Matrix study of irbesartan with hydrochlorothiazide in mild-to-moderate hypertension. Dose finding studies with imidapril--a new ACE inhibitor. Tricenter assessment of the efficacy of the ACE inhibitor, moexipril, by ambulatory blood pressure monitoring. Pharmaceutical care program for patients with uncontrolled hypertension. Report of a double-blind clinical trial with ambulatory blood pressure monitoring. Lowering blood pressure reduces renal events in type 2 diabetes. Distinct time courses of renal protective action of angiotensin receptor antagonists and ACE inhibitors in chronic renal disease. Effect of intensive blood pressure control with valsartan on urinary albumin excretion in normotensive patients with type 2 diabetes. Evaluation of the 24-hour blood pressure effects of eprosartan in patients with systemic hypertension. Comparative efficacy of two angiotensin II receptor antagonists, irbesartan and losartan in mild-to-moderate hypertension. Irbesartan/Losartan Study Investigators. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. Placebo effect and adaptation to noninvasive monitoring of BP. A randomized, double-blind, placebo-controlled, parallel-group, multicenter trial of four doses of tasosartan in patients with essential hypertension. Tasosartan Investigator's Group. Efficacy and safety of a once daily graded-release diltiazem formulation in essential hypertension. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Administration-time-dependent effects of olmesartan on the ambulatory blood pressure of essential hypertension patients. Does metformin decrease blood pressure in patients with Type 2 diabetes intensively treated with insulin? Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Reduction of ACE activity is insufficient to decrease microalbuminuria in normotensive patients with type 1 diabetes. Angiotensin II receptor antagonist telmisartan in isolated systolic hypertension (ARAMIS) study: efficacy and safety of telmisartan 20, 40 or 80 mg versus hydrochlorothiazide 12.5 mg or placebo. [Randomized, comparative study on the treatment of moderate arterial hypertension during pregnancy: methyldopa, acebutolol, labetalol]. Fosinopril monotherapy: relationship between blood pressure reduction and time of administration. A comparison of the efficacy and safety of irbesartan/HCTZ combination therapy with irbesartan and HCTZ monotherapy in the treatment of moderate hypertension. Effects of comprehensive lifestyle modification on blood pressure control: main results of the PREMIER clinical trial. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Efficacy and safety of valsartan, an angiotensin II receptor antagonist, in hypertension after renal transplantation: a randomized multicenter study. Treatment of isolated systolic hypertension: the SHELL study results. The effects of the long-acting angiotensin-converting enzyme inhibitor cilazapril on casual, exercise, and ambulatory blood pressure. Efficacy of ACE inhibitors and ATII receptor blockers in patients with microalbuminuria: a prospective study. The effect on 24 h blood pressure control of an angiotensin converting enzyme inhibitor (perindopril) administered in the morning or at night. 24-hour blood pressure control by once-daily administration of irbesartan assessed by ambulatory blood pressure monitoring. Irbesartan Multicenter Investigators' Group. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Evaluation of a structured treatment and teaching programme on hypertension in general practice. Different effects of antihypertensive regimens based on fosinopril or hydrochlorothiazide with or without lipid lowering by pravastatin on progression of asymptomatic carotid atherosclerosis: principal results of PHYLLIS--a randomized double-blind trial. Liposomal prostaglandin E1 (TLC C-53) in acute respiratory distress syndrome: a controlled, randomized, double-blind, multicenter clinical trial. TLC C-53 ARDS Study Group. Randomized placebo-controlled double-blind study of three aprotinin regimens in primary cardiac surgery. Comparison of tamsulosin and naftopidil for efficacy and safety in the treatment of benign prostatic hyperplasia: a randomized controlled trial. Early ACE-i intervention in microalbuminuric patients with type 1 diabetes: effects on albumin excretion, 24 h ambulatory blood pressure, and renal function. Nonpharmacologic intervention to reduce blood pressure in older patients with mild hypertension.
The purpose of this study was to assess the safety and antihypertensive dose-response effects of irbesartan and hydrochlorothiazide (HCTZ) in patients with mild-to-moderate hypertension. After a 4- to 5-week single-blind placebo lead-in period, 683 patients with seated diastolic blood pressure (SeDBP) between 95 and 110 mm Hg were randomized to receive once-daily dosing with one of 16 different double-blind, fixed combinations of irbesartan (0, 37.5, 100, and 300 mg irbesartan) and HCTZ (0, 6.25, 12.5, and 25 mg HCTZ) for 8 weeks. The primary efficacy variable was the change from baseline in trough SeDBP after 8 weeks of therapy. Data were analyzed by response surface modeling. At Week 8, mean changes from baseline in trough SeDBP (mm Hg) ranged from -3.5 for placebo, -7.1 to -10.2 for the irbesartan monotherapy groups, -5.1 to -8.3 for the HCTZ monotherapy groups, and -8.1 to -15.0 for the combination groups. Irbesartan plus HCTZ produced additive reductions in both SeDBP and seated systolic BP, with at least one combination producing greater BP reduction than either drug alone (P < .001). All treatments were well tolerated; there were no treatment-related serious adverse events. Irbesartan tended to ameliorate the dose-related biochemical abnormalities associated with HCTZ alone. In conclusion, the combination of HCTZ in doses up to 25 mg with irbesartan, in doses up to 300 mg, is safe and produces dose-dependent reductions in BP. 1. We describe an approach involving a smaller, shorter study, leading onto a longer, larger study in which the antihypertensive effects of ascending doses of imidapril, a new ACE inhibitor, were investigated. Both studies were planned prospectively, assuming a clinically useful fall in BP to be 8 mm Hg (s.d. = 9). The studies included patients with mild to moderate essential hypertension (baseline sitting diastolic blood pressure (SDBP) 95-115 mm Hg). After a placebo run-in of 2-3 weeks patients received either placebo or imidapril 2.5, 5, 10 or 20 mg in the 2 week study (n = 91) or imidapril 5, 10, 20 or 40 mg in the 4 week study (n = 162). 2. The overall mean baseline SDBP was 103.4 mm Hg (s.d. 0.62) in the initial study and 101.5 mm Hg (s.d. 0.41) in the 4 week study. 3. Compared with placebo, imidapril 10, 20 and 40 mg significantly reduced SDBP. There was no significant difference between these doses, suggesting that 10 mg achieved maximal ACE inhibition in most patients. The 2.5 mg dose showed no significant effect. The 5 mg dose gave an intermediate effect. In both studies the overall incidence of adverse events was similar in the imidapril and placebo groups, and was not worrying. To assess the efficacy and time-dependent effects of once-daily moexipril, a nonsulfhydryl ester prodrug of the angiotensin-converting enzyme (ACE) inhibitor, moexiprilat, we conducted a multicenter, double-blind, placebo-controlled trial in 51 hypertensive patients using both clinic and ambulatory blood pressure (BP) recordings. Patients were included in the trial based on a minimum of 40% of the daytime diastolic BPs of 90 mm Hg or more during a placebo baseline phase; and the primary endpoint was change in 24-hour ambulatory diastolic BP. Patients were randomized to receive placebo, 7.5 mg of moexipril, or 15 mg of moexipril once daily. Clinic and ambulatory BPs were taken on the first day and after eight weeks of double-blind therapy. After the 7.5-mg dose, there were no significant changes in the acute or prolonged clinic BPs compared with placebo. Compared with adjusted mean changes for placebo, the 15-mg moexipril dose lowered clinic systolic BP, but not diastolic BP. In contrast, acute (1 day) reductions in 24-hour diastolic BPs were -2/-3 mm Hg, -6/-4 mm Hg, and -14/-9 mm Hg on placebo, 7.5 mg of moexipril, and 15 mg of moexipril, respectively (P < .01 for the 15-mg dose). Similarly, after long-term dosing for 8 weeks, reductions in 24-hour diastolic BPs were 1/-2 mm Hg, -6/-4 mm Hg, and -12/-9 mm Hg for the respective treatment groups (P < .01 for the 15-mg dose).(ABSTRACT TRUNCATED AT 250 WORDS) Pharmaceutical care programs may be an option to improve blood pressure (BP) control in patients with uncontrolled hypertension. The aim of this study was to evaluate the efficacy of pharmaceutical care programs in treating patients with resistant hypertension.
                In a double-blind randomized clinical trial, 71 patients with uncontrolled BP were enrolled in a pharmaceutical care program or in a control group and underwent a series of cognitive tests. The primary outcome was change in ambulatory BP (ABP) between the baseline evaluation and the final visit 6 months later. The secondary outcomes were the frequency of drug-related problems and adherence as determined by plasma levels of hydrochlorothiazide.
                The delta-values between the intervention and control groups for ABP in the different daily periods, with the corresponding 95% confidence limits, adjusted for age and baseline BP were: 3 (-1 to 5), 2 (-2 to 4), and 5 (-1 to 6) mm Hg for 24 h, daily and nightly systolic BP, respectively. The corresponding values for diastolic BP were 1 (-1 to 3), 0 (-2 to 2), and 3 (-1 to 4) mm Hg, respectively. Hydrochlorothiazide was detected in the plasma in 21 of 27 patients in the intervention group that attended to all appointments and 24 of 30 patients in the control group (P = .904).
                The pharmaceutical care program tested in this trial was feasible and showed a trend for better BP control in patients with uncontrolled hypertension. BP is an important determinant of kidney disease among patients with diabetes. The recommended thresholds to initiate treatment to lower BP are 130/80 and 125/75 mmHg for people with diabetes and nephropathy, respectively. We sought to determine the effects of lowering BP below these currently recommended thresholds on renal outcomes among 11,140 patients who had type 2 diabetes and participated in the Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study. Patients were randomly assigned to fixed combination perindopril-indapamide or placebo, regardless of their BP at entry. During a mean follow-up of 4.3 yr, active treatment reduced the risk for renal events by 21% (P < 0.0001), which was driven by reduced risks for developing microalbuminuria and macroalbuminuria (both P < 0.003). Effects of active treatment were consistent across subgroups defined by baseline systolic or diastolic BP. Lower systolic BP levels during follow-up, even to <110 mmHg, was associated with progressively lower rates of renal events. In conclusion, BP-lowering treatment with perindopril-indapamide administered routinely to individuals with type 2 diabetes provides important renoprotection, even among those with initial BP <120/70 mmHg. We could not identify a BP threshold below which renal benefit is lost. Although the angiotensin receptor antagonist (ARB) shares the angiotensin-II-blocking activity with the angiotensin-converting enzyme inhibitor (ACE-I), pharmacological mechanisms of action of these agents differ. We evaluated the temporal profiles of action of ACE-I and ARB on urinary protein excretion and nitrate/nitrate (NO(x)) excretion in hypertensive (140 and/or 90 mmHg) patients with chronic renal disease (serum creatinine < 265 (range, 44-265) micromol/l or creatinine clearance > 30 (range, 30-121) ml/min). Patients with mild (<1 g/day; range, 0.4-1.0) and moderate proteinuria (>1 g/day; range, 1.1-6.9) were randomly assigned to ACE-I- and ARB-treated groups, and were treated with ACE-I (trandolapril or perindopril) or ARB(losartan or candesartan) for 48 weeks. In all groups, treatment with ACE-I or ARB decreased blood pressure to the same level, but had no effect on creatinine clearance. In patients with mild proteinuria, neither ACE-I nor ARB altered urinary protein excretion. In patients with moderate proteinuria, ACE-I caused 44 +/- 6% reduction in proteinuria (from 2.7 +/- 0.5 to 1.5 +/- 0.4 g/day, n = 14) at 12 weeks, and this beneficial effect persisted throughout the protocol (48 weeks, 1.2 +/- 0.2 g/day). In contrast, ARB did not produce a significant decrease in proteinuria at 12 weeks (23 +/- 8%, n = 13), but a 41 +/- 6% reduction in proteinuria was observed at 48 weeks. Similarly, although early (12 weeks) increases in urinary NO(x) excretion were observed with ACE-I (from 257 +/- 70 to 1111 +/- 160 micromol/day) and ARB (from 280 +/- 82 to 723 +/- 86 micromol/day), the ARB-induced increase in NO(x) excretion was smaller than that by ACE-I (P < 0.05). In conclusion, although both ACE-I and ARB reduce blood pressure similarly, the effect of these agents on proteinuria differs in chronic renal disease with moderate proteinuria. Relatively early onset of the proteinuria-reducing effect was observed with ACE-I, which paralleled the increase in urinary NO(x) excretion. Conversely, ARB decreased proteinuria and increased urinary NO(x) excretion gradually. These time course-dependent changes in proteinuria and urinary NO(x) may reflect the pharmacological property of ACE-I and ARB, with regard to the action on bradykinin. Diabetes is the most common cause of renal failure in the United States, and data regarding the effects of aggressive blood pressure (BP) therapy in normotensive patients with type 2 diabetes are inadequate.
                A total of 129 type 2 diabetic patients with a BP of <140/80 to 90 mm Hg without overt albuminuria were randomized to either intensive BP control (diastolic BP goal 75 mm Hg) using an angiotensin II receptor blocker, valsartan, versus moderate BP control (diastolic BP 80 to 90 mm Hg with placebo initially) to evaluate the effect on the change in urinary albumin excretion (UAE) from baseline.
                The mean entrance BP was 126 +/- 8.8/84 +/- 2.4 mm Hg. The mean follow-up period was 1.9 +/- 1.0 years. During the follow-up period, the mean BP was 118 +/- 10.9/75 +/- 5.7 for the intensive v 124 10.9/80 6.5 mm Hg for the moderate BP groups (P < .001). No difference was observed in change in creatinine clearance or serum creatinine from baseline between the two groups. An analysis of covariance model for change in log (UAE + 1), adjusting for age, HBA(1c), duration of diabetes, baseline log (UAE + 1), sex, and ethnicity resulted in a significant treatment difference at 2 years (P = .007) with intensive BP control reducing log (UAE+1) compared with moderate BP control.
                Intensive BP control with valsartan to <120/80 mm Hg in normotensive patients with type 2 diabetes and normo- or microalbuminuria significantly decreased the progression of UAE and in some cases caused regression of UAE. 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.
                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.
                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.
                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. The primary objectives of this double-blind study were to compare the antihypertensive efficacy and tolerability of irbesartan and losartan, two angiotensin II (AT1 subtype) receptor antagonists with different pharmacokinetic profiles in patients with mild-to-moderate hypertension. Both drugs are approved for once-daily use (although losartan may also be prescribed twice-daily). After a placebo lead-in, 567 patients were randomized (1:1:1:1) to once-daily therapy with placebo, 100 mg losartan, 150 mg irbesartan, or 300 mg irbesartan for 8 weeks. Treatment groups had comparable demographic and baseline characteristics. After 8 weeks of treatment, reductions from baseline in trough seated diastolic blood pressure (SeDBP) and trough seated systolic blood pressure (SeSBP) with 300 mg irbesartan were greater than with 100 mg losartan (P < .01 for both comparisons), by 3.0 and 5.1 mm Hg, respectively; larger reductions were also demonstrated at weeks 1 and 4 (P < .01 and P = .017, respectively, for SeDBP). Throughout the study, the antihypertensive effect of 150 mg irbesartan did not differ significantly from that of 100 mg losartan. All therapies were well tolerated. The 300 mg dose of irbesartan was associated with the lowest incidence of adverse events (AE) and discontinuations because of AE. This study demonstrates that the maximally effective once-daily doses of two different AT1 receptor antagonists may result in clinically significant differences in blood pressure reductions, and therefore highlights the potential importance of the pharmacokinetic and pharmacodynamic differences between these two members of this class. Hypertension is a leading cause of end-stage renal disease (ESRD) in the United States, with no known treatment to prevent progressive declines leading to ESRD.
                To compare the effects of 2 levels of blood pressure (BP) control and 3 antihypertensive drug classes on glomerular filtration rate (GFR) decline in hypertension.
                Randomized 3 x 2 factorial trial with enrollment from February 1995 to September 1998.
                A total of 1094 African Americans aged 18 to 70 years with hypertensive renal disease (GFR, 20-65 mL/min per 1.73 m(2)) were recruited from 21 clinical centers throughout the United States and followed up for 3 to 6.4 years.
                Participants were randomly assigned to 1 of 2 mean arterial pressure goals, 102 to 107 mm Hg (usual; n = 554) or 92 mm Hg or less (lower; n = 540), and to initial treatment with either a beta-blocker (metoprolol 50-200 mg/d; n = 441), an angiotensin-converting enzyme inhibitor (ramipril 2.5-10 mg/d; n = 436) or a dihydropyridine calcium channel blocker, (amlodipine 5-10 mg/d; n = 217). Open-label agents were added to achieve the assigned BP goals.
                Rate of change in GFR (GFR slope); clinical composite outcome of reduction in GFR by 50% or more (or > or =25 mL/min per 1.73 m2) from baseline, ESRD, or death. Three primary treatment comparisons were specified: lower vs usual BP goal; ramipril vs metoprolol; and amlodipine vs metoprolol.
                Achieved BP averaged (SD) 128/78 (12/8) mm Hg in the lower BP group and 141/85 (12/7) mm Hg in the usual BP group. The mean (SE) GFR slope from baseline through 4 years did not differ significantly between the lower BP group (-2.21 [0.17] mL/min per 1.73 m2 per year) and the usual BP group (-1.95 [0.17] mL/min per 1.73 m2 per year; P =.24), and the lower BP goal did not significantly reduce the rate of the clinical composite outcome (risk reduction for lower BP group = 2%; 95% confidence interval [CI], -22% to 21%; P =.85). None of the drug group comparisons showed consistent significant differences in the GFR slope. However, compared with the metoprolol and amlodipine groups, the ramipril group manifested risk reductions in the clinical composite outcome of 22% (95% CI, 1%-38%; P =.04) and 38% (95% CI, 14%-56%; P =.004), respectively. There was no significant difference in the clinical composite outcome between the amlodipine and metoprolol groups.
                No additional benefit of slowing progression of hypertensive nephrosclerosis was observed with the lower BP goal. Angiotensin-converting enzyme inhibitors appear to be more effective than beta-blockers or dihydropyridine calcium channel blockers in slowing GFR decline. Three 24 h ambulatory monitorings of BP were performed at two-week intervals in 21 untreated hypertensives (mean age 38 +/- 10 yrs, 13 males and 9 females). After the first baseline monitoring, the patients were randomised, according to a cross-over design, to one of the following sequences: no therapy to placebo or placebo to no therapy. At the end of each period, noninvasive ambulatory monitoring was performed. Mean +/- SE 24 h systolic (SBP) and diastolic (DBP) pressures recorded at the first monitoring were 129.2 +/- 3.5 mmHg and 81.7 +/- 2.3 mmHg respectively. At the second and third monitorings, mean 24 h BP differences versus baseline levels were -2.9 +/- 1.8 and -4.7 +/- 1.7 mmHg for SBP, and -2.0 +/- 1.1 and -2.7 +/- 1.5 mmHg for DBP. Both SBP and DBP differences at repeated monitorings were significant by analysis of variance (P less than 0.05). No significant effects on BP of treatment sequence or of placebo administration were found. Analysis of covariance showed a significant relationship between initial 24 h BP and subsequent mean 24 h BP differences (SBP: beta = -0.260, DBP: beta = -0.124). ANOVA performed on waking and sleeping BP separately showed the observed differences to be significant only during waking hours. Regression analysis showed that the decrease in 24 h BP at repeated monitorings was significantly related to the extent of 'white coat'-induced BP increase only for DBP (P = 0.022). For both 24 h SBP and DBP, however, a negative correlation between the alarm reaction to the presence of the physician and 24 h BP decrease at repeated monitorings was observed. It is concluded that noninvasive ambulatory monitoring is subject to adaptative phenomena but not to placebo effect. Factors influencing the defence reactions to manual measurements and to ambulatory monitoring might be partly different. Tasosartan, a new, long-acting, nonpeptide angiotensin II receptor antagonist was evaluated in a randomized, double-blind, placebo-controlled, multicenter trial at 21 sites in the United States and Canada. After a 2-week, placebo washout qualification period, 278 patients (187 men/91 women) with a mean age of 53.4+/-9.5 years (range, 30 to 70 years) and a baseline sitting diastolic blood pressure (DBP) of 95 to 114 mm Hg were randomly assigned to receive placebo (n = 56), or 10 mg (n = 57), 30 mg (n = 55), 100 mg (n = 55), or 300 mg (n = 55) tasosartan for 4 weeks. The treatment period was followed by a 2-week washout period. Ambulatory blood pressure (BP) monitoring was performed at the end of the placebo washout period and after at least 4 weeks of double-blind treatment. Clinically significant placebo-adjusted differences in baseline sitting systolic blood pressure (SBP)/DBP were observed in the 10 mg (5/3 mm Hg), 30 mg (5/4 mm Hg), 100 mg (10/7 mm Hg) and 300 mg (10/7 mm Hg) dose groups (P < .05). A dose-response relationship (P < .001) was observed within 1 to 2 weeks of treatment initiation and was maintained throughout the double-blind period. Discontinuation of tasosartan therapy was not associated with rebound hypertension. Moreover, significant (P < .05) placebo-adjusted differences in ambulatory SBP/DBP and a significant dose-response relationship (P < .001) were observed with all tasosartan dosages during the 24-h, daytime, and nighttime periods. Placebo-adjusted trough-to-peak ratios ranged from 87% to 100% for ambulatory SBP and 64% to 81% for DBP. In general, no significant differences were observed between the tasosartan treatment groups and the placebo group in the incidence of adverse events. Headache incidence was significantly lower in the 300 mg dose group than the placebo group. In conclusion, tasosartan at dosages of 10, 30, 100, or 300 mg given once daily produced a significant and dose-related reduction in both clinic and ambulatory BP that was maintained over the 24-h period. Tasosartan was generally well tolerated. 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.
                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).
                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%).
                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. Although several important studies have been performed in hypertensive type 2 diabetic patients, it is not known whether lowering blood pressure in normotensive (BP <140/90 mm Hg) patients offers any beneficial results on vascular complications. The current study evaluated the effect of intensive versus moderate diastolic blood pressure (DBP) control on diabetic vascular complications in 480 normotensive type 2 diabetic patients.
                The current study was a prospective, randomized controlled trial in normotensive type 2 diabetic subjects. The subjects were randomized to intensive (10 mm Hg below the baseline DBP) versus moderate (80 to 89 mm Hg) DBP control. Patients in the moderate therapy group were given placebo, while the patients randomized to intensive therapy received either nisoldipine or enalapril in a blinded manner as the initial antihypertensive medication. The primary end point evaluated was the change in creatinine clearance with the secondary endpoints consisting of change in urinary albumin excretion, progression of retinopathy and neuropathy and the incidence of cardiovascular disease.
                The mean follow-up was 5.3 years. Mean BP in the intensive group was 128 +/- 0.8/75 +/- 0.3 mm Hg versus 137 +/- 0.7/81 +/- 0.3 mm Hg in the moderate group, P < 0.0001. Although no difference was demonstrated in creatinine clearance (P = 0.43), a lower percentage of patients in the intensive group progressed from normoalbuminuria to microalbuminuria (P = 0.012) and microalbuminuria to overt albuminuria (P = 0.028). The intensive BP control group also demonstrated less progression of diabetic retinopathy (P = 0.019) and a lower incidence of strokes (P = 0.03). The results were the same whether enalapril or nisoldipine was used as the initial antihypertensive agent.
                Over a five-year follow-up period, intensive (approximately 128/75 mm Hg) BP control in normotensive type 2 diabetic patients: (1) slowed the progression to incipient and overt diabetic nephropathy; (2) decreased the progression of diabetic retinopathy; and (3) diminished the incidence of stroke. Previous studies established that a single daily dose of olmesartan remains effective for the entire 24 h without alteration of the day-night blood pressure (BP) pattern. On the other hand, the administration of valsartan or telmisartan at bedtime, as opposed to upon wakening, improves the sleep-time relative BP decline toward a greater dipper pattern without loss of 24 h efficacy. Yet to be determined is whether this administration-time-dependent efficacy is a class-related feature, characteristic of all angiotensin-receptor-blocker (ARB) medications. We studied 123 grade 1 and 2 hypertensive patients, 46.6+/-12.3 yrs of age, randomly assigned to receive olmesartan (20 mg/day) as a monotherapy either upon awakening or at bedtime for three months. BP was measured by ambulatory monitoring for 48 consecutive hours before and after treatment. The 24 h BP reduction was similar for both treatment times. Administration of olmesartan at bedtime, however, was significantly more efficient than morning administration in reducing the nocturnal BP mean. The sleep-time relative BP decline was slightly reduced with olmesartan ingestion upon awakening but significantly increased with ingestion at bedtime, thus reducing the prevalence of non-dipping from baseline by 48%. Olmesartan administration at bedtime, as opposed to in the morning, improved the awake/asleep BP ratio toward a greater dipper pattern without loss of 24 h efficacy. Nocturnal BP regulation was significantly better achieved with bedtime as compared to morning dosing of olmesartan. These effects are comparable to those previously reported for valsartan and telmisartan, thus suggesting that they may be class-related features of ARB medications in spite of differences in their half-life kinetics. These administration-time-dependent effects should be taken into account when prescribing ARB medications for treatment of essential hypertension. We investigated in a double-blind study whether metformin reduces blood pressure (BP) in patients with Type 2 diabetes intensively treated with insulin.
                A total of 220 patients with Type 2 diabetes were asked to undergo 24-h ambulatory BP monitoring (24-h ABPM). One hundred and eighty-two gave informed consent. Eighty-nine were randomized to metformin and 93 to placebo. Thirty-five subjects dropped out (13 placebo, 22 metformin users); 147 patients underwent a second 24-h ABPM, 16 weeks after randomization.
                Systolic BP (SBP), diastolic BP (DBP), pulse BP (PP), mean BP (MP) and heart rate (HR) were measured as office BP measurements and as 24-h ABPM for 24-h, day and night. Office BP measurements did not differ significantly between the placebo- and metformin-treated groups for any BP measure, but showed a non-significant trend for SBP reduction with metformin use (mean baseline-adjusted difference, metformin minus placebo: -4.2 mmHg, 95% CI, -9.9 to +1.5; P = 0.15). The baseline-adjusted differences of the ambulatory measurements were -0.2 mmHg (95% CI, -2.9 to +2.6) for the 24-h SBP, and +1.1 mmHg (95% CI, -0.7 to +2.8) for the 24-h DBP. On the whole, BP differences between metformin- and placebo-treated groups were not statistically significant. The only significant difference was for night-time PP (baseline-adjusted difference: -2.2 mmHg; 95% CI, -4.2 to -0.2). These results were not different after adjustment for age and diabetes duration, or for (changes in) body mass index, glycated haemoglobin, insulin dose or plasma homocysteine.
                Metformin does not significantly affect BP in patients with Type 2 diabetes intensively treated with insulin. There is much uncertainty about the effects of early lowering of elevated blood pressure (BP) after acute intracerebral haemorrhage (ICH). Our aim was to assess the safety and efficiency of this treatment, as a run-in phase to a larger trial.
                Patients who had acute spontaneous ICH diagnosed by CT within 6 h of onset, elevated systolic BP (150-220 mm Hg), and no definite indication or contraindication to treatment were randomly assigned to early intensive lowering of BP (target systolic BP 140 mm Hg; n=203) or standard guideline-based management of BP (target systolic BP 180 mm Hg; n=201). The primary efficacy endpoint was proportional change in haematoma volume at 24 h; secondary efficacy outcomes included other measurements of haematoma volume. Safety and clinical outcomes were assessed for up to 90 days. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00226096.
                Baseline characteristics of patients were similar between groups, but mean haematoma volumes were smaller in the guideline group (12.7 mL, SD 11.6) than in the intensive group (14.2 mL, SD 14.5). From randomisation to 1 h, mean systolic BP was 153 mm Hg in the intensive group and 167 mm Hg in the guideline group (difference 13.3 mm Hg, 95% CI 8.9-17.6 mm Hg; p<0.0001); from 1 h to 24 h, BP was 146 mm Hg in the intensive group and 157 mm Hg in the guideline group (10.8 mm Hg, 95% CI 7.7-13.9 mm Hg; p<0.0001). Mean proportional haematoma growth was 36.3% in the guideline group and 13.7% in the intensive group (difference 22.6%, 95% CI 0.6-44.5%; p=0.04) at 24 h. After adjustment for initial haematoma volume and time from onset to CT, median haematoma growth differed between the groups with p=0.06; the absolute difference in volume between groups was 1.7 mL (95% CI -0.5 to 3.9, p=0.13). Relative risk of haematoma growth >or=33% or >or=12.5 mL was 36% lower (95% CI 0-59%, p=0.05) in the intensive group than in the guideline group. The absolute risk reduction was 8% (95% CI -1.0 to 17%, p=0.05). Intensive BP-lowering treatment did not alter the risks of adverse events or secondary clinical outcomes at 90 days.
                Early intensive BP-lowering treatment is clinically feasible, well tolerated, and seems to reduce haematoma growth in ICH. A large randomised trial is needed to define the effects on clinical outcomes across a broad range of patients with ICH.
                National Health and Medical Research Council of Australia. To study whether administration of 1.25 and 5.0 mg ramipril daily, compared with placebo treatment, reduces the urinary albumin excretion rate (UAER) in normotensive patients with type 1 diabetes.
                Ramipril was administered double blind at two different doses (1.25 [n = 19] and 5.0 mg [n = 18]), and compared with placebo (n = 18) after a single-blind placebo period of 1-4 weeks. The patients (total, n = 55; women, n = 14) were followed for 2 years. To document an effect on the renin-angiotensin system, ACE activity and plasma-renin activity (PRA) were measured. In addition, 24-h ambulatory blood pressure (BP) was recorded at baseline and repeated after 1 and 2 years using a Spacelab 90207 ambulatory BP recording device (Spacelab, Redmont, CA).
                Both doses of ramipril were sufficient to reduce ACE activity and to increase PRA significantly as compared with placebo (P < 0.05 for both). On the other hand, neither ambulatory nor clinic BP was affected by either dose of ramipril compared with the placebo group. There was no progression of UAER in the placebo group during the 2 years of the study. Analysis of covariance showed no differences in UAER between the three treatment groups at year 1 (P = 0.94) or year 2 (P = 0.97), after adjusting for baseline. Furthermore, there were no statistically significant changes from baseline UAER within any of the three treatment groups.
                Treatment with ramipril did not affect microalbuminuria or clinic or ambulatory BP in this study. On the basis of the present study, we question the clinical use of ACE inhibitors in stably normotensive patients with type 1 diabetes and microalbuminuria in whom a concomitant reduction in BP is not demonstrated. To identify telmisartan doses that are more effective than placebo and non-inferior to hydrochlorothiazide (HCTZ) 12.5 mg, and are well tolerated, in lowering systolic blood pressure (SBP) in patients with isolated systolic hypertension (ISH).
                A 2-4-week single-blind placebo run-in was followed by randomization of 1039 patients (age 36-84 years) with ISH [seated SBP 150-179 mmHg and seated diastolic blood pressure (DBP) < 90 mmHg] to once-daily double-blind treatment with telmisartan 20, 40 or 80 mg, HCTZ 12.5 mg, or placebo. The change in seated trough SBP after 6 weeks compared with baseline was the primary end point. Secondary end points were the percentage achieving the target fall in SBP and the change from baseline in seated trough DBP. Incidence and severity of adverse events and physical examination and laboratory parameters were monitored for the safety evaluation.
                Baseline demographics in telmisartan 20 mg (n = 206), 40 mg (n = 210), 80 mg (n = 207), HCTZ 12.5 mg (n = 205) and placebo (n = 211) treatment groups were comparable: (mean +/- SD) age, 63.0 +/- 10.9 years; SBP, 162.9 +/- 8.1 mmHg; and DBP 83.4 +/- 5.0 mmHg. No previous antihypertensive therapy had been received by 66% of the patients. Mean reductions in seated trough SBP (adjusted for baseline and country) were: telmisartan 20 mg, 15.6 mmHg (n = 204); 40 mg, 17.9 mmHg (n = 209); and 80 mg, 16.9 mmHg (n = 205), compared with placebo, 11.4 mmHg (n = 208), and HCTZ 12.5 mg, 15.7 mmHg (n = 204). The target fall in seated trough SBP (< or =140 mmHg or reduction by > or =20 mmHg) was achieved in 46.6% (telmisartan 20 mg), 51.7% (telmisartan 40 mg), 53.9% (telmisartan 80 mg), 27.4% (placebo) and 42.7% (HCTZ 12.5 mg); the response rate was significantly higher for telmisartan 80 mg than for HCTZ 12.5 mg (P = 0.03). All-causality adverse events occurred in 19.9, 17.6 and 20.3% receiving telmisartan 20, 40 and 80 mg, respectively; 20.9% receiving placebo and 22.0% receiving HCTZ 12.5 mg. No drug-related serious adverse events occurred.
                All doses of telmisartan (20-80 mg) were significantly superior to placebo in reducing SBP in patients with ISH and clinically comparable to HCTZ 12.5 mg. Tolerability of telmisartan was similar to that of placebo. The aim of this prospective, monocentric, opened study and with random order for antihypertensive sequence was to compare a betablocker with sympathomimetic activity (ACE) and an alphabetablocker (LAB) to the gold standard treatment (MD) in moderate HDP (BP greater than 90 mmHg). This study (January 1984 to December 1985) includes 63 women, mean age 28.2 years, divided into three comparable subgroups (age, parity, risk factors and initial level of SBP/DBP). Initial doses are 500 mg/bid (MD), and 400 mg/bid (ACE, LAB) and optimal dosages could not be respectively more than 1500 mg/bid (MD) or 1200 mg/bid (ACE, LAB). Usual criteria for maternal and foetal care are taken into account. The chi 2 test, the Student "t" test and the Kruskall Wallis test were used for statistical analysis. The results show: 1--A similar antihypertensive effect for MD and LAB, but significantly less for ACE (initial PAD-37th week PAD: MD +/- 18.8 +/- 2; LAB = -17.9 +/- 3; ACE = - 8.2 +/- 2.7 mmHg, p less than 0.02; 2--A more frequent adjustment of daily dosage with MD (n = 15) than with ACE (n = 10) or LAB (n = 7); 3--The absence of any significant difference for uricemia level, platelet counts, foetal cardiac rythm, and occurrence of pre-eclampsia (MD = 4; ACE = 3; LAB = 4; 4--An equivalent birth-weight (MD = 3110 +/- 628 g; ACE = 3115 +/- 645.(ABSTRACT TRUNCATED AT 250 WORDS) The time to peak antihypertensive effect and the trough-to-peak ratio were determined in 64 Caucasian patients (19 men, 45 women) with mild to moderate hypertension [supine diastolic blood pressure (DBP) 95 to 115 mmHg]. They received placebo or fosinopril 10, 20, or 40 mg once daily for 4 weeks. The study consisted of a 4-week placebo lead-in, 4 weeks' double-blind treatment, and a 1-week placebo washout period. Vital signs were determined biweekly before dosing, and blood pressures were measured every 1 to 2 h during two 27-h periods at the beginning and end of treatment. After the first and last doses of all three regimens, the peak effect on blood pressure occurred 5 to 7 h after all three dosages. Neither peak nor trough blood pressure changes showed a clear dose-response relationship. Trough to peak ratios for the first dose, corrected for placebo effects, were 79% for fosinopril 10 mg, 48% for fosinopril 20 mg, and 74% for fosinopril 40 mg, and the trough-to-peak ratios for the last dose were 41% for fosinopril 10 mg, 32% for fosinopril 20 mg, and 44% for fosinopril 40 mg. In the 38 responders among the 48 patients receiving fosinopril (supine DBP decrease of at least 5 mmHg at 24 h postdose), trough-to-peak ratios ranged from 50 to 81%, and the range indicates that fosinopril is efficacious when administered once daily. Adverse effects were mild to moderate, and no patient discontinued treatment. Changes in the laboratory test results, electrocardiograms, or the results of physical examinations were unremarkable.(ABSTRACT TRUNCATED AT 250 WORDS) This prospective, double-blind, parallel-group study randomized patients with moderate hypertension (seated systolic blood pressure (SeSBP) 160-179 mm Hg when seated diastolic blood pressure (SeDBP) <110 mm Hg; or SeDBP 100-109 mm Hg when SeSBP <180 mm Hg) 3:1:1 to treatment with irbesartan 300 mg/hydrochlorothiazide (HCTZ) 25 mg combination therapy (n=328), irbesartan 300 mg monotherapy (n=106) or HCTZ monotherapy 25 mg (n=104). Treatment was initiated at half dose, with forced titration to full dose after two weeks followed by ten further weeks' treatment. The primary efficacy variable was the mean reduction in SeSBP from baseline to week 8. Baseline characteristics were similar between groups, with mean baseline blood pressure approximately 162/98 mm Hg; the mean age was 55 years. At week 8 there was a reduction in SeSBP of 27.1 mm Hg with irbesartan/HCTZ, compared with 22.1 mm Hg with irbesartan monotherapy (P=0.0016) and 15.7 mm Hg with HCTZ (P<0.0001). Both the rate of decline and the total degree of decline achieved were greatest with irbesartan/HCTZ and least with HCTZ. A significantly greater percentage of patients reached a treatment goal of SeSBP <140 mm Hg and SeDBP <90 mm Hg by week 8 with irbesartan/HCTZ (53.4%), compared with irbesartan (40.6%; P=0.0254) and HCTZ (20.2%; P<0.0001) alone. Treatment was well tolerated in all three-treatment groups with a slight increase in adverse events in the combination therapy group. In conclusion, irbesartan/HCTZ (300/25 mg) is well tolerated and achieves rapid and sustained reductions in both systolic blood pressure and diastolic blood pressure in patients with moderate hypertension. Weight loss, sodium reduction, increased physical activity, and limited alcohol intake are established recommendations that reduce blood pressure (BP). The Dietary Approaches to Stop Hypertension (DASH) diet also lowers BP. To date, no trial has evaluated the effects of simultaneously implementing these lifestyle recommendations.
                To determine the effect on BP of 2 multicomponent, behavioral interventions.
                Randomized trial with enrollment at 4 clinical centers (January 2000-June 2001) among 810 adults (mean [SD] age, 50 [8.9] years; 62% women; 34% African American) with above-optimal BP, including stage 1 hypertension (120-159 mm Hg systolic and 80-95 mm Hg diastolic), and who were not taking antihypertensive medications.
                Participants were randomized to one of 3 intervention groups: (1) "established," a behavioral intervention that implemented established recommendations (n = 268); (2) "established plus DASH,"which also implemented the DASH diet (n = 269); and (3) an "advice only" comparison group (n = 273).
                Blood pressure measurement and hypertension status at 6 months.
                Both behavioral interventions significantly reduced weight, improved fitness, and lowered sodium intake. The established plus DASH intervention also increased fruit, vegetable, and dairy intake. Across the groups, gradients in BP and hypertensive status were evident. After subtracting change in advice only, the mean net reduction in systolic BP was 3.7 mm Hg (P<.001) in the established group and 4.3 mm Hg (P<.001) in the established plus DASH group; the systolic BP difference between the established and established plus DASH groups was 0.6 mm Hg (P =.43). Compared with the baseline hypertension prevalence of 38%, the prevalence at 6 months was 26% in the advice only group, 17% in the established group (P =.01 compared with the advice only group), and 12% in the established plus DASH group (P<.001 compared with the advice only group; P =.12 compared with the established group). The prevalence of optimal BP (<120 mm Hg systolic and <80 mm Hg diastolic) was 19% in the advice only group, 30% in the established group (P =.005 compared with the advice only group), and 35% in the established plus DASH group (P<.001 compared with the advice only group; P =.24 compared with the established group).
                Individuals with above-optimal BP, including stage 1 hypertension, can make multiple lifestyle changes that lower BP and reduce their cardiovascular disease risk. Despite treatment, there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals. Inadequate reduction of their blood pressure is a likely cause, but the optimum target blood pressure is not known. The impact of acetylsalicylic acid (aspirin) has never been investigated in patients with hypertension. We aimed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension.
                18790 patients, from 26 countries, aged 50-80 years (mean 61.5 years) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg (mean 105 mm Hg) were randomly assigned a target diastolic blood pressure. 6264 patients were allocated to the target pressure < or =90 mm Hg, 6264 to < or =85 mm Hg, and 6262 to < or =80 mm Hg. Felodipine was given as baseline therapy with the addition of other agents, according to a five-step regimen. In addition, 9399 patients were randomly assigned 75 mg/day acetylsalicylic acid (Bamycor, Astra) and 9391 patients were assigned placebo.
                Diastolic blood pressure was reduced by 20.3 mm Hg, 22.3 mm Hg, and 24.3 mm Hg, in the < or =90 mm Hg, < or =85 mm Hg, and < or =80 mm Hg target groups, respectively. The lowest incidence of major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82.6 mm Hg; the lowest risk of cardiovascular mortality occurred at 86.5 mm Hg. Further reduction below these blood pressures was safe. In patients with diabetes mellitus there was a 51% reduction in major cardiovascular events in target group < or =80 mm Hg compared with target group < or =90 mm Hg (p for trend=0.005). Acetylsalicylic acid reduced major cardiovascular events by 15% (p=0.03) and all myocardial infarction by 36% (p=0.002), with no effect on stroke. There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group, and 129 versus 70 non-fatal major bleeds in the two groups, respectively (p<0.001).
                Intensive lowering of blood pressure in patients with hypertension was associated with a low rate of cardiovascular events. The HOT Study shows the benefits of lowering the diastolic blood pressure down to 82.6 mm Hg. Acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infarction. There was no effect on the incidence of stroke or fatal bleeds, but non-fatal major bleeds were twice as common. The prevalence of posttransplant hypertension is high, and it appears to be a major risk factor for graft and patient survival. The aim of this study was to assess the efficacy and safety of valsartan, an angiotensin-receptor blocker (ARB), in the treatment of posttransplant hypertension.
                A multinational, multicenter, prospective, randomized, double-blind, placebo-controlled study was performed on the treatment of hypertension (systolic blood pressure [BP] >/= 140 and/or diastolic BP >/= 90 mm Hg) in adult cyclosporin-treated renal transplant recipients randomized to receive either valsartan (80 mg once daily) or a matching placebo for 8 weeks. After the first 4 weeks, furosemide 20 mg twice daily was added on a open basis if systolic BP remained >/= 130 mm Hg and/or diastolic BP remained >/= 85 mm Hg.
                One hundred fifteen (valsartan = 57, placebo = 58) uncontrolled hypertensive patients despite monotherapy for hypertension, other than angiotensin-converting enzyme inhibitor or ARB, were randomized. In the valsartan group, significant decreases were seen in systolic BP (from 153 +/- 11 to 140.9 +/- 18.35 mm Hg at 4 weeks, and 136.5 +/- 15 mm Hg at 8 weeks) and diastolic BP (from 93 +/- 9 to 85.2 +/- 11.28 mm Hg at 4 weeks, and 83.8 +/- 9.2 mm Hg at 8 weeks). There was no significant change in the placebo group. In the valsartan group, a statistically but not clinically significant reduction was observed in the mean hemoglobin concentration (12.9 +/- 1.6 g/dL versus 13.8 +/- 1.6 g/dL at 4 weeks, P < .01; and 12.3 +/- 1.6 versus 13.8 +/- 1.7 at 8 weeks; P < .001) as well as a significant increase in serum potassium (4.4 +/- 0.5 mmol/L versus 4.1 +/- 0.4 mmol/L at 4 weeks, P < .01) vs placebo.
                Valsartan is effective in the treatment of posttransplant hypertension and is well tolerated. Our aim was to compare the effect of lacidipine and chlorthalidone on cardiovascular outcome as a primary parameter and blood pressure as a secondary in elderly patients with isolated systolic hypertension in a prospective study with an open design.
                1882 males and females outpatients > or = 60 years were randomly assigned to the administration of chlorthalidone 12.5 mg o.d. or lacidipine 4 mg o.d. Patients were recruited if sitting systolic blood pressure was > or = 160 mmHg with a diastolic blood pressure equal or lower than 95 mmHg. Primary endpoint was a composite of cardiovascular and cerebrovascular events.
                At randomization mean systolic blood pressure was 178.1 mmHg in the lacidipine and 178.2 mmHg in the chlorthalidone group, the corresponding mean diastolic values being 86.9 and 86.8 mmHg. In both lacidipine and chlorthalidone groups treatment caused a significant (p < 0.001) and marked systolic blood pressure reduction which was maintained throughout the treatment period with a significant (p < 0.001) and steady although less marked reduction in diastolic blood pressure as well. At the end of treatment period (median 32 months), the reduction was 36.8/8.1 mmHg (systolic/diastolic) in the chlorthalidone and 38.4/7.9 mmHg in the lacidipine group, the final on treatment blood pressures being 142.0/79.2 and 143.2/79.5 mmHg, respectively. Treatments were similarly effective in males and females and in age groups between 60 and 69 years (n = 763), 70 and 79 years (n = 744) and > or = 80 years (n = 375). Similar reductions were obtained in a subgroup of patients (n = 209) followed in double-blind fashion for 1 year. The overall incidence of the primary endpoints was 9.3% with no significant between-group difference. Total mortality was also similar between groups.
                In elderly patients with isolated systolic hypertension, administration of lacidipine or chlorthalidone markedly reduced systolic blood pressure with no difference in the incidence of cardiovascular events and total mortality. We assessed blood pressure (BP) and heart rate (HR) responses in a double-blind, randomized study comparing cilazapril, a long-acting, nonsulfhydryl-group converting enzyme inhibitor, with placebo in 18 patients with mild to moderate (sitting diastolic BP, 95 to 114 mm Hg) essential hypertension. The BP and HR parameters were evaluated at rest (casual, 24 hours after administration), during treadmill exercise testing (Bruce protocol), and with 24-hour noninvasive ambulatory BP monitoring. These assessments were made after a 4-week drug washout period and after 8 to 12 weeks of therapy. After 8 weeks of therapy with cilazapril (mean dose 3.6 +/- 0.9 mg/day), casual BP decreased 19/11 mm Hg (p less than 0.01), whereas placebo lowered BP by 4/5 mm Hg (difference not significant) compared with the baseline period. The casual HR was modestly (7 beats/min) but significantly (p less than 0.05) lowered by cilazapril monotherapy. Exercise BP was reduced by cilazapril (reduction at peak HR, 23/11 +/- 10/5 mm Hg; p less than 0.05), and exercise HR was unchanged. Compared with baseline, the duration of exercise was improved with cilazapril but not with placebo (1.0 minute vs -0.2 minute; p less than 0.05). Twenty-four-hour mean, awake, and sleep BPs were reduced with cilazapril with the most impressive reduction occurring during the awake period (19/12 mm Hg; p less than 0.01). These data demonstrate that cilazapril lowers casual, exercise, and ambulatory BP with a modest but significant improvement in exercise time. Thus cilazapril may be particularly effective in the physically active hypertensive patient. We compared the efficacy of treatment protocols with an angiotensin converting enzyme (ACE) inhibitor alone (enalapril, 5 mg) or angiotensin II (ATII) receptor blocker (losartan, 50 mg) or both enalapril plus losartan in patients with microalbuminuria in a prospective, randomized clinical trial. Normotensive type 2 diabetic patients with microalbuminuria documented by at least 3 consecutive urinary albumin excretion analyses were recruited for the study. Patients were grouped randomly into one of the protocols which consisted of treatment with 5 mg enalapril daily (group 1; n=12), 50 mg losartan daily (group 2; n=12) or both drugs (group 3; n=10). They were reevaluated with regard to HbA1c levels, lipid profiles, blood pressure and urinary albumin excretion rates (UAER) at 3-month intervals for 12 months. Mean age, duration of diabetes, body mass index, plasma lipid profiles and blood pressure levels were similar at the initial visit. In group 1, UAER returned to normal levels in 10 patients. Normalization of UAER occurred in 8 and 7 patients in groups 2 and 3, respectively. Percentage of reduction in UAERs at the end of 12 months were 58%, 59% and 60% (p=0.0001; p=0.0002; p=0.0003, respectively). The amount of reduction in UAER did not differ significantly among the three groups (p=0.346). ACE inhibitors and angiotensin II receptor blockers have similar efficacy in treating diabetic microalbuminuria, and the combination of the two drugs does not add any further benefit. To determine the clinic and ambulatory blood pressure when the same dose of perindopril (4 mg) is administered in the morning (0900 h), or at night (2100 h), in particular, to determine whether the early morning blood pressure rise, the duration of effect and the pattern of response differed.
                Twenty male patients with diastolic blood pressure 95-110 mmHg when seated and 24 h mean ambulatory diastolic blood pressure > 85 mmHg after 4 weeks' placebo were allocated randomly to be administered 4 mg perindopril at 0900 h or at 2100 h. Clinic blood pressure (with the patient seated and erect) was measured 2 and 4 weeks after the therapy had been started and ambulatory blood pressure monitoring with a SpaceLabs device was performed for 26 h during week 4. The patients then crossed over to the other time of dosage and the measurements were repeated. The study was conducted from a hospital clinic.
                The clinic analysis concerned all 20 patients but the ambulatory analysis concerned 18 patients because the ambulatory blood pressure monitor data sets were inadequate for two patients. Compliance was high (97 +/- 3%), with a suggestion that it was better with the 0900 h dose. Clinic blood pressure (with the patient seated and erect) was lower under both regimes and the blood pressure with night-time administration of perindopril tended to be lower than that with daytime administration (P = 0.05-0.10). Twenty-four-hour mean, daytime and night-time means were lower with both doses than they were with placebo and did not differ. Both regimes reduced the early morning peak blood pressure rise and the effect tended to be greater with the 2100 h dose (P = 0.05-0.10). The 0900 h dose had an effect that persisted for > 24 h but the effect of the 2100 h dose had dissipated 18 h after the dose. There was no excessive night-time fall in blood pressure with the 2100 h dose. The trough : peak ratio with the 0900 h dose was 0.86 for systolic and 0.70 for diastolic blood pressure.
                The early morning blood pressure rise is reduced more when 4 mg perindopril is administered at 2100 h. However, the 2100 h dose regime does not reduce blood pressure over 24 h whereas 24 h control is achieved with the 0900 h dose. In clinical practice the 2100 h dose would have been titrated to the next dose range in more patients. This study indicates that the response profile obtained with an angiotensin converting enzyme inhibitor cannot be transformed from one dose time to another automatically and that chronobiology has important effects on a drug's action. To compare 24 h ambulatory blood pressure and trough office blood pressure lowerings after 8 weeks of therapy with 75 mg irbesartan once a day, 150 mg irbesartan once a day , and 75 mg irbesartan twice a day versus placebo; and to assess safety and tolerability of irbesartan therapy.
                Multicenter, double-blind, randomized, placebo-controlled trial.
                Sixteen centers in Italy.
                Caucasian patients (n = 215) aged > or = 18 years with seated diastolic blood pressure 95-110 mmHg and ambulatory diastolic blood pressure (ADBP) > or = 85 mmHg.
                Mean 24 h ADBP after 8 weeks of irbesartan therapy.
                Mean changes (value before treatment minus value after treatment) in ADBP for placebo, 75 mg irbesartan once a day, 150 mg irbesartan once a day, and 75 mg irbesartan twice a day were -0.2, -5.4, -7.2, and -7.2 mmHg, respectively; respective changes in ambulatory systolic blood pressure were +1.6, -8.3, -10.5, and -9.7 mmHg. All irbesartan regimens reduced trough office seated diastolic blood pressure and seated systolic blood pressure after 2 and 8 weeks of treatment (all P < 0.01, versus placebo except for seated systolic blood pressure in patients in the 75 mg irbesartan once a day group). Trough: peak ratios were > or = 55% with 150 mg irbesartan once a day. Percentages of patients whose blood pressures were normalized with 150 mg irbesartan once a day (45%) and 75 mg irbesartan twice a day (47%) were greater than those with placebo (14%, P < 0.01) and with 75 mg irbesartan once a day (19%, NS, versus placebo). Adverse events with irbesartan were similar to those with placebo.
                All irbesartan regimens significantly reduced mean 24 h ADBP and ambulatory systolic blood pressure, and were well tolerated. Administration of 150 mg irbesartan once a day provided significant reduction of blood pressure for 24 h, equivalent to that obtained with the same daily dose divided into two separate administrations. Stopping the detrimental effects of the renin-angiotensin system at the most upstream point of the cascade offers theoretical advantages for cardiovascular protection. This study compares the antihypertensive efficacy and safety of the novel oral renin inhibitor aliskiren with placebo and an active comparator.
                The study was a randomized, multicenter, double-blind, placebo-controlled, active-comparator 8-week trial in patients with mild-to-moderate hypertension (mean sitting diastolic blood pressure [DBP] > or =95 and <110 mm Hg). After a 2-week, single-blind placebo run-in, 652 patients were randomized to receive double-blind treatment with once-daily oral doses of aliskiren (150, 300, or 600 mg), irbesartan 150 mg, or placebo. Aliskiren 150, 300, and 600 mg effectively lowered both trough mean sitting DBP and systolic blood pressure (SBP) (P<0.001 versus placebo for both variables). The least-squares mean reductions in trough DBP were 9.3+/-0.8, 11.8+/-0.8, and 11.5+/-0.8 mm Hg, respectively, versus 6.3+/-0.8 mm Hg for placebo, and the least-squares mean reductions in trough SBP were 11.4+/-1.3, 15.8+/-1.2, and 15.7+/-1.2 mm Hg, respectively, versus 5.3+/-1.2 mm Hg for placebo. The antihypertensive effect of aliskiren 150 mg was comparable to that of irbesartan 150 mg (8.9+/-0.7 and 12.5+/-1.2 mm Hg, least-squares reduction in mean sitting DBP and SBP, respectively, for irbesartan). Aliskiren 300 and 600 mg lowered mean sitting DBP significantly more than irbesartan 150 mg (P<0.05). Aliskiren showed safety and tolerability comparable to those of placebo and irbesartan; the incidence of adverse events and number of patients discontinuing therapy were similar in all groups.
                Once-daily oral treatment with aliskiren lowers blood pressure effectively, with a safety and tolerability profile comparable to that of irbesartan and placebo, in patients with mild-to-moderate hypertension. Aliskiren 150 mg is as effective as irbesartan 150 mg in lowering blood pressure. Evaluation of a structured hypertension treatment and teaching programme in general practice.
                Prospective controlled trial; follow-up period 18 months.
                10 primary health care practices. PRACTICES AND PATIENTS: From each practice 20 patients (30 to 60 years old, mean of the last two blood pressure measurements at or above 160 and/or 95 mmHg) were randomly selected; in 5 practices these patients were to participate in the treatment and teaching programme; in the remaining 5 practices hypertension care was continued without the availability of such a programme (controls).
                Structured treatment and teaching programme based upon four group sessions for patients mainly conducted by paramedical personnel.
                Blood pressure, body weight, prescription of antihypertensive drugs - as documented in the patient's records.
                Of the 100 control patients 26 and of the 100 intervention patients 14 were lost to observation; 46 patients had agreed to participate in the programme. The mean number of prescribed antihypertensive agents per patient decreased in the intervention group (1.8 +/- 1.3 at baseline, vs 1.2 +/- 1.2 at follow-up) compared to the control group (1.6 +/- 1.3 vs 1.8 +/- 1.6); difference 0.8 (95% CI 0.4 to 1.1), p < 0.0001. In the control group 9% and in the intervention group 33% of patients had documented reductions of body weight (p < 0.0001). Blood pressure decreased in the intervention group (162 +/- 14/100 +/- 7 mmHg at baseline, vs 154 +/- 16/95 +/- 9 mmHg at follow-up) compared to the control group (161 +/- 13/98 +/- 7 mmHg vs 158 +/- 18/96 +/- 11 mmHg); differences for systolic blood pressure 5 (95% CI 0 to 10) mmHg, p = 0.071; for diastolic blood pressure 4 (1 to 7) mmHg, p = 0.018.
                The introduction of a structured hypertension treatment and teaching programme in general practice may lead to significant improvements of hypertension care. The Plaque Hypertension Lipid-Lowering Italian Study (PHYLLIS) tested whether (1) the angiotensin-converting enzyme (ACE) inhibitor fosinopril (20 mg per day) was more effective on carotid atherosclerosis progression than the diuretic hydrochlorothiazide (25 mg per day), (2) pravastatin (40 mg per day) was more effective than placebo when added to either hydrochlorothiazide or fosinopril, and (3) there were additive effects of ACE inhibitor and lipid-lowering therapies.
                A total of 508 hypertensive, hypercholesterolemic patients with asymptomatic carotid atherosclerosis were randomized to: (A) hydrochlorothiazide; (B) fosinopril; (C) hydrochlorothiazide plus pravastatin; and (D) fosinopril plus pravastatin, and followed up blindly for 2.6 years. B-Mode carotid scans were performed yearly by certified sonographers in 13 hospitals and read centrally. Corrections for drift were calculated from readings repeated at study end. Primary outcome was change in mean maximum intima-media thickness of far and near walls of common carotids and bifurcations bilaterally (CBM(max)).
                CBM(max) significantly progressed (0.010+/-0.004 mm per year; P=0.01) in group A (hydrochlorothiazide alone) but not in groups B, C, and D. CBM(max) changes in groups B, C, and D were significantly different from changes in group A. Changes in group A were concentrated at the bifurcations. "Clinic" and "ambulatory" blood pressure reductions were not significantly different between groups, but total and low-density lipoprotein cholesterol decreased by approximately 1 mmol/L in groups C and D.
                Progression of carotid atherosclerosis occurred with hydrochlorothiazide but not with fosinopril. Progression could also be avoided by associating pravastatin with hydrochlorothiazide. To evaluate the safety and efficacy of an intravenous liposomal dispersion of prostaglandin E1 as TLC C-53 in the treatment of patients with acute respiratory distress syndrome (ARDS).
                Randomized, prospective, multicenter, double-blind, placebo-controlled, phase III clinical trial.
                Forty-seven community and university-affiliated hospitals in the United States.
                A total of 350 patients with ARDS were enrolled in this clinical trial.
                Patients were prospectively randomized in a 1:1 ratio to receive either liposomal prostaglandin E1 or placebo. The study drug was infused intravenously for 60 mins every 6 hrs for 7 days starting with a dosage of 0.15 microg/kg/hr. The dose was increased every 12 hrs until the maximal dose (3.6 microg/kg/hr) was attained or intolerance to further increases developed. Patients received standard aggressive medical/surgical care during the infusion period.
                The primary outcome measure was the time it took to wean the patient from the ventilator. Secondary end points included time to improvement of the PaO2/FIO2 ratio (defined as first PaO2/FIO2 > 300 mm Hg), day 28 mortality, ventilator dependence at day 8, changes in PaO2/FIO2, incidence of and time to development/resolution of organ failure other than ARDS.
                A total of 348 patients could be evaluated for efficacy. The distribution of variables at baseline describing gender, lung injury scores, Acute Physiology and Chronic Health Evaluation II scores, PaO2/FIO2, pulmonary compliance, and time from onset of ARDS or from institution of mechanical ventilation to the first dose of study drug was similar among patients in the liposomal prostaglandin E1 (n = 177) and the placebo (n = 171) treatment arms. There was no significant difference in the number of days to the discontinuation of ventilation in the liposomal prostaglandin E1 group compared with the placebo group (median number of days to off mechanical ventilation, 16.9 in patients receiving liposomal prostaglandin E1 and 19.6 in those administered placebo; p = .94). Similarly, mortality at day 28 was not significantly different in the two groups (day 28 mortality, 57 of 176 (32%) in the liposomal prostaglandin E1 group and 50 of 170 (29%) in patients receiving placebo; p = .55). In contrast, treatment with liposomal prostaglandin E1 was associated with a significantly shorter time to reach a PaO2/FIO2 ratio of >300 mm Hg (median number of days to reaching a PaO2/FIO2 ratio >300 mm Hg: 9.8 days in the liposomal prostaglandin E1 group and 13.7 days in patients receiving the placebo; p = .02). Among the subgroups examined, time to off mechanical ventilation was significantly reduced in patients who received at least 85% of a full dose (i.e., > 45.9 microg/kg) of liposomal prostaglandin E1 (median number of days to discontinuation of ventilation, 10.3 in the liposomal prostaglandin E1 group and 16.3 days in patients receiving placebo; p = .05). The overall incidence of serious adverse events was not significantly different in the liposomal prostaglandin E1 (40%) or placebo-treated (37%) groups. Drug-related adverse events of all kinds were reported in 69% of the patients receiving liposomal prostaglandin E1 compared with 33% of the placebo group, with hypotension and hypoxia (occurring in 52% and 24% of the liposomal prostaglandin E1-treated patients, respectively, and 17% and 5% of the placebo-treated patients, respectively) being noted most frequently.
                In the intent-to-treat population of patients with ARDS, treatment with liposomal prostaglandin E1 accelerated improvement in indexes of oxygenation but did not decrease the duration of mechanical ventilation and did not improve day 28 survival. The serine proteinase inhibitor aprotinin significantly reduces postoperative blood loss in patients requiring cardiac surgery using cardiopulmonary bypass. This study compared two low-dose regimens with administration of high-dose aprotinin and a control protocol to determine whether the dose of aprotinin could be greatly decreased but still maintain efficacy after primary cardiac surgery. Some 100 patients were randomly assigned to one of four groups: control group (0.9 per cent saline placebo, n = 25); high-dose group (aprotinin 2 x 10(6) kallikrein inactivator (KI) units intravenous patient bolus and 0.5 x 10(6) KI units h-1 plus 2 x 10(6) KI units into pump prime, n = 25); prime group (aprotinin 2 x 10(6) KI units added to the pump prime, n = 24); and patient group (aprotinin 10(6) KI units intravenous patient bolus plus 10(6) KI units added to the pump prime, n = 26). Only patients from the high-dose and patient groups had reduced intraoperative blood loss, but patients from all three aprotinin-treated groups demonstrated a significant decrease in median postoperative blood loss compared with the control group (high-dose 350 ml, prime 420 ml, patient 340 ml versus control 780 ml; P < 0.001). There was an even greater reduction in measured median postoperative haemoglobin loss within the chest drains in the treated compared with the control patients (high-dose 15 g, prime 24 g, patient 14 g versus control 47 g; P < 0.001). These decreases were statistically the same for all the treated groups; it is possible to lower the dose of aprotinin to approximately one-third of the currently recommended dosage and still obtain significantly reduced postoperative blood loss in primary cardiac surgery. To compare the efficacy and safety of two alpha1a/alpha1d adrenoceptor (AR) antagonists with different affinity for the alpha1AR subtypes, tamsulosin and naftopidil, in the treatment of benign prostatic hyperplasia (BPH).
                Patients with BPH were randomized to receive either tamsulosin or naftopidil. The primary efficacy variables were the changes in the total International Prostate Symptom Score (IPSS), maximum flow rate on free uroflowmetry, and residual urine volume. The secondary efficacy variables were average flow rate, changes in the IPSS storage score, IPSS voiding score, and quality-of-life (QoL) Index score, from baseline to endpoint (12 weeks). Data on all randomized patients were included in the safety analyses for adverse effects and changes in blood pressure.
                Of the 185 patients enrolled data for 144 who were eligible for inclusion in the efficacy analysis were analysed (75 from the tamsulosin and 69 from the naftopidil group). There was no significant difference in any variable at baseline between the groups. There were statistically significant improvements for all primary and secondary variables in both groups, except for residual urine in the tamsulosin group. However, there was no significant intergroup difference in the improvement of any efficacy variable between the groups. The adverse effects were comparable, with no significant differences in systolic and diastolic blood pressure after treatment in both groups.
                This study suggests that naftopidil is as effective and safe as tamsulosin. Both drugs were effective in improving storage and voiding symptoms. However, there was no difference in clinical efficacy or adverse effects between the alpha1 AR antagonists with different affinity to alpha1 subtypes, alpha1a and alpha1d. To study the effects of ACE-i in type 1 diabetic patients with early microalbuminuria with regard to: i) UAE, ii) 24 h AMBP, including the effect on diurnal BP variation, and iii) renal haemodynamics.
                58 patients with urinary albumin excretion (UAE) between 20-70 microg/min were treated for two years with either the ACE inhibitor (ACE-i) lisinopril (20 mg od) or placebo in two randomised placebo controlled double blind studies. In a subgroup of patients (n=22) we performed 24 h ambulatory blood pressure measurements (AMBP) and renal function tests (constant infusion technique).
                i) Changes in UAE over the two years were significantly different (p<0.01) in the two groups with final UAE in the lisinopril group of 19.1 microg/min x/divide 2.5 (geometric mean x/divide tolerance factor) and 44.1 microg/min x/divide 2.8 in the placebo group. In the lisinopril group 20 patients (60.6%) reversed to normoalbuminuria compared to 6 patients (24%) in the placebo group (p<0.02). ii) Clinical BP measurements revealed no differences between groups, but by AMBP significant reductions were detectable in the lisinopril group, primarily in night AMBP (systolic/diastolic: - 6.9 +/- 8.6/- 6.0 +/- 5.3 mmHg, p<0.01) as opposed to increases in the placebo group (3.1 +/- 9.3/1.9 +/- 7.3 mmHg). iii) Changes in UAE and changes in filtration fraction (FF) were positively correlated in the intervention group (r=0.9, p<0.01), i.e. the patients who showed the greatest fall in UAE were the ones with the greatest fall in FF.
                ACE-i treatment in patients with low-grade microalbuminuria reduces 24 h AMBP without attenuating diurnal blood pressure variation, reduces UAE significantly, with changes in UAE being strongly associated with changes in FF. Furthermore, compared to placebo, ACE-i reverses micro- to normoalbuminuria in a significant fraction of patients. Although nonpharmacologic interventions are widely recommended in the therapy of high blood pressure in older adults, surprisingly little data exist to confirm the efficacy of these interventions in older persons.
                We conducted a randomized, controlled clinical trial in persons aged 60 to 85 years with a diastolic blood pressure of 85 to 100 mm Hg. The experimental arm was a nonpharmacologic intervention combining weight reduction, sodium restriction, and increased physical activity. The nonpharmacologic intervention consisted of eight weekly group and two individual sessions during the intensive phase, followed by four monthly group sessions during the maintenance phase. The control group received no treatment during the study. Blood pressure was assessed by certified technicians (blinded to group assignment) using random zero sphygmomanometers.
                Of 56 participants randomized, 47 completed the entire 6-month trial (21 in the intervention group and 26 in the control group). Attendance at the intervention sessions was excellent. The intervention group lost more weight (-2.1 kg) over 6 months than the control group (+0.3 kg). Trends for decreasing 24-hour urine sodium excretion in both the intervention and control groups, with greater trend in the intervention group, were not statistically significant. The intervention group experienced more reduction in systolic and diastolic blood pressure than did the control group (mean differences between groups at 6 months, 4.2/4.9 mm Hg, respectively).
                Our data indicate that a nonpharmacologic intervention will lower systolic and diastolic blood pressure levels in older people with borderline or mild elevations of diastolic blood pressure.
The evidence from this review suggests that there are no clinically meaningful BP lowering differences between available ARBs. The BP lowering effect of ARBs is modest and similar to ACE inhibitors as a class; the magnitude of average trough BP lowering for ARBs at maximum recommended doses and above is -8/-5 mmHg.  Furthermore, 60 to 70% of this trough BP lowering effect occurs with recommended starting doses. The review did not provide a good estimate of the incidence of harms associated with ARBs because of the short duration of the trials and the lack of reporting of adverse effects in many of the trials.