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Ensuring Appropriate Access to Pulmonary Arterial Hypertension Therapy
Kristin B. Highland, MD, MSCR; Kathleen E. Hughes, MBA; Kenneth J. Williams, MA, MBA; Brigit Kyei-Baffour, MBA; Samantha Ferguson

Ensuring Appropriate Access to Pulmonary Arterial Hypertension Therapy

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.

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