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Unmet needs

New therapies for PAH: a high medical need?

Even though there are a number of approved therapies for PAH, the yearly mortality rate remains high and new treatments that will impact on disease outcome are welcomed

Carmine Dario Vizza MD Pulmonary Hypertension Unit, Department of Cardiovascular and Respiratory Disease, University of Rome La Sapienza, Italy

According to the latest classification of the World Congress on Pulmonary Hypertension, PAH is a group of diseases characterised by a severe form of pre- capillary pulmonary hypertension.1


pathophysiology is a kind of afterload mismatch, thereby the right ventricle, despite an increase in contractility, is not able to deal with the very high afterload2 and the patient develops a severe form of right ventricular dysfunction that leads to congestive heart failure and, ultimately, to death.

In 1980s, the first large registry, that included consecutive patients with primary pulmonary hypertension (now reclassified as idiopathic pulmonary arterial hypertension, and likely including also familial PAH and PAH associated with the use of an anorexigen), showed that patients were diagnosed on average two years from the onset of the symptoms and most in a very advanced stage. In this population, without specific drugs, the median survival was 2.6 years.3


the factors that have an impact on prognosis, the authors found that mortality was related to the haemodynamic impairment, and they validated a formula that was a useful tool for the prediction of survival in naïve patients.

‘Specific’ drugs and impact on disease

A number of randomised controlled trials

(RCTs) have been conducted on patients with PAH – mainly patients with idiopathic PAH and PAH associated with connective tissue disease. Most of these trials had a short double-blind phase (12–16 weeks) and were designed in order to demonstrate an effect on effort capacity evaluated by six-minute walking distance (6MWD) as a surrogate marker of morbi-mortality. The drugs approved could be grouped into the following categories: ● Prostanoids (epoprostenol, treprostinil, iloprost)

● Endothelin receptor antagonists (ERA: bosentan, ambrisentan)

● Phosphodiesterase 5 inhibitors (PDE5-I: sildenafil, tadalafil). These trials were not designed to assess

mortality, but a meta-analysis suggests a significant reduction in mortality for the patients treated with the targeted therapies approved for PAH.4 Despite the positive results of these

trials, it was evident that monotherapy was not a cure for PAH: a single PAH drug was able to decrease the pulmonary vascular resistance by approximately 20% with a concomitant increase of cardiac index of

15% with a trivial effect on mean pulmonary pressure.4

The 2009 European Society of Cardiology/European Respiratory Society guidelines, following the expert consensus and the practical daily approach of the largest referral centres, suggested the use of combination therapy in cases of inadequate clinical response to monotherapy.5

In Nice in 2013, this

or using up-front combination therapy in very advanced cases.

Lesson from registries and observational studies

Data from large registries, which collected data after the introduction of ‘specific’ PAH drugs, and the open label phase of the RCTs suggest that the long-term 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 seen with oral drugs in the open label extension (OLE) of RCTs10

concept was further advanced, with the advice of having an aggressive strategy using combination therapy after four to six months of monotherapy if the patient did not reach specified clinically meaningful goals,6

have generated the wrong


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