15 October 2021

This week in PVD

Iron infusion aids exercise, overall health of PAH patients lacking mineral

Infusion with Ferinject (ferric carboxymaltose) safely treated people with pulmonary arterial hypertension (PAH) and iron deficiency, easing disease symptoms, improving exercise capacity, and lowering their number of hospital visits over a period of 18 months, a long-term study reported.

Ferinject, as this treatment for iron deficiency anemia is known in Europe, is available in the U.S. under the brand name Injectafer. It is approved for people who fail to respond sufficiently to oral iron supplements, or are unable to take such supplements.

The study, “Ferric carboxymaltose in patients with pulmonary arterial hypertension and iron deficiency: a long-term study,” was published in the Journal of Cachexia, Sarcopenia and Muscle.

Iron is essential to the body for functions that include the production of hemoglobin — the protein in red blood cells responsible for carrying oxygen to tissues. Iron deficiency is common to PAH patients — estimated to be found in 43–60% of these people — affecting their ability to exercise and increasing the frequency and severity of disease symptoms.

Oral iron supplements are reported to be of limited benefit to people with PAH and iron deficiency. But a few short-term studies have shown that a single intravenous infusion of Ferinject can improve the ability of muscle cells to carry oxygen, aiding their exercise capacity and quality of life.

Selonsertib fails to reduce pulmonary vascular resistance, improve outcomes in PAH

In the phase 2 ARROW trial, selonsertib for 24 weeks failed to significantly reduce pulmonary vascular resistance or achieve clinical improvement in patients with pulmonary arterial hypertension.

“Selonsertib is a first-in-class small-molecule [apoptosis signal-regulating kinase 1] inhibitor that has been developed for the treatment of diseases with a high burden of oxidative stress, including PAH,” Stephan Rosenkranz, MD, interventional cardiologist at the Heart Center and the Cologne Cardiovascular Research Center and head of the Pulmonary Hypertension Center at the University of Cologne, Germany, and colleagues wrote in Lancet Respiratory Medicine. “The results from non-clinical pharmacology studies show that selonsertib is a potent and selective inhibitor of [apoptosis signal-regulating kinase 1] with the potential to ameliorate disease via multiple mechanism, including modulation of inflammation and oxidative stress and inhibitor of reversal of maladaptive remodeling processes.”

The randomized, double-blind, placebo-controlled, phase 2 ARROW trial included 151 patients at 46 centers. All were aged 18 to 75 years and had a diagnosis of idiopathic or hereditary PAH or PAH-associated with connective tissue disease, drugs or toxins, human immunodeficiency virus or repaired congenital heart defects. From December 2014 to November 2015, patients were stratified by PAH etiolgy and background therapy and underwent random assignment to selonsertib 2 mg (Gilead; n = 39), selonsertib 6 mg (n = 37), selonsertib 18 mg (n = 37) or placebo (n = 37) administered once daily via tablet.

Blocking specific PI3K protein prevents PH in animal models

Targeting a protein called p110a, a part of the PI3K family of enzymes, may be useful for preventing or even reversing pulmonary hypertension, research done in cells and rodent models showed.

“Targeted inhibition of [p110a] offers a disease-modifying treatment approach, which is readily accessible by small molecule inhibitors and warrants further evaluation in clinical trials,” the researchers wrote.

Results of the study “Disrupted PI3K subunit p110α signaling protects against pulmonary hypertension and reverses established disease in rodents,” were published in The Journal of Clinical Investigation.

Pulmonary hypertension (PH) is characterized by changes in the biological activity of pulmonary arterial smooth muscle cells (PASMCs), the cells that line the lung’s blood vessels. In PH, PASMCs tend to grow more than is normal and become resistant to apoptosis, a form of programmed cell death.

These phenomena are thought to be largely driven by the activation of certain protein receptors — specifically, receptors for growth factors — on the surface of pulmonary arterial smooth muscle cells. Growth factors, as its name suggests, are signaling molecules that can prompt cells to grow.

When a growth factor binds to its receptor, it sends biochemical signals into the cell that affect its activity, like prompting cell division and growth.

Triplet therapy for PAH may reduce disease progression vs doublet therapy

New data on treatment for newly diagnosed pulmonary arterial hypertension (PAH) show initial treatment for the progressive disease that includes macitentan has potential to reduce risk of disease progression.

Patients with newly diagnosed pulmonary arterial hypertension (PAH) who have yet to initiate treatment may find subsequent benefit in initial therapy with a triple- vs a double-drug combination, new data from the multicenter, double-blind, randomized phase 3b TRITON trial show.

This, and other findings, were recently published in Journal of the American College of Cardiology.

Oral triplet therapy with macitentan, tadalafil, and selexipag was compared with doublet therapy of macitentan, tadalafil, and placebo among treatment-naive patients, because “combination therapy to target multiple pathways is an essential part of PAH management [and] patients receiving double oral therapy, including initial double therapy, continue to experience PAH progression, providing a rationale for more intensive treatment.”

 Pevious studies, the authors added, have also shown initial triplet therapy to improve hemodynamic status, functional capacity, morbidity, and mortality. Participants in this study (aged 18 to 75 years) were randomized 1:1 to initial triple (n = 123) or double (n = 124) therapy by 28 days after study screening and had to have PAH confirmed in the 6 months leading up to this, a 6-minute walk distance (6MWD) of at least 50 meters, and pulmonary vascular resistance (PVR) of at least 6 WU; they were followed until week 26 for the last randomized patient.

Tenax cleared to start clinical testing of oral imatinib for PAH

The U.S. Food and Drug Administration (FDA) has cleared Tenax Therapeutics to begin clinical testing of its new oral formulation of imatinib in people with pulmonary arterial hypertension (PAH).

The company is planning to conduct a small pharmacological study this year — and then launch a Phase 3 clinical trial by June 2022 to test the therapy’s efficacy.

“Tenax is thrilled we can now advance our imatinib PAH program towards pivotal testing,” Christopher Giordano, Tenax’s CEO, said in a press release. “We remain on track to be the first company to commence a Phase 3 trial of a new formulation of imatinib in patients with PAH.”

Imatinib is a small molecule that blocks the activity of signaling proteins in the body that are involved in driving the growth of certain kinds of cells.

An oral formulation of imatinib — 100 mg and 400 mg tablets, marketed as Gleevec by Novartis — is approved to treat certain types of blood cancers, in which the growth of cancer cells is driven by these signaling molecules. These signals also are thought to contribute to the abnormal growth of blood vessel cells that occurs in PAH, which is the theoretical basis for using imatinib in PAH.

“Imatinib has been shown to block several growth factors that regulate endothelial and vascular smooth muscle cell proliferation in PAH,” said Stuart Rich, MD, chief medical officer of Tenax.

Pharmacomechanical catheter-directed thrombolysis shows promise in PE

Pharmacomechanical catheter-directed thrombolysis using an endovascular catheter was preliminarily safe and effective in patients with pulmonary embolism, according to interim results of the RESCUE trial presented at VIVA 21.

“Systemic thrombolysis is associated with improved mortality and hemodynamic decompensation in patients with intermediate-risk PE, and catheter-directed thrombolysis improves right ventricular function faster than anticoagulation at 24 hours,” Akhilesh K. Sista, MD, FSIR, FAHA, section chief of vascular interventional radiology and associate professor of radiology at NYU Grossman School of Medicine, said during a presentation. “Most of the devices used to perform CDT are not designed for use in large vessels like pulmonary arteries. Pharmacomechanical CDT with the Bashir Endovascular Catheter (Thrombolex) has shown promising early results.”

Sista and colleagues conducted a prospective, multicenter, single-arm study of the catheter in 62 patients (mean age, 59 years; 71% men) with intermediate-risk acute PE (90% with high intermediate-risk PE). All patients had PE symptoms for 14 days or less, a filling defect in at least one main or lobar pulmonary artery and a RV/left ventricular end diastolic diameter ratio of at least 0.9.

The primary efficacy endpoint was reduction in RV/LV ratio at 48 hours, and the interim analysis of 60 evaluable patients required a P value of < .0038 to be significant. The primary safety endpoint was major bleeding and device-related adverse events at 72 hours.

PH patients at high risk of misusing opioids after surgery

People with pulmonary hypertension (PH) who start treatment with opioids to manage pain after undergoing surgery are at high risk of continuing to take these addictive medications for longer than required, new research suggests.

Indeed, hypertension was one of eight specifically identified “top risk factors” for “new persistent post-surgical opioid use,” according to researchers, who said intervention measures could be key for prevention.

“Our findings identify which patients would most benefit from effective preoperative consultation and should be followed especially carefully after surgery,” Gia Pittet, PhD, a researcher at the University of California, Los Angeles (UCLA), and the study’s lead author, said in a press release.

The findings were shared at the Anesthesiology 2021 annual meeting, in the presentation “Identification Of Risk Factors For New Persistent Opioid Use After Surgery.”

People with pulmonary hypertension (PH) who start treatment with opioids to manage pain after undergoing surgery are at high risk of continuing to take these addictive medications for longer than required, new research suggests.

Opioids are a class of drugs derived from compounds found in the poppy plant that are used to relieve pain. These include approved prescription medications like hydrocodone, oxycodone, and morphine, as well as substances that are widely illegal, such as heroin.

Although opioids can be highly effective at easing pain, they also can be very addictive and carry a high risk of overdose, which can be deadly — last year, nearly 100,000 people in the U.S. died of overdoses on opioids and other drugs, according to the Centers for Disease Control and Prevention.

One of the more common prescriptions for opioid use in a clinical context is to help manage pain while recovering from surgery. However, there is a risk that people will use these medicines improperly — often without intending to or realizing that they are doing so.

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