Cardiac Resynchronization Therapy in Patients with Mildly Impaired Left Ventricular Function PAUL W.X. FOLEY, M.R.C.P.,* BERTHOLD STEGEMANN, PH.D.,† RUSSELL E.A. SMITH, M.D., F.R.C.P.,* JOHN E. SANDERSON, M.D., F.R.C.P.,‡ and FRANCISCO LEYVA, M.D., F.R.C.P.* From the *University of Birmingham, Department of Cardiology, Good Hope Hospital, Heart of England NHS Trust, Sutton Coldfield, United Kingdom; †Medtronic Inc., Bakken Research Center, Maastricht, The Netherlands; and Queen Elizabeth Hospital, University of Birmingham, Birmingham, United Kingdom
Aims: We sought to determine the unknown effects of cardiac resynchronization therapy (CRT) in patients with a left ventricular ejection fraction (LVEF) >35%. Because of its technical limitations, echocardiography (Echo) may underestimate LVEF, compared with cardiovascular magnetic resonance (CMR). Methods: Of 157 patients undergoing CRT (New York Heart Association [NYHA] functional class III or IV, QRS ≥ 120 ms), all of whom had a preimplant Echo-LVEF ≤35%, 130 had a CMR-LVEF ≤35% (Group A, 19.7 ± 7.0% [mean ± standard deviation]) and 27 had a CMR-LVEF >35% (Group B, 43.6 ± 7.7%). All patients underwent a CMR scan at baseline and a clinical evaluation, including a 6-minute walk test and a quality of life questionnaire, at baseline and after CRT. Results: Both groups derived similar improvements in NYHA functional class (A = −1.3, B = −1.2, [mean]), quality of life scores (A = −21.6, B = −33.0; all P < 0.0001 for changes from baseline), and 6-minute walking distance (A = 64.5, B = 70.1 m; P < 0.001 and P < 0.0001, respectively). Symptomatic response rates (increase by ≥1 NYHA classes or 25% 6-minute walking distance) were 79% in group A and 92% in group B. Over a maximum follow-up period of 5.9 years for events, patients in group A were at a higher risk of death from any cause, hospitalization for major cardiovascular events (P = 0.0232), or cardiovascular death (P = 0.0411). There were borderline differences in the risk of death from any cause (P = 0.0664) and cardiovascular death or hospitalization for heart failure (P = 0.0526). Conclusions: This observational study suggests that the benefits of CRT extend to patients with a LVEF >35%. (PACE 2009; 32:S186–S189) cardiac resynchronization therapy, ejection fraction, mortality Introduction The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) study1 and the Cardiac Resynchronization in Heart Failure (CARE-HF) study2 showed that, compared to optimum pharmacological therapy alone, cardiac resynchronization therapy (CRT) prolongs survival. These and other studies have shown that CRT also alleviates dyspnea, increases exercise capacity, and improves quality of life. These landmark trials of CRT have adopted a left ventricular ejection fraction (LVEF) ≤35% as an inclusion criterion. It is well recognized, however, Disclosures: P.F. is a research fellow who has been supported by Medtronic Inc. and St. Jude Medical. B.S. is an employee of Medtronic Inc. R.E.A.S., P.J. and F.L. have received sponsorship from Medtronic Inc. F.L. has also received sponsorship from St. Jude Medical. M.F. has received a grant in aid funding for investigator-led studies from Medtronic Inc. and is on the End Points Committee for a study funded by Biotronik. J.E.S. has received research funding from the British Heart Foundation and Medtronic Inc. and speaker fees from BoehringerIngelheim. Address for reprints: Francisco Leyva, M.D., F.R.C.P., Department of Cardiology, University of Birmingham, Good Hope Hospital, Sutton Coldfield, B75 7RR, United Kingdom. Fax: +441-213-786188; e-mail:
[email protected]
that echocardiographically derived (Echo) LVEF, obtained by visual estimation or planimetry, is highly variable, with coefficients of variation of up to 23.9%.3 Therefore, some CRT system recipients selected on the basis of echocardiography have an LVEF >35% measured by cardiovascular magnetic resonance (CMR). This study explores the effects of CRT in patients who were selected on the basis of an Echo-LVEF ≤35%, but whose CMR-LVEF were >35%. Methods The study included 157 patients in New York Heart Association (NYHA) functional class III or IV, with a QRS ≥120 ms and an Echo-LVEF ≤35%, who underwent CRT device implantation. A clinical evaluation, including a 6-minute hall walk test,4 a quality of life assessment (Minnesota Living with Heart Failure questionnaire),5 and echocardiography, was performed on the day prior to implantation and at 1 month, 3 months, and every 6 months after implantation. In patients who died, the follow-up clinical data pertain to the last visit before death. The follow-up data presented relate to a median of 372 days postimplantation. Patients were classified as responders if
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CRT AND MILDLY IMPAIRED LV FUNCTION
they improved by ≥1 NYHA functional classes or by ≥25% in 6-minute walking distance. Device Therapy Implantation was undertaken using standard techniques. Patients in sinus rhythm (n = 118) underwent optimization of atrioventricular delay prior to discharge and at every scheduled visit thereafter. The device was programmed to ventricular-triggered mode in patients in atrial fibrillation. Cardiovascular Magnetic Resonance (CMR) CMR imaging was performed using a 1.5-Tesla Signa scanner (GE Healthcare, Slough, UK). A short-axis LV stack was acquired using a steady state in free precession sequence in sequential slices from the atrioventricular ring to apex. Left ventricular volumes were measured, using manual planimetry of all cine images (MASS, Medis, Leiden, The Netherlands). Echocardiography Two-dimensional echocardiography was performed using Vivid 5 and 7 with off-line analysis using EchoPAC (GE Healthcare). Left ventricular volumes were measured using planimetry of apical four-chamber views and Simpson’s equation. Clinical Endpoints Clinical endpoints included the composite endpoint of death from any cause or an unplanned hospitalization for a major adverse cardiovascular event (MACE), which included cardiac transplantation, hospitalizations for worsening heart failure, myocardial infarction, unstable angina, arrhythmia, stroke, or pulmonary embolism. The composite endpoint of death from any cause and unplanned hospitalization for worsening heart failure was also considered. For these composite endpoints, the first event was included in statistical analysis. The additional endpoints considered were cardiovascular death and death from any cause. Mortality data were collected through medical records, and where appropriate, from interviews with patient’s caregivers. Information regarding clinical outcome was collected by an investigator who was unaware of the results of the CMR study. Statistical Analysis Continuous variables are expressed as mean ± standard deviation (SD). Comparisons between continuous variables were made using the unpaired Student’s t-test. Categorical data were presented as frequencies and were compared using the χ 2 test and Fisher’s exact post hoc test. Changes in continuous variables from baseline to
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follow-up were analyzed using paired Student’s t-tests. The effect of LVEF on the various endpoints was explored using Kaplan-Meier survival curves and the log-rank (Mantel-Cox) test. Statistical analyses were performed using Statview (SAS Institute, Cary, NC, USA). A two-tailed P value of 35% had a narrower QRS complex (P = 0.0033) and were less likely to be in atrial fibrillation (P = 0.001) (Table I). The characteristics of the two groups were otherwise similar. Comparable improvements in NYHA functional class, 6-minute walking distance, and quality of life scores were observed in both groups (Table II). No correlation was observed between CMRLVEF and preimplant NYHA functional class, 6-minute walking distance or quality of life scores, or between CMR-LVEF and changes in these measurements from baseline (data not shown). As
Table I. Baseline Characteristics of Patients with LVEF ≤35% versus >35% on CMR Imaging LVEF ≤35% LVEF >35% (n = 130) (n = 27) LVEF, % Age (yrs) Men, n (%) Atrial fibrillation, n (%) NYHA class Ischemic cardiomyopathy Nonischemic cardiomyopathy Drug regimen, n (%) Loop diuretics ACE inhibitor or ARB Beta-adrenergic blocker Spironolactone QRS duration, ms
P
19.7 ± 7.0 66.1 ± 10.5 100 (77) 33 (25)
43.6 ± 7.7 68.0 ± 11.4 ns 22 (81) ns 2 (8) 0.001
3.19 ± 0.51 83 (64)
3.19 ± 0.62 16 (59)
ns ns
17 (36)
9 (41)
ns
115 (88) 119 (92)
20 (74) 23 (85)
ns ns
71 (55)
16 (59)
ns
51 (39) 16 (59) ns 148.4 ± 27.5 131.4 ± 23.0 0.0033
Values are means ± SD or numbers (%) of observations. ACE = angiotensin-converting enzyme; ARBs = angiotensin II receptor blockers.
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Follow-Up Clinical Measurements in Patients with LVEF ≤35% versus >35% on CMR Imaging LVEF ≤35% (n = 127)
LVEF >35% (n = 26)
Median follow-up, 1122 810 days NYHA functional class Baseline 3.19 ± 0.51 3.19 ± 0.62 2.0 ± 0.83** Follow-up 1.92 ± 0.94** 6-minute walk test, m Baseline 242.4 ± 110.5 284.7 ± 123.2 Follow-up 306.9 ± 114.4** 354.8 ± 133.3* Quality of life score Baseline 55.6 ± 20.4 60.7 ± 23.8 27.7 ± 23.9** Follow-up 34.0 ± 23.4** Responders, 99 (79) 24 (92) n (%)
Survival from death from any cause or hospitalization for MACE
Values are means ± SD or number (%) of observations. *P < 0.001; **P < 0.0001 versus baseline within same group.
1 LVEF≥35%
.8 .6
LVEF35%. The salient finding from this study is that these patients (mean CMR-LVEF of 44%) derived similar improvements in NYHA functional class, 6-minute walking distance, and quality of life as patients with a CMRLVEF ≤35% (mean CMR-LVEF of 20%).
Survival from cardiovascular death or hospitalization for HF
Table II.
.8
LVEF≥35%
.6
LVEF35%.6 Interestingly, the preva-
lence of dyssynchrony was similar in three strata of LVEF (20%–35%, and >35%–50%), indicating that the prevalence of mechanical systolic dyssynchrony is independent of Echo-LVEF. The substrate for CRT, namely mechanical dyssynchrony, thus appears to be present in patients with mildly impaired left ventricular function. Limitations of the Study Because our study did not include a non-CRT group, we cannot ascertain whether the observed changes in the measures considered in this study reflect a clinical benefit. Conclusions We conclude that CRT leads to similar changes in symptoms and functional capacity in patients with either an LVEF >35% or ≤35%. The risk of cardiovascular death and hospitalizations for MACE was lower in patients with an LVEF >35%. These findings suggest that CRT is beneficial in patients with heart failure and an LVEF >35%.
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nance imaging, echocardiography, and radionuclide ventriculography. Int J Cardiovasc Imaging 2002; 18:135–142. 4. Guyatt GH, Sullivan MJ, Thompson PJ. The 6-minute walk: A new measure of exercise capacity in patients with chronic heart failure. Can Med Assoc J 1985; 132:919–923. 5. Rector TS, Kubo SH, Cohn JN. Patient’s self-assessment of their congestive heart failure. Content, reliability and validity of a new measure – The Minnesota living with heart failure questionnaire. Heart Failure 1987; 3:198–207. 6. Chan CP, Zhang Q, Yip GW, Fung JW, Lam YY, Lee PW, Wu EB, et al. Relation of left ventricular systolic dyssynchrony in patients with heart failure to left ventricular ejection fraction and to QRS duration. Am J Cardiol 2008; 102:602–605.
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