K. Ferdinand, F. Balavoine, B. Besse
Jul 9, 2019
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Influential Citations
35
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Quality indicators
Journal
Circulation
Abstract
BACKGROUND Despite existing therapy, successful control of hypertension [HTN] in the United States is estimated at less than 50%. In Blacks, HTN occurs earlier, is more severe, controlled less often and has a higher morbidity and mortality than in Whites. Blacks are also less responsive to monotherapy with angiotensin-I converting enzyme [ACE] inhibitors or angiotensin-II receptor type 1 blockers [ARBs]. Obesity, higher salt-sensitivity and low plasma renin activity are possible reasons of this poor blood pressure [BP] control, especially in Blacks. The aim of the study was to assess efficacy and safety of firibastat, a first-in-class aminopeptidase A inhibitor preventing conversion of brain angiotensin-II into angiotensin-III, in BP lowering in a high-risk diverse hypertensive population. METHODS 256 overweight or obese hypertensive patients, including 54% black and Hispanic individuals, were enrolled in a multicenter, open-label, phase II study. After a 2-week wash-out period, subjects received firibastat for 8 weeks (250 mg b.i.d. orally for 2 weeks, then 500 mg b.i.d. if automated office blood pressure [AOBP] >140/90 mmHg; hydrochlorothiazide 25 mg q.d was added after 1 month if AOPB ≥160/110 mmHg). The primary endpoint was change from baseline in systolic AOBP after 8 weeks of treatment, and secondary endpoints include diastolic AOBP, 24-hour mean ambulatory BP and safety. RESULTS Firibastat lowered systolic AOBP by 9.5 mmHg (p <0.0001) and diastolic AOBP by 4.2 mmHg (p <0.0001). 85% of the subjects did not receive hydrochlorothiazide and were treated with firibastat alone. Significant BP reduction was found across all sub-groups regardless age, sex, body mass index or race. Systolic AOBP decreased by 10.2 mmHg (p <0.0001) in obese patients, by 10.5 mmHg (p <0.0001) in Blacks, and 8.9 mmHg (p <0.0001) in Non-Blacks. Most frequent adverse events were headaches (4%) and skin reactions (3%). No angioedema was reported. No change in potassium, sodium and creatinine blood level were observed. CONCLUSIONS Our results demonstrate the efficacy of firibastat in lowering BP in a high-risk diverse population where monotherapy with ACE inhibitors or ARBs may be less effective and support the strategy to further investigate firibastat in subjects with difficult-to-treat or potentially resistant HTN. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique Identifier: NCT03198793.