Reduced cardiovascular morbidity and mortality in hypertensive diabetic patients on first-line therapy with an ACE inhibitor compared with a diuretic/beta-blocker-based treatment regimen: a subanalysis of the Captopril Prevention Project. Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT): Practical Implications Are Observational Studies More Informative Than Randomized Controlled Trials in Hypertension?: Con Side of the Argument The Australian Therapeutic Trial in Mild Hypertension. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study Trial of Nonpharmacologic Intervention in the Elderly (TONE). Design and rationale of a blood pressure control trial. South African hypertension guideline 2011. Predictors of adverse outcome among patients with hypertension and coronary artery disease. Diclofenac sodium versus pethidine in acute renal colic. Pharmacogenetic Association of the Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism on Blood Pressure and Cardiovascular Risk in Relation to Antihypertensive Treatment: The Genetics of Hypertension-Associated Treatment (GenHAT) Study 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. Antihypertensive therapy in type 2 diabetes: implications of the appropriate blood pressure control in diabetes (ABCD) trial. Relationship of Antihypertensive Treatment Regimens and Change in Blood Pressure to Risk for Heart Failure in Hypertensive Patients Randomly Assigned to Doxazosin or Chlorthalidone: Further Analyses from the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with symptomatic stable angina and hypertension: the ACTION trial The Losartan Intervention For Endpoint reduction (LIFE) in Hypertension study: rationale, design, and methods. The LIFE Study Group. Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. SHEP Cooperative Research Group. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial
OBJECTIVE The Captopril Prevention Project ( CAPPP ) evaluated the effects of an ACE inhibitor-based therapeutic regimen on  cardiovascular mortality and morbidity in hypertension .  One planned sub analysis of the CAPPP was to evaluate the outcome in the diabetic patient group . RESEARCH DESIGN AND METHODS In the CAPPP , 572 ( 4.9 % of 10,985 hypertensive patients ) had diabetes at baseline and were studied according to a prospect i ve , r and omized , open , blinded , end point trial design . Patients aged 25 - 66 years with diastolic blood pressure > or = 100 mmHg were included and r and omized to receive either captopril or conventional antihypertensive treatment ( diuretics and /or beta-blockers ) . RESULTS The primary end point , fatal and nonfatal myocardial infa rct ion and stroke as well as other cardiovascular deaths , was markedly lower in the captopril than in the conventional therapy group ( relative risk [ RR ] = 0.59 ; P = 0.018 ) . Specifically , cardiovascular mortality , defined as fatal stroke and myocardial infa rct ion , sudden death , and other cardiovascular death , tended to be lower in the captopril group ( RR = 0.48 ; P = 0.084 ) , and no difference was observed between the study groups for stroke ( RR = 1.02 ; P = 0.96 ) . Myocardial infa rct ions were less frequent in the captopril group than in the conventional therapy group ( RR = 0.34 ; P = 0.002 ) . Furthermore , total mortality was lower in the captopril as compared with the conventional therapy group ( RR = 0.54 ; P = 0.034 ) . Patients with impaired metabolic control seemed to benefit the most from ACE inhibitor-based therapy . CONCLUSIONS Captopril is superior to a diuretic/beta-blocker antihypertensive treatment regimen in preventing cardiovascular events in hypertensive diabetic patients , especially in those with metabolic decompensation The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) , sponsored by the National Heart , Lung , and Blood Institute ( NHLBI ) , is the largest outcome trial of antihypertensive treatment ever carried out and the only large blood pressure ( BP ) trial to be carried out in a US population in the past decade.1 The rationale for ALLHAT , which was design ed in the early 1990s , was the urgent need to determine which of the several classes of antihypertensive drugs that had been developed and released for clinical use was most effective in preventing coronary heart disease ( CHD ) , defined as fatal CHD and nonfatal myocardial infa rct ion.2 The only r and omized trials that had previously compared representatives of the antihypertensive drug classes , the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents3 and the Treatment of Mild Hypertension Study (TOMHS),4 showed BP reductions with all classes but were not powered to evaluate CHD outcomes . Further , prior outcome trials had shown that the reduction in CHD event rates with antihypertensive treatment was less than expected based on epidemiologic data .5 Adverse effects of study drugs , particularly diuretics , including hypokalemia , hypomagnesemia , hyperuricemia , hyperlipidemia , insulin resistance , and ventricular ectopic activity , had been adduced to account for the disappointing outcomes of earlier trials by off setting the beneficial effects of BP reduction.6,7 To further complicate the picture , benefits beyond BP reduction had been attributed to some antihypertensive drug classes , ie , improved survival and reduced morbidity in persons with heart failure or left ventricular dysfunction treated with angiotensin-converting enzyme ( ACE ) inhibitors8–10 and improved insulin sensitivity and lipid profiles with α-blocker treatment.11 In contrast , another antihypertensive drug class , the dihydropyridine calcium channel blockers ( CCBs ) , had been associated with unfavorable outcomes in patients with acute myocardial infa rct ion or unstable angina.12 There were no data The very first rigorously design ed , r and omized controlled trial ( RCT ) in the history of modern medicine was published in 1948 . The study , design ed and carried out by the Streptomycin in Tuberculosis Trials Committee of the Medical Research Council , demonstrated the efficacy of streptomycin in treating pulmonary tuberculosis on top of bed rest , which was the best available treatment at that time.1 In the field of hypertension treatment and cardiovascular prevention , the history of event-based RCTs began in 1967 , when the cardiovascular benefits and risks of antihypertensive drug treatment were evaluated in the setting of the Veterans Administration Cooperative Study in Hypertension.2 In that trial , 143 patients with severe hypertension were r and omized to receive blood pressure (BP)–lowering drug treatment or matched placebo for 11 months . A major morbid or fatal event was observed in 26 of 70 patients who received placebo ( 37 % ) and in only 1 of 73 patients under active treatment ( 1 % ) . The amazing results of this l and mark trial established beyond any doubt the striking cardiovascular benefits of antihypertensive drug treatment of hypertension at a time when controversy still persisted regarding the supposedly deleterious effects of BP reduction on organ perfusion.3 Ever since , RCTs have represented a formidable tool for evaluating risks and benefits of hypertension treatment . Over the past 50 years , the remarkable progress in treatment and control of high BP , one of the most outst and ing achievements of modern medicine , has been driven by the results of many large , event-based RCTs . The influential position of RCTs in clinical and therapeutic research as opposed to real-world observational studies ( surveys , registries , and retrospective analyses of existing data bases ) originates from their high internal validity ( ie , the power to address clinical questions with a low level of internal bias ) . A list of strengths and weaknesses of RCTs and observational studies is In the Australian Therapeutic Trial in Mild Hypertension treated patients had significantly lower cardiovascular mortality and a significantly lower incidence of cerebrovascular complications than patients given placebos .  There was , however , no difference in the incidence of nonfatal myocardial infa rct ion or other new manifestations of ischaemic heart disease . Although the evidence of benefit from treatment was clear-cut , the number of cardiovascular complications in the control group was small . This was due to several factors . Patients admitted to the trial had no preceding evidence of cardiovascular complications  , the blood pressure fell spontaneously to below 95 mm Hg in almost half the control group , and patients whose blood pressures rose to levels above 110 mm Hg were given treatment , but remained in the placebo group for analysis . In both treated and placebo groups , trial end-points occurred more frequently in persons whose average diastolic blood pressure during the study remained raised . Ischaemic heart disease and many cases of stroke are due to atherosclerotic arterial disease . This appears not to be favourably influenced by antihypertensive drug therapy BACKGROUND The efficacy of new antihypertensive drugs has been question ed . We compared the effects of conventional and newer antihypertensive drugs on cardiovascular mortality and morbidity in elderly patients . METHODS We did a prospect i ve , r and omised trial in 6614 patients aged 70 - 84 years with hypertension ( blood pressure > or = 180 mm Hg systolic , > or = 105 mm Hg diastolic , or both ) . Patients were r and omly assigned conventional antihypertensive drugs ( atenolol 50 mg , metoprolol 100 mg , pindolol 5 mg , or hydrochlorothiazide 25 mg plus amiloride 2.5 mg daily ) or newer drugs ( enalapril 10 mg or lisinopril 10 mg , or felodipine 2.5 mg or isradipine 2 - 5 mg daily ) . We assessed fatal stroke , fatal myocardial infa rct ion , and other fatal cardiovascular disease . Analysis was by intention to treat . FINDINGS Blood pressure was decreased similarly in all treatment groups . The primary combined endpoint of fatal stroke , fatal myocardial infa rct ion , and other fatal cardiovascular disease occurred in 221 of 2213 patients in the conventional drugs group ( 19.8 events per 1000 patient-years ) and in 438 of 4401 in the newer drugs group ( 19.8 per 1000 ; relative risk 0.99 [ 95 % CI 0.84 - 1.16 ] , p=0.89 ) . The combined endpoint of fatal and non-fatal stroke , fatal and non-fatal myocardial infa rct ion , and other cardiovascular mortality occurred in 460 patients taking conventional drugs and in 887 taking newer drugs ( 0.96 [ 0.86 - 1.08 ] , p=0.49 ) . INTERPRETATION Old and new antihypertensive drugs were similar in prevention of cardiovascular mortality or major events . Decrease in blood pressure was of major importance for the prevention of cardiovascular events National and international policy-making organizations advocate nonpharmacologic therapies to reduce blood pressure ( BP ) . However , data to support such recommendations in older persons are virtually nonexistent . The Trials of Nonpharmacologic Intervention in the Elderly ( TONE ) is a r and omized , controlled trial that will test whether weight loss or a reduced sodium ( Na ) intake or both can maintain satisfactory BP control , without unacceptable side effects , after withdrawal of antihypertensive drug therapy . Medication-treated hypertensives ( aged 60 to 80 years ) with a systolic BP less than 145 mm Hg and a diastolic BP less than 85 mm Hg who are taking one antihypertensive medication are r and omly assigned to one of four groups : ( 1 ) weight loss alone , ( 2 ) reduced Na intake alone , ( 3 ) combined weight loss and reduced Na intake , or ( 4 ) usual life-style ( control group ) .  Overweight participants are r and omized to one of these four groups , while nonoverweight individuals are assigned to either the reduced Na intake or the usual life-style group . The interventions , tailored to the needs of older persons , use behavioral approaches to accomplish intervention-specific goals ( weight loss > or = 10 lb , daily Na intake < or = 80 mEqa ) . Three months after the start of intervention , antihypertensive drug therapy is withdrawn . The primary trial end point is a BP of 150/90 mm Hg or higher , resumption of antihypertensive drug therapy , or the occurrence of a BP-related clinical complication during 2 to 3 years of follow-up . It is anticipated that TONE findings may identify an effective and acceptable nonpharmacologic approach to control hypertension in the increasingly large number of older persons treated with antihypertensive drug therapy 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 OBJECTIVES We sought to determine predictors for adverse outcomes in hypertensive patients with coronary artery disease ( CAD ) . BACKGROUND Factors leading to adverse outcomes in hypertensive patients with CAD are poorly understood . The INternational VErapamil-tr and olapril STudy ( INVEST ) compared outcomes in hypertensive patients with CAD that were assigned r and omly to either a verapamil sustained-release (SR)- or an atenolol-based strategy for blood pressure ( BP ) control . Tr and olapril and hydrochlorothiazide were used as added agents . During follow-up ( 61,835 patient-years ) , BP control and the primary outcome ( death , nonfatal myocardial infa rct ion , and nonfatal stroke ) were not different between strategies . METHODS We investigated risk for adverse outcome associated with baseline factors , follow-up BP , and drug treatments using Cox modeling . RESULTS Previous heart failure ( adjusted hazard ratio [ HR ] 1.96 ) , as well as diabetes ( HR 1.77 ) , increased age ( HR 1.63 ) , U.S. residency ( HR 1.61 ) , renal impairment ( HR 1.50 ) , stroke/transient ischemic attack ( HR 1.43 ) , smoking ( HR 1.41 ) , myocardial infa rct ion ( HR 1.34 ) , peripheral vascular disease ( HR 1.27 ) , and revascularization ( HR 1.15 ) predicted increased risk . Follow-up systolic BP < 140 mm Hg or diastolic BP < 90 mm Hg ( HRs 0.82 or 0.70 , respectively ) and tr and olapril with verapamil SR ( HRs 0.78 and 0.79 ) were associated with reduced risk . CONCLUSIONS In hypertensive patients with CAD , increased risk for adverse outcomes was associated with conditions related to the severity of CAD and diminished left ventricular function . Lower follow-up BP and addition of tr and olapril to verapamil SR each were associated with reduced risk 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 Background —Previous studies have reported that blood pressure response to antihypertensive medications is influenced by genetic variation in the renin-angiotensin-aldosterone system , but no clinical trails have tested whether the ACE insertion/deletion ( I/D ) polymorphism modifies the association between the type of medication and multiple cardiovascular and renal phenotypes . Methods and Results —We used a double-blind , active-controlled r and omized trial of antihypertensive treatment that included hypertensives ≥55 years of age with ≥1 risk factor for cardiovascular disease . ACE I/D genotypes were determined in 37 939 participants r and omized to chlorthalidone , amlodipine , lisinopril , or doxazosin treatments and followed up for 4 to 8 years . Primary outcomes included fatal coronary heart disease ( CHD ) and /or nonfatal myocardial infa rct ion . Secondary outcomes included stroke , all-cause mortality , combined CHD , and combined cardiovascular disease .  Fatal and nonfatal CHD occurred in 3096 individuals during follow-up . The hazard rates for fatal and nonfatal CHD and the secondary outcomes were similar across antihypertensive treatments . ACE I/D genotype group was not associated with fatal and nonfatal CHD ( relative risk of DD versus ID and II , 0.99 ; 95 % CI , 0.91 to 1.07 ) or any secondary outcome . The 6-year hazard rate for fatal and nonfatal CHD in the DD genotype group was not statistically different from the ID and II genotype group by type of treatment . No secondary outcome measure was statistically different across antihypertensive treatment and ACE I/D genotype strata . Conclusions —ACE I/D genotype group was not a predictor of CHD , nor did it modify the response to antihypertensive treatment . We conclude that the ACE I/D polymorphism is not a useful marker to predict antihypertensive treatment response 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 As the population ages , the incidence of type 2 diabetes will increase as will the incidence of concomitant vascular complications . Hypertension substantially increases the risk of cardiovascular disease in patients with diabetes . Results from the recent Appropriate Blood Pressure Control in Diabetes ( ABCD ) trial demonstrated an advantage of an angiotensin-converting enzyme ( ACE ) inhibitor ( enalapril ) over a long-acting calcium antagonist ( nisoldipine ) with regard to the incidence of cardiovascular events over a 5-year follow-up period in hypertensive persons with type 2 diabetes . This trial was a prospect i ve , r and omized , blinded study comparing the effects of moderate blood pressure control ( target diastolic pressure 80 - 89 mm Hg ) with those of intensive control ( target diastolic pressure 75 mm Hg ) on the incidence and progression of diabetic vascular complications . The study also compared nisoldipine with enalapril as first-line antihypertensive therapy in terms of prevention and progression of complications of diabetes . In 470 hypertensive patients , the incidence of fatal and nonfatal myocardial infa rct ions was significantly ( p = 0.001 ) higher among those receiving nisoldipine ( n = 25 ) compared with those receiving enalapril ( n = 5 ) . Comparison with previous studies suggests that the difference observed between nisoldipine and enalapril result ed from a beneficial effect of enalapril rather than a deleterious effect from nisoldipine . Since these findings in the ABCD trial are based on a secondary endpoint , they require confirmation . Nevertheless , they suggest that ACE inhibitors should be the initial antihypertensive medication used in patients with type 2 diabetes and hypertension Context Previously published results of this r and omized , double-blind trial showed that hypertensive patients treated with doxazosin rather than chlorthalidone more often developed heart failure . Did differences in blood pressure control or treatment with other drugs explain these findings ? Contribution This analysis shows that the slightly worse blood pressure control achieved with doxazosin did not explain higher risks for heart failure . Risks with doxazosin versus chlorthalidone were highest among patients who received monotherapy ( relative risk , 3.10 ) and lowest among patients who received stepped care with additional drugs ( relative risk , 1.42 ) . Implication s Increased risks for heart failure with doxazosin versus chlorthalidone are attenuated but not eliminated when additional antihypertensive drugs are used . The Editors The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial ( ALLHAT ) , a r and omized , double-blind , multicenter clinical trial including 42 418 participants at 623 clinical sites , is design ed to determine whether treatment begun with a calcium-channel blocker ( amlodipine ) , an angiotensin-converting enzyme inhibitor ( lisinopril ) , or an -adrenergic blocker ( doxazosin ) compared to treatment with a diuretic ( chlorthalidone ) reduces the incidence of fatal coronary heart disease or nonfatal myocardial infa rct ion in high-risk patients with hypertension ( 1 ) . Secondary end points are all-cause mortality , stroke , and other cardiovascular events . A lipid-lowering trial in a subset of 10 356 participants is design ed to determine whether decreasing cholesterol levels with a hydroxymethyl glutamyl coenzyme A reductase inhibitor ( pravastatin ) compared with usual care reduces all-cause mortality in older , moderately hypercholesterolemic patients . In January 2000 , the doxazosin arm of the trial was discontinued ( 2 ) because major cardiovascular disease ( relative risk , 1.25 [ 95 % CI , 1.17 to 1.33 ] ; P < 0.001 ) , especially heart failure ( relative risk , 2.04 [ 95 % CI , 1.79 to 2.32 ] ; P < 0.001 ) , was significantly increased compared with the chlorthalidone arm . Equally important , a low probability existed that doxazosin would show benefit over chlorthalidone for the primary end point by the scheduled study end , given the lack of difference ( relative risk , 1.02 [ 95 % CI , 0.90 to 1.17 ] ; P > 0.2 ] at that time . These intention-to-treat analyses compared patients assigned to chlorthalidone with patients assigned to doxazosin . In this article , we analyze how treatment changes may have affected the comparison of doxazosin with chlorthalidone in terms of heart failure . Our major objectives are to ascertain to what extent the relative risk with doxazosin versus chlorthalidone depends on 1 ) whether the assigned drugs were used as monotherapy or in combination with other agents and 2 ) the difference in decreases in systolic and diastolic blood pressure . Methods Study Design The rationale and design of ALLHAT are described in detail elsewhere ( 1 ) . In brief , eligible participants were men and women 55 years of age or older who had systolic or diastolic hypertension ( 140/90 mm Hg or hypertension controlled with medication ) plus at least one additional risk factor for coronary heart disease events . The risk factors included previous ( > 6 months ) myocardial infa rct ion or stroke , left ventricular hypertrophy on electrocardiography or echocardiography , history of type 2 diabetes , current cigarette smoking , and a low high-density lipoprotein cholesterol level . Persons with a history of hospitalized or treated symptomatic heart failure or a known ejection fraction less than 0.35 were excluded . Unless the drug regimen required tapering for safety , participants who had been taking antihypertensive medications continued to do so until the day of r and omization , at which point they stopped taking all previous medications . On the day after r and omization , treatment with the study drug was initiated . Enrollment occurred from February 1994 through January 1998 . The original reported number of 42 448 participants and 625 sites changed because 30 patients with poor documentation of informed consent were excluded ( 2 ) . Participants were assigned by a computer-generated r and omization schedule in a ratio of 1.7:1 to receive chlorthalidone or doxazosin . R and omization was stratified by center and blocked over time to maintain the ratio . All participants gave written informed consent , and all centers obtained institutional review board approval . Ascertainment of Outcomes At each clinic visit , occurrence of study end points was assessed by the clinical investigator . A hospital discharge summary was required for each hospitalized study outcome , and a death certificate was required for each death . ALLHAT defined symptomatic heart failure as clear-cut signs or symptoms of left or right ventricular dysfunction that can not be attributed to other causes . A patient had to have at least one symptom ( paroxysmal nocturnal dyspnea , dyspnea at rest , New York Heart Association class III dyspnea or other symptoms [ on less than ordinary exertion ] , or orthopnea ) and one sign ( rales , ankle edema , tachycardia , cardiomegaly or characteristic pulmonary pattern on chest radiography , S3 gallop , or jugular venous distention ) ( 3 ) . Symptoms and signs were determined by the clinic investigator through patient history , chart review , or consultation with the treating physician , but such data were not collected central ly . A one-time sample of 24 hospitalized or fatal heart failure events was review ed in a blinded manner by the ALLHAT Endpoints Subcommittee ; 20 of 24 ( 83 % ) were deemed to have complete data for a definitive diagnosis . Of the 20 cases , the agreement rate between the subcommittee and the clinic investigators was 90 % ( 18 of 20 ) and similar in both treatment groups . Details on the validity of diagnosis of heart failure will be provided in a future report . Measurement and Treatment of Blood Pressure The ALLHAT protocol specified a stepped-care treatment program for hypertension . Trained observers using st and ardized techniques measured blood pressures during the trial ( 1 , 2 ) . All blood pressures were calculated as the average of two measurements obtained with a 30-second interval between them . The blood pressure goal in all four study arms was less than 140/90 mm Hg . This level was to be achieved with the lowest possible dose of blinded first-line drug , with addition of second- and third-line open-label therapy as needed after reaching the maximal dose of first-line drug . Chlorthalidone and doxazosin were to be taken once daily in the morning . By design , doses were selected to achieve equivalent blood pressure control in the treatment groups . The first , second , and third dosage levels were 12.5 mg/d , 12.5 mg/d ( sham titration ) , and 25 mg/d , respectively , for chlorthalidone and 2 mg/d , 4 mg/d , and 8 mg/d for doxazosin . Double-blinded 1-mg and 12.5-mg doses of doxazosin and chlorthalidone , respectively , were used for the first week to minimize the frequency of postural hypotension associated with doxazosin . The identity of drugs was masked at each dosage level , but dosage level was not . After r and omization , patients were seen for dose titration as needed at 1 and 3 months per the protocol , but they could return more often until target blood pressure was reached . Subsequently , required visits occurred at 3-month intervals during the first year and at 4-month intervals thereafter . Open-label second-step drugs were added as needed and tolerated . These agents were reserpine ( 0.05 to 0.2 mg/d ) , clonidine ( 0.1 to 0.3 mg twice daily ) , and atenolol ( 25 to 100 mg/d ) . The choice of second-step drug was at the discretion of the treating clinician-investigator . The third-step agent was hydralazine ( 25 to 100 mg twice daily ) . Details of these therapies are provided elsewhere ( 1 ) . Investigators could choose to prescribe open-label antihypertensive drugs other than those provided by the study . However , use of the drug classes under study thiazide diuretics , calcium antagonists , angiotensin-converting enzyme inhibitors , and -adrenergic blockerswas strongly discouraged to avoid dilution of treatment comparisons . When clinical conditions other than uncontrolled hypertension ( for example , angina or heart failure ) were present , drugs from any study class could be used . If a step 1 drug was specifically required for blood pressure control while blinded drug treatment was continued , the step 1 drug could be added as open-label therapy but the dose could not exceed one half the maximum recommended by the Fifth Joint National Committee ( 4 ) . In most such cases , unblinding the patient or the investigator to treatment assignment was not necessary . ( Overall , < 1 % of drug identities were provided to either participant or investigator . ) Any of nine possible open-label drug typesdiuretic , calcium-channel blocker , angiotensin-converting enzyme inhibitor , -adrenergic blocker , atenolol , reserpine , clonidine , hydralazine , and other antihypertensive drug ( which could include nonatenolol -blockers , although drug name was not logged)could be recorded at each visit . Because diuretics , angiotensin-converting enzyme inhibitors , and -blockers are beneficial in preventing or treating heart failure , we call these antihypertensive heart failure drugs . Data on  antihypertensive drug use before study enrollment were collected , but not by drug class . Statistical Analysis Data were analyzed for use of additional drugs according to participants ' r and omized treatment assignments and regardless of continuation of blinded study treatment . The outcomes all heart failure ( treated outside hospital , hospitalized , or fatal ) and hospitalized or fatal heart failure were examined by treatment group for the entire cohort . The time to event for the previously published as-r and omized analyses was the interval from r and omization to first diagnosis of heart failure for patients who had an outcome , or from r and omization to Objective To examine the effects of nifedipine GITS on clinical outcome in patients with concurrent stable angina and hypertension . Methods Data from the double-blind placebo-controlled ACTION trial was stratified for hypertension ( blood pressure ≥ 140/90 mmHg ) , at baseline . Results A total of 52 % of 7665 ACTION patients were hypertensive . Some 80 % were on a β blocker ; hypertensives were more often treated with other blood pressure-lowering drugs . Mean baseline blood pressure was 122/74 mmHg among normotensives and 151/85 mmHg among hypertensives . Follow-up blood pressures were reduced by nifedipine ( P < 0.001 ) on the average by 3.9/2.4 and 6.6/3.5 mmHg among normotensives and hypertensives , respectively . Nifedipine GITS significantly ( P < 0.05 ) reduced the combined incidence of all-cause mortality , myocardial infa rct ion , refractory angina , heart failure , stroke and peripheral revascularization by 13 % in hypertensives only . Nifedipine significantly reduced the incidence of any stroke or transient ischemic attack by almost 30 % in both subgroups and the need for coronary angiography by 21 % in normotensives and 16 % in hypertensives . Among hypertensives , the incidence of new overt heart failure was significantly reduced by 38 % and of debilitating stroke by 33 % . Among normotensives , the need for coronary bypass grafting was significantly reduced by 32 % . Nifedipine did not affect all-cause death , cardiovascular death and myocardial infa rct ion in either normo- or hypertensives , but increased the need for peripheral revascularization . Conclusion The salutary effects of the addition of nifedipine GITS to the basic regimen of patients with concurrent stable symptomatic coronary artery disease and hypertension emphasize the need for blood pressure control The treatment of hypertension mainly with diuretics and beta blockers reduces cardiovascular mortality and morbidity , largely due to a decreased incidence of stroke , whereas the beneficial effects of antihypertensive therapy on the occurrence of coronary events have been less than expected from epidemiological studies . Furthermore , treated hypertensive patients still have a higher cardiovascular complication rate , compared with matched normotensives . This is particularly evident in patients with left ventricular hypertrophy ( LVH ) , a major independent risk indicator for cardiovascular disease . In addition to elevating blood pressure , angiotensin II ( A-II ) exerts an important influence on cardiac structure and function , stimulating cell proliferation and growth . Thus , to further reduce morbidity and mortality when treating hypertensive patients , it may be important to effectively block the effects of A-II . This can be achieved directly at the A-II receptor level by losartan , the first of a new class of antihypertensive agents . It therefore seems pertinent to investigate whether selective A-II receptor blockade with losartan not only lowers blood pressure but also reduces LVH more effectively than current therapy , and thus improves prognosis . The Losartan Intervention For Endpoint reduction ( LIFE ) in Hypertension study is a double-blind , prospect i ve , parallel group study design ed to compare the effects of losartan with those of the beta-blocker atenolol on the reduction of cardiovascular morbidity and mortality in approximately 8,300 hypertensive patients ( initial sitting diastolic blood pressure 95 to 115 mm Hg or systolic blood pressure 160 to 200 mm Hg ) with electrocardiographically documented LVH . The study , which will continue for at least 4 years and until 1,040 patients experience one primary endpoint , has been design ed with a statistical power that will detect a difference of at least 15 % between groups in the incidence of combined cardiovascular morbidity and mortality . It is also the first prospect i ve study with adequate power to link reversal of LVH to reduction in major cardiovascular events . The rationale of the study , which will involve more than 800 clinical centers in Sc and inavia , the United Kingdom , and the United States , is discussed , and the major features of its design and general organization are described . On April 30 , 1997 , when inclusion was stopped , 9,218 patients had been r and omized CONTEXT Heart failure is often preceded by isolated systolic hypertension , but the effectiveness of antihypertensive treatment in preventing heart failure is not known . OBJECTIVE To assess the effect of diuretic-based antihypertensive stepped-care treatment on the occurrence of heart failure in older persons with isolated systolic hypertension . DESIGN Analysis of data from a multicenter , r and omized , double-blind , placebo-controlled clinical trial . PARTICIPANTS A total of 4736 persons aged 60 years and older with systolic blood pressure between 160 and 219 mm Hg and diastolic blood pressure below 90 mm Hg who participated in the Systolic Hypertension in the Elderly Program ( SHEP ) . INTERVENTION Stepped-care antihypertensive drug therapy , in which the step 1 drug is chlorthalidone ( 12.5 - 25 mg ) or matching placebo , and the step 2 drug is atenolol ( 25 - 50 mg ) or matching placebo . MAIN OUTCOME MEASURES Fatal and nonfatal heart failure . RESULTS During an average of 4.5 years of follow-up , fatal or nonfatal heart failure occurred in 55 of 2365 patients r and omized to active therapy and 105 of the 2371 patients r and omized to placebo ( relative risk [ RR ] , 0.51 ; 95 % confidence interval [ CI ] , 0.37 - 0.71 ; P<.001 ; number needed to treat to prevent 1 event [ NNT ] , 48 ) . Among patients with a history of or electrocardiographic evidence of prior myocardial infa rct ion ( MI ) , the RR was 0.19 ( 95 % CI , 0.06 - 0.53 ; P=.002 ; NNT , 15 ) . Older patients , men , and those with higher systolic blood pressure or a history of or electrocardiographic evidence of MI at baseline had higher risk of developing heart failure . CONCLUSION In older persons with isolated systolic hypertension , stepped-care treatment based on low-dose chlorthalidone exerted a strong protective effect in preventing heart failure . Among patients with prior MI , an 80 % risk reduction was observed BACKGROUND Angiotensin-converting-enzyme ( ACE ) inhibitors have been used for more than a decade to treat high blood pressure  , despite the lack of data from r and omised intervention trials to show that such treatment affects cardiovascular morbidity and mortality . The Captopril Prevention Project ( CAPPP ) is a r and omised intervention trial to compare the effects of ACE inhibition and conventional therapy on cardiovascular morbidity and mortality in patients with hypertension . METHODS CAPPP was a prospect i ve , r and omised , open trial with blinded endpoint evaluation . 10,985 patients were enrolled at 536 health centres in Sweden and Finl and . Patients aged 25 - 66 years with a measured diastolic blood pressure of 100 mm Hg or more on two occasions were r and omly assigned captopril or conventional antihypertensive treatment ( diuretics , beta-blockers ) . Analysis was by intention-to-treat . The primary endpoint was a composite of fatal and non-fatal myocardial infa rct ion , stroke , and other cardiovascular deaths . FINDINGS Of 5492 patients assigned captopril and 5493 assigned conventional therapy , 14 and 13 , respectively , were lost to follow-up . Primary endpoint events occurred in 363 patients in the captopril group ( 11.1 per 1000 patient-years ) and 335 in the conventional-treatment group ( 10.2 per 1000 patient-years ; relative risk 1.05 [ 95 % CI 0.90 - 1.22 ] , p=0 - 52 ) . Cardiovascular mortality was lower with captopril than with conventional treatment ( 76 vs 95 events ; relative risk 0.77 [ 0.57 - 1 - 04 ] , p=0.092 ) , the rate of fatal and non-fatal myocardial infa rct ion was similar ( 162 vs 161 ) , but fatal and non-fatal stroke was more common with captopril ( 189 vs 148 ; 1.25 [ 1 - 01 - 1 - 55 ] . p=0.044 ) . INTERPRETATION Captopril and conventional treatment did not differ in efficacy in preventing cardiovascular morbidity and mortality . The difference in stroke risk is probably due to the lower levels of blood pressure obtained initially in previously treated patients r and omised to conventional therapy
There is no RCT evidence demonstrating that anti-hypertensive drugs reduce mortality or morbidity in patients with hypertensive emergencies .
Furthermore , there is insufficient RCT evidence to determine which drug or drug class is most effective in reducing mortality and morbidity .
There were some minor differences in the degree of blood pressure lowering when one class of antihypertensive drug is compared to another .
However , the clinical significance is unknown .
BACKGROUND Hypertensive emergencies , marked hypertension associated with acute end-organ damage , are life-threatening conditions .
Many anti-hypertensive drugs have been used in these clinical setting s. The benefits and harms of such treatment and the best first-line treatment are not known .
OBJECTIVES To answer the following two questions using r and omized controlled trials ( RCTs ): 1 ) does anti-hypertensive drug therapy as compared to placebo or no treatment affect mortality and morbidity in patients presenting with a hypertensive emergency ?
2 ) Does one first-line antihypertensive drug class as compared to another antihypertensive drug class affect mortality and morbidity in these patients ?