ACE inhibitors and angiotensin receptor blockers for progression of non-diabetic renal disease

Evidence Summaries

Level of Evidence = A
ACE inhibitors and angiotensin receptor blockers are more effective than other antihypertensive agents in reducing the development of end-stage non-diabetic renal disease.

A systematic review 1 including 10 RCTs with a total of 1,594 subjects was abstracted in DARE. All patients had non-diabetic renal disease of varying aetiology: hypertensive nephrosclerosis, glomerular disease, interstitial disease, polycystic kidney disease, and other causes. The mean age ranged from 44 years to 66 years. ACE inhibitors studied included enalapril, captopril, cilazepril and benazepril. Control groups received placebo, beta-adrenergic blockers, calcium channel blockers and unspecified combinations of anti-hypertensive agents. The weighted mean systolic blood pressure was 150–151 mmHg and the mean diastolic blood pressure was 92 mmHg in both groups. Decline in weighted mean systolic pressure was 4.9 mmHg greater and the decline in weighted mean diastolic pressure was 1.2 mmHg greater in the ACE inhibitor group as compared to the control groups. The odds ratio for pooled end-stage renal disease was 0.70 (95% CI 0.51 to 0.97). The pooled relative risk of death was 1.24 (95% CI 0.55 to 2.83). If the one study with a very high relative risk (RR = 7.55) was included, the RR of death in the remaining studies was 0.89 (95% CI 0.36 to 2.17).

Another systematic review 2 including 16 studies with a total of 2,031 subjects was abstracted in DARE. ACE inhibitors included: enalapril (5 to 40 mg); captopril (75 to 100 mg); lisinopril (10 to 100 mg); benazepril (10 mg); and ramipril (2.5 to 5 mg). Co-interventions included antihypertensive agents. Post therapy, the average mean arterial pressure was less in ACE inhibitor treated patients across all studies but one. ACE inhibitors significantly reduced the risk of macroalbuminuria, RR = 0.35 (95% CI: 0.24 to 0.53), and the risk of macroalbuminuria, RR = 0.60 (95% CI: 0.49 to 0.73). There was no significant difference in the mortality rate between treatment groups, RR = 1.05 (95% CI: 0.57 to 1.95)

A network meta-analysis 3 included 119 RCTS with a total of 64,768 CKD patients. ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB) reduced the odds of kidney failure by 39% and 30% (ORs of 0.61, 95% credible interval, 0.47 to 0.79 and 0.70, 95% credible interval, 0.52 to 0.89), respectively, compared to placebo, and by 35% and 25% (ORs of 0.65, 95% credible interval, 0.51 to 0.80 and 0.75, 95% credible interval, 0.54 to 0.97), respectively, compared with other active controls, whereas other active controls did not show evidence of a significant effect on kidney failure. Both ACEi and ARB produced odds reductions for major cardiovascular events (ORs of 0.82, 95% credible interval, 0.71 to 0.92 and 0.76, 95% credible interval, 0.62 to 0.89, respectively) versus placebo. Comparisons did not show significant effects on risk for cardiovascular death. ACEi but not ARB significantly reduced the odds of all-cause death versus active controls (OR, 0.72; 95% credible interval, 0.53 to 0.92). Compared with ARB, ACEi were consistently associated with higher probabilities of reducing kidney failure, cardiovascular death, or all-cause death.

A Cochrane review 4 included 6 open-label studies involving a total of 257 peritoneal dialysis (PD) patients. One study compared ACEi with other antihypertensive drugs, 3 compared angiotensin receptor blockers (ARB) with other antihypertensive drugs, and 2 studies compared an ARB with an ACEi. Long-term use (≥ 12 months) of an ARB showed significantly benefit of preserving residual kidney function in continuous ambulatory PD (CAPD) patients (MD 1.11 mL/min/1.73 m², 95% CI 0.38 to 1.83), although there was no significant benefit when an ARB were used short-term (≤ six months). One study showed that compared with other antihypertensive drugs, long-term use (12 months) of the ACEi ramipril showed a significant reduction in the decline of residual kidney function in patients on CAPD (MD -0.93 mL/min/1.73m², 95% CI -0.75 to -0.11), and delayed the progression to complete anuria (RR 0.64, 95% CI 0.41 to 0.99). There was no significant difference in serum potassium, urinary protein excretion, weekly creatinine clearance and blood pressure for ARBs versus other antihypertensive drugs. Compared with an ACEi, ARBs did not show any difference in residual kidney function.

Another meta-analysis 5 included 11 trials with a total of 1856 dialysis patients. Compared with placebo or other active agents groups, ARB therapy reduced the risk of heart failure events by 33% (RR 0.67, 95% CI 0.47 to 0.93) with similar decrement in blood pressure in dialysis patients. The results indicated no significant differences between the two treatment regimens with regard to frequency of myocardial infarction (1.0, 0.45 to 2.22), stroke (1.16, 0.69 to 1.96), cardiovascular death (0.89, 0.64 to 1.26) and all-cause mortality (0.94, 0.75 to 1.17). Five studies reported the renoprotective effect and revealed that ACEI/ARB therapy significantly slowed the rate of decline in both residual renal function (MD 0.93 mL/min/1.73 m2, 0.38 to 1.47 mL/min/1.73 m2) and urine volume (MD 167 ml, 95% CI 21 ml to 357 ml). No difference in drug-related adverse events was observed in both treatment groups.

Another meta-analysis 7 included 7 RCTs with 628 patients, ACEI/ARB + calcium channel blocker (CCB) did not show additional benefit for the incidence of ESRD (RR 0.84; 95% CI 0.52 to 1.33) and cardiovascular events (RR 0.58; 95% CI 0.21 to 1.63) significantly, compared with ACEI/ARB monotherapy. There were no significant differences in change from baseline to the end points in diastolic BP (weighted mean difference [WMD] = -1.28 mmHg; 95% CI -3.18 to -0.62), proteinuria (standard mean difference = -0.55; 95% CI: -1.41 to -0.30), GFR (WMD = -0.32 ml/min; 95% CI -1.53 to -0.89), and occurrence of adverse events (RR = 1.05; 95% CI: 0.72-1.53). However, ACEI/ARB + CCB showed a greater reduction in systolic BP (WMD = -4.46 mmHg; 95% CI -6.95 to -1.97), compared with ACEI/ARB monotherapy.

Another meta-analysis 6 included 8 RCTs with 25,647 patients, assessing renoprotective effect of ACEi or ARB or dihydropyridine CCB. ESRD showed significantly higher frequency with CCB therapy compared with ACEi or ARB, though blood pressure was decreased similarly in both groups in every trial (OR 1.25; 95% CI, 1.05 to1.48; p = 0.01). In contrast, there was no significant difference in the incidence of all-cause mortality between these two groups, though ACEi or ARB exhibited better renoprotective effect compared to CCB (OR, 0.96; 95% CI 0.89 to 1.03; p = 0.24).

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References

1. Giatras I, Lau J, Levey AS. Effect of angiotensin-converting enzyme inhibitors on the progression of nondiabetic renal disease: a meta-analysis of randomized trials. Angiotensin-Converting-Enzyme Inhibition and Progressive Renal Disease Study Group. Ann Intern Med 1997 Sep 1;127(5):337-45.  [PMID:9273824]

2. Kshirsagar AV, Joy MS, Hogan SL, Falk RJ, Colindres RE. Effect of ACE inhibitors in diabetic and nondiabetic chronic renal disease: a systematic overview of randomized placebo-controlled trials. Am J Kidney Dis 2000 Apr;35(4):695-707.  [PMID:10739792]

3. Xie X, Liu Y, Perkovic V et al. Renin-Angiotensin System Inhibitors and Kidney and Cardiovascular Outcomes in Patients With CKD: A Bayesian Network Meta-analysis of Randomized Clinical Trials. Am J Kidney Dis 2016;67(5):728-41.  [PMID:26597926]

4. Zhang L, Zeng X, Fu P et al. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for preserving residual kidney function in peritoneal dialysis patients. Cochrane Database Syst Rev 2014;(6):CD009120.  [PMID:24953826]

5. Liu Y, Ma X, Zheng J et al. Effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on cardiovascular events and residual renal function in dialysis patients: a meta-analysis of randomised controlled trials. BMC Nephrol 2017;18(1):206.  [PMID:28666408]

6. Zhao HJ, Li Y, Liu SM et al. Effect of calcium channels blockers and inhibitors of the renin-angiotensin system on renal outcomes and mortality in patients suffering from chronic kidney disease: systematic review and meta-analysis. Ren Fail 2016;38(6):849-56.  [PMID:27055479]

7. Huang RS, Cheng YM, Zeng XX et al. Renoprotective Effect of the Combination of Renin-angiotensin System Inhibitor and Calcium Channel Blocker in Patients with Hypertension and Chronic Kidney Disease. Chin Med J (Engl) 2016;129(5):562-9.  [PMID:26904991]


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