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impression that monotherapy was successful in the treatment of very severe disease.


The results of the OLE studies should be interpreted in the light of the therapeutic strategy adopted in most of the protocols: patients started oral monotherapy and another drug was added in cases of clinical deterioration or if the patients did not reach a satisfactory clinical response.


This means that in a population of naïve patients in World Health Organization (WHO) Class II and III who started an oral drug, approximately 40% will die or will need a new drug within two years. The independent risk factors for clinical worsening have been identified and include: higher functional class; lower cardiac index; and lower effort capacity (evaluated as 6MWD).


Data from the SERAPHIN trial provided some clues about the rate of clinical worsening in patients on double combination therapy.13


It is important to emphasise that in clinical practice the rate of clinical worsening (and the need for a combination therapy) is approximately 20–25% per year.11,12


their use, even in patients in Class IV, for whom the guidelines give the highest recommendation. In Europe, similar data are not


available, but it is possible that the use of parenteral prostanoids is even less frequent than in the US.


Do we need other drugs for PAH? Despite the improvement in survival, PAH remains a severe and progressive disease with a mortality that is very similar to a cancer in patients who remain in advanced cases (Class III or Class IV) or who do not have a normalisation of cardiac index on therapy.15


Because the use of parenteral prostanoids is limited to expert centres and patients are often referred on oral therapy in a very advanced stage and sometimes cannot accept a permanent infusion line or intradermal needle, availability of new oral drugs could be a step forward in the treatment of PAH. However, the best care should be taken in order to avoid a delay for prostanoid therapy or lung trasplantation.


Analysing the rate


of events in the subgroups of patients who were on background therapy, the patients on monotherapy (mainly PDE5-I) had a clinical worsening rate of 20% per year, whereas patients on combination therapy (PDE5-I + macitentan, an ERA) had a rate of clinical worsening that was around 13% per year. This means that even on oral combo therapy, approximately 25% of patients with clinical worsening at two years is expected.


The use of combination therapy The large US registry (REVEAL registry), that collected data from 2006, analyses the current use of combination therapy in PAH.14


14


Taking into account patients in functional Class III and IV, the pattern of drug use was quite similar despite the different severity. Approximately 13% of patients in both classes were on combination oral therapy and approximately 26% of patients were on combination therapy (oral + prosta) but the percentage of triple combination therapy was higher in Class IV than in Class III (13% versus 7.5%). Overall, the use of parenteral prostanoids as monotherapy or as combination was 34% in Class III and only 48% in Class IV. The complexity of the use of parenteral prostanoids is possibly a limiting factor for


Developments in therapy Macitentan is a dual endothelin receptor blocker that was tested in a large randomised controlled trial (RCT) with an innovative design for PAH (event driven) with a robust clinical primary end-point (time to clinical worsening).13


Riociguat is a soluble guanylate cyclase stimulator – a class of drug that acts on the same pathways as PDE5-I, but causes the production of cGMP, even in the absence of nitric oxide. Riociguat was studied in a RCT with a classic design (12 weeks; primary endpoint, six-minute walking distance).16


Both drugs showed


efficacy in naïve patients and in patients who were on background therapy (mainly PDE5-I in the macitentan trial; mainly ERA in the riociguat trial).


Selexipag, an oral non-prostanoid PGI2 receptor agonist has been evaluated in the largest PAH trial to date – GRIPHON. Preliminary data demonstrate a reduction in the primary outcome of morbidity/mortality events by 40%, with a similar side effect profile to prostacyclins.17 ●


References 1. Simonneau G et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013;62(25 Suppl):D34–41.


2. Kuehne T et al. Magnetic resonance imaging analysis of right ventricular pressure-volume loops:


in vivo validation and clinical application in patients with pulmonary hypertension. Circulation 2004;110(14):2010–16.


3. D’Alonzo GE et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991;115(5):343–9.


4. Galiè N et al. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009;30:394–403.


5. Galiè N et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Respir J 2009;34(6):1219–63.


6. Galiè N et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol 2013;62(25 Suppl):D60–72.


7. Benza RL et al. Development of prognostic tools in pulmonary arterial hypertension: lessons from modern day registries. Thromb Haemost 2012;108(6):1049–60.


8. Humbert M et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 2010;122(2):156–63.


9. Thenappan T et al. A USA-based registry for pulmonary arterial hypertension: 1982–2006. Eur Respir J 2007;30:1103–10.


10. Thenappan T, Glassner C, Gomberg-Maitland M. Validation of the pulmonary hypertension connection equation for survival prediction in pulmonary arterial hypertension. Chest 2012;141(3):642–50.


11. Provencher S et al. Long-term outcome with first-line bosentan therapy in idiopathic pulmonary arterial hypertension. Eur Heart J 2006;27(5): 589–95.


12. Vizza CD et al. Relationship between baseline ET-1 plasma levels and outcome in patients with idiopathic pulmonary hypertension treated with bosentan. Int J Cardiol 2013;167(1):220–4.


13. Pulido T et al; SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013;369(9):809–18.


14. Badesch DB et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest 2010;137(2):376–87.


15. Nickel N et al. The prognostic impact of follow-up assessments in patients with idiopathic pulmonary arterial hypertension. Eur Respir J 2012;39(3): 589–96.


16. Ghofrani HA et al; PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013;369(4):330–40.


17. Galiè N et al. Effect of selexipag on morbidity/ mortality in pulmonary arterial hypertension: Results of the GRIPHON study. J Heart Lung Transpl 2015;34(4):S163.


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