This page contains a Flash digital edition of a book.
Need for new therapies


Why is there still a high need for new therapies in PAH?


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


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 The 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


Analysing 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


In past years, 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 as a surrogate marker of morbi-mortality. The drugs approved could be grouped into three categories: ● prostanoids (epoprostenol, treprostinil, iloprost)


● endothelin receptor antagonists (ERA: bosentan, ambrisentan)


● phosphodiesterase 5 inhibitors (PDE5-I: sildenafil, tadalafil). These trials were not designed for the assessment of mortality, but a meta- analysis suggests a significant reduction in mortality.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 of approximately 20%


with a concomitant increase of cardiac index of 15% with a trivial effect on mean pulmonary pressure.4


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


In the last world meeting,


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


held in Nice in 2013, this 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


13


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44