Pulmonary hypertension (PH) is a progressive and fatal disorder in which diagnostic criteria, treatment, and prognosis may differ substantially for the various types of pulmonary hypertension. The most recent World Health Organization (WHO) clinical classification of pulmonary hypertension illustrates a spectrum of conditions all defined clinically by a pulmonary vascular hypertensive state and a new classification has been proposed for pediatric pulmonary vascular disease, which reflects the developmental etiology of many cases.
Recognizing the importance of improving lung health and disease, the National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of multi-disciplinary expertise on August 11-12, 2011 in Bethesda, Maryland. The purpose of the workshop was: 1) to review the state of scientific knowledge forming the basis for current treatment of children and adults with pulmonary vascular diseases (PVD); 2) to identify current scientific opportunities in PVD research and how to capitalize on these opportunities; 3) to prioritize new research directions that could affect the clinical course of PVD; and 4) to make recommendations to the NHLBI on how to fill the identified gaps in clinical research.
Participants in the workshop were asked to consider the following topics: 1) improved methods of phenotyping in order to identify potential subjects for appropriate PVD clinical studies, 2) potential new endpoints for designing PVD clinical trials, and 3) priorities for specific clinical research needed to advance care of patients with various subsets of PVD from childhood through adulthood.
- Better Characterization of Phenotypes of PH: An issue of major importance for all workshop participants was improved characterization of patients with PH. Opportunities should be explored to better phenotype include using information from institutional and publically available databases and clinical biosamples or scientific biorepositories. There is a need for enhancing the clinical phenotyping of patient populations within pediatrics. Goals for children include the need to better establish the natural history of at-risk pediatric populations, including premature infants, Down syndrome, sickle cell disease, complex congenital heart disease, chronic lung diseases, including CF, and others. Identification of responders and non-responders, predictors of disease progression or stabilization, and related questions are needed for both adult and pediatric patient populations.
- Endpoints and Targets for Clinical Trials: Workshop participants agreed that current endpoints are not ideal and do not necessarily correlate with disease progression. Mortality is the ultimate endpoint but the event rate in WHO Group 1 PH studies (pulmonary arterial hypertension, PAH) makes this, for the most part, an unrealistic primary endpoint. The majority of studies have used change in exercise capacity using six-minute walk distance (6 MWD) as the primary endpoint. However, placebo-controlled studies are no longer possible in this country and patients being enrolled in studies are less ill making improvement in walk distance an even more difficult endpoint to obtain. Recommendations for novel endpoints include: measurement of changes in end-tidal CO2 as a surrogate measure of improved vascular function; increased and innovative use of MRI/MRA, and measurement of changes in pulmonary vascular impedance. There is a need to develop better endpoints for assessing disease course and response to therapy in diverse settings that are age-appropriate. These should be clinically relevant and feasible markers that are sufficiently sensitive to changes in clinical course. In young children there is clearly a lack of applicability of NYHA/WHO functional class, 6 MWD, quality of life, and formal exercise testing and there is a need to modify the definition of "time to clinical worsening" as applicable to pediatrics. Early diagnosis and treatment are likely especially important for all ages.
- Next Generation Clinical Studies: The committee recommended that longer studies extending for 6 months to years are needed to establish if new therapies are truly beneficial in reversing the disease process. In addition, the committee strongly emphasized that there should be a genetic/biomarker component to any clinical study in PAH. Examples of priority clinical trials include: treating functional class I and II PAH patients with aggressive initial therapy; evaluation of the effect of exercise training on clinical status and disease progression; and evaluation of potential treatments for patients failing maximal therapy. As with adult PH, there is a need for testing and implementing disease-modifying therapies in pediatrics. Additional considerations for pediatric studies include 1) the importance of vascular and alveolar growth and assessments of lung surface area in addition to hemodynamic measurements as endpoints, and 2) study of "at risk populations" to develop pediatric PH.
- Establishment of PH Networks for Pediatric and Adult Populations: This recommendation would facilitate improved phenotyping strategies for clinical research in PVD, development of new endpoints for clinical trials, and constructing trials that are of highest priority that would not be accomplished by industry. The PH community is encouraged to consider investigator initiated applications for clinical trials to address these issues.
- Ivan Robbins, MD (Nashville, TN)
- Steve Abman, MD (Denver, Colorado)
- Ian Adatia, MBChB (Edmonton, Alberta, Canada)
- Eric Austin, M.D, (Nashville, TN)
- Raouf Amin, M.D. ( Cincinnati, OH),
- Raymond Benza, M.D. (Pittsburgh, PA)
- Atul Butte, M.D., Ph.D (Stanford, CA)
- Wendy Chung, M.D. Ph.D. (New York, NY)
- James Cimino, MD (Bethesda, MD)
- Gail Deutsch, M.D. (Seattle, WA)
- Raed Dweik, M.D., (Cleveland, OH)
- Jonas Ellenberg, (Philadelphia, PA)
- Allen Everett, M.D. (Baltimore, MD)
- Karen Fagan, (Mobile, AL)
- Jeff Feinstein, M.D., MPH (Stanford, CA)
- Teri Franks, MD (Silver Spring, MD)
- Victor Gordeuk, M.D. (Washington DC)
- Mardi Gomberg-Maitland, MD (Chicago, IL)
- Hakon Hakonarson, MD,PhD (Philadelphia, PA)
- Dunbar Ivy, MD (Aurora, CO)
- Steve Kawut, MD (Philadelphia, PA)
- Roberto Machado, MD (Chicago, IL)
- Kenneth Mandl, MD, MPH (Boston, MA)
- Michael Matthay, MD (San Francisco, CA)
- Fernando Martinez, MD (Ann Arbor, MI)
- Sharon McGrath-Morrow, MD (Baltimore, MD)
- Steve Nathan, MD (Falls Church, VA)
- Lawrence Nogee, MD (Baltimore, MD)
- Myung Park, MD (Baltimore, MD)
- Robin Shandas, PhD (Aurora, CO)
- Virend Somers, MD PhD (Rochester, MN)
- Duncan Stewart, MD (Ottawa, Ontario, Canada)
- Tim Moore, MD, PhD (Bethesda, MD)
- Carol Blaisdell, MD (Bethesda, MD)
- Dorothy Gail, PhD (Bethesda, MD)
- Gail Weinmann, MD (Bethesda, MD)
- James Kiley, PhD (Bethesda, MD)
Last Updated: November 2011