The Low-Risk Profile in Pulmonary Arterial Hypertension Time for a Paradigm Shift to Goal-oriented Clinical Trial Endpoints?
The Low-Risk Profile in Pulmonary Arterial Hypertension Time for a Paradigm Shift to Goal-oriented Clinical Trial Endpoints?
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DOI：
10.1164/rccm.201709-1840pp
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发表时间：
2018-04-01
影响因子：
24.7
通讯作者：
Sitbon, Olivier
中科院分区：
文献类型：
--
作者：
Weatherald, Jason;Boucly, Athenais;Sitbon, Olivier
Pulmonary arterial hypertension (PAH) is a devastating condition characterized by progressive symptoms, right heart failure, and death (1, 2). In the 1980s, the NIH Registry for the Characterization of Primary Pulmonary Hypertension reported a median survival of 2.8 years in untreated patients (3). Since then, advances in medical therapies targeting dysfunctional nitric oxide, endothelin 1, and prostacyclin pathways have dramatically improved the prognosis of PAH (4, 5); however, longterm survival remains poor (6). To accurately prognosticate and inform treatment decisions, clinicians must assess the risk of a poor outcome for each patient. The goals of PAH treatments are to reduce symptoms, improve quality of life, delay the progression of disease, and reduce the risk of a poor outcome, such as death or the need for lung transplant (7). Risk stratification is dependent on several patient factors, including age, sex, etiology of PAH, functional capacity, right ventricular (RV) function, and hemodynamic variables. Some of these factors, such as exercise capacity, RV function, and hemodynamic variables can be modified or improved with treatment (7–9). No single attribute among these is adequate to estimate the risk; however, a combination of such factors is routinely used to predict risk. Several multidimensional tools have been developed to predict prognosis (1–3, 8, 9). Recent studies support that a “low-risk” patient profile can be achieved after initial treatment of PAH and that a low-risk profile is associated with better survival (10–13).A recent statement from the NHLBI emphasized the need for a precision medicine approach to develop innovative new personalized therapies in PAH (14). Future clinical trials in the era of precision medicine will need to have more meaningful endpoints that reflect patient-reported symptoms and function, in addition to survival (14). The objectives of this article are 1) to review current methods for performing multidimensional risk assessment in PAH; 2) to justify the rationale for and potential limitations of using a low-risk profile in clinical trial endpoint designs; 3) to propose methods for how the low-risk profile could be validated as a surrogate outcome in PAH; and 4) to propose definitions for low-risk profile primary endpoints that could be used in future PAH clinical trials.
