Influence of diabetes and type of hypertension on response to antihypertensive treatment. Combined low-dose medication and primary intervention over a 30-month period for sustained high blood pressure in childhood. Subgroup and per-protocol analysis of the randomized European Trial on Isolated Systolic Hypertension in the Elderly. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. Systolic Hypertension in the Elderly Program Cooperative Research Group. Cardiovascular Outcomes in High-Risk Hypertensive Patients Stratified by Baseline Glomerular Filtration Rate Dogma Disputed: Can Aggressively Lowering Blood Pressure in Hypertensive Patients with Coronary Artery Disease Be Dangerous? Diclofenac sodium versus pethidine in acute renal colic. A significant decrease in blood pressure through a family-based nutrition health education programme among community residents in Taiwan. Non-pharmacological treatment of hypertension in primary health care: a 2-year open randomized controlled trial of lifestyle intervention against hypertension in eastern Finland Effects of immediate versus delayed antihypertensive therapy on outcome in the Systolic Hypertension in Europe Trial South African hypertension guideline 2011. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. Comparison of the Effects of Antihypertensive Agents on Central Blood Pressure and Arterial Stiffness in Isolated Systolic Hypertension The Australian Therapeutic Trial in Mild Hypertension. The 2001 Canadian recommendations for the management of hypertension: Part two--Therapy. 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. Blood pressure and isolated systolic hypertension and the risk of coronary heart disease and mortality in elderly men (the Zutphen Elderly Study)
The aim of our investigation was to determine whether the presence of additional risk factors or type of hypertension ( diastolic or isolated systolic ) influences blood pressure ( BP ) response to treatment . The International Nifedipine GITS Study : Intervention as a Goal in Hypertension Treatment ( INSIGHT ) study is a double-blinded outcome comparison of calcium channel blockade with diuretics in high-risk patients aged 55 to 80 years . Dynamic r and omization between nifedipine once daily and hydrochlorothiazide/amiloride was performed to ensure that approximately equal numbers of patients in the 2 groups had each of the major cardiovascular risk factors . Patients with isolated systolic hypertension were also separately r and omized . Atenolol or enalapril was the m and atory second-line drug . In 5669 patients who completed the 18-week titration , BP fell from 172+/-15/99+/-9 mm Hg ( mean+/-SD ) while receiving placebo to 139+/-12/82+/-7 mm Hg . Twenty-six percent of patients required 2 drugs , and 4 % required 3 drugs . Patients with diabetes were the most resistant to treatment , requiring second and third drugs 40 % and 100 % more frequently than patients without diabetes and achieving marginally the highest final BP , for any risk group , of 141+/-13/82+/-8 mm Hg . Age , smoking , gender , hypercholesterolemia , left ventricular hypertrophy , and existing atherosclerosis had little ( < 1 mm Hg ) or no influence on BP at the end of titration , but all except smoking slightly reduced the initial response of either systolic or diastolic BP . Patients with isolated systolic hypertension were slightly more responsive than average to treatment . Our findings suggest that in patients at high absolute risk of cardiovascular complications from hypertension , the risk factors themselves do not prevent the recommended BP targets from being achieved Studies of the pathobiologic consequences of high blood pressure in childhood , as well as those following blood pressure levels into young adulthood , indicate that early intervention in the natural history of essential hypertension is warranted . In an exploratory study of the concept , 95 children out of 1604 ( aged 8 to 18 years ) , who persistently scored higher than the 90th percentile for blood pressure over a 4-month period , considering the race , sex , and height of the children , were studied . Five series of replicate measurements with 30 total observations were obtained . Children with evidence of secondary hypertension were excluded . The study children were r and omly divided into treatment ( n = 48 ) and high-comparison ( n = 47 ) groups . Treatment consisted of low-dose combined drug therapy ( propranolol and chlorthalidone ) with an educational program directed towards hypertension and dietary and exercise modification . Monthly follow-up was continued for 30 months . Significant systolic ( -3.59 mm Hg ) and diastolic ( -1.73 mm Hg ) changes were noted up to 30 months ( p less than 0.05 ) with minimal side effects . Furthermore , analyses suggested that the blood pressure change , at least in the first month , was mostly attributable to drug therapy . Moreover , the mechanism of blood pressure change appeared to be race-specific , with whites having pulse rate changes and blacks having significant weight changes , which were associated with blood pressure change . This trial shows further research is warranted to determine optimum approaches for early treatment of essential hypertension to prevent future hypertensive disease BACKGROUND In 1989 , the European Working Party on High Blood Pressure in the Elderly started the double-blind , placebo-controlled , Systolic Hypertension in Europe Trial to test the hypothesis that antihypertensive drug treatment would reduce the incidence of fatal and nonfatal stroke in older patients with isolated systolic hypertension . This report addresses whether the benefit of antihypertensive treatment varied according to sex , previous cardiovascular complications , age , initial blood pressure ( BP ) , and smoking or drinking habits in an intention-to-treat analysis and explores whether the morbidity and mortality results were consistent in a per- protocol analysis . METHODS After stratification for center , sex , and cardiovascular complications , 4695 patients 60 years of age or older with a systolic BP of 160 to 219 mm Hg and diastolic BP less than 95 mm Hg were r and omized . Active treatment consisted of nitrendipine ( 10 - 40 mg/d ) , with the possible addition of enalapril maleate ( 5 - 20 mg/d ) and /or hydrochlorothiazide ( 12.5 - 25 mg/d ) , titrated or combined to reduce the sitting systolic BP by at least 20 mm Hg , to below 150 mm Hg . In the control group , matching placebo tablets were employed similarly . RESULTS In the intention-to-treat analysis , male sex , previous cardiovascular complications , older age , higher systolic BP , and smoking at r and omization were positively and independently correlated with cardiovascular risk . Furthermore , for total ( P = .009 ) and cardiovascular ( P = .09 ) mortality , the benefit of antihypertensive drug treatment weakened with advancing age ; for total mortality ( P = .05 ) , the benefit increased with higher systolic BP at entry , while for fatal and nonfatal stroke ( P = .01 ) , it was most evident in nonsmokers ( 92.5 % of all patients ) . In the per protocol analysis , active treatment reduced total mortality by 24 % ( P = .05 ) , reduced all fatal and nonfatal cardiovascular end points by 32 % ( P<.001 ) , reduced all strokes by 44 % ( P = .004 ) , reduced nonfatal strokes by 48 % ( P = .005 ) , and reduced all cardiac end points , including sudden death , by 26 % ( P = .05 ) . CONCLUSIONS In elderly patients with isolated systolic hypertension , stepwise antihypertensive drug treatment , starting with the dihydropyridine calcium channel blocker nitrendipine , improves prognosis . The per- protocol analysis suggested that treating 1000 patients for 5 years would prevent 24 deaths , 54 major cardiovascular end points , 29 strokes , or 25 cardiac end points . The effects of antihypertensive drug treatment on total and cardiovascular mortality may be attenuated in very old patients OBJECTIVE To assess the effect of low-dose , diuretic-based antihypertensive treatment on major cardiovascular disease ( CVD ) event rates in older , non-insulin-treated diabetic patients with isolated systolic hypertension ( ISH ) , compared with nondiabetic patients . DESIGN Double-blind , r and omized , placebo-controlled trial : the Systolic Hypertension in the Elderly Program ( SHEP ) . SETTING Multiple clinical and support centers in the United States . PARTICIPANTS A total of 4736 men and women aged 60 years and older at baseline with ISH ( systolic blood pressure [ BP ] , > or = 160 mm Hg ; diastolic BP , < 90 mm Hg ) at baseline , 583 non-insulin-dependent diabetic patients and 4149 nondiabetic patients ( 4 additional patients not so classifiable were r and omized but not included in these analyses ) . Diabetes mellitus defined as physician diagnosis , taking oral hypoglycemic drugs , fasting glucose level of 7.8 mmol/L or more ( > or = 140 mg/dL ) , or any combination of these characteristics . INTERVENTION The active treatment group received a low dose of chlorthalidone ( 12.5 - 25.0 mg/d ) with a step-up to atenolol ( 25.0 - 50.0 mg/d ) or reserpine ( 0.05 - 0.10 mg/d ) if needed . The placebo group received placebo and any active antihypertensive drugs prescribed by patient 's private physician for persistently high BP . MAIN OUTCOME MEASURES The 5-year rates of major CVD events , nonfatal plus fatal stroke , nonfatal myocardial infa rct ion ( MI ) and fatal coronary heart disease ( CHD ) , major CHD events , and all-cause mortality . RESULTS The SHEP antihypertensive drug regimen lowered BP of both diabetic and nondiabetic patients , with few adverse effects . For both diabetic and nondiabetic patients , all outcome rates were lower for participants r and omized to the active treatment group than for those r and omized to the placebo group . Thus , 5-year major CVD rate was lower by 34 % for active treatment compared with placebo , both for diabetic patients ( 95 % confidence interval [ CI ] , 6%-54 % ) and nondiabetic patients ( 95 % CI , 21%-45 % ) . Absolute risk reduction with active treatment compared with placebo was twice as great for diabetic vs nondiabetic patients ( 101/1000 vs 51/1000 r and omized participants at the 5-year follow-up ) , reflecting the higher risk of diabetic patients . CONCLUSION Low-dose diuretic-based ( chlorthalidone ) treatment is effective in preventing major CVD events , cerebral and cardiac , in both non-insulin-treated diabetic and nondiabetic older patients with ISH Context Long-term outcomes of patients with a reduced glomerular filtration rate ( GFR ) who are treated for hypertension are not well-known . Contribution This analysis of a large multicenter trial found that coronary heart disease ( CHD ) was much more common than end-stage renal disease ( 15 % vs. 6 % ) in hypertensive patients with moderate to severe reductions in GFR who were followed for 6 years . Lower baseline GFR was associated with higher risk for CHD independent of other risk factors . Neither amlodipine nor lisinopril is superior to chlorthalidone in preventing CHD , stroke , or combined CVD , and chlorthalidone is superior to both for preventing heart failure , independent of level of renal function . Caution s These are post hoc subgroup findings , and proteinuria was not measured . The Editors It is estimated that more than 10 million Americans have chronic kidney disease ( 1 , 2 ) . The prevalence of chronic kidney disease is particularly high in older adults ; it is estimated to be greater than 25 % in persons older than 70 years of age . Patients with chronic kidney disease are at very high risk for cardiovascular disease ( CVD ) ( 3 - 8 ) . However , the long-term outcomes of older patients who have a mild or moderate reduction in glomerular filtration rate ( GFR )  , particularly with regard to CVD , are not well-known . Because of the large population of older adults with chronic kidney disease , it is important , from a public health and a clinical st and point , to quantify and underst and the comparative risks for CVD and renal disease in these patients . Management of hypertension is an important aspect of management in patients with chronic kidney disease ; in patients with proteinuria , drugs that inhibit the reninangiotensin axis have been shown to be superior to conventional antihypertensive drug therapy for preservation of renal function ( 1 , 9 , 10 ) . However , it is uncertain whether the choice of antihypertensive drug therapy affects risk for CVD in patients with chronic kidney disease ( 11 , 12 ) . The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) is a large clinical trial design ed to compare the efficacy of treatment with different first-line antihypertensive agents on CVD outcomes in high-risk patients with hypertension who are older than 55 years of age ( 13 - 15 ) . The objectives of this report from the ALLHAT data are to 1 ) compare rates of cardiovascular events with rates of development of end-stage renal disease ( ESRD ) in high-risk older adults with hypertension who have reduced GFR ; 2 ) determine whether reduced GFR is independently associated with an increased risk for CVD after adjusting for traditional cardiovascular risk factors ; and 3 ) report the efficacy of first-step treatment with a calcium-channel blocker ( amlodipine ) or an angiotensin-converting enzyme ( ACE ) inhibitor ( lisinopril ) , each compared with a diuretic ( chlorthalidone ) , in modifying CVD outcomes in high-risk patients with hypertension who are stratified by baseline GFR . Methods The rationale and design of ALLHAT have been presented in detail elsewhere ( 13 ) . The study received institutional review board approval , and participants provided written informed consent . Participants were men and women 55 years of age or older who had hypertension with at least 1 additional risk factor for coronary heart disease ( CHD ) . The risk factors included previous ( > 6 months ) myocardial infa rct ion ( MI ) or stroke , left ventricular hypertrophy demonstrated by electrocardiography or echocardiography , history of type 2 diabetes , current cigarette smoking , high-density lipoprotein cholesterol level of less than 0.91 mmol/L ( < 35 mg/dL ) , and documentation of other atherosclerotic CVD . Exclusion criteria included a history of symptomatic heart failure and /or a known left ventricular ejection fraction of less than 0.35 and a serum creatinine level greater than 176.8 mol/L ( > 2 mg/dL ) as reported by the investigator . Participants ( n= 33 357 ) were recruited at 623 centers in the United States , Canada , Puerto Rico , and the U.S. Virgin Isl and s between February 1994 and January 1998 ( Appendix Figure 1 ) . Appendix Figure 1 . R and omization and follow-up of participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) by treatment group . Block r and omization was stratified by center . Participants were r and omly assigned in a double-blind manner and in a 1.7:1:1 ratio to chlorthalidone , amlodipine , or lisinopril . A fourth arm of the study using the -blocker doxazosin was stopped early and is not considered in this report ( 16 ) . The goal blood pressure in each r and omly assigned group was less than 140/90 mm Hg , to be achieved by titrating the assigned study drug ( step 1 ) and by adding study -supplied , open-label agents ( atenolol , clonidine , or reserpine [ step 2 ] or hydralazine [ step 3 ] ) when necessary , at the physician 's discretion ( 16 , 17 ) . Nonpharmacologic lifestyle approaches to treatment of hypertension were recommended according to national guidelines . Other drugs , including low doses of open-label step 1 drug classes , were permitted if clinical ly indicated . Follow-up visits were at 1 month ; 3 , 6 , 9 , and 12 months ; and every 4 months thereafter . Levels of serum creatinine were measured in a single central laboratory using VITROS ( Ortho Clinical Diagnostics , Rochester , New York ) , which had a coefficient of variation of approximately 2 % . Creatinine measurements were calibrated to the Modification of Diet in Renal Disease ( MDRD ) laboratory , and no additional correction was found to be necessary ( 18 ) . A total of 1460 participants ( 4.4 % ) were missing creatinine values , and thus estimated GFR , at baseline . The simplified MDRD Study equation was used to estimate GFR ( mL/min per 1.73 m2 ) according to the following formula : 186.3 ( serum creatinine in mg/dL 1.154 ) ( age in years 0.203 ) 1.212 ( if black ) 0.742 ( if female ) ( 19 ) . Patients were classified into 3 baseline categories of GFR consistent with recommendations in the National Kidney Foundation Kidney Disease Outcomes Quality Initiative Clinical Practice Guidelines on Chronic Kidney Disease : normal or increased ( 90 mL/min per 1.73 m2 ) , mild reduction ( 60 to 89 mL/min per 1.73 m2 ) , and moderate or severe reduction ( < 60 mL/min per 1.73 m2 ) ( 1 ) . Because a serum creatinine level of greater than 176.8 mol/L ( > 2 mg/dL ) was an exclusion criterion , the percentage of patients with severe chronic kidney disease ( estimated GFR 29 mL/min per 1.73 m2 ) at baseline was very small ( 0.6 % ) . Therefore , as in another study ( 6 ) , these participants were considered along with those with moderate chronic kidney disease ( GFR 30 to 59 mL/min per 1.73 m2 ) . Patients were also classified as diabetic or not diabetic by baseline history of diabetes . The primary outcome was fatal CHD or nonfatal MI . Combined CVD was defined as a composite of the primary outcome , coronary revascularization , hospitalized angina , stroke , other treated angina , heart failure ( fatal , hospitalized , or treated nonhospitalized ) , and peripheral arterial disease . Coronary revascularization included coronary artery bypass grafting , percutaneous angioplasty , insertion of stents , and atherectomy . Peripheral vascular disease included intermittent claudication or arterial disease of the lower extremities leading to procedures , such as revascularizations , angioplasty of peripheral arteries , or amputation . End-stage renal disease included death from kidney disease , kidney transplantation , and start of long-term kidney dialysis . Study outcomes were defined in the ALLHAT Manual of Operations ( available from the authors on request ) , were assessed by site investigators at follow-up visits , and were reported to the Clinical Trials Center . Medical review ers from the Clinical Trials Center review ed all events for concordance with study criteria . More detailed information was collected on a r and om ( 10 % ) subset of CHD and stroke events and was review ed by the Endpoints Subcommittee to vali date the procedure of using physician diagnoses . Statistical Analyses Data were analyzed according to the participants ' r and omly assigned treatments regardless of their subsequent medications ( intention-to-treat analysis ) . Baseline characteristics were compared across treatments and the 3 GFR groups by using the Z-test for continuous covariates and contingency table analyses for categorical data . Cox proportional hazards models were used to obtain hazard ratios and 95 % CIs for time to CHD , combined CVD , and stroke to assess the effects of treatment within each of the 3 GFR strata . Because baseline characteristics are similar across treatment groups , no adjustment was deemed necessary . Additional models were used to assess the impact of baseline GFR ( using deciles ) on CHD and combined CVD . Baseline characteristics are not expected to be similar across the various GFR groups defined by deciles ; therefore , adjustments are necessary . Cox test assumptions were examined using loglog plots and tests of treatment by time ( time-dependent ) interaction terms . Because the assumptions were violated in the case of heart failure , logistic models were used to estimate odds ratios for this end point . The consistency of treatment effects across subgroups was examined in the Cox and logistic models by calculating the differences in the log likelihood for models with and without the interaction terms . Treatment effects by GFR subgroup were also analyzed for participants with a history of diabetes by using the aforementioned methods . A P value less than 0.05 indicated statistical significance for the results . Role of the Funding Sources This study was supported by contract NO1-HC-35130 from the National Heart , Lung , and Blood Institute ( NHLBI ) ; the NHLBI was involved in the collection , analysis , and interpretation of the data and the decision to su bmi t the manuscript for publication but was not involved in the direct operations of the study centers . Study medications were supplied by Context Experts debate the consequences of excessive lowering of diastolic pressure in patients with hypertension and coronary artery disease . Contribution This report is a secondary analysis of data from a large trial of 2 antihypertensive drug regimens in patients with known coronary artery disease . The authors found a J-shaped relationship between diastolic blood pressure and all-cause death and myocardial infa rct ion , with the increased risk occurring at diastolic blood pressures below 70 to 80 mm Hg , that is , the lower the diastolic pressure , the higher the risk . Caution s The study examined associations between blood pressure and outcomes ; it could not prove that the antihypertensive therapy that lowered diastolic pressure too much caused the adverse outcomes . The Editors For 2 decades , the hypertension literature has been haunted by the phenomenon of a paradoxical increase in morbidity and mortality with an excessive decrease in blood pressure ( J-curve ) . Indeed , several reports have shown that low diastolic pressure is associated with an increased risk for coronary heart disease and related mortality in older adults and in patients taking antihypertensive medications ( 1 - 13 ) . After doing a review and meta- analysis of pertinent studies , Farnett and colleagues ( 14 ) concluded that although there was no consistent J-shaped relationship between stroke and systolic or diastolic pressure , there was a consistent J-shaped relationship for cardiac events and diastolic pressure . These authors stated that this dichotomy in the relationship between diastolic pressure and target organ disease may leave a clinician with the uncomfortable choice of whether to prevent stroke or renal disease at the expense of coronary heart disease . These findings were at variance with the generally accepted dogma formulated by the sixth report of the Joint National Committee on Prevention , Detection , Evaluation , and Treatment of High Blood Pressure ( JNC VI ) ( 15 ) , which stated that the relationship between pressure and risk was strong , continuous , independent , predictive and etiologically significant . Within the past decade , the phenomenon of a J-curve has been studied in several large trials of normotensive and hypertensive patients ( 16 - 30 ) . Not surprisingly , arguments regarding whether a J-curve could be clinical ly significant have become somewhat contentious . That is , some rely on evidence that on-treatment diastolic pressure below 70 mm Hg does not increase risk for cardiovascular disease and thus deny an impairment of vital organ perfusion within the usual values achievable by antihypertensive treatment . Others , however , consider the J-curve a more real possibility , particularly for the heart . In contrast to other organs , the heart is perfused mostly during diastole and thus could be more vulnerable to diastolic pressure reduction . If a J-curve did exist , it should be most evident in patients with limited coronary perfusion , in other words , in those with manifest coronary artery disease ( CAD ) . Optimal blood pressure in patients with hypertension and CAD remains controversial because few r and omized clinical trials have been done in this population ( 31 , 32 ) . The International Verapamil-Tr and olapril Study ( INVEST ) ( 33 ) , a r and omized trial , evaluated more than 22000 patients with CAD and hypertension . This patient profile , together with unprecedented levels of blood pressure control , provided a unique opportunity to critically investigate the hypothesis that the risk for CAD would increase with an excessive decrease in diastolic pressure . Methods Study Design and Intervention The INVEST design , methods , and principal results have been previously published ( 33 ) . The trial used an open design with blinded end point assessment . In brief , clinical ly stable patients with CAD and hypertension were r and omly assigned to a verapamil sustained-releasebased or atenolol-based strategy .  Patients with previous myocardial infa rct ion ( MI ) within 3 months of enrollment or class IV or V congestive heart failure were excluded .  Blood pressure goals were based on JNC VI ( systolic pressure < 140 mm Hg and diastolic pressure < 90 mm Hg or systolic pressure < 130 mm Hg and diastolic pressure < 85 mm Hg in patients with diabetes or renal impairment ) ( 15 ) . The addition of tr and olapril or hydrochlorothiazide was recommended when necessary to achieve blood pressure goals . Tr and olapril was also recommended for patients with heart failure , diabetes , or renal impairment . Documented CAD was defined as any of the following : remote ( 3 months before enrollment ) confirmed MI , coronary angiography showing more than 50 % narrowing of at least 1 major coronary artery , diagnosis of classic angina pectoris , or concordant abnormalities on 2 different signals ( electrocardiography , echocardiography , or radionuclide scans ) from stress test findings concordant for ischemia ( for example , ST-segment depression or perfusion defects on radionuclide scanning or wall-motion abnormalities on echocardiography or radionuclide scanning ) . Patient Monitoring and Follow-up Protocol visits were scheduled every 6 weeks for the first 6 months and then biannually until 2 years after the last patient was enrolled . Patients were assessed for response to treatment , symptoms , treatment adherence , and adverse effects at each visit and at the end of the study as detailed elsewhere ( 33 ) . Patient follow-up was complete when we received a final assessment form through the online data system or a death report . The Internet-based electronic data collection method used in INVEST did not accept the entry until all required fields were complete . Blood pressure  was measured by using a st and ard mercury sphygmomanometer with an appropriately sized cuff applied to the upper nondominant arm at heart level . By auscultation at the brachial artery , systolic pressure was recorded at the first Korotkoff sound and diastolic pressure was recorded at the disappearance of the fifth Korotkoff sound . Blood pressure was measured twice , at least 2 minutes apart , and the measurements were averaged . Study Outcomes The primary outcome was the first occurrence of all-cause death , nonfatal MI , or nonfatal stroke by intention-to-treat analysis . The MI and stroke definitions are detailed elsewhere ( 34 ) . These 3 components individually were the main secondary outcomes . For this analysis , additional outcomes included fatal and nonfatal MI , fatal and nonfatal stroke , and average on-treatment blood pressure before outcome or censoring . Ascertainment and blinded adjudication of outcomes were described previously ( 32 ) . Follow-up data were available for 22008 ( 97.5 % ) patients . Statistical Analysis The main conclusions of INVEST were that the 2 treatment strategies were equivalent with respect to the primary outcome , main secondary outcomes , and on-treatment systolic and diastolic pressures . Thus , data for all enrolled patients were combined and included in these analyses following the intention-to-treat principle . A P value of 0.05 or less was considered statistically significant . Patients without a primary outcome event were censored at their latest follow-up visit . Average follow-up systolic and diastolic pressures were calculated for each patient by using all post-baseline results , up to the date of primary outcome or censoring . The baseline value was substituted for patients with no post-baseline data ( n= 1154 ) . In this exploratory analysis , the proportions of patients were pooled by 10 mm Hg strata of average follow-up systolic pressure , and the distribution of primary outcome event rate was evaluated to determine whether the relationship was linear . A similar presentation was prepared for diastolic pressure . Because the frequency distributions seemed consistent with a quadratic curve , a quadratic Cox proportional hazards model was formed for the time to primary outcome for each blood pressure variable , with factors for blood pressure and blood pressure squared . Similarly , the relationship between each 10 mm Hg stratum of average systolic pressure and diastolic pressure and all-cause death , fatal and nonfatal MI , and fatal and nonfatal stroke was evaluated . For the time to primary outcome , a second model was fitted , adjusting for the following baseline covariates : age ( 10-year increments ) , sex , race and ethnicity ( white , Asian , black , Hispanic , multiracial , or other ) , previous MI , heart failure ( classes I to III ) , body mass index in increments of 5 kg/m2 , U.S. residency , renal impairment , peripheral vascular disease , left ventricular hypertrophy , smoking history , coronary revascularization , dyslipidemia , stroke or transient ischemic attack , angina pectoris , arrhythmia , diabetes , cancer , aspirin use , and average systolic pressure or diastolic pressure and systolic pressure squared or diastolic pressure squared . To identify clinical ly relevant interactions between the J-shaped curve and baseline diastolic pressure , demographic characteristics , and comorbid conditions for the primary outcome , a 2-step procedure was used . First , baseline covariates were tested individually by adding the variable and 2 interaction terms ( variablediastolic pressure and variable[diastolic pressure squared ] ) to the Cox proportional hazards model . Variables included were age older than 70 years , sex , previous MI , heart failure ( classes I to III ) , previous stroke or transient ischemic attack , diabetes , cancer , renal impairment , hypercholesterolemia , peripheral vascular disease , smoking history , U.S. residency , body mass index greater than 29 kg/m2 ( mean baseline body mass index ) , and diastolic pressure greater than 86 mm Hg ( mean baseline diastolic pressure ) . The change in log likelihood was used to assess the significance of simultaneously adding the 2 interaction terms . The second step in identifying clinical ly relevant interactions between the J-shaped curve and baseline covariates was to plot the hazard ratios for the primary outcome versus diastolic pressure in the hypertension admitted at the same time because the latter tended to be admitted for other reasons , including vascular complications of hypertension , which might be related to smoking . The lack of association between hypertension and cigarette smoking is well documented,2 ' but inclusion ofcontrol cases with end organ damage might have shown a different trend . The smallireduction in cigarette smoking in the United Kingdom over the past 10 years can not account for the observed excess of smoking in patients with malignant hypertension , which has been confirmed elsewhere.14'6 We were unable to confirm the link of smoking with grade s III and IIa retinopathy , although smoking was slightly more common than in control patients . Other authors usually combined their patients with grade III and IV retinopathy in similar analyses . The prognosis of malignant hypertension , if left untreated , is worse than any form of cancer , with up to 90 % of patients dead in one year."2 Controlling blood pressure prolongs life , " and long term follow up studies have reported a dramatic reduction in mortality.'0 The results oftreatment in our patients were disappointing , but this may be because our cases date d back to 1960 , when effective antihypertensive treatment was not so enthusiastically prescribed . Furthermore , this series includes all patients seen in a district general hospital , some of whom were acutely ill and died within hours or days of admission . The Keith Wagener classification with its gradation of retinopathy from one to four suggests a gradation of risk that is not borne out by our findings . The clinical features ofhypertension in patients with grade s III and IV retinopathy are similar and quite distinct from those seen in patients without retinopathy . Although the severity of hypertension and quality of control of blood pressure with antihypertensive drugs are both potent predictors of risk,23 malignant hypertension seems to carry a particularly bad prognosis , probably related to renal damage due to fibrinoid necrosis of intrarenal arterioles . If control of blood pressure had been better mortality might have been further reduced . The Keith Wagener classification of hypertensive retinopathy , however , seems particularly unhelpful as grade -III and IV do not differ , so we suggest that is should be ab and oned . Malignant and accelerated hypertension are one and the same disease , which should be regarded as a medical emergency requiring accurate long term control of blood pressure . JMW was supported by a grant from ICI Pharmaceuticals and MB by the DHSS computer clinics project . We thank Dr J Mackinnon for providing data from the department of cardiology , Dr A Paton for access to his retinal photography archive , Mr Roy Haynesfor access to the Hospital Activity Analysis Archive , Mrs V L Stewart for secretarial help , and Mrs E Thomas for access to medical records OBJECTIVE To evaluate the effect on decrease in blood pressure of modifying risk factors for stroke , such as blood lipid profiles , diet habits and indices of body weight , through a family-based nutrition health education programme among hypertensive patients and pre-hypertensive subjects without taking any antihypertensive drugs . DESIGN AND SETTING This was a community-based prospect i ve study . The study population was r and omly selected from communities in Taipei ; potential subjects were invited by telephone to participate . SUBJECTS After excluding subjects whose blood pressure was normal and those using antihypertensive drugs , there were 390 participants included in the study . Subjects in the intervention group ( n 293 ) received nutrition health education on blood pressure control and stroke-related risk factor modification at each visit . Non-intervention subjects ( n 97 ) only acquired a general education sheet available in clinics . The blood pressure of study subjects was measured at baseline and 6-month follow-up to evaluate the intervention 's effect on decrease in blood pressure . RESULTS Significant decreases of 2.0 mmHg and 5.9 mmHg in systolic blood pressure were observed both in pre-hypertensive and hypertensive subjects in the intervention group . Additionally , intervention subjects with improvement of total cholesterol and LDL cholesterol , decrease in indices of body weight and increase in consumption of fruit and vegetables also had significant lowering of blood pressure . CONCLUSIONS The present study provided evidence that the blood pressure of pre-hypertensive and hypertensive subjects could decrease significantly , without taking antihypertensive drugs , after modifying blood lipid profiles and waist by dietary habits changed through a family-based nutrition heath education programme , result ing in a significant effect on stroke risk reduction Objective To assess whether lifestyle counselling is effective in non-pharmacological treatment of hypertension in primary health care . Design Open r and omized controlled trial . Setting Ten municipal primary health care centres in eastern Finl and . Patients Seven hundred and fifteen subjects aged 25–74 years with systolic blood pressure 140–179 mmHg and /or diastolic blood pressure 90–109 mmHg or antihypertensive drug treatment . Interventions Systematic health counselling given by local public health nurses for 2 years . Main outcome measures Blood pressure , lipids and lifestyle data were collected annually . Results Among participants with no antihypertensive drug treatment , the net reductions after 1 year both in systolic blood pressure [ −2.6 mmHg ; 95 % confidence interval ( CI ) , −4.7 to −0.5 mmHg ] and in diastolic blood pressure ( −2.7 mmHg ; 95 % CI , −4.0 to −1.4 mmHg ) were significant in favour of the intervention group . This difference in blood pressure change was maintained during the second year . In participants with antihypertensive drug treatment , no significant difference in blood pressure reduction was seen between the groups during the study . Conclusions A relatively modest , but systematic counselling in primary health care can , at least among untreated hypertensive subjects , produce reductions in blood pressure levels that are modest for the individual , but very important from the public health point of view Background To assess the impact of immediate versus delayed antihypertensive treatment on the outcome of older patients with isolated systolic hypertension  , we extended the double-blind placebo-controlled Systolic Hypertension in Europe ( Syst-Eur ) trial by an open-label follow-up study lasting 4 years . Methods The Syst-Eur trial included 4695 r and omized patients with minimum age of 60 years and an untreated blood pressure of 160–219 mmHg systolic and below 95 mmHg diastolic . The double-blind trial ended after a median follow-up of 2.0 years ( range 1–97 months ) . Of 4409 patients still alive , 3517 received open-label treatment consisting of nitrendipine ( 10–40 mg daily ) with the possible addition of enalapril ( 5–20 mg daily ) , hydrochlorothiazide ( 12.5–25 mg daily ) , or both add-on drugs .  Non- participants ( n = 892 ) were also followed up . Results Median follow-up increased to 6.1 years . Systolic pressure decreased to below 150 mmHg ( target level ) in 2628 participants ( 75.0 % ) . During the 4-year open-label follow-up , stroke and cardiovascular complications occurred at similar frequencies in patients formerly r and omized to placebo and those continuing active treatment . These rates were similar to those previously observed in the active-treatment group during the double-blind trial . Considering the total follow-up of 4695 r and omized patients , immediate compared with delayed antihypertensive treatment reduced the occurrence of stroke and cardiovascular complications by 28 % ( P = 0.01 ) and 15 % ( P = 0.03 ) , respectively , with a similar tendency for total mortality ( 13 % , P = 0.09 ) . In 492 diabetic patients , the corresponding estimates of long-term benefit ( P < 0.02 ) were 60 , 51 and 38 % , respectively . Conclusions Antihypertensive treatment can achieve blood pressure control in most older patients with isolated systolic hypertension . Immediate compared with delayed treatment prevented 17 strokes or 25 major cardiovascular events per 1000 patients followed up for 6 years . These findings underscore the necessity of early treatment of isolated systolic hypertension OUTCOMES Extensive data from r and omised controlled trials have shown the benefit of treating hypertension . The target blood pressure ( BP ) for antihypertensive management is systolic < 140 mmHg and diastolic < 90 mmHg with minimal or no drug side-effects ; however , stricter BP control is required for patients with end-organ damage , co-existing risk factors and co-morbidity , e.g. diabetes mellitus . The reduction of BP in the elderly and in those with severe hypertension should be achieved gradually over 1 month . Co-existent risk factors should also be controlled . BENEFITS Benefits of management include reduced risks of stroke , cardiac failure , chronic kidney disease and coronary heart disease . RECOMMENDATIONS The correct BP measurement procedure is described , and evaluation of cardiovascular risk factors and recommendations for antihypertensive therapy are stipulated . The total cardiovascular disease risk profile should be determined for all patients to inform management strategies . Lifestyle modification and patient education are cornerstones in the management of every patient . Major indications , pre caution s and contra-indications to each recommended antihypertensive drug are listed . Combination therapy should be considered ab initio if the BP is ≥ 20/10 mmHg . First-line drug therapy for uncomplicated hypertension includes low-dose thiazide-like diuretics , calcium channel blockers ( CCBs ) or angiotensin-converting enzyme inhibitors ( ACE-Is ) ( or ARBs - angiotensin II receptor blockers ) . If the target BP is not obtained , a second antihypertensive should be added from the aforementioned list . If the target BP is still not met , the third remaining antihypertensive agent should be used . In black patients  either thiazide-like diuretics or CCBs can be used initially , because response rates are better than with ACE-Is or β-blockers . In treating resistant hypertension , a central ly acting drug , vasodilator , α-blocker , spironolactone or β-locker should be added . This guideline includes management of specific situations , i.e. hypertensive emergency and urgency , severe hypertension with target organ damage , hypertension in diabetes mellitus , resistant hypertension , fixed drug combinations , new trials in hypertension , and interactions of antihypertensive agents with other drugs . VALIDITY The guideline was developed by the Southern African Hypertension Society 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 Isolated systolic hypertension is an important risk factor for cardiovascular disease and results primarily from elastic artery stiffening . Although various drug therapies are used to lower peripheral blood pressure ( BP ) in patients with isolated systolic hypertension , the effects of the 4 major classes of antihypertensive agents on central BP , pulse pressure ( PP ) amplification , and arterial stiffness in this condition are not clear . Fifty-nine patients over the age of 60 years with untreated isolated systolic hypertension ( systolic BP ≥140 mm Hg and diastolic BP ≤90 mm Hg ) were r and omly assigned to receive 1 of the following 4 antihypertensive agents : perindopril , atenolol , lercanidipine , or bendrofluazide  . BP was measured using a mercury sphygmomanometer , and augmentation index and carotid-femoral ( aortic ) pulse wave velocity were measured at baseline , after 2 weeks of placebo therapy , and at the end of 10 weeks of active therapy . Peripheral systolic BP and peripheral PP were reduced similarly after treatment with all 4 classes of drug . However , central PP was only reduced significantly by perindopril , lercanidipine , and bendrofluazide , whereas atenolol had no effect . Lercanidipine reduced the augmentation index , whereas atenolol increased it . Aortic pulse wave velocity was not changed by any of the drugs . In summary , despite similar reductions in peripheral systolic and PPs with the 4 classes of drug , changes in central pressure and augmentation index varied . Because central PP and increased wave reflections are considered important risk factors in patients with isolated systolic hypertension , the choice of therapy may be influenced by these findings in the future 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 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 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 Objective To investigate the associations of diastolic blood pressure ( DBP ) and systolic blood pressure ( SBP ) with the risk of coronary heart disease , sudden cardiac and all-cause death in elderly men . Design A cohort study . Setting The Dutch town of Zutphen . Subjects Eight hundred and eighty-five r and omly selected men , aged 64 - 84 years . Main outcome measures Relative risks adjusted for age , body mass index , total and high-density lipoprotein cholesterol , cigarette smoking , alcohol consumption , use of blood pressure-lowering medications without a specific indication for hypertension , and the physician who measured the blood pressure . Results Neither DBP nor SBP was associated significantly with the incidence of a first coronary heart disease event and no clear associations were observed with mortality from coronary heart disease . However , positive associations with sudden cardiac death were observed . The adjusted relative risk for men with definite isolated systolic hypertension was 9.20 . The risk of dying from coronary heart disease not recorded additionally as sudden death was highest in men at the lower end of the DBP and SBP distributions and in men using antihypertensives . DBP and SBP were positively associated with all-cause mortality when possible comorbidity at the time of the blood pressure measurement was accounted for . Overall , the highest risk for all endpoints was observed in men on antihypertensive medication , who formed a distinct group with a clustering of cardiovascular risk factors . Conclusion Elevated DBP and SBP , and especially isolated systolic hypertension , are important predictors of sudden cardiac death in elderly men . The highest risk of nonsudden coronary heart disease mortality was found at the lower end of the blood pressure distributions and among men on antihypertensive medication
The adverse events associated with the antihypertensive agents were mostly minor and included headaches , dizziness and upper respiratory infections .
The most data are available for c and esartan , for which there is low- quality evidence of a modest lowering effect on blood pressure .
We did not find evidence of a consistent dose response relationship for escalating doses of angiotensin receptor blockers , calcium channel blockers or angiotensin-converting enzyme inhibitors .
All agents appear safe , at least in the short term
BACKGROUND Hypertension is a major risk factor for stroke , coronary artery disease and kidney damage in adults .
There is a paucity of data on the long-term sequelae of persistent hypertension in children , but it is known that children with hypertension have evidence of end organ damage and are at risk of hypertension into adulthood .
The prevalence of hypertension in children is rising , most likely due to a concurrent rise in obesity rates .
In children with hypertension , non-pharmacological measures are often recommended as first-line therapy , but a significant proportion of children will eventually require pharmacological treatment to reduce blood pressure , especially those with evidence of end organ damage at presentation or during follow-up .
A systematic review of the effects of antihypertensive agents in children has not previously been conducted .
OBJECTIVES To determine the dose-related effects of different classes of antihypertensive medications , as monotherapy compared to placebo ; as combination therapy compared to placebo or a single medication ; or in comparisons of various doses within the same class , on systolic or diastolic blood pressure ( or both ) in children with hypertension .