The existing data regarding the role of QRS duration (QRSd) change on cardiac resynchronization therapy (CRT) response show some inconsistent results. We conducted a meta-analysis of data obtained from observational studies to examine the impact of QRS change after CRT device implantation on the clinical and/or echocardiographic response. We searched the PubMed and EMBASE databases for relevant studies published before January 2016. Twenty-seven studies were retrieved for detailed evaluation of which 12 studies with a total population of 1,545 patients met our eligibility criteria. The analysis demonstrated that QRSd narrowing was a positive predictor of response to CRT (mean difference [MD] = −19.24 ms, 95% CI = −24.00 to −14.48 ms, p <0.00001). This effect was consistent in the studies using clinical criteria (MD = −19.91 ms, 95% CI = −27.20 to −12.62 ms, p <0.00001) and in those that used echocardiographic criteria (MD = −19.51 ms, 95% CI = −25.78 to −13.25 ms, p <0.00001). The heterogeneity test showed moderate differences among the individual studies (I 2 = 42%). Subgroup analysis showed that QRSd change was more pronounced in studies having a follow-up ≤6 months. We did not find significant differences in studies measuring postimplantation QRSd after a certain follow-up period compared with studies measuring QRSd immediately after CRT device implantation. Further studies should clarify the exact timing of QRSd assessments during follow-up. In conclusion, QRSd shortening after CRT device implantation is associated with a favorable clinical and echocardiographic response.
Cardiac resynchronization therapy (CRT) is a well-established treatment for patients with impaired left ventricular systolic function and wide QRS providing considerable clinical benefits such as improvement in the quality of life and functional status as well as reduced risk of death. However, a substantial proportion of CRT recipients do not have clinical and/or echocardiographic response. Apart from baseline parameters associated with favorable outcome, QRS narrowing after CRT device implantation may predict a positive response given that increased baseline QRS width is related to the extent electrical and mechanical dyssynchrony. Although most of the published studies indicate a positive association between QRS narrowing and improved outcomes in this setting, it has been recently pointed out that some contradictory results exist in the reports. We therefore conducted a meta-analysis of the evidence obtained from observational studies to examine the relation of QRS change after CRT device implantation with the observed clinical and/or echocardiographic response. We also sought to investigate further insights in this potential association by performing specific subanalyses.
Methods
Meta-analyses of observational studies present particular challenges because of inherent biases and differences in study designs. Consequently, we performed this analysis according to the Strengthening the Reporting of Observational Studies in Epidemiology statement.
We included prospective or retrospective observational studies with a primary objective to determine whether QRS narrowing would be predictive of a clinical or echocardiographic response in patients undergoing CRT device implantation for heart failure (HF). Titles and abstracts of all studies were evaluated according to the following inclusion criteria: (1) published in the English language; (2) human subjects; (3) clearly divided responders and nonresponders to CRT; and (4) assessed QRS duration (QRSd) and reported the means and SDs of QRSd change before and after CRT.
Two reviewers (ZZ and TL) systematically and independently searched the online databases of PubMed and EMBASE to identify relevant studies published before January 2016. We used the following key terms: “QRS duration” OR “QRS width” OR “QRS change” OR “QRS narrowing” OR “QRS shortening” OR “Electrocardiogram” OR “Electrocardiographic” AND “cardiac resynchronization therapy” OR “biventricular pacing.” In addition, all references of relevant studies and review studies on this topic were manually reviewed. Titles and abstracts as well as the reference lists of all the retrieved studies were manually checked independently by 2 investigators (ZZ and TL).
Two investigators (ZZ and TL) systematically extracted the data in prespecified data forms. All potentially relevant reports were retrieved as complete manuscripts, and then, we assessed them eligibility according to the inclusion criteria. Any disagreements or uncertainties between the 2 investigators were resolved through consensus after rechecking the source data and consultation with a third investigator (PK).
Two investigators (ZZ and TL) independently extracted the related data using a predefined form. The extracted data elements of the meta-analysis included information on the inclusion criteria, publication details, study design, definitions of response, follow-up duration, and baseline patient characteristics. Subsequently, means and SDs of QRSd change before and after CRT in each group were extracted for the meta-analysis. Disagreements were resolved by consensus with a third reviewer (PK). The Newcastle–Ottawa Scale was used to assess the quality of included studies.
Continuous data are reported as mean ± SD. Pooled effect sizes are presented as mean difference (MD) and 95% CI for each trial using inverse variance method for the random-effects model. Statistical heterogeneity was assessed by the chi-square test and quantified using I 2 statistic. An I 2 >50% is indicative of at least moderate heterogeneity. A subgroup analysis based on the response type (clinical response or echocardiographic response) was predefined. Besides, subgroup analyses regarding the timing of postimplantation QRSd measurement for ΔQRS (immediately after CRT implantation or after a certain follow-up), the follow-up duration (≤6 months or >6 months), and the cohort design (prospective or retrospective) were also performed. Moreover, sensitivity analysis was done by leaving out studies and checking the consistency of the overall effect estimate. Publication bias was evaluated by means of funnel plot. Two-tailed p values of <0.05 were considered statistically significant. The statistical analysis was performed using the Review Manager (RevMan, version 5.3; Copenhagen, The Nordic Cochrane Center, The Cochrane Collaboration, 2014).
Results
A flow diagram of the data search and study selection process is presented in Figure 1 . Twelve studies with a total population of 1,545 patients (1,088 classified as responders and 457 classified as nonresponders) were finally included in the meta-analysis. The characteristics and the Newcastle–Ottawa Scale scores of each study are listed in Table 1 , whereas the definitions of CRT response are presented in Table 2 . Patient characteristics of each study are summarized in Table 3 .
| First author, Year | Country | Cohort design | Inclusion Criteria | Patients (n) | Measuring time of post-implanted QRSd for ΔQRS | Follow-up (months) | NOS score | ||
|---|---|---|---|---|---|---|---|---|---|
| NYHA Class | EF (%) | QRS duration | |||||||
| Alonso 1999 | France | Retrospective | III or IV | < 35% | > 120 ms | 26 | Immediately after CRT implantation | 7.5 ± 4 | 8 |
| Molhoek 2004 | Netherlands | Prospective | III or IV | < 35% | > 120 ms | 61 | During follow-up | 6 | 7 |
| Lecoq 2005 | France | Retrospective | III or IV | < 35% | > 150 ms | 138 | Immediately after CRT implantation | 6 | 8 |
| Boriani 2006 | Italy | Prospective | III or IV | < 40% | > 120 ms | 20 | During follow-up | 3 | 6 |
| Lellouche 2007 | USA | Retrospective | III or IV | ≤ 35% | > 130 ms | 164 | During follow-up | 6 | 8 |
| Bonakdar 2009 | Iran | Prospective | III or IV | ≤ 35% | ≥ 120 ms | 82 | Immediately after CRT implantation | 6 | 8 |
| Kamireddy 2009 | USA | Prospective | NA | NA | NA | 113 | During follow-up | 407 ± 290 days | 8 |
| Rickard 2011 | USA | Retrospective | II to IV | ≤ 40% | ≥ 120 ms | 218 | Immediately after CRT implantation | 11.6 ± 9 | 7 |
| Rickard 2012 | USA | Retrospective | NA | ≤ 40% | ≥ 120 ms | 507 | Immediately after CRT implantation | 13.5 | 8 |
| Rickard 2013 | USA | Retrospective | NA | ≤ 35% | NA | 112 | Immediately after CRT implantation | 9.9 | 8 |
| Yang 2014 | China | Prospective | II to IV | ≤ 35% | ≥ 120 m | 74 | Immediately after CRT implantation | 13 | 7 |
| Zhang 2015 | China | Prospective | II or III | ≤ 35% | ≥ 120 ms | 30 | Immediately after CRT implantation | 6 | 7 |
| First author, Year | Definition of response |
|---|---|
| Alonso 1999 | Survival with significantly improved symptoms (at least 1 class down) and exercise tolerance (at least 10% increase on baseline in peak VO 2 ) for at least 6 months |
| Molhoek 2004 | Those patients who improved at least 1 class NYHA classification score after 6 months of CRT |
| Lecoq 2005 | Patients were classified at 6 months as responders to CRT if they were alive, they had not been re-hospitalized for management of CHF, and the NYHA class had decreased by 1 point, and/or peak VO 2 or 6 min hall-walk increased by > 10% |
| Boriani 2006 | A reduction > 15% of LVESV |
| Lellouche 2007 | (1) no cardiovascular death, (2) no hospitalization for decompensated HF, and (3) ≥ 1 point decrease in NYHA functional class. |
| Bonakdar 2009 | Alive without cardiac decompensation and experienced ≥ 15% decrease in LVESV |
| Kamireddy 2009 | A relative increase of ≥ 15% in LVEF after CRT |
| Rickard 2011 | A reduction in LVESV ≥ 10% from baseline |
| Rickard 2012 | No deterioration in LV function (deterioration in LV function was defined as an absolute decrease of 5% or greater in ejection fraction from baseline) |
| Rickard 2013 | A reduction in LVESV ≥15% from baseline |
| Yang 2014 | An absolute improvement in LVEF by ≥ 10% from baseline |
| Zhang 2015 | Those patients exhibiting ≥ 5 mm reduction in LVED after 6 months of CRT |
| First author, Year | Patients (n) | Mean age (years) | Male n (%) | ICM n (%) | AF n (%) | LVEF (%) | LVEDD (mm) | Baseline QRS width (ms) | CRT-P/D | Medication, n (%) | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ACEI/ARB | Beta blocker | Diuretic | ||||||||||
| Alonso 1999 | 26 | 66 ± 7 | 24 (92.3) | 9 (34.6) | 6 (23.1) | 23 ± 8 | 65 ± 9 | 178 ± 24 | 26/0 | NA | NA | NA |
| Molhoek 2004 | 61 | 64 ± 11 | 47 (77) | 28 (45.9) | NA | 28 ± 14 | 68 ± 19 | 177 ± 30 | 33/28 | 49 (80) | 37 (61) | 58 (95) |
| Lecoq 2005 | 138 | 68 ± 9 | 113 (81.9) | 49 (35.3) | 45 (32.4) | 21 ± 6 | 71 ± 8 | 188 ± 28 | 138/0 | NA | NA | NA |
| Boriani 2006 | 20 | 62 ± 8 | 15 (75) | 8 (40) | NA | NA | NA | 157 ± 30.2 | NA | NA | NA | NA |
| Lellouche 2007 | 164 | 65 ± 15 | 125 (76) | 77 (47) | 28 (17) | 22.1 ± 6.6 | 66 ± 11 | 158 ± 37 | 164/0 | 142 (87) | 129 (79) | NA |
| Bonakdar 2009 | 82 | 56 ± 15 | 61 (74.4) | 46 (56) | 7 (8.5) | 17.6 ± 6 | 69 ± 8 | 153 ± 25 | 30/52 | 82 (100) | 82 (100) | 98 (80) |
| Kamireddy 2009 | 113 | 69.3 ± 11.3 | 79 (70) | 82(73) | NA | 24.0 ± 9.1 | 61.2 ± 10.8 | 155.3 ± 31.1 | NA | 73 (65) | 85 (75) | NA |
| Rickard 2011 | 218 | 64.5 ± 11.8 | NA | 114 (52.3) | 116 (53.2) | 23.7 ± 7.6 | NA | 165.6 ± 26.4 | 15/203 | 169 (81.6) | 159 (76.8) | 169 (81.6) |
| Rickard 2012 | 507 | 66.4 ± 11.5 | 351 (69.2) | 270 (53.3) | 271 (53.5) | 21.7 ± 7.5 | 62 ± 11 | 164.1 ± 26.2 | 21/486 | 391 (77.9) | 415 (82.7) | 387 (77.1) |
| Rickard 2013 | 112 | 69.3 ± 11.2 | 79 (70.5) | 62 (55.4) | 79 (70.5) | 22.5 ± 7.7 | NA | 187.8 ± 23.0 | 7/105 | 87 (77.7) | 86 (76.8) | 85 (75.9) |
| Yang 2014 | 74 | 61 ± 9 | 48 (65) | 17 (23) | 0 (0) | 26 ± 6 | 72 ± 9 | 163 ± 24 | NA | 54 (73) | 69 (93) | 65 (88) |
| Zhang 2015 | 30 | 57.10 ± 12.58 | 22 (73.3) | 0 (0) | 1 (3.33) | 29.47 ± 4.91 | 72.30 ± 8.74 | 156 ± 23 | 24/6 | 30 (100) | 30 (100) | 30 (100) |
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