Cost effectiveness of first-line oral therapies for pulmonary arterial hypertension: A modelling study

Background: In recent years, a significant number of costly oral therapies have become available for the treatment of pulmonary arterial hypertension (PAH). Funding decisions for these therapies requires weighing up their effectiveness and costs. Objective: The aim of this study was to assess the cost effectiveness of monotherapy with oral PAH-specific therapies versus supportive care as initial therapy for patients with functional class (FC) II and III PAH in Canada. Methods: A cost-utility analysis, from the perspective of a healthcare system and based on a Markov model, was designed to estimate the costs and quality-adjusted life-years (QALYs) associated with bosentan, ambrisentan, riociguat, tadalafil, sildenafil and supportive care for PAH in treatment-naïve patients. Separate analyses were conducted for cohorts of patients commencing therapy at FC II and III PAH. Transition probabilities, based on the relative risk of improving and worsening in FC with treatment versus placebo, were derived from a recent network meta-analysis. Utility values and costs were obtained from published data and clinical expert opinion. Extensive sensitivity analyses were conducted. Results: Analysis suggests that sildenafil is the most cost-effective therapy for PAH in patients with FC II or III. Sildenafil was both the least costly and most effective therapy, thereby dominating all other treatments. Tadalafil was also less costly and more effective than supportive care in FC II and III; however, sildenafil was dominant over tadalafil. Even given the uncertainty within the clinical inputs, the probabilistic sensitivity analysis showed that apart from sildenafil and tadalafil, the other PAH therapies had negligible probability of being the most cost effective. Conclusion: The results show that initiation of therapy with sildenafil is likely the most cost-effective strategy in PAH patients with either FC II or III disease.This research was supported by funds from the Canadian Agency for Drugs and Technologies in Health (CADTH)

Combination therapy with oral treprostinil for pulmonary arterial hypertension. A double-blind placebo-controlled clinical trial

Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown. Objectives: To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy. Methods: In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response. Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56–0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro–brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil–assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12–60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting. Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening. Clinical trial registered with www.clinicaltrials.gov (NCT01560624)

Effect of wood smoke exposure on vascular function and thrombus formation in healthy fire fighters

Background: Myocardial infarction is the leading cause of death in fire fighters and has been linked with exposure to air pollution and fire suppression duties. We therefore investigated the effects of wood smoke exposure on vascular vasomotor and fibrinolytic function, and thrombus formation in healthy fire fighters. Methods: In a double-blind randomized cross-over study, 16 healthy male fire fighters were exposed to wood smoke (~1 mg/m3 particulate matter concentration) or filtered air for one hour during intermittent exercise. Arterial pressure and stiffness were measured before and immediately after exposure, and forearm blood flow was measured during intra-brachial infusion of endothelium-dependent and -independent vasodilators 4–6 hours after exposure. Thrombus formation was assessed using the ex vivo Badimon chamber at 2 hours, and platelet activation was measured using flow cytometry for up to 24 hours after the exposure. Results: Compared to filtered air, exposure to wood smoke increased blood carboxyhaemoglobin concentrations (1.3% versus 0.8%; P &lt; 0.001), but had no effect on arterial pressure, augmentation index or pulse wave velocity (P &gt; 0.05 for all). Whilst there was a dose-dependent increase in forearm blood flow with each vasodilator (P &lt; 0.01 for all), there were no differences in blood flow responses to acetylcholine, sodium nitroprusside or verapamil between exposures (P &gt; 0.05 for all). Following exposure to wood smoke, vasodilatation to bradykinin increased (P = 0.003), but there was no effect on bradykinin-induced tissue-plasminogen activator release, thrombus area or markers of platelet activation (P &gt; 0.05 for all). Conclusions: Wood smoke exposure does not impair vascular vasomotor or fibrinolytic function, or increase thrombus formation in fire fighters. Acute cardiovascular events following fire suppression may be precipitated by exposure to other air pollutants or through other mechanisms, such as strenuous physical exertion and dehydration.Originally included in thesis in manuscript form.</p

Layer-by-Layer Deposited Chitosan/Silk Fibroin Thin Films with Anisotropic Nanofiber Alignment

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Chitosan/silk fibroin multilayer thin films were assembled using layer-by-layer deposition. The resultant multilayer Films contained nanofibers aligned parallel to the dipping direction. Fiber deposition and orientation was enabled uniquely by a judicious choice of solvent and drying conditions and layer-by-layer assembly with chitosan. The deposition of oriented nanotibers was found to be the result of a unique combination of layer-by-layer and Langmuir-Blodgett type processing. Fiber orientation was confirmed by fast Fourier transform (FFT) analysis of optical micrographs and atomic force microscopy (AFM). Bidirectional fiber alignment was realized by rotating the substrate between multilayer deposition steps. Infrared spectroscopy revealed that the silk fibroin adopted the silk II secondary structure in the deposited films. We anticipate that these anisotropic films are able to combine the biocompatibility of a natural polymer system with the mechanical strength or SF, two properties useful in many biological applications including scaffolds suitable for guiding cell attachment and spreading.261189538958Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)National Science Foundation [DMR-0819762]Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)National Science Foundation [DMR-0819762

Bioactive Polyelectrolyte Multilayers: Hyaluronic Acid Mediated B Lymphocyte Adhesion

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)A strategy was developed to produce thin, biopolymer-based polyelectrolyte multilayer films, based on hyaluronic acid and chitosan, that are able to effectively bind B lymphocytes. These films explore CD44-hyaluronate interactions and provide a method to make surface-bound B cell arrays without the need for nonselective covalent chemistry. The rational design of these films using solution deposition variables, such as ionic strength and pH, allows one to maximize and fine tune this binding efficiency ex vivo. This work suggests two important conditions for successfully attaching B cells to hyaluronate-containing polyelectrolyte multilayer films: (1) hyaluronic acid is required for the proposed CD44-mediated binding mechanism, and (2) hyaluronic acid deposition conditions that favor loops and tails, such as low pH and with added salt, result in more available CD44 binding ligands and higher cell binding efficiency. Chitosan-terminated films prepared without NaCl in the deposition solutions and hyaluronic acid-terminated films prepared with salt, both under pH 3.0 assembly conditions, presented a similar high lymphocyte binding efficiency. In the former case, however, the binding strength was weaker due to a significant electrostatic contribution to the binding. Bioactive polyelectrolyte multilayers for selective binding of lymphocytes hold great promise in fields ranging from cell-based biosensors to immune system engineering.11924072414National Science Foundation [DMR-0819762]Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)National Science Foundation [DMR-0819762]CAPES [1101-08-0