title: Impact of angiotensin receptor blockade in combination with hydrochlorothiazide 25 mg in 2121 patients with stage 1–2 hypertension Valsartan Improves Arterial Stiffness in Type 2 Diabetes Independently of Blood Pressure Lowering Comparative effects of amlodipine monotherapy and combination therapy with betaxolol on cardiac autonomic nervous activity and health-related quality of life in patients with poorly controlled hypertension. Comparative effects of felodipine ER, amlodipine and nifedipine GITS on 24 h blood pressure control and trough to peak ratios in mild to moderate ambulatory hypertension: a forced titration study. Efficacy of captopril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria. The 24 h blood pressure responses of hypertensives to a once-a-day cilazapril regimen. Perindopril as monotherapy in hypertension: A multicenter comparison of two dosing regimens Comparative Evaluation of Effect of Valsartan/Amlodipine and Atenolol/Amlodipine Combinations on Atrial Fibrillation Recurrence in Hypertensive Patients With Type 2 Diabetes Mellitus The Effect of Trandolapril and Its Fixed-Dose Combination with Verapamil on Circulating Adhesion Molecules Levels in Hypertensive Patients with Type 2 Diabetes Effects of dual blockade of renin-angiotensin system in type 2 diabetes mellitus patients with diabetic nephropathy. Cardiovascular responses to verapamil and propranolol in hypertensive patients. Felodipine in hypertensive patients. A dose finding study in patients refractory to beta-blocker monotherapy. Safety and benefits of a tablet combining losartan and hydrochlorothiazide in Japanese diabetic patients with hypertension Contrasting effects of enalapril and metoprolol on proteinuria in diabetic nephropathy. Effects of Ramipril and Vitamin E on Atherosclerosis: The Study to Evaluate Carotid Ultrasound Changes in Patients Treated With Ramipril and Vitamin E (SECURE) Effectiveness of Add-On Low-Dose Diuretics in Combination Therapy for Hypertension: Losartan/Hydrochlorothiazide vs. Candesartan/Amlodipine Comparisons of Once‐Daily Nilvadipine with Enalapril and Diuretic in Patients with Essential Hypertension Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack Effects of BAYl 5240, a fixed combination of low dose nifedipine and acebutolol on hypertension: Comparison with standard dose nifedipine Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies. Lercanidipine, enalapril and their combination in the treatment of elderly hypertensive patients: placebo-controlled, randomized, crossover study with four ABPM Fixed dose combination of perindopril and indapamide improves peripheral vascular function in essential hypertensive patients. Effects of low dose versus conventional dose thiazide diuretic on insulin action in essential hypertension A home blood pressure monitoring study comparing the antihypertensive efficacy of two angiotensin II receptor antagonist fixed combinations. Combination of an ACE inhibitor and indapamide improves blood pressure control, but attenuates the beneficial effects of ACE inhibition on plasma adiponectin in patients with essential hypertension. Reduction of ACE activity is insufficient to decrease microalbuminuria in normotensive patients with type 1 diabetes. The Phase III, double-blind, parallel-group controlled study of amlodipine 10 mg once daily in Japanese patients with essential hypertension who insufficiently responded to amlodipine 5 mg once daily Renoprotective Effect of Calcium Channel Blockers in Combination with an Angiotensin Receptor Blocker in Elderly Patients with Hypertension. A Randomized Crossover Trial Between Benidipine and Amlodipine The Felodipine Event Reduction (FEVER) Study: a randomized long-term placebo-controlled trial in Chinese hypertensive patients Renoprotective Effect of the Addition of Losartan to Ongoing Treatment with an Angiotensin Converting Enzyme Inhibitor in Type-2 Diabetic Patients with Nephropathy Antihypertensive effects of a new sustained-release formulation of nifedipine. Effects of diltiazem and metoprolol on blood pressure, adverse symptoms and general well-being Efficacy of ACE inhibitors and ATII receptor blockers in patients with microalbuminuria: a prospective study Blood Pressure-Lowering Efficacy of Amiloride versus Enalapril as Add-On Drugs in Patients with Uncontrolled Blood Pressure Receiving Hydrochlorothiazide Losartan with hydrochlorothiazide in the treatment of hypertension Antihypertensive effect of doxazosin in hypertensive patients: comparison with atenolol. Angiotensin-II receptor antagonist combined with calcium channel blocker or diuretic for essential hypertension Monotherapy of stable angina with nicardipine hydrochloride: double-blind, placebo-controlled, randomized study. Effects of the angiotensin II receptor blockers telmisartan versus valsartan in combination with hydrochlorothiazide: a large, confirmatory trial Effect of beta-adrenergic blockade on blood pressure variation in patients with moderate hypertension Effect of calcium antagonists on ambulatory blood pressure and its variations. Losartan potassium lowers blood pressure measured by ambulatory blood pressure monitoring Efficacy of a Very‐low‐dose Combination of Perindopril and Indapamide—Preterax Compared with Cilazapril Monotherapy in Patients with Inadequate Blood Pressure Control—A Randomized, Double‐blind, Add‐on Study Long‐term efficacy of a new, fixed, very‐low‐dose angiotensin‐converting enzyme‐inhibitor/diuretic combination as first‐line therapy in elderly hypertensive patients Controlled trial of losartan given concomitantly with different doses of hydrochlorothiazide in hypertensive patients. A multi-centre, placebo controlled comparative study between 200 mg and 400 mg celiprolol in patients with mild to moderate essential hypertension. Combination of amlodipine and enalapril in hypertensive patients with coronary disease. Evaluation of blood pressure response to the combination of enalapril (single dose) and diltiazem ER (four different doses) in systemic hypertension. Supramaximal dose of candesartan in proteinuric renal disease. Antiproteinuric and blood pressure-lowering effects of a fixed-dose combination of losartan and hydrochlorothiazide in hypertensive patients with stage 3 chronic kidney disease. Prophylactic Treatment of Migraine with Bisoprolol Felodipine extended release in mild to moderate hypertension. Efficacy and safety of two treatment combinations of hypertension in very elderly patients. Assessment of electrocardiographic ischemia in hypertensive patients treated with isradipine or placebo. The antihypertensive effect and tolerability of candesartan cilexetil, a new generation angiotensin II antagonist, in comparison with losartan. Antihypertensive Efficacy and Safety of Fixed-Dose Combination Therapy with Losartan plus Hydrochlorothiazide in Japanese Patients with Essential Hypertension Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial Low-dose ramipril reduces microalbuminuria in type 1 diabetic patients without hypertension: results of a randomized controlled trial. A double-blind, randomized study evaluating losartan potassium monotherapy or in combination with hydrochlorothiazide versus placebo in obese patients with hypertension. Efficacy of Low-Dose Hydrochlorothiazide in Combination with Telmisartan on Early Morning Blood Pressure in Uncontrolled Hypertensive Patients Efficacy and Tolerability of the New Calcium Antagonist Isradipine in Essential Hypertension Results of a comparative, phase III, 12-week, multicenter, prospective, randomized, double-blind assessment of the efficacy and tolerability of a fixed-dose combination of telmisartan and amlodipine versus amlodipine monotherapy in Indian adults with stage II hypertension. The case for low dose diuretics in hypertension: comparison of low and conventional doses of cyclopenthiazide. Effect of verapamil, trandolapril and their combination on vascular function and structure in essential hypertensive patients.
abstract: The antihypertensive effects of telmisartan 80 mg versus valsartan 160 mg , both combined with hydrochlorothiazide ( HCTZ ) 25 mg , were assessed in a pooled analysis from two large trials with identical study design s in patients with stage 1–2 hypertension . The trials were double-blind with a 4:4:1 r and omization scheme to compare once-daily telmisartan 80 mg and HCTZ 25 mg versus once-daily valsartan 160 mg and HCTZ 25 mg versus once-daily placebo on reductions in clinic blood pressure ( BP ) . The primary end point was changes from baseline in BP at the end of 8 weeks . In total , 2121 patients were r and omized ( telmisartan – HCTZ , 942 , valsartan – HCTZ , 952 , and placebo , 227 ) and had baseline seated BPs of 154/102 and 155/102 mm Hg in the two studies , respectively .  Changes from baseline in BP after administration of telmisartan – HCTZ ( −24.5/−18.0 mm Hg ) were significantly greater than for both placebo ( −4.1/−6.5 mm Hg ) and valsartan – HCTZ ( −22.3/−16.8 mm Hg ) ( versus placebo , P<0.0001 for systolic and diastolic BP ; versus valsartan – HCTZ , P=0.0004 for systolic BP and P=0.0019 for diastolic BP ) . Adverse event rates were higher in the placebo group than in the active treatment groups ( placebo , 41 % , telmisartan – HCTZ , 30 % , and valsartan – HCTZ , 30 % , P<0.05 ) . These data confirm that telmisartan – HCTZ at doses of 80/25 mg lowered systolic and diastolic BP to a greater extent than valsartan – HCTZ at doses of 160/25 mg in stage 1–2 hypertension . The magnitude of the BP-lowering effect provides support for the use of angiotensin receptor blockers with higher doses of a thiazide diuretic ( 25 mg ) to improve hypertension control Increased arterial stiffness , as estimated from aortic pulse wave velocity ( Ao-PWV ) , and albuminuria are independent predictors for cardiovascular disease in type 2 diabetes mellitus ( T2DM ) . Whether angiotensin receptor blockers ( ARBs ) , drugs with cardio-renal protective effects , improve Ao-PWV to a greater extent than other equipotent antihypertensive medications remains unclear . After a 4-week washout phase , we compared the effects of valsartan ( n=66 ) , an ARB , with that of amlodipine ( n=65 ) , a calcium channel blocker on Ao-PWV in 131 T2DM patients with pulse pressure ( PP ) ≥60 mm Hg and raised albumin excretion rate ( AER ) in a 24-week r and omized , double-blind , parallel group study . Hydrochlorothiazide ( HCTZ ) 25 mg/d was added to valsartan 160 mg and amlodipine 5 mg/od uptitrated to 10 mg/od after 4 weeks to ensure equivalent BP control . After 24 weeks brachial and central aortic PP had fallen to a similar extent with attained mean ( SD ) brachial and central PP of 61.6 ( 13.6 ) and 47.3 ( 14.1 ) mm Hg in the valsartan/HCTZ group and 61.5 ( 12.2 ) and 47.3 ( 9.9 ) mm Hg in the amlodipine group , respectively . Ao-PWV showed a significantly greater reduction , mean ( 95 % CI ) , −0.9 m/s ( −1.4 to −0.3 ) for valsartan/HCTZ compared to amlodipine ( P=0.002 ) . AER fell significantly only with Val/HCTZ from 30.8(20.4 , 46.5 ) to 18.2(12.5 , 26.3 ) mcg/min , ( P=0.01 ) with between treatment difference in favor of Val/HCTZ of −15.3mcg/min ( P<0.001 ) . Changes in AER and Ao-PWV were not correlated . Valsartan/HCTZ improves arterial stiffness and AER to a significantly greater extent than amlodipine despite similar central and brachial BP control . These 2 effects , which appear independent of each other , may explain the specific cardio-renal protective properties of ARBs BACKGROUND The aim of the study was to evaluate whether the combined treatment of calcium channel blocker , amlodipine and beta-blocker , betaxolol , favorably affects cardiac autonomic nervous activity ( CANA ) and health-related quality of life ( HRQL ) . METHODS AND RESULTS A total of 65 patients with a poor blood pressure ( BP ) control with a low dose amlodipine therapy were r and omly assigned to the amlodipine dose-up group ( n=21 ) and betaxolol adding group ( n=44 ) . Before and after a 6-month treatment , BP , heart rate variability ( HRV ) , HRQL and blood chemistries were evaluated . Low frequency ( LF ) spectra/high frequency ( HF ) spectra and HF/total power spectra ( TP ) were calculated as indexes of CANA , and HRQL was assessed by the question naire sheets . BP was well controlled in all patients of the present study . In the betaxolol adding group , LF/HF decreased ( 2.1+/-1.9 to 1.3+/-0.9 , p<0.05 ) and HF/TP reciprocally increased ( 0.41+/-0.17 to 0.52+/-0.18 , p<0.05 ) , whereas the amlodipine dose-up group showed no significant changes in the HRV . HRQL was significantly improved in the betaxolol adding group , whereas it remained unchanged in the amlodipine dose-up group . Blood chemistries remained unchanged except for the slightly increased plasma brain natriuretic peptide concentrations in the betaxolol adding group ( 36+/-47 to 62+/-62 pg/ml , p<0.05 ) . CONCLUSIONS Combined treatment of amlodipine and betaxolol appears to be more useful than amlodipine dose-up therapy , because combined treatment improves CANA and HRQL OBJECTIVE To evaluate the 24 h antihypertensive efficacy and duration of action of felodipine extended release ( ER ) in comparison with two other long acting dihydropyridine calcium antagonists , amlodipine and nifedipine gastrointestinal therapeutic system ( GITS ) , in patients with mild to moderate essential hypertension substantiated by ambulatory blood pressure ( BP ) monitoring . DESIGN R and omized , forced titration , parallel group study . Clinic BP was measured at every patient 's visit , and 24 h ambulatory BP was monitored at baseline and at the end of each dose-titration period . SETTING Single centre : hypertension research unit in Quebec City , Quebec . PATIENTS There were 89 patients enrolled into the study . Eighty-four eligible patients were r and omized , and 83 completed the study and were included in the final efficacy analysis . INTERVENTIONS Following a two-to four-week washout period ( baseline ) , patients were r and omly allocated to receive felodipine ER 5 mg , amlodipine 5 mg or nifedipine GITS 30 mg for four weeks ( low dose ) . All study patients had their daily dose doubled to felodipine ER 10 mg , amlodipine 10 mg or nifedipine GITS 60 mg for a further four weeks ( high dose ) . MAIN RESULTS Significant ( P < 0.001 ) and similar changes from baseline in clinic BP were observed in all treatment groups for low and high doses . Ambulatory BP profiles showed comparable blood pressure reductions with felodipine ER and amlodipine , and a trend towards a lesser reduction with nifedipine GITS during 24 h , daytime and night-time periods . BP loads were similarly reduced with the three treatments . Trough to peak ratios ( T : Ps ) were calculated from 24 h ambulatory BP curves according to two different approaches : for diastolic and systolic BP , respectively , the global approach produced T : Ps of 0.49 and 0.50 with felodipine ER 5 mg ; 0.50 and 0.34 with felodipine ER 10 mg ; 0.70 and 0.60 with amlodipine 5 mg ; 0.88 and 0.82 with amlodipine 10 mg ; 0.65 and 0.55 with nifedipine GITS 30 mg ; 0.68 and 0.53 with nifedipine GITS 60 mg . T : Ps in the individual approach were 0.07 and 0.10 with felodipine ER 5 mg ; 0.23 and 0.31 with felodipine ER 10 mg ; 0.22 and 0.31 with amlodipine 5 mg ; 0.45 and 0.58 with amlodipine 10 mg ; 0.27 and 0.31 with nifedipine GITS 30 mg ; and 0.24 and 0.40 with nifedipine GITS 60 mg . CONCLUSION There was no evidence in this study of a difference among felodipine ER , amlodipine and nifedipine GITS in lowering ambulatory or clinic BP . Treatment based on ambulatory BP may be preferable to treatment guided by T : Ps because ambulatory BP is firmly established as a predictor of cardiovascular risk . Furthermore , there is no consensus on how to calculate T : Ps , and different methods of calculation may give divergent results OBJECTIVE --To assess the effectiveness of angiotensin converting enzyme inhibition in preventing the development of diabetic nephropathy ( albuminuria greater than 300 mg/24h ) . DESIGN --Open r and omised controlled study of four years ' duration . SETTING --Outpatient diabetic clinic in tertiary referral centre . PATIENTS --44 normotensive ( mean blood pressure 127/78 ( SD 12/10 ) mm Hg ) insulin dependent diabetic patients with persistent microalbuminuria ( 30 - 300 mg/24h ) . INTERVENTIONS --The treatment group ( n = 21 ) was initially given captopril ( 25 mg/24 h ) . The dose was increased to 100 mg/24 h during the first 16 months and thiazide was added after 30 months . The remaining 23 patients were left untreated . MAIN OUTCOME MEASURES --Albuminuria , kidney function , development of diabetic nephropathy ( albuminuria greater than 300 mg/24 h ) , and arterial blood pressure . RESULTS -- Clinical and laboratory variables were comparable at baseline . Urinary excretion of albumin was gradually reduced from 82 ( 66 - 106 ) to 57 ( 39 - 85 ) mg/24 h ( geometric mean ( 95 % confidence interval ) ) in the captopril treated group , whereas an increase from 105(77 - 153 ) to 166 ( 83 - 323 ) mg/24 h occurred in the control group ( p less than 0.05 ) . Seven of the untreated patients progressed to diabetic nephropathy , whereas none of the captopril treated patients developed clinical overt diabetic nephropathy ( p less than 0.05 ) . Systemic blood pressure , glomerular filtration rate , haemoglobin A1c concentration , and urinary excretion of sodium and urea remained practically unchanged in the two groups . CONCLUSIONS --The findings suggest that angiotensin converting enzyme inhibition postpones the development of clinical overt diabetic nephropathy in normotensive insulin dependent diabetic patients with persistent microalbuminuria The efficacy of once-a-day cilazapril ( a new long acting converting enzyme inhibitor ) therapy for the 24 h control of hypertension and its effects on the renin-angiotensin axis were investigated . Twenty-four uncomplicated hypertensive patients whose sitting diastolic blood pressures remained within 94 to 114 mmHg after four weeks of placebo were r and omly assigned on a double-blind basis to receive either continued placebo or cilazapril therapy at a single dose of 1.25 , 2.5 or 5.0 mg/day for a further four weeks . At the end of weeks 4 and 8 , systolic and diastolic blood pressures and heart rates were recorded , supine and st and ing , at 0 , 2 , 4 , 6 , 9 , 12 and 24 h following a single dose of drug . At the same times , blood was withdrawn for determination of plasma renin activity and aldosterone . Supine and erect systolic and diastolic blood pressures were lowered to normotensive levels with an optimal response being achieved at a dose of 2.5 mg/day . Supine and erect heart rates were unchanged with respect to drug dosage , and the reflex increase in heart rate and diastolic blood pressure on changing from supine to erect posture was maintained in all groups . Maximum antihypertensive efficacy was from 2 to 6 h after drug ingestion . There were no changes in resting aldosterone , but plasma renin activity was increased at all drug dosages . A single 2.5 mg dose of cilazapril provides blood pressure control for a 24 h period . Cilazapril does not appear to interfere with the reflex autonomic responses to postural change Perindopril erbumine , a new long‐acting , non‐sulfhydryl‐containing angiotensin converting enzyme inhibitor , was evaluated in 289 patients with hypertension in a 16‐week , double‐blind , placebo‐controlled dose‐ranging study . After 4 weeks of single‐blind placebo treatment , patients with supine diastolic arterial pressures from 95 to 114 mm Hg were r and omized to receive placebo , 4 mg perindopril once daily , or 2 mg perindopril twice daily . The daily dose of perindopril was increased by 4 mg every 4 weeks to a maximum of 16 mg per day . Mean decreases in systolic and diastolic arterial pressure were greater with perindopril than with placebo ( p < 0.05 ) . The dose‐response curve flattened after 8 mg per day , and there was no difference in arterial pressure reduction or in the percentage of responders between once‐ and twice‐daily administration of perindopril . Adverse reactions with perindopril were generally mild and , with the exception of cough , were similar with placebo . The findings of this study indicate that perindopril is effective , well tolerated , and suitable for once‐daily administration for the treatment of hypertension The aim of this study was to compare the effect of valsartan/amlodipine and atenolol/amlodipine combination in preventing the recurrence of atrial fibrillation ( AF ) in hypertensive diabetic patients with a history of recent paroxysmal atrial fibrillation . Two hundred ninty-six hypertensive patients with well-controlled type 2 diabetes in sinus rhythm but with at least 2 ECG-documented episodes of AF in the previous 6 months were r and omized to 160 mg of valsartan plus amlodipine ( titrated from 2.5 to 10 mg ) or to 100 mg of atenolol plus amlodipine ( 2.5 to 10 mg ) in addition to their previous antiarrhythmic treatment ( if any ) and were followed up for 1 year . Blood pressure ( BP ) and a 24-hour ECG were evaluated monthly . The patients were asked to report any episode of symptomatic AF and to perform an ECG as early as possible . SBP/DBP values were significantly reduced after 12 months with valsartan/amlodipine ( from 150.4/93.5 to 126.37/7.4 mm Hg , P < 0.001 ) and atenolol/amlodipine ( from 151.1/94.2 to 127.1/77.9 mm Hg , P < 0.001 ) , with no difference between the 2 regimens . At least 1 ECG-documented episode of AF was reported in 20.3 % of the patients treated with valsartan/amlodipine and in 34.1 % of those treated with atenolol/amlodipine , with a significant difference between treatments ( P < 0.01 ) . The positive effect of valsartan/amlodipine combination on AF recurrence was more evident in patients treated with amiodarone or propafenone than in patients treated with other antiarrhythmic drugs or without antiarrhythmic treatment . Despite similar BP reduction , valsartan/amlodipine combination was more effective in patients treated with amiodarone or propafenone than atenolol/amlodipine in preventing new episodes of AF in hypertensive diabetic patients Background and Aim . Endothelial dysfunction in hypertensive type-2 diabetic patients is associated with increased levels of circulating soluble adhesion molecules ( SAM ) . SAM participate in the development of diabetic macroangiopathy and microangiopathy . The aim of this study was to compare the effect of tr and olapril ( T ) and its fixed-dose combination with verapamil ( FDTV ) on SAM levels in hypertensive type-2 diabetic patients . Methods . Forty type-2 diabetic patients with never-treated hypertension were r and omly assigned to two groups . One group ( FDTV ) received 2/180 mg once a day ; the other group received T 2 mg once a day . Study drugs were administered for three months in both groups . VCAM-1 , ICAM , and E-selectin were measured by ELISA at the beginning and end of the study . Patients were evaluated monthly for blood pressure , fasting serum glucose , and adverse events . Statistical analysis was performed with ANOVA . Results . Both therapeutics regimens reduced significantly the levels of the SAM tested . When both groups were compared , we did not find a significant difference in ICAM and E-selectin reduction . However , VCAM-1 presented a significantly greater reduction ( p = 0.022 ) in the tr and olapril-verapamil group . No patient suffered adverse events . Conclusion . Our results show that FDTV produces a greater reduction of VCAM-1 circulating levels than tr and olapril alone . This may explain some of the beneficial effects of this fixed dosed combination that are non-related to its antihypertensive effects BACKGROUND Angiotensin-converting enzyme ( ACE ) inhibitors or angiotensin II receptor blockers ( ARB ) have been shown to delay the progression to proteinuria and kidney failure in hypertensive type 2 diabetic patients with diabetic nephropathy . Further synergistic effect may be obtained by combined therapy with both ARB and ACE inhibitors . OBJECTIVE To evaluate the effect of dual blockage of the renin-angiotensin system by adding maximal recommended dose of ARB with maximal recommended dose of ACE inhibitors in type 2 diabetic patients with diabetic nephropathy . MATERIAL AND METHOD Type 2 diabetic patients with urine protein/creatinine ( UPCr ) > 0.5 gm/gm and hypertension who received maximal recommended dose of ACE inhibitors ( Enalapril 40 mg/day ) over three months were r and omized to two groups .  ARB group received adding maximal recommended dose of ARB ( Telmisartan 80 mg/day ) and control group received previous ACE inhibitors only for 24 weeks . RESULTS Eighty patients were enrolled . ARB group led to significantly reduced UPCr from baseline at week 8 , 12 , and 24 ( 2.65 + /- 1.81 , 2.24 + /- 1.85 , 2.24 + /- 1.88 and 1.98 + /- 1.73 gm/gm respectively , p < 0.05 ) but UPCr in the control group was unchanged ( 1.97 + /- 1.56 , 1.85 + /- 1.27 , 1.97 + /- 1.11 and 1.96 + /- 1.42 gm/gm respectively , p > 0.05 ) . ARB group induced an additional reduction in proteinuria of 29.25 % ( 95 % CI 9.68 - 48.82 ) compared with control group . By the end of the present study , glomerular filtration rate had fallen from 41.76 + /- 12.16 to 37.84 + /- 13.59 ml/min/1.73 m2 in ARB group and 50.89 + /- 29.43 to 49.41 + /- 29.85 ml/min/1.73 m2 in control group ( p > 0.05 ) . Serum potassium had changed from 4.51 + /- 0.48 to 4.58 + /- 0.13 mEq/L in ARB group and 4.60 + /- 0.58 to 4.40 + /- 0.13 mEq/L in the control group ( p > 0.05 ) . No other serious adverse effects were reported during treatment . CONCLUSION Adding maximal recommended dose of ARB with maximal recommended dose of ACE inhibitors in type 2 diabetic patients can reduce proteinuria more than ACE inhibitors alone . This treatment is safe and well tolerated Since there is concern that the potentially useful antihypertensive combination of verapamil and propranolol might lead to adverse cardiovascular responses , we have investigated its effects , not only on blood pressure , but also on electrocardiographic and echocardiographic variables .  Fourteen hypertensive patients participated in a double-blind , r and omized , crossover comparison of verapamil 360 mg , propranolol 240 mg , verapamil 360 mg + propranolol 240 mg , and placebo , each given for 4 weeks . The antihypertensive effect of verapamil + propranolol was greater than that of either drug alone . Pulse rate was reduced by propranolol but not verapamil . However , addition of verapamil to propranolol led to further reduction in pulse rate . The PR interval was prolonged by verapamil + propranolol when compared with all other treatments . The active drugs increased ventricular dimensions and the effect of the combination was statistically significant . Thus , verapamil + propranolol is an effective antihypertensive combination , but heart rate , atrio-ventricular conduction and left ventricular function may be affected adversely , necessitating careful monitoring of therapy In a double-blind study , 128 patients with essential hypertension , refractory to beta-blocker monotherapy , were r and omised to 1 of 4 treatment groups . Felodipine 2.5 mg twice daily , 5 mg twice daily , 10 mg twice daily or matched placebo twice daily were administered in addition to the beta-blocker for 4 weeks . Mean supine blood pressure before r and omisation to treatment was 167/104 + /- 20/7 mm Hg . After 4 weeks of treatment , supine blood pressures 2 hours after dose were 161/98 + /- 20/10 mm Hg ( P ) , 152/92 + /- 23/8 mm Hg ( felodipine 2.5 mg ) , 142/87 + /- 18/7 mm Hg ( felodipine 5 mg ) and 142/86 + /- 17/7 mm Hg ( felodipine 10 mg ) . The falls in systolic and diastolic blood pressures were significantly greater for all 3 felodipine groups than for placebo .  Blood pressure reductions were less marked 14 hours after dosage : 161/100 + /- 20/9 mm Hg ( P ) , 160/97 + /- 24/9 mm Hg ( felodipine 2.5 mg ) , 153/97 + /- 21/11 mm Hg ( felodipine 5 mg ) , and 157/94 + /- 19/9 mm Hg ( felodipine 10 mg ) ; but the two higher doses of felodipine produced a significantly greater sustained fall in blood pressure than placebo . There was a correlation between the dose of felodipine and its antihypertensive effect . St and ing blood pressures were reduced to the same extent as supine measurements . Heart rate was not significantly affected . Bodyweight did not increase during the study . Side effects of felodipine therapy were minor , and mostly attributable to the vasodilatory properties of the drug . Only 4 patients withdrew because of side effects . It is concluded that felodipine is an effective and well tolerated antihypertensive drug , and that 5 mg twice daily is a suitable starting dose in hypertensive patients refractory to beta-blocker monotherapy . It may be necessary to increase this dose to 10 mg twice daily in selected patients This study was conducted to determine the effects of a tablet combining losartan/hydrochlorothiazide ( L/HCTZ ) in comparison with losartan alone in Japanese diabetic patients with hypertension . Thirty consecutive Japanese diabetic patients with hypertension were r and omly assigned to group A , receiving losartan alone for the first 3 months , then L/HCTZ for the next 3 months , or group B , receiving L/HCTZ for the first 3 months , then losartan alone for the next 3 months . Clinical and biological parameters were obtained before , and 3 and 6 months after the start of this study . The decreases in systolic and diastolic blood pressure ( BP ) during treatment with L/HCTZ were significantly greater than in treatment with losartan alone . Both treatments significantly and similarly decreased urinary albumin excretion , the cardio-ankle vascular index ( CAVI ) and augmentation index ( AI ) . There was no significant difference in metabolic change during both the mono- and combination pharmacotherapies . The tablet combining L/HCTZ significantly reduced systolic and diastolic BP compared with the losartan monotherapy , and offered benefits similar to losartan monotherapy for albuminuria , arterial stiffness assessed by the CAVI and AI , and metabolic effects . Thus , the L/HCTZ tablet could be a useful drug for Japanese diabetic patients with hypertension OBJECTIVE --To assess whether angiotensin converting enzyme inhibition reduces proteinuria in diabetic nephropathy more than blood pressure reduction with other antihypertensive treatment . DESIGN -- Prospect i ve , open r and omised study lasting eight weeks in patients with diabetic nephropathy . SETTING --Outpatient nephrology clinics . PATIENTS --40 Patients with type I diabetes and diabetic nephropathy with reduced renal function . INTERVENTION -- Antihypertensive treatment with enalapril or metoprolol , usually combined with frusemide . MAIN OUTCOME MEASURES --Arterial blood pressure and urinary excretion of albumin and protein . RESULTS --Arterial blood pressure after eight weeks was 135/82 ( SD 13/7 ) mm Hg in the group given enalapril and 136/86 ( 16/12 ) mm Hg in the group given metoprolol .  Proteinuria and albuminuria were similar in both groups before r and omisation . After eight weeks ' treatment , the geometric mean albumin excretion was 0.7 ( 95 % confidence interval 0.5 to 1.2 ) g/24 h in the patients given enalapril and 1.6 ( 1.1 to 2.5 ) g/24 h in the patients given metoprolol ( p less than 0.02 ) . The proteinuria was 1.1 ( 0.7 to 1.7 ) and 2.4 ( 1.6 to 3.6 ) g/24 h respectively ( p less than 0.02 ) . CONCLUSIONS --Antihypertensive treatment with enalapril reduced proteinuria in patients with diabetic nephropathy more than an equally effective antihypertensive treatment with metoprolol . This points to a specific antiproteinuric effect of the angiotensin converting enzyme inhibitor independent of the effect on systemic blood pressure Background —Activation of the renin-angiotensin-aldosterone system and oxidative modification of LDL cholesterol play important roles in atherosclerosis . The Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E ( SECURE ) , a sub study of the Heart Outcomes Prevention Evaluation ( HOPE ) trial , was a prospect i ve , double-blind , 3 × 2 factorial design trial that evaluated the effects of long-term treatment with the angiotensin-converting enzyme inhibitor ramipril and vitamin E on atherosclerosis progression in high-risk patients . Methods and Results —A total of 732 patients ≥55 years of age who had vascular disease or diabetes and at least one other risk factor and who did not have heart failure or a low left ventricular ejection fraction were r and omly assigned to receive ramipril 2.5 mg/d or 10 mg/d and vitamin E ( RRR-&agr;-tocopheryl acetate ) 400 IU/d or their matching placebos . Average follow-up was 4.5 years . Atherosclerosis progression was evaluated by B-mode carotid ultrasound . The progression slope of the mean maximum carotid intimal medial thickness was 0.0217 mm/year in the placebo group , 0.0180 mm/year in the ramipril 2.5 mg/d group , and 0.0137 mm/year in the ramipril 10 mg/d group ( P = 0.033 ) . There were no differences in atherosclerosis progression rates between patients on vitamin E and those on placebo . Conclusions —Long-term treatment with ramipril had a beneficial effect on atherosclerosis progression  . Vitamin E had a neutral effect on atherosclerosis progression In guidelines , a combination therapy of two or more antihypertensives is recommended for treatment of hypertension where monotherapy is ineffective . Although diuretics or calcium channel blockers are commonly used as add-ons to angiotensin receptor blocker ( ARB ) , the most effective and safe combination has not been established . In this r and omized 4-month study , the efficacy and safety were compared between an ARB/diuretics ( losartan/hydrochlorothiazide [ HCTZ ] ) combination and the most prescribed combination , ARB/calcium channel blocker ( c and esartan/amlodipine ) in hypertensive patients for whom 8 mg/day of c and esartan proved ineffective . After 36 patients were recruited and allocated into two groups , changes in blood pressure ( BP ) and laboratory values were analyzed in 31 patients : 16 patients received losartan ( 50 mg/day)/HCTZ ( 12.5 mg/day ) ( L/H group ) , and 15 patients received c and esartan ( 8 mg/day)/amlodipine ( 5 mg/day ) ( C/A group ) after 5 patients were withdrawn . After 4 months , L/H significantly ( p<0.001 ) reduced mean systolic BP (SBP)/diastolic BP ( DBP ) from baseline 160/89±13/11 mmHg to 140/80±9/8 mmHg , and C/A reduced BP from 161/90±10/11 mmHg to 141/79±10/7 mmHg . The efficacy in reducing BP was similar between the two combination therapies . L/H significantly reduced serum potassium , but within the normal range , and did not increase serum uric acid or serum triglyceride . With L/H , the percentage of patients who attained the BP goal in SBP was higher in elderly patients than in younger patients . As L/H is more cost-effective than c and esartan/amlodipine and has fewer adverse effects on uric acid and other metabolic parameters than diuretic monotherapy , it is concluded to be useful for the management of hypertension The antihypertensive efficacy of the new dihydro-pyridine derivative nilvadipine given once daily was compared in two r and omized , double-blind studies with that of hydrochlorothiazide/triamterene ( HCT/T ) and of enalapril . In the first study , arterial pressures were compared after 4 weeks of therapy with nilvadipine ( 16 mg q.d . ) or HCT/T ( 25/50 mg q.d . ) in patients with mild-to-moderate hypertension in a parallel-group design . The combination of both treatments was administered after 4 weeks if diastolic arterial pressures were < 90 mm Hg . The blood pressure ( BP ) in the nilvadipine group ( n = 125 ) was 161/102 ± 17/7 ( mean ± SD ) mm Hg after a 2-week placebo period and decreased after 4 weeks by – 16/– 13 ± 22/12 mm Hg . The BP decreased in the HCT/T group ( n = 124 ) compared to the nilvadipine group to a similar degree ( p = 0.91 , n.s . ) from 160/103 ± 17/8 mm Hg by −17/-13 ± 18/11 mm Hg . A combination therapy was started after 4 weeks in 39 patients in the nilvadipine group and in 34 patients in the HCT/T group . This led independently of the treatment sequence , to a similar decrease in BP in the nilvadipine group ( – 17/7 ± 16/10 mm Hg ) and in the HCT/T group ( -12/9 ± 16/9 mm Hg ) . In the second study , the antihypertensive effect of nilvadipine ( 1 x 8 mg ) was compared with that of enalapril ( 1x10 mg ) in a r and omized , double-blind , crossover design . Sixty-one patients with essential hypertension ( WHO I – II ) were treated over two 4-week periods following placebo periods of 2 weeks . Nonresponders ( BP < 90 mm Hg ) were subsequently treated for an additional 4 weeks with a combination of both drugs given at the same dosage . The BP decreased to a similar degree after 4 weeks on nilvadipine from 175/108 ± 13/7 mm Hg by −19/-13 mm Hg and from 176/107 ± 13/6 mm Hg by −21/-13 mm Hg after 4 weeks on enalapril to 156/95 + 14/ 9 mm Hg and 155/94 ± 16/10 mm Hg , respectively . Goal diastolic BPs < 90 mm Hg were not achieved with monotherapy in 27 patients , but 15 of these 27 patients responded favorably to a combination of nilvadipine and enalapril  with diastolic BPs < 90 mm Hg . Combination therapy caused a decrease in the diastolic BP of −14/-13 mm Hg . In conclusion , nilvadipine administered once daily was as effective as  hydrochlorothiazide or enalapril  in lowering the BP . In combination with a diuretic , the sequence of treatments , i.e. , diuretic first or nilvadipine first , had no influence on antihypertensive efficacy . The combination of calcium antagonist and diuretic was as effective as that of the calcium antagonist with enalapril BACKGROUND Blood pressure is a determinant of the risk of stroke among both hypertensive and non-hypertensive individuals with cerebrovascular disease . However , there is uncertainty about the efficacy and safety of blood-pressure-lowering treatments for many such patients . The perindopril protection against recurrent stroke study ( PROGRESS ) was design ed to determine the effects of a blood-pressure-lowering regimen in hypertensive and non-hypertensive patients with a history of stroke or transient ischaemic attack . METHODS 6105 individuals from 172 centres in Asia , Australasia , and Europe were r and omly assigned active treatment ( n=3051 ) or placebo ( n=3054 ) . Active treatment comprised a flexible regimen based on the angiotensin- converting-enzyme inhibitor perindopril ( 4 mg daily ) , with the addition of the diuretic indapamide at the discretion of treating physicians . The primary outcome was total stroke ( fatal or non-fatal ) . Analysis was by intention to treat . FINDINGS Over 4 years of follow up , active treatment reduced blood pressure by 9/4 mm Hg . 307 ( 10 % ) individuals assigned active treatment suffered a stroke , compared with 420 ( 14 % ) assigned placebo ( relative risk reduction 28 % [ 95 % CI 17 - 38 ] , p<0.0001 ) . Active treatment also reduced the risk of total major vascular events ( 26 % [ 16 - 34 ] ) . There were similar reductions in the risk of stroke in hypertensive and non-hypertensive subgroups ( all p<0.01 ) . Combination therapy with perindopril plus indapamide reduced blood pressure by 12/5 mm Hg and stroke risk by 43 % ( 30 - 54 ) . Single-drug therapy reduced blood pressure by 5/3 mm Hg and produced no discernable reduction in the risk of stroke . INTERPRETATION This blood-pressure-lowering regimen reduced the risk of stroke among both hypertensive and non-hypertensive individuals with a history of stroke or transient ischaemic attack . Combination therapy with perindopril and indapamide produced larger blood pressure reductions and larger risk reductions than did single drug therapy with perindopril alone . Treatment with these two agents should now be considered routinely for patients with a history of stroke or transient ischaemic attack , irrespective of their blood pressure Summary 116 patients from 4 clinics participated in a double blind study to assess the efficacy of ( BAYl 5240 ) , a nifedipine-acebutolol fixed combination ( 10 mg+100 mg ) , as compared to nifedipine 20 mg in essential hypertension . During the 10 week study , the mean recumbent blood pressure decreased 1 to 3 h after treatment from 175.5/105.2 to 148.3/88.0 mmHg in the BAY1 5240 group and from 174.3/102.9 to 150.3/86.5 mmHg in the nifedipine group . The results also showed a comparable decrease in the mean systolic ( SBP ) and diastolic ( DBP ) blood pressures before treatment ( 24 h after last tablet ) and after physical exertion before and after either drug given for 4 weeks . Doubling of the dose for 4 additional weeks produced a moderate and similar additional decrease in blood pressure . The results show the possibility of treating essential hypertension with a low dose of a beta-adrenergic blocking agent in combination with 10 mg nifedipine . Both regimens were well tolerated . One patient in the BAYl 5240 group and 2 in the nifedipine group , all treated by the same investigator , were withdrawn from the study because of headache during the nifedipine pre-period BACKGROUND Proteinuria predicts renal disease progression , and its reduction by angiotensin-converting enzyme inhibitors ( ACEi ) or angiotensin II receptor antagonists ( ARA ) is renoprotective . METHODS In this prospect i ve , r and omized , cross-over study of 24 patients with nondiabetic , chronic nephropathies , we compared the effects on proteinuria , renal hemodynamics , and glomerular permselectivity of 8 weeks with comparable blood pressure control achieved by benazepril ( 10 mg/day ) and valsartan ( 80 mg/day ) combined therapy with those achieved by benazepril ( 20 mg/day ) or valsartan ( 160 mg/day ) alone . RESULTS Despite comparable changes in blood pressure and glomerular filtration rate ( GFR ) , combined therapy decreased proteinuria more than benazepril ( -56 % vs. -45.9 % , P=0.02 ) and valsartan ( -41.5 % , P=0.002 ) . Changes in urinary protein to creatinine ratio followed the same trend . Filtration fraction and renal vascular resistances ( RVR ) decreased more with combined ( -14.7%,-23.7 % ) or benazepril ( -12.4 % , -20.5 % ) than with valsartan ( -2.7 % , -12.5 % , P < 0.05 vs. both ) . RVR changes , adjusted for GFR changes , were associated with those in proteinuria ( P < 0.05 ) . Changes in glomerular permeability were comparable and did not predict different changes in proteinuria in the three groups . CONCLUSION At comparable blood pressure , combined ACEi and ARA decreased proteinuria better than ACEi and ARA . The greater antiproteinuric effect most likely depended on an ACEi-related hemodynamic effect , in addition to glomerular size selectivity amelioration . Long-term combined ACEi and ARA therapy may be more renoprotective than treatment with each agent alone This double-blind , placebo-controlled , four-way balanced design crossover study included hypertensive patients aged 60–85 years with mean office-measured sitting systolic blood pressure ( SBP ) 160–179 mm Hg and daytime SBP ⩾135 mm Hg . After a 2-week run-in period , during which previous medications were discontinued , each patient received the following four treatments in r and omized order for 4 weeks each : lercanidipine 10 mg ( L ) , enalapril 20 mg ( E ) , lercanidipine 10 mg plus enalapril 20 mg ( L/E ) and placebo ( P ) . At the end of each treatment period , office trough blood pressure ( BP ) was measured and a 24-h Ambulatory Blood Pressure Monitoring ( ABPM ) was performed . Seventy-five patients ( mean age 66 years , office BP 168/92 mm Hg , daytime SBP 151 mm Hg ) were r and omized and 62 completed the study with four valid post-baseline ABPMs . The administration of P , L , E and L/E was associated with a mean 24-h SBP of 144 , 137 , 133 and 127 mm Hg , respectively . All active treatments significantly reduced the mean 24-h SBP in comparison with placebo , but L/E was significantly more effective than L and E alone . Similarly , office SBP was significantly more reduced with L/E ( −16.9 mm Hg ) than with L ( −5.0 mm Hg ) or E ( −5.9 mm Hg ) . A BP < 140/90 mm Hg was recorded in 18 % of patients with L , 19 % with E and 45 % with L/E. Two patients on P and two on L/E were withdrawn from the study due to adverse events . In conclusion , combination therapy with L/E  has additive antihypertensive effects on both ambulatory and office BP in elderly patients and is well tolerated BACKGROUND The effect on endothelium-dependent and independent vasodilation of 24-week treatment with a fixed-dose combination of perindopril/indapamide ( 2/0.625 mg , daily ) and atenolol ( 50 mg , daily ) , was evaluated in 62 untreated essential hypertensive patients according a double-blind , parallel group , r and omized study . METHODS Brachial artery flow-mediated dilation ( FMD ) , response to sublingual glyceril trinitrate ( GTN , 25 microg ) and to cold pressor test ( CPT )  were measured at baseline and after treatments at 12 and 24 weeks , as change in diameter from ultrasound scans by a computerized system . RESULTS Blood pressure ( BP ) was ( P < 0.001 ) reduced in both groups , but to a greater ( P < 0.01 ) extent in the perindopril/indapamide group . After 24 weeks , FMD was significantly increased ( P < 0.01 ) by perindopril/indapamide ( from 5.0 + /- 2.1 to 6.0 + /- 1.7 % ) but not by atenolol ( from 5.1 + /- 1.8 to 5.5 + /- 1.8 % ) . Improvement in FMD was not statistically related to BP reduction . Response to GTN was also significantly ( P < 0.05 ) increased by perindopril/indapamide ( from 6.2 + /- 1.9 to 6.9 + /- 1.7 % ) , but not by atenolol ( from 6.1 + /- 2.8 to 6.6 + /- 2.6 % ) . Improvement in GTN response was significantly ( P < 0.05 ) related to BP reduction . Response to CPT was significantly increased ( P < 0.001 ) by perindopril/indapamide after 12 and 24 weeks , whereas  atenolol  significantly ( P < 0.05 ) improved it only after 24 weeks . CONCLUSIONS Treatment with perindopril/indapamide improves endothelium-dependent vasodilation in comparison with atenolol . This improvement was observed without significant relations with BP changes , suggesting a pressure-independent effect . Improvement in endothelium-independent and sympathetic-associated vasodilation was also observed . These results suggests that long term therapy with a fixed-dose combination of perindopril/indapamide affords vascular protection in hypertensive patients Objective : To see whether low dose thiazide diuretics given to patients with essential hypertension might avoid the adverse metabolic consequences seen with conventional doses . Design : Double blind r and omised crossover study of two 12 week treatment periods with either low dose ( 1.25 mg ) or conventional dose ( 5.0 mg ) bendrofluazide given after a six week placebo run in period . Setting : Outpatient clinics serving the greater Belfast area . Subjects : 16 white non-diabetic patients ( 9 male ) under 65 with essential hypertension recruited from general practice s within the greater Belfast area . Main outcome measures : Systolic and diastolic blood pressure and peripheral and hepatic insulin action . Results : One man failed to complete the study . There were no differences between doses in their effects on systolic and diastolic blood pressure .  Bendrofluazide 1.25 mg had substantially less effect20on serum potassium concentration than the 5.0 mg dose . There were no intertreatment differences in fasting glucose , insulin , cholesterol , and triglyceride concentrations .  Bendrofluazide 5.0 mg significantly increased postabsorptive endogenous glucose production compared with baseline ( mean 10.9 ( SD 1.2 ) v 10.0 ( 0.8 ) μmol/kg/min ) , whereas bendrofluazide 1.25 mg did not . Postabsorptive endogenous glucose20production was significantly higher with bendrofluazide 5.0 mg compared with 1.25 mg ( 10.9 ( 1.2 ) v 9.9 ( 0.8 ) μmol/kg/min ) but was suppressed to a similar extent after insulin ( bendrofluazide 5.0 mg202.8 ( 1.5 ) μmol/kg/min v bendrofluazide 1.25 mg 2.2 ( 1.5 ) μmol/kg/min ) . Exogenous glucose infusion rates required to maintain euglycaemia were not significantly different between doses and were20similar to baseline . Conclusions : Bendrofluazide 1.25 mg is as effective as conventional doses but has less adverse metabolic effect . In contrast with conventional doses , how dose bendrofluazide has no effect on hepatic insulin action . There is no difference between low and conventional doses of bendrofluazide in their effect on peripheral insulin sensitivity BACKGROUND The objective of this prospect i ve , r and omized , open-label , blinded-endpoint study was to compare the antihypertensive efficacy of valsartan 80 mg v irbesartan 150 mg when combined with hydrochlorothiazide ( HCTZ ) 12.5 mg . METHODS Untreated or uncontrolled hypertensive adults ( n = 800 ) were enrolled by primary care physicians . After a 5-week open-label lead-in phase in which all patients received 12.5 mg HCTZ once daily , subjects whose blood pressure ( BP ) remained uncontrolled were r and omized ( n = 464 ) to valsartan/HCTZ ( 80/12.5 mg ) or irbesartan/HCTZ ( 150/12.5 mg ) for 8 weeks .  Home BP monitoring ( HBPM ) was performed in the morning and in the evening for 5 days , at baseline , and after 8 weeks . Office BP measurements were obtained at baseline and after 8 weeks . RESULTS Irbesartan/HCTZ produced greater reductions in average systolic BP ( SBP ) and diastolic BP ( DBP ) measured by HBPM than valsartan/HCTZ ( SBP : -13.0 v -10.6 mm Hg , P = .0094 ; DBP : -9.5 v -7.4 mm Hg , P = .0007 ) . These differences were more pronounced in the morning ( trough ) than in the evening . Office BP measurements also showed greater reductions in trough seated SBP and DBP with irbesartan/HCTZ compared with valsartan/HCTZ . Normalization rates observed with HBPM ( SBP < 135 mm Hg and DBP < 85 mm Hg ) were significantly greater with irbesartan/HCTZ than with valsartan/HCTZ ( 50.2 v 33.2 % ; P = .0003 ) . The overall safety was similar in the two groups . CONCLUSIONS The superior BP-lowering potency of the fixed combination irbesartan/HCTZ ( 150/12.5 mg ) over valsartan/HCTZ ( 80/12.5 mg ) , evidence d independently from the investigators by HBPM , supports the use of this technique in trials with prospect i ve , r and omized , open-label , blinded-endpoint design BACKGROUND Antihypertensive agents differentially influence the plasma adiponectin concentration and the effects of fixed-dose combination regimens remain unclear . The influence of a combination of an angiotensin-converting enzyme inhibitor ( ACEI ) and a thiazide-type diuretic or an ACEI alone on plasma adiponectin concentrations in patients with essential hypertension was evaluated in the present study . METHODS AND RESULTS After a 2-week placebo run-in phase , 30 patients with essential hypertension were r and omized to receive preterax ( 2 mg perindopril/0.625 mg indapamide ) or cilazapril ( 2.5 mg ) once daily for 12 weeks . Plasma adiponectin and insulin concentrations were measured before and after treatment . Insulin resistance was measured by homeostasis assessment index ( HOMA-IR ) . Treatment with preterax ( P=0.003 ) and cilazapril ( P=0.031 ) significantly reduced systolic blood pressure ( BP ) , but only preterax reduced diastolic BP ( P=0.024 ) . Cilazapril treatment significantly increased the plasma adiponectin concentration ( P=0.025 ) and reduced plasma triglycerides ( P=0.041 ) , whereas preterax treatment increased the plasma insulin concentration ( P=0.041 ) and tended to increase HOMA-IR . CONCLUSIONS The combination of an ACEI and indapamide improved BP control , but attenuated the beneficial effects of ACE inhibition on plasma adiponectin in patients with essential hypertension . Such a combination may be best reserved for improved BP control rather than for metabolic protection in clinical hypertension OBJECTIVE 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 . RESEARCH DESIGN AND METHODS 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 ) . RESULTS 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 h and , 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 . CONCLUSIONS 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 The objective of this Phase III double-blind parallel-group controlled study was to examine the superiority of amlodipine 10 mg once daily ( the amlodipine 10 mg group ) to amlodipine 5 mg once daily ( the amlodipine 5 mg group ) in 305 Japanese out patients with essential hypertension whose systolic blood pressure ( SBP ) had not reached the therapeutic target levels ( < 130–140/80–90 mm Hg ) when treated with amlodipine 5 mg once daily . This study consisted of the 1-week prescreening , 8-week screening and 8-week double-blind periods . Changes in trough SBP from baseline at week 8 of the double-blind period ( week 8) were −7.0 mm Hg and −13.7 mm Hg in the amlodipine 5 and 10 mg groups , respectively ; a significant difference ( P<0.001 ) was found between the two groups . Changes in trough diastolic blood pressure ( DBP ) from baseline at week 8 were −2.7 mm Hg and −6.8 mm Hg in the amlodipine 5 and 10 mg groups , respectively , with a significant difference ( P<0.001 ) between the two groups . At week 8 , responder rates were 28.5 and 44.0 % in the amlodipine 5 mg and 10 mg groups , respectively , with a significant difference ( P=0.002 ) between the two groups . The amlodipine 10 mg group showed no significant difference in the incidences of adverse events against the amlodipine 5 mg group . The incidence of mild peripheral oedema was 4 % only in the amlodipine 10 mg group . In conclusion , amlodipine 10 mg once daily was found to be superior to amlodipine 5 mg once daily , safe , well tolerated and useful for the relevant subjects Anti-hypertensive medication with an angiotensin II receptor blocker ( ARB ) is effective in slowing the progression of chronic kidney disease . The present study was design ed to investigate whether calcium channel blockers ( CCBs ) in combination with an ARB differentially affect kidney function . Elderly hypertensive patients with chronic kidney disease ( n = 17 , 72 ± 6 years old ) were instructed to self-measure blood pressure . They were r and omly assigned to receive either benidipine ( 4–8 mg/day ) or amlodipine ( 5–10 mg/day ) combined with olmesartan ( 10 mg/day ) . After 3 months , CCBs were switched in each patient and the same protocol was applied for another 3 months . At baseline , significant correlation was obtained between urine albumin ( 22.8 ± 16.7 ( median ± median absolute deviation ) mg/g creatinine ) and self-measured blood pressure ( 170 ± 23/87 ± 10 ( mean ± SD ) mmHg , r = 0.65 , p < 0.01 ) . Both regimens reduced blood pressure to a similar extent ( 139 ± 22/75 ± 11 mmHg and 133 ± 17/72 ± 10 mmHg , respectively ; both p < 0.001 ) , while urine albumin decreased only after combination therapy including benidipine ( 11.7 ± 6.1 mg/g creatinine , p < 0.05 ) . Benidipine , but not amlodipine , in combination with olmesartan , reduced urinary albumin excretion in elderly hypertensive patients with chronic kidney disease . The results suggest the importance of selecting medications used in combination with ARB in hypertensive patients with chronic kidney disease Objective To compare the incidence of stroke and other cardiovascular events in hypertensive patients receiving a low-dose diuretic and low-dose calcium antagonist combination with those receiving low-dose diuretic monotherapy  , and assess the effects of a small blood pressure difference at achieved levels lower than those achieved in previous placebo-controlled trials . Methods The Felodipine Event Reduction ( FEVER ) trial was an investigator- design ed , prospect i ve , multicentre , double-blind , r and omized , placebo-controlled , parallel group trial . It enrolled 9800 Chinese patients , of either sex , aged 50–79 years , with one or two additional cardiovascular risk factors or disease , whose blood pressure , 6 weeks after switching from previous antihypertensive therapy to low-dose ( 12.5 mg a day ) hydrochlorothiazide , was in the range 140–180 mmHg ( systolic ) or 90–100 mmHg ( diastolic ) . These patients were r and omly assigned either to low-dose felodipine extended release or placebo , and followed at 3-month intervals for an average of 40 months . Results The intention-to-treat analysis included 9711 r and omly selected patients with only 30 ( 0.3 % ) lost to follow-up . A total of 31 842 patient-years of follow-up were accumulated , with 85.9 % of patients remaining on blinded r and omized treatment . Add-on therapy was given to 33.9 % of the hydrochlorothiazide – felodipine patients and to 42.3 % of the hydrochlorothiazide – placebo patients . In the felodipine  group , systolic blood pressure (SBP)/diastolic blood pressure ( DBP ) decreased ( from r and omization to study end ) from 154.2/91.0 to 137.3/82.5 mmHg , and in the placebo group from 154.4/91.3 to 142.5/85.0 mmHg , with an average difference throughout the trial of 4.2/2.1 mmHg . In the felodipine group , the primary endpoint ( fatal and non-fatal stroke ) was reduced by 27 % ( P = 0.001 ) . Among secondary endpoints , all cardiovascular events were reduced by 27 % ( P < 0.001 ) , all cardiac events by 35 % ( P = 0.012 ) , death by any cause by 31 % ( P = 0.006 ) , coronary events by 32 % ( P = 0.024 ) , heart failure by 30 % ( P = 0.239 ) , cardiovascular death by 33 % ( P = 0.019 ) , cancer by 36 % ( P = 0.017 ) in the felodipine group . No significant differences were found in new-onset diabetes . Both treatments were very well tolerated . Conclusions In moderately complicated hypertensive patients from China even a difference in SBP/DBP as small as 4/2 mmHg , such as that induced by adding low-dose felodipine to low-dose hydrochlorothiazide , is associated with very substantial reductions in the incidence of most types of cardiovascular events . As the SBP achieved in the felodipine group was below the recommended goal of less than 140 mmHg , and SBP in the placebo group was slightly above that level , FEVER provides the required evidence in support of the guidelines recommended goal , even for a hypertensive population not entirely consisting of patients with diabetes or previous cardiovascular events Angiotensin converting enzyme inhibitors ( ACE-Is ) and angiotensin II receptor blockers ( ARBs ) are frequently used for the treatment for glomerulonephritis and diabetic nephropathy because of their albuminuria- or proteinuria-reducing effects . To many patients who are nonresponsive to monotherapy with these agents , combination therapy appears to be a good treatment option . In the present study , we examined the effects of the addition of an ARB ( losartan ) followed by titration upon addition and at 3 and 6 months ( n=14 ) and the addition of an ACE-I followed by titration upon addition and at 3 and 6 months ( n=20 ) to the drug regimen treatment protocol in type 2 diabetic patients with nephropathy for whom more than 3-month administration of an ACE-I or the combination of an ACE-I plus a conventional antihypertensive was ineffective to achieve a blood pressure ( BP ) of 130/80 mmHg and to reduce urinary albumin to < 30 mg/day . During the 12-month treatment , addition of losartan or addition of an ACE-I to the treatment protocol reduced systolic blood pressure ( SBP ) by 10 % and 12 % , diastolic blood pressure ( DBP ) by 7 % and 4 % , and urinary albumin excretion by 38 % and 20 % of the baseline value , respectively . However , the effects on both BP and urinary albumin were not significantly different between the two therapies . In conclusion , addition of losartan or an ACE-I to an ongoing treatment with an ACE-I , or addition of an ACE-I to ongoing treatment with a conventional antihypertensive were equally effective at reducing the urinary albumin excretion and BP , and provided renal protection in patients with type-2 diabetic nephropathy The blood pressure response to a new sustained-release formulation of nifedipine was evaluated in an 8-week , double-blind , placebo-controlled study . Twenty-nine patients with mild essential hypertension were r and omized to receive placebo ( N = 9 ) , 30 mg nifedipine ( N = 10 ) , or 60 mg nifedipine ( N = 10 ) . During treatment , 30-mg and 60-mg doses of nifedipine administered once daily decreased office blood pressures from 137/98 + /- 8/2 mm Hg and 141/98 + /- 15/2 mm Hg at baseline , respectively , to 126/89 + /- 9/7 mm Hg and 126/86 + /- 6/7 mm Hg ( P less than .005 ) . Noninvasive automatic ambulatory blood pressure monitoring demonstrated a marginally significant ( P less than .10 ) reduction in the mean 24-hour blood pressure of 2/6 + /- 8/8 mm Hg and 5/6 + /- 9/9 mm Hg for patients taking 30 mg and 60 mg nifedipine once daily , respectively . Diastolic blood pressure load ( the percentage of ambulatory diastolic blood pressure readings greater than 90 mm Hg ) during 24 hours was decreased by 41 % and 35 % , with 30 mg and 60 mg nifedipine administered once daily , respectively . No significant dose response to nifedipine at these dose levels was observed . Although the once-daily formulation of nifedipine achieved effective control of office blood pressure , similar control was not observed in awake and 24-hour periods in all patients Summary General well-being , adverse effects and antihypertensive efficacy have been investigated in a double blind , parallel-group , dose-response multicentre study of diltiazem and metoprolol monotherapy for hypertension . 128 patients with primary hypertension were included from 10 participating centres . The patients were r and omized to receive oral diltiazem 120–240–360 mg/day or metoprolol 50–100–200 mg/day . Each dose was given for a 4-week period as a forced titration regime . In all 119 patients , 59 and 60 , respectively , on diltiazem and metoprolol completed the study protocol . There were dose-dependent reductions in supine and st and ing blood pressures ( BP ) after both diltiazem and metoprolol therapy . In the diltiazem group , supine BP was reduced by 10 (11)/10 ( 6 ) mm Hg ( SBP/DBP ) at the highest dose level , and the corresponding values for the metoprolol group were 7 (16)/8 ( 9 ) mm Hg ( SBP/DBP ) . Target pressures ( DBP ≤ 90 mm Hg and /or a reduction in DBP of ≥ 10 % ) were reached in 63 % and 48 % of the patients , respectively . The incidence and severity of dose-dependent adverse effects , as evaluated by spontaneous reports or open and direct question ing , did not differ between treatments . Subjective well-being , evaluated by a self-administered question naire , the MSE-profile , did not differ significantly between diltiazem and metoprolol therapy . However , after an initial slight deterioration , contentment and vitality tended to improve with increasing doses of diltiazem , while a dose-related deterioration in these variables was observed on metoprolol therapy . At the highest dose levels , contentment and vitality tended to be better in the diltiazem than the metoprolol group . Thus , diltiazem and metoprolol in daily doses of 120–360 mg and 50–200 mg , respectively , produce comparable and parallel reductions in supine and st and ing BP . However , while subjective well-being tended to improve with increasing doses of diltiazem , there was a negative trend for metoprolol . It is concluded that diltiazem , given as monotherapy to hypertensive patients , does not impair subjective well-being Abstract We compared the efficacy of treatment protocol s 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 prospect i ve , r and omized 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 r and omly into one of the protocol s which consisted of treatment with 5 mg enalapril daily ( group 1 ; n=12 ) , 50 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 A large proportion of patients with hypertension need a second drug to reach satisfactory control of blood pressure ( BP ) , but there are few well- design ed controlled trials comparing the efficacy of drugs added as a second option . In a double-blind r and omized clinical trial , 82 patients with uncontrolled BP , receiving hydrochlorothiazide 25 mg daily , were selected to receive amiloride 2.5–5 mg/day ( n = 39 ) or enalapril 10–20 mg/day ( n = 43 ) .  Ambulatory blood pressure monitoring ( ABPM ) was done before and after 12-weeks of treatment . Office BP was measured in the 4th , 8th , and 12th weeks . The doses of amiloride and enalapril were doubled in the fourth week , and propranolol was added in the 8th week if office BP was above 140/90 mm Hg . There was a greater BP reduction in patients treated with enalapril . The ABPM δ values between the groups were 3.6 ± 2.2 , 3.9 ± 2.2 , and 1.1 ± 2.7 mmHg for 24-h , daily , and nightly systolic blood pressure , respectively , favoring enalapril . For diastolic blood pressure ( DBP ) , the deltas were 1.7 ± 2.0 , 3.2 ± 1.5 , and 1.2 ± 1.9 mmHg , respectively ( p = 0.039 for daily DBP ) . Office SBP decreased more and sooner in patients allocated to enalapril ( p = 0.003 ) . More patients taking amiloride required propranolol to control BP ( p = 0.035 ) . Potassium increased 0.3 mEq/L on the average in both groups . Cough , albeit predominantly mild , was reported more frequently by participants treated with enalapril . We conclude that enalapril is more effective than amiloride to lower BP of patients on hydrochlorothiazide with uncontrolled BP . Trial registration : Clinical Trials.gov identifier : NCT00394394 Aim : To review the efficacy and safety of losartan and hydrochlorothiazide compared to losartan alone , hydrochlorothiazide alone or placebo in the treatment of mild to moderate hypertension in a clinical trial Patients and methods : A r and omly allocated , placebo-controlled , double-blind parallel study was performed in 40 clinical centers throughout the United States . A total of 703 males and females aged 18–75 years with a sitting diastolic blood pressure of 95–115 mmHg entered the trial and 604 completed the 12-week protocol . The participants were r and omly assigned to concomitant therapy once a day with : ( 1 ) 50 mg losartan and 6.25 mg hydrochlorothiazide , ( 2 ) 50 mg losartan and 12.5 mg hydrochlorothiazide , ( 3 ) 50 mg losartan alone , ( 4 ) 12.5 mg hydrochlorothiazide alone or ( 5 ) placebo . All participants were followed for 12 weeks Results : At baseline , mean trough sitting diastolic blood pressure was 100.9 - 101.7 mmHg , with no significant difference between treatment groups . Sitting diastolic blood pressure fell 4.0 mmHg with placebo , 7.2 mmHg with 12.5 mg hydrochlorothiazide , 7.2 mmHg with 50 mg losartan , 9.3 mmHg with 50 mg losartan + 6.25 mg hydrochlorothiazide , and 13.2 mmHg with 50 mg losartan + 12.5 mg hydrochlorothiazide .  The fall in mean trough sitting systolic blood pressure was 2.4 , 9.3 , 10.7 , 12.0 and 17.9 mmHg for the respective groups . After subtracting the placebo effect , the reductions in blood pressure induced by losartan and hydrochlorothiazide were additive for both sitting diastolic and systolic blood pressures and approximately equaled the reduction seen with the combination of losartan and hydrochlorothiazide . There were no significant differences in adverse events between treatment groups Conclusions : The concomitant administration of 50 mg losartan + 12.5 mg hydrochlorothiazide produced additive falls in sitting diastolic and systolic blood pressures which were greater than that achieved with either drug alone . On the basis of the adverse effects reported , the combination was well The antihypertensive effect of doxazosin 1 - 16 mg once-daily was compared with that of atenolol 50 - 100 mg once-daily , and placebo , utilizing a double-blind parallel group ( 12 patients each ) design . Blood pressure ( BP ) and pulse rate were determined in out- patients who returned for clinic visits every 2 weeks for 14 weeks . During the first 4 weeks , all patients received single-blind placebo therapy . During the subsequent 10 weeks , patients were r and omized to placebo , atenolol or doxazosin treatment . After 2 weeks of doxazosin therapy 16 mg daily , there was a significant decrease from baseline ( single-blind placebo period ) in supine diastolic BP ( P less than 0.01 ) and st and ing diastolic BP ( P less than 0.001 ) . The decreases in supine and st and ing diastolic BPs in the doxazosin 16 mg daily group were significantly ( P less than 0.01 ) different from the corresponding BPs of the placebo group . At weeks 12 and 14 , heart rates in the doxazosin group were not significantly different from baseline or from those in the placebo group . After 4 and 6 weeks of atenolol 100 mg daily , there was a significant decrease from baseline in both supine ( P less than 0.001 and P less than 0.05 ) and st and ing ( P less than 0.05 ) diastolic BPs and heart rates ( P less than 0.05 ) . However , when the atenolol group was compared with the placebo group , a significant decrease occurred only with supine diastolic BP at week 12 ( P less than 0.01 ) and not at week 14 ; but significant decreases occurred in supine and st and ing heart rates at weeks 12 and 14 ( P less than 0.05 ) . ( ABSTRACT TRUNCATED AT 250 WORDS To achieve the target blood pressure recommended by the latest guidelines , multiple antihypertensive drugs are needed in most patients . In this study , the efficacy of treatment using an angiotensin II receptor antagonist ( ARB ) combined with a calcium channel blocker ( CCB ) or a diuretic was compared from multiple perspectives in patients with hypertension . Twenty-nine patients with essential hypertension , who had failed to achieve their target blood pressure ( < 130/85 mm Hg for patients < 65 years old and < 140/90 mm Hg for those ⩾65 years ) when treated with the ARB olmesartan at 20 mg day−1 , were additionally given 8–16 mg day−1 of the CCB azelnidipine or 1–2 mg day−1 of trichlormethiazide ( a thiazide diuretic ) in a r and omized crossover manner for 4 months each . At the end of each combination therapy period , blood and urine sample s were collected and arterial stiffness was evaluated by measuring the cardio-ankle pulse wave velocity . Compared with monotherapy , the blood pressure was reduced similarly by adding azelnidipine ( −12/−10 mm Hg ) or trichlormethiazide ( −14/−9 mm Hg ) . The heart rate was decreased with the CCB by 4 b.p.m . ( P<0.05 ) , whereas it was unchanged with the thiazide . Serum K , lipids and blood glucose were not significantly changed with either combination , whereas serum uric acid was increased with the thiazide ( P<0.01 ) but was unchanged with azelnidipine  . Plasma levels of renin , angiotensin II and aldosterone were also increased with the thiazide period , whereas high-sensitivity C-reactive protein and oxidized low-density lipoprotein were decreased with azelnidipine . In addition , the cardio-ankle vascular index , a parameter of arterial stiffness , was decreased with the azelnidipine period but was unchanged with the thiazide period ( P<0.01 ) . It is suggested that the combination of olmesartan and azelnidipine has advantages over the combination of olmesartan and a thiazide with respect to avoiding hyperuricemia , sympathetic activation , renin – angiotensin-aldosterone system stimulation , inflammation , oxidative stress , and increased arterial stiffness in patients with moderate hypertension . These properties may provide cardiovascular protection in addition to the hypotensive effect The effect of nicardipine hydrochloride , a calcium-channel blocking agent , was studied in 46 patients with stable angina in a double-blind , placebo-controlled , r and omized , repeated cross-over protocol , using a 30 or 40 mg dose of nicardipine or placebo three times a day . Mean resting heart rate and blood pressure did not change significantly with 30 mg nicardipine ;  heart rate increased from 81 + /- 10 to 88 + /- 13 beats min-1 , systolic blood pressure decreased from 129 + /- 18 to 119 + /- 16 mmHg , and diastolic blood pressure from 81 + /- 12 to 74 + /- 11 mmHg ( P less than 0.01 for all three variables ) with a 40 mg dose . Using a treadmill exercise protocol , mean exercise duration increased from 5.4 + /- 1.8 to 6.0 + /- 1.8 min ( P less than 0.01 ) with 30 mg nicardipine , and from 5.8 + /- 1.7 to 6.6 + /- 1.9 min ( P less than 0.01 ) with 40 mg . Time to onset of angina increased from 4.6 + /- 1.9 to 5.2 + /- 1.7 min ( P less than 0.05 ) with 30 mg and from 5.1 + /- 1.8 to 5.7 + /- 1.8 min ( P = NS ) with 40 mg . Mean anginal frequency and sublingual nitroglycerin consumption were low during the cross-over placebo period and did not change significantly during therapy with nicardipine .  Non-cardiac side-effects were mild and required the withdrawal of only one patient from the study . However , during nicardipine therapy four patients had unstable angina and two developed a non-Q wave myocardial infa rct ion . Of these patients , five were receiving a beta-adrenergic blocker that was discontinued prior to the study . ( ABSTRACT TRUNCATED AT 250 WORDS In 2004–2005 , the antihypertensive effects of telmisartan 80 mg versus valsartan 160 mg combined with hydrochlorothiazide 25 mg were assessed in a large placebo-controlled trial in patients with stages 1 and 2 hypertension and demonstrated that both agents were highly effective in lowering blood pressure ( BP ) compared with placebo and that telmisartan lowered BP significantly greater than valsartan . To confirm this finding according to Food and Drug Administration guidelines , we performed a second large trial using the same design in an entirely separate patient population . The trial was double-blind with a 4 : 4 : 1 r and omization scheme to compare once daily telmisartan 80 mg plus hydrochlorothiazide 25 mg versus once daily valsartan 160 mg plus hydrochlorothiazide 25 mg versus once daily placebo on reductions in seated clinic BP in patients with stages 1 and 2 hypertension . The primary endpoints were the changes from baseline in seated diastolic and systolic BP at the end of the 8-week treatment period . Safety endpoints included adverse events , changes in laboratory parameters and pulse rate . In total , 1185 patients were r and omized ( of which 1181 were treated and included in the primary analysis : 528 in the  telmisartan-hydrochlorothiazide  group , 523 in the valsartan-hydrochlorothiazide group , and 130 in the placebo group ) , changes from baseline in BP  following telmisartan-hydrochlorothiazide ( −24.6/−18.2 mmHg ) were significantly greater than both placebo ( −4.1/−6.1 mmHg ) and valsartan-hydrochlorthiazide ( −22.5/−17.0 mmHg ) ( versus placebo , P<0.0001 for systolic and diastolic BP ; versus valsartan-hydrochlorothiazide , P=0.017 for systolic BP and P=0.025 for diastolic BP ) . The total number of patients with at least one adverse event reported was similar among the three treatment groups ( placebo , 42 % , telmisartan-hydrochlorothiazide , 36 % , and valsartan-hydrochlorothiazide , 37 % ) . Thus , this large , second trial confirms that telmisartan-hydrochlorothiazide at doses of 80/25 mg lowered both systolic and diastolic BP to a greater extent than valsartan-hydrochlorothiazide at doses of 160/25 mg in stages 1–2 hypertension . Although these are not the highest doses of these agents at present , at the time that the studies were conducted , they were the maximally approved dosages . Both studies support the strategy of using angiotensin receptor blockers with a higher dose of a thazide diuretic ( 25 mg ) for enhancing the control of hypertension Summary The effect of beta-adrenergic blockade on blood pressure variation was studied in ten patients with moderate hypertension .  Supine systolic and diastolic blood pressures were measured every 5 min during six hours sessions , using an ultrasonic method . Systolic and diastolic variation in each six hour session was defined as the st and ard deviation of the mean of systolic and diastolic readings made in that period . After 3 weeks of single-blind placebo , a 12 week double-blind r and omized crossover study was initiated with placebo ( 6 weeks ) and atenolol ( 100 mg b. i. d. for 3 weeks and 200 mg b. i. d. for 3 weeks ) . Systolic and diastolic blood pressure and heart rate decreased significantly ( p<0.01 ) during atenolol treatment . Diastolic variation did not change significantly , whereas systolic variation decreased slightly but significantly ( p<0.05 ) when expressed in absolute values , but not when expressed as a percentage of systolic blood pressure . It is concluded that beta-adrenergic blockade decreases blood pressure and heart rate without causing significant changes in spontaneous systolic or diastolic Our previous studies have shown that blood pressure variability is not linked to activity of the adrenergic nervous system but that a small part of the variation is due to vagal nervous tone . The present work investigates whether myogenic activity of blood vessels could be responsible for the blood pressure variations . To test this hypothesis , variability was measured before and after administration of nifedipine , known to decrease spontaneous vascular contractions . In 17 patients with moderate essential hypertension , blood pressure was measured every 30 min for 12 h with a device recording Korotkoff 's sounds on tape . Blood pressure variability was defined as the st and ard deviation of the mean of all readings . Placebo , nifedipine ( 20 mg b.i.d . in a slow-release formulation ) alone and in combination with atenolol ( 50 mg b.i.d . ) , and atenolol alone were given double-blind for 3 weeks each . At the end of each period , a 12 h blood pressure profile was recorded . Systolic blood pressure significantly decreased with any of the drugs used ; the combination of nifedipine and atenolol caused a greater decrease than that of any of the drugs alone . Diastolic blood pressure only decreased with the combination of nifedipine and atenolol . Nifedipine did not cause significant changes in systolic or diastolic variability ; a small but nonsignificant decrease in diastolic variability was seen with atenolol and the combination of atenolol and nifedipine . The present data do not support the hypothesis that blood pressure variability is linked to myogenic vascular activity because no decrease in blood pressure variability was seen with nifedipine Objectives : To determine the blood pressure lowering effect and safety of losartan potassium 50 mg once or twice daily , or l00 mg once daily , using 24-h ambulatory blood pressure monitoring and conventional trough clinic blood pressure Design : Multicenter , double-blind , r and omized , parallel , placebo-controlled trial Setting : Nine sites in university hospitals and urban centers in the United States Patients : 122 mild to moderate hypertensive adult non-black men and women , 21 years of age and older , who were within 30 % of their ideal body weight Intervention : Qualification required a mean 24-h ambulatory blood pressure measurement of > 85 mmHg and a sitting diastolic blood pressure of 95–115 mmHg . Subjects were then r and omized to placebo or losartan potassium in three different dose regimens Clinic blood pressure evaluations : Trough blood pressure was measured by trained observers using st and ardized methods , and ambulatory blood pressure measurements were obtained for 26 h using a SpaceLabs Model 90207 monitor Results : All doses of losartan potassium significantly decreased mean systolic 24-h ambulatory blood pressure ( range –9.4 to –14.2 mmHg ; P<0.01 ) and mean diastolic 24-h ambulatory blood pressure ( range –5.6 to –9.0 mmHg ; P<0.01 ) compared with placebo . All decreases were significantly different from placebo . The 24-h blood pressure profiles revealed a smooth , sustained antihypertensive effect of losartan potassium at all doses . Similar reductions in blood pressure were observed using trough clinic measurements . There were no significant differences in overall clinical adverse experiences between treatment groups . There were no significant changes in heart rate , body weight , electrocardiograms or mean laboratory measurements Conclusions : Losartan potassium , the first of a new class of potent and specific AT1-selective , non-peptide , angiotensin II antagonists , significantly reduces mean 24-h ambulatory blood pressure and trough clinic sitting blood pressure , and is well Background : Combined regimen may be superior to monotherapy in blood pressure ( BP ) control . Since BP control is crit‐ically related to cardiovascular mortality and morbidity in hypertensive patients , this study aim ed to evaluate the efficacy and safety of a low‐dose combined regimen of preterax compared with cilazapril monotherapy for better BP control in treated hypertensive patients . Methods : Stable hypertensive patients were evaluated if their systolic BP ( SBP ) was > 130 mmHg and /or diastolic BP ( DBP ) was > 85 mmHg even with up to 2 antihypertensive drugs . Patients were excluded if they were on angiotensin‐converting enzyme inhibitors , angiotensin II receptor blockers or a diuretic . They were then r and omized to receive either preterax ( perindopril 2 mg and indapamide 0.625 mg ) or cilazapril 2.5 mg once daily in a double‐blind fashion for a period of 12 weeks after a 2‐week placebo run‐in phase . Sitting BP was recorded and the safety and efficacy were evaluated at each visit every 4 weeks . Response was defined as positive if SBP was ≤140 mmHg and DBP was ≤90 mmHg at the last visit or there was > 20 mmHg reduction in SBP and /or > 10 mmHg reduction in DBP using either treatment . Plasma biochemical analysis was performed both before and after the treatment . Results : Among the 47 patients initially enrolled , 41 completed the study ( 21 in the preterax group , 20 in the cilazapril group ) . There was no difference in the number of adverse events between the 2 groups . SBP was significantly reduced by preterax ( 13.43 ±12.48 mmHg , p < 0.0001 ) and cilazapril ( 9.00 ±13.75 mmHg , p < 0.05 ) . However , DBP was significantly reduced only by preterax ( 7.67 ±9.40 mmHg , p = 0.0009 ) but not by cilazapril ( 3.60 ±8.37 mmHg , p > 0.05 ) . The response rate was significantly higher to preterax ( 100 % ) than to cilazapril ( 70 % ) ( p = 0.0086 ) . Conclusion : Though similar in safety , combined regimen preterax was more effective than cilazapril to facilitate adequate BP control in already‐treated hypertensives . It can be added on to other antihypertensives for better BP control in clinical hypertension . [ J Chin Med Assoc 2008;71(5):247–253 Objective To determine the long-term efficacy and safety of a fixed , very-low-dose tablet combining one-half the st and ard dose of perindopril with one-quarter the st and ard dose of indapamide as first-line treatment in elderly patients . Design Double-blind , r and omized , placebo-controlled study in an outpatient setting . Patients and interventions Following a single-blind , placebo run-in period of 4 weeks , patients [ 65–85 years , with mild-to-moderate essential hypertension or isolated systolic hypertension ( ISH ) ] were r and omized to receive one tablet of perindopril 2 mg/indapamide 0.625 mg ( Per/ Ind ) ( n = 193 ) or placebo ( n = 190 ) , daily for 12 weeks . After this first 12-week period , all patients on Per/Ind ( n = 138 ) and patients responding to placebo ( n = 61 ) were maintained on their previous regimen for a further 48 weeks . Patients in the placebo group whose blood pressure was not normalized , were switched to Per/Ind ( n = 60 ) . Main outcome measure The primary endpoint was the proportion of patients with blood pressure that normalized between weeks 0 and 60 . Results After 1 year of treatment ( intention-to-treat ) supine systolic and diastolic blood pressure decreased by 23.0 ± 15.3 mmHg and 13.3 ± 9.4 mmHg with Per/Ind ( n = 253 : 193 from r and omized Per/Ind group and 60 from the placebo group switched at week 12 ) . The mean decreases in systolic blood pressure were similar in essential hypertension and ISH ( systolic blood pressure 23.2 versus 22.7 mmHg , respectively ) . Per/Ind treatment ( n = 253 ) achieved an initial normalization of blood pressure in 96.2 % [ 95 % confidence interval ( CI ) 93.6–98.9 % ; Kaplan-Meier estimate ] of Per/Ind-treated patients ; 79.8 % ( 95 % CI 74.1–85.5 % ) of these maintained a normalized blood pressure throughout the 1-year follow-up . The incidence of adverse events was similarly low in the placebo and active therapy groups . Efficacy and safety results for the over 75 years subgroup were similar to those for the younger elderly subjects Conclusions The fixed , very low-dose combination of perindopril 2 mg/indapamide 0.625 mg results in sustained blood pressure control when used as first line treatment of elderly hypertensive patients over 1-year , and is well-tolerated The purpose of this trial was to evaluate the antihypertensive efficacy of the concomitant administration of selected doses of hydrochlorothiazide ( HCTZ ) on a background of losartan potassium ( losartan ) 50 mg , a selective angiotensin II receptor antagonist . Patients with essential hypertension ( > or = 95 mmHg inclusion criteria ) with a mean sitting diastolic blood pressure ( SiDBP ) of 105 + /- 0.4 ( S.E. ) mmHg entered a 4-week , single-blind monotherapy period of losartan 50 mg once daily . At the end of the monotherapy period , patients whose blood pressure was adequately controlled were discontinued . Patients whose blood pressure was partially controlled based on a SiDBP > 92 mmHg entered a 12 week double-blind period and were r and omly assigned to either receive placebo ( n = 80 ) , HCTZ 6.25 mg ( n = 80 ) , HCTZ 12.5 mg ( n = 72 ) or HCTZ 25 mg ( n = 80 ) in addition to losartan 50 mg . During the losartan monotherapy period , there was a 4 mmHg fall in SiDBP with a further fall of 5 mmHg after 12 weeks of double-blind therapy in the losartan/placebo control group . Based on the between group differences in BP change from the end of the losartan monotherapy period ( baseline ) to end of 12 weeks of double-blind , the concomitant administration of a very low dose of HCTZ ( 6.25 mg ) with losartan did not significantly decrease SiDBP compared with the fall in blood pressure in the losartan/placebo control group ( diff . between groups = -2 ( 95 % C.I.[-4.1 , + 0.9 ] mmHg ) ) . However , the concomitant administration of HCTZ 12.5 or 25 mg with losartan 50 mg result ed in significantly different ( p < or = 0.05 ) reductions in diastolic blood pressure compared to the losartan/placebo group ( diff . between groups = -4 ( 95 % C.I. [ -6.3 , -1.1 ] mmHg ) for 12.5 mg combination group ; -6 ( 95 % C.I. [ -8.3 , -3.3 ] ) mmHg for the HCTZ 25 mg combination group ) . The proportions of patients treated with losartan plus HCTZ 12.5 mg or 25 mg that achieved a trough SiDBP < 88 mmHg or a trough SiDBP > or = 88 mmHg but with a decrease of at least 5 mmHg were 71 % and 83 % , respectively . The percentage of clinical adverse experiences that were considered drug-related as assessed by the investigator were generally similar across all treatment groups . There were no reports of orthostatic hypotension in any of the treatment groups . Changes in serum glucose , potassium and uric acid were not appreciably different amongst the treatment groups . In summary , in patients with predominantly moderate to severe essential hypertension , the addition of HCTZ 12.5 mg or 25 mg to losartan 50 mg produced effective control of blood pressure in a substantial majority of patients who only partially responded to losartan monotherapy . There were no differences amongst the treatment groups with respect to drug-related adverse experiences in this trial A two-centre , double-blind , placebo controlled , r and omized 3-way crossover study was undertaken to assess the efficacy , tolerability and safety of celiprolol in mild to moderate essential hypertension . A 4-week single-blind placebo run-in/screening period , during which no antihypertensive medication was given , was followed by 3 consecutive 4-week treatment periods with placebo or celiprolol ( 200 mg or 400 mg daily ) . At the end of the 4-week placebo run-in/screening period , 26 hospital out- patients with a seated mean blood pressure ( systolic/diastolic ) of 161.4/101.7 mmHg and a mean pulse rate of 75 beats/min entered the double-blind crossover phase of the study . Results showed that there was no significant difference in seated mean systolic or diastolic blood pressure between 200 mg celiprolol daily ( 149.2/92.3 mmHg ) and 400 mg celiprolol daily ( 149.1/92.5 mmHg ) . However , mean seated systolic and diastolic blood pressures were significantly ( p less than 0.05 ) lower on celiprolol than on placebo ( 157.1/98.2 mmHg ) . Neither dose of celiprolol had a significant effect on seated pulse rate . No patient was withdrawn due to an adverse event and no laboratory assessment outside the normal range was reported to be of any clinical significance . It is concluded that oral celiprolol , 200 mg or 400 mg daily , is effective and well tolerated for controlling mild to moderate essential hypertension . Since both doses had very similar effects on blood pressure there is no advantage in this group of patients for the 400 mg daily dose of celiprolol BACKGROUND Patients ( pts ) with stable coronary artery disease ( CAD ) can benefit from a decrease in the blood pressure ( BP ) , according to recent studies . OBJECTIVE To evaluate the efficacy and tolerability of the fixed combination : amlodipine + enalapril , when compared to amlodipine in the normalization of the diastolic arterial pressure ( DAP ) ( < 85 mmHg ) , in pts with CAD and systemic arterial hypertension ( SAH ) . METHODS Double-blind and r and omized study , with two groups of pts with DAP > or = 90 and < 110 mmHg and CAD . Patients with left ventricular ejection fraction ( LVEF ) < 40 % , symptoms of heart failure or angina class III and IV , severe diseases and DAP > or = 110 mmHg during the four-week wash-out with atenolol treatment alone , were excluded . After the wash-out , pts were r and omly distributed for the use of the combination ( A ) or amlodipine ( B ) and were followed every four weeks up to 98 days . The initial doses ( in mg ) were , respectively : A- 2.5/10 and B- 2.5 ; the doses were increased when DAP > 85mmHg , at the visits . Statistical analysis was carried out with chi2 , Fischer and analysis of variance , for p < 0.05 . RESULTS Of the 110 selected pts , 72 ( A= 32 , B= 40 ) were r and omized . The decreases in DAP and systolic arterial pressure ( SAP ) were significant ( p < 0.01 ) , but with no difference between the groups in mmHg : SAP , A ( 127.7 + /- 13.4 ) and B ( 125.3 + /- 12.6 ) ( p= 0.45 ) and DAP , A ( 74.5 + /- 6.7 mmHg ) and B ( 75.5 + /- 6.7 mmHg ) ( p= 0.32 ) . Group A presented a lower incidence of lower-limb edema : ( 7.1 % vs 30.6 % , p=0.02 ) on the 98th day of follow-up . CONCLUSION The fixed combination of enalapril and amlodipine , as well as isolated amlodipine , was effective in the normalization of BP in pts with CAD and SAH stages I and II , adding blockage of the renin-angiotensin system Angiotensin-converting enzyme inhibitors and calcium antagonists are 2 classes of antihypertensive agents frequently used either as monotherapy or in combination . A 6-week , multicenter , r and omized , double-blind , placebo-controlled trial was conducted in essential hypertensive patients ( diastolic blood pressures [ BP ] when seated , 95 - 115 mm Hg ) to evaluate the efficacy , dose response , and safety profiles of enalapril combined with a new once-daily formulation of diltiazem .  BP and heart rate were measured at 5 ( peak ) and 24 ( trough ) hours after dose to assess the efficacy and pharmacodynamic profile of the combination given once daily . There were 336 patients r and omly assigned to either enalapril 5 mg plus 1 of 4 dose levels of diltiazem ER ( 60 , 120 , 180 , or 240 mg ) , enalapril 5 mg alone , or placebo . Each combination dose level produced statistically significant reductions ( p < 0.05 ) in trough diastolic BP when seated , compared with placebo ( -6.8 , -8.3 , -10.1 , and -10.3 mm Hg for the diltiazem ER doses of 60 , 120 , 180 , and 240 mg , respectively ) . The 3 highest combination dose levels result ed in statistically significant ( p < 0.05 ) decreases in trough diastolic BP when seated , compared with placebo . There was a significant ( p < 0.001 ) linear dose-response relation . A trough-to-peak ratio > or = 0.5 was shown for the 3 highest combination doses . Drug-related adverse events were seen in 8.9 % to 19 % of the combination patients , 14.3 % of the enalapril patients , and 8.6 % of the placebo patients . The frequency and type of adverse events were those currently noted with each drug studied when used as monotherapy High levels of proteinuria predict renal deterioration , suggesting that interventions to reduce proteinuria may postpone the development of severe renal impairment . This multicenter Canadian trial evaluated whether supramaximal dosages of c and esartan would reduce proteinuria to a greater extent than the maximum approved antihypertensive dosage . The authors r and omly assigned 269 patients who had persistent proteinuria ( > or = 1 g/d ) despite 7 wk of treatment with the highest approved dosage of c and esartan ( 16 mg/d ) to 16 , 64 , or 128 mg/d c and esartan for 30 wk . The median serum creatinine level was 130.0 micromol/L ( 1.47 mg/dl ) , and the median urinary protein excretion was 2.66 g/d ; most ( 53.9 % ) patients had diabetic nephropathy . The mean difference of the percentage change in proteinuria for patients receiving 128 mg/d c and esartan compared with those receiving 16 mg/d c and esartan was -33.05 % ( 95 % confidence interval -45.70 to -17.44 ; P < 0.0001 ) . Reductions in BP were not different across the three treatment groups . Elevated serum potassium levels ( K+ > 5.5 mEq/L ) led to the early withdrawal of 11 patients , but there were no dosage-related increases in adverse events . In conclusion , proteinuria that persists despite treatment with the maximum recommended dosage of c and esartan can be reduced by increasing the dosage of c and esartan further , but serum potassium levels should be monitored during treatment STUDY OBJECTIVE To compare the renoprotective and blood pressure-lowering effects of combination losartan-low-dose hydrochlorothiazide with losartan alone in hypertensive patients with stage 3 chronic kidney disease ( CKD ) . DESIGN Prospect i ve , open-label , r and omized , controlled study . SETTING Outpatient clinic at a university-affiliated hospital in Japan . PATIENTS Sixty adults ( mean age 67 yrs ) with stage 3 CKD who had been receiving losartan 50 mg/day and had not achieved their target blood pressure of 130/80 mm Hg . INTERVENTION Patients were r and omly assigned to receive combination losartan 50 mg-hydrochlorothiazide 12.5 mg/day in addition to losartan 50 mg/day ( combination therapy group , 30 patients ) or to receive losartan 100 mg/day ( control group , 30 patients ) over a 24-week period . MEASUREMENTS AND MAIN RESULTS Efficacy was determined by monitoring clinical and laboratory parameters . Mean baseline systolic and diastolic blood pressures were 158/90 mm Hg in both groups ; at 24 weeks of treatment , these blood pressures significantly decreased to 133/79 mm Hg in the combination therapy group compared with both baseline and the values in the control group ( 145/83 mm Hg ) . Although serum creatinine concentration increased and the estimated glomerular filtration rate decreased significantly in both groups , the urinary protein : creatinine ratio was significantly lower in the combination therapy group . With stratification of patients on the basis of whether they had diabetes mellitus , we found that the reduction in the urinary protein : creatinine ratio was more evident in the combination therapy group . No significant increase in the occurrence of adverse metabolic effects was noted in either group . CONCLUSION In these hypertensive patients with stage 3 CKD , combination therapy with the maximum recommended daily dose of losartan of 100 mg and a low dose of hydrochlorothiazide of 12.5 mg ameliorated proteinuria and reduced blood pressure more effectively than treatment with losartan 100 mg alone , irrespective of whether the patients had diabetes The objective of the present study was to assess the efficacy of bisoprolol in  migraine prophylaxis .  A double-blind placebo-controlled study was conducted in 226 patients with migraine with or without aura , a migraine history of at least 2 years and at least 3 documented attacks during the 28 days run-in period . The duration of treatment was 12 weeks following an initial 28 days ' run-in period . Patients reported the number of attacks and their severity in a diary . Treatment with bisoprolol 5 mg result ed in a significant reduction in the frequency of migraine attacks ( 39 % vs 22 % ) compared to placebo treatment ( p<0.05 ) . Treatment had no effect on the duration and severity of the attacks .  Bisoprolol was well tolerated A multi-centre study was carried out to examine the antihypertensive effect and adverse event profile of felodipine in an extended-release ( ER ) formulation given once daily as monotherapy . Doses of 5 mg , 10 mg or 20 mg felodipine ER were compared with placebo in 183 patients with mild or moderate hypertension . All antihypertensive medication was discontinued on entering a 4-week placebo run-in period . If , at the end of the run-in period , supine diastolic blood pressure was in the range greater than 95 less than 120 mmHg , patients were r and omly allocated to double-blind treatment with felodipine , 5 mg , 10 mg or 20 mg , or placebo , to be taken once daily for 4 weeks . Supine and st and ing blood pressure , heart rate and body weight were measured every 2 weeks during the trial . Assessment s were made 24 hours after intake of the study drug . Adverse events were recorded at each review . Over the 4-week treatment period , a dose-related decrease in supine diastolic blood pressure was observed , this reduction occurring already during the first 2 weeks of active treatment . In the placebo group and the felodipine 5 mg , 10 mg and 20 mg groups , supine blood pressure ( systolic/diastolic ) decreased by 7/6 mmHg , 9/8 mmHg , 12/10 mmHg and 14/11 mmHg , respectively . Supine diastolic blood pressure reduction in the felodipine 10 mg group and both systolic and diastolic blood pressure reductions in the 20 mg group were significantly greater than with placebo . St and ing diastolic blood pressure reduction was significantly greater in all three dose groups on felodipine compared with placebo . ( ABSTRACT TRUNCATED AT 250 WORDS The study compared valsartan/amlodipine combination with irbesartan/hydrochlorothiazide ( HCTZ ) combination in very elderly hypertensives . After a 4-week placebo period , 94 hypertensives , aged 75 - 89 years were r and omized to valsartan 160mg/amlodipine 5 mg or irbesartan 300mg/HCTZ 12.5 mg for 24 weeks according to a prospect i ve , parallel group study . After 4 weeks amlodipine or HCTZ was doubled in non-responders . Patients were checked every 4 weeks . At each visit clinical sitting , lying and st and ing blood pressure ( BP ) , systolic BP ( SBP ) and diastolic BP ( DBP ) were evaluated , and an electrocardiogram was performed . At the end of the placebo period and of the treatment period a non-invasive  24-h ambulatory BP monitoring  ( ABPM ) was performed and electrolytes and uric acid were evaluated . Both combinations significantly reduced ambulatory BP . In the valsartan/amlodipine group the mean reduction ( -29.9/-15.6 for 24h , -28.6/-14.5mmHg for day-time and -26.2/-17.4mmHg for night-time SBP/DBP ) was similar to that of the irbesartan/HCTZ group ( -29.6/-15.4 for 24h , -29.3/-14.9mmHg for day-time and -25.4/-16.9mmHg for night-time SBP/DBP ) . Both combinations significantly reduced clinical sitting and lying BP values with no difference between treatments . BP changes from lying to st and ing position were significantly greater in the irbesartan/HCTZ group ( -17.2/-9.1mmHg ) than in the valsartan/amlodipine group ( -10.1/-1.9mmHg , p<0.05 for SBP and p<0.01 for DBP vs. irbesartan/HCTZ ) . Potassium significantly decreased and uric acid significantly increased ( -0.4mmol/l , p<0.05 and + 0.5mg/dl , p<0.05 vs. baseline , respectively ) only in the irbesartan/HCTZ group . In conclusion , both combinations were similarly effective in reducing ambulatory and clinical BP in very elderly hypertensives . However , valsartan/amlodipine offered some advantages in terms of less pronounced BP orthostatic changes and absence of metabolic adverse effects A total of 203 patients with hypertension ( supine diastolic blood pressure of 100 - 119 mm Hg ) from six centers entered into a 3-week placebo baseline followed by 5 weeks of active treatment ( either placebo or isradipine 2.5 , 5 , 7.5 , or 10 mg BID ) to determine the effectiveness of isradipine on blood pressure control . Electrocardiographic criteria for left-ventricular ischemia were coded blindly using the Minnesota Codes 4 - 1 to 4 - 4 and 5 - 1 to 5 - 3 at the end of baseline and active treatment periods . One hundred seventy patients with hypertension and matching and complete electrocardiograms completed the study for analysis : 63 ( 37 % ) were white and 117 ( 69 % ) were men . They were 52.1 + /- 10.3 years old mean + /- SD ; range : 22 - 77 years ) . No myocardial infa rct ion occurred during the active phase . Fifty-eight of 170 ( 34 % ) at baseline and 54 of 116 ( 32 % ) at week 5 had left atrial enlargement . Romhilt-Estes left-ventricular hypertrophy was not significantly different at baseline versus active treatment : 14 of 170 ( 8.2 % ) versus 15 of 170 ( 8.8 % ) . At baseline , the rate of active ischemia was 28.2 % ( 48/170 ) : 27.8 % ( 10/36 ) were r and omized to receive placebo during active treatment and 28.4 % ( 38/134 ) were given isradipine ( P = NS ) . For those without ischemia at baseline , the rate of change to electrocardiographic ischemia during active treatment was 0 % ( 0/26 ) for those receiving placebo and 3.1 % ( 3/96 ) for those taking isradipine ( P = NS ) . For those with ischemia at baseline , the rate of change to no ischemia during active treatment was 20 % ( 2/10 ) for those receiving placebo and 10.5 % ( 4/38 ) for those taking isradipine ( P = NS ) . ( ABSTRACT TRUNCATED AT 250 WORDS This multicentre study compared the antihypertensive effect and tolerability of the novel angiotensin II antagonist c and esartan cilexetil with those of losartan and placebo .  Men and women aged 20 - 80 years , with primary hypertension and sitting diastolic blood pressure ( DBP ) 95 - 114 mm Hg after a 4-week placebo run-in period , were r and omized to once daily double-blind treatment with c and esartan cilexetil 8 mg ( n=82 ) , c and esartan cilexetil 16 mg ( n=84 ) , losartan 50 mg ( n=83 ) or placebo ( n=85 ) for 8 weeks . Blood pressure was measured 6 and 24 h after dose , i.e. at peak and trough . Differences between treatments were analysed by analysis of covariance , and the primary effect variable was reduction in trough sitting DBP . Compared with placebo treatment , trough DBP was significantly reduced by a mean ( 95 % CI ) of 8.9 ( 6.0 ; 11.8 ) mm Hg with 8 mg and 10.3 ( 7.4 ; 13.2 ) mm Hg with 16 mg c and esartan cilexetil . The 8 mg dose was as effective as losartan 50 mg , while 16 mg c and esartan cilexetil was significantly more effective , with a difference between treatments of 3.7 ( 0.8 ; 6.7 ) mm Hg ( p=0.013 ) . The placebo corrected trough/peak ratio was 0.9 - 1.1 with c and esartan cilexetil and 0.7 with losartan . C and esartan cilexetil was similarly well tolerated as placebo . In conclusion , c and esartan cilexetil 8 mg or 16 mg once daily is an effective and well tolerated antihypertensive treatment .  C and esartan cilexetil 16 mg is significantly more effective than losartan 50 mg once daily A r and omized , double-blind , placebo-controlled , parallel-group multicenter study was conducted to evaluate the antihypertensive efficacy and safety of 8-week treatment with one of three fixed-dose combinations — losartan 50 mg plus hydrochlorothiazide 12.5 mg , losartan 50 mg plus hydrochlorothiazide 6.25 mg , or losartan 25 mg plus hydrochlorothiazide 6.25 mg — in comparison with those of hydrochlorothiazide 12.5 mg alone , losartan 50 mg alone , or placebo in Japanese patients with essential hypertension . Significant reductions in sitting diastolic blood pressure ( DBP ) and systolic blood pressure ( SBP ) were seen in all three combination groups compared with the placebo group ( each p<0.001 ) . The greatest reductions in DBP and SBP were observed in the losartan 50 mg plus hydrochlorothiazide 12.5 mg group ( 12.7 and 18.0 mmHg , respectively ) . The reductions in the losartan 50 mg plus hydrochlorothiazide 12.5 mg group were significantly greater ( each p<0.001 ) than those in the placebo group and each of the monotherapy groups . There were no significant differences in the incidences of clinical and laboratory drug-related adverse events between any of the combination groups and the placebo group . All combination groups showed improved hypokalemia and hyperuricemia compared to the hydrochlorothiazide 12.5 mg group . These results demonstrated that once-daily , fixed-dose combination therapy with losartan 50 mg plus hydrochlorothiazide 12.5 mg is well tolerated and more efficacious in lowering DBP and SBP than monotherapy in Japanese hypertensive patients BACKGROUND The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension ( ACCOMPLISH ) trial showed that initial antihypertensive therapy with benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide in reducing cardiovascular morbidity and mortality . We assessed the effects of these drug combinations on progression of chronic kidney disease . METHODS ACCOMPLISH was a double-blind , r and omised trial undertaken in five countries ( USA , Sweden , Norway , Denmark , and Finl and ) . 11 506 patients with hypertension who were at high risk for cardiovascular events were r and omly assigned via a central , telephone-based interactive voice response system in a 1:1 ratio to receive benazepril ( 20 mg ) plus amlodipine ( 5 mg ; n=5744 ) or benazepril ( 20 mg ) plus hydrochlorothiazide ( 12.5 mg ; n=5762 ) , orally once daily . Drug doses were force-titrated for patients to attain recommended blood pressure goals . Progression of chronic kidney disease , a prespecified endpoint , was defined as doubling of serum creatinine concentration or end-stage renal disease ( estimated glomerular filtration rate < 15 mL/min/1.73 m(2 ) or need for dialysis ) . Analysis was by intention to treat ( ITT ) . This trial is registered with Clinical Trials.gov , number NCT00170950 . FINDINGS The trial was terminated early ( mean follow-up 2.9 years [ SD 0.4 ] ) because of superior efficacy of benazepril plus amlodipine compared with benazepril plus hydrochlorothiazide . At trial completion , vital status was not known for 143 ( 1 % ) patients who were lost to follow-up ( benazepril plus amlodipine , n=70 ; benazepril plus hydrochlorothiazide , n=73 ) . All r and omised patients were included in the ITT analysis . There were 113 ( 2.0 % ) events of chronic kidney disease progression in the benazepril plus amlodipine group compared with 215 ( 3.7 % ) in the benazepril plus hydrochlorothiazide group ( HR 0.52 , 0.41 - 0.65 , p<0.0001 ) . The most frequent adverse event in patients with chronic kidney disease was peripheral oedema  ( benazepril plus amlodipine , 189 of 561 , 33.7 % ; benazepril plus hydrochlorothiazide , 85 of 532 , 16.0 % ) . In patients with chronic kidney disease , angio-oedema was more frequent in the benazepril plus amlodipine group than in the benazepril plus hydrochlorothiazide group . In patients without chronic kidney disease , dizziness , hypokalaemia , and hypotension were more frequent in the benazepril plus hydrochlorothiazide group than in the benazepril plus amlodipine group . INTERPRETATION Initial antihypertensive treatment with benazepril plus amlodipine should be considered in preference to benazepril plus hydrochlorothiazide since it slows progression of nephropathy to a greater extent . FUNDING Novartis OBJECTIVE To assess if low ( 1.25 mg ) and /or st and ard ( 5 mg ) doses of the ACE inhibitor ramipril could prevent progression of microalbuminuria ( incipient diabetic nephropathy ) in normotensive type 1 diabetic patients . RESEARCH DESIGN AND METHODS This study , using a multicenter r and omized placebo-controlled double-blind parallel group , was conducted over 2 years in 28 outpatient diabetic clinics in the U.K. and Irel and . We screened 334 type 1 diabetic patients with suspected microalbuminuria and normal blood pressure ; of these , 140 patients 18 - 65 years of age with a diagnosis of type 1 diabetes and persistent microalbuminuria , defined as urinary albumin excretion rate ( AER ) of 20 - 200 microg/min , were enrolled in the study . RESULTS The proportion of patients progressing to macroalbuminuria was reduced in the ramipril groups but did not reach statistical significance over 2 years . AER was significantly lower at year 2 in the combined ramipril-treated patients versus placebo ( P = 0.013 ) . More patients on ramipril regressed to normoalbuminuria ( < 20 microg/min ) , with 11 % for 1.25 mg ramipril , 20 % for 5 mg ramipril , and 4 % for placebo ( P = 0.053 ) . Blood pressure was significantly reduced to a similar extent with both 1.25 and 5 mg ramipril . Supine systolic blood pressure increased from 130 to 134 mmHg in the placebo group and fell in the 1.25 mg ramipril group ( from 132 to 129 mmHg ) and in the 5 mg ramipril group ( from 134 to 130 mmHg ) ( P = 0.003 , compared with placebo ) . No statistically significant changes were observed in glomerular filtration rate ( GFR ) between the placebo- and ramipril-treated groups during the 2-year period . CONCLUSIONS Microalbuminuria is reduced significantly by ramipril treatment in type 1 diabetic patients without hypertension . Although the magnitude of the response was greater , there is no significant difference between responses to 1.25 or 5 mg ramipril . Small but highly significant reductions in systolic and mean arterial pressures occur in ramipril-treated patients . GFR is stable at this stage of the evolution of diabetic nephropathy and is unaffected by ramipril treatment for 2 years OBJECTIVES The objective of this study was to evaluate the effects of losartan + /- hydrochlorothiazide ( HCTZ ) versus placebo in obese patients with systolic and diastolic hypertension . RESEARCH DESIGN AND METHODS R and omized patients ( n = 261 ) were non-diabetic with systolic blood pressure ( SBP ) > or = 140 and < or = 180 mmHg and diastolic BP ( DBP ) > or = 95 and < or = 115 mmHg , body mass index > 30 kg/m(2 ) , and waist circumference > 40 (males)/ > 35 ( females ) inches . Patients were r and omized to placebo or a forced titration of losartan 50 mg titrated at 4-week intervals to losartan 100 mg , losartan 100 mg/HCTZ 12.5 mg , and losartan 100 mg/HCTZ 25 mg . Primary efficacy measurements were change from baseline in SBP and DBP at 12 weeks . Secondary measurements were change from baseline in BPs at 8 and 16 weeks , percent responders at 12 and 16 weeks , and safety/tolerability . Post-hoc analyses were BP at 4 weeks and achievement of controlled BP ( SBP < 140 and /or DBP < 90 mmHg ) at 12 and 16 weeks . RESULTS Losartan 50 mg reduced BP from 151.6/99.2 mmHg at baseline to 140.1/89.8 mmHg at week 4 ( post hoc ) , 139.5/89.6 mmHg with losartan 100 mg at week 8 ( secondary ) , 134.3/85.9 mmHg with losartan 100 mg/HCTZ 12.5 mg at week 12 ( primary ) , and 132.1/84.9 mmHg with losartan 100 mg/HCTZ 50 mg at week 16 ( secondary ) ( all p < 0.05 ) . Rates of clinical adverse experiences were similar between treatment groups . A limitation of these analyses is the relatively rapid rate of study drug titration , which may not have allowed for the evaluation of the full treatment effect at each titration step . CONCLUSIONS We conclude that losartan alone or in combination with HCTZ was generally well tolerated and effective in the treatment of elevated systolic and diastolic BP in obese patients with hypertension Hypertensive patients whose BP was uncontrolled despite the use of antihypertensive agents , including an ARB ( c and esartan 8 mg/day or valsartan 80 mg/day ) , were enrolled . The patients were r and omly assigned to combination therapy with telmisartan 40 mg/day ( changed from current ARB ) and hydrochlorothiazide ( HCTZ ) 12.5 mg/day ( T + H , n = 32 ) or to no change in their current drug regimen ( CTL , n = 32 ) . The observation period was 12 weeks . The office and home BPs were significantly reduced in the T + H compared to those in the CTL . A sufficient and long-acting BP lowering effect , as reflected in decreased early morning BP , was obtained with the combination of low-dose HCTZ and telmisartan without apparent metabolic deterioration The antihypertensive efficacy and tolerability of the new calcium antagonist isradipine was assessed in 86 hypertensive patients who had pretreatment diastolic blood pressures ( DBP ) ± 105 mm Hg and who were r and omly allocated to a double-blind comparison of three different dosage regimens : 1.25 mg  , 2.5 mg , and 5 mg b.i.d  . , and placebo . A 2-week run-in period was followed by a 4-week course of treatment . Isradipine  reduced systolic and diastolic blood pressures dose-dependently : the normalization rate ( DBP ± 90 mm Hg ) was 5 % with placebo and 29 , 55 , and 64 % , with isradipine 1.25 , 2.5 , and 5 mg b.i.d . , respectively . The proportion of patients experiencing at least a 10 mm Hg reduction in sitting DBP was 29 , 67 , 86 , and 91 % , respectively . All three dosages proved to he significantly effective compared to placebo . Neither heart rate nor blood pressure regulation in orthostasis were influenced . The main side effects were headache , dizziness , and flushing : isradipine 1.25 and 2.5 mg b.i.d . were well tolerated ( not significantly different from placebo ) . In conclusion , isradipine 2.5 mg h.i.d . appears to he the potential dose of first choice , exhibiting a favorable benefit-risk profile OBJECTIVE The aim of this study was to evaluate the efficacy and tolerability of a new fixed-dose combination ( FDC ) of telmisartan 40 mg + amlodipine 5 mg ( T+A ) compared with amlodipine 5-mg monotherapy ( A ) in adult Indian patients with stage II hypertension . METHODS This comparative , Phase III , 12-week , multicenter , prospect i ve , r and omized , double-blind study was conducted in Indian patients aged 18 to 65 years with established stage II hypertension . Patients were treated with oral FDC of T+A or A QD before breakfast for 12 weeks ; blood pressure ( BP ) and heart rate were measured in the sitting position . Primary efficacy end points were reduction in clinical systolic BP (SBP)/ diastolic BP ( DBP ) from baseline to study end and number of responders ( ie , patients who achieved target SBP/ DBP < 130/<80 mm Hg ) at end of study . Tolerability was assessed by treatment-emergent adverse events , identified using physical examination , laboratory analysis , and electrocardiography . RESULTS A total of 210 patients were enrolled in the study ; 203 patients ( 143 men , 60 women ) completed the study while 7 were lost to follow-up ( 4 patients in the T+A group and 3 in the A group ) and considered with-drawn . At study end , statistically significant percentage reductions from baseline within groups and between groups were observed in SBP ( T+A [ -27.4 % ] ; A [ -16.6 % ] ) and DBP ( T+A [ -20.1 % ] ; A [ -13.3 % ] ) ( all , P < 0.05 ) . Response rates were 87.3 % ( 89/102 ) in the T+A group and 69.3 % ( 70/101 ) in the A group ( P < 0.05 ) . The prevalences of adverse events were not significantly different between the 2 treatment groups ( T+A , 16.0 % [ 17/106 ] ; A , 15.4 % [ 16/104 ] ) . Peripheral edema was reported in 8.5 % patients ( 9/106 ) in the T+A group compared with 13.5 % ( 14/104 ) in the A group , and cough was reported in 3.8 % patients ( 4/106 ) in the T+A group and 1.0 % ( 1/104 ) patients in the A group ; these differences did not reach statistical significance . The incidences of headache , dizziness , and diarrhea were similar between the 2 groups . CONCLUSIONS Among these Indian patients with stage II hypertension , the FDC of T+A was found to be significantly more effective , with regard to BP reductions , than A , and both treatments were well tolerated In a double blind placebo controlled r and omised parallel study the antihypertensive activity and adverse biochemical effects of three doses of cyclopenthiazide were evaluated in patients with mild essential hypertension that had been recently diagnosed or was being treated with a single drug . After a four week placebo washout period 53 patients with diastolic blood pressures between 90 - 110 mm Hg were r and omly assigned to 50 , 125 , or 500 micrograms cyclopenthiazide or matching placebo for an eight week period of treatment . Blood pressure was measured in the patients ' homes by the same observer every two weeks . Serum urea , electrolytes , urate , and creatinine concentrations and 24 hour urinary sodium excretion were monitored every four weeks and serum magnesium concentration and plasma renin activity at the end of the washout and treatment periods . After eight weeks of treatment systolic and diastolic blood pressures were significantly reduced in patients taking 125 and 500 micrograms cyclopenthiazide when compared with those taking placebo . The decrement in serum potassium concentration ( 0.6 mmol/l ) and increase in serum urate concentration 0.06 mmol/l ) were greatest with the 500 micrograms dose , the increase in serum urate concentration alone being significant . No change in serum magnesium concentration or 24 hour urinary sodium excretion was noted with any dose of cyclopenthiazide . Only the 500 micrograms dose of cyclopenthiazide significantly increased the mean plasma renin activity ( 1.8 ( 95 % confidence interval 0.2 to 3.4)-5.4 ( 3.9 to 6.8 ) nmol angiotensin I/l/h ) ; the other doses like the placebo had no effect . Cyclopenthiazide 125 micrograms , a dose lower than is currently marketed , produced a similar hypotensive response to 500 micrograms of the drug without up setting the biochemical profile AIM The aim of the present study is to evaluate the effect of treatment with verapamil , tr and olapril and their combination on peripheral microcirculation vasoreactivity . METHODS Twenty hypertensive patients were r and omized to receive oral tr and olapril ( 4 mg oid ; TRA ) or verapamil ( 240 mg oid ; VER ) for 6 months and then the combination of the two drugs for additional 6 months . At baseline , 6 months and 12 months , peripheral microcirculation vasoreactivity was evaluated by forearm blood flow technique ( venous plethysmography ) , as vasodilation to an endothelium-dependent ( acetylcholine ) and an endothelium-independent stimulus ( sodium nitroprusside , SNP ) ; minimal forearm vascular resistances ( MFVR ) were also evaluated . RESULTS Blood pressure decreased similarly and progressively in both groups throughout the study period . In VER , 6-month verapamil treatment significantly increased vasodilation to acetylcholine , but not to SNP . The superimposition of tr and olapril increased the response to SNP , and less to acetylcholine . In TRA group , 6-month treatment with tr and olapril improved the response to SNP , but not to acetylcholine . In this group , the superimposition of verapamil caused a significant improvement in the response to acetylcholine , but not to SNP . At the end of the study , MFVR were significantly reduced in both groups , but to a greater extent in TRA . CONCLUSION The present study demonstrates that chronic treatment with verapamil ameliorates endothelial function in the forearm microcirculation of essential hypertensive patients , while tr and olapril protects microcirculation from structural alterations . The combination of the two drugs is potentially a powerful tool to counteract hypertension-related microvascular dysfunction and damage
target: Effects of antihypertensive drugs on SBP variability are dose-dependent and persist when used in combinations .
  Use of a high dose of a calcium channel blocker alone or in combination with other agents is therefore likely to be particularly effective in prevention of stroke
background: BACKGROUND AND PURPOSE Recent studies have shown that visit-to-visit blood pressure variability is a powerful risk factor for stroke , is reduced by calcium channel blockers and diuretics , and increased by β-blockers .
  However , it is unknown whether these effects are dose-dependent and persist in combination with other drugs .