u-62840 and Chronic-Disease

The present review provides an update on treatment of chronic thromboembolic pulmonary hypertension (CTEPH), a rare form of pulmonary hypertension characterized by precapillary pulmonary hemodynamic parameters with chronic thrombotic occlusion of the pulmonary vasculature.. Pulmonary thromboendarectomy (PTE) remains the recommended treatment for patients with surgically accessible disease. Recent data suggest that patients preoperatively bridged with medical therapy may have improved outcomes but further research is needed. Riociguat improves hemodynamics, right ventricular function, quality of life, and functional capacity and is the drug of choice for patients with inoperable/persistent disease. Recently published data suggest that endothelin receptor blockers and treprostinil may also have a role in medical management of this patient population. A growing body of evidence indicates that in experienced centers balloon pulmonary angioplasty (BPA) may be a well tolerated and effective adjunct to pharmacological treatment for patients with inoperable disease affecting subsegmental vasculature.. Untreated CTEPH carries significant morbidity and mortality. Recent publications provide a wealth of data on safety and efficacy of BPA for inoperable subsegmental disease, but its precise fit in the treatment algorithm, both pharmacological and procedural, requires further investigation. PTE remains the procedure of choice for surgically accessible disease.

Topics: Angioplasty, Balloon; Anticoagulants; Antihypertensive Agents; Chronic Disease; Endarterectomy; Endothelin Receptor Antagonists; Enzyme Activators; Epoprostenol; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Pyrazoles; Pyrimidines; Vasodilator Agents

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by unresolved thrombi in the pulmonary arteries and microvasculopathy in nonoccluded areas. If left untreated, progressive pulmonary hypertension will induce right heart failure and, finally, death. Currently, pulmonary endarterectomy (PEA) remains the only method that has the potential to cure CTEPH. Unfortunately, up to 40% of patients are ineligible for this procedure for various reasons. In recent years, refined balloon pulmonary angioplasty (BPA) has become an alternative option for inoperable CTEPH patients, and it may be another curative treatment in the future, particularly in combination with prior PEA. Nevertheless, 23% of patients still suffer from persistent PH after BPA. Given that CTEPH shares many similarities with idiopathic pulmonary arterial hypertension (PAH), targeted drugs developed for PAH are also attractive options for CTEPH, especially for inoperable or persistent/recurrent CTEPH patients. To date, riociguat, macitentan, and subcutaneous treprostinil are the only drugs proven by randomized control trials to be capable of improving the exercise capacity (6-min walking distance) of CTEPH patients. In this review, we summarize the achievements and unresolved problems of PAH-targeted therapy for CTEPH over the last decade.

Topics: Adult; Aged; Angioplasty, Balloon; Antihypertensive Agents; Chronic Disease; Drug Therapy, Combination; Endarterectomy; Endothelin Receptor Antagonists; Epoprostenol; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Male; Molecular Targeted Therapy; Phosphodiesterase 5 Inhibitors; Prostaglandins I; Pulmonary Artery; Pulmonary Embolism; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides; Treatment Outcome; Walk Test

Treprostinil is a stable, long-acting prostacyclin analogue which can be administered as a continuous subcutaneous infusion using a portable miniature delivery system. Subcutaneous treprostinil has been shown in a large multicenter randomized controlled trial to improve exercise capacity, clinical state, functional class, pulmonary hemodynamics, and quality of life in patients with pulmonary arterial hypertension, an uncommon disease of poor prognosis. Side effects include facial flush, headache, jaw pain, abdominal cramping, and diarrhea, all typical of prostacyclin, and manageable by symptom-directed dose adjustments, and infusion site pain which may make further treatment impossible in 7%-10% of the patients. Long-term survival in pulmonary arterial hypertension patients treated with subcutaneous treprostinil is similar to that reported with intravenous epoprostenol. There are uncontrolled data suggesting efficacy of subcutaneous treprostinil in chronic thromboembolic pulmonary hypertension. Treprostinil can also be administered intravenously, although increased doses, up to 2-3 times those given subcutaneously, appear to be needed to obtain the same efficacy. Preliminary results of a randomized controlled trial of inhaled treprostinil on top of bosentan and sildenafil therapies have shown significance on the primary endpoint, which was exercise capacity as assessed by the distance walked in 6 minutes. Trials of oral formulations of treprostinil have been initiated.

Topics: Administration, Cutaneous; Antihypertensive Agents; Chronic Disease; Epoprostenol; Exercise Test; Exercise Tolerance; Humans; Hypertension, Pulmonary; Thromboembolism

Epoprostenol and the structurally related compounds treprostinil, iloprost, and beraprost are collectively referred to as prostanoids. The discovery of epoprostenol in 1976 and unequivocal demonstration of its efficacy in 1996 dramatically altered the approach to therapy for pulmonary arterial hypertension (PAH). Development of prostanoids available through multiple routes of administration and the discovery and development of other agents acting through alternative pathways continue to expand the array of therapeutic options. The use of prostanoids in combination with other PAH drugs and for treating pulmonary hypertensive disorders outside of the PAH classification are areas of ongoing research.

Topics: Antihypertensive Agents; Chronic Disease; Epoprostenol; Heart Defects, Congenital; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Prostaglandins; Randomized Controlled Trials as Topic; Respiratory Distress Syndrome

Chronic thromboembolic pulmonary hypertension (CTEPH) results from non-resolving pulmonary thromboemboli that are resistant to plasmatic anticoagulation. Because of a secondary pulmonary arteriopathy accompanying major vessel obstruction, the disorder may be a target for vasodilator therapy.. In an open-label uncontrolled study, we investigated the prostacyclin analog treprostinil given s.c. in patients with severe inoperable CTEPH.. Between September 1999 and September 2005, 25 patients were included if their World Health Organization (WHO) functional class was III or IV, if their six-minute walking distance (6-MWD)

Topics: Aged; Antihypertensive Agents; Cardiac Output; Case-Control Studies; Chronic Disease; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Infusion Pumps; Kaplan-Meier Estimate; Male; Middle Aged; Natriuretic Peptide, Brain; Odds Ratio; Pain; Pain Measurement; Platelet Aggregation Inhibitors; Proportional Hazards Models; Prospective Studies; Pulmonary Embolism; Risk Assessment; Severity of Illness Index; Thromboembolism; Time Factors; Treatment Outcome; Vascular Resistance; Vasodilator Agents; Walking

Chronic thromboembolic pulmonary hypertension (CTEPH) involves non-resolving thromboemboli in the pulmonary arteries. Treatment for CTEPH includes lifelong anticoagulation and determination of patients who have disease which is operable versus inoperable. Pulmonary arterial hypertension (PAH) targeted therapies are oftentimes used as a bridge to pulmonary thromboendarterectomy (PTE), though riociguat is the only Food and Drug Administration (FDA)-approved therapy for CTEPH. There is a paucity of data regarding the efficacy of other PAH therapies, particularly as a bridge to PTE. Here, we present a case report of severe CTEPH related to ventriculoatrial shunt in which intravenous treprostinil was used as a bridge to PTE.

Topics: Chronic Disease; Endarterectomy; Epoprostenol; Humans; Hypertension, Pulmonary; Pulmonary Embolism

Pregnancy in patients with pulmonary hypertension is associated with increased risk of maternal and fetal death. Physiological changes during pregnancy, labor and the postpartum period may all lead to acute decompensation of chronic right heart failure with rapid progression to circulatory collapse. As such, guidelines discourage planned pregnancies in women suffering from pulmonary hypertension. There are, however, rare cases of pulmonary hypertension which have previously been undiagnosed and only become apparent during late stage pregnancy. These individuals require close monitoring and multidisciplinary management.. We describe the case of a 34-year-old female who presented with acute decompensation of previously undiagnosed pulmonary hypertension during the 30th week of her second pregnancy. Echocardiography and CT scan confirmed severe pulmonary hypertension and right heart failure with no new thromboembolic component. Following stabilization of cardiorespiratory parameters with high FiO. The case described is the first published report of previously undiagnosed pulmonary hypertension presenting with acute right heart failure in late pregnancy successfully managed by pharmacological therapy, noninvasive ventilation and a Cesarean performed under epidural anesthesia. The case illustrates that despite the challenges, acutely discovered right heart failure can be successfully managed with a comprehensive multidisciplinary treatment plan.

Topics: Adult; Antihypertensive Agents; Cesarean Section; Chronic Disease; Computed Tomography Angiography; Dose-Response Relationship, Drug; Drug Therapy, Combination; Echocardiography; Endarterectomy; Epoprostenol; Female; Heparin, Low-Molecular-Weight; Humans; Hypertension, Pulmonary; Pregnancy; Pregnancy Complications, Cardiovascular; Prenatal Diagnosis; Pulmonary Artery; Pulmonary Embolism; Pulmonary Wedge Pressure

This case demonstrates chronic fibrosing pleuritis, as a rare pulmonary aetiology for mortality in patients with Degos disease or malignant atrophic papulosis (MAP). Knowledge of this unusual complication will help physicians identify this entity early and provide appropriate treatment.Patients with MAP die from gastrointestinal and brain involvement within 2-3 years of diagnosis. This case is unique as the patient survived for 9 years and died secondary to respiratory failure, which had not been reported before. Our patient was a young man, diagnosed with MAP at the age of 17. His skin and gastrointestinal disease were controlled with eculizumab and parenteral treprostinil. The patient developed severe restrictive pulmonary disease, required ventilatory support, and died from respiratory failure. An autopsy revealed chronic fibrosis pleuritis. Longer surviving patients with MAP might suffer from significant respiratory disease. Pulmonary function test should be obtained to identify subclinical respiratory limitation.

Topics: Antibodies, Monoclonal, Humanized; Chronic Disease; Complement Inactivating Agents; Conservative Treatment; Diagnosis, Differential; Drug Therapy, Combination; Epoprostenol; Fatal Outcome; Humans; Male; Malignant Atrophic Papulosis; Pleurisy; Respiratory Insufficiency; Young Adult

We examined safety and long-term outcomes of intravenous treprostinil administered via the implantable LENUS Pro pump in patients with severe pulmonary hypertension (PH).. Patients with PH undergoing pump implantation between December 2009 and October 2016 in German referral centers were retrospectively analyzed (end of follow-up: May 2017). The primary objective was to determine long-term safety of the implantable pump. Secondary end points were 3-year survival and prognostic relevance of pre-implantation hemodynamics.. We monitored 129 patients (120 with pulmonary arterial hypertension, 1 with PH due to lung diseases, and 8 with inoperable chronic thromboembolic PH) for 260 patient-years (median follow-up, 19 months; interquartile range, 11-34 months). There were 82 complications/peri-procedural events in 60 patients; of these, 57 were serious adverse events (0.60 per 1,000 treatment-days), including 2 periprocedural deaths due to right heart failure. The incidence of complications related to the pump, catheter, infection, and pump pocket per 1,000 treatment-days was 0.074, 0.264, 0.032 (3 local infections; no bloodstream infections), and 0.380, respectively. Three-year overall and transplant-free survival were 66.5% and 55.7%, respectively (39 patients died; 16 underwent lung transplantation). Baseline cardiac index independently predicted transplant-free survival (multivariate hazard ratio, 1.90; 95% confidence interval, 1.11-3.28; p = 0.019; n = 95).. Our data suggest that intravenous treprostinil via the LENUS Pro pump in advanced PH is associated with a very low risk of bloodstream infections, but other serious adverse events may occur. Therefore, this therapy needs standardization and should be offered in specialized PH centers only. Further technical advances of the pump system and prospective studies are needed.

Topics: Adult; Cause of Death; Chronic Disease; Epoprostenol; Equipment Failure; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Infusion Pumps, Implantable; Lung Transplantation; Male; Middle Aged; Risk Factors; Survival Rate; Treatment Outcome

Chronic thromboembolic pulmonary hypertension (CTEPH) occurs when pulmonary emboli fail to resolve with anticoagulation. For patients with inoperable or residual CTEPH, riociguat is currently the only therapy approved by the United States Food and Drug Administration. However, some patients with CTEPH may require therapy beyond riociguat, such as intravenous prostacyclins, which can present significant administration challenges in patients with complex comorbid conditions. We describe a 42-year-old man with T12 paraplegia complicated by CTEPH (functional class IV with substantial right ventricular dysfunction) and severe pressure ulcers. In order to facilitate goals of care (hospital discharge to a skilled nursing facility where parenteral prostanoids could not be administered), he underwent rapid transition from intravenous treprostinil to oral selexipag in the form of a cross-taper over 6 days. The patient required readmission due to worsening symptoms and was transitioned back to intravenous treprostinil; he tolerated conversion to oral treprostinil for approximately 4 months, but it was subsequently discontinued due to nausea and modified goals of care. The patient underwent transition to hospice care 3 months later and eventually died from clinical deterioration. To our knowledge, this is the first report to describe transition from intravenous treprostinil to selexipag as well as conversion from parenteral treprostinil to oral treprostinil in a patient with CTEPH and illustrates the approaches to and potential issues with prostanoid transitions. Additional observations are necessary to better understand the relative roles of selexipag and oral treprostinil regarding comparative efficacy and tolerability.

Topics: Acetamides; Administration, Oral; Adult; Antihypertensive Agents; Chronic Disease; Epoprostenol; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Paraplegia; Pyrazines; Severity of Illness Index; Ventricular Dysfunction, Right

In the past 18 months, the U.S. Food and Drug Administration approved macitentan, riociguat, and treprostinil as oral agents for the treatment of pulmonary arterial hypertension (PAH); riociguat also became the first agent approved for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH). These new agents are welcome additional therapeutic options for PAH and CTEPH. However, their use can be complicated by potential drug interactions, adverse effects, dosing complexity, and cost. Macitentan, the newest endothelin receptor antagonist, showed significant benefits in a long-term event-driven trial of morbidity and mortality. Dosed once daily and with minimal liver toxicity, it has potential drug interactions with potent CYP 3A4 inhibitors and inducers, and can decrease hemoglobin levels. Riociguat is approved for PAH and clinically inoperable CTEPH to improve exercise capacity and functional status. Riociguat requires dose titration beginning with 1 mg up to 2.5 mg three times a day, as tolerated, and should be used with caution in patients with underlying risk factors for systemic hypotension. Oral treprostinil, approved to improve exercise capacity in PAH, is associated with gastrointestinal side effects and headaches that are often dose limiting. Doses can begin with 0.125 mg or 0.25 mg twice a day with gradual increases on up to a weekly basis, as tolerated. Thrice daily dosing and administration with a meal can improve tolerance. These newer agents represent advances, but their specific roles in relation to pre-existing therapies are undergoing further evaluation. Therefore, close collaboration with clinicians at centers with therapeutic expertise is highly recommended to optimize patient outcomes.

Topics: Administration, Oral; Antihypertensive Agents; Chronic Disease; Drug Approval; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Pyrazoles; Pyrimidines; Sulfonamides; Treatment Outcome; United States; United States Food and Drug Administration

Pulmonary arterial hypertension (PAH) associated with chronic lung disease of infancy can be a life-threatening disease affecting an increasing number of former premature infants. There is a need for improved delivery of targeted PAH therapies for this subgroup of patients who have severe and persistent PAH despite standard respiratory care for chronic lung disease. Currently infants who have severe PAH despite oral or inhaled therapy receive continuous intravenous prostanoid therapy (mostly epoprostenol), which is complicated because of the need for central venous access and associated catheter-related complications. We present a series of 5 infants who were successfully treated with a continuous infusion of subcutaneous treprostinil, which is a longer-acting prostanoid with similar hemodynamic effects. There were improvements in echocardiographic assessment of right ventricular function and estimated pulmonary hypertension, and in respiratory support required within weeks of therapy. Unlike commonly in adults, these 5 infants had no instances of severe site erythema, bleeding, bruising, or infection. In our experience with 5 former extremely preterm infants who had PAH associated with chronic lung disease, subcutaneous treprostinil was safe, efficacious, and well tolerated. We believe that subcutaneous treprostinil can be beneficial in a select group of former premature infants who have chronic lung disease and severe pulmonary arterial hypertension who have not responded adequately to conservative therapies.

Topics: Antihypertensive Agents; Chronic Disease; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Infant; Infusions, Subcutaneous; Lung Diseases; Male

A unique subpopulation of peripheral blood mononuclear cells that exhibit a parallel expression of haematopoietic and mesenchymal markers has been described as "circulating fibrocytes". These cells were demonstrated to obtain a fibroblastic phenotype in tissues or cell culture and contribute to pulmonary fibrotic disorders and tissue remodelling processes. The aim of our study was to characterise the recruitment of circulating fibrocytes in vivo in the model of chronic hypoxic pulmonary hypertension in mice and to analyse the therapeutic effect of the stable prostacyclin analogue trepostinil with respect to this cell population. To track circulating fibrocytes in vivo, we transplanted wild-type mice with bone marrow from ubiquitously eGFP expressing mice and subjected them to chronic hypoxia. We observed significantly increased recruitment of circulating fibrocytes to the remodelled pulmonary resistance arteries in response to hypoxia. Treatment with treprostinil significantly reduced the recruitment of these cells compared to normoxic mice. Treprostinil also reduced right ventricular systolic pressure and slightly reduced the vascular remodelling but failed to reverse the right ventricular hypertrophy. In summary, we show that circulating fibrocytes contribute to hypoxic pulmonary vascular remodelling and may be specifically targeted by a prostacyclin analogue. Further investigations of cellular and paracrine mechanisms are warranted to decipher their role in pulmonary hypertension.

Topics: Animals; Antihypertensive Agents; Blood Circulation; Blood Vessels; Bone Marrow Cells; Chimerism; Chronic Disease; Epoprostenol; Female; Fibroblasts; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Leukocytes, Mononuclear; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle, Smooth, Vascular; Pulmonary Artery

We present a case of a 77-year-old female with distal chronic thromboembolic pulmonary hypertension. Diagnostic and therapeutic difficulties are discussed. Clinical and haemodynamic benefits resulting from treprostinil therapy added to continuous anticoagulation are shown.

Topics: Aged; Antihypertensive Agents; Chronic Disease; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Treatment Outcome