Cardiac rehabilitation performance predicts 1‐year major adverse cardiovascular events

Abstract Background Cardiac Rehabilitation is an essential following major adverse cardiovascular events however there is no current data correlating rehab performance to long term outcomes. Hypothesis Patient exercise performance during cardiac rehabilitation reliably predicts future cardiovascular events. Methods We conducted a single‐center study of 486 consecutive patients who participated in a CR program between January 2018 and August 2021. We assessed patient performance using a novel index, the CR‐score, which integrated duration, speed of work, and workload conducted on each training device (TD). We used a binary recursive partition model to determine the optimal thresholds for cumulative CR score. We used Cox regression analysis to assess the mortality rate among patients who developed MACE (“study group”) and those who did not ("control group”). Results Among 486 eligible patients, 1‐year MACE occurred in 27 (5.5%) patients and was more common in patients with prior cerebrovascular accident or transient ischemic attack (14.8% vs. 3.5%, p < .001). Age, gender, comorbidities, heart failure, and medical treatment did not significantly affect the outcome. The median cumulative CR score of the study group was significantly lower than the control group (595 ± 185.6 vs. 3500 ± 1104.7, p < .0001). A cumulative CR‐score of ≥1132 correlated with the outcome (98.5% sensitivity, 99.6% specificity, 95% CI: 0.985−0.997, area 0.994, p < .0001). Patients older than 55 with a cumulative CR score of <1132 were at particularly high risk (OR: 7.4, 95% CI: 2.84−18.42) for 1‐year MACE (log‐rank p = .03). Conclusion Our proposed CR‐score accurately identifies patients at high risk for 1‐year MACE following the rehabilitation program. Multicenter validation is required.

Conclusion: Our proposed CR-score accurately identifies patients at high risk for 1-year MACE following the rehabilitation program. Multicenter validation is required.

K E Y W O R D S
binary cursive partition model, cardiac rehabilitation, cox regression analysis, CR-score, duration, MACE, outcome, performance score, speed of work, training device, workolad

| INTRODUCTION
The American College of Cardiology and the American Heart Association currently consider cardiac rehabilitation (CR) a class I indication for a multitude of cardiac conditions. 1 These include acute coronary syndrome, percutaneous coronary interventions (PCI), coronary bypass grafting, valvular surgery, and heart failure with reduced ejection fraction. CR requires a multidisciplinary team of providers (i.e., nurses, trainers, dieticians, physicians) and is traditionally divided into three phases. [2][3][4][5][6] Phase I refers to inpatient rehabilitation during the hospitalization while Phases II and III refer to exercise training following discharge. Only in Phase II does the patient follow the structured exercise regimen of the rehabilitation process. 7 CR has been shown to improve quality of life, reduce rates of readmission, and improves overall cardiovascular mortality. [8][9][10][11] The beneficial effects of CR are related to its physiologic effects on the body. The endurance training favorably affects hemodynamic function, vascular tone, and exercise capacity. [12][13][14] In addition, CR programs provide nutritional support and smoking cessation counseling, as well as management of comorbid conditions such as hypertension, dyslipidemia, and diabetes. [15][16][17] Despite growing evidence supporting the health benefits of CR, limited effort has been directed toward quantifying patient performance during rehabilitation and how this may affects outcomes. In this study, we sought to determine the relationship between exercise volume during CR and health outcomes using a novel scoring system.

| Study design and patients' selection
We conducted a single-center retrospective study of 516 consecutive patients who participated in a CR program at Emek Medical Center in Israel between January 2018 and August 2021. The CR program is a twice a week, 3-month government-funded program following recent acute coronary artery syndrome, PCI, chronic stable angina, congestive heart failure, coronary artery bypass surgery, valvular surgery, and cardiac transplantation. A multidisciplinary team consisting of cardiologists, nurse practitioners, physiotherapists, and nutritionists assessed physical performance and follow-up progression. Each CR session performed on four different training-devices (TD): the treadmill, elliptical, bicycle, and handcycle.
Patients were excluded from the study if they did not complete at least 80% of the program, had missing medical records or were lost to follow-up.

| Data collection
Demographic, procedural, and follow-up data entered prospectively by a dedicated team and extracted using the Clalit electronic records systems (Chameleon, Ofek).

| Ethics
The study was approved by the Emek Medical Center institutional review board, which also waived the requirement to obtain informed consent due to the study's retrospective nature.

| Definitions
We defined outcome as the incidence rate of major cardiovascular events (MACE) during 1-year following the CR program. MACE defined as the cumulative events of death, heart failure hospitalizations, coronary catheterizations, and hospitalizations due to cerebrovascular accident (CVA) or transient ischemic attack (TIA).

| Statistical analysis
Continuous variables were compared between the study group and the control group using the two-tailed student's t-test or Mann −Whitney U test and presented as mean ± standard deviation or median and interquartile range, respectively. Categorical variables were expressed as frequencies and percentages and compared using the χ 2 or Fisher exact test.
Multivariable linear logistic regression using forward conditional method was performed using the minimum Akaike Information criteria for variable selection using all CT variables with p < .05 in the univariate analysis as candidates. We constructed the CR score using the integration of statistically significant variables (work time, incline, workload, and speed) found by the logistic regression and their contributions to predicting outcome. The potential of collinearity NAAMI ET AL. | 1037 interactions among the independent variables was assessed using the variance inflation factor (VIF) and the tolerance value.
We assessed accuracy by computing receiver operating curves (ROC) and reported the ROC area (concordance statistic C) and the sensitivity and specificity at maximum accuracy, where accuracy is defined as (sensitivity + specificity)/2. In addition to the logistic models, we used a binary recursive partition (classification tree) model to determine the optimal thresholds for cumulative CR score and predictor of 1-year MACE.
Kaplan−Meyer survival analysis was performed to assess differences in mortality rate among the two groups at 1-year follow-up.
Hazard ratio (HR) was calculated using descriptive analysis in SPSS and linear regression models. Two-sided p values were considered significant if they were less than .05. All statistical analyses were performed using JMP version 15.2.0 (SAS Institute) and SPSS statistical package, version 24.0 (SPSS Inc.).

| CR score assessment
The CR-score was formulated using the probability produced

| Patients baseline characteristics
The baseline characteristics are shown in Table 1. Among the total eligible patients, the occurrence of MACE during follow-up was more common in patients with prior CVA or TIA (14.8% vs. 3.5%, p < .0001) and heart failure (22.2% vs. 8.5%, p = .03).
The CR score was correlated with the occurrence of MACE for each of the TD as well as the cumulative score (p < .0001 for all).
A lower cumulative CR-score was associated with worse

| DISCUSSION
In this study, we assessed the prognostic value of exercise performance during CR using a novel index, the CR-score.
The CR-score value was computed using measurements of endurance through a series of exercise routines including treadmill, bicycling, elliptical, and handcycles. We demonstrated that 1-year MACE, is associated with worse performance during CR.
Moreover, CR-score below a calculated threshold was found to be a powerful predictor of adverse outcomes, particularly among young patients.
CR is an outpatient program formulated to reduce long-term morbidity, hospital admissions, and cardiovascular death following acute coronary syndrome, heart failure exacerbation, and cardiac surgery. Previous reports suggested favorable outcomes of those attending CR. Furthermore, recent studies provided evidence of a continuous, linear, dose−response association between CR participation and MACEs. [18][19][20][21][22][23] Possible explanations for the strong association between attendance and outcomes may include both direct effects of endurance exercise of the cardiovascular system as well as indirect benefits of physical training under medical supervision during the rehabilitation period. The former includes increased maximal oxygen uptake (VO 2 ), improved endothelial function, and weight loss. 24,25 Conversely, adherence to early CR may be a surrogate of goaldirected medical therapy compliance, general activity levels, and adherence to lifestyle choice that promote cardiac health.
This includes physical exercise post-rehab, diet, and smoking cessation. [26][27][28][29][30][31] Limited data exist regarding the prognostic utility of CR performance. Our findings are consistent with previous data suggesting the overall cardiovascular health benefits associated with rigorous endurance training following cardiovascular events Furthermore, The CR score is a novel score and by that, was not validated on a large scale with a different data base. | 1041 a complex ventilatory gas analysis before, during, and after the CR program and shows a strong correlation with the patient's functional capacity and future adverse cardiovascular events. MET may often be misleading, as it is influenced by several factors, including age and gender. The fixed assumption that 1 MET = 3.5 ml O 2 /kg/min has been challenged in numerous studies that indicate a significant overestimation of actual resting energy expenditure in some populations, including coronary patients, the morbidly obese, and individuals taking beta-blockers. 41 Our cohort included a diverse population of patients with heart failure, coronary disease, and valvular pathologies. We designed a simple-to-use model that focuses on participants' progression during the CR program and does not rely upon periodic tests and patients' baseline capacity.
Furthermore, the proposed model does not require specific equipment and can be adapted to any age and fragility status.