Understanding Mortality Risk in Pediatric Pulmonary Arterial Hypertension - AJMC.com Managed Markets Network
Understanding Mortality Risk in Pediatric Pulmonary Arterial Hypertension - AJMC.com Managed Markets Network |
- Understanding Mortality Risk in Pediatric Pulmonary Arterial Hypertension - AJMC.com Managed Markets Network
- Altered Fat Metabolism May Contribute to PAH Development - Pulmonary Hypertension News
- How Treatment May Help Improve PAH Risk Status Sponsored Post - Pulmonary Hypertension News
- Registry highlights 'evolving characteristics' of patients with PAH - Healio
- Uptravi Added to Lower Cost Treatment List for PAH Patients in... - Pulmonary Hypertension News
| Posted: 26 Feb 2021 03:24 PM PST  It found those with idiopathic PAH had a higher risk than those whose PAH was associated with congenital heart disease (CHD) and other etiologies. It also determined that higher resistance to blood flow from the pulmonary artery to the left atrium was connected to risk. However, the authors were unable to determine whether other factors, taken alone or in combination, affected risk. Children with PAH have stiff pulmonary arteries, forcing the heart to work harder to pump blood to the lung, leaving the child out of breath and at risk of failure of the right ventricle. New target therapies have decreased mortality and morbidity in recent decades, but given low pediatric patient numbers in studies, devising treatment strategy has been challenging, the authors wrote. Researchers from Hungary used records from 58 patients with PAH treated between 1995 and 2019. They found that patients with idiopathic PAH had increased mortality risk compared to those whose disease was congenital. There were 12 patients with idiopathic disease in the study group; 32 had PAH associated with CHD. They also found that patients with higher pulmonary vascular resistance index had significantly increased risk. The researchers additionally looked at other factors, including demographics, World Health Organization functional class (WHO FC) as well as various signs of right ventricular failure from echocardiography and cardiac catheterization. The authors found that clinical parameters such as WHO functional state (P = .0866), clinical evidence of right ventricular failure (P = .2760), or growth retardation, (P = .630) had no significant prognostic value. Nor did the presence of pathology in echocardiograms such as right atrium (RA)/right ventricle (RV) enlargement, reduced left ventricle (LV) size, increased RV/LV ratio, reduced tricuspid annular plane systolic excursion, and pericardial effusion (P = .0576). Due to low sample size, however, the authors cautioned against considering these finds as major evidence against their effect and favored further study. The authors also examined several risk factors in combination, but again found no significant impact on survival. Records used in the study showed a 29% mortality rate over a 5.4-year span. Median age of diagnosis was 4.2 years. The risk stratification strategy examined in the study was assembled by the Pediatric Task Force of the 5th World Symposium on Pulmonary Hypertension in 2019 using available evidence to determine at initial diagnosis which child patients were at higher or lower risk levels. Since the physical and financial burden is high for the aggressive combination therapy used for high-risk patients—which includes intravenous or subcutaneous prostacyclin treatment—making such evaluations of risk is critical. The adult risk stratification is inappropriate for children due to differences in cause, the authors said. For example, 4%-12% of adults had PAH associated with congenital heart disease, compared with 36% for children. Reference Ablonczy L, Ferenci T, Somoskövi O, et al. Prognostic value of early risk stratification in pediatric pulmonary arterial hypertension. Transplant Proc. 2021;S0041-1345(21)00081-6. Published online February 20, 2021. doi:10.1016/j.transproceed.2021.01.047.  |
| Altered Fat Metabolism May Contribute to PAH Development - Pulmonary Hypertension News Posted: 15 Feb 2021 05:00 AM PST Adipose (fat) tissue may contribute to the development of pulmonary arterial hypertension (PAH) due to certain metabolic alterations found, for the first time, in patients and also in rodent models of the condition, a study suggests. The study, "Adipokines and Metabolic Regulators in Human and Experimental Pulmonary Arterial Hypertension," was published in the International Journal of Molecular Sciences. PAH is characterized by high blood pressure caused by the narrowing of the pulmonary arteries, blood vessels that transport blood through the lungs. Recent studies suggest PAH is a systemic disorder in which inflammation and metabolic alterations play a role in its development. Metabolic conditions such as obesity, type 2 diabetes, insulin resistance, and cardiovascular disease have been linked to pulmonary hypertension (PH) and may be implicated in disease onset and severity. Low-grade chronic inflammation (meta-inflammation) is often triggered by metabolic imbalances and is commonly found in people with metabolic syndrome. This kind of inflammation is thought to be mediated by immune cells in tissues besides the lungs, including the liver, colon, skeletal muscle, and adipose (fat storage) tissue. Still, its impact on PAH is not entirely understood. Adipose tissue is metabolically active and may be associated with PAH development by producing signaling proteins called adipokines, which regulate several functions, including glucose and fat metabolism, insulin sensitivity, and inflammation. To investigate further, a team led by researchers based at Brigham and Women's Hospital in Massachusetts examined various metabolic regulators in blood and lung tissue isolated from PAH patients, and evaluated lung and adipose tissue in three common rodent models of pulmonary hypertension. "A better understanding of the role of adipokines and meta-inflammation in PAH pathogenesis will provide the basis for therapeutic approaches that may confer benefit in these patients," the researchers wrote. Blood samples were collected from 15 PAH patients, mean age of 38.4 years, including four males and 11 females. Also included were 22 age- and gender-matched healthy controls as a comparison group. Blood test results showed circulating levels of FABP-4 — the primary adipokine produced by adipose tissue involved in fatty acid uptake, transport, and metabolism — were significantly increased in patients with PAH, compared to the control group. Additionally, adipose-derived adiponectin, implicated in regulating glucose levels as well as fatty acid breakdown, was also significantly increased, as was FGF-21, a signaling protein mainly produced by the liver which stimulates the uptake of glucose in adipose tissue. Statistically significant positive correlations were found between increased FGF-21 and higher FABP-4 levels, between adiponectin and FABP-4 levels, and between adiponectin and FGF-21. Analysis of lung tissue isolated from PAH patients found, compared with control tissue samples, increased activity in the genes that encode FABP-4, FGF-21, and related protein PPAR-gamma — a regulator of the formation of adipocytes (fat cells) and insulin responsiveness in adipose tissue. The team tested three rat models of PAH, including: the MCT model, in which PH is triggered by the chemical MCT; the SuHx rat model, where rats are given Sugen injection and exposed to low oxygen levels (hypoxia) for three weeks; and chronic hypoxia model, in which rats are subjected to hypoxia for two weeks. The blood pressure in the right heart ventricle was significantly elevated in all three PH-experimental models compared to controls. There was no difference between controls and rat models in the left heart ventricle, which is an indicator of systemic blood pressure. As seen in human tissues, FABP-4, FGF-21, and PPAR-gamma were significantly upregulated in the lungs in all three PH rat models. While adiponectin was not found in lung tissue, its receptor production was significantly increased in the SuHx model. PPAR-gamma expression levels were elevated in all three rat models, being significantly increased in the MCT model. Levels of adiponectin and related adiponectin receptors R1 and R2 were significantly increased in the MCT and SuHx models. In the hypoxic model, there was a trend towards elevated adiponectin R1 and R2 but their levels did not reach statistical significance. Production of Glut-4, a glucose transporter that facilitates insulin-stimulated glucose uptake, was significantly increased in the MCT and SuHx models, and had a non-significant trend in the hypoxic model. Furthermore, production levels of PFK-1, one of the key regulators in glucose breakdown, were significantly increased in adipose tissue in all three rat models. Pyruvate dehydrogenase beta and citrate synthase, critical enzymes in energy metabolism, were elevated in the MCT and SuHx models, with a non-significant trend in the hypoxic rat model. Finally, significantly elevated production of CD36, which facilitates fatty acid uptake in adipose tissue, was seen in all three rat models, compared to controls. Similar results were observed in other enzymes involved in fatty acid breakdown. "In summary, we report a pattern of dysregulated adipokine circulating levels in humans with idiopathic pulmonary arterial hypertension," the researchers wrote. "Our findings in adipose tissue in three experimental models, support that adipose tissue may be contributing to PAH pathogenesis via adipokine release and altered bioenergetics." "Consistent with the notion that PAH is a systemic disease, we report for the first time adipose tissue metabolic alterations in experimental models," they added. "Additional studies to identify the cellular sources of these adipokines, both within the lung and within adipose tissue, are needed in order to gain mechanistic insights into their potential role in disease pathogenesis."  Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he's helping make medical science information more accessible for everyone. × Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he's helping make medical science information more accessible for everyone. Latest Posts  |
| How Treatment May Help Improve PAH Risk Status Sponsored Post - Pulmonary Hypertension News Posted: 01 Feb 2021 12:00 AM PST How Treatment May Help Improve PAH Risk Status Pulmonary arterial hypertension (PAH) is a progressive disease that involves narrowing of the lung's blood vessels. This narrowing can prevent proper blood flow to the heart. People with the disease often have nonspecific symptoms, such as fatigue, dizziness, shortness of breath, and swelling of lower extremities. A variety of tests, such as an echocardiogram and right heart catheterization, can be performed to help rule out other diseases and diagnose PAH. Once diagnosed with PAH, it is important that your goals are aligned with your healthcare team's goals. Some common goals are to be more physically active, have fewer symptoms, and prevent those symptoms, and the disease, from getting worse. To aid in achieving these goals, it is important to understand, measure, and monitor your PAH risk status. What is PAH risk status? PAH risk status is a prediction of how your disease will progress over the next 5 years. It is determined using a variety of measures, many of which your healthcare provider already assesses. These include how far you can walk in 6 minutes, whether levels of a certain biomarker in the blood are raised, if there is any strain to the heart, and how well you are functioning in daily life. Your healthcare provider will use these and other tests to calculate your PAH risk score to help determine how far your disease has progressed and how it may be responding to any treatments thus far. How does treatment help? Do you know how specific treatments for PAH work to avoid further narrowing of your blood vessels and worsening of symptoms? Understanding some basics about how your medicine may impact your disease, and ultimately affect your PAH risk status, may empower you to help your healthcare provider identify the treatment plan that works best for you. One fundamental thing to know about PAH is that it can involve multiple pathways that affect the blood vessels in the lungs. There are often imbalances in the natural substances in these pathways, and there are several PAH medications that target each of these specific pathways. One of these pathways is the prostacyclin pathway. Prostacyclin is a substance found in blood vessels that helps keep the vessels open, but it may be lower than normal in people with PAH. The prostacyclin class of medications acts like natural prostacyclin to help combat the narrowing of blood vessels in the lungs. These medications can be administered through oral, inhaled, or pump therapy routes. Targeting more than one pathway may help your symptoms While doctors will often start patients with PAH on one oral therapy, combining treatments to target multiple pathways is often highly beneficial for patients. Prostacyclin class therapies tend to be added on after the other treatments, especially when a patient still hasn't reached low-risk status while on other medications. When it is appropriate to add on a drug that targets the prostacyclin pathway, PAH patients may be prescribed Orenitram (treprostinil) in addition to their initial therapy. Orenitram, which is indicated for PAH patients to delay disease progression and improve exercise capacity, is the first oral prostacyclin class treatment to be approved by the U.S. Food and Drug Administration (FDA). It is the tablet form of the same proven and trusted type of medicine that has been available as a pump therapy for more than 18 years. What to expect with Orenitram (treprostinil) Taking Orenitram may impact your PAH risk status. In a clinical study, 9 of 10 patients who added Orenitram to their treatment plan maintained or improved their PAH risk status. Improvement in risk status was seen in over 30% of patients, and it occurred as early as three months after starting treatment. In clinical studies, patients taking Orenitram have also: Many of these parameters are what healthcare providers use to assess your PAH risk status, and ultimately, predict disease progression. In fact, patients taking Orenitram in a clinical study were found to have a 61% less likely chance of disease progression compared to those who didn't add Orenitram to their treatment plan. Patients taking Orenitram may experience side effects. Some of the most common side effects are headache, diarrhea, nausea, vomiting, flushing, and pain in arms, legs, and jaw. Some patients taking Orenitram find that they feel worse before they feel better, but they may eventually see improvements in PAH symptoms that they did not experience with other therapeutic approaches. Your healthcare team will discuss possible side effects with you before starting Orenitram so you know what to expect and can create a plan for how to manage these side effects. Takeaway Improving risk status is a major goal of PAH treatment, but there is no one-size-fits-all solution for achieving this goal. Orenitram is an add-on medication for PAH patients whose disease may still be progressing despite the use of other therapy. With this medication, patients may be able to improve their overall PAH risk status and slow the progression of their disease. Ask your healthcare provider if adding Orenitram may help you do more and help control your PAH. IMPORTANT SAFETY INFORMATION FOR ORENITRAM Who should not take Orenitram? Do not take Orenitram if you have severe liver problems. What should I tell my healthcare provider before taking Orenitram?Tell your healthcare provider: How should I take Orenitram?• Do not change your dose or suddenly stop taking Orenitram without first talking to your healthcare provider. What are the possible side effects of Orenitram?Orenitram can cause serious side effects, including worsening of PAH symptoms. What is Orenitram?Orenitram is a prescription medicine used to treat pulmonary arterial hypertension (PAH) which is high blood pressure in the arteries of your lungs. Orenitram can help slow down the progression of your disease and improve your ability to exercise. It is not known if Orenitram is safe and effective in children. The risk information provided here is not comprehensive. To learn more about Orenitram, talk with your healthcare provider. Please see Full Prescribing Information and Patient Information at www.orenitram.com or call Customer Service at 1-877- UNITHER (1-877-864-8437). References 1. Santos-Ribeiro D, Mendes-Ferreira P, Maia-Rocha C, Adão R, Leite-Moreira AF, Brás-Silva C. Hypertension artérielle pulmonaire : connaissances de base pour les cliniciens. Archives of Cardiovascular Diseases. 2016;109(10):550-561. doi:10.1016/j.acvd.2016.03.004 2. Hsu VM, Moreyra AE, Wilson AC, et al. Assessment of pulmonary arterial hypertension in patients with systemic sclerosis: comparison of noninvasive tests with results of right-heart catheterization. The Journal of Rheumatology. 2008;35(3). 3. Swetz KM, Shanafelt TD, Drozdowicz LB, et al. Symptom burden, quality of life, and attitudes toward palliative care in patients with pulmonary arterial hypertension: Results from a cross-sectional patient survey. Journal of Heart and Lung Transplantation. 2012;31(10):1102-1108. doi:10.1016/j.healun.2012.08.010 4. Galiè N, Rubin L, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. The Lancet. 2008;371(9630):2093-2100. doi:10.1016/S0140-6736(08)60919-8 5. Galiè N, Channick RN, Frantz RP, et al. Risk stratification and medical therapy of pulmonary arterial hypertension. The European respiratory journal. 2019;53(1). doi:10.1183/13993003.01889-2018 6. Raina A, Humbert M. Risk assessment in pulmonary arterial hypertension. European Respiratory Review. 2016;25(142):390-398. doi:10.1183/16000617.0077-2016 7. Benza RL, Gomberg-Maitland M, Elliott CG, et al. Predicting Survival in Patients With Pulmonary Arterial Hypertension: The REVEAL Risk Score Calculator 2.0 and Comparison With ESC/ERS-Based Risk Assessment Strategies. Chest. 2019;156(2):323-337. doi:10.1016/j.chest.2019.02.004 8. Sitbon O, Morrell NW. Pathways in pulmonary arterial hypertension: The future is here. European Respiratory Review. 2012;21(126):321-327. doi:10.1183/09059180.00004812 9. Mitchell JA, Ahmetaj-Shala B, Kirkby NS, et al. Role of prostacyclin in pulmonary hypertension. Global Cardiology Science and Practice. 2014;2014(4):53. doi:10.5339/gcsp.2014.53 10. Bull T, Pugliese S. Clinical use of extended-release oral treprostinil in the treatment of pulmonary arterial hypertension. Integrated Blood Pressure Control. 2016;9:1. doi:10.2147/IBPC.S68230 11. Gaine S, McLaughlin V. Pulmonary arterial hypertension: Tailoring treatment to risk in the current era. European Respiratory Review. 2017;26(146). doi:10.1183/16000617.0095-2017 12. White RJ, Jerjes-Sanchez C, Meyer GMB, et al. Combination therapy with oral treprostinil for pulmonary arterial hypertension: A double-blind placebo-controlled clinical trial. American Journal of Respiratory and Critical Care Medicine. 2020;201(6):707-717. doi:10.1164/rccm.201908-1640OC 13. Chakinala MM, Feldman JP, Rischard F, et al. Transition from parenteral to oral treprostinil in pulmonary arterial hypertension. Journal of Heart and Lung Transplantation. 2017;36(2):193-201. doi:10.1016/j.healun.2016.06.019 14. Kingman M, Archer-Chicko C, Bartlett M, Beckmann J, Hohsfield R, Lombardi S. Management of prostacyclin side effects in adult patients with pulmonary arterial hypertension. Pulmonary circulation. 2017;7(3):598-608. doi:10.1177/2045893217719250  ×  |
| Registry highlights 'evolving characteristics' of patients with PAH - Healio Posted: 29 Jan 2021 12:00 AM PST January 29, 2021 2 min read Source/Disclosures Disclosures: Badlam reports no relevant financial disclosures. Please see the study for all other authors' relevant financial disclosures. We were unable to process your request. Please try again later. If you continue to have this issue please contact customerservice@slackinc.com. The U.S. Pulmonary Hypertension Scientific Registry provides novel insights on patient characteristics, diagnosis delays and treatment trends in adults with pulmonary arterial hypertension. Middle-aged women with idiopathic PAH or associated PAH comprise the majority of patients with group 1 PAH, according to data published in CHEST.  Moreover, delays in diagnosing PAH remain a challenge, and among those with a diagnosis of PAH, use of combinations of PAH-targeted medications is common. "Over the past 4 decades, investigators have described evolving characteristics of patients diagnosed with PAH and improving survival associated with advances in disease management," Jessica B. Badlam, MD, pulmonologist and assistant professor at the University of Vermont, and colleagues wrote. Researchers reported data from the multicenter prospective cohort registry on 499 adults (mean age, 55.8 years; 79% women) diagnosed with group 1 PAH enrolled in the National Biological Sample and Data Repository for PAH within 5 years of a cardiac catheterization demonstrating hemodynamic criteria. Researchers performed a structured interviews and questionnaires to collect exposure and reproductive histories. In the cohort, from 2015 to 2018, 48% had a clinical diagnosis of idiopathic PAH, 51% had familial PAH and 1% had pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. The mean duration between symptom onset and diagnostic catheterization was 1.9 years. Before enrollment, 66% of patients were treated with more than one PAH medication. "Treatment with the combination of an [endothelial receptor antagonist] and a [phosphodiesterase type 5 inhibitor] increased from 12% (REVEAL Registry) to 24% (USPHSR), perhaps reflecting the reported benefit of upfront initiation of an ERA and a PDE5 inhibitor in treatment-naive PAH patients," the researchers wrote. "The proportion of patients with PAH treated with triple combination PAH therapy increased from 8% (REVEAL Registry) to 15% (USPHSR), reflecting both expedient patterns of practice and recent Prostacyclin Receptor Agonist in Pulmonary Hypertension (GRIPHON) trial data showing incremental benefit with the addition of selexipag (Uptravi, Actelion) to background dual therapy." Among women, 37% reported miscarriage, 22.7% premature birth, 18.5% abortion and 4.2% stillbirth. PAH was rarely diagnosed, with only 1.9% diagnosed within 6 months of a pregnancy. Thirteen percent of patients had pathogenic or suspected pathogenic variants, which reclassified 18% of those with idiopathic PAH and 5% of those with associated PAH as having heritable PAH. Prescription use in the past was common, with 16% reporting use of weight-loss drugs, 27% recreational drugs and 77% oral contraception. The most common hormone exposure was oral contraception in 76.9% of all female patients, followed by 19.3% on hormone replacement therapy. Few patients had a history of androgen use (0.8%), diethylstilbestrol treatment (1%) and drugs to induce ovulation (4.4%). "Despite considerable research into understanding how sex hormones may influence the development and progression of PAH, the contribution of estrogens and reproductive factors to the increased susceptibility of women to develop PAH and potentially their improved survival once diagnosed, remains poorly understood," the researchers wrote.  |
| Uptravi Added to Lower Cost Treatment List for PAH Patients in... - Pulmonary Hypertension News Posted: 12 Feb 2021 05:00 AM PST Australia's government has taken a step to ensure that Uptravi (selexipag), an oral therapy for pulmonary arterial hypertension (PAH), is available to people affected by the disease. Janssen's treatment is now included in the country's Pharmaceutical Benefits Scheme (PBS) listing, meaning it is available to residents in this program at a subsidized cost. The co-pay for most patients getting a prescription medicine through the PBS is currently set at a maximum of AU$41.30 (about $32). Retirees, veterans and others holding what are called concession cards face a maximum out-of-pocket charge of AU$6.60. An estimated 420 PAH patients in Australia start treatment for their disease each year, and some — partly depending on their doctor's recommendation — will now be eligible to use Uptravi. "By having Uptravi available on the PBS clinicians now have a more complete arsenal of treatments available to tackle this disease. Our overall treatment goal for people living with PAH is to keep overall disease risk as low as possible. This translates into better long-term outcomes for patients," Helen Whitford, MD, a respiratory physician at Alfred Hospital, said in a press release. Uptravi is to be used in combination with an endothelin receptor antagonist and/or a phosphodiesterase type 5 inhibitor. PAH is characterized by the narrowing of the pulmonary arteries, the smaller blood vessels that transport blood to the lungs. As blood pressure increases, patients typically experience symptoms that include shortness of breath, fatigue, and dizziness. But these symptoms can develop fairly slowly and mimic other heart and lung disorders, including bronchitis and asthma, making PAH difficult to diagnose. Currently, up to 3,800 Australians are believed to have PAH, and 2,300 are diagnosed with this disease. A longer time to a diagnosis delays treatment, risking PAH progression. "We are proud as a company to have achieved a listing for Uptravi on the PBS for this rare disease that can go undiagnosed for too long and is in an area of significant unmet need," said Sophie Glover-Koudounas, executive director, Medical and Scientific Affairs at Janssen Australia and New Zealand. "We commend the Federal Government's commitment to bringing about the best possible health and wellbeing outcomes for Australians living with a rare disease through its National Strategic Action Plan for Rare Disease, with this listing being a tangible demonstration of this," Glover-Koudounas added. According to Mark Brooke, CEO of Lung Foundation Australia, the inclusion of Uptravi on the PBS list will contribute to a fairer access to treatment for PAH patients.  ×  |
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