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Available treatments: PAH

Table 2: Clinical trials evaluating combination therapy for PAH Combination

Study Sildenafil + bosentan25 Tadalafil + ambrisentan26

Bosentan + iloprost (Hoeper, 2006)27

Epoprostenol + bosentan (Humbert 2004)28

Epoprostenol + sildenafil (Simmonneau 2008; Simmonneau, 2014)29,30

Trepostinil + ERA/PDR-5i (Tapson 2012, 2013)31,32

Riociguat + sildenafil (Galiè, 2013)33




PACES-1 and -2



Efficacy and safety

COMPASS-2 No significant delay in time to clinical worsening, improved exercise capacity

Improved time to clinical worsening, exercise capacity, and NT-BNP with upfront combination versus monotherapy

Conflicting results in patients previously treated with bosentan

No significant improvement in haemodynamic parameters or exercise capacity Increased incidence of leg oedema

Improved exercise capacity, symptoms, haemodynamics, quality of life

No significant improvement in exercise capacity

No significant improvement in functional class, haemodynamic parameters or exercise capacity Increased incidence of hypotensive episodes

ERA=endothelin receptor antagonist; PDE-5i=phosphodiesterase type 5 inhibitor

When used as a single agent, oral treprostinil improved 6MWD, but not functional class or time to clinical worsening, in treatment-naïve patients.19 Similar results were obtained with inhaled treprostinil in patients who remained symptomatic on bosentan or sildenafil.20 An inhalation solution of prostaglandin

derivative iloprost has received marketing approval in the USA and in the EU, partially based on results of the AIR study, which showed benefits in patients with PAH and included some patients with chronic thromboembolic pulmonary hypertension (Table 1).3,4,21 Beraprost, an oral prostacyclin analogue, is available in Japan for the treatment of PAH.3,4,22


study, the agent induced short-term improvements in exercise capacity, but clinical worsening was not significantly different at one year in another randomised trial (Table 1).22,23

Selexipag, an oral non-prostanoid PGI2 receptor agonist has recently been evaluated in the largest PAH trial to date – GRIPHON. Preliminary data have been presented demonstrating a reduction in the primary outcome of morbidity/ mortality events by 40%. The effect was seen across age, functional class, etiologic and background therapy subgroups with a similar side effect profile to prostacyclins.24

Combination therapy

Combination regimens are commonly employed at all PH centres, but have been difficult to systematically evaluate in patients who do not respond to first-line therapy. Clearly, targeting multiple pathways with distinct agents has a great

deal of therapeutic appeal, and is used in many other settings such as treatment for systemic arterial hypertension and left heart failure.

While most of the recent studies with newer agents have included large proportions of patients on background therapy, a handful of dedicated combination studies have been performed with mixed results (Table 2). Apart from various issues with the individual combinations and limitations of study design, the strategy of combining agents upfront or after failure of monotherapy may be a major factor in the ability to demonstrate effectiveness of combination therapy. The traditional approach of starting with monotherapy, observing improvement, then a plateau and subsequent deterioration before initiating a second agent may not be as effective upfront combination therapy. The strategy of ‘add-on’ therapy was employed in the COMPASS 2 study where sildenafil-treated patients received bosentan versus placebo. Results from this trial did not meet the primary endpoint of a delay in time to clinical worsening, although exploratory secondary analyses of 6MWD and NT-pro-BNP levels were improved.25

Recently, the widely

anticipated randomised AMBITION study was published, comparing the strategy of combining ambrisentan with tadalafil as an initial approach versus each individual agent.26

The results definitively

demonstrated that the initial combination strategy was superior to monotherapy with either agent, with a 50% reduction in the risk of clinical failure compared to either ambrisentan or tadalafil alone. Secondary

endpoints including NT-pro-BNP and 6MWD were also better with the upfront combination, but WHO functional class and Borg dyspnoea index did not reach statistical significance. These results are suggestive that a more aggressive upfront combination approach should be considered to optimally treat patients with PAH.

Goal-orientated therapy

Recent PAH guidelines have encouraged a more aggressive approach to treatment, with a focus on more effective symptom control and goal-oriented therapy for treatment optimisation.34


assessments and targeting multiple goals including functional class, right ventricular function on echo or cardiac MRI, haemodynamics, 6MWD, and NT-pro- BNP may improve or maintain patients’ clinical and functional status, ultimately translating into survival benefits. The long-term benefits of combination therapy in conjunction with a goal-oriented strategy were demonstrated in severely affected PAH patients. Treatment goals were defined at baseline, based on walking distance, peak oxygen uptake and systolic blood pressure during exercise, before initiating first-line therapy with bosentan. Whenever a goal was not met throughout treatment, additional agents such as sildenafil and iloprost were added.35

Conclusions In general, treatment guidelines for PAH have recommended pharmacotherapy at earlier stages of disease to reduce morbidity and mortality, but current regimens are still associated with limiting symptoms and poor outcomes. There is accumulating evidence that the combination of therapies which target distinct pathobiologic mechanisms is beneficial, and recent studies suggest that an aggressive upfront combination approach may be the best way to improve symptoms and delay progression of this devastating disease. l

References 1. Galiè N et al. Updated treatment algorithm of pulmonary arterial hypertension. JACC 2013;62(25) Suppl:D60–72.

2. Sitbon O, Morrell NW. Pathways in pulmonary arterial hypertension: the future is here. Eur Respir Rev 2012;21(126):321–7.

3. US Food and Drug Administration. www. (accessed 23 October 2015).

4. European Medicines Agency. www.ema.europa. 21

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