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Need for new therapies

survival is improved compared to the survival predicted with the NIH formula7 but it is still unacceptably high. For example, the French registry, that collected prevalent and incident cases of idiopathic, familial and anorexigen- associated, showed a reduction of mortality around 10% per year when the actual survival was compared with the survival estimated with the NIH formula.8

In the

Pulmonary Hypertension Connection registry, the contemporary survival in the cohort was even better (around 20% per year) when compared with the survival predicted by the NIH registry equation.9 By contrast, the good survival obtained with oral drugs in the open label extension (OLE) of RCTs10

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

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


means that in a population of naïve patients in WHO class II and III who started an oral drug, around 40% of the patients 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 six-minute walk distance). Data from the recent trial, SERAPHIN, provides some clues about the rate of clinical worsening in patients on double combination therapy.13

Analysing the rate of

events in the subgroups of patients who were on background therapy, the patients on monotherapy (mainly PDE5 inihibitors) had a clinical worsening rate of 20% per year, while patients on combination (PDE5-I + macitentan, a new endothelin receptor antagonist) 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

have generated

Taking into account patients in functional Class III and IV, despite the different severity, the pattern of drug use was quite similar: approximately 13% of patients in both classes were in combination oral therapy, around 26% of patients were in combination therapy (oral + prosta) whereas the percentage of triple combination therapy was higher in Class IV than in Class III (13% vs 7.5%). Overall, the use of parenteral prostanoids as monotherapy or as combination was 34% in class III and only 48% in class IV. Probably the complexity of the use of parenteral prostanoids is a limiting factor for 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 very 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 are not able to have a normalisation of cardiac index on therapy.15

As 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 do not accept a permanent infusion line or an intradermal needle, it makes sense that the 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.

New drugs recently available Two new compounds have been approved in Europe in 2014: macitentan and riociguat. Macitentan is a dual endothelin receptor blocker that was tested in a large 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 new class of drug that acts on the same pathways as PDE5-I, but causes the production of cGMP, even in 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). ●

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

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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 Feb;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.

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