Table 7Summary of the evidencea

ComparisonNumber of trials, NStrength of the evidence (when NA, quality of individual studies)bConclusion
Key Question 1. What are the comparative effectiveness/efficacy and harms between aliskiren and placebo?
 1a. When used as monotherapy?
 1b. When used in combination with angiotensin converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (AIIRA) drugs?
DIABETIC NEPHROPATHY
Aliskiren plus losartan vs. losartan monotherapy1 trial, N=599NA, FairAs compared with losartan monotherapy, dual therapy with aliskiren plus losartan significantly reduced the mean urinary albumin-to-creatinine ratio by 18% after adjustment for SBP change (95% CI, 7 to 28). There was no significant difference between dual therapy and monotherapy on mean rate of change in eGFR (−1.4 vs. −3.8; P=0.07). There were no significant differences between dual therapy and losartan monotherapy in overall withdrawals (14% vs. 11%), overall adverse events (66.8% vs. 67.1%), withdrawals due to adverse events (5.6% vs. 6.4%), or for any individual adverse events.
HEART FAILURE
Aliskirin compared with placebo (combination therapy with ACE-I or ARB)1 trial, N=302NA, FairIn patients with heart failure and hypertension on an ACE-I or an ARB, there was no significant difference in serum creatinine or discontinuation rates between aliskiren and placebo after 3 months.
Key Question 2. What are the inter-class comparative effectiveness/efficacy between DRI, AIIRAs and ACE-Is?
 2a. When used as monotherapy
 2b. When used in combination with one another
HEART FAILURE AND CARDIOVASCULAR DISEASE (HF and CVD): Monotherapy and combination therapy
HF and CVD: Mortality and composite outcomes including mortality
Candesartan vs. enalapril vs. combinationHeart failure
1 trial (RESOLVD)
N=768
NA
Study quality:
Fair
Overall summary
Monotherapy: AIIRA not inferior to ACE-I (2 trials); AIIRA similar to ACE-I for primary composite outcomes or for mortality (5 trials); earlier ELITE trial reported benefit for losartan vs. captopril for sudden cardiac death.
Combination therapy: AIIRA similar to ACE-I (3 trials)
Specific comparisons
Candesartan vs. enalapril: NSD among groups for rates of death. 43-week follow-up (trial stopped early).
Irbesartan vs. ramipril: NSD in deaths.
Losartan vs. captopril: In the earlier trial (ELITE), death and/or heart failure admissions were decreased with losartan (P=0.075), primarily due to decrease in sudden cardiac deaths. Subsequent 2 trials did not substantiate this difference. In all 3 trials there was NSD between groups in all-cause mortality at follow-up to 2.7 years. Cardiovascular death was more common with losartan than captopril (P=0.032) in OPTIMAAL.
Telmisartan not inferior to ramipril for primary composite outcome (death from cardiovascular causes, MI, stroke, or hospitalization for HF). Combination therapy: NSD from ramipril alone for the primary outcome.
Valsartan vs. captopril: NSD in death rates between monotherapies or between combination therapy and captopril; valsartan not inferior to captopril for mortality (P=0.004) and for composite endpoint of fatal and nonfatal CV events (P<0.001).
Irbesartan vs. ramipril (monotherapy combined with diuretic)Heart failure
1 trial
N=150
NA

Study quality:
Fair
Losartan vs. captopril (monotherapy)Heart failure: ELITE and ELITE II
Acute MI with HF or new Q-wave anterior wall MI: OPTIMAAL
3 trials
N=9351
GRADE:
All-cause mortality, CV deaths, sudden death, CVD events: moderate
Telmisartan vs. ramipril vs. combinationVascular disease or diabetes with end- organ damage but without symptomatic heart failure
1 trial (ONTARGET)
N=25620
NA
Study quality:
good
Valsartan vs. captopril vs. combinationRecent, acute MI complicated by HF or evidence of LVSD
1 trial (VALIANT)
N=14703
NA
Study quality:
good
HF and CVD: Renal
Candesartan vs. enalapril vs. combinationHeart failure
1 trial (RESOLVD)
N=768
NA
Study quality:
Fair
Overall summary
Monotherapy: AIIRA are not significantly different from ACE-I (2 trials)
Combination therapy: renal outcomes significantly worse than ACE-I or AIIRA alone (1 study)
Specific comparisons
Candesartan vs. enalapril: NSD among groups in renal dysfunction at 43-week follow-up (trial stopped early).
Telmisartan vs. ramipril: For the primary renal composite outcome (dialysis, doubling of creatinine, or death) event rates were similar. Composite outcome increased with combination therapy (P=0.037).
Telmisartan vs. ramipril vs. combinationVascular disease or diabetes with end- organ damage but without symptomatic heart failure
1 trial (ONTARGET)
N=25620
NA
Study quality:
good
Candesartan vs. enalapril vs. combinationHeart failure
1 trial (RESOLVD)
N=768
NA
Study quality:
Fair
HF and CVD: Quality of life, symptoms, hospitalizations
Candesartan vs. enalapril vs. combinationHeart failure
1 trial (RESOLVD)
N=768
NA
Study quality:
Fair
Overall summary
AIIRA drugs are not significantly different from, nor are they inferior to, ACE-I drugs for quality of life (8 studies), exercise capacity or symptoms (3 studies), hospital admissions for heart failure (8 studies). No benefit for combination therapy (1 study).
Specific comparisons
Candesartan vs. enalapril: NSD among groups for the 6-minute walk test; NYHA classification; rates heart failure or other hospitalizations; quality of life at 43-week follow-up (trial stopped early).
Irbesartan vs. ramipril: NSD in quality of life or rates of hospitalization.
Losartan vs. captopril: NSD between groups in any outcome, including total hospital admissions, admissions for heart failure, or health related quality of life at follow-up to 2.7 years.
Losartan vs. enalapril: Exercise capacity improved with both losartan and enalapril monotherapy, with NSD groups (2 studies). Effect on HF symptoms inconsistent (2 studies). Quality of life: no significant improvement with monotherapy or combination therapy vs. placebo (1 study).
Telmisartan vs. enalapril: NSD within or between treatments with continuation of enalapril vs. switching to telmisartan at 12 weeks of follow-up for exercise duration, NYHA classification, or quality of life.
Telmisartan vs. ramipril: Telmisartan not inferior to ramipril for admissions for heart failure; combination therapy not significantly different from ramipril for heart failure admissions.
Valsartan was not inferior to enalapril in exercise capacity at 12-weeks follow-up. Quality of life and symptom assessment were similar between groups.
Valsartan vs. captopril: NSD in quality of life and hospitalization rates among the treatment groups.
Irbesartan vs. ramipril (monotherapy combined with diuretic)Heart failure
1 trial
N=150
NA
Study quality:
Fair
Losartan vs. captopril (monotherapy)Heart failure: ELITE and ELITE II
Acute MI with HF or new Q-wave anterior wall MI:
OPTIMAAL
3 trials
N=9351
GRADE:
hospital admissions: moderate
NYHA class, quality of life:
high
Losartan vs. enalapril (monotherapy and combination therapyHeart failure
Monotherapy: 3 trials (+ 2 poor quality), combination therapy: 1 trial
N=302 (excluding poor quality studies)
GRADE: Quality of life and exercise capacity: low
Telmisartan vs. enalapril (monotherapy plus diuretic)Heart failure
1 trial (REPLACE)
N=378
NA
Study quality: fair
Telmisartan vs. ramipril vs. combinationVascular disease or diabetes with end- organ damage but without symptomatic heart failure
1 trial (ONTARGET)
N=25620
NA
Study quality:
good
Valsartan vs. captopril vs. combinationRecent, acute MI complicated by HF or evidence of LVSD
1 trial (VALIANT)
N=14703
NA
Study quality:
good
Valsartan vs. enalapril (monotherapy)Heart failure
1 trial (HEAVEN)
N=141
NA
Study quality: fair
HYPERTENSION: Monotherapy
Hypertension-monotherapy: Mortality
Eprosartan vs. enalapril2 trials, N=853LowOnly reported in 8 (N=3492) of 22 trials. None were powered to measure all-cause mortality as a primary outcome. No deaths were reported for valsartan or ramipril groups over12 months in the longest-term trial (N=369). Event rates ranged from 0% to 2% in the shorter-term trials, with most trials reporting no events, and there were no significant differences between AIIRA and ACEI in any trial.
Valsartan vs. lisinopril2 trials, N=1346Moderate
Losartan vs. fosinopril1 trial, N=33NA, (Good=1, Fair=4)
Valsartan vs. benazepril1 trial, N=90
Valsartan vs. ramipril1 trial, N=369
Telmisartan vs. ramipril1 trial, N=801
Hypertension-monotherapy: CV events
Valsartan vs. ramipril1 trial, N=369NA (Fair=1)Atrial fibrillation recurrence was significantly lower for valsartan (16%) vs. ramipril (28%), P<0.05.
Hypertension-monotherapy: Change in renal function (serum creatinine, creatinine clearance, GFR, albumin)
Losartan vs. enalapril3 trials, N=486Low11 trials (N=1506) did not consistently demonstrate significant differences related to renal function for AIIRAs vs. ACE-Is. In the only trial (N=50) that reported GFR, increases were 12% for losartan and 5% for enalapril over 3 years (statistical analysis not reported). For serum creatinine, changes were consistently minimal (−3% to +8%) across 7 short-terms trials that ranged in duration from 3 to 6 months. For creatinine clearance, changes were minimal in 2 trials (N=80) in adults without additional risk factors, but were larger for losartan and fosinopril in a trial in participants with comorbid diabetes (−34% vs. −17%). For albumin, 6 trials (N=539) did not consistently demonstrate significant differences between AIIRA and ACEI comparators
Losartan vs. captopril1 trial, N=396NA (Good=1, Fair=7)
Losartan vs. fosinopril1 trial, N=33
Losartan vs. perindopril1 trial, N=85
Losartan vs. ramipril1 trial, N=51
Candesartan vs. perindopril1 trial, N=96
Candesartan vs. lisinopril1 trial, N=70
Valsartan vs. benazepril1 trial, N=156
Valsartan vs. lisinopril1 trial, N=133
Hypertension-monotherapy: Quality of life
Candesartan vs. enalapril2 trials, N=585Low5 trials (N=1095) did not consistently demonstrate significant differences related to quality of life for AIIRAs vs. ACE-Is
Candesartan vs. perindopril1 trial, N=96NA (Fair=3)
Eprosartan vs. enalapril1 trial, N=136
Telmisartan vs. enalapril1 trial, N=278
Hypertension-monotherapy: Overall withdrawals
Eprosartan vs. enalapril3 trials, N=999ModerateIn 12 trials (N=4756), overall withdrawal rates ranged from 4% to 19% for AIIRAs and from4% to 25% for ACE-Is and differences were consistently nonsignificant.
Valsartan vs. lisinopril2 trials, N=1346High
Candesartan vs. lisinopril1 trial, N=70NA (Good=1 trial, Fair=7 trials)
Losartan vs. captopril1 trial, N=396
Losartan vs. enalapril1 trial, N=407
Telmisartan vs. enalapril1 trial, N=278
Telmisartan vs. ramipril1 trial, N=801
Valsartan vs. benazepril1 trial, N=90
Valsartan vs. ramipril1 trial, N=369
HYPERTENSION: Combination therapy
Hypertension-Combination Therapy: Change in microalbuminuria
Valsartan-plus-benazepril vs. valsartan or benazepril monotherapies1 trial, N=90NA (Good=1 trial, Fair=2 trials)Significantly greater reduction with AIIRA/ACE- I combination therapy than with ACE-I monotherapy in 3 of 3 trials. Compared with AIIRA monotherapies, significantly greater reduction with valsartan/benazepril and losartan/ramipril, but not valsartan/lisinopril combination therapy.
Losartan-plus-ramipril vs. losartan and ramipril monotherapies1 trial, N=51
Valsartan-plus-lisinopril vs. valsartan or lisinopril monotherapies1 trial, N=133
NONDIABETIC PROTEINURIA AND CHRONIC KIDNEY DISEASE (CKD)-Monotherapy
Nondiabetic proteinuria/CKD-Monotherapy: Composite renal endpoint
Benazepril vs. losartan1 trialNA grade; Good qualityDifferences in the risk of progression to composite renal endpoint were not found.
Nondiabetic proteinuria/CKD-Monotherapy: Reduction in proteinuria
Lisinopril vs. losartan1 trial, N=10NA grade; Fair quality10 of 14 trials did not find a difference between ACEI and AIIRA in the reduction of proteinuria. 8 of these trials provided statistical analysis, and 6 of those trials with analysis found p values not significant between ACEI and AIIRA for reduction in proteinuria. The 2 trials that showed a difference had P values of 0.05 and0.02 favoring ACEI for proteinuria reduction. Among the 6 trials without statistical analysis, 4 showed similar percent reductions in proteinuria for ACEI (ranging from 13–60% reduction) and AIIRA (ranging from 25% to48% reduction). 3 of 14 trials did not demonstrate equivalent blood pressure control between groups.
Enalapril vs. losartan3 trials, N=145LOW grade
Benazepril vs. losartan2 trials, N=390LOW grade
Ramipril vs. valsartan2 trials, N=98LOW grade
Enalapril vs. telmisartan1 trial, N=71NA grade; Fair quality
Trandolapril vs. losartan1 trials, N=62NA grade; Fair quality
Trandolapril vs. Candesartan1 trial, N=62NA grade; Fair quality
Perindopril vs. losartan vs. Candesartan1 trial, N=62NA grade; Fair quality
Lisinopril vs. candesartan1 trial, N=46NA grade; Fair quality
Benazepril vs. valsartan2 trials, N=60LOW grade
Fosinopril vs. irbesartan1 trial, N=11NA grade; Fair quality
Nondiabetic proteinuria/CKD-Monotherapy: Change in renal function (including CrCl, creatinine, and GFR)
Lisinopril vs. losartan1 trial, N=10 (CrCl)NA grade; Fair quality14 trials examined measures of renal function and found either no significant difference between treatment groups, or no significant change in these values overall during the study compared to baseline within groups. 12 of the 14 reported CrCl, 2 reported creatinine, and 3 reported GFR – several trials reported 2 methods of renal assessment. 7 of these 14 trials did analysis to examine differences in measures of renal function between treatment groups, and found no significant difference in change in renal function for ACEI vs. AIIRA. The remaining 7 trials reported no significant change from baseline to end of study in measures of renal function for either treatment group.
Enalapril vs. losartan3 trials, N=145 (all CrCl)VERY LOW
Benazepril vs. losartan2 trials, N=390 (CrCl both trials, 1 trial also GFR, 1 trial also creatinine)LOW
Perindopril or trandolapril vs. candesartan or losartan1 trial, N=62 (CrCl)NA grade; Fair quality
Lisinopril vs. candesartan1 trial, N=46 (CrCl)NA grade; Fair quality
Lisinopril vs. valsartan1 trial, N=37 (GFR)NA grade; Fair quality
Benazepril vs. valsartan1 trial, N=24 (CrCl)NA grade; Fair quality
Ramipril vs. valsartan2 trials, N=98 (one trial used CrCl and creatinine, the other used GFR )LOW
Enalapril vs. telmisartan1 trial, N=71 (CrCl)NA grade; Fair quality
Fosinopril vs. irbesartan1 trial, N=11 (CrCl)NA grade; Fair quality
NONDIABETIC PROTEINURIA AND CHRONIC KIDNEY DISEASE (CKD)-Combination Therapy
Nondiabetic proteinuria/CKD-Combination Therapy: Composite renal endpoint
Candesartan and benazepril vs. candesartan alone
(Renal survival endpoint)
1 trial, N=86NA grade; Fair qualityNo significant difference was noted between treatment groups for renal survival endpoint, but no participants reached threshold for renal survival endpoint in either group. No significant difference was noted between treatment groups for acute renal dysfunction endpoint, but no participants in either group experienced an acute renal dysfunction event
Valsartan and benazepril vs. valsartan alone
(Acute renal dysfunction endpoint)
1 trial, N=109NA grade; Fair quality
Nondiabetic proteinuria/CKD-Combination Therapy: Reduction in proteinuria
Lisinopril with losartan1 trial, N=10NA grade; Fair quality11 of 16 trials found greater proteinuria reduction with combination therapy vs. monotherapy, all of which reported statistical analysis. 10 trials compared combination therapy of ACEI and AIIRA vs. monotherapy; 9 of these trials showed significantly greater reduction in proteinuria with combination therapy. 6 trials compared combination therapy of ACEI and AIIRA vs. ACEI or AIIRA, 4 of which favored combination therapy for proteinuria reduction. 10 of these 16 trials demonstrated equivalent blood pressure control between treatment groups.
Enalapril with losartan2 trials, N=105LOW grade
Benazepril with losartan2 trials, N=60LOW grade
Lisinopril with candesartan1 trial, N=46NA grade; Fair quality
Benazepril with valsartan2 trials, N=60VERY LOW grade
Fosinopril with Irbesartan1 trial, N=11NA grade; Fair quality
Ramipril with valsartan1 trial, N=18NA grade; Fair quality
Lisinopril with losartan vs. Lisinopril1 trial, N=17NA grade; Fair quality
Ramipril with candesartan vs. ramipril2 trials, N=77LOW grade
Ramipril with Irbesartan vs. ramipril1 trial, N=41NA grade; Fair quality
Benazepril with candesartan vs. candesartan1 trial, N=86NA grade; Fair quality
Benazepril with valsartan vs. valsartan1 trial, N=109NA grade; Fair quality
Nondiabetic proteinuria/CKD-Combination Therapy: Change in renal function (including CrCl, creatinine, and GFR)
Lisinopril with losartan1 trial, N=10 (CrCl)NA grade; Fair quality16 trials evaluated renal function in the setting of combination ACEI/AIIRA vs. monotherapy, 14 of which reported statistical analysis. 12 of those 14 trials noted no significant difference in renal function measures between treatment groups. 11 of 14 trials using CrCl reported no statistical difference between groups; the remaining 3 trials showed no significant change from baseline (1) or reported that CrCl values stayed “stable among all groups” (2). 2 of 3 trials reporting GFR showed no significant differences between groups, and 1 showed GFR increased statistically more in the group receiving combination therapy (p=0.017). The single trial using creatinine reported no significant difference between treatment groups.
Enalapril with losartan2 trials, N=105 (both CrCl)LOW grade
Benazepril with losartan2 trials, N=60 (both CrCl)LOW grade
Lisinopril with candesartan1 trial, N=46 (CrCl)NA grade; Fair quality
Benazepril with valsartan2 trials, N=60 (Both CrCl, 1 also GFR)VERY LOW grade
Fosinopril with irbesartan1 trial, N=11 (CrCl)NA grade; Fair quality
Ramipril with valsartan1 trial, N=18 (CrCl)NA grade; Fair quality
Lisinopril with losartan vs. Lisinopril1 trial, N=17 (CrCl and GFR)NA grade; Fair quality
Ramipril with candesartan vs. ramipril2 trials, N=77 (both CrCl)LOW grade
Ramipril with irbesartan vs. ramipril1 trial, N=41 (CrCl)NA grade; Fair quality
Benazepril with candesartan vs. candesartan1 trial, N=86 (GFR)NA grade; Fair quality
Benazepril with valsartan vs. valsartan1 trial, N=109 (creatinine)NA grade; Fair quality
DIABETIC NEPHROPATHY-Monotherapy
Diabetic nephropathy-Monotherapy: Mortality and other CV events
Telmisartan vs. enalapril1 trial, N=250NA, both fair quality2 trials found no significant differences between AIIRAs and ACE-Is. No deaths or CV events occurred in the trial of losartan vs. enalapril. In the trial of telmisartan vs. enalapril, rates were 5% in both groups for mortality, 2.5% vs. 1.5% for CV death, 7.5% vs. 4.6% for nonfatal MI, 7.5% vs. 5.4% for congestive HF, 5% vs. 4.6% for cerebrovascular accident and 0% in both groups for kidney failure/required dialysis
Losartan vs. enalapril1 trial, N=24
Diabetic nephropathy-Monotherapy: Renal changes
Losartan vs. enalapril3 trials, N=143Low8 trials (N=517) consistently found no significant differences between AIIRAs and ACE-Is related to changes in GFR (4 trials, N=389), serum creatinine (6 trials, N=390), or creatinine clearance (2 trials, N=45) For GFR, changes were largest in the longest-term trial of 5 years’ duration (−19.6% for telmisartan and −15.8% for enalapril. Overall, changes in GFR ranged from +2.2% to −19.6% for AIIRAs and ranged from +6.6% to −15.8% for ACE-Is.
Candesartan vs. ramipril1 trial, N=21NA, All Fair
Losartan vs. quinapril1 trial, N=41
Telmisartan vs. enalapril1 trial, N=250
Valsartan vs. benazepril1 trial, N=20
Valsartan vs. enalapril1 trial, N=42
Diabetic nephropathy-Monotherapy: Albuminuria
Losartan vs. enalapril3 trials, N=74LowNo significant differences between AIIRAs and ACE-Is related to changes in albumin levels were found in 7 of 8 trials (N=395). The only significant difference was found in the shortest-term trial (4 weeks), in which the reduction of albuminuria (mg/g) was greater for losartan vs. quinapril (−93 vs. −49; P=0.025). But, although linear regression showed independence from differences in effects on SBP, association with differences in DBP were not analyzed.
Candesartan vs. lisinopril1 trial, N=197NA, All Fair
Candesartan vs. ramipril1 trial, N=21
Losartan vs. quinapril1 trial, N=41
Valsartan vs. benazepril1 trial, N=20
Valsartan vs. enalapril1 trial, N=42
Diabetic nephropathy-Monotherapy: Proteinuria
Candesartan vs. ramipril1 trial, N=21NA, FairNo significant difference in reduction of proteinuria (19.5% vs. −14.6% g/24 hrs).
Diabetic nephropathy-Monotherapy: Overall Withdrawals
Losartan vs. enalapril3 trials, N=143Low7 trials (N=443) consistently found no significant differences between AIIRAs and ACE-Is. Withdrawal rates ranged from 0% to 26% for AIIRAs and ranged from 0% to 28% for ACE-Is.
Candesartan vs. lisinopril1 trial, N=197NA, All Fair
Losartan vs. quinapril1 trial, N=41
Valsartan vs. benazepril1 trial, N=20
Valsartan vs. enalapril1 trial, N=42
Renal outcomes (GFR, serum creatinine, creatinine clearance)
Candesartan+ramipril vs. candesartan or ramipril monotherapies1 trial, N=21NA (Good=1, Fair=4)5 trials (N=287) consistently found no significant advantages for combination therapy related to renal function.
Candesartan+lisinopril vs. candesartan or lisinopril monotherapy1 trial, N=197
Irbesartan+enalapril vs. enalapril monotherapy1 trial, N=23
Losartan+enalapril vs. doubled enalapril1 trial, N=26
Valsartan+benazepril vs. valsartan or benazepril monotherapy1 trial, N=20
DIABETIC NEPHROPATHY-COMBINATION THERAPY
Diabetic nephropathy-combination therapy: Albumin/Protein
Losartan+enalapril vs. doubled enalapril1 trial, N=26NA (Good=1, Fair=5)Albuminuria: Rate of regression from microalbuminuria to normo albuminuria was reported in 1 trial (N=20) and there was no significant difference between combination therapy with valsartan+benazepril (70%) vs. valsartan monotherapy (67%) or benazepril monotherapy (83%). Otherwise, 4 of 5 trials (n=287) found a significant advantage for combination therapy in mean reduction of albuminuria. But, in only 1 (N=20) of those trials was the additional reduction in mean albuminuria (mg/24h) for valsartan+benazepril (43%) found to be independent of arterial change when compared to benazepril monotherapy.
Proteinuria: In the only trial (N=21) that reported this outcome, 24-h urinary protein excretion was significantly lower with candesartan+ramipril (2.9) compared with candesartan (3.3) and ramipril (3.5) monotherapies.
Losartan+enalapril vs. losartan or enalapril monotherapy1 trial, N=34
Valsartan+benazepril vs. valsartan or benazepril monotherapy1 trial, N=20
Irbesartan+enalapril vs. enalapril monotherapy1 trial, N=23
Candesartan+lisinopril vs. candesartan or lisinopril monotherapy1 trial, N=197
Candesartan+ramipril vs. candesartan or ramipril monotherapies1 trial, N=21
Diabetic nephropathy-combination therapy: Overall Withdrawals
Valsartan+benazepril vs. valsartan or benazepril monotherapy1 trial, N=203 trials (N=240) consistently found no differences in rates of overall withdrawals for combination therapy (range, 0% to 27%) vs. monotherapy (range, 0% to 28%)
Irbesartan+enalapril vs. enalapril monotherapy1 trial, N=23
Candesartan+lisinopril vs. candesartan or lisinopril monotherapy1 trial, N=197
Key Question 3. What are the inter-class comparative harms between DRI, AIIRAs and ACE-Is?
 3a. When used as monotherapy
 3b. When used in combination with one another?
HEART FAILURE AND CARDIOVASCULAR DISEASE: Monotherapy and combination therapy
Candesartan vs. enalapril vs. combinationHeart failure
1 trial (RESOLVD)
N=768
NA
Study quality: Fair
Overall summary
Rates of cough and withdrawal were generally less with ARBs than ACE. Hypotension was more common with combination therapy.
Specific comparisons
Captopril vs. enalapril vs. combination: NSD symptomatic hypotension.
Irbesartan vs. ramipril: No data on adverse events.
Losartan vs. captopril: Withdrawals (total, due to adverse events, and due to cough) were significantly lower with losartan than captopril (3 studies). Hypotension not different between the 2 groups (2 studies).
Losartan vs. enalapril: Data were sparse on AEs; minor increases in blood urea nitrogen, creatinine, and potassium (2 studies). Cough similar between drugs (1 study).
Telmisartan vs. enalapril: Adverse event rates including cough were similar between telmisartan and enalapril.
Telmisartan vs. ramipril: Permanent discontinuation was more common with ramipril as monotherapy or as combination therapy due to cough or angioedema than telmisartan monotherapy. More subjects stopped telmisartan due to hypotension symptoms than ramipril. Discontinuation due to hypotension, syncope, diarrhea, or renal impairment was more likely to occur with combination therapy than with ramipril monotherapy (P<0.05).
Valsartan vs. captopril: Discontinuation rates were higher with combination therapy than with captopril alone (P=0.007).
Hypotension and renal disease were more common reasons for therapy discontinuation with combination therapy than with captopril (P≤0.05). Cough was a more common reason with captopril monotherapy (P<0.05).
Valsartan vs. enalapril: The rate of overall adverse events was similar between groups.
Irbesartan vs. ramipril (monotherapy combined with diuretic)Heart failure
1 trial
N=150
Study quality: Fair
NA
Losartan vs. captopril (monotherapy)Heart failure: ELITE and ELITE II
Acute MI with HF or new Q-wave anterior wall MI:
OPTIMAAL
3 trials
N=9351
NA
Study quality: fair 2, good 1
Losartan vs. enalapril vs. combinationHeart failure
Monotherapy: 3 trials (+ 2 poor quality), combination therapy: 1 trial
N=302 (excluding poor quality studies)
NA
Study quality: fair 2, fair-poor 1 (poor 2)
Telmisartan vs. enalapril (monotherapy plus diuretic)Heart failure
1 trial (REPLACE)
N=378
NA
Study quality: fair
Telmisartan vs. ramipril vs. combinationVascular disease or diabetes with end-organ damage but without symptomatic heart failure
1 trial (ONTARGET)
N=25620
NA
Study quality: good
Valsartan vs. captopril vs. combinationRecent, acute MI complicated by HF or evidence of LVSD
1 trial (VALIANT)
N=14703
NA
Study quality: good
Valsartan vs. enalapril (monotherapy)Heart failure
1 trial (HEAVEN)
N=141
NA
Study quality: fair
HYPERTENSION: Monotherapy
Hypertension-Monotherapy: Overall adverse events
Eprosartan vs. enalapril2 trials, N=863LowIn 10 trials (N=4616), overall adverse event rates ranged widely; from 5% to 76% for AIIRAs and from 6% to 81% for ACE-Is. Rates were generally lower for AIIRAs, but differences were only significant in the 3 shortest-term trials (3 to 4 months).
Valsartan vs. lisinopril2 trials, N=1346Low
Candesartan vs. enalapril1 trial, N=429NA (All fair quality)
Candesartan vs. perindopril1 trial, N=96
Losartan vs. captopril1 trial, N=396
Losartan vs. enalapril1 trial, N=407
Telmisartan vs. enalapril1 trial, N=278
Telmisartan vs. ramipril1 trial, N=801
Hypertension-Monotherapy: Cough
Candesartan vs. enalapril2 trials, N=585ModerateIn 14 trials (N=4987), rates of cough-related adverse events were generally lower for AIIRAs (range, 0% to 35%) compared with ACE-Is (range, 4% to 68%). Differences were statistically significant in favor of AIIRAs in 9 of 14 trials. Lack of statistical significance was likely due to small sample sizes in 4 of the other 5 trials.
Eprosartan vs. enalapril3 trials, N=999High
Losartan vs. enalapril3 trials, N=486Low
Valsartan vs. lisinopril2 trials, N=1346Low
Candesartan vs. perindopril1 trial, N=96NA (All fair quality)
Losartan vs. captopril1 trial, N=396
Telmisartan vs. enalapril1 trial, N=278
Telmisartan vs. ramipril1 trial, N=801
Hypertension-Monotherapy: Withdrawals due to adverse events
Eprosartan vs. enalapril2 trials, N=665ModerateIn 14 trials (N=4724), rates of withdrawals due to adverse events were generally similar for AIIRAs and ACE-Is, ranging from 0% to 12% in both drug groups. One exception, however, was that in the largest trial (N=1213), and the only trial rated good quality, rates were significantly lower for valsartan vs. lisinopril (1% vs. 4%, P=0.01).
Losartan vs. enalapril2 trials, N=457Moderate
Valsartan vs. lisinopril2 trials, N=1346Low
Candesartan vs. enalapril1 trial, N=156NA (All fair quality)
Candesartan vs. lisinopril1 trial, N=70
Candesartan vs. perindopril1 trial, N=96
Losartan vs. captopril1 trial, N=396
Telmisartan vs. enalapril1 trial, N=278
Telmisartan vs. ramipril1 trial, N=801
Valsartan vs. benazepril1 trial, N=90
Valsartan vs. ramipril1 trial, N=369
HYPERTENSION: COMBINATION THERAPY
Valsartan-plus-benazepril vs. valsartan or benazepril monotherapies1 trial, N=90NA (Good=1 trial, Fair=2 trials)None of the trials reported any significant differences between AIIRA/ACE-I combination therapy groups and the AIIRA or ACE-I monotherapy groups.
Losartan-plus-ramipril vs. losartan and ramipril monotherapies1 trial, N=51
Valsartan-plus-lisinopril vs. losartan and lisinopril monotherapies1 trial, N=133
NONDIABETIC PROTEINURIA/CKD: MONOTHERAPYc
Nondiabetic proteinuria/CKD-monotherapy: Cough
Benazepril vs. losartan1 trial, N=360NA grade; Good quality1 of 3 trials found statistically greater incidence of cough in those treated with ACEI. Of the 2 remaining studies, 1 found no cough with use of either agent, and 1 found a rate of cough of 4% for those on ACEI vs. zero for those on AIIRA.
Enalapril vs. telmisartan1 trial, N=71NA grade; Fair quality
Fosinopril vs. irbesartan1 trial, N=11NA grade; Fair quality
Nondiabetic proteinuria/CKD-monotherapy: Hyperkalemia
Lisinopril vs. losartan1 trial, N=10NA grade; Fair quality3 of 5 trials found greater incidence of hyperkalemia in those treated with ACEI vs. AIIRA. One of these trials provided statistical analysis to support this difference. Among trials that reported overall numbers of events, rates of hyperkalemia for ACE ranged from 4–22% and for AIIRA ranged from 4% to 11%.
Benazepril vs. losartan1 trial, N=360NA grade; Good quality
Lisinopril vs. candesartan1 trial, N=46NA grade; Fair quality
Benazepril vs. valsartan1 trial, N=24NA grade; Fair quality
Fosinopril vs. irbesartan1 trial, N=11NA grade; Fair quality
Nondiabetic proteinuria/CKD-monotherapy: Acute kidney injury
Benazepril vs. losartan1 trial, N=360NA grade; Good quality2 of 3 trials reported higher numerical rates for those on ACEI vs. AIIRA, no statistical analyses performed. Using absolute numbers of events, the rate of AKI for those on ACE ranged from 2.8% to18%, and for those on AIIRA was 3.3%.
Enalapril vs. telmisartan1 trial, N=71NA grade; Fair quality
Fosinopril vs. irbesartan1 trial, N=11NA grade; Fair quality
NONDIABETIC PROTEINURIA/CKD: Combination Therapyc
Nondiabetic proteinuria/CKD-combination therapy: Dizziness/light-headedness
Lisinopril with losartan1 trial, N=10NA grade; Fair quality2 of 4 trials reporting rates of dizziness or lightheadedness between treatment groups noted higher rates of dizziness/light-headedness with combination vs. monotherapy % to 20% with combination therapy vs. 0% to 10% with monotherapy). One trial noted no difference in rates of dizziness/lightheadedness between treatment groups. One larger trial (N=109) reported similar rates of dizziness/lightheadedness between treatment groups (4.5% to 6.8%). Statistical analysis was not provided.
Fosinopril with irbesartan1 trial, N=11NA grade; Fair quality
Ramipril with irbesartan vs. ramipril1 trial, N=41NA grade; Fair quality
Benazepril with valsartan vs. valsartan1 trial, N=109NA grade; Fair quality
Nondiabetic proteinuria/CKD-combination therapy: Hyperkalemia
Lisinopril with losartan1 trial, N=10NA grade; Fair quality4 of 6 trials reporting rates of hyperkalemia between treatment groups noted higher rates of hyperkalemia with combination vs. monotherapy (10% to 20% with combination vs. 0% to 10% with monotherapy). One small trial (N=24) found no difference in rates of hyperkalemia between treatment groups, and 1 found higher rates of hyperkalemia with ACEI (ramipril) vs. AIIRA (irbesartan) (trial with N=46). Statistical analysis was not provided.
Fosinopril with irbesartan1 trial, N=11NA grade; Fair quality
Lisinopril with candesartan1 trial, N=46NA grade; Fair quality
Benazepril and valsartan1 trial, N=24NA grade; Fair quality
Ramipril with irbesartan vs. ramipril1 trial, N=41NA grade; Fair quality
Benazepril with valsartan vs. valsartan1 trial, N=109NA grade; Fair quality
DIABETIC NEPHROPATHY: MONOTHERAPY
Diabetic Nephropathy-Monotherapy: Overall adverse events
Candesartan vs. ramipril1 trial, N=21NA, All Fair3 of 4 trials (N=416) found no significant differences between AIIRAs and ACE-Is. However, in 1 trial (N=42) rates were significantly lower for valsartan vs. enalapril after 1 year (14% vs. 45%; P=0.015).
Losartan vs. enalapril1 trial, N=103
Telmisartan vs. enalapril1 trial, N=250
Valsartan vs. enalapril1 trial, N=42
Diabetic Nephropathy-Monotherapy: Cough
Candesartan vs. ramipril1 trial, N=21NA, All FairIn 3 of 3 trials (N=166), incidence of cough was 0% in the AIIRA groups and ranged from 5% to 35% in the ACE-I groups. The difference between AIIRA and ACE-I groups was statistically significant in the 2 larger and longer-term trials (duration=1 year), but was nonsignificant in the smaller (N=21), shorter-term trial (16 weeks).
Losartan vs. enalapril1 trial, N=103
Valsartan vs. enalapril1 trial, N=42
Diabetic Nephropathy-Monotherapy: Withdrawals due to adverse events
Candesartan vs. lisinopril1 trial, N=197NA, All Fair6 trials (N=633) consistently found no significant differences between AIIRAs (range, 0% to 17%) and ACE-Is (range, 2% to 23%)
Candesartan vs. ramipril1 trial, N=21
Losartan vs. enalapril1 trial, N=103
Telmisartan vs. enalapril1 trial, N=250
Valsartan vs. benazepril1 trial, N=20
Valsartan vs. enalapril1 trial, N=42
DIABETIC NEPHROPATHY: COMBINATION THERAPY
Diabetic nephropathy-combination therapy: Overall adverse events, withdrawals due to adverse events, cough, gastrointestinal events, and hypotension
Losartan+enalapril vs. losartan or enalapril monotherapy1 trial, N=34NA (Good=1, Fair=4)5 trials (N=295) consistently found no significant differences between combination therapy and monotherapy related to harms. For withdrawals due to adverse events (3 trials, N=238), rates ranged from 0% to 5% for combination therapy, 0% to 5% for AIIRAs, and 0% to 11% for ACE-Is. For hypotension (3 trials, N=64), rates ranged from 9% to 33% for combination therapy, 0% to 5% for AIIRAs and 0% to 11% for ACE-Is. Overall adverse event rates (2 trials, N=55) ranged from 0% to 19% in all groups. Cough was only reported in 1 trial (N=21) and was 0% for candesartan+ramipril, 0% for candesartan and 5% for ramipril.
Valsartan+benazepril vs. valsartan or benazepril monotherapy1 trial, N=20
Irbesartan+enalapril vs. enalapril monotherapy1 trial, N=23
Candesartan+lisinopril vs. candesartan or lisinopril monotherapy1 trial, N=197
Candesartan+ramipril vs. candesartan or ramipril monotherapy1 trial, N=21
Key Question 4. Are there subgroups based on demographics (age, racial groups, gender), other medications, or co-morbidities for which there are inter-class differences between DRI, ACE-I and AIIRA drugs
HEART FAILURE AND CARDIOVASCULAR DISEASE
Losartan vs. captopril (monotherapy)Heart failure: ELITE and ELITE II
Acute MI with HF or new Q-wave anterior wall MI:
OPTIMAAL
3 trials
N=9351
NA
Study quality: fair 2, good 1
Overall summary
Only 8 of 14 studies reported any data on population subgroups. There was NSD between AIIRAs and ARBs for subgroups based on age, ejection fraction, NYHA functional class (7 studies). Among patients on prior B-blocker therapy, more of the primary composite outcome occurred with losartan than with captopril.
Specific comparisons
Losartan vs. captopril: Among patients on prior B-blocker therapy, more events occurred with losartan than with captopril for the composite outcomes of all-cause mortality and hospital admissions (P=0.024) and for heart-failure-related mortality and admissions (P=0.015). NSD for primary outcome of all-cause mortality (P>0.05) (ELITE II). NSD for groups based on age, ejection fraction, NYHA functional class (3 studies).
Losartan vs. enalapril: No significant interactions between treatment and subgroups based on age, sex, and NYHA functional class (2 studies).
Telmisartan vs. ramipril vs. combination: For the primary composite outcome, results were similar between ramipril and telmisartan and between ramipril and combination therapy for subgroups based on cardiovascular disease, systolic blood pressure, diabetes, age, and sex.
Valsartan vs. captopril vs. combination: Subgroups based on age, race (African-American vs. white) sex, diabetes, prior MI, heart failure, LVED, or prior ACE-I use did not produce significant differences in treatment effects. African Americans developed angioedema more than whites (2.1% vs. 1.2%, P=0.2).
Valsartan vs. enalapril: Age, sex, pre-randomization B-blocker use, NYHA class, and etiology of HF produced no significant difference between the 2 groups in quality of life and dyspnea-fatigue index.
Losartan vs. enalapril (monotherapy and combination therapyHeart failure
Monotherapy: 3 trials (+ 2 poor quality), combination therapy: 1 trial
N=302 (excluding poor quality studies)
NA
Study quality: fair 2, fair-poor 1 (poor 2)
Telmisartan vs. ramipril vs. combinationVascular disease or diabetes with end-organ damage but without symptomatic heart failure
1 trial
(ONTARGET)
N=25620
NA
Study quality: good
Valsartan vs. captopril vs. combinationRecent, acute MI complicated by HF or evidence of LVSD
1 trial (VALIANT)
N=14703
NA
Study quality: good
Valsartan vs. enalapril (monotherapy)Heart failure
1 trial (HEAVEN)
N=141
NA
Study quality: fair
HYPERTENSION
Eprosartan vs. enalapril1 trial, N=529NA (Fair)Rate of cough was significantly lower for eprosartan vs. enalapril regardless of age (above or below 65 years) or Black race.
NONDIABETIC PROTEINURIA AND CHRONIC KIDNEY DISEASE (CKD)
Losartan/enalapril1 trial, N=40NA, FairOverall summary: Only 6 of a total of 22 trials comparing monotherapy ACEI vs. AIIRA, combination therapy ACEI with AIIRA, or both conducted subgroup analyses. Two trials, losartan/enalapril and valsartan vs. lisinopril did not examine outcomes of interest within subgroup analyses. Only 2 trials examined the same outcomes, and each used different ACEI and AIIRA agents. The limited number of subgroups, different outcomes examined, and different drug comparisons used limits the generalizability and utility of these results.
Losartan/benazepril conducted a subgroup analysis of participants with > 2 grams/day vs. <2 grams/day to examine antiproteinuric response to losartan vs. benazepril and Combination vs. monotherapy based on level of proteinuria. Those with >2 grams/day proteinuria had significantly greater reduction in proteinuria regardless of therapy.
Two trials, irbesartan/ramipril and valsartan/ramipril examined differences in proteinuria reduction by CKD etiology (diabetic vs. non-diabetic CKD). There was no difference in proteinuric response for mono vs. mono therapy in 1 trial, and no difference for combination vs. mono therapy in either trial based on CKD etiology.
Candesartan/ramipril examined differences in proteinuria reduction by CKD etiology (IgA disease vs. diabetic nephropathy). Combination therapy resulted in significantly greater proteinuria reduction for IgA patients, but there was no significant difference in proteinuria reduction with combination therapy for those with diabetic nephropathy.
Losartan/benazepril1 trial, N=30NA, Fair
Valsartan vs. lisinopril1 trial, N=37NA, Fair
Valsartan/ramipril1 trial, N=18NA, Fair
Candesartan with ramipril vs. ramipril1 trial, N=43NA, Fair
Irbesartan with ramipril vs. ramipril1 trial, N=41NA, Fair
DIABETIC NEPHROPATHY
Aliskiren plus losartan vs. losartan monotherapy1 trial, N=599NA, FairDual therapy with aliskiren and losartan resulted in a greater reduction in the albumin-to-creatinine ratio vs. losartan monotherapy regardless of sex, race or age.

Abbreviations: AE, adverse event; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; CVD, cardiovascular disease; GFR, glomerular filtration rate; HF, heart failure; LVED, left ventricular end-diastolic dysfunction; LVSD, left ventricular systolic dysfunction; MI, myocardial infarction; NA, not applicable; NSD, no significant difference; NYHA, New York Heart Association.

a

Information about studies which received a rating of “poor” was not included in this summary table, but can be found in the Evidence Tables.

b

We did not grade bodies of evidence in which only a single study was available. Therefore, “Strength of Evidence” grades are listed as “not applicable”.

c

Only those harms reported in 3 or more trials were summarized here. Information on additional outcomes reported in 2 or fewer trials are available in the Results section and in the Evidence Tables.

From: Summary

Cover of Drug Class Review: Direct Renin Inhibitors, Angiotensin Converting Enzyme Inhibitors, and Angiotensin II Receptor Blockers
Drug Class Review: Direct Renin Inhibitors, Angiotensin Converting Enzyme Inhibitors, and Angiotensin II Receptor Blockers: Final Report [Internet].
Norris S, Weinstein J, Peterson K, et al.
Portland (OR): Oregon Health & Science University; 2010 Jan.
Copyright © 2009, Oregon Health & Science University, Portland, Oregon.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.