Choices of pharmacologic therapies for pulmonary arterial hypertension (PAH) are ideally guided by high-level evidence. The objective of this guideline is to provide clinicians advice regarding ...pharmacologic therapy for adult patients with PAH as informed by available evidence.
This guideline was based on systematic reviews of English language evidence published between 1990 and November 2013, identified using the MEDLINE and Cochrane Library databases. The strength of available evidence was graded using the Grades of Recommendations, Assessment, Development, and Evaluation methodology. Guideline recommendations, or consensus statements when available evidence was insufficient to support recommendations, were developed using a modified Delphi technique to achieve consensus.
Available evidence is limited in its ability to support high-level recommendations. Therefore, we drafted consensus statements to address many clinical questions regarding pharmacotherapy for patients with PAH. A total of 79 recommendations or consensus statements were adopted and graded.
Clinical decisions regarding pharmacotherapy for PAH should be guided by high-level recommendations when sufficient evidence is available. Absent higher level evidence, consensus statements based upon available information must be used. Further studies are needed to address the gaps in available knowledge regarding optimal pharmacotherapy for PAH.
Pulmonary arterial hypertension (PAH) is a progressive, fatal disease. Current prognostic models are not ideal, and identifying more accurate prognostic variables is needed. The objective of this ...study was to evaluate the relative prognostic value of the right atrial pressure/pulmonary artery wedge pressure (RAP/PAWP) ratio in PAH patients. We hypothesized that the RAP/PAWP ratio is more predictive of survival than any of the other measured or calculated hemodynamic variables.
We performed a secondary analysis of a PAH cohort (Cohort 1) and validated our results in a separate cohort (Cohort 2). Cohort 1 included primarily patients enrolled in prospective, short-term, randomized clinical trials and subsequently followed long term. Cohort 2 included patients prospectively enrolled in a PAH registry at a tertiary PAH referral center.
Cohort 1 (n = 847) and Cohort 2 (n = 697) had a mean age of 47 and 54 years, respectively. Most were female (78% and 73%, respectively), Caucasian (83% and 82%), with advanced functional class disease status (New York Heart Association Functional Class III/IV 85% and 68%) and with significantly elevated hemodynamics (mean RAP/PAWP ratio: 1.2 and 1.0; pulmonary vascular resistance: 13.5 and 9.4 Wood units). RAP/PAWP ratio indicated a 1-year hazard ratio of 1.44 (p = 0.0001) and 1.35, respectively (p < 0.0001), and was the most consistently predictive hemodynamic variable across the 2 cohorts. These results remain valid even when adjusted for other covariables in multivariable regression models.
The RAP/PAWP ratio is a more specific predictor of survival than any other hemodynamic variable, and we recommend that it be used in clinical prognostication and PAH predictive models.
Pulmonary arterial hypertension (PAH) is a progressively fatal disease, and the goal in treatment is to prevent disease progression. The standard of care often involves medications from multiple ...therapeutic classes, and there has been significant interest both in the choice of agent as well as the timing of initiation. There is a growing body of support for starting multiple medications at the time of diagnosis, or ‘upfront ’, rather than using sequential addition to prevent clinical deterioration.
Although previous literature suggests that interleukin (IL)-13, a T-helper type 2 cell effector cytokine, might be involved in the pathogenesis of pulmonary hypertension (PH), direct proof is ...lacking. Furthermore, a potential mechanism underlying IL-13-induced PH has never been explored. This study's goal was to investigate the role and mechanism of IL-13 in the pathogenesis of PH. Lung-specific IL-13-overexpressing transgenic (Tg) mice were examined for hemodynamic changes and pulmonary vascular remodeling. IL-13 Tg mice spontaneously developed PH phenotype by the age of 2 mo with increased expression and activity of arginase 2 (Arg2). The role of Arg2 in the development of IL-13-stimulated PH was further investigated using Arg2 and IL-13 receptor α2 (Rα2) null mutant mice and the small-interfering RNA (siRNA)-silencing approach in vivo and in vitro, respectively. IL-13-stimulated medial thickening of pulmonary arteries and right ventricle systolic pressure were significantly decreased in the IL-13 Tg mice with Arg2 null mutation. On the other hand, the production of nitric oxide was further increased in the lungs of these mice. In our in vitro evaluations, the recombinant IL-13 treatment significantly enhanced the proliferation of human pulmonary artery smooth muscle cells in an Arg2-dependent manner. The IL-13-stimulated cellular proliferation and the expression of Arg2 in hpaSMC were markedly decreased with IL-13Rα2 siRNA silencing. Our studies demonstrate that IL-13 contributes to the development of PH via an IL-13Rα2-Arg2-dependent pathway. The intervention of this pathway could be a potential therapeutic target in pulmonary arterial hypertension.
Chronic thromboembolic pulmonary hypertension is one of the few forms of pulmonary hypertension that is surgically curable. It is likely underdiagnosed and must be considered in every patient ...presenting with pulmonary hypertension to avoid missing the opportunity to cure these patients. This article discusses the epidemiology, risk factors, natural history, diagnosis, and preoperative evaluation of patients with this disorder. Also covered are putative mechanisms for the conversion of acute emboli into fibrosed thrombembolic residua. Mechanical obstruction of the central pulmonary vasculature is rarely the sole cause of the pulmonary hypertension, and a discussion of the small vessel arteriopathy present in these patients is offered. Technical aspects of pulmonary endartectomy and the data supporting its role are discussed, as are the limited data on pulmonary arterial hypertension specific medical therapies for patients deemed noncandidates for the operation.
Macitentan is the most recently approved dual endothelin-receptor antagonist (ERA) for the treatment of symptomatic pulmonary arterial hypertension. Compared to other available ERAs, it demonstrates ...superior receptor-binding properties, with consequently improved tissue penetration, and a longer duration of action allowing for once-daily dosing. It has a favorable adverse-effect profile, with notably no demonstrable increase in the risk of hepatotoxicity or peripheral edema, but like other ERAs, it is potentially limited by significant anemia. Phase I data have demonstrated a favorable drug-drug interaction profile and no need for dose adjustment with hepatic and renal impairment. In the pivotal SERAPHIN study, treatment of symptomatic pulmonary arterial hypertension patients with macitentan led to statistically significant improvements in functional class, exercise tolerance, and hemodynamic parameters, in addition to a reduction in morbidity in an event-driven long-term trial.
Accurate diagnosis of pulmonary arterial hypertension can be challenging and often requires a high index of clinical suspicion. Use of a variety of noninvasive tests can help define the population of ...patients in whom invasive cardiac catheterization should be pursued. An understanding of the historical, physical exam, electrocardiographic, radiographic, and echocardiographic clues in the diagnosis is important. A ventilation-perfusion scan and careful assessment for left-to-right shunting are mandatory to avoid missing reasons for pulmonary hypertension that may require nonpharmacologic management. Right heart, and sometimes concomitant left heart, catheterization is required to establish the diagnosis and distinguish pulmonary arterial from pulmonary venous hypertension.
Recent advances in pulmonary arterial hypertension (PAH) research have created a new era of PAH-specific therapies. Although these therapeutics have revolutionized PAH therapy, their innovation was ...predated by supportive but nonspecific medical therapies adapted from their use in more common cardiopulmonary diseases. These therapies include oxygen therapy, diuretics, digoxin, anticoagulation, and high-dose calcium channel blockers. Expert opinion continues to support the use of adjunct therapies based on current pathologic understandings of PAH combined with some evidence extrapolated from small studies. This article discusses why these therapies continue to play an important role in the treatment of patients with PAH.
Summary Various treatments approved by the United States Food and Drug Administration for the management of pulmonary arterial hypertension (PAH) target three of the many pathways implicated in the ...development of PAH: prostacyclin-, endothelin-1 (ET-1)-, and nitric oxide-mediated pathways. The objectives of this manuscript are to provide background information on the role of ET-1 in the pathogenesis of PAH, to provide theoretical considerations for the advantages and disadvantages of dual vs single endothelin receptor antagonists (ERAs) for the management of PAH, and to describe the clinical study results from randomized, double-blind, placebo-controlled trials for the various ERAs. ET receptors (ETA and ETB ) have different densities and distributions throughout the body and are dynamically regulated, such that blockade of ETA and ETB receptors may have different results in normal vs pathological conditions. Although differences in biological effects can be found in studies of isolated cells, blood vessels and animal models, clinical treatment studies have not identified clear differences in efficacy among the various ERAs. The main differences appear to be in safety profiles, with a greater frequency of serum liver function abnormalities occurring with the available dual ETA /ETB antagonist, and possibly higher rates of peripheral edema noted with selective ETA agents. Head-to-head studies will be necessary to resolve the question of whether single vs dual blockade produces better clinical results with fewer side effects in patients with PAH.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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