Jason Weatherald

Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension

Current European guidelines recommend periodic risk assessment for patients with pulmonary arterial hypertension (PAH). The aim of our study was to determine the association between the number of low-risk criteria achieved within 1 year of diagnosis and long-term prognosis. Incident patients with idiopathic, heritable and drug-induced PAH between 2006 and 2016 were analysed. The number of low-risk criteria present at diagnosis and at first re-evaluation were assessed: World Health Organization (WHO)/New York Heart Association (NYHA) functional class I or II, 6-min walking distance (6MWD) >440 m, right atrial pressure <8 mmHg and cardiac index ≥2.5 L·min−1·m−2. 1017 patients were included (mean age 57 years, 59% female, 75% idiopathic PAH). After a median follow-up of 34 months, 238 (23%) patients had died. Each of the four low-risk criteria independently predicted transplant-free survival at first re-evaluation. The number of low-risk criteria present at diagnosis (p<0.001) and at first re-evaluation (p<0.001) discriminated the risk of death or lung transplantation. In addition, in a subgroup of 603 patients with brain natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-proBNP) measurements, the number of three noninvasive criteria (WHO/NYHA functional class, 6MWD and BNP/NT-proBNP) present at first re-evaluation discriminated prognostic groups (p<0.001). A simplified risk assessment tool that quantifies the number of low-risk criteria present accurately predicted transplant-free survival in PAH. Simplified risk assessment using the number of low-risk criteria predicts prognosis at baseline and follow-up in PAH http://ow.ly/KMsj30cPNbm

Prognostic Value of Follow-Up Hemodynamic Variables After Initial Management in Pulmonary Arterial Hypertension

Background: Hemodynamic variables such as cardiac index and right atrial pressure have consistently been associated with survival in pulmonary arterial hypertension (PAH) at the time of diagnosis. Recent studies have suggested that pulmonary arterial compliance may also predict prognosis in PAH. The prognostic importance of hemodynamic values achieved after treatment initiation is less well established. Methods: Our objective was to evaluate the prognostic importance of clinical and hemodynamic variables during follow-up, including pulmonary arterial compliance, after initial management in PAH. We evaluated incident patients with idiopathic, drug- and toxin-induced, or heritable PAH enrolled in the French pulmonary hypertension registry between 2006 and 2016 who had a follow-up right-sided heart catheterization (RHC). The primary outcome was death or lung transplantation. We used stepwise Cox regression and the Kaplan-Meier method to assess variables obtained at baseline and at first follow-up RHC. Results: Of 981 patients, a primary outcome occurred in 331 patients (33.7%) over a median follow-up duration of 2.8 years (interquartile range, 1.1–4.6 years). In a multivariable model considering only baseline variables, no hemodynamic variables independently predicted prognosis. Median time to first follow-up RHC was 4.6 months (interquartile range, 3.7–7.8 months). At first follow-up RHC (n=763), New York Heart Association functional class, 6-minute walk distance, stroke volume index (SVI), and right atrial pressure were independently associated with death or lung transplantation, adjusted for age, sex, and type of PAH. Pulmonary arterial compliance did not independently predict outcomes at baseline or during follow-up. The adjusted hazard ratio for SVI was 1.28 (95% confidence interval, 1.11–1.49; P<0.01) per 10-mL/m2 decrease and for right atrial pressure was 1.05 (95% confidence interval, 1.02–1.09; P<0.01) per 1–mm Hg increase. Among patients who had 2 (n=355) or 3 (n=193) low-risk prognostic features at follow-up, including a cardiac index ≥2.5 L·min−1·m−2, 6-minute walk distance >440 m, and New York Heart Association class I or II functional class, lower SVI was still associated with higher rates of death or lung transplantation (P<0.01). Conclusions: SVI and right atrial pressure were the hemodynamic variables that were independently associated with death or lung transplantation at first follow-up RHC after initial PAH treatment. These findings suggest that the SVI could be a more appropriate treatment target than cardiac index in PAH.

Long-term outcomes of dasatinib-induced pulmonary arterial hypertension: a population-based study

This study aimed to describe the long-term outcomes of pulmonary arterial hypertension (PAH) induced by dasatinib. 21 incident, right heart catheterisation-confirmed cases of dasatinib-induced PAH were identified from the French Pulmonary Hypertension Registry. Clinical and haemodynamic variables were compared from baseline to last follow-up (median (range) 24 (1–81) months). Median age was 52 years and 15 patients were female (71%). 19 patients received dasatinib for chronic myelogenous leukaemia for a median (range) duration of 42 (8–74) months before PAH diagnosis. No bone morphogenic protein receptor-2 (BMPR2) mutations were found in the 10 patients tested. Dasatinib was uniformly discontinued and 11 patients received PAH medications. Four patients died during follow-up. New York Heart Association functional class improved from 76% in class III/IV to 90% in class I/II (p<0.01). Median (range) 6-min walk distance improved from 306 (0–660) to 430 (165–635) m (p<0.01). Median (range) mean pulmonary arterial pressure improved from 45 (30–70) to 26 (17–50) mmHg (p<0.01) and pulmonary vascular resistance from 6.1 (3.2–27.3) to 2.6 (1.2–5.9) Wood units (p<0.01). Patients treated with PAH medications had worse baseline haemodynamics but similar long-term outcomes to untreated patients. PAH persisted in 37% of patients. Dasatinib-induced PAH frequently improves after discontinuation but persisted in over one-third of patients, therefore systematic follow-up is essential. Dasatinib-induced pulmonary arterial hypertension persists in over one-third of patients despite stopping dasatinib http://ow.ly/xRPt30csyk9

Management and long-term outcomes of sarcoidosis-associated pulmonary hypertension

Studies reporting the effects of modern strategies with pulmonary arterial hypertension (PAH)-targeted therapies in sarcoidosis-associated pulmonary hypertension (S-APH) are limited. Clinical and haemodynamic data from newly diagnosed patients with severe S-APH (mean pulmonary artery pressure (mPAP) >35 mmHg or mPAP 25–35 mmHg with cardiac index <2.5 L·min−1·m−2) were collected from the French Pulmonary Hypertension Registry between 2004 and 2015. Data from 126 patients with severe S-APH were analysed (mean±sd age 57.5±11.6 years, 74% radiological stage IV). 97 patients (77%) received PAH-targeted therapy and immunosuppressive therapy was initiated or escalated in 33 patients at the time of pulmonary hypertension diagnosis. Four months after PAH-targeted therapy initiation, mean±sd pulmonary vascular resistance decreased from 9.7±4.4 to 6.9±3.0 Wood units (p<0.001), without significant improvement in exercise capacity. Among the 11 patients treated only with immunosuppressive therapy, a haemodynamic improvement was observed in four patients, including two with compressive lymph nodes. After a median follow-up of 28 months, 39 patients needed PAH-targeted therapy escalation, nine underwent lung transplantation and 42 had died. Survival at 1, 3 and 5 years was 93%, 74% and 55%, respectively. PAH-targeted therapy improved short-term pulmonary haemodynamics in severe S-APH without change in exercise capacity. Immunosuppressive therapy improved haemodynamics in selected patients. Pulmonary hypertension in sarcoidosis remains associated with a poor prognosis. Severe pulmonary hypertension remains a life-threatening complication of sarcoidosis in the modern management era http://ow.ly/fIln30etYkE

Heritable pulmonary hypertension: from bench to bedside

Mutations in the BMPR2 gene, and more rarely in ACVRL1, endoglin, caveolin-1, KCNK3 and TBX4 genes predispose to heritable pulmonary arterial hypertension, an autosomal dominant disease with incomplete penetrance. Bi-allelic mutations in the EIF2AK4 gene predispose to heritable pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis, an autosomal recessive disease with an unknown penetrance. In France, the national pulmonary hypertension referral centre offers genetic counselling and testing to adults and children. Predictive testing is also proposed to adult relatives at risk of carrying a predisposing mutation. In that context, we offer all asymptomatic BMPR2 mutation carriers a programme to detect pulmonary arterial hypertension at an early phase, as recommended by the 2015 European Society Society of Cardiology/European Respiratory Society pulmonary hypertension guidelines. Finally, pre-implantation genetic diagnosis has been conducted on five embryos from two couples in which the fathers were carriers of a pathogenic BMPR2 mutation. Genetic counselling and testing available in France for patients at risk of PAH and PVOD/PCH http://ow.ly/m0MA30dBnkF

Pulmonary arterial hypertension secondary to adult-onset Still's disease: Response to cyclosporine and sildenafil over 15 years of follow-up.

Adult onset Still’s disease (AOSD) is an autoimmune disease characterized by systemic inflammation and is a rarely reported cause of pulmonary arterial hypertension (PAH). We describe the clinical course of a 40-year-old woman who presented with PAH 19 months after a diagnosis of AOSD. Sildenafil and immunosuppressive therapy with cyclosporine resulted in clinical and hemodynamic improvement with long-term survival 15 years after her initial presentation of AOSD. We review the literature for published cases of PAH due to AOSD and discuss the potential mechanisms relating inflammatory diseases and PAH.

Ventilatory response to exercise in cardiopulmonary disease: the role of chemosensitivity and dead space

The lungs and heart are irrevocably linked in their oxygen (O2) and carbon dioxide (CO2) transport functions. Functional impairment of the lungs often affects heart function and vice versa. The steepness with which ventilation (V′E) rises with respect to CO2 production (V′CO2) (i.e. the V′E/V′CO2 slope) is a measure of ventilatory efficiency and can be used to identify an abnormal ventilatory response to exercise. The V′E/V′CO2 slope is a prognostic marker in several chronic cardiopulmonary diseases independent of other exercise-related variables such as peak O2 uptake (V′O2). The V′E/V′CO2 slope is determined by two factors: 1) the arterial CO2 partial pressure (PaCO2) during exercise and 2) the fraction of the tidal volume (VT) that goes to dead space (VD) (i.e. the physiological dead space ratio (VD/VT)). An altered PaCO2 set-point and chemosensitivity are present in many cardiopulmonary diseases, which influence V′E/V′CO2 by affecting PaCO2. Increased ventilation–perfusion heterogeneity, causing inefficient gas exchange, also contributes to the abnormal V′E/V′CO2 observed in cardiopulmonary diseases by increasing VD/VT. During cardiopulmonary exercise testing, the PaCO2 during exercise is often not measured and VD/VT is only estimated by taking into account the end-tidal CO2 partial pressure (PETCO2); however, PaCO2 is not accurately estimated from PETCO2 in patients with cardiopulmonary disease. Measuring arterial gases (PaO2 and PaCO2) before and during exercise provides information on the real (and not “estimated”) VD/VT coupled with a true measure of gas exchange efficiency such as the difference between alveolar and arterial O2 partial pressure and the difference between arterial and end-tidal CO2 partial pressure during exercise. The “appropriate” V′E exercise response depends on V′CO2, arterial PCO2, VD/VT and respiratory mechanics http://ow.ly/M1IZ30gGNIw

Validation of a risk assessment instrument for pulmonary arterial hypertension

In this issue of the journal, Kylhammar et al. aimed to validate the pulmonary arterial hypertension (PAH) risk stratification instrument presented in the 2015 ESC/ERS guidelines. For 530 patients from the Swedish PAH registry, they calculated a risk score by assigning a grade from 1 to 3 for each available variable according to the risk level of that variable (low risk = 1, intermediate risk = 2, high risk = 3) and obtaining the mean grade for each patient, rounded to the nearest integer, thereby defining their risk group (low, intermediate, or high) at baseline. They then recalculated the mean grade at the time of follow-up for 383 patients who had a follow-up assessment within 1 year of diagnosis. At baseline, the vast majority of patients were intermediate risk (67%), with 23% classified as low risk and 10% as high risk. Surprisingly, there was little change in the proportions of patients who were low risk (29%), intermediate risk (60%) or high risk (11%) at follow-up, after PAH treatment was initiated. They found that the application of their risk score approach predicted the 1-, 3-, and 5-year risk of death at baseline and follow-up. This held true in important subgroups with idiopathic, familial, and connective tissue disease-associated PAH, and when older idiopathic PAH patients (>65 years old) were excluded. The 1-year mortality rates in the low-, intermediate-, and high-risk groups at baseline were 1, 17, and 26%, respectively, with a mortality risk in the intermediate group somewhat higher than the expected 5–10% in the guidelines. Repeating the risk assessment at follow-up, the 1-year mortality rates for low-, intermediate-, and high-risk patients were 1, 9, and 30%, which correspond well to the estimates proposed in the guidelines. They also confirmed previous findings by demonstrating the importance of improvements and maintenance of low-risk features during follow-up. Patients who worsened from low risk at baseline to intermediate or high risk at follow-up had much worse survival than those who were intermediate or high risk at baseline and improved to a low-risk profile. Perhaps most importantly, survival consistently improved as an increasing proportion of available variables at followup were in the ‘low-risk’ profile. Validation of guideline recommendations in independent, realworld cohorts is a crucial step in guideline dissemination and implementation, and, in this vein, Kylhammar et al. succeed in demonstrating that the risk assessment instrument proposed in the 2015 ESC/ERS guidelines has prognostic utility. Importantly, their study illustrates the prognostic significance of response to therapy, irrespective of baseline values. Their results also suggest that longterm prognosis is better with an increasing number of variables in the low-risk range during follow-up, akin to a dose–response effect between low-risk features and survival. Thus, an optimal treatment response can be considered the achievement and maintenance of all clinical, functional, and exercise variables in the low-risk zone. However, the results from this study are a sobering reminder that, despite the progress made in treating PAH, significant functional impairment persists and survival remains poor for a large proportion of PAH patients. The risk stratification instrument in the 2015 ESC/ERS guidelines is based on variables and cut-off points derived from several studies, but the risk assessment tool itself has a level of evidence C (consensus of opinion of the experts, and/or small studies, retrospective studies, and registries). Although this study was also a retrospective registry analysis, it should increase confidence that this risk assessment instrument is valid in a real-world cohort in the modern treatment era. However, the efficacy of a goal-oriented approach remains to be tested in a prospective or randomized study. While Kylhammar et al. have validated the risk assessment in an incident cohort within the first year, it remains to be shown whether it performs as well at predicting short-term prognosis in prevalent cohorts, who may achieve a low-risk profile later on in the disease course (after 1 year) and who may differ substantially from incident patients.

Pulmonary arterial hypertension induced by tyrosine kinase inhibitors

Purpose of review Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of several neoplastic conditions; however, pulmonary arterial hypertension (PAH) has been reported as a complication of TKIs, predominantly with dasatinib. Recent studies have elucidated the potential mechanisms of TKI-induced PAH and have better clarified the long-term outcomes. Recent findings In addition to the known association between dasatinib and PAH, several other TKIs have recently been reported to cause PAH, including ponatinib, bosutinib and lapatinib. Dasatinib causes direct pulmonary artery endothelial cell toxicity through the production of mitochondrial reactive oxygen species, but likely requires the presence of a second risk factor to cause PAH. Symptoms and haemodynamic abnormalities frequently resolve after discontinuation of the TKI, but PAH persists in over a third of patients and can reoccur when other TKIs are used, which warrants close follow-up. Rare fatal cases have occurred; therefore, treatment with PAH-specific therapy is recommended for patients with right heart failure or persistent PAH after discontinuation of the TKI. Summary PAH is a rare but important complication of several TKIs. Management includes discontinuation of the TKI, close follow-up and PAH-specific therapy in severe cases.

The Low-Risk Profile in Pulmonary Arterial Hypertension. Time for a Paradigm Shift to Goal-oriented Clinical Trial Endpoints?

Advances in treatment options and combination therapies have improved outcomes for patients with pulmonary arterial hypertension (PAH). Periodic risk stratification, using risk scores that incorporate combinations of clinical variables and markers of right ventricular function, is important for prognosticating and guiding treatment decisions. Validated tools for risk stratification include the risk assessment table from recent European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines and the Registry to Evaluate Early And Long-term PAH Disease Management (REVEAL) score. In observational studies, PAH patients who achieve multiple low-risk features with treatment have better long-term outcomes, supporting a goal-oriented treatment strategy with the low-risk profile as the ultimate treatment objective. However, a low-risk profile has not yet been rigorously tested as a clinical outcome in a trial setting. Because PAH is a rare disease, it is difficult to power clinical trials to demonstrate an effect on mortality. Instead, hemodynamic variables, the 6-minute walking distance, and composite endpoints including death and other important clinical morbidity events have been used in PAH clinical trials. Such endpoints overlook the importance of achieving a low-risk status as opposed to achieving clinical stability or delaying clinical events such as hospitalizations. A low-risk profile is clinically meaningful and warrants further validation as a potential surrogate outcome. With the emergence of precision medicine and molecular phenotyping, better patient selection and a valid surrogate endpoint could increase the efficiency, statistical power, and impact of future clinical trials in PAH.