Background/Purpose:

Fostamatinib (Fosta) is a spleen tyrosine kinase (SYK) inhibitor in clinical trials in patients (pts) with rheumatoid arthritis (RA). Previous clinical studies showed blood pressure (BP) elevation with Fosta treatment using clinical measurements. As 24-hour ambulatory BP monitoring (ABPM) improves the sensitivity of detecting BP changes over the dosing period, OSKIRA-ABPM was developed as a randomized, placebo-controlled clinical trial to assess the effects of Fosta 100 mg twice daily (bid), taken on a background of a disease-modifying antirheumatic agent on ambulatory systolic BP (SBP) in pts with active RA. 

Methods:

After a screening visit and a 4-wk run-in period, pts were randomized to receive Fosta 100mg bid or placebo (PBO) bid for 4 weeks (wks), followed by a 1-wk washout of study drug. The ABPM was obtained at baseline and Wk 4; clinic BP was assessed at scheduled clinic visits; and home BP during 4 x 1 week periods, including 1 wk pre-randomization and the washout period. The primary safety endpoint was change from baseline in 24-hour mean SBP on Fosta vs PBO. Changes from baseline in 24-hour diastolic BP (DBP), BP assessed by clinic and home measurements, as well as the persistence and/or reversibility of any effect in BP after discontinuation of Fosta treatment were secondary endpoints.

Results: Of 135 randomized pts, 68 received Fosta and 67 received PBO, with balanced characteristics at baseline. There were 2 discontinuations in each group due to adverse events (1 in each group due to high BP), and 2 further discontinuations in the Fosta group that were non-adverse event related. Nine pts in the Fosta group vs 1 in the PBO group received newly prescribed and/or dose increase of existing antihypertensive medication after randomization. Compared to placebo, Fosta increased the 24-hour mean SBP by 2.9 mmHg (95% CI, 0.4–5.5; p = 0.023) and the 24-hour mean DBP by 3.5 mmHg (95% CI, 2.0–5.0; p < 0.001). There was no impact of Fosta on the circadian variation of BP. Individual changes of >5 mmHg in 24-hour mean SBP were seen in approx. 47% vs 27% of pts, and in 24-hour mean DBP in 41% vs 13% of pts in the Fosta and PBO groups, respectively. Individual changes of >10 mmHg in 24-hour mean SBP were seen in approx. 22% vs 12% of patients in the Fosta and PBO groups, respectively. Pts randomized to Fosta who were treated with antihypertensives or with steroids at baseline had numerically higher BP increases from baseline compared to those without. Baseline treatment with nonsteroidal anti-inflammatory drugs did not affect the BP response to Fosta. The magnitudes of clinic- and home-measured BP changes were similar to that of the ABPM-derived values. No effect on heart rate was observed by any measurement method. The effect of Fosta on clinic BP was seen at Wk 1 and plateaued thereafter. After treatment discontinuation, mean values of BP returned to baseline levels. 

Conclusion:

Fosta induced small but significant elevations in ambulatory BP in pts with active RA. Most elevations were <10 mmHg in individual pts and these elevations resolved with discontinuation of Fosta by 1 wk. In addition, there were no alterations to the circadian pattern of BP and there were no changes in heart rate.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-effects-of-the-spleen-tyrosine-kinase-inhibitor-fostamatinib-on-ambulatory-blood-pressure-in-patients-with-active-rheumatoid-arthritis-results-of-the-oskira-ambulatory-blood-pressure-mon/