The goal of this study was to describe the predictors and significance of poor exercise tolerance after left ventricular assist device (LVAD) implantation. Despite LVAD therapy, some patients continue to exhibit exercise intolerance. The predictors and outcomes of these patients are unknown. A retrospective review of 65 LVAD recipients who performed 6-minute walk tests was conducted. Patients walking <300 m were considered to have poor exercise tolerance. Twenty patients exhibited poor exercise tolerance (221 ± 45 m), compared to 45 patients with better exercise tolerance (406 ± 76 m). Postoperatively, poor performers were not easily identified by functional symptoms alone, because 42% of these patients reported New York Heart Association functional class I or II symptoms. Preoperative New York Heart Association class, inotrope therapy, and intra-aortic balloon pump use were similar between the 2 groups. Multivariate analysis using all adequately powered (n >50) univariate predictors identified diabetes mellitus (odds ratio 10.493, p = 0.003) and elevated 1-month right atrial pressure (odds ratio 2.985 for every 5 mm Hg, p = 0.003) as significant predictors of poor performance (<300 m; area under the curve 0.85). The poorly performing group had increased mortality (p = 0.011), with 21% increased risk for overall mortality for every 10 m short of 300 m (fitted Cox model: hazard ratio 1.211, p = 0.0001). The distance walked in meters in a postoperative 6-minute walk test was the strongest predictor of late post-LVAD mortality (p = 0.0002). In conclusion, despite similar severity of heart failure preoperatively, some LVAD recipients may have persistent exercise intolerance postoperatively as assessed by the 6-minute walk test that is independently associated with subsequent reduced survival.
The large multicenter left ventricular (LV) assist device (LVAD) trials for destination therapy and bridge to transplantation have demonstrated that 20% of patients continue to have persistent symptoms of severe heart failure despite LVAD implantation. However, the characteristics of these patients, the predictors of poor exercise tolerance after LVAD implantation, and their outcomes are not clear. The aim of the present study was to describe the predictors and significance of poor exercise tolerance after LVAD implantation, defined as patients who walk <300 m during a 6-minute walk test (6MWT).
Methods
A retrospective analysis of the first available 6MWT performed after recovery from LVAD implantation as bridge to transplantation or destination therapy was conducted in a consecutive cohort of patients with advanced heart failure who received the HeartMate II axial flow LVAD (Thoratec Corporation, Pleasanton, California) at our center from February 2007 to October 2010. Patients were divided into 2 groups dependent on the distance covered in the 6MWT (poor performers, <300 m, or better performers, ≥300 m). All patients underwent a detailed clinical evaluation before LVAD implantation, including history, physical examination, laboratory evaluation, echocardiography, and cardiac catheterization. Renal function was evaluated using the modified Modification of Diet in Renal Disease (MDRD) equation. To evaluate for complicated perioperative course, we determined the total number of days on initial ventilatory support as well as the need for repeat ventilation. Ventilator support for >3 days or need for repeat ventilation after extubation was defined as complex ventilatory course. After implantation, patients were followed with routine visits, usually at 1 month, 3 months, and 3- to 6-month intervals thereafter. Follow-up echocardiography was performed in the outpatient setting at the first follow-up visit. All-cause mortality and causes of death were documented. The study was approved by the Mayo Clinic institutional review board.
The 6MWT was performed after LVAD implantation in an ambulatory setting. Sixty-five outpatients performed the test when first able to do so. Tests performed <2 or >12 months after LVAD implantation were excluded from the analysis. Patients walked as far as they could for 6 minutes, as previously described. Two-dimensional transthoracic echocardiography was performed in a standard manner, as previously described. Right atrial pressure was estimated by the inferior vena cava diameter and its response to inspiration. Right ventricular function and tricuspid and mitral regurgitation severity were qualitatively graded using a 4-point scale (normal, mild, moderate, or severe) using all views. Right ventricular function was assessed using tissue Doppler assessment of lateral tricuspid annular motion, systolic tricuspid regurgitation duration, and the right ventricular index of myocardial performance and was characterized as normal or with mild, moderate, or severe dysfunction. We corrected the time intervals of right ventricular ejection time and the time between the onset and the cessation of tricuspid regurgitation flow for heart rate using the correction formula time of tricuspid regurgitation flow corrected for heart rate = tricuspid regurgitation flow time/ √ RR.
Descriptive analysis was performed by presenting the mean ± SD for numeric data unless markedly non-normal, in which case the median and interquartile range (25th and 75th percentiles) were used, unless specified otherwise. Assessment of normality for numeric variables was performed using the Shapiro-Wilk method. Comparisons between groups were performed using Fisher’s exact test, Student’s t test, or Wilcoxon’s test as appropriate. To analyze independent determinants of poor exercise tolerance, univariate and multivariate analyses based on a logistic regression model were performed with 6-minute walk distance < 300 m as the dependent variable and the different clinical, hemodynamic, and echocardiographic parameters as independent variables. For the multivariate analysis, only parameters that were collected in >50 patients were considered. The multivariate model considered marginally significant univariate variables (p <0.10) with model selection using stepwise combined selection. Survival probabilities were derived using the product-limit estimate whereby patients first enter the risk set upon classification using the 6-minute walk distance (left censoring) and (right) censored upon heart transplantation or at last follow-up if alive at that time. Association between the 6-minute walk distance and survival was evaluated using Cox proportional-hazards regression, again allowing for the entry of patients into the risk set at the time of their walk assessments. Distance walked in meters (a continuous variable) as well as walking >300 or <300 m (nominal) were tested. To evaluate the functional form between distance walked and mortality risk, we fit a smoothing spline in the Cox regression model (using the cox.zph function of the coxph package in R; R Project for Statistical Computing, Vienna, Austria). We also evaluated Cox models for predictors on the basis of different cut-off values under which a decreased walking distance would result in increased mortality (eg, with values <300 m as the distance <300 m and values >300 m considered as zero). Comparison between parameters as to their associations with mortality was performed by comparing chi-square values for the univariate Cox models and verification using a multivariate model. All p values were 2 sided, and p values ≤0.05 were considered to indicate statistical significance. All data were analyzed using JMP version 8.0 (SAS Institute Inc., Cary, North Carolina), SAS version 9.2 (SAS Institute Inc.), or R.
Results
The study groups are outlined in Figure 1 . Of 105 potential patients, 65 were eligible for analysis. Causes of not performing a 6MWT were death, transplantation, debility, and inability to perform the test. Twenty patients (31%) walked <300 m (poor performers), and 45 patients (69%) walked ≥300 m (better performers). The median time periods after LVAD implantation when the 6MWT was performed were 3.6 months (interquartile range 3.0 to 5.9) for poor performers and 4.1 months (interquartile range 3.1 to 6.1) for better performers; there was no significant difference between the 2 groups (p = 0.326). In the entire cohort, there were 83% men (n = 54), and the median age of the group was 65 years. The cause of heart failure was ischemic in 49% of the patients (n = 32). Twenty-three patients (35%) underwent LVAD implantation as bridge to transplantation and the rest as destination therapy. All patients had New York Heart Association functional class III or IV symptoms before LVAD implantation; most (60%) had class IV symptoms. The patients had a median N-terminal pro–brain natriuretic peptide level of 4,600 pg/ml (interquartile range 2,100 to 8,100) and moderately elevated Leitz-Miller prognostic scores (mean 9.3 ± 5.9). Sixteen patients (25%) had INTERMACS scores of 1 or 2. Patients had low LV ejection fractions (mean 20 ± 7%) and cardiac indexes (mean 1.9 ± 0.5 L/min/m 2 ), with increased pulmonary capillary wedge pressures (mean 23 ± 6 mm Hg). Preoperative right ventricular dysfunction by echocardiography was characterized as being greater than moderate severity in 36 of 61 patients (59%).
A detailed comparison between the poor and better performers on the 6MWT is listed in Tables 1 and 2 . Patients in the poor-performance group were older, had a higher prevalence of co-morbidities such as diabetes and hypertension, and had lower preoperative (but not admission) glomerular filtration rates. Patients in the poor-performance group had a lower right ventricular index of myocardial performance. Perioperatively, the poor performers required prolonged inotropic support (median 141 hours) compared to the better-performing group (median 72 hours) (p = 0.008) and complex ventilator support (p = 0.007), translating to a significantly increased length of hospital stay (median 33 days) compared to the better-performing group (median 22 days) (p = 0.003). There were no significant differences in pump settings and other pump parameters between the 2 groups that could account for the difference in exercise capacity. Postoperative echocardiography 1 month after implantation identified poor 6MWT performers to have significantly higher right atrial pressures, shorter tricuspid regurgitation times, and shorter mitral E-wave deceleration times.
| Variable | Distance Walked <300 m | Distance Walked ≥300 m | p Value |
|---|---|---|---|
| (n = 20) | (n = 45) | ||
| Age (years) | 68 (59–74) | 65 (53–69) | 0.046 ⁎ |
| Men | 15 (75%) | 39 (87%) | 0.292 |
| Hypertension | 11 (55%) | 14 (31%) | 0.098 |
| Diabetes mellitus | 11 (55%) | 8 (18%) | 0.006 ⁎ |
| Chronic kidney disease | 13 (65%) | 23 (51%) | 0.418 |
| Bridge to transplantation | 5 (25%) | 18 (40%) | 0.276 |
| Ischemic cause of heart failure | 12 (60%) | 20 (44%) | 0.290 |
| Weight (kg) | 89 ± 21 | 85 ± 17 | 0.487 |
| Atrial fibrillation | 4 (20%) | 10 (22%) | 1.000 |
| Glomerular filtration rate on admission (ml/min/1.73 m 2 ) | 47 ± 20 | 57 ± 20 | 0.065 |
| Glomerular filtration rate preoperatively (ml/min/1.73 m 2 ) | 55 ± 15 | 72 ± 24 | 0.001 ⁎ |
| New York Heart Association class IV | 12 (60%) | 27 (61%) | 1.000 |
| 6-minute walk distance | >180 ± 106 (n = 4) | >333 ± 85 (n = 19) | 0.056 |
| Peak oxygen consumption (ml/kg/min) preoperatively | >9 ± 4 (n = 11) | >11 ± 2 (n = 22) | 0.128 |
| INTERMACS score | 4 (2.5–5.5) | 4 (3–5) | 1.000 |
| Leitz-Miller score | 10 ± 6 | 9 ± 6 | 0.372 |
| Intra-aortic balloon pump | 8 (40%) | 16 (36%) | 0.788 |
| Inotropic support | 11 (55%) | 30 (68%) | 0.401 |
| Angiotensin inhibitors | 14 (70%) | 29 (66%) | 1.000 |
| β blockers | 19 (95%) | 36 (82%) | 0.252 |
| Diuretics | 18 (95%) | 39 (89%) | 0.658 |
| Intracardiac defibrillator/resynchronization | 11 (58%) | 27 (61%) | 1.000 |
| Hemoglobin (g/dl) | 11.6 ± 2.0 | 12.4 ± 1.8 | 0.151 |
| Bilirubin (mg/dl) | 0.9 (0.7–1.2) | 1.3 (0.8–1.7) | 0.087 |
| Aspartate aminotransferase (u/L) | 28 (20–40) | 36 (29–50) | 0.058 |
| N-terminal pro–brain natriuretic peptide/100 (pg/ml) | 37 (20–63) (n = 12) | 48 (24–84) (n = 32) | 0.452 |
| Platelets/1,000 | 157 (129–231) | 153 (130–222) | 0.759 |
| Albumin (g/dl) | 3.7 ± 0.5 | >3.8 ± 0.5 (n = 42) | 0.226 |
| Echocardiography | |||
| Right ventricular index of myocardial performance | >0.5 ± 0.2 (n = 17) | >0.6 ± 0.3 (n = 38) | 0.049 ⁎ |
| Tricuspid regurgitation time (corrected) (ms) | 457 ± 53 | >474 ± 71 (n = 41) | 0.287 |
| Right ventricular dysfunction (greater than moderate) | 11/18 (61%) | 25/43 (58%) | 1.000 |
| Right atrial pressure (mm Hg) | 20 (10–20) (n = 18) | 14 (10–20) (n = 41) | 0.174 |
| LV end-diastolic diameter (mm) | 67 ± 8 | >68 ± 9 (n = 43) | 0.674 |
| Left atrial volume index | 61 (47–77) | 63 (51–78) (n = 38) | 0.572 |
| Mitral valve E (m/s) | 0.9 (0.8–1.2) (n = 15) | 1 (0.8–1.1) (n = 37) | 0.799 |
| E wave deceleration time (ms) | >136 ± 31 (n = 14) | >137 ± 29 (n = 35) | 0.961 |
| Ejection fraction (%) | 20 (16–20) | 17 (15–23) | 0.457 |
| Tricuspid regurgitation greater than moderate | 7 (35%) | 12 (27%) | 0.560 |
| Mitral regurgitation greater than moderate | 4 (20%) | 18 (40%) | 0.159 |
| Catheterization | |||
| Right atrial mean pressure (mm Hg) | >18 ± 8 (n = 18) | >14 ± 6 (n = 41) | 0.063 |
| Right ventricular stroke work index (g/m) | >6.5 ± 4.1 (n = 18) | >7.7 ± 3.7 (n = 40) | 0.313 |
| Stroke index (ml/beat/m 2 ) | 26 (19–34) (n = 19) | 24 (19–29) (n = 40) | 0.501 |
| Cardiac index (L/min/m 2 ) | >1.9 ± 0.6 (n = 18) | >1.9 ± 0.5 (n = 41) | 0.688 |
| Systemic vascular resistance (Wood units) | 18 (12–22) (n = 15) | 20 (10–23) (n = 28) | 0.868 |
| Pulmonary vascular resistance (Wood units) | 3.1 (2.2–4.7) (n = 17) | 4.9 (2.8–8.6) (n = 39) | 0.084 |
| Wedge pressure (mm Hg) | >24 ± 6 (n = 18) | >23 ± 6 (n = 39) | 0.710 |
| Pulmonary artery mean pressure (mm Hg) | >36 ± 8 (n = 19) | >37 ± 9 (n = 41) | 0.706 |
| Variable | Distance Walked <300 m | Distance Walked ≥300 m | p Value |
|---|---|---|---|
| (n = 20) | (n = 45) | ||
| Surgery and postoperative | |||
| Bypass time (minutes) | 91 (77–118) (n = 19) | 87 (67–114) (n = 39) | 0.619 |
| Complex ventilatory course † | 11/18 (61%) | 10/44 (23%) | 0.007 ⁎ |
| Inotropic support (hours) | 141 (84–205) | 72 (48–121) | 0.008 ⁎ |
| Inotropes >168 hours | 6 (30%) | 5 (11%) | 0.083 |
| Hospital stay (days) | 33 (27–41) | 22 (14–33) | 0.003 ⁎ |
| Discharge medications | |||
| β blocker | 7 (35%) | 18 (40%) | 0.787 |
| Angiotensin inhibitors | 7 (35%) | 15 (33%) | 1.000 |
| Loop diuretics (furosemide equivalent) (mg/day) | 40 (0–80) | 40 (20–80) | 0.268 |
| Spironolactone | 6 (30%) | 10 (22%) | 0.542 |
| Discharge pump speed >9,200 rpm | 15 (75%) | 31 (72%) | 1.000 |
| Discharge pump flow (L/min) | 5.2 ± 0.6 | 5.3 ± 0.7 | 0.473 |
| Discharge pump pulsatility index | 5.0 ± 0.6 (n = 19) | 5.0 ± 0.7 (n = 42) | 0.991 |
| Early follow-up | |||
| New York Heart Association class >II | 11 (58%) | 4 (9%) | <0.001 ⁎ |
| Hemoglobin (g/dl) | 10.4 ± 1.5 (n = 18) | 10.6 ± 2.0 (n = 36) | 0.661 |
| Platelets/1,000 | 248 (226–296) (n = 18) | 276 (228–370) (n = 36) | 0.209 |
| Albumin (g/dl) | 3.6 ± 0.5 (n = 13) | 3.6 ± 0.5 (n = 31) | 0.952 |
| Creatinine (mg/dl) | 0.9 (0.8–1.4) (n = 17) | 0.9 (0.8–1.1) (n = 39) | 0.495 |
| Tricuspid regurgitation time (corrected) (ms) | 399 ± 43 (n = 16) | 430 ± 41 (n = 34) | 0.025 ⁎ |
| Right ventricular index of myocardial performance | 0.2 (0.1–0.3) (n = 12) | 0.3 (0.2–0.4) (n = 24) | 0.274 |
| Right atrial pressure (mm Hg) | 10 (10–20) (n = 18) | 5 (5–10) (n = 38) | 0.001 ⁎ |
| E-wave deceleration time (ms) | 142 ± 27 (n = 11) | 205 ± 51 (n = 21) | <0.001 ⁎ |
| LV end-diastolic diameter (mm) | 54 ± 10 (n = 17) | 57 ± 9 (n = 26) | 0.381 |
| Ejection fraction (%) | 20 (20–27) (n = 17) | 25 (20–31) (n = 26) | 0.363 |
| Aortic valve not opening | 10/19 (53%) | 23/39 (59%) | 0.779 |
| Heart rate at peak 6MWT | 98 ± 14 (n = 16) | 103 ± 18 (n = 40) | 0.223 |
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