Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT): Practical Implications Effects of antihypertensive treatment after acute stroke in the Continue Or Stop post-Stroke Antihypertensives Collaborative Study (COSSACS): a prospective, randomised, open, blinded-endpoint trial Effects of different antihypertensive drugs on blood pressure variability in patients with ischemic stroke. A randomized trial of special packaging of antihypertensive medications. Apparent effect on blood pressure is only partly responsible for the risk reduction due to antihypertensive treatments. Comparison of the Effects of Antihypertensive Agents on Central Blood Pressure and Arterial Stiffness in Isolated Systolic Hypertension Double-blind, placebo-controlled crossover comparison of five classes of antihypertensive drugs Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial 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. [The effect of an antihypertensive drug during psychological stress. A double-blind study]. Subgroup and per-protocol analysis of the randomized European Trial on Isolated Systolic Hypertension in the Elderly. Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. SHEP Cooperative Research Group. 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 Statistical analysis plan for the ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) trial Rational Prescribing in Primary Care (RaPP): A Cluster Randomized Trial of a Tailored Intervention 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 Lower target blood pressures are safe and effective for the prevention of recurrent stroke: the PROGRESS trial
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 BACKGROUND Up to 50 % of patients with acute stroke are taking antihypertensive drugs on hospital admission . However , whether such treatment should be continued during the immediate post-stroke period is unclear . We therefore aim ed to assess the efficacy and safety of continuing or stopping pre-existing antihypertensive drugs in patients who had recently had a stroke . METHODS The Continue or Stop Post-Stroke Antihypertensives Collaborative Study ( COSSACS ) was a UK multicentre , prospect i ve , r and omised , open , blinded-endpoint trial . Patients were recruited at 49 UK National Institute for Health Research Stroke Research Network centres from January 1 , 2003 , to March 31 , 2009 . Patients aged over 18 years who were taking antihypertensive drugs were enrolled within 48 h of stroke and the last dose of antihypertensive drug . Patients were r and omly assigned ( 1:1 ) by secure internet central r and omisation to either continue or stop pre-existing antihypertensive drugs for 2 weeks . Patients and clinicians who r and omly assigned patients were unmasked to group allocation . Clinicians who assessed 2-week outcomes and 6-month outcomes were masked to group allocation . The primary endpoint was death or dependency at 2 weeks , with dependency defined as a modified Rankin scale score greater than 3 points . Analysis was by intention to treat . This trial is registered with the International St and ard R and omised Controlled Trial Register , number IS RCT N89712435 . FINDINGS 763 patients were assigned to continue ( n=379 ) or stop ( n=384 ) pre-existing antihypertensive drugs . 72 of 379 patients in the continue group and 82 of 384 patients in the stop group reached the primary endpoint ( relative risk 0.86 , 95 % CI 0.65 - 1.14 ; p=0.3 ) . The difference in systolic blood pressure at 2 weeks between the continue group and the stop group was 13 mm Hg ( 95 % CI 10 - 17 ) and the difference in diastolic blood pressure was 8 mm Hg ( 6 - 10 ; difference between groups p<0.0001 ) . No substantial differences were observed between groups in rates of serious adverse events , 6-month mortality , or major cardiovascular events . INTERPRETATION Continuation of antihypertensive drugs did not reduce 2-week death or dependency , cardiovascular event rate , or mortality at 6 months . Lower blood pressure levels in those who continued antihypertensive treatment after acute mild stroke were not associated with an increase in adverse events . These neutral results might be because COSSACS was underpowered owing to early termination of the trial , and support the continuation of ongoing research trials . FUNDING The Health Foundation and The Stroke Association OBJECTIVE Blood pressure variation is one of the factors that affects the risk of stroke recurrence and prognosis . This study investigates the effects of calcium channel blockers and beta-blockers on blood pressure variability in severe ischemic stroke patients . PATIENTS AND METHODS The clinical data of 24 patients with ischemic stroke in our intensive care unit were analyzed , and received amlodipine or metoprolol for more than 14 days with 24-hour ambulatory blood pressure monitoring .  All patients aged 61 - 90 years , with GCS score ≤ 8 or associated with other organ dysfunction . RESULTS Among these 24 ischemic stroke patients , 12 received amlodipine and 12 received metoprolol . The observation period was divided into two phases : 1 - 6 days and 7 - 14 days . The decrease in blood pressure was faster in the metoprolol group than in the amlodipine group , while the average st and ard deviation was significantly greater and the smoothness index was less . CONCLUSIONS Metoprolol has faster onset  than amlodipine  and less blood pressure variability than metoprolol This article reports a r and omized controlled trial design ed to test the effects of special packaging of antihypertensive medication on compliance and blood pressure control . One hundred eighty subjects who had exhibited elevated blood pressure greater than 90 mmHg in the two years prior to the study were recruited from patients receiving care at a community hospital-based family medicine practice . After completing preenrollment interviews and blood pressure measurements , subjects were r and omly assigned to receive their antihypertensive medications either in the usual vials or in special unit dose-reminder packaging . Follow-up interviews  , pill counts , and blood pressure measurements were performed at three-month intervals . There were no statistically significant differences between the control and experimental groups with regard to age , sex , race , employment , education , marital status , insurance coverage , or blood pressure regimens . Prior to the intervention , the experimental group had slightly lower diastolic blood pressure and reported better compliance than the control group . Analyses performed on 165 subjects completing the first follow-up visit revealed no significant improvements in blood pressure control or compliance for patients receiving special medication packaging . While some patients found it easy to remember to take pills packaged using this format , they also found the packages somewhat more difficult and inconvenient to use . In contrast to previously reported work , this study did not demonstrate any significant improvement in compliance with special packaging of antihypertensive medications The mechanism of risk reduction obtained by blood pressure-lowering pharmacological treatment remains unclear . We explored the amount of risk reduction attributable to the apparent effect of antihypertensive medicines on blood pressure by using the capture approach . Five r and omized , placebo or nil controlled trials with a total of 28,997 subjects and 1,935 cardiovascular fatal or non-fatal events from the INDANA data base met the eligibility criteria . Computations were performed on the original individual records using multiple Cox 's proportional hazard regression models design ed for meeting the assumed treatment mode of action and comparing relevant assumptions . For coronary event , the results are inconclusive essentially because the risk reduction is mild . However , for stroke the risk reduction adjusted for baseline risk factors is 34 % ( P<0.0001 ) . The part explained by the effect of treatment on systolic blood pressure is 49 % of this reduction , with 95 % confidence interval not including 100 % . This result suggests that the apparent effect on blood pressure is not the only cause of stroke risk reduction in hypertensive subjects su bmi tted to an antihypertensive medicine 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 Objective Hypertension guidelines recommend initial treatment with a β-blocker or diuretic and adding the other drug where blood pressure is not controlled . We hypothesized that systematic rotation through the major classes of antihypertensive drugs would demonstrate substantial differences in the pattern of an individual patient 's response , and suggest a more rational approach to choosing best treatment . Design Thirty-four young hypertensives ( age 28–55 , median 47 ) rotated in a double-blind , Latin-square , crossover fashion through 6 weeks of treatment each with amlodipine , doxazosin , lisinopril , bisoprolol , bendrofluazide and placebo . Blood pressure was measured at each visit . ‘ Best ’ drug , defined by efficacy and tolerability , was repeated at the end . Results Rotation doubled the number of patients reaching target blood pressure ( systolic < 140 mmHg ) on one drug ( P = 0.03 ) . All five drugs were represented among the ‘ best ’ drugs . In six patients , the blood pressure on ‘ best ’ drug was at least 10 mmHg lower than on any other . Response to the ‘ best ’ drug was highly correlated ( r = 0.79 ) with its previous administration . By contrast , there were only weak correlations between responses to pairs of drugs , except for angiotensin-converting enzyme ( ACE ) inhibitor ( A ) with β-blocker ( B ) , and calcium blocker ( C ) with diuretic ( D ) – each r = 0.71 , P < 0.005 ) . In these young patients , the majority of patients ( 23/34 ) responded best to a drug suppressing the renin system ( A and B ) . Conclusions Patients vary reproducibly in their response to initial treatment , and switching among drugs can increase the efficacy of monotherapy . The results support an AB/CD scheme for choosing therapy , in which the first drug is taken from one of these pairs , and uncontrolled patients switch to one of the other pair Summary Background High blood pressure is associated with poor outcome after stroke . Whether blood pressure should be lowered early after stroke , and whether to continue or temporarily withdraw existing antihypertensive drugs , is not known . We assessed outcomes after stroke in patients given drugs to lower their blood pressure . Methods In our multicentre , partial-factorial trial , we r and omly assigned patients admitted to hospital with an acute ischaemic or haemorrhagic stroke and raised systolic blood pressure ( systolic 140–220 mm Hg ) to 7 days of transdermal glyceryl trinitrate ( 5 mg per day ) , started within 48 h of stroke onset , or to  no glyceryl trinitrate ( control group ) . A subset of patients who were taking antihypertensive drugs before their stroke were also r and omly assigned to continue or stop taking these drugs . The primary outcome was function , assessed with the modified Rankin Scale at 90 days by observers masked to treatment assignment . This study is registered , number IS RCT N99414122 . Findings Between July 20 , 2001 , and Oct 14 , 2013 , we enrolled 4011 patients .  Mean blood pressure was 167 ( SD 19 ) mm Hg/90 ( 13 ) mm Hg at baseline ( median 26 h [ 16–37 ] after stroke onset ) , and was significantly reduced on day 1 in 2000 patients allocated to glyceryl trinitrate compared with 2011 controls ( difference −7·0 [ 95 % CI −8·5 to −5·6 ] mm Hg/–3·5 [ –4·4 to −2·6 ] mm Hg ; both p<0·0001 ) , and on day 7 in 1053 patients allocated to continue antihypertensive drugs compared with 1044 patients r and omised to stop them ( difference −9·5 [ 95 % CI −11·8 to −7·2 ] mm Hg/–5·0 [ –6·4 to −3·7 ] mm Hg ; both p<0·0001 ) . Functional outcome at day 90 did not differ in either treatment comparison — the adjusted common odds ratio ( OR ) for worse outcome with glyceryl trinitrate versus no glyceryl trinitrate was 1·01 ( 95 % CI 0·91–1·13 ; p=0·83 ) , and with continue versus stop antihypertensive drugs OR was 1·05 ( 0·90–1·22 ; p=0·55 ) . Interpretation In patients with acute stroke and high blood pressure , transdermal glyceryl trinitrate lowered blood pressure and had acceptable safety but did not improve functional outcome . We show no evidence to support continuing prestroke antihypertensive drugs in patients in the first few days after acute stroke . Funding UK Medical Research Council 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 A sample of 20 patients suffering hypertension ( with a moderate rise in blood pressure ) was r and omly divided into two treatment groups of equal size . The patients of one group received antihypertension treatment with the combination drug Briserin ¿ ( containing 0.1 mg reserpine , 5 mg clopamide , 0.5 mg dihydroergocristin/per tablet ) ; the other patients who served as  control group  , received a matched placebo . After a fortnight 's treatment , the responsiveness of both groups to five different psychologically stressing situations ( those with cognitive and /or emotional overload ) was tested . Analysis of covariance revealed clinical ly significant differences in the mean systolic and diastolic pressure scores of the two groups . The scores of the treatment group were lower not only under stress but also at rest . There was in interaction between rise of blood pressure under stress and kind of stress in the two groups , i.e. , in situations with heavy emotional and /or cognitive load the differences in the pressure scores of the two groups were less substantial than in situations with a low or medium load . The treatment had no systematic effect on heart rate in this sample . In the treatment group reaction time , perceptual speed , and short-term memory were impaired as compared with the control group ; but these differences did not reach a level of significance 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 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 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 High blood pressure is common during the acute phase of stroke and is associated with a poor outcome . However , the management of high blood pressure remains unclear . The ‘ Efficacy of Nitric Oxide in Stroke ’ trial tested whether transdermal glyceryl trinitrate , a nitric oxide donor that lowers blood pressure , is safe and effective in improving outcome after acute stroke . Efficacy of Nitric Oxide in Stroke is an international multicenter , prospect i ve , r and omized , single-blind , blinded endpoint trial , with funding from the UK Medical Research Council . Patients with acute ischemic stroke or intracerebral hemorrhage and systolic blood pressure 140–220 mmHg were r and omized to glyceryl trinitrate or no glyceryl trinitrate and , where relevant , to continue or stop prestroke antihypertensive therapy . The primary outcome is shift in modified Rankin Scale at three-months . Patients or relatives gave written informed ( proxy ) consent , and all sites had research ethics approval . Analyses will be done by intention to treat . This paper and attachment describe the trial 's statistical analysis plan , developed prior to unblinding of date . The statistical analysis plan contains design and methods for analyses , and unpopulated tables and figures for the two primary publications and some secondary publications . The data base will be locked in late February 2014 in preparation for presentation of the results in May 2014 . The data from the trial will improve the precision of the estimates of the overall treatment effects ( efficacy and safety ) of results from completed trials of blood pressure management in acute stroke , and provide the first large-scale r and omized evidence on transdermal glyceryl trinitrate , and of continuing ( vs. stopping ) prestroke antihypertensive medications , in acute stroke Background A gap exists between evidence and practice regarding the management of cardiovascular risk factors . This gap could be narrowed if systematic ally developed clinical practice guidelines were effectively implemented in clinical practice . We evaluated the effects of a tailored intervention to support the implementation of systematic ally developed guidelines for the use of antihypertensive and cholesterol-lowering drugs for the primary prevention of cardiovascular disease . Methods and Findings We conducted a cluster-r and omized trial comparing a tailored intervention to passive dissemination of guidelines in 146 general practice s in two geographical areas in Norway . Each practice was r and omized to either the tailored intervention ( 70 practice s ; 257 physicians ) or control group ( 69 practice s ; 244 physicians ) . Patients started on medication for hypertension or hypercholesterolemia during the study period and all patients already on treatment that consulted their physician during the trial were included . A multifaceted intervention was tailored to address identified barriers to change . Key components were an educational outreach visit with audit and feedback , and computerized reminders linked to the medical record system . Pharmacists conducted the visits . Outcomes were measured for all eligible patients seen in the participating practice s during 1 y before and after the intervention . The main outcomes were the proportions of ( 1 ) first-time prescriptions for hypertension where thiazides were prescribed , ( 2 ) patients assessed for cardiovascular risk before prescribing antihypertensive or cholesterol-lowering drugs , and ( 3 ) patients treated for hypertension or hypercholesterolemia for 3 mo or more who had achieved recommended treatment goals . The intervention led to an increase in adherence to guideline recommendations on choice of antihypertensive drug . Thiazides were prescribed to 17 % of patients in the intervention group versus 11 % in the control group ( relative risk 1.94 ; 95 % confidence interval 1.49–2.49 , adjusted for baseline differences and clustering effect ) . Little or no differences were found for risk assessment prior to prescribing and for achievement of treatment goals . Conclusions Our tailored intervention had a significant impact on prescribing of antihypertensive drugs , but was ineffective in improving the quality of other aspects of managing hypertension and hypercholesterolemia in primary care 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 explore the likely optimum blood pressure ( BP ) level for patients with a history of cerebrovascular disease . Methods The Perindopril Protection Against Recurrent Stroke Study ( PROGRESS ) was a r and omized , placebo-controlled trial that established the beneficial effects of BP lowering in 6105 patients with cerebrovascular disease . The present study comprises two series of post hoc analyses . The first was design ed to investigate the effects of r and omized treatment on recurrent stroke by baseline BP levels , and the second was a corresponding observational analysis investigating the association between achieved follow-up BP levels and recurrent stroke risk . Results Analyses of the r and omized treatment comparisons showed that BP lowering with combination therapy produced similar risk reductions in each of four subgroups defined by baseline BP of less than 120 , 120–139 , 140–159 , and 160 mmHg or greater ( P homogeneity = 0.5 ) . The effects of single-drug therapy were also comparable across these subgroups ( P homogeneity = 0.2 ) , but consistently greater benefits were observed with combination compared to single-drug therapy . The analyses of achieved follow-up BP showed that the lowest risk of recurrence was among the one-quarter of participants with the lowest follow-up BP levels ( median 112/72 mmHg ) , and that risks rose progressively with higher follow-up BP levels . Minor side-effects were progressively more common at lower BP levels ( P homogeneity = 0.04 ) , but there was no excess of serious complications ( all P homogeneity > 0.2 ) . Conclusion These analyses provide no evidence of a J-curve relationship between BP level and stroke risk among patients with cerebrovascular disease , and identify no patient group among whom more intensive BP lowering would not be expected to produce greater risk reductions
INTERPRETATION Drug-class effects on interindividual variation in blood pressure can account for differences in effects of antihypertensive drugs on risk of stroke independently of effects on mean SBP .
INTRODUCTION Unexplained differences between classes of antihypertensive drugs in their effectiveness in preventing stroke might be due to class effects on intraindividual variability in blood pressure .
We did a systematic review to assess any such effects in r and omised controlled trials .