Drug-induced Pulmonary Arterial Hypertension Research Articles

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)/NewYork 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-21017 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.

Drug-induced pulmonary arterial hypertension: a review.

Pulmonary arterial hypertension (PAH) is a subgroup of PH patients characterized hemodynamically by the presence of pre-capillary PH, defined by a pulmonary artery wedge pressure (PAWP) ≤15mmHg and a PVR >3 Wood units (WU) in the absence of other causes of pre-capillary PH. According to the current classification, PAH can be associated with exposure to certain drugs or toxins such as anorectic agents, amphetamines, or selective serotonin reuptake inhibitors. With the improvement in awareness and recognition of the drug-induced PAH, it allowed the identification of additional drugs associated with an increased risk for the development of PAH. The supposed mechanism is an increase in the serotonin levels or activation of serotonin receptors that has been demonstrated to act as a growth factor for the pulmonary artery smooth muscle cells and cause progressive obliteration of the pulmonary vasculature. PAH remains a rare complication of several drugs, suggesting possible individual susceptibility, and further studies are needed to identify patients at risk of drug-induced PAH.

Drug-Induced Pulmonary Hypertension: The First 50 Years.

Drug-induced pulmonary arterial hypertension (D-PAH) is a form of World Health Organization Group 1 pulmonary hypertension (PH) characterized by severe small vessel loss and obstructive vasculopathy, which leads to progressive right heart failure and death. To date, 16 different compounds have been associated with D-PAH, including anorexinogens, recreational stimulants, and more recently, several Food and Drug Administration-approved medications. While the clinical manifestations, pathology, and hemodynamic profile of D-PAH are indistinguishable from other forms of PAH, its clinical course can be unpredictable and largely dependent on removal of the offending agent. Since only a subset of individuals develop D-PAH, it is likely that genetic susceptibility plays a role in pathogenesis, but characterization of the genetic factors responsible for disease susceptibility remains incomplete. Besides aggressive treatment with PH-specific therapies, the major challenge in the management of D-PAH remains the early identification of compounds capable of injuring the pulmonary circulation in susceptible individuals. Institution of pharmacovigilance, precision medicine strategies, and global warning systems will help facilitate identification of high-risk drugs and institute regulation strategies to prevent further outbreaks of D-PAH.

Drug-induced Pulmonary Hypertension - a Current Review

The current classification of pulmonary Hypertension (PH) consists of five clinical groups, and drug-induced pulmonary arterial hypertension (PAH) is classified under Group 1 as a distinct entity. Our present work encompasses the available data concerning the association between the intake of a wide range of drugs and development of PAH. A selective literature search was performed in Pubmed to include published work between the years 1960 - 2015. For this search, the terms pulmonary hypertension, pulmonary arterial hypertension, pulmonary veno-occlusive disease, drug induced pulmonary hypertension and chemotherapy induced PVOD were used. Mainly German, English and French publications regarding this topic were considered. An association between drug intake and PH development was described for different medications, among them appetite-suppressant drugs, interferon alpha and beta, but also several chemotherapeutic drugs. The present literature regarding drug-induced PH mainly comprises case reports and small patient cohorts. Drug-induced PH has become increasingly discussed in recent years and needs further elucidation. A close cooperation between clinicians, PH expert centers and regulatory agencies is mandatory to identify other potential drugs at an early stage that may be linked to PH development. For the clinician, a thorough patient interview including drug history is necessary in the evaluation of a patient with PH.

Real-Life Data and a Single Center Experience on Dasatinib-Induced Pulmonary Arterial Hypertension in Patients with Philadelphia Chromosome-Positive Leukemias

▪Background: Drug-induced pulmonary arterial hypertension (PAH) can be observed as an adverse event (AE) during the administration of dasatinib (DAS), which is a second generation tyrosine kinase inhibitor (TKI), used in the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The occurence of DAS-induced PAH at a late onset in most of the cases suggests a chronic pathological mechanism rather than an acute inflammatory or cardiac etiology. The treatment strategies of DAS-induced PAH include the cessation of the drug and PAH-specific therapies.Aim: The aim of the study was to evaluate the frequency, clinical features, management strategies and outcomes of patients with DAS-induced PAH among a cohort consisted of CML and Ph+ ALL patients who had received DAS as a salvage treatment after imatinib (IM) failure or intolerance.Patients and Methods: Forty patients with Ph+ leukemias who received second-line DAS were enrolled. Patients' demographics, Sokal risk scores, molecular and cytogenetic responses, comorbidities [including preexisting cardiac disease, renal insufficiency, hypertension and chronic obstructive pulmonary disease (COPD)], DAS dose, dosing intervals and treatment durations, durations of IM therapy prior to DAS, and if any, treatments prior to IM (interferon (IFN), cytarabine (Ara-C), and hydroxyurea (HU)) and follow-up periods were noted retrospectively. TKI response criteria were based on the recommendations of European LeukemiaNet, and the definitions of the CML phases and responses were as described elsewhere.Results: Twenty-four patients were male, and the median age was 45 years (range, 18-81 years). There were 39 patients with CML and one with Ph+ ALL. Among the thirty-nine CML patients, 3 were in accelerated phase (CML-AP), two with blast crisis (CML-BC), and the rest were in chronic phase (CML-CP). The percentanges of low, intermediate, and high Sokal risk scores were 46%, 33%, and 21%, respectively. Thirteen patients received only IM prior to DAS, whereas the others had used HU, IFN and Ara-C prior to IM. After a median duration of 41.5 months (range, 1-93 months) of IM, the reason for switching to DAS were IM failure and intolerance in 37 and 3 patients, respectively. DAS was administered with a median of 50 months (range, 2-78 months). During DAS treatment hematological AEs were observed in 6 patients, whereas in twenty-one pulmonary complications including exacerbation of COPD and pneumonia (n=1), pleuro/pericaridal effusions (n=19), PAH (n=5) and gastrointestinal bleeding (n=1) were detected. DAS therapy was ceased in 13 patients, of which ten were switched to nilotinib (NIL) due to AEs (n=7) and failure (n=3). Also, two patients received cytotoxic treatment due to BC and one had allogeneic hematopoietic stem cell transplantation (allo-HSCT).Five patients (12.5%) had DAS-induced PAH (Table 1). Four of them were in CML-CP at diagnosis, and one was in CML-AP. All cases received DAS due to IM failure. At the time of DAS initiation, 4 cases were in CML-CP and one in CML-BC. PAH was diagnosed by transthoracic echocardiography (TTE) in 3 patients, and by right heart catheterization (RHC) in 2, and it was observed after a median of 8 months (range, 2-25 months) of DAS. Three patients had accompanying pleuro/pericardial effusions. All patients with DAS-induced PAH were alive at the time of the analysis, and the management of PAH included dose reduction in two, and DAS was switched to NIL in 2 cases and allo-HSCT was performed in one.Conclusion: DAS-induced PAH seems to be reversible with the cessation and/or modification of DAS ± PAH-specific treatments. As pulmonary vascular toxicity related to DAS is thought to be molecule-related rather than class-related, it seems reasonable to switch to another TKI. The patients in our cohort had good responses to dose modification and drug cessation and none received PAH-specific therapy. Although DAS-induced PAH is mainly defined as a late complication, we detected that PAH can be observed even after 2 months of drug exposure.PAH can be observed during DAS treatment and physicians should be aware of this AE. Routine cardiopulmonary evaluation prior to and/or during DAS may be beneficial. Mechanisms under this pathological condition, preceding and prognostic factors, and treatment strategies are needed to be evaluated with prospective trials. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Therapy of Pulmonary Arterial Hypertension

Pulmonary hypertension (PH) is classified into five distinct groups according to the fifth world conference in Nice 2013. Pulmonary arterial hypertension (PAH) comprises idiopathic PAH, hereditary PAH, drug-induced and associated PAH. Right heart catheterization is essential for the diagnosis of PH and should precede initiation of a targeted PAH therapy. Besides general measures and supportive therapy, four different classes of targeted drugs have been approved for the treatment of PAH. Combination therapy, either sequential or initial (up-front), is increasingly gaining recognition. Risk stratification and treatment goals have been defined to guide therapeutic decisions. However, cure is still far from reach and lung transplantation is an important treatment option for patients with end-stage disease under optimal supportive and targeted drug therapy.

Drug-induced pulmonary arterial hypertension: a recent outbreak

Pulmonary arterial hypertension (PAH) is a rare disorder characterised by progressive obliteration of the pulmonary microvasculature resulting in elevated pulmonary vascular resistance and premature death. According to the current classification PAH can be associated with exposure to certain drugs or toxins, particularly to appetite suppressant intake drugs, such as aminorex, fenfluramine derivatives and benfluorex. These drugs have been confirmed to be risk factors for PAH and were withdrawn from the market. The supposed mechanism is an increase in serotonin levels, which was demonstrated to act as a growth factor for the pulmonary artery smooth muscle cells. Amphetamines, phentermine and mazindol were less frequently used, but are considered possible risk factors, for PAH. Dasatinib, dual Src/Abl kinase inhibitor, used in the treatment of chronic myelogenous leukaemia was associated with cases of severe PAH, potentially in part reversible after dasatinib withdrawal. Recently, several studies have raised the issue of potential endothelial dysfunction that could be induced by interferon, and a few cases of PAH have been reported with interferon therapy. PAH remains a rare complication of these drugs, suggesting possible individual susceptibility, and further studies are needed to identify patients at risk of drug-induced PAH.

Radionuclide Angiographic Assessment of Right Ventricular Ejection Fraction Is Pronostic in Pulmonary Arterial Hypertension

Purpose The performance of the right ventricle is considered as a cornerstone of the patients’ outcome in pulmonary arterial hypertension (PAH). We evaluated the prognostic value of right ventricle ejection fraction (RVEF) assessed by planar equilibrium radionuclide angiography at baseline, and of its change after initiating PAH specific therapy. Methods and Materials Among 222 newly diagnosed patients with idiopathic, heritable or drug-induced PAH (1995-2011), 101 patients had a RVEF measurement at diagnosis before treatment as part of routine evaluation, 78 with a follow-up measurement 3-6 months after initiation of therapy [endothelin receptor antagonists (47%), sildenafil (27%), prostacyclin (9%), and calcium channel blockers (2%)]. Results After a median follow-up of 2.6 years (range: 0.11-15.2 years), 31 deaths occurred, including 25 from a cardiovascular cause. Patients with RVEF ≥25% had a better survival than those with RVEF Conclusions RVEF assessed with conventional planar radionuclide angiography at baseline and after initiation of PAH therapy predicts outcomes in patients with PAH.

Spontaneously Remitted Pulmonary Arterial Hypertension Associated with the Herbal Medicine "Bofutsushosan"

Although the link between pulmonary arterial hypertension (PAH) and exposure to certain drugs has already been identified, we herein present the first case of herbal medicine-associated PAH in which the patient demonstrated spontaneous remission. A 38-year-old woman took the herbal medicine "bofutsushosan" for two weeks then stopped taking it due to exertional dyspnea. However, her dyspnea continued, and right heart catheterization revealed a mean pulmonary arterial pressure of 41 mmHg with a normal wedge pressure. Several months after treatment with oxygen therapy, the patient's dyspnea disappeared, and her pulmonary arterial pressure normalized. Further studies focusing on susceptibility factors to drug-induced pulmonary arterial hypertension are needed.

Circulation: Clinical Summaries

<i>Circulation:</i> Clinical Summaries