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Available treatments: PAH

Table 2: Clinical trials evaluating combination therapy for PAH Combination


Bosentan + iloprost (McLaughlin, 2006; Hoeper, 2006)26,27

Sildenafil + bosentan28

Epoprostenol + bosentan (Humbert 2004)31

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

Trepostinil + ERA/PDR-5i (Tapson 2012, 2013)32,33

Riociguat + sildenafil (Galiè, 2013)32

Tadalafil + ambrisentan25



PACES-1 and -2



AMBITION Efficacy and safety

Conflicting results in patients previously treated with bosentan

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

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

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

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

patients also find prostanoids difficult to tolerate due to many potentially limiting adverse effects that can include flushing, diarrhoea, and jaw pain. Because of its effectiveness, epoprostenol is used in the most severe cases (WHO Class IV) or for patients who have an insufficient response to oral agents. In many situations it can be used as a bridge to lung transplantation.

Treprostinil has a longer half-life than epoprostenol and can be administered via continuous subcutaneous or intravenous infusion.18

Subcutaneous delivery avoids

the complications of intravenous infusions, but also is associated with site pain and local complications that can be limiting. Oral treprostinil potentially circumvents the limitations associated with injectable and inhaled PGI2 agents. 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, a non-prostanoid PGI2 receptor agonist is under evaluation in the GRIPHON trial. Preliminary data reported by the manufacturer showed that the primary efficacy endpoint of the trial, reduction in risk of morbidity/ mortality, was met across age, functional class and aetiology. Its tolerability profile was similar to that of 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. While the details of the study have yet to be published, preliminary results from this trial did not meet the primary endpoint of a delay in time to clinical worsening, although exploratory analyses were encouraging.24

Recently, the widely

anticipated randomised AMBITION study reported preliminary results investigating the strategy of combining ambrisentan with tadalafil as an initial approach versus each individual agent. 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.25

Secondary endpoints

including NT-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 efforts in the pharmacological treatment of PAH have focussed not only on the development of improved agents for rapid and effective control of symptoms, but also on goal-oriented therapy for treatment optimisation.34 This approach establishes multiple goals and incorporates regular reassessment in routine practice in order to 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


In general, treatment guidelines for PAH have recommended pharmacotherapy at earlier stages of disease to reduce morbidity and mortality, but current


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