CardioExchange Archive

CardioExchange’s John Ryan interviews Corey E. Ventetuolo about her research group’s study of hemodynamic endpoints in clinical trials of patients with pulmonary arterial hypertension. The study is published in Circulation.

Ryan: Please summarize the main finding of your paper.

Ventetuolo: We conducted a large patient-level analysis of 1119 participants from four randomized clinical trials in pulmonary arterial hypertension (PAH). Our aim was to determine whether treatment-induced changes in hemodynamics are valid surrogate endpoints in this population. We found that although active therapy was associated with favorable hemodynamic changes and a reduction in clinical events (such as death, lung transplantation, hospitalization for worsening PAH and escalation in PAH therapy) at 12 weeks, these changes only partially affect the probability of short-term outcomes. At most, decreases in pulmonary vascular resistance explained about 14% of the treatment effect. The findings, which suggest that short-term changes in resting hemodynamics are not valid surrogate endpoints in clinical trials, challenge our understanding of how PAH therapies work.

Ryan: If the hemodynamic changes are not accounting for the changes in short-term outcomes, what do you think is the cause of the improvements in the outcomes?

Ventetuolo: We were surprised by the findings, since PAH is a hemodynamic disease by definition. Our therapies may be acting via alternative mechanisms not previously defined or studied, perhaps by exerting systemic effects or by changing right ventricular adaptation. Of course, because of the short-term design of traditional PAH trials, we cannot know whether hemodynamic changes with longer-term therapy would reliably predict clinical events beyond 12 weeks.

Ryan: After starting therapeutic agents for PAH, what is your practice for obtaining follow-up hemodynamic measures?

Ventetuolo: There are minimal data to guide practice in this area, and each patient needs to be considered individually. Generally if a patient is doing well on therapy by other noninvasive tests (making gains in their symptoms, functional class, 6-minute walk distance, and markers of right ventricular function), we try to repeat hemodynamic measurements annually. Patients with a robust response to therapy may have longer periods between testing. If a patient is doing poorly or certainly in patients treated with prostacyclins, we may repeat hemodynamic measurements more frequently, sometimes within weeks.

 Ryan: As you know, the trials and your results exclusively address resting hemodynamics. What role, if any, do you think exercise hemodynamics play in these patients?

Ventetuolo: This is a great point. We need to better understand hemodynamic changes with exercise in normal individuals (as they age or develop comorbid conditions), as well as in PAH, to better define cut-points and protocols that can be highly standardized. For these reasons, exercise-induced pulmonary hypertension is not included in current definitions of pulmonary vascular disease. In clinical practice, we sometimes use exercise hemodynamics to unmask diastolic abnormalities and distinguish pulmonary venous hypertension from PAH in patients who have risk factors for Group 2 disease but have low or high-normal left-heart filling pressures at rest. However, exercise measurements are not ready for prime time use in clinical trials.

Ryan: With the minimal impact of invasive hemodynamics on outcomes, do you think we should focus our efforts on no-invasive imaging in clinical trials (MRI, echo, etc.)?

Ventetuolo: Trials to-date have not incorporated endpoints that track changes in right ventricular performance in a large-scale fashion. A number of advanced or novel RV imaging techniques that may prove useful now exist, but it is important to validate potential noninvasive surrogates before using them in clinical trials. Alternatively, we could design trials that aim to improve the ultimate endpoints for our patients (survival, patient-reported outcomes, clinical events) with PAH therapies.

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