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Nazzareno Galiè, MD, Institute of Cardiology, University of Bologna
Pulmonary Arterial Hypertension: Where Are We and Where Are We Going?
The progress made in the medical treatment of pulmonary arterial hypertension (PAH) in the past 15 years is unique, in particular for a rare and severe condition: 27 randomized controlled trials (RCTs) have been completed and more than 10 are either ongoing or planned; 8 drugs belonging to 3 pharmacological classes (endothelin receptor antagonists, phosphodiesterase type-5 inhibitors, and prostanoids) and administered by 4 different routes (oral, inhaled, subcutaneous, and intravenous) have been currently approved by the Food and Drug Administration and by the European Medicines Agency. A meta-analysis including 23 published RCTs has shown a 43% reduction in mortality of PAH patients treated with the approved compounds as compared to patients randomized to placebo after 14 weeks of average treatment period. In addition, reductions in the hospitalization rate and improvements of functional and exercise capacity, hemodynamics, and quality of life were also observed. Despite these results, the current treatment strategy remains inadequate because the mortality rate continues to be high and the functional and hemodynamic impairments are still extensive in many patients. The specific drugs approved for PAH are able to slow the progression of the disease, but cannot be considered a cure for the majority of the patients.
The current and future plans devoted to increase our ability to treat PAH are facing new challenges which require scientific creativity and new research strategies.
Paradoxically, there is no shortage of novel candidate therapies for PAH including drugs, gene, and stem cell approaches or combinations of therapies. New drugs with ongoing or planned Phase III studies include oral compounds such as NO-independent stimulators and activators of cGMP, tyrosine kinase inhibitors (platelet-derived growth factor inhibitors), tissue-specific dual endothelin receptor antagonists, prostanoids and non-prostanoid prostacyclin receptor agonists, and inhaled vasoactive intestinal peptide.
The real current difficulty is to identify the most efficient development plan and the more appropriate study designs to demonstrate the efficacy-to-safety ratio of novel therapies in PAH patients. The replication of the traditional Phase III strategy (placebo-controlled design in treatment-naïve patients, exercise capacity as primary end point assessed after 3 to 4 months of treatment) appears not suitable in a changing clinical environment.
It appears not any more ethical to include treatment-naïve patients in placebo-controlled studies in countries with available therapies for PAH. The efficacy-to-safety ratio of the new compounds needs to be demonstrated on top of the available approved drugs for PAH to avoid any delay in the initiation of effective medications. Therefore, future studies with new drugs will be exclusively "combination studies" and "placebo patients" will continue to be treated with traditional compounds. This obviously will reduce our ability to demonstrate a difference with the "actively treated group," in particular if exercise capacity is the primary end point. This phenomenon has been observed in the more recent completed RCTs in which the treatment effect on the six-minute walk test has been ranging from 15 to 25 meters as compared to the traditional 35 to 55 meters observed in the historical monotherapy studies. A possible solution is the adoption of different primary endpoints acceptable by regulatory agencies such as the combination of morbidity and mortality. Also, this approach presents challenges including the objective definition of the composite endpoint (death, hospitalization, disease progression), the study sample size (event-based vs pre-specified duration), and the lack of precise knowledge of the rate of events with the available treatments. Additional problems of multicenter and international studies are linked to the country-related heterogeneity of PAH-approved medication, of attitudes for hospitalization, and of availability of expert centers.
This extensive list of challenges cannot be considered an excuse to avoid our involvement in current and future RCTs. The traditional enthusiasm and collaboration of the PAH community is currently required to continue the difficult path toward additional advances in this complex field.
Address for reprints and other correspondence: nazzareno.galie@unibo.it