Chronic Thromboembolic Pulmonary Hypertension clinical trials at UCLA

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are severe clinical conditions that, despite advances in therapeutics over the past 20 years, lead to serious morbidity and mortality. Guidelines on the diagnosis and treatment of pulmonary hypertension (PH) recommend the use of a multiparametric risk stratification tool to determine severity of disease, which should guide initial therapy and therapy modulation. This multiparametric risk stratification schema includes objective assessment of exercise capacity, right ventricular function and hemodynamic parameters in order to classify patients into severity categories. Cardiac index (CI) and right atrial pressure (RAP), measured via right heart catheterization (RHC), are the hemodynamic parameters used in risk assessment of PH. Arguably, stroke volume index (SVI) is the most important hemodynamic parameter for assessment of PH severity and there is currently no validated method for noninvasive measurement of cardiac output (CO), CI or SVI. Currently, a major obstacle in the field is that hemodynamic measurements are not obtained on a regular basis in the risk assessment and therapy modulation of patients with PAH and CTEPH. If a noninvasive method of hemodynamic measurement could be correlated with other objective measurements of risk assessment, it could become an invaluable tool in therapy initiation and modulation in the ambulatory setting. This is a single center study to evaluate the use of non-invasive measurement of CO and stroke volume to assess risk and response to treatment in patients with PAH and non- operable CTEPH. We anticipate to enroll a total of 100 subjects at Ronald Reagan UCLA Medical Center. A maximum of 10 hour in total for the study including the consent process, pre-procedure care, RHC procedure, and follow up visit. The initial visit will be approximately 4 hours with the RHC procedure itself will only be 20 minutes. Each follow up visit will be 1.5 hour. Patients with known or suspected PAH or CTEPH will undergo a RHC as part of his or her standard of care. Three techniques of CO measurement will be performed sequentially at the time of the RHC. The device that will be used is the Edwards ClearSight system and EV1000 clinical platform, a device that measures NIBP. Patients will be followed over the period of 1 year every 3 months to obtain serial measurements for six-minute walk distance (6MWD), World Health Organization (WHO)/New York Heart Association Functional Class (FC), B-type natriuretic peptide (BNP) or N-terminal-pro hormone BNP (NT-proBNP), and non-invasive hemodynamic measurements. Additional visits will be scheduled to obtain the serial measurements one month prior and one month following if a patient is initiating or changing PH-specific therapy. As this is a study looking at the feasibility of non-invasive measurement of cardiac output and stroke volume for risk assessment and response to therapy in pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH), study personnel performing the study procedures will not be blinded to the clinical diagnosis and the management of the subject.

Potential outcomes after PE occur on a spectrum: complete recovery, exercise intolerance from deconditioning/anxiety, dyspnea from concomitant cardiopulmonary conditions, dyspnea from residual pulmonary vascular occlusion, chronic thromboembolic disease and chronic thromboembolic pulmonary hypertension. Although a battery of advanced diagnostic tests could distinguish each of those conditions, the yield of individual tests among all post- PE patients is low enough that routine testing of all PE patients is not typically performed. Although the various possible post-PE outcomes have enormous implications for patient care, they are rarely distinguished clinically. Perhaps for this reason, chronic conditions after PE are rarely (if ever) used as endpoints in randomized clinical trials of acute PE treatment. The proposed project will validate a clinical decision tree to distinguish among the various discrete outcomes cost-effectively through a hierarchical series of tests with the acronym SEARCH (for symptom screen, exercise function, arterial perfusion, resting heart function, confirmatory imaging and hemodynamics). Each step of the algorithm sorts a subset of patients into a diagnostic category unequivocally in a cost-effective manner. The categories are mutually exclusive and collectively exhaustive, so that each case falls into one, and only one, category. Each individual test used in the algorithm has been clinically validated in pulmonary embolism patients, including the cardiopulmonary exercise test (CPET) technique that the investigators developed and validated. However, the decision tree approach to deploying the tests has not yet been validated. Aim 1 will determine whether the SEARCH algorithm will yield concordant post-PE diagnoses when multiple reviewers independently evaluate multiple cases (reliability). Aim 2 will determine whether the post-PE diagnoses are stable, according to the SEARCH algorithm, between the first evaluation and the subsequent one six months later (validity).