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.

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.

 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.

PAH is 1 of 5 groups of pulmonary hypertension (PH) (

). While the most common causes of PH include left heart disease (group 2) and lung disease (group 3),

 group 1 PAH (idiopathic) is rare, with a prevalence estimated at 12 per million to 50 per million,

 and an incidence estimated at 2.4 to 7.6 new cases per million per year.

 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.

 More recently, methamphetamines have been seen as a cause of PAH for some patients.

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,

 while the French registry lists a reference center mean of 49 ± 14 SD and 53 ± 16 SD at other centers.

However, PAH may also be seen in newborns and in the 7th and 8th decade of life.

 The REVEAL registry lists female patients at 79.5% of those enrolled.

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 (

 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.

 Similarly, in the French registry, three-fourths of patients were already at WHO FC III or IV when diagnosed.

Unsurprisingly, delayed diagnosis decreases chances for survival (

 Left untreated, median survival is estimated at 2.8 years.

 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.

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.

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.

 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%.

 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.

 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.

 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%).

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.

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&mdash;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.

 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.

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.

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.

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 (

 Annual medical costs were higher than pharmacy costs and were 10 to 11 times higher for patients with PAH than for average Medicare patients (

 The high HRU in these patients underscores the need for accurate diagnosis and appropriate treatment by experts.

Another retrospective database study identified patients with PAH in a large US population of health-plan beneficiaries with commercial or Medicare coverage to assess timing, rates, costs, and length of stay (LOS) for hospitalizations.

 The data source was the nationally representative Optum Research Database of medical and pharmacy claims from US health plans providing commercial and Medicare Advantage with Part D coverage, with approximately 30 million lives during the study period.

 A total of 5566 hospitalizations were identified; 3322 of the hospitalized patients had commercial insurance, and 2244 had Medicare Advantage (

Averaged across all admissions for Medicare patients with PAH for any diagnosis (PAH or a comorbidity), the mean (SD) LOS was longer than for patients with commercial insurance: 12.8 (21.2) days versus 10.9 (20.4) days, respectively. Because Medicare patients are older, they have more overall comorbidities, which may contribute to the longer LOS. Patients with PAH are hospitalized often, whether for PAH or comorbid conditions; frequently, they are rehospitalized within a year. In fact, of the 2275 patients hospitalized during the study, 954 (79.3%) were readmitted 1 or more times within 1 year of the initial hospitalization; 225 (23.6%) were rehospitalized 3 or more times.

Rehospitalization accounts for the majority of hospital costs. Averaged over all patients hospitalized during the study period, mean cost of readmission was $35,188 (SD =  $152,006) for commercially insured patients and $19,170 (SD =  $41,905) for Medicare patients. Averaged over just the 954 patients who were readmitted at least once, the 1-year readmission costs were $95,254 (SD =  $238,506) for commercially insured patients and $36,543 (SD =  $52,106) for Medicare patients.

Number of hospitalizations and LOS are key contributors to HRU by patients with PAH. Of the rehospitalizations in the database study,

30 days after discharge from the initial hospitalization.

Retrospective claims database research studies provide evidence of the high HRU of patients with PAH and suggest that treatments that can decrease this utilization could lead to cost savings in addition to improving patient health.

Expert Commentary: Practical Measures of Success

The experts agreed that treating patients early with the right medication can improve patient health and activities of daily living. “My goal is: You can walk in a grocery store, or you can walk in Walmart—or whatever activity is important for the patient to be able to resume,” Dr Kingman said.

Dr Studer said the best measure of success is “preventing hospitalization”; however, he added, “We’d love to say that on a given day we’ve improved you to the point that you’re very functional and can do your job, or whatever it is that makes you [the patient] feel productive.”

Therapies for PAH target endothelial cell dysregulation and abnormal proliferation of smooth muscle cells. Three major pathways are involved: 1) the endothelin pathway, which includes the 3 endothelin receptor antagonists; 2) the nitric oxide pathway, which includes phosphodiesterase type-5 inhibitors and soluble guanylate cyclase stimulators; and 3) the prostacyclin pathway (prostanoid and an IP receptor agonist).

The prostacyclin pathway is the oldest and most targeted pathway. The first prostacyclin that offered specific treatment for PAH was Flolan (epoprostenol), approved in 1995.

 Since then, other prostanoids have been developed and approved, including intravenous (IV), room temperature stable IV, subcutaneous, inhaled, and oral formulations. Additionally, a highly specific agonist for the IP receptor—the receptor responsible for vasodilation within the lung&mdash;was recently approved.

Treatment recommendations based on European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines to be considered include background therapy, general measures, and supportive therapy. (

 If the patient is fortunate enough to demonstrate vasoreactivity, that patient can be on high-dose calcium channel blockers (CCBs) as long as they are monitored for continued medication response.

 Vasoreactivity testing for CCB suitability is currently recommended for idiopathic, heritable, or drug-induced PAH, and only about 10% of these PAH patients meet the criteria.

 The majority of cases are nonreactive, categorized as either low/intermediate risk (FC II/III) or high risk (FC IV). The ESC/ERS guidelines call for monotherapy or combination oral therapy for low- and intermediate-risk patients, and combination therapy including prostacyclin agents for high-risk patients; if the patient has inadequate clinical response, then double or triple therapy is recommended.

Dr Kingman offered further perspective on determining how to treat patients with PAH. “If a patient is low risk, we’re going to start with oral therapy; if they fall into a high-risk category, then those are the patients that we’re going to look at putting on IV therapy quickly,” she said. Generally, the slower that a patient’s illness progresses, the better prognosis they will have. “If a patient was fine 2 or 3 weeks ago but is [now] having trouble walking across the room, that’s going to put that patient on the worse prognosis side,” she said. Another measure to consider is the 6-minute walk distance: “If it’s low, less than about 380 meters, that’s a higher-risk patient. Cardiopulmonary stress testing is sometimes used; if peak O

 consumption is less than 12 mL/(kg/min), the patient is in a higher-risk category,” she said. Additionally, if brain natriuretic peptide (BNP) or pro-BNP levels are very high, the patient is high risk. “Echocardiogram findings are really important,” she added. “Presence of any sized pericardial effusion is a high-risk indicator, along with right ventricular enlargement or right ventricular dysfunction. When we see that, that’s a higher-risk indicator. And then on hemodynamics, a right atrial pressure over 15 mm Hg or cardiac index less than 2 1/min/m

Dr Kingman also emphasized the importance of early treatment. “Studies show that the placebo group doesn’t catch up,” she said, referring to a meta-analysis of 21 PAH randomized, controlled clinical trials (3140 patients) reviewed for all-cause mortality.

 The average study duration was 14 weeks,

 Active treatment was associated with a reduction in mortality of 43% (

 The sensitivity analysis confirmed a reduction in mortality of 38% (

 The number of patients needed to be treated to prevent 1 death was 61.6.

 Approximately 16.2 deaths were prevented in each 1000 patients treated.

 Hospitalization rate in the actively treated group was 3.2% versus 8.03% in the placebo group; this was a 61% risk reduction for hospitalization in the treated group (

 It is important to note, however, that none of the newer agents (eg, macitentan, riociguat, oral treprostinil, and selexipag) were available at the time of this meta-analysis, and thus were not included.

Dr Studer said a treatment is considered successful “if you can get a patient to low risk, FC I or II—get the 6-minute walk test to be longer, get the BNP to be normal, and have normal or near-normal cardiac output and RV size and function” (

 Measuring success in PAH, as opposed to in some other disease states, isn’t easy, he noted: “For diabetes, you could say, if they’re taking their drug and their hemoglobin A1C isn’t yet normal, we would consider adding other medications; but in PAH, we just don’t have that type of granularity.”

Roundtable Commentary: Making Decisions in Partnership

Dr James noted the importance of social determinants of health. “Increasingly,” he said, “we’re using case management and other kinds of tools to help make some of these therapeutic decisions with the practitioner as to how we go about managing these individuals”—for example, determining whether the patient is capable of using intravenous therapy, which requires mixing, or whether the patient is capable of taking a medication that is dosed 3 times per day.

Dr Lewis agreed, taking the concept a step further. “The focus isn’t on the managing price anymore, it’s working in partnership with physicians, because we’re putting much more IT infrastructure and resources into trying to develop an algorithm that will help us with outcomes,” she said, referring to her company’s practice of using information technology and models to “focus on best practice so we can truly pick the right drug and care combination for the right patient.”

Dr Kingman offered an example of where the provider-insurer relationship can break down. Because of the new trial data from the AMBITION study, she will try to get tadalafil approved, but “9 times out of 10 the tadalafil is not approved, so we have to use sildenafil,” which is “dosed 3 times a day, so it’s more difficult for the patient to take. But sometimes we’re at the mercy of what the insurance will allow.”

The experts advised that management of PAH should incorporate evidence-based treatment. Regarding the efficacy of specific treatments, the highest level of evidence in clinical trials requires end points of time to clinical failure or clinical worsening or reduction in all-cause mortality.

 Consequently, newer trials in PAH have had morbidity and mortality composite end points. Positive trials include SERAPHIN, which showed the broadest evidence in a wide range of patients for macitentan, and AMBITION, which studied ambrisentan in combination with tadalafil for treatment-naïve patients.

 COMPASS-2 was a negative trial of bosentan and sildenafil.

“Look at the evidence and make decisions based on the evidence,” said Dr Kingman, “and create your programs according to the clinical trial data.”

“First and foremost,” said Dr Studer, “make sure your diagnosis is correct—let’s make sure we’re treating the right patients.” To illustrate, for a disease such as cystic fibrosis, “you wouldn’t presume anyone had it without testing and involving a center of excellence,” even just by phone or consultation, he said. “We want to make sure we have the right patient group”&mdash;which can be confirmed by right heart catheterization.

Dr Kingman agreed on the importance of a right heart catheterization to make the correct diagnosis. “All of us who are specialists in PAH have often had a patient referred who is a group II patient with heart failure, because that’s much more common than PAH. I know the insurance company is acting appropriately when the outside physician has tried to get a PAH drug and the insurance company has denied it because there wasn’t a right heart catheterization,” she said.

Dr Studer advised insurers, “Use the evidence base, make sure you have the right diagnosis upfront, and then make the centers prove that they need additional therapy [for PAH patients]. If [the patients are] on 2 [drugs] and they want to go to the third, you say, ‘Show me the data.’ Show me you went through a methodical process. Prove it to me—evidence, diagnosis, guideline recommendations, and prove to me that you need more.”

Stakeholders at the roundtable noted how they have seen the profile of PAH change over the years. One remembered that when he first joined his health plan about a decade ago, “There was a lot of discussion around PAH and what are the appropriate criteria for the health plan to have. Every single request for PAH drugs went up to medical directors, some of whom were cardiologists. And then about 5 or 6 years ago we lessened some step criteria and adjusted criteria. We have criteria that you need a right heart catheterization, but the in-depth PA

review by a physician is no longer needed with more straightforward PA criteria.”

Looking back 10 years, Dr Dunn remembered PAH as involving high-profile PAs that would be denied and then go through appeals. He has since seen an evolution in awareness and diagnosis: “It seemed to be a lot noisier 8 to 10 years ago,” he said.

Other specialty categories have become far costlier today, said Dr Cannon; PAH is no longer in the forefront. However, he said, it’s important to establish appropriate criteria for PAH treatment: “Let’s collaborate, and let’s make sure that if we get a request, more importantly than approving it or denying it, we’re funneling that person over to care management so that we can make sure that we’ve got enhanced coordination of care [through case managers with the health plan or specialty pharmacy].”

Dr Lewis noted another factor that has changed. “The emphasis on contracting in PAH has decreased with patent expirations and because we have more transparent partnerships with our physicians, ACOs, centers of excellence, and medical homes,” she said. “PAH is not in our top 10 [in amount of expense as a specialty drug spend category]. And I think that’s because we have more outcomes reimbursements with physicians.”

The future of treatment for PAH could become more complicated now that PAH has gone in the direction of multiple combination therapy, similar to cancer in its multiple-drug scenario. “I think we’re going to be in a triple drug regimen,” said Dr Studer, “because what disease do we really know of where there are multiple pathways known? There’s been varying evidence that treating all those pathways helps, and treating it in various circumstances and combination helps, and yet we don’t utilize all 3 pathways. If we had a cancer cocktail and we said, ‘Well, the 4-drug regimen works well, but let’s give you just 1 drug and see if the cancer gets worse,’ everyone would recoil immediately from that.”

Expert Commentary: Identifying Criteria for a Center of Excellence

Dr Studer described how centers of excellence in PAH are formed. “It’s become an organized process through the Pulmonary Hypertension Association,” he said, which is modeled somewhat on the Cystic Fibrosis Foundation; the 2 associations discussed how the system should work, he said. “There will be a 2-tier system that persists for a while, the comprehensive center—trials, multiple specialists&mdash;and then a community-type regional care center that doesn’t necessarily have trials.” The association will make site visits, where, he said, “they look at your records&mdash;you can’t be treating in a way that’s totally inconsistent. You need to go through a careful diagnostic process. You have to evidence-base your treatment&mdash;there needs to be documentation to your follow-ups.”

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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.

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

Chief Clinical Officer/Senior Vice President

Filias Healthcare Marketing Strategy Group, LLC

University of Texas Southwestern Medical Center at Dallas

University of Colorado School of Pharmacy

New York University at Woodhull Medical Center

These faculty report relationships with the following organizations:

Reports no additional relationships or financial interests with any entity that would pose a

conflict of interest with the subject matter of this supplement.

LECTURE FEES FOR SPEAKING AT THE INVITATION OF A COMMERCIAL SPONSOR:

Considerations for Optimal Management of Patients With Pulmonary Arterial Hypertension: A Multi-Stak

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

Participating Faculty