Treatment with sildenafil and treprostinil allows successful liver transplantation of patients with moderate to severe portopulmonary hypertension

Authors

  • Trina J. Hollatz,

    1. Division of Pulmonary and Critical Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
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  • Alexandru Musat,

    1. Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
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  • Susanne Westphal,

    1. Division of Pulmonary and Critical Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
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  • Catherine Decker,

    1. Division of Pulmonary and Critical Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
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  • Anthony M. D'Alessandro,

    1. Division of Transplant Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
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  • Jon Keevil,

    1. Division of Cardiology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
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  • Li Zhanhai,

    1. Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI
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  • James R. Runo

    Corresponding author
    1. Division of Pulmonary and Critical Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
    • Division of Pulmonary and Critical Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, MC 9988, Madison, WI 53792
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    • Telephone: 608-263-3035; FAX: 608-263-3104


  • Potential Conflicts of Interest: James R. Runo has served as a consultant/and or speaker for Actelion, Gilead, United Therapeutics, and Pfizer; his last activity with any company occurred in 2008, and there has been none since. He is also an investigator in a United Therapeutics–sponsored trial (Open-Label Study to Assess the Safety and Efficacy of Treprostinil to Facilitate Liver Transplantation in Patients With Portopulmonary Hypertension; ClinicalTrials.gov identifier NCT01028651), but he has not enrolled any patients. In addition, he has served as a local investigator for multicenter studies with Actelion.

Abstract

Portopulmonary hypertension (PoPH) refers to pulmonary arterial hypertension associated with portal hypertension with or without evidence of an underlying liver disease. Despite the potential for curing PoPH with liver transplantation, the presence of moderate or severe PoPH is associated with increased morbidity and mortality and is, therefore, a contraindication to transplantation. Previous studies have predominantly used intravenous epoprostenol for treatment in order to qualify patients for liver transplantation. In this retrospective case series, we describe the clinical course of 11 patients whom we successfully treated (predominantly with oral sildenafil and subcutaneous treprostinil) in order to qualify them for liver transplantation. The mean pulmonary artery pressure significantly improved from 44 to 32.9 mm Hg, and the pulmonary vascular resistance decreased from 431 to 173 dyn second cm−5. There were significant improvements in the cardiac output and the transpulmonary gradient with these therapies as well. All 11 patients subsequently received liver transplants with a 0% mortality rate to date; the duration of follow-up ranged from 7 to 60 months. After transplantation, 7 of the 11 patients (64%) were off all pulmonary vasodilators, and only 2 patients required transiently increased doses of prostacyclins. In conclusion, an aggressive approach to the treatment of PoPH with sildenafil and/or treprostinil and subsequent liver transplantation may be curative for PoPH in some patients. Liver Transpl 18:686–695, 2012. © 2012 AASLD.

Portopulmonary hypertension (PoPH) refers to pulmonary arterial hypertension associated with portal hypertension with or without evidence of an underlying liver disease. It is defined as a mean pulmonary artery pressure (mPAP) greater than 25 mm Hg, a pulmonary vascular resistance (PVR) greater than 240 dyn second cm−5, and a pulmonary arterial occlusion pressure (PAOP) less than 15 mm Hg in patients with portal hypertension.1 A classification of disease severity in patients with PoPH is based on mPAP values: mild, moderate, and severe are defined as 25 to 35, 35 to 45, and >45 mm Hg, respectively.1

PoPH occurs in up to 6% of patients with portal hypertension and portends a poor prognosis if it is untreated.2-5 Although worsening liver disease is a poor prognostic sign in patients with PoPH, no clear association has been found with the severity of PoPH and hepatic dysfunction or portal pressures.6 The presence of moderate to severe PoPH increases the perioperative mortality of patients undergoing orthotopic liver transplantation. Krowka et al.7 reported that an initial mPAP value of 50 mm Hg or higher (determined preoperatively or intraoperatively) was associated with 100% mortality for attempted liver transplantation, and an mPAP value of 35 to 50 mm Hg along with a PVR greater than 250 dyn second cm−5 was associated with a mortality rate of 50%. Those with mPAPs less than 35 mm Hg had the best outcomes, and there were no deaths. However, a follow-up study by the same authors did not show such clear-cut outcomes according to pulmonary pressures or other hemodynamic parameters, but pretransplant therapy with prostacyclins was more common in survivors than nonsurvivors.8

In this study, we report our single-center experience with 11 PoPH patients who successfully underwent orthotopic liver transplantation after treatment primarily with sildenafil and/or subcutaneous (SQ) treprostinil. To our knowledge, this is the largest study of individuals with PoPH undergoing transplantation with pulmonary vasodilator agents other than epoprostenol.

Abbreviations:

6MW, 6-minute walk; CO, cardiac output; EN, enlargement; EtOH, alcohol; EV, esophageal varices; GAVE, gastric antral vascular ectasia; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HE, hepatic encephalopathy; HRS, hepatorenal syndrome; MELD, Model for End-Stage Liver Disease; mPAP, mean pulmonary artery pressure; NA, not available; NASH, nonalcoholic steatohepatitis; NYHA, New York Heart Association; PAOP, pulmonary arterial occlusion pressure; PBC, primary biliary cirrhosis; PG, portal gastropathy; PoPH, portopulmonary hypertension; PVR, pulmonary vascular resistance; RF, reduced function; RFA, radiofrequency ablation; RHC, right heart catheterization; RV, right ventricle; s/p, status post; SQ, subcutaneous; tid, 3 times a day; TIPS, transjugular intrahepatic portosystemic shunt; TPG, transpulmonary gradient.

PATIENTS AND METHODS

This retrospective chart review was approved by the institutional review board of the University of Wisconsin. We reviewed charts from 2005 through July 2011 for patients referred to the pulmonary hypertension clinic at the University of Wisconsin for PoPH.

The diagnosis of PoPH was suspected in patients with portal hypertension who complained about dyspnea and/or had an echocardiogram revealing an estimated right ventricle (RV) systolic pressure greater than 50 mm Hg.2 Patients subsequently underwent right heart catheterization (RHC), which included an assessment of vasoreactivity with inhaled nitric oxide for most, for confirmation of PoPH before the initiation of therapy. In addition, other etiologies of pulmonary hypertension were excluded by history, laboratory, and imaging data. All patients were eligible for transplantation except for the presence of PoPH according to the liver transplant selection committee of our institution.

According to the severity of their disease (based on RHC) as well as the magnitude of their symptoms, their insurance coverage, and the physician's discretion, patients were initially started on either oral sildenafil or SQ treprostinil. Patients were seen at the pulmonary hypertension clinic approximately every 3 months for serial echocardiograms, laboratory evaluations, and 6-minute walk (6MW) distance testing. If sufficient improvements in pulmonary pressures were not achieved according to follow-up echocardiograms or RHC or if patients worsened symptomatically, either the initial agent was increased or, in several cases, an additional agent or additional agents were added. Beta-blockers were discontinued for all patients because of reported detrimental effects on pulmonary hemodynamics and functional capacity.9 Screening upper endoscopy with variceal banding was performed as necessary with the discontinuation of beta-blockers. Finally, diuretics were adjusted according to a clinical assessment of the volume status. RHC was repeated according to improvements in signs/symptoms of right heart failure and echocardiogram results. The goal hemodynamic parameters were an mPAP less than 35 mm Hg and/or a PVR less than 240 dyn second cm−5.1 An improvement in RV function on an echocardiogram together with the overall cardiopulmonary status still allowed patients to be considered and listed for transplantation in select cases, regardless of their hemodynamic parameters.

After transplantation, the weaning and discontinuation of pulmonary vasodilators were based on functional status stability and/or improvements and maintenance of normal RV function as assessed by an echocardiogram.

Statistical Methods

Hemodynamic parameters at the times of diagnosis and listing were compared with a paired t test. The Model for End-Stage Liver Disease (MELD) scores at the times of diagnosis and transplantation were also compared with a paired t test. All tests with a P value < 0.05 were considered significant.

RESULTS

Eleven patients who were seen at our pulmonary hypertension clinic (all by J.R.R.) for PoPH eventually underwent successful liver transplantation between July 2006 and July 2011. The baseline clinical characteristics are displayed in Table 1. This cohort consisted of 6 women and 5 men with a mean age of 51.4 years (range = 40-61 years). Two patients were asymptomatic at the time of diagnosis and were identified by a pretransplant screening echocardiogram. The remaining patients reported symptoms of dyspnea, lightheadedness, near syncope, and fatigue anywhere from 5 days to 1 year before diagnosis. Notably, 2 patients had undergone splenectomy as children, and 1 patient had undergone splenectomy after liver transplantation for hypersplenia. No patients had documented splenorenal or portocaval shunts. As noted in Table 1, 3 patients (1, 3, and 8) had transjugular intrahepatic portosystemic shunt (TIPS) procedures for variceal bleeding several years before the PoPH diagnosis.

Table 1. Patient Characteristics and Demographics
PatientSexAge (Years)Liver Disease EtiologyEnd-Stage Liver Disease ComplicationsNYHA Functional Class
1Female50EtOHAscites, EV, GAVE, s/p TIPS, HRSIII
2Male51EtOH/HCVEV, HEI
3Male46EtOHEV, s/p TIPSIII
4Female50EtOHEVIII
5Male53EtOH/HCVAscites, EV, HEII-III
6Female40Biliary atresiaEVII
7Male57EtOH/HCVEV, HEII
8Female61EtOH/NASH/PBCEV, PG, HE, s/p TIPSII
9Female55EtOHEV, Ascites, HEII
10Female45EtOHAscites, HEII
11Male57HCVAscites, HE, EV, PG, HCC, s/p RFA, HRSIII

The initial and follow-up RHC data are presented in Table 2. All patients were deemed to have moderate or severe PoPH on the basis of their mPAP results.1 Two patients (2 and 9) had PAOPs greater than 15 at the time of diagnostic RHC but had transpulmonary gradients (TPGs) of 35 and 25, respectively; they thus met the modified diagnostic criteria.2, 10 Six of the 11 patients were tested for reactivity to nitric oxide at the time of the initial RHC, but none had an acute response.11 In 3 of the tested patients, PAOP increased (1, 1, and 5 mm Hg). For 1 patient, PAOP was not measured after nitric oxide. The patients underwent 2 to 4 catheterizations (including the initial RHC) before they were listed for transplantation. The average treatment duration before eligibility was 11 ± 3.8 months for all patients (Table 3). For the 10 patients treated primarily at our clinic, the average treatment duration before eligibility for transplantation was 7.3 months.

Table 2. Hemodynamic Parameters at the Time of the PoPH Diagnosis and After Treatment When the Criteria Were Met for Transplant Listing
PatientmPAP (mm Hg)PVR (dyn second cm−5)CO (L/minute)TPG (mm Hg)*PAOP (mm Hg)6MW (m)RV Size/Function
DiagnosisListingDiagnosisListingDiagnosisListingDiagnosisListingDiagnosisListingDiagnosisListingDiagnosisListing
  • *

    TPG is defined as mPAP minus PAOP; values greater than 12 mm Hg indicate an obstruction of pulmonary flow in the setting of elevated PVR and are suggestive of PoPH. Two patients (2 and 9) had PAOPs greater than 15 at the time of diagnostic RHC but had TPGs of 35 and 25, respectively; they thus met the modified diagnostic criteria.2, 10

  • During the early years of PoPH treatment, we performed fewer echocardiograms, so in many cases these reports were made 6 or more months before the qualifying RHC.

13825748303.110.5294921231261Moderate EN/ moderate RFModerate EN/mild RF
255463411698.212.335262020297333Moderate EN/ moderate RFModerate EN/mild RF
341333641445.71026181515347477Normal/ normalNA
436274942093.46.121161511200400Mild EN/ mild RFNA
548393601627.4710.238211018366331Mild EN/ mild RFNormal/ normal
648486833924.87.64137711427NAMild EN/ normal
749245312045.357.23518146349427Mild EN/ mild RFModerate EN/mild RF
842352721928.88.830211214132138Mild EN/ mild RFNormal/ normal
941312861617.210.425211610Mild EN/ normalNormal/ normal
1044282891369.41034171011403365Severe EN/ moderate RFModerate EN/mild RF
1143263761007.4712.73516810273Moderate EN/ moderate RFNormal/ normal
Table 3. Postoperative Course of the Transplant Patients
PatientTherapy Before Transplant Eligibility (Months)Transplant List (Days)Calculated MELD Score at TransplantPoPH Medication at TransplantIntensive Care Unit Length of Stay/Total Hospital Stay After Transplantation (Days)Postoperative Course
  • *

    The patient had a MELD exception score.

  • A MELD exception score had been previously granted, but the actual MELD score was higher at the time of transplantation.

198225SQ treprostinil (26 ng/kg/minute)3/14Sildenafil was started 3 months after transplantation. Treprostinil was stopped 5 months after transplantation. The patient was off all medications 8 months after transplantation. The most recent echocardiogram showed normal RV size and function.
21219410*Sildenafil (40 mg tid) Iloprost (5 μg 6 times a day)8/20Iloprost was stopped 1 month after transplantation. Ambrisentan was started 16 months after transplantation because of severe RV dysfunction on the echocardiogram. The patient remained on sildenafil (40 mg tid) and ambrisentan (5 mg/day) 47 months after transplantation. The most recent echocardiogram showed a mildly dilated RV with mild RF.
371927*SQ treprostinil (19 ng/kg/minute)3/9Sildenafil was started 2 months after transplantation. Treprostinil was discontinued 7 months after transplantation. The patient was off all PoPH medications 24 months after transplantation. The most recent echocardiogram showed normal RV size and function.
41012511*SQ treprostinil (53 ng/kg/minute)7/16Sildenafil was started 3 months after transplantation. Treprostinil was stopped 4 months after transplantation. The patient was off all PoPH medications 14 months after transplantation. The most recent echocardiogram showed normal RV size and function.
595827Epoprostenol (6 ng/kg/minute) Sildenafil (40 mg tid)1/17Epoprostenol was increased on postoperative day 13. Sildenafil was increased to 80 mg tid. Ambrisentan was started at 5 mg/day 11 months after transplantation. Epoprostenol was discontinued 17 months after transplantation per the patient's request. The patient stopped all PoPH medications 23 months after transplantation. The echocardiogram at that time showed the RV to be mildly dilated with mild RF.
648411*SQ treprostinil (45 ng/kg/minute) Sildenafil (40 mg tid)2/10Treprostinil was increased 3 months after transplantation. Sildenafil was also increased to 80 mg tid. The patient was started on ambrisentan 2 years after transplantation as the patient was weaned from treprostinil. Treprostinil was discontinued 28 months after liver transplantation. Forty-one months after transplantation, the patient was still on sildenafil (80 mg tid) and ambrisentan (5 mg/day). The RV size and function were normal on the most recent echocardiogram.
7625511*SQ treprostinil (32 ng/kg/minute)2/6Sildenafil was started 3 months after transplantation. Treprostinil was discontinued 7 months after transplantation. The patient was off all PoPH medications 17.5 months after transplantation. The most recent echocardiogram showed normal RV size and function.
862147*Sildenafil (20 mg tid)16/29Sildenafil was stopped 9 months after transplantation. The most recent echocardiogram showed a mildly dilated RV with normal function.
914028Sildenafil (40 mg tid)2/131Sildenafil was stopped 8 days after transplantation because of new-onset seizures. The echocardiogram 4 months after transplantation showed normal RV function. Prolonged posttransplant hospitalization was due to an altered mental status.
107630Sildenafil (20 mg tid) Bosentan (125 mg tid) Epoprostenol (3 ng/kg/minute)4/13Epoprostenol was stopped on postoperative day 3. Sildenafil was increased to 40 mg tid, and bosentan was decreased to 62.5 mg tid. Shortly after transplantation, the patient was transitioned from bosentan to ambrisentan, which was discontinued 4 months after transplantation. The patient remained on sildenafil (20 mg tid) 13 months after transplantation. The most recent echocardiogram showed normal RV size and function.
1162530Epoprostenol (8 ng/kg/minute) Sildenafil (50 mg tid)5/17The patient was doing well 7 months after transplantation and was starting to be weaned from epoprostenol. The patient was started on ambrisentan 7 months after transplantation. The patient remained on sildenafil (50 mg tid). The most recent echocardiogram showed a mildly dilated RV with normal function.

Seven patients were originally started on sildenafil; 3 of the patients (5, 10, and 11) had already been prescribed sildenafil by referring physicians when they arrived at our clinic. Sildenafil monotherapy was insufficient in 5 patients, and treprostinil was the second agent of choice. Four patients required agents other than treprostinil because of side effects or an insurance mandate. Four patients (3, 4, 6, and 7) were started on SQ treprostinil as their first-line therapy. Patient 6 was treated at an outside facility initially with treprostinil and then with sildenafil for 3 years before she was seen at our clinic. The remaining 3 patients achieved their goal hemodynamics on treprostinil monotherapy.

With pulmonary vasodilator therapy, mPAP, PVR, and cardiac output (CO) all showed significant improvements, but no changes were observed in PAOP (Fig. 1). There was a nonsignificant improvement in the 6MW distance for tested patients (from 288.7 ± 29.4 to 351 ± 34.2 m, P = 0.12). The calculated MELD score was 15.4 ± 2.4 at the time of transplant listing and 17.9 ± 3.0 at the time of transplantation. MELD exception scores were sought on a case-by-case basis for PoPH. Seven of the 11 patients were given MELD exception scores of 20 to 22, and 4 of these 7 patients had their MELD exception scores increased for time spent on the wait list. No patient died while awaiting transplantation.

Figure 1.

Hemodynamic parameters at diagnosis and after treatment.

Once patients were approved for transplantation, the mean duration on the list was 108.6 ± 27.6 days (median = 82 days). Pulmonary vasodilators and their doses are listed in Table 3. Intraoperatively, patients on SQ treprostinil were continued on SQ or intravenous treprostinil at the same dose. Patients on epoprostenol had their preoperative dose continued during surgery. If a patient was receiving oral medications only, low-dose epoprostenol (1-4 ng/kg/minute) was substituted intraoperatively and postoperatively until oral medications could be restarted.

As shown in Table 3, the postoperative courses varied, and there were no immediate complications related to PoPH in any patient. Two patients (5 and 6) did require early additional therapy for PoPH (increased doses of prostacyclins as well as oral agents) because of worsening right heart failure according to an echocardiogram and/or RHC. Only 1 of the remaining 9 patients (patient 2) required increased oral vasodilator therapy.

Besides patients 5 and 6, the other 4 patients on long-term intravenous/SQ prostacyclins began weaning from the drugs within 2 to 3 months after transplantation. The duration of prostacyclin therapy after transplantation for these 4 patients ranged from 4 to 7 months. While prostacyclins were being tapered, sildenafil or ambrisentan was started, or the dosage was increased. At the time of this writing, 7 of the 11 patients (64%) were off all therapies for PoPH. For those who were off all medications, the duration of therapy after transplantation ranged from 8 days to 24 months, with the average being 13.7 months. With the exception of patient 5 (whose care was transferred for insurance reasons), all the patients continued to receive follow-up care at our pulmonary hypertension clinic or liver transplant clinic on a regular basis; the duration of follow-up ranged from 7 to 60 months with an average follow-up duration of 30 months. There were no episodes of graft failure or PoPH reoccurrence in those patients able to come off pulmonary vasodilators.

Other patients not included in this case series were seen at our facility for PoPH. As shown in Table 4, we evaluated 11 additional patients who were found to have PoPH but did not undergo transplantation. At the time of this writing, 2 individuals were active on the transplant list, 5 were deceased, and the remaining 4 patients either had declined liver transplantation or had contraindications.

Table 4. PoPH Patients Not Transplanted
PatientSexAge at PoPH Diagnosis (Years)End-Stage Liver Disease EtiologymPAP at PoPH Diagnosis (mm Hg)PVR at PoPH Diagnosis (dyn second cm−5)Status at Writing
1Male45HCV34256The patient was alive. He was on sildenafil, and he was on the liver transplant list.
2Male53HCV/ hemochromatosis48616The patient died. He refused to start SQ treprostinil.
3Female42EtOH47600The patient was alive. She was on sildenafil (75 mg tid) and was continuing to abuse EtOH.
4Male56HCVThe patient died. There was an echocardiogram for pulmonary hypertension; however, the patient had a cardiac arrest and died before a definitive diagnosis or treatment.
5Male61EtOH46440The patient was alive. He was on sildenafil (40 mg by mouth tid) and was not interested in transplantation.
6Male57HCV57750The patient was alive. He was on sildenafil (80 mg tid) and ambrisentan (10 mg/day) and was not interested in transplantation.
7Male47HCV/EtOH55607The patient died. Sildenafil was started for PoPH; however, the patient was diagnosed with metastatic non–small cell lung cancer several months later and died shortly thereafter.
8Male53HCV/EtOH50553The patient was alive. He was on sildenafil (80 mg tid) and epoprostenol (15 ng/kg/ minute) and was on the liver transplant list.
9Male50HCV/EtOH36225The patient died. Sildenafil was recommended; however, the patient did not tolerate it and died of multiorgan failure.
10Male64HCV35303The patient was alive. He was started on sildenafil and was initially listed for transplantation; however, he was taken off the list because of enlarged pulmonary nodules.
11Female44HCV/EtOH62705The patient died. She was actively drinking at the time of diagnosis.

DISCUSSION

In our single-center experience, we successfully performed transplantation for 11 patients with moderate to severe PoPH who used primarily oral sildenafil and SQ treprostinil; at the time of this writing, there were 0 deaths with a mean follow-up of 30 months. Before this report, epoprostenol was used in the majority of case series concerning therapy for PoPH,12, 13 although a few case reports examining treprostinil14, 15 and sildenafil13, 16-19 have been published. At our institution, we have primarily employed sildenafil and SQ treprostinil in order to avoid the complications and inconveniences associated with long-term epoprostenol use and the need for a tunneled central venous catheter.

The reduction of mPAP below 35 mm Hg and/or the reduction of PVR below 240 dyn second cm−5 are usually considered sufficient for listing for liver transplantation, and we were able to achieve these predefined hemodynamic criteria in 10 of our 11 patients. However, other hemodynamic parameters are likely important. This was illustrated by the Mayo series in which 2 patients with mPAPs less than 35 mm Hg died.8 Recent data from the registry to evaluate early and long-term PAH disease management trial showed that the mean right atrial pressure was the only predictor of survival.20 Although we had no deaths, 2 patients in our study did require increased doses of prostacyclins within 3 months of transplantation, and 2 patients continued to require therapy at 40+ months. We hypothesize that for the patients (5 and 6) who required increased doses of prostacyclins after transplantation, mPAP may have been insufficiently lowered before transplantation (39 and 48 mm Hg, respectively), but this did not reach statistical significance when these patients were analyzed against the other individuals. Swanson et al.14 noted that a PAOP less than 10 mm Hg was associated with death after transplantation in their analysis, but neither of our 2 patients fell into this category. We also wonder if there is higher clearance of prostacyclins by the liver allograft.

Despite our excellent outcomes at this point, a major question is whether we should perform transplantation for patients who have low MELD scores and whose PoPH is stable on therapy because of the risks and mortality associated with liver transplantation. Six patients in our cohort had MELD scores of 11 or less. Swanson et al.14 reported patients on treatment for PoPH with an average MELD score of 13. Nine patients were listed for transplantation, and all 9 died while they were on the waiting list (6 because of liver-related causes and 2 because of PoPH).14 Among patients not on medical therapy and patients who received medical therapy without undergoing transplantation, there were no significant differences in any hemodynamic parameters between those who survived and those who died. This suggests that we are unable to predict who will have a poor outcome on the basis of hemodynamic parameters or the severity of liver disease. In addition, large studies have noted higher mortality rates for PoPH patients versus patients with idiopathic pulmonary arterial hypertension, with a nearly 25% higher risk of death at 5 years in the REVEAL trial.20, 21

Although we do not currently have sufficient follow-up data at our facility for 5-year survival, we have documented a 100% survival rate with an average follow-up of 30 months after transplantation. Because liver transplantation after advanced pulmonary arterial hypertension therapies has shown the best prognosis with a 5-year survival rate of 67% versus 45% with medical therapy alone and because we are unable to predict outcomes, a watch and wait approach may lead to unnecessary morbidity and mortality.14 Therefore, we feel that an aggressive strategy of PoPH treatment for eventual liver transplantation should be undertaken. In addition, MELD exception scores should be applied because this will often decrease the time on the waiting list and improve survival.14, 22

Further support for attempting transplantation in individuals with PoPH comes from the ability to possibly improve their pulmonary vascular disease after transplantation by taking away the etiology (ie, portal hypertension). Seven of the 11 patients in our cohort were off all pulmonary vasodilators. Other centers have had success in stopping vasodilator therapies in 50% to 82% of their patients after liver transplantation.13, 14, 22

In conclusion, we have reported 11 patients with moderate to severe PoPH who underwent an aggressive approach to improving their pulmonary hemodynamics in an attempt to undergo orthotopic liver transplantation. A stepwise treatment was used with sildenafil and/or SQ treprostinil, and once they were listed for transplantation, a MELD exception score for PoPH was sought. Our data support such an approach, in that all our patients successfully underwent transplantation and were alive at the time of this writing, with only our most recent patient remaining on prostacyclin therapy. Furthermore, most patients were able to discontinue all therapy, although the potential for early worsening of PoPH exists, and future studies will be needed to identify risk factors. We hope that an ongoing prospective trial (ClinicalTrials.gov identifier NCT01028651) using treprostinil in PoPH patients will be able to evaluate and answer many of the questions that we have raised.

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