Ensuring Appropriate Access to Pulmonary Arterial Hypertension Therapy - AJMC.com Managed Markets Network
Ensuring Appropriate Access to Pulmonary Arterial Hypertension Therapy - AJMC.com Managed Markets Network |
- 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
- HFpEF With Severe Pulmonary Hypertension Linked to Increased Mortality - Pulmonology Advisor
- PH With Chronic Lung Disease Survival Predicted by Echocardiographic Parameters - Pulmonology Advisor
- Lower RVSP Threshold Linked to Mortality Risk in Pulmonary Hypertension - Pulmonology Advisor
| 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.6-8The 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.  |
| Posted: 01 Jul 2019 07:03 AM PDT 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 25th 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."  |
| HFpEF With Severe Pulmonary Hypertension Linked to Increased Mortality - Pulmonology Advisor Posted: 25 Jun 2019 12:45 AM PDT  Patients with heart failure, severe pulmonary hypertension, and a preserved ejection fraction of ≥50% had a worse prognosis when compared with other patients with heart failure and severe pulmonary hypertension, according to a study published in Heart and Lung. Researchers of this prospective, observational study analyzed The Israeli Association for Cardiovascular Trials database for baseline characteristics, comorbidities, renal and heart status, and long-term prognosis of patients with heart failure and pulmonary hypertension. Using conventional trans-thoracic echocardiograms, patients were categorized by left ventricular ejection fraction into reduced ejection fraction (<40% ejection fraction), mid-range ejection fraction (40%-49% ejection fraction), or preserved ejection fraction (≥50% ejection fraction). Using echocardiography, severe pulmonary hypertension was classified as an estimated systolic pulmonary arterial pressure of ≥50 mmHg. Demographics, echocardiography, and biochemical blood analysis were collected at baseline, follow-up evaluations were completed at 12 months, and mortality rates were assessed at 2 years. Of the 372 patients included in this study, 56% were men, the mean age was 77.3 years old, and the mean duration of heart failure was 6.5 years. The reduced ejection fraction cohort consisted of 159 patients, the mid-range ejection fraction cohort consisted of 50 patients, and the preserved ejection fraction cohort consisted of 163 patients. The reduced ejection fraction cohort was predominantly associated with smokers who had coronary artery disease and renal failure. The preserved ejection fraction cohort was predominantly associated with older women who were obese and had atrial fibrillation. The mid-range ejection fraction cohort did not show patterns in baseline characteristic. Overall, 15% of the patients died by the 2-year mortality rate follow-up. Multivariable analysis indicated New York Heart Association functional class 3-4 (hazard ratio [HR] 2.41; 95% CI, 1.17-4.97; P =.017) and renal failure (HR 2.53; 95% CI 1.45-4.42; P =.001) were independent predictors for mortality. Kaplan-Meier survival curves indicated an association between severe pulmonary hypertension and mortality in the preserved ejection fraction cohort (adjusted HR 2.99; 95% CI, 1.29-6.91; P =.010) but not in the other cohorts. Limitations of this study include only evaluating demographic, clinical, and echocardiographic information from a database, not assessing right heart parameters, and the potential for selection bias. Researchers concluded that patients with heart failure with preserved ejection fraction and pulmonary hypertension "are likely to have different pathophysiology and worse prognosis" and "defining these patients as an independent subgroup may be more appropriate for their management and treatment." Reference Zafrir B, Carasso S, Goland S, et al. The impact of left ventricle ejection fraction on heart failure patients with pulmonary hypertension [published online June 5, 2019]. Heart Lung. doi:10.1016/j.hrtlng.2019.05.006 This article originally appeared on The Cardiology Advisor  |
| Posted: 12 Jun 2019 12:00 AM PDT The ratio of tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure (PASP) is a simple echocardiographic parameter that shows hemodynamic severity and can predict survival in pulmonary hypertension (PH) due to lung diseases, according to study results published in European Respiratory Journal. Complete echocardiographic and invasive hemodynamic data from patients with PH due to lung diseases was retrospectively analyzed for the ratio of TAPSE as a surrogate for contractility and PASP as a surrogate for afterload. Correlations between these values and disease severity were evaluated. Of the 172 patients with pulmonary hypertension due to lung diseases, 78 had PH due to chronic obstructive pulmonary disease (COPD), and the remaining 94 due to interstitial lung disease. In total, 65 of the 172 study participants were considered severe. The forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio was higher in patients with severe vs nonsevere PH due to COPD, but FEV1 was not different. There was also no correlation between FEV1/FVC or FEV1 and the TAPSE/PASP ratio in the severe and nonsevere groups. Receiver operating characteristic analysis identified a cutoff of 0.26 mm·mm Hg-1 for TAPSE/PASP with a sensitivity of 80.6% and a specificity of 71.2% to discriminate between severe and nonsevere PH due to lung diseases. "The TAPSE/PASP ratio is a straightforward and clinically relevant measurement to differentiate between the haemodynamic phenotypes of patients with pulmonary hypertension due to lung diseases," the researchers wrote. "The TAPSE/PASP ratio might prove to be an important non-invasive tool for the evaluation of future therapeutic interventions in patients with PH-[lung disease]." Reference Tello K, Ghofrani H, Heinze C, et al. A simple echocardiographic estimate of right ventricular-arterial coupling to assess severity and outcome in pulmonary hypertension on chronic lung disease [published online May 9, 2019]. Eur Respir J. doi:10.1183/13993003.02435-2018  |
| Lower RVSP Threshold Linked to Mortality Risk in Pulmonary Hypertension - Pulmonology Advisor Posted: 11 Jun 2019 12:00 AM PDT  A distinctly lower threshold of pulmonary hypertension (PH) was linked to an increased risk for mortality, according to a study published in the Journal of the American College of Cardiology. Utilizing the National Echo Database Australia, investigators evaluated individual echocardiographic measurement and report data as of October 2017. Patients with peak tricuspid regurgitation velocity (TRV)/estimated right ventricular systolic pressure (eRVSP) from their last recorded echocardiographic examinations were included (n=157,842). Investigators categorized eRVSP by current clinical guidelines: normal (eRVSP <40 mm Hg), mildly elevated (eRVSP 40-49.9 mm Hg), moderately elevated (eRVSP 50.-59.9 mm Hg), and severely elevated (eRVSP ≥60 mm Hg). Fatal events were identified during a median follow-up of 4.2 years for all patients. Patients with eRVSP levels indicative of mild (n=17,955 [11.4%]), moderate (n=7016 [4.4%]), and severe (n=4515 [2.9%]) PH were more likely to die during long-term follow-up. Adjusting for age and sex, patients with severely elevated eRVSP were almost 10-fold more likely to die within 5 years (adjusted hazard ratio, 9.73; 95% CI, 8.6-11; P <.001). Patients without eRVSPs were less likely to die in long-term follow-up (adjusted hazard ratio, 0.861; 95% CI, 0.847-0.876). Post hoc analyses confirmed a clear and consistent threshold of an eRVSP of 30 mm Hg persisted when examining cardiovascular- and respiratory-related mortality (including 1- and 5-year actuarial mortality). Limitations of this study include incomplete data from echocardiography that do not capture other important clinical details that are pivotal to health outcomes. The researchers confirmed that current recommendations that patients should be carefully clinically evaluated for symptoms that may be consistent with PH, and symptomatic patients should undergo echocardiography. Patients with either low (TRV <2.8 m/s) or high (TRV >3.4 m/s) TRV levels should be considered at risk for PH and/or a poorer prognostic outcome. Further investigation should be taken to unmask any underlying disease that may be more proactively managed than suggested by current expert guidelines. There is still an area of uncertainty around the clinical management of patients currently classified at intermediate risk for PH (TRV 2.9 to 3.4 m/s, correlating to a range of eRVSP of 33 to 46 mm Hg). Disclosure: The National Echo Database Australia was initially supported (database engineering and infrastructure costs) through unrestricted research grants from Actelion, Bayer, and GlaxoSmithKline. David S. Celermajer, MD, PhD, works at an institution that has received clinical trials funding and educational grants from Actelion. David Prior, MBBS, PhD, has received payments for talks from Actelion. Reference Strange G, Stewart S, Celermajer DS, et al; NEDA Contributing Sites. Threshold of pulmonary hypertension associated with increased mortality. J Am Coll Cardiol. 2019;73(21):2660-2672. This article originally appeared on The Cardiology Advisor  |
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