Abstract
Background and Aims:
Single-center studies in patients undergoing TIPS suggest that elevated right atrial pressure (RAP) may influence survival. We assessed the impact of pre-TIPS RAP on outcomes using the Advancing Liver Therapeutic Approaches (ALTA) database.
Approach and Results:
Total 883 patients in ALTA multicenter TIPS database from 2010 to 2015 from 9 centers with measured pre-TIPS RAP were included. Primary outcome was mortality. Secondary outcomes were 48-hour post-TIPS complications, post-TIPS portal hypertension complications, and post-TIPS inpatient admission for heart failure. Adjusted Cox Proportional hazards and competing risk model with liver transplant as a competing risk were used to assess RAP association with mortality. Restricted cubic splines were used to model nonlinear relationship. Logistic regression was used to assess RAP association with secondary outcomes. Pre-TIPS RAP was independently associated with overall mortality (subdistribution HR: 1.04 per mm Hg, 95% CI, 1.01, 1.08, p = 0.009) and composite 48-hour complications. RAP was a predictor of TIPS dysfunction with increased odds of post-90-day paracentesis in outpatient TIPS, hospital admissions for renal dysfunction, and heart failure. Pre-TIPS RAP was positively associated with model for end-stage liver disease, body mass index, Native American and Black race, and lower platelets.
Conclusions:
Pre-TIPS RAP is an independent risk factor for overall mortality after TIPS insertion. Higher pre-TIPS RAP increased the odds of early complications and overall portal hypertensive complications as potential mechanisms for the mortality impact.
INRTODUCTION
TIPS is a procedure that mitigates portal hypertension by enhancing blood flow from the portal circulation into the systemic venous circulation.[1,2] This shunting of blood causes an increase in the cardiac preload in an already existing hyperdynamic circulatory state of cirrhosis.[3,4] Hence, overt congestive heart failure (CHF) and severe pulmonary hypertension, where right atrial function is impaired,[5,6] are considered absolute contraindications to TIPS because of worsening cardiac hemodynamics and failure to reduce portal pressures (PPs). However, whether there is a broader association between right atrial pressure (RAP) measured before TIPS and cardiac function and PP lowering after TIPS has not been widely studied. Prior single-center studies found that elevated RAP immediately after insertion of the TIPS shunt was associated with increased mortality, especially in the subgroup of patients who underwent urgent TIPS for the variceal bleed.[1,7] However, large multicenter studies in the era of covered stents have not been performed. Therefore, we investigated the relationship between the RAP measured before insertion of a TIPS shunt (the pre-TIPS RAP) on the efficacy of TIPS, portal hypertension-related complications, and mortality after TIPS in a large multicenter study.
MATERIALS AND METHODS
This is a multicenter retrospective cohort study of all adult patients with cirrhosis who underwent a TIPS placement between January 2010 and December 2015 across 9 US medical centers participating in the Advancing Liver Therapeutic Approaches (ALTA) group.
In the primary ALTA database, cirrhosis patients who underwent TIPS procedures were identified based on the appropriate international classification of disease codes and current procedural terminology codes, and patients who underwent TIPS for portal hypertension not related to cirrhosis were excluded. Our analysis included patients who underwent a TIPS procedure with a covered stent and had a documented RAP measured before TIPS. Because of the increased association between TIPS dysfunction and the recurrence of portal hypertension-related complications with uncovered TIPS stents,[8] patients using uncovered TIPS stents were excluded.
Patients were followed from the day of TIPS insertion until the last study follow-up (December 31, 2016) or death or liver transplantation. The primary outcome was mortality. We evaluated all-cause mortality, with a competing risk of LT and short-term 90-day mortality. The secondary outcomes were (1) early post-TIPS complications, (2) recurrence of portal hypertension-related events, and (3) CHF-related inpatient hospitalization after TIPS. Early post-TIPS complications were defined as a composite of cardiac events (including arrhythmia, cardiac arrest, CHF, and myocardial infarction), sepsis, bleeding, renal failure, and death occurring within 48 hours of TIPS procedure. Recurrence of portal hypertension-related events included (1) therapeutic paracentesis after 90 days of TIPS, (2) variceal bleed after TIPS confirmed on endoscopy, and (3) renal dysfunction and electrolyte abnormalities related admission after TIPS.
The following data were abstracted from medical records using electronic methods and manual chart review: Patient demographics, including age, sex, race, ethnicity, etiology of liver cirrhosis, and presence of complications from portal hypertension such as ascites, HE, and esophageal varices. Pre-TIPS CHF diagnosis was verified by systolic and diastolic dysfunction features of ejection fraction <50% or grade 2 diastolic dysfunction seen on pre-TIPS echocardiogram. In addition, details about the TIPS procedure, including indication and hospitalization status, were collected. The primary indication for TIPS was categorized into 3 groups: ascites and hepatic hydrothorax, esophageal varices, PVT, and other indications. Emergent variceal bleeding was defined as cases with TIPS performed within 4 days of pre-TIPS endoscopy showing suspicion or confirmation of variceal bleeding. The inpatient status for TIPS was defined as those hospitalized > 48 hours before the TIPS date or if TIPS was performed emergently after admission but <48 hours. Elective TIPS was defined as TIPS scheduled as an outpatient or a planned admission for observation on the same day as TIPS. All the pertinent model for end-stage liver disease (MELD) lab values collected within 2–28 days before TIPS were used.
Institution-specific protocols were followed to perform the TIPS procedure, and the interventional radiologists performed the procedure. Hemodynamic measurements were collected, including pre-TIPS RAP, pre-TIPS IVC pressure, pre-TIPS–free hepatic venous pressure, pre-TIPS PP, post-TIPS RAP, and post-TIPS PP. Study data were collected and managed at the organizing center, Northwestern University. Institutional board approval from all the 9 participating centers was obtained for this study. Informed consent requirement was waived by the Instituitional review board.
Statistical analysis
The data were analyzed to estimate the association between the pre-TIPS RAP and mortality (primary outcome), the composite of early 48-hour complications, and the recurrence of portal hypertension-related complications (secondary outcomes). Data were also analyzed to study the associations between patient factors associated with RAP. All data were described using descriptive statistics, including median, interquartile range (IQR), and proportions.
Cox proportional hazards regression survival model was used to study the associations between the predictor variables and all-cause mortality. Since 20% of our study population underwent LT, which could have affected the cox regression model, competing risk analysis using the Fine-Gray methodology was also performed, with LT as a competing event. The starting time for the survival analyses was the day of TIPS insertion. Patients were censored at death, liver transplantation, or study end date. Those lost to follow-up were censored on the last day known to be alive. Age at TIPS, sex, race, body mass index (BMI), etiology of liver disease, indications for TIPS, pre-TIPS RAP, and pre-TIPS PP, MELD-Na, and hospitalization status at the time of TIPS were among the covariates evaluated based on prior literature on factors that influence post-TIPS outcomes. The results were expressed as HR and subdistribution HR, respectively. We used the cubic splines method to model the relationship between continuous variables and the outcome (death) that did not follow a simple linear relationship. The nonlinear relationship was identified by plotting the locally weighted scatterplot smoothing curves of the continuous variable versus the mortality. Univariable, followed by multivariable analysis, was performed, and the backward stepwise selection method was used for variable selection, with the criteria for retaining the variables in the model being a p-value of <0.2. Statistical significance was defined as an alpha of 0.05, with 2-sided alternative hypotheses. Multivariable logistic regression was used to study the effect of patient factors and RAP on 90-day mortality and all the secondary outcomes. Hosmer-Lemeshow test evaluated the goodness of fit. Multiple linear regression method was used to identify patient factors that predicted the level of pre-TIPS RAP. Correlations between the covariates were checked to be below 1.05 to indicate no collinearity. Data were analyzed using STATA 16, College Station, TX.
RESULTS
The ALTA database included 1260 patients, of which 883 with a covered TIPS stent and a documented pre-TIPS RAP met the inclusion criteria. Demographics and patient characteristics of the cohort are summarized in Table 1. The median age of the cohort was 58 years, of whom 57.8% were males. Hepatitis C and alcohol-associated cirrhosis were the most common causes of liver disease (31% each). The median MELD-Na of the cohort at the time of TIPS was 17.5 (IQR: 13.5, 21.8). TIPS was indicated for ascites and hepatic hydrothorax in 493 (55.8%) and esophageal varices in 297 (33.6%). Four hundred fifteen (47%) had an inpatient hospitalization status at the time of TIPS.
TABLE 1.
Patient demographics and characteristics of the cohort
| Characteristic | TIPS (n = 883) |
|---|---|
| Age, median (IQR), y | 58 (52–63) |
|
| |
| Male, n (%) | 511 (57.8) |
|
| |
| BMI, median (IQR) | 27.6 (23.7–32.4) |
|
| |
| Race, n (%) | |
| White | 665 (75.3) |
| American Indian or Native American | 7 (0.8) |
| Black/African American | 34 (3.8) |
| Asian | 13 (1.5) |
| Others | 164 (18.5) |
|
| |
| Liver disease etiology, n (%) | |
| Hepatitis C | 278 (31.5) |
| Alcoholic cirrhosis | 301 (31.1) |
| NASH | 174 (19.7) |
| Others | 130 (14.7) |
|
| |
| Complications of liver disease, n (%) | |
| Ascites | 624 (73.4) |
| SBP | 79 (9.32) |
| HE | 369 (43.3) |
| HCC | 50 (5.9) |
| Variceal bleed | 289 (33.9) |
| PVT | 101 (11.8) |
|
| |
| Comorbidities before TIPS, n (%) | |
| Congestive heart failure | 48 (5.4) |
| Diabetes mellitus | 216 (24.4) |
| Renal disease | 213 (24.1) |
|
| |
| Laboratory values at the time of TIPS, median (IQR) | |
| Serum sodium | 136 (132–138) |
| Serum INR | 1.4 (1.2–1.6) |
| Serum creatinine | 1 (0.8–1.3) |
| Platelets | 93 (62–135) |
| Serum albumin | 2.9 (2.5–3.3) |
| Serum total bilirubin | 1.5 (1–2.5) |
|
| |
| MELD-Na score at the time of TIPS, median (IQR) | 17.5 (13.5–21.8) |
|
| |
| Indications for TIPS, n (%) | |
| Refractory ascites/hepatic hydrothorax | 493 (55.8) |
| Esophageal variceal bleed | 297 (33.6) |
| Others | 93 (10.5) |
|
| |
| Inpatient status at the time of TIPS | 415 (47) |
|
| |
| Hemodynamic measures, median (IQR), mm Hg | |
| Pre-TIPS RAP | 9 (6–13) |
| Post-TIPS RAP | 15 (12–19) |
| Pre-TIPS PPG | 26 (22–31) |
| Delta RAP | 5 (3–8) |
Abbreviations: BMI, body mass index; IQR, interquartile range; MELD, model for end-stage liver disease; PPG, portal pressure gradient; RAP, right atrial pressure; SBP, spontaneous bacterial peritonitis.
Survival analysis
The median follow-up period for the study was 17.7 months (IQR: 3.7–35.6). At the end of the study period, 176 (19.9%) patients underwent LT; of the remaining patients without LT, there were 281 (31.8%) deaths. The median survival time was 44.8 months (IQR: 12.9–75.9). In the cox proportional hazard regression survival analyses, pre-TIPS RAP was a significant predictor of mortality in univariable and multivariate analysis (per 1 mm Hg, adjusted HR 1.04, 95% CI, 1.02, 1.07; p = 0.002). In addition, age, MELD-Na, and inpatient hospitalization status at the time of TIPS were other independent predictors of post-TIPS mortality (Table 2). In the competing risk analysis with LT as a competing event, pre-TIPS RAP remained an independent predictor of mortality in univariate and multivariate analysis (per 1 mm Hg, adjusted subdistribution HR: 1.04, 95% CI, 1.01, 1.08; p = 0.009) (Table 3).
TABLE 2.
Univariable and multivariable cox proportional regression model evaluating overall pretransplant mortality after TIPS insertion
| Characteristic | Univariable HR (95% CI) | p | Multivariable HR (95% CI) | p |
|---|---|---|---|---|
| Age at the time of TIPS (per 1 y) | 1.04 (1.03, 1.05) | < 0.001 | 1.06 (1.04, 1.07) | <0.001 |
| Male | 1.07 (0.86, 1.85) | 0.536 | ||
| Native American (compared with White) | 0.49 (0.12, 1.97) | 0.317 | ||
| Asian (compared with White) | 1.82 (0.81, 4.11) | 0.146 | ||
| Black (compared with White) | 1.09 (0.59, 1.99) | 0.778 | ||
| Other race (compared with White) | 1.15 (0.85, 1.58) | 0.359 | ||
| BMI | 0.99 (0.977, 1.01) | 0.516 | ||
| Hepatitis C (compared with NASH) | 1.12 (0.82, 1.54) | 0.467 | ||
| Alcohol-associated liver disease (compared with NASH) | 0.88 (0.63, 1.21) | 0.436 | ||
| Other liver disease etiologies (compared with NASH) | 1.02 (0.69, 1.5) | 0.921 | ||
| EV as TIPS indication (compared with refractory ascites/HH) | 0.76 (0.59, 0.97) | 0.034 | — | |
| Others as TIPS indication (compared with refractory ascites/HH) | 0.78 (0.52, 1.16) | 0.226 | ||
| MELD-Na at the time of TIPS | 1.12 (1.09, 1.14) | < 0.001 | 1.11 (1.09, 1.42) | < 0.001 |
| Pre-TIPS RAP (per 1 mm Hg) | 1.05 (1.02, 1.07) | < 0.001 | 1.04 (1.02, 1.07) | 0.002 |
| Pre-TIPS portal pressure (per 1 mm Hg) | 1.00 (0.98, 1.01) | 0.811 | ||
| Inpatient status at the time of TIPS (compared with outpatient) | 1.70 (1.35, 2.13) | < 0.001 | 1.61 (1.25, 2.09) | < 0.001 |
| Congestive heart failure | 1.34 (0.81, 2.23) | 0.245 |
Note: (−) Dash indicates that the variable was included in the model but did not remain statistically significant.
Abbreviations: BMI, body mass index; EV, esophageal varices; MELD, model for end-stage liver disease; RAP, right atrial pressure.
TABLE 3.
Univariable and multivariable competing risk model evaluating overall pretransplant mortality after TIPS insertion with liver transplant as a competing event.
| Characteristic | Univariable sHR (95% CI) | p | Multivariable sHR (95% CI) | p |
|---|---|---|---|---|
| Age at the time of TIPS (per 1 y) | 1.03 (1.02, 1.05) | < 0.001 | 1.05 (1.03, 1.06) | < 0.001 |
| Male | 1.01 (0.80, 1.28) | 0.89 | ||
| Native American (compared with White) | 0.64 (0.18, 2.35) | 0.51 | ||
| Asian (compared with White) | 1.23 (0.49, 3.12) | 0.65 | ||
| Black (compared with White) | 0.98 (0.54, 1.75) | 0.95 | ||
| Other race (compared with White) | 0.86 (0.61, 1.31) | 0.39 | ||
| BMI | 0.99 (0.97, 1.01) | 0.49 | ||
| Hepatitis C (compared with NASH) | 1.00 (0.73, 1.38) | 0.98 | ||
| Alcohol-associated liver disease (compared with NASH) | 0.88 (0.63, 1.23) | 0.46 | ||
| Other liver disease etiologies (compared with NASH) | 0.85 (0.57, 1.26) | 0.43 | ||
| EV as TIPS Indication (compared with refractory ascites/HH) | 0.83 (0.63, 1.07) | 0.17 | — | |
| Others as TIPS indication (compared with refractory ascites/HH) | 0.69 (0.46, 1.04) | 0.08 | 0.51 (0.31, 0.85) | 0.01 |
| MELD-Na at the time of TIPS | 1.05 (1.03, 1.07) | < 0.001 | 1.04 (1.02, 1.07) | < 0.001 |
| Pre-TIPS RAP (per 1 mm Hg) | 1.04 (1.01, 1.06) | 0.01 | 1.04 (1.01, 1.08) | 0.009 |
| Pre-TIPS portal pressure (per 1 mm Hg) | 1.00 (0.98, 1.01) | 0.76 | — | |
| Inpatient status at the time of TIPS (compared with outpatient) | 1.82 (1.45, 2.31) | < 0.001 | 1.84 (1.41, 2.41) | < 0.001 |
| Congestive heart failure | 1.10 (0.65, 1.86) | 0.72 |
Note: (−) Dash indicates that the variable was included in the model but did not remain statistically significant.
Abbreviations: BMI, body mass index; EV, esophageal varices; MELD, model for end-stage liver disease; RAP, right atrial pressure; sHR, Subdistribution HR.
Pre-TIPS RAP was associated with an increased odds of 90-day mortality without transplantation in multivariable logistic regression analysis (per 1 mm Hg OR: 1.06; 95% CI, 1.01, 1.12; p < 0.01). Pre-TIPS RAP had a nonlinear relationship with mortality. Hence, we used restricted cubic splines to model their association with mortality. We fitted a cubic spline logistic regression model for the outcome of post-TIPS 90-day mortality without LT with the continuous pre-TIPS RAP variable to determine the cubic spline categories (Supplemental Figure, http://links.lww.com/HEP/B793), and the model with 4 knots had a good fit (knots at Pre-TIPS RAP = 2, 8, 11, and 18.8 mm Hg).
Pre-TIPS RAP, with spline transformed categories, was independently associated with mortality in the competing risk analysis. To enhance the interpretation of the coefficients and subdistribution HR of the cubic spline pre-TIPS RAP categories of the spline transformed model, a graph depicting the relationship between the pre-TIPS RAP and the subhazards of post-TIPS mortality relative to RAP of 1 mm Hg is shown in Figure 1. In addition to the pre-TIPS RAP, age, spline transformed MELD-Na, and inpatient hospitalization status at the time of TIPS were other independent predictors of mortality post-TIPS in both models.
FIGURE 1.
Competing risk-adjusted relationship between pre-TIPS RAP and the relative subhazard of post-TIPS mortality.
We performed subgroup survival analyses of patients with TIPS performed as an outpatient procedure without emergent variceal bleeding as a TIPS indication. Pre-TIPS RAP remained an independent predictor of mortality, with a stronger association (subdistribution HR: 1.07 per mm Hg, 95% CI, 1.02, 1.11, p = 0.005, n = 419). The results remained similar with the exclusion of patients with CHF in the above group (subdistribution HR: 1.07 per mm Hg, 95% CI, 1.01, 1.11, p = 0.007, n = 394). Pre-TIPS RAP did not predict mortality in the 85 (9.6%) patients who had TIPS performed for an emergent variceal bleed, in whom only the MELD-Na score remained a significant predictor for mortality.
In addition, to assess the association between outcomes and center TIPS volume, we categorized the frequency of TIPS performed by each center into 3 groups low (<5%), intermediate (5%–12%), and high (13%–35%), and performed a separate analysis with the center volume as a variable. The center volume was not significantly associated with mortality or post-TIPS complications, whereas pre-TIPS RAP remained a significant predictor of mortality in the multivariable analysis after adjusting for center volume.
Secondary outcomes and association between pre-TIPS RAP and TIPS dysfunction
Pre-TIPS RAP was an independent predictor of the composite of early 48-hour complications (per 1 mm Hg, adjusted OR, 1.10 95% CI, 1.05, 1.16, p < 0.001). Age, MELD-Na, BMI, and inpatient status at the time of TIPS were other independent predictors. In addition, pre-TIPS RAP was associated with several complications related to TIPS dysfunction (Table 4). In our cohort, 86 (9.7%) patients underwent paracentesis for ascites after 90 days of TIPS insertion, and pre-TIPS RAP was an independent predictor of needing paracentesis after 90 days of TIPS performed in the outpatient setting. After adjusting for covariates, including pre-TIPS serum creatinine, pre-TIPS RAP was likewise an independent predictor of post-TIPS hospital admission for renal dysfunction and electrolyte abnormalities [n = 84 (9.5%)]. In contrast, pre-TIPS RAP was not a predictor for post-TIPS variceal bleed (n = 16, 1.8%). Finally, after adjusting for pre-TIPS systolic and diastolic dysfunction and other covariates, pre-TIPS RAP was associated with increased odds of CHF admissions after TIPS.
TABLE 4.
Univariable and multivariable regression models assessing the association between pre-TIPS RAP and secondary outcomes
| Secondary outcomes | Univariable model |
Adjusted model |
||
|---|---|---|---|---|
| n | OR (95% CI) for Pre-TIPS RAP | n | OR (95% CI) for Pre-TIPS RAP | |
| Recurrence of portal hypertension complications post-TIPS | ||||
|
| ||||
| Ascites needing paracentesis after 90 d in outpatient TIPS | 468 | 1.1 (1.04, 1.17) | 410 | 1.07 (1.01, 1.15) |
|
| ||||
| Variceal bleed | 883 | 1.04 (0.97, 1.12) | 742 | 1 (0.92, 1.14) |
|
| ||||
| Renal dysfunction needing hospital admissions | 883 | 1.07 (1.03, 1.12) | 797 | 1.06 (1.01, 1.12) |
|
| ||||
| Early 48-h post-TIPS complications | 883 | 1.09 (1.05, 1.15) | 782 | 1.10 (1.05, 1.16) |
|
| ||||
| CHF needing hospital admissions post-TIPS | 883 | 1.06 (0.98, 1.14) | 661 | 1.15 (1.04, 1.28) |
Note: Models adjusted for age at TIPS, sex, race, BMI, etiology of liver disease, indications for TIPS, hospitalization status during TIPS, systolic or diastolic dysfunction on echocardiogram, MELD-Na at the time of TIPS, pre-TIPS PP.
Abbreviations: BMI, body mass index; CHF, congestive heart failure; MELD, model for end-stage liver disease; RAP, right atrial pressure.
Clinical, echocardiographic, and demographic features associated with Pre-TIPS RAP
Among the 75.3% (n = 665) of patients with echocardiogram parameters, there was a small positive correlation between LVEF and pre-TIPS RAP (r = 0.126, p < 0.001). We did not find any significant correlation between the pre-TIPS pulmonary arterial systolic pressure on echocardiogram and pre-TIPS RAP measured at the time of TIPS [r (377) = 0.03, p = 0.5], although pulmonary arterial systolic pressure was only available in only 42.9% (n = 379) of patients. Similarly, diastolic dysfunction and tricuspid regurgitation did not correlate with pre-TIPS RAP. The median pre-TIPS RAP was 9 mm Hg (IQR: 6, 13). Pre-TIPS RAP was found to be strongly correlated with pre-TIPS IVC pressure [r (66) = 0.96, p < 0.0001], and pre-TIPS–free hepatic venous pressure [r (77) = 0.72, p < 0.0001]. There was a significant increase in RAP after the insertion of TIPS (median increase of 5 mm Hg, (IQR: 3, 5) p < 0.001, n = 848). TIPS performed as an elective or outpatient procedure had a lower average pre-TIPS RAP than TIPS performed as an emergent or inpatient procedure (9.2 vs. 10.2, p = 0.005). In addition, the mean pre-TIPS RAP was significantly higher in TIPS placed for emergent variceal bleed versus TIPS placed for non-emergent variceal bleed and ascites (12.2 vs. 9.9; p = 0.0017).
We found that several patient factors were associated with pre-TIPS RAP. On univariable analysis, Native American and Black ethnicity, NASH cirrhosis, diabetes mellitus, esophageal varices as TIPS indication, inpatient status at the time of TIPS, higher BMI, MELD-Na score, low platelets, age at TIPS, and albumin were associated with higher pre-TIPS RAP. On multiple linear regression, patient factors significantly associated with pre-TIPS RAP were Native American and Black race, BMI, platelets, MELD at the time of TIPS, and esophageal varices as TIPS indication (Table 5, adjusted R2 = 9.7%, p < 0.001). When we included pre-TIPS diuretic use and center volume as variables in the analysis, we found that pre-TIPS diuretic use was significantly associated with lower pre-TIPS RAP. Specifically, pre-TIPS diuretic use was associated with a 0.87 mm Hg lower pre-TIPS RAP (±0.388; p = 0.026, n = 758).
TABLE 5.
Multivariable linear regression model with pre-TIPS RAP as the dependent variable
| Patient characteristics | n | Beta | SE | p |
|---|---|---|---|---|
| Native American (compared with White) | 883 | 5.11 | 1.97 | 0.01 |
| Black (compared with White) | 883 | 2.15 | 0.87 | 0.014 |
| BMI | 870 | 0.15 | 0.03 | < 0.001 |
| EV as TIPS indication (compared with refractory ascites/HH) | 883 | 1.45 | 0.41 | < 0.001 |
| MELD-Na score at the time of TIPS | 861 | 0.11 | 0.03 | < 0.001 |
| Platelets (per 1K/uL) | 811 | −0.007 | 0.003 | 0.01 |
Abbreviations: BMI, body mass index; EV, esophageal varices; HH, hepatic hydrothorax; MELD, model for end-stage liver disease; RAP, right atrial pressure.
Finally, we compared the excluded group of patients without a recorded pre-TIPS RAP with the included patients with a recorded pre-TIPS RAP. The 2 groups did not differ significantly in age, comorbidities, etiology, and severity of cirrhosis based on the MELD score. In addition, the post-TIPS 90-day and 1-year transplant-free mortality were not significantly different among the groups. However, the excluded patient group included more males (66.8% vs. 57.8%; p = 0.013), more TIPS done for variceal bleeding (50.2% vs. 33.6%; p < 0.001), and TIPS performed as an inpatient procedure (60.8% vs. 47%; p < 0.001).
DISCUSSION
In this large multicenter study of patients who underwent TIPS with a covered stent, pre-TIPS RAP was an independent predictor of all-cause mortality post-TIPS after adjusting for TIPS indications, age, MELD sodium, and the hospitalization status at the time of TIPS. The association between pre-TIPS RAP and mortality was nonlinear, and the subdistribution hazard of death, with LT as a competing event, increased with increasing pre-TIPS RAP. Increased pre-TIPS RAP was significantly associated with greater odds of post-TIPS complications, including early events within 48 hours, CHF-related inpatient hospitalizations, and TIPS dysfunction, including increased odds of recurrence of ascites needing paracentesis after 90 days, and renal dysfunction. Native American and Black race, elevated BMI, MELD-Na, and lower platelets predicted elevated pre-TIPS RAP in the cohort.
RAP is an important clinical parameter that reflects effective circulating blood volume and right ventricular preload.[9,10] Normal RAP ranges between 1 and 7 mm Hg,[11] and in patients with cirrhosis and portal hypertension, a number of factors may increase RAP. These include the high output hyperdynamic circulatory state of cirrhosis,[3,12] where increased cardiac filling pressures increase RAP;[13] cirrhotic cardiomyopathy, where right ventricular dysfunction may increase RAP;[14,15] and portopulmonary hypertension where increased pulmonary vascular resistance drives increased RAP. In our study, the mean pre-TIPS RAP was 9.7 mm Hg (SD of 5 mm Hg), similar to prior studies where the mean pre-TIPS RAP ranged from 8.3 to 12.4 mm Hg.[16,17] Our study reflects real-world practice across all indications and multiple centers in the US, which is substantially different from previous smaller-sized studies with lower pre-TIPS RAP where emergent TIPS were not included[18] or had a relatively lower fraction of TIPS performed as rescue therapy in emergent conditions.[19] Moreover, we found that the mortality risk associated with RAP begins at levels above 8 mm Hg and rises thereafter but is not confined to those with marked elevations. Elevated pre-TIPS RAP levels (particularly low-level increases) could be a marker for the presence of cardiopulmonary abnormalities that are unmasked after TIPS and directly impact outcomes, or higher levels could reduce TIPS effectiveness by limiting the reduction in PP.
A significant proportion of our patients had an elevated resting pre-TIPS RAP (66% RAP > 7 mm Hg), leading us to investigate clinical factors that might identify individuals at higher risk for mortality or TIPS dysfunction. African American and Native American ethnicity, elevated BMI, esophageal varices as the indication for TIPS, low platelets, and elevated MELD-Na were clinical factors that predicted higher pre-TIPS RAP in our cohort. The association between parameters of liver dysfunction and RAP is in line with prior studies where lower platelet counts, elevated MELD, and PP levels were associated with higher pre-TIPS RAP.[1] Moreover, higher MELD and low platelet counts as markers of liver disease severity have been correlated with an increased right atrial diameter and pulmonary arterial pressures on echocardiography.[20,21] The association between African American and Native American ethnicity and pre-TIPS RAP has not been previously observed. RAP, in general, is higher in African American individuals than in Caucasian individuals,[6,22,23] with genetic predisposition, higher prevalence of hypertension, and increased endothelin signaling as putative mechanisms.[24] Native Americans have an increased risk for coronary artery disease[25] and severe liver disease, although contributions to elevated pre-TIPS RAP are unknown. Finally, elevated BMI and obesity are associated with obesity hypoventilation syndrome and metabolic dysfunction associated pulmonary vascular remodeling,[26] which can elevate RAP and drive PAH.[27] The association between clinical factors and elevated pre-TIPS RAP provides a potential opportunity to enhance the recognition and risk stratification of subgroups of patients being considered for TIPS.
We also assessed whether echocardiographic features or pre-TIPS diuretic use were associated with pre-TIPS RAP. We did not find a correlation between pulmonary arterial systolic pressure measured on echocardiography before TIPS with either RAP or outcomes after TIPS in the subset of patients with both measures. However, we found that increased ejection fraction on echocardiogram had a small positive correlation with pre-TIPS RAP, and conversely, pre-TIPS diuretic use was significantly associated with lower pre-TIPS RAP. These associations suggest that elevated pre-TIPS RAP may be related to the hyperdynamic circulation of cirrhosis and might be modulated by diuretic use. Hence, optimizing volume status before and after TIPS in patients with elevated RAP has the potential to impact post-TIPS outcomes and needs prospective evaluation.
The dynamics of change in cardiac pressures after TIPS might also influence outcomes. Immediately after TIPS placement, shunting of blood and vasoactive substances from the portal to the systemic circulation is associated with increased cardiac preload and output and right-sided pressures,[4] an observation consistent with our post-TIPS RAP measures. The elevation in RAP and right atrial volume, in addition to other cardiac chamber volumes, can last from 3 to 7 months after TIPS.[28–30] There is also a report of a biphasic pattern of pulmonary arterial systolic pressures after TIPS, with initial elevation immediately after TIPS with subsequent decrease, followed by a late phase of increasing pressures.[31] Our findings that increased pre-TIPS RAP increases the odds of early complications, renal dysfunction, and admissions for CHF within a year after TIPS could reflect the effects of early cardiac dysfunction and later rising pulmonary artery systolic pressures. If so, the contribution of cardiac dysfunction to adverse outcomes after TIPS may be underestimated.
Elevated pre-TIPS RAP could also adversely impact the effectiveness of TIPS in improving portal hypertensive complications and thereby influence mortality. Higher RAP may increase back pressure in the liver and could limit the effectiveness of TIPS in reducing PPs.[17] We did find that there was a trend for pre-TIPS RAP to be higher in those where the post-TIPS PP gradient was not decreased to <12 mm Hg relative to those where the gradient was decreased to <12 mm Hg (mean pre-RAP of 9.6 vs. 10.9, p = 0.09). We also found that elevated pre-TIPS RAP increased the odds of needing post-TIPS paracentesis after 90 days in outpatient TIPS and increased the incidence of renal dysfunction. Our findings align with prior studies where elevated RAP negatively impacts renal function and predicts mortality in CHF.[32] The association between the need for paracentesis > 90 days after TIPS and mortality has been shown.[33] Prior ALTA analyses have linked 30-day post-TIPS renal dysfunction with increased mortality.[34]
In two prior single-center studies, pre-TIPS RAP was not found to be an independent predictor of mortality,[7] although, in one, post-TIPS RAP was.[1] Our study builds on these studies and extends the findings in several important ways. First, our study is multicenter and significantly larger than the prior analyses. Second, our population was more evenly distributed relative to hospitalization status at the time of TIPS and indications for the procedure. Both prior studies were skewed toward inpatient procedures performed for variceal bleeding. Finally, we included only those with covered stents to exclude complications related to older uncovered stents.
Accurate measurement of RAP currently requires the insertion of a central venous catheter and is not practical to risk stratify patients before TIPS. Echocardiography is routinely used to assess cardiac function before TIPS, including RAP, which is estimated using the maximum IVC diameter and the IVC collapsibility index.[11,35] However, studies show only modest precision in measuring RAP.[36–38] Bedside techniques, including jugular venous pressure and abdominojugular reflex, have low sensitivity with inter-observer variability,[39] and bedside ultrasound has poor reliability with the risk of overestimating pressures.[11] Newer techniques, including near-infrared spectroscopy, which estimates RAP using near-infrared light technology with a portable device placed on the external jugular vein, have shown a good correlation with echocardiographic measurements.[37] Compared with the standard echocardiogram parameters alone, a multiparameter approach with the addition of cardiac collapsibility and IVC size has been shown to predict RAP more accurately.[40] More recently, the role of pre-TIPS cardiovascular magnetic resonance imaging in predicting post-TIPS heart failure has been explored in a small study,[28] although cost, utility, and scalability may create challenges. Evaluating the accuracy of newer noninvasive techniques for measuring RAP before TIPS and defining if they predict outcomes following TIPS are important areas for investigation.
Our study has several limitations. First, it is retrospective, with the possibility of selection bias, as patients with clinically evident elevated RAP might not have been offered the TIPS procedure. Second, residual confounding might have influenced our results by the potential influence of unmeasured factors that were not controlled for, such as frailty, nutritional status, and other comorbidities. Third, although the RAP measurement obtained during the TIPS procedure is highly accurate, variations and nonstandardization in pressure measurements and TIPS techniques across centers could have influenced the findings. Fourth, we do not have comprehensive data on echocardiographic parameters for all the patients, which could have helped us understand the correlation between RAP measured during the TIPS procedure and that measured during echocardiography, as well as providing more granularity regarding cardiac function. Fifth, our study did not evaluate the role of current technology using controlled expansion TIPS stents, which may impact outcomes after TIPS. Next, we do not have the important information on the cause of death after TIPS. Lastly, there was heterogeneity among the included and excluded patients. Because the excluded group had more frequent features associated with increased RAP, we hypothesize that this difference might have only attenuated the strength of associations of pre-TIPS RAP in the included group.
In conclusion, in patients with cirrhosis and portal hypertension, RAP measured before TIPS placement is an independent risk factor for short-term and long-term mortality. Pre-TIPS RAP levels have a nonlinear association with mortality and are predicted by patient factors such as BMI, liver disease severity, TIPS indication, African American, Native American ethnicity, and pre-TIPS diuretic use. Elevated RAP negatively impacts cardiac function and the efficacy of TIPS, which are likely mechanisms that contribute to mortality. Noninvasive techniques to accurately assess pre-TIPS RAP, a more detailed assessment of pre-TIPS and post-TIPS cardiac function, and potential treatment to lower pressure, particularly in patients at increased risk, are needed to understand the mechanisms and the impact on outcomes.
Supplementary Material
ACKNOWLEDGMENTS
The authors thank ALTA for scientific content and consistency of data interpretation with previous ALTA publications.
FUNDING INFORMATION
The ALTA Study is funded by an investigator-initiated grant from W.L. Gore and Associates. The sponsor (W.L. Gore and Associates) had no input into the overall design and conduct of the ATLA Study.
CONFLICTS OF INTEREST
Nadim Mahmud received investigator-initiated funding from Grifols for work unrelated to this project. Justin R. Boike receives consulting fees and investigator-initiated grant support from W.L. Gore and Associates; and consulting fees from Fujifilm Holdings Corporation. Bartley G. Thornburg received personal fees from W.L. Gore and Associates. Kanti Pallav Kolli consults for Becton, Dickinson, and Company and OncoSec Medical. Jennifer C. Lai serves on the advisory board for Novo Nordisk. Research is sponsored by Genentech, Vir Biotechnologies, Axcella Health, Lipocine, and W.L. Gore and Associates. Erin Spengler owns stock in Abbott. Sonali Paul has received grants from Intercept, Target Pharmasolutions, and Genfit. Catherine Frenette is employed at Gilead. Elizabeth C. Verna has received grants from Salix Pharmaceuticals. Lisa B. VanWagner receives investigator-initiated grant support paid to the institution from W.L. Gore and Associates, serves as an expert witness, and consults for Noble insights and Gerson Lehrman group.
Abbreviations:
- BMI
body mass index
- CHF
congestive heart failure
- EV
esophageal varices
- IQR
interquartile range
- LT
liver transplantation
- MELD
model for end-stage liver disease
- PAH
pulmonary arterial hypertension
- PP
portal pressure
- RAP
right atrial pressure
- sHR
subdistribution HR
Footnotes
Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website, www.hepjournal.com.
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