Comparison of the efficacy of morning versus evening administration of telmisartan in essential hypertension

Valsartan administration at bedtime as opposed to on wakening improves the sleep time-relative blood pressure decline toward a more dipper pattern without loss in 24-hour efficacy. Yet to be determined is whether this administration time-dependent efficacy is a class-related feature, characteristic of all angiotensin receptor blockers or specific only to valsartan. Terminal half-life is a major difference between angiotensin receptor blockers, being largest ( approximately 24 hours) for telmisartan. This trial investigated the administration time-dependent antihypertensive efficacy of telmisartan. We studied 215 patients with hypertension (114 men and 101 women), 46.4+/-12.0 years of age, randomly assigned to receive telmisartan (80 mg/d) as a monotherapy either on awakening or at bedtime. Blood pressure was measured for 48 hours before and after 12 weeks of treatment. The significant blood pressure reduction after treatment was similar for both groups. Bedtime administration of telmisartan, however, was more efficient than morning dosing in reducing the nocturnal blood pressure mean. The sleep time-relative blood pressure decline was slightly reduced after telmisartan on awakening but significantly increased with bedtime dosing, thus reducing the prevalence of nondipping from baseline by 76%. Telmisartan administered at bedtime, as opposed to morning dosing, improved the sleep time-relative blood pressure decline toward a more dipper pattern without loss in 24-hour efficacy. Nocturnal BP regulation is significantly better achieved with bedtime dosing of telmisartan. Results from this prospective trial suggest that these beneficial features of bedtime dosing may be class related for angiotensin receptor blockers. These results should be taken into account when prescribing this class of antihypertensive medication for treatment of essential hypertension.     

Effects of time of day of treatment on ambulatory blood pressure pattern of patients with resistant hypertension

Patients with resistant hypertension present high prevalence of a non-dipper blood pressure pattern. Recent results indicate that non-dipping is related partly to the absence of 24-hour therapeutic coverage in patients treated with single morning doses. Accordingly, we investigated the impact of treatment time on the blood pressure pattern in 700 patients with resistant hypertension on the basis of clinic measurements who were studied by 48-hour ambulatory monitoring. Among them, 299 patients received all their medication on awakening, and 401 were taking > or =1 antihypertensive drug at bedtime. The percentage of patients with controlled ambulatory blood pressure was double in patients taking 1 drug at bedtime (P=0.008). Among the 578 patients with true resistant hypertension, subjects receiving 1 drug at bedtime showed a significant reduction in the 24-hour mean of systolic and diastolic blood pressure (3.1 and 1.6 mm Hg, respectively; P<0.011). This reduction was much more prominent during nighttime (5.1 and 3.0 mm Hg; P<0.001). Accordingly, the diurnal/nocturnal blood pressure ratio was significantly increased by 2.7 and the prevalence on non-dipping reduced (56.9 versus 81.9%; P<0.001) in patients taking 1 drug at bedtime. Compared with patients receiving all drugs on awakening, subjects with 1 drug at bedtime also showed significant reductions in the average values of glucose, cholesterol, fibrinogen, and urinary albumin excretion (P<0.011). In patients with resistant hypertension, pharmacological therapy should take into account when to treat with respect to the rest-activity cycle of each patient to improve control and to avoid the non-dipper pattern associated to higher cardiovascular risk.     

The bedtime administration of doxazosin controls morning hypertension and albuminuria in patients with type-2 diabetes: evaluation using home-based blood pressure measurements

The control of high blood pressure (BP) after awakening in the morning (morning hypertension) as determined by home BP (HBP), as well as BP control throughout the day, may prevent diabetic vascular complications. We examined the effect of an alpha-adrenergic blocker (doxazosin) on BP measurements taken by HBP after awakening and during clinic visits (CBP) in 50 patients with type-2 diabetes and morning hypertension. We evaluated the urinary albumin excretion rate as an indicator of nephropathy. Doxazosin was taken orally once at bedtime for 1 to 3 months. The mean (+/- SD) dose was 2.9 +/- 2.1 mg/day (1 to 8 mg/day). The BP was measured monthly at the clinic during the day and at home after awakening in the morning. In this short-term trial (2.8 +/- 0.4 months), the systolic HBP decreased significantly from 164 +/- 17 mmHg before treatment to 146 +/- 19 mmHg after treatment, and the diastolic HBP decreased significantly from 85 +/- 14 mmHg before treatment to 80 +/- 9 mmHg after treatment. The systolic, but not the diastolic CBP, decreased significantly after treatment. There was no significant difference in the systolic or diastolic values between the HBP and the CBP after treatment. The percentage change in the systolic HBP after treatment was three times greater than for the systolic CBP. The median (interquartile) urinary albumin excretion rate decreased significantly (P < 0.001) from 62 (25-203) mg/g creatinine before treatment to 19 (9-76) mg/g creatinine after treatment. On multiple regression analysis, the decrease in the systolic HBP with treatment positively correlated with the reduction in urinary excretion of albumin. The control of morning hypertension reduced the albuminuria found in both untreated and treated hypertensive patients with type-2 diabetes. Bedtime administration of doxazosin appears to be safe and effective in reducing morning hypertension as measured by HBP. This finding also demonstrates that HBP taken in the morning has a stronger predictive power for the albuminuria level than does CBP.     

Chronotherapy improves blood pressure control and reverts the nondipper pattern in patients with resistant hypertension

Therapeutic strategies in resistant hypertension include adding another drug or changing drugs in search for a better synergic combination. Most patients, however, receive all of their drugs in a single morning dose. We have evaluated the impact on the circadian pattern of blood pressure on modifying the time of treatment without increasing the number of prescribed drugs. We studied 250 hypertensive patients who were receiving 3 antihypertensive drugs in a single morning dose. Patients were randomly assigned to 1 of 2 groups according to the modification in their treatment strategy: changing 1 of the drugs but keeping all 3 in the morning or the same approach but administering the new drug at bedtime. Blood pressure was measured for 48 hours before and after 12 weeks of treatment. There was no effect on ambulatory blood pressure when all of the drugs were taken on awakening. The baseline prevalence of nondipping (79%) was slightly increased after treatment (86%; P=0.131). The ambulatory blood pressure reduction was statistically significant (9.4/6.0 mm Hg for systolic/diastolic blood pressure; P<0.001) with 1 drug at bedtime. This reduction was larger in the nocturnal than in the diurnal mean of blood pressure. Thus, whereas only 16% of the patients in this group were dippers at baseline, 57% were dippers after therapy (P<0.001). Results indicate that, in resistant hypertension, time of treatment may be more important for blood pressure control and for the proper modeling of the circadian blood pressure pattern than just changing the drug combination.     

24-Hour and Nighttime Blood Pressures in Type 2 Diabetic Hypertensive Patients Following Morning or Evening Administration of Olmesartan

Ambulatory blood pressure monitoring (ABPM) allows determining of the nocturnal blood pressure fall (NBPF). An NBPF below 10% (nondipper pattern) has been related to increased cardiovascular risk, and it is a common finding in type 2 diabetic hypertensive patients. The authors evaluated the impact on 24-hour blood pressure, NBPF, and albuminuria of olmesartan 40 mg, administered in a morning- vs a nocturnal-based dosing scheme, in type 2 diabetic patients with newly diagnosed hypertension. Using a crossover design, 40 patients (42.1% men) received olmesartan 40 mg once daily at wake up or bedtime for 8 weeks. Patients underwent 24-hour ABPM at baseline and at weeks 8 and 16, and albumin to creatinine ratio was measured at baseline and 8 weeks. Night systolic blood pressure (BP) ( P =.007) and mean BP ( P =.012) were significantly reduced following the bedtime dose, compared with morning dosing. Night BP fall (%) was significantly reduced by bedtime dosing, compared with morning dosing ( P =.0001). No differences were seen for urinary albumin excretion between both arms at week 8. Without affecting 24-hour BP control, night dosing of olmesartan increases nocturnal BP fall significantly more than conventional morning dosing, increasing the number of dipper diabetic hypertensive patients.     

The Bedtime Administration of Doxazosin Controls Morning Hypertension and Albuminuria in Patients with Type-2 Diabetes: Evaluation Using Home-Based Blood Pressure Measurements

The control of high blood pressure (BP) after awakening in the morning (morning hypertension) as determined by home BP (HBP), as well as BP control throughout the day, may prevent diabetic vascular complications. We examined the effect of an α-adrenergic blocker (doxazosin) on BP measurements taken by HBP after awakening and during clinic visits (CBP) in 50 patients with type-2 diabetes and morning hypertension. We evaluated the urinary albumin excretion rate as an indicator of nephropathy. Doxazosin was taken orally once at bedtime for 1 to 3 months. The mean (± SD) dose was 2.9 ± 2.1 mg/day (1 to 8 mg/day). The BP was measured monthly at the clinic during the day and at home after awakening in the morning. In this short-term trial (2.8 ± 0.4 months), the systolic HBP decreased significantly from 164 ± 17 mmHg before treatment to 146 ± 19 mmHg after treatment, and the diastolic HBP decreased significantly from 85 ± 14 mmHg before treatment to 80 ± 9 mmHg after treatment. The systolic, but not the diastolic CBP, decreased significantly after treatment. There was no significant difference in the systolic or diastolic values between the HBP and the CBP after treatment. The percentage change in the systolic HBP after treatment was three times greater than for the systolic CBP. The median (interquartile) urinary albumin excretion rate decreased significantly (P < 0.001) from 62 (25–203) mg/g creatinine before treatment to 19 (9–76) mg/g creatinine after treatment. On multiple regression analysis, the decrease in the systolic HBP with treatment positively correlated with the reduction in urinary excretion of albumin. The control of morning hypertension reduced the albuminuria found in both untreated and treated hypertensive patients with type-2 diabetes. Bedtime administration of doxazosin appears to be safe and effective in reducing morning hypertension as measured by HBP. This finding also demonstrates that HBP taken in the morning has a stronger predictive power for the albuminuria level than does CBP.     

Chronotherapy of Hypertension with Angiotensin Receptor Blockers–A Meta-Analysis of Blood Pressure Measured by Ambulatory Blood Pressure Monitoring in Randomized Trials

BackgroundWe performed this meta-analysis evaluating the efficacy of chronotherapy of hypertension with angiotensin receptor blockers (ARBs).MethodsWe searched Pubmed, Web of Science, and Cochrane for all published randomized trials that compare antihypertensive effects of ARBs between bedtime dosing and awakening dosing. Blood pressure (BP) was measured by ambulatory BP monitoring in patients with mild or moderate essential hypertension.ResultsThe effects of ARBs on BP were assessed in 805 essential hypertensive patients included in 8 trials with a follow-up of 12 ± 3 weeks. The sleep-time systolic and diastolic BP (SBP, DBP) with bedtime dosing greatly decreased as compared with awakening dosing (weighted mean differences [WMD] for SBP WMD ?5.23 [95% confidence intervals (CI), ?7.27, ?3.20] mm Hg, p < 0.001; WMD for DBP ?2.94 [95% CI, ?4.52, ?1.36] mm Hg, p < 0.001). The reduction of daytime SBP (WMD 0.98 [95% CI, ?0.20, 2.17] mm Hg, p = 0.10), DBP (WMD 0.11 [95% CI, ?0.68, 0.89] mm Hg, p = 0.79), 24 hour SBP (WMD ?0.75 [95% CI, ?1.93, 0.42] mm Hg, p = 0.21) and DBP (WMD ?0. 77 [95% CI, ?1.55 0.01] mm Hg, p = 0.05) with bedtime dosing was similar with awakening dosing.ConclusionsBedtime dosing with ARBs is more effective in lowering sleep-time BP than awakening dosing in patients with essential hypertension, suggesting a utilization of chronotherapy of hypertension with ARBs to reduce sleep-time high BP. Larger multi-ethnic studies are needed to investigate the efficacy of chronotherapy of hypertension.     

Assessment of single versus twice daily dosing of ramipril by ambulatory blood pressure monitoring in patients similar to those included in the HOPE study

Ramipril has been used in twice daily dose of 5 mg in most heart failure trials, whereas the dose used in Heart Outcomes Prevention Evaluation (HOPE) study was 10 mg once at bedtime. The HOPE investigators in an ambulatory blood pressure (ABP) substudy observed a fall of nighttime but not daytime blood pressure (BP). We examined the effects of once daily ramipril 10 mg versus 5 mg twice a day. Twenty-nine patients were recruited based on the original criteria for the HOPE study and were given ramipril either in twice-daily dose (5 mg b.d.) or once daily (10 mg o.d.) each morning in randomized, prospective crossover trial. Twenty-four hour ABP recordings were taken just before commencement of ramipril therapy and after treatment with twice-daily and once-daily ramipril. Our results show that ramipril causes a significant reduction of BP over 24-h period as compared with baseline. The mean baseline ABP was 124/73 mm Hg, which reduced to 117/69 mm Hg for the twice-a-day regimen (P<0.001) and 115/68 mm Hg for the once a day regimen (P<0.001). Both regimes effectively lower BP to a similar extent. Ramipril causes significant BP reduction in both once- and twice-daily dosing. The fall in BP after daytime dosing is greater than that observed in the HOPE study (including ABP substudy). Once-daily dosing in the morning seems to be effective in causing a significant reduction in the ABP profile of patients at high-risk of a future vascular event.     

Efficacy and safety of a once daily graded-release diltiazem formulation in essential hypertension

BACKGROUND: The efficacy and safety of a chronotherapeutic, graded-release diltiazem HCl extended-release (GRD) 120-, 240-, 360- and 540-mg dose administered once-daily at bedtime (10 PM) were evaluated in a 7-week randomized, double-blind comparison to placebo and to GRD 360 mg administered once-daily at 8 AM in 478 patients with moderate-to-severe essential hypertension. METHODS: We assessed the change from baseline to end point in trough diastolic blood pressure (DBP) at 6 PM to 10 PM and in mean DBP from 6 AM to 12 noon between GRD 360 mg PM and GRD 360 mg AM, measured by ambulatory BP monitoring (ABPM). RESULTS: Bedtime doses of GRD showed dose-related mean reductions in trough DBP that were significant for GRD doses of 240 mg and higher. Bedtime GRD 360 mg was associated with a significantly greater reduction in mean DBP between 6 AM and 12 noon compared to morning GRD 360 mg with a least squares mean for treatment difference of -3.3 mm Hg (P =.0004). Similar dose-related and significant reductions in systolic BP (SBP) and heart rate (HR) were obtained. Incidence of adverse events (AEs) for all GRD groups (44.5%) was less than that obtained for the placebo group (49.3%). The 540-mg group showed an incidence of AEs (43.5%) similar to that observed for the 240-mg group (42.6%). CONCLUSIONS: The GRD dose-dependently significantly reduces BP and HR over the 24-h interval after once-daily bedtime dosing. Further greater reductions were obtained between 6 AM and 12 noon, when circadian BP is highest, compared to morning administration of the same dose. The 540-mg GRD was safe, well tolerated, and offers further therapeutic option for patients with severe hypertension who required additional BP control.     

Dose Timing of an Angiotensin II Receptor Blocker/Calcium Channel Blocker Combination in Hypertensive Patients With Paroxysmal Atrial Fibrillation

It has long been thought that there is a close association between hypertension and atrial fibrillation (AF). However, the efficacy of an angiotensin II receptor blocker for the prevention of organ damage in hypertensive individuals with AF is still controversial. The present study was a multicentered, prospective, randomized, open‐label clinical trial investigating the differences in the effect of treatment with telmisartan/amlodipine combination tablets on blood pressure (BP) levels and BP variability between morning and bedtime administration in hypertensive patients with paroxysmal AF, using ambulatory BP monitoring (ABPM) and home BP. With this treatment, the patients' 24‐hour BP, nighttime BP, preawake BP, and morning BP shown by ABPM were significantly reduced, and the antihypertensive effects were similar regardless of the timing of the drug administration. The standard deviation of day‐by‐day home systolic BP and the maximum home systolic BP were also significantly reduced, and these effects were similar regardless of the treatment timing. The N‐terminal pro‐brain natriuretic peptide level was significantly decreased only in the bedtime administration group. A larger study will demonstrate whether the bedtime administration of telmisartan/amlodipine combination tablets maximizes the risk‐lowering effect against AF recurrence in paroxysmal AF hypertensive patients.     

Both morning and evening dosing of nebivolol reduces trough mean blood pressure surge in hypertensive patients

The morning blood pressure surge (MBPS) has been shown to be an independent predictor of cardiovascular events. There is insufficient evidence on the effect of nebivolol, a vasodilating β1-receptor blocker, on the MBPS when given in the morning or the evening. This is a prospective, randomized, double-blind, crossover study designed to test morning vs. evening dosing of nebivolol in nondiabetic, hypertensive patients. Patients received nebivolol 5 mg/day (force-titrated to 10 mg/day after 1 week) in the morning or evening and corresponding placebos. Patients underwent ambulatory BP monitoring at baseline and after each treatment phase. Forty-two patients were randomized, of whom 38 completed both study periods. Both morning and evening dosed nebivolol significantly lowered daytime, nighttime, and 24-hour BP after 3 weeks of treatment. Evening (but not morning) dosing significantly reduced prewaking systolic BP from baseline (8.64 ± 26.46 mm Hg, P = .048). Nebivolol given in the morning or the evening significantly reduces 24-hour BP parameters. Evening dosed nebivolol may confer some advantage over morning dosing in reducing prewaking systolic BP.     

Relation of regression of left ventricular hypertrophy to changes in ambulatory blood pressure after long-term therapy with perindopril versus nifedipine.

Casual as well as ambulatory 24-hour blood pressure (BP) and echocardiographic parameters were studied in 40 patients with untreated or insufficiently treated mild to moderate essential hypertension. Left ventricular (LV) hypertrophy was assessed before and after 24 weeks of therapy with either the converting enzyme inhibitor perindopril or the calcium antagonist nifedipine. The design was a double-blind parallel study with a placebo run-in period. Patients received a daily oral dosage of either 4 to 8 mg of perindopril or 40 to 80 mg of nifedipine in slow-release form. A diuretic (25 mg/day of hydrochlorothiazide) was added in nonresponders (greater than 90 mm Hg casual diastolic BP). Once-daily perindopril and twice-daily nifedipine comparably reduced both casual and ambulatory BP throughout 24 hours (p less than 0.01) without affecting 24-hour heart rate. Six subjects withdrew from the nifedipine group and 4 from the perindopril group. After 12 and 24 weeks of therapy, LV hypertrophy was significantly reduced by both agents. Before active treatment was begun, LV mass index was more closely correlated to 24-hour (p less than 0.001) than to casual BP. This correlation disappeared after treatment with both agents. The correlation between ambulatory systolic day-time BP and LV mass was only still present (r = 0.54; p less than 0.05) after 24 weeks of treatment with nifedipine. It is concluded that regression of LV hypertrophy during converting enzyme inhibition or calcium antagonism may be partly independent of dosage and magnitude of 24-hour BP decrease.     

Baroreflex sensitivity changes with calcium antagonist therapy in elderly subjects with isolated systolic hypertension

In order to study the effects of calcium-blocking therapy on cardiovascular homeostasis in elderly subjects with isolated systolic hypertension, we performed a randomised double-blind placebo-controlled crossover study of 6 weeks therapy with modified-release nifedipine or placebo. Changes with calcium-blocker treatment in clinic and 24-h blood pressure (BP), heart rate, BP variability, baroreflex sensitivity (BRS) by three methods (Valsalva manoeuvre, phenylephrine and sodium nitroprusside injection), and in baroreflex- and non-baroreflex-mediated reflexes (tilt and cold face stimulus) were studied in 14 elderly subjects (mean age [+/- SEM] 70 +/- 1 years) with sustained isolated systolic hypertension (clinic BP 179 +/- 3/85 +/- 1 mm Hg). Clinic systolic BP, but not diastolic BP, was reduced with treatment (by 14 +/- 6 mm Hg, P = 0.03, diastolic BP 4 +/- 3 mm Hg, P = 0.16). Twenty-four hour BP was also reduced by nifedipine treatment (by 18 +/- 3/9 +/- 2 mm Hg, both P < 0.001). Clinic and 24-h heart rate, and daytime BP variability, were unchanged with treatment. BRS was significantly increased during nifedipine therapy by all three measurement methods (all P < 0.05). With 60 degrees tilt during active treatment, subjects exhibited a greater heart rate increase (P < 0.01), and a reduced fall in systolic (P < 0.05) and diastolic BP (P < 0.05). Thus despite the arteriosclerosis and reductions in large artery compliance described in elderly patients with isolated systolic hypertension, clinically important improvements in clinic and ambulatory BP and some aspects of cardiovascular homeostasis can be achieved with calcium-channel blocking therapy.     

Treatment of non-dipper hypertension with bedtime administration of valsartan

BACKGROUND: Previous results have indicated that valsartan administration at bedtime, as opposed to upon wakening, may improve the diurnal: nocturnal ratio of blood pressure without loss in 24-h coverage and efficacy. OBJECTIVES: To investigate the administration time-dependent antihypertensive efficacy of valsartan in non-dipper patients. METHODS: We studied 148 non-dipper patients with grade 1-2 essential hypertension, aged 53.0+/-12.6 years, who were randomly assigned to receive valsartan (160 mg/day) as a monotherapy either on awakening or at bedtime. Blood pressure was measured every 20 min during the day and every 30 min at night for 48 consecutive hours before and after 3 months of treatment. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately calculate the diurnal and nocturnal means of blood pressure on a per subject basis. RESULTS: The significant blood pressure reduction after 3 months of valsartan (P<0.001) was similar for both treatment times (13.1 and 8.5 mmHg reduction in the 24-h mean of systolic and diastolic blood pressure with morning administration; 14.7 and 10.3 mmHg with bedtime administration; P>0.126 for treatment-time effect). The diurnal: nocturnal ratio of blood pressure was significantly increased only when valsartan was administered before bedtime, which resulted in 75% of the patients in this group reverting to dippers, a significant increase in the percentage of patients with controlled blood pressure over 24 h, and a reduction in urinary albumin excretion. CONCLUSIONS: In non-dipper hypertensive patients, dosing time with valsartan should be chosen at bedtime, for improved efficacy during the nocturnal resting hours, as well as the potential associated reduction in cardiovascular risk.     

Aspirin administered at bedtime, but not on awakening, has an effect on ambulatory blood pressure in hypertensive patients.

OBJECTIVES: The purpose of this research was to investigate in untreated hypertensive patients the effects on ambulatory blood pressure (BP) of aspirin (ASA) administered at different times of the day. BACKGROUND: Previous studies have shown that ASA produces an administration time-dependent inhibition of angiotensin II. Low-dose ASA has also been shown to reduce BP when administered before bedtime, as opposed to upon awakening, in normotensive and hypertensive volunteers, and in pregnant women at high risk for preeclampsia. METHODS: We studied 328 untreated patients with grade 1 hypertension, 44.0 +/- 12.6 years of age, randomly divided into three groups: nonpharmacological hygienic-dietary recommendations, the same recommendations and ASA (100 mg/day) on awakening, or the same recommendations and ASA before bedtime. Blood pressure was measured every 20 min during the day and every 30 min at night for 48 consecutive h before and after 3 months of intervention. RESULTS: After three months of nonpharmacological intervention, there was a small and nonsignificant reduction of BP (<0.2 mm Hg; p = 0.648). Blood pressure was slightly elevated after aspirin on awakening (2.6/1.6 mm Hg in the 24-h mean of systolic/diastolic BP; p = 0.002). A significant BP reduction, however, was observed in the patients who received aspirin before bedtime (6.8/4.6 mm Hg in systolic/diastolic BP; p < 0.001). CONCLUSIONS: This prospective trial documents a significant administration time-dependent effect of low-dose ASA on BP in untreated hypertensive patients. The timed administration of low-dose ASA could provide a valuable approach, beyond the secondary prevention of cardiovascular disease, in the added BP control of patients with mild essential hypertension.     

Comparison of valsartan and amlodipine on ambulatory and morning blood pressure in hypertensive patients

BACKGROUND: Cardiovascular events occur most frequently in the morning. We aimed to study the effects of monotherapy with the long-acting angiotensin II receptor blocker valsartan compared with the long-acting calcium antagonist amlodipine on ambulatory and morning blood pressure (BP). METHODS: We performed ambulatory BP monitoring before and after once-daily dose of valsartan (valsartan group, n = 38) and amlodipine (amlodipine group, n = 38) therapy in 76 hypertensive patients. To achieve the target BP of < or =140/90 mm Hg, valsartan was titrated from 40 mg/day to 160 mg/day (mean dose 124 mg/day) and amlodipine was titrated from 2.5 mg/day to 10 mg/day (mean dose 6.4 mg/day). RESULTS: Both drugs significantly reduced clinic and 24-h systolic BP (SBP) and diastolic BP (DBP) (P <.002). However, the antihypertensive effect of amlodipine was superior to that of valsartan in clinical SBP (-26 mm Hg v -13 mm Hg, P =.001) and 24-h SBP (-14 mm Hg v -7 mm Hg, P =.008). In addition, morning SBP was significantly reduced by amlodipine from 156 to 142 mm Hg (P <.001) but not by valsartan. Both agents reduced lowest night SBP to a similar extent (amlodipine 121 to 112 mm Hg, P <.001; valsartan 123 to 114 mm Hg, P <.002). Reduction in morning SBP surge (morning SBP minus lowest night SBP) was significantly greater in patients treated with amlodipine compared with those treated with valsartan (-6.1 mm Hg v +4.5 mm Hg, P <.02). CONCLUSIONS: Amlodipine monotherapy was more effective than valsartan monotherapy in controlling 24-h ambulatory BP and morning BP in hypertensive patients.     

Preventing increases in early-morning blood pressure,heart rate,and the rate-pressure product with controlled onset extended release verapamil at bedtime versus enalapril,losartan, and placebo on arising

Background Therapeutic agents for the treatment of hypertension may differ in their efficacy during the early-morning period, a time when both morbid and mortal cardiovascular events are increased compared with other times of the day. Methods We studied the effects of a chronotherapeutic delivery system of verapamil (controlled-onset extended release [COER]-24 system) dosed at bedtime versus conventional morning administration of both enalapril and losartan on the blood pressure (BP), heart rate, and the heart rate systolic BP product during the first 4 hours after awakening in a placebo-controlled, forced-titration trial. There were 357 men and women enrolled in the trial with an untreated sitting diastolic BP of 95 to 114 mm Hg and ambulatory daytime diastolic BP ≥85 mm Hg. Patients were randomized to either COER-verapamil hydrochloride each evening (240 mg titrated to 360 mg), enalapril each morning (10 mg titrated to 20 mg), losartan each morning (50 mg titrated to 100 mg), or placebo. Early morning assessments of BP, heart rate, and the heart rate systolic BP product were performed by use of 24-hour ambulatory recordings after 4 weeks (low dose) and 8 weeks (high dose) of therapy. Results Results were similar at weeks 4 and 8 for all treatment groups except that the magnitude of change was greater at week 8. After 8 weeks of treatment, reductions in early morning BP by COER-verapamil were significantly greater (−15/−10 mm Hg) than enalapril (−9/−7 mm Hg, P < .01) and losartan (−8/−5 mm Hg, P < .001). COER-verapamil also led to greater reductions in morning heart rate, the rate-pressure product, and the rate-of-rise of BP compared with the other 2 active treatment groups. Reductions in mean 24-hour BP were greater in patients treated with COER-verapamil compared with placebo and losartan, and similar to reductions in patients treated with enalapril. Conclusions Bedtime administration of an agent designed to parallel the circadian rhythm of BP and heart rate led to significantly greater early morning hemodynamic effects compared with other conventional once-daily antihypertensive agents dosed in the morning. (Am Heart J 2002;144:657-65.)     

Bedtime administration of cilnidipine controls morning hypertension

Morning blood pressure (BP) level plays an important role in the incidence of cardiovascular disease. Recently, Kario, et al proposed the usefulness of ME difference (morning minus evening systolic BP) and ME average (average of morning and evening systolic BP) for the evaluation of antihypertensive treatment. Cilnidipine is a novel calcium channel blocker (CCB) that exerts inhibitory actions not only on L-type but also on N-type calcium channels. We investigated the effect of bedtime administration of cilnidipine (10 mg) in addition to the antihypertensive treatment for uncontrolled morning hypertension. Twenty-three hypertensive outpatients (13 males and 10 females; mean age, 66.9 years) with stable antihypertensive medication and uncontrolled morning BP were studied using self-measured BP monitoring in the morning and evening. Morning SBP (P < 0.001) and DBP (P < 0.001) decreased significantly from 150.2 +/- 8.7 and 87.8 +/- 9.3 to 132.7 +/- 7.4 and 77.5 +/- 8.5 mmHg, respectively, after the addition of cilnidipine. Morning heart rate did not change (63.3 +/- 7.0 to 64.1 +/- 9.4). The evening SBP, but not DBP, decreased significantly after treatment. Both the ME average (P < 0.001) and ME difference (P < 0.01) significantly decreased from 143.0 +/- 9.2 and 14.3 +/- 12.4 to 131.3 +/- 7.2 and 2.8 +/- 9.2 mmHg after treatment, respectively. The microalbuminuria decreased from 39.6 +/- 13.2 to 27.3 +/- 8.4 mg/g Cr. In conclusion, L-/N-type CCB cilnidipine may be useful for patients with uncontrollable morning hypertension by reducing both ME average and ME difference.     

An alpha-adrenergic blocker titrated by self-measured blood pressure recordings lowered blood pressure and microalbuminuria in patients with morning hypertension: the Japan Morning Surge-1 Study

BACKGROUND: The impact on microalbuminuria of strict treatment aimed at lowering of self-measured morning blood pressure using an adrenergic blockade is unclear. METHODS: We conducted an open-label multicenter trial, the Japan Morning Surge-1 Study, that enrolled 611 hypertensive patients, whose self-measured morning systolic blood pressure levels were more than 135 mmHg while taking antihypertensive drugs. These were randomly allocated to an experimental group, whose members received bedtime administration of 1-4 mg doxazosin (doxazosin group) or a control group whose members continued without any add-on medication (control group). The urinary albumin/creatinine ratio was investigated at the baseline and 6 months after the randomization. RESULTS: Both the morning and evening blood pressures and urinary albumin/creatinine ratio (-3.4 vs. 0.0 mg/gCr for urinary albumin/creatinine ratio; P < 0.001) were more markedly reduced in the doxazosin group than in the control group. This difference in the urinary albumin/creatinine ratio between the two groups was more marked in the patients with microalbuminuria (n = 238, -27.9 vs. -8.1 mg/gCr, P < 0.001). The reduction of urinary albumin/creatinine ratio was significantly associated with the use of doxazosin, and the change in all self-measured blood pressures (morning, evening, the average morning-evening), and these associations were independent of each other (P < 0.001). CONCLUSION: Adding a bedtime dose of an alpha-adrenergic blocker titrated by self-measured morning blood pressure in treated hypertensive patients with uncontrolled morning hypertension significantly reduced blood pressure and urinary albumin excretion rate, particularly in those with microalbuminuria.     

The optimal timing of antihypertensive medication administration for morning hypertension in patients with cerebral infarction

Morning hypertension is an independent risk factor for cardiovascular diseases, particularly stroke. However, the optimal time at which to take antihypertensive medication to treat morning hypertension remains unclear. We prospectively enrolled elderly patients (over 65 years old) with morning hypertension who had suffered an ischemic stroke (or strokes). Additional treatments (one of six arms) were randomly administered for 10 weeks in the morning, in the evening or at bedtime (n=15 for each time point/medication). The patients measured their blood pressure and heart rate at home for 14 days prior to the intervention and for the final 14 days, and recorded the data in a blood pressure diary. The patients' urinary albumin/creatinine ratios were evaluated before and after the 10-week intervention. A total of 270 patients were enrolled in this study (mean age: 75.6±5.8 years; female/male ratio: 125/145). Their morning and evening systolic blood pressures were significantly decreased after following any of the study medication dosing schedules (P<0.001). However, the reductions in the differences between the morning and evening systolic blood pressures were significant only when the medication was taken in the evening or at bedtime (P<0.001 with repeated measures analysis of variance). Furthermore, the recovery rate from morning hypertension was also higher when the medication was taken in the evening (40.0%) or at bedtime (45.6%), rather than in the morning (22.2%; P=0.003 with the χ(2)-test). Antihypertensive medication taken in the evening or at bedtime is the most effective in treating morning hypertension when the patient adheres to the medication regimen.