Survival Outcomes and Impact of Targeted PAH Therapy in Portopulmonary Hypertension in the PVRI GoDeep Meta-Registry

Abstract

Portopulmonary hypertension (PoPH), a type of pulmonary arterial hypertension (PAH) in patients with liver disease, is associated with high morbidity and mortality. The relationship between cardiopulmonary hemodynamics, PAH therapy, and survival in PoPH remains unclear. We performed a retrospective cohort study of PoPH patients from the international pulmonary hypertension (PH) meta-registry, PVRI GoDeep. PAH was defined by a mean pulmonary arterial pressure > 20 mmHg, pulmonary arterial wedge pressure ≤ 15 mmHg, and a pulmonary vascular resistance (PVR) > 2 Wood Units. PoPH diagnoses were assigned by each center's PH specialist based on international guidelines at the time of enrollment. 246 incident PoPH patients met eligibility criteria and were included in the analysis, equally split between males (51%) and females (49%), with a median age of 54 years. When compared to both patients with IPAH and those with other subtypes of PAH (not classified as PoPH or IPAH), those with PoPH had significantly lower 5-year survival rates (46% vs. 68% vs. 65%, log-rank p < 0.001). Amongst the PoPH patients, however, there was no significant difference in 5-year survival when dichotomized by disease severity, either by a PVR of 5 Wood Units or a CI of 2.5 L/min/m². Treatment of the PoPH patients with PAH-targeted therapies was associated with significantly higher 5-year survival rates compared to those not receiving such treatments, as shown by Kaplan-Meier analysis. This survival benefit was observed for PDE5i (50% vs. 34%, log-rank p = 0.029), ERA (58% vs. 34%, log-rank p < 0.001), and the combination of PDE5i and/or ERA (51% vs. 22%, log-rank p < 0.001), as well as any PAH-targeting treatment (50% vs. 26%, log-rank p = 0.007). Corresponding survival advantage was noted when including only PoPH patients with MELD Score ≥ 13. PoPH is a disease with significantly worse long-term survival than other PAH subtypes, but targeted PAH therapy is associated with a robust survival benefit. Survival did not differ across high-risk PVR and cardiac index thresholds, suggesting the factors that influence prognosis and survival in PoPH may be unique as compared to other PAH subtypes, and warrant further investigation.

Figure 1

Patient flow chart. mPAP = mean pulmonary arterial pressure, PAWP = pulmonary artery wedge pressure, PH = pulmonary hypertension, PoPH = portopulmonary hypertension, PVR = pulmonary vascular resistance, PVRI = Pulmonary Vascular Research Institute.

Figure 2

Kaplan–Meier analysis by PH group and hemodynamic severity. Kaplan–Meier survival estimates with 95% confidence bands. (a) PoPH patients compared to PAH and IPAH patients contained in the PVRI‐GoDeep meta‐registry. (b) PoPH patients stratified by hemodynamic severity, defined as a PVR > 5 WU. (c) PoPH patients stratified by hemodynamic severity, defined as a CI < 2.5 L/min/m². IPAH = idiopathic pulmonary arterial hypertension, PAH = pulmonary arterial hypertension, PH = pulmonary hypertension, PoPH = portopulmonary hypertension, WU = Wood Units.

Figure 3

Kaplan–Meier analysis by treatment. Kaplan–Meier survival estimates with 95% confidence bands stratified by (a) PDE5i treatment, (b) ERA treatment, (c) PDE5i and/or ERA treatment, and (d) any PAH‐targeted treatment for PoPH patients. ERA = endothelin receptor antagonists; PDE5i = phosphodiesterase‐5 inhibitors; PoPH = Portopulmonary hypertension.

Figure 4

Cox proportional hazard models. Hazard ratios for patients with specific treatment compared to patients without the specific treatment from Cox proportional hazards models for the PoPH patients. The diagrams show the estimates with 95% confidence intervals. The p‐values are from Wald z‐tests. (a) Results from the base‐model for the unimputed data set. Additional to treatment, the model is adjusted for center, diagnosis decade and sex as strata and age, as natural spline with 2 degrees of freedom. (b) Results from the base model, but additionally using the landmark approach. (c) Results from the full model using the unimputed data set similar to (a). The model is additionally adjusted for WHO functional class, body mass index, mPAP, PVR, INR, ALT, AST, eGFR, and sodium. All lab values were log‐transformed. (d) Results from the full model similar to (c) using the imputed data set. (e) Results from the full model, using the imputed data set similar to (d) but including additionally the landmark approach. ALT = alanine transaminase, AST = aspartate aminotransferase, eGFR = estimated glomerular filtration rate, ERA = endothelin receptor antagonists, HR = hazard ratio, INR = international normalized ratio, mPAP = mean pulmonary arterial pressure, PDE5i = phosphodiesterase‐5 inhibitors, PoPH = Portopulmonary hypertension, PVR = pulmonary vascular resistance, lower/upper = lower and upper limits of the 95% confidence interval of the HR.

Figure 5

Sensitivity analyses. Sensitivity analyses for the full models with landmark approach and imputed data set for PoPH patients. (a) Impact of adding or removing covariable terms to/from the Cox proportional hazards model on the estimated hazard ratio for treatment. The diagram shows the estimates with 95% confidence intervals. The P‐values are from Wald z‐tests. The upper half shows the estimates from the full model from which the respective terms were removed, the lower half shows the estimates from the base model with the respective terms added. The last lines in each half refer to the addition or removal of all terms to or from the model that refer to the indicated groups of variables (RHC: right‐heart catheterization). The hazard ratios estimated from the full model and the base model are given as reference. (b) Variable importance assessed by Heller's explained relative risk scores for the full model with landmark approach. BMI = body mass index, ERA = endothelin receptor antagonists, HR = hazard ratio, mPAP = mean pulmonary arterial pressure, PDE5i = phosphodiesterase‐5 inhibitors, PoPH = Portopulmonary hypertension, PVR = pulmonary vascular resistance, RHC = right‐heart catheterization, se = standard error of the coefficient, WHO FC = WHO functional class, lower/upper = lower and upper limits of the 95% confidence intervals of the hazard ratio; p‐value = p‐values from the Wald z‐test of beta = 0.