Health Disparities and Differences in Health-Care-Utilization in Patients With Pulmonary Arterial Hypertension.

Introduction: Mental disorders are common in patients with pulmonary arterial hypertension (PAH) and contribute to impaired quality of life (QoL). The impact of mental disorders on access to health care, differences in clinical parameters and treatment in patients with PAH is unclear. In this study we sought to assess the impact of mental disorders and other health disparities on health-care-utilization in patients with PAH. Methods: In a cross-sectional observational study of patients with PAH, mental disorders were characterized using a structed clinical interview. In addition, patients completed a self-administered questionnaire to assess QoL, symptoms of anxiety and depression, lifestyle-factors and educational status. Number of outpatient visits and communication events per year were calculated as a surrogate for health-care-utilization and were compared by the presence of mental disorder. Linear regression analysis was conducted to assess the impact on health-care-utilization. Results: 117 patients with PAH participated in this study (70% female, median age 59 (interquartile range, 49-70) years). Significant differences between patients with or without mental disorders were found in anxiety, depression and QoL. There were no significant differences in clinical parameters. Patients with mental disorders had higher rates of outpatient visits and communication events than patients without mental disorders. Linear regression revealed a gain of 2.2 communication events per year in the presence of any mental disorders. Conclusion: Mental disorders in patients with PAH are common and significantly affect health-care-utilization. This higher demand in patients with mental disorder needs to be addressed by physicians, psychiatrists and specialized nurses offering therapeutic strategies.

COMPERA 2.0: a refined four-stratum risk assessment model for pulmonary arterial hypertension.

BACKGROUND: Risk stratification plays an essential role in the management of patients with pulmonary arterial hypertension (PAH). The current European guidelines propose a three-stratum model to categorise risk as low, intermediate or high, based on the expected 1-year mortality. However, with this model, most patients are categorised as intermediate risk. We investigated a modified approach based on four risk categories, with intermediate risk subdivided into intermediate-low and intermediate-high risk. METHODS: We analysed data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), a European pulmonary hypertension registry, and calculated risk at diagnosis and first follow-up based on World Health Organization functional class, 6-min walk distance (6MWD) and serum levels of brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP), using refined cut-off values. Survival was assessed using Kaplan-Meier analyses, log-rank testing and Cox proportional hazards models. RESULTS: Data from 1655 patients with PAH were analysed. Using the three-stratum model, most patients were classified as intermediate risk (76.0% at baseline and 63.9% at first follow-up). The refined four-stratum risk model yielded a more nuanced separation and predicted long-term survival, especially at follow-up assessment. Changes in risk from baseline to follow-up were observed in 31.1% of the patients with the three-stratum model and in 49.2% with the four-stratum model. These changes, including those between the intermediate-low and intermediate-high strata, were associated with changes in long-term mortality risk. CONCLUSIONS: Modified risk stratification using a four-stratum model based on refined cut-off levels for functional class, 6MWD and BNP/NT-proBNP was more sensitive to prognostically relevant changes in risk than the original three-stratum model.

Risk assessment in pulmonary arterial hypertension: Insights from the GRIPHON study.

BACKGROUND: Approaches to risk assessment in pulmonary arterial hypertension (PAH) include the noninvasive French risk assessment approach (number of low-risk criteria based on the European Society of Cardiology and European Respiratory Society guidelines) and Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) 2.0 risk calculator. The prognostic and predictive value of these methods for morbidity/mortality was evaluated in the predominantly prevalent population of GRIPHON, the largest randomized controlled trial in PAH. METHODS: GRIPHON randomized 1,156 patients with PAH to selexipag or placebo. Post-hoc analyses were performed on the primary composite end-point of morbidity/mortality by the number of low-risk criteria (World Health Organization functional class I-II; 6-minute walk distance >440 m; N-terminal pro-brain natriuretic peptide <300 ng/liter) and REVEAL 2.0 risk category. Hazard ratios and 95% confidence intervals were calculated using Cox proportional hazard models. RESULTS: Both the number of low-risk criteria and the REVEAL 2.0 risk category were prognostic for morbidity/mortality at baseline and any time-point during the study. Patients with 3 low-risk criteria at baseline had a 94% reduced risk of morbidity/mortality compared to patients with 0 low-risk criteria and were all categorized as low-risk by REVEAL 2.0. The treatment effect of selexipag on morbidity/mortality was consistent irrespective of the number of low-risk criteria or the REVEAL 2.0 risk category at any time-point during the study. Selexipag-treated patients were more likely to increase their number of low-risk criteria from baseline to week 26 than placebo-treated patients (odds ratio 1.69, p = 0.0002); similar results were observed for REVEAL 2.0 risk score. CONCLUSIONS: These results support the association between risk profile and long-term outcome and suggest that selexipag treatment may improve risk profile.

Therapeutic plasma exchange in acute liver failure.

BACKGROUND: Multi-organ dysfunction in acute liver failure (ALF) has been attributed to a systemic inflammatory response directly triggered by the injured liver. High-volume therapeutic plasma exchange (HV-TPE) has been demonstrated in a large randomized controlled trial to improve survival. Here, we investigated if a more cost-/ resource effective low-volume (LV) TPE strategy might have comparable beneficial effects. METHODS: This retrospective study evaluated the effect of LV-TPE on remote organ failure, hemodynamical and biochemical parameters as well as on survival in patients with ALF. Twenty patients treated with LV-TPE in addition to standard medical therapy (SMT) were identified and 1:1 matched to a historical ALF cohort treated with SMT only. Clinical and biochemical parameters were recorded at admission to the intensive care unit and the following 7 days after LV-TPE. RESULTS: Mean arterial pressure increased following first LV-TPE treatments (d0: 68 [61-75] mm Hg vs d7: 88 [79-98] mm Hg, P = .003) and norepinephrine dose was reduced (d0: 0.264 [0.051-0.906] µg/kg/min vs d3: 0 [0-0.024] µg/kg/min, P = .016). Multi-organ dysfunction was significantly diminished following LV-TPE (CLIF-SOFA d0: 17 [13-20] vs d7: 7 [3-11], P = .001). Thirty-day in-hospital survival was 65% in the LV-TPE cohort and 50% in the SMT cohort (Hazard-ratio for TPE: 0.637; 95% CI: 0.238-1.706, P = .369). CONCLUSIONS: Patients treated with LV-TPE showed improved surrogate parameters comparable with the effects reported with HV-TPE. These data need to be interpreted with caution due to their retrospective character. Future controlled studies are highly desirable.

Risk assessment in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

BACKGROUND: Current pulmonary hypertension treatment guidelines recommend use of a risk stratification model encompassing a range of parameters, allowing patients to be categorised as low, intermediate or high risk. Three abbreviated versions of this risk stratification model were previously evaluated in patients with pulmonary arterial hypertension (PAH) in the French, Swedish and COMPERA registries. Our objective was to investigate the three abbreviated risk stratification methods for patients with mostly prevalent PAH and chronic thromboembolic pulmonary hypertension (CTEPH), in patients from the PATENT-1/2 and CHEST-1/2 studies of riociguat. METHODS: Risk was assessed at baseline and at follow-up in PATENT-1 and CHEST-1. Survival and clinical worsening-free survival were assessed in patients in each risk group/strata. RESULTS: With all three methods, riociguat improved risk group/strata in patients with PAH after 12 weeks. The French non-invasive and Swedish/COMPERA methods discriminated prognosis for survival and clinical worsening-free survival at both baseline and follow-up. Furthermore, patients achieving one or more low-risk criteria or a low-risk stratum at follow-up had a significantly reduced risk of death and clinical worsening compared with patients achieving no low-risk criteria or an intermediate-risk stratum. Similar results were obtained in patients with inoperable or persistent/recurrent CTEPH. CONCLUSIONS: This analysis confirms and extends the results of the registry analyses, supporting the value of goal-oriented treatment in PAH. Further assessment of these methods in patients with CTEPH is warranted.

Risk assessment in medically treated chronic thromboembolic pulmonary hypertension patients.

Abbreviated versions of the risk stratification strategy of the European Society of Cardiology (ESC)/European Respiratory Society (ERS) pulmonary hypertension guidelines have been recently validated in patients with pulmonary arterial hypertension. We aimed to investigate their prognostic value in medically treated chronic thromboembolic pulmonary hypertension (CTEPH) patients from the COMPERA registry, which collects six variables of interest (World Health Organization Functional Class, 6-min walk distance, brain natriuretic peptide, right atrial pressure, cardiac index and mixed venous oxygen saturation).We included patients with at least one follow-up visit, no pulmonary endarterectomy and at least three of the six variables available, and classified the patients into low-, intermediate- and high-risk groups. As a secondary analysis, the number of noninvasive low-risk criteria was counted. The association between risk assessment and survival was evaluated.Data from inclusion and follow-up (median 7 months) visits were available for 561 and 231 patients, respectively. Baseline 1- and 5-year survival estimates were significantly different (p<0.0001) in the baseline low-risk (98.6% and 88.3%, respectively), intermediate-risk (94.9% and 61.8%, respectively) and high-risk (75.5% and 32.9%, respectively) cohorts. Follow-up data were even more discriminative, with 100%, 92% and 69% 1-year survival, respectively. The number of low-risk noninvasive criteria was also associated with survival.These analyses suggest that the ESC/ERS risk assessment may be applicable in patients with medically treated CTEPH.

Risk stratification strategy and assessment of disease progression in patients with pulmonary arterial hypertension: Updated Recommendations from the Cologne Consensus Conference 2018.

In the summer of 2016, delegates from the German Respiratory Society, the German Society of Cardiology and the German Society of Pediatric Cardiology met in Cologne, Germany, to define consensus-based practice recommendations for the management of patients with pulmonary arterial hypertension (PAH). These recommendations were built on the 2015 European Pulmonary Hypertension guidelines and included new evidence, where available, and were last updated in the spring of 2018. This article focusses on the proposed risk stratification and assessment of disease progression in patients with pulmonary arterial hypertension (PAH), covering 3 parts: In part 1, methods and markers that are recommended to assess severity and progression of PAH are discussed and commented. These updated comments incorporate most recent data as well as challenges arising from the variability of phenotypes of PAH patients with increasing cardiopulmonary comorbidities. In part 2, the proposed ESC/ERS risk stratification strategy is discussed, together with a review of the recent validation studies from different European registries. Finally, in part 3, the working group of the Cologne Consensus Conference provides recommendations on how risk assessment may be implemented in routine clinical practice and may serve clinical decision making.

Quantitation of Perfused Lung Volume Using Hybrid SPECT/CT Allows Refining the Assessment of Lung Perfusion and Estimating Disease Extent in Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: We evaluated the feasibility of perfusion SPECT/CT for providing quantitative data for estimation of perfusion defect extent in chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: Thirty patients with CTEPH underwent Tc-human serum albumin lung perfusion SPECT/CT. Perfusion defects were quantified using 3 different methods: (1) visual, semiquantitative scoring of perfusion defect extent in each lung segment, (2) threshold-based segmentation of perfused lung volumes, and (3) threshold-based segmentation of perfused lung volumes divided by segmented lung volumes at CT (perfusion index). Imaging findings were correlated with right-sided heart catheterization results and N-terminal pro-B-type natriuretic peptide. Receiver operating characteristic analysis was performed to identify SPECT thresholds for mean pulmonary arterial pressure (PAPm) greater than 50 mm Hg. RESULTS: Assessment of lung perfusion provided similar results using all 3 methods. The perfusion defect score correlated with PAPm (rs = 0.60, P = 0.0005) and was associated with serum levels of N-terminal pro-B-type natriuretic peptide (rs = 0.37, P = 0.04). Perfused lung volume (40% threshold, rs = -0.48, P = 0.007) and perfusion index (40% threshold, rs = -0.50, P = 0.005) decreased as PAPm increased. Receiver operating characteristic analysis showed that perfusion defect score (sensitivity, 88%; specificity, 77%; area under the curve [AUC] = 0.89, P = 0.001), perfused lung volume (sensitivity, 88%; specificity, 64%; AUC = 0.80, P = 0.01), and perfusion index (sensitivity, 88%; specificity, 64%; AUC = 0.82, P = 0.009) could identify patients with PAPm of greater than 50 mm Hg. CONCLUSIONS: Quantitative analysis of perfusion defects at SPECT is feasible, provides a measure of disease severity, and correlates with established clinical parameters. Quantitation of perfusion SPECT may refine the diagnostic approach in CTEPH providing a quantitative imaging biomarker, for example, for therapy monitoring.

Demographics, clinical characteristics, health resource utilization and cost of chronic thromboembolic pulmonary hypertension patients: retrospective results from six European countries.

BACKGROUND: Chronic Thromboembolic Pulmonary Hypertension (CTEPH) results from incomplete resolution of a pulmonary embolus, leading to pulmonary hypertension and progressive right heart failure and death. We aimed to describe the demographics, treatment patterns, health resource utilization and related costs of patients with CTEPH. METHODS: In specialized PH centres across six European countries, medical charts of CTEPH patients on PH medication were retrospectively extracted (chart review between 2006 and 2009). Resource utilization was valued using country-specific unit costs. Descriptive statistical analyses were performed. RESULTS: Twenty-one hospitals documented 119 consecutive CTEPH patients over an average of 25.4 months. Patients were inoperable (83.9%) or persistent after surgery (16.0%) with mean age 67.5 ± 12.3 years, 61% were female. The average 6-minute walking distance was 298 ± 120 meters, and NYHA class II/III/IV was 27/59/14%. At baseline, 59.7% patients received endothelin receptor antagonist, 34.4% phosphodiesterase-5 inhibitors, and 5.8% prostacyclin. Adding a second PH medication was the most common regimen change. CTEPH patients experienced 1.8 ± 2.2 hospitalizations per year accounting for 14.8 ± 26.1 days in hospital. Patients paid on average 2.8 office visits per year to their general practitioner and 1.3 visits to a specialist. Unadjusted annual mortality rate was 6.0%. Annual cost of PH specific medication was the predominant economic factor averaging € 36,768 per year. Costs for hospitalizations (€ 4,496) and concomitant medications (€ 2,510) were substantially lower. Other health care resource items only accounted for marginal additional costs. CONCLUSION: CTEPH patients are characterised by substantial morbidity and mortality. Health care utilisation, predominantly due to off-label use of PH drugs, is significant.

Diagnosis and assessment of pulmonary arterial hypertension.

The diagnosis and assessment of pulmonary arterial hypertension is a rapidly evolving area, with changes occurring in the definition of the disease, screening and diagnostic techniques, and staging and follow-up assessment. The definition of pulmonary hypertension has been simplified, and is now based on currently available evidence. There has been substantial progress in advancing the imaging techniques and biomarkers used to screen patients for the disease and to follow up their response to therapy. The importance of accurate assessment of right ventricular function in following up the clinical course and response to therapy is more fully appreciated. As new therapies are developed for pulmonary arterial hypertension, screening, prompt diagnosis, and accurate assessment of disease severity become increasingly important. A clear definition of pulmonary hypertension and the development of a rational approach to diagnostic assessment and follow-up using both conventional and new tools will be essential to deriving maximal benefit from our expanding therapeutic armamentarium.

Diagnosis, assessment, and treatment of non-pulmonary arterial hypertension pulmonary hypertension.

The 4th World Symposium on Pulmonary Hypertension was the first international meeting to focus not only on pulmonary arterial hypertension (PAH) but also on the so-called non-PAH forms of pulmonary hypertension (PH). The term "non-PAH PH" summarizes those forms of PH that are found in groups 2 to 5 of the current classification of PH, that is, those forms associated with left heart disease, chronic lung disease, recurrent venous thromboembolism, and other diseases. Many of these forms of PH are much more common than PAH, but all of them have been less well studied, especially in terms of medical therapy. The working group on non-PAH PH focused mainly on 4 conditions: chronic obstructive lung disease, interstitial lung disease, chronic thromboembolic PH, and left heart disease. The medical literature regarding the role of PH in these diseases was reviewed, and recommendations regarding diagnosis and treatment of PH in these conditions are provided. Given the lack of robust clinical trials addressing PH in any of these conditions, it is important to conduct further studies to establish the role of medical therapy in non-PAH PH.