Advances in the Management of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is characterized by nonspecific symptoms, which can lead to a delay in diagnosis. Without treatment, patients with PAH have a poor prognosis, but development and availability of PAH-specific therapies have improved the overall prognosis of the disease.

At the Fall Managed Care Forum 2015 in Las Vegas, Nevada, David B. Badesch, MD, professor of medicine at the University of Colorado, discussed updates in pulmonary arterial hypertension (PAH) therapy, with an emphasis on relevance for the managed care audience.

PAH is a condition characterized by nonspecific symptoms, including dyspnea and fatigue, and the lack of specific symptoms in this disease state contributes to diagnostic uncertainty and delay, according to Dr Badesch. For definitive diagnosis, methodical evaluation is required, including cardiac catheterization. Partly because of this diagnostic requirement and partly due to the nonspecific symptom complex of PAH, a typical patient with PAH receiving a diagnosis will already have had symptoms for nearly 3 years. Without treatment, patients with PAH have a poor prognosis.

The development and availability of PAH-specific therapies have improved the overall prognosis of the disease. Unfortunately, even with treatment, patients with PAH do not have a normal life expectancy. Furthermore, the cause of the disease is unknown in a large proportion of cases, with nearly half (46.2%) of patients with PAH having idiopathic disease. Most cases of PAH occur in women, and cases may manifest at any time in life, with diagnoses spanning a broad age range. For most patients, definitive diagnosis occurs late in the course of disease, further contributing to the disease burden.

Several prognostic factors may be helpful in predicting the course of PAH, including right ventricular failure, higher World Health Organization functional classification (WHO FC), and shorter 6-minute walk distance (6MWD). Other parameters that may help establish a patient's prognosis, including hemodynamic factors, such as right atrial pressure, and brain naturietic peptide (BNP) levels.

Available treatment for PAH includes 3 broad classes of therapies: the endothelin receptor antagonists (ERAs), phosphodiesterase type 5 inhibitors (PDE5is), and prostacyclins. Use of intravenous prostacyclin therapy in patients with PAH is associated with improvements in 6MWD (an exercise capacity test), and treatment with a specific type of prostacyclin—epoprostenol—has been shown to improve survival. The PDE5is tadalafil and sildenafil have been shown to improve exercise capacity in PAH, and tadalafil is approved for use in combination with the endothelin receptor antagonist (ERA) ambrisentan. Other ERAs include bosentan, which has been shown to delay clinical worsening. However, unlike other ERAs, use of bosentan requires hepatic function monitoring on a monthly basis.

Macitentan is another ERA available for treatment of PAH. Macitentan is a dual ERA that antagonizes 2 subtypes of the endothelin receptor and was developed by modifying the structure of bosentan for sustained receptor binding and enhanced tissue penetration. As shown in the SERAPHIN trial, macitentan delays a combined end point of morbidity and mortality in patients with PAH.

In the pivotal trial for macitentan, SERAPHIN, patients were randomized to receive either placebo or macitentan daily at a dose of 3 mg or 10 mg. In this long-term, event-driven trial, investigators measured the time to clinical worsening as the prespecified primary end point.

Patients enrolled in the study were allowed to use either oral or inhaled therapy for PAH, provided that a stable background dose of medication was used, and that no other ERAs were used. In this study, the primary end point from initiation of treatment was defined by worsening of PAH with a decrease in 6MWD of 15% or more from baseline, a worsening of PAH-related symptoms, and a need for additional PAH treatment, including intravenous or subcutaneous prostanoids. In the SERAPHIN trial, all-cause mortality was also an outcome included in this combined primary end point.

Secondary end points included the change from baseline to month 6 in 6MWD, the percentage of patients with an improvement in WHO FC at month 6, PAH-related mortality, as well as adverse event rates and laboratory abnormalities.

Another treatment for PAH is the soluble guanylate cyclase stimulator riociguat, which has a dual mode of action, both in directly stimulating guanylate cyclase, and in increasing the sensitivity of guanylate cyclase to stimulation by nitric oxide. In the pivotal trial for riociguat (PATENT), patients received placebo or riociguat titrated to dose of up to 2.5 mg 3 times daily. In this trial, patients receiving ERAs or prostanoids, as well as patients not receiving any PAH-specific therapy were eligible for trial inclusion.

Researchers measured a primary end point of change from baseline to week 12 in 6MWD, and secondary end points of changes in peripheral vascular resistance (PVR), N-terminal prohormone brain natriuretic peptide (NT-proBNP) level, WHO FC, time to clinical worsening, Borg dyspnea score, and quality of life (QOL). In the final analysis, riociguat significantly improved exercise capacity (6MWD), PVR, NT-proBNP, and WHO FC, the Borg dyspnea score, and reduced the risk of clinical worsening.

Riociguat also has an indication for use in chronic thromboembolic pulmonary hypertension (CTEPH), a vascular disorder resulting from thrombotic obstruction of the pulmonary arteries. Like PAH, CTEPH may be associated with vasculopathies of the small vessels, resulting in confusion between CTEPH and idiopathic PAH.

Unlike PAH, however, CTEPH is a consequence of an acute pulmonary embolism (PE). Pulmonary vasculature obstruction may result in increased PVR and right ventricular failure. Of the 600,000 patients who develop a PE in the United States each year, approximately 4% will develop CTEPH within 2 years of the first PE episode. In many of these patients, the initial PE event is never clinically overt. Five-year mortality rates in patients with CTEPH range from 70% to 90%. Without early treatment, patients are likely to have a poor prognosis.

Standard treatment for CETPH is a surgical procedure called pulmonary thromboendarterectomy (PTE). This is the only potential curative treatment for CTEPH. Unfortunately, surgery is not an option for all patients. Patients with coexisting conditions, occlusion of distal vessels, and patients unwilling to undergo surgery or unable to access surgical centers may be candidates for treatment with riociguat.

In the phase 3, multicenter, double-blind, placebo-controlled trial for riociguat, patients with CTEPH were randomized to receive riociguat or placebo. Eligible patients had either experienced persistent CTEPH symptoms following PTE, or were unable to undergo the PTE procedure. In this trial, patients were evaluated on the primary end point of a change from baseline to the end of week 16 in 6MWD.

Secondary end points included changes from baseline to week 16 in PVR, NT-proBNP level, WHO FC, time to clinical worsening, Borg dyspnea score, and QOL. Results showed significant improvements in exercise capacity (6MWD), PVR, and NT-proBNP levels. Common adverse events included headache, dizziness, dyspepsia, and hypotension.

In the recent AMBITION study, patients with PAH were treated with ambrisentan plus tadalafil combination therapy, either medication used alone, or placebo, and were evaluated based on a primary end point of time to clinical failure. Results showed a significantly lower risk of clinical failure with combination therapy versus placebo (HR: 0.53; 95% CI: 0.34-0.83; P = .005). Improvements in secondary end points were also noted, including 6MWD, and WHO functional class.

Common adverse events with combination therapy included urinary tract infections, arthralgia, back pain, fatigue, dyspepsia, palpitations, vomiting, bronchitis, noncardiac chest pain, and myalgia. In patients receiving combination therapy, adverse events resulting in treatment discontinuation occurred in 12% of cases. This trial supports combination therapy in patients with PAH, including early combination therapy.

Concluding his presentation, Dr Badesch noted the multidisciplinary nature of PAH management, noting that optimal management requires collaboration between pulmonary units, cardiology units, catheterization labs, echocardiography experts, radiology experts, rheumatologists, interventional radiologists, pharmacists, nurses, and researchers. Through a full understanding of the therapeutic options in PAH, managed care professionals can help support the complete health care team in fighting this deadly disease.