New guidance on potentially fatal blood clots published today - European Society of Cardiology

Posted: 31 Aug 2019 12:06 AM PDT

Paris, France – 31 Aug 2019: The European Society of Cardiology (ESC) Guidelines on acute pulmonary embolism are published online today in European Heart Journal (1), and on the ESC website. (2) They were developed in collaboration with the European Respiratory Society (ERS).

Acute pulmonary embolism is the third most common cause of cardiovascular death in Europe, after heart attack and stroke, contributing to more than 350,000 deaths each year. A blood clot (thrombus) in a deep vein, usually in the legs, is dislodged and travels to the lungs where it blocks one or more vessels. This typically occurs if the vein wall is damaged, blood flow is too slow, or the blood becomes too thick.

Major surgery such as knee or hip replacement, serious injury, prolonged bed rest and cancer are common risk factors for acute pulmonary embolism. It can also happen after long travel and in women who are pregnant or taking the oral contraceptive pill.

"Symptoms including shortness of breath and chest pain resemble other diseases so the diagnosis is often missed, or the severity of the situation is underestimated, and many patients die before getting appropriate therapy," said Professor Stavros Konstantinides, Chairperson of the guidelines Task Force and medical director, Centre for Thrombosis and Haemostasis, Johannes Gutenberg University Mainz, Germany.

The guidelines clarify how to diagnose acute pulmonary embolism step by step. The process begins with clinical suspicion based on symptoms combined with blood tests (D-dimers). Depending on the severity and urgency of the scenario, a computed tomography (CT) scan may be used to visualise the lung vessels, or cardiac ultrasound to look at the heart chambers.

A new table shows how CT scans and lung scans compare in their ability to diagnose or exclude pulmonary embolism, and how much radiation the patient receives with each of these tests.

"The aim is to get to the diagnosis as reliably and quickly as possible, in order to start lifesaving therapy and prevent other clots from reaching the lungs," said Professor Guy Meyer, Co‐Chairperson of the guidelines Task Force and respiratory medicine physician, Hôpital Européen Georges-Pompidou, Paris, France.

Anticoagulant drugs (blood thinners) help the body dissolve clots and reopen the blocked vessels. If the patient is in shock and about to collapse, the clot must be removed immediately, and this can be achieved using thrombolytic drugs (clot busters), catheters, or surgery.

The guidelines recommend how to judge the severity of pulmonary embolism based on a combination of clinical, imaging and laboratory results. This will dictate whether blood thinners alone are sufficient or if clot busters, a catheter intervention, or surgical removal is necessary. There is new advice on how to distinguish, in the CT scan, fresh thrombi in the lungs from chronic obstructions due to a disease called chronic thromboembolic pulmonary hypertension (CTEPH), which requires a different type of therapy.

Also new is the guidance on which drugs to use in a patient with pulmonary embolism and cancer. Patients with cancer have a high risk of recurrence, and indefinite anticoagulation is often necessary.

Acute pulmonary embolism is a leading cause of maternal death in high-income countries, but diagnosis can be challenging because symptoms often overlap with those of normal pregnancy. Novel recommendations outline how to diagnose and treat pulmonary embolism in the pregnant patient.

Updated instructions state when it is safe to send patients home from the hospital. Some have a lifelong increased risk of another event. Anticoagulants are used to treat the acute episode and prevent recurrence but raise the risk of bleeding. The guidelines describe how to decide the duration of treatment. They also specify when and how (with which tools and tests) to follow patients, and which findings suggest chronic disease (CTEPH) requiring diagnosis and treatment in an expert centre.

Last but not least, the 2019 ESC Guidelines endorse a multidisciplinary approach to pulmonary embolism after the acute phase and discharge of the patient. Teams should include physicians, appropriately qualified nurses, and other allied health professionals, aiming to ensure smooth transitions between hospital specialists and practitioners, optimised long term care and prevention of recurrence.

Advice for patients

Be aware of conditions that predispose to acute pulmonary embolism.
If you are at increased risk or have previously had pulmonary embolism or deep vein thrombosis, and are admitted to hospital for another disease, ask what is being done to prevent thrombosis.
If you have one or more risk factors for pulmonary embolism and feel shortness of breath, chest discomfort or chest pain, lightheaded or faint, call a doctor or ambulance immediately. Lie down and do not move around. Do not walk or drive to the hospital or physician's practice.
If you had an acute pulmonary embolism and are on blood thinners, when you are discharged from hospital ask when you need to see a doctor again. At the follow-up visit, report any bleeding and whether you have returned to normal or still have symptoms such as shortness of breath.

ENDS

Phase 2a Trial of Potential Oral PAH Therapy, Rodatristat Ethyl, Begins Dosing - Pulmonary Hypertension News

Posted: 07 Aug 2019 12:00 AM PDT

A Phase 2a trial testing the potential oral treatment rodatristat ethyl in patients with pulmonary arterial hypertension (PAH) has begun dosing, its developer announced.

Rodatristat ethyl (or RVT-1201), the lead therapy candidate of Altavant Sciences, is an inhibitor of the enzyme tryptophan hydroxylase. The therapy is designed to block the production of circulating serotonin, a hormone implicated in the tightening and growth of pulmonary artery muscle cells, subsequently narrowing arteries and triggering PAH. (Altavant is part of Roivant Pharma group.)

Besides PAH, excessive levels of serotonin are also found in people with idiopathic pulmonary fibrosis and sarcoidosis. By lowering serotonin levels, scientists believe that rodatristat ethyl – given in an immediate-release tablet formulation — may halt or reverse these diseases.

The double-blind, multi-center study (NCT03924154), named ELEVATE 1, is designed to assess the therapy's safety, tolerability, pharmacological profile, and ability to bind to its target in adults with PAH. Exploratory efficacy measures, including exercise capacity, breathlessness, and World Health Organization functional class, will also be analyzed.

Up to 36 PAH patients, ages 18 to 75, will be recruited at nearly 20 centers across the U.S. and Canada. Enrollment is ongoing at six U.S. locations; more information on sites and contacts can be found here.

Join the PH forums: an online community especially for patients with pulmonary hypertension.

To join the 12-week trial, participants are required to undergo a six-minute walk distance test to assess exercise capacity, and to be taking PAH medications for at least three months. These can include endothelin receptor antagonists, phosphodiesterase inhibitors, and Adempas (riociguat, marketed by Bayer).

Due to rodatristat ethyl's complementary mechanism of action relative to existing medications, those enrolled will be allowed to continue on their current treatments, Altavant said in a press release.

Following a four-week screening period, patients will be randomized 2:1 to either rodatristat ethyl or placebo, both given twice daily along with food for six weeks. They will then be followed for another two weeks.

The trial is expected to be completed by February 2020, and data collected will be used to inform a Phase 2b efficacy study.

"Initiating the ELEVATE 1 Study is a significant milestone for Altavant, and represents our commitment to the rare respiratory disease community, and our approach to patient-centric, transparent clinical development," William T. Symonds, PharmD, Altavant's CEO, said in the release.

"Rodatristat ethyl is a first-in-class investigational medicine for the treatment of PAH," Symonds said, adding that the trial's goal is to provide evidence of the therapy's mechanism in PAH, "which we believe could halt or reverse the pulmonary vascular remodeling characteristic of the disease. Success in this study would take us one step closer to being able to provide a much-needed, new therapeutic option to PAH patients."

Marc Humbert, MD, PhD, a professor of respiratory medicine at Université Paris-Saclay, and director of the French National Reference Centre for Pulmonary Hypertension, added: "while the introduction of vasodilators was a significant advancement in treating PAH … there is still a need to develop novel treatment options to further improve lifespan."

Humbert, who is also a member of Altavant's scientific advisory board, emphasized that "new R&D efforts … may ultimately give us an opportunity to offer a new treatment option to PAH patients that provides better outcomes."

In line with evidence from healthy volunteers, preclinical results presented this year at the 13^th Annual World Congress on Pulmonary Vascular Disease in Barcelona indicated that the median effective dose of rodatristat ethyl lowered serotonin production by about 50%. This led to a reduction of pulmonary artery wall thickness in rats.

Preliminary results from a study in healthy volunteers demonstrated dose-proportional increases in exposure following administration of rodatristat ethyl. All tested doses and regimens were generally well-tolerated.

Author Details

José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer's disease.

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