Oral anticoagulants (NOAC and VKA) in chronic thromboembolic pulmonary hypertension

EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study in patients with pulmonary hypertension treated with riociguat. Patients were followed for 1-4 years, and the primary outcomes were adverse events (AEs) and serious AEs (SAEs), including embolic/thrombotic and hemorrhagic events. Here we report data on patients with chronic thromboembolic pulmonary hypertension (CTEPH) receiving a vitamin K antagonist (VKA; n = 683) or a non-vitamin K antagonist oral anticoagulant (NOAC; n = 198) at baseline. AEs and SAEs were reported in 438 patients (64.1%) and 257 patients (37.6%), respectively, in the VKA group, and in 135 patients (68.2%) and 74 patients (37.4%) in the NOAC group. Exposure-adjusted hemorrhagic event rates were similar in the two groups, while exposure-adjusted embolic and/or thrombotic event rates were higher in the NOAC group, although the numbers of events were small. Further studies are required to determine the long-term effects of anticoagulation strategies in CTEPH

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms. Results: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial [CHEST-2]). Conclusion: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified

Riociguat treatment in patients with pulmonary arterial hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits (usually every 3-6 months) and collated via case report forms. Results: In total, 326 patients with PAH were included in the analysis. The most common AEs in these patients were dizziness (11.7%), right ventricular (RV)/cardiac failure (10.7%), edema/peripheral edema (10.7%), diarrhea (8.6%), dyspnea (8.0%), and cough (7.7%). The most common SAEs were RV/cardiac failure (10.1%), pneumonia (6.1%), dyspnea (4.0%), and syncope (3.4%). The exposure-adjusted rate of hemoptysis/pulmonary hemorrhage was 2.5 events per 100 patient-years. Conclusion: Final data from EXPERT show that in patients with PAH, the safety of riociguat in clinical practice was consistent with clinical trials, with no new safety concerns identified and a lower exposure-adjusted rate of hemoptysis/pulmonary hemorrhage than in the long-term extension of the Phase 3 trial in PAH

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

ObjectiveThe soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice.MethodsEXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms.ResultsIn total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial [CHEST-2]).ConclusionData from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified.</div

Riociguat treatment in patients with pulmonary arterial hypertension: Final safety data from the EXPERT registry

ObjectiveThe soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice.MethodsEXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits (usually every 3–6 months) and collated via case report forms.ResultsIn total, 326 patients with PAH were included in the analysis. The most common AEs in these patients were dizziness (11.7%), right ventricular (RV)/cardiac failure (10.7%), edema/peripheral edema (10.7%), diarrhea (8.6%), dyspnea (8.0%), and cough (7.7%). The most common SAEs were RV/cardiac failure (10.1%), pneumonia (6.1%), dyspnea (4.0%), and syncope (3.4%). The exposure-adjusted rate of hemoptysis/pulmonary hemorrhage was 2.5 events per 100 patient-years.ConclusionFinal data from EXPERT show that in patients with PAH, the safety of riociguat in clinical practice was consistent with clinical trials, with no new safety concerns identified and a lower exposure-adjusted rate of hemoptysis/pulmonary hemorrhage than in the long-term extension of the Phase 3 trial in PAH.</p

Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology

In this review, we discuss the role of transforming growth factor-beta (TGF-β) in the development of pulmonary vascular disease (PVD), both pulmonary arteriovenous malformations (AVM) and pulmonary hypertension (PH), in hereditary hemorrhagic telangiectasia (HHT). HHT or Rendu-Osler-Weber disease is an autosomal dominant genetic disorder with an estimated prevalence of 1 in 5000 persons and characterized by epistaxis, telangiectasia and AVMs in more than 80% of cases, HHT is caused by a mutation in the ENG gene on chromosome 9 encoding for the protein endoglin or activin receptor-like kinase 1 (ACVRL1) gene on chromosome 12 encoding for the protein ALK-1, resulting in HHT type 1 or HHT type 2, respectively. A third disease-causing mutation has been found in the SMAD-4 gene, causing a combination of HHT and juvenile polyposis coli. All three genes play a role in the TGF-β signaling pathway that is essential in angiogenesis where it plays a pivotal role in neoangiogenesis, vessel maturation and stabilization. PH is characterized by elevated mean pulmonary arterial pressure caused by a variety of different underlying pathologies. HHT carries an additional increased risk of PH because of high cardiac output as a result of anemia and shunting through hepatic AVMs, or development of pulmonary arterial hypertension due to interference of the TGF-β pathway. HHT in combination with PH is associated with a worse prognosis due to right-sided cardiac failure. The treatment of PVD in HHT includes medical or interventional therapy

Treatment options in massive pulmonary embolism during pregnancy; A case-report and review of literature

Systemic thrombolysis with recombinant tissue plasminogen activator (rt-PA), streptokinase or urokinase is considered as high-risk treatment in pregnancy. However, several reports have described the successful use of systemic thrombolysis in pregnant patients with massive pulmonary embolism and haemodynamic instability. Case: We describe a 34-year old, pregnant female, who presented at 25 weeks of gestation with an acute collapse with reduced consciousness and shortness of breath caused by massive pulmonary embolism. Because of significant haemodynamic instability, increased right ventricular pressure and no improvement after intravenous heparin, thrombolytic therapy was administered. The response to thrombolytic therapy was excellent. No severe haemorrhagic complications were observed. Anticoagulant therapy with LMWH was continued until delivery. A healthy child was born at term. Review: In English literature, 13 patients received thrombolysis during pregnancy because of pulmonary embolism. No maternal deaths, four non-fatal maternal major bleeding complications, 30.8%;95%CI(9.1-61.4), two fetal deaths, 15.4%;95%CI(1.9-45.5), and five preterm deliveries, 38.5%;95%CI(13.9-68.4), were observed. Surgical embolectomy and catheter embolectomy or catheter thrombolysis has only been performed in 12 patients. Conclusion: The number of reports on thrombolytic therapy, surgical embolectomy and catheter embolectomy or thrombolysis for massive pulmonary embolism during pregnancy are limited. We suggest an international registry for pregnant patients undergoing thrombolysis or embolectomy to gain more information about these treatment options. Nevertheless, complication rates of thrombolytic therapy are acceptable in the light of the underlying disease, and in the meantime, current data do not justify withholding pregnant women from thrombolytic therapy in case of life-threatening PE. (C) 2009 Elsevier Ltd. All rights reserved

Low Complication Rates With Totally Implantable Access Port Use in Epoprostenol Treatment of Pulmonary Hypertension

Background: Among patients with advanced pulmonary arterial hypertension (PAH) who are receiving epoprostenol treatment, complications due to the delivery system are known to be a cause of serious morbidity and mortality. In this study, we aimed to outline the complications associated with the use of a totally implantable access port (TIAP) and their consequences in continuous intravenous epoprostenol treatment. Methods: One hundred eleven pulmonary hypertension (PK) patients treated with epoprostenol through a totally implantable access port (FLAT) between May 1998 and July 2006 at three Dutch PH referral centers were retrospectively studied. Results: During a mean follow-up period of 946 +/- 719 days, TIAP-related complications included local port site infections, bloodstream infections, port site skin perforations and incorrect port placement, with incidence rates of 0.11, 0.15, 0.06 and 0.04 per patient-year, respectively. Fatal, serious, moderate and minor consequences of these complications had incidence rates of 0.01, 0.50, 0.09 and 0.01 per patient-year, respectively. The median complication-free survival was 371 days. Staphylococcus aureus was the dominant infectious agent. The median TIAP. life duration was 677 days. Female patients showed significantly longer first TLAT survival (p = 0.004). Conclusions: The use of a TIAP showed long-lasting port survival and relatively low complication rates. Our data suggest that the TLAT is well suited for continuous intravenous epoprostenol delivery in patients with pulmonary hypertension. J Heart Lung Transplant 2009;28:273-9. Copyright (C) 2009 by the International Society for Heart and Lung Transplantation

Hereditary Hemorrhagic Telangiectasia (HHT) and Survival: The Importance of Systematic Screening and Treatment in HHT Centers of Excellence

Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disease, is characterized by telangiectases and arteriovenous malformations (AVMs). Untreated AVMs, especially in the lungs&mdash;pulmonary AVMs (PAVMs)&mdash;can result in morbidity with a decreased life expectancy. We have investigated whether HHT patients, systematically screened for HHT-related organ involvement and treated if needed, have a similar survival as persons without HHT. We included all individuals screened for HHT between 2004 and 2016 with a genetically or clinically confirmed diagnosis (HHT group) or excluded diagnosis (non-HHT control group). The social security number was used to confirm status as dead or alive in December 2019. We included 717 HHT patients and 471 controls. There was no difference in survival between the HHT and the non-HHT control group. The HHT group had a life expectancy of 75.9 years (95% confidence interval (CI) 73.3&ndash;78.6), comparable to the control group (79.3 years, 95% CI 74.8&ndash;84.0, Mantel&ndash;Cox test: p = 0.29). In conclusion, the life expectancy of HHT patients systematically screened for HHT-related organ involvement and treated if needed in an HHT center of excellence was similar compared to their controls, justifying systematic screening and treatment in HHT patients

Pulmonary Arterial Hypertension and Hereditary Haemorrhagic Telangiectasia

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disease characterised by multisystemic vascular dysplasia. Heritable pulmonary arterial hypertension (HPAH) is a rare but severe complication of HHT. Both diseases can be the result of genetic mutations in ACVLR1 and ENG encoding for proteins involved in the transforming growth factor-beta (TGF-&beta;) superfamily, a signalling pathway that is essential for angiogenesis. Changes within this pathway can lead to both the proliferative vasculopathy of HPAH and arteriovenous malformations seen in HHT. Clinical signs of the disease combination may not be specific but early diagnosis is important for appropriate treatment. This review describes the molecular mechanism and management of HPAH and HHT