Vascular disease and the renin-angiotensin system in the patient with hypertension.
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Humans↗
Biomedical subjects
W B White
Publications and source records attributed to W B White.
The evaluation of antihypertensive therapy using 24-h ambulatory monitoring technology.
Several specific features of ambulatory monitoring of the blood pressure have made it important in clinical trials that assess antihypertensive drug therapy. These include the removal of observer bias, improved short-term and long-term blood pressure reproducibility compared with clinic readings, elimination of the 'white-coat' effect during patient selection and the ability to assess the effects of long-acting once daily therapies on diurnal and nocturnal blood pressure. In this article, an overview of the utility of ambulatory blood pressure monitoring in clinical trials is provided, with specific examples that use data from recent studies of the newer compounds that block the renin-angiotensin system.
Antihypertensive Agents↗
Vascular disease and the renin-angiotensin system in the patient with hypertension: panel discussion and questions from the audience.
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Humans↗
Ambulatory blood pressure monitoring: dippers compared with non-dippers.
Epidemiologic studies have demonstrated that the peak incidence of most types of cardiovascular disease follows a circadian (24 h) pattern. Ambulatory monitoring studies have documented a reproducible 24 h rhythm for blood pressure, characterized by a period of low values during sleep, an early-morning increase in pressures, and a plateau period while the individual is awake and active. Hypertensive patients who display the typical nocturnal decrease in blood pressure are termed 'dippers', whereas patients in whom the nocturnal decrease in blood pressure is absent or blunted are termed 'non-dippers'. The circadian rhythm may be influenced by demographic, neurohormonal, and pathophysiologic factors. The non-dipper profile appears to be of prognostic significance because it is associated with increased target-organ damage and a worsened cardiovascular outcome. Chronotherapy is a new pharmacologic concept whereby medication is delivered at a time and in a concentration that varies according to physiologic need during the dosing period. Of greatest interest is the reduction in blood pressure during the early-morning blood pressure surge, as that time is associated with an increased risk for myocardial infarction and stroke. Factors that may increase the early-morning blood pressure include activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. In the near future, the benefits of a chronotherapeutic approach to the management of hypertension should be elucidated by large-scale outcome studies.
Antihypertensive Agents↗
Cardiovascular risk and ambulatory blood pressure.
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Blood Pressure↗
Assessment of once-daily eprosartan, an angiotensin II antagonist, in patients with systemic hypertension. Eprosartan Study Group.
A multicenter, randomized, double-masked, placebo-controlled trial was conducted to assess the efficacy of once-daily eprosartan, a nonbiphenyl, nontetrazole angiotensin II-receptor antagonist, in 243 patients with mild-to-moderate systemic hypertension (sitting diastolic blood pressure [SitDBP], 95-114 mm Hg). After a 3-to 5-week single-masked placebo run-in period to obtain baseline values, patients were randomly allocated to receive 600 mg eprosartan once daily or placebo for 8 weeks. All clinic blood pressure measurements were made 24 hours +/-90 minutes after dosing. Eprosartan produced statistically and clinically significant reductions in SitDBP(-7.5+/-0.8 mm Hg) and sitting systolic blood pressure (SitSBP) (-6.0+/-1.3 mm Hg) compared with placebo (SitDBP -1.9+/-0.7 mm Hg; SitSBP 0.8+/-1.2 mm Hg). The 95% confidence intervals for the difference from placebo were -8.1 to 4.1 for SitDBP and -11.0 to -4.0 for SitSBP (both, P<0.0001). The proportion of patients responding (SitDBP was <90 mm Hg or had decreased by > or =10 mm Hg from baseline at study end point) to eprosartan was significantly higher than the proportion of those responding to placebo (42% vs. 21%, respectively; P = 0.0003). Similar results were obtained in a subgroup analysis comparing patients aged <65 years with those aged > or =65 years. The total number of adverse events was similar in the eprosartan and placebo groups. Eprosartan 600 mg once daily was both well tolerated and effective, providing significant blood pressure reduction 24 hours after dosing in patients with mild-to-moderate systemic hypertension, regardless of age.
Acrylates↗
Heart rate and the rate-pressure product as determinants of cardiovascular risk in patients with hypertension.
Inability to supply oxygen to the myocardium when demand is high appears to be related to several cardiovascular events, including transient myocardial ischemia, acute myocardial infarction, and sudden death. Myocardial oxygen consumption is correlated with the rate-pressure product (heart rate x systolic blood pressure) and this hemodynamic parameter has been shown to follow a circadian pattern similar to that observed with cardiovascular events. However, the clinical implications of this observation and the appropriate clinical interventions have not been studied. Therefore, the impact of the chronotherapeutic controlled-onset extended release delivery (COER-verapamil) on heart rate and the rate-pressure product was assessed and compared with that of nifedipine gastrointestinal therapeutic system (GITS), which is designed to provide a constant or homeostatic drug effect. A total of 557 hypertensive patients were enrolled in the 51-center, randomized, double-blind prospective study. Twenty-four-hour ambulatory blood pressure (BP) monitoring was performed at baseline, after 4 weeks of stable-dose therapy, and after 10 weeks of treatment; heart rate was assessed concomitantly. Heart rate, rate of rise (slope) of BP and heart rate, and the rate-pressure product were all reduced to a greater extent by COER-verapamil during the early morning hours compared with the nifedipine GITS treatment. Thus, COER-verapamil exerted a beneficial hemodynamic profile for the treatment of the increases in rate-pressure product typically observed in the early morning in patients with hypertension.
Blood Pressure↗
Differential effects of morning and evening dosing of nisoldipine ER on circadian blood pressure and heart rate.
The time of administration of once-daily antihypertensive agents may have a significant impact on blood pressure control during awake and sleep periods. Using 24-h ambulatory monitoring, we compared the effects of morning and evening dosing of the long-acting dihydropyridine calcium channel blocker, nisoldipine extended-release (ER), on circadian blood pressure (BP) and heart rate in patients with mild-to-moderate hypertension. After completing a 3-week placebo run-in period, 85 patients were randomized to morning versus evening nisoldipine ER treatment at a fixed 20-mg dose. Patients were treated for 4 weeks, followed by crossover to the alternate dosing regimen for 4 additional weeks. Twenty-four-hour ambulatory monitoring was performed at baseline and at 4 and 8 weeks after randomization. Awake and sleep times were determined by electronic activity recorders (Actigraphy). Similar least-squares (+/-SE) mean changes from baseline in 24-h BP (systolic BP/diastolic BP: -11.9/-7.4 +/- 0.6/0.5 v -11.6/-6.5 +/- 0.6/0.5 mm Hg) and heart rate (1.0/1.7 +/- 0.4/0.4 beats/min) occurred with morning and evening administration, respectively. A significantly greater effect on awake diastolic BP (systolic BP/diastolic BP: -12.6/-8.1 +/- 0.7/0.4 v -11.3/-6.4 +/- 0.7/0.4 mm Hg; P = .16/.01) was observed with morning dosing compared with evening dosing. In addition, small increases in sleep and early morning heart rate were seen with evening compared with morning administration of nisoldipine (sleep, 3.1 +/- 0.4 v 0.4 +/- 0.4 beats/min; P < .001; early morning, 3.5 +/- 0.7 v 0.5 +/- 0.7 beats/min; P = .002). These differential effects on awake BP and sleep heart rate were also observed in patients who had normal (dippers) and elevated (nondippers) BP values during sleep. Appropriate evaluation of the efficacy and safety of long-acting antihypertensive agents is essential when evening administration is being considered. In the present study, the timing of nisoldipine ER administration had no effect on mean changes in BP and heart rate over a 24-h period. However, nisoldipine ER had some differential effects during sleep and awake periods with morning relative to evening dosing.
Antihypertensive Agents↗
Clinical experience with transdermal clonidine in African-American and Hispanic-American patients with hypertension: evaluation from a 12-week prospective, open-label clinical trial in community-based clinics.
The objective of this study was to assess the efficacy and tolerability of transdermal clonidine in inner-city African-American and Hispanic-American patients with essential hypertension. A multiclinic open-label, prospective trial for 12 weeks was used. Dose titration was based on office blood pressure (BP) measurements of > 140/90 mm Hg. Clinical sites were community-based primary care centers. Untreated and treated hypertensive patients whose diastolic BP exceeded 90 mm Hg were administered transdermal clonidine at 0.1 mg or 0.2 mg delivery daily. The drug was titrated after 1 month if diastolic BP was greater than 90 mm Hg. At 12 weeks of treatment, change in blood pressure from baseline as well as adverse effects and patient satisfaction were assessed. A total of 357 patients entered the treatment phase of the study, and 315 patients (244 African-Americans, 67 Hispanic-Americans) had evaluable data. Transdermal clonidine significantly (P <.001) lowered BP in all patients by 15.7/12.8 +/- 18.1/9.6 mm Hg, and heart rate was reduced by 3 +/- 9 beats/min (P <.001). There were no differences in BP reduction according to race and ethnicity, gender, or age. The most common adverse effects were pruritus or discomfort at the patch site, dizziness, dry mouth, and fatigue. Eleven percent of the patients discontinued treatment because of one of these adverse effects. A large proportion of patients (67%) reported that transdermal clonidine was more convenient to use than oral therapy. Transdermal clonidine, alone or in combination with other antihypertensive therapies, significantly lowered BP and heart rate in inner-city hypertensive patients. The drug was generally well tolerated, with 89% of the patients remaining in the trial. Patient acceptability was high with the once-weekly treatment, which is an important feature for this particular hypertensive population.
Administration, Cutaneous↗
Task force VI: Self-monitoring of the blood pressure.
BACKGROUND: Self-monitoring of the blood pressure by patients at home or in other nonclinical settings has become increasingly common in recent years. This phenomenon has been fueled in part by the increase in availability of automatic sphygmomanometers, which are now both affordable and easy for patients to use. BENEFITS OF SELF-MONITORING: Self-monitoring of the blood pressure can be an important adjunct to management of hypertension. The technique allows patients to participate more in their care. Self-measured values of blood pressure are more likely to be representative of the average daily blood pressure than is a clinic measurement and may be better related to hypertensive involvement of target organs and cardiovascular morbidity than is the clinic blood pressure. Finally, the self-monitoring of blood pressure has the potential to reduce the costs of hypertension-related care. LIMITATIONS OF SELF-MONITORING: There are several issues that prevent the more widespread use of self-monitoring of the blood pressure in clinical practice. First, devices marketed for use by patients have advanced technically during the 1990s, but many have not been subjected to rigorous clinical validation for precision and reliability (e.g. in terms of Association for the Advancement of Medical Instrumentation and British Hypertension Society guidelines). It is recommended that devices for measuring blood pressure used by patients at home be subjected to the same validation processes as those that are applied to ambulatory recordings. Second, although the upper limits of normal for self-monitored blood pressure of a general population can be defined statistically (it is approximately 135/85 mmHg), it is not yet possible to determine the normal self-monitored blood pressure because these values must be linked to classical clinical cardiovascular endpoints or outcomes. Third, the relationships among self-monitored, clinic, and ambulatory blood pressures are defined for some populations but their behaviors according to age, sex, ethnicity, and treatment status require further study. Fourth, several different schedules for self-monitoring of the blood pressure by patients have been used in clinical research and practice. It will be necessary to determine the optimal schedule and number of recordings required when patients perform self-monitoring of the blood pressure. Fifth, self-monitoring of the blood pressure in clinical trials of antihypertensive therapies is certainly feasible but has typically not been included in their design, either by investigators or by the pharmaceutical sponsors. Sixth, there have been data suggesting that self-monitoring of the blood pressure reduces the comprehensive costs associated with hypertension care on an annual basis. However, since most work on the economic impact of self-monitoring of the blood pressure has been performed in managed-care environments in the USA, it is not known whether this reduction in health-care costs would be applicable to other types of practice environments on a worldwide basis. CONCLUSIONS: Self-monitoring of the blood pressure is at present useful as an adjunct measurement for the management of hypertensive patients and might provide benefits in clinical trials of antihypertensive therapy. Nevertheless, the available data on self-monitoring of the blood pressure are inadequate as grounds for clinicians to make primary diagnostic or therapeutic decisions and should not override the blood pressure obtained by clinical measurement or via ambulatory monitoring.
Blood Pressure↗
Is white-coat hypertension innocent or detrimental?
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Blood Pressure↗
Effects of the chronotherapeutic delivery of verapamil on circadian blood pressure in African-American patients with hypertension.
OBJECTIVE: To evaluate the effects of COER-verapamil on circadian blood pressure (BP) and heart rate in African-American patients with hypertension. DESIGN: Retrospective pooled analyses of efficacy and tolerability data from three prospective, randomized, double-blind, placebo-controlled trials with COER-verapamil in hypertension. PATIENTS/PARTICIPANTS: Sixty-eight African-American patients with stages I-III hypertension (seated diastolic BP, 95-114 mm Hg) were randomized to receive placebo or treatment with 180-540 mg of COER-verapamil once daily at bedtime for 4 to 8 weeks. METHODS: Using ambulatory monitoring, efficacy was assessed by measuring change from baseline in systolic and diastolic BP, heart rate, and the heart rate-systolic pressure product during three time intervals: early morning (0600 to 1000), daytime (0800 to 2200), and nighttime (2200 to 0800). Changes also were compared to data from the non-African-American population. Adverse effects were tabulated at each visit. RESULTS: Mean changes from baseline in early-morning BP, heart rate, and rate-pressure product for patients treated with COER-verapamil were -13.8/-11.2 mm Hg, -6.2 beats/minute, and -1960 mm Hg-beats/min, respectively (P<0.01 for all parameters compared to placebo). Significant and similar reductions also were observed for daytime and nighttime BP, heart rate, and the rate-pressure product. The incidence of side effects in the COER-verapamil-treated patients was similar to placebo and the African-American patients had similar incidences to the non-African-American patients. CONCLUSIONS: The chronotherapeutic delivery of verapamil significantly reduced circadian BP, heart rate, and the rate-pressure product. The side effect profile of COER-verapamil was similar to that of placebo. Thus, this therapy for delivery of a heart-rate lowering calcium channel blocker is a useful antihypertensive strategy for African-American patients with hypertension.
Black or African American↗
Circadian variation of blood pressure and the assessment of antihypertensive therapy.
The inherent variability of activity and the awake-sleep cycle creates changes in hemodynamics that may influence the outcome of a variety of cardiovascular disorders. Recently, data suggest that increased variability of blood pressure may promote excessive hypertensive target organ disease. Several epidemiologic studies have demonstrated that myocardial ischemia, myocardial infarction and sudden cardiac death have an excess incidence in the first several hours post-awakening. Additionally, surveys of the incidence of stroke (both ischemic and hemorrhagic) have shown an excess for the hours between 8 a.m. and noon. The pathophysiologic bases for the increased number of cardiac and cerebrovascular events in the early morning hours may be both due to hemodynamic and hematorrheologic factors. During the past several years, therapeutic studies have evaluated the effects of antihypertensive therapies on blood pressure and heart rate during the circadian or 24 h period. There are a few studies that have evaluated nighttime dosing of conventional antihypertensive therapies but these have generally been statistically underpowered to demonstrate differences of morning versus evening dosing on circadian blood pressure. Since the timing of dosing (and hence the delivery of antihypertensive therapy) may be clinically relevant, prospective and well-performed clinical trials of chronotherapy are necessary. In this review, we evaluate new data on the clinical impact of cardiovascular chronotherapy and the importance of timing of dosing on pharmacodynamics.
Antihypertensive Agents↗
How well does ambulatory blood pressure predict target-organ disease and clinical outcome in patients with hypertension?
For many years, it has been evident that ambulatory blood pressure monitoring is superior to the measurement of office blood pressure as a predictor of target-organ involvement in patients with hypertension. Until recently, there were far fewer data on the relationship between 24 h ambulatory blood pressure and cardiovascular outcomes such as myocardial infarction, stroke, and cardiovascular death. In 1983, Perloff et al. published their seminal report on awake ambulatory blood pressure as a predictor of cardiovascular outcomes. During the 16 years that have passed since that publication, several additional prospective ambulatory blood pressure studies have been completed, in five different countries. The basis for all these investigations has been to assess the predictive value of ambulatory blood pressure as a determinant of either cardiovascular morbidity (myocardial infarction, cerebrovascular accidents, and vascular surgical procedures) or mortality. With the exception of the Systolic Hypertension in Europe (Syst-Eur) trial, all these studies have been uncontrolled for therapeutic interventions. Typically, the average follow-up period for each trial has been 3-9 years. All these studies have shown that ambulatory blood pressure is a much better predictor of cardiovascular events than the standard office or clinic pressure. In addition, hypertensive patients whose nocturnal (or sleep) blood pressure remains high (that is, those who have a 'non-dipper' circadian blood pressure profile) have a worse outcome than patients whose nocturnal blood pressure decline is at least 10%. These data all support the desirability of increased utilization of 24 h ambulatory blood pressure monitoring in clinical trials of antihypertensive drugs and in the management of hypertensive patients in clinical practice.
Blood Pressure↗
Effects of candesartan cilexetil in patients with systemic hypertension. Candesartan Cilexetil Study Investigators.
The objectives of this double-blind, multicenter, randomized, parallel-arm, placebo-controlled study were to evaluate the dose-related efficacy, tolerability, and safety of candesartan cilexetil, a potent, AT1 selective, long-acting angiotensin II receptor blocker, in 365 adult patients with systemic hypertension and mean sitting diastolic blood pressure (BP) of 95 to 114 mm Hg. Patients received either placebo or candesartan cilexetil 2, 4, 8, 16, or 32 mg once daily for 8 weeks. All doses of candesartan cilexetil reduced trough (24 hours after treatment) sitting diastolic and systolic BP significantly compared with placebo (p < 0.005). A significant (p < or = 0.0001) dose response was evident, with greater decreases in BP at higher doses. Mean changes in BP were -10.7/-7.8 mm Hg and -12.6/-10.2 mm Hg in the 16- and 32-mg groups, respectively, versus -0.3/-2.6 mm Hg in the placebo group. The 16- and 32-mg doses were consistently significantly superior to placebo in antihypertensive effect with regard to all BP measurements, including peak (6 hours after treatment), trough, sitting, and standing measurements of diastolic and systolic BP. Responder rates (trough sitting diastolic BP < 90 or > or = 10 mm Hg BP decrease) were 54% and 64% for the 16- and 32-mg groups, respectively. Tolerability and safety profiles were similar to placebo at all doses. In conclusion, candesartan cilexetil administered once daily effectively reduces BP in a dose-related manner while maintaining safety and tolerability; doses of 16 and 32 mg are most effective for treatment of hypertension.
Adult↗
Comparison of effects of controlled onset extended release verapamil at bedtime and nifedipine gastrointestinal therapeutic system on arising on early morning blood pressure, heart rate, and the heart rate-blood pressure product.
We assessed the differential effects of a chronotherapeutic agent (controlled-onset extended release [COER] verapamil), administered at bedtime versus a conventional, homeostatic therapy (nifedipine gastrointestinal therapeutic system [GITS]) taken in the morning, on early morning and 24-hour blood pressure (BP), heart rate (HR), and the HR x systolic BP product. The study was a multicenter (n = 51), randomized, double-blind prospective clinical trial with a 10-week treatment period. Dose titration was performed by study investigators based on systolic and diastolic BP values at the doctor's office. Ambulatory BP monitoring was performed at placebo baseline, after 4 weeks of stable double-blind therapy, and at end of the study. Twenty-four-hour BP profiles were studied in 557 hypertensive patients. Changes in BP, HR, slope of the rate of rise of BP and HR, and the HR-systolic BP product during the 4 hours from 1 hour before to 3 hours after awakening were evaluated. The study was powered to show equivalence between the 2 regimens, predefined as a difference between treatment groups in mean change from baseline in early morning BP of +/- 5 mm Hg systolic and +/- 3 mm Hg diastolic. Changes in the early morning BP fell within the definition of equivalence for the 2 treatment strategies (-12.0/-8.2 mm Hg for COER-verapamil and -13.9/-7.3 mm Hg for nifedipine GITS). Changes in both the early morning HR and rate-pressure product were significantly greater following COER-verapamil therapy versus nifedipine GITS (HR, -3.8 beats/minute vs +2.6 beats/minute, p < 0.001 and HR-systolic BP product, -1,437 beats/min x mm Hg vs -703 beats/min x mm Hg, respectively, p < 0.001). Changes in ambulatory BP demonstrated clinically similar reductions for the awake period, but nifedipine GITS lowered systolic BP to a greater extent than COER-verapamil during sleep (-11.0 vs -5.8 mm Hg, p < 0.001). COER-verapamil and nifedipine GITS had equivalent effects (+/- 5/3 mm Hg) on early morning BP. In addition, both extended-release calcium antagonists effectively lowered 24-hour BP. However, COER-verapamil had greater effects than nifedipine GITS on early morning hemodynamics (HR, HR-systolic BP product, rate of rise of BP and HR) and lesser effects during sleep due to its intrinsic pharmacologic properties and chronotherapeutic delivery system.
Analysis of Variance↗
Rationale and design for the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Trial.
The Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Trial is a randomized, prospective, double-blind, parallel-group, two-arm, actively controlled, multicenter, international 5-year clinical trial involving 15,000 patients. CONVINCE will compare the incidence of fatal or nonfatal myocardial infarction (MI), fatal or nonfatal stroke, or cardiovascular-disease-related death in two antihypertensive treatment regimens. One treatment arm begins with controlled onset-extended release (COER)-verapamil, which has its major antihypertensive effect 6-12 hours after administration. The other arm (standard of care (SOC)) begins with either hydrochlorothiazide (HCTZ) or atenolol, one of which is preselected by the investigator for an individual patient prior to randomization. Secondary objectives include comparisons of the regimens for each of the components of the primary endpoint (separately), death or hospitalization related to cardiovascular disease, efficacy in lowering blood pressure to goal, primary events occurring between 6 am and noon, all-cause mortality, withdrawals from blinded therapy, cancer, and hospitalizations due to bleeding. Patients may be enrolled if they are hypertensive and at least 55 years of age and have an established second risk factor for cardiovascular disease. Initial medications include COER-verapamil (180 mg/d), HCTZ (12.5 mg/d), or atenolol (50 mg/d). Initial doses are doubled if blood pressure (BP) does not reach goal (systolic BP < 140 mm and diastolic BP < 90 mm Hg). If BP is not controlled by the higher dose of the initial medication, HCTZ is added to COER-verapamil, or the SOC choice not initially selected is added in the SOC arm. An ACE-inhibitor is recommended (although nearly any open-label medication is allowed) as the third step for patients whose BP is not adequately controlled or who have a contraindication to one of the two SOC medications. Patients take two sets of tablets daily, one in the morning and one in the evening. Although most patients switch from an established antihypertensive medication to randomized treatment, untreated patients with stages I-III hypertension (SBP between 140 and 190 or DBP between 90 and 110 mm Hg) are eligible. Outcomes are monitored by an independent Data and Safety Monitoring Board. Enrollment began during the third quarter of 1996, and follow-up is to be completed in the third quarter of 2002.
Aged↗
Circadian blood pressure variation in hypertensive patients with primary hyperaldosteronism.
A less-than-normal decline in nocturnal blood pressure (BP) has been associated with excessive hypertensive complications. This is concerning because secondary hypertension is often associated with this so-called nondipper BP profile. A nondipping pattern is more frequently found in the presence of pheochromocytoma, Cushing's syndrome, and sleep apnea syndrome, but the prevalence is unclear in patients with primary hyperaldosteronism. We therefore studied ambulatory BP profiles in 16 hypertensive patients with primary hyperaldosteronism and an equal number of essential hypertensive subjects. The awake-sleep BP difference of the hyperaldosteronism patients was similar to that of essential hypertensives (15/14 +/- 3/2 versus 14/9 +/- 3/2 mm Hg, P=NS). The prevalence of dippers and nondippers (according to two distinct criteria) in the two groups was similar. Repeat ambulatory BP monitoring in 12 subjects with primary hyperaldosteronism after specific intervention (3 after surgical removal of an adrenal adenoma and 9 after commencement and titration of spironolactone therapy) showed highly significant reductions in office BP (22/10 +/- 6/4 mm Hg, P<.05) and awake and sleep BP. However, the extent of nocturnal BP decline was unchanged between the two studies (17/16 +/- 3/3 versus 16/12 +/- 2/2 mm Hg, P=NS). There was no correlation between the awake-sleep difference and serum or urinary aldosterone levels or the aldosterone-to-renin ratio. In this study, we did not detect any differences in the awake-sleep differences between a group of hypertensives with primary hyperaldosteronism and a control group of essential hypertensives.
Adult↗