Cardiac resynchronization therapy (CRT) is an established treatment of patients with heart failure. Several baseline characteristics can influence the CRT outcomes, and little is known about the effect of gender. The aim of the present study was to elucidate the gender-related differences in long-term survival after CRT. A total of 578 consecutive patients with heart failure underwent CRT. At baseline and 6 months after CRT, the clinical and echocardiographic parameters were obtained. All-cause mortality was compared between the men and women. The study population included 431 men (67 ± 9 years) and 147 women (65 ± 11 years). No differences in the clinical and echocardiographic characteristics were observed between the men and women, except for left bundle branch block and a nonischemic etiology of heart failure, which were more frequent in women (81% vs 68% and 63% vs 33%, respectively; p <0.01), and atrial fibrillation, which was more prevalent in men (20% vs 10%, respectively; p = 0.01). During a mean follow-up of 34 ± 25 months, 197 patients died (158 men and 39 women). Kaplan-Meier analysis showed a significant difference in long-term survival between the women and men (p = 0.007). The 2-year all-cause mortality rate was 15% in men and 8% in women (p = 0.025). Cox proportional hazard analysis revealed female gender is an independent predictor of long-term survival, together with heart failure etiology and renal function. In particular, women with heart failure due to a nonischemic etiology showed the best long-term survival rate. In conclusion, female gender and nonischemic etiology were independently associated with better long-term survival after CRT.
Previous studies have suggested that the natural history and response to therapy of different cardiovascular diseases, including coronary artery disease and heart failure, might be different between men and women. The initial studies also explored the effect of gender on cardiac resynchronization therapy (CRT) outcomes but were limited by small patient numbers and/or short follow-up. Thus, the aim of the present study was to evaluate in a large cohort of patients whether a difference exists between men and women in the long-term outcomes after CRT and whether gender is an independent predictor of mortality, beyond other clinical and echocardiographic characteristics.
Methods
The patient population consisted of 578 consecutive patients from the ongoing registry of patients with heart failure who had undergone CRT. The indication for CRT was determined by current guideline criteria, including New York Heart Association (NYHA) class III or IV despite optimal pharmacologic treatment, QRS duration >120 ms, and left ventricular (LV) ejection fraction ≤35%. The etiology of heart failure was considered ischemic in the presence of significant coronary artery disease (>50% stenosis in ≥1 major epicardial coronary artery) found on the coronary angiographic examination and/or a history of myocardial infarction and previous coronary artery revascularization.
All patients underwent clinical and echocardiographic evaluation before implantation and at 6 months of follow-up. After the 6-month follow-up examination, the patients were scheduled for regular visits to the outpatient clinic.
The clinical evaluation at baseline and at 6 months of follow-up included classification of the heart failure symptom severity (NYHA functional class), assessment of the quality of life (Minnesota Living with Heart Failure questionnaire), and evaluation of the exercise capacity using the 6-minute walking test.
Patients underwent imaging in the left lateral decubitus position, using a commercially available system (Vivid 7, General Electric Vingmed Ultrasound, Horton, Norway). Standard 2-dimensional and Doppler images were recorded and saved in cine-loop format for off-line analysis (EchoPac, version 108.1.5, General Electric Vingmed, Horton, Norway). From the apical 2- and 4-chamber views, the LV end-systolic volume (LVESV), LV end-diastolic volume (LVEDV), and LV ejection fraction were measured using the biplane Simpson technique. Both LVESV and LVEDV were indexed using the body surface area. Echocardiographic measurements were performed before implantation and the 6-month follow-up visit.
After obtaining a venogram by inflating a balloon-guiding catheter, a LV lead was inserted into the coronary sinus using an 8Fr guiding catheter. The preferred position of the catheter was in the lateral or posterolateral vein. The right atrial and ventricular leads were positioned conventionally. Of the 578 patients, 36 (6%) received CRT without implantable cardioverter-defibrillator backup, and 542 (94%) received a device with implantable cardioverter-defibrillator backup. The implanted devices were Contak Renewal, Contak TR, or Contak CD (Guidant, Indianapolis, Indiana), Insync Marquis, Insync III, or Insync Sentry (Medtronic, Minneapolis, Minnesota), Epic HF or Atlas HF (St. Jude Medical, Secaucus, New Jersey), and Lumax (Biotronik, Berlin, Germany).
The outcomes data were collected by chart review, device interrogation, and telephone interview. The primary end point was defined as all-cause mortality or cardiac transplantation. The secondary end point was defined as death from a cardiac cause (including death for worsening heart failure, sudden cardiac death, or other cardiac causes, such as myocardial infarction, complications after a cardiac procedure, death from endocarditis) or cardiac transplantation.
The categorical variables are expressed as frequencies and percentages. Continuous data are summarized as the mean ± SD. Differences in the baseline characteristics between the men and women were analyzed using unpaired Student’s t test (continuous data) or Pearson chi-square analysis (categorical data). The paired Student t test was used to compare continuous data at the 6-month evaluation. The survival curves were determined using the Kaplan-Meier method, with comparisons of cumulative event rates using the log-rank test. For evaluation of potential predictors of all-cause mortality, a Cox proportional hazards analysis was performed. All factors that showed significance on univariate analysis were evaluated in the multivariate Cox proportional hazards model. The number of variables that could enter the multivariate model was limited using the P < m/10 rule to prevent overfitting the model. All analyses were performed using the Statistical Package for Social Sciences, for Windows, version 16.0 (SPSS, Chicago, Illinois). A p value of <0.05 was considered significant.
Results
A total of 578 patients were included in the present study. The baseline characteristics of the patient population are summarized in Table 1 . The cohort consisted of 431 men (75%) and 147 women (25%). The etiology of heart failure was ischemic in 342 patients (59%). Echocardiographic evaluation revealed severe LV dilation with depressed LV systolic function. A total of 99 patients (17%) were in atrial fibrillation at the moment of implantation.
| Variable | Total (n = 578) | Men (n = 431) | Women (n = 147) | p Value ⁎ |
|---|---|---|---|---|
| Age (years) | 67 ± 10 | 67 ± 9 | 65 ± 11 | 0.066 |
| Nonischemic etiology | 236 (41%) | 144 (33%) | 92 (63%) | <0.001 |
| QRS duration (ms) | 166 ± 25 | 166 ± 26 | 166 ± 22 | 0.919 |
| Atrial fibrillation | 99 (17%) | 84 (20%) | 15 (10%) | 0.010 |
| Left bundle branch block | 406 (71%) | 288 (68%) | 118 (81%) | 0.002 |
| Medication | ||||
| Diuretics | 508 (88%) | 377 (88%) | 131 (89%) | 0.598 |
| Spironolactone | 304 (53%) | 223 (52%) | 81 (55%) | 0.481 |
| Angiotensin-converting enzyme inhibitor/angiotensin receptor II blocker | 513 (89%) | 385 (89%) | 128 (87%) | 0.455 |
| β Blocker | 395 (68%) | 299 (69%) | 96 (65%) | 0.360 |
| Anticoagulants | 522 (90%) | 393 (91%) | 129 (88%) | 0.225 |
| New York Heart Association functional class | 3.1 ± 0.3 | 3.1 ± 0.3 | 3.1 ± 0.3 | 0.530 |
| Quality of life score | 40 ± 18 | 39 ± 18 | 41 ± 17 | 0.376 |
| Six-minute walk test (m) | 278 ± 107 | 283 ± 107 | 263 ± 105 | 0.088 |
| Body surface area (m 2 ) | 1.95 ± 0.35 | 2.01 ± 0.38 | 1.78 ± 0.18 | <0.001 |
| Diabetes mellitus | 132 (23%) | 105 (24%) | 27 (18%) | 0.135 |
| Estimated glomerular filtration rate (ml/min/1.73 m 2 ) | 64 ± 29 | 65 ± 29 | 61 ± 28 | 0.092 |
| Left ventricular end-diastolic volume (ml) | 228 ± 81 | 235 ± 82 | 208 ± 78 | 0.001 |
| Left ventricular end-diastolic volume index (ml/m 2 ) | 118 ± 42 | 118 ± 41 | 118 ± 46 | 0.972 |
| Left ventricular end-systolic volume (ml) | 177 ± 71 | 183 ± 72 | 161 ± 67 | 0.002 |
| Left ventricular end-systolic volume index (ml/m 2 ) | 92 ± 37 | 92 ± 36 | 92 ± 39 | 0.942 |
| Left ventricular ejection fraction (%) | 23 ± 7 | 23 ± 7 | 23 ± 7 | 0.713 |
No significant differences in the clinical characteristics were observed between the men and women, except for the etiology of heart failure, which was more frequently nonischemic in women, the presence of left bundle branch block, and the prevalence of atrial fibrillation. Of note, no significant differences between the 2 groups were noted for LVEDV and LVESV, after indexing for body surface area.
Before the 6-month follow-up visit, 32 patients (6%) had died (28 men [7%] and 4 women [3%]), and 1 had undergone cardiac transplantation. Also, for 29 patients, the 6-month follow-up evaluation was not available, and the clinical evaluation was performed only at long-term follow-up. Of the 516 patients evaluated 6 months after implantation, the mean NYHA class had improved from 3.1 ± 0.3 to 2.2 ± 0.6 (p <0.001), the quality of life score had improved from 40 ± 18 to 26 ± 19 (p <0.001) and the 6-minute walking distance had increased from 278 ± 107 m to 366 ± 116 m (p <0.001; Table 2 ). Moreover, significant LV reverse remodeling and improvement in LV function was observed in the study population (the LVEDV had decreased from 228 ± 81 ml to 203 ± 78 ml, the LVESV had decreased from 177 ± 71 ml to 145 ± 67 ml, and the LV ejection fraction had improved from 23 ± 7% to 30 ± 9%; p <0.001 for all). The changes at 6 months of follow-up for LVEDV and LVESV were consistent after indexing for the body surface area ( Table 2 ).
| Variable | Total (n = 516) | Men (n = 380) | Women (n = 136) | p Value ⁎ |
|---|---|---|---|---|
| New York Heart Association functional class | 2.2 ± 0.6 | 2.2 ± 0.7 | 2.2 ± 0.6 | 0.601 |
| Quality of life score | 26 ± 19 | 26 ± 19 | 26 ± 19 | 0.838 |
| 6-Minute walk test (m) | 366 ± 116 | 370 ± 113 | 349 ± 124 | 0.111 |
| Delta 6-minute walk test (m) | 82 ± 96 | 82 ± 98 | 81 ± 93 | 0.924 |
| Left ventricular end-diastolic volume (ml) | 203 ± 78 | 212 ± 78 | 178 ± 73 | <0.001 |
| Left ventricular end-diastolic volume index (ml/m 2 ) | 105 ± 41 | 107 ± 39 | 101 ± 43 | 0.176 |
| Delta left ventricular end-diastolic volume index (ml/m 2 ) | −9 ± 18 | −8 ± 18 | −12 ± 20 | 0.066 |
| Left ventricular end-systolic volume (ml) | 145 ± 67 | 151 ± 67 | 126 ± 63 | <0.001 |
| Left ventricular end-systolic volume index (ml/m 2 ) | 75 ± 35 | 76 ± 34 | 72 ± 38 | 0.224 |
| Delta left ventricular end-systolic volume index (ml/m 2 ) | −17 ± 21 | −15 ± 21 | −20 ± 21 | 0.033 |
| Left ventricular ejection fraction (%) | 30 ± 9 | 30 ± 9 | 31 ± 10 | 0.228 |
| Delta left ventricular ejection fraction (%) | 7 ± 8 | 7 ± 8 | 8 ± 9 | 0.293 |
The observed decrease in the indexed LV volumes was more outspoken in the women than in the men, with a delta-indexed LVEDV of −12 ± 20 ml/m 2 for women versus −8 ± 18 ml/m 2 for men (p = 0.066, borderline significance) and a delta-indexed LVESV of −20 ± 21 ml/m 2 for women versus −15 ± 21 ml/m 2 for men (p = 0.033; Table 2 ). When comparing the men and women stratified by etiology, the delta-indexed LVESV (LV reverse remodeling) was comparable between the nonischemic men and nonischemic women (19 ± 23 ml/m 2 vs 17 ± 22 ml/m 2 , p = 0.365). In contrast, LV reverse remodeling appeared to be more outspoken in the nonischemic men compared to the ischemic men (19 ± 23 ml/m 2 versus 13 ± 20 ml/m 2 , p = 0.005). Finally, ischemic men had less reverse remodeling than ischemic women (13 ± 20 ml/m 2 vs 20 ± 23 ml/m 2 , p = 0.026).
Long-term follow-up (mean 34 ± 25 months) data were available for all 578 patients. During long-term follow-up, 197 patients (34%) reached the primary end point (193 patients died and 4 patients underwent cardiac transplantation). The 1- and 2-year mortality rate was 8% and 15%, respectively. The secondary end point was met by 133 patients (23%): 107 patients (80%) died from worsening heart failure, 13 (10%) died from sudden cardiac death, and 13 (10%) died from other cardiac causes.
When comparing the men and women, women showed significantly better survival. The survival curves for the primary and secondary end points are displayed in Figure 1 . In particular, 158 men (37%) and 39 women (27%; p = 0.007) reached the primary end point. Of these patients, 108 men (68%) and 25 women (64%; p = 0.017) died from a cardiac cause or underwent cardiac transplantation, reaching the secondary end point. The 1-year mortality rate for all-cause mortality was 8% and 4% in the men and women (p = 0.162), and the 2-year mortality rate was 15% and 8% (p = 0.025), respectively.
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