Predictors of Response to Cardiac Resynchronization Therapy in the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT)
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Abstract
Background—
We hypothesized that combined assessment of factors that are associated with favorable reverse remodeling after cardiac resynchronization-defibrillator therapy (CRT-D) can be used to predict clinical response to the device.
Methods and Results—
The study population comprised 1761 patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT). Best-subset regression analysis was performed to identify factors associated with echocardiographic response (defined as percent reduction in left ventricular end-diastolic volume 1 year after CRT-D implantation) and to create a response score. Cox proportional hazards regression analysis was used to evaluate the CRT-D versus defibrillator-only reduction in the risk of heart failure or death by the response score. Seven factors were identified as associated with echocardiographic response to CRT-D and made up the response score (female sex, nonischemic origin, left bundle-branch block, QRS ≥150 milliseconds, prior hospitalization for heart failure, left ventricular end-diastolic volume ≥125 mL/m2, and left atrial volume <40 mL/m2). Multivariate analysis showed a 13% (P<0.001) increase in the clinical benefit of CRT-D per 1-point increment in the response score (range, 0–14) and a significant direct correlation between risk reduction associated with CRT-D and response score quartiles: Patients in the first quartile did not derive a significant reduction in the risk of heart failure or death with CRT-D (hazard ratio=0.87; P=0.52); patients in the second and third quartiles derived 33% (P=0.04) and 36% (P=0.03) risk reductions, respectively; and patients in the upper quartile experienced a 69% (P<0.001) risk reduction (P for trend=0.005).
Conclusion—
Combined assessment of factors associated with reverse remodeling can be used for improved selection of patients for cardiac resynchronization therapy.
Clinical Trial Registration—
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.
Introduction
During the past 10 years, several randomized clinical trials have shown that cardiac resynchronization therapy (CRT) is associated with reduced morbidity and mortality in patients with left ventricular dysfunction and advanced heart failure (HF) symptoms who have a wide QRS duration.1–5 Recently, the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) trail and the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT) have extended the observed benefit to patients with less advanced (New York Heart Association [NYHA] class I/II) signs and symptoms.6–8 Although most treated patients respond to CRT, approximately one third are considered nonresponders in clinical trials using a variety of measures of clinical responsiveness.9–12 Currently, however, there are limited data on factors that can distinguish responders from nonresponders among eligible patients.
Clinical Perspective on p 1536
Cardiac resynchronization therapy is associated with reverse remodeling, a process characterized by a reduction in left ventricular volumes leading to improved systolic and diastolic function.1–8 Recent data suggest that the magnitude of reverse remodeling can be used to predict the subsequent outcome of CRT-treated patients.13–15 We hypothesized that combined assessment of factors that are associated with favorable reverse remodeling can be used to predict clinical response to CRT.
Methods
Study Population
The design and primary results of MADIT-CRT have been published recently.8 Briefly, MADIT-CRT was designed to determine whether CRT with a defibrillator (CRT-D) would reduce the risk of death or HF events in patients with mild cardiac symptoms, a reduced ejection fraction, and wide QRS complex compared with implantable cardioverter-defibrillator (ICD) therapy. The patients were randomly assigned in a 3:2 ratio to receive either CRT-D or ICD. From December 22, 2004, through April 23, 2008, a total of 1820 patients were enrolled at 110 hospital centers. The protocol was approved by the institutional review board at each of the participating centers. Patients of either sex who were at least 21 years of age were enrolled in the study if they had ischemic cardiomyopathy (NYHA class I or II) or nonischemic cardiomyopathy (NYHA class II only), sinus rhythm, an ejection fraction of ≤0.30, and prolonged intraventricular conduction with a QRS duration of ≥130 milliseconds. All eligible subjects met guideline indications for ICD therapy.16 Patients were excluded from enrollment for a variety of reasons, as previously reported.8 The present study population comprised 1761 patients (97%) for whom complete information on baseline clinical, echocardiographic, and laboratory variables was available.
Echocardiographic Studies
Echocardiograms were obtained according to a study specific protocol at baseline, which was before device implantation (n=1809), and at 1 year. Paired echocardiograms from baseline and at 12 months with the device turned on were available in 718 of 1089 CRT-D–treated patients (66%).
Echocardiograms were sent on videotape or digital storage to the echocardiographic core laboratory at Brigham and Women's Hospital, where they were screened for quality and left ventricular, right ventricular, and left atrial measurements were made. Echocardiographic parameters were measured according to established American Society of Echocardiography protocols.17 Left ventricular and atrial volumes were measured by the Simpson method of disks in the apical 4- and 2-chamber views and averaged. Left ventricular ejection fractions were calculated according to standard methods. Reproducibility of the primary volumetric measures was assessed by having the primary observer reanalyze 101 random studies. The coefficients of variation for left ventricular end-diastolic volume (LVEDV), end-systolic volume (LVESV), and ejection fraction were 5.2%, 6.2%, and 5.5%, respectively.
Outcome Measures
Remodeling Effects
An echocardiographic response was defined as percent reduction in LVEDV (assessed as a continuous measure) between enrollment and 1 year (calculated as the difference between 1-year cardiac volumes and baseline cardiac volumes divided by baseline cardiac volumes). It was alternatively assessed as percent reduction in LVESV and by dichotomizing percentage reduction in cardiac volumes (prespecified as 10% and 15% reductions in LVEDV and LVESV, respectively, based on prior studies that assessed response to CRT1–7).
Clinical Response
The primary end point for clinical response was defined as a first HF event or death, whichever came first, during follow-up. The secondary end point was defined as the first occurrence of HF, death, or advancement to NYHA class >II during follow-up. The change in the 6-minute walk test at 1 year after enrollment (among the 1500 patients with available data) and the separate occurrence of all-cause mortality were also assessed as secondary end points.
Study Design
The present study was carried out in 3 steps (Figure 1). In the first step, we identified factors associated with a favorable echocardiographic response to CRT-D therapy among the 718 CRT-D–allocated patients (66%) with active CRT-D use for 1 year and paired baseline and 1-year echocardiograms. In the second step, we constructed a response score to CRT-D by combined assessment of the relative contribution of the factors that were identified to be associated with a favorable echocardiographic response to CRT-D. In the third step, we assessed the clinical benefit of CRT-D versus ICD-only therapy by response score quartile in MADIT-CRT patients with complete baseline information variables (n=1761 [97%]) and by assessing the interaction with treatment of the total response score; the benefit was likewise assessed with individual response scores.
Figure 1. Flow diagram of study design showing the number of patients and the corresponding number of clinical events (comprising the first occurrence of heart failure or death) in each step of the analysis. In the derivation analyses, 371 patients of the 1089 in the cardiac resynchronization-defibrillator therapy (CRT-D) group (34%) were omitted because of missing paired echocardiographic data; in the validation, 59 patients of the 1820 study population (3%) were omitted owing to missing information on at least 1 of the 7 chosen covariates. ICD indicates implantable cardioverter-defibrillator.
The sample sizes available for each step in the analysis and the corresponding end point events are shown inFigure 1. The methods used in each of the 3 steps of the analysis are described in the Statistical Analysis section.
Statistical Analysis
Covariates Associated With Echocardiographic Response to Cardiac Resynchronization-Defibrillator Therapy
We included 31 potential clinical, electrocardiographic, and laboratory binary risk factors (listed in Table I in the online-only Data Supplement) for the echocardiographic response model. Numeric variables were made binary by the use of cut points with the goal of finding a simple, easily implemented scoring method to be derived from them. Thresholds for categorization of numeric variables were prespecified using clinical and laboratory-accepted criteria. Univariate relationships between candidate covariates and an echocardiographic response (as defined above) in the CRT-D arm of the trial were assessed by t tests (χ2 for binary responses). The covariates with values of P<0.20 were further evaluated by carrying out a best-subset regression analysis in the CRT-D arm, examining the models created from all possible combinations of predictor variables, and using a penalty of 3.84 on the likelihood ratio χ2 value for any additional factor included (corresponds to a P of 5% for a 1-df χ2 test). Model selection was repeated after unselected factors were dropped, one at a time, to minimize the effects of missing data. However, because of the relatively small number of patients without complete baseline information (n=59 [3.2%]), no further adjustment was made for missing data.
Response Score
After selection of binary covariates, each was assigned a numeric value based on the relative value of its regression coefficient in the multivariate regression model (specifically, the response factor with the lowest regression coefficient among the 7 factors in the model was assigned a numeric value of 1, and the other 6 factors were assigned numeric values based on the relative values of their regression coefficients to that of the lowest value). A response score was constructed in each patient by adding the assigned numeric values of the factors identified in each patient, and the study population was categorized into approximate quartiles based on the distribution of the response scores (assessed as an ordinal measure) among patients. The clinical characteristics of study patients were compared across treatment groups by response score quartiles using the χ2 test for categorical variables and the Wilcoxon rank-sum test for continuous variables.
Clinical Benefit of Cardiac Resynchronization-Defibrillator Therapy Versus Implantable Cardioverter-Defibrillator–Only Therapy
Kaplan–Meier estimates for HF or death in each response quartile, stratified by treatment arm, were determined and statistically evaluated with the log-rank test. Cox proportional hazards regression analyses were carried out in the total population for the assessment of the primary (first occurrence of HF or death) and secondary (first occurrence of HF, death, or advancement to NYHA class >II) end points. The following covariates were included in the regression models: response score quartiles, treatment arm, and their interactions (CRT-D effect in each response score quartile). The response score was assessed for its linearity in relationship with the primary end point by analyzing smaller response score subgroups than were used in the quartile analysis. The hazard ratios for each of these subgroups were plotted across the response score subgroups. In an additional analysis, the response score was assessed as a continuous measure (by replacing the response score quartile covariate in the Cox models with a single response score numeric covariate), again with assessment for linearity. Checks were made for validity of the proportional hazards assumption.
Multivariate regression analysis was used to evaluate the change in 6-minute walk test at 1 year compared with baseline among CRT-D versus ICD-only patients by response score quartiles after assessment of linearity in smaller response score subgroups of CRT-D patients. Covariates in the regression models were the same as in the Cox proportional hazards regression analysis.
All P values were 2 sided, and values of P<0.05 were considered significant. Analyses were performed with SAS software (version 9.20).
Sensitivity and Bootstrap Validation Studies
Several analyses were carried out (described in more detail in the Appendix in the online-only Data Supplement). First, the response score was developed in a subgroup of the CRT-D patients, whereas the clinical benefit was assessed using all patients, including this subgroup, subgroup A. As a sensitivity analysis, we partitioned the remaining CRT-D group into 2 subgroups, subgroups B and C, with subgroup B similar to subgroup A in that all patients had active CRT-Ds at baseline and at 12 months but did not have paired echocardiographic studies. Subgroup C consisted of the remainder of the CRT-D group, including those dying or withdrawing within 12 months and others not having an active CRT-D for 12 months. We then assessed the clinical benefit in each of the 3 subgroups relative to ICD-only patients. Other analyses included consideration of other choices of baseline factors for the echocardiographic response score and by bootstrapping the selection of factors, bootstrapping the scoring derived from the selected factors, and bootstrapping the use of the response score in distinguishing risk for the CRT-D versus ICD-only groups.
Results
Predictors of Echocardiographic Response to Cardiac Resynchronization-Defibrillator Therapy
A best-subset regression analysis in the CRT-D arm of the trial identified 7 factors (from the 31 candidate covariates listed in Table II in the online-only Data Supplement) as being jointly associated with a favorable echocardiographic response to CRT-D therapy (Table 1). These factors were female sex, nonischemic origin of cardiomyopathy, QRS ≥150 milliseconds, the presence of left bundle-branch block on the baseline ECG, hospitalization for HF at any time before enrollment, baseline LVEDV ≥125 mL/m2 (above the first quartile), and baseline left atrial volume <40 mL/m2 (below the first quartile). The same 7 factors were identified when a favorable echocardiographic response was defined as percent reduction in LVESV (Table 2) and when percent reductions for LVEDV and LVESV were dichotomized at >10% and >15%, respectively (Tables 1 and 2).
| High Response
|
Low Response
|
High vs Low*
|
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|---|---|---|---|---|---|---|---|---|---|---|---|
| Risk Factor (Covariate) | Definition | n | Reduction (SD), % | >10% Reduction, % | Definition | n | Reduction (SD), % | >10% Reduction, % | Difference in Reduction (SE), %* | P | Score† |
| Sex | Women | 275 | −24 (11) | 91 | Men | 814 | −19 (11) | 83 | −2.9 (1.0) | 0.003 | 2 |
| CMP origin | Nonischemic | 491 | −24 (12) | 90 | Ischemic | 598 | −18 (10) | 82 | −4.2 (0.9) | <0.001 | 2 |
| QRS | ≥150 ms | 688 | −22 (12) | 88 | <150 ms | 383 | −18 (9) | 79 | −2.7 (0.9) | 0.003 | 2 |
| QRS pattern | LBBB | 750 | −22 (11) | 88 | Non-LBBB | 321 | −12 (10) | 79 | −3.4 (1.0) | <0.001 | 2 |
| Prior HF hospitalization | Yes | 493 | −22 (12) | 87 | No | 578 | −19 (11) | 82 | −1.9 (0.8) | 0.02 | 1 |
| Baseline LVEDV | ≥125 mL/m2 | 803 | −21 (11) | 88 | <125 mL/m2 | 267 | −18 (11) | 83 | −4.2 (1.1) | <0.001 | 2 |
| Baseline LAV | <40 mL/m2 | 258 | −23 (12) | 87 | ≥40 mL/m2 | 811 | −20 (11) | 78 | −5.6 (1.0) | <0.001 | 3 |
| High Response
|
Low Response
|
High vs Low*
|
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Definition | n | Reduction (SD), % | >15% Reduction, % | Definition | n | Reduction (SD), % | >15% Reduction, % | Difference in Reduction (SE), %* | P | Score | |
| Sex | Women | 275 | −38 (15) | 94 | Men | 814 | −31 (15) | 88 | −4.4 (1.3) | 0.01 | 2 |
| CMP origin | Nonischemic | 491 | −37 (16) | 93 | Ischemic | 598 | −29 (14) | 87 | −4.6 (1.2) | <0.001 | 2 |
| QRS | ≥150 ms | 688 | −34 (15) | 92 | <150 ms | 383 | −28 (14) | 85 | −3.6 (1.1) | 0.004 | 2 |
| QRS pattern | LBBB | 750 | −35 (15) | 92 | Non-LBBB | 321 | −26 (15) | 85 | −5.3 (1.4) | <0.001 | 2 |
| Prior HF hospitalization | Yes | 493 | −32 (15) | 91 | No | 578 | −27 (14) | 87 | −2.9 (1.2) | 0.02 | 1 |
| Baseline LVEDV | ≥125 mL/m2 | 803 | −33 (15) | 91 | <125 mL/m2 | 267 | −29 (16) | 84 | −3.9 (1.4) | 0.006 | 2 |
| Baseline LAV | <40 mL/m2 | 258 | −35 (16) | 93 | ≥40 mL/m2 | 811 | −30 (15) | 87 | −6.5 (1.2) | <0.001 | 3 |
Categorization of Response Score Groups
After selection of the 7 covariates, each was assigned a numeric value based on its relative effect in the regression model (as reflected by the point estimate of each covariate in the 7-variable model). The regression model showed that the contribution was lowest for prior hospitalization for HF; intermediate for female sex, nonischemic cardiomyopathy, left bundle-branch block, QRS ≥150 milliseconds, and LVEDV; and highest for left atrial volume. Accordingly, prior HF hospitalization was assigned a numeric value of 1; the intermediate factors, a value of 2 each; and left atrial volume, a value of 3 (Table 1). A response score was constructed by adding the numeric values of the factors identified in each patient. The response score ranged from 0 to 14. Subsequently, the study population was categorized into approximate quartiles based on the distribution of the response scores. Group 1 comprised 391 patients in the lowest response score quartile (with a score of 0–4); group 2 comprised 401 patients in the second response score quartile (with a score of 5–6); group 3 comprised 469 patients in the third response score quartile (with a score of 7–8); and group 4 comprised 500 patients in the upper response score quartile (with a score of 9–14).
The baseline clinical characteristics of study patients by response quartiles are shown inTable 3. Patients with higher response scores showed somewhat more favorable clinical characteristics, including a younger age and a lower serum creatinine, but had higher use of digitalis and aldosterone antagonists (Table 3). Response score quartiles showed a direct correlation with percent reduction in cardiac volumes among patients randomized to CRT-D therapy (Figure 2A and 2B). In contrast, in the ICD-only arm of the trial, percent reductions in cardiac volumes were significantly lower (<7% mean percent reduction of both LVEDV and LVESV) and related only to the origin of cardiomyopathy (Tables IIA and IIB in the online-only Data Supplement).
| Response Score Quartile
|
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|---|---|---|---|---|---|
| Characteristic | 1 | 2 | 3 | 4 | P |
| Score | 0–4 | 5–6 | 7–8 | ≥9 | |
| n | 391 | 401 | 469 | 500 | |
| Age, mean (SD), y | 66 (10) | 66 (10) | 64 (11) | 62 (11) | <0.001 |
| CRT-D, % | 58 | 62 | 60 | 59 | 0.64 |
| Nonischemic CMP, % | 9 | 22 | 53 | 85 | NA |
| BUN, mean (SD), mg/dL | 22 (9) | 22 (9) | 21 (8) | 21 (9) | 0.05 |
| Creatinine, mean (SD), mg/dL | 1.2 (0.3) | 1.3 (0.5) | 1.2 (0.3) | 1.1 (0.3) | <0.001 |
| Female sex, % | 3 | 12 | 21 | 55 | NA* |
| NYHA class II, % | 72 | 79 | 88 | 99 | <0.001 |
| Hypertension, % | 68 | 66 | 60 | 61 | 0.06 |
| Diabetes mellitus, % | 33 | 37 | 29 | 24 | <0.001 |
| Past CABG, % | 54 | 39 | 23 | 5 | <0.001 |
| Past PCI, % | 43 | 36 | 24 | 11 | <0.001 |
| QRS duration ≥150 ms, % | 18 | 57 | 81 | 90 | NA* |
| LBBB, % | 22 | 63 | 88 | 97 | NA* |
| Prior HF hospitalization, % | 36 | 45 | 48 | 57 | NA* |
| Atrial fibrillation >1 mo before enrollment, % | 10 | 15 | 15 | 8 | 0.001 |
| Prior ventricular arrhythmias, % | 6 | 10 | 8 | 5 | 0.01 |
| Cigarette smoking, % | 15 | 12 | 10 | 12 | 0.32 |
| SBP, mean (SD), mm Hg | 123 (18) | 123 (17) | 122 (17) | 122 (17) | 0.31 |
| DBP, mean (SD), mm Hg | 72 (11) | 71 (10) | 72 (11) | 71 (10) | 0.79 |
| BMI, mean (SD), kg/m2 | 29 (5) | 29 (5) | 29 (5) | 28 (6) | 0.06 |
| EF, mean (SD), % | 29 (3) | 29 (3) | 20 (3) | 30 (4) | <0.001 |
| LVESV, mean (SD), mL/m2 | 82 (18) | 85 (22) | 92 (24) | 92 (25) | NA* |
| LVEDV, mean (SD), mL/m2 | 115 (23) | 120 (28) | 128 (30) | 129 (31) | NA* |
| LAV, mean (SD), mL/m2 | 48 (9) | 47 (10) | 48 (10) | 45 (11) | NA* |
| Apical position of LV lead, %† | 12 | 14 | 16 | 13 | 0.86 |
| ACE inhibitors, % | 76 | 77 | 77 | 80 | 0.89 |
| ARBs, % | 20 | 19 | 20 | 21 | 0.94 |
| Digitalis, % | 24 | 22 | 26 | 30 | 0.05 |
| Diuretics, % | 73 | 76 | 73 | 77 | 0.45 |
| β-blockers, % | 93 | 91 | 93 | 96 | 0.02 |
| Aldosterone antibody, % | 28 | 28 | 33 | 38 | 0.006 |
Figure 2. Average percent reduction in left ventricular end-diastolic volume (LVEDV; A) and end-systolic volume (LVESV; B), among CRT-D-allocated patients in a given response category.
Relation of Response Score to Clinical Benefit of Cardiac Resynchronization-Defibrillator Therapy
During follow-up, 367 patients (20%) experienced the primary clinical end point of the study (the first occurrence of HF or death during follow-up), and 629 patients (35%) experienced the secondary end point (the first occurrence of HF, death, or advancement to NYHA class >II during follow-up).
The benefits of CRT-D versus ICD-only therapy for the reduction in the primary and secondary end points are shown inTables 4and 5 respectively. Cox proportional hazards regression modeling showed that among patients in the lowest response score quartile, CRT-D therapy was not associated with a statistically significant reduction in the risk of HF or death compared with ICD-only therapy (hazard ratio=0.87; P=0.52); among patients in the second and third response score quartiles, CRT-D therapy was associated with 33% (P=0.04) and 36% (P=0.03) risk reductions, respectively; and among patients in the upper response score quartile, CRT-D was associated with a pronounced 69% (P<0.001) reduction in the risk of HF or death. Accordingly, there was a significant direct correlation between the clinical benefit of CRT-D therapy and response score quartiles (P for trend=0.005). Furthermore, CRT-D therapy was shown to be associated with a significantly greater clinical benefit among patients in the upper response score quartile than among patients in each of the lower 3 response score quartiles (P for all treatment-by-response quartile interactions <0.05; Table 4). Assessing the response score as a continuous measure showed that the benefit of CRT-D therapy for the reduction in the risk of HF or death was increased by 13% (95% confidence interval, 4–19; P<0.001) for each 1-point increment in the response score (range, 0–14); likewise, reductions were increased by an estimated 24%, 50%, and 75%, for 2-, 5-, and 10-point increments in the response score, respectively.
| CRT-D vs ICD-Only Risk of HF or Death
|
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|---|---|---|---|---|---|
| Response Groups | Score | HR | 95% CI | P | P for Trend† |
| All patients (n=1761) | 0–14 | 0.62 | 0.51–0.77 | <0.001 | NA |
| By response score quartile | |||||
| 1 (n=391) | 0–4 | 0.87 | 0.58–1.32 | 0.52 | 0.005 |
| 2 (n=401) | 5–6 | 0.67 | 0.46–0.98 | 0.04 | |
| 3 (n=469) | 7–8 | 0.64 | 0.43–0.97 | 0.03 | |
| 4 (n=500)‡ | ≥9 | 0.31 | 0.20–0.53 | <0.001 | |
| By individual response scores (per unit increment) | 0.87§ | 0.81–0.96 | <0.001 | ||
| CRT-D vs ICD-Only Risk of HF, Death, or Advancement to New York Heart Association Class >II
|
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|---|---|---|---|---|---|
| Response Groups | Score | HR | 95% CI | P | P† |
| All patients (n=1761) | 0–14 | 0.62 | 0.50–0.76 | <0.001 | NA |
| By response score quartile | |||||
| 1 (n=391) | 0–4 | 0.97 | 0.71–1.32 | 0.83 | 0.002 |
| 2 (n=401) | 5–6 | 0.74 | 0.54–1.01 | 0.06 | |
| 3 (n=469) | 7–8 | 0.68 | 0.50–0.93 | 0.02 | |
| 4 (n=500)‡ | ≥9 | 0.47 | 0.34–0.65 | <0.001 | |
| By individual response scores (per unit increment) | 0.90§ | 0.85–0.95 | <0.001 | ||
A similar pattern showing a significant direct correlation between risk reduction associated with CRT-D and response score quartiles was also shown when the secondary end point of HF, death, or advancement to NYHA >II was assessed (P for trend=0.002;Table 5). The risk of this end point was reduced by 10% (95% confidence interval, 5–15; P<0.001) for each 1-point increment in the response score. Furthermore, regression analysis showed that, compared with ICD-only therapy, treatment with CRT-D was associated with an average of a 16-m increment (standard error, ±6 m) in the 6-minute walk test at 1 year per each response score quartile (P for trend=0.01).
Notably, when the response score was created with replacement of left atrial volume and LVEDV with the respective atrial and ventricular diameters (left atrial diameter ≤2 cm/m2 [lower quartile]; left ventricular diastolic diameter ≥3 cm/m2 [upper 3 quartiles], respectively), the CRT-D versus ICD-only therapy for the reduction of HF or death was also shown to have a significant direct correlation with increasing response score quartiles (P for trend=0.003; Table III in the online-only Data Supplement).
Consistent with these findings, Kaplan–Meier analysis showed that, among patients in the lowest response score quartile, the cumulative probability of HF or death at 3 years of follow-up was virtually identical between the 2 treatment arms (Figure 3A); patients in the intermediate response score quartiles (quartiles 2 and 3) experienced 26% and 36% reductions in cumulative event rates, respectively, at 3 years with CRT-D therapy (Figure 3B and 3C, respectively), whereas patients in the upper response score quartile experienced a pronounced 65% reduction in the cumulative rate of HF or death with CRT-D therapy at 3 years of follow-up (Figure 3D).
Figure 3. Cumulative probability of heart failure (HF) or death by treatment arm in response score quartiles 1 through 4 (A–D, respectively). CRT-D indicates cardiac resynchronization therapy-defibrillator; ICD, implantable cardioverter-defibrillator.
Relation of Response Score to Mortality Reduction Associated With Cardiac Resynchronization-Defibrillator Therapy
Among patients in the upper response score quartile, CRT-D therapy was associated with a statistically significant reduction in the risk of all-cause mortality compared with ICD-only therapy (hazard ratio=0.39; 95% confidence interval, 0.16–0.98; P=0.04). Accordingly, 3-year mortality rates in the upper response score quartile were significantly higher in the ICD-only arm (8%) compared with the CRT-D arm (5%; log-rank P=0.039 for the overall mortality difference during follow-up). In contrast, among patients with a lower response score (score <9), treatment with CRT-D was not associated with a significant survival benefit (hazard ratio=1.07; 95% confidence interval, 0.72–1.59; P for treatment-by-response-score interaction=0.05).
Model Stability and Sensitivity Analyses
Several methods were used to validate the stability of model selection for echocardiographic response to CRT-D and its relationship to the clinical response to the device in the trial. Results of some of these analyses are described in the Appendix in the online-only Data Supplement. Briefly, assessing the clinical benefit in each of the 3 subgroups (subgroups A–C) led to very similar hazard rates for the individual response score in the 3 subgroups (Table IV in the online-only Data Supplement), providing justification for pooling the 3 subgroups for the primary analyses. Second, substitutions of individual identified covariates with other choices resulted in weaker conclusions, and bootstrapping the selection of covariates showed moderate stability associated with echocardiographic response. Third, bootstrapping the scoring derived from the selected factors showed high correlations among the derived response scores. Finally, bootstrapping also demonstrated considerable stability in the effects of scores on evaluation of the relative risk for the primary end point.
Discussion
Our findings from the MADIT-CRT population have several important implications in terms of selection of patients for treatment with CRT. We have identified 7 simple baseline clinical and echocardiographic factors that were associated with a favorable reverse remodeling effect in MADIT-CRT. Combined assessment of the identified factors (through a response score) showed a direct correlation with the clinical benefit of CRT-D therapy in the trial. Accordingly, study patients in the upper response score quartile (score ≥9) derived significantly greater clinical benefit from CRT-D therapy compared with patients with a lower response score, including a 69% reduction in the risk of HF or death and a 61% reduction in the risk of all-cause mortality. In contrast, CRT-D therapy was not associated with a statistically significant clinical benefit among patients with a low response score (score, 0–4).
In patients with NYHA class III and ambulatory class IV systolic HF and ECG evidence of ventricular dyssynchrony, CRT (with and without a defibrillator) improves quality of life and functional status, reduces HF-related hospitalizations, and prolongs survival.1–5 Thus, there is a strong clinical mandate for the use of CRT in eligible patients that is supported by current guidelines.16 However, the echocardiographic and clinical benefit of CRT is not uniform, and approximately one third of eligible patients have been considered nonresponders in clinical trials using a variety of measures of clinical responsiveness.9–12 Similar to prior studies among patients with more advanced HF symptoms, the benefit of CRT-D therapy in the MADIT-CRT population was not uniform, and treatment with the device in the study was shown to be associated with a significant differential effect when related to baseline factors, including sex, QRS duration, and left bundle-branch block status.8,18 These consistent findings suggest that more appropriate selection of patients for treatment with CRT is needed. Improved patient selection may also reduce the relatively high costs associated with treatment with the device in eligible patients.19,20
MADIT-CRT showed that CRT is associated with both a reverse remodeling effect (including significant reductions in LVESV and LVEDV and improvement in ejection fraction at 1 year of follow-up) and a clinical benefit (resulting in a significant 34% reduction in the risk of HF or death with CRT-D compared with ICD-only therapy) in mildly symptomatic patients with left ventricular dysfunction.8 Furthermore, the echocardiographic effects of CRT in the trial were shown to be concordant with the subsequent clinical outcome of study patients.13 Our findings extend these observations and show that combined assessment of factors that were associated with a favorable echocardiographic response to CRT-D therapy during the trial can be used to distinguish between patients in whom CRT-D was associated with pronounced HF and mortality reductions and those in whom treatment with the device was not associated with a significant clinical benefit.
Of the 7 identified baseline clinical and echocardiographic covariates that made up the response score in the present study, 4 clinical variables were also previously reported to predict reverse remodeling in patients with more advanced HF symptoms: a nonischemic origin of cardiomyopathy,15,21,22 female sex,22,23 QRS width,2,22,24 and the presence of left bundle-branch block on the baseline ECG.25,26 In contrast, prior studies did not identify baseline cardiac volumes and a history of HF hospitalization as independent predictors of LV reverse remodeling in patients with advanced HF symptoms.22 Thus, it is possible that the relationships between the last 3 predictors of reverse remodeling in MADIT-CRT are specific to the study population, or our sample from it, that was made up of patients with less advanced HF symptoms.
Notably, the presence of prior revascularization displayed an inverse correlation with response score quartiles (Table 3) but was not identified as independently related to the echocardiographic and clinical response to CRT-D therapy. These findings may be due to the fact that the presence of prior revascularization is correlated with factors that provide a more significant and independent contribution to the response score (including a history of prior hospitalization for HF, a prolonged QRS duration, the presence of left bundle-branch block, and left ventricular and left atrial volumes).
It should be noted that the lack of an individual factor in a patient does not indicate a lack of clinical response to CRT. Rather, the present results suggest that the combined presence of factors that are associated with more favorable echocardiographic response to CRT-D is directly related to the degree of clinical response to the device. Thus, individual unfavorable factors were present in various degrees in patients in response score quartiles 2 through 4 in whom CRT therapy was associated with increasing clinical benefit. These findings stress the importance of a comprehensive approach to risk assessment in candidates for CRT-D therapy.
Limitations
Patients in MADIT-CRT were followed up over an average of 2.4 years. Therefore, further studies are needed to validate the longer-term consistency of the present results in terms of risk assessment for CRT-D therapy. It should also be stressed that the present results concerning factors associated with echocardiographic response (and their relative contribution to clinical response) to CRT-D therapy are applicable only to the MADIT-CRT population, who were patients with mild HF symptoms.
The present response score comprises 2 components that rely on echocardiographic assessment (including measurements of atrial and ventricular volumes). It should be noted, however, that the echocardiographic assessment in MADIT-CRT was carried out in a core laboratory with excellent reproducibility, whereas the repeatability of echocardiographic measurements in individual laboratories may be less consistent. The fact that similar results were obtained when left atrial and ventricular diameters replaced the corresponding volumes as covariates in the response score suggests that these more common and easily derived measurements can also be used as part of a response score for the prediction of response to CRT-D therapy.
An apical position of the LV lead was recently shown to be associated with attenuated CRT-D benefit in the MADIT-CRT population.26a However, the present study shows that lead position did not correlate with either echocardiographic response to CRT-D therapy (−0.22% reduction in LVEDV for apical versus nonapical lead position; P=0.88) or the response score (Table 3), suggesting that the combined assessment of simple clinical and echocardiographic variables provides prognostic information among CRT-D recipients incremental to sole assessment of LV lead position. Nevertheless, it is possible that the relation between LV lead position and scar location also relates to response to CRT-D therapy. This information, however, was not available in the present study. Furthermore, recent studies have shown that additional clinical parameters, including scar burden and areas of delayed activation, affect response to CRT-D therapy.27–29 These parameters, however, were not assessed in the present study. Thus, unmeasured parameters may also affect CRT response beyond the 7 covariates that were identified in the present study.
Our findings are derived from a single population study. Thus, despite the fact that results of the present study were consistent in several sensitivity analyses, the present findings should be considered largely descriptive of what occurred in the MADIT-CRT study rather than predictive of what might occur in other or future settings.30 Thus, there is a great need to carry out similar analyses in other sets of clinical trial data. These analyses would provide important confirmatory data for the proposed response score.
Conclusions and Clinical Implications
Prior studies failed to demonstrate improved response rates to CRT when adding echocardiographic measures of dyssynchrony.21,31,32 Thus, QRS width currently is the sole criterion for treatment with the device in eligible patients, resulting in a nonuniform effect of this costly technology in implanted patients. Our findings suggest that baseline factors that are associated with a favorable echocardiographic response to CRT-D therapy can be used to identify patients who derive clinical benefit from the device. Furthermore, we have shown that the degree of clinical response to CRT-D therapy is directly related to the number of factors associated with echocardiographic response that are present in an individual patient. These findings, if appropriately validated in similar populations of CRT-D recipients, may be used for improved selection of patients for treatment with CRT for the prevention of HF or death.
Acknowledgments
We want to thank the members of the Executive Committee of MADIT-CRT: Mary W. Brown, MS; David S. Cannom, MD; James P. Daubert, MD; Steven L. Higgins, MD; Mark Estes III, MD; Mark A. Pfeffer, and Henry Greenberg, MD.
Sources of Funding
MADIT-CRT was supported by a research grant from
Disclosures
Drs Moss, Solomon, Klein, Foster, Hall, and Zareba have received research support for the conduct of the MADIT-CRT trial from Boston Scientific through a grant to the University of Rochester. The other authors report no conflicts.
Footnotes
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Clinical Perspective
The Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT) trial showed that cardiac resynchronization-defibrillator therapy is associated with a significant reduction in the risk of heart failure or death compared with defibrillator-only therapy. Currently, however, there is limited information on the factors that can be used to distinguish between responders and nonresponders in this population. In the present study, we developed a response score that was based on 7 factors we identified as being associated with favorable reverse remodeling in MADIT-CRT: female sex, a nonischemic origin of cardiomyopathy, left bundle-branch block, QRS ≥150 milliseconds, prior hospitalization for heart failure, left ventricular end-diastolic volume ≥125 mL/m2, and left atrial volume <40 mL/m2. The score was then used to assess the clinical benefit of cardiac resynchronization-defibrillator therapy during the trial. We show a direct correlation between an increasing response score and the magnitude of the reduction in the risk of heart failure or death with cardiac resynchronization therapy. There was a significant 13% increase in the clinical benefit of cardiac resynchronization-defibrillator therapy per 1-point increment in the response score and a significant direct correlation between risk reduction associated with cardiac resynchronization-defibrillator therapy and response score quartiles. Thus, our findings suggest that combined assessment of factors associated with reverse remodeling can be used for improved selection of patients for cardiac resynchronization therapy.
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