7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cardiac resynchronization therapy in heart failure: Indications and choice of system : Evan Adelstein, MD, Samir Saba, MD : Frederick Masoudi, MD, MSPH, FACC, FAHA : Todd F Dardas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 14, 2023. INTRODUCTION Cardiac resynchronization therapy (CRT) is a modality of cardiac pacing used in patients with left ventricular (LV) systolic dysfunction and dyssynchronous ventricular activation that provides simultaneous or nearly simultaneous electrical activation of the LV and right ventricle (RV) via stimulation of the LV and RV (biventricular pacing) or LV alone. This is performed by either a CRT- pacemaker (CRT-P) or by a combined CRT-implantable cardioverter-defibrillator (CRT-D). CRT devices include a transvenous pacing lead placed in a branch of the coronary sinus (or, less commonly, an epicardial or endocardial LV lead) for LV pacing, in addition to leads in the RV and right atrium. These leads are attached to a pulse generator typically located in the subcutaneous tissue of the upper chest. (See "Cardiac resynchronization therapy in heart failure: System implantation and programming".) Many of the indications for implantable cardioverter-defibrillators (ICDs) overlap with those for CRT. The indications and evidence for ICD use are discussed separately. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis".) https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 1/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate CRT and ICD therapy are key components of the management of heart failure (HF) with reduced ejection fraction in addition to pharmacologic therapy, as discussed separately. (See "Overview of the management of heart failure with reduced ejection fraction in adults".) Use of CRT in patients with atrial fibrillation is discussed separately. (See "Cardiac resynchronization therapy in atrial fibrillation".) RATIONALE FOR CRT CRT involves pacing the LV and usually simultaneous or nearly simultaneous pacing of the RV to restore ventricular synchrony and thus improve LV systolic function and clinical outcomes for selected patients with LV systolic dysfunction and electrocardiographic evidence of electrical dyssynchrony. (See 'Evidence' below.) Observational studies suggest that electrical dyssynchrony (manifest as a prolonged QRS complex on the surface electrocardiogram [ECG]) is associated with adverse clinical outcomes. Approximately one-third of patients with HF with reduced ejection fraction (HFrEF) have a "wide" QRS complex, defined as >120 ms [1]. Mortality among patients with HFrEF increases with increasing QRS complex duration [2,3]. Left bundle branch block (LBBB) is itself associated with increased mortality among patients with HFrEF of any etiology, whereas right bundle branch block is not [4]. These observations prompted studies demonstrating that LV electromechanical activation in patients with native or pacing-induced LBBB is hemodynamically disadvantageous. In the cardiomyopathic state, this inefficiency further reduces cardiac output, exacerbates functional mitral regurgitation, and worsens adverse LV remodeling (ie, dilatation) [5]. Electroanatomic mapping of the LV demonstrates that LBBB is associated with delayed activation of the basal posterolateral wall compared with nearly simultaneous electrical activation in the setting of normal His-Purkinje activation. This mechanical "dyssynchrony" was first observed with echocardiographic M-mode imaging, followed by tissue Doppler imaging and, later, speckle- tracking strain imaging. In the presence of LBBB, mechanical activation of the posterolateral LV is typically delayed compared with the interventricular septum, mirroring the findings from electroanatomic mapping. MECHANISMS OF BENEFIT Among those who respond to CRT, therapy induces immediate hemodynamic benefits, improves LV systolic function, and promotes LV reverse remodeling, whereby the LV decreases in size and https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 2/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate becomes less spherical. Acute hemodynamic benefits of CRT include increased systolic blood pressure, increased cardiac output, and increased contractility (dP/dt). In the CARE-HF trial, CRT therapy was associated with increases in LV ejection fraction of 3.7 percent at three months and 6.9 percent at 18 months and decreases in LV end-systolic volume index by 16.7 percent at three months and 29.6 percent at 18 months [6]. These findings highlight the fact that CRT confers progressive structural benefits. Unlike inotrope therapy, CRT enhances myocardial contractility without increasing myocardial oxygen consumption. The molecular mechanisms of CRT are poorly understood; this therapy is associated with potentially beneficial upregulation of HF-related genes, including sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a), phospholamban, and the beta-1 adrenergic receptor [7]. The clinical benefits of CRT are discussed below. (See 'Evidence' below.) INDICATIONS FOR REFERRAL FOR CRT Our approach Our approach to referral for CRT is presented here. The evidence to support this approach is presented below. (See 'Evidence' below.) When to consider CRT Patients with HF with reduced ejection fraction (HFrEF) with LV ejection fraction (LVEF) 35 percent should be evaluated for indications for CRT. This assessment should be performed after patients have received optimal (maximum tolerated up to target doses) evidence-based medical therapy for at least three months after initial diagnosis of HFrEF (or for at least 40 days after myocardial infarction) and after identification and treatment of any reversible causes of LV systolic dysfunction (such as myocardial ischemia or tachycardia-induced cardiomyopathy) [8]. In addition, some patients with LVEF between 35 and 50 percent may be candidates for CRT, including those anticipated to require frequent ventricular pacing (generally >40 percent of the time) or who have a QRS 150 ms with left bundle branch block (LBBB) and refractory symptoms of HF despite optimal medical therapy. Determine if an indication is present Indications for CRT and the evidence supporting these indications are discussed below. Candidacy for CRT is based upon LVEF, QRS duration, QRS pattern, New York Heart Association (NYHA) functional class, and need for ventricular pacing ( algorithm 1 and algorithm 2). (See 'CRT indications in sinus rhythm' below and 'Evidence for general indications' below.) https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 3/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate Perform an individualized risk-benefit assessment For patients with an indication for CRT, an individualized risk-benefit assessment is performed to determine whether and how to proceed with CRT. Factors associated with less expected benefit or increased periprocedural and long-term risks are described below. For patients with less compelling indications for CRT, the threshold to proceed with therapy is higher in patients who already have a pacemaker or implantable cardioverter-defibrillator (ICD), particularly if upgrade to CRT would require a stand-alone procedure (ie, considered outside the setting of a generator that has reached end-of-service). (See 'Individualized risk-benefit assessment' below.) Assess for contraindications The above individualized risk-benefit assessment includes evaluation of any contraindications as described below. (See 'Contraindications' below.) CRT indications in sinus rhythm Indications for CRT for patients in sinus rhythm are based upon LVEF, QRS duration, QRS morphology, NYHA functional class, and need for ventricular pacing as described in this section. CRT is indicated in selected patients with HFrEF with LVEF 35 percent and wide QRS (see 'For patients with LVEF 35 percent' below). CRT is also indicated in selected patients with LVEF between 35 and 50 percent who are anticipated to require frequent ventricular pacing or who have a QRS 150 ms with LBBB and symptoms of HF despite optimal medical therapy. (See 'For patients with LVEF between 35 and 50 percent' below.) Indications for CRT in patients in sinus rhythm are presented here. Recommendations for patients with persistent atrial fibrillation are discussed separately. (See "Cardiac resynchronization therapy in atrial fibrillation".) Major society guidelines that include indications for CRT include the 2012 American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) focused update of the 2008 guidelines for device-based therapy for cardiac rhythm abnormalities, the 2013 ACC/AHA HF guidelines and the 2016 European Society of Cardiology (ESC) HF guidelines, and the 2021 ESC guidelines on cardiac pacing and CRT [8-11]. (See 'Society guideline links' below.) For patients with LVEF 35 percent The following general indications apply to patients in sinus rhythm with LVEF 35 percent on optimal evidence-based medical therapy for at least three months after initial diagnosis (or for at least 40 days after myocardial infarction) and after treatment of any reversible causes of persistent HF (such as myocardial ischemia or tachycardia- induced cardiomyopathy) ( algorithm 1) [8]. Evidence supporting these recommendations is presented below. (See 'Evidence for general indications' below.) QRS 150 ms with LBBB (See 'For QRS duration 150 ms' below.) https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 4/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate For patients with QRS 150 ms with LBBB and NYHA class II to ambulatory class IV HF, we recommend referral for CRT. These patients also meet criteria for ICD therapy for primary prevention of sudden cardiac death. (See 'NYHA class III or ambulatory class IV HF' below and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) We also suggest referral for CRT in patients with NYHA class I HF and ischemic cardiomyopathy (ICM). Patients with ICM with LVEF 30 percent on medical therapy also meet criteria for ICD placement. (See 'NYHA class I or II' below.) Based on indirect evidence from patients with ICM, some experts (including the authors of this topic) also refer patients with NYHA class I HF and nonischemic cardiomyopathy (NICM) for an individualized risk-benefit assessment of CRT. These patients do not generally meet criteria for ICD placement. (See 'Individualized risk-benefit assessment' below and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) QRS 150 ms with non-LBBB (See 'For QRS duration 150 ms' below.) For patients with QRS 150 ms with non-LBBB pattern and NYHA functional class III or ambulatory class IV HF symptoms, we suggest referral for CRT. (See 'NYHA class III or ambulatory class IV HF' below.) For patients with mild (NYHA class II) HF symptoms, we refer for an individualized risk- benefit assessment of CRT including acknowledgment of the limited evidence of benefit. (See 'For QRS duration 120 to 149 ms and/or non-LBBB morphology' below and 'Individualized risk-benefit assessment' below.) QRS <150 ms (See 'For QRS duration 120 to 149 ms and/or non-LBBB morphology' below.) For patients with QRS 130 to 149 ms with LBBB and NYHA class II to ambulatory class IV HF, we suggest referral for CRT. For patients with QRS 120 to 149 ms with non-LBBB pattern, persistent NYHA functional class III or ambulatory class IV HF, and recurrent HF hospitalizations despite optimal medical therapy, we refer for an individualized risk-benefit assessment of CRT. (See 'Individualized risk-benefit assessment' below.) For patients with LVEF between 35 and 50 percent Additional recommendations apply to selected patients in sinus rhythm with LVEF >35 and <50 percent ( algorithm 2). Evidence https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 5/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate supporting these recommendations is presented below. (See 'Evidence for patients with LVEF between 35 and 50 percent' below.) For patients who require a pacemaker (including patients undergoing atrioventricular [AV] junction ablation), have an LVEF <50 percent, and are anticipated to require frequent ventricular pacing (>40 percent of the time), we suggest referral for CRT. (See 'Evidence for patients with LVEF between 35 and 50 percent' below.) For patients with QRS duration 150 ms with LBBB (native or paced) and persistent severe HF (NYHA functional class III or IV) despite optimal evidence-based medical therapy for at least three months, we refer for an individualized risk-benefit assessment of CRT- pacemaker (CRT-P). The efficacy of CRT in this population is not established. The rationale for CRT in this setting is based upon indirect evidence from trials in patients with LVEF 35 percent and a single trial in pacemaker candidates. (See 'Evidence for patients with LVEF between 35 and 50 percent' below.) Choice between CRT-D versus CRT-P Most patients with LVEF 35 percent and an indication for CRT have an indication for a concomitant ICD. Thus, a key component of the initial consultation for CRT includes a discussion with patients of both CRT-P and CRT-defibrillator (CRT- D). Generally, with a concomitant indication for an ICD, CRT-D therapy is recommended. Importantly, there are no prospective data demonstrating a survival benefit of CRT-D over CRT-P. In observational studies [12], those less likely to benefit from CRT-D compared with CRT-P include older patients (age 75 years), patients without coronary artery disease particularly if they are without dilated LV or midwall fibrosis, and pacemaker-dependent patients without coronary artery disease. (See 'Evidence for general indications' below.) Compared with CRT-D devices, CRT-P devices are smaller, less expensive, possibly incur less risk of infection, and have been subject to fewer recalls and advisories. Only CRT-D devices provide antitachycardia pacing or high-energy shocks to terminate potentially lethal ventricular arrhythmias; their use also risks the possibility of inappropriate shocks. Additionally, the high- voltage leads used in the RV for CRT-D devices historically have been less reliable than low- voltage pacing leads, which is particularly relevant to patients with pacemaker dependency [13]. Evidence Evidence for general indications For QRS duration 150 ms Randomized clinical trials have demonstrated that CRT reduces mortality, reduces hospitalizations, and improves functional status in patients with LVEF https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 6/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate 35 percent and QRS duration 150 ms (largely with LBBB) with NYHA functional class II, III, or ambulatory IV HF. NYHA class III or ambulatory class IV HF In a meta-analysis of 14 randomized trials including 4420 patients (nearly all with NYHA class III or IV symptoms, mean QRS range 155 to 209 ms), CRT increased the likelihood of improving by at least one NYHA class (59 versus 37 percent, relative risk [RR] 1.6, 95% CI 1.3-1.9). Hospitalizations for HF were reduced 37 percent, and all-cause mortality was reduced 22 percent, primarily because of a lower risk of HF-related death (RR 0.64, 95% CI 0.49-0.84) [14]. This meta-analysis included early crossover and randomized trials that demonstrated significant improvement in patients with NYHA class III to IV HF symptoms, six-minute walk distance, and NYHA functional class (MUSTIC, MIRACLE, VENTAK-CHF, CONTAK-CD) [15,16], as well as longer-term trials that corroborated these findings (COMPANION, CARE-HF) [6,17]. Additional support comes from imaging data demonstrating that CRT improves LVEF and reduces LV end-systolic volume (LVESV). For example, in the MIRACLE trial at six months, LVEF increased 3.6 percent in CRT patients versus 0.4 percent in controls, and LVESV decreased 25.6 mL compared with no change in controls [18]. Reduction in LVESV at six months by 10 percent, or "reverse remodeling," is associated with improved survival [19]. This relationship is graded; as LVESV decreases, survival improves incrementally [20]. NYHA class I or II A meta-analysis that included six trials with 4572 patients with QRS 150 ms and NYHA class I or II HFrEF (including patients with ICM and class I symptoms) found that CRT reduced HF events and improved functional status [21]. CRT significantly reduced the risk of death for patients with class II but not for class I HF [22]. There are limited data for CRT in patients with NYHA class I HF with NICM. Patients with NYHA class I and II HF were included in MADIT-CRT, REVERSE, and RAFT randomized trials [17,19,23,24]. These trials demonstrated a reduction in HF hospitalizations, improved LVEF, and reverse remodeling in patients who received CRT. Long-term follow-up (average of 2.4 years) of patients enrolled in the MADIT-CRT trial (85 percent with NYHA class II HF at baseline) demonstrated improved survival among patients receiving CRT with LBBB, LVEF 30 percent, and QRS duration 150 ms [25,26]. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 7/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate For QRS duration 120 to 149 ms and/or non-LBBB morphology For patients with LVEF 35 percent and either LBBB with QRS duration 120 to 149 ms or non-LBBB with QRS duration 150 ms, the benefits of CRT are less clear [6,16,17,23,25,27,28]. While subgroup analyses should be interpreted with some caution, a frequent finding in the trials and meta-analyses is that subgroups with shorter QRS durations or non-LBBB morphology appeared to benefit less from CRT than patients meeting more stringent QRS duration and morphology criteria [29-31]. However, a patient-level meta-analysis of randomized trials found that CRT reduced the risk of all-cause mortality in patients with a nonspecific intraventricular conduction delay >150 ms (all- cause mortality 32 versus 35 percent without CRT; adjusted hazard ratio [HR] 0.5, 95% CI 0.29- 0.89) [32]. However, the applicability of these findings to modern practice is limited by the small numbers of patients with non-LBBB and absence of modern medical and device therapies for HFrEF (eg, sodium-glucose co-transporter 2 inhibitors, multisite CRT pacing). The evidence for clinical benefit from CRT is stronger in patients with native QRS duration of 150 ms or greater than in patients with QRS duration between 120 and 149 ms [28,30,32-36]. A meta- analysis demonstrated that the risk of death or HF hospitalization was 42 percent lower (HR 0.58, 95% CI 0.50-0.68) in patients with QRS duration 150 ms or greater who received CRT-D compared with a standard ICD, whereas there was no difference in those with QRS duration 120 to 149 ms who received CRT-D (HR 0.95, 95% CI 0.83-1.10) [28]. Some experts have suggested that a true complete LBBB requires a QRS duration of at least 130 ms in women and 140 ms in men [34]. Evidence of lack of benefit and possible harm in patients with QRS duration <120 or <130 ms is discussed below. (See 'Groups unlikely to benefit' below.) Among patients treated with CRT, patients with non-LBBB QRS patterns, particularly right bundle branch block (RBBB), have less reverse remodeling and higher mortality compared with patients with LBBB [26,37,38]. There are inconsistent findings from post hoc studies and meta-analyses on the benefit of CRT in patients with RBBB regardless of QRS duration; a large patient-level meta-analysis of randomized trials found no clear benefit of CRT in this population [32,39,40]. There are limited data suggesting a benefit of CRT in patients with LVEF 35 percent and non- LBBB with QRS duration 120 to 149 ms. Meta-analyses of clinical trials have generated conflicting results on whether QRS morphology (LBBB versus non-LBBB) is a predictor of clinical benefit from CRT in patients with a QRS between 120 to 149 ms. [29,30,32,41]. Evidence for patients with LVEF between 35 and 50 percent The evidence to support use of CRT in selected patients with LVEF >35 and <50 percent is limited. The following studies support use of CRT to prevent adverse outcomes in patients with LVEF between 35 and 50 percent [42] and in patients who are anticipated to require frequent https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 8/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate ventricular pacing (>40 percent) [42,43]. The BLOCK-HF trial demonstrated that in HF patients (NYHA class I, II, and III symptoms and an LVEF between 30 and 50 percent) with AV block, CRT was superior to conventional RV pacing for the composite end point of death, HF event requiring intervention, or ventricular remodeling (45.8 versus 55.6 percent; HR 0.74, 95% CI 0.60-0.90) [42]. A similar effect was seen for the secondary end points of death or urgent HF visit (HR 0.73, 95% CI 0.57-0.92) and hospitalization for HF (HR 0.70, 95% CI 0.52-0.93). There was no significant difference in the risk of death (HR 0.83, 95% CI 0.61-1.14). The PAVE randomized trial demonstrated that patients undergoing AV junction ablation for atrial fibrillation had a better six-minute walk and LVEF with CRT compared with RV pacing, particularly in those with baseline HF symptoms and impaired systolic function [43]. Additional evidence on the effects of CRT in patients with atrial fibrillation is discussed separately. (See "Cardiac resynchronization therapy in atrial fibrillation".) For patients with an LVEF >35 and <50 percent with QRS duration 150 ms with LBBB (native or paced) and persistent severe HF (NYHA functional class III or IV) despite optimal evidence-based medical therapy for at least three months, the efficacy of CRT is not established. The rationale for CRT in this setting is based upon indirect evidence from trials in patients with LVEF 35 percent as well as the results of the BLOCK-HF trial in candidates for a pacemaker. We refer such patients for an individualized risk-benefit assessment of CRT-P. Groups unlikely to benefit CRT is unlikely to provide benefit and is probably associated with harm in the following clinical settings. Patients with a QRS duration <120 ms should not receive CRT based upon several randomized clinical trials showing no benefit from CRT-D compared with ICD in patients without QRS prolongation with NYHA class II to IV HF and echocardiographic evidence of mechanical dyssynchrony (RethinQ, Echo-CRT) [44,45]. In the EchoCRT trial in patients with a QRS duration <130 ms, overall mortality and cardiovascular mortality were higher with CRT-D compared with ICD [45]. Thus, for patients with QRS duration <120 ms, mechanical dyssynchrony should not be assessed with the objective of determining candidacy for CRT [45]. Patients with LVEF 50 percent should not receive CRT, as there are no clinical trials demonstrating CRT benefit in this context. For example, the PACE study demonstrated that while CRT was associated with the preservation of LVEF compared with RV pacing among https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 9/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate 177 patients with bradycardia, there were no differences in six-minute walk distance or quality of life at 12 months [46] or two years [47]. Nonrandomized, single-center studies suggest that CRT should not be used in nonambulatory NYHA class IV HF patients. Patients on chronic inotropic therapy for HF who receive CRT-D therapy have a poor prognosis and may not experience greater survival from CRT-D compared with ICD alone [48,49]. Evidence on CRT-D versus CRT-P Major society guidelines do not delineate the role of CRT-D versus CRT-P due to limited evidence. Only one randomized trial evaluated outcomes in separate arms for CRT-D and CRT-P (COMPANION) [17] but did not have adequate power to exclude clinically important differences. In an analysis not included in the original COMPANION report, all-cause mortality was nominally lower for CRT-D compared with CRT-P, but the difference was not significant (odds ratio 0.79, 95% CI 0.60-1.06) [50]. Other evidence is more circumstantial: The CARE-HF trial in patients with LVEF 35 percent, QRS prolongation, and NYHA class III or IV HF (nearly all class III) almost exclusively employed CRT-P. This therapy resulted in significantly lower risks of death compared with medical therapy alone at mean 29 months follow-up (20 versus 30 percent, HR 0.64, 95% CI 0.48-0.85) [6]. Most patients (62 percent) enrolled in CARE-HF had NICM. The trial provides strong evidence for use of CRT-P in this population with the objective of increasing survival but does not provide comparison with CRT-D. The DANISH trial in patients with NICM with LVEF 35 percent and NYHA class II to IV HF found no difference in mortality between those who received an ICD versus no ICD [51]. A sizable proportion of patients in both arms of the study (58 percent in both) received CRT (ie, CRT-D or CRT-P), suggesting that the benefit of CRT-P may be similar to that of CRT-D in this population. Some patient populations without prior sustained ventricular tachyarrhythmias may derive similar benefit from CRT-P compared with CRT-D. However, there are no randomized clinical trials addressing this issue, and there are no official recommendations in this respect in either European or United States guidelines. Older adults Most clinical trials did not enroll many older adult patients, particularly those 80 years old. Observational studies suggest that the frequency of ICD therapies decreases with age; among CRT recipients in the ALTITUDE registry, ICD shocks were 50 percent less common in CRT-D patients 80 years old compared with those <50 years old [52]. In https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 10/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate another study, appropriate CRT-D shocks were infrequent in patients 80 years of age (8 percent among 258 patients followed for 52 months) and were significantly less frequent than in CRT-D recipients <80 years of age [53,54]. NICM and LBBB This population may derive adequate benefit from CRT to obviate the need for defibrillator functionality [55]. The previously discussed DANISH trial provides indirect evidence of this hypothesis [51]. In an analysis from our center, smaller LV dimensions at CRT implant in NICM patients with "strictly defined" LBBB [34] were associated with lower risk of appropriate CRT-D shocks, and no patients with indexed LV 2 end-diastolic dimension (LVEDD) <3.36 cm/m height received a shock over 59 months follow-up [53,54]. NICM and pacemaker dependency These patients may also derive a benefit from CRT; in fact, many normalize LV function. In a study from our center, smaller LV dimensions (LVEDD <58 mm, LV end-systolic dimension <48 mm) and shorter time from cardiomyopathy diagnosis (<24 months) were associated with a higher likelihood of normalization of LVEF [56]. These findings are particularly relevant in patients who develop LV dysfunction with RV pacing in the setting of spontaneous or iatrogenic complete heart block. Pacemaker-dependent patients with NICM undergoing CRT upgrade had a much lower risk of device therapies for ventricular tachyarrhythmias than similar patients with known coronary artery disease in another small study [57]. NICM and lack of ventricular midwall fibrosis An observational study suggested that patients with NICM and without significant ventricular midwall fibrosis on cardiovascular magnetic resonance imaging may be a low-risk group in whom there may be no benefit from CRT-D compared with CRT-P, so some experts may favor CRT-P in this population [58]. Early implantation in new cardiomyopathy with LBBB There are data suggesting that, unlike patients with new cardiomyopathy and narrow QRS, patients with new cardiomyopathy and LBBB often do not achieve LVEF improvement with initial medical therapy [59]. Whether these patients should receive CRT-P before awaiting the outcome of medical therapy for three to nine months is unclear. Patients with congenital heart block who require ventricular pacing may also benefit from CRT. In a study of 42 patients with congenital heart block, patients who received a standard pacemaker were more likely to develop a cardiomyopathy than patients who did not require a pacemaker [60]. In four patients who subsequently underwent placement of a CRT device, LV dysfunction improved or stabilized. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 11/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate Patients with normalized or nearly normalized LVEF, with NICM who have no history of recorded ventricular tachyarrhythmias, should be counseled on whether to continue with a CRT-D device or switch to a CRT-P device at the time of generator change provided that switching hardware does not require insertion of new leads. In a meta-analysis of patients with significant improvement in LVEF ( 45 percent) after CRT and no secondary indication for ICD implantation, the incidence of appropriate ICD therapy during follow-up was significantly lower. Similarly, in a study from our group, patients who normalized their LV dimensions with CRT had a very low incidence of appropriate ICD therapy [61,62]. However, a MADIT-CRT post hoc analysis demonstrated that although the risk of ventricular tachyarrhythmias among CRT patients who had improved LVEF and no longer met a primary prevention ICD indication was reduced by over 50 percent, there remained a significant risk of arrhythmias during the ensuing two years [63]. Risks The risks of CRT are greater than those of single- or dual-chamber devices, as LV lead implantation increases procedural complexity, increases risk of infection, and reduces battery longevity, necessitating more frequent generator changes. In addition, there are reports of LV pacing inducing ventricular arrhythmias in a minority of CRT recipients [64]. Complications of CRT are discussed separately. (See "Cardiac resynchronization therapy in heart failure: System implantation and programming".) SHARED DECISION MAKING FOR CRT General considerations Because of the heterogeneity of benefit conferred by treatment as a function of patient factors, the lack of compelling data in some patient populations, and the frequency of comorbidities in patients with HF, decision making around CRT is often complex. Ultimately, the decision to pursue the therapy should be informed by best estimates of both benefits and risks in the context of shared decision making, which is defined as selecting therapy from the reasonable options that is aligned with the patient s values, goals, and preferences [65]. Indeed, the ACC/AHA/HRS guidelines specifically recommend informed shared decision making as integral to the provision of implantable cardioverter-defibrillator (ICD) and CRT therapy. Because many patients considered for CRT have advanced symptomatic HF, the discussion about device therapy will be part of a larger discussion about prognosis. (See "Palliative care for patients with advanced heart failure: Indications and systems of care", section on 'Disease course and prognosis'.) The capacity to estimate the benefits of CRT varies substantially based upon patient characteristics. In cases where benefits are not well established, the limitations of existing data should be openly acknowledged in the decision-making process. A patient-level analysis of five randomized trials of CRT found that quality of life (QoL) benefits at three months were predicted https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 12/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate by patient age, baseline QoL, and QRS duration [66]. Such statistical models may be useful in determining the likely advantages of undergoing CRT implantation. Further, clinicians must also elicit and consider the patient's care-related goals and preferences in order to achieve shared decision making [67]. Individualized risk-benefit assessment Because CRT is associated with risk, both acutely during implantation and chronically, the risk-benefit ratio of CRT implant must be considered in each individual patient, particularly in those with less compelling indications. The CRT implantation procedure is longer, entails more procedural risk, and may increase the risk of infection compared with standard ICD or pacemaker implantations. LV leads have an increased risk of dislodgment or pacing the phrenic nerve compared with traditional RV leads. Battery longevity is generally shorter for CRT devices compared with conventional ICDs or pacemakers. Another consideration is that not all patients with similar indications for CRT derive similar benefits, but a means of identifying patients with indications for CRT who will fail to benefit has not been established. Approximately one-third of CRT recipients are deemed "nonresponders" [68], although the definition of "response" is not standardized [69]. Definitions of response include improvement in exercise capacity, improved QoL via standardized assessments, improvement in New York Heart Association (NYHA) status by at least one class, prevention of HF hospitalizations, and LV reverse remodeling. A subset of patients may be "negative responders" and become worse with CRT. Increased risk with an upgrade procedure Intervening on a device system already in place (ie, CRT "upgrade") entails increased risk of infection and complications compared with de novo implant or generator change only. In the REPLACE registry, the six-month major complication rate for CRT upgrades was 18.7 percent, compared with 4.0 percent for patients undergoing generator change only [70]. The threshold for upgrading an existing device to CRT is thus higher than for a de novo implant. A stand-alone "upgrade" procedure in patients with an existing pacemaker or ICD should be considered only after careful consideration of the risk-benefit balance. Factors associated with less benefit from CRT Greater scar burden, as assessed by either myocardial perfusion or cardiovascular magnetic resonance imaging, is associated with less improvement in LV ejection fraction, less reverse remodeling, and higher mortality among patients treated with CRT [71]. However, there are no randomized trials assessing whether patients with high scar burden benefit less from CRT. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-heart-failure-indications-and-choice-of-system/print 13/32 7/6/23, 10:50 AM Cardiac resynchronization therapy in heart failure: Indications and choice of system - UpToDate As discussed above, among patients treated with CRT, non-left bundle branch block (LBBB) QRS patterns, particularly right bundle branch block, are associated with less reverse remodeling and higher mortality compared with LBBB. (See 'Groups unlikely to benefit' above.) As discussed above, a native QRS duration between 120 and 149 ms predicts less clinical benefit from CRT than QRS duration 150 ms or greater. (See 'Groups unlikely to benefit' above.) Because milder HF symptoms are associated with a lower baseline risk of morbidity and mortality, the estimated absolute risk reduction from CRT is lower in those with less severe symptoms. For patients with less compelling indications and in patients for whom CRT would be a stand-alone upgrade procedure rather than a de novo implant, NYHA functional class is an important factor in decision making, as the risk-benefit balance may favor CRT in more advanced HF symptoms and not favor CRT in those patients with less severe symptoms. Competing causes of cardiopulmonary morbidity and mortality Patients with severe chronic obstructive pulmonary disease (COPD) may not derive symptomatic benefit from CRT if their symptoms are predominantly caused by COPD [72]. Clinically, identifying the cause of dyspnea in patients with both HF and COPD can be challenging. Patients with severe renal insufficiency may benefit less from CRT and may also not benefit from ICDs [73,74]. Median survival after an appropriate CRT-D shock in patients with severe renal insufficiency was only 90 days in one observational study [75]. The risk of device- related infection is also higher in this population [24]. Hemodialysis is associated with a high rate of device complications, including hematoma, pocket infection, bacteremia with endovascular lead infection, and compromise of hemodialysis access [76]. Patients on hemodialysis also may have limited access for intravascular lead placement. There are no randomized trials demonstrating mortality benefit in older adult patients, particularly those over 80 years of age. The risk of sudden cardiac death decreases with advancing age, whereas the risk of progressive pump failure increases. CRT-pacemaker may be a better option in clinically eligible older patients with significant symptoms of HF compared with CRT-defibrillator. (See 'Indications for referral for CRT' above.)