Session: 114. Hemoglobinopathies, Excluding Thalassemia—Clinical: Poster II
Hematology Disease Topics & Pathways:
sickle cell disease, sickle cell trait, Diseases, thalassemia, Hemoglobinopathies
We analyzed data collected on secondary end points during the phase I study, including Tricuspid regurgitant jet velocity (TRV), Transcranial Doppler (TCD) velocities in distal internal carotid (dICA) and middle cerebral (MCA) arteries, and eGFR (calculated with CKD-Epi formula). Fig. 1a shows eGFRs in ambrisentan and placebo groups; Fig. 1b and Fig. 1c show a breakdown of ambrisentan and placebo groups based on concomitant ACEi/ARB usage. There is a reduction in glomerular hyperfiltration in the ambrisentan group compared to placebo, more pronounced in the subgroup who have not been on ACEi/ARBs. Fig. 1d depicts the change in flow velocity in MCA (TAMMV, Time Averaged Mean Maximal Velocity, cm/sec) between the ambrisentan and placebo groups; similarly, Fig. 1e and 1f show the breakdown of baseline and Day 85 TAMMVs in MCA according to ACEi/ARB usage. A similar trend is also observed in dICA flow (fig. 1g-1i), and suggests a synergistic effect of ETA receptor blockade with ACEi/ARBs in preventing an increase in blood flow velocities. TRV was available on 7 subjects, 6 of which were in the ambrisentan group. Fig. 1j shows the change in TRV in the ambrisentan group, and again is suggestive of a synergistic effect of ambrisentan and ACEi/ARBs in decreasing TRV. These data are clearly very preliminary, and are obtained on a small number of subjects, and as such, do not warrant any conclusions and or speculations. Nevertheless, an interesting observation is the apparent interaction of ETA receptor blockade and ACEi/ARBs in altering vascular flow/function in SCD patients. Decrease in microalbuminuria has been reported with ACEi and ARBs in SCD (Yee et al, 2018), without any effect on GFR. A reduction in hyperfiltration would likely have a significant renoprotective effect, at an earlier stage in the development of sickle nephropathy. ETA receptor antagonists are approved for the treatment of pulmonary arterial hypertension; thus, a decrease in TRV would have a beneficial effect. Increase in blood flow velocity in major intracranial vessels is a well established risk factor for ischemic stroke in children with SCD; however, much less is known in adults. In summary, the effect of ETA receptor blockade with or without ACEi/ARB, may have a significant effect on vascular function/blood flow in different organ systems, and should be explored in a large, multi-center phase II trial, with and without concomitant and or serial ACEi/ARBs, for a longer period of time, with a dose escalation, to further clarify the pleiotropic effects on multiple aspects of SCD pathology.
Disclosures: No relevant conflicts of interest to declare.
See more of: Oral and Poster Abstracts