Table 2.
Dual renin‐angiotensin system blockade and nephroprotection
| Reference | Population | Comparison groups | Mean follow‐up | BP achieved | Results | Adverse events |
|---|---|---|---|---|---|---|
| Randomized clinical trial | ||||||
| Mogensen et al.53(CALM) (2000) | 197 pts with MA, Ht and T2DM; mean age 60 y, female 35% | ARB (Candesartan 16 mg) vs ACEi (lisinopril 20 mg) vs both (Candersartan 16 mg + Lisinopril 20 mg) | 12 wk’ monotherapy with ARB or ACEi followed by 12 wk’ monotherapy or combination treatment | At 24 wk the mean reduction in SBP and DBP with combination treatment were significantly greater than that with ARB (P = 0.002 and P = 0.0003) or ACEi (P = 0.02 and P = 0.005) | UACR reduction with combination treatment (50%, P < 0.001) was greater than with ARB (24%, P = 0.05) and ACEi (39%, P < 0.001) | Creatinine clearance was slightly decreased over 24 wk in the groups treated with ACEi (adj. mean decrease 0.0835 mL/s, P = 0.04) and the combination treatment (0.0735 mL/s, P = 0.05) while was not affected in the group treated with ARB |
| Epstein et al.54 (2006) | 268 pts with T2DM and UACR ≥50 mg/g; mean age 59 y, female 38% | ACEi (Enalapril 20 mg)+placebo vs ACEi (enalapril 20 mg) + ARA50 (eplerenone 50 mg) vs ACEi (enalapril 20 mg) + ARA100 (eplerenone 100 mg) | 12 wk | SBP decreased significantly and similarly in all treatment groups | Treatment with ARA50 (41%) or ARA100 (48.4%) but not placebo (7.4%) significantly reduced UACR from baseline (both ARA groups, P < 0.001 vs placebo) | The incidences of sustained and severe hyperkalemia was similar in the three treatment arms and did not differ on the basis of quartile of estimated GFR |
| Bakris et al.55 (IMPROVE) (2007) | 405 pats with Ht at high CV risk and with MA despite prior treatment with ACEi; mean age 66 y, female 38%;MA: 70%; Overt nephropathy: 30% | ACEi (Ramipril) + ARB (irbesartan) vs ACEi (ramipril) + placebo | 20 wk | Reduction in both DBP (P = 0.019) and SBP (P = 0.047) was greater in patients receiving ACEi+ARB compared with those receiving ACEi + placebo | Change in AER: adj. week 20 baseline geometric ratios for ACEi+ARB and ACEi + placebo were similar (P = 0.540) | The incidence of AE was similar in both groups. (including hyperkalemia 2.5% of patients in both treatment groups) |
| Menne et al.56 (VALERIA) (2008) | 133 pts with Ht and MA; mean age 58 y, female 38% | ACEi (lisinopril 40 mg) vs ARB (valsartan 320 mg) vs ACEi (Lisinopril 20 mg) + ARB (valsartan 320 mg) | 30 wk | BP reduction was similar in the three groups | ACEi+ARB was more effective in reduction of microalbuminuria than monotherapy with either ACEi or ARB and the difference fron ACEi was stastically significant (P = 0.034). | All treatments were safe and well tolerated. |
| Parving et al.57 (AVOID) (2008) | 599 pts with Ht and T2DM with nephropathy (UACR of >300 mg/g or >200 mg/g in pts receiving RAAS inhibitors); mean age 60 y, female 29% | DRI (Aliskiren 150‐300 mg) + ARB (Losartan 100 mg) vs placebo + ARB (Losartan 100 mg) | 6 mo | In the DRI+ARB group was observed a small, not significant greater reduction of SBP (P = 0.07) and DBP (P = 0.08) | DRI reduced mean UACR more effectively as compared to placebo (P < 0.001), with a reduction of ≥50% in 24.7% of the patients treated with DRI as compared with 12.5% of those who received placebo (P < 0.001). The mean rate of decline in eGFR during the study period was 2.4 mL/min×1.73 m2 in the DRI group and 3.8 mL/min×1.73 m2 in the placebo group (P = 0.07) | The total numbers of AE and serious AE were similar in the groups |
| Mann et al.32 (ONTARGET) (2008) | 25 620 pts ≥ 55 y with coronary, peripheral or cerebrovascular disease or diabetes with end‐organ damage; mean age 66 y, female 27%; eGFR < 60: 24%; MA: 13.1%; Macroalbuminuria: 4% | ARB (Telmisartan 80 mg) vs ACEi (Ramipril 10 mg) vs ARB (Telmisartan 80 mg) + ACEi (Ramipril 10 mg) | 4.7 y | Pts in the ARB group and the ACEi+ARB group had slightly lower BP throughout the study period than did patients in the R group | The incidence of the composite primary renal outcome (all cause death, doubling serum creatinine, ESRD) was similar with ARB and ACEi but increased with ARB+ACEi (ACEi+ARB vs ACEi HR 1.09, P = 0.037) | The incidence of acute dialysis was similar with ARB and ACEi but increased with ARB+ACEi (ACEi+ARB vs ACEi HR 2.19, P = 0.020) Renal abnormalities and reason for permanent stopping medication were similar with ARB and ACEi but increased with ARB+ACEi (ARB+ACEi vs ACEi RR 1.33, P < 0.0001 and RR 1.58, P < 0.0050). |
| The secondary renal endpoint (ESRD or doubling of serum creatinine) was similar with ARB and ACEi but was more frequent with ACEi+ARB (ACEi+ARB vs ACEi HR 1.24, P = 0.038) | ||||||
| Development of MA or macroalbuminuria was similar with ARB and ACEi, reduced with ACEi+ARB (ACEi+ARB vs ACEi HR 0.88, P = 0.003) | ||||||
| Mehdi et al.58(2009) | 81 pts with T2DM, Ht, and albuminuria (UACR ≥300 mg/g) in treatment with lisinopril (80 mg once daily); mean age 50 y, female 64% | ACEi (Lisinopril 80 mg) + placebo vs ACEi (lisinopril 80 mg) + ARB (losartan 100 mg) vs ACEi (lisinopril 80 mg) + ARA (spironolactone 25 mg) | 48 wk | Both 24‐h ambulatory SBP, clinical SBP and clinical DBP decreased significantly from the baseline at 24 and 48 wk in all three groups, but equally | Compared with ACEi+placebo, UACR decreased by 34.0% (P = 0.007) in the group ACEi+ARA and by 16.8% (P = 0.20) in the group ACEi+ARB | Serum potassium level was significantly higher with the addition of either ARA or ARB |
| Imai et al.59 (ORIENT) (2011) | 566 pts with T2DM and with overt nephropathy; mean age 69 y, female 31% | ARB (Olmesartan from 10 to 40 mg) + ACEi vs placebo+ACEi | 3.2 y | Time‐averaged differences of systolic and diastolic BP were greater in ARB+ACEi group compared to placebo+ACEi (P < 0.01) | There was no difference in the primary renal composite outcome (doubling of serum creatinine, ESRD and death) (ARB+ACEi vs placebo+ACEi HR 0.97 P = 0.791, after adjustement for BP HR 1.02; P = 0.852) | Hyperkalemia was more frequent in the ARB+ACEi group than the placebo+ACEi group (9.2% vs 5.3%) |
| Olmesartan ARB+ACEi significantly decreased proteinuria (P = 0.005) and rate of change of reciprocal serum creatinine | ||||||
| Parving et al.33 (ALTITUDE) (2012) | 8561 pts with T2DM at high cardiorenal risk; mean age 64 y, female 32%;eGFR < 60%:68%; MA: 25%; Macroalbuminuria: 58% | DRI (Aliskiren 150‐300 mg) vs placebo on top of optimal treatment with an ACEi or an ARB | Prematurely stopped after a median follow up of 33 mo | SBP and DBP were lower with DRI (between‐group differences, 1.3 and 0.6 mm Hg, respectively) | The incidence of renal composite outcome (ESRD, death attributable to kidney failure, or the need for RRT with no dialysis or transplantation available or initiated; or a serum creatinine value that was at least double the baseline value and that exceeded the upper limit of the normal range (>0.9 mg/dL in women and >1.2 mg/dL in men), sustained for at least a month) was similar in the two groups (HR 1.03, P = 0.74). There were no significant differences between study groups for any component of the renal outcome | Hyperkalemia was significantly higher in the DRI group than in the placebo group (11.2% vs 7.2%), as was the proportion with reported hypotension (12.1% vs 8.3%) (P < 0.001 for both comparisons) |
| Reduction in UACR was greater in DRI group (between‐group difference, 14%; 95% CI: 11‐17%) | ||||||
| Fried et al.34 (VA NEPHRON‐D) (2013) | 1448 pts with T2DM and proteinuric CKD (1‐3 stages); mean age 64 y, female 28%;eGFR<60: 62% | ARB (Losartan 100 mg) + ACEi (Lisinopril 10‐40 mg) vs ARB (Losartan 100 mg)+placebo | Prematurely stopped owing to safety concerns after a median follow‐up of 2.2 y | After adjustment of the ACEi or placebo dose, the ARB + ACEi had a slightly lower blood pressure than the ARB+placebo group (within 2 mm Hg) | The incidence of renal composite outcome (first occurrence of a change in the eGFR, ie a decline of ≥30 mL/min× 1.73 m2 if the initial eGFR was ≥60 mL/min× 1.73 m2 or a decline of ≥50% if the initial eGFR was <60 mL/min× 1.73 m2, ESRD, or death) was similar in the two groups (ARB+ACEi vs ARB+placebo HR 0.88, P = 0.30) | ARB+ACEi increased the risk of hyperkalemia (P < 0.001) and AKI (P < 0.001) |
| Torres et al.60 (HALT‐PKD) (2014) | 486 pts with autosomal dominant polycystic kidney disease with eGFR from 25 to 60 mL/min× 1.73 m2; mean age 48 y, female 52% | ACEi (lisinopril) + placebo vs ACEi (lisinopril) + an ARB (telmisartan), with the doses adjusted to achieve a BP of 110‐130/70‐80 mm Hg | 5.2 y | The two treatments controlled BP similarly | There was no significant difference between the study groups in the incidence of the composite primary outcome (death, ESRD, or a 50% reduction from the baseline eGFR) (HR with ACEi+ARB, 1.08; 95% confidence interval, 0.82‐1.42) | AE, including hyperkalemia and AKI, were similar in the two groups |
| Bakris et al.61 (ARTS‐DN) (2015) | 821 pts with T2DM and high or very high albuminuria who are receiving an ACEi or an ARB; mean age 64 y, female 22%UACR ≥300 mg/g: 36.7% eGFR ≤60: 40% | ARA (Finerenone from 1.25 to 25 mg) vs placebo on top of ACEi or an ARB | 90 d | Post hoc analysis showed that no significant correlation across all treatment groups between the ratio of UACR and the change in SBP | The primary outcome, the placebo‐corrected mean ratio of the UACR at day 90 relative to baseline, was reduced in the ARA groups respect to placebo (P < 0.01 for all comparisons) | Increases in serum potassium of at least 5.6 mmol/L, in 12 of 821 patients (1.5%), all of whom were receiving ARA, leading to subsequent discontinuation of study treatment |
| The incidences of a decrease in eGFR at least of 40% were similar in the placebo and ARA groups (all doses) and no occurrences of eGFR decreases of at least 57% | ||||||
| Retrospective cohort study | ||||||
| McAlister et al.62 (2011) | 32 312 elderly pts who were new users of an ACEi, an ARB or a combination of both medications between May 1, 2002, and Dec 31, 2006 | ACEi+ARB vs ACEi or ARB alone | 6 mo | NA | The primary composite outcome (doubling of serum creatinine or development of ESRD requiring dialysis or all‐cause death within 6 mo among new users of combination therapy vs monotherapy) was more common among patients given ACEi+ARB (5.2 events per 1000 pts per month) than among patients given monotherapy (2.4 events per 1000 pts per month), even after multivariable adjustment (adj.HR 2.36, 95% CI: 1.51‐3.71) | Hyperkalemia was more common among patients who received combination therapy than among patients who received monotherapy (adju. HR 2.42, 95% CI: 1.36‐4.32) |
| Meta‐analysis and systematic review | ||||||
| Kunz et al.63 (2008) | 571 pts with or without diabetes and with MA or proteinuria mean age 76 y eGFR ≤60:40.7% | ACEi+ARB vs ACEi or ARB alone | 1‐4 mo5‐12 mo | NA | ACEi+ARB therapy reduced proteinuria more effectively than either agent alone in the short term while in the long term this was true only in comparison with ARB | Many of the smaller studies did not provide reliable data on AE |
| Navaneethan et al.64 (2009) | Pts already on RAS inhibition therapy (ACEi or ARB) with CKD stages 1‐4 with albuminuria or proteinuria secondary to both diabetic and nondiabetic CKD. Seven trials (372 patients) compared non‐selective ARA+ACEi and/or ARB to ACEi and/or ARB alone | Adding non selective ARA (spironolactone from 25 to 50 mg) | Nonselective ARA along with ACEi and/or ARB significantly reduced SBP and DBP | In comparison to ACEi and/or ARB alone nonselective ARA + ACEi and/or ARB significantly reduced 24 h proteinuria without an improvement in GFR | There was a significant increase in the risk of hyperkalemia with the addition of nonselective ARA to ACEi and/or ARB (RR 3.06, 95% CI: 1.26, 7.41) | |
| Maione et al.65 (2011) | 4969 pts with albuminuria (MA or macroalbuminuria) and ≥1 cardiovascular risk factor | Combination therapy (ACEi+ARB) vs each monotherapy | NA | NA | There was no significant reduction in the risk of ESRD or doubling of serum creatinine with combined therapy (ACEI+ARB) when compared to each monotherapy but a significant reduction in the risk of progression from MA to macroalbuminuria (RR 0.80, 95% CI: 0.69‐0.92) and no significant reduction in the risk of regression from MA to normoalbuminuria | ACEi+ARB was associated with comparable AE rates, except for a higher risk of cough compared with ARB alone and a higher risk of hypotension compared with ACEI alone |
| Susantitaphong et al.66 (2013) | 4975 CKD patients with proteinuria or low eGFR (<60 mL/min×1.73 m2); mean age ranged from 25 to 66 y; eGFR < 60:48.5% | Combined (ACEI+ARB, ACEI or ARB+ARA, ACEI or ARB+DRI) vs. single RAS blockade (ACEI and ARB and ARA) | Ranged from 1 to 49 mo | Combined RAS blockade therapy was associated with absolute net decreases in SBP and DBP | Combined RAS blockade therapy was associated with a significant net decrease in eGFR (−1.8 mL/min×1.73 m2; P = 0.005), albuminuria (−90 mg/g of creatinine; P = 0.001), and proteinuria (−291 mg/g; P = 0.003). Combined RAS blockade therapy was associated with a 9.4% higher rate of regression to normoalbuminuria | Combined RAS blockade therapy was associated with a significant net increase in serum potassium level, a 3.4% higher rate of hyperkalemia, and a 4.6% higher rate of hypotension |
| Bolignano et al.67 (2014) | 596 pts with CKD stages 1‐4 with MA or proteinuria | ARA (both selective (eplerenone) and non‐selective (spironolactone)) alone or in combination with ACEi or ARB vs other anti‐hypertensive strategies or placebo | NA | There was a significant reduction in both SBP and DBP with additional non‐selective aldosterone antagonist therapy | Compared with ACEi or ARB (or both), non‐selective ARA (spironolactone) combined with ACEi or ARB (or both) significantly reduced 24‐h protein excretion. The effect on eGFR was uncertain (9 studies, 528 participants; MD −2.55 mL/min/1.73 m², 95% CI: −5.67 to 0.51) as compared to ACEi or ARB | Spironolactone + ACE or ARB (or both) doubled the risk of hyperkalaemia and increased the risk of gynaecomastia compared to ACEi or ARB (or both) |
| Palmer et al.68 (2015) | 43 256 adults with T2DM and kidney disease | Any orally administered blood pressure‐lowering agent alone or in combination vs a second blood pressure agent or combination, placebo, or control. | NA | ACEi+CCB treatment lowered DBP to a greater extent than did monotherapy with a CCB, ACE i, ARB, or β blocker | ESRD: ACEi+ARB was better than placebo (OR 0.77, 95% CI: 0.65‐0.92), CCB (OR 0.74, 95% CI: 0.56‐0.98) and DRI (OR 0.64, 95% CI: 0.44‐0.94). Doubling serum creatinine: ACEI+ARB was better than DRI and BB, similar to ACEi or ARB. Regression of albuminuria: ACEi+ARB was similar to ARB or ACEI alone | ACEi+ARB was associated with a borderline increases in estimated risks of hyperkaliemia (odds ratio 2.69, 95% CI: 0.97‐7.47) and AKI (OR 2.69, 0.98‐7.38) |
| Catalá‐López et al.69 (2016) | 69 380 adults with T2DM; mean age 60 y, female 49% | ACEi or ARB as monotherapy vs combination of RAS blockers (ACEi, ARB and DRI) | 3.2 y | NA | Progression of renal disease (doubling of serum creatinine + ESRD + all cause mortality) no RAS blockers combination was associated with any significant reduction of progression of renal disease respect to ACEi or ARB alone | |
ACEi, angiotensin converting enzyme inhibitors; Adj, adjusted; AE, adverse effects; AER, album excretion rate; AKI, acute kidney injury; ARA, aldosterone receptor antagonist; ARB, angiotensin receptor blockers; BP, blood pressure; CCB, calcium channel blockers; CV, cardiovascular; DBP, diastolic blood pressure; DRI, direct renin inhibitors; eGFR, estimated glomerular filtration rate; ESRD, end‐stage renal disease; Ht, hypertension; MA, microalbuminuria; NA, not available; pts, patients; RAS, renin angiotensin system; RRT, renal replacement therapy; SBP, systolic blood pressure; T2DM, type 2 diabetes mellitus; UACR, urinary albumin:creatinine ratio.