Cardiac resynchronization therapy (CRT) is underused. Recent guidelines have expanded indications for CRT to include less severe symptoms but now favor left bundle branch block morphology in patients with moderate QRS prolongation. The prevalence of CRT eligibility according to historical and current guidelines is uncertain. The aim of this review was to identify and synthesize all existing published research reporting the prevalence of CRT eligibility. A systematic review of electronic databases including MEDLINE, Embase, and the Cochrane Library was performed. The primary outcome was the proportion of patients eligible for CRT according to historical and current criteria. Secondary outcomes included the individual components of eligibility (the ejection fraction, symptoms, and QRS duration and morphology). Eligibility estimates were pooled using random-effects models because of marked heterogeneity in between-study variance. Thirty studies were identified. No study used current guideline criteria. On the basis of historical criteria, 11 ± 3% of ambulatory and 9 ± 3% of hospitalized patients are eligible for CRT. However, New York Heart Association class II in current guidelines is at least as frequent as New York Heart Association III or IV. Approximately 1/3 of patients have QRS prolongation, 2/3 of whom have left bundle branch block. Only a few patients have non–left bundle branch block with QRS duration <150 ms. Medical contraindication or ineligibility was rarely assessed. In conclusion, current estimates of need are outdated. Inclusion of milder symptoms potentially doubles the eligible population. Studies in unselected cohorts are needed to accurately define the individual components of eligibility, together with the prevalence and reasons for ineligibility.
Cardiac resynchronization therapy (CRT) is among the most effective treatments in cardiovascular medicine, significantly reducing morbidity and mortality in patients with heart failure (HF) and reduced left ventricular ejection fractions (LVEFs). Despite implantation and device costs, CRT is cost effective within short periods, largely because of fewer hospitalisations. Achieving widespread uptake of CRT is important for patients and health care payers alike. Recent guidelines expanded the indications for CRT to include less severe symptoms. In parallel, evidence is accruing of efficacy in patients with atrial fibrillation and milder left ventricular systolic dysfunction (LVSD) requiring bradycardia pacing. However, CRT is underused, with marked variation in implantation rates within and among countries. Estimating CRT need is essential for regional and national resourcing, including implantation facility provision, personnel recruitment, and budget forecasting. We therefore conducted a systematic review to appraise the reported proportion of patients eligible for CRT among those with HF using historical and current guidelines.
Methods
MEDLINE, Embase, and the Cochrane Library were searched to February 2015, limited to adult humans, without date or language restriction. Case reports, reviews, and conference abstracts were excluded. Search terms were selected by consensus, iterative database queries, keyword mapping, and published research. The population of interest was patients with HF eligible for CRT. Medical Subject Headings and Emtree terms were combined with keywords as outlined in the search strategy ( Supplementary Appendix 1 ). The primary outcome was the proportion of patients with HF eligible for CRT according to historical and current guidelines. Secondary outcomes included the proportion of patients fulfilling individual criteria: the LVEF, New York Heart Association (NYHA) functional class, and QRS duration (QRSd) and morphology. Two reviewers (NMH and MT) screened titles and abstracts (binary yes/no) with reconciliation through discussion. Variables of interest were decided a priori.
The American College of Cardiology and American Heart Association 2008 and European Society of Cardiology 2007 guidelines recommended CRT in patients with LVEFs ≤35%, NYHA class III or IV symptoms, sinus rhythm, and QRSd ≥120 ms. Similar criteria applied to atrial fibrillation or concomitant or anticipated ventricular pacing, with a lower class (IIa or IIb, respectively) and level of evidence (B or C). Current guidelines include milder NYHA class I and II symptoms, alongside clearer support for patients with atrial fibrillation and long-term right ventricular pacing ( Table 1 ). A minor concomitant contraction in eligibility has occurred, with QRSd ≥150 ms preferred for non–left bundle branch block (LBBB) morphology (with non-LBBB QRSd 120 to 150 ms now receiving a class IIb recommendation only). To improve readability, contemporary guidelines are referred to throughout as “current,” and 2007 and 2008 guidelines as “historical.” Meta-analysis including all studies demonstrated marked heterogeneity (Q statistic = 8,497, I 2 = 99.7%, 95% confidence interval [CI] 99.6% to 99.7%). Results are therefore presented as a narrative synthesis to explore this heterogeneity. Statistical analysis was restricted to summary proportions with 95% CI’s using a random-effects model for the ambulatory and hospitalized subgroups.
| Rhythm, QRS, Morphology | NYHA Class LVEF ≤35 | ESC 2013 | ACC/AHA 2012 |
|---|---|---|---|
| SR LBBB | |||
| ≥150 | II – IV | I (A) | I (A or B) |
| ≥150 | I (LVEF ≤30) | – | IIb (C ischemic) |
| 120 to 150 | II – IV | I (B) | IIa (B) |
| Non LBBB | |||
| ≥150 | II – IV | IIa (B) | IIa (A NYHA III/IV) IIb (B NYHA II) |
| 120 to 150 | II – IV | IIb (B) | – |
| 120 to 150 | III or IV | – | IIb (B) |
| AF or pacing | |||
| ≥120 | II – IV | – | IIa (B) |
| ≥120 | III or IV | IIa (B) | – |
| high Pacing | III or IV | I (B upgrade) IIa (B denovo) | IIa (C upgrade) |
Results
The search identified 1,511 reports in MEDLINE and Embase and 93 in the Cochrane Library, totaling 1,083 records after duplicate removal ( Figure 1 ). Of these, 30 reported CRT eligibility in 3 broad patient groups ( Table 2 ): ambulatory or clinic, hospitalized, and specialized populations (e.g. those who underwent transplantation evaluation and those receiving implantable cardioverter-defibrillator therapy). All of the studies predated current CRT recommendations and applied historical criteria. No study separated class of indication. We therefore accepted “eligibility” to include class I, IIa, and IIb recommendations.
| Cohort | n | LVEF Inclusion (%) | Dates | Prospective | Consecutive | Centers | LVEF Available (%) | QRS Available (%) | |
|---|---|---|---|---|---|---|---|---|---|
| Ambulatory | |||||||||
| Asghar 10 | HF/general cardiology | 563 | ≤35 | 2005–2006 | no | no | Single | inclusion criteria | 100 |
| Atwater 12 | Medical center | 178 | ≤45 | 2010 | no | no | Single | inclusion criteria | 100 |
| Boriani 10 | IN-CHF | 4977 | any | 1995–2000 | no | yes | Multicenter | nr | nr |
| Curtis 09 | IMPROVE-HF | 15,381 | ≤35 | 2005–2007 | yes | Random sampling | Multicenter | inclusion criteria | 70 |
| Fauchier 06 | DCM clinic | 201 | any | 1992–2004 | no | yes | Single | 100 | 100 |
| Fonarow 10 | IMPROVE-HF | 15,177 | ≤35 | 2005–2007 | yes | Random sampling | Multicenter | inclusion criteria | 67 |
| Gupta 03 | HF clinic | 121 | <40 | Unknown | Unknown | yes | Single | inclusion criteria | 100 |
| Grimm 03 | DCM clinic | 566 | ≤50 | 1991–2001 | yes | yes | Single | inclusion criteria | 100 |
| Hebert 06 | HF care program | 451 | ≤40 | 2002–2004 | no | no | Multicenter | inclusion criteria | 100 |
| Komura 04 | DCM clinic | 357 | any | 1988–2001 | no | yes | Multicenter | 100 | 100 |
| McAlister 06 | HF clinic | 263 | any | 2003–2004 | yes | yes | Single | 97 | 100 |
| Oh 12 | HF clinic | 1345 | any | 2007–2009 | no | yes | Single | 100 | 100 |
| Shen 04 | HF care program | 1129 | any | To 2001 | no | no | Single | 100 | 100 |
| Sulaiman 08 | HF clinic | 263 | any | 2005 | no | no | Single | 80 | 100 |
| Yang 02 | Medical clinic | 203 | <45 | 2000 | no | yes | Single | inclusion criteria | 100 |
| Hospitalisation | |||||||||
| De Sutter 11 | HFH | 368 | any | 2008 | yes | yes | Multicenter | Missing excluded | Missing excluded |
| Farwell 00 | HFH | 721 | any | 1997–1998 | no | yes | Single | 35 | 91 charts Available |
| Garcia-Pinilla 07 | HFH | 674 | any | 2004 | yes | yes | Multicenter | 63 | 100 |
| Guyomar 03 | HFH | 108 | any | 2000 | yes | no | Single | nr | nr |
| Lucas 06 | HFH | 861 | any | 2000–2004 | yes | yes | Single | nr | 100 |
| McAlister 06 | HFH EFFECT | 2640 | any | 1999–2001 | yes | yes | Multicenter | 57 | 100 |
| Nayar 13 | HFH | 770 | any | 2009–2010 | no | yes | Single | 58 | 100 |
| Specialized cohorts | |||||||||
| Dodson 14 | ICD recipients | 88,989 | any | 2009–2010 | no | no | Multicenter | nr | nr |
| Molhoek 03 | ICD recipients | 390 | any | 1996–2001 | no | yes | Single | 100 | 100 |
| Paisey 05 | ICD recipients | 60 | any | 1989–1997 | no | yes | Single | 100 | 100 |
| Scott 12 | ICD recipients | 399 | any | 2003–2007 | no | yes | Single | 100 | 100 |
| Stellbrink 99 | ICD recipients | 384 | any | nr | no | yes | Multicenter | 100 | 100 |
| Werling 02 | ICD recipients | 360 | any | 1992–1998 | no | no | Single | 100 | 100 |
| Galizio 03 | Transplant evaluation | 200 | any | nr | no | no | Single | 100 | 100 |
| Pedone 04 | Transplant clinic | 161 | any | 1996–2002 | no | yes | Single | 100 | 100 |
| Sims 10 | Cardiopulmonary exercise | 274 | any | nr | no | yes | Single | 100 | 95 |
In ambulatory patients, overall CRT eligibility according to historical criteria ranged from 1% to 33% ( Table 3 ). The pooled random-effects estimate was 11.0% (95% CI 8.1% to 14.3%), acknowledging significant heterogeneity (Q statistic = 500, I 2 = 97.6%, 95% CI 96.9% to 98.2%). The variability was explained largely by QRSd cutoffs and NYHA class and LVEF inclusion criteria. Eligibility was lowest (1% to 7%) in studies with higher QRSd cutoffs or fewer patients with severe LVSD or symptoms. The higher estimates of eligibility (14% to 33%) derived from cohorts with more severe LVSD or higher NYHA class. These were typically heart function or cardiomyopathy clinics at academic centers. A single study in 201 patients with idiopathic dilated cardiomyopathy was noteworthy in applying criteria analogous to historical and current guidelines. Including NYHA class II expanded eligibility from 14% to 23%.
| LVEF <35% (%) | I/II/III-IV (%) | QRSd ≥150 (%) | QRSd ≥120 (%) | LBBB (%) (% of QRSd ≥120) | RBBB (%) (% of QRSd ≥120) | IVCD (%) (% of QRSd ≥120) | AF (%) | Paced | Candidates Fulfilling Historic Criteria (%) LVEF<35% NYHA III/IV QRSd >120 ms | CRT Contra-indication | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Ambulatory | |||||||||||
| Asghar | 100 | 15/45/40 | – | 42 | – | – | – | 9 | 13 | 33 (186/563) | 9 (53/563) |
| Atwater | – | 25/39/36 | – | – | – | – | – | 43 | – | 15 (27/178) | 21 (7/34) |
| Boriani | – | 13/54/33 | – | 30 | – | – | – | 20 | – | 7 (337/4977) | – |
| Curtis | 100 | – | – | – | – | – | – | 31 | – | 9 (1373/15,381) | 1 (20/1393) |
| Fauchier | – | −/−/43 | – | – | 28 | – | – | – | – | 14 (28/201) | – |
| Fonarow | 100 | 37/39/25 | – | 53 | – | – | – | 40 | – | 10 (1540/15,177) | – |
| Gupta | – | −/−/68 | – | 36 | 25 (70) | 11 (30) | – | – | – | – | – |
| Grimm | 58 | 11/55/34 | 24 | 39 | 25 (64) | 4 (10) | 10 (26) | 23 | 2 | 14 (78/566) | – |
| Hebert | 59 | 28/46/36 | – | – | – | – | – | – | – | 7 (33/451) | – |
| Komura | – | 55/33/12 | 29 ≥ 130 ms | 39 | 17 (48) | 6 (19) | 11 (33) | – | 1 | 7 (25/357) ∗ 130 ms | – |
| McAlister | 58 | – | – | 54 | two thirds | – | – | – | – | 24 (62/263) | – |
| Oh | – | Exclude/ 31/69 | – | – | – | – | – | 33 | – | 18 (235/1345) | – |
| Shen | 43 | – | 25 > 130 ms | 44 > 110 ms | 14 (58) | 6 (23) | 5 (20) | 5 | 9 | 4 (43/1138) ∗ 130 ms | – |
| Sulaiman | 31 | 32/63/5 | – | – | 17 to 30 | – | – | 39 | – | 1 (3/263) | – |
| Yang | 56 | 8/29/63 | 17 | – | – | – | – | – | – | 6 (12/203) ∗ 150 ms | – |
| Hospitalisation | |||||||||||
| De Sutter | 40 | 0/0/100 | 24 | 48 | (67) | – | – | – | – | 21 (79/368) | – |
| Farwell | – | 39/33/28 | – | 25 | 15 (59) | 7 (26) | 4 (15) | 40 | exc | 10 (72/721) | – |
| Garcia-Pinilla | – | 2/15/83 | – | 31 | 27 (87) | – | – | 42 | – | 6 (38/674) | – |
| Guyomar | – | 0/0/100 | 32 | – | 15 (75) | 5 (25) | – | – | – | 4 unclear derivation | – |
| Lucas | 36 | 0/0/100 | – | 43 of LVSD | 11 to 31 | 10 | – | 38 | 7 | 14 (123/861) | – |
| McAlister | 50 | – | – | 22 | two thirds | – | – | – | – | 7 (179/2640) | 2 (225/9943) |
| Nayar | 31 | 0/10/90 | – | 61 of LVSD | – | – | – | 31 | – | 6 (82/1349) | 9 (8 of 90) |
| Specialized cohorts | |||||||||||
| Dodson | – | – | – | – | – | – | – | – | – | 31 (27,367/88,989) | – |
| Molhoek | – | −/−/20 | – | – | – | – | – | 8 | – | 20 (79/390) | – |
| Paisey | 47 | 47/44/9 | 32 > 130 ms | – | – | – | – | – | – | 8 (5/60) | – |
| Scott | 54 | – | 21 | 53 | – | – | – | 9 | – | 29 (158/549) ∗ 130 ms | – |
| Stellbrink | – | 19/54/28 | 13 | 34 | – | – | – | 18 | – | 11 (44/384) | 1 (2/384) |
| Werling | 31 | – | – | 27 | – | – | – | – | – | 9 (34/360) | – |
| Galizio | 54 | 4/26/71 | 34 | 54 | 38 (71) | 8 (14) | 8 (15) | 11 | – | 27 (54/200) ∗ 130 ms | – |
| Pedone | – | – | – | – | – | – | – | 15 | – | 24 (38/161) ∗ 130 ms | – |
| Sims | 82 | – | – | 52 | – | – | – | 11 | 2 | 38 (105/274) | – |
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