Of fads, fashion, surrogate endpoints and dual RAS blockade. Comparison of the Effects of Quinapril and Losartan on Carotid Artery Intima-Media Thickness in Patients with Mild-to-Moderate Arterial Hypertension Hyperkalemia as a constraint to therapy with combination Renin-Angiotensin system blockade: the elephant in the room. Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy. Protocol of the Long-term Impact of RAS Inhibition on Cardiorenal Outcomes (LIRICO) randomized trial. Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy. South African hypertension guideline 2011. Comparison of antihypertensive treatments in preventing cardiovascular events in elderly diabetic patients: results from the Swedish Trial in Old Patients with Hypertension–2 ACE-I and ARBs in early diabetic nephropathy Inhibition of renin–angiotensin system affects prognosis of advanced pancreatic cancer receiving gemcitabine A prospective evaluation of persistence on antihypertensive treatment with different antihypertensive drugs in clinical practice Medical treatment of hypertension in Switzerland. The 2009 Swiss Hypertension Survey (SWISSHYPE). Comparison of the effects of angiotensin receptor antagonist, angiotensin converting enzyme inhibitor, and their combination on regression of left ventricular hypertrophy of diabetes type 2 patients on recent onset hemodialysis therapy. Safety and tolerability of the direct renin inhibitor aliskiren: a pooled analysis of clinical experience in more than 12,000 patients with hypertension. Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy: a randomized double-blind crossover trial. Effects of dual blockade of renin-angiotensin system in type 2 diabetes mellitus patients with diabetic nephropathy. Beneficial impact of spironolactone in diabetic nephropathy. Antiproteinuric effects of combined antihypertensive therapies in patients with overt type 2 diabetic nephropathy. Combination of half doses of angiotensin type 1 receptor antagonist and angiotensin-converting enzyme inhibitor in diabetic nephropathy. Renoprotective Effect of the Addition of Losartan to Ongoing Treatment with an Angiotensin Converting Enzyme Inhibitor in Type-2 Diabetic Patients with Nephropathy Blockade of the renin-angiotensin system increases graft survival in patients with chronic allograft nephropathy. Beneficial effect of lisinopril plus telmisartan in patients with type 2 diabetes, microalbuminuria and hypertension. The Effects of Angiotensin Blocking Agents on the Progression of Liver Fibrosis in the HALT-C Trial Cohort
BACKGROUND Dual renin-angiotensin system ( RAS ) blockade , mostly by combining an angiotensin converting enzyme ( ACE ) inhibitor with an angiotensin receptor blocker ( ARB ) , is increasingly used in patients with hypertension and diabetes and /or proteinuria and in those with resistant heart failure . However , in the zest of achieving greater nephroprotection and cardioprotection , even patients with uncomplicated essential hypertension are not uncommonly treated with dual RAS blockade . EVIDENCE In 2003 the COOPERATE trial , seemed to confirm that dual RAS blockade was beneficial and that proteinuria reduction was synonymous with nephroprotection . This study had to be withdrawn recently attesting to the suspicion that the data looked to good to be true . Moreover , the large prospect i ve ONTARGET data argue against a nephroprotective effect of dual RAS blockade and together with renal findings from ACCOMPLISH , cast doubt on albuminuria/proteinuria being a reliable surrogate endpoint for renal outcome . Although in heart failure , dual RAS blockade had some benefit without reducing mortality , there remains a distinct safety issue with regard to hyperkalemia and elevated creatinine . Neither in ischaemic heart disease nor in left ventricular hypertrophy had dual RAS blockade any benefits when compared with single RAS blockade . Of note , the combination of an ACE inhibitor with an ARB was recently shown to reduce the risk of dementia . All dual RAS blockade may be created equal and the combination of valsartan with aliskiren , a direct renin inhibitor will be evaluated in diabetic patients in the prospect i ve , r and omized ALTITUDE study . CONCLUSIONS For the time being , given the adverse effects and lack of consistent survival benefits , the use of dual RAS blockade should be avoided unless ironclad data emerge to the contrary Background : Ultrasonographic evidence of increased carotid intima-media thickness ( IMT ) is known to be associated with generalized atherosclerosis . Therapeutic blockade of the renin-angiotensin system ( RAS ) with angiotensin-converting enzyme ( ACE ) inhibitors reportedly reduces carotid IMT in humans . However , there has been no head-to-head comparison of the effects of ACE inhibitor and angiotensin receptor blocker ( ARB ) , a newer type of RAS inhibitor , on carotid IMT . Methods : 57 hypertensive patients were r and omly assigned to treatment with one of two antihypertensive drugs : ACE inhibitor ( quinapril ; n = 25 , group Q ) or ARB ( losartan ; n = 18 , group L ) . Results : After 1 year of treatment , a similar decrease in mean blood pressure was observed in all groups . Carotid IMT was decreased significantly in group Q ( 10 % decrease , p < 0.05 ) but did not change in group L. There were no significant changes in other atherosclerotic factors between these two groups . Conclusion : Our findings suggest that the antiatherosclerotic effect of quinapril is more potent than that of losartan in hypertensive patients . This effect appears unrelated to the drug ’s antihypertensive action or to traditional atherosclerotic factors The renin-angiotensin-aldosterone system ( RAAS ) is an established mediator of progressive renal and cardiovascular disease . Angiotensin II plays a key role in the progression of cardiovascular and renal disease , and drugs that interfere with angiotensin II actions such as angiotensin-converting enzyme inhibitors ( ACEIs ) and angiotensin receptor blockers ( ARBs ) can offer cardiovascular and renal protection beyond their effects on blood pressure . 1–6 Recently , a number of experimental and clinical investigations have implicated aldosterone , independent of angiotensin II , in the pathogenesis of progressive  cardiovascular and renal disease . 7–9 These studies have generated intense interest in aldosterone receptor antagonism , either alone or in combination with an ACEI or an ARB , in the treatment of a wide range of cardiovascular diseases as well as progressive renal injury . Blockade of the renin-angiotensin system ( RAS ) with either an ACEI or an ARB is important in patients with hypertension , heart failure , myocardial infa rct ion , stroke , and various forms of nephropathy , the most common of which is due to diabetes mellitus . Support for RAS blockade derives from large r and omized , controlled , clinical trials demonstrating that these agents attenuate progression of renal disease . 1–6 Lowering blood BACKGROUND Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in diabetic patients . We tested whether dual blockade of the renin-angiotensin system ( RAS ) with both an angiotensin-converting enzyme ( ACE ) inhibitor and an angiotensin II receptor blocker ( ARB ) is superior to maximal recommended dose of ACE inhibitor in type 1 diabetic patients with diabetic nephropathy ( DN ) . METHODS We performed a r and omized , double-blind , crossover trial with 8 weeks treatment with placebo and irbesartan 300 mg ( once daily ) , added on top of enalapril 40 mg ( once daily ) . We included 24 type 1 patients with DN . At the end of each treatment period , albuminuria , 24-hour blood pressure , and glomerular filtration rate ( GFR ) were measured . RESULTS Values on ACE inhibitors + placebo were : albuminuria [ mean ( 95 % CI ) ] , 519 ( 342 to 789 ) mg/24 hours ; blood pressure [ mean ( SEM ) ] , 131 (3)/74 ( 1 ) mm Hg , and GFR [ mean ( SEM ) ] , 65 ( 5 ) mL/min/1.73 m2 . Dual blockade of the RAS induced a reduction in albuminuria [ mean ( 95 % CI ) ] of 25 % ( 15 , 34 ) ( P < 0.001 ) , a reduction in systolic blood pressure of 8 mm Hg ( 4 , 12 ) ( P = 0.002 ) , and a reduction of 4 mm Hg ( 2 , 7 ) ( P = 0.003 ) in diastolic blood pressure . GFR and plasma potassium remained unchanged during both treatment regimes . Dual blockade was safe and well tolerated . CONCLUSION Dual blockade of the RAS is superior to maximal recommended dose of ACE inhibitors with regard to lowering of albuminuria and blood pressure in type 1 patients with DN . Long-term trials are needed to further establish the role of dual blockade of the RAS in renal and cardiovascular protection Microalbuminuria is a strong , consistent and independent risk factor for cardiovascular and renal disease in patients with diabetes and /or hypertension and in the general population . Several r and omized trials have shown the efficacy of inhibiting the renin-angiotensin system ( RAS ) with angiotensin-converting enzyme inhibitors ( ACEIs ) and angiotensin II receptor blockers ( ARBs ) to prevent cardiovascular events and the progression of kidney disease . These 2 classes of drugs are equally effective for renal outcomes in patients with diabetic nephropathy , but only ACEIs have been found to significantly impact the risk of all-cause mortality , predominantly cardiovascular , in patients with diabetic nephropathy . Studies on the cardiorenal efficacy of combined therapy with ACEIs and ARBs in individuals with microalbuminuria or macroalbuminuria and other cardiovascular risk factors have been inconclusive . The Long-term Impact of RAS Inhibition on Cardiorenal Outcomes ( LIRICO ) study aims to address existing questions in this setting . This is a phase III , r and omized , comparative , pragmatic trial with prospect i ve r and omized open blinded endpoint ( PROBE ) design . It will evaluate the comparative efficacy of combined therapy with ACEIs and ARBs versus monotherapy with either ACEIs or ARBs in improving cardiovascular and renal outcomes in microalbuminuric or macroalbuminuric individuals at cardiorenal risk . The study will enroll 2,100 patients , selected in a network of internal medicine , diabetology or nephrology outpatient clinics . Patients will be r and omly allocated to ACEIs , ARBs or their combination . The study has been approved and funded by the Agenzia Italiana del Farmaco ( A.I.F.A. ) within the 2005 funding plan for independent research on drugs Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in diabetic patients . This study tested whether dual blockade of the renin-angiotensin system ( RAS ) with both an angiotensin-converting enzyme ( ACE ) inhibitor ( ACE-I ) and an Angiotensin-II receptor blocker ( ARB ) is superior to either drug alone in type I diabetic patients with diabetic nephropathy ( DN ) . A r and omized double-blind crossover trial was performed with 8-wk treatment with placebo , 20 mg of benazepril once daily , 80 mg of valsartan once daily , and the combination of 20 mg of benazepril and 80 mg of valsartan .  Twenty type I diabetic patients with DN were included . At the end of each treatment period , albuminuria , 24-h BP , and GFR were measured . Eighteen patients completed the study .  Placebo values were : albuminuria [ mean ( 95 % CI ) ] , 701 ( 490 to 1002 ) mg/24 h ; BP [ mean ( SEM ) ] , 144 (4)/79 ( 2 ) mmHg , and GFR [ mean ( SEM ) ] , 82 ( 7 ) ml/min per 1.73 m(2 ) . Treatment with benazepril , valsartan , or dual blockade significantly reduced albuminuria and BP compared with placebo . Benazepril and valsartan were equally effective . Dual blockade induced an additional reduction in albuminuria of 43 % ( 29 to 54 % ) compared with any type of monotherapy , and a reduction in systolic BP of 6 ( 0 to 13 ) mmHg and 7 ( 1 to 14 ) mmHg ( versus benazepril and valsartan , respectively ) and a reduction of 7 ( 4 to 10 ) mmHg diastolic compared with both monotherapies . GFR was reversibly reduced on dual blockade compared with monotherapy and placebo . All treatments were safe and well tolerated . In conclusion , dual blockade of the RAS may offer additional renal and cardiovascular protection in type I diabetic patients with DN OUTCOMES Extensive data from r and omised controlled trials have shown the benefit of treating hypertension . The target blood pressure ( BP ) for antihypertensive management is systolic < 140 mmHg and diastolic < 90 mmHg with minimal or no drug side-effects ; however , stricter BP control is required for patients with end-organ damage , co-existing risk factors and co-morbidity , e.g. diabetes mellitus . The reduction of BP in the elderly and in those with severe hypertension should be achieved gradually over 1 month . Co-existent risk factors should also be controlled . BENEFITS Benefits of management include reduced risks of stroke , cardiac failure , chronic kidney disease and coronary heart disease . RECOMMENDATIONS The correct BP measurement procedure is described , and evaluation of cardiovascular risk factors and recommendations for antihypertensive therapy are stipulated . The total cardiovascular disease risk profile should be determined for all patients to inform management strategies . Lifestyle modification and patient education are cornerstones in the management of every patient . Major indications , pre caution s and contra-indications to each recommended antihypertensive drug are listed . Combination therapy should be considered ab initio if the BP is ≥ 20/10 mmHg . First-line drug therapy for uncomplicated hypertension includes low-dose thiazide-like diuretics , calcium channel blockers ( CCBs ) or angiotensin-converting enzyme inhibitors ( ACE-Is ) ( or ARBs - angiotensin II receptor blockers ) . If the target BP is not obtained , a second antihypertensive should be added from the aforementioned list . If the target BP is still not met , the third remaining antihypertensive agent should be used . In black patients  either thiazide-like diuretics or CCBs can be used initially , because response rates are better than with ACE-Is or β-blockers . In treating resistant hypertension , a central ly acting drug , vasodilator , α-blocker , spironolactone or β-locker should be added . This guideline includes management of specific situations , i.e. hypertensive emergency and urgency , severe hypertension with target organ damage , hypertension in diabetes mellitus , resistant hypertension , fixed drug combinations , new trials in hypertension , and interactions of antihypertensive agents with other drugs . VALIDITY The guideline was developed by the Southern African Hypertension Society Background The benefits of treating hypertension in elderly diabetic patients , in terms of achieving reductions in cardiovascular morbidity and mortality , have been documented in several recent prospect i ve trials . There has , however , been some controversy regarding the effect of different antihypertensive drugs on the frequency of myocardial infa rct ion in this group of patients . Design STOP Hypertension-2 was a prospect i ve , r and omized , open trial with blinded endpoint evaluation . Methods We studied 6614 elderly patients aged 70–84 years ; 719 of them had diabetes mellitus at the start of the study ( mean age 75.8 years ) . Patients were r and omly assigned to one of three treatment strategies : conventional antihypertensive drugs ( diuretics or β-blockers ) , calcium antagonists , or angiotensin converting enzyme ( ACE ) inhibitors . Results Reduction in blood pressure was similar in the three treatment groups of diabetics . The prevention of cardiovascular mortality was also similar ; the frequency of this primary endpoint did not differ significantly between the three groups . There were , however , significantly fewer ( P = 0.025 ) myocardial infa rct ions during ACE inhibitor treatment ( n = 17 ) than during calcium antagonist treatment ( n = 32 ; relative risk 0.51 , 95 % confidence interval 0.28–0.92 ) ; but a ( non-significant ) tendency to more strokes during ACE inhibitor treatment ( n = 34 compared with n = 29 ; relative risk 1.16 , 95 % confidence interval 0.71–1.91 ) . Conclusion Treatment of hypertensive diabetic patients with conventional antihypertensive drugs ( diuretics , β-blockers , or both ) seemed to be as effective as treatment with newer drugs such as calcium antagonists or ACE inhibitors Introduction Antihypertensive treatment of patients with clinical manifestations of diabetic nephropathy , and especially , renin-angiotensin system ( RAS ) inhibition , slows , but may not fully arrest progression towards end-stage renal disease . Studies using ` hard ' endpoints such as doubling of serum creatinine , dialysis , or death that are initiated before emergence of any renal functional abnormalities in diabetes , would be of impractical length and size . We therefore undertook a primary prevention study ( The Renin-Angiotensin System Study or RASS ) to determine if inhibition of the RAS could slow the development of a key diabetic glomerulopathy structural endpoint , increase in mesangial fractional volume ( Vv[Mes/glom ] ) . Methods This is a parallel group , double-blind , placebo-controlled trial with 285 patients with Type 1 diabetes mellitus ( 95 per group ) r and omised to receive the angiotensin-converting enzyme inhibitor , enalapril , the angiotensin II receptor blocker , losartan , or placebo .  All patients are normotensive , normoalbuminuric and have normal or increased glomerular filtration rates at study entry . The study is based on primary endpoint of change in Vv(Mes/glom ) from baseline to the five-year renal biopsy , with baseline and interval measures of albumin excretion rate , glomerular filtration rate , blood pressure , and glycaemia . Baseline , mid-point , and five-year retinal fundus photography are also performed . Results One thous and and sixty-five patients were interviewed , 707 refused participation and 73 were excluded . The target of 285 subjects were r and omised and their clinical and demographic characteristics are described . Biopsy complications occurred in 17 ( 6 % ) , only one of which required hospitalisation . There were no permanent biopsy-related sequelae . Conclusions Renal structural variables are reasonable surrogate endpoints for studies of progression of early diabetic nephropathy . Although requiring substantial recruitment effort , diabetic nephropathy primary prevention trials based on change in renal structure are feasible Background : The renin – angiotensin system ( RAS ) is thought to have a role in carcinogenesis , and RAS inhibition may prevent tumour growth . Methods : We retrospectively investigated the impact of angiotensin I-converting enzyme inhibitors ( ACEIs ) and angiotensin II type-1 receptor blockers ( ARBs ) in 155 patients with pancreatic cancer receiving gemcitabine monotherapy .  Patients were divided into three groups : the ACEI/ARB group ( 27 patients receiving an ACEI or ARB for hypertension ( HT ) ) , the non-ACEI/ARB with HT group ( 25 patients receiving antihypertensive drugs other than ACEIs or ARBs ) , and the non-HT group ( 103 patients receiving no antihypertensive drugs ) . Results : Patient characteristics were not different , except for age and HT medications . Progression-free survival ( PFS ) was 8.7 months in the ACEI/ARB group , 4.5 months in the non-ACEI/ARB with HT group , and 3.6 months in the non-HT group . Overall survival ( OS ) was 15.1 months in the ACEI/ARB group , 8.9 months in the non-ACEI/ARB with HT group , and 9.5 months in the non-HT group . The use of ACEIs/ARBs was a significant prognostic factor for both PFS ( P=0.032 ) and OS ( P=0.014 ) in the multivariate analysis . Conclusions : The ACEIs/ARBs in combination with gemcitabine might improve clinical outcomes in patients with advanced pancreatic cancer . Prospect i ve trials are needed to test this hypothesis Persistence on treatment affects the efficacy of antihypertensive treatment . We prospect ively investigated the persistence on therapy and the extent of  blood pressure ( BP ) control  in 347 hypertensive patients ( age 59.4 ± 6 years ) r and omly allocated to a first-line treatment with : angiotensin-converting enzyme ( ACE ) inhibitors , calcium-channel blockers ( CCBs ) , ß-blockers , angiotensin-II receptor blockers ( ARBs ) , or diuretics and followed-up for 24-months . Persistence on treatment was higher in patients treated with ARBs ( 68.5 % ) and ACE inhibitors ( 64.5 % ) vs CCBs ( 51.6 % ; p < 0.05 ) , β-blockers ( 44.8 % , p < 0.05 ) , and diuretics ( 34.4 % , p < 0.01 ) . No ARB , ACE inhibitor , β-blocker , or diuretic was associated with a higher persistence in therapy compared with the other molecules used in each therapeutic class . The rate of persistence was significantly higher in patients treated with lercanidipine vs others CCBs ( 59.3 % vs 46.6 % , p < 0.05 ) . Systolic and diastolic BP was decreased more successfully in patients treated with ARBs ( −11.2/−5.8 mmHg ) , ACE inhibitors ( −10.5/−5.1 mmHg ) , and CCBs ( −8.5/−4.6 mmHg ) compared with ß-blockers ( −4.0/−2.3 mmHg p < 0.05 ) and diuretics ( −2.3/−2.1 mmHg , p < 0.05 ) . No ARB , ACE inhibitor , β-blocker , or diuretic was associated with a higher BP control compared with the other molecules used in each therapeutic class . A trend toward a better BP control was observed in response to lercanidipine vs other CCBs ( p = 0.059 ) . The present results confirm the importance of persistence on treatment for the management of hypertension in clinical practice OBJECTIVES Despite a broad and efficient pharmacological antihypertensive armamentarium , blood pressure ( BP ) control is suboptimal and heterogeneous throughout Europe . Recent representative data from Switzerl and are limited . The goal of the present survey was therefore to assess the actual control rate of high BP in Switzerl and in accordance with current guidelines . The influence of risk factors , target organ damage and medication on BP levels and control was also evaluated . METHODS A cross-sectional visit-based survey of ambulatory hypertensive patients was performed in 2009 in Switzerl and . 281 r and omly selected physicians provided data on 5 consecutive hypertensive patients attending their practice s for BP follow-up . Data were anonymously collected on demographics , comorbidities and current medication , and BP was recorded . Subsequent modification of pharmacological antihypertensive therapy was assessed . RESULTS Data from 1376 patients were available . Mean age was 65 ± 12 years , 53.9 % were male subjects . 26.4 % had complicated hypertension . Overall , BP control ( < 140/90 mm Hg for uncomplicated and < 130/80 mm Hg for complicated hypertension ) was achieved in 48.9 % . Compared to patients with complicated hypertension , BP control was better in patients with uncomplicated hypertension ( 59.4 % vs. 19.2 % , p < 0.001 ) . As a monotherapy the most prescribed drug class were angiotensin receptor blockers ( ARB , 41 % ) , followed by angiotensin converting enzyme ( ACE ) inhibitors ( 21.5 % ) , betablockers ( 20.8 % ) and calcium channel blockers ( CCB , 10.8 % ) . The most prescribed drug combinations were ARB + diuretic ( 30.1 % ) and ACE inhibitors + diuretic ( 15.3 % ) . 46 % were receiving a fixed drug combination . In only 32.7 % of patients with uncontrolled hypertension was a change in drug therapy made . CONCLUSION This representative survey on treated adult hypertensive patients shows that , compared to earlier reports , the control rate of hypertension has improved in Switzerl and for uncomplicated but not for complicated , particularly diabetes-associated hypertension . ARBs and ACE inhibitors are the most prescribed antihypertensive drugs for monotherapy , whereas diuretics and ARBs were the most used for combination therapy Left ventricular hypertrophy ( LVH ) is frequently found at the initiation of dialysis therapy of diabetic and hypertensive patients , and is highly predictive of future cardiac morbidity and mortality . In patients with hypertension and LVH , both an angiotensin converting enzyme ( ACE ) inhibitor and an angiotensin type 1 receptor ( AT1 ) antagonist regress LVH . However , it remains controversial whether dual blockade of the renin-angiotensin system will regress LVH in these patients using a combination of ACE inhibitor and AT1 antagonist . Thirty-three type II diabetic patients with end-stage renal disease who had just entered into hemodialysis therapy and were diagnosed as having LVH evaluated by echocardiography were selected from three dialysis units staffed by the faculty of Saitama Medical School , Saitama , Japan between 1999 and 2001 . The study was carried out for 1 year . All patients were assigned r and omly to three groups with equal number : group I , an ACE inhibitor , enalapril 10 mg daily ; group II , an AT1 antagonist , losartan 100 mg daily ; group III , combination of enalapril 10 mg and losartan 100 mg daily . All antihypertensive drugs were given 30 min after the cessation of dialysis therapy .  LVH was evaluated by echocardiography before the start of administration of drugs , at 6 months and 12 months after the start of drug therapy . Systolic blood pressure levels less than 140 mmHg were the target for the three groups . Using repeated measures analysis of variance , applied to those with four echocardiograms , there were progressive decreases over time in left ventricular mass index , posterior wall thickness and interventricular septum thickness . There were no significant differences in regression of LVH as well as blood pressure control between enalapril and losartan groups ; however , dual blockade induced an additional 28 % reduction in left ventricular mass index compared with any type of monotherapy . Both ACE inhibitors and AT1 antagonists benefit the regression of LVH in diabetic patients who start dialysis therapy . Moreover , combination therapy with ACE inhibitors and AT1 antagonists would provide more beneficial effects on LVH in these patients than monotherapy While the safety of renin-angiotensin system (RAS)-blocking drugs such as angiotensin-converting enzyme ( ACE ) inhibitors and angiotensin receptor blockers is well known , less is known about the new direct renin inhibitor aliskiren . The authors pooled data from 12 r and omized controlled trials of aliskiren in patients with hypertension and analyzed the incidence and types of adverse events ( AEs ) and laboratory abnormalities . Studies were characterized as short-term ( ≤2 months ) placebo-controlled or long-term ( > 2 months ) active-controlled . Relative risks for AEs of particular interest for RAS blockers were calculated . In short-term studies , AEs occurred in similar proportions of aliskiren 150 mg and 300 mg ( 33.6 % and 31.6 % , respectively ) and placebo treatment groups ( 36.8 % ) . In long-term studies , a lower proportion of patients treated with aliskiren 150 mg and 300 mg had AEs ( 33.7 % and 43.2 % , respectively ) than those treated with ACE inhibitors ( 60.1 % ) , angiotensin receptor blockers ( 53.9 % ) , and thiazide diuretics ( 48.9 % ) . Events of special interest , including angioedema , hyperkalemia , and diarrhea occurred in similar proportions of patients taking aliskiren , placebo , and comparator agents . In studies of up to 36 weeks , patients treated with aliskiren were significantly less likely to develop cough than those treated with ACE inhibitors . At the registered doses of 150 mg and 300 mg daily , aliskiren  has safety and tolerability profiles  similar to placebo , other RAS blockers , and diuretics . Cough rates are lower with aliskiren compared with ACE inhibitors OBJECTIVE We evaluated the renoprotective effects as reflected by short-term changes in albuminuria of dual blockade of the renin-angiotensin system ( RAS ) by adding an angiotensin II receptor blocker ( ARB ) to treatment with maximal recommended doses of an ACE inhibitor ( ACEI ) in patients with type 2 diabetes and nephropathy . RESEARCH DESIGN AND METHODS A total of 20 patients ( 17 men and 3 women ) with type 2 diabetes along with hypertension and nephropathy were enrolled in this double-blind , r and omized , two-period , crossover trial of 8 weeks of treatment with the ARB c and esartan 16 mg daily and placebo added in r and om order to existing treatment with lisinopril/enalapril 40 mg daily or captopril 150 mg daily . At the end of each treatment period , we evaluated albuminuria in three 24-h urinary collection s by turbidimetry , 24-h ambulatory blood pressure ( ABP ) using the Takeda-TM2420 , and glomerular filtration rate ( GFR ) by the (51)Cr-EDTA plasma-clearance technique . RESULTS During monoblockade of the RAS by ACEI treatment , albuminuria was 706 ( 349 - 1,219 ) mg/24 h [ geometric mean ( IQR ) ] ; 24-h ABP was 138 + /- 3/72 + /- 2 mmHg ( mean + /- SE ) ; and GFR was 77 + /- 6 ml x min(-1 ) x 1.73 m(-2 ) ( mean + /- SE ) . During dual blockade of the RAS by addition of c and esartan 16 mg daily , there was a mean ( 95 % CI ) reduction in albuminuria of 28 ( 17 - 38 ) compared with ACEI alone ( P < 0.001 ) . There was a modest reduction in systolic/diastolic 24-h ABP of 3/2 mmHg ( -2 to 8 systolic , -2 to 5 diastolic ; NS ) . Changes in albuminuria did not correlate to changes in ABP . Addition of c and esartan 16 mg daily induced a small , insignificant decrease in GFR of 4 ( -1 to 9 ) ml x min(-1 ) x 1.73 m(-2 ) . CONCLUSIONS Dual blockade of the RAS provides superior short-term renoprotection independent of systemic blood pressure changes in comparison with maximally recommended doses of ACEI in patients with type 2 diabetes as well as nephropathy BACKGROUND Angiotensin-converting enzyme ( ACE ) inhibitors or angiotensin II receptor blockers ( ARB ) have been shown to delay the progression to proteinuria and kidney failure in hypertensive type 2 diabetic patients with diabetic nephropathy . Further synergistic effect may be obtained by combined therapy with both ARB and ACE inhibitors . OBJECTIVE To evaluate the effect of dual blockage of the renin-angiotensin system by adding maximal recommended dose of ARB with maximal recommended dose of ACE inhibitors in type 2 diabetic patients with diabetic nephropathy . MATERIAL AND METHOD Type 2 diabetic patients with urine protein/creatinine ( UPCr ) > 0.5 gm/gm and hypertension who received maximal recommended dose of ACE inhibitors ( Enalapril 40 mg/day ) over three months were r and omized to two groups .  ARB group received adding maximal recommended dose of ARB ( Telmisartan 80 mg/day ) and control group received previous ACE inhibitors only for 24 weeks . RESULTS Eighty patients were enrolled . ARB group led to significantly reduced UPCr from baseline at week 8 , 12 , and 24 ( 2.65 + /- 1.81 , 2.24 + /- 1.85 , 2.24 + /- 1.88 and 1.98 + /- 1.73 gm/gm respectively , p < 0.05 ) but UPCr in the control group was unchanged ( 1.97 + /- 1.56 , 1.85 + /- 1.27 , 1.97 + /- 1.11 and 1.96 + /- 1.42 gm/gm respectively , p > 0.05 ) . ARB group induced an additional reduction in proteinuria of 29.25 % ( 95 % CI 9.68 - 48.82 ) compared with control group . By the end of the present study , glomerular filtration rate had fallen from 41.76 + /- 12.16 to 37.84 + /- 13.59 ml/min/1.73 m2 in ARB group and 50.89 + /- 29.43 to 49.41 + /- 29.85 ml/min/1.73 m2 in control group ( p > 0.05 ) . Serum potassium had changed from 4.51 + /- 0.48 to 4.58 + /- 0.13 mEq/L in ARB group and 4.60 + /- 0.58 to 4.40 + /- 0.13 mEq/L in the control group ( p > 0.05 ) . No other serious adverse effects were reported during treatment . CONCLUSION Adding maximal recommended dose of ARB with maximal recommended dose of ACE inhibitors in type 2 diabetic patients can reduce proteinuria more than ACE inhibitors alone . This treatment is safe and well tolerated BACKGROUND Aldosterone has been suggested to play a role in the initiation and progression of diabetic nephropathy . Currently recommended treatment with angiotensin-converting enzyme ( ACE ) inhibitors or angiotensin II receptor blockers [ renin-angiotensin system ( RAS ) blockade ] does not suppress circulating aldosterone sufficiently . We therefore aim ed to evaluate the short-term effect of aldosterone antagonism with spironolactone on albuminuria and blood pressure in diabetic nephropathy . METHODS Twenty Caucasian type 1 diabetic patients with persistent macroalbuminuria despite antihypertensive treatment , including RAS blockade , completed this double-masked , r and omized cross-over trial . Patients were treated in r and om order with spironolactone 25 mg once daily and matched placebo for two months , respectively , on top of usual antihypertensive treatment . After each treatment period albuminuria , 24-hour blood pressure , and glomerular filtration rate ( GFR ) were determined . RESULTS Spironolactone on top of usual antihypertensive treatment induced a 30 % ( 95 % CI 17 to 41 ) reduction in albuminuria from [ geometric mean ( 95 % CI ) ] 831 ( 624 to 1106 ) mg/24-hour on placebo treatment ( P < 0.001 ) , and a reduction in fractional albumin clearance of 35 % ( 20 to 46 , P < 0.001 ) . Twenty-four-hour blood pressure showed an insignificant reduction of [ mean reduction ( 95 % CI ) ] 8 ( -1 to 17)/3 ( -0.2 to 7 ) mm Hg ( P < 0.10 ) . There was an insignificant reversible reduction in GFR during treatment with spironolactone . On spironolactone treatment , one patient was excluded due to  hyperkalemia  ( plasma potassium 5.7 mmol/L ) and one due to orthostatic dizziness . Otherwise treatment was well tolerated . CONCLUSION Our results suggest that spironolactone treatment on top of recommended antihypertensive treatment reduces blood pressure and may offer additional renoprotection in type 1 diabetic patients with diabetic nephropathy Combined antihypertensive therapy plays a crucial role in achieving targeted blood pressure reductions and renoprotection . We therefore compared the antihypertensive and antiproteinuric effects of combined therapy with either a calcium channel blocker ( CCB ) plus an angiotensin II receptor blocker ( ARB ) or an angiotensin converting enzyme inhibitor ( ACE-I ) plus an ARB in patients with type 2 diabetes mellitus complicated by overt nephropathy and mild to moderate hypertension . After a 12-week dietary control period , diabetic patients with mildly to moderately impaired renal function were r and omly assigned to either a CCB ( amlodipine 5 mg once daily ) or an ACE-I ( temocapril 2 mg once daily ) for 12 weeks ( monotherapy period ) . Both groups then received add-on therapy with an ARB ( c and esartan 4 mg once daily ) for an additional 12 weeks . During the monotherapy period , blood pressure was decreased equally well in both groups . Daily urinary protein excretion remained unchanged in the CCB-treated group ( control period , 4.0 + /- 1.8 g/day vs. CCB period , 4.1 + /- 1.9 g/day ; ns ; n = 8) , but decreased in the ACE-I-treated group ( control period , 4.3 + /- 1.8 g/day vs. ACE-I period , 3.5 + /- 1.7 g/day ; p < 0.05 ; n = 9 ) . After the combined therapy period , blood pressure was decreased to the same degree in both groups . Although ARB plus CCB significantly reduced urinary protein excretion ( to 3.5 + /- 1.5 g/day ; p < 0.05 vs. control period ; n = 8) , a more profound reduction was achieved with ARB plus ACE-I ( to 2.6 + /- 1.3 g/day ; p < 0.01 vs. control period ; n = 9 ) . Monotherapy with the ACE-I increased the serum potassium concentration , and this elevation was sustained after addition of the ARB . In contrast , the serum potassium concentration was not influenced by monotherapy with the CCB , but was significantly increased after addition of the ARB . A decreased hematocrit was observed in the ARB plus ACE-I group . The present study suggests that combined antihypertensive therapy with either a CCB plus an ARB or an ACE-I plus an ARB exerts an antiproteinuric effect in patients with type 2 diabetic nephropathy with mildly impaired renal function . Although the latter combination had a more profound effect , it was associated with an increased serum potassium concentration and worsening of renal anemia . Thus , the combination of a CCB and an ARB should be the first line antihypertensive therapy in those with overt diabetic nephropathy . The long-term efficacy of these combined antihypertensive therapies will need to be further addressed in a future study BACKGROUND To investigate the renoprotective effect of combination therapy with an angiotensin I converting enzyme inhibitor and an angiotensin type I receptor blocker ( ARB ) on diabetic kidney disease , half doses of each monotherapy were given to type 2 diabetic patients with albuminuria . METHODS Urinary albumin index ( UAI ) and blood pressure ( BP ) were measured in a total of 27 out patients with type 2 diabetes mellitus receiving 10 mg imidapril or 8 mg c and esartan per day . Either agent was then substituted with a combination of 5 mg imidapril and 4 mg c and esartan . After 3 months of combination therapy , UAI and BP were measured . Changes in the parameters were assessed by paired t test . RESULTS Although BP was not significantly different prior to and at the end of combination therapy , log-transformed UAI was significantly reduced ( P = 0.003 ) from an initial UAI ( mean log-transformed UAI + /- SD ) of 79.4 (27.4 - 231)mg/g Cre to 52.5 (17.1 - 161)mg/g Cre at the end of combination therapy . The reduction was not associated with the initial UAI , initial BP , decrease in BP , pretreatment medication or other concomitant antihypertensive agents . CONCLUSIONS In patients with type 2 diabetes and nephropathy , dual blockade of the renin system with an angiotensin-converting enzyme inhibitor and angiotensin receptor blocker significantly reduces albuminuria and , thus , may be renoprotective even when the doses of the agents are reduced by one half Angiotensin converting enzyme inhibitors ( ACE-Is ) and angiotensin II receptor blockers ( ARBs ) are frequently used for the treatment for glomerulonephritis and diabetic nephropathy because of their albuminuria- or proteinuria-reducing effects . To many patients who are nonresponsive to monotherapy with these agents , combination therapy appears to be a good treatment option . In the present study , we examined the effects of the addition of an ARB ( losartan ) followed by titration upon addition and at 3 and 6 months ( n=14 ) and the addition of an ACE-I followed by titration upon addition and at 3 and 6 months ( n=20 ) to the drug regimen treatment protocol in type 2 diabetic patients with nephropathy for whom more than 3-month administration of an ACE-I or the combination of an ACE-I plus a conventional antihypertensive was ineffective to achieve a blood pressure ( BP ) of 130/80 mmHg and to reduce urinary albumin to < 30 mg/day . During the 12-month treatment , addition of losartan or addition of an ACE-I to the treatment protocol reduced systolic blood pressure ( SBP ) by 10 % and 12 % , diastolic blood pressure ( DBP ) by 7 % and 4 % , and urinary albumin excretion by 38 % and 20 % of the baseline value , respectively . However , the effects on both BP and urinary albumin were not significantly different between the two therapies . In conclusion , addition of losartan or an ACE-I to an ongoing treatment with an ACE-I , or addition of an ACE-I to ongoing treatment with a conventional antihypertensive were equally effective at reducing the urinary albumin excretion and BP , and provided renal protection in patients with type-2 diabetic nephropathy BACKGROUND Chronic allograft nephropathy ( CAN ) is the leading cause of late allograft failure , with only limited treatment options . Blockade of the renin-angiotensin system ( RAS ) decreases progression in diabetic and non-diabetic renal disease , but the effect on CAN is as yet unclear . Therefore , we have studied retrospectively the effect of RAS blockade on renal survival in patients with biopsy-proven CAN . METHODS The medical records of 72 patients with biopsy-proven CAN were evaluated with regard to time course of graft function , proteinuria , blood pressure , and antihypertensive and immunosuppressive treatment . Cox 's proportional hazards model was used for analysing renal graft survival after the index biopsy . RESULTS On univariate analysis , histological determinants influencing renal survival were the chronic interstitial and chronic tubular score , and clinical parameters were the serum creatinine level at the time of the biopsy , the relative change in serum creatinine level between 12 months post-transplantation and at the time of the biopsy , mean systolic and diastolic blood pressure after the biopsy , and RAS blockade by angiotensin-converting enzyme inhibitor or angiotensin receptor blocker . On multivariate analysis , graft outcome was influenced by the relative change in serum creatinine level between 12 months post-transplantation and the time of the index biopsy , the urinary protein excretion , the mean diastolic blood pressure after the index biopsy , and RAS blockade . Renal graft survival after treatment with RAS blockade was 6.3 ( 0.9 - 10.9 ) years as opposed to 1.8 ( 0.1 - 6.7 ) years in untreated patients ( P = 0.003 ) . CONCLUSION RAS blockade increases graft survival in CAN . In view of the limited treatment options for CAN , this finding is of importance and needs confirmation by a prospect i ve r and omized trial Angiotensin-converting enzyme ( ACE ) inhibitors have favourable effects on hypertension and diabetic nephropathy , but persistent use may result in incomplete blockade of the renin-angiotensin system . Long-term effects of dual blockade using the ACE inhibitor lisinopril and the long-acting angiotensin II receptor blocker ( ARB ) telmisartan on blood pressure and albumin excretion rate ( AER ) were evaluated . Patients with type 2 diabetes mellitus , hypertension ( systolic blood pressure [ SBP ] > or=140 mmHg or diastolic blood pressure [ DBP ] > or=90 mmHg ) and microalbuminuria ( AER 30 - 300 mg/24h ) received 20 mg of lisinopril or 80 mg of telmisartan once a day for 24 weeks . Patients were then r and omised to continuing treatment with the respective monotherapy or with lisinopril plus telmisartan for a further 28 weeks . Significant ( P<0.001 ) declines in SBP ( 11.1 mmHg versus 10.0 mmHg ) , DBP ( 5.6 mmHg versus 5.3 mmHg ) and AER ( 98 mg/24 h versus 80 mg/24 h ) were achieved with lisinopril ( n=95 ) or telmisartan ( n=97 ) , respectively , after 24 weeks . Subsequent treatment with lisinopril plus telmisartan for 28 weeks result ed in further significant reductions ( P<0.001 ) in SBP , DBP and AER compared with either monotherapy . All treatments were well tolerated . Lisinopril plus telmisartan thus provides superior blood pressure and AER control than either monotherapy . We conclude that use of dual blockade may provide a new approach to prevention of diabetic nephropathy in patients with type 2 diabetes , hypertension and microalbuminuria Background Therapies that can slow the progression of liver fibrosis in chronic liver disease are needed . Evidence suggests that the renin-angiotensin system ( RAS ) contributes to inflammation and fibrosis in chronic liver disease . Both animal and limited human studies have shown that RAS inhibition with angiotensin-converting enzyme inhibitors ( ACEi ) and angiotensin receptor-1 [ AT-1 ] blockers ( ARBs ) has antifibrogenic properties . Aims In this study , we evaluated the effects of continuous ACEi/ARB use for 3.5 years on histological liver fibrosis progression in the HALT-C Trial cohort . Methods In the HALT-C Trial , subjects with chronic hepatitis C and advanced hepatic fibrosis ( Ishak stage ≥3 ) underwent serial liver biopsies at baseline , 1.5 years , and 3.5 years after r and omization . The primary outcome was a ≥2-point increase in Ishak fibrosis score in at least one of the two serial biopsies . Sixty-six subjects were continuously taking ACEi/ARBs over the observation period , 126 were taking other antihypertensive medications , and 343 subjects took no antihypertensive medications . Results The three groups were similar in baseline fibrosis scores , and the two groups being treated with antihypertensives were taking a similar number of antihypertensive medications . Fibrosis progression occurred in 33.3 % of the ACEi/ARB group , 32.5 % of the other antihypertensive medications group , and in 25.7 % of subjects taking no antihypertensive medications . No significant associations between ≥2-point increases in fibrosis scores and continuous ACEi/ARB use were apparent at either 1.5 or 3.5 years in diabetes-adjusted and unadjusted odds ratios . Conclusions ACEi/ARB therapy did not retard the progression of hepatic fibrosis
We found predominantly moderate quality evidence that all-cause mortality is similar when first-line RAS inhibitors are compared to other first-line antihypertensive agents .
First-line thiazides caused less HF and stroke than first-line RAS inhibitors .
Compared with first-line CCBs , first-line RAS inhibitors reduced HF but increased stroke .
The magnitude of the reduction in HF exceeded the increase in stroke .
The small differences in effect on blood pressure between the different classes of drugs did not correlate with the differences in the primary outcomes
BACKGROUND Renin-angiotensin system ( RAS ) inhibitors are widely prescribed for treatment of hypertension , especially for diabetic patients on the basis of postulated advantages for the reduction of diabetic nephropathy and cardiovascular morbidity and mortality .
Despite widespread use of angiotensin converting enzyme ( ACE ) inhibitors and angiotensin receptor blockers ( ARBs ) for hypertension in both diabetic and non-diabetic patients , the efficacy and safety of RAS inhibitors compared to other antihypertensive drug classes remains unclear .
OBJECTIVES To evaluate the benefits and harms of first-line RAS inhibitors compared to other first-line antihypertensive drugs in patients with hypertension .