title: A comparison of outcomes with angiotensin-converting--enzyme inhibitors and diuretics for hypertension in the elderly. Blood pressure lowering and potassium conservation by triamterene‐hydrochlorothiazide and amiloride‐hydrochlorothiazide in hypertension Initial blood pressure as a predictor of the response to antihypertensive therapy. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT) Low-renin status in therapy-resistant hypertension: a clue to efficient treatment Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. Treatment of elderly hypertensive patients with epithelial sodium channel inhibitors combined with a thiazide diuretic reduces coronary mortality and sudden cardiac death. Mortality and Morbidity Results from the European Working Party on High Blood Pressure in the Elderly Trial Ventricular ectopic activity with diuretic therapy. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).
abstract: BACKGROUND Treatment of hypertension with diuretics , beta-blockers , or both leads to improved outcomes . It has been postulated that agents that inhibit the renin-angiotensin system confer benefit beyond the reduction of blood pressure alone . We compared the outcomes in older subjects with hypertension who were treated with angiotensin-converting-enzyme ( ACE ) inhibitors with the outcomes in those treated with diuretic agents . METHODS We conducted a prospect i ve , r and omized , open-label study with blinded assessment of end points in 6083 subjects with hypertension who were 65 to 84 years of age and received health care at 1594 family practice s. Subjects were followed for a median of 4.1 years , and the total numbers of cardiovascular events in the two treatment groups were compared with the use of multivariate proportional-hazards models . RESULTS At base line , the treatment groups were well matched in terms of age , sex , and blood pressure . By the end of the study , blood pressure had decreased to a similar extent in both groups ( a decrease of 26/12 mm Hg ) . There were 695 cardiovascular events or deaths from any cause in the ACE-inhibitor group ( 56.1 per 1000 patient-years ) and 736 cardiovascular events or deaths from any cause in the diuretic group ( 59.8 per 1000 patient-years ; the hazard ratio for a cardiovascular event or death with ACE-inhibitor treatment was 0.89 [ 95 percent confidence interval , 0.79 to 1.00 ] ; P=0.05 ) . Among male subjects , the hazard ratio was 0.83 ( 95 percent confidence interval , 0.71 to 0.97 ; P=0.02 ) ; among female subjects , the hazard ratio was 1.00 ( 95 percent confidence interval , 0.83 to 1.21 ; P=0.98 ) ; the P value for the interaction between sex and treatment-group assignment was 0.15 . The rates of nonfatal cardiovascular events and myocardial infa rct ions decreased with ACE-inhibitor treatment , whereas a similar number of strokes occurred in each group ( although there were more fatal strokes in the ACE-inhibitor group ) . CONCLUSIONS Initiation of antihypertensive treatment involving ACE inhibitors in older subjects , particularly men , appears to lead to better outcomes than treatment with diuretic agents , despite similar reductions of blood pressure Effects of once‐daily doses of 50 mg triamterene with 25 mg hydrochlorothiazide and 5 mg amiloride with 50 mg hydrochlorothiazide were compared in a r and omized , multicenter study of 84 adult subjects with mild to moderate hypertension ( diastolic blood pressure 90 to 114 mm Hg ) . After a 3‐wk placebo lead‐in period , the subjects entered a 6‐wk treatment period . The two drug regimens were compared with respect to antihypertensive effects and effects on serum potassium and magnesium levels during the final week of drug therapy , with the use of the last week of placebo therapy as a covariate . Both drug regimens substantially reduced mean supine systolic and diastolic blood pressures to well within normal limits ; there was no significant difference between the two groups . Twenty‐four of the 41 subjects receiving triamterene‐hydrochlorothiazide ( 59 % ) and 29 of the 43 patients receiving amiloride‐hydrochlorothiazide ( 67 % ) had diastolic blood pressure < 90 mm Hg at week 9 . Five subjects receiving amiloride‐hydrochlorothiazide ( 12 % ) and two subjects receiving triamterene‐hydrochlorothiazide ( 5 % ) had hypokalemia ( serum potassium level < 3.5 mEq/l ) at week 9 . The average decrease in serum potassium levels  during amiloride‐hydrochlorothiazide therapy ( −0.33 ± 0.08 mEq/l ) was greater than that after triamterene‐hydrochlorothiazide ( −0.08 ± 0.07 mEq/l ) . Serum magnesium levels were not changed by either regimen . Weight loss was greater in the amiloride‐hydrochlorothiazide group than in the triamterene‐hydrochlorothiazide group . It is reasonable to assume that the greater potassium loss during amiloride‐hydrochlorothiazide therapy than during triamterene‐hydrochlorothiazide therapy was a consequence of the larger dose of hydrochlorothiazide in the former ( 50 mg ) compared with the latter ( 25 mg ) . Although the effect on lowering blood pressure by amiloride‐hydrochlorothiazide was slightly greater than that by triamterene‐hydrochlorothiazide ( also consistent with the larger dose of hydrochlorothiazide ) , the difference was small and not significant . Triamterene‐hydrochlorothiazide at low doses is effective in the treatment of hypertension 1 . The relationship between fall in systolic blood pressure and initial systolic blood pressure has been investigated in 255 mixed normotensive and hypertensive subjects given placebo or one of five types of antihypertensive drug ( ACE inhibitors , calcium antagonists , direct vasodilators , alpha-adrenoceptor blocker , beta-adrenoceptor blocker ) .  2 . In all cases there was a significant correlation between the change in blood pressure and initial blood pressure . When Oldham 's transformation was used ( replacing the initial blood pressure by the mean of the initial and minimum pressures ) the correlation coefficients were all reduced , although five out of six were still statistically significant . 3 . In a subset of 43 hypertensive subjects given four antihypertensive agents , concentration-effect analysis was carried out . For three of the agents a linear model was used to relate effect to concentration ; for the remaining agent a Langmuir type model was used . 4 . For all four sets of data for which concentration-effect analysis was carried out , there was a significant correlation between the sensitivity of response and the initial blood pressure . 5 . The observed relationships between initial blood pressure , change in blood pressure and sensitivity of response can be qualitatively explained by postulating a general form of dose-response relationship for all antihypertensive agents BACKGROUND The efficacy of antihypertensive drugs newer than diuretics and beta-blockers has not been established . We compared the effects of the calcium-channel blocker nifedipine once daily with the diuretic combination co-amilozide on cardiovascular mortality and morbidity in high-risk patients with hypertension . METHODS We did a prospect i ve , r and omised , double-blind trial in Europe and Israel in 6321 patients aged 55 - 80 years with hypertension ( blood pressure > or = 150/95 mm Hg , or > or = 160 mm Hg systolic ) . Patients had at least one additional cardiovascular risk factor . We r and omly assigned patients nifedipine 30 mg in a long-acting gastrointestinal-transport-system ( GITS ) formulation ( n=3157 ) , or co-amilozide ( hydrochlorothiazide 25 mg [ corrected ] plus amiloride 2.5 mg ; n=3164 ) . Dose titration was by dose doubling , and addition of atenolol 25 - 50 mg or enalapril 5 - 10 mg . The primary outcome was cardiovascular death , myocardial infa rct ion , heart failure , or stroke . Analysis was done by intention to treat . FINDINGS Primary outcomes occurred in 200 ( 6.3 % ) patients in the nifedipine group and in 182 ( 5.8 % ) in the co-amilozide group ( 18.2 vs 16.5 events per 1000 patient-years ; relative risk 1.10 [ 95 % CI 0.91 - 1.34 ] , p=0.35 ) . Overall mean blood pressure fell from 173/99 mm Hg ( SD 14/8 ) to 138/82 mm Hg ( 12/7 ) . There was an 8 % excess of withdrawals from the nifedipine group because of peripheral oedema ( 725 vs 518 , p<0.0001 ) , but serious adverse events were more frequent in the co-amilozide group ( 880 vs 796 , p=0.02 ) . Deaths were mainly non-vascular ( nifedipine 176 vs co-amilozide 172 ; p=0.81 ) . 80 % of the primary events occurred in patients receiving r and omised treatment ( 157 nifedipine , 147 co-amilozide , difference 0.33 % [ -0.7 to 1.4 ] ) . INTERPRETATION Nifedipine once daily and co-amilozide were equally effective in preventing overall cardiovascular or cerebrovascular complications . The choice of drug can be decided by tolerability and blood-pressure response rather than long-term safety or efficacy Objective Therapy resistance is an enduring problem in clinical hypertension . Our aims were to estimate : ( 1 ) the contribution of a low-renin status in therapy resistance ; ( 2 ) whether such status could give a clue to more successful treatment ; and ( 3 ) the contribution by adrenal cortical adenomas and by primary aldosteronism . Setting Patients were referred from general and internal medicine practice s following written invitations and included consecutively . Participants were examined and followed-up on an outpatient basis . Design and interventions Patients were divided according to renin status . Low-renin patients were treated with an aldosterone inhibitor in a prospect i ve , r and omized , placebo-controlled , double-blind , cross-over study . Main outcome measures Prevalence of low-renin status in therapy resistance . Blood pressure and hormonal responses to specific treatment . Numbers of adrenocortical adenomas and primary aldosteronism . Results In 90 treatment-resistant hypertensive , 67 % had plasma renin activity ( PRA ) below 0.5 nmol/l per hour . Of the 60 low-renin patients , 38 were studied on a fixed combination of amiloride and hydrochlorothiazide . Three weeks ’ treatment reduced blood pressure by 31/15 mmHg compared to placebo  ( P ⩽ 0.0001 ) . Serum aldosterone and plasma renin activity increased substantially during active treatment . Through the subsequent 6–12 months of open treatment , seven patients ( 18 % ) showing an escape phenomenon had their high blood pressure effectively treated by extra amiloride . Of the 60 low-renin patients , eight had adrenal adenoma . Conclusion A low-renin status characterized two-thirds of patients with treatment-resistant hypertension , who could be treated efficiently by aldosterone inhibition . Patients with an escape phenomenon ( 18 % ) could effectively be treated by increasing the aldosterone inhibitor . Low-renin hypertensives had high prevalence of adrenocortical adenomas and primary aldosteronism BACKGROUND The optimal combination drug therapy for hypertension is not established , although current U.S. guidelines recommend inclusion of a diuretic . We hypothesized that treatment with the combination of an angiotensin-converting-enzyme ( ACE ) inhibitor and a dihydropyridine calcium-channel blocker would be more effective in reducing the rate of cardiovascular events than treatment with an ACE inhibitor plus a thiazide diuretic . METHODS In a r and omized , double-blind trial , we assigned 11,506 patients with hypertension who were at high risk for cardiovascular events to receive treatment with either benazepril plus amlodipine or benazepril plus hydrochlorothiazide . The primary end point was the composite of death from cardiovascular causes , nonfatal myocardial infa rct ion , nonfatal stroke , hospitalization for angina , resuscitation after sudden cardiac arrest , and coronary revascularization . RESULTS The baseline characteristics of the two groups were similar . The trial was terminated early after a mean follow-up of 36 months , when the boundary of the prespecified stopping rule was exceeded . Mean blood pressures after dose adjustment were 131.6/73.3 mm Hg in the benazepril-amlodipine group and 132.5/74.4 mm Hg in the benazepril-hydrochlorothiazide group . There were 552 primary - outcome events in the benazepril-amlodipine group ( 9.6 % ) and 679 in the benazepril-hydrochlorothiazide group ( 11.8 % ) , representing an absolute risk reduction with benazepril-amlodipine therapy of 2.2 % and a relative risk reduction of 19.6 % ( hazard ratio , 0.80 , 95 % confidence interval [ CI ] , 0.72 to 0.90 ; P<0.001 ) . For the secondary end point of death from cardiovascular causes , nonfatal myocardial infa rct ion , and nonfatal stroke , the hazard ratio was 0.79 ( 95 % CI , 0.67 to 0.92 ; P=0.002 ) . Rates of adverse events were consistent with those observed from clinical experience with the study drugs . CONCLUSIONS The benazepril-amlodipine combination was superior to the benazepril-hydrochlorothiazide combination in reducing cardiovascular events in patients with hypertension who were at high risk for such events . ( Clinical Trials.gov number , NCT00170950 . 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 Summary The latter was due to a reduction in cardiac mortality ( −38 % , p=0.036 ) and a nonsignificant decrease in cerebrovascular mortality ( −32 % , p=0.16 ) . In the double-blind part of the trial , the total mortality rate was not significantly reduced ( −26 % , p=0.077 ) . However , cardiovascular mortality was reduced in the actively treated group ( −38 % , p=0.023 ) , owing to a reduction in cardiac deaths ( −47 % , p=0.048 ) and a non-significant decrease in cerebrovascular mortality ( −43 % , p=0.15 ) . Deaths from myocardial infa rct ion were reduced ( −60 % , p=0.043 ) , and study -terminating morbid cardiovascular events were significantly reduced by active treatment ( −60 % , p=0.0064 ) . Non-terminating cerebrovascular events were reduced ( −52 % , p=0.026 ) , but the non-terminating cardiac events were not ( + 3 % , p=0.98 ) . In the patients r and omised to active treatment there were 29 fewer cardiovascular events and 14 fewer cardiovascular deaths per 1000 patient years during the double-blind part of the trial . A double-blind r and omised placebo-controlled trial of antihypertensive treatment was conducted in patients over the age of 60 . Entry criteria included both a sitting diastolic blood pressure on placebo treatment in the range 90 to 119 mm Hg and a systolic pressure in the range 160 to 239 mm Eg . 840 patients were r and omised either to active treatment ( hydrochlorothiazide and triamterene ) or to  matching placebo  . If the blood pressure remained raised , methyldopa was added to the active regimen and matching placebo in the placebo group . An overall intention-to-treat analysis , combining the double-blind part of the trial and all subsequent follow-up , revealed a non-significant change in total mortality rate ( −9 % , p=0.41 ) but a significant reduction in cardiovascular mortality rate ( −27 % , p=0.037 ) The arrhythmogenic potential of diuretic-induced hypokalemia in patients with uncomplicated hypertension has been controversial . Thirty-two hypertensive patients with previous diuretic-induced hypokalemia , normal 24-hour ambulatory ECG monitoring , and normal exercise testing were treated with 100 mg hydrochlorothiazide ( HCTZ ) daily ( Group 1 ) to induce hypokalemia or with a combination of HCTZ with amiloride ( Group 2 ) to attempt to maintain plasma potassium levels in the normal range during diuretic therapy . Those Group 1 patients ( Group 1A ) with increased ventricular ectopic activity ( VEA ) during HCTZ therapy were subsequently potassium-repleted with amiloride and with supplemental potassium chloride to evaluate the effect of these treatments on VEA . One Group 1 patient died suddenly after 12 days of HCTZ therapy . Autopsy findings suggested an arrhythmic death . Six Group 1 patients who had increased VEA with HCTZ treatment had reductions in VEA with amiloride or supplemental potassium chloride . Group 2 patients did not have a significant increase in VEA . Thus , diuretic therapy appears to cause VEA primarily by electrolyte changes that are induced Hypertension is the most common condition seen in primary care and leads to myocardial infa rct ion , stroke , renal failure , and death if not detected early and treated appropriately . Patients want to be assured that blood pressure ( BP ) treatment will reduce their disease burden , while clinicians want guidance on hypertension management using the best scientific evidence . This report takes a rigorous , evidence -based approach to recommend treatment thresholds , goals , and medications in the management of hypertension in adults . Evidence was drawn from r and omized controlled trials , which represent the gold st and ard for determining efficacy and effectiveness . Evidence quality and recommendations were grade d based on their effect on important outcomes . There is strong evidence to support treating hypertensive persons aged 60 years or older to a  BP goal  of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg ; however , there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal , or in those younger than 30 years for a diastolic goal , so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion . The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease ( CKD ) as for the general hypertensive population younger than 60 years . There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor , angiotensin receptor blocker , calcium channel blocker , or thiazide-type diuretic in the nonblack hypertensive population , including those with diabetes . In the black hypertensive population , including those with diabetes , a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy . There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes . Although this guideline provides evidence -based recommendations for the management of high BP and should meet the clinical needs of most patients , these recommendations are not a substitute for clinical judgment , and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient
target: Differences in antihypertensive effect were due to potency rather than efficacy .
  This synthesis accomplishes for PSDs what has already been achieved for thiazide-type diuretics and other antihypertensives and can guide the application of these underutilized medicines
background: BACKGROUND Potassium-sparing diuretics ( PSDs ) are valuable antihypertensives with additional benefits unrelated to control of systolic blood pressure ( SBP ) .
  However , their key parameters affecting SBP and serum potassium are poorly defined , fostering underutilization .