Whatever Happened to Oral Monotherapy?

Pulmonary arterial hypertension (PAH) is characterized by pulmonary arteriopathy leading to elevated pulmonary vascular resistance (PVR), right ventricular dysfunction, and, if untreated, death.1 The development of effective therapies for PAH highlights our understanding of the mechanisms underlying the vascular changes. These targeted therapies are directed at abnormalities in the endothelin, nitric oxide, and prostacyclin pathways.2–5

Given the number of available therapies for PAH, it is not surprising that no single treatment regimen is appropriate for every patient. It must be emphasized that complex decisions such as which therapy or therapies should be initiated, how patients should be monitored, and when therapy should be adjusted are best made by expert treatment centers.16 In general, initial treatment has been based on degree of severity of disease, such as functional class (FC). The guidelines recommend, for instance, that in FC IV patients, intravenous epoprostenol be used.

What is the appropriate strategy for patients with less severe PAH? Two basic treatment strategies are now considered: goal-directed escalation therapy or up-front combination therapy.78 The latter approach, starting multiple drugs initially, is supported by only one study, the AMBrIsentan and Tadalafil in patients with pulmonary arterial hypertensION (AMBITION) trial. In this double-blind, randomized, controlled trial (RCT), the initial combination therapy with ambrisentan and tadalafil was compared with monotherapy.9 This trial showed 50% risk reduction in clinical failure events when compared to the pooled monotherapy group; and initial combination therapy resulted in statistically significant improvement in 6-minute walk distance, N-terminal pro b-type natriuretic peptide level reduction, and cardiac index, as well as PVR9. Even in this true combination therapy study, many patients in the monotherapy arm had clinical success, raising the question of how to better identify patients who will do well on a single agent and thus avoid costs and side effects.

Contrasting with this one study are numerous trials suggesting that there is still a role for oral monotherapy. Long-term, open-label follow-up from early pivotal trials, in the “precombination therapy” era, of drugs including bosentan, ambrisentan, sildenafil, and tadalafil demonstrated sustained benefits. 10–13

In the modern era of multiple drugs, even if monotherapy is adequate for many patients, the approach of adding therapies “as needed” is attractive, and supported by recent trials and guidelines. 78 A meta-analysis of several clinical trials studied the efficacy of general combination therapy without differentiating the route of administration, and concluded that while the combination therapy showed no mortality benefit, it was associated with improved clinical outcomes.14–16 More recent trials, such as PATENT-1, FREEDOM-C, FREEDOM-C2, COMPASS-2, SERAPHIN, and GRIPHON, in which many patients were on background therapy, generally supported the efficacy of combination therapy (Table 1).15 The majority of these studies (COMPASS-217 and FREEDOM18–20 being exceptions) met their primary endpoints, and, on subgroup analysis, demonstrated an equivalent treatment effect whether or not patients were treatment-naive or on background therapy.15 Although the efficacy of these long-term trials is unquestionable, do these results “mandate” that all patients on background monotherapy have additional drugs prescribed? It is important to note that the majority of studied patients were clinically stable on background therapy even prior to escalation of treatment to sequential combination therapy.21 Although patients randomized to placebo had a higher likelihood of a morbidity/mortality event, many of these patients did not (study the placebo curves of patients on background PAH therapy). In addition, it is fair to question whether the benefits observed with the combination therapy is due to a true synergistic effect or to an empiric coverage that addresses all pathways, one of which could be a treatment that targets patient's PAH phenotype specifically. It is conceivable that switching to a different target class could be just as efficacious and more cost-effective. While this hypothesis does not undermine the clinical efficacy of combination therapy, it underscores the potential need for future studies on therapy “switches.”

Table 1. Oral Combination Therapy Studies

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In addition to the finding that the majority of patients on monotherapy remain stable, 2 additional advantages deserve mention: reduction in side effects and cost. Oral PAH medications are associated with significant side effects including headaches, flushing, nasal congestion, dyspepsia, and diarrhea.16 Not surprisingly, added therapy led to added side effects, as in the AMBITION trial, in which the combination therapy group suffered more peripheral edema, headache, nasal congestion, and anemia.9

There have been very few studies looking at the comparative cost-effectiveness of the therapies. One study looked at the economic burden of PAH and illustrated that PAH advance medications were associated with significant reduction in medical costs, largely driven by decreased hospitalization, but also associated with substantial increase in pharmacy costs.22 While some mitigation in hospitalization costs exists due to clinical efficacy, there remains no doubt that PAH medications are extremely costly. Health care plans, both private and public, are starting to focus on controlling costs while maximizing the quality of care; these mandates may necessitate an initial monotherapy approach.

In a recent Canadian study, cost-effectiveness for each available PAH treatment was evaluated.23 For patients with both FC II and III, sildenafil was reported as the most affordable option with the greatest efficacy, delaying disease better than other available oral agents. Endothelin receptor antagonists (ERAs) were also efficacious in improving quality of life, but at triple the cost of phosphodiesterase type 5 (PDE5) inhibitors.23 Further studies are needed, but at least in this study, an initial oral monotherapy approach with a PDE5 inhibitor is cost-effective.2324

Moreover, AMBITION was a first trial, looking at up-front combination of specific ERAs with specific PDE5 inhibitors, ambrisentan and tadalafil.9 While drugs in the same class generally behave similarly, there are unknown drug-drug interactions that can produce different effects—positive or negative. Therefore, clinical efficacy of combining ambrisentan to tadalafil as an initial therapy cannot be generalized to other agents in their respective classes. One of the disadvantages of combination therapy is added cost.

CONCLUSION

There is still a role for initial oral monotherapy for PAH patients, especially in earlier FC (II, early III). PAH management should be specifically tailored to each patient; patients should be identified and referred to a specialist as early as possible. Early initiation of a single agent, with close follow-up and consideration of additional therapies as needed, remains a reasonable approach. Although trials like AMBITION inform a more aggressive up-front combination therapy approach, further studies on up-front combination therapy and its cost-benefit analysis are needed. As more trials delve into all possible permutations of available treatments or even novel agents, physicians should use these data carefully to make appropriate clinical decisions, weighing the benefits of clinical improvement against costs of treatment strategies. Lastly, there must be a concerted effort to explore cost-effectiveness of these treatment strategies to ensure that PAH treatments are practical and fiscally sustainable.