Background-Neurohormones are considered markers of heart failure progression. We examined whether changes in brain natriuretic peptide (BNP) and norepinephrine (NE) over time are associated with corresponding changes in mortality and morbidity in the Valsartan Heart Failure Trial. Methods and Results-Plasma BNP and NE were measured before randomization and during follow-up in Ϸ4300 patients in the Valsartan Heart Failure Trial. The relation between baseline BNP and NE and all-cause mortality and first morbid event (M&M) was analyzed in subgroups, with values above and below the median, and by quartiles. The change and percent change from baseline to 4 and 12 months in BNP and NE were also analyzed by quartiles for subsequent M&M. Risk ratios for M&M were calculated using a Cox proportional hazard model. Risk ratio of M&M for patients with baseline BNP or NE above the median was significantly higher than that for patients with values below the median. Baseline BNP and NE in quartiles also showed a quartile-dependent increase in M&M. BNP had a stronger association with M&M than NE. Patients with the greatest percent decrease in BNP and NE from baseline to 4 and 12 months had the lowest whereas patients with greatest percent increase in BNP and NE had the highest M&M. Conclusions-Not only are plasma BNP and NE important predictors of heart failure M&M, but changes in these neurohormones over time are associated with corresponding changes in M&M. These data further reinforce their role as significant surrogate markers in HF and underscore the importance of including their measurement in HF trials.

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Abstract-Many patients with hypertension require Ն3 agents to achieve target blood pressure (BP). The efficacy/safety of the dual combinations of valsartan (Val)/hydrochlorothiazide (HCTZ) and amlodipine (Aml)/Val in hypertension are well established. This randomized, double-blind study evaluated the efficacy/safety of triple therapy with Aml/Val/ HCTZ for moderate or severe hypertension (mean sitting systolic BP: Ն145 mm Hg; mean sitting diastolic BP: Ն100 mm Hg). The study included a single-blind, placebo run-in period, followed by double-blind treatment for 8 weeks; patients were randomly assigned to 1 of 4 groups titrated to Aml/Val/HCTZ 10/320/25 mg, Val/HCTZ 320/25 mg, Aml/Val 10/320 mg, or Aml/HCTZ 10/25 mg once daily. Dual-therapy recipients received half of the target doses of both agents for the first 2 weeks, titrating to target doses during week 3. Those on triple therapy received Val/HCTZ 160.0/12.5 mg during week 1, Aml/Val/HCTZ 5.0/160.0/12.5 mg during week 2, and target doses of all 3 of the agents during week 3. Of the 4285 patients enrolled, 2271 were randomly assigned to treatment, and 2060 completed the study. Key Words: amlodipine Ⅲ valsartan Ⅲ hydrochlorothiazide Ⅲ hypertension Ⅲ triple therapy H ypertension treatment guidelines recommend a target blood pressure (BP) goal of Ͻ140/90 mm Hg for uncomplicated hypertension. Target goals are lower (Ͻ130/ 80 mm Hg) for patients with hypertension complicated by diabetes mellitus or renal disease or for those considered at high risk (eg, history of stroke or myocardial infarction). 1,2 To facilitate attainment of these target goals in at-risk patients, the guidelines recommend dual therapy as the initial treatment. 1,2 However, despite extensive evidence of the negative effects of poorly controlled BP and the numerous antihypertensive agents available, only approximately one third of hypertensive patients achieve adequate BP control in the United States. 3 Because of the multifactorial nature of hypertension, most patients require treatment with Ͼ1 antihypertensive agent to achieve target pressure, 4 with many patients requiring Ն3 agents. 5,6 Antihypertensive regimens that include Ն2 agents with complementary mechanisms of action may result in greater reductions in BP than the single-agent components. For example, the use of a calcium channel blocker, an angiotensin receptor blocker, and a thiazide diuretic represents a logical choice for combination therapy. A calcium channel blocker inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle, an angiotensin receptor blocker inhibits angiotensin II-mediated vasoconstriction and renal sodium retention, and a thiazide diuretic reduces intravascular volume and total body sodium. In addition to potential efficacy benefits when used in combination, one antihypertensive agent may attenuate certain adverse effects of another. 7,8 For example, in addition to valsartan (Val) and hydrochlorothiazide (HCTZ) providing a greater antihypertensive effect in combination over ...