Trials In Pulmonary Hypertension Research Articles

Novel composite clinical endpoints and risk scores used in clinical trials in pulmonary arterial hypertension.

This manuscript on endpoints incorporates the broad experience of members of Pulmonary Vascular Research Institute’s Innovative Drug Development Initiative as an open debate platform for academia, the pharmaceutical industry and regulatory experts surrounding the future design of clinical trials in pulmonary hypertension. It reviews our current understanding of endpoints used in phase 2 and 3 trials for pulmonary hypertension and discusses in detail the value of newer approaches. These include the roles of composite endpoints and how these can be developed and validated. The newer concept of risk analysis is also discussed, including how such risk scores might be utilised as endpoints in clinical trials.

Clinical trial design in phase 2 and 3 trials for pulmonary hypertension.

This article on clinical trial design incorporates the broad experience of members of the Pulmonary Vascular Research Institute’s (PVRI) Innovative Drug Development Initiative (IDDI) as an open debate platform for academia, the pharmaceutical industry and regulatory experts surrounding the future design of clinical trials in pulmonary hypertension. It is increasingly clear that the design of phase 2 and 3 trials in pulmonary hypertension will have to diversify from the traditional randomised double-blind design, given the anticipated need to trial novel therapeutic approaches in the immediate future. This article reviews a wide range of differing approaches and places these into context within the field of pulmonary hypertension.

Repurposing of medications for pulmonary arterial hypertension.

This manuscript on drug repurposing incorporates the broad experience of members of the Pulmonary Vascular Research Institute’s Innovative Drug Development Initiative as an open debate platform for academia, the pharmaceutical industry and regulatory experts surrounding the future design of clinical trials in pulmonary hypertension. Drug repurposing, use of a drug in a disease for which it was not originally developed, in pulmonary arterial hypertension has been a remarkable success story, as highlighted by positive large phase 3 clinical trials using epoprostenol, bosentan, iloprost, and sildenafil. Despite the availability of multiple therapies for pulmonary arterial hypertension, mortality rates have modestly changed. Moreover, pulmonary arterial hypertension patients are highly symptomatic and frequently end up on parental therapy and lung transplant waiting lists. Therefore, an unmet need for new treatments exists and drug repurposing may be an important avenue to address this problem.

Memos

Deborah Jo Levine, MDProfessor of Medicine, Pulmonary and Critical Care, Medical Director Lung Transplantation, Director of Pulmonary Hypertension, University of Texas Health Science Center San Antonio, San Antonio, TXIt is a great pleasure to introduce this issue's Guest Editors of Advances in Pulmonary Hypertension. Drs Mark Nicolls and Marc Humbert lead an elite group of experts in a timely compilation on drug development and clinical trials in pulmonary hypertension (PH).The opening article by Drs Martin Wilkins and Marlene Rabinovitch eloquently illustrates novel exciting targets for drug development. These targets are based on the understanding of the mechanisms driving pulmonary arterial hypertension (PAH). They discuss this “mechanism-driven” focused approach to developing new therapies. The authors detail many of these targets and where they are in the pathway of development.Dr Tsukasa Shimauchi and colleagues follow with an important discussion of the challenges and limitations in the design of preclinical PH trials. They emphasize the need for the rigorous assessment of study design from each part of the development, including researchers, peer reviewers, funding agencies, and academic institutions, among others.This is followed by the expert roundtable discussion focused on the topics of drug development, clinical trials, and the importance of publishing of negative trial results. Drs Marc Humbert, Mark Nicolls, Norman Stockbridge, and Roham Zamanian examine the importance and the opportunities that a negative clinical trial provides to all of us as a community.In our “Ask the Expert” column, Drs Christine Garnett and Norman Stock-bridge, both experts on trial regulation from the US Food and Drug Administration, discuss the challenges of finding new therapies with a novel mechanism of action, of improving the efficiency of clinical trials, and of developing endpoints that reflect benefits in patient symptoms and quality of life.We conclude this issue with a poignant discussion by Lena Bolivar. Lena, a patient who was diagnosed with PAH in 2011, takes us through her experience, starting with diagnosis of PAH, initiating therapy, going through a clinical trial, and ultimately receiving a heart-lung transplant. It is because of Lena and all of our patients that we as a community continue to work together to define new targets and develop improved therapies for the present and the future.Congratulations and thank you, Drs Nichols and Humbert, for an exceptional issue.Mark Nicolls, MD and Marc Humbert, MDProfessor of Medicine, Stanford University of Medicine, Stanford, CA and Professor of Medicine, Paris-Saclay University, Paris, FranceThis issue of Advances in Pulmonary Hypertension addresses the challenges and opportunities of drug development for pulmonary arterial hypertension (PAH) patients. As combinational vasodilator regimens continue to improve the lives of PAH patients, there is growing interest in also targeting novel pathways implicated in disease pathogenesis. To this end, Drs Martin Wilkins and Marlene Rabinovitch summarize exciting new disease pathways which show promise as therapeutic targets. Enthusiasm for these emerging therapies are linked to high-impact preclinical publications. In a review that highlights the importance of experimental rigor, Dr Tsukasa Shimauchi and colleagues make a compelling call for strong study design to optimize the likelihood of subsequent successful clinical trials. However, even trials that fail to show benefit for a drug can educate the PAH community. In a wide-ranging roundtable discussion, we moderate a discussion with Drs Roham Zamanian and Norman Stockbridge to address the merits of publishing negative trials, as well as the current obstacles for developing new drug treatments. Lena Bolivar, a PAH patient, then describes what it's like to participate in a clinical trial. Finally, this compendium of articles concludes with a perspective written by two US Food and Drug Administration leaders who discuss strategies for improving trial design, primary endpoints, disease biomarkers, and pediatric care.

Soluble Guanylate Cyclase Activators Increase cGMP Expression and Improve Vascular Function and Placental Ischemia‐Induced Hypertension

Preeclampsia (PE) is a pregnancy specific disorder associated with maternal hypertension and endothelial dysfunction caused by the release of anti‐angiogenic and pro‐inflammatory factors from the ischemic placenta. In addition, nitric oxide (NO), which typically binds to soluble guanylate cyclase (sGC), and synthesizes cGMP, to facilitate vasodilation, is depleted in PE and contributes to vascular dysfunction. A novel class of drug, sGC activators, which are in clinical trials for pulmonary hypertension and heart failure, have been shown to bind to the sGC molecule and increase cGMP activity independently of NO. However, the therapeutic potential of sGC activators during PE is not known. We tested the hypothesis that sGC activators attenuate blood pressure in a placental ischemic rat model of PE by increasing cGMP production and improving vascular function. Sprague‐Dawley rats underwent Sham or RUPP (Reduced Uterine Perfusion Pressure) surgery on gestational day (GD) 14, where silver clips were placed on the abdominal aorta and branches of the ovarian artery to induce placental ischemia. Animals were then placed on placebo (P) or sGC activator (sGC‐A, 16 ppm, BAY 60‐2770) ‐supplemented diets, ad libitum, from GD14–19. On GD19, blood pressure was measured via indwelling catheter and uterine arteries were harvested to determine endothelium‐dependent vasorelaxation and cGMP expression. To determine the effect of sGC activator treatment on vascular function, uterine arteries from placebo or sGC activator‐supplemented rats were mounted on a wire myograph and pre‐constricted, followed by endothelium‐dependent vasorelaxation. A subset of uterine arteries from these rats were also prepared to determine expression of cGMP. RUPP surgery significantly increased mean arterial blood pressure (Sham+P, n=20, 105±9 mmHg; RUPP+P, n=19, 126±13 mmHg; P<0.05), and this was attenuated by treatment with the sGC activator (RUPP+sGC‐A, n=11, 107±8 mmHg; P<0.05). RUPP surgery induced endothelial dysfunction in uterine arteries (% relaxation, Sham+P, n=6, 92±2 %; RUPP+P, n=5, 34±12%, P<0.05), which was restored in the sGC activator treated group (RUPP+sGC‐A, n=5, 103±2%, P<0.05). Finally, cGMP was reduced in uterine arteries of RUPP‐operated animals (Sham+P, n=3, 0.11±0.009 pmol/mg; RUPP+P, n=3, 0.033±0.009 pmol/mg, P<0.05); however, sGC activation significantly increased cGMP production in the treated group (RUPP+sGC‐A, n=3, 0.127±0.013 pmol/mg, P<0.05). The results of this study demonstrate that activating sGC can reduce blood pressure by restoring cGMP production and improving vascular function in the RUPP rat. In conclusion, these findings suggest there could be a therapeutic potential for treating PE with sGC activators.Support or Funding InformationThis research was supported by the American Heart Association (18POST33990293) and the National Institutes of Health (P01HL051971, P20GM104357).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Editorial introductions

Editorial introductions

Standards and Methodological Rigor in Pulmonary Arterial Hypertension Preclinical and Translational Research.

Despite advances in our understanding of the pathophysiology and the management of pulmonary arterial hypertension (PAH), significant therapeutic gaps remain for this devastating disease. Yet, few innovative therapies beyond the traditional pathways of endothelial dysfunction have reached clinical trial phases in PAH. Although there are inherent limitations of the currently available models of PAH, the leaky pipeline of innovative therapies relates, in part, to flawed preclinical research methodology, including lack of rigour in trial design, incomplete invasive hemodynamic assessment, and lack of careful translational studies that replicate randomized controlled trials in humans with attention to adverse effects and benefits. Rigorous methodology should include the use of prespecified eligibility criteria, sample sizes that permit valid statistical analysis, randomization, blinded assessment of standardized outcomes, and transparent reporting of results. Better design and implementation of preclinical studies can minimize inherent flaws in the models of PAH, reduce the risk of bias, and enhance external validity and our ability to distinguish truly promising therapies form many false-positive or overstated leads. Ideally, preclinical studies should use advanced imaging, study several preclinical pulmonary hypertension models, or correlate rodent and human findings and consider the fate of the right ventricle, which is the major determinant of prognosis in human PAH. Although these principles are widely endorsed, empirical evidence suggests that such rigor is often lacking in pulmonary hypertension preclinical research. The present article discusses the pitfalls in the design of preclinical pulmonary hypertension trials and discusses opportunities to create preclinical trials with improved predictive value in guiding early-phase drug development in patients with PAH, which will need support not only from researchers, peer reviewers, and editors but also from academic institutions, funding agencies, and animal ethics authorities.

Characteristics of pediatric pulmonary hypertension trials registered on ClinicalTrials.gov.

The investigation of pediatric pulmonary hypertension (PH) drugs has been identified as a high priority by the United States National Institutes of Health (NIH). Studying pediatric PH is challenging due to the rare and heterogeneous nature of the disease. We sought to define the pediatric PH clinical trials landscape, to evaluate areas of trial success or failure, and to identify potential obstacles to the study of pediatric PH drugs. Interventional pediatric (ages 0–17 years) PH trials registered on ClinicalTrials.gov from June 2005 through December 2014 were analyzed. There were 45 pediatric PH trials registered during the study period. Median (IQR) projected trial enrollment was 40 (24–63), with seven trials (16%) targeting > 100 participants. Industry was the most common trial sponsor (n = 23, 50%), with only two (4.4%) NIH-sponsored trials. Phosphodiesterase inhibitors were the most frequently studied drug (n = 18, 39%). Single group study designs were used in 44% (n = 20) with an active comparator (parallel, factorial, or cross-over designs) in 25 trials, including 22 with randomization and ten that were double-blinded. Study outcomes varied markedly with inconsistent use of known surrogate and composite endpoints. One-third of trials (n = 15, 33%) were terminated, predominantly due to poor participant enrollment. Of the 17 completed trials, 11 had published results and only three efficacy trials met their primary endpoint. There are unique challenges to drug development in pediatric PH, including enrolling patients, identifying appropriate study endpoints, and conducting randomized, controlled, double-blind trials where the likelihood of meeting the study endpoint is optimized.

Landmark trials in pulmonary hypertension and pulmonary embolism

Landmark trials in pulmonary hypertension and pulmonary embolism

The changing paradigm in pulmonary hypertension trials: longer duration, new endpoints.

Approved therapies for pulmonary arterial hypertension (PAH) currently consist of 12 agents, the majority of which were approved following short-term randomized clinical trials using change in 6 minute walk distance (6MWD) as the primary outcome. However, there is growing concern that significant improvements in this measure do not translate into morbidity and mortality benefits. As a result of data questioning the association between improvements in 6 minute walk distance and improvements in outcome, PAH clinical trial design is increasingly utilizing morbidity and mortality events as a composite primary outcome. This concept was recently illustrated in the published phase 3 trial of macitentan versus placebo, during which the clinical worsening event rate was decreased by 45%. Several additional unpublished trials have been similarly designed, all of which will require extended blinded treatment time in order to accrue sufficient event rates. The definition of morbidity events has varied across clinical studies; further standardization of this parameter is necessary. Although multiple direct and surrogate outcomes have been studied in PAH clinical research, rate of clinical worsening events, using prolonged, event-driven trial design, has emerged as the new standard.

Abstract W MP85: Prostacyclin Receptor Activation With MRE-269 Reduces Infarct Size and Improves Long-term Neurological Recovery Following Ischemic Stroke in Both Young and Aged Rats

Activation of the prostacyclin (PGI2) IP receptor is protective in brain ischemia. However, there is very limited information of the molecular mechanisms of protection and the feasibility to target this pathway in stroke. MRE-269, a highly selective PGI2/IP receptor agonist, has been recently discovered. This IP agonist has a long half-life in vivo and is currently in phase III clinical trials for pulmonary hypertension. We hypothesized that post-ischemic treatment with MRE-269 provides neuroprotection in a rat ischemic stroke model. Young male rats (3-4-month old) were subjected to middle cerebral artery occlusion (MCAO) for 90 min and treated intravenously with either vehicle (n=14) or MRE-269 (0.1, 0.25, 0.5, and 1 mg/kg, n=10-14/group) at the start of reperfusion. At 48 h post-MCAO, rats were sacrificed to determine infarct size, blood-brain barrier (BBB) damage (IgG extravasation), hemorrhagic transformation (brain hemoglobin levels), and matrix metalloproteinase (MMP)-9 activity. In a separate experiment, aged male rats (18-20-month old) underwent 90 min of MCAO and randomly selected to receive intravenously either vehicle (n=11) or MRE-269 (0.25 mg/kg, n=11) starting at 4.5 h post-MCAO. Additional doses were given every 12 h for the first 48 h, and then one injection daily for 7 days post-MCAO. The accelerating rotarod and the adhesive removal tests were conducted before and at 3, 7, 14 and 21 days after MCAO by an investigator blinded to treatment groups. Infarct volume was quantified by MRI at 48 h and 21 days post-MCAO. In young rats, MRE-269 dose-dependently reduced cortical infarct size. MRE-269-treated rats (0.25 mg/kg) had significantly reduced BBB damage and less hemorrhagic transformation. Compared with the vehicle group, MRE-269-treated animals showed a significant reduction in brain MMP-9 activity. In aged rats, MRE-269 treatment resulted in a significant long-term recovery in both locomotor and somatosensory functions following MCAO. Quantitative MRI data showed that MRE-269 significantly reduced infarct volume compared with vehicle-treated rats. Our data suggest that targeting the PGI2/IP receptor with MRE-269 is a novel strategy to reduce neurovascular injury and promote long-term neurological recovery in ischemic stroke.

The first annual Drug Discovery and Development Symposium for Pulmonary Hypertension.

The first annual Drug Discovery and Development Symposium for Pulmonary Hypertension.

Concise Review: Current Status of Stem Cells and Regenerative Medicine in Lung Biology and Diseases

AbstractLung diseases remain a significant and devastating cause of morbidity and mortality worldwide. In contrast to many other major diseases, lung diseases notably chronic obstructive pulmonary diseases (COPDs), including both asthma and emphysema, are increasing in prevalence and COPD is expected to become the third leading cause of disease mortality worldwide by 2020. New therapeutic options are desperately needed. A rapidly growing number of investigations of stem cells and cell therapies in lung biology and diseases as well as in ex vivo lung bioengineering have offered exciting new avenues for advancing knowledge of lung biology as well as providing novel potential therapeutic approaches for lung diseases. These initial observations have led to a growing exploration of endothelial progenitor cells and mesenchymal stem (stromal) cells in clinical trials of pulmonary hypertension and COPD with other clinical investigations planned. Ex vivo bioengineering of the trachea, larynx, diaphragm, and the lung itself with both biosynthetic constructs as well as decellularized tissues have been used to explore engineering both airway and vascular systems of the lung. Lung is thus a ripe organ for a variety of cell therapy and regenerative medicine approaches. Current state-of-the-art progress for each of the above areas will be presented as will discussion of current considerations for cell therapy-based clinical trials in lung diseases. Stem Cells 2014;32:16–25

Challenges in Endpoint Development for Pulmonary Hypertension Trials in Children

There are currently 12 medications approved for use in the treatment of pulmonary arterial hypertension (PAH) in adults. These include endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, and prostacyclins. However, in children there are no approved targeted PAH medications, with the exception of inhaled nitric oxide for treatment of hypoxemic respiratory failure in neonates. This review will address some of the challenges in the development of treatments for children, including lessons from recent trials, endpoints for clinical trials, and challenges with drug approval in children.

Geometry of the Randomized Evidence for Treatments of Pulmonary Hypertension

We studied the entire agenda of randomized clinical trials in pulmonary hypertension (PH) using sociological methods. We explored the geometry of the PH network to interpret the evidence on multiple competing treatments for the same indication. We searched MEDLINE, Embase and Cochrane Library Databases for published studies. We queried clinicaltrials.gov and WHO International Clinical Trials Registry platform for non-published studies. We found 75 randomized trials (41 published [n=4136 participants] and 34 registered unpublished [planned n=3470 participants]). Of the published randomized studies, all used placebo as the comparator arm except for two nonindustry-sponsored comparisons between phosphodiestearase-5 (PDE-5) inhibitors and endothelin receptor antagonists (ERA), and one study comparing two different regimens of treprostinil. Similarly, only five unpublished/ongoing trials used an active PH treatment as comparator (PDE-5 inhibitors versus ERA (n=3), different doses of sildenafil (n=1) and two formulations of epoprostenol (n=1). Of the 75 trials, 47 were sponsored by the manufacturer of the tested active product(s), and only two trials were sponsored by two companies comparing their products. The relative merits of different treatment options are not directly known, as there are very few head-to-head comparisons. A limited number of ongoing studies are using active FDA-approved PH-treatments for comparison. This lack of information can be overcome by carefully designing comparative effectiveness trials.

The Practicability of New Endpoint Measures in Pulmonary Hypertension Trials

Dear Editor, I read with interest the thoughtful article by Hassoun et al.1 titled “Updating clinical endpoint definitions.” One of the primary tasks in my role as a pulmonary hypertension (PH) research nurse coordinator is to identify PH patients in our clinic who are eligible and willing to participate in research studies. This is not always an easy task. As Hassoun et al. point out in their article, PH studies historically have run 12 weeks, requiring several hundred patients, based on a primary endpoint of 6-minute walk distance (6-MWD) test, an endpoint which has fallen out of vogue in the PH community. More recent studies have used morbidity/mortality as primary endpoint. These types of studies require very large numbers of patients (some 1,000 or more) and take many years, some five or more years, to complete. At the recent American Thoracic Society meeting in Philadelphia, vocal PH experts declared this endpoint the be-all-end-all solution to future PH studies. The worrisome scenario that comes to my mind is that in the near future, when a truly novel and potentially curative agent comes to phase II/III testing, there will be no eligible, willing, and available PH patients left to enroll because most will be committed to years-long morbidity/mortality trials. Given the rarity of PH, requiring morbidity/mortality outcomes for all clinical trials may have the unintended consequence of suppressing innovation of novel therapies in the field, thereby reducing any progress in this disease. Progress will come to a slow crawl. While I do not claim to have the answer for what should be the best endpoint of study, I suggest that there could be a compromise between a historic 12-week outcome measure like the 6-MWD test and a multiyear outcome measure like morbidity/mortality. Practicability ought to be taken into account. I can only hope that regulatory agencies, along with the PH physician community and pharmaceutical companies, consider recruitment implications and keep the best interest of the PH patient in mind when determining the future of drug trial design in this patient population.

P2: Sodium nitrite disrupts biotic biofilm formation by Pseudomonas aeruginosa on polarized human airway epithelial cells

Background Cystic fibrosis is marked by recurrent infections with Pseudomonas aeruginosa . Evidence suggests that P. aeruginosa in the CF airway are refractory to existing antibiotics due to the formation of highly antibiotic-resistant bacterial biofilm communities. Inhaled nitrite is currently in human trials for pulmonary hypertension, and it may also prove useful in cystic fibrosis. Sodium nitrite has antimicrobial activity against P. aeruginosa and may represent a novel inhaled antimicrobial agent that can be used in cystic fibrosis to eradicate P. aeruginosa colonization. Previous work has shown that sodium nitrite has antimicrobial effects in planktonic culture and in abiotic biofilm systems against P. aeruginosa . The purpose of this study is to determine the efficacy of sodium nitrite in a biotic co-culture model system and to define the interaction between nitrite and antibiotics commonly used in cystic fibrosis care. Methods A human bronchial epithelial cell line and P. aeruginosa co-culture system was use as previously described by Moreau-Marquis et al. (2008). The biofilms were treated with increasing concentrations of sodium nitrite either to prevent biofilm formation or treat established biofilms. In a second series of experiments, tobramycin, ciprofloxacin, colistin and other antibiotics were added in combination with nitrite at concentrations achieved in vivo to determine if nitrite and antibiotics are synergistic. The end point for both experiments was bacterial colony forming units. Results Sodium nitrite reduced biotic biofilm formation by 100-fold (2 logs) when applied prior to biofilm maturation at concentrations of 15–300 mM. These are concentrations that are achieved and well tolerated in trails of nebulized sodium nitrite for other indications. The reduction of P. aeruginosa biofilms was 2- to 10-fold when nitrite was applied to mature biofilms. Nitrite appeared to cause a dose dependent increase in tobramycin and ciprofloxacin antibiotic resistance. In contrast, nitrite was synergistic with colistin. Conclusion Sodium nitrite offers potential as a novel inhaled antimicrobial agent for chronic Pseudomonas infection. Further pre-clinical work is needed to determine the interaction between sodium nitrite and antibiotics commonly used in cystic fibrosis care. Funded by: NIH grants R00HL098342-01 and P30DK072506. Disclosure A.C. Zemke, L.P. Lashua and J.M. Bomberger have no disclosures. Funded by: NIH grants R00HL098342-01 and P30DK072506.

Clinical Trials in Pulmonary Hypertension: Time for a Consortium

Current and past clinical trials in pulmonary hypertension, while valuable, are limited by the absence of mechanistic aims, by dissatisfaction with endpoints and the inability to share data. Clinical studies in pulmonary hypertension might be enhanced by a consortium approach that utilizes the expertise of academic medicine, the treatment initiatives of the pharmaceutical industry and study design from funding agencies interested in biological mechanisms. A meeting of interested parties, the Pulmonary Hypertension Academic Research Consortium (PHARC), was held from 30 April to 1 May 2012 in Bethesda, Maryland. Members at the conference were from the USA Federal Drug Administration (FDA); pharmaceutical industry (Pfizer, Novartis, Bayer and Gilead); USA National Institutes of Health (NHLBI); the Pulmonary Vascular Research Institute (PVRI), a non-governmental organization (NGO); and research and clinical members of pulmonary hypertension programs of international scope. A recommendation to develop a clinical trials consortium was the product of the working group on academic standards in clinical trials. The working group concluded that clinical trials hold immense promise to move the field of pulmonary hypertension forward if the trials are designed by a consortium with input from multiple groups. This would result in study design, conduct and analysis determined by consortium members with a high degree of independent function. The components of a well-balanced consortium that give it scientific effectiveness are: (1) the consortium can work with multiple companies simultaneously; (2) sponsors with special interests, such as testing biological mechanisms, can add investigations to a study at lower cost than with present granting strategies; (3) data handling including archiving, analysis and future sharing would be improved; (4) ancillary studies supported by the collection and dissemination of tissues and fluids would generate a broader approach to discovery than is now possible; and (5) development of improved endpoints in consultation with regulatory agencies, industry and academia would be possible.

Future of Clinical Trials for Pulmonary Hypertension

> “It is better to lose the battle and win the war.” > > —Sun Tzu (circa 6th century BCE Chinese General and military strategist) In 1995, the first successful randomized controlled trial (RCT) for pulmonary arterial hypertension (PAH) led to the approval of the pulmonary vasodilator epoprostenol.1 Under the assumption that PAH was a disease of inappropriate pulmonary vasoconstriction, testing a drug that had vasodilator properties seemed reasonable. The 6-minute walk test was the primary end point in the trial because it was in keeping with the Food and Drug Administration precedent that an outcome assessment in a patient with cardiopulmonary disease needs to reflect how the patient feels, functions, or survives. Article see p 2985 There are now 7 vasodilator therapies for PAH, all approved because they improved exercise capacity for 3 to 4 months.2 Whether they affect long-term survival remains a valid question.3 Recently, a sobering report from a highly respected referral center in France noted that the current 3-year survival for patients with pulmonary hypertension managed with state-of-the-art multiple drug therapy was only 58%, marginally better than in 1980s when there were no treatments at all.4 In addition, it appears that these drugs do not protect patients from developing severe pulmonary vascular disease.5,6 Our knowledge of the pathobiology of PAH today is quite different from what it was 20 years ago. Scientific studies have demonstrated that cellular proliferation, inflammation, and thrombosis are the dominant underlying pathobiological processes and that chronic pulmonary vasoconstriction appears to play a relatively minor role.7 It is therefore understandable why the RCT by Kawut et al8 in this issue of Circulation chose to study the safety and efficacy of simvastatin and/or aspirin, therapies directed at normalizing endothelial cell function and platelet activation, as a treatment for …

Cell-based therapies in pulmonary hypertension: who, what, and when?

pulmonary hypertension (PH), diagnosed when mean pulmonary arterial pressure exceeds the upper limits of normal (i.e., >25 mmHg) at rest (2), occurs in a variety of clinical situations and is associated with a broad spectrum of histological patterns and abnormalities. PH is currently classified into five distinct World Health Organization (WHO) groups, based on common clinical parameters, potential etiological mechanisms, and responses to treatment (22). Although any form of PH can contribute to increased patient morbidity and mortality, pulmonary arterial hypertension (PAH) (WHO group 1) is a particularly severe and progressive form associated with right heart failure and premature death (1). At present, therapeutic approaches to stabilize or reverse this debilitating condition involve treatment with one or a combination of up to three specific classes of agents, including prostacyclin analogs, endothelin-1 receptor antagonists, and/or phosphodiesterase-5 inhibitors. Retrospective (meta)analyses of these therapeutic strategies have demonstrated a reduction in mortality with their use (7, 12); however, many experts believe that current PAH treatment is inadequate given the persistently high mortality rate and functional hemodynamic impairment in many patients. These observations have led to continued intensive investigation into pathogenetic mechanisms and many proposals for additional alternative new therapies (20, 24). Among the potential new therapies, increasing interest in the role of endothelial progenitor cells (EPCs) as a cell-based therapy has emerged. However, issues remain regarding what group of PH patients are most likely to benefit from treatment, at what point in the disease is treatment most likely to be successful, and what types of cells should be utilized for therapy.