Are Hemodynamics Surrogate End Points in Pulmonary Arterial Hypertension?

Abstract

Background While frequently assessed in trials and clinical practice, hemodynamic response to therapy has never been validated as a surrogate endpoint for clinical events in pulmonary arterial hypertension (PAH). Methods and Results We performed a patient-level pooled analysis of four randomized placebo-controlled trials to determine if treatment-induced changes in hemodynamic values at 12 weeks accounted for the relationship between treatment assignment and the probability of early clinical events (death, lung transplantation, atrial septostomy, PAH hospitalization, withdrawal for clinical worsening, escalation in PAH therapy). We included 1119 subjects with PAH. The median (interquartile range) age was 48 (37 – 59), and 23% were men. 656 (59%) received active therapy (101 [15%] iloprost, 118 [18%] sitaxsentan, 204 [31%] sildenafil, and 233 [36%] subcutaneous treprostinil). Active treatment significantly lowered right atrial pressure (RAP), mean pulmonary artery pressure (mPAP), and pulmonary vascular resistance and increased cardiac output and index (p < 0.01 for all). Changes in hemodynamic values (except for RAP and mPAP) were significantly associated with the risk of a clinical event (p ≤ 0.01 for all). While active treatment approximately halved the odds of a clinical event compared to placebo (p < 0.001), changes in hemodynamics accounted for only 1.2 – 13.9% of the overall treatment effect. Conclusions Treatment-induced changes in hemodynamics at 12 weeks only partially explain the impact of therapy on the probability of early clinical events in PAH. These findings suggest that resting hemodynamics are not valid surrogate endpoints for short-term events in PAH clinical trials.

Anastrozole in Pulmonary Arterial Hypertension. A Randomized, Double-Blind, Placebo-controlled Trial

“…The hemodynamic response to AN would have been of interest; however, the requirement for multiple right heart catheterizations on otherwise stable, treated patients would have rendered the trial infeasible. In addition, we have shown that short-term hemodynamics are not adequate surrogate endpoints in PAH trials, so that conclusions based on early hemodynamic findings (or lack thereof) might be in error (42). We also did not measure E2 metabolites, which may have been of interest based on previous studies (25,43,44).…”

What's the (end) point?

“…We and others have found that while changes in these measures were associated with outcomes in PAH clinical trials (as in prior observational studies), the drug-induced changes (compared with placebo) explained very little of the variances in outcomes [11][12][13][14]. At most, the changes in 6MWD and pulmonary vascular resistance respectively explained only 22% and 14% of the effect of treatment on clinical events at 12 weeks, falling short of the desired 50% mark and suggesting that they are not valid surrogates for short-term outcomes.…”

What's the (end) point?

“…Therefore, surrogate measures come into place. VENTETUOLO and KAWUT correctly emphasise that adequate validation of surrogate measures is crucial and they have demonstrated that this has not been done properly for many of the clinical endpoints or treatment targets that have been proposed for adult patients with PAH [4][5][6][7]. In our study in children with PAH, we identified three intermediates in which therapy-induced changes predicted comparable directional changes in the ultimate outcome: survival [1,8].…”

“…Kawut depreciate the value of clinical end points in adults with PAH, requires some considerations. Recent surrogate end point validation studies in adults [4][5][6][7] evaluated therapy-induced changes in relation to composites of "soft" clinical events (including hospitalisation, clinical worsening and escalation of therapy) that have not undeniably demonstrated a correlation with the hard outcome, survival. Furthermore, analyses had to be restricted to the short duration of clinical trials (mostly 12 weeks).…”

“…Furthermore, analyses had to be restricted to the short duration of clinical trials (mostly 12 weeks). Thus, relations to hard outcomes in the long term could not be assessed and one should therefore be careful to reject potential treatment targets prematurely [4][5][6][7]. In this respect, the current paediatric study is unique in allowing the evaluation of therapy-induced changes in relation to hard outcomes (transplant-free survival) during a median follow up of >3 years.…”