There are limited data regarding risk factors for the development of ischemic events (IEs) among patients with ischemic cardiomyopathy (IC) who receive cardiac resynchronization therapy with a defibrillator (CRT-D) and their effect on the efficacy of the device. The present study population comprised 1,045 patients with IC enrolled in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy. We used multivariate Cox proportional hazards regression modeling to identify risk factors for the development of IE (comprising hospitalization for acute coronary syndromes and/or coronary interventions during the trial) among study patients. Time-dependent analysis was performed to identify the effect of IE on the risk for subsequent heart failure (HF) or death in CRT-D recipients. Independent predictors for the development of IE among study patients included previous revascularization (coronary artery bypass surgery: hazard ratio [HR] 1.88, p = 0.003; percutaneous coronary intervention: HR 3.21, p <0.001) and increased systolic blood pressure (HR 1.67, p = 0.02), whereas a left bundle branch block pattern on the baseline electrocardiogram was associated with reduced risk for IE (HR 0.62, p = 0.02). Treatment with CRT-D did not have a significant effect on IE risk compared with defibrillator-only therapy (HR 0.87, p = 0.51). Time-dependent analysis showed that the development of IEs among CRT-D recipients was associated with more than twofold (p = 0.01) increased risk for subsequent heart failure or death. In conclusion, our data suggest that treatment with CRT-D does not reduce the risk of IE in patients with IC and that the benefit of CRT-D is attenuated after the development of IEs in this population.
The Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT) showed that treatment with cardiac resynchronization therapy with a defibrillator (CRT-D) was associated with a significant 34% reduction in death or nonfatal heart failure (HF) compared with defibrillator-only therapy in patients with mildly symptomatic HF. Notably, the clinical and echocardiographic benefit of CRT-D in the MADIT-CRT population was somewhat less pronounced among patients with ischemic cardiomyopathy (IC) compared with those with a nonischemic origin of their cardiac dysfunction. Thus, it is possible that the presence of ischemic heart disease may limit therapeutic response to CRT-D. Currently, however, there are limited data regarding risk factors for the development of ischemic event (IE) among patients with IC who receive CRT-D therapy and their effect on the efficacy of the device. Accordingly, the present study was carried out among 1,045 patients with IC enrolled in MADIT-CRT and was designed to (1) identify risk factors for IE in patients with IC who receive the device therapy, (2) evaluate whether treatment with CRT-D in patients with IC reduces the risk for the development of IE, and (3) assess the effect of the development of IE after CRT-D implantation on the subsequent risk of HF or death.
Methods
The design and results of the MADIT-CRT study have been reported previously. Briefly, 1,820 patients with IC (New York Heart Association class I or II) or non-IC (New York Heart Association class II), LVEF ≤0.30, and prolonged intraventricular conduction with QRS ≥130 ms were randomized to receive either CRT-D or implantable cardioverter-defibrillator (ICD) therapy in a 3:2 ratio. The randomization process was stratified by disease origin (IC vs non-IC). The present study comprises the 1,045 patients with IC who were enrolled in MADIT-CRT.
For the diagnosis of IC, study patients had to have at least 1 of the following: (1) a documented history of myocardial infarction (Q-wave or enzyme-positive), (2) a history of a coronary revascularization procedure (≥1 previous coronary artery bypass graft [CABG] surgeries or percutaneous coronary interventions [PCI; balloon and/or stent angioplasty]), (3) documented significant coronary artery disease at coronary angiography, or (4) aggregate clinical findings, for example, history of angina pectoris or other coronary-related symptoms or signs, such that the enrolling physician assessed the patient as having IC.
An IE during follow-up was defined as hospitalization for acute coronary syndromes and/or coronary interventions (either PCI or CABG) after enrollment in the trial. The diagnosis of HF required signs and symptoms consistent with congestive HF that was responsive to intravenous decongestive therapy on an outpatient basis or an augmented decongestive regimen with oral or parenteral medications during an in-hospital stay. All ischemic and HF events were adjudicated by an independent committee which was blinded to treatment assignment.
The outcome measurements of the present study included (1) the occurrence of a first IE during follow-up or the composite end point of a first IE or death (to account for a possible bias associated with the occurrence of mortality events due to an IE) and (2) the effect of time-dependent IEs during follow-up on the occurrence of HF or death among CRT-D recipients.
The characteristics of patients who did or did not develop IEs during follow-up were compared by the Wilcoxon rank sum test or chi-square test, as appropriate. The probability of IE by origin by treatment group and by QRS morphology was graphically displayed according to the method of Kaplan and Meier, with comparison of cumulative events by the log-rank test. Multivariate analysis was carried out using Cox proportional hazards regression modeling using clinically selected covariates deemed important risk factors for the development of postenrollment IE. Independent factors associated with IE risk among 24 candidate covariates were identified using the best subsets procedure. In the analysis of factors associated with the risk of HF or death among CRT-D recipients, the development of postenrollment IE was assessed as a time-dependent covariate. Survival curves for the end point of HF or death were constructed for the entire study population from the date of initial implant to the first IE. Among the patients who experienced and survived a first IE, survival curves were created from the time of the first IE to the occurrence of HF or death. All p values were 2-sided, and a p value <0.05 was considered significant. Analyses were conducted with SAS software (version 9.2; SAS Institute, Cary, North Carolina).
Results
Among the 1,045 patients with IC enrolled in MADIT-CRT, 100 patients (9.5%) developed an IE during follow-up. Of the IEs, 95% were associated with an acute coronary syndrome and 13% with a revascularization procedure (7% CABG and 6% PCI). The clinical characteristics of study patients who did and did not develop IE are presented in Table 1 . The 2 groups were similar with regard to most baseline clinical characteristics and in the extent of guideline-based therapies for the management of coronary artery disease and HF. In addition, baseline and follow-up echocardiographic parameters were similar between the 2 groups. However, several risk factors were more frequent among study patients who developed IE during follow-up, including a non–left bundle branch block (LBBB) morphology and a history of revascularization ( Table 1 ).
| Characteristic | IEs, % (n = 100) | No IEs, % (n = 945) | p |
|---|---|---|---|
| Randomized to CRT-D | 59 | 60 | 0.80 |
| Age ≥65 yrs | 65 | 63 | 0.73 |
| Women | 8 | 14 | 0.10 |
| Ischemic class I | 21 | 26 | 0.30 |
| Ischemic class II | 77 | 70 | 0.12 |
| Worst New York Heart Association class >II | 11 | 9 | 0.67 |
| LBBB | 47 | 59 | 0.03 |
| Heart rate ≥80 beats/min | 11 | 12 | 0.74 |
| Body mass index ≥30 kg/m 2 | 41 | 34 | 0.15 |
| Blood urea nitrogen >25 mg/dl | 19 | 29 | 0.04 |
| Systolic blood pressure ≥140 mm Hg | 28 | 18 | 0.02 |
| Any hospitalization in the year before enrollment | 67 | 53 | 0.006 |
| Previous CABG | 61 | 49 | 0.02 |
| Diabetes | 43 | 34 | 0.08 |
| Hypertension | 80 | 69 | 0.02 |
| Previous non–coronary bypass revascularization | 71 | 45 | <0.001 |
| Previous myocardial infarction | 85 | 76 | 0.04 |
| Smoker | 70 | 59 | 0.04 |
| Past ventricular arrhythmias | 12 | 8 | 0.16 |
| Baseline medications | |||
| Aspirin | 79 | 76 | 0.53 |
| Angiotensin-converting enzyme inhibitors | 77 | 77 | 0.93 |
| β Blockers | 89 | 92 | 0.21 |
| Aldospirone | 29 | 27 | 0.67 |
| Statins | 91 | 84 | 0.06 |
| Antiarrhythmics | 11 | 10 | 0.87 |
| Baseline echocardiographic parameters | |||
| Left ventricular ejection fraction ≤25% | 9 | 10 | 0.36 |
| Left ventricular end-systolic volume >170 ml/m 2 | 44 | 43 | 0.88 |
| Left ventricular end-diastolic volume change at 1 yr >15% | 26 | 37 | 0.08 |
| Left ventricular end-systolic volume change at 1 yr >15% | 53 | 59 | 0.27 |
| Left atrial volume change >15% | 54 | 57 | 0.60 |
Multivariate Cox proportional hazards regression modeling ( Table 2 ) showed that treatment with CRT-D was not associated with a significant reduction in the risk of IE compared with ICD-only therapy. Independent predictors for the development of IE among study patients included a history of revascularization (either CABG or PCI) and increased systolic blood pressure at baseline examination ( Table 2 ). In contrast, patients with LBBB experienced a significant reduced risk for the development of IE compared with patients without LBBB ( Table 2 ). Similar findings were obtained when the secondary end point of IEs or death was assessed ( Table 2 ). Consistent with the multivariate findings, the cumulative probability for the development of IE was similar between CRT-D and ICD-only patients ( Figure 1 ) and significantly less among patients with LBBB compared with those without LBBB ( Figure 2 ).
| Variable | End Point: IE | End Point: IEs or Death | ||
|---|---|---|---|---|
| Hazard Ratio (95% Confidence Interval) | p | Hazard Ratio (95% Confidence Interval) | p | |
| CRT-D vs ICD | 0.87 (0.58–1.31) | 0.51 | 0.90 (0.69–1.18) | 0.45 |
| LBBB | 0.62 (0.42–0.93) | 0.02 | 0.76 (0.54–0.97) | 0.04 |
| CABG | 1.88 (1.23–2.88) | 0.003 | 1.42 (1.07–1.89) | 0.01 |
| Previous PCI | 3.21 (2.04–5.05) | <0.001 | 1.67 (1.26–2.21) | <0.001 |
| Systolic blood pressure ≥140 mm Hg | 1.67 (1.07–1.62) | 0.02 | 1.47 (0.98–1.63) | 0.06 |
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