ipsilateral contrast injection from a peripheral vein (contralateral device placement, lead extraction, venoplasty, tunneling, or direct surgical epicardial lead placement) and referral of patients to more experienced implantation centres might be helpful in procedural planning. These more complex procedures should be performed in high volume centres with low complication rates.
      • Wazni O.
      • Epstein L.M.
      • Carrillo R.G.
      • et al.
      Lead extraction in the contemporary setting: the LExICon study: an observational retrospective study of consecutive laser lead extractions.
      These considerations should be explored well in advance of a CRT upgrade procedure to best assess the most successful approach for a given patient.

      Lead placement to optimize response

      As recommended in part 1 of the CRT Guidelines, LV leads should be placed in a nonapical location.
      • Exner D.V.
      • Birnie D.H.
      • Moe G.
      • et al.
      Canadian Cardiovascular Society guidelines on the use of cardiac resynchronization therapy: evidence and patient selection.
      • 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.
      Challenges in precisely defining the location of the lead on the LV, the extent of myocardial scarring, and the etiology of LV dysfunction might partially explain the poor relationship between the location of LV pacing and the likelihood of benefit from CRT.
      • 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.
      • Ypenburg C.
      • Schalij M.J.
      • Bleeker G.B.
      • et al.
      Impact of viability and scar tissue on response to cardiac resynchronization therapy in ischaemic heart failure patients.
      Areas of scar might be identified using imaging techniques such as echocardiography, nuclear, and cardiac magnetic resonance (CMR).
      • 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.
      It is known that the site of latest LV activation in patients with nonischemic LV dysfunction and LBBB typically is lateral or posterior, but this might be very different in patients with ischemic LV dysfunction. There appears to be a “sweet spot” for LV pacing
      • Exner D.V.
      • Auricchio A.
      • Singh J.P.
      Contemporary and future trends in cardiac resynchronization therapy to enhance response.
      that is large in patients with nonischemic etiologies for LV dysfunction, but more restricted and variable in ischemic LV dysfunction or in patients with non-LBBB conduction patterns.
      • Ypenburg C.
      • Schalij M.J.
      • Bleeker G.B.
      • et al.
      Impact of viability and scar tissue on response to cardiac resynchronization therapy in ischaemic heart failure patients.
      Three small RCTs (INCREMENTAL [Investigating Non-response to Cardiac Resynchronization: Evaluation of Methods to Eliminate Non-response & Target Appropriate Lead Location], TARGET [Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy], STARTER [Speckle Tracking Assisted Resynchronization Therapy for Electrode Region]) have demonstrated
      • Exner D.V.
      • Auricchio A.
      • Singh J.P.
      Contemporary and future trends in cardiac resynchronization therapy to enhance response.
      • 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.
      • Saba S.
      • Marek J.
      • Schwartzman D.
      • et al.
      Echocardiography-guided left ventricular lead placement for cardiac resynchronization therapy: results of the speckle tracking assisted resynchronization therapy for electrode region trial.
      that LV lead placement in a viable late-contracting LV segment improves response to CRT. CMR might also provide a 3-D roadmap for LV lead positioning, although this has yet to be assessed in clinical trials.
      • Nezafat R.
      • Han Y.
      • Peters D.C.
      • et al.
      Coronary magnetic resonance vein imaging: imaging contrast, sequence, and timing.
      CMR myocardial tagging provides accurate measurement of interventricular and intraventricular dyssynchrony with high reliability and specificity and appears to be a promising method for identifying an optimal site for LV pacing.
      • 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.
      The presence of transmural posterolateral scar identified using late gadolinium enhancement or global LV necrosis are important predictors of the lack of benefit from CRT.
      • 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.
      • 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.
      The integration of imaging technologies might facilitate the planning and delivery of LV pacing. Preprocedural evaluation of mechanical dyssynchrony and intraprocedural integration with venous mapping appears promising,
      • Tournoux F.
      • Chan R.C.
      • Manzke R.
      • et al.
      Integrating functional and anatomical information to guide cardiac resynchronization therapy.
      but requires prospective validation (Table 2).

      Practical tip

      In patients with an ischemic etiology or non-LBBB patterns of QRS morphology, correlation of venous anatomy using CMR with mechanical dyssynchrony might be helpful in guiding LV lead placement and optimizing response to CRT.
      Even though concordance between the position of the LV lead and the area of latest activation seem to predict a better response to CRT, at the time of implantation, the anatomy of the venous system remains the most important limitation. Other electrical parameters that have shown some benefit are shown in Table 3. A secondary analysis of the SmartDelay Determined AV Optimization: A Comparison of AV Optimization Methods Used in Cardiac Resynchronization Therapy (SMART-AV) study revealed that a Q-LV > 95 ms was associated with improved reverse remodelling.
      • Gold M.R.
      • Birgersdotter-Green U.
      • Singh J.P.
      • et al.
      The relationship between ventricular electrical delay and left ventricular remodelling with cardiac resynchronization therapy.
      The basic determinants of a successful LV lead implantation remain the same: pacing with an adequate threshold, avoiding capture of the nearby phrenic nerve, and long-term stability of the LV lead. Emerging technologies to assist in 3-D reconstruction of the venous anatomy and its electrical activation patterns are being investigated.
      Table 3Experimental tools to optimize LV pacing site
      ToolMeasurement
      ImagingEchocardiography, nuclear, CMR
      Anatomic positionLV lead to latest activation site determined using imaging
      Greatest distance between LV and RV lead
      TimingGreatest delay from onset of QRS to local LV electrogram
      ContractilityAcute increase in dP/dtmax or pulse pressure (systolic minus diastolic blood pressure)
      CMR, cardiac magnetic resonance; LV, left ventricular; RV, right ventricular.

      Endocardial pacing

      Initial human studies evaluating endocardial LV pacing have shown either no differences or small improvements in LV contractility (dP/dtmax) with this approach vs standard epicardial pacing.
      • Spragg D.D.
      • Dong J.
      • Fetics B.J.
      • et al.
      Optimal left ventricular endocardial pacing sites for cardiac resynchronization therapy in patients with ischemic cardiomyopathy.
      Although there might be a future role for endocardial pacing it has a limited role at present because of a lack of long-term data on its safety and efficacy.

      Device Follow-up

      Factors to consider in CRT follow-up

      Follow-up of CRT devices, whether pacemaker or ICD, should be done in accordance with published guidelines.
      • Gillis A.M.
      • Philippon F.
      • Cassidy M.R.
      • et al.
      Guidelines for implantable cardioverter defibrillator follow-up in Canada: a consensus statement of the Canadian Working Group on Cardiac Pacing.
      CRT implantation is the first step in optimal delivery of CRT. There are many more factors to consider when the implant has been successful. These are shown in Figure 2. Collaboration between the heart rhythm service, HF specialists, and other caregivers is necessary to enhance the likelihood of benefit from CRT.
      Figure thumbnail gr2
      Figure 2Follow-up and optimization of CRT delivery. AF, atrial fibrillation; CRT, cardiac resynchronization therapy; LV, left ventricular; PVC, premature ventricular contraction.

      Optimization of medications

      Before CRT delivery, optimal medical therapy might not have been possible because of hemodynamic limitations or bradycardia. However, after initiation of CRT, the clinical condition might improve, and attempts should be made to introduce medications previously not tolerated, or an increase of the dose of guideline-recommended medications should be undertaken.

      Definition of response

      Response to CRT can be defined in various ways (Table 4).
      • 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.
      • Ellenbogen K.A.
      • Huizar J.F.
      Foreseeing super-response to cardiac resynchronization therapy: a perspective for clinicians.
      • Lecoq G.
      • Leclercq C.
      • Leray E.
      • et al.
      Clinical and electrocardiographic predictors of a positive response to cardiac resynchronization therapy in advanced heart failure.
      • Achilli A.
      • Peraldo C.
      • Sassara M.
      • et al.
      Prediction of response to cardiac resynchronization therapy: the selection of candidates for CRT (SCART) study.
      • Yeim S.
      • Bordachar P.
      • Reuter S.
      • et al.
      Predictors of a positive response to biventricular pacing in patients with severe heart failure and ventricular conduction delay.
      • Mollema S.A.
      • Bleeker G.B.
      • van der Wall E.E.
      • Schalij M.J.
      • Bax J.J.
      Usefulness of QRS duration to predict response to cardiac resynchronization therapy in patients with end-stage heart failure.
      • Chung E.S.
      • Leon A.R.
      • Tavazzi L.
      • et al.
      Results of the Predictors of Response to CRT (PROSPECT) trial.
      • Buck S.
      • Maass A.H.
      • Nieuwland W.
      • Anthonio R.L.
      • van Veldhuisen D.J.
      • Van Gelder I.C.
      Impact of interventricular lead distance and the decrease in septal-to-lateral delay on response to cardiac resynchronization therapy.
      • 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.
      • Goldenberg I.
      • Moss A.J.
      • Hall W.J.
      • et al.
      Predictors of response to cardiac resynchronization therapy in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT).
      • Hsing J.M.
      • Selzman K.A.
      • Leclercq C.
      • et al.
      Paced left ventricular QRS width and ECG parameters predict outcomes after cardiac resynchronization therapy: PROSPECT-ECG substudy.
      The correlation between these methods is poor
      • Fornwalt B.K.
      • Sprague W.W.
      • BeDell P.
      • et al.
      Agreement is poor among current criteria used to define response to cardiac resynchronization therapy.
      and the relationship of many of these outcomes to more objective clinical outcomes such as survival and HF hospitalization is unclear. Cardiac performance has been studied in several trials and an improvement in the 6-minute walk, peak VO2, NYHA class, and quality of life (QOL) were commonly used.
      • Ellenbogen K.A.
      • Huizar J.F.
      Foreseeing super-response to cardiac resynchronization therapy: a perspective for clinicians.
      Remodelling end points have been studied such as a decrease in the LV end-systolic volume (LVESV) or an improvement in LVEF. Such remodelling effects have also been associated with a reduction in mortality. A reduction of ≥ 30% in the LVESV was associated with a 2% reduction in total mortality compared with a 29% increase in mortality if the reduction in LVESV was between 0 and 14%.
      • Ypenburg C.
      • van Bommel R.J.
      • Borleffs C.J.
      • et al.
      Long-term prognosis after cardiac resynchronization therapy is related to the extent of left ventricular reverse remodeling at midterm follow-up.
      Neurohormones such as N-terminal pro-type B natriuretic peptide can be used as a surrogate measure of improvement.
      • Fruhwald F.M.
      • Fahrleitner-Pammer A.
      • Berger R.
      • et al.
      Early and sustained effects of cardiac resynchronization therapy on N-terminal pro-B-type natriuretic peptide in patients with moderate to severe heart failure and cardiac dyssynchrony.
      However, there is imperfect correlation between these variables and survival. Other parameters such as improved diastolic dysfunction, decreased mitral regurgitation, and prevention of LV dilatation are associated with clinical benefit from CRT, but are not routinely assessed.
      Table 4Large clinical studies (≥ 99 patients) assessing predictors of CRT response
      Modified from Ellenbogen et al.
      • Ellenbogen K.A.
      • Huizar J.F.
      Foreseeing super-response to cardiac resynchronization therapy: a perspective for clinicians.
      with permission from Elsevier.
      StudyDefinition of CRT responseFollow-up (months)Predictors of CRT response
      Lecoq et al.
      • Lecoq G.
      • Leclercq C.
      • Leray E.
      • et al.
      Clinical and electrocardiographic predictors of a positive response to cardiac resynchronization therapy in advanced heart failure.
      Alive, no HF readmission, > 1 NYHA class improvement (or > 10% increase in peak VO2 and 6MW)6QRS shortening during CRT
      Achilli et al.
      • Achilli A.
      • Peraldo C.
      • Sassara M.
      • et al.
      Prediction of response to cardiac resynchronization therapy: the selection of candidates for CRT (SCART) study.
      Improved clinical composite score and LVEF increase ≥ 5%6Smaller LVESD, longer interventricular mechanical delay
      MIRACLE/

      MIRACLE ICD
      • 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.
      Alive and > 1 NYHA class improvement1, 3, and 6None
      Yeim et al.
      • Yeim S.
      • Bordachar P.
      • Reuter S.
      • et al.
      Predictors of a positive response to biventricular pacing in patients with severe heart failure and ventricular conduction delay.
      > 1 NYHA class improvement and no HF admission6Nonischemic etiology, wider baseline QRS width, QRS shortening during CRT
      Mollema et al.
      • Mollema S.A.
      • Bleeker G.B.
      • van der Wall E.E.
      • Schalij M.J.
      • Bax J.J.
      Usefulness of QRS duration to predict response to cardiac resynchronization therapy in patients with end-stage heart failure.
      ≥ 1 NYHA class improvement or 10% decrease in LVESV6None
      PROSPECT
      • Chung E.S.
      • Leon A.R.
      • Tavazzi L.
      • et al.
      Results of the Predictors of Response to CRT (PROSPECT) trial.
      Improved clinical composite score and LVESV decrease ≥ 15%6None
      Buck et al.
      • Buck S.
      • Maass A.H.
      • Nieuwland W.
      • Anthonio R.L.
      • van Veldhuisen D.J.
      • Van Gelder I.C.
      Impact of interventricular lead distance and the decrease in septal-to-lateral delay on response to cardiac resynchronization therapy.
      LVESV decrease > 10%6Interlead distance > 127 mm, septal-lateral delay > 60 ms, nonischemic etiology, LV end-diastolic diameter < 67 mm, use of ACE inhibitor, absence of tricuspid regurgitation
      Rickard et al.
      • 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.
      LVESV decrease ≥ 10%> 2Wider QRS
      MADIT-CRT
      • Goldenberg I.
      • Moss A.J.
      • Hall W.J.
      • et al.
      Predictors of response to cardiac resynchronization therapy in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT).
      % decrease in LVEDV and response score12Female, nonischemic etiology, LBBB, QRS > 150 ms, previous HF hospitalization, LVEDV > 125 mL/m2, left atrial volume < 40 mL/m2
      PROSPECT-ECG
      • Exner D.V.
      • Auricchio A.
      • Singh J.P.
      Contemporary and future trends in cardiac resynchronization therapy to enhance response.
      • Hsing J.M.
      • Selzman K.A.
      • Leclercq C.
      • et al.
      Paced left ventricular QRS width and ECG parameters predict outcomes after cardiac resynchronization therapy: PROSPECT-ECG substudy.
      Improved clinical composite score, LVESV decrease ≥ 15%6LBBB morphology, LV paced QRS width and QRS shortening
      ACE, angiotensin-converting enzyme; CRT, cardiac resynchronization therapy; HF, heart failure; LBBB, left bundle branch block; LV, left ventricular; LVEF, LV ejection fraction; LVEDV, LV end-diastolic volume; LVESD, LV end-systolic dimension; LVESV, LV end-systolic volume; MADIT-CRT, Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy; MIRACLE, Multicenter InSync Randomized Clinical Evaluation; MIRACLE ICD, Mulitcenter Insync ICD Randomized Clinical Evaluation; 6MW, 6-minute walk; NYHA, New York Heart Association; PROSPECT, Predictors of Response to Cardiac Resynchronization Therapy; PROSPECT-ECG, Predictors of Response to Cardiac Resynchronization Therapy ECG.

      Practical tip

      Use of a “treatment effect” based on individual patient goals of improved QOL, symptom reduction, fewer hospitalizations, and improved survival should be used to define response to CRT. This should include validated composite end points (death, hospitalization, QOL) and is preferred over the more ambiguous “response rate” comprised of a myriad of variables that might not correspond with clinical outcomes or be relevant to CRT recipients.
      • Fornwalt B.K.
      • Sprague W.W.
      • BeDell P.
      • et al.
      Agreement is poor among current criteria used to define response to cardiac resynchronization therapy.

      Evaluation of response during follow-up and approach to CRT nonresponse

      Response to CRT depends on the delivery of biventricular or LV pacing. Patient-related factors including atrial arrhythmias, and in particular AF with a poorly controlled ventricular rate, will lead to a reduction in CRT delivery. In a large cohort study, patients with AF and ≤ 98.5% biventricular pacing had a higher mortality rate compared with patients in sinus rhythm, whereas those with a biventricular pacing rate ≥ 98.5% had survival rates equivalent to those in patients without AF.
      • Saxon L.A.
      • Hayes D.L.
      • Gilliam F.R.
      • et al.
      Long-term outcome after ICD and CRT implantation and influence of remote device follow-up: The ALTITUDE Survival Study.
      However, it is not known if the lack of rate control itself is a marker of a poorer prognosis vs the lack of biventricular pacing (ie, confounding). If AF developed, or was present at the time of CRT delivery, the ventricular response rate in AF should be controlled and due consideration given to restoration and maintenance of sinus rhythm or nonpharmacological rate control if a high percentage of biventricular pacing cannot be achieved using medications. AV junctional ablation appears to be a useful approach to facilitate biventricular pacing in patients with AF and suboptimal rate control, but there is a lack of randomized trial data to support the routine use of this nonreversible intervention.
      • 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.
      Planned and ongoing RCTs will better define the appropriate role of rate vs rhythm control, and the role of routine AV junctional ablation in these patients. In addition, a high burden of ventricular ectopy (> 10,000 in 24 hours) has been linked with HF and a reduction in biventricular pacing. There are preliminary data that suggest enhanced CRT response after catheter ablation of premature ventricular beats, but additional data are needed.
      • Lakkireddy D.
      • Di B.L.
      • Ryschon K.
      • et al.
      Radiofrequency ablation of premature ventricular ectopy improves the efficacy of cardiac resynchronization therapy in nonresponders.
      Loss of LV pacing because of lack of capture or lead dislodgement will impair the delivery of CRT. A 12-lead electrocardiogram should be used to compare QRS morphology pre- and post-CT and a postoperative chest radiograph is useful to document LV lead placement and changes in position (ie, dislodgement). Although optimization of atrioventricular (AV) and interventricular (VV) timing was thought to be important in enhancing response to CRT, several large clinical trials have uniformly shown no benefit using mandatory optimization vs usual care.
      • Boriani G.
      • Biffi M.
      • Muller C.P.
      • et al.
      A prospective randomized evaluation of VV delay optimization in CRT-D recipients: echocardiographic observations from the RHYTHM II ICD study.
      • Ritter P.
      • Delnoy P.P.
      • Padeletti L.
      • et al.
      A randomized pilot study of optimization of cardiac resynchronization therapy in sinus rhythm patients using a peak endocardial acceleration sensor vs. standard methods.
      • Rao R.K.
      • Kumar U.N.
      • Schafer J.
      • Viloria E.
      • De L.D.
      • Foster E.
      Reduced ventricular volumes and improved systolic function with cardiac resynchronization therapy: a randomized trial comparing simultaneous biventricular pacing, sequential biventricular pacing, and left ventricular pacing.
      • Abraham W.T.
      • Gras D.
      • Yu C.M.
      • Guzzo L.
      • Gupta M.S.
      Rationale and design of a randomized clinical trial to assess the safety and efficacy of frequent optimization of cardiac resynchronization therapy: the Frequent Optimization Study Using the QuickOpt Method (FREEDOM) trial.
      • Ellenbogen K.A.
      • Gold M.R.
      • Meyer T.E.
      • et al.
      Primary results from the SmartDelay determined AV optimization: a comparison to other AV delay methods used in cardiac resynchronization therapy (SMART-AV) trial: a randomized trial comparing empirical, echocardiography-guided, and algorithmic atrioventricular delay programming in cardiac resynchronization therapy.
      These data suggest that factors other than AV and VV timing are important in explaining a lack of benefit with CRT.

      Super-response to CRT

      The definition of super-response to CRT is variable amongst studies.
      • Ellenbogen K.A.
      • Huizar J.F.
      Foreseeing super-response to cardiac resynchronization therapy: a perspective for clinicians.
      • Hsu J.C.
      • Solomon S.D.
      • Bourgoun M.
      • et al.
      Predictors of super-response to cardiac resynchronization therapy and associated improvement in clinical outcome: the MADIT-CRT (multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy) study.
      This typically refers to a significant improvement in either functional capacity or LVEF to a significant degree after CRT. Some studies have used a definition of improvement in the LVEF to ≥ 50%, and others have used an absolute increase in LVEF, with or without improvement in functional capacity. Despite these differences in definition, there are predictors common to many of the studies that predict a super response in 10%-38% of CRT recipients including female sex,
      • Chung E.S.
      • Leon A.R.
      • Tavazzi L.
      • et al.
      Results of the Predictors of Response to CRT (PROSPECT) trial.
      • Goldenberg I.
      • Moss A.J.
      • Hall W.J.
      • et al.
      Predictors of response to cardiac resynchronization therapy in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT).
      presence of typical LBBB,
      • 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.
      • Goldenberg I.
      • Moss A.J.
      • Hall W.J.
      • et al.
      Predictors of response to cardiac resynchronization therapy in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT).
      nonischemic LV dysfunction,
      • Chung E.S.
      • Leon A.R.
      • Tavazzi L.
      • et al.
      Results of the Predictors of Response to CRT (PROSPECT) trial.
      smaller left atrial volume, shorter duration of HF symptoms,
      • Antonio N.
      • Teixeira R.
      • Coelho L.
      • et al.
      Identification of ‘super-responders' to cardiac resynchronization therapy: the importance of symptom duration and left ventricular geometry.
      and a QRS duration of ≥ 150 ms.
      • Chung E.S.
      • Leon A.R.
      • Tavazzi L.
      • et al.
      Results of the Predictors of Response to CRT (PROSPECT) trial.
      • Goldenberg I.
      • Moss A.J.
      • Hall W.J.
      • et al.
      Predictors of response to cardiac resynchronization therapy in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT).
      Super response is also linked to reduced mortality and fewer HF hospitalizations.
      • Moss A.J.
      • Hall W.J.
      • Cannom D.S.
      • et al.
      Cardiac-resynchronization therapy for the prevention of heart-failure events.

      Optimal timing for assessment of response

      There is no definitive evidence to guide the optimal timing for the assessment of benefit from CRT (Table 5) . Large RCTs have reported CRT “response rates” at 3 (Cardiac Resynchronization in Heart Failure [CARE-HF]) and 6 months (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction [REVERSE]) with further improvements in echocardiographic assessment at 1 year.
      • Cleland J.
      • Freemantle N.
      • Ghio S.
      • et al.
      Predicting the long-term effects of cardiac resynchronization therapy on mortality from baseline variables and the early response a report from the CARE-HF (Cardiac Resynchronization in Heart Failure) Trial.
      • Cleland J.G.
      • Daubert J.C.
      • Erdmann E.
      • et al.
      The effect of cardiac resynchronization on morbidity and mortality in heart failure.
      • Linde C.
      Cardiac resynchronization therapy in mild heart failure.
      The earliest reported assessment of improvement in LVESV index and mitral regurgitation was at 3 months in the CARE-HF trial. This same study reported a statistically significant improvement in NYHA class and health-related QOL as early as 90 days after a successful CRT implant.
      Recommendation
      • 8.
        We recommend that alterations in clinical parameters after vs before CRT be assessed within 6 to 12 months after CRT implantation to guide ongoing HF management (Strong Recommendation, Low-Quality Evidence).
      Values and preferences. This recommendation is based on the importance of ensuring optimal medical therapy and deriving important benefit in improvement in reverse remodelling and QOL with CRT delivery.
      Table 5Select trials assessing optimization of intracardiac timing
      Modified from Exner et al.
      • Exner D.V.
      • Auricchio A.
      • Singh J.P.
      Contemporary and future trends in cardiac resynchronization therapy to enhance response.
      with permission from Elsevier.
      StudyComparisonResults
      RHYTHM II
      • Boriani G.
      • Biffi M.
      • Muller C.P.
      • et al.
      A prospective randomized evaluation of VV delay optimization in CRT-D recipients: echocardiographic observations from the RHYTHM II ICD study.
      Echo-optimized VV timing vs nominal VV settingsNo difference in QOL, NYHA or 6MW
      DECREASE-HF
      • Rao R.K.
      • Kumar U.N.
      • Schafer J.
      • Viloria E.
      • De L.D.
      • Foster E.
      Reduced ventricular volumes and improved systolic function with cardiac resynchronization therapy: a randomized trial comparing simultaneous biventricular pacing, sequential biventricular pacing, and left ventricular pacing.
      Simultaneous VV pacing vs EGM optimized VV timingNo difference in LV volumes or EF
      FREEDOM
      • Abraham W.T.
      • Gras D.
      • Yu C.M.
      • Guzzo L.
      • Gupta M.S.
      Rationale and design of a randomized clinical trial to assess the safety and efficacy of frequent optimization of cardiac resynchronization therapy: the Frequent Optimization Study Using the QuickOpt Method (FREEDOM) trial.
      Clinically optimized AV and VV timing vs serial EGM optimized AV and VV timingNo difference in clinical outcomes or functional measures
      CLEAR
      • Ritter P.
      • Delnoy P.P.
      • Padeletti L.
      • et al.
      A randomized pilot study of optimization of cardiac resynchronization therapy in sinus rhythm patients using a peak endocardial acceleration sensor vs. standard methods.
      Echo optimized AV and VV timing vs automatic adjustment of AV delays via contractility sensorImproved clinical response with the contractility sensor
      SMART AV
      • Ellenbogen K.A.
      • Gold M.R.
      • Meyer T.E.
      • et al.
      Primary results from the SmartDelay determined AV optimization: a comparison to other AV delay methods used in cardiac resynchronization therapy (SMART-AV) trial: a randomized trial comparing empirical, echocardiography-guided, and algorithmic atrioventricular delay programming in cardiac resynchronization therapy.
      Echo optimized AV and VV timing vs EGM optimized AV and VV timing vs fixed AV (120 ms) and VV (0 ms)No difference in LV volumes, EF, or functional measures
      AV, atrioventricular; CLEAR, Clinical Evaluation on Advanced Resynchronization; DECREASE-HF, Device Evaluation of CONTAK RENEWAL 2 and EASYTRAK 2: Assessment of Safety and Effectiveness in Heart Failure; EF, ejection fraction; EGM, electrogram; FREEDOM, Frequent Optimization Study Using the QuickOpt Method; LV, left ventricular; 6MW, 6-minute walk; NYHA, New York Heart Association; QOL, quality of life; RHYTHM II, Resynchronization for Hemodynamic Treatment for Heart Failure Management II; SMART-AV, SmartDelay Determined AV Optimization: A Comparison of AV Optimization Methods Used in Cardiac Resynchronization Therapy; VV, interventricular.
      Practical tip. See Figure 2. The process of LV remodelling is a dynamic process that begins at the time of CRT implantation, but requires ongoing reassessment throughout follow-up.

      Remote monitoring

      Remote monitoring (RM) of devices is integral to the care of patients with CRT and other CIED implants. A recent CCS/Canadian Heart Rhythm Society (CHRS) position statement provides further guidance on this topic.
      • Yee R.
      • Verma A.
      • Beardsall M.
      • Fraser J.
      • Philippon F.
      • Exner D.V.
      Canadian Cardiovascular Society/Canadian Heart Rhythm Society Joint Position Statement on the Use of Remote Monitoring for Cardiovascular Implantable Electronic Device Follow-up.

      Practical tip

      Alternating RM visits with direct device clinic follow-up visits in a 1:1 ratio is a suggested starting point. The proportion of RM-based follow-up assessments might increase or decrease as dictated by individual patient circumstances.

      Referral for cardiac transplantation and mechanical circulatory support

      Not all CRT recipients will derive benefit despite what appears to be optimal delivery of this therapy and aggressive medical management. Hence, progressive HF might ensue, requiring other interventions, such as ventricular assist devices or cardiac transplantation. The CCS HF Management Guideline update provides additional information on the role of ventricular assist devices and cardiac transplantation.
      • 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.

      Assessment of a patient at the time of pulse generator change

      Issues requiring consideration at the time of a generator replacement in CRT recipients are summarized in Figure 3. A change in the clinical status of the patient might occur between the time of the original implant and the time of generator replacement. Clinical deterioration, alteration in cognitive function, other illnesses (eg, cancer), and QOL should also be considered in the decision-making process. A multidisciplinary approach (HF team, geriatrician, family) might be of value in the decision-making process. In some patients, downgrading from a CRT-D to a CRT-P device at time of replacement is worth considering depending on the goals of care.
      Figure thumbnail gr3
      Figure 3Evaluation process at the time of generator change. CRT, cardiac resynchronization therapy; CRT-D, CRT defibrillator; CRT-P, CRT pacemaker; LV, left ventricular; PG, pulse generator.

      Device and lead advisories

      With the increased use of ICD and CRT devices, there have been increases in the number of advisories or safety alerts.
      • Maisel W.H.
      • Sweeney M.O.
      • Stevenson W.G.
      • Ellison K.E.
      • Epstein L.M.
      Recalls and safety alerts involving pacemakers and implantable cardioverter-defibrillator generators.
      The device follow-up clinic (and implanting centre) should have standard operating procedures for safety alerts and advisories. Although general recommendations are available on the CHRS Web site to help in the management, risks should be individualized. With increasing device complexity the likelihood of system-related problems increases. For example, the risk vs benefit of reusing a lead under advisory at time of generator replacement vs adding or extracting leads needs to be carefully considered and individualized.
      • Parkash R.
      • Crystal E.
      • Bashir J.
      • et al.
      Complications associated with revision of Sprint Fidelis leads: report from the Canadian Heart Rhythm Society Device Advisory Committee.
      • Parkash R.
      • Thibault B.
      • Sterns L.
      • et al.
      Sprint Fidelis lead fractures in patients with cardiac resynchronization therapy devices: insight from the Resynchronization/Defibrillation for Ambulatory Heart Failure (RAFT) study.
      However, lead revisions are best deferred to the time of a generator change to reduce the likelihood of complications including infection and bleeding.

      Deactivation of ICD therapy

      ICD deactivation is recommended when the goals of care, based on patient HF deterioration, other comorbidities or patient values, shift from one of prevention of death from ventricular arrhythmias to symptom-managed care. ICD therapy can be deactivated without affecting CRT delivery, when a decision for palliative care has been made. This option for choice needs to be addressed before the device implant and at subsequent visits when a worsening in clinical status is noted. A detailed discussion on this topic, can be found in the 2011 CCS HF management guidelines update.
      • 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.

      Health Economics and Accessibility of CRT

      Regional issues

      The expanded indication for CRT is yet to be effectively translated into practice. Data from the United States and Europe show utilization rates vary widely between regions, hospitals, and even patients based on nonclinical determinants such as sex, ethnicity, and race, with underuse and potentially inappropriate use suggested.
      • Fein A.S.
      • Wang Y.
      • Curtis J.P.
      • Masoudi F.A.
      • Varosy P.D.
      • Reynolds M.R.
      Prevalence and predictors of off-label use of cardiac resynchronization therapy in patients enrolled in the National Cardiovascular Data Registry Implantable Cardiac-Defibrillator Registry.
      Considering the established mortality and QOL benefits of CRT on the one hand, and the high cost of the technology on the other, the accumulation and dissemination of such data should be a priority for providers and policy-makers across Canada to ensure appropriate and equitable use. Acquiring such data from the relatively few hospitals across the country capable of providing CRT should be relatively easy, and the development and linkage of device registries at such centres should be encouraged and supported by provincial authorities to ensure clinical and cost-effective use.

      Wait times

      There are no direct data regarding wait-times for CRT. Previous reports have advocated for an acceptable wait-list mortality of 0.5% from death and a HF hospitalization rate of < 10%.
      • O'Neill B.J.
      • Simpson C.S.
      Canadian Cardiovascular Society Access to Care Workshop proceedings and next steps.
      • Simpson C.S.
      • Healey J.S.
      • Philippon F.
      • et al.
      Universal access–but when? Treating the right patient at the right time: access to electrophysiology services in Canada.
      Using these benchmarks, the CCS Access to Care Working Group, in conjunction with the CHRS, have recommended that CRT be implanted within 6-8 weeks of referral. Invariably, access, and hence waits, for procedures can vary by physician, centre and, in Canada, by province. Such data, as with those relating to potential regional variation in CRT referral and implantation, should also be a matter of surveillance priority for patients, providers, and policy-makers. Adequate resources for the delivery of CRT are required to meet the expanding indications for CRT and the low utilization of this therapy in some regions.
      Recommendation
      • 9.
        We suggest that CRT implantation occur within 6-8 weeks from the decision to implant to avoid preventable adverse events, such as HF hospitalizations and death (Conditional Recommendation, Low-Quality Evidence).

      Cost/benefit

      Several analyses of the cost-effectiveness of CRT have now been published including from a Canadian perspective.
      • Bentkover J.D.
      • Dorian P.
      • Thibault B.
      • Gardner M.
      Economic analysis of a randomized trial of biventricular pacing in Canada.
      • Nichol G.
      • Kaul P.
      • Huszti E.
      • Bridges J.F.
      Cost-effectiveness of cardiac resynchronization therapy in patients with symptomatic heart failure.
      • Calvert M.J.
      • Freemantle N.
      • Yao G.
      • et al.
      Cost-effectiveness of cardiac resynchronization therapy: results from the CARE-HF trial.
      • Feldman A.M.
      • de L.G.
      • Bristow M.R.
      • et al.
      Cost effectiveness of cardiac resynchronization therapy in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial.
      • Linde C.
      • Mealing S.
      • Hawkins N.
      • Eaton J.
      • Brown B.
      • Daubert J.C.
      Cost-effectiveness of cardiac resynchronization therapy in patients with asymptomatic to mild heart failure: insights from the European cohort of the REVERSE (Resynchronization Reverses remodeling in Systolic Left Ventricular Dysfunction).
      • Noyes K.
      • Veazie P.
      • Hall W.J.
      • et al.
      Cost-effectiveness of cardiac resynchronization therapy in the MADIT-CRT trial.
      Most studies now suggest that, using a lifetime time horizon, CRT in comparison with optimal medical therapy appears consistently to meet the traditional USD$50,000/quality-adjusted life-year benchmark for health care interventions in the United States and elsewhere.
      • Boriani G.
      • Biffi M.
      • Martignani C.
      • et al.
      Is cardiac resynchronization therapy cost-effective?.
      The most significant limitation of current cost-effectiveness analyses is that it has been analyzed from RCTs with limited follow-up, and these data might not be generalizable to population-based use because of differences in patient selection, use of CRT-D vs CRT-P, and appropriateness of use.

      Summary and Future Directions

      These guidelines provide direction on how to apply CRT in more complex patient cases, manage patients perioperatively, and optimize CRT delivery. Many of the areas are lacking in high-quality evidence. As more information becomes available, these recommendations will be updated accordingly.

      Acknowledgements

      Secondary Panel members: Malcolm Arnold (HF), Jeff Healey (Electrophysiology), Jonathan Howlett (HF), Francois Marcotte (Knowledge Translation), Finlay McAlister (Knowledge Translation), John Sapp (Electrophysiology), Mario Talajic (Electrophysiology), Lyall Higginson (General Cardiology), Michel White (HF), and Robert McKelvie (HF).
      Dr Exner is Canada Research Chair in Cardiovascular Clinical Trials. Dr Cox is Heart and Stroke Foundation Chair in Cardiovascular Outcomes. Dr Essebag is a Canadian Institute of Health Research Clinician Scientist.

      Supplementary Material

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