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Drug therapy often fails to control hypertension. Azilsartan medoxomil (AZL-M) is a newly developed angiotensin II receptor blocker with high efficacy and good tolerability. This double-blind, controlled, randomised trial compared its antihypertensive efficacy and safety vs the angiotensin-converting enzyme inhibitor ramipril (RAM) in patients with clinic systolic blood pressure (SBP) 150-180 mm Hg. Patients were randomised (n=884) to 20 mg AZL-M or 2.5 mg RAM once daily for 2 weeks, then force-titrated to 40 or 80 mg AZL-M or 10 mg RAM for 22 weeks. The primary endpoint was change in trough, seated, clinic SBP. Mean patient age was 57±11 years, 52.4% were male, 99.5% were Caucasian. Mean baseline BP was 161.1±7.9/94.9±9.0 mm Hg. Clinic SBP decreased by 20.6±0.95 and 21.2±0.95 mm Hg with AZL-M 40 and 80 mg vs12.2±0.95 mm Hg with RAM (P<0.001 for both AZL-M doses). Adverse events leading to discontinuation were less frequent with AZL-M 40 and 80 mg (2.4% and 3.1%, respectively) than with RAM (4.8%). These data demonstrated that treatment of stage 1-2 hypertension with AZL-M was more effective than RAM and better tolerated.

Aim: As there have been concerns that some classes or agents for the treatment of type 2 diabetes may increase CV risk, we evaluated the cardiovascular profile of the dipeptidyl peptidase-4 inhibitor alogliptin., Methods: We evaluated the incidence of CV events in patients treated with alogliptin, placebo or comparator antihyperglycaemic drugs in the clinical trial database for alogliptin using the composite major adverse cardiovascular event (MACE) endpoints of CV death, non-fatal myocardial infarction and non-fatal stroke., Results: The pooled analysis included 4168 patients exposed to alogliptin 12.5 and 25 mg daily for 2023 patient-years compared to 691 patients treated with placebo for 263 patient-years and 1169 patients treated with other antidiabetic agents (metformin, sulfonylureas and thiazolidinediones) for 703 patient-years. CV events were adjudicated by an expert endpoint committee blinded to treatment allocation. The incidence rates of the combined MACE were not significantly different between patients treated with alogliptin and comparator therapies (hazard ratio=0.635, 95% confidence interval, 0.0, 1.41). Additionally, other types of serious CV events were not significantly different between patients treated with alogliptin and comparator therapies., Conclusion: These analyses have not shown a signal of increased CV risk with alogliptin in patients with type 2 diabetes. Future results from the adequately powered EXAMINE trial will definitively assess the CV safety profile of aloglipin in patients with type 2 diabetes mellitus., (© 2013 Blackwell Publishing Ltd.)

Context: Endothelial function is abnormal in chronic obstructive pulmonary disease (COPD); whether endothelial dysfunction causes COPD is unknown., Objective: Test associations of endothelial biomarkers with FEV1 using instrumental variables., Methods: Among 26 907 participants with spirometry, ICAM-1, P-selectin, E-selectin and endothelin-1 were measured in subsets., Results: ICAM-1 and P-selectin were inversely associated with FEV1 among European-Americans (-29 mL and -34 mL per standard deviation of log-transformed biomarker, p < 0.001), as was endothelin-1 among African-Americans (-22 mL, p = 0.008). Genetically-estimated ICAM-1 and P-selectin were not significantly associated with FEV1. The instrumental variable for endothelin-1 was non-informative., Conclusion: Although ICAM-1, P-selectin and endothelin-1 were inversely associated with FEV1, associations for ICAM-1 and P-selectin do not appear causal.

Although it is known that reproducibility of ambulatory blood pressure (BP) is superior to office BP in middle-aged subjects, little is known in older age groups. Hence, we compared the long-term reproducibility of ambulatory and office BP readings in subjects over the age of 75 years. A cohort of 72 subjects 75-90 years of age (mean, 82 years at baseline) had repeat office and ambulatory BPs 2 years apart under similar conditions. On the same day, patients underwent office BP measurements by a semi-automated device and then by ambulatory BP monitoring. Awake and sleep periods were divided according to a diary kept by each patient. The agreement between studies was assessed using the standard deviation of the differences (SDD) and Bland-Altman plots. There were minimal mean changes in office, 24-h, and awake and sleep mean BP values between baseline and 2 years later. The SDDs between visits were lower for 24-h BP compared with the office BP (11.7/5.9 mm Hg versus 17.8/9.0 mm Hg, P<0.01). The SDD for 24-h BP was also lower than the SDDs for the awake and sleep BP (P<0.05). Nocturnal BPs defined by absolute values were more reproducible than categories of dippers and non-dippers. These data demonstrate that long-term reproducibility of 24-h BP is superior to office measurements for very elderly subjects. In a clinical trial involving this age group, far fewer subjects would be required if 24-h BP was the primary efficacy endpoint rather than the office BP.

The antihypertensive effects of telmisartan 80 mg versus valsartan 160 mg, both combined with hydrochlorothiazide (HCTZ) 25 mg, were assessed in a pooled analysis from two large trials with identical study designs in patients with stage 1-2 hypertension. The trials were double-blind with a 4:4:1 randomization scheme to compare once-daily telmisartan 80 mg and HCTZ 25 mg versus once-daily valsartan 160 mg and HCTZ 25 mg versus once-daily placebo on reductions in clinic blood pressure (BP). The primary end point was changes from baseline in BP at the end of 8 weeks. In total, 2121 patients were randomized (telmisartan-HCTZ, 942, valsartan-HCTZ, 952, and placebo, 227) and had baseline seated BPs of 154/102 and 155/102 mm Hg in the two studies, respectively. Changes from baseline in BP after administration of telmisartan-HCTZ (-24.5/-18.0 mm Hg) were significantly greater than for both placebo (-4.1/-6.5 mm Hg) and valsartan-HCTZ (-22.3/-16.8 mm Hg) (versus placebo, P<0.0001 for systolic and diastolic BP; versus valsartan-HCTZ, P=0.0004 for systolic BP and P=0.0019 for diastolic BP). Adverse event rates were higher in the placebo group than in the active treatment groups (placebo, 41%, telmisartan-HCTZ, 30%, and valsartan-HCTZ, 30%, P<0.05). These data confirm that telmisartan-HCTZ at doses of 80/25 mg lowered systolic and diastolic BP to a greater extent than valsartan-HCTZ at doses of 160/25 mg in stage 1-2 hypertension. The magnitude of the BP-lowering effect provides support for the use of angiotensin receptor blockers with higher doses of a thiazide diuretic (25 mg) to improve hypertension control.

Angiotensin-converting enzyme inhibitors combined with higher doses of hydrochlorothiazide (HCT), that is, 25 mg daily, have been recognized as an effective form of antihypertensive therapy. To evaluate the coadministration of 20 mg ramipril with 25 mg HCT, we carried out a randomized, double-blind, controlled trial with two dose schedules of ramipril (20 mg q.d. and 10 mg b.i.d.) and HCT monotherapy arms as comparators in 354 patients with stage 2 hypertension. The clinic blood pressure (BP) was assessed using a semiautomatic digital device and 24-h BP was measured using ambulatory BP recordings at baseline and after 8 weeks of therapy. At baseline, the demographics and baseline BP values were similar in the four treatment groups (age: 51-53 years, 52-58% male, 64-68% non-black, clinic BP: 155-158/103-104 mm Hg). Ramipril-HCT induced significantly greater reductions in both the clinic and ambulatory BP than the HCT and ramipril monotherapy treatments (for example, additional reductions in ambulatory BP on ramipril-HCT ranged from -7.3/-5.2 to -10.3/-7.4 mm Hg compared to the monotherapies, all P<0.001). Reductions from baseline were still numerically greater for the clinic BPs derived from device measurements than those for the BP values derived from 24-h ambulatory BP measurements (changes in clinic diastolic BP ranged from -8.5 to -15.5 mm Hg across treatment groups, whereas changes in ambulatory diastolic BP were -4.7 to -12.0 mm Hg for the same groups). Thus, these data support the use of ambulatory BP monitoring even when automated BP devices are used for the assessment of clinical BP in trials that attempt to differentiate BP responses among active comparator groups. In conclusion, based on its efficacy and tolerability profile the combination of ramipril and HCT was shown to be effective therapy for the treatment of stage 2 hypertension.

The circadian blood pressure (BP) rhythm is associated with worsened cardiovascular outcomes in patients who have an excessive morning BP surge and in those who lack the normal nocturnal BP fall (non-dippers). There are multiple pathophysiologic mechanisms underlying abnormalities in circadian BP, most importantly abnormalities in sympathetic nervous system activity, salt and volume balance, and activation of the renin-angiotensin system. Several of these factors can be modified by clinical interventions, either related to lifestyle changes and/or antihypertensive drug therapy. The timing of drug administration or specific drug delivery systems that lead to a greater effect at night and/or mitigate the early morning BP surge can correct abnormal circadian rhythms. Although these strategies have not yet been shown to alter clinical outcomes, it is reasonable to understand their biologic basis and take them into consideration when designing antihypertensive therapy.

Hypertension is one of the most important risk factors for the development of cardiovascular disease. The prevalence of hypertension increases with age and also after the menopause; therefore, blood pressure monitoring and effective control of elevated blood pressure are very important in postmenopausal women. The knowledge that aldosterone is a dual cardiovascular and endocrine hormone has blurred the once distinct boundary between gynecology and cardiovascular medicine. Aldosterone plays a major role in salt and water homeostasis, but also binds to mineralocorticoid receptors in the cardiovascular system, leading to structural and functional changes and consequent organ damage. Highly selective aldosterone blockade via the mineralocorticoid receptor has long-term antihypertensive effects. Drospirenone is a novel progestogen with aldosterone receptor antagonism (PARA), and therefore has antihypertensive effects through reduced salt and water retention. A new hormone therapy that combines 17beta-estradiol with drospirenone has been shown in several clinical studies to have a blood pressure-lowering effect in postmenopausal women with elevated blood pressure, in addition to effectively relieving symptoms of the menopause. These findings suggest a potential additional benefit on the cardiovascular system for the drospirenone/17beta-estradiol combination in the treatment of women with menopausal symptoms and elevated blood pressure.

Traditional blood pressure (BP) methodology is subject to observer error such as terminal digit preference and single number preference leading to inaccuracies in measurement. A high percentage (60-90%) of terminal BP readings digit being zero has been reported from general medical- and hospital-based clinics. This study examined terminal digit preference in a hypertension specialty practice and assessed clinical factors that may be associated with zero preference in this setting. A retrospective chart review of patients presenting to the hypertension clinic at the University of Connecticut Health Center during the month of September 2001 was performed. Data were extracted on age, gender, height, weight, treatment status, and systolic and diastolic BP measurements taken by nursing staff and attending physicians. Terminal digit preference was apparent in BP readings taken by both nursing staff and physicians. Zero was the terminal systolic BP digit in 40% of readings taken by the nursing staff and 31% of readings taken by physicians. For diastolic BP readings, the percentages were 23 and 36%, respectively. Nurses also recorded 43% of diastolic BP readings with terminal digit 2. Age was significantly higher in those persons in whom the physician diastolic BP terminal digit was zero than in those with nonzero terminal digits (67+/-14 vs 59+/-18 years, P=0.008). Body mass index was lower in the patient group with diastolic terminal digit zero bias compared to those with nonzero terminal digits (28+/-5 vs 32+/-6 kg/m(2), P=0.02). In conclusion, although the frequency of zero digit preference did not reach the 60-80% levels found in previous studies, there was evidence of terminal digit preference in the systolic and diastolic measurements taken by nursing staff and attending physicians in a specialist hypertension clinic. We believe that the lower levels of terminal digit preference observed are an effect of increased training in proper BP measurement and technique. However, the observed bias in measurement even in a hypertension unit argues for regular monitoring and feedback to minimize such errors.

Background: Our purpose was to study the safety of controlled-onset, extended-release (COER) verapamil in patients with hypertension or coronary artery disease, with a focus on elderly patients., Methods: Adverse event data were pooled from 7 double-blind, multicenter, randomized trials including 1999 patients with hypertension or chronic stable angina pectoris. There were 1042 patients who received COER verapamil 180 to 540 mg once daily in the evening for up to 10 weeks, 373 patients who received placebo, and 584 who received an active comparator agent. Data were analyzed according to the following groups: all patients, patients with hypertension, patients with angina, older patients (>/=65 years old), and younger patients (<65 years old). Adverse event rates were compared across the treatment groups by the Fisher exact test., Results: In all patients combined, the incidence of constipation (13% vs 2%), dizziness (6% vs 2%), and back pain (3% vs 1%) was higher in patients treated with COER verapamil than with placebo. Patients with hypertension had more back pain (4% vs 1%) and constipation (12% vs 1%) with COER verapamil than with placebo, whereas patients with angina had more bradycardia (2.6% vs 0%), dizziness (8% vs 2%), and constipation (15% vs 3%). Older patients treated with COER verapamil had more bradycardia, constipation, dizziness, and fatigue and had fewer headaches compared with younger patients treated with COER verapamil. Second- or third-degree atrioventricular block was not observed after administration of COER verapamil in any subgroup., Conclusion: These data demonstrate that COER verapamil has an acceptable safety profile that is largely unrelated to age in patients with hypertension or coronary artery disease.

Background: The aim of this study was to assess potential differences in the 24-h antihypertensive response to treatment with the controlled-onset, extended-release (COER) calcium antagonist, verapamil in men versus women and older versus younger patients with hypertension., Methods: Meta-analyses were performed of three prospective randomized, double-blind, placebo-controlled trials with COER-verapamil in patients with mid-stage I to stage III essential hypertension. The trials were conducted at medical clinics in the US and Canada in patients with a mean office diastolic blood pressure (BP) of 95 to 115 mm Hg on 2 consecutive weeks and a mean daytime diastolic BP >90 mm Hg. Patients were randomized to treatment with 180 to 540 mg/day of COER-verapamil (N = 273) or placebo (N = 125). Changes from baseline in ambulatory BP and heart rate after COER-verapamil were compared in men versus women and in older versus younger patients., Results: Treatment with COER-verapamil caused significant reductions in 24-h and early-morning systolic and diastolic BP in all of the subpopulations as compared with placebo (P < .001). COER-verapamil induced a greater reduction in both 24-h systolic (-15.1 v -10.0 mm Hg; P < .001) and diastolic (-10.4 v -8.2 mm Hg; P = .003) BP in women compared with men. Older patients showed a greater mean reduction in 24-h diastolic BP (-10.2 v -8.2 mm Hg; P < .05) and heart rate (-5.7 v -4.4 beats/min; P < .05) compared with younger patients. Side effects were similar in all of the COER-verapamil treatment groups., Conclusions: Both gender and age were significant determinants of the response to COER-verapamil. The antihypertensive effect of verapamil is greater in women than in men and in older patients compared with younger patients.

Background: Eprosartan is a new nonphenyl angiotensin II receptor blocker, which has been approved for the treatment of hypertension. Although the drug has a relatively short plasma half-life of 5 to 9 h, clinical studies have suggested that its antihypertensive effect persists for 24 h., Methods: We assessed both the changes in 24-h and trough blood pressure (BP) (last 4 h of the ambulatory BP while the patient was awake) of eprosartan at doses of 600 and 1,200 mg once daily in a randomized, double-blind, placebo-controlled trial. Ambulatory BP was monitored at placebo baseline and after 8 weeks of double-blind therapy., Results: Two hundred patients randomized in the study with 177 patients completing the trial. The 24-h change in BP from baseline was 0.2/0.1 +/- 1.4/1.0 mm Hg, -7.9/ -5.4 +/- 1.0 mm Hg (P < .0001), and -7.4/-5.0 +/- 0.9 mm Hg (P < .0001) in the placebo, 600-mg eprosartan, and 1,200-mg eprosartan groups, respectively. Changes in trough ambulatory BP showed significant reductions of -6.3/-4.1 +/- 1.6/1.1 mm Hg and -7.7/-5.5 +/- 1.5/1.0 mm Hg for 600 mg of eprosartan and 1,200 mg of eprosartan, respectively., Conclusions: These data demonstrate that eprosartan at doses of 600 or 1200 mg significantly reduced BP throughout an entire 24-h dosing period. There were no differences between the 600- and 1,200-mg dose; thus, 600 mg once daily should be the only dose used in the treatment of hypertension with eprosartan.

Ambulatory blood pressure monitoring has become a widely used method of blood pressure and heart rate evaluation in the free-living subject. Recently, ambulatory monitoring has become covered by Medicare for the evaluation of "white-coat" hypertension. Although the technique provides only intermittent readings throughout the 24-hour period, average blood pressures obtained in this way correlate well with a variety of hypertensive disease processes and are also a better prognostic marker for future cardiovascular events than office blood pressure. Ambulatory blood pressure averages also correlate well with indices of diastolic dysfunction. In patients with congestive cardiac failure and systolic dysfunction, ambulatory monitoring suggests an impaired circadian blood pressure profile with high nocturnal blood pressure. Further research is needed on the relationship between ambulatory blood pressure and cardiac dysfunction, as well as the impact of observed circadian blood pressure changes on outcome. (c)2001 CHF, Inc.

Background: Smoking and hypertension interact to increase the incidence of cardiovascular disease; however, little is known about the effects of smoking cessation on blood pressure (BP) control. We prospectively evaluated the impact of smoking cessation on clinic and ambulatory BP and heart rate (HR) in stage 1 hypertensive and normotensive postmenopausal women., Methods: A total of 66 women were randomly assigned using a 3:1 randomization scheme to immediate smoking cessation or to a wait list control group. Clinic and ambulatory BP and HR, and 24-h urinary catecholamine concentrations were obtained at baseline and again at 6 weeks. Carbon monoxide levels and self-report were used to assess compliance with smoking cessation., Results: Ambulatory monitoring showed that the awake SBP decreased by 3.6+/-1.9 mm Hg in the treated subjects who quit smoking (n=19), whereas in the control group (n=15) there was an increase of 1.7+/-2.4 mm Hg (P=.045). Awake HR decreased after smoking cessation by 7+/-1 beats/min and did not change (0+/-1 beat/min) in the control group (P=.001). Blood pressure and HR did not significantly change during sleep after smoking cessation. Changes in the awake HR correlated with changes in urinary epinephrine concentrations (r= 0.58, P=.001), and norepinephrine concentrations (r= 0.45, P=.001), There was no significant change in clinic systolic BP, diastolic BP, or HR between groups., Conclusions: Smoking cessation reduces systolic BP and HR during the daytime, when patients typically smoke. These hemodynamic changes are due in part to reductions in sympathetic nervous system activity.

An 8-week, multicentre (72 sites in the US), double-blind, randomised, parallel group, forced titration study compared the antihypertensive efficacy of candesartan cilexetil and losartan. A total of 611 patients with essential hypertension (diastolic blood pressure 95 to 114 mm Hg) were randomised initially to candesartan cilexetil 16 mg once daily or losartan 50 mg once daily. After 2 weeks of randomised treatment, the doses of candesartan cilexetil and losartan were doubled to 32 mg and 100 mg once daily and continued respectively for 6 weeks. At week 8, candesartan cilexetil lowered the blood pressure (BP) at 24 h (trough), 6 h (peak) and 48 h post dose to a significantly greater extent (P < 0.05) than losartan: candesartan cilexetil lowered trough BP by 13.4/10.5 mm Hg, peak BP by 15.5/12.9 mm Hg and 48-h BP by 10.5/9.9 mm Hg compared to a reduction of trough BP by 10.1/9.1 mm Hg, peak BP by 12.0/9.5 mm Hg, and 48-h BP by 5.9/7.0 mm Hg by losartan. The responder and control rates were numerically higher in the candesartan cilexetil group, but the differences did not reach statistical significance; the responder rates were 58.8% for the candesartan cilexetil group and 52.1% for the losartan group and control rates were 49.0% for the candesartan cilexetil group and 44.6% for the losartan group. Overall, both treatment regimens were well tolerated. A total of 15 of the 611 (2.5%) patients withdrew from the study due to an adverse event, including nine (2.9%) in the candesartan cilexetil group and six (2.0%) in the losartan group. In conclusion, this forced titration study confirms that candesartan cilexetil is more effective in lowering BP than losartan when compared at once daily maximum doses.

Background: Non-invasive self blood pressure monitoring has become increasingly popular. To assure the accuracy of devices used for this purpose, all need to be validated independently prior to marketing. The objective of this study was to assess the accuracy of the HEM-907, a new semi-automatic, non-invasive, oscillometric blood pressure monitoring device specifically designed to be used in the clinic or physician's office setting., Methods: Blood pressure measurements taken employing this device were compared with the results obtained by two experienced observers using a mercury sphygmomanometer on 100 subjects and patients (384 measurements). The limits of agreement were calculated for the device compared with the results of the two observers according to the standards of the Association for the Advancement of Medical Instrumentation (AAMI)., Results: The agreement between the two observers was -0.36+/-2.32mmHg for systolic blood pressure and 0.02+/-2.42mmHg for diastolic blood pressure. The agreement between the device and the observers was 1.56+/-4.42mmHg and 3.49+/-4.61mmHg for systolic and diastolic blood pressure respectively., Conclusions: The Omron HEM-907 satisfied the AAMI criteria for accuracy for a non-invasive blood pressure monitoring device.

The incidence of most adverse cardiovascular events appears to follow a circadian pattern, reaching a peak in the morning shortly after wakening and arising. The activities of many physiologic parameters, including hemodynamic, hematologic and humoral factors, also fluctuate in a cyclical manner over the 24h. It has been suggested that, during the post-awakening hours, the phases of these cycles synchronize to create an environment that predisposes to atherosclerotic plaque rupture and thrombosis in susceptible individuals, thereby accounting for the heightened cardiovascular risk at this time of day. Blood pressure and heart rate are part of this physiologic process, following a clear circadian rhythm characterized by a fall during sleep and a sharp rise upon awakening. This so-called 'morning surge' in blood pressure may act as a trigger for cardiovascular events, including myocardial infarction and stroke. The clinical implication of these observations is that antihypertensive therapy should provide blood pressure control over the entire interval between doses. For agents taken once daily in the morning, the time of trough plasma drug level (and lowest pharmacodynamic effect) will often coincide with the early morning surge in blood pressure and heart rate. For these reasons, chronotherapeutic formulations of drugs and intrinsically long-acting antihypertensive agents provide the most logical approach to the treatment of hypertensive patients since they provide 24 h blood pressure control from a single daily dose as well as attenuating the early morning rise in blood pressure (and in some instances heart rate).

Background: The effect of controlled-onset, extended-release (COER) verapamil on haemodynamic parameters in obese and non-obese patients is evaluated in this analysis., Methods: Data were pooled from three clinical trials evaluating efficacy and tolerability of COER-verapamil. Hypertensive men and women (stage I to III) were randomised to COER-verapamil (180-540 mg at bedtime) or placebo for 4-8 weeks and stratified according to body mass index (BMI-obese > 28 kg/m2). Efficacy was assessed as change from baseline in blood pressure (BP), heart rate, and rate-pressure product during four time periods throughout the dosing interval. Safety and tolerability were assessed by monitoring all adverse events and changes in metabolic laboratory parameters., Results: Reductions in all haemodynamic parameters were significantly greater following COER-verapamil compared with placebo for all time periods. The haemodynamic effects of COER-verapamil in obese (n = 166, BMI = 32.8 kg/m2) and non-obese patients (n = 115, BMI = 25.0 kg/m2) were similar. COER-verapamil was well tolerated in both subgroups, but the incidence of constipation was significantly less in obese patients (P < 0.001)., Conclusions: COER-verapamil is effective in reducing BP, heart rate, and rate-pressure product independently of BMI.

Ambulatory blood pressure monitoring (ABPM) has been increasingly used in hemodialysis (HD) practice and research; however, no study has evaluated the reproducibility of ABPM in this population. To address this question, we performed 48-hour interdialytic ABPM on 21 HD patients (mean age, 53 +/- 16 years; 7 women) on two different occasions 68 +/- 34 days (range, 30 to 154 days) apart. To qualify for the protocol, patients had to be at the same dry weight and on the same vasoactive drug regimen at both monitoring periods. BP was analyzed according to three different methods: isolated pre-HD and post-HD values, average pre-HD and post-HD values for the five HD sessions surrounding each monitoring period, and 48-hour interdialytic ABPM. Reproducibility was determined by analysis of the SD of the differences (SDD) between the two monitoring periods and the coefficient of variation of each method of BP determination. Our results show better reproducibility of ABPM (SDD, 10.6/6.6 mm Hg; coefficient of variation, 7.5%/8.1%) compared with isolated pre-HD BP (SDD, 24.4/11.3 mm Hg; coefficient of variation, 16.7%/14.1%) or post-HD BP (SDD, 16.8/14.5 mm Hg; coefficient of variation, 11.7%/17.8%), and averaged pre-HD BP (SDD, 14.7/7.2 mm Hg; coefficient of variation, 10.1%/9.1%) or post-HD BP (SDD, 12.4/8.7 mm Hg; coefficient of variation, 8.9%/11.1%). The reproducibility of the decrease in BP during sleep was poor, with up to 43% of the subjects changing dipping category within or between interdialytic periods. We conclude that ABPM is the most accurate method to study BP in HD patients over time. However, variability is significant, and there is poor reproducibility of the nocturnal decline in BP.

Background: Changes in heart rate (HR) may contribute to the higher incidence of cardiovascular events in the morning., Hypothesis: The objectives of this analysis were to assess HR patterns in two populations (patients with chronic stable angina or stage I to III hypertension) and to compare the effects of various antianginal and antihypertensive treatments on HR., Methods: This was a retrospective analysis of HR data from two clinical trials evaluating the efficacy of controlled-onset, extended-release (COER)-verapamil. The effects of COER-verapamil were compared with placebo, nifedipine gastrointestinal therapeutic system (GITS), amlodipine, and the combination of amlodipine and atenolol., Results: In patients with angina (n = 498), the change from baseline in HR following 4 weeks of treatment was -6.7 +/- 10.5 beats/min in the COER-verapamil group, -10.8 +/- 10.8 beats/min in the amlodipine/atenolol group, + 2.5 +/- 9.1 beats/ min in the amlodipine monotherapy group, and -1.3 +/- 10.5 beats/min in the placebo group (p<0.001). Data were stratified based on whether patients experienced asymptomatic ischemia during baseline ambulatory electrocardiographic monitoring. The circadian HR pattern was morphologically similar in all groups; however, differences in the magnitude of HR response were evident. In the subset of patients with asymptomatic ischemia (n = 101), treatment with amlodipine monotherapy increased HR compared with placebo. In this same subset of patients, HR reductions were achieved with COER-verapamil and amlodipine/atenolol. In patients with hypertension (n = 557), the change in HR following 10 weeks of treatment was -3.3 beats/min for patients treated with COER-verapamil compared with + 2.0 beats/min for patients treated with nifedipine GITS (p < 0.0001, between-group differences)., Conclusion: This analysis demonstrates that morphologically similar circadian patterns of HR occur in both hypertensive patients and those with angina. In addition, significant variation exists among antianginal and antihypertensive agents regarding HR effects.

We studied how closely changes in electronically monitored physical activity are reflected in changes in blood pressure and heart rate in a group of untreated hypertensive subjects. Thirty-nine hypertensive patients (office blood pressure > 140/ 90 mm Hg) of mean age 57 +/- 10 years (mean +/-SD) wore an ambulatory blood pressure monitor and a wrist actigraph simultaneously. Both average and peak activity for 5 min before each valid blood pressure reading were determined, as was average activity for awake and sleep periods, determined by patient kept diaries. For the overall group, awake and 24-h activities were inversely correlated to age (n = 39, r = -0.42; P = 0.01 and n = 39, r = -0.38; P = 0.01, respectively). No correlation was found between group awake activity and group-average blood pressure or heart rate. For individual patients, there was marked variation in the degree of correlation between awake activity measures (both peak and average) and blood pressure and heart rate. The strongest positive correlation was between activity levels and the heart rate-pressure product. Nondipper profile hypertensives had higher sleep activity than dipper hypertensives (44 +/- 28 units/min v 25 +/- 20 units/min, df = 37, t = 2.12; P = 0.04), but awake activity levels were similar. The higher sleep activity remained after adjustment for age. These findings indicate that the relationship between actigraphic activity and hemodynamic parameters is highly variable and that the rate-pressure product is the strongest correlate of short-term activity. Furthermore, hypertensives with the nondipper profile have higher sleep activity than dipper hypertensives. These findings stress the need for further study into the role of day-to-day activity in determining ambulatory blood pressure and heart rate variability.

Diabetes mellitus is common in patients with hypertension, and greatly increases the risk of cardiovascular disease, including myocardial infarction, stroke, and peripheral vascular disease. "The pharmacologic therapy of patients with hypertension and diabetes has been surrounded by controversy because of concerns about the metabolic effects of several antihypertensive agents, as well as concerns about the safety of calcium antagonists. The objective of this review is to re-evaluate the management of diabetic patients with hypertension in light of the latest clinical trials. We also review the importance of intensive blood pressure control in these patients.

The discovery of two forms of secondary hypertension in the same patient is unusual and suggests similar pathophysiological mechanisms, a predisposition to one type in the presence of the other or a chance occurrence. We describe two patients with renal artery stenosis who after successful correction of the stenotic lesions were discovered to have primary hyperaldosteronism associated with bilateral adrenal hyperplasia. Initially prior to revascularisation of the renal artery stenosis, the diagnosis of primary hyperaldosteronism was not evident. Both patients were subjected to further diagnostic evaluation after the appearance of hypokalaemia in one patient and continued resistant hypertension in both patients. The addition of spironolactone therapy reduced blood pressure impressively in both patients. Clinicians should be aware of the possibility that these two forms of secondary hypertension may be present in the same patient and that optimal blood pressure control requires diagnostic assessment and intervention for both disorders.

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.

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.

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.

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.

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.

Since the early 1980s, when Perloff and colleagues published their seminal report on awake ambulatory blood pressure as a predictor of cardiovascular outcomes, there have been several additional prospective ambulatory blood pressure studies that have been completed in five different countries. The basis for all of these investigations was to assess the predictive value of ambulatory blood pressure as a determinant of either cardiovascular morbidity (typically myocardial infarction, cerebrovascular accidents, and vascular surgical procedures) or mortality. With the exception of Syst-Eur, all of these studies have been uncontrolled for therapeutic interventions. Typically, the average follow-up period for each trial has been three to nine years. Despite these limitations, all of the studies have shown that ambulatory blood pressure is a far better predictor of cardiovascular events than the standard office or clinic blood pressure. Furthermore, the hypertensive patients whose nocturnal (or sleep) blood pressure remains high (i.e. non-dipper circadian blood pressure profile) have a much worse outcome compared with patients whose nocturnal blood pressure decline is over 10%.

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.

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.

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.

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.

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.

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.

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.

Chronotherapeutics, or delivery of a medication in concentrations that vary according to physiological need at different times during the dosage period, is a relatively new practice in clinical medicine. Epidemiological studies document that the incidence of many cardiovascular diseases, including myocardial infarction and stroke, varies predictably in time over 24 hours (the circadian period). Advanced diagnostic technologies using ambulatory monitoring of the blood pressure and electrocardiogram have also demonstrated that there is marked variability in the level of pressure in hypertensive patients and the degree of myocardial ischaemia in patients with coronary disease. These diagnostic techniques also allow us to study the effects of varying the timing of administration or delivery of a concentration of a drug on end-points such as changes in blood pressure, heart rate or intensity of angina. The first chronotherapeutic agent for hypertension and angina pectoris, controlled onset, extended release (COER-24) verapamil, has recently been developed and registered in the US, Brazil, Canada and Mexico. The theoretical advantage of this formulation is that delivery of the active drug, verapamil, has been tailored to the typical circadian rhythm of blood pressure and heart rate in patients with hypertension and angina to better cover the early morning hours when cardiovascular need appears to be the greatest. An outcome study (CONVINCE) that evaluates primary prevention of cardiovascular events with this chronotherapy versus standard of care therapy is under way in several countries in North and South America and Europe.

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.

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.