|Year : 2017 | Volume
| Issue : 1 | Page : 5-12
Cardiac resynchronization therapy for the treatment of mild heart failure: A review of the clinical data
Timothy P Phelan, Judith A Mackall
Center for Cardiac Electrophysiology and Pacing, Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
|Date of Web Publication||19-Jun-2017|
Judith A Mackall
Center for Cardiac Electrophysiology and Pacing, Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, 11100 Euclid Avenue, Cleveland, Ohio 44106
Source of Support: None, Conflict of Interest: None
Cardiac resynchronization therapy (CRT) was originally established as an effective treatment for patients with systolic heart failure (HF) with New York Heart Association Class III–IV symptoms, reduced left ventricular ejection fraction and prolonged QRS duration ≥120 ms. Subsequent studies expanded the role of CRT to the treatment of patients with mildly symptomatic HF as these patients experienced similar improvement in clinical symptoms and reverse remodeling of the left ventricle. These clinical trial results were incorporated into the 2013 guidelines on cardiac pacing and CRT from the European Society of Cardiology and the 2012 American College of Cardiology Foundation/American Heart Association/Heart Rhythm Society Focused Update on Device-based Therapy of Cardiac Rhythm Abnormalities. Additional data from careful post hoc and substudy analyses as well as long-term follow-up of the original study cohorts have been performed. These results attempt to identify subgroups more likely to benefit from CRT, to define the association between response and QRS morphology/duration and to demonstrate the sustained benefit of CRT in this population. More importantly, these results highlight that patients with mildly symptomatic HF who respond to CRT not only have improvement in clinical symptoms but also receive a therapy that may prevent or delay progression of HF. A review of the clinical trials in mildly symptomatic HF and the results of subsequent post hoc analysis are summarized herein.
Keywords: Cardiac resynchronization therapy, heart failure, review
|How to cite this article:|
Phelan TP, Mackall JA. Cardiac resynchronization therapy for the treatment of mild heart failure: A review of the clinical data. Int J Heart Rhythm 2017;2:5-12
|How to cite this URL:|
Phelan TP, Mackall JA. Cardiac resynchronization therapy for the treatment of mild heart failure: A review of the clinical data. Int J Heart Rhythm [serial online] 2017 [cited 2018 Jan 24];2:5-12. Available from: http://www.ijhronline.org/text.asp?2017/2/1/5/208455
| Introduction|| |
Over the past decade, cardiac resynchronization therapy (CRT) has become an established treatment for patients with symptomatic New York Heart Association (NYHA) Class III–IV heart failure (HF), left ventricular ejection fraction (LVEF) ≤35%, and QRS duration of over 120 ms. Patients undergoing CRT demonstrated improvement in quality-of-life (QOL), exercise capacity, and heart function as well as a decrease in HF hospitalizations and mortality.,, Subsequent studies were undertaken to evaluate the effectiveness of CRT in patients with asymptomatic (NYHA Class I) and mildly symptomatic (NYHA Class II) patients. These studies are the basis for current practice guidelines and are reviewed herein [Table 1].
|Table 1: Randomized clinical trials of cardiac resynchronization therapy in mild heart failure|
Click here to view
| Early Studies|| |
Two early trials prompted investigation into the utility of CRT in the mildly symptomatic HF patient. The Cardiac Resynchronization Therapy for the Treatment of Heart Failure in Patients with Intraventricular Conduction Delay and Malignant Ventricular Tachyarrhythmias (CONTAK CD) trial randomized patients with NYHA Class II to IV HF, LVEF ≤35%, and QRS ≥120 ms to an implantable cardioverter defibrillator (ICD) plus CRT (CRT activated) or to ICD alone (CRT deactivated). Of the 241 patients with NYHA Class II HF, CRT resulted in significant improvement in left ventricular (LV) systolic and diastolic dimensions at 6 months. The Multicenter InSync ICD Randomized Clinical Evaluation II (MIRACLE ICD II) study was the first trial designed to evaluate the safety and efficacy of CRT in NYHA Class II HF. This small trial randomized 186 patients with LVEF ≤35%, QRS ≥130 ms, and LV end-diastolic diameter ≥55 mm on optimal medical therapy to ICD plus CRT (CRT-ON) or to ICD alone (CRT-OFF). CRT resulted in significant LV reverse remodeling (improved systolic and diastolic dimension and LVEF) and significantly improved exercise capacity and NYHA class at 6 months compared to medical therapy alone. These small studies, although positive, did not include NYHA Class I patients and had limited follow-up.
| Resynchronization Reverses Remodeling in Systolic Ventricular Dysfunction Study and Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy|| |
The Resynchronization Reverses Remodeling in Systolic Ventricular Dysfunction (REVERSE) study enrolled 610 patients with NYHA Class I and II HF between 2004 and 2006 on optimal medical therapy to CRT device implantation and randomized patients in 2:1 fashion to either CRT-ON or CRT-OFF. Additional inclusion criteria included LVEF ≤40%, QRS ≥120 ms, and LV end-diastolic diameter ≥55 mm. NYHA Class II symptoms were present in 83% of patients at enrollment. CRT with pacemaker alone was implanted in 17% of cases. Patients were followed for 1 year in North America and 2 years in Europe. The primary end point was a worsening in the clinical composite end point of death, significant HF leading to hospitalization or trial arm cross-over, and worsening NYHA class or reported HF symptoms. The statistically powered secondary end point was LV end-systolic volume index (LVESVI). All devices were switched to CRT-ON at the end of the study period.
At 1 year, there was no significant difference in worsened clinical composite end point with 16% of patients assigned to CRT-ON with worsened HF compared to 21% in the CRT-OFF arm (P = 0.10). At 2 years, however, the European cohort revealed a significantly worsened HF composite end point in 34% of patients in the CRT-OFF arm versus 19% of patients in the CRT-ON group (P = 0.01). This difference was driven largely by hospitalizations due to HF with a 53% relative risk reduction in CRT-ON patients. There was no significant difference in mortality. The secondary end point of LVESVI was significantly improved in the CRT-ON arm at both 1 and 2 years with a mean change of − 18.4 ml/m 2 as compared to −1.3 ml/m 2 in the CRT-OFF arm. Other echocardiographic parameters including LV end-diastolic volume index and LVEF were also significantly improved in CRT-ON patients. There was no significant difference in other reported parameters including 6-minute walk distance (6-MWD) and QOL scores; however, the study was not adequately powered for these end points.
The Multicenter Automatic Defibrillator Implantation Trial with CRT (MADIT-CRT) enrolled 1820 patients between 2004 and 2008 with LVEF ≤ 30%, QRS ≥ 130 ms, and NYHA Class I (ischemic cardiomyopathy only) or II (ischemic and nonischemic cardiomyopathy) HF. Patients were assigned in 3:2 fashion to ICD-CRT versus ICD-only. The primary end point was a composite of all-cause death and nonfatal HF events. Patients were followed for an average of 2.4 years. The trial was stopped early by recommendation of the data and safety monitoring board.
At trial's end, the composite end point occurred in 17.2% of ICD-CRT patients and 25.3% of ICD-only patients. This resulted in a 34% relative risk reduction of nonfatal HF or death. This difference was driven by a 41% reduction in HF events; there was no significant difference in mortality. Echocardiographic measurements at 1 year showed significantly improved LV end-systolic and diastolic volumes and LVEF in the ICD-CRT cohort.
REVERSE and MADIT-CRT were the first large trials of CRT in asymptomatic and minimally symptomatic patients with LV dysfunction and a widened QRS. Both studies demonstrated that CRT resulted in a significant reduction in HF symptoms as well as reverse LV remodeling when coupled with optimal medical therapy. These benefits persisted with long-term follow-up of up to 5 years. In addition, a subsequent analysis of the MADIT-CRT data demonstrated a significant improvement in the QOL for patients receiving CRT when compared to the ICD-only group.
| Mortality Benefit|| |
The Resynchronization-defibrillation for Ambulatory Heart Failure Trial (RAFT) was undertaken to determine if the addition of CRT to an ICD resulted in a mortality benefit. The study randomized 1798 patients between 2003 and 2009 with NYHA Class II or III HF, LVEF ≤30%, and QRS ≥120 ms (or paced QRS ≥200 ms) to either ICD-CRT or to ICD-only. While RAFT initially included patients with moderately symptomatic HF (NYHA Class III), the protocol was modified to include only NYHA Class II symptoms. Thus, mildly symptomatic patients ultimately predominated and comprised 80% of total enrollment. The primary end point was a composite of all-cause death and HF leading to hospitalization. Secondary end points were all-cause death, death from any cardiovascular cause, and hospitalization due to HF.
The primary composite end point occurred in 33.2% of ICD-CRT patients as compared to 40.3% of ICD-only patients (P < 0.001). This represented a 24% relative risk reduction in the ICD-CRT group. The secondary end point of all-cause death was also significantly reduced in ICD-CRT patients at 20.8% as compared to 26.1% in the ICD-only arm (P = 0.003). Both of these differences remained significant when only NYHA Class II patients were included in the analysis. Similar to the previous trials, there was also a significant reduction in HF requiring hospitalization with ICD-CRT use at 16.2% as compared to ICD-only at 21.8% (P = 0.003).
Thus, RAFT was the first individual trial to show a significant mortality benefit in mildly symptomatic HF. Additional evidence, however, does support increased survival with CRT. A meta-analysis by Wells et al. including patients from the MIRACLE ICD II, REVERSE, MADIT-CRT, and RAFT trials reported a significant relative risk reduction of 20% in mortality for patients with NYHA Class I or II HF with the use of an ICD-CRT compared to ICD-only although these results were driven primarily by RAFT.
Long-term follow-up data of 854 MADIT-CRT patients up to 7 years after trial enrollment showed a significant survival benefit in ICD-CRT patients with 18% mortality as compared to 29% mortality in ICD-only patients (P < 0.001) in the subset of patients with left bundle-branch block (LBBB). Survival models applied to REVERSE 5-year follow-up data predicted a 22.8% survival benefit in CRT-ON patients as compared to CRT-OFF; however, the trial protocol to switch all patients to CRT-ON at 2 years limited the ability to gain prospective comparative data of these therapies.
| Cardiac Resynchronization Therapy in Chronic Pacing|| |
Trials examining the role of CRT for patients meeting indications for bradycardic pacing have incorporated patients with mild HF. The LV-based cardiac stimulation post-atrioventricular nodal ablation evaluation (PAVE) study randomized 184 patients with chronic atrial fibrillation undergoing atrioventricular (AV) node ablation and with NYHA Class I–III HF in 2:1 fashion to either biventricular pacing or right ventricular (RV) pacing. NYHA Class I and II HF was present in 68% of patients and the mean LVEF was <50%. The primary end point was changed in 6-MWD at 6 months as compared to before AV nodal ablation. Secondary end points were changes in QOL survey and LVEF. Overall, 6-MWD and LVEF at 6 months were significantly higher in the patients receiving CRT pacing. In patients with NYHA Class I HF, there was no difference in 6-MWD at 6 months. There was a significant improvement in 6-MWD with CRT among the NYHA Class II/III subgroup; however, the outcomes for mildly symptomatic patients were not separately reported.
The biventricular versus RV pacing in HF patients with AV block (BLOCK HF) trial randomized 691 patients from 2003 to 2009 with NYHA Class I–III HF, LVEF ≤50%, and indication for ventricular pacing due to high-grade AV nodal block, after implantation of a biventricular device to either biventricular (CRT-ON, n = 349) or RV pacing (CRT-OFF, n = 342). NYHA Class I and II HF was present in 73% of patients at the time of enrollment. QRS morphology and duration were not part of the inclusion or exclusion criteria. Lower LVEF was more prevalent in CRT-ICD patients than CRT-pacemaker patients due to primary prevention guidelines. The primary outcome was a composite of time to first episode of all-cause death, HF requiring intravenous therapy, or an increase of LVESVI of ≥15% from baseline. The secondary end points were composite outcomes and individual outcomes of all-cause death, HF requiring urgent care visit, and HF requiring hospitalization.
The primary composite outcome occurred less frequently in the CRT-ON group (45.8%) than the CRT-OFF group (55.6%) for a hazard ratio (HR) of 0.74. A similar rate of occurrence was observed in the secondary outcome of death or urgent care visit for HF with an HR of 0.73. The event-free survival of patients with CRT devices occurred irrespective of whether a CRT-ICD or CRT-pacemaker was implanted. This suggested that the response to CRT was not tightly linked to LVEF. Primary and secondary outcomes were not categorized based on initial NYHA class although nearly three-quarters of patients had class I or II symptoms at enrollment.
| Impact of Qrs Properties|| |
QRS duration was a key inclusion criterion for all of the CRT trials with exception to those focused on chronic pacing. The relationship between QRS morphology and QRS duration as a measure of underlying dyssynchrony whether interventricular, intraventricular, or intramural is not completely understood. The impact of both QRS duration and morphology on outcome of CRT therapy has subsequently been examined more closely in subgroup analyses.
In the REVERSE trial, the odds ratio (OR) for the subset of patients with QRS ≥152 ms greatly favored CRT-ON over CRT-OFF (OR = 0.42) for combined end point of death and HF events (OR = 0.42). In patients with QRS <152 ms, there was no difference in end point between the two treatment groups. Reduction in LVESVI increased progressively with initial QRS duration to a mean reduction as large as 33.3 ml/m 2 for QRS ≥168 ms as compared to 5.2 ml/m 2 for QRS <134 ms. This finding was due primarily to patients with LBBB.
In MADIT-CRT, a significant benefit was observed in the composite end point of death and HF events within the prespecified subgroup of QRS ≥150 ms in the ICD-CRT treatment arm as compared to ICD-only. There was no outcome difference between treatment arms for patients with QRS <150 ms. These outcomes benefit from ICD-CRT did extend to the QRS <150 ms cohort when LBBB was present when followed long term up to 7 years after trial enrollment.
In addition, in RAFT, the ICD-CRT cohort showed significantly reduced HRs for the end point of death and HF events in patients with QRS ≥150 ms when compared to ICD-only. There was no difference in HRs between ICD-CRT and ICD-only outcomes for QRS <150 ms or paced QRS ≥200 ms. In patients with LBBB, there was a continuous relationship between broader QRS ≥160 ms and clinical benefit with ICD-CRT. It was less clear if this benefit was also conferred to non-LBBB patients.
When REVERSE patients were categorized by QRS morphology, CRT significantly improved the clinical composite score in LBBB patients (P = 0.0034) but had no significant effect for the non-LBBB group (P = 0.21). In addition, CRT resulted in LV reverse remodeling in the LBBB cohort. There was a large reduction in LVESVI with CRT in the LBBB group (25.3 ml/m 2 mean reduction) as compared to the non-LBBB group (6.7 ml/m 2). There was also a significant mean increase of 6.9% in LVEF with CRT-ON in the LBBB group, whereas no significant change was noted in non-LBBB patients. The previously mentioned incremental improvement in LVESVI by CRT with increasing QRS durations was noted in LBBB patients; no interaction between QRS duration and non-LBBB morphologies was observed. Within non-LBBB subcategories, patients with nonspecific intraventricular conduction delay (NIVCD) had modestly reduced LVESVI compared to right bundle-branch block (RBBB) (7.8 ml/m 2 vs. 3.5 ml/m 2) but a less favorable clinical composite score odds ratio. Overall, CRT benefited patients with LBBB and longer QRS durations.
Analysis of MADIT-CRT patients by QRS morphology showed a 53% risk reduction in the end point of death, HF events, and arrhythmias for LBBB patients treated with ICD-CRT (HR: 0.47) as compared to ICD-only (HR: 1.24). These benefits were seen in LBBB regardless of QRS duration, LVEF, or LV volumes. When stratified by gender, however, female patients responded to CRT regardless of QRS duration whereas male patients appeared to benefit at QRS durations ≥160 ms. No clinical benefit was seen in non-LBBB treated with ICD-CRT (HR: 1.24). There was a significantly higher reduction in LV end-systolic volume in LBBB patients treated with ICD-CRT than in non-LBBB, with average reductions of 35% and 26%, respectively. LVEF increased an average of 11.9% in LBBB patients treated with ICD-CRT compared to 8.8% in non-LBBB (P < 0.001). The long-term survival benefit of MADIT-CRT patients in the ICD-CRT cohort of 18% mortality at 7 years as compared to 29% mortality in ICD-only patients was seen only in LBBB. This benefit was seen regardless of QRS duration. There was no difference in 7-year mortality between ICD-CRT and ICD-only in non-LBBB patients (P = 0.58). In addition, significant improvements in QOL for patients receiving CRT as compared to ICD-only were only seen in those with LBBB.
In RAFT, the ICD-CRT cohort had significantly reduced HRs for death or HF events in the LBBB group. There was no difference in outcomes between ICD-CRT and ICD-only when QRS morphology was RBBB, NIVCD, or paced. Subsequent analysis has shown a trend toward harm with increased HRs for ICD-CRT in patients with non-LBBB.
Interestingly, analysis of QRS characteristics from REVERSE identified 57 patients with narrow QRS ≤120 ms at the time of enrollment. This was the only QRS morphology subgroup with which CRT therapy was associated with an increased HR for the composite outcome of death and HF events. These findings mirror the poor outcomes observed in larger trials of CRT use in patients with NYHA Class III and IV and a QRS ≤120.,,, Currently, there is no evidence to support the use of CRT in patients with mild HF and a narrow QRS complex.
| Influence of Patient Characteristics on Cardiac Resynchronization Therapy Response|| |
Etiology of heart failure
The effect of CRT with respect to HF etiology was evaluated in post hoc analyses of both REVERSE and MADIT-CRT patients. In REVERSE, 277 patients with a nonischemic etiology of HF were compared to 333 patients with ischemic heart disease. Patients with ischemic heart disease were significantly older and had more comorbidities. The presence of LBBB and a wider QRS were predictors of CRT response. Patients with nonischemic etiology showed significantly greater reverse remodeling with CRT; however, both groups demonstrated a clinical response. HF etiology was not an independent predictor of clinical response.
In MADIT-CRT, 1046 patients with ischemic heart disease were compared to 774 patients with nonischemic heart disease. Once again, patients with ischemic heart disease were older and had more comorbidities including hypertension, diabetes, and renal dysfunction. The nonischemic group had more female patients and a higher percentage of LBBB. The nonischemic group demonstrated significantly more reverse remodeling and improvement in LVEF; however, both groups demonstrated a significant reduction in the risk of HF or death with ICD-CRT compared to ICD-only. The ischemic group had a 34% risk reduction (P = 0.001) and the nonischemic group had a 44% risk reduction (P = 0.002) for the combined end point of HF or death.
Chronic kidney disease
In patients with mild HF, renal dysfunction is associated with an increased risk of death and HF. The effect of CRT in patients with chronic kidney disease (CKD) was evaluated in both the REVERSE and MADIT-CRT study populations., In the REVERSE cohort, 29% of patients (n = 160) had glomerular filtration rate (GFR) <60 ml/min/1.73 m 2. These patients were more likely to be older, diabetic, and have underlying hypertension and ischemic heart disease. Among patients assigned to CRT, those without CKD had significantly greater improvements in LV remodeling. In addition, regardless of CRT status, patients with CKD demonstrated a progressive decline in LVEF with LV dilation over the 12-month follow-up. Despite the attenuation of structural reverse remodeling, the presence of CKD was not an independent predictor of the clinical composite response.
A retrospective subgroup analysis of the MADIT-CRT population stratified patients into those with LBBB (n = 1274) and without LBBB (n = 546), and then further stratified by GFR >or <60 ml/min/1.73 m 2. In patients with LBBB, those with a reduced GFR (n = 413) had a higher risk of death (HR: 2.09) and a higher risk of HF or death. Yet, in both GFR subgroups, ICD-CRT was associated with mortality reduction as well as less HF events. In the non-LBBB group, low GFR predicted outcomes and no benefit from CRT was observed.
Both of these subgroup analyses highlight the progressive LV remodeling that occurs in patients with CKD. These patients often have more comorbidities including ischemic heart disease. No data are available for patients with mild HF and end-stage renal disease (creatinine >3.0 mg/dL) as these patients were excluded from the study. While LV reverse remodeling appears to be attenuated in the patient with CKD, the clinical benefit to CRT persists, especially in the presence of LBBB. The current guidelines do not incorporate the presence or severity of CKD in patient selection criteria.
Left ventricular ejection fraction
BLOCK HF, as described previously, enrolled patients in need of pacing with both mild HF as well as mild LV dysfunction. The clinical and structural response to CRT was evident across the range of LVEF including those with mildly reduced LVEF. REVERSE was the only large randomized trial of CRT in mild HF to include patients with LVEF >30%. A total of 177 patients (23.7%) had LVEF >30% (35.1% ±3.8%). CRT-ON resulted in significant improvement in the clinical composite score of death and HF events at 12 months when compared to CRT-OFF in patients with LVEF ≤30% and >30%. There were overall more events in the LVEF ≤30% cohort. CRT-ON also resulted in significant reverse remodeling including LVESVI and LVEF for both LVEF groups although changes were more pronounced in the LVEF ≤30% patients.
MADIT-CRT enrolled patients with LVEF of <30% by echocardiogram; however, the echocardiograms performed at enrollment were not read at a core laboratory. In a post hoc analysis, it was recognized that significant variability in EF measurement can occur and therefore the baseline echocardiogram study was reassessed by a core laboratory and LVEF was recalculated. Patients were then placed in prespecified subgroups of LVEF <25%, LEVF 26%–30%, and LVEF >30%, and outcomes were examined. Thirty-eight percent or 696 of the 1809 patients enrolled had an LVEF >30%. Although there were more NYHA Class I patients in this cohort, the difference between groups was not statistically significant. As expected the LVEDV and LVESV were smaller, yet the reverse remodeling was more pronounced in the group with EF >30%. Thus, the clinical benefit of CRT was present regardless of LVEF subgroup. Other smaller series have reported similar improvements in functional status, exercise capacity, and QOL.
Cost-effectiveness and quality-adjusted life year (QALY) models were applied to 262 patients in the European cohort of REVERSE comparing CRT-ON versus CRT-OFF over 10 years. CRT-ON was estimated to gain 0.80 QALY as compared to CRT-OFF with a number needed to treat of 4.9 to avoid one death at 10 years. The estimated probability of CRT being cost-effective was as high as 79.6%. Again, the trial protocol to switch all patients to CRT-ON at 2 years limited the ability to gain prospective comparative data of these therapies for cost-effectiveness.
Associated cost and QOL assessments of ICD-only versus ICD-CRT were carried out prospectively alongside the main MADIT-CRT trial in the USA cohort of patients and the average values at 4 years were reported. Information collected included hospitalizations (including that of initial implant), health care visits, outpatient surgeries, and diagnostic tests and procedures. The overall average cost was slightly higher in the ICD-CRT cohort which was attributable to cost at initial implant. There was no significant difference in overall QALY between the ICD-only and ICD-CRT cohorts; however, patients with LBBB did derive a significant benefit from CRT when compared to non-LBBB and the CRT cohort as a whole. There was a significant benefit in HF-free QALY in the ICD-CRT with 0.24 years gained at 4 years compared to ICD alone. This improvement was even more striking in patients with LBBB with 0.46 QALY gained by ICD-CRT. The estimated probability of CRT being cost-effective at 4 years, particularly in patients with LBBB, was between 40% and 80% and would be expected to become even more favorable over a longer course of follow-up.
| Conclusion|| |
Results of randomized trials in mildly symptomatic HF patients (MADIT-CRT, RAFT, and REVERSE) have shown that CRT in patients with reduced LVEF ≤35%, prolonged QRS duration >120–130 ms, NYHA Class II HF results in clinical benefit, with reverse remodeling, improvement in QOL, exercise tolerance, and life expectancy. Subgroup and meta-analysis suggest that the QRS morphology may be more predictive of response than QRS duration although both morphology and duration remain important in patient selection and outcome. Based on these results, patients with NYHA Class II HF, EF ≤35%, and LBBB with QRS >120 ms have a Class I indication per the 2013 European Society of Cardiology guidelines on cardiac pacing and cardiac resynchronization. Patients who are asymptomatic (NYHA Class I) are not indicated for CRT based on the lack of clinical data in this patient population. The 2012 American College of Cardiology Foundation/American Heart Association/Heart Rhythm Society focused update to the 2008 Guidelines for Device-Based Therapy reserve the Class I indication for patients with LBBB and QRS ≥150 ms and assigned a Class IIa indication for patients with LBBB and QRS 120–149 ms. Patients with asymptomatic or NYHA Class I HF, LVEF <30%, and LBBB ≥150 ms received a Class IIb indication per these guidelines.
Patients with mild HF who meet criteria for CRT can expect not only clinical improvement but also lasting effects which may halt or slow disease progression. More data are needed to determine if asymptomatic patients with reduced LVEF would receive a similar benefit. The relationship between QRS morphology and duration as a measure of dyssynchrony is not completely understood. Patients with other QRS characteristics may derive benefit from CRT; however, further evidence is needed to define these populations as well the optimal method to deliver CRT.
Financial support and sponsorship
Conflicts of interest
Dr. Mackall has received honoraria for speaking and consulting from St. Jude Medical and research grants from St. Jude Medical, Medtronic, and Boston Scientific.
| References|| |
Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, et al.
Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845-53.
Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, et al.
Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140-50.
Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, et al.
The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539-49.
Higgins SL, Hummel JD, Niazi IK, Giudici MC, Worley SJ, Saxon LA, et al.
Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias. J Am Coll Cardiol 2003;42:1454-9.
Abraham WT, Young JB, León AR, Adler S, Bank AJ, Hall SA, et al.
Effects of cardiac resynchronization on disease progression in patients with left ventricular systolic dysfunction, an indication for an implantable cardioverter-defibrillator, and mildly symptomatic chronic heart failure. Circulation 2004;110:2864-8.
Linde C, Abraham WT, Gold MR, St. John Sutton M, Ghio S, Daubert C; REVERSE (REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction) Study Group. Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. J Am Coll Cardiol 2008;52:1834-43.
Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, et al.
Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009;361:1329-38.
Tang AS, Wells GA, Talajic M, Arnold MO, Sheldon R, Connolly S, et al.
Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med 2010;363:2385-95.
Doshi RN, Daoud EG, Fellows C, Turk K, Duran A, Hamdan MH, et al
. Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study). J Cardiovasc Electrophysiol 2005;16:1160-5.
Curtis AB, Worley SJ, Adamson PB, Chung ES, Niazi I, Sherfesee L, et al
. Biventricular pacing for atrioventricular block and systolic dysfunction. N
Engl J Med 2013;368:1585-93.
Linde C, Gold MR, Abraham WT, St. John Sutton M, Ghio S, Cerkvenik J, et al.
Long-term impact of cardiac resynchronization therapy in mild heart failure: 5-year results from the REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) study. Eur Heart J 2013;34:2592-9.
Veazie PJ, Noyes K, Li Q, Hall WJ, Buttaccio A, Thevenet-Morrison K, et al.
Cardiac resynchronization and quality of life in patients with minimally symptomatic heart failure. J Am Coll Cardiol 2012;60:1940-4.
Wells G, Parkash R, Healey JS, Talajic M, Arnold JM, Sullivan S, et al.
Cardiac resynchronization therapy: A meta-analysis of randomized controlled trials. CMAJ 2011;183:421-9.
Goldenberg I, Kutyifa V, Klein HU, Cannom DS, Brown MW, Dan A, et al.
Survival with cardiac-resynchronization therapy in mild heart failure. N Engl J Med 2014;370:1694-701.
Gold MR, Padhiar A, Mealing S, Sidhu MK, Tsintzos SI, Abraham WT. Long-term extrapolation of clinical benefits among patients with mild heart failure receiving cardiac resynchronization therapy: Analysis of the 5-year follow-up from the REVERSE study. JACC Heart Fail 2015;3:691-700.
Gold MR, Thebault C, Linde C, Abraham WT, Gerritse B, Ghio S, et al
. Effect of QRS duration and morphology on cardiac resynchronization therapy outcomes in mild heart failure: Results from the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) study. Circulation 2012;126:822-9.
Birnie DH, Ha A, Higginson L, Sidhu K, Green M, Philippon F, et al.
Impact of QRS morphology and duration on outcomes after cardiac resynchronization therapy: Results from the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT). Circ Heart Fail 2013;6:1190-8.
Zareba W, Klein H, Cygankiewicz I, Hall WJ, McNitt S, Brown M, et al.
Effectiveness of cardiac resynchronization therapy by QRS morphology in the multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT). Circulation 2011;123:1061-72.
Beshai JF, Grimm RA, Nagueh SF, Baker JH 2nd
, Beau SL, Greenberg SM, et al.
Cardiac-resynchronization therapy in heart failure with narrow QRS complexes. N Engl J Med 2007;357:2461-71.
Donahue T, Niazi I, Leon A, Stucky M, Herrmann K; ESTEEM-CRT Investigators. Acute and chronic response to CRT in narrow QRS patients. J Cardiovasc Transl Res 2012;5:232-41.
Thibault B, Harel F, Ducharme A, White M, Ellenbogen KA, Frasure-Smith N, et al.
Cardiac resynchronization therapy in patients with heart failure and a QRS complex<120 milliseconds: The Evaluation of Resynchronization Therapy for Heart Failure (LESSER-EARTH) trial. Circulation 2013;127:873-81.
Ruschitzka F, Abraham WT, Singh JP, Bax JJ, Borer JS, Brugada J, et al.
Cardiac-resynchronization therapy in heart failure with a narrow QRS complex. N Engl J Med 2013;369:1395-405.
Linde C, Abraham WT, Gold MR, Daubert C; REVERSE Study Group. Cardiac resynchronization therapy in asymptomatic or mildly symptomatic heart failure patients in relation to etiology: Results from the REVERSE (REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction) study. J Am Coll Cardiol 2010;56:1826-31.
Barsheshet A, Goldenberg I, Moss AJ, Eldar M, Huang DT, McNitt S, et al.
Response to preventive cardiac resynchronization therapy in patients with ischaemic and nonischaemic cardiomyopathy in MADIT-CRT. Eur Heart J 2011;32:1622-30.
Mathew J, Katz R, St. John Sutton M, Dixit S, Gerstenfeld EP, Ghio S, et al.
Chronic kidney disease and cardiac remodelling in patients with mild heart failure: Results from the REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction (REVERSE) study. Eur J Heart Fail 2012;14:1420-8.
Daimee UA, Moss AJ, Biton Y, Solomon SD, Klein HU, McNitt S, et al.
Long-term outcomes with cardiac resynchronization therapy in patients with mild heart failure with moderate renal dysfunction. Circ Heart Fail 2015;8:725-32.
Linde C, Daubert C, Abraham WT, St. John Sutton M, Ghio S, Hassager C, et al.
Impact of ejection fraction on the clinical response to cardiac resynchronization therapy in mild heart failure. Circ Heart Fail 2013;6:1180-9.
Kutyifa V, Kloppe A, Zareba W, Solomon SD, McNitt S, Polonsky S, et al.
The influence of left ventricular ejection fraction on the effectiveness of cardiac resynchronization therapy: MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy). J Am Coll Cardiol 2013;61:936-44.
Foley PW, Stegemann B, Smith RE, Sanderson JE, Leyva F. Cardiac resynchronization therapy in patients with mildly impaired left ventricular function. Pacing Clin Electrophysiol 2009;32 Suppl 1:S186-9.
Linde C, Mealing S, Hawkins N, Eaton J, Brown B, Daubert JC; REVERSE Study Group. 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). Eur Heart J 2011;32:1631-9.
Noyes K, Veazie P, Hall WJ, Zhao H, Buttaccio A, Thevenet-Morrison K, et al.
Cost-effectiveness of cardiac resynchronization therapy in the MADIT-CRT trial. J Cardiovasc Electrophysiol 2013;24:66-74.
Sipahi I, Chou JC, Hyden M, Rowland DY, Simon DI, Fang JC. Effect of QRS morphology on clinical event reduction with cardiac resynchronization therapy: Meta-analysis of randomized controlled trials. Am Heart J 2012;163:260-7.e3.
European Society of Cardiology (ESC); European Heart Rhythm Association (EHRA), Brignole M, Auricchio A, Baron-Esquivias G, Bordachar P, Boriani G, et al.
2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: The task force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Europace 2013;15:1070-118.
Tracy CM, Epstein AE, Darbar D, Dimarco JP, Dunbar SB, Estes NA 3rd
, et al.
2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2012;60:1297-313.
Poole JE, Singh JP, Birgersdotter-Green U. QRS duration or QRS morphology: What really matters in cardiac resynchronization therapy? J Am Coll Cardiol 2016;67:1104-17.