Pulmonary Hypertension | Pulmonology - Consultant360

Pulmonary Hypertension | Pulmonology - Consultant360
Epoprostenol via High-Flow Nasal Cannula Improves Severe Hypoxemia in PH - The Cardiology Advisor
Ensuring Appropriate Access to Pulmonary Arterial Hypertension Therapy - AJMC.com Managed Markets Network
Pfizer Reports Failure in Persistent Pulmonary Hypertension, Progress in Duchenne Muscular Dystrophy - BioSpace
Domiciliary Oxygen Increases Exercise Capacity in Pulmonary Hypertension - Pulmonology Advisor

Posted: 10 Jul 2019 07:20 AM PDT

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Epoprostenol via High-Flow Nasal Cannula Improves Severe Hypoxemia in PH - The Cardiology Advisor

Posted: 10 Jul 2019 01:00 AM PDT

For patients with severe hypoxemia with pulmonary hypertension or right heart dysfunction, inhaled epoprostenol through high-flow nasal cannula increases oxygenation, according to a study published in Pharmaceutics.

The researchers of this retrospective study assessed the effect of inhaled epoprostenol using a high-flow nasal cannula on oxygenation and future mechanical ventilation in patients with hypoxemia comorbid with pulmonary hypertension or right heart dysfunction in an intensive care unit setting.

A chart review was completed on adult patients who were admitted into the respiratory care department of the Rush University Medical Center for severe hypoxemia between July 2015 and April 2018 and treated with inhaled epoprostenol through the high-flow nasal cannula. Demographic information, intake Acute Physiology Assessment and Chronic Health Evaluation (APACHE) II scores, and clinical measurements were retrieved from patients' charts.

Of the 11 individuals included, 4 were men, 5 were white, the mean age was 57.5 years old, the mean APACHE II score was 18.5, 10 patients had chronic heart or lung comorbidities, and 7 patients used home oxygen. One patient did not respond to the inhaled epoprostenol.

Overall, the inhaled epoprostenol increased the average peripheral capillary oxygen saturation (SpO2)/fraction of inspired oxygen ratio from 107.5 to 125.5 (P =.026) in 30 to 60 minutes, and responders (n=5) significantly improved SpO2 from 87.6% to 96.6% (P =.03).

There were no differences found among heart rate, blood pressure, and respiratory rate before and after inhaled epoprostenol. Outcomes included 7 patients not requiring intubation and 7 patients who were discharged.

Limitations of this study include its retrospective nature, the lack of a control group, the small sample size, and using SpO2/fraction of inspired oxygen ratio to evaluate oxygenation, rather than the partial pressure of oxygen/fraction of inspired oxygen ratio.

The researchers concluded that "[t]his retrospective study demonstrated the feasibility of inhaled epoprostenol via [high-flow nasal cannula] in improving oxygenation in adult subjects with severe hypoxemia with pulmonary hypertension or right heart dysfunction."

Reference

Li J, Harnois LJ, Markos B, et al. Epoprostenol delivered via high flow nasal cannula for ICU subjects with severe hypoxemia comorbid with pulmonary hypertension or right heart dysfunction.Pharmaceutics. 2019;11(6):281.

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Pulmonary Hypertension Pulmonary Vasculature

Ensuring Appropriate Access to Pulmonary Arterial Hypertension Therapy - AJMC.com Managed Markets Network

Posted: 27 Jun 2019 01:05 PM PDT

Kristin B. Highland, MD, MSCR; Kathleen E. Hughes, MBA; Kenneth J. Williams, MA, MBA; Brigit Kyei-Baffour, MBA; Samantha Ferguson

Pulmonary arterial hypertension (PAH) is a progressive, complex disease. PAH is a type of pulmonary hypertension (PH) and can be further categorized into 7 subdivisions, representing a variety of causal and phenotypic factors. Patients with PH, including PAH, are typically fragile and experience multiple comorbidities; they therefore require individualized treatment plans based on their risk status and etiology. Based on a review of clinical evidence, a wide variety of treatment options exist for PAH, including general measures (eg, physical activity and oral anticoagulants), nonspecific pharmacologic intervention (eg, calcium channel blockers), and targeted pharmacologic intervention. Guidelines point to a flexible approach, frequently including upfront or sequential combination therapy, to mitigate disease progression. Payer-driven drug exclusion policies, including formulary restrictions and noncoverage policies, can detract from the ability of providers to offer treatments consistent with guidelines, as they limit access to the range of treatment options needed for individualized patients. Providers must be able to work with each patient to develop a tailored strategy through open access to treatments, leveraging all available options, to mitigate against exacerbation of comorbidities and optimize care.

Am J Manag Care. 2019;25:-S0

Pulmonary arterial hypertension (PAH) is a severe, complex, and rare disease.¹ It is characterized by vascular remodeling of the pulmonary arteries which carry blood from the heart to the lungs. This leads to a progressive increase in pulmonary vascular resistance that leads to right ventricular failure and significant morbidity and mortality.² PAH incidence and prevalence rates vary significantly.³ Registry-based estimates vary from 2.3-7.6 patients per million and 15 to 26 patients per million, respectively.^4,5 Patients with PAH typically experience dyspnea on exertion, fatigue, chest pain, syncope, and peripheral edema. Furthermore, they often have multiple comorbidities, such as systemic hypertension, obesity, connective tissue disease, sleep apnea, and diabetes.^6-8

The 6th World Symposium on Pulmonary Hypertension Task Force on hemodynamic definitions and clinical classifications defined pulmonary hypertension (PH) as a mean pulmonary artery pressure at rest of >20 mmHg, confirmed by right heart catheterization and a pulmonary vascular resistance of ≥3 Wood units.⁹ The current guidelines from the European Society of Cardiology/European Respiratory Society classify PH into 5 diagnostic categories by shared pathobiology and pathophysiology.³

As seen in Figure 1, PH group 1, PAH, is further divided into 7 subcategories.¹⁰ Although this framework helps categorize patients and inform treatment decisions, patients with PH may present and respond to treatment differently based on their risk level, individual etiology, and comorbidities.¹¹ Diagnostic and treatment strategies for patients with PH must be developed on an individual basis, driven by a provider's knowledge of each patient's specific needs.

PAH Treatment Journey

Diagnosis of PAH

Practitioners and patients face difficulties in identifying and diagnosing PAH because it requires a clinical suspicion based on symptoms, a physical examination, known risk factors, and/or incidental findings on tests ordered for other purposes. Evaluation to detect the presence of PH and determine whether a patient also has PAH requires a comprehensive set of tests, which typically include laboratory testing, echocardiography, pulmonary function testing, assessment of exercise capacity with six-minute walk distance (6MWD) or cardiopulmonary exercising testing (CPET), imaging (chest x-ray, chest computed tomography scan, cardiac magnetic resonance [CMR] imaging, ventilation/perfusion lung scan), nocturnal oximetry and/or overnight polysomnography, and right heart catheterization (Figure 2).³ Some patients also require pulmonary angiography or left heart catheterization with angiography. Together, these tests confirm the presence of PH, allow patients to be categorized into one of the 7 PAH groups, and may lead to further identification of the underlying disease etiology. These tests are also used to stratify patients by "risk level" for clinical worsening, which further informs treatment decisions.³

This extensive testing, which is required to positively diagnose a patient with PH, frequently necessitates referral to a PH center or expert—particularly since clinical presentation can be complicated by individual patient characteristics and comorbidities. On average, patients report visiting their primary care provider more than 5 times and being referred to 3 specialists before being referred to a PH expert, resulting in an average delay of 47±34 months from symptom onset to diagnosis by right heart catheterization.¹² This delay is associated with a deterioration of patients' functional status, which is, in turn, associated with increased mortality.^12,13

Retrospective data from a French regional referral center revealed that the median overall long-term survival post-diagnosis for PAH is 46.0±1.4 months, which may be worsened by delayed diagnosis and/or with a greater number of comorbidities.¹¹ Conversely, early diagnosis and access to effective treatment can contribute to improvement in survival rates. The Registry to Evaluate Early and Long-Term Pulmonary Arterial Disease Management (REVEAL) was initiated in the United States in 2006 to better understand the clinical course, treatment, and predictors of outcomes in patients with PAH. The REVEAL data demonstrated an almost 3-fold improvement in patient survival rates compared with results gathered nearly 3 decades ago from the National Institutes of Health PAH registry, which followed 194 patients in the 1980s as the first PAH registry.¹⁴ The authors of this analysis suggest that the considerable improvement in survival rates could be attributed to a combination of factors, including changes in treatments and improved patient-support strategies.

Assessment of Disease Severity

Assessment of patients' risk status is a key component of the PAH treatment strategy, allowing clinicians to predict survival, monitor disease progression, and inform treatment decisions.³ The 2015 European Society of Cardiology/European Respiratory Society PH guidelines, which include treatment guidelines for PAH, link treatment approaches for individual patients to an assessment of patients' "risk" for clinical worsening and 1-year mortality based on clinical status, functional status, exercise, right ventricular function, and hemodynamic parameters.³ The guidelines categorize patient risk into low-, medium-, or high-risk categories based on anticipated 1-year mortality. In 2018, researchers validated the connection between methodical risk assessment and treatment strategy through retrospective analysis of 3 independent registries, demonstrating that a multiparametric approach could predict survival or event-free survival.¹⁵ Each registry—REVEAL, the Swedish PAH Register, and COMPERA—defines parameters for low-risk PAH based on a scoring algorithm and assesses 1-year mortality by risk group, with individual risk assessed at baseline and first follow-up (Table 1).¹⁵

Provider assessment of patients' status incorporates a multidimensional approach, including findings of right heart failure on physical examination, laboratory values (creatine, N-terminal pro brain natriuretic peptide, or brain natriuretic peptide), World Health Organization (WHO) functional classifications, exercise testing (6MWD, CPET), progression of symptoms, echocardiography, CMR imaging, syncope, and hemodynamics.¹⁵ These tests are performed regularly to monitor patient prognosis and guide treatment decisions beyond initial determination of risk. Furthermore, the guidelines specify that no one variable may be used to determine risk; instead, providers must make a comprehensive assessment of each individual patient, incorporating rate of disease progression, comorbidities, age, sex, background therapy, and PAH subtype in addition to the modifiable parameters listed previously.³

Because of the unique patient profiles of those with PAH , a "one size fits all" treatment paradigm will not result in optimal care. The unique characteristics of each patient's profile warrants a tailored treatment approach that considers the impact of each patient's characteristics on responsiveness to treatment and symptom improvement.

PAH Treatment Options

Following diagnosis and assessment of disease severity, a wide variety of treatment options exist for patients with PAH, ranging from general measures to targeted pharmacological interventions.³ The treatment approach for patients with PAH can be summarized in the following algorithm, which is aligned with the most recent treatment guidelines:

General Measures

Patients should adopt general measures (eg, physical activity, supervised rehabilitation, infection prevention, psychosocial support), initiate supportive therapy (eg, oral anticoagulants, diuretics, oxygen, and digoxin), and be referred to a PH expert center.

Pharmacologic Measures

Non–PAH-specific therapy: After diagnosis of PAH, acute vasoreactivity testing should be performed to predict responsiveness to calcium channel blockers (CCBs).*

PAH-specific therapy: Five classes of PAH-specific therapy are available to patients with PAH (Table 2).³ The guidelines provide an overview of use.

Oral Combination Therapy

Patients who are nonvasoreactive and vasoreactive without an adequate treatment response to CCBs who are at low or intermediate risk should be treated initially with an endothelin receptor antagonis (ERA) and a phosphodiesterase-5 inhibitor. These drugs may be initiated concomitantly or in rapid sequence. In patients who are nonvasoreactive and treatment-naïve at high risk, initial combination therapy is recommended. Combinations that include a parenteral prostanoid receive the strongest recommendation, although other combinations may be considered according to individual patient needs. There also should be a low threshold for referral for lung transplantation.

Oral Monotherapy with PAH-Specific Agents

Combination therapy may not be appropriate for patients with PAH who have certain comorbidities (eg, patients aged >75 years with idiopathic PAH and multiple risk factors for left heart failure, patients with severe liver disease); these patients should be treated with monotherapy. As there have been no head-to-head clinical trials, the choice of drug may depend on a variety of factors, including approval status, labeling, route of administration, adverse effect profile, potential interaction with background therapies, patient preferences, comorbidities, physician experience, and cost.

Continued Pharmacologic Therapy

When the initial treatment approach results in a low-risk status within 3 to 6 months, the therapy should be continued. When the initial treatment approach results in an intermediate-risk status, escalation to triple combination therapy is recommended (or double combination if monotherapy was initially selected). When the initial treatment approach results in a high-risk status, maximal medical therapy is recommended. Referral for lung transplantation should also be considered.

Procedural Intervention

Lung transplantation should be considered if the patient is refractory to maximal medical therapeutic intervention. Balloon atrial septostomy should be regarded as a palliative or bridging procedure in patients who are deteriorating despite maximal medical therapy.

Pfizer Reports Failure in Persistent Pulmonary Hypertension, Progress in Duchenne Muscular Dystrophy - BioSpace

Posted: 01 Jul 2019 07:03 AM PDT

Pfizer logo on large outdoor sign

Roman Tiraspolsky / Shutterstock.com

Pfizer's intravenous (IV) Revatio (sildenafil), when added to inhaled nitric oxide (iNO), failed to meet its primary efficacy endpoint in treating newborns with persistent pulmonary hypertension (PPHN).

Revatio is approved to treat adults with pulmonary arterial hypertension (PAH). PPHN is another type of high blood pressure which can be life-threatening. Prior to birth, a baby's blood circulates differently in the uterus. With PPHN, the child does not shift over from fetal to normal newborn circulation, and blood is forced away from the lungs because of the high blood pressure in the arteries leading to the lungs. This decreases oxygen supply to the body.

The Phase III clinical trial had two consecutive parts. The first, Part A, was a randomized, placebo-controlled, double-blind interventional phase. It assessed the efficacy and safety of the therapy. The results reported today are based on Part A.

Part B is the non-interventional phase with follow-up at 12 and 24 months after the end of the trial to evaluate developmental progress. Part B is ongoing.

The trial did not result in a statistically significant decrease in treatment failure rate or time on iNO compared to treatment with iNO alone.

Pfizer also reported initial Phase Ib clinical data on PF-06939926, a gene therapy for Duchenne muscular dystrophy (DMD). They presented the data at the 25^th Annual Parent Project Muscular Dystrophy (PPMD) Connect Conference held in Orlando, Florida.

The primary endpoint of the Phase Ib trial is safety and tolerability of the therapy. Secondary endpoints measured expression of mini-dystrophin distribution within muscle fibers.

DMD is a genetic disease marked by progressive muscle degeneration and weakness. It primarily affects boys. Boys with the disease often die in their 20s, although there are now treatments, primarily Sarepta Therapeutics' controversial Exondys 51, which was approved by the U.S. Food and Drug Administration (FDA) in 2016.

The disease is the result of an absence of dystrophin, a protein that helps keep muscle cells intact. One of the difficulties in developing gene therapies for DMD is the size of the dystrophin gene, the largest in the human genome. It is too large to be inserted into cells using traditional viral vectors. As a result, most approaches for gene therapy use gene-skipping technology or truncated versions of the dystrophin gene that produce partial but still functional dystrophin proteins.

Pfizer's gene therapy uses recombinant adeno-associated virus serotype 9 (AAV9s ) to carry a shortened version of the human dystrophin gene under the control of a human muscle-specific promoter.

The preliminary data showed the most common adverse events were nausea, vomiting, decreased appetite, tiredness and/or fever. Preliminary efficacy data included muscle biopsies of the biceps taken two months after dosing in a small subgroup of the trial. It showed detectable mini-dystrophin immunofluorescence signals with a mean of 38% positive fibers at one dose and 69% at a higher dose.

"Gene therapy for single-gene disorders is at a formative stage in tis evolution, and the initial data we've seen in our study for Duchenne muscular dystrophy may exemplify the potential for this modality to change patients' lives," stated Seng Cheng, senior vice president and chief scientific officer of Pfizer's Rare Disease Research Unit. "We are looking forward to building on these initial data and advancing the development of this therapeutic modality."

Domiciliary Oxygen Increases Exercise Capacity in Pulmonary Hypertension - Pulmonology Advisor

Posted: 17 Jun 2019 12:00 AM PDT

Patients with pulmonary arterial hypertension (PAH) or distal chronic thromboembolic pulmonary hypertension (CTEPH) were able to increase 6-minute walk distance (6MWD) and improve physical status on domiciliary oxygen therapy, according to the results of a study published in the European Respiratory Journal.

This double-blind cross-over protocol evaluated 6MWD and the physical functioning scale of the Short Form Medical Outcome Questionnaire-36 in patients with PAH or distal CTEPH with exercise-induced hypoxemia. Measurements were taken at baseline and following random assignment to 1 of 2 groups: domiciliary oxygen therapy or ambient air placebo. There was a 2-week washout between treatments. Results from domiciliary oxygen therapy and ambient air placebo therapy were compared between groups.

Of the 30 patients who were randomly assigned and represented the intention-to-treat population, 2 patients withdrew consent after randomization. The per-protocol analysis included 28 patients who completed the entire protocol. From baseline, domiciliary oxygen therapy increased 6MWD an average of 19 meters vs 1 meter in the placebo group. Changes in the physical functioning scale were 4 points and -2 points for the treatment and placebo groups, respectively. Between-treatment differences in changes were 6MWD 18 meters (1-35 m; P =.042) and 6 points in the physical functioning scale of Short Form Medical Outcome Questionnaire-36 (95% CI, 1-11; P =.029).

"This first randomized trial in PAH/CTEPH patients with exercise-induced hypoxemia demonstrates that [domiciliary oxygen therapy] improves exercise capacity, quality of life and functional class," the authors wrote. "The results support large long-term randomized trial[s] of domiciliary oxygen therapy in PAH/CTPEH."

Reference

Ulrich S, Saxer S, Hasler ED, et al. Effect of domiciliary oxygen therapy on exercise capacity and quality of life in patients with pulmonary arterial or chronic thromboembolic pulmonary hypertension: a randomised, placebo-controlled trial [published online May 9, 2019]. Eur Respir J. doi:10.1183/13993003.002762019

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