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End points and clinical trial designs in pulmonary arterial hypertension

Clinical and regulatory perspectives

Marius M. Hoeper, MD^*,*, Ronald J. Oudiz, MD, Andrew Peacock, MD, Victor F. Tapson, MD, Sheila G. Haworth, MD^||, Adaani E. Frost, MD^¶ and Adam Torbicki, MD

^* Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
Division of Cardiology, Harbor—UCLA Medical Center, Torrance, California, USA
Scottish Pulmonary Vascular Unit, Glasgow, Scotland, UK
Pulmonary Hypertension Center, Duke University Medical Center, Durham, North Carolina, USA
^|| Institute of Child Health, London, United Kingdom
^¶ Baylor College of Medicine, Houston, Texas, USA
Institute of Tuberculosis and Lung Diseases, University of Warsaw, Warsaw, Poland

Manuscript received November 26, 2003; accepted February 3, 2004.

^* Reprint requests and correspondence: Dr. Marius M. Hoeper, Department of Respiratory Medicine, Hannover Medical School, 30623 Hannover, Germany.
hoeper.marius{at}mh-hannover.de

To date, randomized controlled clinical trials performed in pulmonary arterial hypertension (PAH) have been relatively short-term studies involving mainly patients with advanced disease. The primary end points in these trials have addressed exercise capacity, usually by using the 6-min walk test. Although this approach is still warranted in future trials assessing new treatments, it is likely that the focus will shift toward trials of longer duration, involving patients with less advanced disease, and that different drugs and drug-combination regimens will be compared. In such trials, it is possible that a composite of markers indicating clinical deterioration (e.g., hospitalization for right heart failure, the requirement for the introduction of an alternative treatment, and predefined indicators of worsening exercise tolerance) may be more useful as primary end points. Quality of life will become a very important issue; however, appropriate quality-of-life questionnaires for PAH have yet to be developed. In addition, hemodynamics will likely remain valuable as secondary end points, but future clinical trials should include hemodynamics obtained both during exercise and at rest. Finally, cardiopulmonary exercise testing, echocardiographic studies, and biochemical parameters, such as brain natriuretic peptide or troponin T, may also prove useful as secondary end points in the future.

Abbreviations and Acronyms   BNP = brain natriuretic peptide   CO = cardiac output   CPET = cardiopulmonary exercise testing   EMEA = European Agency for the Evaluation of Medicinal Products   FDA = Food and Drug Administration   LV = left ventricle/ventricular   NYHA = New York Heart Association   PAH = pulmonary arterial hypertension   PAP = pulmonary artery pressure   PAPm = mean pulmonary artery pressure   PCWP = pulmonary capillary wedge pressure   PVR = pulmonary vascular resistance   QoL = quality of life   RV = right ventricle/ventricular   VO 2 = oxygen consumption   WHO = World Health Organization

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