Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a progressive increase in pulmonary vascular resistance, ultimately leading to right heart failure and death. Throughout the past 20 years, numerous specific pharmacologic agents, including phosphodiesterase-5 inhibitors, endothelin receptor antagonists, prostaglandins, and more recently, soluble guanylate cyclase stimulators and selective IP prostacyclin receptor agonist, have emerged for the treatment of PAH. Early clinical trials were typically of short-term duration, comparing the effects of PAH-targeted therapies versus placebo and using exercise tolerance as the primary endpoint in most trials. A meta-analysis of these trials documented a reduction in short-term mortality of ∼40% with monotherapy. More recently, we have witnessed a progressive shift in PAH study designs using longer event-driven trials comparing the effects of upfront and sequential combination therapy on clinical worsening that is perceived as a more clinically relevant outcome measure. Recent meta-analyses also documented that combination therapy significantly reduced the risk of clinical worsening by ∼35% compared with monotherapy alone. In this review article, we will discuss the evolution of treatments and clinical trial design in the field of PAH over the past decades with a special focus on combination therapy and its current role in the management of PAH. We will also detail unresolved questions regarding the future of PAH patients' care and the challenges of future clinical trials.

https://journals.sagepub.com/doi/pdf/10.1177/2045893217710639

Combination therapy in pulmonary arterial hypertension: recent accomplishments and future challenges.

April 16, 2019 1861 Bradley A. Maron, MD John J. Ryan, MD, MB, BCh, BAO P ulmonary hypertension (PH) is an abnormal elevation in pulmonary arterial blood pressure. Regardless of the underlying cause, PH is an independent risk factor for adverse outcome. Pulmonary arterial hypertension (PAH) is a rare form of PH, which is characterized by plexogenic vascular remodeling. Although therapeutic advances have been made in PAH, currently there are no approved therapies for PH from left-sided heart disease (World Health Organization [WHO] group 2) or chronic hypoxic lung disease (WHO group 3) PH. The importance of this treatment gap is amplified when considering that the prevalence of WHO group 2 or 3 is >2500-fold greater than PAH. Furthermore, the elevated pulmonary artery pressure in patients with WHO group 2 and 3 PH corresponds to an adjusted mortality risk increase of ≥50%.1 Perhaps it is for these reasons that significant emphasis has been placed on the potential for PAH therapies to modulate clinical risk in other forms of PH. Specifically, the efficacy of endothelin receptor antagonists and phosphodiesterase type V inhibitors has been assessed in numerous observational studies and some prospective clinical trials involving patients with WHO group 2 or 3 PH (Table). Although data from some small studies may appear encouraging, overall, these data have prompted a class III recommendation (treatment is not useful or effective, and may be harmful) from international expert consensus panels for the use of PAH therapy in patients with WHO group 2 or 3 PH.2 Despite these strong recommendations against using PAH therapies in non-PAH forms of PH, a troubling pattern suggesting the indiscriminant off-label use of PAH therapies has emerged in these populations. In the Giessen PH registry, published in 2017, from one of the world’s leading PH centers, 40% of patients referred to the center with a diagnosis of WHO group 2 PH were on PAH therapies. In patients referred for WHO group 3 PH, 78% were on PAH therapies.3 In addition, a recently published population-based cohort study in Ontario, Canada showed that phosphodiesterase type V inhibitor was cumulatively prescribed for more patients with WHO group 2 PH than patients with PAH, and the use of phosphodiesterase type V inhibitors and endothelin receptor antagonists continues to rise in this cohort.4 It is particularly sobering that, in both of these studies, the prognosis was poorer in patients with WHO group 2 and WHO group 3 PH than in patients with PAH. Although speculative, it is worth considering whether this is attributable, at least in part, to the frequent use of contraindicated PAH medicines. These medicines affect systemic vascular beds as well, which may result in adverse hemodynamic consequences. A number of potential reasons may account for widespread use of PAH treatments in patients with WHO group 2 or 3 PH. First, alternative pharmacotherapies with proven benefit specific to the lung circulation do not exist. Thus, it may be perceived as tempting by (well-intended) practitioners to prescribe PAH therapies in an effort to mitigate PH-associated clinical risk. Second, anecdotal experience © 2019 American Heart Association, Inc. ON MY MIND

A Concerning Trend for Patients With Pulmonary Hypertension in the Era of Evidence-Based Medicine.

Epigenetics is an emerging field of research and clinical trials in cancer therapy that also has applications for pulmonary arterial hypertension (PAH), as there is evidence that epigenetic control of gene expression plays a significant role in PAH. The three types of epigenetic modification include DNA methylation, histone modification, and RNA interference. All three have been shown to be involved in the development of PAH. Currently, the enzymes that perform these modifications are the primary targets of neoplastic therapy. These targets are starting to be explored for therapies in PAH, mostly in animal models. In this review we summarize the basics of each type of epigenetic modification and the known sites and molecules involved in PAH, as well as current targets and prospects for clinical trials.

https://journals.sagepub.com/doi/pdf/10.1086/687765

The emerging role of epigenetics in pulmonary arterial hypertension: an important avenue for clinical trials (2015 Grover Conference Series).

The field of pulmonary vascular disease remains a rapidly growing area of research. In 2014, investigators discovered new genetic determinants of pulmonary hypertension (PH) risk and described novel molecular mechanisms of disease pathogenesis. New studies have provided significant insights into our understanding of disease complexity, highlighting critical roles of cellular metabolism, inflammation, and regulatory function of microRNAs that could lead to development of novel targeted therapeutics (1). Studies of the prediction of outcomes in pulmonary vascular disease and venous thromboembolism could lead to more efficient and effective management strategies. This review provides a brief summary of the many scientific accomplishments in the field of pulmonary vascular disease during the past year.

/pdf/update-in-pulmonary-vascular-disease-2015-41g2iswavp.pdf

Update in Pulmonary Vascular Disease 2015

See Article by Wijeratne et al. 

Pulmonary hypertension (PH) is a heterogeneous syndrome characterized by elevated pulmonary pressures. Although often suspected based on symptoms of dyspnea and elevated estimates of pulmonary arterial systolic pressures on echocardiogram, PH can only be diagnosed by right heart catheterization demonstrating a mean pulmonary artery pressure ≥25 mm Hg. Clinically, PH can result from various comorbid conditions, including underlying cardiac, pulmonary, thromboembolic, and miscellaneous diseases. PH in the absence of these comorbid conditions constitutes a small subset of PH, known as pulmonary arterial hypertension (PAH).

Over the last several years, determining the incidence and prevalence of PH in population-based studies has proven challenging, in part, because of the lack of specificity of diagnosis codes commonly used in reimbursement system databases. These codes do not align with the current classification system and thus are unable to accurately distinguish disease phenotypes. In addition, proper classification of PH, according to guideline recommendations, requires not only a high clinical suspicion but also extensive targeted testing, which is often not completed in clinical practice.1 As shown in prior studies, (1) only a minority (<6%) of patients with a diagnosis of PAH complete the entire recommended testing algorithm and (2) nearly one third of patients referred to a tertiary center for PH have a change in their diagnosis after completing the entire workup.2,3 Thus, the clinical diagnosis of PH at both the …

The Growing Burden of Pulmonary Hypertension in the Modern Era: A Zebra No More?

Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance caused by remodeling of distal pulmonary arterioles that occurs as a consequence of a complex interplay between molecular and genetic factors.1 The incidence of PAH is estimated at 7 to 10 individuals per million people,2 with a prevalence of ≤50 cases per million.3 The most recent World Health Organization clinical classification of pulmonary hypertension4 distinguishes group 1 pulmonary hypertension from pulmonary vascular disease related to lung disease, left atrial hypertension or venothromboemoblism by including PAH in association with anorexigen exposure, connective tissue disease, HIV, or portal hypertension, among other specific comorbidities. In turn, idiopathic PAH is diagnosed in patients without a hereditary or other identifiable cause of PAH. Because of the diversity of diseases implicated in the pathogenesis of PAH, an evolving goal among pulmonary hypertension care centers5 is pathophenotyping patients with pulmonary vascular disease to calibrate suitable therapy.6

Before PAH-specific drug treatment availability, diagnosing PAH functioned principally to inform (a dismal) patient prognosis as treatment was relegated primarily to the careful use of warfarin, digoxin, diuretics, and oxygen.7 The discovery of calcium channel blocker efficacy in this disease was a breakthrough, but this therapy was considered to be appropriate for only a minority of patients, which remains true today.8,9 However, subsequent seminal discoveries of key signaling pathways implicated in the pathogenesis of PAH in some patients exposed for the first time disease-specific treatment targets.10 In turn, results from conventional randomized clinical trials (RCTs) validated their translational relevance and introduced 4 novel drug classes to clinical practice that improve incrementally quality of life or longevity in patients with PAH.8,11–17 Even in the era of contemporary PAH therapies, however, progressive heart failure and diminished …

Building the Case for Novel Clinical Trials in Pulmonary Arterial Hypertension

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Building the Case for Novel Clinical Trials in Pulmonary Arterial Hypertension