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LB-OR-01

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Blood pressure and brain volumes: lower is not always better: the ages-reykjavik study

Majon Muller,1,2 Thor Aspelund,2 Sigurdur Sigurdsson,3 Palmi V. Jonnson,3 Mark van Buchem,4 Vilmundur Gudnason,3 Lenore J. Launer1

1 National Institute on Aging; 2VU University Medical Center Amsterdam, The Netherlands; 3The Icelandic Heart Association, Iceland and 4Leiden Univeristy Medical Center, The Netherlands.

Background:  Midlife hypertension increases risk for brain pathology later in life. The effects of late-life BP on brain pathology is less consistent, with some studies even showing that low BP has detrimental effects on the brain. An explanation for these conflicting findings could be that chronic hypertension causes cerebrovascular pathology, making the brain more vulnerable for hypoperfusion and possibly low BP levels. We therefore hypothesize that in subjects with hypertension since midlife, lower late-life BP levels will lead to more brain pathology.

Methods:  Within the AGES-Reykjavik study (2002-06), a population-based study, analyses were performed in 4306 non-demented older individuals (mean age 76±5 years) with data on vascular risk and brain volumes on MRI. Total brain (TB) volume was calculated by summing the gray matter (GM), white matter (WM), and white matter lesion (WML) volumes. Mid-life assessment of vascular factors was conducted between 1967–96. Hypertension was defined as BP ≥140/90 mm Hg and/or use of antihypertensives.

Results:  Regression analyses adjusted for age, sex, intracranial volume, vascular risk, WML, and brain infarcts showed that the association of late-life diastolic BP (DBP), but not systolic BP (SBP), with TB and GM was modified by midlife hypertension status (P-interaction<0.01). In subjects with midlife hypertension (n=1464), but not in those without midlife hypertension, lower late-life DBP was associated with smaller TB and GM volumes (Figure 1). No interaction between midlife hypertension and late-life BP on WM was observed, but higher BP was related with smaller WM volume.

Conclusion:  Midlife hypertension in combination with lower late-life BP is associated with smaller brain volumes. These findings provide evidence of a cumulative effect of early hyper- and late hypo-perfusion that leads to certain subgroups in old age with increased susceptibility to brain atrophy.

Keywords:  Hypertension; Blood Pressure; Brain Atrophy

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LB-OR-02

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Cardiovascular outcomes in the first trial of antihypertensive therapy guided by the self-measured home blood pressure

Kei Asayama,1,2 Takayoshi Ohkubo,1,3 Hirohito Metoki,1 Taku Obara,1 Ryusuke Inoue,1 Masahiro Kikuya,1 Lutgarde Thijs,2 Jan A. Staessen,2,4 Yutaka Imai,1 HOMED-BP Investigators1,2,3

1 Tohoku University, Sendai, Japan; 2University of Leuven, Leuven, Belgium; 3Shiga University of Medical Science, Otsu, Japan and 4Maastricht University, Maastricht, The Netherlands.

Hypertension guidelines recommend blood pressure self-measurement at home (HBP), but no previous trial assessed cardiovascular outcomes in hypertensive patients treated according to HBP.

Four hundred and fifty-seven general practices throughout Japan participated in the multicenter Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure trial (HOMED-BP; 2001-2010) which involved 3518 patients (50% women; mean age 59.6 years) with an untreated systolic/diastolic HBP of 135–179/85–119 mm Hg. In a 2 × 3 design, patients were randomized to usual (125–134/80–84 mm Hg [UC]) vs. tight [<125/<80 mm Hg (TC)] control of HBP and to initiation of drug treatment with angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) or calcium channel blockers (CCBs). During follow-up, a computer algorithm automatically generated treatment recommendations based on HBP. The primary endpoint was cardiovascular death plus stroke and myocardial infarction.

At last follow-up (median 5.3 years), TC compared with UC patients used more antihypertensive drugs (1.82 vs. 1.74 defined daily doses, P=0.045), had more HBP reduction (21.3/13.1 mm Hg vs. 22.7/13.9 mm Hg, P=0.018/0.020), but less frequently achieved the lower HBP targets (37.4% vs. 63.5%, P<0.0001). The primary endpoint occurred in 25 UC and 26 TC patients (relative risk TC vs. UC, 1.02; 95% confidence interval [CI], 0.59–1.77; P=0.94). Rates were similar (P≥0.13) on ACEIs (2.81 per 1000 patient-years; CI, 1.43–4.18), ARBs (2.28; CI, 1.04–3.51) and CCBs (3.81; CI, 3.54–4.08). In all patients combined, the risk of the primary endpoint independently increased by 41% (6–89%; P=0.019) and 47% (15–87%; P=0.0020) for a 1-SD increase in baseline (12.5 mm Hg) and follow-up (13.2 mm Hg) systolic HBP. The 5 year risk was minimal (≤1%) if on-treatment systolic HBP was 131.6 mm Hg or less.

In conclusion, HOMED-BP proved the feasibility of adjusting antihypertensive drug treatment based on HBP and suggests that 130 mm Hg systolic should be an achievable and safe target of antihypertensive drug treatment.

Keywords:  Antihypertensive Drug Treatment; Blood Pressure Control; Home Blood Pressure; Randomized Clinical Trial

LB-OR-03

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Effect of body mass on cardiovascular outcomes during hypertension treatment: an accomplish analysis

Michael A. Weber,1 Kenneth Jamerson,2 George L. Bakris,3 Matthew Weir,4 Richard Devereux,5 Shawna Nesbitt,6 Dion Zappe,7 Ying Zhang,7 Bjorn Dahlof,8 Eric Velazquez,9 Bertram Pitt2

1 SUNY Downstate College of Medicine, Brooklyn, NY; 2University of Michigan, Ann Arbor, MI; 3University of Chicago, Chicago, IL; 4University of Maryland, Baltimore, MD; 5New York Hospital – Cornell Medical Center, New York, NY; 6UT Southwest Medical Center, Dallas, TX; 7Novartis Pharmaceuticals, East Hanover, NJ; 8Sahlgrenska University Hospital, Goteborg, Sweden and 9Duke University, Durham, NC.

Background:  Previous trials, including SHEP and INVEST, reported apparently paradoxical findings of higher CV event rates during treatment in normal weight patients than in obese.

Methods:  We divided the full ACCOMPLISH cohort (who were randomized into treatment with benazepril+hydrochlorothiazide [B+H] or benazepril+amlodipine [B+A]) into obese (BMI ≥30, n=5709)[OB], overweight (≥25–<30, n=4157)[OW] and normal (<25, n=1616)[NL] subgroups and compared event rates (adjusted for age, sex, diabetes, prior CV events, stroke or CKD) for a primary endpoint of CV death, MI or stroke, or the individual outcomes.

Results:  For the pooled patients (B+H plus B+A), event rates (per 1000 patient years) of the primary endpoint were 24.6 in NL, 19.5 in OW and 17.2 in OB (P=0.025 for trend); CV death was also lowest in OB (P=0.0005 for trend). Likewise, in the B+H patients, event rates for the primary endpoint (NL=30.7, OW=21.9 and OB=18.2, P=0.0034 for trend), as well as CV death (13.8, 8.4 and 5.7, P=0.0004 for trend) were lowest in OB patients. However, in the B+A patients, primary endpoint rates did not differ in the 3 BMI groups (18.2, 16.9 and 16.5, P=0.9721 for trend). In the OB patients, primary event rates during B+H and B+A were similar, but were significantly lower with B+A than B+H in OW patients: HR=0.76 (0.59–0.94), P=0.0369, and in the NL patients: HR=0.57 (0.39–0.84), P=0.0037.

Conclusion:  Thiazide-based therapy, as in previous trials, provides reduced CV protection in overweight or normal weight patients. In contrast, amlodipine-based therapy is equally effective across BMI subgroups and thus offers superior outcomes benefits in non-obese hypertensive patients.

Keywords:  Obesity; Clinical Trials; Combination Therapy; Cardiovascular Outcomes

LB-OR-04

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Long-term effects of dulaglutide, a novel GLP-1 agonist, on ambulatory blood pressure and heart rate in patients with type 2 diabetes

K. C. Ferdinand,1 D. A. Calhoun,2 E. M. Lonn,3 W. B. White,4 H. Jiang,5 R. J. Threlkeld,5 K. E. Robertson,5 M. J. Geiger5

1 Tulane University School of Medicine, New Orleans, LA; 2University of Alabama at Birmingham, Birmingham, AL; 3McMaster University, Hamilton, ON, Canada; 4University of Connecticut Health Center, Farmington, CT and 5Lilly Research Laboratories, Indianapolis, IN.

Introduction:  Glucagon-like peptide-1 (GLP-1) agonists, used for the treatment of type 2 diabetes mellitus (T2DM), have been associated with reductions in systolic BP (SBP) and increases in heart rate (HR). However, these findings are based primarily on studies using clinic measurements which may be inadequate for assessment of the complete pharmacodynamic profile. We investigated the effects of a novel GLP-1 agonist, dulaglutide (dula) administered once weekly, on BP and HR using ambulatory blood pressure monitoring (ABPM) in a large trial of patients with T2DM.

Methods:  Seven hundred and fifity-five patients with T2DM, who had an HbA1c ≥7.0% to ≤9.5% while taking ≥1 oral antihyperglycemic agent and a clinic BP >90/60 mm Hg and <140/90 mm Hg on ≤3 antihypertensive agents, were randomized to either placebo, dula 0.75 mg, or dula 1.5 mg SQ once weekly for 26 weeks. Twenty-four-hour ABPM was obtained at baseline and 4, 16, and 26 weeks post-randomization. The primary endpoint was change from baseline to Week 16 in the 24-hour SBP. A tree gatekeeping strategy was used to control type I error and compare the effects of both dula doses to placebo using a noninferiority (NI) margin of 3 mm Hg. Superiority testing was performed only if the NI margin was met.

Results:  Patients in the trial were 56±10 years, 81% were Caucasian, and 48% were female. The average BMI was 33±6 kg/m2 and HbA1c 7.9±0.8%. Most (67%) were hypertensive and 71% were on antihypertensive therapy. Results (Table) demonstrated significant reductions from baseline in 24-hour SBP but not diastolic BP on dula 1.5 mg. Increases in 24-hour HR were observed with both doses (figure 1).

Abbreviation:  DBP=diastolic blood pressure; LSM=least squares mean; SBP=systolic blood pressure; SD = standard deviation.

NI test: 1-sided α=0.0135, *P<0.001; Superiority test: 1-sided α=0.0135, †P<0.001.

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Conclusions:  This was the first large, prospective, randomized trial to demonstrate the chronic effects of a GLP-1 agonist on ambulatory BP and HR. Mechanisms of reductions in SBP on dula are yet to be elucidated as are the clinical implications of these findings.

LB-OR-05

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Altered lymphatic function and architecture in mice and rats fed a high salt diet

Sunkuk Kwon, Germaine D. Agollah, Eva M. Sevick-Muraca

University of Texas Health Science Center, Houston, TX.

The lymphatic system plays an important role maintaining the fluid homeostasis between the blood vascular and interstitial tissue compartment and there is recent evidence that its transport capabilities may regulate blood pressure in salt-induced hypertension. Yet, there is little known how the lymphatic contractile function and architecture responds to dietary salt-intake. We longitudinally characterized lymphatic contractile function and vessel remodeling non-invasively using dynamic near-infrared fluorescence (NIRF) imaging in animal models of salt-induced hypertension.

The lymphatics of mice and rats were imaged following intradermal (i.d.) injection of indocyanine green (ICG) to the base of the tail before and during two weeks of either a high salt diet (HSD) or normal chow. Our non-invasive imaging data demonstrated dilated lymphatic vessels in the skin of mice and rats on a HSD as compared to baseline. In addition, our dynamic imaging results showed increased lymphatic contraction frequency in HSD-fed mice and rats. Depletion of macrophages using clodronate liposomes in HSD-fed rats significantly increased contraction frequency as compared to control rats, but reduced contraction frequency as compared to rats fed a HSD alone and fed a HSD with treatment of PBS liposomes, suggesting vascular endothelial growth factor (VEGF)-C secreted by macrophages is an important mediator for lymphatic contractility.

Lymphatic contractile function and vessel remodeling occurs in response to salt-induced hypertension suggesting a possible role for the lymphatics in the regulation of vascular blood pressure. The work presented herein provides preclinical evidence for the use of the novel NIRF imaging technology for evaluating lymphatic response in different types of hypertension as well as in other emerging therapeutics that ameliorate hypertension.

Keywords:  Functional Lymphatic Imaging; Near-Infrared Fluorescence Imaging; Salt-Induced Hypertension; Lymphatic Contractile Function

LB-OR-06

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Effects of a novel anemia treatment, FG-4592 – an oral hypoxia-inducible prolyl hydroxylase inhibitor (HIF-PHI) on blood pressure and cholesterol in patients with chronic kidney disease

George L. Bakris,1 Kin-Hung Peony Yu,2 Robert Leong,2 Wen Shi,2 Tyson Lee,2 Khalil Saikali,2 Eugenia Henry,2 Thomas B. Neff2

1 ASH Comprehensive Hypertension Center, The University of Chicago Medicine, Chicago, IL and 2FibroGen, Inc., San Francisco, CA.

Background:  Chronic kidney disease (CKD) is associated with comorbidities including hypertension, dyslipidemia, and anemia. FG-4592 is an oral HIF-PHI being developed for anemia treatment.

Methods:  Two randomized, open-label studies are presented. Study 1: 144 adult, epoetin naïve, Stages 3–4 CKD subjects, with stable Hb ≤10.5 g/dl were randomized to FG-4592 for 16 or 24 weeks. Study 2: 159 dialysis subjects receiving epoetin alfa (EPO) to maintain Hb 9–13.5 g/dl were randomized to FG-4592 or EPO for up to 19 weeks. Primary efficacy assessment was change in Hb levels. For subjects with paired baseline (BL) and subsequent time points, lipid and ambulatory blood pressure (BP) changes were evaluated using paired t-test and ANCOVA.

Results:  Study 1: 91% of the first 96 subjects to complete treatment achieved a Hb response (mean Hb ≥11 g/dl and Hb increase from BL ≥1 g/dl). Study 2: FG-4592 maintained/increased Hb in dialysis subjects switched from EPO. Table 1 summarizes total cholesterol (TC) changes. In Study 1, about two-thirds of the subjects were receiving lipid-lowering agents (primarily statins and fibrates); comparable mean % reductions in TC were observed between those taking lipid-lowering medication(s) and those not. Subjects with BL TC >200 mg/dl had greater mean TC reductions than those with BL ≤200 mg/dl. Preliminary lipid testing in a subset of subjects (n=28) revealed mean reductions from BL at week 9 in LDL (18±23%), HDL (8±17%), triglycerides (13±45%), and VLDL (14±44%).

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The HDL/LDL ratio increased from a mean of 0.56 at BL to 0.67 at week 9 (P=0.013). Antihypertensive medications were used by 90% of subjects at study entry in Study 1. The BL mean sBP was 133±13.9 mm Hg and dBP was 69.2±9.2 mm Hg. An analysis of subjects on study medication at study end showed that (N=48/96) 50% had no change in BP medication during treatment. Additionally, FG-4592 reduced mean arterial pressure (−2.6±9.6 mm Hg, P=0.03) at end of treatment. Overall, FG-4592 was well tolerated with no drug-related serious adverse events.

Conclusion:  FG-4592 corrects/maintains Hb with favorable effects on TC, increasing HDL/LDL ratio, and lowering BP. Additionally, the hypertension rate with FG-4592 appears lower than in historical EPO studies (Figure 1). Authors 1 and 2 are equal contributors.