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Comorbidity Burden and Adverse Outcomes After Transcatheter Aortic Valve Replacement

Background Transcatheter aortic valve replacement (TAVR) has become the preferred treatment for symptomatic patients with aortic stenosis and elevated procedural risk. Many deaths following TAVR are because of noncardiac causes and comorbid disease burden may be a major determinant of postprocedure outcomes. The prevalence of comorbid conditions and associations with outcomes after TAVR has not been studied. Methods and Results This was a retrospective single‐center study of patients treated with TAVR from January 2015 to October 2018. The association between 21 chronic conditions and short‐ and medium‐term outcomes was assessed. A total of 341 patients underwent TAVR and had 1‐year follow‐up. The mean age was 81.4 (SD 8.0) years with a mean Society of Thoracic Surgeons predicted risk of mortality score of 6.7% (SD 4.8). Two hundred twenty (65%) patients had ≥4 chronic conditions present at the time of TAVR. There was modest correlation between Society of Thoracic Surgeons predicted risk of mortality and comorbid disease burden (r=0.32, P<0.001). After adjusting for Society of Thoracic Surgeons predicted risk of mortality, age, and vascular access, each additional comorbid condition was associated with increased rates of 30‐day rehospitalizations (odds ratio, 1.21; 95% CI, 1.02–1.44), a composite of 30‐day rehospitalization and 30‐day mortality (odds ratio, 1.20; 95% CI, 1.02–1.42), and 1‐year mortality (odds ratio, 1.29; 95% CI, 1.05–1.59). Conclusions Comorbid disease burden is associated with worse clinical outcomes in high‐risk patients treated with TAVR. The risks associated with comorbid disease burden are not adequately captured by standard risk assessment. A systematic assessment of comorbid conditions may improve risk stratification efforts.

A ortic stenosis (AS) is increasingly common with advancing age 1 and if left untreated has a mortality rate of 50% 2 years after the onset of symptoms. 2 In recent years, transcatheter aortic valve replacement (TAVR) has revolutionized the treatment of AS for many patients with symptomatic disease. 3,4 While TAVR improves quality of life and decreases mortality, for high-risk patients mortality is ≈24% 1 year after treatment. 5 Approximately half of deaths after TAVR are noncardiac in nature 6 , an observation that highlights the importance of understanding chronic disease burden for patients considering treatment.
Patients with cardiovascular disease are commonly affected by comorbid conditions 7 that impact quality of life, overall prognosis, treatment decisions, and increase healthcare costs. 8 Chronic conditions may decrease the absolute benefit of diseasespecific interventions by presenting competing risks. For patients with cardiovascular disease, the most common comorbid conditions are hypertension, Feldman et al Comorbid Conditions and Outcomes After TAVR dyslipidemia, and diabetes mellitus. 9 Chronic conditions for older adults with advanced cardiac disease, in particular those seeking interventional treatments, have not been systematically studied. TAVR, which has seen rapid adoption over the past few years, provides an opportunity to study chronic conditions for high-risk patients with advanced cardiovascular disease.
There is no consensus on how to assess chronic disease burden, and it is likely that different conditions are relevant for distinct clinical settings. Recently, a score based on the presence or absence of 21 cardiac and noncardiac conditions was shown to be predictive of 1-year mortality for older adults. 10 The clinical relevance of these conditions for patients with advanced cardiovascular disease remains unknown. Here, using detailed chart review, our aim is to determine the association between comorbid disease burden and short-and medium-term clinical outcomes after TAVR, and to determine whether comorbid disease burden has added prognostic significance beyond standard approaches to risk stratification.

Cohort Description
This is a retrospective single-center cohort study that was performed at Tufts Medical Center (Boston, MA). The data that support the findings of this study are available from the corresponding author upon reasonable request. The study cohort included patients with symptomatic AS who underwent TAVR between January 2015 and October 2018. Severe AS was defined by standard echocardiographic criteria, 11 and all patients had symptoms at the time of treatment. All patients were deemed to be at elevated risk for conventional surgical aortic valve replacement. Patients were excluded from the study if they had a previous history of either a prior surgical or prior TAVR that was implanted before the study dates. This study was approved by the Tufts institutional review board and the informed consent requirement was waived.

Baseline Characteristics and Outcomes
The STS/ACC TVT Registry (Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry) was used to evaluate basic demographic data including the STS predicted risk of mortality (STS-PROM) score. Morbidity and mortality were assessed by investigating the 30-day rehospitalization rate, 30-day mortality (a composite of 30-day rehospitalization and 30-day mortality), and 1-year mortality from the studied patient population. The 1-year mortality outcome was determined through a combination of chart review and events identified in the Institutional STS/ACC TVT Registry report.

Comorbid Disease Burden
Comorbidity burden was assessed based on physician review of the electronic medical record. Consensus definitions of the 21 distinct conditions present in the Combined Comorbidity Score 10 were created. The clinical definitions are shown in Table S1 and are consistent with the originally presented definitions. 12,13 Presence or absence of a condition was defined based on whether or not the condition was present in the electronic medical record at any point in the year before TAVR. Two physician members of the study team (D.R.F. and M.D.R.) reviewed all records. Discrepancies and instances of diagnostic ambiguity were discussed by the study group to arrive at consensus.

CLINICAL PERSPECTIVE
What Is New?
• This retrospective cohort study assessed the significance of comorbid diseases in 358 highrisk patients treated with transcatheter aortic valve replacement. • Increased comorbid disease burden present at the time of transcatheter aortic valve replacement was associated with worse outcomes following treatment. • Risks associated with comorbid disease burden are not adequately captured by standard risk assessment and should be incorporated into decision making for high-risk patients with AS.
What Are the Clinical Implications?
• Multiple chronic conditions are common for high-risk patients treated with transcatheter aortic valve replacement, and risks associated with multiple chronic conditions should be incorporated into procedural decision making.

Statistical Analysis
The overall prevalence of comorbid conditions was assessed. The 30-day follow-up was available for 346/358 (96.6%) patients and the 1-year follow-up was available for 341/358 (95%) patients. We present a complete case analysis of patients with 1-year follow-up. Event rates are presented across tertiles of comorbid diseases present at the time of TAVR. The association between comorbid disease burden and rates of 30day rehospitalization, 30-day mortality, composite of 30-day rehospitalization and 30-day mortality, and 1year mortality was assessed using logistic regression. Multivariable logistic regression was used to evaluate the association between comorbid disease burden with clinical outcomes after adjusting for age, STS-PROM, and vascular access site. Comorbid disease burden was plotted against STS-PROM at the time of TAVR. Correlation was assessed using the Pearson correlation coefficient.

RESULTS
The cohort consisted of 358 patients treated with TAVR during this timeframe. Our analysis focuses on the 341 patients (95%) with available 1 year followup. Baseline demographic, clinical, and echocardiographic parameters are shown in Table 1. The mean patient age was 81.4 years old (SD 8.0 years) and 51.9% of the patients were female. A transfemoral approach was performed with 86.8% of these patients. The average STS-PROM score was 6.7% (SD 4.8).

Comorbid Disease Burden
The average number of comorbid conditions present in the year leading up to TAVR was 4.4 (SD 1.9). A total of 325 (95%) of patients had ≥2 chronic conditions in the year before TAVR and 220 (65%) patients had ≥4 chronic conditions. The graphical representation of these comorbid conditions among the studied population is shown in Figure 1, while the full list of comorbid conditions is shown in The association between burden of comorbid conditions and STS-PROM is shown in Figure 2. One hundred sixty-six (49%) patients had a STS-PROM score ≥4.0% and high comorbid disease burden that was defined as ≥4 comorbid conditions (Q1, concordant risk markers). Sixty-five (19%) patients had a

Association with Clinical Outcomes
As the burden of comorbid disease present at the time of TAVR increases, rates of 30-day rehospitalization, 30-day rehospitalization or death, and 1year mortality increase (Table 3). Average length of stay also increased as comorbid disease burden increased (P=0.0017). There was no association between comorbid disease burden and inpatient mortality or 30-day mortality, though rates of these events were low (4 total inpatient deaths, 10 total deaths by 30 days). The association between comorbid disease burden and outcomes is shown in

DISCUSSION
These data demonstrate that comorbid conditions are common for patients with elevated procedural risk and symptomatic AS who are treated with TAVR and that chronic disease burden present at the time of TAVR is associated with worse outcomes and increased resource utilization after the procedure. Two thirds of high-risk patients have ≥4 chronic conditions present at the time of treatment and of those, 25% have STS-PROM <4.0%. Taken together, these observations suggest that for patients considered for treatment with TAVR, there are clinically relevant short-and medium-term risks associated with comorbid illness that are not adequately captured by standard risk assessment.

Feldman et al Comorbid Conditions and Outcomes After TAVR
The STS-PROM was used for inclusion in early TAVR clinical trials and is a prediction tool that continues to play a role in preprocedure risk stratification. This was the primary motivation for including this variable in our analysis. There are known limitations to these predictive models applied to TAVR. These regression models were originally created to predict 30-day outcomes for patients undergoing surgical aortic valve replacement with or without coronary artery bypass grafting 14 and as a result, tend to perform poorly when used to predict in-hospital and 30-day mortality after TAVR. 15 This poor performance may be because important risk predictors are not included in these models-in the effort to achieve a parsimonious (and usable) model. Newer models 16,17 exclude many of the chronic conditions studied here and thus are unlikely to fully capture the risks associated with comorbid disease burden present at the time of treatment. A more comprehensive approach to risk stratification should include conceptions of procedural risk and also consideration of the competing risks that may be present from comorbid conditions.
It is increasingly recognized that information about comorbid diseases should be considered when making treatment decisions for older adults with advanced cardiac disease. This issue is especially important in the context of treatment decisions for patients with structural heart disease since older adults with increased procedural risk are regularly treated with these advanced procedures. Comorbid disease burden has historically been difficult to define and quantify 18 and as a result there is no consensus method of assessment. The Combined Comorbidity Score 10 was recently proposed as a way to combine existing models to predict 1-year mortality. In a claims-based environment, this score demonstrated better performance (discrimination and calibration) than preexisting models for predicting long-term mortality for older adults. Given the strengths of this score (it captures both cardiac and noncardiac conditions) and the potential applicability to large databases, we studied electronic medical record-based definitions of the chronic conditions contained in this index. We demonstrate that worse outcomes are seen as the number of chronic conditions present at the time of TAVR increases. The associations seen with these conditions stand to be replicated in larger (multicenter) databases since the comorbidity index used here is compatible with claims-based data resources.
Many of the comorbid conditions studied here, when evaluated in isolation, have been shown to be associated with worse outcomes after TAVR. For example, patients with end-stage renal disease 19 and chronic pulmonary disease 20 are documented to have worse outcomes after TAVR. Unfortunately, analyses of lone chronic conditions do not adequately capture the complexity of older adults encountered in real-world practice who often have more than 1 condition and who would have been excluded from pivotal clinical trials (eg, an 88-year-old who has symptomatic AS, peptic ulcer disease, thrombocytopenia, and endstage renal disease and who is referred for treatment). Multiple conditions (and multiple treatments) that may interact with each other can increase the risk of adverse outcomes over time and present competing risks that often persist after AS is treated. Ultimately, understanding the comorbid disease burden and specific interactions between conditions and treatments and planned procedures as well as patient-centered goals can enhance shared decision-making for these highrisk older adults.

Limitations
There are several limitations to this analysis. Because this is a single-center retrospective study, the relevance to other electronic medical records and other health systems needs to be further explored. The limited sample size and rare outcomes do not allow us to create a usable predictive model and that is HIV/AIDS 0 (0.0) Full list of comorbid conditions for our studied population. Data provided as n (%). The most common conditions were hypertension (284, 83.3%), cardiac arrhythmias (231, 67.7%), and congestive heart failure (223, 65.4%). The most common noncardiac comorbid conditions seen in this patient population were anemias (132, 38.7%), chronic pulmonary disease (112, 32.8%), electrolyte disorders (73, 21.4%), and coagulopathy (71, 20.8%). not our intent, because there are numerous predictive models available for TAVR. While we assessed comorbid diseases based on detailed chart review, the reproducibility of these results should be explored using claims data so that these observations can be assessed in larger data sets. The comorbidity index that was used here was originally derived using claims data. Additionally, the outcomes that were evaluated here were hard clinical outcomes that are relatively easily measured (rehospitalizations and Figure 2. STS-PROM vs comorbidity count: a graphic representation of STS-PROM plotted against comorbid disease burden. Q1 identifies a STS-PROM score ≥4.0% and high comorbidity burden (≥4 comorbid conditions), which represents 166 patients (49%) from the studied population. Q2 represents a STS-PROM score ≥4.0% and low comorbidity burden (<4 comorbid conditions), which represents 65 patients (19%) from the studied population. Q3 represents a STS-PROM score <4.0% and low comorbidity burden (<4 comorbid conditions), which represents 56 patients (16%) from the studied population. Q4 highlights a STS-PROM score <4.0% and high comorbidity burden (>4 comorbid conditions), which represents 54 patients (16%) from the studied population. STS-PROM indicates Society of Thoracic Surgeons predicted risk of mortality.