title: Effects of Angiotensin-Converting Enzyme Inhibition in Low-Risk Patients Early After Coronary Artery Bypass Surgery Effects of Manidipine and Delapril in Hypertensive Patients With Type 2 Diabetes Mellitus: The Delapril and Manidipine for Nephroprotection in Diabetes (DEMAND) Randomized Clinical Trial Effect of metoprolol on death and cardiac events during a 2-year period after coronary artery bypass grafting. The MACB Study Group. Effects of Fosinopril and Pravastatin on Cardiovascular Events in Subjects With Microalbuminuria Results of the pilot study for the Hypertension in the Very Elderly Trial Cardiovascular outcomes in the first trial of antihypertensive therapy guided by self-measured home blood pressure Target Blood Pressure for Treatment of Isolated Systolic Hypertension in the Elderly: Valsartan in Elderly Isolated Systolic Hypertension Study Irbesartan in patients with atrial fibrillation. Telmisartan, ramipril, or both in patients at high risk for vascular events. 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abstract: Background — Early after  coronary artery bypass surgery ( CABG ) , activation of numerous neurohumoral and endogenous vasodilator systems occurs that could be influenced favorably by angiotensin-converting enzyme inhibitors . Methods and Results — The Ischemia Management with Accupril post – bypass Graft via Inhibition of the coNverting Enzyme ( IMAGINE ) trial tested whether early initiation ( ≤7 days ) of an angiotensin-converting enzyme inhibitor after CABG reduced cardiovascular events in stable patients with left ventricular ejection fraction ≥40 % . The trial was a double-blind , placebo-controlled study of 2553 patients r and omly assigned to quinapril , target dose 40 mg/d , or placebo , who were followed up to a maximum of 43 months . The mean ( SD ) age was 61 ( 10 ) years . The incidence of the primary composite end point ( cardiovascular death , resuscitated cardiac arrest , nonfatal myocardial infa rct ion , coronary revascularization , unstable angina or heart failure requiring hospitalization , documented angina , and stroke ) was 13.7 % in the quinapril group and 12.2 % in the placebo group ( hazard ratio 1.15 , 95 % confidence interval 0.92 to 1.42 , P=0.212 ) over a median follow-up of 2.95 years . The incidence of the primary composite end point increased significantly in the first 3 months after CABG in the quinapril group ( hazard ratio 1.52 , 95 % confidence interval 1.03 to 2.26 , P=0.0356 ) . Adverse events also increased in the quinapril group , particularly during the first 3 months after CABG . Conclusions — In patients at low risk of cardiovascular events after CABG , routine early initiation of angiotensin-converting enzyme inhibitor therapy does not appear to improve clinical outcome up to 3 years after CABG ; however , it increases the incidence of adverse events , particularly early after CABG . Thus , early after CABG , initiation of angiotensin-converting enzyme inhibitor therapy should be individualized and continually reassessed over time according to risk To assess whether angiotensin-converting enzyme inhibitors and third-generation dihydropyridine calcium channel blockers ameliorate diabetic complications , we compared glomerular filtration rate ( GFR ; primary outcome ) , cardiovascular events , retinopathy , and neuropathy in 380 hypertensive type 2 diabetics with albuminuria < 200 mg/min included in a multicenter , double-blind , placebo-controlled trial ( DEM AND [ Delapril and Manidipine for Nephroprotection in Diabetes ] ) and r and omized to 3-year treatment with manidipine/delapril combination ( 10/30 mg/d ; n=126 ) , delapril ( 30 mg/d ; n=127 ) , or placebo ( n=127 ) . GFR was central ly measured by iohexol plasma clearance . Median monthly GFR decline ( interquartile range [ IQR ] ) was 0.32 mL/min per 1.73 m2 ( IQR : 0.16–0.50 mL/min per 1.73 m2 ) on combined therapy , 0.36 mL/min per 1.73 m2 ( IQR : 0.18–0.53 mL/min per 1.73 m2 ) on delapril , and 0.30 mL/min per 1.73 m2 ( IQR : 0.12–0.50 mL/min per 1.73 m2 ) on placebo ( P=0.87 and P=0.53 versus combined therapy or delapril , respectively ) . Similar findings were observed when baseline GFR values were not considered for slope analyses . Albuminuria was stable in the 3 treatment groups . The hazard ratio ( 95 % CI ) for major cardiovascular events between combined therapy and placebo was 0.17 ( 0.04–0.78 ; P=0.023 ) . Among 192 subjects without retinopathy at inclusion , the hazard ratio for developing retinopathy between combined therapy and placebo was 0.27 ( 0.07–0.99 ; P=0.048 ) . Among 200 subjects with central ized neurological evaluation , the odds ratios for peripheral neuropathy at 3 years between combined therapy or delapril and placebo were 0.45 ( 0.24–0.87 ; P=0.017 ) and 0.52 ( 0.27–0.99 ; P=0.048 ) , respectively . Glucose disposal rate decreased from 5.8±2.4 to 5.3±1.9 mg/kg per min on placebo ( P=0.03 ) but did not change on combined or delapril therapy . Treatment was well tolerated . In hypertensive type 2 diabetic patients , combined manidipine and delapril therapy failed to slow GFR decline but safely ameliorated cardiovascular disease , retinopathy , and neuropathy and stabilized insulin sensitivity PURPOSE To evaluate the effect of long-term treatment with metoprolol after coronary bypass grafting on death and cardiac events . METHODS Patients in western Sweden on whom coronary artery bypass grafting was performed between June 1988 and June 1991 were evaluated for inclusion during the first 3 weeks after surgery . Major exclusion criteria were age > 75 years , concomitant valve surgery , traditional contraindications to beta-blockers and unwillingness to participate . Patients were r and omized in a double-blind fashion to 100 mg of metoprolol/placebo daily for 2 weeks and thereafter 200 mg daily for 2 years . RESULTS Of 2365 patients who were operated on , 967 were r and omized to either metoprolol ( n = 480 ) or placebo ( n = 487 ) . Primary end points ( death , non-fatal myocardial infa rct ion , unstable angina pectoris , need for coronary artery bypass grafting or percutaneous transluminal angioplasty ) , were reached by 42 patients in the metoprolol group ( 8.8 % ) , as compared with 39 in the placebo group ( 8.0 % ) ( P = 0.73 ) . Of all the patients r and omized to metoprolol , 34 % withdrew from blind treatment prematurely compared with 44 % for placebo ( P < 0.01 ) . CONCLUSION Prophylactic treatment with metoprolol over a 2-year period after coronary artery bypass grafting did not reduce death or the development of cardiac events . However , the 95 % confidence limits ranged from the possibility of a 30 % reduction in events to a 68 % increase in events if patients were treated with metoprolol as compared with placebo Background —Microalbuminuria is associated with increased risk of cardiovascular events . We assessed whether therapeutic intervention aim ed at lowering urinary albumin excretion would reduce cardiovascular events in microalbuminuric subjects ( 15 to 300 mg/24 hours ) . Methods and Results —From the Prevention of Renal and Vascular Endstage Disease ( PREVEND ) cohort ( n=8592 ) , 1439 subjects fulfilled the inclusion criteria of the PREVEND Intervention Trial ( PREVEND IT ) . Of these subjects , 864 were r and omized to fosinopril 20 mg or matching placebo and to pravastatin 40 mg or matching placebo . The mean follow-up was 46 months , and the primary end point was cardiovascular mortality and hospitalization for cardiovascular morbidity . Mean age was 51±12 years ; 65 % of subjects were male , and 3.4 % had a previous cardiovascular event . Mean cholesterol level was 5.8±1.0 mmol/L , mean systolic/diastolic blood pressure was 130±18/76±10 mm Hg , and median urinary albumin excretion was 22.8 ( 15.8 to 41.3 ) mg/24 hours . The primary end point occurred in 45 subjects ( 5.2 % ) . Fosinopril  reduced urinary albumin excretion by 26 % ( P<0.001 ) . Subjects treated with fosinopril showed a 40 % lower incidence of the primary end point ( hazard ratio 0.60 [ 95 % CI 0.33 to 1.10 ] , P=0.098 , log-rank ) . Pravastatin did not reduce urinary albumin excretion , and subjects treated with pravastatin showed a 13 % lower incidence of the primary end point than subjects in the placebo group ( 0.87 [ 0.49 to 1.57 ] , P=0.649 , log-rank ) . Conclusions —In microalbuminuric subjects , treatment with fosinopril had a significant effect on urinary albumin excretion . In addition , fosinopril treatment was associated with a trend in reducing cardiovascular events  . Treatment with pravastatin did not result in a significant reduction in urinary albumin excretion or cardiovascular events Background The risks and benefits of treating hypertension in individuals older than 80 years are uncertain . A meta- analysis has suggested that a reduction in stroke events of 36 % may have to be balanced against a 14 % increase in total mortality . Objectives To report the results of the pilot study of the Hypertension in the Very Elderly Trial ( HYVET ) , which is in progress to address these issues . Methods The HYVET-Pilot was a multicentre international open pilot trial . In 10 European countries , 1283 patients older than 80 years and with a sustained blood pressure of 160–219/90–109 mmHg were allocated r and omly to one of three treatments : a diuretic-based regimen ( usually bendroflumethiazide ; n = 426 ) , an angiotensin-converting enzyme inhibitor regimen ( usually lisinopril ; n = 431 ) or no treatment ( n = 426 ) . The procedure permitted doses of the drug to be titrated and diltiazem slow-release to be added to active treatment . Target blood pressure was < 150/80 mmHg and mean follow-up was 13 months . Results In the combined actively treated groups , the reduction in stroke events relative hazard rate ( RHR ) was 0.47 [ 95 % confidence interval ( CI ) 0.24 to 0.93 ] and the reduction in stroke mortality RHR was 0.57 ( 95 % CI 0.25 to 1.32 ) . However , the estimate of total mortality supported the possibility of excess deaths with active treatment ( RHR 1.23 , 95 % CI 0.75 to 2.01 ) . Conclusions The preliminary results support the need for the continuing main HYVET trial . It is possible that treatment of 1000 patients for 1 year may reduce stroke events by 19 ( nine non-fatal ) , but may be associated with 20 extra non-stroke deaths Hypertension guidelines recommend blood pressure self-measurement at home ( HBP ) , but no previous trial has assessed cardiovascular outcomes in hypertensive patients treated according to HBP . The multicenter Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure ( HOMED-BP ; 2001–2010 ) trial involved 3518 patients ( 50 % women ; mean age 59.6 years ) with an untreated systolic/diastolic HBP of 135–179/85–119 mm Hg . In a 2 × 3 design , patients were r and omized to usual control ( 125–134/80–84 mm Hg ( UC ) ) vs. tight control ( < 125/<80 mm Hg ( TC ) ) of HBP and to initiation of drug treatment with angiotensin converting enzyme inhibitors , angiotensin receptor blockers or calcium channel blockers . During follow-up , a computer algorithm automatically generated treatment recommendations based on HBP . At the last follow-up ( median 5.3 years ) , TC patients used more antihypertensive drugs than UC patients ( 1.82 vs. 1.74 defined daily doses , P=0.045 ) and had a greater HBP reduction ( 21.3/13.1 mm Hg vs. 22.7/13.9 mm Hg , P=0.018/0.020 ) , but they less frequently achieved the lower HBP targets ( 37.4 vs. 63.5 % , P<0.0001 ) . The primary end point , cardiovascular death plus stroke and myocardial infa rct ion , occurred in 25 UC and 26 TC patients ( hazard ratio , 1.02 ; 95 % confidence interval , 0.59–1.77 ; P=0.94 ) . Rates were similar ( P⩾0.13 ) in the three drug groups . In all patients combined , the risk of the primary end point independently increased by 41 % ( 6–89 % ; P=0.019 ) and 47 % ( 15–87 % ; P=0.0020 ) for a 1-s.d . increase in baseline ( 12.5 mm Hg ) and follow-up ( 13.2 mm Hg ) systolic HBP . The 5-year risk was minimal ( ⩽1 % ) if on-treatment systolic HBP was 131.6 mm Hg or less . HOMED-BP proved the feasibility of adjusting antihypertensive drug treatment based on HBP and suggests that a systolic HBP level of 130 mm Hg should be an achievable and safe target In this prospect i ve , r and omized , open-label , blinded end point study , we aim ed to establish whether strict blood pressure control ( < 140 mm Hg ) is superior to moderate blood pressure control ( ≥140 mm Hg to < 150 mm Hg ) in reducing cardiovascular mortality and morbidity in elderly patients with isolated systolic hypertension . We divided 3260 patients aged 70 to 84 years with isolated systolic hypertension ( sitting blood pressure 160 to 199 mm Hg ) into 2 groups , according to strict or moderate blood pressure treatment . A composite of cardiovascular events was evaluated for ≥2 years . The  strict control ( 1545 patients ) and moderate control ( 1534 patients ) groups were well matched ( mean age : 76.1 years ; mean blood pressure : 169.5/81.5 mm Hg ) . Median follow-up was 3.07 years . At 3 years , blood pressure reached 136.6/74.8 mm Hg and 142.0/76.5 mm Hg , respectively . The blood pressure difference between the 2 groups was 5.4/1.7 mm Hg . The overall rate of the primary composite end point was 10.6 per 1000 patient-years in the strict control group and 12.0 per 1000 patient-years in the moderate control group ( hazard ratio : 0.89 ; [ 95 % CI : 0.60 to 1.34 ] ; P=0.38 ) . In summary , blood pressure targets of < 140 mm Hg are safely achievable in relatively healthy patients ≥70 years of age with isolated systolic hypertension , although our trial was underpowered to definitively determine whether strict control was superior to less stringent blood pressure targets BACKGROUND The risk of cardiovascular events among patients with atrial fibrillation is high . We evaluated whether irbesartan , an angiotensin-receptor blocker , would reduce this risk . METHODS We r and omly assigned patients with a history of risk factors for stroke and a systolic blood pressure of at least 110 mm Hg to receive either irbesartan at a target dose of 300 mg once daily or double-blind placebo . These patients were already enrolled in one of two trials ( of clopidogrel plus aspirin versus aspirin alone or versus oral anticoagulants ) . The first co primary outcome was stroke , myocardial infa rct ion , or death from vascular causes ; the second was this composite outcome plus hospitalization for heart failure . RESULTS A total of 9016 patients were enrolled and followed for a mean of 4.1 years . The mean reduction in systolic blood pressure was 2.9 mm Hg greater in the irbesartan group than in the placebo group , and the mean reduction in diastolic blood pressure was 1.9 mm Hg greater . The first co primary outcome occurred at a rate of 5.4 % per 100 person-years in both groups ( hazard ratio with irbesartan , 0.99 ; 95 % confidence interval [ CI ] , 0.91 to 1.08 ; P=0.85 ) . The second co primary outcome occurred at a rate of 7.3 % per 100 person-years among patients receiving irbesartan and 7.7 % per 100 person-years among patients receiving placebo ( hazard ratio , 0.94 ; 95 % CI , 0.87 to 1.02 ; P=0.12 ) . The rates of first hospitalization for heart failure ( a prespecified secondary outcome ) were 2.7 % per 100 person-years among patients receiving irbesartan and 3.2 % per 100 person-years among patients receiving placebo ( hazard ratio , 0.86 ; 95 % CI , 0.76 to 0.98 ) . Among patients who were in sinus rhythm at baseline , there was no benefit of irbesartan in preventing hospitalization for atrial fibrillation or atrial fibrillation recorded on 12-lead electrocardiography , nor was there a benefit in a subgroup that underwent transtelephonic monitoring . More patients in the irbesartan group than in the placebo group had symptomatic hypotension ( 127 vs. 64 ) and renal dysfunction ( 43 vs. 24 ) . CONCLUSIONS Irbesartan did not reduce cardiovascular events in patients with atrial fibrillation . ( Funded by Bristol-Myers Squibb and Sanofi-Aventis ; Clinical Trials.gov number , NCT00249795 . ) BACKGROUND In patients who have vascular disease or high-risk diabetes without heart failure , angiotensin-converting-enzyme ( ACE ) inhibitors reduce mortality and morbidity from cardiovascular causes , but the role of angiotensin-receptor blockers ( ARBs ) in such patients is unknown . We compared the ACE inhibitor ramipril , the ARB telmisartan , and the combination of the two drugs in patients with vascular disease or high-risk diabetes . METHODS After a 3-week , single-blind run-in period , patients underwent double-blind r and omization , with 8576 assigned to receive 10 mg of ramipril per day , 8542 assigned to receive 80 mg of telmisartan per day , and 8502 assigned to receive both drugs ( combination therapy ) . The primary composite outcome was death from cardiovascular causes , myocardial infa rct ion , stroke , or hospitalization for heart failure . RESULTS Mean blood pressure was lower in both the telmisartan group ( a 0.9/0.6 mm Hg greater reduction ) and the combination-therapy group ( a 2.4/1.4 mm Hg greater reduction ) than in the ramipril group . At a median follow-up of 56 months , the primary outcome had occurred in 1412 patients in the ramipril group ( 16.5 % ) , as compared with 1423 patients in the telmisartan group ( 16.7 % ; relative risk , 1.01 ; 95 % confidence interval [ CI ] , 0.94 to 1.09 ) . As compared with the ramipril group , the telmisartan group had lower rates of cough ( 1.1 % vs. 4.2 % , P<0.001 ) and angioedema ( 0.1 % vs. 0.3 % , P=0.01 ) and a higher rate of hypotensive symptoms ( 2.6 % vs. 1.7 % , P<0.001 ) ; the rate of syncope was the same in the two groups ( 0.2 % ) . In the combination-therapy group , the primary outcome occurred in 1386 patients ( 16.3 % ; relative risk , 0.99 ; 95 % CI , 0.92 to 1.07 ) ; as compared with the ramipril group , there was an increased risk of hypotensive symptoms ( 4.8 % vs. 1.7 % , P<0.001 ) , syncope ( 0.3 % vs. 0.2 % , P=0.03 ) , and renal dysfunction ( 13.5 % vs. 10.2 % , P<0.001 ) . CONCLUSIONS Telmisartan was equivalent to ramipril in patients with vascular disease or high-risk diabetes and was associated with less angioedema . The combination of the two drugs was associated with more adverse events without an increase in benefit . ( Clinical Trials.gov number , NCT00153101 [ Clinical Trials.gov ] . ) BACKGROUND The most appropriate targets for systolic blood pressure to reduce cardiovascular morbidity and mortality among persons without diabetes remain uncertain . METHODS We r and omly assigned 9361 persons with a systolic blood pressure of 130 mm Hg or higher and an increased cardiovascular risk , but without diabetes , to a systolic blood-pressure target of less than 120 mm Hg ( intensive treatment ) or a target of less than 140 mm Hg ( st and ard treatment ) . The primary composite outcome was myocardial infa rct ion , other acute coronary syndromes , stroke , heart failure , or death from cardiovascular causes . RESULTS At 1 year , the mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the st and ard-treatment group . The intervention was stopped early after a median follow-up of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group than in the st and ard-treatment group ( 1.65 % per year vs. 2.19 % per year ; hazard ratio with intensive treatment , 0.75 ; 95 % confidence interval [ CI ] , 0.64 to 0.89 ; P<0.001 ) . All-cause mortality was also significantly lower in the intensive-treatment group ( hazard ratio , 0.73 ; 95 % CI , 0.60 to 0.90 ; P=0.003 ) . Rates of serious adverse events of hypotension , syncope , electrolyte abnormalities , and acute kidney injury or failure , but not of injurious falls , were higher in the intensive-treatment group than in the st and ard-treatment group . CONCLUSIONS Among patients at high risk for cardiovascular events but without diabetes , targeting a systolic blood pressure of less than 120 mm Hg , as compared with less than 140 mm Hg , result ed in lower rates of fatal and nonfatal major cardiovascular events and death from any cause , although significantly higher rates of some adverse events were observed in the intensive-treatment group . ( Funded by the National Institutes of Health ; Clinical Trials.gov number , NCT01206062 . ) Background The prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure study addresses the issue of whether progression to manifest hypertension in patients with high-normal blood pressure can be prevented with treatment . Methods A total of 1008 participants with high-normal office blood pressure were r and omized to ramipril treatment group ( n = 505 ) and a control group ( n = 503 ) . The patients were followed up for 3 years . Primary endpoint was to prevent or delay the progression to manifest hypertension . Secondary endpoints were reduction in the incidence of cerebrovascular and cardiovascular events , as well as the development of hypertension as defined by ambulatory blood pressure monitoring . Findings One hundred and fifty-five patients ( 30.7 % ) in the ramipril group , and 216 ( 42.9 % ) in the control group reached the primary endpoint ( relative risk reduction 34.4 % , P = 0.0001 ) . Ramipril also proved to be more effective in reducing the incidence of manifest office hypertension in patients with baseline ambulatory blood pressure monitoring high-normal blood pressure . The incidence of cerebrovascular and cardiovascular events showed no statistically significant differences between the two groups . Cough was more frequent in the ramipril group ( 4.8 vs. 0.4 % ) . Interpretation There is now good clinical evidence that patients with high-normal blood pressure ( prehypertension ) are more likely to progress to manifest hypertension than patients with optimal or normal blood pressure . Additional ambulatory blood pressure monitoring seems to be essential to achieve correct diagnosis . Treatment of patients with high-normal office blood pressure with the angiotensin-converting enzyme inhibitor was well tolerated , and significantly reduced the risk of progression to manifest hypertension Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more BACKGROUND It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure . METHODS We r and omly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan ( 300 mg daily ) , amlodipine ( 10 mg daily ) , or  placebo .  The target blood pressure was 135/85 mm Hg or less in all groups . We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration , the development of end-stage renal disease , or death from any cause . We also compared them with regard to the time to a secondary , cardiovascular composite end point . RESULTS The mean duration of follow-up was 2.6 years . Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group ( P=0.02 ) and 23 percent lower than that in the amlodipine group ( P=0.006 ) . The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group ( P=0.003 ) and 37 percent lower in the irbesartan group than in the amlodipine group ( P<0.001 ) . Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups ( P=0.07 for both comparisons ) . These differences were not explained by differences in the blood pressures that were achieved . The serum creatinine concentration increased 24 percent more slowly in the irbesartan group than in the placebo group ( P=0.008 ) and 21 percent more slowly than in the amlodipine group ( P=0.02 ) . There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point . CONCLUSIONS The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes . This protection is independent of the reduction in blood pressure it causes BACKGROUND The multicenter double-blind , r and omized Bergamo Nephrologic Diabetes Complications Trial ( BENEDICT ) was design ed to assess whether angiotensin-converting-enzyme inhibitors and non-dihydropyridine calcium-channel blockers , alone or in combination , prevent microalbuminuria in subjects with hypertension , type 2 diabetes mellitus , and normal urinary albumin excretion . METHODS We studied 1204 subjects , who were r and omly assigned to receive at least three years of treatment with tr and olapril  ( at a dose of 2 mg per day ) plus verapamil ( sustained-release formulation , 180 mg per day ) , tr and olapril alone ( 2 mg per day ) , verapamil alone ( sustained-release formulation , 240 mg per day ) , or placebo .  The target blood pressure was 120/80 mm Hg . The primary end point was the development of persistent microalbuminuria ( overnight albumin excretion , > or = 20 microg per minute at two consecutive visits ) . RESULTS The primary outcome was reached in 5.7 percent of the subjects receiving tr and olapril plus verapamil , 6.0 percent of the subjects receiving tr and olapril , 11.9 percent of the subjects receiving verapamil , and 10.0 percent of control subjects receiving placebo . The estimated acceleration factor ( which quantifies the effect of one treatment relative to another in accelerating or slowing disease progression ) adjusted for predefined baseline characteristics was 0.39 for the comparison between verapamil plus tr and olapril and placebo ( P=0.01 ) , 0.47 for the comparison between tr and olapril and placebo ( P=0.01 ) , and 0.83 for the comparison between verapamil and placebo ( P=0.54 ) . Tr and olapril plus verapamil and tr and olapril alone delayed the onset of microalbuminuria by factors of 2.6 and 2.1 , respectively . Serious adverse events were similar in all treatment groups . CONCLUSIONS In subjects with type 2 diabetes and hypertension but with normoalbuminuria , the use of tr and olapril plus verapamil and tr and olapril alone decreased the incidence of microalbuminuria to a similar extent . The effect of verapamil alone was similar to that of placebo Background Prehypertension is associated with higher  cardiovascular risk ,  target organ damage , and incidence of hypertension . The Prevention of Hypertension in Patients with PreHypertension ( PREVER‐Prevention ) trial aim ed to evaluate the efficacy and safety of a low‐dose diuretic for the prevention of hypertension and end‐organ damage . Methods and Results This r and omized , parallel , double‐blind , placebo‐controlled trial was conducted in 21 Brazilian academic medical centers . Participants with prehypertension who were aged 30 to 70 years and who did not reach optimal blood pressure after 3 months of lifestyle intervention  were r and omized to a chlorthalidone/amiloride combination pill or placebo and were evaluated every 3 months during 18 months of treatment . The primary outcome was incidence of hypertension . Development or worsening of microalbuminuria , new‐onset diabetes mellitus , and reduction of left ventricular mass were secondary outcomes . Participant characteristics were evenly distributed by trial arms . The incidence of hypertension was significantly lower in 372 study participants allocated to diuretics compared with 358 allocated to placebo ( hazard ratio 0.56 , 95 % CI 0.38–0.82 ) , result ing in a cumulative incidence of 11.7 % in the diuretic arm versus 19.5 % in the placebo arm ( P=0.004 ) . Adverse events ; levels of blood glucose , glycosylated hemoglobin , creatinine , and microalbuminuria ; and incidence of diabetes mellitus were no different between the 2 arms . Left ventricular mass assessed through Sokolow‐Lyon voltage and voltage‐ duration product decreased to a greater extent in participants allocated to diuretic therapy compared with placebo ( P=0.02 ) . Conclusions A combination of low‐dose chlorthalidone and amiloride effectively reduces the risk of incident hypertension and beneficially affects left ventricular mass in patients with prehypertension . Clinical Trial Registration URL : http://www . Clinical Trials.gov , www.ensaiosclinicos.gov . Unique identifiers : NCT00970931 , RBR‐74rr6s BACKGROUND Calcium antagonists are widely prescribed for angina pectoris but their effect on clinical outcome is controversial . We aim ed to investigate the effect of the calcium antagonist nifedipine on long-term outcome in patients with stable angina pectoris . METHODS We r and omly assigned 3825 patients with treated stable symptomatic coronary disease to double-blind addition of nifedipine GITS  ( gastrointestinal therapeutic system ) 60 mg once daily and 3840 to placebo . The primary endpoint was the combination of death , acute myocardial infa rct ion , refractory angina , new overt heart failure , debilitating stroke , and peripheral revascularisation . Mean follow-up was 4.9 years ( SD 1.1 ) . Analysis was by intention to treat . FINDINGS 310 patients allocated nifedipine  died ( 1.64 per 100 patient-years ) compared with 291 people allocated placebo  ( 1.53 per 100 patient-years ; hazard ratio 1.07 [ 95 % CI 0.91 - 1.25 ] , p=0.41 ) . Primary endpoint rates were 4.60 per 100 patient-years for nifedipine and 4.75 per 100 patient-years for placebo ( 0.97 [ 0.88 - 1.07 ] , p=0.54 ) . With nifedipine , rate of death and any cardiovascular event or procedure was 9.32 per 100 patient-years versus 10.50 per 100 patient-years for placebo ( 0.89 [ 0.83 - 0.95 ] , p=0.0012 ) . The difference was mainly attributable to a reduction in the need for coronary angiography and interventions in patients assigned nifedipine , despite an increase in peripheral revascularisation . Nifedipine had no effect on the rate of myocardial infa rct ion . INTERPRETATION Addition of nifedipine GITS to conventional treatment of angina pectoris has no effect on major cardiovascular event-free survival .  Nifedipine GITS is safe and reduces the need for coronary angiography and interventions OBJECTIVE The Appropriate Blood Pressure Control in Diabetes ( ABCD ) Trial is a prospect i ve r and omized blinded clinical trial that compares the effects of intensive versus moderate blood pressure control on the incidence and progression of type 2 diabetic complications . The current article discusses the results of 5.3 years of follow-up of 470 patients with hypertension and evaluates the effects of intensive and moderate blood pressure therapy using nisoldipine versus enalapril as the initial antihypertensive medication for nephropathy , retinopathy , and neuropathy . RESEARCH DESIGN AND METHODS The 470 hypertensive subjects , defined as having a baseline diastolic blood pressure of > or = 90 mmHg , were r and omized to intensive blood pressure control ( diastolic blood pressure goal of 75 mmHg ) versus moderate blood pressure control ( diastolic blood pressure goal of 80 - 89 mmHg ) . RESULTS The mean blood pressure achieved was 132/78 mmHg in the intensive group and 138/86 mmHg in the moderate control group . During the 5-year follow-up period , no difference was observed between intensive versus moderate blood pressure control and those r and omized to nisoldipine versus enalapril with regard to the change in creatinine clearance . After the first year of antihypertensive treatment , creatinine clearance stabilized in both the intensive and moderate blood pressure control groups in those patients with baseline normo- or microalbuminuria . In contrast , patients starting with overt albuminuria demonstrated a steady decline in creatinine clearance of 5 - 6 ml.min-1.1.73 m-2 per year throughout the follow-up period whether they were on intensive or moderate therapy . There was also no difference between the interventions with regard to individuals progressing from normoalbuminuria to microalbuminuria ( 25 % intensive therapy vs. 18 % moderate therapy , P = 0.20 ) or microalbuminuria to overt albuminuria ( 16 % intensive therapy vs. 23 % moderate therapy , P = 0.28 ) . Intensive therapy demonstrated a lower overall incidence of deaths , 5.5 vs. 10.7 % , P = 0.037 . Over a 5-year follow-up period , there was no difference between the intensive and moderate groups with regard to the progression of diabetic retinopathy and neuropathy . In addition , the use of nisoldipine versus enalapril had no differential effect on diabetic retinopathy and neuropathy . CONCLUSIONS Blood pressure control of 138/86 or 132/78 mmHg with either nisoldipine or enalapril as the initial antihypertensive medication appeared to stabilize renal function in hypertensive type 2 diabetic patients without overt albuminuria over a 5-year period . The more intensive blood pressure control decreased all-cause mortality Abstract Objective To investigate whether a low dose of the angiotensin converting enzyme ( ACE ) inhibitor ramipril lowers cardiovascular and renal events in patients with type 2 diabetes who have microalbuminuria or proteinuria . Design R and omised , double blind , parallel group trial comparing ramipril ( 1.25 mg/day ) with placebo ( on top of usual treatment ) for cardiovascular and renal outcomes for at least three years . Setting Multicentre , primary care study conducted mostly by general practitioners in 16 European and north African countries . Participants 4912 patients with type 2 diabetes aged > 50 years who use oral antidiabetic drugs and have persistent microalbuminuria or proteinuria ( urinary albumin excretion 20 mg/l in two consecutive sample s ) , and serum creatinine ≤ 150 μmol/l . Main outcome measures The primary outcome measure was the combined incidence of cardiovascular death , non-fatal myocardial infa rct ion , stroke , heart failure leading to hospital admission , and end stage renal failure . Results Participants were followed for 3 to 6 ( median 4 ) years . There were 362 primary events among the 2443 participants taking ramipril ( 37.8 per 1000 patient years ) and 377 events among the 2469 participants taking placebo ( 38.8 per 1000 patient years ; hazard ratio 1.03 ( 95 % confidence interval 0.89 to 1.20 , P = 0.65 ) ) . None of the components of the primary outcome was reduced . Ramipril  lowered systolic and diastolic blood pressures ( by 2.43 and 1.06 mm Hg respectively after two years ) and favoured regression from microalbuminuria ( 20 - 200 mg/l ) or proteinuria ( > 200mg/l ) to normal level ( < 20 mg/l ) or microalbuminuria ( P < 0.07 ) in 1868 participants who completed the study . Conclusions Low dose ( 1.25 mg ) ramipril once daily has no effect on cardiovascular and renal outcomes of patients with type 2 diabetes and albuminuria , despite a slight decrease in blood pressure and urinary albumin . The cardiovascular benefits of a daily higher dose ( 10 mg ) ramipril observed elsewhere are not found with an eightfold lower daily dose BACKGROUND Whether the treatment of patients with hypertension who are 80 years of age or older is beneficial is unclear . It has been suggested that antihypertensive therapy may reduce the risk of stroke , despite possibly increasing the risk of death . METHODS We r and omly assigned 3845 patients from Europe , China , Australasia , and Tunisia who were 80 years of age or older and had a sustained systolic blood pressure of 160 mm Hg or more to receive either the diuretic indapamide ( sustained release , 1.5 mg ) or matching placebo .  The angiotensin-converting-enzyme inhibitor perindopril ( 2 or 4 mg ) , or matching placebo , was added if necessary to achieve the target blood pressure of 150/80 mm Hg . The primary end point was fatal or nonfatal stroke . RESULTS The active-treatment group ( 1933 patients ) and the placebo group ( 1912 patients ) were well matched ( mean age , 83.6 years ; mean blood pressure while sitting , 173.0/90.8 mm Hg ) ; 11.8 % had a history of cardiovascular disease . Median follow-up was 1.8 years . At 2 years , the mean blood pressure while sitting was 15.0/6.1 mm Hg lower in the active-treatment group than in the placebo group . In an intention-to-treat analysis , active treatment was associated with a 30 % reduction in the rate of fatal or nonfatal stroke ( 95 % confidence interval [ CI ] , -1 to 51 ; P=0.06 ) , a 39 % reduction in the rate of death from stroke ( 95 % CI , 1 to 62 ; P=0.05 ) , a 21 % reduction in the rate of death from any cause ( 95 % CI , 4 to 35 ; P=0.02 ) , a 23 % reduction in the rate of death from cardiovascular causes ( 95 % CI , -1 to 40 ; P=0.06 ) , and a 64 % reduction in the rate of heart failure ( 95 % CI , 42 to 78 ; P<0.001 ) . Fewer serious adverse events were reported in the active-treatment group ( 358 , vs. 448 in the placebo group ; P=0.001 ) . CONCLUSIONS The results provide evidence that antihypertensive treatment with indapamide ( sustained release ) , with or without perindopril , in persons 80 years of age or older is beneficial . ( Clinical Trials.gov number , NCT00122811 [ Clinical Trials.gov ] . ) CONTEXT Hypertension is a leading cause of end-stage renal disease ( ESRD ) in the United States , with no known treatment to prevent progressive declines leading to ESRD . OBJECTIVE To compare the effects of 2 levels of blood pressure ( BP ) control and 3 antihypertensive drug classes on glomerular filtration rate ( GFR ) decline in hypertension . DESIGN R and omized 3 x 2 factorial trial with enrollment from February 1995 to September 1998 . SETTING AND PARTICIPANTS A total of 1094 African Americans aged 18 to 70 years with hypertensive renal disease ( GFR , 20 - 65 mL/min per 1.73 m(2 ) ) were recruited from 21 clinical centers throughout the United States and followed up for 3 to 6.4 years . INTERVENTIONS Participants were r and omly assigned to 1 of 2 mean arterial pressure goals , 102 to 107 mm Hg ( usual ; n = 554 ) or 92 mm Hg or less ( lower ; n = 540 ) , and to initial treatment with either a beta-blocker ( metoprolol 50 - 200 mg/d ; n = 441 ) , an angiotensin-converting enzyme inhibitor ( ramipril 2.5 - 10 mg/d ; n = 436 ) or a dihydropyridine calcium channel blocker , ( amlodipine 5 - 10 mg/d ; n = 217 ) . Open-label agents were added to achieve the assigned BP goals . MAIN OUTCOME MEASURES Rate of change in GFR ( GFR slope ) ; clinical composite outcome of reduction in GFR by 50 % or more ( or > or = 25 mL/min per 1.73 m2 ) from baseline , ESRD , or death . Three primary treatment comparisons were specified : lower vs usual BP goal ; ramipril vs metoprolol ; and amlodipine vs metoprolol . RESULTS Achieved BP averaged ( SD ) 128/78 ( 12/8 ) mm Hg in the lower BP group and 141/85 ( 12/7 ) mm Hg in the usual BP group . The mean ( SE ) GFR slope from baseline through 4 years did not differ significantly between the lower BP group ( -2.21 [ 0.17 ] mL/min per 1.73 m2 per year ) and the usual BP group ( -1.95 [ 0.17 ] mL/min per 1.73 m2 per year ; P = .24 ) , and the lower BP goal did not significantly reduce the rate of the clinical composite outcome ( risk reduction for lower BP group = 2 % ; 95 % confidence interval [ CI ] , -22 % to 21 % ; P = .85 ) . None of the drug group comparisons showed consistent significant differences in the GFR slope . However , compared with the metoprolol and amlodipine groups , the ramipril group manifested risk reductions in the clinical composite outcome of 22 % ( 95 % CI , 1%-38 % ; P = .04 ) and 38 % ( 95 % CI , 14%-56 % ; P = .004 ) , respectively . There was no significant difference in the clinical composite outcome between the amlodipine and metoprolol groups . CONCLUSIONS No additional benefit of slowing progression of hypertensive nephrosclerosis was observed with the lower BP goal . Angiotensin-converting enzyme inhibitors appear to be more effective than beta-blockers or dihydropyridine calcium channel blockers in slowing GFR decline The pilot study of the Systolic Hypertension in the Elderly Program was a r and omized , double-blind , placebo-controlled trial of drug therapy for isolated systolic hypertension . It followed 551 elderly participants with untreated blood pressures of greater than 160/less than 90 mm Hg for an average of 34 months . Mean age of the participants was 72 years ; 63 % were women , and 82 % were white . Pretreatment blood pressures averaged 172/75 mm Hg . Participants were r and omly assigned to treatment with chlorthalidone or placebo as Step I medication . Blood pressures at annual visits averaged 141/68 and 157/73 mm Hg for the drug-treated and placebo-treated groups , respectively , with 60 % and 33 % of the survivors on blinded medication having systolic blood pressures of less than 160 mm Hg at their last annual visit . All-cause mortality rates for the drug-treated and placebo-treated groups were 25.4 and 22.7 deaths per 1,000 participant-years of risk , and rates for definite " first stroke " were 8.3 and 12.8 per 1,000 years of risk . Differences between groups were significant for systolic and diastolic blood pressure but not for death or stroke rates . A full-scale study has begun to determine the effects of drug therapy for isolated systolic hypertension on stroke and mortality rates BACKGROUND Lowering of blood pressure prevents stroke but optimum target levels to prevent recurrent stroke are unknown . We investigated the effects of different blood-pressure targets on the rate of recurrent stroke in patients with recent lacunar stroke . METHODS In this r and omised open-label trial , eligible patients lived in North America , Latin America , and Spain and had recent , MRI-defined symptomatic lacunar infa rct ions . Patients were recruited between March , 2003 , and April , 2011 , and r and omly assigned , according to a two-by-two multifactorial design , to a systolic-blood-pressure target of 130 - 149 mm Hg or less than 130 mm Hg . The primary endpoint was reduction in all stroke ( including ischaemic strokes and intracranial haemorrhages ) . Analysis was done by intention to treat . This study is registered with Clinical Trials.gov , number NCT 00059306 . FINDINGS 3020 enrolled patients , 1519 in the higher-target group and 1501 in the lower-target group , were followed up for a mean of 3·7 ( SD 2·0 ) years . Mean age was 63 ( SD 11 ) years . After 1 year , mean systolic blood pressure was 138 mm Hg ( 95 % CI 137 - 139 ) in the higher-target group and 127 mm Hg ( 95 % CI 126 - 128 ) in the lower-target group . Non-significant rate reductions were seen for all stroke ( hazard ratio 0·81 , 95 % CI 0·64 - 1·03 , p=0·08 ) , disabling or fatal stroke ( 0·81 , 0·53 - 1·23 , p=0·32 ) , and the composite outcome of myocardial infa rct ion or vascular death ( 0·84 , 0·68 - 1·04 , p=0·32 ) with the lower target . The rate of intracerebral haemorrhage was reduced significantly ( 0·37 , 0·15 - 0·95 , p=0·03 ) . Treatment-related serious adverse events were infrequent . INTERPRETATION Although the reduction in stroke was not significant , our results support that in patients with recent lacunar stroke , the use of a systolic-blood-pressure target of less than 130 mm Hg is likely to be beneficial . FUNDING National Institutes of Health-National Institute of Neurological Disorders and Stroke ( NIH-NINDS ) BACKGROUND This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease , cardiovascular disease , or both . METHODS In a double-blind fashion , we r and omly assigned 8561 patients to aliskiren ( 300 mg daily ) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker . The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation ; nonfatal myocardial infa rct ion ; nonfatal stroke ; unplanned hospitalization for heart failure ; end-stage renal disease , death attributable to kidney failure , or the need for renal-replacement therapy with no dialysis  or transplantation available or initiated ; or doubling of the baseline serum creatinine level . RESULTS The trial was stopped prematurely after the second interim efficacy analysis . After a median follow-up of 32.9 months , the primary end point had occurred in 783 patients ( 18.3 % ) assigned to aliskiren as compared with 732 ( 17.1 % ) assigned to placebo ( hazard ratio , 1.08 ; 95 % confidence interval [ CI ] , 0.98 to 1.20 ; P=0.12 ) . Effects on secondary renal end points were similar . Systolic and diastolic blood pressures were lower with aliskiren ( between-group differences , 1.3 and 0.6 mm Hg , respectively ) and the mean reduction in the urinary albumin-to-creatinine ratio was greater ( between-group difference , 14 percentage points ; 95 % CI , 11 to 17 ) . The proportion of patients with hyperkalemia ( serum potassium level , ≥6 mmol per liter ) was significantly higher in the aliskiren group than in the placebo group ( 11.2 % vs. 7.2 % ) , as was the proportion with reported hypotension ( 12.1 % vs. 8.3 % ) ( P<0.001 for both comparisons ) . CONCLUSIONS The addition of aliskiren to st and ard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful . ( Funded by Novartis ; ALTITUDE Clinical Trials.gov number , NCT00549757 . ) BACKGROUND Microalbuminuria is an early predictor of diabetic nephropathy and premature cardiovascular disease . We investigated whether treatment with an angiotensin-receptor blocker ( ARB ) would delay or prevent the occurrence of microalbuminuria in patients with type 2 diabetes and normoalbuminuria . METHODS In a r and omized , double-blind , multicenter , controlled trial , we assigned 4447 patients with type 2 diabetes to receive olmesartan ( at a dose of 40 mg once daily ) or placebo for a median of 3.2 years . Additional antihypertensive drugs ( except angiotensin-converting-enzyme inhibitors or ARBs ) were used as needed to lower blood pressure to less than 130/80 mm Hg . The primary outcome was the time to the first onset of microalbuminuria . The times to the onset of renal and cardiovascular events were analyzed as secondary end points . RESULTS The target blood pressure ( < 130/80 mm Hg ) was achieved in nearly 80 % of the patients taking olmesartan and 71 % taking placebo ;  blood pressure measured in the clinic was lower by 3.1/1.9 mm Hg in the olmesartan group than in the placebo group . Microalbuminuria developed in 8.2 % of the patients in the olmesartan group ( 178 of 2160 patients who could be evaluated ) and 9.8 % in the placebo group ( 210 of 2139 ) ; the time to the onset of microalbuminuria was increased by 23 % with olmesartan ( hazard ratio for onset of microalbuminuria , 0.77 ; 95 % confidence interval , 0.63 to 0.94 ; P=0.01 ) . The serum creatinine level doubled in 1 % of the patients in each group . Slightly fewer patients in the olmesartan group than in the placebo group had nonfatal cardiovascular events--81 of 2232 patients ( 3.6 % ) as compared with 91 of 2215 patients ( 4.1 % ) (P=0.37)--but a greater number had fatal cardiovascular events--15 patients ( 0.7 % ) as compared with 3 patients ( 0.1 % ) ( P=0.01 ) , a difference that was attributable in part to a higher rate of death from cardiovascular causes in the olmesartan group than in the placebo group among patients with preexisting coronary heart disease ( 11 of 564 patients [ 2.0 % ] vs. 1 of 540 [ 0.2 % ] , P=0.02 ) . CONCLUSIONS Olmesartan was associated with a delayed onset of microalbuminuria , even though blood-pressure control in both groups was excellent according to current st and ards . The higher rate of fatal cardiovascular events with olmesartan among patients with preexisting coronary heart disease is of concern . ( Funded by Daiichi Sankyo ; Clinical Trials.gov number , NCT00185159 . ) BACKGROUND It is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance . METHODS In this double-blind , r and omized clinical trial with a 2-by-2 factorial design , we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan ( up to 160 mg daily ) or placebo ( and nateglinide or placebo ) in addition to lifestyle modification . We then followed the patients for a median of 5.0 years for the development of diabetes ( 6.5 years for vital status ) . We studied the effects of valsartan on the occurrence of three co primary outcomes : the development of diabetes ; an extended composite outcome of death from cardiovascular causes , nonfatal myocardial infa rct ion , nonfatal stroke , hospitalization for heart failure , arterial revascularization , or hospitalization for unstable angina ; and a core composite outcome that excluded unstable angina and revascularization . RESULTS The cumulative incidence of diabetes was 33.1 % in the valsartan group , as compared with 36.8 % in the placebo group ( hazard ratio in the valsartan group , 0.86 ; 95 % confidence interval [ CI ] , 0.80 to 0.92 ; P<0.001 ) . Valsartan , as compared with placebo , did not significantly reduce the incidence of either the extended cardiovascular outcome ( 14.5 % vs. 14.8 % ; hazard ratio , 0.96 ; 95 % CI , 0.86 to 1.07 ; P=0.43 ) or the core cardiovascular outcome ( 8.1 % vs. 8.1 % ; hazard ratio , 0.99 ; 95 % CI , 0.86 to 1.14 ; P=0.85 ) . CONCLUSIONS Among patients with impaired glucose tolerance and cardiovascular disease or risk factors , the use of valsartan for 5 years , along with lifestyle modification , led to a relative reduction of 14 % in the incidence of diabetes but did not reduce the rate of cardiovascular events . ( Clinical Trials.gov number , NCT00097786 . OBJECTIVES The primary objective of this study was to investigate the effects of the angiotensin-converting enzyme ( ACE ) inhibitor , ramipril , on carotid atherosclerosis in patients with coronary , cerebrovascular or peripheral vascular disease . BACKGROUND Angiotensin-converting enzyme inhibitors have been shown to reduce the risk of coronary events in various patient groups and to prevent the development of atherosclerosis in animal models . It has been hypothesized that the clinical benefits of ACE inhibitors may , therefore , be mediated by effects on atherosclerosis . METHODS Six hundred seventeen patients were r and omized in equal proportions to ramipril ( 5 - 10 mg daily ) or placebo . At baseline , two years and four years , carotid atherosclerosis was assessed by B-mode ultrasound , and left ventricular mass was assessed by M-mode echocardiography . RESULTS Blood pressure ( BP ) was reduced by a mean of 6 mm Hg systolic and 4 mm Hg diastolic in the ramipril group compared with the placebo group ( p<0.001 ) . There was no difference between groups in the changes in common carotid artery wall thickness ( p = 0.58 ) or in carotid plaque ( p = 0.93 ) . Left ventricular mass index decreased by 3.8 g/m2 ( 4 % ) in the ramipril group compared with the placebo group ( 2p = 0.04 ) . CONCLUSIONS The results provide no support for the hypothesis that reduced atherosclerosis is responsible for the beneficial effects of ACE inhibitors on major coronary events . It is more likely that the benefits are due to lower BP , reduced left ventricular mass or other factors such as reversal of endothelial dysfunction 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 Background The prognostic benefits of blood pressure lowering treatment in elderly hypertensive patients were established more than a decade ago , but are less clear in those with mildly to moderately elevated blood pressure . Objective To assess whether c and esartan-based antihypertensive treatment in elderly patients with mildly to moderately elevated blood pressure confers a reduction in cardiovascular events , cognitive decline and dementia . Design Prospect i ve , double-blind , r and omized , parallel-group study conducted in 1997–2002 . Setting and participants The study was of 4964 patients aged 70–89 years , with systolic blood pressure 160–179 mmHg , and /or diastolic blood pressure 90–99 mmHg , and a Mini Mental State Examination ( MMSE ) test score ⩾ 24 . A total of 527 centres in 15 countries participated in the study . Intervention Patients were assigned r and omly to receive the angiotensin receptor blocker c and esartan or placebo , with open-label active antihypertensive therapy added as needed . As a consequence , active antihypertensive therapy was extensively used in the control group ( 84 % of patients ) . Mean follow-up was 3.7 years . Main outcome measures The primary outcome measure was major cardiovascular events , a composite of cardiovascular death , non-fatal stroke and non-fatal myocardial infa rct ion . Secondary outcome measures included cardiovascular death , non-fatal and fatal stroke and myocardial infa rct ion , cognitive function measured by the MMSE and dementia . Results Blood pressure fell by 21.7/10.8 mmHg in the c and esartan group and by 18.5/9.2 mmHg in the control group . A first major cardiovascular event occurred in 242 c and esartan patients and in 268 control patients ; risk reduction with c and esartan was 10.9 % [ 95 % confidence interval ( CI ) , −6.0 to 25.1 , P = 0.19 ] . C and esartan-based treatment reduced non-fatal stroke by 27.8 % ( 95 % CI , 1.3 to 47.2 , P = 0.04 ) , and all stroke by 23.6 % ( 95 % CI , −0.7 to 42.1 , P = 0.056 ) . There were no significant differences in myocardial infa rct ion and cardiovascular mortality . Mean MMSE score fell from 28.5 to 28.0 in the c and esartan group and from 28.5 to 27.9 in the control group ( P = 0.20 ) . The proportions of patients who had a significant cognitive decline or developed dementia were not different in the two treatment groups . Conclusions In elderly hypertensive patients , a slightly more effective blood pressure reduction during c and esartan-based therapy , compared with control therapy , was associated with a modest , statistically non-significant , reduction in major cardiovascular events and with a marked reduction in non-fatal stroke . Cognitive function was well maintained in both treatment groups in the presence of substantial blood pressure reductions . Both treatment regimens were generally well tolerated BACKGROUND Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction , whether or not they have heart failure . We assessed the role of an angiotensin-converting-enzyme inhibitor , ramipril , in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure . METHODS A total of 9297 high-risk patients ( 55 years of age or older ) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were r and omly assigned to receive ramipril ( 10 mg once per day orally ) or matching placebo for a mean of five years . The primary outcome was a composite of myocardial infa rct ion , stroke , or death from cardiovascular causes . The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper . RESULTS A total of 651 patients who were assigned to receive  ramipril ( 14.0 percent ) reached the primary end point , as compared with 826 patients who were assigned to receive placebo ( 17.8 percent ) ( relative risk , 0.78 ; 95 percent confidence interval , 0.70 to 0.86 ; P<0.001 ) . Treatment with ramipril reduced the rates of death from cardiovascular causes ( 6.1 percent , as compared with 8.1 percent in the placebo group ; relative risk , 0.74 ; P<0.001 ) , myocardial infa rct ion ( 9.9 percent vs. 12.3 percent ; relative risk , 0.80 ; P<0.001 ) , stroke ( 3.4 percent vs. 4.9 percent ; relative risk , 0.68 ; P<0.001 ) , death from any cause ( 10.4 percent vs. 12.2 percent ; relative risk , 0.84 ; P=0.005 ) , revascularization procedures ( 16.3 percent vs. 18.8 percent ; relative risk , 0.85 ; P<0.001 ) , cardiac arrest ( 0.8 percent vs. 1.3 percent ; relative risk , 0.62 ; P=0.02 ) , [ corrected ] heart failure ( 9.1 percent vs. 11.6 percent ; relative risk , 0.77 ; P<0.001 ) , and complications related to diabetes ( 6.4 percent vs. 7.6 percent ; relative risk , 0.84 ; P=0.03 ) . CONCLUSIONS Ramipril significantly reduces the rates of death , myocardial infa rct ion , and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure This study was performed to investigate whether intensive antihypertensive treatment with achieved blood pressure ( BP ) ≤140/90 mm Hg , as compared with st and ard treatment with achieved BP ≤150/90 mm Hg , could further improve cardiovascular outcomes in Chinese hypertensive patients older than 70 years . A total of 724 participants were r and omly assigned to intensive or st and ard antihypertensive treatment . After a mean follow-up of 4 years , the mean achieved BP was 135.7/76.2 mm Hg in the intensive treatment group and 149.7/82.1 mm Hg in the st and ard treatment group . The visit-to-visit variability in systolic BP and diastolic BP was lower in the intensive group than that in the st and ard group . Intensive antihypertensive treatment , compared with the st and ard treatment , decreased total and cardiovascular mortality by 41.7 % and 50.3 % , respectively , and reduced fatal/nonfatal stroke by 42.0 % and heart failure death by 62.7 % . Cox regression analysis indicated that the mean systolic BP ( P=.020 ; 95 % confidence interval , 1.006 - 1.069 ) and the st and ard deviation of systolic BP ( P=.033 ; 95 % confidence interval , 1.006 - 1.151 ) were risk factors for cardiovascular endpoint events . Intensive antihypertensive treatment with achieved 136/76 mm Hg was beneficial for Chinese hypertensive patients older than 70 years . Long-term visit-to-visit variability in systolic BP was positively associated with the incidence of cardiovascular events BACKGROUND Despite treatment , there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals . Inadequate reduction of their blood pressure is a likely cause , but the optimum target blood pressure is not known . The impact of acetylsalicylic acid ( aspirin ) has never been investigated in patients with hypertension . We aim ed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension . METHODS 18790 patients , from 26 countries , aged 50 - 80 years ( mean 61.5 years ) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg ( mean 105 mm Hg ) were r and omly assigned a target diastolic blood pressure . 6264 patients were allocated to the target pressure < or = 90 mm Hg , 6264 to < or = 85 mm Hg , and 6262 to < or = 80 mm Hg . Felodipine was given as baseline therapy with the addition of other agents , according to a five-step regimen . In addition , 9399 patients were r and omly assigned 75 mg/day acetylsalicylic acid ( Bamycor , Astra ) and 9391 patients were assigned  placebo . FINDINGS Diastolic blood pressure was reduced by 20.3 mm Hg , 22.3 mm Hg , and 24.3 mm Hg , in the < or = 90 mm Hg , < or = 85 mm Hg , and < or = 80 mm Hg target groups , respectively . The lowest incidence of major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82.6 mm Hg ; the lowest risk of cardiovascular mortality occurred at 86.5 mm Hg . Further reduction below these blood pressures was safe .  In patients with diabetes mellitus there was a 51 % reduction in major cardiovascular events in target group < or = 80 mm Hg compared with target group < or = 90 mm Hg ( p for trend=0.005 ) . Acetylsalicylic acid reduced major cardiovascular events by 15 % ( p=0.03 ) and all myocardial infa rct ion by 36 % ( p=0.002 ) , with no effect on stroke . There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group , and 129 versus 70 non-fatal major bleeds in the two groups , respectively ( p<0.001 ) . INTERPRETATION Intensive lowering of blood pressure in patients with hypertension was associated with a low rate of cardiovascular events . The HOT Study shows the benefits of lowering the diastolic blood pressure down to 82.6 mm Hg . Acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infa rct ion . There was no effect on the incidence of stroke or fatal bleeds , but non-fatal major bleeds were twice as common BACKGROUND Previous trials have shown that the use of statins to lower cholesterol reduces the risk of cardiovascular events among persons without cardiovascular disease . Those trials have involved persons with elevated lipid levels or inflammatory markers and involved mainly white persons . It is unclear whether the benefits of statins can be extended to an intermediate-risk , ethnically diverse population without cardiovascular disease . METHODS In one comparison from a 2-by-2 factorial trial , we r and omly assigned 12,705 participants in 21 countries who did not have cardiovascular disease and were at intermediate risk to receive rosuvastatin at a dose of 10 mg per day or placebo . The first co primary outcome was the composite of death from cardiovascular causes , nonfatal myocardial infa rct ion , or nonfatal stroke , and the second co primary outcome additionally included revascularization , heart failure , and resuscitated cardiac arrest . The median follow-up was 5.6 years . RESULTS The overall mean low-density lipoprotein cholesterol level was 26.5 % lower in the rosuvastatin group than in the placebo group . The first co primary outcome occurred in 235 participants ( 3.7 % ) in the rosuvastatin group and in 304 participants ( 4.8 % ) in the placebo group ( hazard ratio , 0.76 ; 95 % confidence interval [ CI ] , 0.64 to 0.91 ; P=0.002 ) . The results for the second co primary outcome were consistent with the results for the first ( occurring in 277 participants [ 4.4 % ] in the rosuvastatin group and in 363 participants [ 5.7 % ] in the placebo group ; hazard ratio , 0.75 ; 95 % CI , 0.64 to 0.88 ; P<0.001 ) . The results were also consistent in subgroups defined according to cardiovascular risk at baseline , lipid level , C-reactive protein level , blood pressure , and race or ethnic group . In the rosuvastatin group , there was no excess of diabetes or cancers , but there was an excess of cataract surgery ( in 3.8 % of the participants , vs. 3.1 % in the placebo group ; P=0.02 ) and muscle symptoms ( in 5.8 % of the participants , vs. 4.7 % in the placebo group ; P=0.005 ) . CONCLUSIONS Treatment with rosuvastatin at a dose of 10 mg per day result ed in a significantly lower risk of cardiovascular events than placebo in an intermediate-risk , ethnically diverse population without cardiovascular disease . ( Funded by the Canadian Institutes of Health Research and AstraZeneca ; HOPE-3 Clinical Trials.gov number , NCT00468923 . ) Angiotensin-converting enzyme inhibitors improve endothelial function , inhibit experimental atherogenesis , and decrease ischemic events . The Quinapril Ischemic Event Trial was design ed to test the hypothesis that quinapril 20 mg/day would reduce ischemic events ( the occurrence of cardiac death , resuscitated cardiac arrest , nonfatal myocardial infa rct ion , coronary artery bypass grafting , coronary angioplasty , or hospitalization for angina pectoris ) and the angiographic progression of coronary artery disease in patients without systolic left ventricular dysfunction . A total of 1,750 patients were r and omized to quinapril 20 mg/day or placebo  and followed a mean of 27 + /- 0.3 months . The 38 % incidence of ischemic events was similar for both groups ( RR 1.04 ; 95 % confidence interval 0.89 to 1.22 ; p = 0.6 ) . There was also no significant difference in the incidence of patients having angiographic progression of coronary disease ( p = 0.71 ) . The rate of development of new coronary lesions was also similar in both groups ( p = 0.35 ) . However , there was a difference in the incidence of angioplasty for new ( previously unintervened ) vessels ( p = 0.018 ) . Quinapril was well tolerated in patients after angioplasty with normal left ventricular function . Quinapril 20 mg did not significantly affect the overall frequency of clinical outcomes or the progression of coronary atherosclerosis . However , the absence of the demonstrable effect of quinapril may be due to several limitations in study design OBJECTIVE To compare six antihypertensive interventions for the treatment of mild hypertension . DESIGN R and omized , double-blind , placebo-controlled clinical trial . SETTING Four hypertension screening and treatment centers in the United States . PARTICIPANTS Hypertensive men and women , aged 45 to 69 years , with diastolic blood pressure less than 100 mm Hg . INTERVENTION Sustained nutritional-hygienic advice to all participants to reduce weight , dietary sodium intake , and alcohol intake , and increase physical activity . Participants were r and omly allocated to take ( 1 ) placebo ( n = 234 ) ; ( 2 ) chlorthalidone ( n = 136 ) ; ( 3 ) acebutolol ( n = 132 ) ; ( 4 ) doxazosin mesylate ( n = 134 ) ; ( 5 ) amlodipine maleate ( n = 131 ) ; or ( 6 ) enalapril maleate ( n = 135 ) . MAIN OUTCOME MEASURES Blood pressure , quality of life , side effects , blood lipid levels and analysis of other serum components , echocardiographic and electrocardiographic changes , and incidence of cardiovascular events over an average of 4.4 years of follow-up . RESULTS Blood pressure reductions were sizable in all six groups , and were significantly greater for participants assigned to drug treatment than placebo ( -15.9 vs -9.1 mm Hg for systolic blood pressure and -12.3 vs -8.6 mm Hg for diastolic blood pressure ; P < .0001 ) . After 4 years , 59 % of participants assigned to placebo and 72 % of participants given drug treatment continued on their initial medication as monotherapy . A smaller percentage of participants assigned to the drug-treatment groups died or experienced a major nonfatal cardiovascular event than those assigned to the placebo group ( 5.1 % vs 7.3 % ; P = .21 ) . After including other clinical events , the percentage of participants affected was 11.1 % for those in the drug-treatment groups and 16.2 % for those in the placebo group ( P = .03 ) . Incidence rates of most resting electrocardiographic abnormalities were lower and quality of life was improved more for those assigned to drug-treatment groups rather than the placebo group . Differences among the five drug treatments did not consistently favor one group in terms of regression of left ventricular mass , blood lipid levels , and other outcome measures . CONCLUSIONS As an initial regimen , drug treatment in combination with nutritional-hygienic intervention was more effective in preventing cardiovascular and other clinical events than was nutritional-hygienic treatment alone . Drug-treatment group differences were minimal . Pending results from large-scale clinical trials to evaluate drug treatments for their effect on cardiovascular clinical events , these findings support the recommendations of the new fifth Joint National Committee report regarding treatment choices for people with stage 1 ( " mild " ) hypertension OBJECTIVE To assess the ability of antihypertensive drug treatment to reduce the risk of nonfatal and fatal ( total ) stroke in isolated systolic hypertension . DESIGN Multicenter , r and omized , double-blind , placebo-controlled . SETTING Community-based ambulatory population in tertiary care centers . PARTICIPANTS 4736 persons ( 1.06 % ) from 447,921 screenees aged 60 years and above were r and omized ( 2365 to active treatment , 2371 to placebo ) . Systolic blood pressure ranged from 160 to 219 mm Hg and diastolic blood pressure was less than 90 mm Hg . Of the participants , 3161 were not receiving antihypertensive medication at initial contact , and 1575 were . The average systolic blood pressure was 170 mm Hg ; average diastolic blood pressure , 77 mm Hg . The mean age was 72 years , 57 % were women , and 14 % were black . INTERVENTIONS -- Participants were stratified by clinical center and by antihypertensive medication status at initial contact . For step 1 of the trial , dose 1 was chlorthalidone , 12.5 mg/d , or matching placebo ; dose 2 was 25 mg/d . For step 2 , dose 1 was atenolol , 25 mg/d , or matching placebo ; dose 2 was 50 mg/d . MAIN OUTCOME MEASURES Primary . Nonfatal and fatal ( total ) stroke . Secondary . Cardiovascular and coronary morbidity and mortality , all-cause mortality , and quality of life measures . RESULTS Average follow-up was 4.5 years . The 5-year average systolic blood pressure was 155 mm Hg for the placebo group and 143 mm Hg for the active treatment group , and the 5-year average diastolic blood pressure was 72 and 68 mm Hg , respectively . The 5-year incidence of total stroke was 5.2 per 100 participants for active treatment and 8.2 per 100 for placebo . The relative risk by proportional hazards regression analysis was 0.64 ( P = .0003 ) . For the secondary end point of clinical nonfatal myocardial infa rct ion plus coronary death , the relative risk was 0.73 . Major cardiovascular events were reduced ( relative risk , 0.68 ) . For deaths from all causes , the relative risk was 0.87 . CONCLUSION In persons aged 60 years and over with isolated systolic hypertension , antihypertensive stepped-care drug treatment with low-dose chlorthalidone as step 1 medication reduced the incidence of total stroke by 36 % , with 5-year absolute benefit of 30 events per 1000 participants . Major cardiovascular events were reduced , with 5-year absolute benefit of 55 events per 1000 BACKGROUND Treatment with angiotensin-converting-enzyme ( ACE ) inhibitors reduces the rate of cardiovascular events among patients with left-ventricular dysfunction and those at high risk of such events . We assessed whether the ACE inhibitor perindopril reduced cardiovascular risk in a low-risk population with stable coronary heart disease and no apparent heart failure . METHODS We recruited patients from October , 1997 , to June , 2000 . 13655 patients were registered with previous myocardial infa rct ion ( 64 % ) , angiographic evidence of coronary artery disease ( 61 % ) , coronary revascularisation ( 55 % ) , or a positive stress test only ( 5 % ) . After a run-in period of 4 weeks , in which all patients received perindopril , 12218 patients were r and omly assigned perindopril 8 mg once daily ( n=6110 ) , or matching placebo ( n=6108 ) . The mean follow-up was 4.2 years , and the primary endpoint was cardiovascular death , myocardial infa rct ion , or cardiac arrest . Analysis was by intention to treat . FINDINGS Mean age of patients was 60 years ( SD 9 ) , 85 % were male , 92 % were taking platelet inhibitors , 62 % beta blockers , and 58 % lipid-lowering therapy . 603 ( 10 % ) placebo and 488 ( 8 % ) perindopril patients experienced the primary endpoint , which yields a 20 % relative risk reduction ( 95 % CI 9 - 29 , p=0.0003 ) with perindopril . These benefits were consistent in all predefined subgroups and secondary endpoints . Perindopril was well tolerated . INTERPRETATION Among patients with stable coronary heart disease without apparent heart failure , perindopril can significantly improve outcome . About 50 patients need to be treated for a period of 4 years to prevent one major cardiovascular event . Treatment with perindopril , on top of other preventive medications , should be considered in all patients with coronary heart disease BACKGROUND Microalbuminuria and hypertension are risk factors for diabetic nephropathy . Blockade of the renin-angiotensin system slows the progression to diabetic nephropathy in patients with type 1 diabetes , but similar data are lacking for hypertensive patients with type 2 diabetes . We evaluated the renoprotective effect of the angiotensin-II-receptor antagonist irbesartan in hypertensive patients with type 2 diabetes and microalbuminuria . METHODS A total of 590 hypertensive patients with type 2 diabetes and microalbuminuria were enrolled in this multinational , r and omized , double-blind , placebo-controlled study of irbesartan , at a dose of either 150 mg daily or 300 mg daily , and were followed for two years . The primary outcome was the time to the onset of diabetic nephropathy , defined by persistent albuminuria in overnight specimens , with a urinary albumin excretion rate that was greater than 200 microg per minute and at least 30 percent higher than the base-line level . RESULTS The base-line characteristics in the three groups were similar . Ten of the 194 patients in the 300-mg group ( 5.2 percent ) and 19 of the 195 patients in the 150-mg group ( 9.7 percent ) reached the primary end point , as compared with 30 of the 201 patients in the placebo group ( 14.9 percent ) ( hazard ratios , 0.30 [ 95 percent confidence interval , 0.14 to 0.61 ; P < 0.001 ] and 0.61 [ 95 percent confidence interval , 0.34 to 1.08 ; P=0.081 for the two irbesartan groups , respectively ) . The average blood pressure during the course of the study was 144/83 mm Hg in the placebo group , 143/83 mm Hg in the 150-mg group , and 141/83 mm Hg in the 300-mg group ( P=0.004 for the comparison of systolic blood pressure between the placebo group and the combined irbesartan groups ) . Serious adverse events were less frequent among the patients treated with irbesartan ( P=0.02 ) . CONCLUSIONS Irbesartan is renoprotective independently of its blood-pressure-lowering effect in patients with type 2 diabetes and microalbuminuria BACKGROUND Angiotensin-converting-enzyme ( ACE ) inhibitors are effective in reducing the risk of heart failure , myocardial infa rct ion , and death from cardiovascular causes in patients with left ventricular systolic dysfunction or heart failure . ACE inhibitors have also been shown to reduce atherosclerotic complications in patients who have vascular disease without heart failure . METHODS In the Prevention of Events with Angiotensin Converting Enzyme Inhibition ( PEACE ) Trial , we tested the hypothesis that patients with stable coronary artery disease and normal or slightly reduced left ventricular function derive therapeutic benefit from the addition of ACE inhibitors to modern conventional therapy . The trial was a double-blind , placebo-controlled study in which 8290 patients were r and omly assigned to receive either  tr and olapril  at a target dose of  4 mg  per  day ( 4158 patients ) or matching placebo ( 4132 patients ) . RESULTS The mean ( + /-SD ) age of the patients was 64+/-8 years , the mean blood pressure 133+/-17/78+/-10 mm Hg , and the mean left ventricular ejection fraction 58+/-9 percent . The patients received intensive treatment , with 72 percent having previously undergone coronary revascularization and 70 percent receiving lipid-lowering drugs . The incidence of the primary end point -- death from cardiovascular causes , myocardial infa rct ion , or coronary revascularization -- was 21.9 percent in the tr and olapril group , as compared with 22.5 percent in the placebo group ( hazard ratio in the tr and olapril group , 0.96 ; 95 percent confidence interval , 0.88 to 1.06 ; P=0.43 ) over a median follow-up period of 4.8 years . CONCLUSIONS In patients with stable coronary heart disease and preserved left ventricular function who are receiving " current st and ard " therapy and in whom the rate of cardiovascular events is lower than in previous trials of ACE inhibitors in patients with vascular disease , there is no evidence that the addition of an ACE inhibitor provides further benefit in terms of death from cardiovascular causes , myocardial infa rct ion , or coronary revascularization The benefits of lowering a systolic blood pressure below 140 mmHg in elderly hypertension remain controversial . This study is a prospect i ve , r and omized , open-label study with blinded assessment of endpoints to compare the 2-year effect of strict treatment to maintain systolic blood pressure below 140 mmHg with that of mild treatment to maintain systolic blood pressure below 160 but at or above 140 mmHg in elderly hypertensive patients . Patients with essential hypertension ( 65–85 years old , with a pretreatment systolic blood pressure of above 160 mmHg ) were r and omly assigned to receive strict treatment ( n=2,212 ) or mild treatment ( n=2,206 ) . The baseline drug was efonidipine hydrochloride , a long-acting calcium antagonist . The primary endpoint was the combined incidence of cardiovascular disease and renal failure , and the secondary endpoints were total deaths and any safety problems . Although final blood pressures ( systolic/diastolic ) were significantly lower in the strict-treatment group compared with the mild-treatment group ( 135.9/74.8 vs. 145.6/78.1 mmHg ; p<0.001 ) , the incidence of the primary endpoint was similar in the two groups ( 86 patients in each group ; p=0.99 ) . Total deaths were 54 in the strict-treatment group vs. 42 in the mild-treatment group ( p=0.22 ) , and treatment was withdrawn because of adverse events in 36 patients in each group ( p=0.99 ) . An interaction between age and treatment for the primary endpoints ( p=0.03 ) was seen . Complex clinical features associated with aging seem to have obscured the difference in effect between the two treatments . Further studies are needed to assess the optimal treatment strategy for hypertension in the elderly A r and omised trial of the treatment of hypertension in 884 patients aged 60 to 79 years at the onset showed a reduction of 18/11 mm Hg in blood pressure over a mean follow up period of 4.4 years . The principal antihypertensive agents were atenolol and bendrofluazide . There was a reduction in the rate of fatal stroke in the treatment group to 30 % of that in the control group ( 95 % confidence interval 11 - 84 % , p less than 0.025 ) . The rate of all strokes ( fatal and non-fatal ) in the treatment group was 58 % of that in the control group ( 95 % confidence interval 35 - 96 % , p less than 0.03 ) . The incidence of myocardial infa rct ion and total mortality was unaffected by treatment . Question naires completed by the patients and their relatives failed to identify any differences in symptoms that were likely to be due to treatment In 1972 - -1973 , 785 symptom-free men , aged 40 to 49 years , without target organ damage , with systolic blood pressures between 150 and 179 mm Hg and diastolic blood pressure below 110 mm Hg , were assigned at r and om to one of two groups : ( 406 to a drug treatment group and 379 to a control group ) for a five-year controlled drug treatment trial to evaluate the effect of therapy on cardiovascular complications . Drug treatment started with hydrochlorothiazide . If systolic blood pressure remained above 140 mm Hg and /or diastolic blood pressure above 90 mm Hg , alphamethyldopa was added . If there were side effects , methyldopa was replaced with propranolol . The control group was not given a placebo . The mean observation time was 66 months ( range 60 to 78 months ) . A difference in blood pressure between groups of about 17 mm Hg systolic and 10 mm Hg diastolic was maintained throughout the study . The study protocol had a rather low " ethical " blood pressure roof , 180 mm Hg systolic and /or 110 mm Hg diastolic . Seventeen percent of the control group had an increase in blood pressure above this level during the trial , and drug treatment was started . There was no effect on major cardiovascular morbidity comparing groups as established by r and omization , with 18 events in the treatment group and 20 events in the control group . There was no difference between the groups in total mortality and mortality from cardiovascular events . However , in the subgroups with diastolic blood pressure greater than or equal to 100 mm Hg before r and omization , there was a probable reduction in total morbidity from cardiovascular events in favor or the group receiving drug therapy , 7.6 and 16.4 percent events in the treated and control groups , respectively . Cerebrovascular events occurred only in the control group , 7 versus 0 . Two cases of fatal aortic aneurysms also occurred in the control group . Other " pressure " complications , such as marked left ventricular hypertrophy in the electrocardiogram and left ventricular failure , occurred only in the control group . However , regarding coronary heart disease , including sudden death , the incidence tended to be higher in the treated group , although it was not statistically significant . Only 13 men ( 1.7 percent ) failed to meet for regular examinations . At the end of the study these men were also followed up with regard to possible cardiovascular events Abstract Aims /hypothesisThe renal and cardiovascular protective effects of angiotensin receptor blocker ( ARB ) remain controversial in type 2 diabetic patients treated with a contemporary regimen including an angiotensin converting enzyme inhibitor ( ACEI ) . Methods We examined the effects of olmesartan , an ARB , on primary composite outcome of doubling of serum creatinine , endstage renal disease and death in type 2 diabetic patients with overt nephropathy . Secondary outcome included composite cardiovascular outcomes , changes in renal function and proteinuria . R and omisation and allocation to trial group were carried out by a central computer system . Participants , caregivers , the people carrying out examinations and people assessing the outcomes were blinded to group assignment . Results Five hundred and seventy-seven ( 377 Japanese , 200 Chinese ) patients treated with antihypertensive therapy ( 73.5 % [ n = 424 ] received concomitant ACEI ) , were given either once-daily olmesartan ( 10–40 mg ) ( n = 288 ) or placebo ( n = 289 ) over 3.2 ± 0.6 years ( mean±SD ) . In the olmesartan group , 116 developed the primary outcome ( 41.1 % ) compared with 129 ( 45.4 % ) in the placebo group ( HR 0.97 , 95 % CI 0.75 , 1.24 ; p = 0.791 ) . Olmesartan significantly decreased blood pressure , proteinuria and rate of change of reciprocal serum creatinine . Cardiovascular death was higher in the olmesartan group than the placebo group ( ten vs three cases ) , whereas major adverse cardiovascular events ( cardiovascular death plus non-fatal stroke and myocardial infa rct ion ) and all-cause death were similar between the two groups ( major adverse cardiovascular events 18 vs 21 cases , all-cause deaths ; 19 vs 20 cases ) . Hyperkalaemia was more frequent in the olmesartan group than the placebo group ( 9.2 % vs 5.3 % ) . Conclusions /interpretationOlmesartan was well tolerated but did not improve renal outcome on top of ACEI . Trial registration : Clinical Trials.gov NCT00141453 Funding : The ORIENT study was supported by a research grant from Daiichi Sankyo OBJECTIVE --To establish whether treatment with diuretic or beta blocker in hypertensive older adults reduces risk of stroke , coronary heart disease , and death . DESIGN --R and omised , placebo controlled , single blind trial . SETTING --226 general practice s in the MRC general practice research framework . SUBJECTS--4396 patients aged 65 - 74 r and omised to receive diuretic , beta blocker , or placebo . Patients had mean systolic pressures of 160 - 209 mm Hg and mean diastolic pressures less than 115 mm Hg during an eight week run in and were not taking antihypertensive treatment . INTERVENTION-- Patients were r and omised to atenolol 50 mg daily ; hydrochlorothiazide 25 mg or 50 mg plus amiloride 2.5 mg or 5 mg daily ; or placebo . The regimens were adjusted to achieve specified target pressures . Mean follow up was 5.8 years . MAIN OUTCOME MEASURES --Strokes , coronary events , and deaths from all causes . RESULTS --Both treatments reduced blood pressure below the level in the placebo group . Compared with the placebo group , actively treated subjects ( diuretic and beta blocker groups combined ) had a 25 % ( 95 % confidence interval 3 % to 42 % ) reduction in stroke ( p = 0.04 ) , 19 % ( -2 % to 36 % ) reduction in coronary events ( p = 0.08 ) , and 17 % ( 2 % to 29 % ) reduction in all cardiovascular events ( p = 0.03 ) . After adjusting for baseline characteristics the diuretic group had significantly reduced risks of stroke ( 31 % ( 3 % to 51 % ) p = 0.04 ) , coronary events ( 44 % ( 21 % to 60 % ) , p = 0.0009 ) , and all cardiovascular events ( 35 % ( 17 % to 49 % ) , p = 0.0005 ) compared with the placebo group . The beta blocker group showed no significant reductions in these end points . The reduction in strokes was mainly in non-smokers taking the diuretic . CONCLUSION --Hydrochlorothiazide and amiloride reduce the risk of stroke , coronary events , and all cardiovascular events in older hypertensive adults The concept of microalbuminuria has had a major impact on diabetes research and clinical care of patients with diabetes [ 1 - 5 ] . Initial albuminuria is regarded by most research ers as an independent predictor of subsequent progression of nephropathy and risk for cardiovascular morbidity and mortality [ 6 - 8 ] . Angiotensin-converting enzyme ( ACE ) inhibitors have been found to attenuate progression of nephropathy in both types of diabetes in hypertensive [ 9 - 12 ] and normotensive patients [ 13 - 15 ] with microalbuminuria . They were also found to lower urinary albumin excretion in normotensive and normoalbuminuric patients with type 1 diabetes [ 16 ] . The relation between albuminuria and later progression of nephropathy in these patients has not been established , possibly because of short follow-up periods . No data are available on the effect of early introduction of ACE inhibitors in normotensive and normoalbuminuric patients with type 2 diabetes mellitus . We design ed a r and omized , double-blind , placebo-controlled trial of the effect of ACE inhibition on the course of nephropathy in 156 patients with type 2 diabetes . These patients had normal blood pressure and normal urinary albumin excretion at baseline . Methods Patients Potential c and i date s were identified through the computerized records of the central regional laboratory for the northern part of the greater Tel-Aviv area . Persons with hyperglycemia and normal urinalysis results were located through their family physicians . Consent was sought once eligibility was established . Inclusion criteria were age younger than 60 years ; age 40 years or older at diagnosis ; duration of diabetes mellitus less than 10 years with no clinical evidence of malignant , autoimmune , hepatic , cardiovascular , or renal disease ; body mass index less than 30 kg/m2 ; normal blood pressure on at least two consecutive visits ( systolic pressure 140 mm Hg and diastolic pressure 90 mm Hg ; mean pressure 107 mm Hg ) ; serum creatinine concentration of 123 mol/L or less ; and urinary albumin excretion of 30 mg/24 h or less . All baseline data were obtained twice during the run-in prer and omization period . Patients were eligible only if values within the predetermined range were found on both examinations . The average of the values was used as the baseline value . A total of 255 patients who had type 2 diabetes according to World Health Organization criteria [ 17 ] and attended one of eight clinics in the greater Tel-Aviv area were found to be eligible and were contacted during 1990 and 1991 . Of these patients , 214 gave informed consent to participate . Twenty patients were excluded during the observation period : Six had blood pressure values above normal , 5 had microalbuminuria , 3 had serum creatinine concentrations above the trial criterion , 1 patient developed unstable angina pectoris , and 5 withdrew consent . Of the 194 patients included in the study , 102 were women and 92 were men ( mean age SD , 54.9 3.2 years [ range , 37 to 59 years ] ) . The known duration of diabetes was 0 to 9 years ( mean duration , 5.75 2.8 years ) . Patients were instructed to use the st and ard isocaloric diet recommended by the Israeli Diabetic Association , and 69 study patients used diet alone to control their hyperglycemia . Pharmacologic therapy for diabetes was insulin in 34 patients and oral hypoglycemic agents in 91 patients . Protocol The protocol was approved by the hospital review board . After a 2-month observation period , patients were r and omly assigned in a double-blind manner to receive enalapril ( Assia-Riezel Ltd. , Ramat-Gan , Israel ) , 10 mg/d , or placebo .  Ninety-seven patients were assigned to receive enalapril  , and 97 were assigned to receive placebo . R and omization was done central ly by telephone with a r and om number table [ 18 ] . Patient allocation to placebo or enalapril was recorded and kept by one of the authors . The placebo tablets were similar in appearance to the enalapril tablets . The medications , which came in sealed , numbered packages , were central ly prepared and were given to the patients at each visit by one nurse who was otherwise not involved in the study . Patients were followed by their family physicians , who were unaware of allocation . Two semiannual prescheduled visits took place each year , and interim visits were scheduled as clinical ly indicated . At the semiannual visits , hemoglobin A1c values , serum creatinine concentrations , serum electrolyte levels , and 24-hour albumin excretion and urinary creatinine concentrations were measured . Blood pressure was measured by the physicians twice at each visit by using mercury sphygmomanometers with the patients seated after a 5-minute rest ; physicians recorded the average of the two values . The diastolic pressure was determined at Korotkoff phase V. If a systolic blood pressure of 145 mm Hg or more or a diastolic blood pressure of 95 mm Hg or more was found , measurements were repeated weekly . If elevated values persisted on two consecutive visits , a long-acting calcium-channel blocker ( diltiazem or verapamil ) , hydrochlorothiazide , or both were administered . If systolic blood pressure values of 100 mm Hg or less were repeatedly found , the enalapril dosage was reduced to 5 mg/d ( half of a 10-mg enalapril tablet or half of a placebo tablet ) . Fundoscopy was done yearly by an ophthalmologist , and the presence of retinopathy was recorded . For each patient , follow-up was terminated 6 years after r and omization . Measurements All blood and urine sample s were examined by a central laboratory . Assays were not changed during the study period . Glycosylated hemoglobin values were measured by affinity chromatography with a commercial kit ( Isolab , Biochemical Methodology , Akron , Ohio ) . The normal range of this assay is a hemoglobin A1c value of 3.5 % to 5.6 % and an intra-assay and interassay coefficient of variability of less than 3 % . Urinary albumin concentration was measured twice in 24-hour urine sample s by an automated immunoturbidimetric method [ 19 ] . This procedure has intra-assay and interassay coefficients of variability of 5.9 % and 7.6 % , respectively . Creatinine concentrations were determined by using the automated method of Bartels and colleagues [ 20 ] . Creatinine clearance , normalized for 1.73 m2 of body surface area , was calculated for each visit by using the st and ard formula ( urine creatinine x urine volume/plasma creatinine ) . The mean blood pressure ( defined as the diastolic pressure plus one third of the pulse pressure ) was calculated at each visit . Statistical Analysis Data are expressed as the mean ( SD ) with ranges . A P value less than 0.05 was considered significant . On the basis of the assumptions that 15 % of normotensive , normoalbuminuric patients with type 2 diabetes will develop microalbuminuria during 6 years and that treatment with enalapril will reduce the risk for microalbuminuria by 12 % , we calculated that 69 patients were required in each group for a type 1 error of 0.05 and a power of 0.80 [ 21 ] . To test for adequate r and omization and to compare the patients who completed the trial with those who did not complete the trial , the enalapril and placebo groups and the 38 patients who dropped out were compared for mean age ; mean duration of diabetes ; and mean baseline albumin excretion , creatinine clearance , glycosylated hemoglobin value , and blood pressure by using pooled-variance Student t-tests for independent groups and one-way analysis of variance . To compare the annual means of the various measurements between the two groups and within each group , one between-group factor and one repeated- measures factor were used in analysis of variance . For variables shown to be different by analysis of variance , unpaired t-tests were used for between-group parallel annual means and paired t-tests were used for comparison of intragroup sequential annual means . The rate of decrease of creatinine clearance and the rate of increase of albumin excretion were computed by doing linear regression analysis with all of the semiannual values included in the equation . Urinary albumin values were logarithmically transformed before analysis . The degree of albuminuria at baseline was used as a covariate . The funding source had no involvement in the design , conduct , or reporting of the trial . Results Figure 1 shows the flow of participants during the trial . Thirty-eight patients did not complete the trial . Five patients died ( 3 in the enalapril group and 2 in the placebo group ) ; death was related to coronary heart disease in 3 patients , stroke in 1 patient , and ovarian carcinoma in 1 patient . Six patients violated the protocol ( 2 patients in the enalapril group stopped taking their medication for more than 6 months , and 4 patients in the placebo group took an ACE inhibitor prescribed by consultant physicians for more than 6 months ) . Ten patients were lost to follow-up ( 6 in the enalapril group and 4 in the placebo group ) . The trial medication was discontinued in 12 patients : Six developed a disturbing cough ( 4 in the enalapril group and 2 in the placebo group ) , 4 had an allergic skin reaction ( 2 in the enalapril group and 2 in the placebo group ) , 1 patient in the enalapril group developed leukopenia , and 1 patient in the placebo group developed hyperkalemia . Finally , 5 patients developed severe urinary tract infections that had a detectable influence on renal function ( 2 in the enalapril group and 3 in the placebo group ) . A total of 156 patients completed the trial , of whom 77 received enalapril and 79 received placebo . Figure 1 . Flow of participants through the trial . Baseline data for the two groups and for patients who did not complete the trial are shown in Table 1 . The baseline characteristics of patients in the study groups and those who dropped out did not differ significantly . A modest but steady decrease in hemoglobin A1c values was seen in the enalapril and the placebo groups and may reflect the change in attitude toward glucose control among family physicians in the early 1990s . However , Background This long-term , multicenter , r and omized , double-blind , placebo-controlled , 2 × 2 factorial , angiographic trial evaluated the effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis in normocholesterolemic patients . Methods and Results There were a total of 460 patients : 230 received simvastatin and 230 , a simvastatin placebo , and  229 received enalapril and 231 , an enalapril placebo ( some subjects received both drugs and some received a double placebo ) . Mean baseline measurements were as follows : cholesterol level , 5.20 mmol/L ; triglyceride level , 1.82 mmol/L ; HDL , 0.99 mmol/L ; and LDL , 3.36 mmol/L. Average follow-up was 47.8 months . Changes in quantitative coronary angiographic measures between simvastatin and placebo , respectively , were as follows : mean diameters , −0.07 versus −0.14 mm ( P = 0.004 ) ; minimum diameters , −0.09 versus −0.16 mm ( P = 0.0001 ) ; and percent diameter stenosis , 1.67 % versus 3.83 % ( P = 0.0003 ) . These benefits were not observed in patients on enalapril when compared with placebo . No additional benefits were seen in the group receiving both drugs . Simvastatin patients had less need for percutaneous transluminal coronary angioplasty ( 8 versus 21 events;P = 0.020 ) , and fewer enalapril patients experienced the combined end point of death/myocardial infa rct ion/stroke ( 16 versus 30;P = 0.043 ) than their respective placebo patients . Conclusions This trial extends the observation of the beneficial angiographic effects of lipid-lowering therapy to normocholesterolemic patients . The implication s of the neutral angiographic effects of angiotensin-converting enzyme inhibition are uncertain , but they deserve further investigation in light of the positive clinical benefits suggested here and seen elsewhere Objectives To address whether nondihydropyridine calcium-channel blocker added-on angiotensin-converting-enzyme inhibitor therapy ameliorates albuminuria and cardiovascular outcomes in type 2 diabetes patients . Design The Bergamo Nephrologic Diabetes Complications Trial-B was a multicentre , prospect i ve , double-blind , parallel-group trial comparing renal and cardiovascular outcomes in 281 hypertensive type 2 diabetes patients with microalbuminuria r and omized to at least 2-year VeraTran ( verapamil/tr and olapril 180 mg/2 mg daily ) or tr and olapril ( 2 mg daily , identical image ) treatment . Main outcome was persistent macroalbuminuria ( albuminuria > 200 μg/min in two consecutive visits ) . Treatment targets were SBP/DBP less than 120/80 mmHg and HbA1C less than 7 % . Results Over a median follow-up of 4.5 years , 18 patients ( 13 % ) on VeraTran vs. 15 ( 10.5 % ) on tr and olapril [ unadjusted hazard ratio ( 95 % confidence interval [ CI ] ) 1.07 ( 0.54–2.12 ) , P = 0.852 ] progressed to macroalbuminuria , respectively ; 62 ( 44.9 % ) vs. 71 ( 49.7 % ) [ 0.80 ( 0.57–1.12 ) , P = 0.198 ] regressed to normoalbuminuria ( urinary albumin excretion < 20 μg/min ) , and 20 ( 14.5 % ) vs. 21 ( 14.7 % ) [ hazard ratio 0.93 ( 0.50–1.72 ) , P = 0.816 ] had major cardiovascular events . BP and metabolic control were similar between groups . Patients with cardiovascular events were significantly less [ 13 ( 9.8 % ) vs. 28 ( 18.9 % ) , hazard ratio : 0.37 ( 0.19–0.71 ) , P = 0.003 ] among those regressing to normoalbuminuria than those without regression . Difference was independent of treatment allocation and was significant also after adjusting for baseline characteristics [ 0.40 ( 0.20–0.79 ) , P = 0.009 ] , follow-up SBP [ 0.40 ( 0.20–0.80 ) , P = 0.010 ] or DBP [ 0.36 ( 0.18–0.73 ) , P = 0.004 ] BP or HbA1C [ 0.43 ( 0.21–0.88 ) , P = 0.021 ] . Conclusion In hypertensive type 2 diabetes patients with microalbuminuria , verapamil added-on tr and olapril did not improve renal or cardiovascular outcomes . Independent of verapamil , tr and olapril normalized albuminuria in half of patients and this translated into significant cardioprotection BACKGROUND Although several important studies have been performed in hypertensive type 2 diabetic patients , it is not known whether lowering blood pressure in normotensive ( BP < 140/90 mm Hg ) patients offers any beneficial results on vascular complications . The current study evaluated the effect of intensive versus moderate diastolic blood pressure ( DBP ) control on diabetic vascular complications in 480 normotensive type 2 diabetic patients . METHODS The current study was a prospect i ve , r and omized controlled trial in normotensive type 2 diabetic subjects . The subjects were r and omized to intensive ( 10 mm Hg below the baseline DBP ) versus moderate ( 80 to 89 mm Hg ) DBP control . Patients in the moderate therapy group were given placebo , while the patients r and omized to intensive therapy received either nisoldipine or enalapril in a blinded manner as the initial antihypertensive medication . The primary end point evaluated was the change in creatinine clearance with the secondary endpoints consisting of change in urinary albumin excretion , progression of retinopathy and neuropathy and the incidence of cardiovascular disease . RESULTS The mean follow-up was 5.3 years . Mean BP in the intensive group was 128 + /- 0.8/75 + /- 0.3 mm Hg versus 137 + /- 0.7/81 + /- 0.3 mm Hg in the moderate group , P < 0.0001 . Although no difference was demonstrated in creatinine clearance ( P = 0.43 ) , a lower percentage of patients in the intensive group progressed from normoalbuminuria to microalbuminuria ( P = 0.012 ) and microalbuminuria to overt albuminuria ( P = 0.028 ) . The intensive BP control group also demonstrated less progression of diabetic retinopathy ( P = 0.019 ) and a lower incidence of strokes ( P = 0.03 ) . The results were the same whether enalapril or nisoldipine was used as the initial antihypertensive agent . CONCLUSION Over a five-year follow-up period , intensive ( approximately 128/75 mm Hg ) BP control in normotensive type 2 diabetic patients : ( 1 ) slowed the progression to incipient and overt diabetic nephropathy ; ( 2 ) decreased the progression of diabetic retinopathy ; and ( 3 ) diminished the incidence of stroke Myocardial infa rct ion , sudden cardiac death , cerebrovascular accidents , blood pressure control and treatment tolerability were studied in a r and omized double-blind trial conducted in 6357 men and women aged 40 - 64 years with uncomplicated essential hypertension ( diastolic blood pressures 100 - 125 mmHg ) . At the start of the trial 3185 patients received treatment based on a beta-blocker ( oxprenolol )  , while in the remaining 3172 placebo replaced oxprenolol .  Supplementary drugs , excluding beta-blockers , were used as necessary in both treatment groups , with the aim of reducing diastolic pressure to 95 mmHg or less . Patients were followed for 3 - 5 years , a total of 25 651 patient years at risk . In most respects the two groups fared equally well ; sudden death ( relative risk [ RR ] 1.08 ; 95 % confidence interval [ Cl ] 0.68 and 1.72 ) , myocardial infa rct ion ( RR 0.83 ; Cl 0.59 and 1.16 ) and cerebrovascular accident ( RR 0.97 ; Cl 0.64 and 1.47 ) rates were similar . Beta-blocker based therapy was associated with significantly lower average blood pressures , earlier ECG normalization , less hypokalaemia and fewer withdrawals from double-blind treatment for uncontrolled hypertension . Doctor-elicited and patient-assessed unwanted effects demonstrated overall good tolerability . In smokers the cardiac event rate was doubled . We propose that beta-blocker treatment effects depend on smoking status , with a significant interaction benefiting non-smoking men . Lower blood pressures during treatment were associated with substantially lower rates for cardiac as well as cerebrovascular events . Proportional hazards analysis also underlines the importance of other cardiovascular risk factors . The IPPPSH stresses the need for a comprehensive approach to the management of blood pressure and other risk factors in hypertensive patients BACKGROUND The level to which systolic blood pressure should be controlled in hypertensive patients without diabetes remains unknown . We tested the hypothesis that tight control compared with usual control of systolic blood pressure would be beneficial in such patients . METHODS In this r and omised open-label trial undertaken in 44 centres in Italy , 1111 non-diabetic patients with systolic blood pressure 150 mm Hg or greater were r and omly assigned to a target systolic blood pressure of less than 140 mm Hg ( usual control ; n=553 ) or less than 130 mm Hg ( tight control ; n=558 ) . After stratification by centre , we used a computerised r and om function to allocate patients to either group . Observers who were unaware of r and omisation read electrocardiograms and adjudicated events . Open-label agents were used to reach the r and omised targets . The primary endpoint was the rate of electrocardiographic left ventricular hypertrophy 2 years after r and omisation . Analysis was by intention to treat . This study is registered with Clinical Trials.gov , number NCT00421863 . RESULTS Over a median follow-up of 2.0 years ( IQR 1.93 - 2.03 ) , systolic and diastolic blood pressure were reduced by a mean of 23.5/8.9 mm Hg ( SD 10.6/7.0 ) in the usual-control group and by 27.3/10.4 mm Hg ( 11.0/7.5 ) in the tight-control group ( between-group difference 3.8 mm Hg systolic [ 95 % CI 2.4 - 5.2 ] , p<0.0001 ; and 1.5 mm Hg diastolic [ 0.6 - 2.4 ] ; p=0.041 ) . The primary endpoint occurred in 82 of 483 patients ( 17.0 % ) in the usual-control group and in 55 of 484 patients ( 11.4 % ) of the tight-control group ( odds ratio 0.63 ; 95 % CI 0.43 - 0.91 ; p=0.013 ) . A composite cardiovascular endpoint occurred in 52 ( 9.4 % ) patients in the usual-control group and in 27 ( 4.8 % ) in the tight-control group ( hazard ratio 0.50 , 95 % CI 0.31 - 0.79 ; p=0.003 ) . Side-effects were rare and did not differ significantly between the two groups . INTERPRETATION Our findings lend support to a lower blood pressure goal than is recommended at present in non-diabetic patients with hypertension . FUNDING Boehringer-Ingelheim , Sanofi-Aventis , Pfizer Background Statins reduce cardiovascular events and progression of carotid intima-media thickness ( IMT ) . & bgr;-Blockers are also known to reduce cardiovascular events , but less is known about their effects on carotid IMT . Methods and Results We conducted a r and omized , double-blind , placebo-controlled , single-center trial to compare the effects of low-dose metoprolol CR/XL ( 25 mg once daily ) and fluvastatin ( 40 mg once daily ) on the progression of carotid IMT during 36 months of treatment in 793 subjects who had carotid plaque but no symptoms of carotid artery disease . Changes in mean IMT in the common carotid artery and maximal IMT in the bulb were the main outcome variables . Death and cardiovascular events were monitored . Progression of IMTmax in the carotid bulb at both 18 and 36 months was reduced by metoprolol CR/XL ( −0.058 mm/y ; 95 % CI , −0.094 to −0.023;P = 0.004 ; and −0.023 mm/y ; 95 % CI , −0.044 to −0.003;P = 0.014 , respectively ) . Incidence of cardiovascular events tended to be lower in metoprolol CR/XL – treated patients ( 5 versus 13 patients , P = 0.055 ) . Rate of IMTmean progression in the common carotid at 36 months was reduced by fluvastatin ( −0.009 mm/y ; 95 % CI , −0.015 to −0.003;P = 0.002 ) . Women in the fluvastatin group had increased frequency of transiently high liver enzymes . Conclusions This is the first r and omized trial to show that a & bgr;-blocker can reduce the rate of progression of carotid IMT in clinical ly healthy , symptom-free subjects with carotid plaque . This suggests that & bgr;-blockers may have a favorable effect on atherosclerosis development BACKGROUND There is no evidence from r and omized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus . We investigated whether therapy targeting normal systolic pressure ( i.e. , < 120 mm Hg ) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events . METHODS A total of 4733 participants with type 2 diabetes were r and omly assigned to intensive therapy , targeting a systolic pressure of less than 120 mm Hg , or st and ard therapy , targeting a systolic pressure of less than 140 mm Hg . The primary composite outcome was nonfatal myocardial infa rct ion , nonfatal stroke , or death from cardiovascular causes . The mean follow-up was 4.7 years . RESULTS After 1 year , the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the st and ard-therapy group . The annual rate of the primary outcome was 1.87 % in the intensive-therapy group and 2.09 % in the st and ard-therapy group ( hazard ratio with intensive therapy , 0.88 ; 95 % confidence interval [ CI ] , 0.73 to 1.06 ; P=0.20 ) . The annual rates of death from any cause were 1.28 % and 1.19 % in the two groups , respectively ( hazard ratio , 1.07 ; 95 % CI , 0.85 to 1.35 ; P=0.55 ) . The annual rates of stroke , a prespecified secondary outcome , were 0.32 % and 0.53 % in the two groups , respectively ( hazard ratio , 0.59 ; 95 % CI , 0.39 to 0.89 ; P=0.01 ) . Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group ( 3.3 % ) and 30 of the 2371 participants in the st and ard-therapy group ( 1.3 % ) ( P<0.001 ) . CONCLUSIONS In patients with type 2 diabetes at high risk for cardiovascular events , targeting a systolic blood pressure of less than 120 mm Hg , as compared with less than 140 mm Hg , did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events . ( Clinical Trials.gov number , NCT00000620 . Summary The latter was due to a reduction in cardiac mortality ( −38 % , p=0.036 ) and a nonsignificant decrease in cerebrovascular mortality ( −32 % , p=0.16 ) . In the double-blind part of the trial , the total mortality rate was not significantly reduced ( −26 % , p=0.077 ) . However , cardiovascular mortality was reduced in the actively treated group ( −38 % , p=0.023 ) , owing to a reduction in cardiac deaths ( −47 % , p=0.048 ) and a non-significant decrease in cerebrovascular mortality ( −43 % , p=0.15 ) . Deaths from myocardial infa rct ion were reduced ( −60 % , p=0.043 ) , and study -terminating morbid cardiovascular events were significantly reduced by active treatment ( −60 % , p=0.0064 ) . Non-terminating cerebrovascular events were reduced ( −52 % , p=0.026 ) , but the non-terminating cardiac events were not ( + 3 % , p=0.98 ) . In the patients r and omised to active treatment there were 29 fewer cardiovascular events and 14 fewer cardiovascular deaths per 1000 patient years during the double-blind part of the trial . A double-blind r and omised placebo-controlled trial of antihypertensive treatment was conducted in patients over the age of 60 . Entry criteria included both a sitting diastolic blood pressure on placebo treatment in the range 90 to 119 mm Hg and a systolic pressure in the range 160 to 239 mm Eg . 840 patients were r and omised either to active treatment ( hydrochlorothiazide and triamterene ) or to  matching placebo  . If the blood pressure remained raised , methyldopa was added to the active regimen and matching placebo in the placebo group . An overall intention-to-treat analysis , combining the double-blind part of the trial and all subsequent follow-up , revealed a non-significant change in total mortality rate ( −9 % , p=0.41 ) but a significant reduction in cardiovascular mortality rate ( −27 % , p=0.037 ) BACKGROUND The aim of this study is to compare the long-term effect of amlodipine and fosinopril in monotherapy or in combination on urinary albumin excretion ( UAE ) in hypertensive diabetic patients . METHODS We selected 453 hypertensive patients with type 2 diabetes and microalbuminuria and r and omized them to amlodipine ( 5 to 15 mg/day ) , fosinopril ( 10 to 30 mg/day ) , or amlodipine plus fosinopril ( 5/10 to 15/30 mg/day ) for a 3-month titration period . The nonresponder patients or those complaining of side effects during the titration period were discontinued ( n = 144 ) ; the remaining 309 patients were enrolled in the trial and treated with the same therapy for 4 years . Every 6 months , blood pressure ( BP ) , heart rate ( HR ) , UAE , creatinine clearance , and glycosylated hemoglobin ( HbA1c ) were evaluated . RESULTS The combination therapy was more effective in reducing BP than either drug alone at any time of the study without affecting glucose homeostasis . All three treatments provided a significant decrease in UAE during the 48-month study period . However , this effect was more pronounced and became evident earlier with fosinopril than with amlodipine monotherapy ( after 3 v 18 months of therapy ) . In addition , the combination therapy provided a greater antialbuminuric effect than the single drugs . This could be due to the greater antihypertensive effects , although other drug-specific effects can not be excluded . The cardiovascular outcomes were similar in the amlodipine and in the fosinopril group , but they were lower in the combination group . CONCLUSIONS These results strengthen the rationale to use a calcium-antagonist/angiotensin converting enzyme inhibitor combination in the treatment of hypertensive patients with type 2 diabetes The BBB study ( Swedish for Beh and la Blodtryck Bättre or Treat Blood Pressure Better ) was a multicenter trial design ed to investigate three aspects of antihypertensive treatment : i ) Is it possible to lower the diastolic blood pressure further in " well-treated " hypertensive patients through intensified therapy ? ii ) Can this aim be fulfilled without increasing the incidence or severity of side-effects ? iii ) If i ) and ii ) can be answered in the affirmative , will the further reduction in diastolic blood pressure be associated with a further reduction in hypertension-associated mortality and morbidity ? Altogether 2127 hypertensive men and women with an average age of 59.8 years ( 46 - 71 ) were recruited at 142 primary health care centers in Sweden . Approximately 10,000 patient-years were accumulated . All patients had treated essential hypertension and all had diastolic blood pressures in the range 90 - 100 mmHg on three consecutive visits before entering the study . The patients were r and omized to either intensified treatment aim ing at a blood pressure < or = 80 mmHg diastolic ( group A ) or to unchanged therapy ( group B ) . A difference between group A and group B in diastolic blood pressure of 7 - 7.5 mmHg was achieved for > 4 years . Adverse effects were studied in detail in 100 r and omly selected patients from each group using a special question naire and a visual analogue scale . The adverse effect score fell significantly in group A but remained unchanged in group B. Regarding cardiovascular morbidity and mortality there were no significant differences between groups A and B , the total number of strokes and myocardial infa rcts being 28 in group A and 29 in group B. ( ABSTRACT TRUNCATED AT 250 WORDS In the Australian Therapeutic Trial in Mild Hypertension treated patients had significantly lower cardiovascular mortality and a significantly lower incidence of cerebrovascular complications than patients given placebos .  There was , however , no difference in the incidence of nonfatal myocardial infa rct ion or other new manifestations of ischaemic heart disease . Although the evidence of benefit from treatment was clear-cut , the number of cardiovascular complications in the control group was small . This was due to several factors . Patients admitted to the trial had no preceding evidence of cardiovascular complications  , the blood pressure fell spontaneously to below 95 mm Hg in almost half the control group , and patients whose blood pressures rose to levels above 110 mm Hg were given treatment , but remained in the placebo group for analysis . In both treated and placebo groups , trial end-points occurred more frequently in persons whose average diastolic blood pressure during the study remained raised . Ischaemic heart disease and many cases of stroke are due to atherosclerotic arterial disease . This appears not to be favourably influenced by antihypertensive drug therapy BACKGROUND Angiotensin-converting enzyme ( ACE ) inhibitors reduce major cardiovascular events , but are not tolerated by about 20 % of patients . We therefore assessed whether the angiotensin-receptor blocker telmisartan would be effective in patients intolerant to ACE inhibitors with cardiovascular disease or diabetes with end-organ damage . METHODS After a 3-week run-in period , 5926 patients , many of whom were receiving concomitant proven therapies , were r and omised to receive telmisartan 80 mg/day ( n=2954 ) or placebo ( n=2972 ) by use of a central automated r and omisation system . R and omisation was stratified by hospital . The primary outcome was the composite of cardiovascular death , myocardial infa rct ion , stroke , or hospitalisation for heart failure . Analyses were done by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00153101 . FINDINGS The median duration of follow-up was 56 ( IQR 51 - 64 ) months . All r and omised patients were included in the efficacy analyses . Mean blood pressure was lower in the telmisartan group than in the placebo group throughout the study ( weighted mean difference between groups 4.0/2.2 [ SD 19.6/12.0 ] mm Hg ) . 465 ( 15.7 % ) patients experienced the primary outcome in the telmisartan group compared with 504 ( 17.0 % ) in the placebo group ( hazard ratio 0.92 , 95 % CI 0.81 - 1.05 , p=0.216 ) . One of the secondary outcomes -a composite of cardiovascular death , myocardial infa rct ion , or stroke-occurred in 384 ( 13.0 % ) patients on telmisartan compared with 440 ( 14.8 % ) on placebo ( 0.87 , 0.76 - 1.00 , p=0.048 unadjusted ; p=0.068 after adjustment for multiplicity of comparisons and overlap with primary outcome ) . 894 ( 30.3 % ) patients receiving telmisartan were hospitalised for a cardiovascular reason , compared with 980 ( 33.0 % ) on placebo ( relative risk 0.92 , 95 % CI 0.85 - 0.99 ; p=0.025 ) . Fewer patients permanently discontinued study medication in the telmisartan group than in the placebo group ( 639 [ 21.6 % ] vs 705 [ 23.8 % ] ; p=0.055 ) ; the most common reason for permanent discontinuation was hypotensive symptoms ( 29 [ 0.98 % ] in the telmisartan group vs 16 [ 0.54 % ] in the placebo group ) . INTERPRETATION Telmisartan was well tolerated in patients unable to tolerate ACE inhibitors . Although the drug had no significant effect on the primary outcome of this study , which included hospitalisations for heart failure , it modestly reduced the risk of the composite outcome of cardiovascular death , myocardial infa rct ion , or stroke . FUNDING Boehringer Ingelheim Hypertension is the most common condition seen in primary care and leads to myocardial infa rct ion , stroke , renal failure , and death if not detected early and treated appropriately . Patients want to be assured that blood pressure ( BP ) treatment will reduce their disease burden , while clinicians want guidance on hypertension management using the best scientific evidence . This report takes a rigorous , evidence -based approach to recommend treatment thresholds , goals , and medications in the management of hypertension in adults . Evidence was drawn from r and omized controlled trials , which represent the gold st and ard for determining efficacy and effectiveness . Evidence quality and recommendations were grade d based on their effect on important outcomes . There is strong evidence to support treating hypertensive persons aged 60 years or older to a  BP goal  of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg ; however , there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal , or in those younger than 30 years for a diastolic goal , so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion . The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease ( CKD ) as for the general hypertensive population younger than 60 years . There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor , angiotensin receptor blocker , calcium channel blocker , or thiazide-type diuretic in the nonblack hypertensive population , including those with diabetes . In the black hypertensive population , including those with diabetes , a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy . There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes . Although this guideline provides evidence -based recommendations for the management of high BP and should meet the clinical needs of most patients , these recommendations are not a substitute for clinical judgment , and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient BACKGROUND Combination therapy with angiotensin-converting-enzyme ( ACE ) inhibitors and angiotensin-receptor blockers ( ARBs ) decreases proteinuria ; however , its safety and effect on the progression of kidney disease are uncertain . Methods We provided losartan ( at a dose of 100 mg per day ) to patients with type 2 diabetes , a urinary albumin-to-creatinine ratio ( with albumin measured in milligrams and creatinine measured in grams ) of at least 300 , and an estimated glomerular filtration rate ( GFR ) of 30.0 to 89.9 ml per minute per 1.73 m(2 ) of body-surface area and then r and omly assigned them to receive lisinopril ( at a dose of 10 to 40 mg per day ) or placebo . The primary end point was the first occurrence of a change in the estimated GFR ( a decline of ≥ 30 ml per minute per 1.73 m(2 ) if the initial estimated GFR was ≥ 60 ml per minute per 1.73 m(2 ) or a decline of ≥ 50 % if the initial estimated GFR was < 60 ml per minute per 1.73 m(2 ) ) , end-stage renal disease ( ESRD ) , or death . The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD . Safety outcomes included mortality , hyperkalemia , and acute kidney injury . Results The study was stopped early owing to safety concerns . Among 1448 r and omly assigned patients with a median follow-up of 2.2 years , there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group ( hazard ratio with combination therapy , 0.88 ; 95 % confidence interval [ CI ] , 0.70 to 1.12 ; P=0.30 ) . A trend toward a benefit from combination therapy with respect to the secondary end point ( hazard ratio , 0.78 ; 95 % CI , 0.58 to 1.05 ; P=0.10 ) decreased with time ( P=0.02 for nonproportionality ) . There was no benefit with respect to mortality ( hazard ratio for death , 1.04 ; 95 % CI , 0.73 to 1.49 ; P=0.75 ) or cardiovascular events . Combination therapy increased the risk of hyperkalemia ( 6.3 events per 100 person-years , vs. 2.6 events per 100 person-years with monotherapy ; P<0.001 ) and acute kidney injury ( 12.2 vs. 6.7 events per 100 person-years , P<0.001 ) . Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events  among patients with diabetic nephropathy . ( Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development ; VA NEPHRON-D Clinical Trials.gov number , NCT00555217 . ) BACKGROUND Antihypertensive therapy reduces the risk of cardiovascular events among high-risk persons and among those with a systolic blood pressure of 160 mm Hg or higher , but its role in persons at intermediate risk and with lower blood pressure is unclear . METHODS In one comparison from a 2-by-2 factorial trial , we r and omly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to receive either c and esartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day or placebo . The first co primary outcome was the composite of death from cardiovascular causes , nonfatal myocardial infa rct ion , or nonfatal stroke ; the second co primary outcome additionally included resuscitated cardiac arrest , heart failure , and revascularization . The median follow-up was 5.6 years . RESULTS The  mean blood pressure of the participants at baseline was 138.1/81.9 mm Hg ; the decrease in blood pressure was 6.0/3.0 mm Hg greater in the active-treatment group than in the placebo group . The first co primary outcome occurred in 260 participants ( 4.1 % ) in the active-treatment group and in 279 ( 4.4 % ) in the placebo group ( hazard ratio , 0.93 ; 95 % confidence interval [ CI ] , 0.79 to 1.10 ; P=0.40 ) ; the second co primary outcome occurred in 312 participants ( 4.9 % ) and 328 participants ( 5.2 % ) , respectively ( hazard ratio , 0.95 ; 95 % CI , 0.81 to 1.11 ; P=0.51 ) . In one of the three prespecified hypothesis-based subgroups , participants in the subgroup for the upper third of systolic blood pressure ( > 143.5 mm Hg ) who were in the active-treatment group had significantly lower rates of the first and second co primary outcomes than those in the placebo group ; effects were neutral in the middle and lower thirds ( P=0.02 and P=0.009 , respectively , for trend in the two outcomes ) . CONCLUSIONS Therapy with c and esartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day was not associated with a lower rate of major cardiovascular events than placebo among persons at intermediate risk who did not have cardiovascular disease . ( Funded by the Canadian Institutes of Health Research and AstraZeneca ; Clinical Trials.gov number , NCT00468923 . )
target: In primary prevention , the association of BP-lowering treatment with major cardiovascular events was dependent on baseline systolic BP ( SBP ) .
  Conclusions and Relevance Primary preventive BP lowering is associated with reduced risk for death and CVD if baseline SBP is 140 mm Hg or higher .
  At lower BP levels , treatment is not associated with any benefit in primary prevention but might offer additional protection in patients with CHD
background: Importance High blood pressure ( BP ) is the most important risk factor for death and cardiovascular disease ( CVD ) worldwide .
  The optimal cutoff for treatment of high BP is debated .
  Objective To assess the association between BP lowering treatment and death and CVD at different BP levels .