Summary and Clinical Application

As demonstrated in the AMBITION trial, upfront combination therapy with ambrisentan and tadalafil, an ERA and PDE5i respectively, is superior to either monotherapy alone in the treatment of PAH. ⁶ This important trial has emphasized the importance of initial combination therapy for patients with PAH. This systematic review summarizes the evidence for combination therapy using agents targeting the NO and PGI₂ pathways to assist healthcare providers who may be considering an alternative regimen for patients for whom this drug combination may be a reasonable and, in some cases, preferred treatment option.

In selecting a prostacyclin class agent to combine with a PDE5i or sGC stimulator it is important to note the potential for systemic hypotension when combining either agent, in particular riociguat, with a parenteral prostanoid. This is often addressed by simply discontinuing a patient’s other antihypertensive agents or allowing a patient to acclimate to the prostanoid; alternatively, midodrine may be prescribed to increase systemic blood pressure without increasing pulmonary pressures. As noted, inhaled prostanoid formulations appear to be best tolerated in terms of blood pressure and side effect profile. Patients often prefer the convenience of oral prostacyclin class agents but oral treprostinil and selexipag are often associated with higher incidences of gastrointestinal side effects. SC and IV prostacyclin mimetics are viewed as the gold standard treatments for PAH patients but there is a high burden placed on patients who need to wear a continuous infusion pump. Treatment decisions must be carefully weighed based on the individual patient and disease characteristics. For example, the authors have anecdotal experience that PAH associated with connective tissue disease is often more aggressive and less responsive to oral non-prostacyclin therapies therefore SC or IV prostanoid treatment may be required earlier for this subgroup. To date, no specific PAH patient subgroups have been identified as being more responsive than another to NO pathway and PGI₂ combination therapy.

Titration of a prostacyclin class agent in combination with a PDE5i or sGC stimulator in patients with PAH also needs to be individualized and grounded on patient risk stratification as assessed by the European Society of Cardiology (ESC) risk assessment model. When using NO pathway agents with a prostanoid, it is not uncommon for sGC stimulator or PDE5i dosing to be maximized prior to the addition of the second agent to minimize adverse events such as hypotension and headache. Conversely, prostacyclin class agents, in particular parenteral prostanoids, are often considered for initial treatment in patients with severe PAH or rapidly progressing disease. ²⁰ If a patient is not meeting clinical goals or exhibits clinical worsening, an NO pathway drug can then be added.

Often, clinical decisions related to the sequence of addition may be influenced by drug formulary status at a particular site, with initiation of the first drug in the combination being one that is approved and accessible. The selection of subsequent treatments may also be influenced by payor-factors. Concerning cost, AMBITION therapy using ambrisentan and tadalafil is available in generic form making them desirable from a payor perspective.

Currently, it is unclear whether the cooperative effects between NO and prostacyclin pathway agents allows for lower doses of drugs to be used without compromising efficacy. As mentioned by other researchers, this theoretical biochemical synergism may translate clinically into lower doses of prostacyclin class agents combined with a NO pathway drug. ²⁹ This could reduce prostacyclin adverse effects, such as headache, flushing, jaw pain, nausea, and vomiting, which often limit dose escalation and may result in discontinuation of an otherwise efficacious treatment for PAH.

NO donors, in particular NO gas by inhalation, has been shown to be beneficial to patients with pulmonary hypertension, particularly in pediatric patients. ^47,48 Unfortunately, delivery of inhaled NO gas is challenging from a technical perspective and has thus far been limited to use in the hospital setting. Several studies are underway investigating the use of portable NO delivery systems in patients with PAH and this could represent an additional avenue to target the NO pathway in a more practical manner. ^49,50 Oral nitrates and nitrites have been used with some success to treat pulmonary hypertension in animal models and are also a theoretical modality for enhancing the NO pathway. ^51,52 Molsidomine, an NO prodrug administered orally, has been shown to reduce pulmonary pressure in patients with chronic obstructive lung disease as well as patients with pulmonary hypertension secondary to Takayasu’s arteritis. ^53,54 L-arginine is a nitrogen donor for the synthetic pathway of nitric oxide and has been used with success in patients with pulmonary hypertension. ^55,56 Further research on these latter 2 compounds is warranted to investigate their therapeutics benefits in combination with prostacyclin agents.

We acknowledge the potential limitations of a narrative review, such that despite search efforts to identify all relevant studies and previous publications, some may have not been included, as well, the restriction to English language literature may have also been a limitation of the work.

The pathophysiology of PAH is complex and a thorough understanding of mechanisms of action of different agents is necessary to evaluate their use in combination therapy. Prospective and controlled trials are needed to confirm and compare the efficacy of different modes of combination therapy, and treatment decisions need to be individualized to each patient’s clinical features and preferences. Although there are clinical nuances to combination therapy and managing side-effect profiles, the clinical and preclinical data summarized here provide a strong rationale for the use of combination therapy simultaneously targeting the NO and PGI₂ signaling pathways to treat patients with PAH.