Takotsubo cardiomyopathy (TC) is a syndrome mimicking an acute coronary syndrome including symptoms, electrocardiogram changes suggestive of an acute myocardial infarction (MI), and troponin release without critical coronary lesions to explain the ventricular dysfunction. Classic TC has the characteristic apical akinetic appearance on left ventriculography.
The exact pathophysiology of TC remains controversial, and data remain inconsistent with regard to the optimal long-term medical treatment for TC. Meanwhile, although it is well established that adjunct therapy, such as an exercise program, is beneficial for patients with heart failure and reduced ejection fraction and acute MI,1 the benefit of a cardiac rehabilitation (CR) program in the TC population has never been explored and the overall referral rates are unknown. This is likely due to insufficient sample size at a single institution and the notion that TC is a transient and reversible syndrome that has no long-term effect on morbidity and mortality. However, studies have shown that TC is not benign, with in-hospital mortality rates of about 9%, 1-year mortality rates of up to 15%, and 5-year long-term mortality rates of up to 24%, which exceeds that of patients with ST-segment elevation MI.2–4
The aim of the study was to determine the overall referral and completion rates to CR for patients diagnosed with TC and to determine any potential benefits of CR for this population in terms of functional status and weight change.
Retrospective data from January 2008 to March 2015 were reviewed of adult patients with a diagnosis of TC who were hospitalized at the 2 academic medical centers in Rhode Island with the only cardiac surgery and percutaneous coronary intervention (PCI) capability in the state. A total of 564 patient cases were identified using the International Statistical Classification of Diseases and Related Health Problems, 9th Revision (ICD-9) code 429.83. The study protocol and data analysis were approved by the institutional review board.
The Mayo Clinic diagnostic criteria were adopted as inclusion criteria5: (1) transient hypokinesis, akinesis, or dyskinesis in the left ventricular mid-segments with or without apical involvement; regional wall motion abnormalities that extend beyond a single epicardial vascular distribution; and frequently, but not always, a stressful trigger; (2) the absence of obstructive coronary disease or angiographic evidence of acute plaque rupture of the culprit vessel responsible for the observed regional myocardial dysfunction; (3) new electrocardiogram abnormalities (ST-segment elevation and/or T-wave inversion) or modest elevation in cardiac troponin; and (4) the absence of pheochromocytoma and myocarditis.
A total of 380 unique patients were identified as having TC who survived the index hospitalization (9 deaths were excluded). Those without a catheterization or incorrectly coded were excluded. Angiography of the patients with significant coronary artery disease (CAD) on reports was reviewed by an interventional cardiologist and only those with obstruction that was not considered to be the culprit of myocardial dysfunction, such as a significant obstruction in the right coronary artery that does not explain an apical akinesis, were included. Basic characteristic data were obtained by reviewing patient medical records. These patients were then cross-referenced with the Cardiovascular Institute Cardiac Rehabilitation Database, the largest CR center in Rhode Island affiliated with the 2 hospitals, to determine the referral rate and outcomes after completion of the program. Referral enrollment database from the CR center was reviewed for documented self-reported reasons that referred patients (n = 18) did not enroll (n = 3). For those who enrolled (n = 15), data were obtained from chart review for participation and outcomes, and if a patient dropped out prior to completion, reasons were obtained from charts. One-year rehospitalization data were obtained by reviewing patient medical records within the same 2 academic medical centers.
Unless contraindicated because of safety or refused by physicians or patients, patients received maximal effort entrance and post-completion exercise tests using standard protocols (Bruce, modified Bruce) or individualized ramp treadmill tests for assessment of functional status and exercise prescription (performed in 4 out of 15 in our study sample). The program consisted of 3 sessions/wk for 12 wk. Each session comprised 60 min of exercise and 30 min of education and/or behavioral counseling. Aerobic and resistance training was personalized to the functional and occupational goals and needs. Each exercise session usually consisted of 30 min of aerobic training based on target heart rate, metabolic equivalents (METs) achieved during the exercise test, or rating of perceived exertion, followed by 15 min of resistance training (at 50-60% of the maximum tolerated weight load), and finished with 15 min of stretching and relaxation. In addition, patients were prescribed to perform at least 30 min of aerobic exercise of moderate intensity at home on at least 5 d/wk.
Data are presented as means ± SD for continuous variables and as frequency (%) for categorical variables. Given the small sample size, we compared the baseline characteristics of patients who were referred versus those who were not and CR completers versus noncompleters using Fisher's exact test for discrete variables and Wilcoxon's rank test for continuous variables. We used paired-samples t test to compare change from baseline in exercise duration and weight for those who completed CR, given the null hypothesis of no difference.
CLINICAL FEATURES OF TC PATIENTS AND REFERRAL TO CARDIAC REHABILITATION
The baseline characteristics of those who were not referred versus referred are shown in Table 1. There were no statistical differences between those referred and not referred for age (68 ± 12 vs 67 ± 13 yr), % female (92 vs 100), and % white (92 vs 89). Presenting symptoms for both groups were most commonly chest pain (77%), followed by shortness of breath (33%). Having undergone PCI on a nonculprit vessel at the time of diagnosis was the only significant predictor for referral to CR (11% vs 1%, P = .01). Referred patients had a trend of a lower likelihood of having a history of significant CAD (0% vs 15%, P = .09).
CARDIAC REHABILITATION OUTCOMES
Baseline characteristics of those who completed CR versus those who either did not enroll or terminated the program early are shown in Table 2. Among the 10 (out of 18) patients who completed the CR, attendance was 33 ± 6 sessions (91% of prescheduled 36; range, 20-36 sessions). Systolic and diastolic blood pressures (n = 7) were 125 ± 17 and 64 ± 4 mm Hg pre-CR and 122 ± 5 and 62 ± 4 mm Hg post-CR. Weight and body mass index changes from pre-CR to post-CR (n = 9) were 2.8 ± 3.5 lb (P = .04) and 0.6 ± 0.7 kg/m2 (P = .04), respectively. Exercise duration increased (n = 7) from 24 ± 6 min pre-CR to 37 ± 4 min post-CR (P < .01). The MET difference on exercise test (n = 4) was 6.0 ± 2.3 pre-CR versus 7.1 ± 2.8 post-CR (P = .17). Early CR termination rate was 33% (5/15 patients). Self-reported reasons for not completing CR included high co-pays (n = 1), physically limiting comorbidities (n = 2), transportation difficulties (n = 1), or later deemed unnecessary by cardiology physicians (n = 1). Amongst CR completers, only 2 out of 10 patients entered the phase III maintenance program.
One-year follow up data were available for the 18 patients referred to CR. Rehospitalization rates were 0% versus 13% for cardiac-related rehospitalization (P = .47) and 22% versus 38% for non–cardiac-related rehospitalization (P = .62) in those who completed CR (n = 10) versus those who were referred but did not enroll or complete CR (n = 8).
This is the first study to examine the referral rate and outcomes to CR in the TC population. Our study showed that CR is underutilized in the TC population with a 5% referral rate, with PCI in nonculprit vessel as the only predictor of CR referral. Once referred, CR enrollment and completion rates were adequate and may help with weight reduction and improve exercise time.
The finding of PCI as the only predictor of physician referral is important since CR enrollment and completion rates were adequate once the physician referral was received. Studies have identified several barriers to CR referral, such as older age, female gender, nonwhite race, lack of insurance, longer traveling distance to CR centers, and having multiple comorbidities.6 We postulate that one reason for low referral rates may be related to provider-level barriers, since the majority of patients are women, who are known to have lower referral rates than men.6 The lack of CR outcome data in TC patients may have also contributed to the lack of physician referral. In the case of TC, the misconception of the syndrome being a benign condition with complete resolution without long-term morbidity and mortality may be contributing as the greatest barrier to physician referral, as both physicians and patients may have a misconstrued lack of perceived benefits for CR. Prior studies have shown that patients cited statements such as “my doctor does not really think I need it” as a reason not to enroll in CR.6 However, TC can contribute to significant morbidity and mortality that exceeds that of ST-segment elevation MI.2–4 Long-term recurrence rates had been reported as high as 12% by 4 yr,7 and one study showing all-cause mortality that is higher than matched general population.8 Recent studies have also raised the issue of incomplete recovery,9 with the presence of late gadolinium enhancement on cardiac MRI suggestive of myocardial fibrosis9,10 and chronic symptoms of chest pain and dyspnea in the absence of left ventricular dysfunction.11
Our results suggest that CR completers achieved improvements in exercise duration and weight reduction. However, we were underpowered to detect a significant association between 1-yr rehospitalization rates and CR in TC patients, as previously demonstrated in the literature for the CAD population in general.12
This study had several limitations, including data from 1 medical system and geographic area with consequent limited generalizability, and a small sample size of TC patients who completed CR, which make our results hypothesis generating rather than being conclusive. In addition, records of reasons of nonreferral to CR by physicians were not available for us to understand the rationale for nonreferral. It is also possible that CR referral rates were underestimated since patients could have been referred by their physicians to be enrolled in another CR program but not documented in the hospital records, although the frequency of this occurrence is likely low since the 2 academic medical centers in this study are the only ones with PCI and cardiac surgery capabilities in Rhode Island during the study period. We also have significant missing data on exercise tests pre-and post-CR, exercise duration, blood pressure, and weight, which may have introduced type 2 errors on CR outcomes due to insufficient sample size with assumption that the missing data was random. Nonetheless, the limited data seemed to support the benefits of CR in TC that mirrored standard CAD patients undergoing CR.
This analysis showed that CR may help with weight reduction and improvement in exercise duration in patients with TC. These findings provide the foundation for the much-needed physician and patient engagement efforts to increase referral rates for the TC population, which are currently very low. Future research is needed to target barriers to referral, reasons for patient dropout, as well as potential long-term outcomes after CR completion for the TC population.
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