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The Myth of the Stable Pulmonary Arterial Hypertension Patient
Gary M. Besinque, PharmD; Cassandra A. Lickert, MD; Janis A. Pruett, EdD, MSN, RN, FNP-BC

The Myth of the Stable Pulmonary Arterial Hypertension Patient

Gary M. Besinque, PharmD; Cassandra A. Lickert, MD; Janis A. Pruett, EdD, MSN, RN, FNP-BC
Pulmonary arterial hypertension (PAH) is a rare, progressive disease that often leads to right heart failure and premature death. Despite increased awareness and an expanding treatment landscape in recent decades, long-term prognosis is poor for patients with PAH. Recently, emphasis has evolved from goal-oriented therapy to risk-assessment and achieving low-risk status. Findings from recent clinical trials suggest that functional class II patients, long assumed to be stable, are not stable. Therefore, frequent assessment of all patients with PAH is essential toward escalating treatment as indicated to optimize clinical outcomes. Lowering mortality risk, preventing disease progression, and optimizing quality of life of patients with PAH is paramount.
Am J Manag Care. 2019;25:-S0
Pulmonary arterial hypertension (PAH) is a rare progressive disease, with an estimated prevalence ranging from 10 to 52 cases per million.1 PAH is characterized by increased pulmonary vascular resistance, increased pulmonary artery pressure, and right ventricular dysfunction, which often leads to right heart failure, morbidity, and mortality.2 Over the past 2 decades, substantial progress has been made in treating patients with PAH, including multiple new pharmacologic therapies. However, patients continue to experience disease progression and high rates of healthcare resource (HCR) utilization.2-4

The awareness, knowledge of impact, and pharmacotherapeutic options have expanded, but the course of PAH remains uncertain. Although some patients can live for decades, some will die within a few months of diagnosis, and others can appear to be doing well and then abruptly decline and die.5-7 Ultimately, the long-term prognosis for patients with PAH remains poor, with an unacceptable high mortality rate of almost 40% over 5 years.8 Thus, the sustained clinical stability of patients with PAH cannot be assured, as even those thought to be “less severe” may progress and die. Because it is well known that PAH is a progressive disease, it is important to frequently assess patients with PAH to optimize their outcomes and escalate treatment as clinically indicated.

Prognostic Indicators
Historically, functional class (FC), a measure of disease severity, has been considered the strongest prognostic indicator. The World Health Organization (WHO) FC system characterizes patients by classifying compromise in their functional ability (FC I-IV) according to symptoms, such as dyspnea, fatigue, chest pain, and syncope (at rest or on exertion).9 FC assessment of patients with PAH was adapted from the New York Heart Association classification system and was first adopted at the second World Symposium on Pulmonary Hypertension (WSPH) (Table).9 Using a simple assessment, FC can be identified at diagnosis and at follow-up to assess the impact of therapies, and it is accepted as a predictor of survival in patients with PAH.10-12 The importance of this classification is appreciated in that all currently marketed PAH-specific therapies include FC in their indication and usage statement.9 Today, after several meetings of the experts at subsequent WSPH, attainment of FC I or FC II status continues to be an important goal for PAH treatment. However, FC II patients still experience disease progression events and even death.13-15 These patients cannot be considered stable. To say a patient is stable is to look at the past rather than the future. Additionally, stable is not clinically defined in current literature and we do not actually know who the stable patient is and what that patient looks like. We lack a full understanding of the predictors of decline that may enable an improved phenotyping of patients and delineation of risk. Several factors may account for the lack of stability.

Patients with PAH are a heterogenous population, with different prognoses based on etiology. For example, patients with PAH with portal hypertension16 and those with scleroderma have a higher mortality risk than do patients with idiopathic PAH.17 Benza et al found that any connective tissue disease (CTD) was a contributing factor to increase the risk of mortality among patients who participated in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL), a multicenter, observational, US registry designed to assess demographic, clinical, and management data on patients diagnosed with PAH.5 Further, a study from van de Veerdonk et al elucidates the danger in underestimating the risk of progression for patients with FC II to FC III.18 In a cohort of patients who experienced disease progression resulting in death or lung transplantation after >5 years of clinical stability, it was noted that disease progression was preceded by changes in the right ventricle (RV) structure and function, but no change in FC, exercise capacity, and hemodynamics, suggesting that a clinically stable profile may mask development of RV failure.18

A landmark analysis demonstrated that a PAH-related morbidity event, defined in both the SERAPHIN and GRIPHON studies, was predictive of an increased risk of mortality.19 Morbidity events include atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, worsening of pulmonary arterial hypertension, initiation of long-term oxygen therapy, or the need for lung transplantation or balloon atrial septostomy.13,14,20 In the SERAPHIN trial, compared with those patients without a morbidity event at the 3-month landmark, those with an event had an increased risk of mortality (hazard ratio [HR], 3.39; 95%; CI, 1.94-5.92). Results from the GRIPHON trial demonstrated an elevated risk in mortality in patients who experienced a prior morbidity event (HR, 4.48; 95% CI, 2.98-6.73) compared with patients who did not have a morbidity event. Analyses based on both a 6-month and 12-month landmark also showed an increased mortality risk for patients who experienced morbidity events.19

It was demonstrated in REVEAL that patients with either newly or previously diagnosed PAH, regardless of PAH etiology, and who improved from FC III to FC I/II had better survival outcomes compared with patients who remained in FC III.21 It has been well documented that those patients in FC I/II compared with FC III/IV have better survival rates.4

Although FC I/II patients have better survival rates, it is understood that patients with PAH frequently have multiple comorbidities. For example, in REVEAL, the most common comorbidities among patients included hypertension, clinical depression, diabetes, obesity (body mass index ≥30 kg/m2), obstructive airway disease (OAD), sleep apnea, and thyroid disease. Patients with obesity or OAD occupied a significantly worsened FC; those with OAD or diabetes demonstrated an increased risk for mortality in comparison with the other comorbidity subgroups.22 More recently, the OPsumit USers Registry (OPUS) (NCT02126943) showed that the most common comorbidities among patients (N = 1136) were hypertension, edema, diabetes mellitus, anemia, signs of right heart failure, autoimmune disease, and renal insufficiency.23

Retrospective studies have also demonstrated that patients with PAH have multiple comorbidities. In a claims database study using the Pharmetrics Plus database that covers more than 150 million US patients, Hill et al identified 2623 patients who were treated with endothelin receptor antagonists (ERAs, n = 805) or phosphodiesterase type 5 inhibitors (PDE-5i, n = 1818) and found that among the total cohort, the most common comorbidities included renal failure/dialysis, congenital heart disease, connective tissue disease, clinical depression, liver disease, systemic hypertension, diabetes, and obesity.24 Using the OPTUM research database covering more than 50 million US patients, Hull et al identified a cohort of 1637 patients with International Classification of Diseases, Ninth Revision codes of 416.0 and 416.8 with a claim for a PAH-specific medication. Common comorbidities included diseases of the heart; other lower respiratory disease; hypertension; diseases of arteries, arterioles and capillaries; lipid disorders; diseases of the urinary system; chronic obstructive pulmonary disease; CTD; and diabetes.25

Patients with PAH bring with them their entire medical past and often have multiple comorbidities which may contribute to their poor PAH prognoses. Further, these conditions may exacerbate minor disorders, such as upper respiratory conditions, and complicate major insults, such as pneumonia and surgery. Thus, Gaine and McLaughlin asserted that patients with PAH “can never be considered truly stable.”11

From an economic perspective, a higher FC is associated with increased healthcare resource utilization (HCRU), including more frequent inpatient stays, longer lengths of stay, more emergency department service utilization, higher all-cause medical costs, and higher total costs. Dufour et al showed that patients who declined to FC IV used more HCRs and experienced more costs compared with FC II/III patients.4 Surprisingly, HCR utilization and costs were similar for FC II and FC III patients. The reasons for this are not clear, but this finding may reflect patient comorbidities or use of additional combination therapies.

Randomized Clinical Trials
Long-term, event-driven trials have shown that FC II patients demonstrated significant improvement when additional therapy was added. In the SERAPHIN trial, 52.4% of patients were FC II and 64% were on concomitant PAH-specific therapy.* For patients on combination therapy, there was a 38% risk reduction in the composite morbidity/mortality primary end point.14 In the GRIPHON trial 46% of patients were FC II and 80% were on concomitant PAH-specific therapy. There was an overall 40% risk reduction in the composite morbidity/mortality primary end point.13

Four-year data from the open-label extension of the EARLY trial, which was conducted with PAH-targeted therapy in WHO FC II patients, reinforced that FC II patients can have severe and often fatal progressive disease: “PAH worsening occurred at a rate of approximately 5% annually, and mortality, estimated at 15% over 4 years, remains substantial.”26 Specific factors were identified as predictive of death in FC II patients, including 6-minute walking distance (6MWD) of ≤437 m, PAH diagnosis of <16 months, mixed venous oxygen saturation of ≤68%, high N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels, and PAH-CTD. It was concluded that patients with these risk factors should prompt clinicians to employ treatment strategies such as more regular assessments and more aggressive treatments, including combination therapy. A death rate of 15% over 4 years in a mildly symptomatic PAH population26 shows the need for further research and demonstrates that FC II patients may not be stable.

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