Feasibility of Treating Prehypertension with an Angiotensin-Receptor Blocker

Stevo Julius, M.D., Sc.D., Shawna D. Nesbitt, M.D., Brent M. Egan, M.D., Michael A. Weber, M.D., Eric L. Michelson, M.D., Niko Kaciroti, Ph.D., Henry R. Black, M.D., Richard H. Grimm, Jr., M.D., Ph.D., Franz H. Messerli, M.D., Suzanne Oparil, M.D., M. Anthony Schork, Ph.D., for the Trial of Preventing Hypertension (TROPHY) Study Investigators

ABSTRACT

Background Prehypertension is considered a precursor of stage 1 hypertension and a predictor of excessive cardiovascular risk. We investigated whether pharmacologic treatment of prehypertension prevents or postpones stage 1 hypertension.

Methods Participants with repeated measurements of systolic pressure of 130 to 139 mm Hg and diastolic pressure of 89 mm Hg or lower, or systolic pressure of 139 mm Hg or lower and diastolic pressure of 85 to 89 mm Hg, were randomly assigned to receive two years of candesartan (Atacand, AstraZeneca) or placebo, followed by two years of placebo for all. When a participant reached the study end point of stage 1 hypertension, treatment with antihypertensive agents was initiated. Both the candesartan group and the placebo group were instructed to make changes in lifestyle to reduce blood pressure throughout the trial.

Results A total of 409 participants were randomly assigned to candesartan, and 400 to placebo. Data on 772 participants (391 in the candesartan group and 381 in the placebo group; mean age, 48.5 years; 59.6 percent men) were available for analysis. During the first two years, hypertension developed in 154 participants in the placebo group and 53 of those in the candesartan group (relative risk reduction, 66.3 percent; P<0.001).> years, hypertension had developed in 240 participants in the placebo group and 208 of those in the candesartan group (relative risk reduction, 15.6 percent; P<0.007).> occurred in 3.5 percent of the participants assigned to candesartan and 5.9 percent of those receiving placebo.

Conclusions Over a period of four years, stage 1 hypertension developed in nearly two thirds of patients with untreated prehypertension (the placebo group). Treatment of prehypertension with candesartan appeared to be well tolerated and reduced the risk of incident hypertension during the study period. Thus, treatment of prehypertension appears to be feasible. (ClinicalTrials.gov number, NCT00227318 [ClinicalTrials.gov] .)

Treatment of Hypertension in Patients 80 Years of Age or Older

Nigel S. Beckett, M.B., Ch.B., Ruth Peters, Ph.D., Astrid E. Fletcher, Ph.D., Jan A. Staessen, M.D., Ph.D., Lisheng Liu, M.D., Dan Dumitrascu, M.D., Vassil Stoyanovsky, M.D., Riitta L. Antikainen, M.D., Ph.D., Yuri Nikitin, M.D., Craig Anderson, M.D., Ph.D., Alli Belhani, M.D., Françoise Forette, M.D., Chakravarthi Rajkumar, M.D., Ph.D., Lutgarde Thijs, M.Sc., Winston Banya, M.Sc., Christopher J. Bulpitt, M.D., for the HYVET Study Group

ABSTRACT

Background Whether the treatment of patients with hypertension who are 80 years of age or older is beneficial is unclear. It has been suggested that antihypertensive therapy may reduce the risk of stroke, despite possibly increasing the risk of death.

Methods We randomly assigned 3845 patients from Europe, China, Australasia, and Tunisia who were 80 years of age or older and had a sustained systolic blood pressure of 160 mm Hg or more to receive either the diuretic indapamide (sustained release, 1.5 mg) or matching placebo. The angiotensin-converting–enzyme inhibitor perindopril (2 or 4 mg), or matching placebo, was added if necessary to achieve the target blood pressure of 150/80 mm Hg. The primary end point was fatal or nonfatal stroke.

Results The active-treatment group (1933 patients) and the placebo group (1912 patients) were well matched (mean age, 83.6 years; mean blood pressure while sitting, 173.0/90.8 mm Hg); 11.8% had a history of cardiovascular disease. Median follow-up was 1.8 years. At 2 years, the mean blood pressure while sitting was 15.0/6.1 mm Hg lower in the active-treatment group than in the placebo group. In an intention-to-treat analysis, active treatment was associated with a 30% reduction in the rate of fatal or nonfatal stroke (95% confidence interval [CI], –1 to 51; P=0.06), a 39% reduction in the rate of death from stroke (95% CI, 1 to 62; P=0.05), a 21% reduction in the rate of death from any cause (95% CI, 4 to 35; P=0.02), a 23% reduction in the rate of death from cardiovascular causes (95% CI, –1 to 40; P=0.06), and a 64% reduction in the rate of heart failure (95% CI, 42 to 78; P<0.001).> were reported in the active-treatment group (358, vs. 448 in the placebo group; P=0.001).

Conclusions The results provide evidence that antihypertensive treatment with indapamide (sustained release), with or without perindopril, in persons 80 years of age or older is beneficial. (ClinicalTrials.gov number, NCT00122811 [ClinicalTrials.gov] .)

Modulation of Blood Pressure by Central Melanocortinergic Pathways

Jerry R. Greenfield, M.D., Ph.D., Jeffrey W. Miller, M.D., Julia M. Keogh, B.Sc., Elana Henning, B.Soc.Sc., Julie H. Satterwhite, Ph.D., Gregory S. Cameron, Ph.D., Beatrice Astruc, M.D., John P. Mayer, Ph.D., Soren Brage, Ph.D., Teik Choon See, M.D., David J. Lomas, M.D., Stephen O'Rahilly, M.D., and I. Sadaf Farooqi, M.D., Ph.D.

ABSTRACT

Background Weight gain and weight loss are associated with changes in blood pressure through unknown mechanisms. Central melanocortinergic signaling is implicated in the control of energy balance and blood pressure in rodents, but there is no information regarding such an association with blood pressure in humans.

Methods We assessed blood pressure, heart rate, and urinary catecholamines in overweight or obese subjects with a loss-of-function mutation in MC4R, the gene encoding the melanocortin 4 receptor, and in equally overweight control subjects. We also examined the effects of an MC4R agonist administered for 7 days in 28 overweight or obese volunteers.

Results The prevalence of hypertension was markedly lower in the MC4R-deficient subjects than in the control subjects (24% vs. 53%, P=0.009). After the exclusion of subjects taking antihypertensive medications, blood-pressure levels were significantly lower in MC4R-deficient subjects than in control subjects, with mean (±SE) systolic blood pressures of 123±14 mm Hg and 131±12 mm Hg, respectively (P=0.02), and mean diastolic blood pressures of 73±10 mm Hg and 79±7 mm Hg, respectively (P=0.03). As compared with control subjects, MC4R-deficient subjects had a lower increase in heart rate on waking (P=0.007), a lower heart rate during euglycemic hyperinsulinemia (P<0.001), and lower 24-hour urinary norepinephrine excretion (P=0.04). The maximum tolerated daily dose of 1.0 mg of the MC4R agonist led to significant increases of 9.3±1.9 mm Hg in systolic blood pressure and of 6.6±1.1 mm Hg in diastolic blood pressure (P<0.001> with placebo. Differences in blood pressure were not explained by changes in insulin levels; there were no significant adverse events.

Conclusions Results of our genetic and pharmacologic studies implicate melanocortinergic signaling in the control of human blood pressure through an insulin-independent mechanism.