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 (
) 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.
Epoprostenol was the first therapy to be approved for the treatment of pulmonary arterial hypertension (PAH). In the 20 years since the introduction of this prostacyclin analogue, the outlook for ...patients with PAH has improved, with survival rates now double those from the era before the development of disease-specific treatments. Today, there are a large amount of data on the clinical role of prostacyclin treatments and a body of evidence attesting the efficacy of epoprostenol in improving exercise capacity, key haemodynamic parameters and PAH symptoms, as well as in reducing mortality. The place of epoprostenol in the therapeutic management of PAH continues to evolve, with the development of new formulations and use in combination with other drug classes. In this review, we provide a historical perspective on the first 20 years of epoprostenol, a therapy that led to evidence-based study of PAH-specific treatments and the subsequent expansion of treatment options for PAH.
Introduction
Contemporary risk assessment tools categorise patients with pulmonary arterial hypertension (PAH) as low, intermediate or high risk. A minority of patients achieve low risk status with ...most remaining intermediate risk. Our aim was to validate a four-stratum risk assessment approach categorising patients as low, intermediate-low, intermediate-high or high risk, as proposed by the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) investigators.
Methods
We evaluated incident patients from the French PAH Registry and applied a four-stratum risk method at baseline and at first reassessment. We applied refined cut-points for three variables: World Health Organization functional class, 6-min walk distance and N-terminal pro-brain natriuretic peptide. We used Kaplan–Meier survival analyses and Cox proportional hazards regression to assess survival according to three-stratum and four-stratum risk approaches.
Results
At baseline (n=2879), the four-stratum approach identified four distinct risk groups and performed slightly better than a three-stratum method for predicting mortality. Four-stratum model discrimination was significantly higher than the three-stratum method when applied during follow-up and refined risk categories among subgroups with idiopathic PAH, connective tissue disease-associated PAH, congenital heart disease and portopulmonary hypertension. Using the four-stratum approach, 53% of patients changed risk category from baseline compared to 39% of patients when applying the three-stratum approach. Those who achieved or maintained a low risk status had the best survival, whereas there were more nuanced differences in survival for patients who were intermediate-low and intermediate-high risk.
Conclusions
The four-stratum risk assessment method refined risk prediction, especially within the intermediate risk category of patients, performed better at predicting survival and was more sensitive to change than the three-stratum approach.
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/m 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·m, 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.
The previous definition of exercise pulmonary hypertension (PH) with a mean pulmonary artery pressure (mPAP) >30 mmHg was abandoned because healthy individuals can exceed this threshold at high ...cardiac output (CO). We hypothesised that incorporating assessment of the pressure-flow relationship using the mPAP/CO ratio, i.e. total pulmonary resistance (TPR), might enhance the accuracy of diagnosing an abnormal exercise haemodynamic response.Exercise haemodynamics were evaluated in 169 consecutive subjects with normal resting mPAP ≤20 mmHg. Subjects were classified into controls without heart or lung disease (n=68) versus patients with pulmonary vascular disease (PVD) (n=49) and left heart disease (LHD) (n=52).TPR and mPAP at maximal exercise produced diagnostic accuracy with area under the receiver operating curve of 0.99 and 0.95, respectively, for discriminating controls versus patients with PVD and LHD. The old criterion of mPAP >30 mmHg had sensitivity of 0.98 but specificity of 0.77. Combining maximal mPAP >30 mmHg and TPR >3 mmHg·min·L(-1) retained sensitivity at 0.93 but improved specificity to 1.0. The accuracy of the combined criteria was high across different age groups, sex, body mass index and diagnosis (PVD or LHD).Combining mPAP >30 mmHg and TPR >3 mmHg·min·L(-1) is superior to mPAP >30 mmHg alone for defining a pathological haemodynamic response of the pulmonary circulation during exercise.
Until 20 years ago the treatment of pulmonary arterial hypertension (PAH) was based on case reports and small series, and was largely ineffectual. As a deeper understanding of the pathogenesis and ...pathophysiology of PAH evolved over the subsequent two decades, coupled with epidemiological studies defining the clinical and demographic characteristics of the condition, a renewed interest in treatment development emerged through collaborations between international experts, industry and regulatory agencies. These efforts led to the performance of robust, high-quality clinical trials of novel therapies that targeted putative pathogenic pathways, leading to the approval of more than 10 novel therapies that have beneficially impacted both the quality and duration of life. However, our understanding of PAH remains incomplete and there is no cure. Accordingly, efforts are now focused on identifying novel pathogenic pathways that may be targeted, and applying more rigorous clinical trial designs to better define the efficacy of these new potential treatments and their role in the management scheme. This article, prepared by a Task Force comprised of expert clinicians, trialists and regulators, summarises the current state of the art, and provides insight into the opportunities and challenges for identifying and assessing the efficacy and safety of new treatments for this challenging condition.
It is well established that the endothelin, nitric oxide and prostacyclin pathways play an important role in the development of pulmonary arterial hypertension (PAH). Indeed, the therapeutic options ...currently available for the management of PAH all act on one of these mechanistic pathways. However, this is an exciting time for both clinicians and scientists, as increased understanding of the mechanisms involved in the pathogenesis and progression of PAH has resulted in the development of a number of novel therapeutic options. This article highlights how the introduction of new compounds such as macitentan, riociguat and selexipag, which act on the endothelin, nitric oxide and prostacyclin pathways, respectively, have the potential to further improve the prognosis for patients with PAH.
Historically, pulmonary arterial hypertension (PAH) has been considered a disease of young adults, but over the last three decades, the average age at diagnosis has increased, presenting clinicians ...with some unique challenges. Clinical symptoms of PAH, including shortness of breath and reduced functional capacity, are not specific for the disease and may be present in older patients because of their age or as a result of comorbid conditions. Eliminating other causes for these symptoms can delay PAH diagnosis and initiation of PAH-specific treatment compared with younger patients. Currently, there are no specific guidelines relating to PAH in older patients and existing guidelines for identifying patients at potential risk of PAH may not be appropriate for patients aged over 65 years. Even though older patients tend to be diagnosed with more advanced symptoms, and evidence suggests that they are less responsive to PAH-specific therapies, treatment is often less aggressive than in younger patients. Even after adjusting for age, survival rates remain disproportionately lower in the older vs. younger PAH populations. Specific guidelines for diagnosis and treatment of older patients with PAH are needed to improve care and outcomes in this growing population. This review aims to assess the challenges associated with diagnosing and managing PAH in older patients, based on literature searches, authors' experiences, and expert opinions.
Pulmonary veno-occlusive disease (PVOD) is a rare and devastating cause of pulmonary hypertension that is characterized histologically by widespread fibrous intimal proliferation of septal veins and ...preseptal venules and is frequently associated with pulmonary capillary dilatation and proliferation. PVOD is categorized into a separate pulmonary arterial hypertension-related group in the current classification of pulmonary hypertension. PVOD presents either sporadically or as familial cases with a seemingly recessive mode of transmission. Using whole-exome sequencing, we detected recessive mutations in EIF2AK4 (also called GCN2) that cosegregated with PVOD in all 13 families studied. We also found biallelic EIF2AK4 mutations in 5 of 20 histologically confirmed sporadic cases of PVOD. All mutations, either in a homozygous or compound-heterozygous state, disrupted the function of the gene. These findings point to EIF2AK4 as the major gene that is linked to PVOD development and contribute toward an understanding of the complex genetic architecture of pulmonary hypertension.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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