Moutchia, Jude

Abstract Rationale Non-selective beta-blockers (BB) are the standard of care for variceal prophylaxis in patients with cirrhosis. It is unclear whether BB negatively affect exercise capacity in patients with portopulmonary hypertension (POPH) or hepatopulmonary syndrome (HPS). We hypothesize that BB use is associated with shorter six-minute walk distance (6MWD) in HPS and POPH than in patients without pulmonary vascular complications of liver disease. Methods The Pulmonary Vascular Complications of Liver Disease 2 (PVCLD2) Study enrolled patients evaluated for liver transplantation or pulmonary hypertension at eight U.S. centers (2013-2017). We conducted a retrospective analysis of 333 patients with HPS, POPH, and portal hypertension without lung complications to evaluate whether disease state modified the association of BB on 6MWD. Multivariable linear regression adjusted for a priori covariates including age, sex, body mass index (BMI), MELD-Na, and WHO functional class. An interaction term between disease category and BB use was included. Results We included 85 patients with HPS, 48 with POPH, and 200 patients with liver disease. Compared to liver disease controls, those with HPS were younger, had higher MELD-Na scores, and more often had worse WHO functional class. POPH patients were similar to controls in age and liver disease severity but had higher WHO functional class. Sex, BMI, and left ventricular ejection fraction did not differ significantly between groups. Higher age, BMI, MELD-Na, and WHO functional class were all significantly associated with lower 6MWD while male sex was associated with higher 6MWD. Adjusting for age, sex, BMI, MELD-Na score, and WHO functional class, there was a significant interaction between BB use and disease category (p = 0.024). Patients with HPS had a 53.4 m longer 6MWD with BB use (95% CI 4.21- 102.5, p = 0.03 for interaction) compared to liver disease controls, whereas patients with POPH had a 72.4 m longer 6MWD (95% CI 7.60- 137.2, p = 0.03 for interaction) compared to liver disease controls. Conclusion The association of BB with 6MWD in advanced liver disease appears to be modified by whether a person has a pulmonary vascular complication including HPS or POPH. The mechanisms for these differences and their clinical implications require further study. This abstract is funded by: NIH T32 Grant

Abstract Rationale: Since the initial descriptions of pulmonary arterial hypertension (PAH), there has been a significant increase in PAH diagnoses among the geriatric population. Studies suggest that older PAH patients exhibit unique hemodynamic profiles and treatment responses. We hypothesized that patients ≥80 years old would have a unique clinical profile and worse outcomes. Methods: The Pulmonary Hypertension Association Registry (PHAR) is a prospective cohort of PAH and chronic thromboembolic pulmonary hypertension (CTEPH) patients new to care at a Pulmonary Hypertension Care Center in the US. Individuals <18 years of age and those with CTEPH were excluded. Clinical data, quality of life measures, and functional capacity were recorded at time of enrollment and at follow up visits. Octogenarians were defined as those ≥80 years old and non-octogenarians as <80 years old. Associations between age subgroups with the change in six-minute walk distance (6MWD), and worsened WHO functional class (WHO FC) at the next visit, and time to all-cause mortality were assessed using linear, binomial, and Cox regression, respectively. Results: The study sample included 87 PAH octogenarian patients and 2,583 non-octogenarian patients at enrollment. The Table shows that octogenarian PAH patients were of similar sex and race distribution as others, but had lower body mass index. Octogenarians were more likely to have idiopathic or CTD-related PAH, and differed from younger patients in terms of several sociodemographic variables. PAH treatment, WHO FC, quality of life, and hemodynamic also differed between the groups. Octogenarians had a lower change in 6MWD (-26m, 95%CI -52 – -2, p = 0.066) and worse WHO FC (2.0, 95%CI 1.1 – 3.8, p = 0.038) over time compared to other adults after adjustment for sex, BMI, PAH etiology, annual income, marital status, right atrial pressure, mean pulmonary artery pressure, and PAH treatment. Octogenarians had an increased risk of death compared to younger adults (hazard ratio 1.7, 95%CI 1.1 – 2.6, p = 0.022) after adjustment for covariates. Conclusions: While the eldest PAH patients may have some comparable features to younger patients, they are different in a variety of socioeconomic variables, disease type, hemodynamics, and number of PAH therapies. The eldest PAH patients demonstrate worse exercise and functional capacity with time and a 70% increased risk of death compared to younger patients. Further studies are needed to better characterize PAH in the elderly, as this may lead to more effective treatments and enhanced quality of life.

Patients with chronic liver disease commonly have abnormal lung function; however, the impact of smoking on outcomes in these patients is unknown. We hypothesized current or past smoking would be associated with worse survival in patients with advanced liver disease. The Pulmonary Vascular Complications in Liver Disease Study 2 (PVCLD2) was a prospective cohort of patients with advanced liver disease undergoing evaluation for liver transplantation (LT). Patients were classified by self-report as a “non-smoker,” “past smoker,” or “current smoker.” We used Cox proportional hazards models and Fine-Gray models with LT as a competing risk. Models were adjusted for age, sex, body mass index, race, family income, liver disease etiology, and Model for End-Stage Liver Disease-Sodium score. Of the 410 patients included, most (65%) were male and the mean age at enrollment was 56.5 years. One hundred sixty (39%) patients were nonsmokers, 183 (45%) were past smokers, and 67 (16%) were current smokers. In total, 151 (37%) patients received an LT, and 88 (20%) patients died. When compared to nonsmokers, current smokers had a 2.17-fold increase in risk of death overall (95% CI: 1.12–4.18, p = 0.02). There was a 7% increase in overall risk of death for every 5 pack-years increase (95% CI: 1.01–1.13, p = 0.02). With LT as a competing risk, the subdistributional HR of current smokers versus nonsmokers for death was 2.45 (95% CI: 1.31–4.60, p = 0.005). In this model, past smokers displayed a nonsignificant increase in the risk of death compared to nonsmokers (subdistributional HR: 1.58, 95% CI: 0.91–2.72, p = 0.10). Patients with advanced liver disease undergoing evaluation for LT who smoke have an increased risk of death. Smoking cessation could lead to improved overall survival with or without LT.

Abstract Rationale Inhibition of aromatase with anastrozole reduces pulmonary hypertension in experimental models. Objectives We aimed to determine whether anastrozole improved the 6-minute-walk distance (6MWD) at 6 months in pulmonary arterial hypertension (PAH). Methods We performed a randomized, double-blind, placebo-controlled phase II clinical trial of anastrozole in subjects with PAH at seven centers. Eighty-four postmenopausal women with PAH and men with PAH were randomized in a 1:1 ratio to receive anastrozole 1 mg or placebo by mouth daily, stratified by sex using permuted blocks of variable sizes. All subjects and study staff were masked. The primary outcome was the change from baseline in 6MWD at 6 months. By intention-to-treat analysis, we estimated the treatment effect of anastrozole using linear regression models adjusted for sex and baseline 6MWD. Assuming 10% loss to follow-up, we anticipated having 80% power to detect a difference in the change in 6MWD of 22 meters. Measurements and Main Results Forty-one subjects were randomized to placebo and 43 to anastrozole, and all received the allocated treatment. Three subjects in the placebo group and two in the anastrozole group discontinued the study drug. There was no significant difference in the change in 6MWD at 6 months (placebo-corrected treatment effect, −7.9 m; 95% confidence interval, −32.7 to 16.9; P = 0.53). There was no difference in adverse events between the groups. Conclusions Anastrozole did not show a significant effect on 6MWD compared with placebo in postmenopausal women with PAH and in men with PAH. Anastrozole was safe and did not have adverse effects. Clinical trial registered with www.clincialtrials.gov (NCT03229499).

A 6-minute walk test is a simple tool for assessing submaximal exercise capacity. We sought to determine whether a 6-minute walk distance (6MWD) predicts outcomes in patients with cirrhosis. The Pulmonary Vascular Complications of Liver Disease 2 study is a multicenter, prospective cohort study that enrolled adults with portal hypertension during liver transplantation evaluation. We excluded subjects with an incident or prevalent portopulmonary hypertension. The 6-minute walk test was performed using standardized methods. Cox proportional hazards modeling and multivariable linear regression analysis were performed to determine the relationship between baseline 6MWD and outcomes. The study sample included 352 subjects. The mean 6MWD was 391±101 m. For each 50-meter decrease in 6MWD, there was a 25% increase in the risk of death (HR 1.25, 95% CI [1.11, 1.41], p < 0.001) after adjustment for age, gender, body mass index, MELD-Na, and liver transplant as a time-varying covariate. In a multistate model, each 50-meter decrease in 6MWD was associated with an increased risk of death before the liver transplant ( p < 0.001) but not after the transplant. 6MWD was similar to MELD-Na in discriminating mortality. Each 50-meter decrease in 6MWD was associated with an increase in all-cause ( p < 0.001) and transplant-free hospitalizations ( p < 0.001) in multivariable models for time-to-recurrent events. Shorter 6MWD was associated with worse Short Form-36 physical ( p < 0.001) and mental component scores ( p = 0.05). In conclusion, shorter 6MWD is associated with an increased risk of death, hospitalizations, and worse quality of life in patients evaluated for liver transplantation. The 6-minute walk distance may be a useful adjunct for risk assessment in patients undergoing liver transplant evaluation.