Treatment of elderly hypertensive patients with epithelial sodium channel inhibitors combined with a thiazide diuretic reduces coronary mortality and sudden cardiac death. Antihypertensive Drug Therapy and the Initiation of Treatment for Diabetes Mellitus Comparative effects of different antihypertensive treatments on progression of diabetic renal disease. Primary prevention of sudden cardiovascular death in hypertensive patients. Mortality results from the MAPHY Study. Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT): Practical Implications 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. Low-dose antihypertensive treatment with a thiazide diuretic is not diabetogenic. A 10-year controlled trial with bendroflumethiazide. Results of combination anti-hypertensive therapy after failure of each of the components. Department of Veterans Affairs Cooperative Study Group on Anti-hypertensive Agents. 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. Effect of single-drug therapy on reduction of left ventricular mass in mild to moderate hypertension: comparison of six antihypertensive agents. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Additional Antihypertensive Effect of Drugs in Hypertensive Subjects Uncontrolled on Diltiazem Monotherapy: A Randomized Controlled Trial Using Office and Home Blood Pressure Monitoring Beta-blockers versus diuretics in hypertensive men: main results from the HAPPHY trial. Beta-blocker/thiazide combination for treatment of hypertensive children: a randomized double-blind, placebo-controlled trial. Effectiveness of Add-On Low-Dose Diuretics in Combination Therapy for Hypertension: Losartan/Hydrochlorothiazide vs. Candesartan/Amlodipine Baseline Characteristics of Participants in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) The Eurevie Study: contrasting effect of piretanide and thiazides in mild to moderate hypertension. Double-blind, placebo-controlled crossover comparison of five classes of antihypertensive drugs
BACKGROUND No reduction in either coronary mortality or sudden cardiac death ( SCD ) has been demonstrated in overviews of r and omized trials of treatment of hypertension with diuretics . METHODS An overview was conducted of coronary mortality and SCD in r and omized controlled antihypertensive trials in which an  epithelial sodium channel ( ENaC ) inhibitor/ hydrochlorthiazide ( HCTZ ) combination was used . Secondarily , an analogous overview in which thiazide diuretic was used alone was performed . R and omized trials that used an ENaC inhibitor/ HCTZ combination ( or , alternatively , thiazide diuretic alone ) were identified from previous meta-analyses , search es of PubMed , search of the Cochrane Clinical Trials data base , and review of publications that addressed the consequences of treating hypertension . Trials in which participants were r and omized to either an ENaC inhibitor combined with a thiazide diuretic ( or to a thiazide diuretic alone ) or to control treatment for at least one year and in which coronary mortality was reported were included . Numbers of events in individual trials were abstract ed independently by 2 authors . RESULTS Significant reductions in both coronary mortality and SCD were observed in the overview of trials in which elderly patients received an ENaC inhibitor/ HCTZ combination . The odds ratio ( OR ) for coronary mortality was 0.59 ( 95 % confidence interval [ CI ] 0.44 , 0.78 ) and for SCD was 0.60 ( 95 % CI 0.38 , 0.94 ) . In contrast , an overview of the trials using thiazide diuretics alone showed no significant reductions of either coronary mortality ( OR 0.94 ; 95 % CI 0.81 , 1.09 ) or SCD ( OR 1.27 ; 95 % CI 0.93 , 1.75 ) . CONCLUSIONS Use of an ENaC inhibitor combined with HCTZ for treatment of hypertension in the elderly results in favorable effects on coronary mortality and SCD Although several antihypertensive medications have been associated with impaired glucose tolerance [ 1 ] , thiazide diuretics have received the most attention in this regard . Since the introduction of chlorothiazide in 1957 , several cases have been reported in which thiazide diuretics were associated with glucose intolerance [ 2 - 5 ] . In addition , many clinical studies have provided information on the effects of thiazide diuretics on glucose homeostasis . The Veterans Administration Cooperative Study Group on Antihypertensive Agents [ 6 ] found that hydrochlorothiazide increased the average fasting plasma glucose level by approximately 0.3 mmol/L after 10 weeks of treatment . In the Systolic Hypertension in the Elderly Program study [ 7 ] , the treatment group showed an increase of 0.4 mmol/L in mean serum glucose levels over the baseline level after 1 year of thiazide diuretic therapy , whereas the placebo group showed an increase of 0.1 mmol/L. In the study conducted by the European Working Party on Hypertension in the Elderly [ 8 ] , the thiazide treatment group showed an increase of 0.5 mmol/L in the fasting serum glucose level after 2 years , whereas the placebo group showed a decrease of 0.2 mmol/L ( P < 0.001 ) . In a r and omized , crossover study of 50 patients , Pollare and coworkers [ 9 ] found that , when compared with placebo , hydrochlorothiazide reduced insulin-stimulated glucose uptake in patients with essential hypertension after 18 weeks of treatment . In contrast , patients treated with captopril showed improved carbohydrate metabolism , including an increase in insulin-stimulated glucose uptake , when compared with placebo recipients . Previous efforts to quantify the clinical risk for development of hyperglycemia requiring treatment in patients taking various antihypertensive regimens have been limited by the relative infrequency of this event and the limited range of antihypertensive agents used in large clinical trials [ 10 ] . For the same reasons , the risks of different agents have not been adequately compared . To address these issues , we conducted a casecontrol study of 11 855 New Jersey Medicaid enrollees newly started on hypoglycemic therapy . Methods Sources of Data The study sample was drawn from the state of New Jersey 's Medicaid program for the years 1981 to 1990 . Enrollment in the program was ascertained through the Medicaid eligibility file , which identifies all program participants , their date s of coverage , and demographic characteristics including age , gender , and race . Data on medication use were taken from the Medicaid pharmacy cl aims file , which contains information on all prescriptions filled by Medicaid recipients , including the National Drug Code and the date dispensed . Medications of interest were identified using the National Drug Code specific for each agent . Hospitalization data for all Medicaid recipients were also ascertained . Medicaid recipients who were eligible to receive Medicare benefits ( crossover enrollees ) were identified to acquire full information on utilization of hospital services . Medicaid covers payment for medications for these Medicare recipients , which enabled us to ascertain all prescription information for this group . Case Patients Case patients were Medicaid enrollees 35 to 99 years of age who filled a first prescription for a hypoglycemic agent between 1981 and 1990 . All oral hypoglycemic medications and insulin preparations were included . The date of the first prescription for a hypoglycemic medication was defined as the index date . To ensure that study patients were active users of the Medicaid system , each case patient was required to be continuously eligible in the program for at least 120 days before the index date and to have filled a prescription for at least one drug of any kind during this period . No cl aims for a hypoglycemic agent could be made before the index date . Drug cl aims were search ed back to 1981 to ensure that case patients and controls had not previously filled a prescription for a hypoglycemic agent .  Of the 35 202 patients who filled a first prescription for a hypoglycemic agent during the defined study period , 443 had deficient eligibility records , and 4753 did not meet the specified age criteria . The additional requirement that case patients be continuously enrolled in Medicaid during the 120 days before the index date eliminated 9292 persons . Another 8859 patients were excluded from the case group because they had not filled a prescription for any other drug during the 120 days preceding the index date . The final case group included 11 855 patients . Controls We identified controls by selecting a r and om sample of Medicaid enrollees who met the same criteria for eligibility and use of the health care system as did case patients but who had not filled a prescription for a hypoglycemic agent on or before a r and omly assigned index date . One control was r and omly selected for each case . Definitions of Antihypertensive Drug Use To characterize current exposure to antihypertensive agents , all prescriptions filled during the 120 days before the index date were review ed for both case patients and controls . Medications of principal interest included thiazide diuretics ; angiotensin-converting enzyme inhibitors ; central ly acting antiadrenergic agents ; peripherally acting antiadrenergic agents ; -blockers ; calcium-channel blockers ; and vasodilators . Categorization of patients taking multiple-agent regimens representing more than one category of antihypertensive agent was based on whether the regimen did or did not contain a thiazide diuretic . Drug-exposure categories were mutually exclusive so that patients were either characterized as exposed to a single category of antihypertensive therapy or placed in one of the multiple-category groups , but not both . Three time windows of exposure before the index date were created : 1 to 45 days , 1 to 90 days , and 91 to 120 days . A patient was considered to be currently exposed to an agent if he or she filled a prescription for a medication of interest in the 45 days before the index date . This was the exposure window of primary interest . In addition , we examined records of patients who filled a prescription for a medication of interest 1 to 90 days before the index date and 91 to 120 days before the index date to study people with evidence of a more prolonged duration of exposure . Covariates Because other medications can also directly and indirectly affect glucose metabolism , we measured exposure to potassium supplements , potassium-sparing diuretics , oral glucocorticoids , estrogen-containing compounds , and niacin . In addition , exposure status for these agents was characterized according to the previously defined exposure windows . Other covariates included demographic variables ( age , gender , race , residence in a nursing home ) the number of days hospitalized , and the number of prescriptions filled in the 120-day period before the index date . Statistical Analysis Differences in categorical variables between case patients and controls were assessed with chi-square tests . Relative risks for new use of a hypoglycemic agent within each exposure category were estimated from odds ratios calculated by unconditional logistic regression [ 11 ] using the SAS CATMOD program [ 12 ] . For these analyses , the reference category was the absence of exposure to any antihypertensive medication . Models were constructed with patients characterized according to the study definitions of duration of exposure ( current exposure or exposure of more prolonged duration ) . Covariates in the models included age , gender , race , nursing home residency , number of days in the hospital , number of drug cl aims , glucocorticoid exposure , potassium supplementation , estrogen exposure , and niacin exposure . Because of temporal trends in the pattern of antihypertensive drug prescribing [ 13 ] , the study sample was stratified according to index date ( pre-1985 or 1985 to 1990 ) , and models were constructed for each sub sample . Confidence intervals ( CIs ) for the estimated odds ratios and significance tests for differences between individual odds ratios were calculated using the estimated st and ard errors . To control for potential surveillance bias ( that is , the possibility that patients receiving antihypertensive agents may have had closer medical supervision and may have had more laboratory tests than patients not receiving antihypertensive therapy ) and to make the case and control groups more comparable , we did a separate analysis of the 8005 current users of antihypertensive medications ( 4794 case patients and 3211 controls ) . In these models , current exposure to thiazide diuretics was the reference exposure . This model also included the same potential confounding variables mentioned above . Results We found no consistent trend when examining the relation between age and the likelihood of starting a hypoglycemic medication ( Table 1 ) in the age range studied . Patients 55 to 74 years of age were more likely to be started on a hypoglycemic agent than patients 35 to 54 years of age , although no significant difference was found between patients 75 years of age or older and patients 35 to 54 years of age . No significant differences in gender distribution were observed between case patients and controls . Blacks and other non-whites were more likely to be started on hypoglycemic therapy than whites . Patients in nursing homes were less likely to start hypoglycemic therapy than noninstitutionalized patients . Patients who had a greater number of hospital days or who filled more prescriptions were more likely to be started on a hypoglycemic medication . No relation was found between index date ( pre-1985 or 1985 to 1990 ) and the likelihood of being started on hypoglycemic therapy . Table 1 . Characteristics of the Study Sample and Their Relation to Starting a Hypoglycemic Medication The relative risk for the initiation of hypoglycemic therapy  was significantly increased among patients who were current BACKGROUND Given the same level of arterial pressure control , studies in diabetic animal models have demonstrated certain classes of antihypertensive medication to confer better overall preservation of renal histologic features and function as well as reduced albuminuria when compared with other agents . The present study was design ed to assess whether any differences exist among antihypertensive agents with regard to progression of diabetic renal disease and albuminuria in human subjects . METHODS The study was a r and omized , prospect i ve , parallel group design that evaluated the effects of a converting enzyme inhibitor ( lisinopril ; group 1 ) , a calcium antagonist ( diltiazem hydrochloride ; group 2 ) , and a combination of a loop diuretic and a beta-blocker ( furosemide and atenolol ; group 3 ) in 30 subjects . All subjects received a low-salt , low-protein diet .  Metabolic ( blood glucose , cholesterol profiles , and urine urea nitrogen and sodium levels ) as well as renal hemodynamic ( renal blood flow and glomerular filtration rate ) profiles and arterial pressure measurements were performed at various intervals during an 18-month period . RESULTS Both groups 1 and 2 had significantly slower rates of decline in glomerular filtration rate compared with group 3 . No significant differences were observed in renal hemodynamics between groups 1 and 2 at 18 months . Group 3 had the worst metabolic , lipid , and side-effect profile of any group . Reductions in albuminuria were not different between groups 1 and 2 , but both were significantly reduced compared with group 3 . CONCLUSIONS Given a similar level of arterial pressure control , both lisinopril and diltiazem slow progression of diabetic renal disease and reduce albuminuria to a greater extent than does the combination of a loop diuretic and beta-adrenoreceptor antagonist . These drugs were also better tolerated and produced no adverse metabolic effects In a r and omized primary prevention trial including 3,234 men with mild to moderate uncomplicated hypertension , the effect of the beta-blocker metoprolol or a thiazide diuretic as an initial antihypertensive therapy was compared regarding the risk of sudden cardiovascular death during a follow-up ranging from 2.3 to 10.8 years ( median of 4.2 years ) . Only men aged 40 to 64 years were included in the study . The r and omization of patients into the metoprolol ( n = 1,609 ) or diuretic group ( n = 1,625 ) was performed after stratification for age , smoking habits , serum cholesterol , and systolic blood pressure . At baseline the two treatment groups were well matched . Metoprolol was given in a mean dose of 174 mg daily and the mean dose of thiazide diuretic was either 46 mg hydrochlorothiazide daily or 4.4 mg bendroflumethiazide daily . Identical blood pressure control was achieved using the fixed therapeutic schedule . Total and cardiovascular mortality were significantly lower for metoprolol than for diuretics , owing to fewer deaths from coronary heart disease and stroke . Of the cardiovascular deaths , 78 % were classified as sudden cardiovascular deaths ( occurred within 24 h after the onset of symptoms ) . There were significantly fewer sudden cardiovascular deaths in the metoprolol group compared to the diuretic group ( 32 v 45 , P = .017 ) . The present results suggest that initial antihypertensive therapy with metoprolol is associated with a lesser incidence of sudden cardiovascular deaths than initial diuretic treatment in uncomplicated hypertension 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 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 Blood pressure ( BP ) and metabolic variables were determined initially and after 1 , 2 , 4 , 6 and 10 years ' treatment in two groups of hypertensive men ( n = 53 each ) r and omized to bendroflumethiazide 2.5 - 5 mg/day or propranolol 160 - 320 mg daily . There was no significant differences in BP or metabolic variables between the two groups at entry . BP was reduced to the same degree by both treatments . Five men in the propranolol group and one man in the thiazide group developed clinical ly overt diabetes during follow-up . Fasting blood sugar increased slightly but significantly though equally in both groups . Oral glucose tolerance was initially impaired to the same degree in both groups but improved significantly during treatment with both drugs . Fasting insulin increased slightly but to the same degree . While serum potassium decreased significantly in the thiazide group , the total body potassium was unchanged in this group . In the propranolol group , serum potassium rose , while total body potassium decreased significantly . Serum urate increased in both groups , though slightly more during thiazide treatment . One case of gout was found in each group . There was no difference in serum lipids between the two groups . The finding in this long-term trial indicate that in middle-aged men with mild to moderate hypertension a low-dose thiazide diuretic like bendroflumethiazide is as effective and safe an antihypertensive agent as the beta-blocker propranolol is and that it does not induce diabetes . The total clinical picture favors the retention of thiazide diuretics as a first choice drug in hypertension We r and omised ambulatory men with diastolic blood pressure ( BP ) 95 - 109 mmHg without anti-hypertensive medication to single drug treatment with either  hydrochlorothiazide 12.5 - 50 mg/day , atenolol 25 - 100 mg/day , captopril 25 - 100 mg/day , clonidine 0.2 - 0.6 mg/day , diltiazem-SR 120 - 360 mg/day , prazosin 4 - 20 mg/day or placebo in a double-blind prospect i ve trial . The assigned drug was titrated to a goal BP of < 90 mm Hg . Patients not achieving goal BP were rer and omised to an alternative single active drug . Non-responders to the second drug received the first drug in combination with the second . Of the 102 non-responders to both drugs who qualified for the combination , 59 ( 57.8 % ) responded . The combination pairs that included a diuretic achieved diastolic goal BP in 69 % and < 140 mm Hg systolic in 77 % compared with 51 % and 46 % , respectively , for those combinations without a diuretic ( P = 0.067 ; P = 0.002 ) . Six of the eight terminations due to adverse drug reactions were in combinations containing prazosin ; three of these six were hypotensive reactions . We conclude that two single drugs of insufficient efficacy to control BP individually have a high probability of achieving goal BP when combined , especially if the combination contains a diuretic 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 BACKGROUND Antihypertensive drugs may differ in their ability to reduce LV mass . Covariates other than drug selection , such as pretreatment LV mass , body weight , the magnitude of blood pressure reduction , race , and age may modify the response of LV mass to therapy . METHODS AND RESULTS Patients with mild to moderate hypertension ( diastolic blood pressure , 95 to 109 mm Hg ) were r and omly allocated to treatment with atenolol , captopril , clonidine , diltiazem , hydrochlorothiazide , or prazosin in a double-masked trial . Patients achieving the goal diastolic blood pressure of < 90 mm Hg during drug titration entered a 1-year maintenance period . Longitudinal analysis examined changes from baseline echocardiogram in LV mass at 8 weeks and at 1 year , statistically adjusted for pretreatment LV mass , systolic blood pressure , body weight , sodium excretion , physical activity , race , and age . Significant reductions at 1 year in adjusted LV mass were seen for patients in the highest tertile of pretreatment LV mass treated with hydrochlorothiazide ( mean , -42.9 ; 95 % confidence limits , -65.5 , -20.2 g ) , captopril ( mean , -38.7 ; 95 % confidence limits , -61.0 , -16.4 g ) , and atenolol ( mean , -28.1 ; 95 % confidence limits , -50.9 , -5.3 g ) . These treatment effects differed from those of prazosin , diltiazem , or clonidine . CONCLUSIONS Antihypertensive drugs have disparate effects on LV mass independent of the magnitude of blood pressure reduction . Patients with adequate blood pressure control on captopril , hydrochlorothiazide , and atenolol show a reduction of LV mass after 1 year of treatment , whereas patients on diltiazem , clonidine , or prazosin do not The purpose of this study was to compare several diltiazem-based antihypertensive drug combinations and assess the usefulness of home blood pressure monitoring in the evaluation of the efficacy of combination pharmacotherapy . Sixteen general practitioners recruited hypertensive subjects uncontrolled on diltiazem monotherapy , who were r and omized to receive eight weeks of add-on therapy with a diuretic ( chlorthalidone ) , a dihydropyridine calcium antagonist ( felodipine ) , an ACE inhibitor ( lisinopril ) , or an angiotensin blocker ( valsartan ) .  Sitting office and home blood pressure was measured using electronic devices A&D 767 . A total of 211 patients were r and omized , and 185 completed the study . Of 52 subjects r and omized to felodipine  , 15 were withdrawn due to ankle edema . The additional antihypertensive effect of the second drug was smaller in 18 subjects with a white coat effect ( p < 0.01 ) . All combinations produced a significant decline in office ( 21.2 ± 14.8 / 7.7 ± 9.7 mmHg ) and home ( 17.1 ± 11.9 / 6.0 ± 7.0 ) blood pressure ( systolic / diastolic , p < 0.001 ) . There were no differences in the efficacy of the four combinations assessed using office or home blood pressure monitoring . These data suggest that diuretics , dihydropyridines , ACE inhibitors , and angiotensin receptor blockers provide significant additional antihypertensive effects in hypertensive patients uncontrolled on diltiazem monotherapy . The diltiazem-dihydropyridine combination is often intolerable because of ankle edema . Home blood pressure monitoring is useful in the assessment of the efficacy of combination pharmacotherapy and also allows for the detection of subjects who do not require treatment intensification Men aged 40 - 64 years with mild to moderate hypertension [ diastolic blood pressure ( DBP ) 100 - 130 mmHg ] were r and omized to treatment with a  diuretic ( n = 3272 ) or a  beta-blocker ( n = 3297 ) , with additional drugs if necessary , to determine whether a beta-blocker based treatment differs from thiazide diuretic based treatment with regard to the prevention of coronary heart disease ( CHD ) events and death .  Patients with previous CHD , stroke or other serious diseases , or with contraindications to diuretics or beta-blockers were excluded . If normotension ( DBP less than 95 mmHg ) was not achieved by monotherapy , other antihypertensive drugs were added , but the two basic drugs were not crossed over . Patients were assessed at 6-monthly intervals . The mean follow-up for end-points was 45.1 months . Blood pressure ( BP ) side effects and end-points were recorded in a st and ardized manner . Entry characteristics and the BP reduction achieved were very similar in both treatment groups . All analyses were made on an intention-to-treat basis . The incidence of CHD did not differ between the two treatment groups . The incidence of fatal stroke tended to be lower in the beta-blocker treated group than in the diuretic treated group . Total mortality and the total number of end-points were similar in both groups . The percentage of patients withdrawn due to side effects was similar , whereas the number of reported symptoms , according to a question naire , was higher for patients on beta-blockers . The incidence of diabetes did not differ between the two groups . Subgroup analyses did not detect a difference in the effect of beta-blockers compared with diuretics in smokers as opposed to non-smokers , and beta-blockers also had the same effects as diuretics in the quartile with the highest predicted risk for CHD . Beta-blockers and thiazide diuretics were approximately equally well tolerated . The two drugs had a similar BP reducing effect although additional drugs had to be given more often in the diuretic group . Antihypertensive treatment based on a beta-blocker or on a thiazide diuretic could not be shown to affect the prevention of hypertensive complications , including CHD , to a different extent Antihypertensive medications are used extensively in children despite a paucity of r and omized , placebo-controlled trials . This study was among the first r and omized , controlled pediatric antihypertensive medication trials , in which the combination drug bisoprolol fumarate/hydrochlorothiazide ( B/HT ) was compared with placebo . The study comprised a 2-week single-blind placebo screening period , a 6-week double-blind dose titration period , a 4-week double-blind dose maintenance period , and a 2-week double-blind dose-tapering period . One hundred and forty subjects were enrolled to achieve 94 r and omized subjects treated either with B/HT ( n=62 ) or placebo ( n=32 ) . B/HT induced significant reductions compared with placebo for average sitting systolic blood pressure ( SiSBP ) ( 9.3 vs. 4.9 mmHg , P<0.05 ) and sitting diastolic blood pressure ( SiDBP ) ( 7.2 vs. 2.7 mmHg , P<0.05 ) . The placebo-subtracted BP reductions were greater in younger children and those with more-severe baseline hypertension . The percentage of subjects with BP less than the 90th percentile at study completion was 45 % for B/HT and 34 % for placebo ( P = NS ) . Although the study demonstrated that B/HT  reduced BP safely compared with placebo , the large placebo effect and failure of most subjects to achieve target BP control make it uncertain whether B/HT is appropriate first-line therapy for pediatric hypertension , particularly in adolescents with mild-to-moderate BP elevation In guidelines , a combination therapy of two or more antihypertensives is recommended for treatment of hypertension where monotherapy is ineffective . Although diuretics or calcium channel blockers are commonly used as add-ons to angiotensin receptor blocker ( ARB ) , the most effective and safe combination has not been established . In this r and omized 4-month study , the efficacy and safety were compared between an ARB/diuretics ( losartan/hydrochlorothiazide [ HCTZ ] ) combination and the most prescribed combination , ARB/calcium channel blocker ( c and esartan/amlodipine ) in hypertensive patients for whom 8 mg/day of c and esartan proved ineffective . After 36 patients were recruited and allocated into two groups , changes in blood pressure ( BP ) and laboratory values were analyzed in 31 patients : 16 patients received losartan ( 50 mg/day)/HCTZ ( 12.5 mg/day ) ( L/H group ) , and 15 patients received c and esartan ( 8 mg/day)/amlodipine ( 5 mg/day ) ( C/A group ) after 5 patients were withdrawn . After 4 months , L/H significantly ( p<0.001 ) reduced mean systolic BP (SBP)/diastolic BP ( DBP ) from baseline 160/89±13/11 mmHg to 140/80±9/8 mmHg , and C/A reduced BP from 161/90±10/11 mmHg to 141/79±10/7 mmHg . The efficacy in reducing BP was similar between the two combination therapies . L/H significantly reduced serum potassium , but within the normal range , and did not increase serum uric acid or serum triglyceride . With L/H , the percentage of patients who attained the BP goal in SBP was higher in elderly patients than in younger patients . As L/H is more cost-effective than c and esartan/amlodipine and has fewer adverse effects on uric acid and other metabolic parameters than diuretic monotherapy , it is concluded to be useful for the management of hypertension Diuretics and & bgr;-blockers have been shown to reduce the risk of cardiovascular morbidity and mortality in people with hypertension in long-term clinical trials . No study has compared newer more costly antihypertensive agents ( calcium antagonists , ACE inhibitors , and & agr;-adrenergic blockers ) with diuretics for reducing the incidence of cardiovascular disease in an ethnically diverse group of middle-aged and elderly hypertensive patients . The study is a r and omized , double-blind , active-controlled clinical trial design ed to determine whether the incidence of the primary outcome , fatal coronary heart disease or nonfatal myocardial infa rct ion , differs between treatment initiation with a diuretic versus each of 3 other antihypertensive drugs . Men and women aged ≥55 years with at least 1 other cardiovascular disease risk factor were r and omly assigned to chlorthalidone ( 12.5 to 25 mg/d ) , amlodipine ( 2.5 to 10 mg/d ) , lisinopril ( 10 to 40 mg/d ) , or doxazosin ( 2 to 8 mg/d ) for planned follow-up of 4 to 8 years . This report describes the baseline characteristics of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) participants . A total of 42 448 participants were r and omized from 625 sites in the United States , Canada , Puerto Rico , and the US Virgin Isl and s. The mean age was 67 years , with 35 % aged ≥70 years . Among those r and omized , 36 % were black , 19 % were Hispanic , and 47 % were women . The sample includes a high proportion of people with diabetes ( 36 % ) , patients with existing cardiovascular disease ( 47 % ) , and smokers ( 22 % ) . There were no important differences between the r and omized treatment groups at baseline . ALLHAT will add greatly to our underst and ing of the management of hypertension by providing an answer to the following question : are newer antihypertensive agents similar , superior , or inferior to traditional treatment with diuretics UNLABELLED This study compares the loop diuretic piretanide 6 mg in a slow-release formulation ( PIR ) with hydrochlorothiazide 25 mg ( HCT ) and the fixed combination altizide 15 mg-spironolactone 25 mg ( ALT-SP ) in hypertension . 1105 mild to moderate hypertensive patients entered a three-week placebo wash-out period ; 899 were r and omized in a 6-month , double-blind , parallel group treatment phase ; 800 completed the study . Primary end-points ; serum potassium concentration and quality of life at one month ; secondary end-points : ionic , renal and metabolic variables ; blood pressure ( BP ) measurements . HCT and ALT-SP were compared only to PIR using Dunnett 's or chi 2 tests . RESULTS No difference was found for the overall quality of life . No change of serum potassium concentration at one month was found in PIR while small decreases were detected with ALT-SP ( -0.1 mM ) and HCT ( -0.26 mM ) . Serum creatinine concentration increased significantly in ALT-SP when compared to PIR . All the drugs were effective in reducing BP : HCT had a higher rate of responders than PIR with similar mean BP falls and ALT-SP induced greater falls in blood pressure . CONCLUSION PIR proves to be a potent antihypertensive drug without significant effect on serum electrolytes , plasma glucose and lipids . HCT was slightly more potent but induced a fall in serum potassium concentration with a significant risk of hypokalaemia . The addition of SP to ALT led to a more potent diuretic with a higher level of serum potassium and plasma creatinine disturbances 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
We found no clinical ly meaningful blood pressure-lowering differences between different drugs within the loop diuretic class .
BACKGROUND Antihypertensive drugs from the thiazide diuretic drug class have been shown to reduce mortality and cardiovascular morbidity .
Loop diuretics are indicated and used to treat hypertension , but a systematic review of their blood pressure-lowering efficacy or effectiveness in terms of reducing cardiovascular mortality or morbidity from r and omized controlled trial ( RCT ) evidence has not been conducted .
OBJECTIVES To determine the dose-related decrease in systolic or diastolic blood pressure , or both , as well as adverse events leading to participant withdrawal and adverse biochemical effects ( serum potassium , uric acid , creatinine , glucose and lipids profile ) due to loop diuretics versus placebo control in the treatment of people with primary hypertension .