Inhibition of renin–angiotensin system affects prognosis of advanced pancreatic cancer receiving gemcitabine Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy. Hyperkalemia as a constraint to therapy with combination Renin-Angiotensin system blockade: the elephant in the room. Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy: a randomized double-blind crossover trial. Combination is better than monotherapy with ACE inhibitor or angiotensin receptor antagonist at recommended doses Of fads, fashion, surrogate endpoints and dual RAS blockade. A comparison of outcomes with angiotensin-converting--enzyme inhibitors and diuretics for hypertension in the elderly. Design of combination angiotensin receptor blocker and angiotensin-converting enzyme inhibitor for treatment of diabetic nephropathy (VA NEPHRON-D). Combination of half doses of angiotensin type 1 receptor antagonist and angiotensin-converting enzyme inhibitor in diabetic nephropathy. Protocol of the Long-term Impact of RAS Inhibition on Cardiorenal Outcomes (LIRICO) randomized trial. Dual blockade of the renin-angiotensin system in type 1 patients with diabetic nephropathy. Effect of dual blockade of the renin-angiotensin system on the progression of type 2 diabetic nephropathy: a randomized trial. Renoprotective Effect of the Addition of Losartan to Ongoing Treatment with an Angiotensin Converting Enzyme Inhibitor in Type-2 Diabetic Patients with Nephropathy Effect of the Direct Renin Inhibitor Aliskiren, the Angiotensin Receptor Blocker Losartan, or Both on Left Ventricular Mass in Patients With Hypertension and Left Ventricular Hypertrophy 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. Nifedipine retard was as effective as angiotensin converting enzyme inhibitors in preventing cardiac events in high-risk hypertensive patients with diabetes and coronary artery disease: the Japan Multicenter Investigation for Cardiovascular Diseases-B (JMIC-B) subgroup analysis. Dual blockade of the renin-angiotensin-aldosterone system is safe and effective in reducing albuminuria in Asian type 2 diabetic patients with nephropathy.
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 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 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 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 Objective The combination of an angiotensin-converting enzyme ( ACE ) inhibitor and an angiotensin II ( Ang II ) receptor antagonist ( ARB ) could provide a higher degree of blockade of the renin-angiotensin system(RAS ) than either agent alone . The primary aim of this study was to look at the effect of three therapeutic regimens ( titrated ACE inhibitor ( ACE-I ) versus titrated ARB versus the combination of an ACE-I and an ARB ) on the attainment of adequate blood pressure ( BP ) control and antiproteinuric effect . Both ACE-I and ARB were titrated as monotherapy up to the maximal recommended dose . Methods A pilot r and omised , parallel group open-label study was conducted in 36 patients with primary renal disease , proteinuria above 1.5 g/day and BP > 140/90 mmHg while on therapy with an ACE-I.  Patients were r and omly assigned to ( 1 ) benazepril , n=12 ; ( 2 ) valsartan , n=12 ; or ( 3 ) benazepril plus valsartan , n=12 . Other antihypertensive therapies could also be added to attain goal BP ( < 140/90 mmHg ) . The primary endpoint was the change in proteinuria during six months of follow-up . Results In the presence of similar BP decreases and stable creatinine clearance values , mean proteinuria decreases were 0.5±1.7 , 1.2±2.0 and 2.5±1.8 g/day in groups 1 , 2 and 3 , respectively . When compared with baseline values , only the fall induced by the combination of ARB and ACE-I attained statistical significance ( p<0.05 ) . Conclusion The antiproteinuric capacity of monotherapy at recommended doses with either an ACE-I or an ARB is lower than that obtained with the combination of the two drugs 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 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 Both angiotensin-converting enzyme inhibitors ( ACEIs ) and angiotensin receptor blockers ( ARBs ) can slow the progression of diabetic nephropathy . Even with ACEI or ARB treatment , the proportion of patients who progress to end-stage renal disease ( ESRD ) remains high . Interventions that achieve more complete blockade of the renin-angiotensin system , such as combination ACEI and ARB , might be beneficial . This approach may decrease progression of nondiabetic kidney disease . In diabetic nephropathy , combination therapy decreases proteinuria , but its effect in slowing progression is unknown . In addition , the potential for hyperkalemia may limit the utility of combined therapy in this population . VA NEPHRON-D is a r and omized , double-blind , multicenter clinical trial to assess the effect of combination losartan and lisinopril , compared with losartan alone , on the progression of kidney disease in 1850 patients with diabetes and overt proteinuria . The primary endpoints are time to ( 1 ) reduction in estimated GFR ( eGFR ) of > 50 % ( if baseline < 60 ml/min/1.73 m(2 ) ) ; ( 2 ) reduction in eGFR of 30 ml/min/1.73 m(2 ) ( if baseline > or = 60 ml/min/1.73 m(2 ) ) ; ( 3 ) progression to ESRD ( need for dialysis , renal transplant , or eGFR < 15 ml/min/1.73 m(2 ) ) ; or ( 4 ) death . The secondary endpoint is time to change in eGFR or ESRD . Tertiary endpoints are cardiovascular events , slope of change in eGFR , and change in albuminuria at 1 yr . Specific safety endpoints are serious hyperkalemia ( potassium > 6 mEq/L , requiring admission , emergency room visit , or dialysis ) , all-cause mortality , and other serious adverse events . This paper discusses the design and key method ological issues that arose during the planning of the 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 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 BACKGROUND Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in patients with diabetes . Approximately 30 % of type 1 patients with diabetic nephropathy ( DN ) have albuminuria > 1 g/day , and blood pressure > 135 and /or > 85 mmHg despite antihypertensive therapy with recommended doses of ACE inhibitor ( ACEI ) and diuretics . We tested the effect of dual blockade of the renin-angiotensin system ( RAS ) in these patients . METHODS We performed a r and omised double blind crossover trial with 2 months treatment with Irbesartan 300 mg o.d . and placebo added on top of previous antihypertensive treatment . We included 21 type 1 patients with DN responding insufficiently to ACEI and diuretics , as defined above . At the end of each treatment period , albuminuria , 24-h blood pressure and glomerular filtration rate ( GFR ) were measured . RESULTS Addition of 300 mg Irbesartan to the patients ' usual antihypertensive therapy induced a mean reduction in albuminuria of 37 % ( 95 % CI 20 - 49 , P<0.001 ) ; from 1574 mg/24 h ( 95 % CI 1162 - 2132 ) to 996 mg/24 h ( 95 % CI 699 - 1419 ) , a reduction in 24-h blood pressure of 8 mmHg systolic ( 95 % CI -2 to 18 ) and 5 mmHg diastolic ( 95 % CI 1 - 9 ) ( P=0.11 and 0.01 , respectively ) ( from placebo , mean ( SE ) 146 (4)/80 ( 2 ) mmHg ) . GFR remained unchanged . Serum potassium increased ( mean 4.3 to 4.6 mmol/l , P=0.02 ) . Intervention to reduce serum potassium was needed in two patients with GFR < 35 ml/min/1.73 m(2 ) . Otherwise the dual blockade with Irbesartan was safe and well tolerated . CONCLUSIONS Dual blockade of the RAS may offer additional renal and cardiovascular protection in type 1 patients with DN responding insufficiently to conventional antihypertensive therapy , including recommended doses of ACEI and diuretics BACKGROUND Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers has been shown to lessen the rate of decrease in glomerular filtration rate in patients with diabetic nephropathy . STUDY DESIGN A multicenter open-label r and omized controlled trial to compare the efficacy of combining the angiotensin-converting enzyme inhibitor lisinopril and the angiotensin II receptor blocker irbesartan with that of each drug in monotherapy ( at both high and equipotent doses ) in slowing the progression of type 2 diabetic nephropathy . SETTING & POPULATION 133 patients with type 2 diabetic nephropathy ( age , 66 ± 8 years ; 76 % men ) from 17 centers in Spain . INTERVENTION Patients were r and omly assigned ( 1:1:2 ) to lisinopril ( n = 35 ) , irbesartan ( n = 28 ) , or the combination of both ( n = 70 ) . OUTCOMES The primary composite outcome was a > 50 % increase in baseline serum creatinine level , end-stage renal disease , or death . RESULTS Baseline values for mean estimated glomerular filtration rate and blood pressure were 49 ± 21 mL/min/1.73 m(2 ) and 153 ± 19/81 ± 11 mm Hg . Mean geometric baseline proteinuria was protein excretion of 1.32 ( 95 % CI , 1.10 - 1.62 ) g/g creatinine . After a median follow-up of 32 months , 21 ( 30 % ) patients in the combination group , 10 ( 29 % ) in the lisinopril group , and 8 ( 29 % ) in the irbesartan group reached the primary outcome . HRs were 0.96 ( 95 % CI , 0.44 - 2.05 ; P = 0.9 ) and 0.90 ( 95 % CI , 0.39 - 2.02 ; P = 0.8 ) for the combination versus the lisinopril and irbesartan groups , respectively . There were no significant differences in proteinuria reduction or blood pressure control between groups . The number of adverse events , including hyperkalemia , was similar in all 3 groups . LIMITATIONS The study was not double blind . The sample size studied was small . CONCLUSIONS We were unable to show a benefit of the combination of lisinopril and irbesartan compared to either agent alone at optimal high doses on the risk of progression of type 2 diabetic nephropathy 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 — Left ventricular ( LV ) hypertrophy , a marker of cardiac end-organ damage , is associated with an increased risk of cardiovascular morbidity and mortality . Inhibitors of the renin-angiotensin-aldosterone system may reduce LV mass to a greater extent than other antihypertensive agents . We compared the effect of aliskiren , the first orally active direct renin inhibitor , the angiotensin-receptor blocker losartan , and their combination on the reduction of LV mass in hypertensive patients . Methods and Results — We r and omized 465 patients with hypertension , increased ventricular wall thickness , and body mass index > 25 kg/m2 to receive  aliskiren 300 mg , losartan 100 mg , or their combination daily for 9 months . Patients were treated to st and ard blood pressure targets with add-on therapy , excluding other inhibitors of the renin-angiotensin-aldosterone system and β-blockers . Patients underwent cardiovascular magnetic resonance imaging for assessment of LV mass at baseline and at study completion . The primary objective was to compare change in LV mass index from baseline to follow-up in the combination and losartan arms ; the secondary objective was to determine whether aliskiren was noninferior to losartan in reducing LV mass index from baseline to follow-up . Systolic and diastolic blood pressures were reduced similarly in all treatment groups ( 6.5±14.9/3.8±10.1 mm Hg in the aliskiren group ; 5.5±15.6/3.7±10.7 mm Hg in the losartan group ; 6.6±16.6/4.6±10.5 mm Hg in the combination arm ; P<0.0001 within groups , P=0.81 between groups ) . LV mass index was reduced significantly from baseline in all treatment groups ( 4.9- , 4.8- , and 5.8 g/m2 reductions in the aliskiren , losartan , and combination arms , respectively ; P<0.0001 for all treatment groups ) . The reduction in LV mass index in the combination group was not significantly different from that with losartan alone ( P=0.52 ) . Aliskiren was as effective as losartan in reducing LV mass index ( P<0.0001 for noninferiority ) . Safety and tolerability were similar across all treatment groups . Conclusions — Aliskiren was as effective as losartan in promoting LV mass regression . Reduction in LV mass with the combination of aliskiren plus losartan was not significantly different from that with losartan monotherapy , independent of blood pressure lowering . These findings suggest that aliskiren was as effective as an angiotensin receptor blocker in attenuating this measure of myocardial end-organ damage in hypertensive patients with LV hypertrophy 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 We stratified findings from the Japan Multicenter Investigation for Cardiovascular Diseases-B according to whether or not the patients had diabetes and compared the incidence of cardiac events occurring over a 3-year period between treatment with nifedipine retard and angiotensin converting enzyme ( ACE ) inhibitor . The primary endpoint was the overall incidence of cardiac events ( cardiac death or sudden death , myocardial infa rct ion , hospitalization for angina pectoris or heart failure , serious arrhythmia , and coronary interventions ) , and the secondary endpoints were a composite of other events ( cerebrovascular accidents , worsening of renal dysfunction , non-cardiovascular events , and total mortality ) . The results showed no significant difference in the incidence of the primary endpoint between the nifedipine group ( n=199 ) and the ACE inhibitor group ( n=173 ) in diabetic patients : 15.08 % vs. 15.03 % , relative risk 1.06 , p=0.838 . Also in nondiabetic patients , no significant difference was observed between the former ( n=629 ) and the latter ( n=649 ) : 13.67 % vs. 12.33 % , relative risk 1.04 , p=0.792 . Similar results were obtained for the incidence of the secondary endpoints : in diabetic patients , 5.03 % vs. 5.20 % , relative risk 0.89 , p=0.799 ; in nondiabetic patients , 2.70 % vs. 2.47 % , relative risk 1.07 , p=0.842 . Achieved blood pressure levels were 138/76 and 136/77 mmHg in the nifedipine group and 140/78 and 138/79 mmHg in the ACE inhibitor group in diabetic and nondiabetic patients , respectively . This study showed that nifedipine retard was as effective as ACE inhibitors in reducing the incidence of cardiac events in extremely high-risk hypertensive patients with complications of diabetes and coronary artery disease INTRODUCTION Blockade of the renin-angiotensin-aldosterone system ( RAAS ) by either the angiotensin converting enzyme inhibitor ( ACE-I ) or the angiotensin II receptor blocker ( ARB ) has been shown to reduce albuminuria and delay the progression of diabetic nephropathy . This study evaluated the effect of dual blockade of the RAAS by adding an ACEI or an ARB to the administration of either drug alone on albuminuria in Asian type 2 diabetic patients with nephropathy . METHODS 34 patients were r and omly assigned to receive either enalapril 20 mg or losartan 100 mg once daily for eight weeks . Following this , all patients received a combination of enalapril 10 mg and losartan 50 mg daily for eight weeks , followed by enalapril 20 mg and losartan 100 mg daily for another eight weeks . The blood pressure and 24-hour urinary albumin excretion ( UAE ) were monitored . RESULTS Following monotherapy with enalapril , there was a mean and st and ard error ( SE ) reduction in the UAE and mean arterial pressure ( MAP ) of 9.8 ( SE 6.8 ) percent ( p-value is 0.061 ) and 5.3 ( SE 2.2 ) mmHg ( p-value is 0.026 ) , respectively ; the reduction in UAE and MAP following monotherapy with losartan was by 10.9 ( SE 14.1 ) percent ( p-value is 0.053 ) and 4.5 ( SE 1.9 ) mmHg ( p-value is 0.034 ) , respectively . Combination therapy with enalapril and losartan further reduced the UAE ( 11.2 [ SE 8.7 ] percent , p-value is 0.009 ] despite there being no significant change in the MAP ( -1.2 [ SE 1.47 ] mmHg , p-value is 0.42 ) . The adverse effects included dry cough ( seven [ 19.4 percent ] patients , result ing in the withdrawal of medication in two patients ) , and transient hyperkalaemia ( two [ six percent ] patients ) . CONCLUSION Dual blockade of the RAAS is safe and effective in reducing albuminuria in Asian type 2 diabetic patients with nephropathy
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 .