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Considerations for Optimal Management of Patients With Pulmonary Arterial Hypertension: A Multi-Stakeholder Roundtable Discussion
Sean M. Studer, MD, MSc; Martha Kingman, FNP-C; DNP; Luis Calo, MD, MMM, FAAFP; H. Eric Cannon, PharmD, FAMCP; Jeffrey D. Dunn, PharmD, MBA; Thomas James III, MD; Sonya J. Lewis, PharmD, MBA; Robert J

Considerations for Optimal Management of Patients With Pulmonary Arterial Hypertension: A Multi-Stakeholder Roundtable Discussion

Sean M. Studer, MD, MSc; Martha Kingman, FNP-C; DNP; Luis Calo, MD, MMM, FAAFP; H. Eric Cannon, PharmD, FAMCP; Jeffrey D. Dunn, PharmD, MBA; Thomas James III, MD; Sonya J. Lewis, PharmD, MBA; Robert J
Stakeholders, including national and regional managed care decision makers and providers, met to discuss the clinical background, health economics, and management strategies for pulmonary arterial hypertension (PAH) at a roundtable meeting on December 10, 2016, in Dallas, Texas.
A roundtable panel of national and regional managed care decision makers and providers met to discuss pulmonary arterial hypertension (PAH) and strategies for management. As a rare, complex disease with high economic costs and potentially devastating outcomes, PAH necessitates that managed care providers balance optimal care with efficient use of healthcare resources. PAH specialists are recognized by health plans as knowledgeable experts and integral partners in managing patients and resources. The diagnosis of PAH must be confirmed by a right heart catheterization. Available therapies are indicated almost exclusively for patients with PAH (riociguat is also indicated in chronic thromboembolic pulmonary hypertension) and target 1 of 3 pathways: endothelin receptor antagonists for the endothelin pathway; phosphodiesterase type-5 inhibitors and soluble guanylate cyclase stimulators for the nitric oxide pathway; and prostanoids as well as a prostacyclin receptor agonist for the prostacyclin pathway, with combination therapy becoming more common. Even in the modern treatment era, as shown in the REVEAL and French registries, PAH is often diagnosed years after symptoms first appear, which leads to a poor prognosis and increased burden on the healthcare system. Facilitating treatment of patients with PAH through centers of excellence, and coordinating care management between health plans and providers with evidence-based approaches can lead to both better results for patients and lower healthcare costs. When PAH experts have access to the right treatments for the right patients at the right time, they can work with insurers to improve the health of patients with PAH while helping to reduce the impact on the healthcare system.
The goal of this meeting was to determine how to strengthen the collaboration between practitioners, health plans, and industry to optimize cost-effective treatment. The meeting was also designed to recognize the extent to which experienced practitioners should be supported in making treatment decisions for patients with PAH. To meet these objectives, strategies included: a review of the current landscape regarding treatments for PAH with patient case studies; identifying practical challenges and opportunities to achieve successful outcomes for patients with PAH; and discussing population-based PAH treatment management strategies.

Clinical Background on PAH

PAH is a rare, progressive, serious, and complex lung disease. Hemodynamically, PAH is defined as mean pulmonary arterial pressure ≥25 mm Hg, with a pulmonary arterial wedge pressure ≥15 mm Hg and pulmonary vascular resistance (PVR) >3 Wood units. These hemodynamic measurements are obtained on right heart catheterization, which is the gold standard for diagnosis of this disease.1 Characterized by increasing PVR related to restricted flow through the pulmonary arterial circulation, PAH involves vasoconstriction, which may lead to right ventricular (RV) overload, RV failure, and premature death. Increased PVR is related to changes in pulmonary arterioles, including pulmonary vessel remodeling, inflammation, and in-situ thrombosis.2,3

PAH is 1 of 5 groups of pulmonary hypertension (PH) (Table 11,4). While the most common causes of PH include left heart disease (group 2) and lung disease (group 3),1 group 1 PAH (idiopathic) is rare, with a prevalence estimated at 12 per million to 50 per million,5,6 and an incidence estimated at 2.4 to 7.6 new cases per million per year.7,8 Based on the prevalence and incidence numbers, a hypothetical health plan with about 5 million patients could expect to have about 60 to 250 patients with PAH, with about 12 to 38 new cases annually.

New cases of PAH may be triggered by certain medications. The practitioner roundtable members recalled that historically, PAH came to the forefront after the introduction of the once-popular anorexigen combination of phentermine with fenfluramine or dexfenfluramine (fen-phen); fenfluramine and dexfenfluramine were withdrawn from the market in the late 1990s. The products were considered a cause of PAH in some cases.1,9 More recently, methamphetamines have been seen as a cause of PAH for some patients.1,10

The mean age at diagnosis for a patient with PAH is approximately 50 years: specifically, the REVEAL registry lists a mean of 50.1 ±  14.4 SD,11 while the French registry lists a reference center mean of 49 ± 14 SD and 53 ± 16 SD at other centers.7 However, PAH may also be seen in newborns and in the 7th and 8th decade of life.8,12 It is more common in women than in men.5 The REVEAL registry lists female patients at 79.5% of those enrolled.11

PAH is often diagnosed long after symptoms have begun. As explained by experts at the roundtable, patients may present with vague symptoms (shortness of breath, fatigue, activity limitation) to their family practice or internal medicine physician; patients who are obese and sedentary may be told to exercise, change their diet, or stop smoking, or they may be diagnosed with asthma or chronic obstructive pulmonary disease (COPD). Unfortunately, there are no simple tests, as with diabetes or hypertension, to diagnose PAH early in the course of illness. Eventually many patients get referred to a center of excellence for PAH or a pulmonologist, cardiologist, or rheumatologist experienced with the condition. According to the REVEAL and French National registries, it may take 2.3 to 2.8 years for an accurate diagnosis, at which point patients may have progressed significantly (Figure 17).7 In the United States, 73.6% of patients are diagnosed after they have progressed to a later stage (World Health Organization [WHO] functional class [FC] III or IV), according to the REVEAL registry; that percentage dropped to 55.6% at the time of enrollment, which was a median of 25 months after diagnosis.11 Similarly, in the French registry, three-fourths of patients were already at WHO FC III or IV when diagnosed.7

Unsurprisingly, delayed diagnosis decreases chances for survival (Figure 213).13 Left untreated, median survival is estimated at 2.8 years.3,13 Based on historical data, median survival for patients at FC I and II is 4.9 years; patients at FC III, 2.6 years; and patients at FC IV, 6 months without treatment.13

The WHO Functional Class System is derived from the New York Heart Association (NYHA) functional class system. Class I consists of patients with PAH who do not have a resulting limitation of physical activity; ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope. Class II patients have PAH resulting in slight limitation of physical activity; they are comfortable at rest, but ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope. Class III patients have PAH resulting in marked limitation of physical activity; they are comfortable at rest, but less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope. Class IV patients have an inability to carry out any physical activity without experiencing symptoms; they manifest signs of right heart failure, and dyspnea or fatigue may be present even at rest, with discomfort increased by any physical activity.14

PAH experts at the roundtable, including Dr Studer and Dr Kingman, explained the classification system on a practical level. The NYHA and the more detailed WHO FC systems, according to the clinical experts, are used somewhat interchangeably in practice. Although the NYHA system is used in other diseases, such as heart failure and COPD, the WHO FC system is reserved for PAH. Providers routinely assess FC, but it is often not documented in the chart.15 The experts also agreed that categories II and III can be difficult to distinguish from each other (because there is some subjectivity in the determination); however, it is generally easy to distinguish FC I and FC IV.

A goal of treatment for the PAH patient is to achieve low-risk status, with the risk of 1-year mortality less than 5%.1,16 Patients with a 1-year mortality rate of more than 10% are high risk—complex, very ill patients. To define low risk, parameters that are determined include absence of signs of clinical heart failure, the ability to exercise, specific biomarkers, and hemodynamics.1 According to the roundtable experts, a goal for these low-risk patients is for them to successfully perform their job outside the household and/or function within their household.

Individuals with PAH are complicated, fragile patients who are often older, with numerous comorbidities. The most common comorbidities with PAH, according to the REVEAL registry, are hypertension, obesity, collagen vascular disease/connective tissue disease (such as scleroderma), clinical depression, obstructive lung disease, sleep apnea, thyroid disease, diabetes, and ischemic cardiac events. Other comorbidities with PAH include lupus, rheumatoid arthritis, non-skin cancer, valvular heart disease, cirrhosis, renal insufficiency, history of pulmonary embolism, history of deep vein thrombosis, and cardiomyopathy.11 Across subsequent calendar years, the most common comorbidities among patients with PAH in the REVEAL registry were renal disease (39.4%-44.1%), diabetes (22.5%-26.1%), and coronary heart disease (23.1%-26.6%).17

In addition to the clinical burdens of PAH, there are economic burdens. Recently, several pharmacoeconomic studies have been published that provide valuable data and insight into the financial burden of PAH.

Expert Commentary: Diagnosing PAH

To diagnose a patient with PAH, Dr Kingman first offered this scenario: “If you have a patient who has shortness of breath, the inhaler hasn’t worked, if you haven’t found any other cause and its continuing to progress—or a high-risk patient, like a scleroderma patient—get an echocardiogram. That should be your first screening test.” History of fen-phen use would also be a contributing factor.

Although echocardiogram pressure estimates can be unreliable, they can show, especially in more advanced cases, an enlarged right ventricle or a right ventricle not pumping normally, which are clues that someone might have PAH. On the other hand, added Dr Studer, the echocardiogram can show that a patient does not have PAH but might have something else.

Ultimately, the diagnosis of PAH should be confirmed by a right heart catheterization.

Pharmacoeconomic Research: What Is the Burden and Impact of PAH on the Healthcare System?

PAH has an impact on the healthcare system, but to what extent? A retrospective observational study was undertaken to determine the correlation of functional decline in PAH patients, as measured by a higher FC, with increased healthcare resource utilization (HRU) and costs.15 Data were obtained from the Humana Research Database (Humana, Louisville, KY), which contains data from geographically dispersed US commercial and Medicare health plans providing coverage for about 19 million members. The data set included integrated medical, pharmacy, and laboratory claims. Prior authorization (PA) records for PAH therapies and medical chart abstraction were also used to obtain provider-documented FC.15

The FC III cohort was nearly 3 times larger than the FC II cohort, similar to the percentages found in the REVEAL registry. PAH severity, as indicated by higher FC, was associated with greater likelihood of inpatient episodes and significantly higher PAH-related costs. This pattern suggests that patients who progress to a higher FC will utilize more services; thus, preventing this progression through early treatment is desirable.15

Although all 3 cohorts showed high HRU, patients in FC IV had the highest pharmacy and medical costs, which supports the validity of the FC system. Further, 30% of patients in FC III and 35% of patients in FC IV were given an additional PAH-specific medication. Patients in FC IV experienced more PAH inpatient and outpatient episodes, with higher median total costs than patients in FC II or III.15

As further evidence of PAH disease severity, as well as the comorbidities and complexity of these patients, annual pharmacy costs for patients with PAH were 17 to 21 times higher than for average Medicare Advantage with Part D patients (Figure 315).15 Annual medical costs were higher than pharmacy costs and were 10 to 11 times higher for patients with PAH than for average Medicare patients (Figure 315).15 The high HRU in these patients underscores the need for accurate diagnosis and appropriate treatment by experts.

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