Although transcatheter aortic valve implantation (TAVI) for severe aortic stenosis is becoming an established technique, the effect of gender-related differences is poorly described. We performed a gender-based comparison of high-risk patients undergoing TAVI with the self-expandable CoreValve Revalving System for severe aortic stenosis to evaluate early and mid-term clinical outcomes. From the Italian prospective CoreValve registry, 659 consecutive patients (55.8% women) who underwent TAVI were included in the present study. We analyzed the gender-based differences in terms of clinical, angiographic, and procedural features and the differences in the rate of early and mid-term major adverse cardiac and cerebrovascular events. The men were younger, presented more often with severe left ventricular dysfunction, and had a greater rate of previous myocardial infarction, coronary revascularization, peripheral artery disease, renal failure, and heart conduction disorders than the women. The logistic European System for Cardiac Operative Risk Evaluation score did not differ between the 2 groups. The overall unadjusted and adjusted analyses failed to show significant differences between genders in terms of major adverse cardiac and cerebrovascular events at a median follow-up of 13 months (range 8 to 18). At late follow-up (landmark analysis >12 months), a survival benefit was observed in women (hazard ratio 0.27, 95% confidence interval 0.09 to 0.84, p = 0.02). In conclusion, in this multicenter registry, the gender-based comparison of TAVI patients showed that men, despite the younger age, had more extensive atherosclerotic burden compared to women. Overall, the early and mid-term outcomes were similar between genders, although women might have a survival benefit with longer follow-up.
Aortic stenosis (AS) is one of the most common valvular heart disease in Western countries. Women have a longer life expectancy than men and thus a greater likelihood of developing AS. Although female gender has been identified by the European System for Cardiac Operative Risk Evaluation score as a predictor of perioperative mortality after cardiac surgery, the effect of gender on the clinical outcomes after surgical aortic valve replacement is not straightforward. Moreover, women with AS tended to be undertreated and underdiagnosed compared to men. More recently, transcatheter aortic valve implantation (TAVI) emerged as a promising alternative to conventional surgery for patients considered at very high surgical risk or inoperable ; however, few data are available on the effect of gender-related differences in this context. The aim of the present study was to perform a gender-based comparison of high-risk patients undergoing TAVI with the self-expandable CoreValve Revalving System (Medtronic, Mounds View, Minnesota) for severe AS to evaluate the gender-related differences in terms of early and mid-term clinical outcomes.
Methods
From June 2007 to December 2009, 659 consecutive patients with severe AS treated by TAVI with the third-generation 18F CoreValve Revalving System (CRS) were prospectively included in a dedicated Web-based database and compared according to the gender. Patient eligibility criteria, registry design, features of the CRS, technical information of the procedure, and data collection have been previously described. Patients with a bicuspid aortic valve were excluded. The pretreatment consisted of aspirin (100 mg/day, indefinitely) and clopidogrel (300-mg loading dose followed by 75 mg/day for 3 months) orally ≥1 day before the procedure. Heparin was administered according to a weight-based regimen to achieve an activated clotting time >250 seconds. Each locally appointed ethics committee approved the research protocol, and all patients provided informed consent.
The outcome measures included death and major adverse cardiac and cerebrovascular events (MACCE) defined as the composite of death, myocardial infarction (MI), or major stroke. Also the single rate of MI, major stroke, hospitalization for heart failure, permanent pacemaker implantation, major bleeding, and major vascular complications were assessed. Death was considered as overall and cardiovascular mortality. Cardiovascular mortality included sudden or unexplained death, any death of cardiac cause, all procedure-related deaths, and death from cerebrovascular events. MI was defined as the increase of creatine kinase myocardial band ≥3 times the upper limit of normal. Major stroke included cerebrovascular events, of either ischemic or hemorrhagic cause, which led to permanent disability or required surgical intervention. Major vascular complications were defined as vascular rupture with fatal bleeding or need for surgical or percutaneous repair. Major bleeding included fatal hemorrhage, hemorrhage in critical organs (retroperitoneal, intracranial, intraocular, pericardial, intraspinal), and hemorrhage associated with a ≥3 g/dl decrease in hemoglobin level or leading to the transfusion of ≥3 U of packed red blood cells. Procedural success was defined as the implantation of a functioning CRS in the presence of stable hemodynamic conditions and in the absence of severe (≥3+ or 4) paravalvular regurgitation or patient death.
Continuous variables are presented as the mean ± SD or median and interquartile range, and comparisons between groups were performed with Student’s t or Mann-Whitney U tests, as appropriate. Categorical variables are reported as counts and percentages and were compared by chi-square test or Fisher’s exact test, as appropriate. The rate of mortality and MACCE during follow-up was estimated with the Kaplan-Meier method, and differences between genders were assessed using the log-rank test. Patients who were lost to follow-up or with follow-up <1 year were considered at risk until the date of last contact, at which point they were censored. To determine the effect of gender on outcome, a multivariate Cox regression analysis was performed. All variables with p <0.1 in relation to MACCE and those judged to be of clinical importance from previous published data were used as covariables in the model. The following influence factors were included: age, gender, body surface area, diabetes mellitus, previous coronary revascularizations, peripheral artery disease, chronic renal failure, previous heart failure, systolic pulmonary artery pressure ≥60 mm Hg, left ventricular ejection fraction, severe mitral regurgitation, and major bleeding. To provide separate descriptions of early and late relative risks of events, we performed a “landmark analysis,” with a prespecified landmark set at 12 months. Adjusted relative risks were estimated with the use of the Cox regression model. All probability values are 2-sided, and p <0.05 was considered statistically significant. All data were processed using the Statistical Package for Social Sciences, version 18 (SPSS, Chicago, Illinois).
Results
Of the 659 enrolled patients, 368 were women (55.8%) and 291 were men (44.2%). Their mean age was 81 ± 6 years (range 55 to 95). The baseline data were significantly different between groups ( Table 1 ). The women were older, with a smaller body surface area and aortic annulus. They more frequently had hypertension and greater transvalvular aortic gradients and systolic pulmonary pressure, and a better left ventricular ejection fraction. In contrast, the men presented with more extensive atherosclerotic disease and a greater rate of previous coronary revascularization, MI, and renal failure. Although the body surface area differed significantly between genders, the minimal ileofemoral diameters did not (7.49 ± 1.11 vs 7.98 ± 1.53 mm, p = 0.11). The rate of right bundle branch block before TAVI was lower in the women than in the men (5.7% vs 11.9%, p = 0.01). The procedural data are reported in Table 2 . The implantation of a 26-mm device was significantly more common in the women than in the men.
| Variable | All Patients (n = 659) | Men (n = 291) | Women (n = 368) | p Value |
|---|---|---|---|---|
| Age (yrs) | 81 ± 6 | 80 ± 7 | 82 ± 5 | <0.001 |
| Body surface area (m 2 ) | 1.7 ± 0.2 | 1.8 ± 0.2 | 1.7 ± 0.2 | <0.001 |
| Hypertension | 494 (75%) | 192 (66%) | 302 (82%) | <0.001 |
| Diabetes mellitus | 173 (26%) | 77 (26%) | 96 (26%) | 0.91 |
| Hyperlipidemia | 369 (56%) | 187 (64%) | 182 (49%) | <0.001 |
| Coronary artery disease | 356 (54%) | 197 (68%) | 159 (43%) | <0.001 |
| Previous myocardial infarction | 143 (22%) | 94 (32%) | 49 (13%) | <0.001 |
| Previous percutaneous coronary intervention | 188 (29%) | 106 (36%) | 82 (22%) | <0.001 |
| Previous coronary bypass | 104 (16%) | 81 (28%) | 23 (6.3%) | <0.001 |
| Peripheral vascular disease | 126 (19%) | 83 (29%) | 43 (12%) | <0.001 |
| Chronic renal failure ∗ | 154 (23%) | 83 (295%) | 71 (19%) | 0.005 |
| Glomerular filtration rate (ml/min) | 47 ± 21 | 42 ± 17 | 50 ± 23 | <0.001 |
| Previous stroke | 48 (7.3%) | 23 (7.9%) | 25 (6.8%) | 0.59 |
| Atrial fibrillation | 108 (16%) | 45 (16%) | 63 (17%) | 0.57 |
| “Porcelain” aorta | 72 (11%) | 32 (11%) | 40 (11%) | 0.95 |
| Chronic obstructive pulmonary disease | 139 (21%) | 78 (27%) | 61 (17%) | 0.31 |
| Previous neoplasia | 86 (13%) | 44 (15%) | 42 (11%) | 0.16 |
| Previous heart failure | 212 (32%) | 86 (30%) | 126 (34%) | 0.21 |
| New York Heart Association class III or IV | 471 (72%) | 199 (68%) | 272 (74%) | 0.12 |
| Angina pectoris | 116 (18%) | 59 (20%) | 57 (16%) | 0.11 |
| Syncope | 82 (12%) | 36 (12%) | 46 (13%) | 0.96 |
| Logistic European System for Cardiac Operative Risk Evaluation score (%) | 23 ± 5 | 23 ± 14 | 23 ± 14 | 0.67 |
| Echocardiographic measurements | ||||
| Peak left ventricular aortic gradient (mm Hg) | 83 ± 25 | 77 ± 22 | 88 ± 26 | <0.001 |
| Mean ventricular aortic gradient (mm Hg) | 52 ± 17 | 47 ± 14 | 55 ± 18 | <0.001 |
| Aortic annulus diameter (mm) | 22 ± 2 | 23 ± 2 | 21 ± 2 | <0.001 |
| Left ventricular ejection fraction (%) | 51 ± 13 | 49 ± 13 | 53 ± 13 | <0.001 |
| Left ventricular ejection fraction <40% | 135 (21%) | 78 (27%) | 57 (16%) | <0.001 |
| Systolic pulmonary artery pressure >60 mm Hg | 76 (12%) | 25 (9%) | 51 (14%) | 0.04 |
| Severe mitral regurgitation | 41 (6.2%) | 17 (5.8%) | 24 (6.5%) | 0.72 |
| Severe aortic regurgitation | 35 (5.3%) | 14 (4.8%) | 21 (5.7%) | 0.61 |
∗ Chronic renal failure was defined as glomerular filtration rate <60 ml/min.
| Variable | All (n = 659) | Men (n = 291) | Women (n = 368) | p Value |
|---|---|---|---|---|
| General anesthesia | 183 (28%) | 87 (30%) | 96 (26%) | 0.28 |
| Vascular access | <0.001 | |||
| Femoral | 595 (90%) | 249 (86%) | 346 (94%) | |
| Subclavian | 64 (10%) | 42 (14%) | 22 (5.9%) | |
| Device size | <0.001 | |||
| 26 mm | 403 (61%) | 85 (29%) | 316 (86%) | |
| 29 mm | 256 (39%) | 206 (71%) | 52 (14%) | |
| Valve-in-valve implantation | 24 (3.6%) | 11 (3.8%) | 13 (3.5%) | 0.87 |
| Success | 648 (98%) | 285 (98%) | 363 (99%) | 0.48 |
| Death | 6 (0.9%) | 4 (1.4%) | 2 (0.5%) | 0.26 |
| Severe aortic regurgitation | 5 (0.8%) | 3 (0.1%) | 2 (0.5%) | 0.45 |
| Conversion to surgery | 5 (0.8%) | 1 (0.3%) | 4 (1.1%) | 0.28 |
The follow-up data (median 13 months, interquartile range 8 to 18) were complete for 94% of the patients, without significant differences between groups. The cumulative rates of combined and single adverse events during follow-up are reported in Table 3 . The estimated adverse events survival curves, including MACCE, all-cause death, and cardiovascular death, did not differ between genders ( Figure 1 ). On Cox multivariate analysis, the independent predictors of MACCE were diabetes mellitus (hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.28 to 2.71, p = 0.001), chronic renal failure (HR 1.75, 95% CI 1.19 to 2.56, p = 0.004), previous heart failure (HR 1.64, 95% CI 1.14 to 2.38, p = 0.008), severe mitral regurgitation (HR 2.25, 95% CI 1.31 to 3.85, p = 0.003), and major bleeding (HR 2.19, 95% CI 1.01 to 4.74, p = 0.047). Residual aortic regurgitation did not result as significant predictor of MACCE (HR 0.97, 95% CI 0.68 to 1.39, p = 0.86) on univariate Cox analysis. In the unadjusted 1-year landmark analysis, MACCE, all-cause death, and cardiovascular death were significantly more frequent in the men than in the women ( Figure 1 ). The adjusted analysis confirmed a significant interaction between gender and MACCE after 1-year follow-up, with a significant event-free survival benefit for women (HR for MACCE in women 0.27, 95% CI 0.09 to 0.84, p = 0.02). Of the 15 deaths that occurred after 1 year, 37% were cardiovascular related (25% in women and 41% in men) and 63% were from neoplasia or sepsis.
| Variable | All (n = 659) | Men (n = 291) | Women (n = 368) | p Value |
|---|---|---|---|---|
| Major adverse cardiac and cerebrovascular events ∗ | 126 (19%) | 62 (21%) | 64 (17%) | 0.20 |
| All-cause death | 114 (17%) | 55 (19%) | 59 (16%) | 0.33 |
| Cardiovascular death | 47 (7.1%) | 26 (8.9%) | 21 (5.7%) | 0.88 |
| Myocardial infarction | 7 (1.1%) | 6 (2.1%) | 1 (0.3%) | 0.03 |
| Major stroke | 17 (2.6%) | 10 (3.4%) | 7 (1.9%) | 0.22 |
| Pacemaker implantation | 127 (19%) | 70 (24%) | 57 (16%) | 0.01 |
| Heart failure | 55 (8.3%) | 25 (8.6%) | 30 (8.2%) | 0.84 |
| Major bleeding | 21 (3.2%) | 8 (2.7%) | 13 (3.5%) | 0.57 |
| Major vascular complication | 13 (2.0%) | 5 (1.7%) | 8 (2.2%) | 0.68 |
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