Association Between Pulmonary Hypertension and Its Effect on 30-Day Mortality, Readmission, and Cost After Transcatheter Aortic Valve Replacement: A Multicenter Study

Background Pulmonary hypertension (PH) is commonly seen in patients with severe aortic stenosis. Transcatheter aortic valve replacement (TAVR) has been shown to improve PH, however, its impact on clinical outcomes and cost remains unclear. Methods We did a multicenter, retrospective analysis of patients undergoing TAVR in our system between December 2012 to November 2020. The initial sample size was 1356. We excluded patients with prior history of heart failure, with a left ventricular ejection fraction of 40% or less, and patients who had active symptoms of heart failure within two weeks of the procedure. Patients were divided into four groups based on their pulmonary pressures, using right ventricular systolic pressure (RVSP) as a surrogate for PH. Groups included patients with normal pulmonary pressures (<35mmHg), mild (35-45mmHg) moderate (46-60mmHg), and severe PH (>60mmHg). Primary outcomes included 30-day mortality and readmission. Secondary outcomes included length of ICU stay and cost of admission. We used Chi-square and T-tests for demographic analysis of categorical continuous variables respectively. Adjusted regression was used for the reliability of correlation between variables. Multivariate analysis was used for final outcomes. Results Final sample size was 474. Average age was 78.9 years (SD: 8.2, 53% Male). Thirty-one percent (n=150) had normal pulmonary pressures, 33% (n=156) had mild PH, 25% (n=122) had moderate and 10% (n=46) had severe PH. Patients with history of hypertension (p-value<0.001), diabetes (p-value<0.001), chronic lung disease (p-value=0.006) and those on supplemental oxygen (p-value=0.046), had significantly higher proportion of patients with moderate and severe PH. We found significantly higher odds of 30-day mortality in patients with severe PH (OR: 6.77, CI: 1.09-41.98: p-value 0.04) compared with normal or mild PH. There was no significant difference in 30-day readmission (p-value=0.859) between the four groups. Cost did not change with severity of PH (Avg: $261,075: p-value=0.810). Patients with severe PH spent a significantly higher number of hours in ICU, compared with the other three groups (Mean: 18.2, p=value <0.001). Conclusions Severe pulmonary hypertension significantly increased the odds of 30-day mortality and ICU stay in TAVR patients. We did not see any significant difference in 30-day readmission and cost of admission, based on PH severity.


Introduction
It is estimated that approximately 1% of the global population is affected by pulmonary hypertension (PH) [1]. PH is commonly associated with aortic stenosis, and PH in patients with severe aortic stenosis is correlated with increased mortality rates [2]. Prior studies have also suggested greater costs and readmission rates for patients with PH [3,4]. Thus, it is important to determine how medical interventions can improve outcomes for patients with PH while simultaneously reducing costs. Patients with preexisting pulmonary hypertension are considered high risk for undergoing aortic valve replacement. Patients with aortic stenosis who undergo transcatheter aortic valve replacement (TAVR) demonstrate reduced PH levels [5]. However, the effects of preexisting PH on clinical outcomes and cost in patients undergoing TAVR remain unclear.
Prior studies have examined clinical outcomes among patients with PH who undergo TAVR. These studies stratified patients according to the severity of PH and demonstrated higher mortality rates with greater pulmonary arterial pressures [5,6]. However, neither of these studies examined how the severity of PH affects morbidity, short-term mortality and total cost of admission.
This study seeks to clarify how PH severity affects 30-day mortality rates, 30-day readmission rates, the total time in the intensive care unit (ICU), and cost of admission in patients undergoing TAVR.

Materials And Methods
A retrospective study of 1356 patients who underwent TAVR at Saint Francis Medical Center between December 2012 and November 2020 was conducted. IRB approval was granted by the University of Illinois at Chicago IRB Department.
The initial sample size was 1356. Patients with a prior history of heart failure, left ventricular ejection of 40% or less, or active heart failure symptoms within two weeks of the procedure were excluded from the study. After excluding these patients, a final sample size of 474 was obtained.
The clinical variables studied included age, gender, race, smoking habits, history of hypertension, history of diabetes, current use of dialysis, history of chronic lung disease, current supplemental oxygen use, current atrial fibrillation or flutter, history of peripheral artery disease, history of prior aortic valve replacement, current use of a pacemaker, and history of coronary artery bypass graft surgery (CABG).

Outcome comparison
Thirty-day mortality and readmission were primary variables, while length of ICU admission and cost were secondary variables.

Statistical analysis
Clinical data and baseline characteristics across the four groups were compared. Percentages and proportions were used to represent categorical variables, while mean ± standard deviation (SD) was used to represent continuous variables. Chi-square tests were used to analyze categorical variables, and t-tests were used to analyze continuous variables. Adjusted regression was applied to ensure the reliability of correlations between clinical variables. Multivariate analysis was performed to determine 30-day mortality, 30-day readmission, mean number of ICU hours, and cost. All calculations were performed using Stata software (StataCorp., College Station, TX, USA).   As seen in Figure 1, patients with severe pulmonary hypertension had a higher 30-day mortality rate when compared to patients with normal and mild pulmonary pressure (OR: 6.77, CI: 1.09-41.98: p-value=0.04). Patients with moderate pulmonary pressure did not demonstrate statistically significant increases in 30-day mortality (OR: 1.07, CI: 0.15-7.53, p-value=0.943).

Moderate Pulmonary Hypertension (PH)
We did not find any significant differences in 30-day readmission between the four groups ( Figure 2). Patients with severe PH had lower odds of being readmitted to hospital in 30 days compared with patients with normal pulmonary pressures (OR: 0.4, CI: 0.1-1.62, p-value=0.202).

Hypertension (PH)
Univariate regression model also did not find any significant differences in 30-day readmission between the four groups ( Figure 3). Patients with severe PH had lower odds of being readmitted to hospital in 30 days compared with patients with normal pulmonary pressures (OR: 0.63, CI: 0.17-2.27, p-value=0.478).

FIGURE 3: Odds Ratio for Univariate Regression of 30-Day Readmission in Patients With Severe, Moderate, and Mild Pulmonary Hypertension (PH)
There was no significant difference in the time spent in the ICU amongst the four groups ( Figure 4). On average, patients with severe PH spent slightly more hours in the ICU than the other groups (mean: 16.2 vs 15.5 hours: p-value=0.941).   According to Figure 5, there was no significant difference in cost amongst the four groups (p-value=0.810). On average, patients with severe PH had slightly lower costs than the other groups (mean: $258,138 vs 261,075: p-value=0.738).

FIGURE 5: Pulmonary Hypertension Severity vs Cost
There was no difference in the mean cost between patients with normal, mildly elevated, moderately elevated, or severely elevated pulmonary pressure (p=0.810) (  There was no significant difference in the mean cost between patients with normal, mildly elevated, moderately elevated, or severely elevated pulmonary pressure (p=0.810) (

Discussion
Transcatheter aortic valve replacement has been the recommended therapy for moderate to severe symptomatic aortic stenosis in patients with moderate or high-surgical risk. Several studies were performed to outline the effects of different comorbidities on procedural outcomes. Pulmonary hypertension is commonly present in patients with aortic stenosis with prevalence recorded up to 75% in previous studies [5,7,8]. Pulmonary pressures were shown to improve post aortic stenosis intervention; however, it is noted that TAVR outcomes are impacted by the presence of pulmonary hypertension [6,9,10].
Previous studies demonstrated increased one-year mortality rates in patients with elevated pulmonary pressures post aortic valve replacements [11]. A study by Lindman et al. surprisingly showed increased hazard of death in females with PH, but no significant mortality changes were found in similar male patients [6]. In this study there was no association between hemodynamic factors and one-year mortality risk; other clinical factors however, such as oxygen-dependent lung disease, difficulty performing six-minute walk, or poor renal function independently increased that risk [6].
Our study categorized the severity of disease into normal pulmonary pressure, mildly, moderately, and severely elevated pressures for further risk stratification, then investigated the short-term outcomes for each group. Multivariable analysis was performed and did not demonstrate significant difference in overall cost of admission between all four groups. There was no association between the severity of pressure elevation and the odds of 30-day readmission rates, with P-values of 0.  [12]. Here in this study, further risk stratification based on PH severity showed significantly worse outcomes only in the severe PH group.
Although data showed significant reduction in PASP post TAVR in most patients with pulmonary hypertension and aortic stenosis, the findings of this study established the clinical impact of severely elevated pulmonary pressures on outcomes [5]. When evaluating patients for aortic valve replacements in the setting of significant PH, there may be benefits of optimizing their hemodynamics prior to undergoing the procedure, to minimize the risks of complications [13]. This, however, should not prevent or even delay the intervention for this group, given the substantial benefits including improving the functional status regardless of PH severity [11,14,15].

Limitations
The study has an inherent limitation of being retrospective, which limits the ability to create a causal relationship between the variable (pulmonary hypertension) and the outcomes. We had to exclude a lot of patients because of lack of complete data, which dropped the number of patients included in the study. We excluded the patients with systolic heart failure, however we cannot exclude patients with group 2 pulmonary hypertension secondary to diastolic heart failure, Although the incidence of diastolic heart failure leading to pulmonary hypertension is low, this can still lead to a potential sampling error.

Conclusions
Severe pulmonary hypertension significantly increased the odds of 30-day mortality and ICU stay in TAVR patients. We did not see any significant difference in 30-day readmission and cost of admission based on PH severity.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. University of Illinois at Chicago Institutional Review Board (IRB) Department issued approval 1197310. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an