Efficacy and Safety of Nighttime Dosing of Antihypertensives: Review of the Literature and Design of a Pragmatic Clinical Trial

Blood pressure exhibits circadian variability, and nighttime blood pressure is one of the best predictors of cardiovascular (CV) events. Adults with hypertension who lack a nighttime dipping pattern are at particularly high risk. Several studies have found that bedtime dosing of antihypertensive agents reduces sleep blood pressure and improves the dipping pattern in nondippers. One small study and 2 substudies of diabetes and chronic kidney disease suggest that bedtime dosing of ≥1 antihypertensives significantly reduced CV events. A Cochrane review of 5 studies found no difference in adverse events between morning and evening dosing. However, several evaluations in ophthalmology have found that nocturnal arterial hypotension precipitated ocular vascular disorders such as ischemic optic neuropathy. Some authors have suggested that additional studies of nighttime dosing of antihypertensive agents that evaluate CV events need to be conducted. The authors describe a randomized controlled pragmatic trial that is being planned at the University of Iowa and Duke University. Patients with hypertension and other comorbid conditions will be randomized to either continue morning dosing of all antihypertensive agents or to switch their nondiuretic medications to bedtime dosing. Patients will be followed for 36 to 42 months. This study will determine whether nighttime dosing reduces CV risk when compared with traditional morning dosing of antihypertensive agents.     

不同服药方法对高血压患者降压有效性和平稳性的影响

目的 探讨不同服药方法 对于高血压治疗有效性和平稳性的影响.方法 采用随机、单盲、平行对照设计,对90例2级及以上原发性高血压患者,随机分为早晨服用非洛地平和缬沙坦组(A组30例,男15例,女15例),早晨服用缬沙坦晚上服非济地平组(B组30例,男17例,女13例),早晨服用非洛地平晚上服缬沙坦组(C组30例,男16例,女14例),患者均于服药前及服药后2周进行动态血压监测求得平滑指数等指标.结果 服药2周后,各组夜间时段及24 h的平均收缩压的下降值依此为:19.3、28.8、30.5、22.9、28.3及29.1 mm Hg(1 mm Hg=0.133 kPa).组间比较,A组0.05).夜间及24 h平均收缩压平滑指数符组依次为:2.43,3.12,3.22及1.92,2.49,2.27,组间比较,夜间平均收缩压平滑指数A组0.05).结论 联合用药的降压效果显著,早晚分次服药较早晨顿服两种药物能更有效控制夜间血压,早晚分次服药使夜间及24 h血压下降更平稳.     

The antihypertensive efficacy and safety of a chronotherapeutic formulation of propranolol in patients with hypertension

This study evaluated the antihypertensive efficacy and tolerability of a chronotherapeutic formulation of propranolol designed for nighttime dosing (propranolol controlled release [CR]). A total of 434 patients with mild-to-moderate hypertension were randomized to placebo or to one of four doses of propranolol CR (80, 120, 160, or 640 mg/d). At baseline, the mean morning blood pressures were similar in each treatment group and averaged 152/101 mm Hg. After 8 weeks of treatment, morning diastolic blood pressure, the primary efficacy measurement, was significantly reduced from baseline in placebo (-6.98 mm Hg) and all propranolol groups (p<0.001). The decreases ranged from 10.1 mm Hg in the 80-mg/d group to 11.0 mm Hg in the 120-mg/d group and were significantly larger than placebo in the 120-, 160-, and 640-mg/d groups (p<0.05). Blood pressure measured in the evening (trough) demonstrated similar antihypertensive efficacy. Heart rate and rate-pressure product were reduced in a dose-related manner by propranolol CR. The formulation was well tolerated with only fatigue and dizziness being reported more frequently than in the placebo group. Propranolol CR is an effective antihypertensive formulation that may reduce blood pressure during the morning period of maximum cardiovascular risk.     

Comparable morning versus evening administration of once-daily mometasone furoate dry powder inhaler

BACKGROUND: The control of daytime and nighttime symptoms is an important measure of effectiveness of asthma therapy, especially, when administered once-daily. OBJECTIVE: To evaluate the efficacy of evening and morning administrations of mometasone furoate administered via a dry powder inhaler (MF-DPI) 400mug once-daily (QD) to show equivalence. METHODS: Open-label, randomized, parallel-group study in adult patients with mild to moderate asthma with a >/=3-month history of ICS use. Patients received MF-DPI 400mug QD either in the morning (AM) or evening (PM) for 12 weeks. The primary measure was the change in asthma symptoms from baseline to week 12. Secondary outcomes included response to treatment, adherence, inhaler device evaluation, use of rescue medication, urinary cortisol levels, and differential white blood cell count. RESULTS: A total of 1537 patients were randomized; the efficacy population comprised 543 and 479 patients in the MF-DPI QD morning and evening groups, respectively. Mean improvements from baseline in daytime symptom scores at week 12 with morning and evening administration of MF-DPI 400mug were -0.11+/-0.59 and -0.12+/-0.68, respectively (95% CI, -0.095 to 0.061) and the corresponding improvements in nighttime symptom scores were -0.08+/-0.59 and -0.07+/-0.50, respectively (95% CI, -0.067 to 0.068). Use of rescue medication was the same in both groups (1 puff/day). MF-DPI QD was well tolerated regardless of time of administration. CONCLUSIONS: This open-label study did not identify differences between morning and evening dosing of MF-DPI 400mug QD. A better effect of evening dosing compared to morning dosing found in previous double-blind placebo-controlled studies could not be confirmed.     

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.     

Once-daily budesonide/formoterol in a single inhaler in adults with moderate persistent asthma

Patients with moderate persistent asthma (n = 523; mean FEV1 77.4%) not fully controlled with inhaled corticosteroids (ICS; 400-1000 microg/day) were randomized to receive either once-daily budesonide/formoterol (160/4.5 microg, two inhalations); or twice-daily budesonide/formoterol (160/4.5 microg, one inhalation); or budesonide (400 microg) once-daily for 12 weeks. Once-daily dosing was administered in the evening and twice-daily dosing was administered in the morning and evening. All patients received twice-daily budesonide (200 microg) during a 2-week run-in. Compared with budesonide alone, change in mean morning and evening peak expiratory flow was greater in the once-daily budesonide/formoterol group (27 and 171 min(-1), respectively; P < 0.001) and twice-daily budesonide/formoterol group (23 and 24 l min(-1), respectively; P < 0.001). Night awakenings, symptom-free days, reliever-use-free days and asthma-control days were all improved during once-daily budesonide/formoterol therapy vs. budesonide (P < or = 0.05). Similar improvements were also seen with twice-daily budesonide/formoterol (P < or = 0.05). The risk of a mild exacerbation was reduced after once- and twice-daily budesonide/formoterol vs. budesonide (38% and 35%, respectively; P < 0.002). All treatments were well tolerated. Budesonide/formoterol, once- or twice-daily, in a single inhaler improved asthma symptoms and exacerbations compared with budesonide. In the majority of patients with moderate persistent asthma requiring ICS and long-acting beta-agonists, once-daily formoterol/budesonide provided sustained efficacy over 24 h, similar to twice-daily dosing.     

Differential effects of morning and evening dosing of nisoldipine ER on circadian blood pressure and heart rate

The time of administration of once-daily antihypertensive agents may have a significant impact on blood pressure control during awake and sleep periods. Using 24-h ambulatory monitoring, we compared the effects of morning and evening dosing of the long-acting dihydropyridine calcium channel blocker, nisoldipine extended-release (ER), on circadian blood pressure (BP) and heart rate in patients with mild-to-moderate hypertension. After completing a 3-week placebo run-in period, 85 patients were randomized to morning versus evening nisoldipine ER treatment at a fixed 20-mg dose. Patients were treated for 4 weeks, followed by crossover to the alternate dosing regimen for 4 additional weeks. Twenty-four–hour ambulatory monitoring was performed at baseline and at 4 and 8 weeks after randomization. Awake and sleep times were determined by electronic activity recorders (Actigraphy). Similar least-squares (±SE) mean changes from baseline in 24-h BP (systolic BP/diastolic BP: −11.9/−7.4 ± 0.6/0.5 v −11.6/−6.5 ± 0.6/0.5 mm Hg) and heart rate (1.0/1.7 ± 0.4/0.4 beats/min) occurred with morning and evening administration, respectively. A significantly greater effect on awake diastolic BP (systolic BP/diastolic BP: −12.6/−8.1 ± 0.7/0.4 v −11.3/−6.4 ± 0.7/0.4 mm Hg; P = .16/.01) was observed with morning dosing compared with evening dosing. In addition, small increases in sleep and early morning heart rate were seen with evening compared with morning administration of nisoldipine (sleep, 3.1 ± 0.4 v 0.4 ± 0.4 beats/min; P < .001; early morning, 3.5 ± 0.7 v 0.5 ± 0.7 beats/min; P = .002). These differential effects on awake BP and sleep heart rate were also observed in patients who had normal (dippers) and elevated (nondippers) BP values during sleep. Appropriate evaluation of the efficacy and safety of long-acting antihypertensive agents is essential when evening administration is being considered. In the present study, the timing of nisoldipine ER administration had no effect on mean changes in BP and heart rate over a 24-h period. However, nisoldipine ER had some differential effects during sleep and awake periods with morning relative to evening dosing.     

mRNA levels of circadian clock components Bmal1 and Per2 alter independently from dosing time-dependent efficacy of combination treatment with valsartan and amlodipine in spontaneously hypertensive rats

Chronopharmacological effects of antihypertensives play a role in the outcome of hypertension therapy. However, studies produce contradictory findings when combination of valsartan plus amlodipine (VA) is applied. Here, we hypothesized different efficacy of morning versus evening dosing of VA in spontaneously hypertensive rats (SHR) and the involvement of circadian clock genes Bmal1 and Per2. We tested the therapy outcome in short-term and also long-term settings. SHRs aged between 8 and 10 weeks were treated with 10 mg/kg of valsartan and 4 mg/kg of amlodipine, either in the morning or in the evening with treatment duration 1 or 6 weeks and compared with parallel placebo groups. After short-term treatment, only morning dosing resulted in significant blood pressure (BP) control (measured by tail-cuff method) when compared to placebo, while after long-term treatment, both dosing groups gained similar superior results in BP control against placebo. However, mRNA levels of Bmal1 and Per2 (measured by RT-PCR) exhibited an independent pattern, with similar alterations in left and right ventricle, kidney as well as in aorta predominantly in groups with evening dosing in both, short-term and also long-term settings. This was accompanied by increased cardiac mRNA expression of plasminogen activator inhibitor-1. In summary, morning dosing proved to be advantageous due to earlier onset of antihypertensive action; however, long-term treatment was demonstrated to be effective regardless of administration time. Our findings also suggest that combination of VA may serve as an independent modulator of circadian clock and might influence disease progression beyond the primary BP lowering effect.     

Little Effect of Ordinary Antihypertensive Therapy on Nocturnal High Blood Pressure in Patients with Sleep Disordered Breathing

The antihypertensive effects of four different antihypertensive medications (β-blocking agent, atenolol 50 mg; calcium-antagonist, isradipine SRO [slow release] 2.5 mg; diuretic, hydrochlorothiazide [HCTZ] 25 mg; and angiotension converting enzyme-inhibitor, spirapril 6 mg) on obese patients with sleep disordered breathing and hypertension were compared by the ambulatory blood pressure measurement (ABPM).Eighteen patients were randomized in a double-blind, crossover fashion to receive each of the four different medications for 8 weeks. ABPM was performed at baseline and after an 8-week treatment with these medications. A 2- to 3-week washout period occurred both at baseline and between each of the four medications. Three patients were omitted from statistical analysis because of technical problems of ABPM.Atenolol, isradipine SRO, and spirapril decreased significantly (P < .01) the mean 24-h systolic blood pressure, whereas HCTZ did not. The mean 24-h diastolic blood pressure decreased significantly after all four medications: 12 (SD ± 14) mm Hg with atenolol, 7 (SD ± 10) mm Hg with isradipine SRO, 3 mm Hg (SD ± 14) with HCTZ, and 6 (SD ± 15) mm Hg with spirapril (P < .01). During nighttime none of the medications reduced the mean diastolic or systolic blood pressure significantly. According to the 24-h blood pressure curve the influence of these four medications during the whole measurement period was not similar. Atenolol and spirapril lost their antihypertensive effect during the early morning hours. The antihypertensive effect of HCTZ varied markedly from hour to hour. The trough-to-peak ratio of no medication was >0.50.Negative correlation was observed between the apnea time and the mean systolic 24-h (r = −0.604, P = NS) and the mean systolic nocturnal blood pressure change (r = −0.590, P = NS).Our study revealed that the daytime high blood pressure was quite easily controlled by the ordinary monotherapy in these patients with partial upper airway obstruction and hypertension. Instead none of the medications used decreased nocturnal high blood pressure markedly.     

Circadian variation of blood pressure and the assessment of antihypertensive therapy

The inherent variability of activity and the awake-sleep cycle creates changes in hemodynamics that may influence the outcome of a variety of cardiovascular disorders. Recently, data suggest that increased variability of blood pressure may promote excessive hypertensive target organ disease. Several epidemiologic studies have demonstrated that myocardial ischemia, myocardial infarction and sudden cardiac death have an excess incidence in the first several hours post-awakening. Additionally, surveys of the incidence of stroke (both ischemic and hemorrhagic) have shown an excess for the hours between 8 a.m. and noon. The pathophysiologic bases for the increased number of cardiac and cerebrovascular events in the early morning hours may be both due to hemodynamic and hematorrheologic factors. During the past several years, therapeutic studies have evaluated the effects of antihypertensive therapies on blood pressure and heart rate during the circadian or 24 h period. There are a few studies that have evaluated nighttime dosing of conventional antihypertensive therapies but these have generally been statistically underpowered to demonstrate differences of morning versus evening dosing on circadian blood pressure. Since the timing of dosing (and hence the delivery of antihypertensive therapy) may be clinically relevant, prospective and well-performed clinical trials of chronotherapy are necessary. In this review, we evaluate new data on the clinical impact of cardiovascular chronotherapy and the importance of timing of dosing on pharmacodynamics.     

Evening Dosing of Antihypertensive Therapy to Reduce Cardiovascular Events: A Third Type of Evidence Based on a Systematic Review and Meta‐Analysis of Randomized Trials

Nighttime blood pressure strongly predicts cardiovascular events (CVEs). Further, a preliminary trial has shown decreased CVEs from evening vs morning dosing of antihypertensive therapy. Is there additional evidence for evening dosing? The authors systematically classified all hypertension trials as evening dosing trials (EDTs) or usual dosing trials (UDTs). Meta‐analyses provided standardized hazard ratios for CVEs for EDTs (HR_{EDT s}) and UDTs (HR_{UDT s}). HR_{EDT s}/HR_{UDT s} gave the relative risk (RR) from evening vs usual dosing. Among 175 trials, 5 EDTs were discovered. The RR for CVEs (95% confidence limits) from evening vs usual dosing was 0.63 (0.43–0.92; P=.016). After adjustment for drug class, the RR was 0.54 (0.34–0.85; P=.008). Unlike other EDTs, the Heart Outcomes Prevention Evaluation (HOPE) study administered its entire antihypertensive dose prior to sleep and gave the greatest risk reduction. This study provides a third type of evidence suggesting a beneficial effect from evening dosing of antihypertensive therapy. Head‐to‐head, multicenter trials are needed to test this strategy.

More than 40 years ago, the US Veterans Administration conducted two small placebo‐controlled trials in men with very high clinic blood pressures (BPs). These trials demonstrated striking reductions (73 to 95%) in major cardiovascular events (CVEs) for patients randomized to receive antihypertensive therapy vs placebo.¹, ² Since then, there has been increasing interest in the use of home, 24‐hour ambulatory, and central arterial BP measurements. Nonetheless, 4 decades after these landmark trials, clinic BP remains the primary target for reducing cardiovascular risk from hypertension.³, ⁴, ⁵ Two types of observations suggest that targeting nighttime BP may be more relevant than targeting clinic, home, or daytime ambulatory BP. (1) In a longitudinal study of individuals randomly sampled from the general population, simultaneous adjustment for daytime and nighttime systolic blood pressures led to sustained prognostic value from nighttime but less so for daytime systolic blood pressure;⁶ in a longitudinal study of 13,844 patients with hypertension from 9 regions, simultaneous adjustment for clinic, daytime, and nighttime systolic blood pressures led to sustained prognostic value for nighttime systolic blood pressure while clinic and daytime systolic blood pressures lost their prognostic value entirely.⁷ (2) Hermida and colleagues⁸ have reported that patients randomized to receive ≥1 antihypertensive agent in the evening compared with patients receiving all antihypertensive agents in the morning had substantial reductions in CVEs and total mortality. However, as pointed out by its authors, this trial had important limitations because of its relatively modest sample size, lack of blinding, and limitation to a single center.Because data are unavailable that directly compare timing of dosing regimens in large, multicenter, double blind trials, we compared the risk reduction in CVEs in trials whose protocols specifically dictated evening dosing of an antihypertensive with the risk reduction in CVEs in trials without this requirement.     

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.     

Aspirin intake in the morning is associated with suboptimal platelet inhibition,as measured by serum Thromboxane B2, during infarct-prone early-morning hours

Aspirin is traditionally taken once daily in the morning and considered to be effective throughout the 24h interval. Cardiovascular events occur most frequently in the early morning, suggesting that these hours are critical in terms of adequate platelet inhibition. This study therefore assed platelet function in the early morning—8.00 AM—in healthy volunteers, during a once-daily (OD) 80 mg morning in comparison with an OD evening regimen and a twice-daily (BID) 40 mg regimen. It was an open-label randomized cross-over study, comprising 12 healthy subjects. Subjects were allocated to three sequential dosage regimens: 80 mg OD at 8.00 AM, 80mg OD at 8.00 PM, and 40 mg BID at 8.00 AM and PM. Platelet function 12 and 24 hours after aspirin intake was measured by means of serum thromboxane B₂ (sTxB₂) levels, the collagen/epinephrine closure time (Platelet Function Analyzer(PFA)-200^®) and the Aspirin Reaction Units (ARU, VerifyNow^®). The results demonstrated that early morning sTxB₂ concentrations were 5843pg in the morning regimen, 2877pg in the evening OD regimen, and 3343pg in the BID regimen (morning- vs evening regimen p = < 0.01; morning- vs BID regimen p = < 0.01). Early morning PFA-closure time (p = 0.12)) as well as VerifyNow ARU (p = 0.17) mean values were similar for all three regimens. In conclusion, the OD-morning regimen seems to acquire the lowest level of platelet inhibition during the critical early morning window. Switching to an OD-evening or BID intake seems prudent, although further research on clinical cardiovascular outcome in patients with stable cardiovascular disease is needed.     

Long-term efficacy and safety of fluticasone propionate powder administered once or twice daily via inhaler to patients with moderate asthma

OBJECTIVE: To evaluate the efficacy and safety of fluticasone propionate administered as a once-daily or twice-daily regimen over a period of 1 year to patients with moderate asthma. DESIGN: Double-blind, randomized, parallel group, and placebo-controlled phase (12 weeks) and an open-label phase (54 weeks). SETTING: Multicenter study in an outpatient setting. PARTICIPANTS: Patients (n = 253; age, > or = 12 years) with a mean FEV(1) of 67% predicted normal were stratified according to baseline therapy of maintenance inhaled corticosteroids vs beta(2)-agonists alone. MEASUREMENTS AND INTERVENTIONS: Fluticasone propionate (250 microg bid or 500 microg qd) or placebo (bid) was administered via the Diskus multidose powder inhaler (Glaxo Wellcome; Research Triangle Park, NC) for 12 weeks. During open-label treatment, patients were re-randomized to once-daily or twice-daily fluticasone propionate. RESULTS: Compared to placebo, fluticasone propionate administered qd or bid significantly improved FEV(1) (p < 0.001), morning (p < 0.001) and evening peak expiratory flow (PEF; p < 0.001), asthma symptom scores (p < or = 0.001), and albuterol use (p 相似文献   

Effect of sildenafil citrate on blood pressure and heart rate in men with erectile dysfunction taking concomitant antihypertensive medication. Sildenafil Study Group

OBJECTIVES: To assess the acute effect of sildenafil citrate on blood pressure and heart rate in men with erectile dysfunction taking concomitant antihypertensive medication. DESIGN: Post-hoc subanalysis of five, 12- or 24-week, prospective, randomized, double-blind, placebo-controlled studies. SETTING: Private-practice and academic urology clinics. PATIENTS: A total of 1685 men with erectile dysfunction of > or = 6 months duration, of whom 667 (sildenafil n = 406, placebo n = 261) were taking antihypertensive medication (diuretic, beta-blocker, alpha-blocker, angiotensin converting enzyme inhibitor, and/or calcium antagonist). Of the patients taking antihypertensive medication, 608 (91%) completed the studies (374 of 406 receiving sildenafil, 234 of 261 receiving placebo). INTERVENTIONS: The last dose of oral sildenafil (25-200 mg) or placebo was taken at home on the morning of the final clinic visit. Patients taking antihypertensive medication maintained usual dosing schedules. MAIN OUTCOME MEASUREMENTS: Sitting systolic (SBP)/diastolic blood pressure (DBP) and heart rate at baseline and after dosing with sildenafil or placebo (end-of-treatment visit). RESULTS: Mean changes from baseline in SBP/DBP for men taking antihypertensive medication were -3.6/-1.9 mmHg for those receiving sildenafil and -0.8/-0.1 mmHg for those receiving placebo compared with -2.2/-2.0 mmHg and -0.1/0.4 mmHg, respectively, for men not taking antihypertensive medication. Mean changes from baseline in heart rate for men taking antihypertensive medication were -0.6 beats/min after sildenafil and 0.9 beats/min after placebo compared with 0.4 beats/min and -0.6 beats/min, respectively, for patients not taking antihypertensive medication. Differences in SBP, DBP, and heart rate between the patients taking and those not taking antihypertensive medication were small. CONCLUSIONS: The acute, short-term effects of oral sildenafil on blood pressure and heart rate in men with erectile dysfunction were small and not likely to be clinically significant in those taking concomitant antihypertensive medication.     

Lack of adequate blood pressure control in the morning and evening periods in medicated hypertensive patients considered to be controlled in the office.

BACKGROUND AND AIM: In hypertensive patients tight blood pressure (BP) control during the critical morning and evening periods may be relevant for preventing cardiovascular events, which most frequently occur at these times of the day. METHODS: In a prospective study we evaluated 24h ambulatory BP (ABP) values (24h, daytime, nighttime, morning period between 6-10 am and evening period between 6-10 pm), in 103 hypertensive patients (HTs), aged between 18-79 years, considered to be controlled in the office in the previous two months (office BP < 140/90 mmHg, 2 x 3 readings, before taking medication), who were being treated with antihypertensive drugs taken once daily in the morning. Based on ABP data, HTs were considered to have good BP control if daytime BP values were < 135/85 mmHg, < 133.1/85.4 mmHg during the morning period, and < 138.1/89.3 mmHg during the evening period. Otherwise control of ABP was considered poor. These limits correspond to the upper 95% confidence limits of BP calculated for each period in a normotensive control population of 210 subjects age-matched to the HTs. RESULTS: Of the 103 HTs, 39 were under monotherapy and the remaining 64 on combination regimens (34 with two drugs, 29 with three and one with four). Based on ABP data of the 103 HTs, poor ABP control was observed in 36 (35%) in the morning period, in 24 (23%) in the evening period and in 29 (28%) for daytime BP values. ABP values during both the morning and evening periods correlated significantly with daytime values (r = 0.72 and r = 0.89 respectively, p < 0.01) but not with office values. CONCLUSIONS: A significant proportion of treated HTs who are considered to be controlled in the office present abnormally high ABP levels, particularly in the critical early morning period, but also during the evening and throughout the daytime period.     

Once-daily dosing with budesonide/formoterol compared with twice-daily budesonide/formoterol and once-daily budesonide in adults with mild to moderate asthma

Adherence to maintenance therapy is often poor in patients with asthma. Simplifying dosing regimens has the potential to improve both adherence and asthma-related morbidity. In this 12-week, randomized, double-blind, double-dummy, parallel-group study, 617 patients with mild to moderate persistent asthma (mean forced expiratory volume in 1s [FEV1] 78.5% predicted) who were not optimally controlled on inhaled corticosteroids (200-500 microg/day) were randomized to once-daily budesonide/formoterol (80/4.5 microg, 2 inhalations in the evening), twice-daily budesonide/formoterol (80/4.5 microg, 1 inhalation), or a corresponding dose of budesonide once-daily (200 microg, 1 inhalation in the evening). All patients received budesonide (100 microg twice daily) during a 2-week run-in. Changes in mean morning peak expiratory flow (PEF) were similar for od budesonide/formoterol (23.4 l/min) and twice-daily budesonide/formoterol (24.1 l/min), and both were greater than with budesonide (5.5 l/min; both P<0.001). Evening PEF, symptom-free days, reliever-free days, and asthma control days were improved with budesonide/formoterol therapy vs. budesonide (P<0.05 vs. budesonide for all variables). All treatments were well tolerated. Budesonide/formoterol administered once daily in the evening is a convenient treatment regimen that is as effective in improving asthma control as twice-daily dosing in patients with mild to moderate persistent asthma.     

The velocity of home blood pressure reduction in response to low-dose eplerenone combined with other antihypertensive drugs determined by exponential decay function analysis

Background/objective: Eplerenone is a highly selective aldosterone blocker, which has the potential to lower blood pressure (BP) in patients with hypertension. The objective of this study was to assess the hypotensive effects of low-dose eplerenone (25?mg) using home BP measurements. We also assessed the time required to reach 95% of the maximum antihypertensive effect (stabilization time) by analyzing exponential decay functions using home BP measurements.

Methods: We reviewed the medical records of 83 hypertensive patients who were taking eplerenone 25?mg (age, 68.6?±?11.8?years; men, 36.1%) in addition to other antihypertensive agents. Home BPs were averaged in each patient for the last 5?days of each observation period. The morning versus evening effect (M/E ratio) and the evening versus morning effect (E/M ratio) were calculated to assess the duration of action of eplerenone.

Results: The mean home systolic/diastolic BPs at baseline were 136.8?±?8.8/77.2?±?9.3?mmHg, respectively. After 8?weeks of treatment with eplerenone, home systolic/diastolic BP significantly decreased by ?7.1?±?10.1/?2.6?±?5.0?mmHg (p?p?=?0.006) and 16.5 days (p?=?0.001), respectively. When eplerenone was administered in the morning, the M/E ratio was 1.1?±?0.3. The corresponding E/M ratio for evening administration was 0.9?±?0.6. Although no nocturia was observed, there was a slight but significant increase in serum potassium levels (p?=?0.03).

Conclusions: Our data suggest that the combination of eplerenone with other antihypertensive drugs may be a promising therapeutic strategy for the treatment of essential hypertension.