Long-term Pulmonary Arterial Hypertension Research Articles

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

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. 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. 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. These results support the association between risk profile and long-term outcome and suggest that selexipag treatment may improve risk profile.

The burden of comorbidities in pulmonary arterial hypertension.

Patients with comorbidities are often excluded from clinical trials, limiting the evidence base for pulmonary arterial hypertension (PAH)-specific therapies. This review aims to discuss the effect of comorbidities on the diagnosis and management of PAH. The comorbidities discussed in this review (systemic hypertension, obesity, sleep apnoea, clinical depression, obstructive airway disease, thyroid disease, diabetes, and ischaemic cardiovascular event) were chosen based on their prevalence in patients with idiopathic PAH in the REVEAL registry (Registry to EValuate Early and Long-term PAH disease management). Comorbidities can mask the symptoms of PAH, leading to delays in diagnosis and also difficulty evaluating disease progression and treatment effects. Due to the multifactorial pathophysiology of pulmonary hypertension (PH), the presence of comorbidities can lead to difficulties in distinguishing between Group 1 PH (PAH) and the other group classifications of PH. Many comorbidities contribute to the progression of PAH through increased pulmonary artery pressures and cardiac output, therefore treatment of the comorbidity may also reduce the severity of PAH. Similarly, the development of one comorbidity can be a risk factor for the development of other comorbidities. The management of comorbidities requires consideration of drug interactions, polypharmacy, adherence and evidence-based strategies. A multidisciplinary team should be involved in the management of patients with PAH and comorbidities, with appropriate referral to supportive services when necessary. The treatment goals and expectations of patients must be managed in the context of comorbidities.

Risk Reduction and Right Heart Reverse Remodeling by Upfront Triple Combination Therapy in Pulmonary Arterial Hypertension

Combinations of therapies are currently recommended for patients with severe pulmonary arterial hypertension (PAH), and excellent results have been reported with triple upfront combination of these drugs. We evaluated the effects of this approach on right ventricular (RV) function and outcome in patients with severe PAH. Twenty-one patients (age, 44 ± 15 years) with newly diagnosed high-risk idiopathic PAH that was nonreversible by the inhalation of nitric oxide were treated upfront with a combination of ambrisentan, tadalafil, and subcutaneous treprostinil between 2014 and 2018. Clinical evaluation, World Health Organization functional class, 6-min walk distance, biomarkers, echocardiography, and right-sided heart catheterization data were recorded at baseline and during follow-up. At a median follow-up of 2 years, all patients were still alive. The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management score decreased from 10 ± 1 to 5 ± 1, right-sided atrial pressure decreased from 13 ± 3 to 5 ± 2mmHg, mean pulmonary artery pressure decreased from 60 ± 9 to 42 ± 5mmHg, pulmonary vascular resistance (PVR) decreased from 16.4 ± 4.4 to 5.5 ± 1.3 Wood units, N-terminal pro-brain natriuretic peptide decreased from 3,379 ± 1,921 to 498 ± 223 pg/mL, and World Health Organization functional class decreased from 3.4 ± 0.5 to 2.0 ± 0.4 (all P< .001). Cardiac index increased from 1.8 ± 0.3 to 3.5 ± 0.8 L/min/m2 and 6-min walk distance increased from158 ± 130 to 431 ± 66m (both P< .001). Echocardiography showed decreased right-sided atrial and RV areas, improved left ventricular eccentricity index, and increased fractional area change (all P< .001) in proportion to treatment-induced decrease in PVR. Triple upfront combination therapy with ambrisentan, tadalafil, and subcutaneous treprostinil in severe nonreversible PAH is associated with considerable clinical and hemodynamic improvement and right-sided heart reverse remodeling.

Retrospective Validation of the REVEAL 2.0 Risk Score With the Australian and New Zealand Pulmonary Hypertension Registry Cohort

Pulmonary arterial hypertension (PAH) prognosis has improved with targeted therapies; however, the long-term outlook remains poor. Objective multiparametric risk assessment is recommended to identify patients at risk of early morbidity and mortality, and for optimization of treatment. The US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0 risk score is a new model proposed for the follow-up of patients with PAH but has not been externally validated. The REVEAL 2.0 risk score was applied to a mixed prevalent and incident cohort of patients with PAH (n= 1,011) from the Pulmonary Hypertension Society of Australia and New Zealand (PHSANZ) Registry. Kaplan-Meier survival was estimated for each REVEAL 2.0 risk score strata and for a simplified three-category (low, intermediate, and high risk) model. Sensitivity analysis was performed on an incident-only cohort. The REVEAL 2.0 model effectively discriminated risk in the large external PHSANZ Registry cohort, with a C statistic of 0.74 (both for full eight-tier and three-category models). When applied to incident cases only, the C statistic was 0.73. The three-category REVEAL 2.0 model demonstrated robust separation of 12- and 60-month survival estimates (all risk category comparisons P< .001). Although the full eight-tier REVEAL 2.0 model separated patients at low, intermediate, and high risk, survival estimates overlapped within some of the intermediate- and high-risk strata. The REVEAL 2.0 risk score was validated in a large external cohort from the PHSANZ Registry. The REVEAL 2.0 model can be applied for risk assessment of patients with PAH at follow-up. The simplified three-category model may be preferred for clinical use and for future comparison with other prognostic models.

Validation of the REVEAL Prognostic Equation and Risk Score Calculator in Incident Systemic Sclerosis-Associated Pulmonary Arterial Hypertension.

A prognostic equation and risk score calculator derived from the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) are being used to predict 1-year survival in patients with pulmonary arterial hypertension (PAH), but little is known about the performance of these REVEAL survival prediction tools in systemic sclerosis (SSc)-associated PAH (SSc-PAH). Prospectively gathered data from the Johns Hopkins Pulmonary Hypertension Program and Pulmonary Hypertension Assessment and Recognition of Outcome in Scleroderma Registries were used to evaluate the predictive accuracy of the REVEAL models for predicting the probability of 1-year survival in patients with SSc-PAH. Model discrimination was assessed by comparison of the Harrell's C-index, model fit was assessed using multivariable regression techniques, and model calibration was assessed by comparing predicted to observed survival estimates. The validation cohort consisted of 292 SSc-PAH patients with a 1-year survival rate of 87.4%. The C-index for predictive accuracy of the REVEAL prognostic equation (0.734, 95% confidence interval [95% CI] 0.652-0.816) and for the risk score (0.743, 95% CI 0.663-0.823) demonstrated good discrimination, comparable to that in the model development cohort. The calibration slope was 0.707 (95% CI 0.400-1.014), indicating that the overall model fit was marginal (P = 0.06). The magnitude of risk assigned to low distance on the 6-minute walk test (6MWD) and elevated serum levels of brain natriuretic peptide (BNP) was lower in the validation cohort than was originally seen in the REVEAL derivation cohort. Model calibration was poor, particularly for the highest risk groups. In predicting 1-year survival in patients newly diagnosed as having SSc-PAH, the REVEAL prognostic equation and risk score provide very good discrimination but poor calibration. REVEAL prediction scores should be interpreted with caution in newly diagnosed SSc-PAH patients, particularly those with higher predicted risk of poor 1-year survival resulting from a low 6MWD or a high BNP serum level.

Relationship between Race/Ethnicity and Survival in Patients with Pulmonary Arterial Hypertension (PAH)

Purpose Prior research suggests that PAH prevalence and subtype may vary by race/ethnicity. Although some data suggest that disease severity and clinical outcomes also differ by race/ethnicity, these data are limited and based on single-center analyses. The relationship between race/ethnicity and survival was evaluated in a US prospective multicenter registry of WHO group 1 PAH, the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL). Methods Included patients were ≥18 years of age with pulmonary capillary wedge pressure ≤15 mmHg. Cox proportional hazard models were used to assess the association between race/ethnicity and survival, unadjusted or adjusted for prognostic factors of age, diagnostic status (i.e. newly or previously diagnosed), PAH etiology, and sex. The relationship between race/ethnicity and survival was also analyzed using a left-truncation which adjusts for time from diagnosis to study enrollment with covariates of age and PAH etiology. Results This analysis included 3,046 patients: 2,202 identified as white, 393 as black, 263 as Hispanic, 100 as Asian or Pacific Islander, and 88 as other. A Kaplan-Meier estimate of survival by race/ethnicity indicated that white patients had the lowest survival rate. Results of an unadjusted Cox model were consistent with this, in that Asian or Pacific Islander (HR=0.46, 95% CI 0.28-0.76, p=0.002) or Hispanic (HR=0.74, 95% CI 0.56-0.97, p=0.029) patients had a lower risk of death than white patients; black patients had a similar risk as white patients. An evaluation of potentially prognostic factors by race/ethnicity revealed that white patients were older than patients of other races/ethnicities. When the Cox model was adjusted for age and other variables of potential prognostic impact that varied by race/ethnicity in this population, race/ethnicity was no longer significantly associated with survival (Asian or Pacific Islander vs. white HR=0.69, 95% CI 0.46-1.05, p=0.09; Hispanic vs. white HR=1.05, 95% CI 0.82-1.33, p=0.71; black vs white; HR=1.04, 95% CI 0.86-1.23; p=0.72). Survival analysis using left-truncation also showed no effect of race/ethnicity on survival. Conclusion Contrary to earlier analyses and other diseases in which race/ethnicity substantially impacts outcome, these data suggest that race/ethnicity is not a predictor of survival in patients with PAH.

Low plasma stem cell factor combined with high transforming growth factor-α identifies high-risk patients in pulmonary arterial hypertension

In pulmonary arterial hypertension (PAH), severe vasoconstriction and remodelling of small pulmonary arteries result in high mortality. Receptor tyrosine kinases and their ligands, such as transforming growth factor (TGF)-α, modulate proliferation in PAH. Although the receptor tyrosine kinase c-Kit has been shown to be overexpressed in PAH, the expression and role of its ligand stem cell factor (SCF) remain unknown. However, low plasma SCF levels are known to be linked to higher cardiovascular mortality risk.Using proximity extension assays, we measured SCF and TGF-α in venous plasma from treatment-naïve PAH patients and healthy controls. Patients were stratified into risk classes based on PAH guidelines.Plasma SCF was decreased (p=0.013) and TGF-α was increased (p<0.0001) in PAH patients compared to controls. SCF correlated to pulmonary vascular resistance (r=−0.66, p<0.0001), cardiac index (r=0.66, p<0.0001), venous oxygen saturation (r=0.47, p<0.0008), mean right atrial pressure (r=−0.44, p<0.002) and N-terminal pro-brain natriuretic protein (r=−0.39, p<0.006). SCF was lower in “high-risk” compared to “intermediate-risk” (p=0.0015) or “low-risk” (p=0.0009) PAH patients. SCF and TGF-α levels combined (SCF/TGF-α) resulted in 85.7% sensitivity and 81.5% specificity for detecting high-risk patients (p<0.0001). Finally, REVEAL (Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management) risk scores in PAH patients correlated to SCF/TGF-α levels (r=−0.50, p=0.0003).In conclusion, low plasma SCF combined with high TGF-α identifies high-risk PAH patients at baseline. Lower circulating SCF levels, which are associated with worse haemodynamics, may be related to the c-Kit accumulation previously observed in PAH.

APPLICATION OF A BAYESIAN NETWORK MODEL TO PREDICT OUTCOMES IN PULMONARY ARTERIAL HYPERTENSION

SESSION TITLE: Comorbidities and the Management of Pulmonary Hypertension SESSION TYPE: Original Investigations PRESENTED ON: 10/10/2018 08:45 AM - 09:45 AM PURPOSE: In spite of emerging new therapeutic options, pulmonary arterial hypertension (PAH) remains a highly morbid and fatal disease. The Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) developed a multivariable, weighted risk formula to predict the risk of one-year survival using multiple clinical variables, which was recently updated (REVEAL 2.0). This study aimed to develop an improved prognostic model by employing dynamic machine learning tools and Bayesian modeling on the REVEAL data and compare the results to the COMPERA and French registry risk assessment when applied on the same data set. METHODS: Data sets from the REVEAL registry, comprised of 54 US sites and 2,964 adult patients with PAH, were used to develop a Bayesian network (BN) risk model to predict 1-year survival. The model was learned from 80% (n=2347) of the patients using the Tree Augmented Naive Bayes (TAN) algorithm and validated in the remaining 20% (n=617). We used the same variables found in the REVEAL 2.0 calculator (e.g. BNP, PVR, DLCO, NYHA class, 6MWD etc.) and the same discretization cut points. We then applied the same methods for the discretized variable cutoffs published in the COMPERA and French registry to the patients in the REVEAL database to compare their relative performance as measured by areas under the ROC curve (AUC). RESULTS: The Bayesian model demonstrated an accuracy of 90% with an AUC of 0.83 for predicting one-year survival. This was an improvement to the existing AUC of 0.76 for the REVEAL 2.0 calculator. It also significantly outperformed the risk stratification in the COMPERA and French registry (AUC of 0.67 and 0.63 respectively). Bayesian analytic algorithms also allowed the demonstration of the impact of each of these variables on each other, as well as the final outcome (survival), which is a unique feature of Bayesian analysis. CONCLUSIONS: A Bayesian model for PAH demonstrated a modest improvement in accuracy over the existing multi-variate model of the REVEAL 2.0 calculator. It also outperformed the risk predictions based on COMPERA and French registry. CLINICAL IMPLICATIONS: Our long-term goal is to generate a personalized risk assessment tool to aid in bedside decision making for managing patients with PAH. DISCLOSURES: No relevant relationships by James Antaki, source=Web Response Consultant relationship with Bayer, actelion, arena, Please note: $1001 - $5000 Added 02/28/2018 by Raymond Benza, source=Web Response, value=Grant/Research Support Owner/Founder relationship with BayesFusion, LLC Please note: $1-$1000 Added 03/02/2018 by Marek Druzdzel, source=Web Response, value=Ownership interest No relevant relationships by Manreet Kanwar, source=Web Response No relevant relationships by Jidapa Kraisangka, source=Web Response No relevant relationships by Lisa Lohmueller, source=Web Response Employee relationship with Actelion Pharmaceuticals US, Inc Please note: >$100000 Added 02/20/2018 by Mona Selej, source=Web Response, value=Salary No relevant relationships by Judith Speck, source=Web Response No relevant relationships by Carol Zhao, source=Web Response

Pulmonary arterial hypertension in a multi-ethnic Asian population: Characteristics, survival and mortality predictors from a 14-year follow-up study.

Pulmonary arterial hypertension (PAH) is a rare and fatal disease. Data from Asia are lacking compared with the West. We aim to describe disease characteristics in an ethnically diverse South-East Asian population and assess predictors for survival. We consecutively enrolled patients with PAH referred to our pulmonary hypertension specialty centre from January 2003 to December 2016. Baseline characteristics and survival were analysed. Based on a forward predictor selection procedure, a multi-level structural equation model was applied to identify predictors associated with mortality. Out of 148 patients enrolled, 77% were females and mean age was 50.8 ± 15.9 years. Racial distribution was consistent with our population census. The most common aetiologies were congenital heart disease-associated PAH (35.8%), idiopathic PAH (29.7%) and then connective tissue disease-associated PAH (24.3%). Most patients presented in World Health Organization (WHO) Functional Class (FC) II (48.6%), followed by FC III (28.8%). Majority of patients (54.1%) were on phosphodiesterase type 5 (PDE5) inhibitor monotherapy. Survival rates were 85.8% at the end of the first year, 70.9% at 3 years, 66.9% at 5 years, 61.5% at 7 years and 55.4% at 10 years. The Registry to Evaluate Early And Long-term PAH Disease Management (REVEAL) score (RS) was found to be the best predictor of mortality. A score > 6 was identified as a cut-off. Other predictors include mean right atrial pressure, heart rate, aetiology, age and N-terminal pro-brain natriuretic peptide. In this first registry study from a South-East Asian population, our survival rates are comparable with other national registries. The RS is validated in our population to be a good predictor of mortality.

Risk stratification in pulmonary arterial hypertension.

Periodic risk stratification is recommended for patients with pulmonary arterial hypertension (PAH). The purpose of this article is to review the available risk stratification tools in PAH. Validated tools, such as the REVEAL (Registry to Evaluate Early And Long-term PAH Disease Management) score or European Society of Cardiology/European Respiratory Society (ESC/ERS) risk assessment table incorporate clinical, exercise, imaging, and hemodynamic variables to obtain a multidimensional estimate of prognosis. Recent studies from REVEAL and European registries have further validated these tools and improved our understanding of prognostic factors in PAH. Serial risk assessment over time, especially after treatment initiation or modification, provides more useful information than at a single time point, with changes in risk profiles being particularly informative. A brief, simplified approach includes counting the number of ESC/ERS low-risk criteria achieved, with 3 or 4 low-risk criteria associated with an excellent prognosis. When a more precise estimation of risk is desired, the REVEAL score can delineate five risk groups with 1-year survival rates between 97.3% (low risk) and 50.2% (very high risk). The REVEAL and ESC/ERS risk table are useful, validated, multidimensional risk stratification tools that should be periodically applied to patients with PAH in practice.

Tolerability and clinical efficacy of inhaled treprostinil in patients with group 1 pulmonary arterial hypertension.

Treprostinil is a prostacyclin analogue that directly vasodilates pulmonary and systemic arterial vascular beds. The United States Food and Drug Administration approved inhaled treprostinil in July 2009 for the treatment of group 1 pulmonary arterial hypertension. Inhaled treprostinil avoids issues with continuous infusion prostanoids. This study describes a single institutional experience with inhaled treprostinil. This was a retrospective review of group 1 pulmonary arterial hypertension patients receiving inhaled treprostinil from July 2009 through September 2015. Patient demographics, vital signs, prognostic indicators, pulmonary arterial hypertension assessments, treprostinil dosing, pulmonary arterial hypertension medications, and physician assessment were collected. Prognostic indicators and the physician assessment were used to assess treatment response. A modified Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) risk score was calculated prior to and after initiation of inhaled treprostinil. The mean time on inhaled treprostinil for the 16 patients was 21 ± 17 months. A total of 31% discontinued treatment. The New York Heart Association Functional Class, right ventricular size, and right ventricular function improved after inhaled treprostinil. Directional improvement in B-type natriuretic peptide, 6-minute walk distance, right arterial pressure and mean pulmonary artery pressure were also observed. The mean modified REVEAL risk score (RRS) was 7 ± 3 at baseline. The RRS decreased in 7 of the 11 patients that improved and remained stable in 2 patients. The majority of patients in this consecutive series receiving inhaled treprostinil tolerated treatment. Most patients remained on therapy for over 12 months. Clinical assessments of disease severity all changed directionally toward improvement and the overall risk assessment was improved or stable in 56% by the RRS.

Use of supplemental oxygen in patients with pulmonary arterial hypertension in REVEAL.

Supplemental low-flow oxygen is recommended by treatment guidelines as supportive therapy for patients with pulmonary arterial hypertension (PAH), based largely on expert opinion. Reduced diffusing capacity of lung carbon monoxide (DLCO) is associated with increased mortality in PAH. Reduced DLCO is also associated with relative hypoxemia, making the effects of supplemental oxygen use of particular interest in this sub-population. Patients in the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), a 5-year observational study of Group 1 PAH, were categorized by presence or absence of supplemental oxygen use and by degree of DLCO reduction. Kaplan-Meier survival estimates were calculated by group. Of 3,046 patients, 57% used supplemental oxygen and 43% did not. Supplemental oxygen users had worse prognostic factors and more PAH-specific medication use. Of the 424 patients with severe DLCO reduction (<40% of predicted), 76% used oxygen and 24% did not. Patients with severe DLCO reduction who used supplemental oxygen had a significantly lower risk of all-cause mortality than those who did not (hazard ratio 0.56; 95% confidence interval 0.39 to 0.83; p = 0.0033). This was true for newly diagnosed and previously diagnosed patients. There was no relationship between oxygen use and outcomes in patients with no, mild, or moderate DLCO reduction. In this observational study, the risk of death was significantly lower for patients with severe DLCO reduction who received supplemental oxygen compared with those who did not. A randomized trial is warranted to further investigate the relationship between supplemental oxygen use and outcomes in PAH.

Baseline and Serial Brain Natriuretic Peptide Level Predicts 5-Year Overall Survival in Patients With Pulmonary Arterial Hypertension: Data From the REVEAL Registry

Plasma brain natriuretic peptide (BNP) level is a prognostic biomarker in pulmonary arterial hypertension (PAH). Its impact on long-term overall survival (OS) was investigated in the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL), a 5-year observational, multicenter, US registry of patients with PAH. Patients were≥ 18 years of age, met right heart catheterization criteria at rest, had World Health Organization group I PAH, and had BNP measurement at enrollment. Optimal BNP threshold was obtained via receiver operating characteristic curve analysis. OS was compared in patients with low (≤ 340 pg/mL) vshigh (> 340 pg/mL) BNP at baseline; changes between baseline and last assessment were also examined. Patients were categorized based on baseline (low or high) and follow-up (low or high) BNP values; hazard ratios (HRs) for OS were estimated and compared using Cox regression. Overall, 1,426 patients were analyzed. Mortality risk was significantly higher in patients with baseline high vslow BNP (HR, 3.6; 95%CI, 3.0-4.2). BNP change analysis at≤ 1 year postenrollment demonstrated that the low-low group had the lowest and the high-high group had the highest 5-year mortality risk (HR, 0.23; 95%CI, 0.19-0.27). Changes in BNP score also correlated with change of risk of death. Baseline BNP threshold of 340 pg/mL strongly predicted survival up to 5 years in patients with PAH. A BNP reduction at 1 year since enrollment was associated with decreased mortality risk, whereas an increase in BNP at 1 year was associated with an increased mortality risk, supporting BNP as a surrogate marker of PAH survival.

Risk Assessment in Pulmonary Arterial Hypertension Patients: The Long and Short of it

Pulmonary arterial hypertension (PAH) is a chronic and rapidly progressive disease that is characterized by extensive narrowing of the pulmonary vasculature, leading to increases in pulmonary vascular resistance, subsequent right ventricular dysfunction, and eventual death. There are currently multiple approved drugs—developed as single or combination therapies in the last few years—that have improved outcome and functionality in PAH. However, despite improvement in short-term survival with these new effective therapies, PAH remains an incurable disease with a median survival of 7 years (Figure 1).1 This chronic disease state may be characterized by morbid events such as hospitalizations that herald rapid disease progression and account for a significant disease burden (Figure 2).23 Physician ability to predict PAH disease progression is critical for determining optimal care of patients. Accurate risk assessment allows clinicians to determine the patient's prognosis, identify treatment goals, and monitor disease progression and the patient's response to treatment. Risk assessment for PAH patients should include a range of clinical, hemodynamic, and exercise parameters, performed in a serial fashion over the treatment course. Patient risk stratification can also help physicians better allocate treatment resources in settings where they are scarce. If widely adopted, risk prediction can enhance the consistency of treatment approaches across PAH practitioners and improve the timeliness of referral for lung transplantation. Hence, along with advancing PAH treatment options, comprehensive risk prediction is essential to make individualized treatment decisions in the current treatment era. Several tools are currently available for assessing risk in PAH (Figure 3). These include the 2015 European Society of Cardiology/European Respiratory Society pulmonary hypertension guidelines' risk variables,4 the French registry equation,5 the National Institutes of Health risk equation,6 or a risk score such as the one derived from the Registry to Evaluate Early And Long-term PAH Disease Management.1 These registries and evaluations of clinical trial sets have provided important insights into the importance of both modifiable (eg, 6-minute walk distance, functional class, brain natriuretic peptide, and nonmodifiable (eg, age, gender, PAH etiology) risk factors that predict survival. The following review explores commonly cited risk factors, both modifiable and nonmodifiable, and their implications for patient outcomes.

REVEAL risk scores applied to riociguat-treated patients in PATENT-2: Impact of changes in risk score on survival

The Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) risk score (RRS) calculator was developed using data derived from the REVEAL registry, and predicts survival in patients with pulmonary arterial hypertension (PAH) based on multiple patient characteristics. Herein we applied the RRS to a pivotal PAH trial database, the 12-week PATENT-1 and open-label PATENT-2 extension studies of riociguat. We examined the effect of riociguat vs placebo on RRS in PATENT-1, and investigated the prognostic implications of change in RRS during PATENT-1 on long-term outcomes in PATENT-2. RRS was calculated post hoc for baseline and Week 12 of PATENT-1, and Week 12 of PATENT-2. Patients were grouped into risk strata by RRS. Kaplan-Meier estimates were made for survival and clinical worsening-free survival in PATENT-2 to evaluate the relationship between RRS in PATENT-1 and long-term outcomes in PATENT-2. A total of 396 patients completed PATENT-1 and participated in PATENT-2. In PATENT-1, riociguat significantly improved RRS (p = 0.031) and risk stratum (p = 0.018) between baseline and Week 12 compared with placebo. RRS at baseline, and at PATENT-1 Week 12, and change in RRS during PATENT-1 were significantly associated with survival (hazard ratios for a 1-point reduction in RRS: 0.675, 0.705 and 0.804, respectively) and clinical worsening-free survival (hazard ratios of 0.736, 0.716 and 0.753, respectively) over 2 years in PATENT-2. RRS at baseline and Week 12, and change in RRS, were significant predictors of both survival and clinical worsening-free survival. These data support the long-term predictive value of the RRS in a controlled study population.

Impact of declining renal function on outcomes in pulmonary arterial hypertension: A REVEAL registry analysis

Renal dysfunction is associated with abnormal cardiopulmonary hemodynamics, in-hospital death and poor survival in patients with pulmonary arterial hypertension (PAH), and thus it may be a prognostic biomarker. In our analysis we assess the relationship between change in estimated glomerular filtration rate (eGFR) and outcomes in PAH patients in the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL). Overall 2,368 patients were classified into chronic kidney disease (CKD) stages based on baseline eGFR: normal or Stages 1 or 2 (n = 1,699); Stage 3a (n = 399); Stage 3b (n = 196); and Stages 4 or 5 (n = 74). We evaluated the relationship between baseline CKD stage and survival, as well as the composite end-point of survival and freedom from all-cause hospitalization. The relationships between change in eGFR at ≥1 year and these clinical end-points were also evaluated. Patients with a ≥10% decline in eGFR from baseline over ≥1 year had a significantly increased risk of death (hazard ratio 1.66; p < 0.0001) and the composite of all-cause hospitalization and death (hazard ratio 1.33; p = 0.002). This decline predicted survival independently of changes in 6-minute walk distance and functional class. However, a ≥10% increase in eGFR was not significantly associated with either end-point. In REVEAL, a ≥10% decline in eGFR over ≥1 year independently predicted poorer survival. Thus, eGFR may be a simple and economical biomarker in PAH.

Prognostic relevance of right heart reverse remodeling in idiopathic pulmonary arterial hypertension

Right ventricular (RV) failure is a major determinant of symptoms and shortened survival in pulmonary arterial hypertension (PAH). This study assessed the prognostic relevance of increased right heart (RH) dimensions determined by echocardiography and RH reverse remodeling (RHRR) with targeted therapies in idiopathic PAH (IPAH). The study prospectively monitored 102 therapy-naïve IPAH patients for the presence of clinical worsening. Baseline evaluation included RH catheterization and echocardiography. RHRR at the 1-year follow-up was defined by a decrease in RV end-diastolic area, right atrial area, and the left ventricular systolic eccentricity index. At the 1-year follow-up, 18 of 102 patients (17.6%) presented with RHRR. A decrease in pulmonary vascular resistance was the only independent determinant of RHRR. The 94 surviving patients were monitored for 995 ± 529 days. RHRR was an independent prognostic factor and significantly improved the power of the prognostic model based on traditional clinical and hemodynamic parameters. The respective event-free survival rates at 1, 3, and 5 years were 94%, 94%, and 94% in patients with RHRR and 75%, 55%, and 24% in those without RHRR (p = 0.0001). Interestingly, RHRR was able to further stratify patients' risk assessment through the Registry to Evaluate Early And Long-term PAH Disease Management risk score. RHRR after 1 year of treatment is an independent predictor of prognosis in IPAH. The likelihood of RHRR is proportional to decreased pulmonary vascular resistance.

High-risk echocardiographic features predict mortality in pulmonary arterial hypertension

Echocardiography is the most common imaging modality for assessment of the right ventricle in patients with pulmonary arterial hypertension (PAH). Echocardiographic parameters were identified as independent risk factors for mortality in the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) and other PAH cohorts. We sought to identify readily obtained echocardiographic features associated with PAH survival. Retrospective analysis of 175 patients with Group 1 was performed. Baseline clinical and laboratory assessment including REVEAL risk criteria were obtained and standard 2-Dimensional and Doppler echocardiography performed at baseline was reviewed. Univariate and multivariate analyses of echocardiographic parameters were performed. Estimated right atrial pressure> 15 mmHg (HR 2.39, P = .02), tricuspid regurgitation ≥ moderate (HR 2.16, P = .04), and presence of pericardial effusion (HR 1.8, P = .05) were identified as independent, high-risk echocardiographic features in PAH. A validation cohort of 677 patients was identified and Kaplan-Meier survival analysis was performed in both cohorts. High-risk echocardiographic features stratified survival curves of both cohorts (P < .01 for all). The presence of 3 high-risk echocardiographic features greatly increased risk of 1-year (RR 4.86) and 3-year (RR 3.35) mortality (P < .05 for both). Estimated right atrial pressure> 15, tricuspid regurgitation ≥ moderate, and presence of pericardial effusion are high-risk echocardiographic features in PAH. When seen in combination, these features greatly increase risk of mortality in PAH and may lead to more timely enhanced therapy for patients identified as having an increased risk for death.

(29) - REVEAL Risk Score in Patients with Chronic Thromboembolic Pulmonary Hypertension Receiving Riociguat

The Registry to Evaluate Early And Long-term pulmonary arterial hypertension (PAH) disease Management (REVEAL) risk score (RRS) predicts 1-year survival in patients with PAH. We applied a RRS to patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) in the 16-week, double-blind CHEST-1 study and open-label CHEST-2 extension. Relationships between RRS and riociguat treatment, and RRS and long-term outcomes were examined.

Plasma 12- and 15-hydroxyeicosanoids are predictors of survival in pulmonary arterial hypertension.

This study aimed to characterize alterations in select eicosanoids in experimental and human pulmonary arterial hypertension (PAH) and to assess their potential utility as predictors of outcome. Using liquid chromatography-mass spectrometry, we performed targeted lipidomic analyses of the lungs and right ventricles (RVs) of chronically hypoxic rats and plasma of consecutive PAH patients and healthy controls. In rat lungs, chronic hypoxia was associated with significantly decreased lung prostacyclin (PGI2)/thromboxane B2 (TXB2) ratio and elevated lung 8-hydroxyeicosanoid (HETE) acid concentrations. RV eicosanoids did not exhibit any changes with chronic hypoxia. PAH treatment-naïve patients had significantly increased plasma concentrations of TXB2 and 5-, 8-, 12-, and 15-HETE. The PGI2/TXB2 ratio was lower in PAH patients than in controls, especially in the treatment-naïve cohort (median: 2.1, 0.3, and 1.3 in controls, treatment-naïve, and treated patients, respectively, P = 0.001). Survival was significantly worse in PAH patients with 12-HETEhigh (≥57 pg/mL) and 15-HETEhigh (≥256 pg/mL) in unadjusted and adjusted analyses (hazard ratio [HR]: 2.8 [95% confidence interval (CI): 1.1-7.3], P = 0.04 and HR: 4.3 [95% CI: 1.6-11.8], P = 0.004, respectively; adjustment was performed with the REVEAL [Registry to Evaluate Early and Long-Term PAH Disease Management] risk score). We demonstrate significant alterations in eicosanoid pathways in experimental and human PAH. We found that 12- and 15-HETE were independent predictors of survival in human PAH, even after adjusting for the REVEAL score, suggesting their potential role as novel biomarkers.