1.1. Disease Prevalence and Incidence

Pulmonary arterial hypertension (PAH) is an uncommon, debilitating, progressive, and life-threatening disease of the pulmonary vasculature, characterized by vascular proliferation and remodelling of small pulmonary arteries. If left untreated, it can lead to right heart failure and premature death. PAH is defined by an increase in mean pulmonary arterial pressure (mPAP) ≥ 25 mm Hg.¹

The symptoms of PAH include breathlessness, fatigue, weakness, chest pain, light-headedness or fainting, and edema or ascites. Severity of disease is based on symptoms and assessed using the New York Heart Association (NYHA) or World Health Organization (WHO) functional classification of heart failure symptoms, ranging from functional class (FC) I to IV, with FC IV being the most severe (Table 2).

Table 2

World Health Organization Functional Classification of Pulmonary Hypertension.

PAH is classified as Group 1 of the pulmonary hypertension (PH) classification, which was recently revised and updated in the Fifth World Symposium on Pulmonary Hypertension, held in Nice, France, in 2013.² The four main categories of Group 1 include idiopathic PAH, heritable or familial PAH, drug- and toxin-induced PAH, and PAH associated with other conditions such as connective tissue disease, HIV infection, portal hypertension, congenital heart disease, or schistosomiasis (Table 3).

Table 3

2013 (Nice, France) Pulmonary Arterial Hypertension Categories.

There are no published data on the incidence or prevalence of PAH in Canada; however, data from US and European registries provide some information.^10-13 The incidence of PAH ranges from 2.3 to 7.6 cases per million based on data from the US, France, Spain, and Scotland. Data on the prevalence of PAH vary from 12.4 (US), 15 to 16 (France, Spain), and 26 to 52 cases per million (Scotland). Based on these figures, and 2014 Canadian population data, the manufacturer estimated there are 434 to 1,820 prevalent cases of PAH, with 81 to 266 new cases developing each year.¹⁴

1.2. Standards of Therapy

Treatment of PAH is generally categorized as supportive therapy or advanced therapy. Supportive therapy includes use of diuretics, oxygen, anticoagulants, and digoxin. Advanced therapy is targeted at the disease itself. As supportive therapies are generally not effective in PAH, advanced therapy is almost always needed.

Health Canada has approved nine advanced treatment options covering four different classes of drugs for PAH, WHO Group 1:

• Prostacyclin therapies (epoprostenol, treprostinil, selexipag)
• Endothelin receptor antagonist (ERAs) (bosentan, ambrisentan, macitentan)
• Phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, tadalafil)
• Soluble guanylate cyclase (sGC) stimulator (riociguat).

In 2015, CADTH published a Therapeutic Review to assess the comparative efficacy and safety and to determine the cost-effectiveness of pharmacologic treatments for adults with PAH.³ Results from the systematic review and network meta-analysis suggest that there were no significant differences in clinical worsening and FC worsening between drugs used to treat PAH as monotherapy. For FC improvement and six-minute walk distance (6MWD), epoprostenol appeared to be the most effective treatment option in improving clinical status, while there were no apparent differences among other treatments. Addition of macitentan on PDE5 inhibitor or prostanoids background therapy and addition of riociguat or tadalafil on ERA background therapy produce improvement in clinical worsening, FC improvement, FC worsening, and/or 6MWD versus monotherapy with background therapy. There were no differences between combination therapy of riociguat plus ERA and tadalafil plus ERA in all four clinical outcomes. All drugs showed improvement in pulmonary hemodynamics and health-related quality of life compared with placebo. Adverse events were treatment specific.³

Based on the Therapeutic Review and patient group input, the CADTH Canadian Drug Expert Committee (CDEC) recommended the following:

• That sildenafil or tadalafil be the preferred initial therapy for adult patients with FC II and III PAH; and
• Add-on therapy should be used in adult PAH patients who are unable to achieve disease control with a single drug.⁴

CDEC could not make a specific recommendation pertaining to subgroups of patients (based on disease severity or other disease characteristics) who may benefit more from specific drugs of combinations of drugs based on the evidence reviewed.⁴

PAH has a significant impact on the lives of patients and caregivers. Patients with PAH have a day-to-day life that is difficult and exhausting, and they progressively lose the ability to care for themselves. While therapy may delay progression, reduce the severity of symptoms, and make certain tasks easier, there is still no cure for PAH.

1.3. Drug

Selexipag is an oral, selective, IP receptor agonist, and is structurally and pharmacologically distinct from prostacyclin and its analogues. Selexipag is hydrolyzed by carboxylesterase 1 to yield its active metabolite, which is approximately 37-fold more potent than selexipag. Selexipag and the active metabolite are high-affinity IP receptor agonists with a high selectivity for the IP receptor versus other prostanoid receptors (EP1–EP4, DP, FP, and TP). Stimulation of the IP receptor by selexipag and the active metabolite leads to vasodilatory as well as anti-proliferative and anti-fibrotic effects.

The recommended starting dose is 200 mcg given twice daily. The dose is increased in increments of 200 mcg given twice daily, usually at weekly intervals, until adverse pharmacological effects that cannot be tolerated or medically managed are experienced, or until a maximum dose of 1,600 mcg twice daily is reached. The highest tolerated dose reached during dose titration should be maintained. If the therapy over time is less tolerated at a given dose, symptomatic treatment or a dose reduction to the next lower dose should be considered.

Table 4

Key Characteristics of Pulmonary Arterial Hypertension Drugs Available in Canada.