We sought to measure the impact of cardiac rehabilitation (CR) on mortality in patients with mitral or aortic heart valve surgery (HVS) and nonobstructive coronary artery disease. We surveyed all patients (or a close family member if the patient was deceased) who had HVS without coronary artery bypass in 2006 through 2010 at the Mayo Clinic to assess if they attended CR after their HVS. We performed a propensity-adjusted landmark analysis to test the association between CR attendance and long-term all-cause mortality conditional on surviving the first year after HVS. Survey response rate was 40% (573/1,420), with responders more likely to be older, have longer hospitalizations, and have more aortic valve disease. A total of 547 patients (59% aortic surgery, ejection fraction 64%) with valid survey responses and 1-year follow-up were included in the propensity analysis, of whom 296 (54%) attended CR. There were 100 deaths during a median follow-up of 5.8 years. For all patients, the propensity-adjusted model suggested no impact of CR on mortality (hazard ratio [HR] 1.03, 95% CI 0.66 to 1.62). When stratified by procedure, results suggested a potentially favorable, but nonsignificant, effect in patients with mitral valve surgery (HR 0.49, 95% CI 0.15 to 1.56), but not in patients with aortic valve surgery (HR 1.00, 95% CI 0.61 to 1.64.) In conclusion, we found no survival advantage for patients with normal preoperative ejection fraction who attended CR after surgical “correction” of their severe aortic or mitral valve disease.
Although cardiac rehabilitation (CR) improves mortality in patients with atherosclerotic cardiovascular disease in observational studies, there is little evidence to date that CR improves mortality after isolated heart valve surgery (HVS.) Furthermore, given the significant differences in disease etiology and disease pathophysiology, the effects of CR may differ in patients with HVS compared with those with coronary artery disease (CAD). Accordingly, we examined the impact of CR on mortality after HVS and hypothesized that CR attendance would be associated with improved survival.
Methods
We used the cardiothoracic surgical database at Mayo Clinic in Rochester, Minnesota to identify all patients who underwent valve-only surgery during a 5-year period from January 2006 to December 2010. This database is modeled after the Society of Thoracic Surgery database and uses standard definitions for valve disease severity, clinical risk factors, surgical interventions, and postoperative complications. This database also recorded hospital-initiated referral to CR and the Charlson Comorbidity Index.
We included patients who underwent isolated surgical aortic valve repair or replacement, mitral valve repair or replacement, or a combination of these valve procedures, while excluding patients with concurrent coronary artery bypass graft surgery. We excluded patients who underwent transcutaneous aortic valve replacement, isolated tricuspid or pulmonary valve surgery, and patients <50 years old because of their small numbers and heterogeneity of disease states. We further excluded patients with in-hospital mortality, international home mailing addresses, or those without a valid consent for medical record–based retrospective research.
Because most patients lived outside Olmsted County, Minnesota, we could not confirm attendance at CR through direct medical record review. As a result, we surveyed patients (or a close family member if the patient was deceased) to assess if the patient attended CR in the year after their HVS. We mailed the initial survey in spring 2013 and received the final survey response in fall 2013. If no response to the initial mailing was received, we sent a second survey about 4 weeks later. To increase our response rate, we additionally telephone-surveyed family members of decease patients if there was no response to the second mailing. Attempts to complete the telephone survey continued until family members completed the survey, could not be contacted, or declined to participate. All survey administration, survey collection, and data entry were performed by Mayo Clinic Survey Research Center personnel after standard protocols. All patients participating in the survey gave written informed consent. This study was approved by the Mayo Clinic Institutional Review Board.
Survey questions were developed primarily by the principal investigator (QP) with help from research staff in the survey research center. Co-authors carefully reviewed the full survey for face and content validity. To further increase our accuracy and reliability, we performed cognitive testing of the survey questionnaire with 5 patients to further improve the survey as necessary. The survey contained 9 primary questions that assessed referral to CR, attendance at CR orientation, and the length and frequency of CR attendance. In the survey, CR was defined as an exercise-based intervention commonly coupled with medical educational sessions with the overall goal of hastening recovery from surgery. We used slightly different wording depending on which group was being surveyed. See Online Appendix for the 2 survey instruments.
The primary predictor variable was attendance at CR, as determined by the response to survey question #6, which asked, “In the year following your heart surgery, did you ever attend at least 1 exercise session in an outpatient cardiac rehabilitation program?” We excluded patients who skipped this question, did not remember, or gave inconsistent answers to follow-up questions about when and where they attended CR. We assessed the reliability of our primary predictor by comparing survey-reported attendance at CR with medical record–verified CR attendance among the small portion of eligible patients who were living in Olmsted County, Minnesota at the time of their surgery during the years 2006 to 2008. During the study period, the Mayo Clinic CR program was the only CR program available in Olmsted County.
The primary outcome was all-cause mortality as assessed in October 2014. We used the Mayo Clinic registration database in conjunction with the Minnesota death tapes and obituaries in the local newspapers to determine patient’s vital status. For anyone not indicated as deceased by Mayo Clinic records, patients were censored as alive at their last known medical visit or at the date of survey completion (for self-respondents only.) The cause of death was unknown.
Descriptive statistics on baseline patient characteristics and survey responses were presented as frequency (%) for categorical variables and as quartiles (median, 25th and 75th percentiles) for continuous variables, as appropriate. To assess potential survey response bias, group differences between respondents and nonrespondents were determined using standard 2-sample tests (Wilcoxon rank-sum test, chi-square test, or Fisher’s exact test, as appropriate). The survey-based indication of CR attendance was assessed for concordance using the Kappa statistic. Median follow-up time was estimated using the reverse Kaplan–Meier method.
Given the possibility that baseline factors played a role in the decision to attend CR (participation bias), this potential confounding on the association of CR attendance with long-term mortality was addressed using propensity score adjustment. In particular, >50 factors were entered as possible explanatory variables into a multivariable logistic regression model to predicted CR attendance. The logit-transformed predicted probability of attending CR from this model determined the propensity score, which was then included as an adjusting covariate along with CR attendance for predicting time-to-death. We also performed alternative forms of propensity score analysis that involved matching, weighting, and stratifying.
We then analyzed the association between attending any CR within 1-year of HVS with long-term mortality, with and without propensity score risk adjustment, using Cox proportional hazards regression. We used a landmark analysis approach that conditioned on patients having 1-year censor-free survival, thus allowing CR attendance within 1 year to be treated as a baseline predictor of post–1-year mortality. We further augmented this multivariate model by adjusting for factors considered to be predictive of mortality, including age, gender, atrial fibrillation, end-stage renal disease, peripheral vascular disease, and Charlson Index. We then repeated the propensity analyses within clinically relevant subgroups of mitral or aortic valve surgery. Given the small number of patients with combined aortic and mitral valve surgery, these patients were included in both subgroups (aortic and mitral) for respective subset analyses. All data analysis was performed using the SAS statistical software package, version 9.3 (SAS Institute, Cary, North Carolina). A type I error rate of 0.05 was used to determine statistical significance.
Results
We identified 1,460 potentially eligible patients, excluded 40 patients because of lack of valid research consent and then surveyed the remaining 1,420 patients including 208 who were known to be deceased. A total of 573 patients returned a completed survey for a response rate of 40%. Family members completed 123 (21%) of these surveys, whereas patients completed 450 (79%). Survey respondents were different from nonrespondents in several ways. See Table 1 .
| Variable | N | Survey Respondent | P-value | |
|---|---|---|---|---|
| Yes (n=573) | No (n=847) | |||
| Age at surgery (median, IQR, years) | 1420 | 72.0 (63.9, 78.3) | 70.2 (61.4, 78.6) | 0.009 |
| Male | 1420 | 368 (64%) | 523 (62%) | 0.34 |
| Body mass index (median, IQR, kg/m 2 ) | 1420 | 27.7 (24.9, 31.6) | 28.0 (25.2, 31.8) | 0.29 |
| White | 1370 | 539 (98%) | 793 (97%) | 0.27 |
| Geographic region: | 1420 | 0.84 | ||
| Minnesota | 222 (39%) | 340 (40%) | ||
| States (ND, SD, IA, WI, IL) ‡ | 186 (32%) | 273 (32%) | ||
| All other states | 165 (29%) | 234 (28%) | ||
| Medicare/Medicaid insurance | 1420 | 411 (72%) | 564 (67%) | 0.04 |
| Hospital length of stay | 1420 | 6.0 (5.0, 8.0) | 6.0 (4.0, 8.0) | 0.003 |
| Readmission within 30 days | 1420 | 61 (11%) | 50 (6%) | 0.001 |
| Cardiac rehabilitation referral in hospital | 1420 | 324 (57%) | 474 (56%) | 0.83 |
| Coronary artery disease risk factors | ||||
| Smoking (current, former) | 1420 | 309 (54%) | 428 (51%) | 0.21 |
| Family history of coronary artery disease | 1420 | 45 (8%) | 64 (8%) | 0.84 |
| Peripheral vascular disease | 1420 | 39 (7%) | 61 (7%) | 0.78 |
| Cerebral vascular disease | 1420 | 67 (12%) | 118 (14%) | 0.22 |
| Hypertension | 1420 | 404 (71%) | 558 (66%) | 0.07 |
| Normal coronary arteries | 1337 | 161 (30%) | 241 (30%) | 0.90 |
| Coronary artery disease ∗ | 1420 | 171 (30%) | 219 (26%) | 0.10 |
| Comorbidities | ||||
| Charlson index | 1420 | 2.0 (1.0, 4.0) | 2.0 (1.0, 4.0) | 0.70 |
| Moderate/severe renal disease | 1420 | 89 (16%) | 126 (15%) | 0.74 |
| Chronic pulmonary disease | 1420 | 153 (27%) | 229 (27%) | 0.89 |
| Infectious endocarditis | 1420 | 29 (5%) | 48 (6%) | 0.62 |
| Creatinine level | 1420 | 1.0 (0.9, 1.2) | 1.0 (0.9, 1.2) | 0.05 |
| Dialysis | 1420 | 7 (1%) | 12 (1%) | 0.75 |
| Heart failure | 1420 | 94 (16%) | 159 (19%) | 0.25 |
| Prior cardiac interventions | ||||
| Cardiac operations | 1420 | 136 (24%) | 157 (19%) | 0.018 |
| Coronary artery bypass surgery | 1420 | 84 (15%) | 88 (10%) | 0.016 |
| Valve surgery | 1420 | 66 (12%) | 94 (11%) | 0.81 |
| Aortic valve replacement | 1420 | 29 (5%) | 48 (6%) | 0.62 |
| Mitral valve replacement | 1420 | 10 (2%) | 30 (4%) | 0.045 |
| Pulmonary valve repair | 1420 | 37 (6%) | 39 (5%) | 0.13 |
| Atrial septal defect | 1420 | 4 (1%) | 2 (0%) | 0.19 |
| Aortic aneurysm (ascending) | 1420 | 3 (1%) | 4 (0%) | 0.89 |
| Internal cardiac defibrillator | 1420 | 9 (2%) | 17 (2%) | 0.55 |
| Pacemaker | 1420 | 24 (4%) | 41 (5%) | 0.56 |
| Percutaneous coronary intervention | 1420 | 55 (10%) | 92 (11%) | 0.44 |
| Heart rhythm: | 1419 | 0.03 | ||
| Normal sinus rhythm | 530 (92%) | 749 (89%) | ||
| Atrial fibrillation or flutter | 33 (6%) | 85 (10%) | ||
| Heart block | 0 (0%) | 1 (0%) | ||
| Paced | 10 (2%) | 11 (1%) | ||
| Any arrhythmia | 1420 | 95 (17%) | 173 (20%) | 0.07 |
| Cardiac function | ||||
| Ejection fraction, % | 1420 | 64.0 (59.0, 68.0) | 64.0 (57.0, 67.0) | 0.11 |
| Cardiac output, L/Min | 1420 | 5.9 (5.2, 6.7) | 5.9 (5.4, 6.7) | 0.13 |
| Cardiac index, L/Min/M 2 | 1420 | 3.0 (2.7, 3.5) | 3.0 (2.7, 3.5) | 0.66 |
| Aortic valve stenosis | 1420 | 370 (65%) | 463 (55%) | <.001 |
| Aortic valve insufficiency (severity∼) | 1420 | 1.0 (1.0, 2.0) | 1.0 (0.0, 2.0) | 0.31 |
| Mitral valve stenosis | 1420 | 62 (11%) | 55 (6%) | 0.004 |
| Mitral valve insufficiency (severity∼) | 1420 | 2.0 (1.0, 4.0) | 3.0 (2.0, 4.0) | <.001 |
| Aortic valve surgery: | 1420 | <.001 | ||
| No | 169 (29%) | 349 (41%) | ||
| Replacement | 398 (69%) | 488 (58%) | ||
| Repair/Reconstruction/Other | 6 (1%) | 10 (1%) | ||
| Mitral valve surgery: | 1420 | <.001 | ||
| No | 365 (64%) | 450 (53%) | ||
| Annuloplasty only | 18 (3%) | 22 (3%) | ||
| Replacement | 69 (12%) | 105 (12%) | ||
| Reconstruction w/annuloplasty | 111 (19%) | 257 (30%) | ||
| Reconstruction w/o annuloplasty | 10 (2%) | 13 (2%) | ||
| Operative characteristics | ||||
| Robotic-assisted op approach | 1420 | 6 (1%) | 87 (10%) | <.001 |
| Intra-aortic ballon pump used | 1420 | 14 (2%) | 22 (3%) | 0.86 |
| Intra-operative blood products | 1420 | 306 (53%) | 409 (48%) | 0.06 |
| Post-operative blood products | 1420 | 249 (43%) | 333 (39%) | 0.12 |
| Ventilation hours | 1420 | 9.0 (5.6, 14.4) | 7.5 (5.0, 12.8) | <.001 |
| Hospital complications | ||||
| Any in-hospital complication | 1420 | 279 (49%) | 412 (49%) | 0.99 |
| Operative complication | 1420 | 29 (5%) | 27 (3%) | 0.08 |
| Infection complication | 1420 | 32 (6%) | 41 (5%) | 0.53 |
| Neurologic complication | 1420 | 15 (3%) | 19 (2%) | 0.65 |
| Pulmonary complication | 1420 | 35 (6%) | 52 (6%) | 0.98 |
| Renal complication | 1420 | 10 (2%) | 13 (2%) | 0.76 |
| Other complication | 1420 | 249 (43%) | 372 (44%) | 0.86 |
| Medications at Discharge | ||||
| Aspirin | 1420 | 459 (80%) | 651 (77%) | 0.15 |
| ACE inhibitors | 1420 | 167 (29%) | 221 (26%) | 0.21 |
| Beta blockers | 1420 | 450 (79%) | 681 (80%) | 0.39 |
| Warfarin | 1420 | 317 (55%) | 533 (63%) | 0.004 |
| Lipid lowering medication | 1420 | 348 (61%) | 475 (56%) | 0.08 |
| Antiarrhythmics | 1420 | 200 (35%) | 315 (37%) | 0.38 |
| ADP inhibitors | 1420 | 24 (4%) | 40 (5%) | 0.63 |
| Non-home discharge location | 1420 | 80 (14%) | 143 (17%) | 0.17 |
| Deaths (Survival rate until time of survey) † | 1420 | <.001 | ||
| 2 years | 27 (95%) | 47 (91%) | ||
| 4 years | 63 (88%) | 81 (81%) | ||
| 6 years | 91 (80%) | 109 (61%) | ||
| Total# deaths | 96 | 112 | ||
∗ Any coronary artery disease defined by as having one or more coronary arteries with >50% stenosis.
† K-M (# events); p value derived from log-rank test.
‡ North Dakota, South Dakota, Wisconsin, Illinois, and Iowa.
We identified 19 patients who resided in Olmsted County, Minnesota at the time of their surgery from 2006 to 2007, in whom their attendance in the Mayo Clinic CR program was previously known through chart abstraction. In this subset, there was “moderate to substantial” agreement between survey-reported attendance and medical record–verified CR attendance. Agreement was 84% with a κ= 0.62 (95% CI 0.23 to 1.00).
For the survival analysis, we excluded 11 patients (2%) because of incomplete or inconsistent answers about CR attendance and 15 patients (3%) because of insufficient follow-up (censor-free survival was <1 year). Of the remaining 547 patients, 296 (54%) reported attending CR for ≥1 exercise session. The reported median (interquartile range) frequency was 3 (2 to 3) CR sessions per week for 6 (6 to 10) total weeks, corresponding to an estimated median of 18 (12 to 26) total CR sessions. Most patients (235 of 275 [85%]) reported completing their recommended course of CR.
On propensity analysis, several factors were associated with CR attendance on univariate analysis ( Table 2 ) although all available factors were included in the multivariate model that derived the propensity scores. On outcomes analysis, we recorded 100 deaths between the first year after surgery and the end of follow-up, with an estimated median (interquartile range) follow-up time of 5.8 (4.8 to 6.8) years after surgery. There was no impact of CR on all-cause mortality rate, either from unadjusted, propensity-adjusted, or propensity- and covariate-adjusted analyses ( Table 3 ). Sensitivity analyses using different forms of propensity score adjustment, such as propensity-matched analyses, showed similar nonsignificant effects of CR (results not shown.) Subgroup results were similar for patients with aortic valve surgery. However, for patients who underwent mitral valve surgery, there was a nonsignificant ∼51% improvement in long-term survival in both unadjusted and propensity-adjusted analyses ( Table 3 ). Finally, in a dose–response analysis performed only on CR participants, the estimated number of CR sessions completed was not significantly associated with long-term mortality (hazard ratio, per 10-session increment 1.10, 95% CI 0.93 to 1.29; p = 0.27).
| Variable | CR Exercise (n=296) | No CR Exercise (n=251) | P-value |
|---|---|---|---|
| Age at surgery (median, IQR, years) | 71.8 (63.6, 77.6) | 72.0 (63.6, 79.1) | 0.86 |
| Male | 200 (68%) | 152 (61%) | 0.09 |
| Body mass index (median, IQR, kg/m 2 ) | 28.1 (25.4, 32.3) | 26.6 (24.2, 30.9) | 0.003 |
| Caucasian race, yes (missing, n=22) | 282 (98%) | 232 (98%) | 0.98 |
| Geographic Region: | 0.81 | ||
| Minnesota | 111 (38%) | 100 (40%) | |
| States (ND, SD, IA, WI, IL) | 97 (33%) | 82 (33%) | |
| All other states | 88 (30%) | 69 (27%) | |
| Medicare/Medicaid insurance, | 213 (72%) | 175 (70%) | 0.57 |
| Hospital length of stay | 6.0 (5.0, 8.0) | 6.0 (5.0, 8.0) | 0.57 |
| Readmission within 30 days | 28 (9%) | 27 (11%) | 0.62 |
| Cardiac rehabilitation referral while in hospital | 214 (72%) | 94 (37%) | <.001 |
| Coronary artery disease risk factors | |||
| Smoking | 169 (57%) | 125 (50%) | 0.09 |
| Family history of coronary artery disease | 20 (7%) | 23 (9%) | 0.30 |
| Hypertension | 212 (72%) | 173 (69%) | 0.49 |
| Normal coronary arteries (missing, n=32) | 90 (32%) | 65 (27%) | 0.20 |
| Diagnosis of coronary artery disease | 80 (27%) | 80 (32%) | 0.21 |
| Comorbidities | |||
| Charlson index | 2.0 (1.0, 4.0) | 2.0 (1.0, 4.0) | 0.63 |
| Moderate/severe renal disease | 38 (13%) | 47 (19%) | 0.06 |
| Chronic pulmonary disease | 77 (26%) | 64 (25%) | 0.89 |
| Peripheral vascular disease | 18 (6%) | 18 (7%) | 0.61 |
| Cerebral vascular disease | 34 (11%) | 30 (12%) | 0.87 |
| Infectious endocarditis | 13 (4%) | 15 (6%) | 0.40 |
| Creatinine level | 1.0 (0.9, 1.2) | 1.1 (0.9, 1.2) | 0.044 |
| Dialysis | 0 (0%) | 5 (2%) | 0.02 |
| Heart failure | 46 (16%) | 43 (17%) | 0.62 |
| Prior cardiac interventions | |||
| Cardiac operations | 70 (24%) | 60 (24%) | 0.94 |
| Coronary artery bypass surgery | 46 (16%) | 33 (13%) | 0.43 |
| Valve surgery | 30 (10%) | 34 (14%) | 0.22 |
| Aortic valve replacement | 12 (4%) | 15 (6%) | 0.30 |
| Mitral valve replacement | 4 (1%) | 6 (2%) | 0.37 |
| Pulmonary valve repair | 17 (6%) | 20 (8%) | 0.30 |
| Atrial septal defect | 3 (1%) | 1 (0%) | 0.63 |
| Aortic aneurysm (ascending) | 1 (0%) | 2 (1%) | 0.60 |
| Internal cardiac defibrillator | 5 (2%) | 3 (1%) | 0.63 |
| Pacemaker | 14 (5%) | 10 (4%) | 0.67 |
| Percutaneous coronary intervention | 33 (11%) | 20 (8%) | 0.21 |
| Heart rhythm: | 0.93 | ||
| Normal sinus rhythm | 274 (93%) | 233 (93%) | |
| Atrial fibrillation /flutter | 16 (5%) | 14 (6%) | |
| Paced | 6 (2%) | 4 (2%) | |
| Any arrhythmia | 50 (17%) | 39 (16%) | 0.67 |
| Cardiac function | |||
| Ejection fraction, % | 64.0 (58.0, 68.0) | 65.0 (58.0, 68.0) | 0.70 |
| Cardiac output, L/Min | 5.9 (5.2, 6.7) | 5.9 (5.1, 6.6) | 0.57 |
| Cardiac index, L/Min/M 2 | 3.0 (2.7, 3.3) | 3.0 (2.7, 3.6) | 0.24 |
| Aortic valve stenosis | 201 (68%) | 149 (59%) | 0.04 |
| Aortic valve insufficiency (severity∼) | 1.5 (1.0, 2.0) | 1.0 (0.0, 2.0) | 0.18 |
| Mitral valve stenosis | 29 (10%) | 27 (11%) | 0.71 |
| Mitral valve insufficiency (severity∼) | 2.0 (1.0, 4.0) | 2.0 (1.0, 4.0) | 0.06 |
| Aortic valve surgery: | 0.15 | ||
| None | 78 (26%) | 85 (34%) | |
| Replacement | 215 (73%) | 163 (65%) | |
| Repair/Reconstruction | 3 (1%) | 3 (1%) | |
| Mitral valve surgery: | 0.69 | ||
| None | 195 (66%) | 151 (60%) | |
| Annuloplasty only | 9 (3%) | 9 (4%) | |
| Replacement | 35 (12%) | 31 (12%) | |
| Reconstruction with annuloplasty | 52 (18%) | 55 (22%) | |
| Reconstruction w/o annuloplasty | 5 (2%) | 5 (2%) | |
| Operative Characteristics | |||
| Robotic-assisted op approach | 2 (1%) | 4 (2%) | 0.30 |
| Intra-aortic ballon pump used | 9 (3%) | 4 (2%) | 0.27 |
| Intra-operative blood products used | 153 (52%) | 137 (55%) | 0.50 |
| Post-operative blood products used | 125 (42%) | 107 (43%) | 0.93 |
| Ventilation hours | 8.0 (5.5, 13.5) | 9.5 (6.4, 14.5) | 0.045 |
| Hospital complications | |||
| Any in-hospital complication | 153 (52%) | 111 (44%) | 0.08 |
| Operative complication | 18 (6%) | 10 (4%) | 0.27 |
| Infection complication | 17 (6%) | 14 (6%) | 0.93 |
| Neurologic complication | 8 (3%) | 4 (2%) | 0.38 |
| Pulmonary complication | 16 (5%) | 15 (6%) | 0.78 |
| Renal complication | 2 (1%) | 7 (3%) | 0.05 |
| Other complication | 137 (46%) | 98 (39%) | 0.09 |
| Medications at Discharge | |||
| Aspirin | 240 (81%) | 200 (80%) | 0.68 |
| ACE inhibitors | 84 (28%) | 73 (29%) | 0.86 |
| Beta blockers | 246 (83%) | 185 (74%) | 0.007 |
| Warfarin | 165 (56%) | 139 (55%) | 0.93 |
| Lipid lowering medication | 180 (61%) | 152 (61%) | 0.95 |
| Antiarrhythmics | 113 (38%) | 79 (31%) | 0.10 |
| ADP inhibitors | 13 (4%) | 10 (4%) | 0.81 |
| Non-home discharge location | 40 (14%) | 35 (14%) | 0.88 |
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