Pulmonary arterial hypertension (PAH) is a rare, chronic, progressive disease of various etiologies, which affects the pulmonary vessels. PAH is an orphan disease with an estimated prevalence of 15 patients per 1.000.000 population and an estimated incidence of 2.4 patients per 1.000.000 population per year. The term PAH describes a group of PH patients characterized haemodynamically by the presence of pre-capillary PH, defined by pulmonary artery wedge pressure (PAWP) ≤15 mmHg and a PVR .3 Wood units (WU) in the absence of other causes of precapillary PH such as PH due to lung diseases, CTEPH or other rare diseases. Pathological changes in the pulmonary vasculature eventually lead to right ventricular failure and premature death. Over the last two decades, the European Commission has encouraged the development of drug therapies, specific for the treatment of PAH through tailored regulatory channels, and the payoff for this kind of incentive was the registration of new medicines. Drug therapies, specific to the treatment of PAH interfere with three signaling pathways: prostacyclin, nitric oxide, and endothelin pathway. The latter also represent the possibility of treatment with more than one drug (combination therapy), if interfering with only one signaling pathway (monotherapy) does not achieve the treatment goals in a PAH patient. New clinical research has expanded the knowledge of the efficacy of both new and "old" drug therapies, as not only patients with a newly diagnosed PAH but also patients pre-treated with such therapy have participated in the research. Nevertheless, randomized controlled trials (RCTs), as a source of unbiased information on drug efficacy, are still a lacking source of comparative efficacy information for the prescriber, as there is very little research that would directly compare more than one drug agent with placebo or compare the efficacy of at least two drug agents.
The guidelines for the diagnosis and treatment of pulmonary hypertension of the European Respiratory Society (ERS) and the European Society of Cardiology (ESC) contain, among other, recommendations for the initiation of drug therapy, specific for the treatment of PAH, either monotherapy or combination therapy, following a complex diagnostic algorithm (initial or re-evaluation) of the patient's medical condition (hereinafter referred to as the Guidelines). The quality of the evidence and its source on which the recommendations for each group of drug therapy are based, is comparable (ie. at least one randomized clinical trial), but it does not provide data on the comparative-effectiveness. For this purpose, we conducted the first research and have systematically reviewed published randomized clinical trial data and developed a Bayesian network meta-analysis (NMA) model to evaluate the comparative effectiveness of PAH-specific drugs in treatment naive patients. Randomized controlled trials on PAH-specific drug therapies were searched and a Bayesian network meta-analysis was performed. The 6-minute walking distance (6MWD) and all-cause mortality were efficacy outcomes, whereas discontinuation due to adverse events was a safety-related outcome. Analysis included 3.713 patients from 21 trials, reporting on the following drugs ambrisentan, bosentan, beraprost, epoprostenol, iloprost, riociguat, sildenafil, tadalafil and treprostinil. Combination of ambrisentan and tadalafil demonstrated the greatest impact on 6MWD, followed by epoprostenol and i.v. treprostinil (high dose intervention). A favorable effect of comparable size for the outcome all-cause mortality was demonstrated by epoprostenol, ERA, i.v. treprostinil (high dose intervention) and iloprost. None of the interventions showed statistical significance for the outcome all-cause mortality and discontinuation of treatment due to adverse events. In another research, the comparative effectiveness of PAH-specific drugs as add-on therapies in patients was evaluated by the Bayesian NMA. The 6MWD and all-cause mortality were the efficacy outcomes. Another outcome, associated with safety of drugs, was evaluated (discontinuation due to adverse events). Sixteen clinical trials were eligible for analysis with total of 4.112 patients. For the outcome 6MWD, data was collected on patients, who were pre-treated with drug therapy, specific for the treatment of PAH, and identified six different background pharmacotherapies. In general, patients receiving combination therapy (sequential add-on therapy) walked a longer distance within six minutes compared to patients who continued to receive only background therapy during the study. The study found that in patients already receiving endothelin receptor antagonists (ERAs), tadalafil had the greatest effect on the outcome of 6MWD over other interventions. Patients on background therapy with PDE5i, who were sequentially given bosentan or macitentan (sequential add-on therapy), walked longest distances within six minutes, when compared to the other interventions. In general, combinations of interventions with an existing PAH-specific drug therapy have shown a patient-favorable trend for the outcome all-cause mortality but have more frequently led to treatment discontinuation due to adverse events; these differences were not statistically significant. In the last research, we have evaluated the cost-effectiveness of PAH-specific drugs available in the Slovenian market in July 2019. We considered the results of the first research for the 6MWD outcome. Based on the Markov model we established that compared to patients on supportive care, none of the strategies were cost-effective with respect to the limit value for ICER in Slovenia (25.000 EUR/QALYg). We have demonstrated that sildenafil treatment was generally the most affordable treatment compared to other treatment strategies (ambrisentan, bosentan, epoprostenol, iloprost, ambrisentan and tadalafil combination, riociguat, tadalafil, s.c. and i.v. treprostinil), whereas i.v. treprostinil has proven to be the most expensive treatment strategy.The results of our research support the recommendations of the current PAH treatment Guidelines and provide additional guidance to prescribers in deciding on a PAH-specific drug, either for initial treatment or add-on therapy, by quantitatively evaluating differences between them.
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