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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.
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.18 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.18 A total of 5566 hospitalizations were identified; 3322 of the hospitalized patients had commercial insurance, and 2244 had Medicare Advantage (Figure 418).18

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.18

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.18

Number of hospitalizations and LOS are key contributors to HRU by patients with PAH. Of the rehospitalizations in the database study, 21.2% occurred within 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.19

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.”

Treatment for PAH

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).20,21

The prostacyclin pathway is the oldest and most targeted pathway. The first prostacyclin that offered specific treatment for PAH was Flolan (epoprostenol), approved in 1995.22 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—was recently approved.23

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. (Figure 51)1 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.1 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.1 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.1

Assessing PAH Patients for Treatment

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 O2 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/m2 portends a very poor prognosis.”24,25

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.26 The average study duration was 14 weeks,26 and all trials were placebo-controlled.26 Active treatment was associated with a reduction in mortality of 43% (P = .023).26 The sensitivity analysis confirmed a reduction in mortality of 38% (P = .048).26 The number of patients needed to be treated to prevent 1 death was 61.6.26 Approximately 16.2 deaths were prevented in each 1000 patients treated.26 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 (P <.001).26 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.26

Determinants of Successful Treatment

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” (Table 21,16).1,24 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.”

Evidence-Based Treatment Approaches

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.1 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.27-29 COMPASS-2 was a negative trial of bosentan and sildenafil.30 “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”—which can be confirmed by right heart catheterization.

Copyright AJMC 2006-2018 Clinical Care Targeted Communications Group, LLC. All Rights Reserved.
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