European Heart Journal Advance Access published online on May 30, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn221
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The magnitude of reverse remodelling irrespective of aetiology predicts outcome of heart failure patients treated with cardiac resynchronization therapy
1 Department of Cardiovascular Medicine, Section of Cardiac Electrophysiology and Pacing, Cleveland Clinic, Cleveland, OH, USA
2 Department of Cardiology, University of Foggia, Foggia, Italy
3 Division of Cardiology, Fondazione Cardiocentro Ticino, Lugano, Switzerland
4 Service of Biometry and Clinical Epidemiology, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy
5 Department of Cardiology, Stanford University, Palo Alto, CA, USA
6 Texas Cardiac Arrhythmia Institute at St David's Medical Center, Austin, TX, USA
Received 20 December 2007; revised 17 April 2008; accepted 6 May 2008.
* Corresponding author. Tel: +1 440 247 0011, Fax: +1 440 247 0011, Email: nataleam{at}roadrunner.com
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Abstract |
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Aims: We assessed the relationship between cardiac resynchronization therapy (CRT)-induced reverse remodelling and mortality during a long-term follow-up in a prospective observational study.
Methods and results: We analyzed data from a prospective registry including 398 consecutive patients who underwent CRT between September 1998 and September 2007. Left ventricular ejection fraction (LVEF) was assessed before CRT and in the period between 3 and 6 months following implant. All-cause mortality, urgent transplantation and implantation of left ventricular assist device were all considered relevant events. A total of 398 (179 non-ischaemic and 219 ischaemic) patients were analysed. Overall, the increase of LVEF was statistically significant and was computed with 7.0 points (95% CI 5.8–8.3, P < 0.001). Non-ischaemic patients had a larger increase [9.2 points (95% CI 7.0–11.1), P < 0.001] of their LVEF from baseline, when compared with the ischaemic group. The median duration of follow-up was 4.4 years. The cumulative incidence of all events at the end of the 96 months period of follow-up was 55% and it was 34% (95% CI 29–40) at 5 years. At the multivariable analysis of the event-free survival, aetiology lost its predictive value (HR 0.92, P = 0.47), while a change in LVEF 
6 points still significantly decreased the risk of event during the follow-up (HR 0.30, P = 0.001).
Conclusion: Reverse remodelling measured by LVEF after 3 months is a good predictor of long-term outcome. Patients with an increase in LVEF 6 points have an excellent event-free survival approaching 66% at 5 years of follow-up.
Key Words: Cardiac resynchronization therapy • Heart failure • Ejection fraction • Ischaemic and non-ischaemic aetiology
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Introduction |
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Randomized clinical trials have shown that cardiac resynchronization therapy (CRT) improves symptoms, exercise capacity, and induces reverse remodelling in patients with moderate-to-severe heart failure and a wide QRS.1–4 There is also growing evidence that the degree of improvement in CRT recipients is dependent on the aetiology of the cardiomyopathy. Specifically, the extent of reverse remodelling may be two-fold greater in patients with non-ischaemic cardiomyopathy as compared with ischaemic cardiomyopathy.3,5,6 Studies have also indicated that reverse remodelling is time-dependent, and that a progressive increase in left-ventricular ejection fraction (LVEF) occurs over time in both ischaemic and non-ischaemic cardiomyopathy patients.3 Non-ischaemic cardiomyopathy heart failure patients however were more likely to have a sustained reduction in left-ventricular size after 1 year of CRT.5
It has been shown that CRT reduces mortality and hospitalization for major cardiovascular events;3,7,8 this reduction usually becomes apparent after 6 months of CRT3 and may be related to the degree of reverse remodelling. Because patients with non-ischaemic cardiomyopathy showed mean larger reverse remodelling than ischaemic patients, one might expect better survival in this subgroup of patients. In contrast, both randomized controlled trials and a large registry in post hoc analysis have shown similar hazard ratio in patients with ischaemic and non-ischaemic cardiomyopathy, thus indicating similar survival benefit in both groups after CRT. The long-term link between the extent of reverse remodelling and the magnitude of mortality and morbidity reduction including the need for transplantation and their relation to underlying heart disease is still not elucidated.
We sought to determine the relationship between the effect of CRT-induced reverse remodelling and mortality during a long-term follow-up. Furthermore, we examined the relationship between aetiology, magnitude of reverse remodelling and long-term outcome defined by deaths and need of transplantation in a group of CRT patients treated in daily clinical practice.
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Methods |
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A prospective pre-defined registry protocol included 398 consecutive heart failure patients treated with CRT at the Cleveland Clinic, Cleveland, USA (337, 60.8%) and at Fondazione Cardiocentro Ticino, Lugano, Switzerland (61, 39.2%). Indication to CRT was defined by functional New York Heart Association (NYHA) class III–IV despite medical treatment optimized according to currently available guidelines,9 LVEF
35% of ischaemic and non-ischaemic origin, ventricular conduction delay (QRS duration >120 ms). Patients who had a major cardiovascular event in the previous 6 weeks were not considered for CRT and included in the present registry. Coronary angiogram was performed in each patient to differentiate the ischaemic group of patients from the non-ischaemic one. Moreover, no echocardiographic criterion of mechanical dyssynchrony was used for selecting patients. The registry, included all CRT patients implanted between September 1998 and September 2007, was designed and approved by each Institutional Review Board. All patients were evaluated at 1, 3, 6, 9, and 12 months following the procedure, and every 6 months thereafter. Demographic and clinical data extracted from medical records included age, sex, race, type of medication, aetiology of heart failure, concurrent medical problems, NYHA class, family history of CAD, heart transplant, and death. Standard medications were adjusted as appropriate at these visits.
LVEF was assessed during routine echocardiographic examination by the biplane Simpson's rule.
LVEF values used for the analysis belong to the period between 3 and 6 months following implant. Furthermore, in a subgroup of 100 consecutive patients left ventricular end-diastolic (LVEDV) and end-systolic volumes (LVESV) were also assessed. At each centre, measurement of LVEF and volumes was done independently by two experienced operators and in case of discrepancy of more than two absolute points LVEF or more than 5% for volumes was given by consensus. Outcome data were collected at each participating centre by reviewing outpatients clinical files or by telephone interview with relatives and/or family doctors.
Implanted device and leads
The two centres began using CRT at different point in time, which influenced implantation techniques and indication to CRT. Patients considered at risk of sudden cardiac death for both primary and secondary prevention received a CRT including implantable cardioverter-defibrillator (CRT-D). Transvenous lead positioning was guided by venogram with preference for a lateral or posterolateral vein as an implantation site. In case of failure or technical difficulties of transvenous approach, an epicardial steroid-eluting passive lead was implanted through a limited thoracotomy.
Statistical analysis
Data were described as mean and standard deviation (SD) if continuous and as counts and percent if categorical. The Student's t test and the Fisher's exact test were used to compare patients with and without ischaemic cardiomyopathy. The paired Student's t test was used to compare pre- and post-implant LVEF. The predictive role of ischaemic cardiomyopathy on the change in LVEF (on a continuous scale) was assessed in a multivariable regression model, while controlling for clinical relevant characteristics (age, gender, pre-implant LVEF, diabetes, chronic obstructive pulmonary disease, supraventricular arrhythmias, creatinine value, treatment with beta-blockers, ACE Inhibitor/ARB, spironolactone, loop diuretic, and for centre). The adjusted difference between groups and its 95% confidence interval (95% CI) was retrieved from the model. Model adequacy was assessed graphically by inspecting residuals. Kaplan–Meier cumulative survival and event-free survival (death/transplant) were computed. The median follow-up time was calculated according to the inverse Kaplan–Meier method. Cox regression was used to assess the prognostic role of aetiology and the change in LVEF on survival and event-free survival in a multivariable analysis, including also age, gender, pre-implant LVEF, diabetes, chronic obstructive pulmonary disease, supraventricular arrhythmias, creatinine value as possible confounders. NYHA functional class was not included given collinearity with LVEF. As the change of LVEF was assessed at 3–6 months (median 4.5 months), it was treated as a time-dependent variable in the Cox model. The interaction between ischaemic aetiology and change in LVEF was also evaluated. Hazard ratios (HR) and 95% CI were computed. The proportional hazards assumption was tested by means of Schoenfeld residuals. For the purpose of the analysis the change in LVEF was dichotomized at the median of its distribution (</6 absolute points) and at its upper tertile (<11/11 absolute points). Stata 9.2 (Stata Corporation, USA) was used for computation. All tests were two-sided and a P-value < 0.05 was retained for statistical significance. Finally, in a power analysis, the available sample size and the recorded number of events allowed to detect and effect size ranging from 0.5 to 0.4, with a power of 80% and a type I error ranging from 0.05 to 0.01 (to account for multiple tests).
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Results |
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Outcome information was available in all patients. Table 1 summarizes the clinical and demographic data of the 398 patients included into the registry. No major difference between the two enrolling centres was noted. Most of the patients were male and all patients had left bundle branch block and received tailored optimal medical treatment (Table 1). All the patients underwent successful implantation of their respective device with 318 patients (80%) receiving a CRT-D device. There were statistical differences regarding the age, male gender, diabetes, and the numbers of ICD implanted between the ischaemic and non-ischaemic group of patients.
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Magnitude of volumetric changes and ejection fraction change
Overall, the mean increase of LVEF assessed 3–6 months of post-CRT was statistically significant and was computed to 7.0 points (95% CI 5.8–8.3, P < 0.001), while the mean reduction in LVESV reached 19.2 mL (95% CI 10.11–28.22, P < 0.001) and the mean reduction in LVEDV reached 18.1 mL (95% CI 8.00–28.03, P < 0.001) (Figure 1).
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Forty-two percent of patients increased their LVEF by <5 points, 19% increased by 5 to 10 points and 39% increased by >10 points. Non-ischaemic patients increased significantly more, by 9.1 points (95% CI 7.0–11.1) their LVEF from baseline, when compared with the ischaemic group which increased their LVEF from baseline up to 5.7 points (P = 0.006) (Figure 1). Correspondingly a significantly larger proportion of non ischaemic patients (52 vs. 38%, P = 0.010) reached an increase in LVEF of 6 points or more.
Systolic volume changes >10% of the baseline volume was observed in 54 patients (61%). This proportion was lower, but not significantly, in ischaemic than in non-ischaemic patients (59 vs. 64%, P = 0.67). The vast majority of patients (82%) in whom end-systolic volume changed <10% of baseline volume also showed a change in LVEF <6 points. On the other hand, 70% of patients showing a major change in end-systolic volume >10% had a change of >6 points in LVEF (P < 0.001).
Predictors of change in LVEF
Aetiology retained its predictive value when controlling for clinically relevant characteristics (see Methods) in a multivariable analysis, with an adjusted difference in the LVEF change maintained at 3.8 points (95% CI 0.6–7.1, P = 0.020), favouring the non-ischaemic group. Other significant predictors of a lesser change in LVEF were CRT-D (P = 0.008) and male gender (P = 0.049), as shown in Table 2.
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Event-free survival
By the end of the study, the survival status of all patients was known. The median duration of follow-up was 4.4 years (25–75th percentiles, 2.6–5.9). The survival and event-free analysis (combined for death and heart transplant) revealed that overall 120 events occurred. The cumulative incidence of all events at the end of the 96 months period of follow-up was 55% (95% CI 45–67). It was 5% (95% CI 4–8) and 34% (95% CI 29–40) at 1 and 5 years, respectively, while the event-rate was of 8.47 per 100 person-years (95% CI 7.09–10.14).
Ischaemic aetiology was a determinant of both survival and event-free survival (HR 1.57, 95% CI 1.04–2.36, P = 0.031 and HR 1.45, 95% CI 1.00–2.10, P = 0.049, respectively, at the univariable analysis; Figure 2). There were 101 deaths (66 in the ischaemic group of patients) and 19 heart transplants (9 in the ischaemic group of patients). Death rates were 5.3 (95% CI 3.8–7.4) and 8.7 (95% CI 6.8–11.0) per 100 person year for the non-ischaemic and ischaemic groups of patients, respectively. Event rates were 6.9 (95% CI 5.1–9.2) and 9.8 (95% CI 7.8–12.3), respectively. Patients with a change in LVEF 6 points (the median of change) appeared to have a better survival and event-free survival (HR 0.34, 95% CI 0.21–0.59, P < 0.001 and HR 0.31, 95% CI 0.20–0.60, P < 0.001, respectively, at the univariable analysis; Figure 3A and B). The benefit was larger when considering patients with a change in LVEF 11 points (the upper tertile of change) (HR, 0.23; 95% CI, 0.12–0.46; P < 0.001 and HR, 0.21; 95% CI, 0.11–0.42; P < 0.001, respectively, for the univariable analysis of survival and event-free survival; Figure 3C and D). Patients with change in LV end-systolic volume >10% had a slightly better survival (HR 0.29, 95% CI 0.05–1.60, P = 0.140) and significantly better event-free survival (HR 0.16, 95% CI 0.03–0.79, P = 0.011) (Figure 4) compared with patients with minor (<10% of baseline) or no LV end-systolic volume change.
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In a multivariable analysis of the event-free survival including aetiology, the change in LVEF dichotomized at its median and a series of clinically relevant characteristics (see Methods), ischaemic aetiology lost its predictive ability (HR 0.92, 95% CI 0.56–1.53, P = 0.47), while a change in LVEF
6 points still significantly decreased the risk of event during the follow-up (HR 0.34, 95% CI 0.20–0.59, P < 0.001) (Figure 5). Similar results were obtained when including change in LVEF, age, and creatinine on a continuous scale. No interaction between them was shown in this prognostic model; thus we can assume a similar prognostic role for LVEF in ischaemic and non ischaemic patients. We obtained comparable results when the cut-off for change in LVEF was set at 11 (upper tertile of the distribution: role of ischaemic aetiology on event HR = 0.79, 95% CI 0.50–1.25, P = 0.32, role of change in LVEF11 on event HR = 0.22, 95% CI 0.11–0.47, P < 0.001).
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Discussion |
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Our study showed that the survival benefit of heart failure patients treated with CRT is related to the extent of reverse remodelling observed at 3 months of follow-up, and this was independent from the aetiology. These results of CRT on mortality are novel and expand those of previous randomized controlled trials3,5,7 as well as of a large observational prospectively conducted registry.8 The cumulative 1 and 5 year mortalities were 5 and 34%, respectively, being slightly lower than that reported in the MILOS registry;8 this may be related to the significant higher proportion of patients receiving a CRT-D in our study (80%) than in the MILOS registry (56%), thus further suggesting the survival benefit provided by to CRT-D in heart failure patients.
Magnitude of reverse remodelling and underlying aetiology
Consistent with observations in several earlier studies, CRT in our series increased LVEF and decreased LV end-systolic volume. The magnitude of this effect is comparable to that observed with ß-blockers, ACE inhibitors in similarly symptomatic populations. Both randomized and non-randomized studies with CRT have shown a similar mean LVEF increase ranging from 4.6 of the MIRACLE trial to 6.1 of the DECREASE-HF trial.10 Moreover, the distribution in the change of LVEF in our study was similar to that reported in other trials; about 40% of the patients did not show any appreciable change in LVEF, in about 20% a modest increase, and finally in 40% of the patients we observed a large increase of LVEF. Consistent with our data is the most recently published DECREASE-HF study which has shown that about 34% of patients had a marked (10 units) increase in LVEF by 6 months.
However, the underling cardiomyopathy influenced the magnitude of reverse remodelling. Ischaemic patients were more likely to have a change of LVEF of <6% when compared with the non-ischaemic group, in a multivariable analysis. This finding confirms MIRACLE4–5 and DECREASE-HF study,10 but also expands on previous description about predictors of a smaller increase of LVEF after CRT such as supraventricular arrhythmias, renal failure, and younger age.
Reverse remodelling and long-term outcome
Reversal of maladaptive remodelling mechanism in heart failure patients by both pharmacological and non-pharmacological interventions is viewed as a surrogate of improved outcome. Initial studies have arbitrarily defined responders to LV reverse remodelling either by a reduction in LV end-systolic volume or LVEF 3–6 months after CRT.1,2 Yu et al.11 have proposed a reduction of at least 10% in LV end-systolic volume, whereas Mangiavacchi et al.12 have recently proposed a change in LVEF of at least 4 absolute points. Yu et al. have recently examined in a series of 141 CRT patients the relation between LV reverse remodelling and outcome; they showed that reduction of end-systolic volume of at least 10% was related at a very low event rate (6.9% all-cause mortality) at a mean follow-up time of 695 days. We confirmed the data by Yu et al.11 but also expanded their findings showing that over a significantly longer follow-up time patients with a significantly reduction of end-systolic volume of at least 10% have an excellent outcome.
In addition to changes in LV end-systolic volume we examined the role of LVEF, a more frequently used index in routine clinical practice for predicting outcome. For the first time, we have been able to show that an increase in LVEF of 6 points or more is related to a very low event rate. These findings expand previous knowledge indicating that evaluation of LVEF between 3 and 6 months after CRT in severely symptomatic heart failure patients is extremely useful and clinically relevant for predicting long-term prognosis of the individual patient.
Of great interest is the notion that once reverse remodelling occurred, no matter how it is defined (change of LVEF of at least 6 absolute points or change of LV end-systolic volume at least 10% of baseline volume), the aetiology of the underlying cardiac disease, does not impact outcomes anymore. In addition to that, our study suggests that up a certain value of change in LVEF, the outcome will not greatly change. It is entirely possible that the excellent overall survival and low event rate in our study may make very difficult to detect minor long-term all-cause mortality changes between two strata of LVEF. In this respect our study may be underpowered. Although this finding may be surprising, it is entirely possible that the loss of aetiology as determinant for the outcome is an indirect demonstration of the importance of large mechanically viable areas and/or small scars. Indeed, the possible role of large scar tissue in limiting reverse remodelling in CRT patients presenting with coronary artery disease has been demonstrated.13 On the other hand, location and magnitude of scar tissue in predicting outcome even in patients with idiopathic dilated cardiomyopathy has been recently demonstrated.14
The importance of treating patients with CRT-D has been well established by COMPANION trial and recently supported by MILOS registry.7–8 Our data further confirm the additional benefits of combined electrical and pharmacological treatment in advanced heart failure patients.
Clinical implications
The results of the present study have clinical, practical, and socio-economic implications for heart failure patients treated with CRT. Indeed, change of LVEF above 6 absolute points may indicate that a different follow-up schedule and important reassurance for long-term prognosis of a specific patient. This is important in the view of the incremental follow-up burden expected in out-patient clinics due to a significant increase in the number of device treated patients.
Limitations
This study has several limitations. Although there is a correlation between changes of LVEF and LV end-systolic volume which suggest an equivalent value of these two measurements, volume measurements were performed only in a subgroup of 100 patients.
No data were available for analysis on dyssynchrony. However, we do not believe that this can be considered a main limitation given the most recent results of the PROSPECT and RethinQ trials.15 These studies showed no additional benefit in the outcome of CRT-treated heart failure patients when using echocardiocardiographic parameters of mechanical dyssynchrony to select patients. Moreover, all guidelines including the most recently published ECS/EHRA guideline on CRT never considered measurement of mechanical dyssynchrony as selection criteria for CRT.9
Due to the non-blinded nature of our study, the ECHO evaluation performed at 3–6 months after CRT implantantion could be biased.
However, considering that all patients received active therapy, it is unlikely that such test would falsely predict the survival status of patients at the end of the long follow-up period.
No information about the mode of death was collected. Mitral insufficiency data and their relation with muscle dyssincrony were not presented in this study.
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Conclusions |
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Reverse remodelling measured either by LVEF or LV end-systolic volume after 3 months is a good predictor of long-term outcome. Both ischaemic and non-ischaemic patients have a poor outcome when no reverse remodelling occurs, but patients who have an increase in their LVEF at least 6 absolute points or show a reduction in LV end-systolic volume of at least 10% of the baseline value have an excellent event-free survival approaching 66% at 5 years of follow-up.
Conflict of interest: Dr Natale received research grants from St. Jude Medical and honoraria from Medtronic, Boston Scientific, St. Jude Medical Center, Stereotaxis, Biosense Webster and has served as a consultant and/or advisory board member for St. Jude Medical, Stereotaxis and Biosense Webster. Angelo Auricchio is consultant to Boston Scientific, Medtronic, Sorin, Biotronik. His institution has received research grants from Boston Scientific and Medtronic. Antonio Sorgente is a research fellow at Fondazione Cardiocentro Ticino sponsored by Medtronic, Switzerland. Cristina Conca is a research fellow at Fondazione Cardiocentro Ticino sponsored by Boston Scientific, Switzerland. Catherine Klersy is statistical consultant to Boston Scientific and Medtronic. Bruce Wilkoff have received research grants from Medtronic, Boston Scientific, and St. Jude Medical Center, as well as honoraria from Medtronic, Boston Scientific, St. Jude Medical Center, and Stereotaxis and has served as a consultant and/or advisory board member for Medtronic, Boston Scientific, St. Jude Medical Center, and Stereotaxis. All the other authors have no special financial or other relations and interest conflicts to be disclosed.
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Dr Luigi Di Biase is a Research Fellow supported by a grant from the Italian Society of Cardiology (SIC).
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Appendix I |
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List of additional investigators participating to this study:
Cleveland Clinic: Rong Bai, M.D; Claude S. Elayi, M.D; Chi Keong Ching, M.D; Pascal Lim, M.D; Conor Barrett, MD; Karen Phillips, MD; Mohamed Kanj, M.D; Oussama M. Wazni, M.D; Jennifer E. Cummings, M.D; J. David Burkhardt, M.D; Thomas Dresing, M.D; Mandeep Bhargava, M.D.
Fondazione Cardiocentro Ticino: Cristina Conca, MD; Elena Pasotti, MD; Giovanni B. Pedrazzini, MD.
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Footnotes |
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L.B. and A.A. gave an equivalent contribution on the drafting of the manuscript. 
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