title: Effect of lower targets for blood pressure and LDL cholesterol on atherosclerosis in diabetes: the SANDS randomized trial. Telmisartan, ramipril, or both in patients at high risk for vascular events. The Hypertension Optimal Treatment Study (the HOT Study). J-shaped relation between blood pressure and stroke in treated hypertensives. A decrease in diastolic blood pressure combined with an increase in systolic blood pressure is associated with a higher cardiovascular mortality in men. Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. Statin Adherence and Risk of Accidents: A Cautionary Tale Hypertension in Diabetes Study IV. Therapeutic requirements to maintain tight blood pressure control
  Hypertension in Diabetes Study Group* Rationale and design for the blood pressure intervention of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Achievement and safety of a low blood pressure goal in chronic renal disease. The Modification of Diet in Renal Disease Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38 Benefits and risks of more intensive blood pressure lowering in hypertensive patients of the HOT study with different risk profiles: does a J-shaped curve exist in smokers? The Hypertension Optimal Treatment (HOT) Study--patient characteristics: randomization, risk profiles, and early blood pressure results. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial Effect of intensive blood pressure control on the course of type 1 diabetic nephropathy. Collaborative Study Group. Prospective randomized open blinded end-point (PROBE) study. A novel design for intervention trials. Prospective Randomized Open Blinded End-Point. Blood pressure, stroke, and coronary heart disease: Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias Quantitative Synthesis in Systematic Reviews The 2001 Canadian recommendations for the management of hypertension: Part two--Therapy. Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial Pulse pressure as a risk factor for cardiovascular events in the MRC Mild Hypertension Trial. Effects of individual risk factors on the incidence of cardiovascular events in the treated hypertensive patients of the Hypertension Optimal Treatment Study. HOT Study Group. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. The Hypertension Optimal Treatment (HOT) Study: 12-month data on blood pressure and tolerability. With special reference to age and gender. The Hypertension Optimal Treatment (HOT) Study: 24-month data on blood pressure and tolerability. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. "Strict" blood pressure control and progression of renal disease in hypertensive nephrosclerosis. Blood pressure as a cardiovascular risk factor: prevention and treatment. The Effect of a Lower Target Blood Pressure on the Progression of Kidney Disease: Long-Term Follow-up of the Modification of Diet in Renal Disease Study Effects of intensive glucose lowering in type 2 diabetes.
abstract: CONTEXT Individuals with diabetes are at increased risk for cardiovascular disease ( CVD ) , but more aggressive targets for risk factor control have not been tested . OBJECTIVE To compare progression of sub clinical atherosclerosis in adults with type 2 diabetes treated to reach aggressive targets of low-density lipoprotein cholesterol ( LDL-C ) of 70 mg/dL or lower and systolic blood pressure ( SBP ) of 115 mm Hg or lower vs st and ard targets of LDL-C of 100 mg/dL or lower and SBP of 130 mm Hg or lower . DESIGN , SETTING , AND PARTICIPANTS A r and omized , open-label , blinded-to-end point , 3-year trial from April 2003-July 2007 at 4 clinical centers in Oklahoma , Arizona , and South Dakota . Participants were 499 American Indian men and women aged 40 years or older with type 2 diabetes and no prior CVD events . INTERVENTIONS Participants were r and omized to aggressive ( n=252 ) vs st and ard ( n=247 ) treatment groups with stepped treatment algorithms defined for both . MAIN OUTCOME MEASURES Primary end point was progression of atherosclerosis measured by common carotid artery intimal medial thickness ( IMT ) . Secondary end points were other carotid and cardiac ultrasonographic measures and clinical events . RESULTS Mean target LDL-C and SBP levels for both groups were reached and maintained . Mean ( 95 % confidence interval ) levels for LDL-C in the last 12 months were 72 ( 69 - 75 ) and 104 ( 101 - 106 ) mg/dL and SBP levels were 117 ( 115 - 118 ) and 129 ( 128 - 130 ) mm Hg in the aggressive vs st and ard groups , respectively . Compared with baseline , IMT regressed in the aggressive group and progressed in the st and ard group ( -0.012 mm vs 0.038 mm ; P < .001 ) ; carotid arterial cross-sectional area also regressed ( -0.02 mm(2 ) vs 1.05 mm(2 ) ; P < .001 ) ; and there was greater decrease in left ventricular mass index ( -2.4 g/m(2.7 ) vs -1.2 g/m(2.7 ) ; P = .03 ) in the aggressive group . Rates of adverse events ( 38.5 % and 26.7 % ; P = .005 ) and serious adverse events ( n = 4 vs 1 ; P = .18 ) related to blood pressure medications were higher in the aggressive group . Clinical CVD events ( 1.6/100 and 1.5/100 person-years ; P = .87 ) did not differ significantly between groups . CONCLUSIONS Reducing LDL-C and SBP to lower targets result ed in regression of carotid IMT and greater decrease in left ventricular mass in individuals with type 2 diabetes . Clinical events were lower than expected and did not differ significantly between groups . Further follow-up is needed to determine whether these improvements will result in lower long-term CVD event rates and costs and favorable risk-benefit outcomes . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00047424 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 ] . ) The Hypertension Optimal Treatment ( HOT ) Study is a prospect i ve , r and omized , multicenter study which will be conducted in some 20 countries world-wide . Two major issues will be investigated : i ) What is the optimal target diastolic blood pressure during antihypertensive treatment with regard to the reduction in cardiovascular morbidity and mortality ? In order to address this question patients will be r and omized to three different therapeutic goals : a diastolic blood pressure < or = 90 mmHg , < or = 85 mmHg or < or = 80 mmHg ; ii ) The second aim is to evaluate the effect of a low dose acetylsalicylic acid ( ASA , aspirin ) 75 mg o.d . in comparison with placebo on cardiovascular morbidity and mortality . The first aim will be investigated in accordance with the PROBE design ( Prospect i ve R and omized Open Blinded Endpoint evaluation ) , whereas the evaluation of aspirin versus placebo will be conducted under double blind conditions . It is estimated that 1,100 clinical events will be needed in order to answer the question regarding the relationship between target diastolic blood pressure and major cardiovascular events . The collection of these events will require the enrollment of at least 18,000 hypertensive men and women aged 50 - 80 years to be followed for 2.5 years ( about 40,000 patient years ) . All patients will be given felodipine 5 mg o.d . as basic antihypertensive treatment with the addition of a beta-blocker or an ACE-inhibitor in a second step , with further predetermined increments in dosage as required in order to obtain the r and omized therapeutic goal The objective of this study was to investigate the relationship between  hypertension and risk of stroke in the elderly . The study was performed within the framework of the Rotterdam Study , a prospect i ve population -based cohort study . The risk of first-ever stroke was associated with hypertension ( relative risk , 1.6 ; 95 % CI , 1.2 to 2.0 ) and with isolated systolic hypertension ( relative risk , 1.7 ; 95 % CI , 1.1 to 2.6 ) . We found a continuous increase in stroke incidence with increasing blood pressure in nontreated subjects . In treated subjects , we found a J-shaped relation between blood pressure and the risk of stroke . In the lowest category of diastolic blood pressure , the increase of stroke risk was statistically significant compared with the reference category . Hypertension and isolated systolic hypertension are strong risk factors for stroke in the elderly . The increased stroke risk in the lowest stratum of blood pressure in treated hypertensive patients may indicate that the therapeutic goal of " the lower the better " is not the optimal strategy in the elderly OBJECTIVES The study evaluated the risk of cardiovascular mortality according to combined spontaneous ( non-treatment-related ) changes in both systolic and diastolic blood pressure ( BP ) . BACKGROUND Long-term longitudinal changes in blood pressure may be a more accurate determinant of cardiovascular risk since changes in systolic or diastolic blood pressure over a period of time reflect the evolution of arterial and arteriolar alterations . METHODS Two independent French male cohorts were studied : the IPC cohort ( Investigations Préventives et Cliniques ) composed of 15,561 men aged 20 to 82 years who had had two visits spaced four to 10 years apart , and the Paris Prospect i ve Study composed of 6,246 men aged 42 to 53 years , examined annually for a period of four years . None of the subjects were taking antihypertensive medication . Annual changes in BP were estimated , and subjects were divided into groups according to the increase , lack of change , or decrease of systolic or diastolic BP . Nine groups were formed by combining the changes of systolic and diastolic BP . Cardiovascular mortality was assessed for a mean period of 13.5 years for the IPC Study and 17 years for the Paris Prospect i ve Study . RESULTS In both cohorts , after adjustment for age and major risk factors , the group with an increase in systolic and a decrease in diastolic BP presented the highest relative risk of cardiovascular mortality compared to the group with no changes in either systolic or diastolic BP ( relative risk : 2.07 [ 1.05 to 4.06 ] in the IPC Study and 2.16 [ 1.16 to 4.01 ] in the Paris Prospect i ve Study ) . CONCLUSIONS Assessment of spontaneous changes of BP over a long period of time can contribute to the evaluation of cardiovascular risk . Subjects whose systolic BP increased while their diastolic BP decreased had the highest cardiovascular risk independently of absolute values of BP or other risk factors 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 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 Background — Bias in studies of preventive medications can occur when healthier patients are more likely to initiate and adhere to therapy than less healthy patients . We sought evidence of this bias by examining associations between statin exposure and various outcomes that should not be causally affected by statin exposure , such as workplace and motor vehicle accidents . Methods and Results — We conducted a prospect i ve cohort study of  statin patients using data from British Columbia , Canada , a multiethnic society with a population of 4.3 million people . Study subjects were 141 086 patients who initiated statins for primary prevention . We examined the association between adherence and multiple outcomes such as accidents and screening procedures using multivariable-adjusted Cox proportional hazards models . The study population was 49 % female and had an average age of 61 years . The results from our multivariable-adjusted models showed that more adherent patients were less likely to have accidents than less adherent patients . This effect was greatest for motor vehicle accidents ( hazard ratio , 0.75 ; 95 % confidence interval , 0.72 to 0.79 ) and workplace accidents ( hazard ratio , 0.77 ; 95 % confidence interval , 0.74 to 0.81 ) . More adherent patients had a greater likelihood of using screening services ( hazard ratio , 1.17 ; 95 % confidence interval , 1.15 to 1.20 ) and a lower likelihood of developing other diseases likely to be unrelated to a biological affect of a statin ( hazard ratio , 0.87 ; 95 % confidence interval , 0.86 to 0.89 ) . Conclusions — Our study contributes compelling evidence that patients who adhere to statins  are systematic ally more health seeking than comparable patients who do not remain adherent . Caution is warranted when interpreting analyses that attribute surprising protective effects to preventive medications Summary We report the efficacy of therapy over 5 years follow-up in 758 non-insulin-dependent diabetic patients in a prospect i ve , r and omised controlled study of therapy of mild hypertension . Patients were recruited who on antihypertensive therapy had systolic blood pressure over 150 mmHg or diastolic over 85 mmHg , or if not on therapy had systolic blood pressure over 160 mmHg or diastolic over 90 mmHg . Their mean blood pressure at entry to the study was 160/94 mmHg at a mean age of 57 years . They were allocated to tight control ( aim ing for systolic < 150/diastolic < 85 mmHg ) or to less tight control ( aim ing for systolic < 180/ diastolic < 105 mmHg ) . The tight control group were allocated to primary therapy either with a beta blocker ( atenolol ) or with an antiotensin converting enzyme inhibitor ( captopril ) , with addition of other agents as required . Over 5 years , the mean blood pressure in the tight control group was significantly lower ( 143/82 vs 154/88 mmHg , p < 0.001 ) . No difference was seen between those allocated to atenolol or captopril . The proportion of patients requiring three or more antihypertensive therapies to maintain tight control in those allocated to atenolol or captopril increased from 16 and 15 % , respectively at 2 years to 25 and 26 % , respectively at 5 years , whereas in the less tight control group at 2 and 5 years only 5 and 7 % , respectively required three or more therapies . There was no difference in the incidence of side effects or hypoglycaemic episodes between those allocated to atenolol or captopril , but those allocated to atenolol increased their body weight by a mean of 2.3 kg compared with 0.5 kg in those allocated to captopril ( p < 0.01 ) . Allocation to atenolol was also associated with small increases in triglyceride , and decreases in LDL and HDL cholesterol , which are of uncertain clinical relevance . The study is continuing to determine whether the improved blood pressure control , which was obtained , will be beneficial in maintaining the health of patients by decreasing the incidence of major clinical complications , principally myocardial infa rct ion and strokes , and microvascular complications , such as severe retinopathy requiring photocoagulation and deterioration of renal function . [ Diabetologia ( 1996 ) 39 : 1554–1561 The Action to Control Cardiovascular Disease in Diabetes ( ACCORD ) blood pressure trial is an unmasked , open-label , r and omized trial with a sample size of 4,733 participants . This report describes the rationale , design , and methods of the blood pressure interventions in ACCORD . Participants eligible for the blood pressure trial are r and omized to 1 of 2 groups with different treatment goals : systolic blood pressure < 120 mm Hg for the more intensive goal and systolic blood pressure < 140 mm Hg for the less intensive goal .  The primary outcome measure for the trial is the first occurrence of a major cardiovascular disease ( CVD ) event , specifically nonfatal myocardial infa rct ion or stroke , or cardiovascular death during a follow-up period ranging from 4 - 8 years . The ACCORD blood pressure trial should provide the first definitive clinical trial data on the possible benefit of treating to a more aggressive systolic blood pressure goal in reducing CVD events in patients with diabetes mellitus The Modification of Diet in Renal Disease Study showed a beneficial effect of a lower-than-usual blood pressure ( BP ) goal on the progression of renal disease in patients with proteinuria . The purpose of the present analyses was to examine the achieved BP , baseline characteristics that helped or hindered achievement of the BP goals , and safety of the BP interventions . Five hundred eighty-five patients with baseline glomerular filtration rate between 13 and 55 mL/min per 1.73 m2 ( 0.22 to 0.92 mL/s per 1.73 m2 ) were r and omly assigned to either a usual or low BP goal ( mean arterial pressure < or = 107 or < or = 92 mm Hg , respectively ) . Few patients had a history of cardiovascular disease . All antihypertensive agents were permitted , but angiotensin-converting enzyme inhibitors ( with or without diuretics ) followed by calcium channel blockers were preferred . The mean ( + /- SD ) of the mean arterial pressures during follow-up in the low and usual BP groups was 93.0 + /- 7.3 and 97.7 + /- 7.7 mm Hg , respectively . Follow-up BP was significantly higher in subgroups of patients with preexisting hypertension , baseline mean arterial pressure > 92 mm Hg , a diagnosis of polycystic kidney disease or glomerular diseases , baseline urinary protein excretion > 1 g/d , age > or = 61 years , and black race . The frequency of medication changes and incidence of symptoms of low BP were greater in the low BP group , but there were no significant differences between BP groups in stop points , hospitalizations , or death . When data from both groups were combined , each 1-mm Hg increase in follow-up systolic BP was associated with a 1.35-times greater risk of hospitalization for cardiovascular or cerebrovascular disease . Lower BP than usually recommended for the prevention of cardiovascular disease is achievable by several medication regimens without serious adverse effects in patients with chronic renal disease without cardiovascular disease . For patients with urinary protein excretion > 1 g/d , target BP should be a mean arterial pressure of < or = 92 mm Hg , equivalent to 125/75 mm Hg Abstract Objective : To determine whether tight control of blood pressure prevents macrovascular and microvascular complications in patients with type 2 diabetes . Design : R and omised controlled trial comparing tight control of blood pressure aim ing at a blood pressure of < 150/85 mm Hg ( with the use of an angiotensin converting enzyme inhibitor captopril or a β blocker atenolol as main treatment ) with less tight control aim ing at a blood pressure of < 180/105 mm Hg . Setting : 20 hospital based clinics in Engl and , Scotl and , and Northern Irel and . Subjects : 1148 hypertensive patients with type 2 diabetes ( mean age 56 , mean blood pressure at entry 160/94 mm Hg ) ; 758 patients were allocated to tight control of blood pressure  and 390 patients to less tight control  with a median follow up of 8.4 years . Main outcome measures : Predefined clinical end points , fatal and non-fatal , related to diabetes , deaths related to diabetes , and all cause mortality . Surrogate measures of microvascular disease included urinary albumin excretion and retinal photography . Results : Mean blood pressure during follow up was significantly reduced in the group assigned tight blood pressure control ( 144/82 mm Hg ) compared with the group assigned to less tight control ( 154/87 mm Hg ) ( P<0.0001 ) . Reductions in risk in the group assigned to tight control compared with that assigned to less tight control were 24 % in diabetes related end points ( 95 % confidence interval 8 % to 38 % ) ( P=0.0046 ) , 32 % in deaths related to diabetes ( 6 % to 51 % ) ( P=0.019 ) , 44 % in strokes ( 11 % to 65 % ) ( P=0.013 ) , and 37 % in microvascular end points ( 11 % to 56 % ) ( P=0.0092 ) , predominantly owing to a reduced risk of retinal photocoagulation . There was a non-significant reduction in all cause mortality . After nine years of follow up the group assigned to tight blood pressure control also had a 34 % reduction in risk in the proportion of patients with deterioration of retinopathy by two steps ( 99 % confidence interval 11 % to 50 % ) ( P=0.0004 ) and a 47 % reduced risk ( 7 % to 70 % ) ( P=0.004 ) of deterioration in visual acuity by three lines of the early treatment of diabetic retinopathy study ( ETDRS ) chart . After nine years of follow up 29 % of patients in the group assigned to tight control required three or more treatments to lower blood pressure to achieve target blood pressures . Conclusion : Tight blood pressure control in patients with hypertension and type 2 diabetes achieves a clinical ly important reduction in the risk of deaths related to diabetes , complications related to diabetes , progression of diabetic retinopathy , and deterioration in visual acuity Background The Hypertension Optimal Treatment ( HOT ) Study investigated 18 790 hypertensives r and omized to three diastolic blood pressure ( DBP ) targets ( ⩽ 90 , ⩽ 85 , ⩽ 80 mmHg ) for 3.8 years and found marked , significant reductions in cardiovascular events and mortality the lower the target DBP in the subset of diabetics . We investigated whether the benefits of intensive DBP lowering could be extended to other subgroups , and whether there are hypertensives in whom the risk of aggressive DBP lowering may outnumber the benefits . Methods and results The 18 790 patients were stratified as : medium/high – very high global cardiovascular risk ; men/women ; older/younger ; current smokers/non-smokers ; higher/lower serum cholesterol ; higher/lower serum creatinine ; with/without diabetes ; with/without ischaemic heart disease ( IHD ) . Comparisons were made between the less aggressive target group ( DBP < 90 mmHg ) and the two more aggressive target groups together ( ⩽ 85 and ⩽ 80 mmHg ) . A Cox proportional hazards model was used to calculate treatment – subgroup interactions and relative risks ( RR ) with 95 % confidence intervals . Benefits were greatest in diabetics ( RR 0.53 for cardiovascular events , and 0.67 for cardiovascular death ) , whereas in smokers more intensive DBP lowering was associated with increased risk of all types of cardiovascular event ( RR 1.71–2.67 ; P = 0.01–0.001 ) , except myocardial infa rct ion . After excluding smokers , intensive  DBP lowering was associated with significant reductions in cardiovascular events in diabetics ( −49 % ) , high – very high risk patients ( −23 % ) , IHD patients ( −32 % ) , patients with lower creatinine ( −18 % ) , women ( −33 % ) and older patients ( −23 % ) . Conclusions Although subanalyses have only a descriptive value , it appears reasonable to recommend intensive antihypertensive treatment to hypertensives with diabetes , IHD and high global cardiovascular risk . In smokers , treatment intensification should be associated with the greatest efforts to induce smoking cessation The Hypertension Optimal Treatment ( HOT ) Study is a prospect i ve , r and omized , multicenter trial being conducted in 26 countries . Its main aim is to evaluate the relationship between three levels of target diastolic blood pressure ( < or = 90 , < or = 85 or < or = 80 mmHg ) and cardiovascular morbidity and mortality in hypertensive patients . In addition , the study will examine the effects on morbidity and mortality of a low dose , 75 mg daily , of acetylsalicylic acid ( ASA , aspirin ) or placebo . In the HOT Study , basic antihypertensive treatment is initiated with the calcium antagonist felodipine at a dose of 5 mg daily . If target blood pressure is not reached , additional antihypertensive therapy with either an angiotensin converting enzyme ( ACE ) inhibitor or a beta-adrenoceptor blocking agent is given . Further dosage adjustments are made in accordance with a set protocol . As a fifth and final step , a diuretic may be added . Inclusion of patients was stopped on April 30 , 1994 . At that time 19,196 patients had been r and omized . There were 9,055 ( 47 % ) women and 10,141 ( 53 % ) men with an average age of 61.5 + /- 7.5 ( SD ) years . At enrollment , 52 % of patients were receiving antihypertensive treatment . These patients entered a wash-out period of at least 2 weeks before r and omization . The average r and omization blood pressure in untreated patients was 169 + /- 14/106 + /- 3 mmHg and in the treated patients 170 + /- 14/105 + /- 3 mmHg . On August 15 , 1994 , blood pressure data were available for 14,710 and 10,275 patients , who had completed 3 and 6 months treatment , respectively . The average reduction in diastolic blood pressure was 22 mmHg after 6 months . ( ABSTRACT TRUNCATED AT 250 WORDS 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 Diabetic nephropathy is the most common cause of end-stage renal disease in the United States . We undertook a study to assess the impact of assignment to different levels of blood pressure control on the course of type 1 diabetic nephropathy in patients receiving angiotensin-converting enzyme ( ACE ) inhibitor therapy .  We also examined the long-term course of this well-characterized cohort of patients receiving ACE inhibitor therapy . One hundred twenty-nine patients with type 1 diabetes and diabetic nephropathy who had previously participated in the Angiotensin-Converting Enzyme Inhibition in Diabetic Nephropathy Study who had a serum creatinine level less than 4.0 mg/dL were r and omly assigned to a mean arterial blood pressure ( MAP ) goal of 92 mm Hg or less ( group I ) or 100 to 107 mm Hg ( group II ) . Patients received varying doses of ramipril as the primary therapeutic antihypertensive agent . All patients were followed for a minimum of 2 years . Outcome measures included iothalamate clearance , 24-hour creatinine clearance , creatinine clearance estimated by the Cockcroft and Gault formula , and urinary protein excretion . The average difference in MAP between groups was 6 mm Hg over the 24-month follow-up . The median iothalamate clearance in group I was 62 mL/min/1.73 m(2 ) at baseline and 54 mL/min/1.73 m(2 ) at the end of the study compared with a baseline of 64 mL/min/1.73 m(2 ) and final 58 mL/min/1.73 m(2 ) in group II . There were no statistically significant differences in the rate of decline in renal function between groups . There was a significant difference in follow-up total urinary protein excretion between group I ( 535 mg/24 h ) and group II ( 1,723 mg/24 h ; P = 0.02 ) . Thirty-two percent of 126 patients achieved a final total protein excretion less than 500 mg/24 h. Patients from groups I and II had equivalent rates of adverse events . In patients with type 1 diabetes mellitus and diabetic nephropathy , the MAP goal should be 92 mm Hg or less for optimal renoprotection , if defined as including decreased proteinuria . With the combination of ACE inhibition and intensive blood pressure control , many patients can achieve regression or apparent remission of clinical evidence of diabetic nephropathy A novel design for intervention studies is presented , the so called PROBE study ( Prospect i ve R and omized Open , Blinded End-point ) . This design is compared to the classical double-blind design . Among the advantages of the PROBE design are lower cost and greater similarity to st and ard clinical practice , which should make the results more easily applicable in routine medical care . Since end-points are evaluated by a blinded end-point committee it is obvious that there should be no difference between the two types of trials in this regard The associations of  diastolic blood pressure ( DBP )  with  stroke  and with coronary heart disease ( CHD ) were investigated in nine major prospect i ve observational studies : total 420,000 individuals , 843 strokes , and 4856 CHD events , 6 - 25 ( mean 10 ) years of follow-up . The combined results demonstrate positive , continuous , and apparently independent associations , with no significant heterogeneity of effect among different studies . Within the range of DBP studied ( about 70 - 110 mm Hg ) , there was no evidence of any " threshold " below which lower levels of DBP were not associated with lower risks of stroke and of CHD . Previous analyses have described the uncorrected associations of DBP measured just at " baseline " with subsequent disease rates . But , because of the diluting effects of r and om fluctuations in DBP , these substantially underestimate the true associations of the usual DBP ( ie , an individual 's long-term average DBP ) with disease . After correction for this " regression dilution " bias , prolonged differences in usual DBP of 5 , 7.5 , and 10 mm Hg were respectively associated with at least 34 % , 46 % , and 56 % less stroke and at least 21 % , 29 % , and 37 % less CHD . These associations are about 60 % greater than in previous uncorrected analyses . ( This regression dilution bias is quite general , so analogous corrections to the relations of cholesterol to CHD or of various other risk factors to CHD or to other diseases would likewise increase their estimated strengths . ) The DBP results suggest that for the large majority of individuals , whether conventionally " hypertensive " or " normotensive " , a lower blood pressure should eventually confer a lower risk of vascular disease A quantitative systematic review , or meta- analysis , uses statistical methods to combine the results of multiple studies . Meta-analyses have been done for systematic review s of therapeutic trials , diagnostic test evaluations , and epidemiologic studies . Although the statistical methods involved may at first appear to be mathematically complex , their purpose is simple : They are trying to answer four basic questions . Are the results of the different studies similar ? To the extent that they are similar , what is the best overall estimate ? How precise and robust is this estimate ? Finally , can dissimilarities be explained ? This article provides some guidance in underst and ing the key technical aspects of the quantitative approach to these questions . We have avoided using equations and statistical notations ; interested readers will find implementations of the described methods in the listed references . We focus here on the quantitative synthesis of reports of r and omized , controlled , therapeutic trials because far more meta-analyses on therapeutic studies than on other types of studies have been published . For practical reasons , we present a stepwise description of the tasks that are performed when statistical methods are used to combine data . These tasks are 1 ) deciding whether to combine data and defining what to combine , 2 ) evaluating the statistical heterogeneity of the data , 3 ) estimating a common effect , 4 ) exploring and explaining heterogeneity , 5 ) assessing the potential for bias , and 6 ) presenting the results . Deciding Whether To Combine Data and Defining What To Combine By the time one performs a quantitative synthesis , certain decisions should already have been made about the formulation of the question and the selection of included studies . These topics were discussed in two previous articles in this series [ 1 , 2 ] . Statistical tests can not compensate for lack of common sense , clinical acumen , and biological plausibility in the design of the protocol of a meta- analysis . Thus , a reader of a systematic review should always address these issues before evaluating the statistical methods that have been used and the results that have been generated . Combining poor- quality data , overly biased data , or data that do not make sense can easily produce unreliable results . The data to be combined in a meta- analysis are usually either binary or continuous . Binary data involve a yes/no categorization ( for example , death or survival ) . Continuous data take a range of values ( for example , change in diastolic blood pressure after antihypertensive treatment , measured in mm Hg ) . When one is comparing groups of patients , binary data can be summarized by using several measures of treatment effect that were discussed earlier in this series [ 3 ] . These measures include the risk ratio ; the odds ratio ; the risk difference ; and , when study duration is important , the incidence rate . Another useful clinical measure , the number needed to treat ( NNT ) , is derived from the inverse of the risk difference [ 3 ] . Treatment effect measures , such as the risk ratio and the odds ratio , provide an estimate of the relative efficacy of an intervention , whereas the risk difference describes the intervention 's absolute benefit . The various measures of treatment effect offer complementary information , and all should be examined [ 4 ] . Continuous data can be summarized by the raw mean difference between the treatment and control groups when the treatment effect is measured on the same scale ( for example , diastolic blood pressure in mm Hg ) , by the st and ardized mean difference when different scales are used to measure the same treatment effect ( for example , different pain scales being combined ) , or by the correlation coefficients between two continuous variables [ 5 ] . The st and ardized mean difference , also called the effect size , is obtained by dividing the difference between the mean in the treatment group and the mean in the control group by the SD in the control group . Evaluating the Statistical Heterogeneity of the Data This step is intended to answer the question , Are the results of the different studies similar ( homogeneous ) ? It is important to answer this question before combining any data . To do this , one must calculate the magnitude of the statistical diversity ( heterogeneity ) of the treatment effect that exists among the different sets of data . Statistical diversity can be thought of as attributable to one or both of two causes . First , study results can differ because of r and om sampling error . Even if the true effect is the same in each study , the results of different studies would be expected to vary r and omly around the true common fixed effect . This diversity is called the within- study variance . Second , each study may have been drawn from a different population , depending on the particular patients chosen and the interventions and conditions unique to the study . Therefore , even if each study enrolled a large patient sample , the treatment effect would be expected to differ . These differences , called r and om effects , describe the between- study variation with regard to an overall mean of the effects of all of the studies that could be undertaken . The test most commonly used to assess the statistical significance of between- study heterogeneity is based on the chi-square distribution [ 6 ] . It provides a measure of the sum of the squared differences between the results observed and the results expected in each study , under the assumption that each study estimates the same common treatment effect . A large total deviation indicates that a single common treatment effect is unlikely . Any pooled estimate calculated must account for the between- study heterogeneity . In practice , this test has low sensitivity for detecting heterogeneity , and it has been suggested that a liberal significance level , such as 0.1 , should be used [ 6 ] . Estimating a Common Effect The questions that this step tries to answers are , 1 ) To the extent that data are similar , what is their best common point estimate of a therapeutic effect , and 2 ) how precise is this estimate ? The mathematical process involved in this step generally involves combining ( pooling ) the results of different studies into an overall estimate . Compared with the results of individual studies , pooled results can increase statistical power and lead to more precise estimates of treatment effect . Each study is given a weight according to the precision of its results . The rationale is that studies with narrow CIs should be weighted more heavily than studies with greater uncertainty . The precision is generally expressed by the inverse of the variance of the estimate of each study . The variance has two components : the variance of the individual study and the variance between different studies . When the between- study variance is found to be or assumed to be zero , each study is simply weighted by the inverse of its own variance , which is a function of the study size and the number of events in the study . This approach characterizes a fixed-effects model , as exemplified by the Mantel-Haenszel method [ 7 , 8 ] or the Peto method [ 9 ] for dichotomous data . The Peto method has been particularly popular in the past . It has the advantage of simple calculation ; however , although it is appropriate in most cases , it may introduce large biases if the data are unbalanced [ 10 , 11 ] . On the other h and , r and om-effects models also add the between- study variance to the within- study variance of each individual study when the pooled mean of the r and om effects is calculated . The r and om-effects model most commonly used for dichotomous data is the DerSimonian and Laird estimate of the between- study variance [ 12 ] . Fixed- and r and om-effects models for continuous data have also been described [ 13 ] . Pooled results are generally reported as a point estimate and CI , typically a 95 % CI . Other quantitative techniques for combining data , such as the Confidence Profile Method [ 14 ] , use Bayesian methods to calculate posterior probability distributions for effects of interest . Bayesian statistics are based on the principle that each observation or set of observations should be viewed in conjunction with a prior probability describing the prior knowledge about the phenomenon of interest [ 15 ] . The new observations alter this prior probability to generate a posterior probability . Traditional meta- analysis assumes that nothing is known about the magnitude of the treatment effect before r and omized trials are performed . In Bayesian terms , the prior probability distribution is noninformative . Bayesian approaches may also allow the incorporation of indirect evidence in generating prior distributions [ 14 ] and may be particularly helpful in situations in which few data from r and omized studies exist [ 16 ] . Bayesian analyses may also be used to account for the uncertainty introduced by estimating the between- study variance in the r and om-effects model , leading to more appropriate estimates and predictions of treatment efficacy [ 17 ] . Exploring and Explaining Heterogeneity The next important issue is whether the common estimate obtained in the previous step is robust . Sensitivity analyses determine whether the common estimate is influenced by changes in the assumptions and in the protocol for combining the data . A comparison of the results of fixed- and r and om-effects models is one such sensitivity analysis [ 18 ] . Generally , the r and om-effects model produces wider CIs than does the fixed-effects model , and the level of statistical significance may therefore be different depending on the model used . The pooled point estimate per se is less likely to be affected , although exceptions are possible [ 19 ] . Other sensitivity analyses may include the examination of the residuals and the chi-square components [ 13 ] and assessment of the effect of deleting each study in turn . Statistically significant results that depend on a single study may require further exploration . Cumulative Meta- Analysis OBJECTIVE To provide up date d , evidence -based recommendations for the therapy of hypertension in adults . OPTIONS For patients with hypertension , a number of antihypertensive agents may control blood pressure . R and omized trials evaluating first-line therapy with thiazides , beta-adrenergic antagonists , angiotensin-converting enzyme inhibitors , calcium channel blockers , alpha-blockers , central ly acting agents or angiotensin II receptor antagonists were review ed . OUTCOMES The health outcomes that were considered were changes in blood pressure , cardiovascular morbidity , and cardiovascular and /or all-cause mortality rates . Economic outcomes were not considered due to insufficient evidence . EVIDENCE MEDLINE was search ed for the period March 1999 to October 2001 to identify studies not included in the 2000 revision of the Canadian Recommendations for the Management of Hypertension . Reference lists were scanned , experts were polled , and the personal files of the subgroup members and authors were used to identify other published studies . All relevant articles were review ed and appraised , using prespecified levels of evidence , by content experts and method ological experts . VALUES A high value was placed on the avoidance of cardiovascular morbidity and mortality . BENEFITS , HARMS AND COSTS Various antihypertensive agents reduce the blood pressure of patients with sustained hypertension . In certain setting s , and for specific classes of drugs , blood-pressure lowering has been associated with reduced cardiovascular morbidity and /or mortality . RECOMMENDATIONS The present document contains detailed recommendations pertaining to treatment thresholds , target blood pressures , and choice of agents in various setting s in patients with hypertension . The main changes from the 2000 Recommendations are the addition of a section on the treatment of hypertension in patients with diabetes mellitus , the amalgamation of the previous sections on treatment of hypertension in the young and old into one section , increased emphasis on the role of combination therapies over repeated trials of single agents and expansion of the section on the treatment of hypertension after stroke . Implicit in the recommendations for therapy is the principle that treatment for an individual patient should take into consideration global cardiovascular risk , the presence and /or absence of target organ damage , and comorbidities . VALIDATION All recommendations were grade d according to strength of the evidence and voted on by the Canadian Hypertension Recommendations Working Group . Individuals with potential conflicts of interest relative to any specific recommendation were excluded from voting on that recommendation . Only those recommendations achieving high levels of consensus are reported here . These guidelines will continue to be up date d annually BACKGROUND In chronic nephropathies , inhibition of angiotensin-converting enzyme ( ACE ) is renoprotective , but can further renoprotection be achieved by reduction of blood pressure to lower than usual targets ? We aim ed to assess the effect of intensified versus conventional blood-pressure control on progression to end-stage renal disease . METHODS We undertook a multicentre , r and omised controlled trial of patients with non-diabetic proteinuric nephropathies receiving background treatment with the ACE inhibitor ramipril ( 2.5 - 5 mg/day ) . We r and omly assigned participants either conventional ( diastolic < 90 mm Hg ; n=169 ) or intensified ( systolic/diastolic < 130/80 mm Hg ; n=169 ) blood-pressure control . To achieve the intensified blood-pressure level , patients received add-on therapy with the dihydropyridine calcium-channel blocker felodipine ( 5 - 10 mg/day ) . The primary outcome measure was time to end-stage renal disease over 36 months ' follow-up , and analysis was by intention to treat . FINDINGS Of 338 patients who were r and omised , three ( two assigned intensified and one allocated conventional blood-pressure control ) never took study drugs and they were excluded . Over a median follow-up of 19 months ( IQR 12 - 35 ) , 38/167 ( 23 % ) patients assigned to intensified blood-pressure control and 34/168 ( 20 % ) allocated conventional control progressed to end-stage renal disease ( hazard ratio 1.00 [ 95 % CI 0.61 - 1.64 ] ; p=0.99 ) . INTERPRETATION In patients with non-diabetic proteinuric nephropathies receiving background ACE-inhibitor therapy , no additional benefit from further blood-pressure reduction by felodipine could be shown OBJECTIVES The aim of this study was to determine whether pulse pressure is a risk factor for coronary artery disease using data from the MRC trial of treatment of mild hypertension , and whether the effect of anti-hypertensive drug therapy on pulse pressure may be a determinant of outcome in treated patients . METHODS Logistic regression and Cox regression analyses were used to compare systolic and diastolic blood pressure , pulse pressure and mean blood pressure as predictors of coronary events and stroke in the MRC Mild Hypertension Trial . The effects of anti-hypertensive drug treatment with bendrofluazide and propranolol on pulse pressure were assessed using 1-year follow-up data . Event rates in the placebo-treated group and responses to anti-hypertensive treatment were measured in quartiles of age-adjusted entry pulse pressure . A ' four-corners ' analysis was performed , with subjects divided into the upper and lower halves of the distributions of systolic and diastolic blood pressure at entry . RESULTS Pulse pressure was a stronger predictor of coronary events than systolic , diastolic or mean blood pressure in males by logistic regression .  Pulse pressure was similar to systolic pressure as a coronary event predictor on Cox regression . Stroke was predicted most strongly by mean blood pressure . Fatal and non-fatal coronary event rates increased progressively in ascending quartiles of age-adjusted pulse pressure , but there was also a strong correlation with systolic blood pressure . The values of partial logistic regression coefficients in models containing both systolic and diastolic blood pressure also supported a role for pulse pressure in predicting coronary events and for mean blood pressure in predicting stroke . Coronary risk , but not stroke , was inversely related to diastolic blood pressure in the four-corners analysis . In a Cox model , regressions of coronary event probability on systolic blood pressure at entry were significantly and inversely related to diastolic blood pressure categorized in quartiles . Bendrofluazide but not propranolol decreased pulse pressure significantly and was associated with a reduction in cardiovascular events overall , but no definite relationship between the effect of drugs on pulse pressure and specific responses to treatment was seen . CONCLUSION Pulse pressure is a strong risk factor for coronary events in untreated hypertensive male subjects in the MRC Mild Hypertension Trial , whereas stroke is best predicted by mean blood pressure .  Bendrofluazide and propranolol have different effects on pulse pressure which may be related to their relative efficacy in the treatment of hypertension , but this possibility requires further study in more suitable population BACKGROUND The Hypertension Optimal Treatment ( HOT ) Study has provided information about cardiovascular events in 18790 hypertensives , subjected to pronounced blood pressure ( BP ) lowering for a mean of 3.8 years . The HOT study data have subsequently been analysed after stratification of the patients according to global cardiovascular risk , and it has been found that , despite intensive blood pressure lowering in all risk strata , morbid event rates increased with increasing risk stratum . OBJECTIVES Previously analysed global risk strata were based on combinations of risk factors . The analyses presented here were intended to provide information on the relative role that the presence of each individual factor may have in increasing cardiovascular risk , despite good BP control . METHODS Risk ratios ( RR ) for patients with and those without a risk factor were calculated with 95 % confidence intervals ( CI ) using a Cox proportional hazard model , and adjusted for all variables except the one under examination . RESULTS For all risk factors considered and for all types of event , RR were always greater than 1 , indicating a greater risk in the presence , compared with that in the absence of each factor . The male gender was a statistically significant risk for cardiovascular ( CV ) events , CV and total mortality and particularly for myocardial infa rct ion ( MI ) ; age > or = 65 years for CV events , stroke , CV and particularly total mortality ; smoking for all events analysed , but particularly for total mortality ( twice higher in smokers than in non-smokers ) ; high serum cholesterol ( > 6.8 mmol/l ) for CV events , MI and CV mortality ; high serum creatinine ( > 155 micromol/l ) for CV events , stroke , CV and total mortality ; diabetes for CV events , stroke , total mortality and particularly CV mortality ; and ischaemic heart disease for all events analysed . Adjusted RR were often close to or greater than 2 . CONCLUSIONS Each of the risk factors considered was found to be an important cause of residual risk , despite good BP control . These findings emphasize the importance of addressing other correctable risk factors , e.g. smoking , hypercholesterolaemia and diabetes , as well as rigorous control of blood pressure , and of initiating antihypertensive therapy before cardiovascular and renal damage becomes manifest 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 The Hypertension Optimal Treatment ( HOT ) Study is an ongoing prospect i ve , r and omized , multicenter trial conducted in 26 countries . Its two main aims are to evaluate the relationship between three levels of target diastolic blood pressure ( < or = 90 , < or = 85 or < or = 80 mmHg ) and the incidence of cardiovascular morbidity and mortality in hypertensive patients and the effects on morbidity and mortality of a low dose , 75 mg daily , of acetylsalicylic acid ( ASA , aspirin ) compared with placebo .  Altogether 19,193 patients have been recruited and r and omized and one-year data are now available for all patients . This is a report on the blood pressures achieved , the tolerability and other available data after 12 months of follow-up of all patients . Special reference will be given to the subgroup of elderly patients ( > or = 65 years , n = 6,113 ) as compared to younger patients ( < 65 years , n = 13,080 ) . On average , the target group < or = 90 mmHg in diastolic blood pressure has reached 86 mmHg , the target group < or = 85 mmHg has reached 83 mmHg and the target group < or = 80 mmHg has reached 81 mmHg . The percentage of patients that has obtained their target blood pressures is 84 % in the target group < or = 90 mmHg , 72 % in the target group < or = 85 mmHg and 57 % in the target group < or = 80 mmHg at 12 months of follow-up . In the elderly subgroup ( > or = 65 years of age ) the percentage of patients at target is higher for all target groups , being 86 , 76 and 61 % , respectively , at 12 months . Antihypertensive treatment is initiated with a calcium antagonist , felodipine , at a dose of 5 mg once daily . If target blood pressure is not reached , additional antihypertensive therapy , with either an angiotensin converting enzyme ( ACE ) inhibitor or a beta-adrenoceptor blocking agent , is given . Further dose adjustments are made in accordance with a set protocol . As a fifth and final step a diuretic may be added . Side effects have been relatively few in this large multinational series of intensively treated hypertensive patients . Only ankle edema , 2.6 % and 3.0 % , and coughing , 1.3 % and 0.8 % , in young and elderly patients , respectively , exceed a frequency of 1 % , and 88 % of all patients are still taking their baseline therapy felodipine after one year . The one-year data presented here indicate that it should be possible to fulfill the primary aims of the HOT Study The Hypertension Optimal Treatment ( HOT ) Study is an ongoing prospect i ve r and omized , multicentre trial conducted in 26 countries . There are two main aims of the study . The first is to evaluate the relationship between three levels of target diastolic blood pressure ( < or = 90 , < or = 85 or < or = 80 mmHg ) and the incidence of cardiovascular morbidity and mortality in hypertensive patients . The second is to determine the effect on morbidity and mortality of a low dose , 75 mg daily , of acetylsalicylic acid ( ASA , aspirin ) compared with placebo .  Altogether 18,790 patients have been recruited and r and omized , and two-year data are now available for all patients . This is a report on the blood pressures achieved , the tolerability , and other available data after 24 months of follow-up of all patients . Special emphasis is given to the subgroup of elderly patients ( > or = 65 years , n = 5988 ) compared with young patients ( < 65 years , n = 12 802 ) . On average , patients in the < or = 90 mmHg diastolic blood pressure target group have reached 85 mmHg , in the < or = 85 mmHg target group patients have reached 83 mmHg and in the < or = 80 mmHg target group patients have reached 81 mmHg . The percentage of those achieving target blood pressure in each target group at 24 months of follow-up is 85 % in the < or = 90 mmHg target group , 75 % in the < or = 85 mmHg target group and 57 % in the < or = 80 mmHg target group . In the elderly subgroup ( > or = 65 years of age ) , the percentage of patients achieving target at 24 months is higher for all target groups , namely 89 % in the < or = 90 mmHg group , 80 % in the 85 mmHg group and 62 % in the 80 mmHg group . Antihypertensive treatment was initiated with a calcium antagonist , felodipine , at a dose of 5 mg once daily . If target blood pressure was not reached , additional antihypertensive therapy , with either an angiotensin converting enzyme ( ACE ) inhibitor or a beta-adrenoceptor blocking agent , was given . Further dose adjustments were made in accordance with a set protocol . As a fifth , and final , step , a diuretic could be added . There have been relatively few side effects in this large , multinational study of hypertensive patients . Only ankle oedema and coughing exceed a frequency of 0.5 % ( ankle oedema 1.3 % in young and 1.7 % in elderly ; coughing 0.5 % in young and elderly ) . After two years , 84 % of all patients are still taking their baseline therapy , felodipine . The 24-month data presented here indicate that it should be possible to fulfil the primary aims of the HOT Study BACKGROUND Cardiovascular morbidity is a major burden in patients with type 2 diabetes . In the Steno-2 Study , we compared the effect of a targeted , intensified , multifactorial intervention with that of conventional treatment on modifiable risk factors for cardiovascular disease in patients with type 2 diabetes and microalbuminuria . METHODS The primary end point of this open , parallel trial was a composite of death from cardiovascular causes , nonfatal myocardial infa rct ion , nonfatal stroke , revascularization , and amputation .  Eighty patients were r and omly assigned to receive conventional treatment in accordance with national guidelines and 80 to receive intensive treatment , with a stepwise implementation of behavior modification and pharmacologic therapy that targeted hyperglycemia , hypertension , dyslipidemia , and microalbuminuria , along with secondary prevention of cardiovascular disease with aspirin . RESULTS The mean age of the patients was 55.1 years , and the mean follow-up was 7.8 years . The decline in glycosylated hemoglobin values , systolic and diastolic blood pressure , serum cholesterol and triglyceride levels measured after an overnight fast , and urinary albumin excretion rate were all significantly greater in the intensive-therapy group than in the conventional-therapy group . Patients receiving intensive therapy also had a significantly lower risk of cardiovascular disease ( hazard ratio , 0.47 ; 95 percent confidence interval , 0.24 to 0.73 ) , nephropathy ( hazard ratio , 0.39 ; 95 percent confidence interval , 0.17 to 0.87 ) , retinopathy ( hazard ratio , 0.42 ; 95 percent confidence interval , 0.21 to 0.86 ) , and autonomic neuropathy ( hazard ratio , 0.37 ; 95 percent confidence interval , 0.18 to 0.79 ) . CONCLUSIONS A target-driven , long-term , intensified intervention aim ed at multiple risk factors in patients with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and microvascular events by about 50 percent Hypertensive nephrosclerosis is a progressive renal disease and the leading cause of end-stage renal disease ( ESRD ) in blacks in the United States . It is generally believed that hypertensive renal injury is responsible for progressive renal failure ; however , it is not known whether pharmacologic lowering of blood pressure to any level prevents progression of renal disease . Accordingly , we performed a long-term prospect i ve r and omized trial to determine whether " strict " [ diastolic blood pressure ( DBP ) 65 to 80 mm Hg ] versus " conventional " ( DBP 85 to 95 mm Hg ) blood pressure control is associated with a slower rate of decline in glomerular filtration rate . Eighty-seven non-diabetic patients ( age 25 to 73 ; 68 black , 58 male ) with long-st and ing hypertension ( DBP > or = 95 mm Hg ) , chronic renal insufficiency ( GFR < or = 70 m/min/1.73 m2 ) and a normal urine sediment were studied . DBP was pharmacologically lowered to < or = 80 mm Hg ( 3 of 4 consecutive measurements at 1 to 4 weeks intervals ) after which patients were r and omized . DBP and GFR ( renal clearance of 125I-iothalamate ) were measured at baseline , at three months and every six months post-r and omization . The rate of decline in GFR ( GFR slope , in ml/min/1.73 m2/year ) , estimated by the method of maximum likelihood in a mixed effects model , was the primary outcome variable . In a secondary analysis , 50 % reduction in GFR ( or a doubling of serum creatinine ) from baseline , ESRD and death were combined . ( ABSTRACT TRUNCATED AT 250 WORDS OBJECTIVE - To examine the prevalence , incidence , predisposing factors for hypertension , its hazards as an ingredient of the cardiovascular risk profile , and the implication s of this information for prevention and treatment . METHODS - Prospect i ve longitudinal analysis of 36-year follow-up data from the Framingham Study of the relation of antecedent blood pressure to occurrence of subsequent cardiovascular morbidity and mortality depending on the metabolically linked burden of associated risk factors . RESULTS - Hypertension is one of the most prevalent and powerful contributors to cardiovascular diseases , the leading cause of death in the United States . There is , on average , a 20 mm Hg systolic and 10 mm Hg diastolic increment increase in blood pressure from age 30 to 65 years . Isolated systolic hypertension is the dominant variety . There is no evidence of a decline in the prevalence of hypertension over 4 decades despite improvements in its detection and treatment . Hypertension contributes to all of the major atherosclerotic cardiovascular disease outcomes increasing risk , on average , 2- to 3-fold . Coronary disease , the most lethal and common sequela , deserves highest priority . Hypertension clusters with dyslipidemia , insulin resistance , glucose intolerance , and obesity , occurring in isolation in less than 20 % . The hazard depends on the number of these associated metabolically linked risk factors present . Coexistent overt cardiovascular disease also influences the hazard and choice of therapy . CONCLUSION - The absence of a decline in the prevalence of hypertension indicates an urgent need for primary prevention by weight control , exercise , and reduced salt and alcohol intake . The urgency and choice of therapy of existing hypertension should be based on the multivariate cardiovascular risk profile that more appropriately targets hypertensive persons for treatment and prevention of cardiovascular sequelae Context We do not know the optimal blood pressure needed to slow progression of chronic kidney disease . Contribution In this multicenter trial , 840 adults with mostly nondiabetic kidney disease and moderately to severely decreased glomerular filtration rate were r and omly assigned to usual blood pressure control ( target : mean arterial pressure < 107 mm Hg ) or a low blood pressure goal ( target : mean arterial pressure < 92 mm Hg ) . Approximately 10 years later , the hazard ratio for kidney failure in the low compared with the usual blood pressure group was 0.68 ( 95 % CI , 0.57 to 0.82 ) . Implication s A low blood pressure target slows progression of nondiabetic kidney disease . The Editors The Seventh Report of the Joint National Commission on Prevention , Detection , Assessment and Treatment of Hypertension and the National Kidney Foundation Kidney Disease Outcome Quality Initiative Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease recommend a target blood pressure of less than 130/80 mm Hg in patients with chronic kidney disease ( 1 , 2 ) . These guidelines are based on data from observational studies demonstrating that persons with chronic kidney disease are at high risk for cardiovascular disease and from subgroup analyses of the Modification of Diet in Renal Disease ( MDRD ) Study suggesting that a low target blood pressure may slow the decline in kidney function in persons with moderate to high levels of proteinuria ( 3 ) . However , no published trials in diabetic or nondiabetic kidney disease have demonstrated that a lower target blood pressure reduces the incidence of kidney failure . Many types of chronic kidney disease progress slowly , requiring years for the onset of kidney failure . In clinical trials , progression of kidney disease is usually assessed by change in kidney function , which is measured as the glomerular filtration rate ( GFR ) or serum creatinine concentration . Two r and omized , controlled trials in nondiabetic kidney disease have compared the effects of a low target blood pressure with those of a usual target blood pressure on the decline in GFR ( 3 , 4 ) . The MDRD Study enrolled participants with predominantly nondiabetic kidney diseases , a baseline GFR of 13 to 55 mL/min per 1.73 m2 , and median proteinuria of 0.35 g/d ( 3 ) . In that study , a low target blood pressure did not produce a slower projected mean decline in GFR at 3 years compared with the usual target blood pressure . However , participants with greater proteinuria significantly benefited from the low target blood pressure ( 3 ) . On the basis of these findings , it was recommended that participants with proteinuria greater than 1 g/d have a lower target blood pressure . The African American Study of Kidney Disease and Hypertension ( AASK ) enrolled participants with hypertensive nephrosclerosis , a baseline GFR of 20 to 70 mL/min per 1.73 m2 , and median baseline proteinuria of 0.081 g/d ( 4 ) . In that study , a lower target blood pressure did not reduce the mean decline in GFR or the risk for the composite outcome of reduction in GFR of at least 50 % , kidney failure , or all-cause mortality during a median follow-up of 4 years . The average rates of decline in GFR in the MDRD Study and AASK were 4 mL/min per 1.73 m2 per year and 2 mL/min per 1.73 m2 per year , respectively , and relatively few participants developed kidney failure during the observation period . The long-term effect of a low target blood pressure on the onset of kidney failure may differ from the effect on decline in GFR observed during the trial . Therefore , we evaluated the effects of a low target blood pressure on the onset of kidney failure and all-cause mortality through extended follow-up after completion of the MDRD Study . Methods The MDRD R and omized , Controlled Trial The MDRD Study was a r and omized , controlled trial of the effect of dietary protein restriction and strict control of blood pressure  on the progression of kidney disease . Details of the design and r and omization criteria are provided elsewhere ( 5 , 6 ) . The trial was conducted from 1989 to 1993 . Eligibility criteria for enrollment were age 18 to 70 years and presence of chronic kidney disease , with a serum creatinine concentration of 123.8 mol/L ( 1.4 mg/dL ) to 618.8 mol/L ( 7.0 mg/dL ) in men and 106.1 mol/L ( 1.2 mg/dL ) to 618.8 mol/L ( 7.0 mg/dL ) in women . Persons with diabetes requiring therapy with insulin , class III or IV congestive heart failure , renal artery stenosis , history of kidney transplantation , or frequent hospitalizations were excluded . Eight hundred forty participants were enrolled : Study A included 585 participants with a baseline GFR of 25 to 55 mL/min per 1.73 m2 , and study B included 255 participants with a baseline GFR of 13 to 24 mL/min per 1.73 m2 . Participants in both studies were r and omly assigned to a low or a usual target blood pressure . The low target blood pressure was a mean arterial pressure less than 92 mm Hg ( equivalent to a blood pressure less than 125/75 mm Hg ) for participants 60 years of age or younger and less than 98 mm Hg for participants 61 years of age or older . The usual target blood pressure was a mean arterial pressure less than 107 mm Hg ( equivalent to a blood pressure of 140/90 mm Hg ) for participants 60 years of age or younger and less than 113 mm Hg for participants 61 years of age or older . Participants in study A were r and omly assigned to receive a usual-protein diet ( 1.0 g/kg of body weight daily ) or a low-protein diet ( 0.6 g/kg daily ) , whereas participants in study B were r and omly assigned to receive a low-protein diet ( 0.6 g/kg daily ) or a very-low-protein diet ( 0.28 g/kg daily , with keto acid and amino acid supplementation ) . No interactions were noted between the dietary intervention and the blood pressure intervention ( 3 ) . Participants were followed up to 4 years . The rate of decline in GFR , measured as kidney clearance of 125I-iothalamate , was the primary outcome . Long-Term Follow-up ( 19932000 ) of the MDRD Study The investigational review boards of the Clevel and Clinic ( Data Coordinating Center for the MDRD Study ) and Tufts-New Engl and Medical Center approved the long-term follow-up study . Kidney failure , defined by the requirement for dialysis or kidney transplantation , and a composite of kidney failure or all-cause mortality were the outcomes of interest for our analysis . All-cause mortality before kidney failure was included in the composite outcome because it is a competing risk factor for kidney failure . Participants were censored on 31 December 2000 if neither of these outcomes had occurred . Blood Pressure Measurement During the Trial ( 19891993 ) Trained personnel measured blood pressure monthly by using a r and om-zero mercury sphygmomanometer . Therapeutic regimens were modified monthly or more often as needed to achieve target blood pressure . For our analysis , mean follow-up blood pressure during the study was defined as the average of all blood pressure measurements obtained after the 4th month of follow-up . This definition differs from that of previous studies , in which the average of all blood pressure measurements during follow-up was calculated ( 3 , 7 ) . The change in definition was introduced to allow comparison with the AASK Study . During Long-Term Follow-up ( 19932000 ) No specific target blood pressure was recommended after completion of the trial . Blood pressure was measured by using the same methods in a large subgroup of participants 9 months after the end of the study ( phase V ) . Thereafter , blood pressure measurements are not available . Antihypertensive Regimens During the Trial ( 19891993 ) After r and om allocation , therapeutic regimens were modified to achieve the target blood pressure . Nonpharmacologic therapy consisted of recommendations for exercise and weight loss and reductions in intake of dietary sodium and alcohol . For pharmacologic therapy , use of all agents was allowed , in the interest of achieving blood pressure goals . However , angiotensin-converting enzyme ( ACE ) inhibitors , with or without a diuretic , were encouraged as agents of first choice . Calcium-channel blockers , with or without a diuretic , were encouraged as agents of second choice . During Long-Term Follow-up ( 19932000 ) Because the MDRD Study did not evaluate the effects of individual antihypertensive agents on decline in kidney function , no specific pharmacologic therapy was recommended after completion of the trial . Outcomes The onset of kidney failure was ascertained from the U.S. Renal Data System by using participants ' Social Security number , name , sex , and date of birth . Data on all-cause mortality were obtained from the National Death Index by using the same identifying information . One hundred eighty-five participants were recorded as starting dialysis or receiving a kidney transplant during or shortly after the r and omized trial in both the MDRD Study data base and the U.S. Renal Data System data base . The recorded date of kidney failure agreed between the 2 data bases to within 1 day for 50 % of these participants , to within 30 days for 90 % , and to within 120 days for 97 % . Nine participants recorded as reaching kidney failure in the MDRD Study data base were not found in the U.S. Renal Data System data base . Except in the case of these 9 participants ( 4 of whom were in the usual target blood pressure group and 5 of whom were in the low target blood pressure group ) , data obtained from U.S. Renal Data System data base were used in all analyses to define the date of kidney failure . All deaths that were coded in the U.S. Renal Data System data base were confirmed in the National Death Index . For all analyses , the date in the National Death Index was used as the date of death so as to maintain consistency with participants who died but had not reached kidney failure and therefore were not included in the U.S. Renal Data System data base . Statistical Analyses We combined participants from studies A and B to improve statistical power . This approach was BACKGROUND Epidemiologic studies have shown a relationship between glycated hemoglobin levels and cardiovascular events in patients with type 2 diabetes . We investigated whether intensive therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors . METHODS In this r and omized study , 10,251 patients ( mean age , 62.2 years ) with a median glycated hemoglobin level of 8.1 % were assigned to receive intensive therapy ( targeting a glycated hemoglobin level below 6.0 % ) or st and ard therapy ( targeting a level from 7.0 to 7.9 % ) . Of these patients , 38 % were women , and 35 % had had a previous cardiovascular event . The primary outcome was a composite of nonfatal myocardial infa rct ion , nonfatal stroke , or death from cardiovascular causes . The finding of higher mortality in the intensive-therapy group led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up . RESULTS At 1 year , stable median glycated hemoglobin levels of 6.4 % and 7.5 % were achieved in the intensive-therapy group and the st and ard-therapy group , respectively . During follow-up , the primary outcome occurred in 352 patients in the intensive-therapy group , as compared with 371 in the st and ard-therapy group ( hazard ratio , 0.90 ; 95 % confidence interval [ CI ] , 0.78 to 1.04 ; P=0.16 ) . At the same time , 257 patients in the intensive-therapy group died , as compared with 203 patients in the st and ard-therapy group ( hazard ratio , 1.22 ; 95 % CI , 1.01 to 1.46 ; P=0.04 ) . Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group ( P<0.001 ) . CONCLUSIONS As compared with st and ard therapy , the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events . These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes . ( Clinical Trials.gov number , NCT00000620 .
target: Treating patients to lower than st and ard BP targets , < /=140 - 160/90 - 100 mmHg , does not reduce mortality or morbidity .
background: BACKGROUND When treating elevated blood pressure , doctors need to know what blood pressure ( BP ) target they should try to achieve .
  The st and ard of clinical practice for some time has been < /= 140 - 160/ 90 - 100 mmHg .
  New guidelines are recommending BP targets lower than this st and ard .
  It is not known whether attempting to achieve targets lower than the st and ard reduces mortality and morbidity .
  OBJECTIVES To determine if lower BP targets ( < /= 135/85 mmHg ) are associated with reduction in mortality and morbidity as compared with st and ard BP targets ( < /= 140 - 160/ 90 - 100 mmHg ) .