Coverage from the 23rd Annual Scientific Meeting and Exposition of the American Society of Hypertension

Cardiology Review® Online, June 2008, Volume 25, Issue 6

Bedtime aspirin lowers blood pressure in prehypertensive patients

In individuals with prehypertension, daily aspirin significantly reduces systolic blood pressure, but only when taken at bedtime, said Ramón C. Hermida, MD, director of bioengineering and chronobiology, University of Vigo, Spain. The significant systolic blood pressure-lowering effect of bedtime aspirin in patients with prehypertension mirrors the findings previously observed in hypertensive subjects. The systolic blood pressure drop with nighttime aspirin is consistent with a higher level of activation of the renin-angiotensin system overnight, said Dr Hermida.

The effect of 100 mg of aspirin on systolic blood pressure was explored in 244 prehypertensive subjects (those with a systolic blood pressure of 120 to 139 mm Hg or a diastolic blood pressure of 80 to 90 mm Hg on multiple readings) who received aspirin at different times of the day according to their rest-activity cycle. Patients were randomized to 1 of 3 groups: (1) a group that received hygienic-dietary recommendations only; (2) a group that received hygienic-dietary recommendations plus 100 mg of aspirin on awakening; and (3) a group that received hygienic-dietary recommendations plus 100 mg of aspirin at bedtime. Blood pressure and heart rate were sampled throughout a 48-hour period before treatment and again 3 months posttreatment.

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There were no changes in ambulatory systolic blood pressure in the groups assigned to hygienic-dietary measures and morning administration of aspirin. In contrast, the group assigned to aspirin at bedtime had reductions in systolic blood pressure in excess of 5 mm Hg compared with baseline during awake hours (< .001), while asleep (< .001), and over 24 hours (< .001), without any change in heart rate or physical activity compared with baseline values.

By administering bedtime aspirin to those with prehypertension, “we can delay the threshold for reaching hypertensive values,” said Dr Hermida. “This is a cost-effective and valuable approach to patients with prehypertension.” Previously, aspirin administered in the evening, but not the morning, had been found to increase the inhibition of platelet aggregation by 62% and inhibit angiotensin II formation by more than 30%.

“Aspirin has a significant effect on plasma renin activity,” said Dr Hermida. The highest values for plasma renin activity occur about 3 hours after going to bed, which may explain the blood pressure regulation by administering aspirin just before bedtime. In addition, previous research has shown that the safety profile of aspirin with respect to bleeding events is also superior with evening dosing, he noted.

Screening based on arterial elasticity identifies high-risk prehypertensive patients

Screening prehypertensive individuals for early vascular disease using a comprehensive vascular evaluation that includes measurements of arterial elasticity is superior to using conventional risk factors to identify risk for morbid cardiovascular events, said Jay N. Cohn, MD, director of the Rasmussen Center for Cardiovascular Disease Prevention, Minneapolis, Minnesota.

At the Rasmussen Center, a comprehensive vascular evaluation includes pulse contour analysis to measure small and large artery elasticity, blood pressure measurements during rest and exercise, a retinal digital photograph, calculation of the microalbumin/creatinine ratio, an ultrasound measurement of carotid intimamedial thickness (IMT), an electrocardiogram, cardiac ultrasonography, and measurement of plasma B-type natriuretic peptide. The entire evaluation takes about 1 hour. “We think this is the future of cardiovascular disease prevention efforts,” said Dr Cohn. “People don’t have myocardial infarction and stroke because of a statistical association with blood pressure, but because of abnormalities of the arteries or the heart.”

Tracking cardiovascular risk using such tools as pulse contour analysis, ultrasonography, and retinal photography, rather than blood pressure, is analogous to the superiority of Doppler radar over a barometer to track weather patterns, he said. In explaining the rationale for the use of pulse contour analysis in the evaluation, Dr Cohn said that small artery disease manifests as a decrease in small artery elasticity, microalbuminuria, retinal vascular changes, an abnormal diastolic blood pressure response to exercise, and an elevated resting blood pressure. Large artery disease manifests as a decrease in large artery elasticity, an increase in carotid IMT and carotid plaque formation, an abnormal systolic blood pressure response to exercise, and a wider pulse pressure.

A score of 0 (normal), 1 (borderline), or 2 (abnormal) is assigned to each test result to obtain a disease score (total: 0 to 20), called the Rasmussen Risk Score. “We view a score of 3 to 5 as the presence of clear-cut [vascular] disease,” said Dr Cohn. Many people with scores of 6 or greater have advancing disease, he said.

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The association between events and traditional risk factors and the Rasmussen Risk Score was tracked using data obtained from approximately 2,000 patients without a baseline event and who received such screenings at the Rasmussen Center. There was no significant difference in levels of traditional risk factors (ie, blood pressure, low-density lipoprotein cholesterol, glucose, and high-sensitivity C-reactive protein) between patients who had cardiovascular events and those who did not; however, the mean Rasmussen Risk score was 7.3 in those with events and 4.7 in those without events, a highly significant difference (< .001).

In a series of patients who were screened and followed-up for subsequent morbid events, no events occurred among the 115 with a Rasmussen Risk Score of 0 to 2 (no disease). The event rate was 6% among the 142 with a score of 3 to 5 (early disease) and 13% among the 155 with a score of 6 or greater (advanced disease).

In assessing 622 prehypertensive subjects who were screened, 34.9% had Rasmussen Risk Scores of 0 to 2, 41.3% had scores of 3 to 5, and 23.8% had advanced disease. Traditional risk factors did not identify the prehypertensive patients with early or advanced disease, noted Dr Cohn. “You cannot use traditional risk factors to determine whom with prehypertension needs treatment,” he said. “You have to define the presence of disease...the sooner we recognize this, the sooner we can be precise and not treat everyone based on blood pressure.”

Newly approved beta blocker lacks traditional side effects

Nebivolol, the newest approved (January 2008) beta blocker for the treatment of hypertension, carries few of the side effects associated with typical beta blockers, such as sexual dysfunction and depression, according to a pooled safety analysis conducted by Alan H. Gradman, MD, director, division of cardiovascular diseases at the Western Pennsylvania Hospital, and professor of medicine, Temple University, Pittsburgh.

Nebivolol is a vasodilating beta blocker that maintains cardiac output and increases stroke volume while decreasing peripheral vascular resistance. Its enhancement of endothelial nitric oxide is thought to be responsible for its vasodilator effects.

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Three multicenter, double-blind, placebo-controlled trials of nebivolol monotherapy in patients with stage 3 hypertension were used for the pooled analysis. In the studies, a total of 2,016 patients were randomized to placebo or once-daily nebivolol (1.25 to 40 mg). The primary end point in these trials was sitting diastolic blood pressure at trough at the end of therapy (84 days). Among patients randomized to 5 to 20 mg/day, nebivolol exhibited dose-dependent reductions in sitting diastolic blood pressure from 9.7 mm Hg (5 mg) to 11.1 mm Hg (20 mg), which was statistically superior (< .001) to placebo (5.0 mm Hg reduction in systolic blood pressure).

Fatigue occurred in 3.6% of the nebivolol group and 1.5% of the placebo recipients in these studies. Of the other adverse events most commonly associated with beta blockers, dyspnea occurred in 1.0% of the nebivolol-treated patients versus 0.5% of the placebo recipients; the incidence of bradycardia was 0.8% with nebivolol versus 0.5% with placebo; erectile dysfunction occurred less often with nebivolol compared with placebo (0.6% vs. 0.9%, respectively); and depression occurred in 0.3% of the nebivolol group and 0% of the placebo group. The incidence of discontinuations because of adverse events was low in the nebivolol-treated patients, ranging from 0 to 0.2%. “Further study is required to determine whether the low rates of typical beta blocker adverse events with nebivolol are the result of this agent’s unique mechanism of action, which couples cardioselectivity with endothelial nitric oxide-dependent vasodilator effects,” said Dr Gradman.

The blood pressure response to nebivolol monotherapy is significantly greater than that with placebo, when more stringent criteria than usual are used to define response, said Albert A. Carr, MD, from Southern Clinical Research and Management in Augusta, Georgia. A traditional criterion for response to antihypertensive therapy uses a diastolic blood pressure reduction ≥ 10 mm Hg, but this criterion may not adequately reflect blood pressure control because of the biological variability in steady-state blood pressure measurements, he said. Because this variability in diastolic blood pressure is as high as 15 mm Hg, defining response as a ≥ 15 mm Hg reduction is more clinically relevant.

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“If you can show that a particular dose is better than placebo using this criterion [reduction in diastolic blood pressure ≥ 15 mm Hg], it really works,” said Dr Carr. “We have been told to use partitions—less than 140/90 mm Hg and less than 130/80 mm Hg for diabetics—but maybe we should say that you need a really big change. When I see someone with left ventricular mass enlargement, if I get their blood pressure controlled by this criterion [≥15 mm Hg], the mass is lower.” Using data from randomized, controlled clinical trials of nebivolol monotherapy (1.25 to 40 mg/day) in 909 patients with stage 1 or 2 hypertension, 21.2% to 35.5% of patients treated with nebivolol experienced a decline in diastolic blood pressure of at least 15 mm Hg in a dose-dependent manner, which was significantly superior to the 9.9% response rate observed among the placebo recipients (= .038 to < .001, depending on the dose). When using an even more stringent criterion to define response—a decline in diastolic blood pressure ≥ 20 mm Hg—response rates were 8.4% to 18.1% with nebivolol compared with only 1.2% with placebo (= .032 to < .001, depending on the dose).