Cardiac-resynchronization therapy in patients with systolic heart failure and QRS interval 130 ms: insights from a meta-analysis

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1 Europace (2015) 17, doi: /europace/euu214 CLINICAL RESEARCH Pacing and resynchronization therapy Cardiac-resynchronization therapy in patients with systolic heart failure and QRS interval 130 ms: insights from a meta-analysis Rachit M. Shah 1, Dhavalkumar Patel 1, Janos Molnar 2, Kenneth A. Ellenbogen 1, and Jayanthi N. Koneru 1 * 1 Cardiac Electrophysiology, Department of Cardiology, Virginia Commonwealth University Hospital, Gateway Building, 3rdFl, PO Box , Richmond, VA , USA; and 2 Department of Cardiology, Rosalind Franklin University, North Chicago, IL, USA Received 15 June 2014; accepted after revision 3 July 2014; online publish-ahead-of-print 27 August 2014 Aims Cardiac-resynchronization therapy (CRT) reduces morbidity and mortality in patients with chronic systolic heart failure (SHF) and a wide QRS complex. It is unclear whether the same benefit extends to patients with QRS dun (QRSd),130 ms.... Methods Our aim was to perform a meta-analysis of all randomized controlled trial (RCTs) and to evaluate the effect of implantable and results CRT defibrillator(crtd) on all-cause mortality, HF mortality, and HF hospitalization in patients with QRSd,130 ms. We performed a systematic literature search to identify all RCTs, comparing CRTD therapy with implantable cardiac defibrillator (ICD) therapy in patients with SHF (ejection fraction,35%) and QRS 130 ms, published in Pubmed, Medline, EMBASE, Cochrane library, and Google scholar from June 1980 through June The search terms included CRT, QRS dun, narrow QRS, clinical trial, RCT, biventricular pacing, heart failure, systolic dysfunction, dyssynchrony, left ventricular remodelling, readmission, mortality, survival, and various combinations of these terms. We studied the trends of overall mortality, SHF mortality, and hospitalizations due to SHF between the two groups. Heterogeneity of the studies was analysed by Q statistic. A fixed-effect model was used to compute the relative risk (RR) of mortality due to SHF, while a random-effects model was used to compare hospitalization due to SHF. Out of a total of citations, four RCTs comparing CRTD vs. ICD therapy in patients with SHF and QRS 130 ms fulfilled the inclusion criteria. The median follow-up was 12 months and the cumulative number of patients was Relative for all-cause mortality in patients treated with CRTD was 1.66 with a 95% CI of (P ¼ 0.017) while for SHF mortality was 1.29 with 95% CI of (P ¼ 0.42). Relative risk for HF hospitalization in patients treated with CRTD was 0.94 with 95% CI of (P ¼ 0.84) in comparison to the ICD group.... Conclusion Cardiac-resynchronization therapy defibrillator has no impact on SHF mortality and SHF hospitalization in patients with systolic HF with QRS dun 130 ms and is associated with higher all-cause mortality in comparison with ICD therapy Keywords CRT QRS dun LV dyssynchrony HF mortality All-cause mortality HF hospitalization Introduction Heart failure is the modern epidemic and a common cause of morbidity and mortality. 1 The salutary effects of cardiac-resynchronization therapy (CRT) have been iteratively demonstrated in well-designed clinical studies that involved patients with systolic heart failure (SHF, ejection fraction,35%) and a prolonged QRS dun (QRSd). 1 4 However, many patients with systolic failure have QRS duns,130 ms and nearly half of these patients demonstrate echocardiographic evidence of left ventricular mechanical dyssynchrony. 5,6 Data from a few single center observational studies, have suggested that CRT could be beneficial in patients with QRS dun,130 ms However, the results of subsequent, larger randomized controlled trials (RCTs) are controversial and suggest * Corresponding author. Tel: ; fax: , address: jkoneru@mcvh-vcu.edu Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oup.com.

2 268 R.M. Shah et al. What s new? In patients with systolic heart failure and QRSd,130 ms, when CRTD is compared to ICD therapy: Cardiac-resynchronization therapy defibrillator has no impact on SHF mortality. Cardiac-resynchronization therapy defibrillator has no impact on hospitalization rate in patients. Cardiac-resynchronization therapy defibrillator is associated with higher all-cause mortality. possible deleterious effects of CRT when used in patients with SHF and QRSd,130 ms. Hence, we conducted this meta-analysis of RCTs to assess the impact of CRT-D therapy on clinical endpoints: SHF mortality, all-cause mortality and HF hospitalization in comparison to ICD therapy alone in patients SHF and QRSd,130 ms. Methods We conducted this meta-analysis in accordance with the Quality of Reporting of Meta-analysis statement and the Consolidated Standards of Reporting Trials group recommendation. 16 Literature search We performed a computerized search to identify all RCTs, comparing CRTD therapy vs. ICD therapy in patients with SHF (ejection fraction,35%) and QRS complex dun of,130 ms, published in Pubmed, Medline, EMBASE, Cochrane library, and Google scholar from June 1980 through June References of retrieved studies were also checked to identify additional studies. The search terms included CRT, QRS dun, narrow QRS, biventricular pacing, heart failure, systolic dysfunction, dyssynchrony, left ventricular remodeling, readmission, mortality, survival, clinical trial, RCT, and various combinations of these terms. outcomes in our meta-analysis were all cause mortality; deaths due to SHF, and hospitalization due to SHF. Statistical analysis We used Comprehensive Meta-analysis Software (Version 2, BioStat, Englewood) for our analysis. Continuous variables are reported in mean + standard deviation, whereas categorical variables are reported as number (percentages). Cochran Q statistics and I 2 was computed to quantify heterogeneity. Random effects model was used when statistically significant heterogeneity was present among studies; otherwise fixed-effect model was used. Relative risk (RR) and 95% confidence interval were calculated to demonstrate the overall effect of CRT on dichotomous outcomes such as all-cause mortality, SHF-related deaths, and hospitalizations. A two-sided a error of,0.05 was considered to be statistically significant (P, 0.05). Results The computerized literature search yielded a total of citations. After title and abstract screening, six studies were deemed relevant to our objective of evaluating the role of CRT in HF patients with narrow complex QRS and they underwent an in-depth review. Out of those we excluded ESTEEM-CRT study 18 due to the observational study design and lack of outcomes of interest for this meta-analysis, while the RESPOND study 19 was excluded because it compared patients with CRT with patients with only medical therapy. After this rigorous scrutiny, four RCTs were included for this meta-analysis. As mentioned above, the main reasons for exclusion were lack of randomized, prospective study design, a comparable defibrillator group and reported outcomes of interest. Figure 1 summarizes the selection and adjudication process for studies included in this meta-analysis. Table 1 shows the basic characteristics of studies included in the meta-analysis, while Table 2 details the patient characteristics from these studies. Three studies included patients with significant Study selection All titles and abstracts obtained from the initial computerized search were reviewed by two authors to determine eligibility for inclusion of the study in meta-analysis. Studies were selected for further review if they met the following inclusion criteria: (1) RCT design, (ii) Studies that included patients with QRSd,130 ms and compared outcomes between patients with CRTD therapy vs. ICD therapy alone, (iii) studies that reported clinical outcomes relevant to our meta-analysis: allcause mortality, deaths due to SHF, and HF-related hospitalizations. Validity assessment and data abstraction We used the criteria developed by US preventive services task force to determine the internal validity of studies included in this meta-analysis. 17 Based on these criteria, two authors rated these studies in three categories: good, fair, and poor. Disagreement on collected data was resolved by the third investigator. We extracted the following data from each RCT selected for meta-analysis: characteristics of the study (author, year, dun, and sample size, inclusion and exclusion criteria, randomization, follow-up); demographic data (age and sex), clinical characteristics (diabetes, hypertension, MI, history of revascularization, NYHA class, ischaemic cardiomyopathy), baseline laboratory data, dun of QRS (ms) and left ventricular ejection fraction (LVEF). Two authors independently extracted data and assessed studies outcomes. The main clinical 12,092 citations screened at title/abstract level 11 articles retrieved in full for further review 6 articles appraised by authors according to the selection criteria 4 Randomized controlled trials met inclusion criteria and included in meta-analysis (3 with echocardiographic evidence of mechanical dyssynchrony) Figure 1 Review process. 12,081 articles were not pertinent and were excluded 5 studies excluded due to lack of comparison group Two studies didn t meet inclusion criteria. A) One study compared CRT with optimal medical therapy. B) Second study was excluded due to observational study design

3 Table 1 Characteristics of studies included in the meta-analysis Study Study design Patient selection LV Randomization Scheduled Primary Dun Internal dyssynchrony follow-up outcomes validity... Thibault et al. 13 (LESSER-EARTH) 12 (RethinQ ) Ruschitzka et al. 14 (The echocrt study) 15 (The NARROW-CRT study) Randomized double blinded, Randomized double blinded, Randomized double blinded, Randomized single blind, LVEF 35%, QRSd,120 ms, NYHA class III LVEF,35%, NYHA Class III, QRSd 130 ms LVEF 35%, NYHA Class III or IV, QRSd 130ms LVEF,35%, NYHA Class II and III, QRSd 120 ms Not assessed Present Present Present CRTD implanted and randomized to CRT programme active and inactive CRTD implanted and randomized 1 : 1 with CRTD programme on and off CRTD implanted and then randomized 1 : 1 with CRT on and off 1 : 1 implantation of CRTD vs. DDD-ICD(dual-chamber ICD) 6 months 12 months Submaximal exercise dun 6 months Change in peak oxygen consumption 1 month, 3 month, then every 3 months until trial terminated 6 months and then 12 months Combination of death and HF hospitalization HF clinical composite score CRTD, cardiac resynchronization therapy defibrillator; ICD, implantable cardiac defibrillator; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; QRSd, QRS dun. Table 2 Baseline characteristics of patients included in meta-analysis October 2003 January August 2005 January 2007 August 2008 March 2013 January 2008 May 2010 Study Group No. of Sex (male) No. Age (years) QRSd (ms) NYHA class No. of Ischaemic CMP LVEF (%) Intraventricular patients of patients (%) (mean + SD) (mean + SD) patients (%) No. of patients (%) (mean + SD) mechanical delay (mean + SD)... Thibault et al. 13 (LESSER-EARTH) CRT on (64%) III IV 17 (39.5%) 32 (73%) NA CRT off (78%) III IV 12 (29.3%) 27 (66%) NA 12 (RethinQ ) CRT- D on (71%) III 87 (100%) 47 (54%) CRT- D off (58%) III 84 (99%) 43 (51%) Ruschitzka et al. 14 CRT- D on (73%) II 7(1.7%), III (54%) NA (The echocrt study) (95.3%), IV 10 (2.5%) CRT- D off (72%) II 12 (3%), III 374 (92.3%), IV 16 (4%) 214 (53%) NA 15 (The NARROW-CRT study) CRT (88%) II 23 (38%) III 37 (62%) D-ICD (83%) II 25 (42%) III 35 (58%) 60 (100%) (100%) CMP, cardiomyopathy; CRTD, cardiac-resynchronization therapy defibrillator; ICD, implantable cardiac defibrillator; LVEF, left ventricular ejection fraction; NA, not applicable; NYHA, New York Heart Association; QRSd, QRS dun; SD, standard deviation. CRTD in patients with SHF and QRS 130 ms 269

4 270 R.M. Shah et al. Table 3 Definition of mechanical dyssynchrony Study Definition for Mechanical Dyssynchrony (RethinQ) Septal-to-posterior wall delay in peak velocity of an interval 130 ms and opposing wall delay between the anteroseptal-to-posterior wall and the septal-to-lateral wall of 65 ms Ruschitzka et al. 14 (The echocrt study) 15 (The NARROW-CRT study) mechanical dyssynchrony on 2-D echocardiogram, 12,14,15 while LESSER EARTH study included patients with narrow QRS complex irrespective of the evidence of mechanical dyssynchrony. 13 Table 3 details the definition of mechanical dyssynchrony used in each study. Three studies randomized patients after successful implantation of CRT-D in all patients to those who have active CRT programmed and those who did not randomized heart failure patients into CRT-D and DDD-ICD group. Heart failure therapy was optimized for all patients by the treating physician. The majority of the included studies had a follow-up period of 12 months. A total of 1186 patients with SHF and a narrow QRS complex (,130 ms) are included in our analysis, of which 595 were treated with CRT and 591 did not. Echo CRT study contributes to the majority of patients (n ¼ 809) in our meta-analysis. 14 Table 2 shows baseline characteristics of patients included in meta-analysis. There was no significant difference in age, sex, and NYHA heart failure class. The frequency of patients with ischaemic cardiomyopathy, diabetes, hypertension, previous MI, and revascularization procedures was similar between the two groups in each study. All studies included patients with LVEF 35% and baseline ejection fraction (EF) was similar between the two groups. QRS dun was also similar between the two groups. Outcomes Opposing-wall delay in the peak systolic velocity of 80 ms or delay in the anteroseptal-to-posterior wall of 130 ms Difference of peak systolic velocity between the septal and lateral delays of 60 ms Figure 2A C shows the clinical effect of CRTD among heart failure patients with QRS,130 ms. Heart failure patients who were treated with CRTD had increased all-cause mortality compared with those who did not (RR ¼ 1.66, CI ¼ , P ¼ 0.017). There was no statistically significant difference in mortality related to SHF (RR ¼ 1.29, CI ¼ , P ¼ 0.429). The rate of hospitalizations due to worsening of SHF was similar between the two groups (RR ¼ 0.99, CI ¼ , P ¼ 0.979). We also performed subgroup analysis including three studies which involved heart failure patients with narrow QRS complex and if the echocardiogram showed evidence of mechanical dyssynchrony (Figure 3A C). The subgroup analysis showed CRT therapy increased all-cause mortality (RR ¼ 1.63, CI ¼ , P ¼ 0.023) even among the heart failure patients with narrow QRS complex who have echocardiographic evidence of dyssynchrony. Moreover, heart failure mortality (RR ¼ 1.25, CI ¼ , P ¼ 0.499) and heart failure hospitalization (RR ¼ 0.75, CI ¼ , P ¼ 0.416) were similar between groups in subgroup analysis. Discussion This systematic review and meta-analysis is, to the best of our knowledge, the first to compare the effects of CRT-D therapy on all-cause mortality, HF mortality, and HF hospitalizations in patients with SHF and QRS,130 ms to stand-alone ICD therapy. The results of our analysis suggest that (i) CRT-D does not reduce HF mortality or HF hospitalizations in symptomatic SHF patients with QRS dun 130 ms in comparison with ICD alone, (ii) CRT-D is associated with higher all-cause mortality in comparison with ICD therapy in this patient population. Cardiac-resynchronization therapy has been shown to improve mortality and morbidity rates in patients with SHF with QRS dun.150 ms, but not in patients with QRS dun,150 ms in a meta-analysis of five clinical trials involving a total of 6501 patients. 20 Subgroup analyses from two large clinical trials suggested that a QRS dun of,150 ms is a risk factor for poor response to CRT therapy. 2,3 However, many patients with heart failure have QRS dun of,130 ms. 5 Up to 50% of these patients show echocardiographic evidence of left ventricular mechanical dyssynchrony. 5,6 Small-scale observational studies have reported improved outcomes with CRT in patients with narrow QRS Such observations have led to frequent off label use of CRT in patients with QRS,130 ms. 14 The understanding of mechanical dyssynchrony has led to enthusiasm for extending benefits of CRT to patients with a narrow QRS who demonstrate dyssynchrony. The mechanism for poor response to CRT-D therapy among patients with narrow QRS complex even when mechanical dyssynchrony is present is not understood. The ations of current imaging modalities to accurately define mechanical dyssynchrony as well as the inability to embrace a universally adopted definition of dyssynchrony are obvious barriers, not to mention the inter and intra-observer variations in measuring dyssynchrony. The ESTEEM-CRT study 18 evaluated the haemodynamic, clinical, and structural effects of CRT in patients with SHF, a narrow QRS, and mechanical dyssynchrony. In this study, LV dyssynchrony was evaluated by 13 different echo indices and there was wide disagreement in the prevalence of dyssynchrony (0 74%) in the study group, depending on the echo index chosen. Moreover, none of the echo dyssynchrony indices (baseline value or acute change with CRT) were able to predict chronic outcomes as measured by EF, peak oxygen consumption (VO2), left ventricular end systolic volume, left ventricular end diastolic volume, or quality of life. Forced biventricular pacing may in fact lead to worsening of heart failure in these patients. 14 In the same study, continuous pacing at shorter AV delay (60% or less than intrinsic AV delay) caused reductions in LV dp/dt max. Placement of an LV lead obviously adds to procedural dun, complexity and the risks. In the EchoCRT study, the rate of adverse events related to a CRT device implantation was significantly higher than the control group. 14 Limitation Our study has all the ations inherent to a meta-analysis. Few studies were included and the EchoCRT study contributed the

5 CRTD in patients with SHF and QRS 130 ms 271 A All cause mortality Study name Statistics for each study Events/Total and 95% CI Thibault et al Z-Value P-Value CRTD Control /56 45/404 2/44 5/87 26/405 0/41 Fixed Effect Model B Heart failure related mortality Study name Statistics for each study Events/Total and 95% CI Thibault et al Z-Value P-Value CRTD Control /56 17/404 1/44 2/87 10/405 0/41 Fixed Effect Model C Hospitalization Due to Heart Failure Study name Statistics for each study Events/Total and 95% CI Z-Value P-Value CRTD Control /56 229/404 11/55 181/405 Thibault et al /44 24/87 4/41 41/85 Random Effect Model Figure 2 Clinical outcomes among heart failure patients with EF 35% and QRS interval 130 ms or less who received CRTD compared with those who had ICD therapy (control) alone. majority of patients. We studied only hard clinical endpoints and did not evaluate the softer endpoints: improvement in symptoms, quality of life or change in echocardiographic parameters with CRT therapy. Studies included in our meta-analysis did not have tailored LV lead placement to derive optimal benefit from CRT which might affect overall results; however, this is a ation that extends to most CRT studies. In summary, our meta-analysis indicates that CRT-D does not reduce all-cause mortality, HF mortality, or HF readmissions in symptomatic SHF patients with QRS dun 130 ms. Instead, CRT-D therapy is associated with increased overall mortality in this patient population. Clinical implications and future direction This meta-analysis not only emphasizes the futility of CRT in patients with QRS dun 130 ms, but also points to potential adverse outcome of higher all-cause mortality. When we performed subgroup analysis of three clinical trials involving patients with LV mechanical dyssynchrony and QRSd,130 ms (, Ruschitzka et al., and ), we found that there was a higher all-cause mortality in these patients as well compared with the control group. Until future research provides robust measures of dyssynchrony and clear insights into how to improve outcomes of CRT in

6 272 R.M. Shah et al. A All cause mortality Study name Statistics for each study Events/Total and 95% CI Z-Value P-Value CRTD Control /56 45/404 5/87 26/405 Fixed Effect Model B Heart failure related mortality Study name Statistics for each study Events/Total and 95% CI Z-Value P-Value CRTD Control /56 17/404 2/87 10/405 Fixed Effect Model C Hospitalization Due to Heart Failure Study name Statistics for each study Events/Total and 95% CI Z-Value P-Value CRTD Control / /404 24/87 11/55 181/405 41/85 Random Effect Model Figure 3 Clinical outcomes among heart failure patients with EF 35% and echocardiographic evidence of mechanical dyssynchrony with QRSd,130 ms who received CRTD therapy compared with those who had ICD therapy (control) alone. heart failure patients with narrow QRS complex, its use should be strongly discouraged in this population. Conflict of interest: J.N.K has received honoraria from Medtronik, Biotronik, St Jude Medical (all,$5000). This has no bearing on the manuscript. K.A.E is a consultant for Medtronik, Boston Science, Biotronik and has received honoraria for speaking. References 1. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E et al. MIRACLE Study Group. Multicenter InSync Randomized Clinical Evaluation. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346: Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L et al. Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352: Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T et al. Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac-resynchronizationtherapywith orwithoutanimplantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350: Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA 3rd, Freedman RA, Gettes LS et al. American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; Heart Rhythm Society ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for devicebased therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2013;61: e Ghio S, Constantin C, KlersyC, Serio A, FontanaA, Campana Cet al. Interventricular and intraventricular dyssynchronyare common in heart failure patients, regardless of QRS dun. Eur Heart J 2004;25: Leclercq C, Kass DA. Retiming the failing heart: principles and current clinical status of cardiac resynchronization. J Am Coll Cardiol 2002;39: Achilli A, Sassara M, Ficili S, Pontillo D, Achilli P, Alessi C et al. Long-term effectiveness of cardiacresynchronization therapyin patients with refractory heart failure and narrow QRS. J Am Coll Cardiol 2003;42:

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