Rationale and Design for the UNC Duke Acute Decompensated Heart Failure with Hypertension Study (UNDU ADHF-HTN)

Abstract

Introduction: Registry data indicate that ADHF patients (pts) are commonly hypertensive at admission. In ADHERE, the first recorded SBP was ≥ 140 mmHg in 52% of pts, and only 2% had a SBP < 90 mmHg. In contrast, baseline SBP in ADHF trials ranges from 106-121 mmHg. Pathophysiology and drug response in ADHF pts with elevated SBP may differ from pts with normal/low SBP. Nesiritide (NES) is a novel vasodilator that increases lusitropy and reduces filling pressure, peripheral arteriolar resistance, and systemic pressure. This profile may be associated with symptomatic or clinical benefit in hypertensive ADHF pts. This study will test the hypothesis that NES, initiated early, in ADHF pts presenting with SBP ≥ 140 mmHg safely lowers SBP, reduces symptoms, and improves biomarkers. Methods: UNDU ADHF-HTN is a prospective, multicenter, randomized, double-blind, placebo-controlled study. Pts with dyspnea at rest/minimal exertion within 3 hours (hrs) of ADHF presentation, pulmonary/systemic congestion, and SBP ≥ 140 mmHg at presentation (≥ 120 mmHg at randomization) will be enrolled. Major exclusions are STEMI, dialysis, NES contraindication, or non-cardiac pulmonary edema. Pts (n = 200) will be randomized 1:1 to NES or matching placebo (2 mg/kg IV bolus, then 0.01 mg/kg/min infusion for 48 hrs), on top of diuretics. IV furosemide ≤ 40 mg may be given before study drug. Subsequent diuretics will be given based on physician assessment. Pts given IV vasoactives after randomization will be considered treatment failures. Follow-up will be 180 days (d). The primary endpoint is change in SBP from baseline to 3 hrs. Secondary endpoints are change in SBP (24 hrs), change in NT-pro BNP (24 hrs), adverse outcome (worsening HF within 7 d or death at 30 d or HF rehospitalization at 30 d), symptomatic improvement (24 hrs), and total diuretic dose (48 hrs). Safety endpoints include change in estimated GFR, adverse events, and 180 d mortality. Mechanistic substudies will assess vascular compliance and neurohormones. Results: Enrollment start is planned for 08/07. Results are expected 1st quarter 2010. Conclusions: ADHF pts with HTN comprise half of the ADHF population, yet their pathophysiology is incompletely defined and no evidenced-based treatments specific to these pts are established. This study will evaluate the safety and efficacy of NES and will explore unique mechanisms that may precipitate ADHF or HF progression in hypertensive ADHF pts.