Table 4AIIRA drugs compared with ACE-I drugs in populations with heart failure or cardiovascular disease

Study, year
Country
Trial name
Quality
Study design
Follow-up interval
Population
InterventionResultsWithdrawals and adverse events
Candesartan compared with enalapril
McKelvie RS 199933
Tsuyuki RT, 199739

Canada, Switzerland, US, Italy

RESOLVD: Randomized Evaluation of Strategies for LV Dysfunction, Pilot Study

Fair
RCT

Follow-up: 43 weeks

Heart failure
Stage 1:
E: Enalapril 10 mg bid + placebo (n=109)

E+C: Enalapril 10 mg bid + candesartan 4 or 8 mg qd (n=332)

C: Candesartan: randomized to 4, 8, or 16 mg qd (n=327)
CHF hospitalization (P=0.09), any hospitalization, renal dysfunction: NSD among groups

Deaths at up to 43w: C 16 mg 4.6%, C 16 mg + E 11.4%; E 20 mg 3.7% (P=0.15)

6-min walk test at 43w: NSD among groups

NYHA classification: NSD among 3 groups at 18 or 43w

Quality of life: NSD between groups
Withdrawals:NR

Symptomatic hypotension: NSD between groups: C 16 mg 0.9%; C+E: 1.8%; E 20 mg 0.93%
Irbesartan compared with ramipril
Yip GWK 200837

Hong Kong

Fair
RCT

Follow-up 52 weeks

Heart failure
D: Diuretic: either furosemide or thiazide (n=50)

I: Irbesartan 18.75 mg qd titrated to 75 mg qd + diuretic (n=56)

R: Ramipril 2.5 titrated to 10 mg qd + diuretic (n=45)
6-min walk test: increased slightly in all groups; NSD within or between groups (between-group P=0.8)

Cardiovascular deaths (number): diuretic 1, irbesartan 1, ramipril 0

Quality of life measured with Minnesota Heart Failure Symptom Questionnaire: improved all 3 groups by 12w (P<0.01); NSD between groups (P value NR)

Readmission for HF: diuretic 12.2%, irbesartan 11.1%, ramipril 11.4% (P values NR)
Withdrawals: 12 total

AEs: NR
Losartan compared with captopril
Dickstein K 200227

Norway, USA, UK, Germany, Sweden, Ireland, Denmark

OPTIMAAL: Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan

Good
RCT, parallel group

Mean follow-up 2.7 (0.9) years

Acute MI and HF or decreased EF or other evidence CHD
L: Losartan 12.5 mg qd, titrated to 50 mg qd (n=2744)

C: Captopril 12.5 mg tid, titrated to 50 mg tid (n=2733)
All-cause mortality (%): L 18%, C 16%, RR, 1.13 (95% CI, 0.99 to 1.28), P=0.07; did not satisfy the non-inferiority criterion

Sudden death: RR, 1.19 (95% CI, 0.99 to 1.43), P=0.072)

Fatal or nonfatal reinfarction: RR, 1.03 (95% CI, 0.89 to 1.18), P=0.72

Cardiovascular deaths: RR, 1.17 (95% CI, 1.10 to1.34), P=0.032

All-cause hospital admission: RR, 1.03 (95% CI, 0.97 to 1.10), P=0.36
Discontinuation of study drug for any reason: L 17%, C 23%, RR, 0.77 (95% CI, 0.62 to 0.79), P<0.0001
Discontinuation due to AEs: L 7%, C 14%, RR, 0.50 (95% CI, 0.42 to 0.59), P<0.001

Angioedema: L 0.4%, C 0.8%, P=0.034
Hypotension: L 13.3%, C 16.3%, P=0.002
CHF: L 14.6%, C 14.0%, P=0.537
Angioedema: L 0.1%, C 0.5%, P=0.019
Pitt B, 199734
Cowley AJ, 200040
Konstam MA 200048 (ventricular function substudy)
Pitt B 199549 (rationale and design)
Houghton AR 199950 (exercise effects substudy)

289 centers in 46 countries

ELITE (Evaluation of Losartan in the Elderly)

Fair
RCT

Follow-up 48 weeks

Heart failure
C: Captopril: 6.25 mg titrated to 12.5, 25, 50 mg tid + losartan placebo; mean dosage achieved 122.7 mg qd (n=370)

L: Losartan: 12.5 mg titrated to 25, 50, qd + captopril placebo; mean dosage achieved 42.6 mg qd (n=352)
Renal dysfunction (primary composite endpoint): C: 10.5%, L: 10.5%; risk reduction 2% (95% CI, −51 to 36%), P=0.63

Death and/or HF admissions: C: 13.2%, L: 9.4%; risk reduction 32% (95% CI, −4 to 55), P=0.075

NSD within or between groups in 100-m corridor walk test or in pedometer scores (Houghton 1999)

Hospital admissions (Pitt 1997)
Total: C 29.7%, L 22.2%, P=0.014
For HF: C 5.7%, L 5.7%, P=0.89
Total withdrawals (including deaths): C: 30.0%, L: 18.5%, P<0.0001

Withdrawals due to AEs (excluding death): C: 20.8%, L: 12.2%, P≤0.002

Deaths (per protocol): L: 3.7%, C: 8.5%, P=0.013

Persisting increase in potassium of ≥ 0.5 mmll/L C; 22.7%, L 18.8%, P=0.069
Hypotension-related symptoms: 24% overall, P>0.05
Worsening HF: C 9/370; L 3/352 (P value NR)
Pitt B, 200014
Konstam MA, 200551
Pitt B 199952 (rationale, design, baseline characteristics)

US, UK, Norway, Germany

ELITE II (Evaluation of Losartan in the Elderly)

Fair
RCT

Follow-up: median for each group: 1.5 years

Heart failure
C: Captopril: 6.25 mg titrated to 12.5, 25, 50 mg tid + losartan placebo (n=1574)

L: Losartan: 12.5 mg titrated to 25, 50, qd + captopril placebo (n=1578)
All-cause mortality (%): L 17.7; C 15.9; hazard ratio, 1.13 (95% CI, 0.95 to 1.35) P=0.16
Sudden death or resuscitated arrest, %: C 7.3, L 9.0, hazard ratio, 1.25 (95% CI, 0.98 to 1.60), P=0.08

NSD hospital admissions or admissions for heart failure

Health-related quality of life: no significant change in either group overall; among survivors both groups improved with NSD between groups
Total withdrawals (excluding deaths): C 14.0%, L 7.9% (P value NR)
Withdrawals due to AEs: C 20.8%, L 12.2%, P<0.001

Worsening HF: C 25%, L 25%
Losartan compared with enalapril
Dickstein K 199526

Norway, Sweden, Finland

Fair
RCT

Follow-up: 8 weeks

Heart failure
L25: Losartan 25 mg qd (n=52)

L50: Losartan 50 mg qd (n=56)

E: Enalapril 20 mg qd (n=58)
Exercise capacity (6-min walk test) at 8w: P>0.05 within and between groups

Dyspnea-fatigue Index profile (8w): improved with losartan 25 mg (P<0.05) and enalapril (P<0.001); NSD between groups

Incidence of worsening symptoms (exertional dyspnea, edema, orthopnea, worsening NYHA class): NSD among treatment groups; functional class improved in 30% overall, evenly distributed across groups

Pulmonary rales, increased in all groups, L50 > E, P<0.05
Withdrawal due to AEs (number patients): losartan25: 1, losartan50: 2, enalapril5:
(NSD among groups)

Blood urea nitrogen, creatinine, potassium: increased with enalapril, decrease in losartan (both groups), P<0.05; none considered clinically significant
Guazzi M 199729

Italy

Poor
RCT, cross-over, 3 weeks of treatment for each treatment

Each treatment for 8 weeks

Heart failure
Total n=16 + 8 healthy controls
Randomized to receive the following sequence, or in reverse order (3w each):

P: Placebo
E: Enalapril 10 mg bid
L: Losartan 50 mg qd
E+A: Enalapril + ASA 325 mg qd
L+A: Losartan + ASA
Exercise tolerance: NSD between any 2 groupsNR
Guazzi M 199930

Italy

Fair
RCT, cross-over (at 8-week intervals)

Each treatment for 8 weeks

Heart failure
Total n=20
Randomized to receive the following sequence, or in reverse order:
P: Placebo+placebo
E: Enalapril 20 + placebo
L: Losartan 50 mg + placebo
E+L: Enalapril + losartan

Each treatment lasted 8w
Minnesota Living with Heart Failure questionnaire: slight improvement while on E+P and L+P compared with P (P>0.05); no further improvement with E+L; NSD between groups1 patient withdrew due to hypotension on E=P; 1 withdrew due to cough on E
Lang RM 199732

US

Fair-poor
RCT, parallel group

Follow-up: 12 weeks

Heart failure
L25: Losartan 12.5 to 25 mg qd (n=38)

L50: Losartan 12.5 to 50 mg qd (n=40)

E: Enalapril 2.5 to 10 mg bid (n=38)
6-min walk test (meters) at 12w: NSD between groups

Treadmill test: increase L25 P=0.028; L 50 P=006; E 20 P=0.03; NSD between any 2 groups

Dyspnea-fatigue index: improved with L25 only (P=0.03)

HF symptoms, worsening HF, change in NYHA class: NSD between groups
Total withdrawals: NR
Withdrawals due to AEs: 1 patient from each of 3 treatment groups

Any AE (%): L25 65.8, L50 67.5; E20 60.5%

Deaths: L25: 1 (sudden death); L 50 5 (sudden death, worsening HF, V arrhythmia, septicemia, unknown cause); E20: 0

NSD between groups at 12w in blood urea nitrogen, potassium, Na+, uric acid
Increase in serum Cr (mg/dL) at 12w: L50 < E 20, P<0.05; E 20 follow-up > baseline E20, P<0.05
Vescovo G 199835

Italy

Poor
RCT, parallel group

Follow-up: 6 months

Heart failure
Total n=16 (with an additional 8 healthy controls)

L: Losartan: to 50 mg qd

E: Enalapril: to 10 mg bid
Exercise duration: increase in both groups, P=0.03 for both L and E; between-group P value NRNR
Telmisartan compared with enalapril
Dunselman PHJM 200128

The Netherlands

REPLACE (the replacement of angiotensin converting enzyme inhibition)

Fair
RCT, parallel-group

Follow-up: 12 weeks

Heart failure
E: Enalapril 10 mg bid (continued from screening phase) (n=77)

T10: Telmisartan 10 mg qd (n=75)
T20: Telmisartan 20 mg qd (n=72)
T40: Telmisartan 40 mg qd (n=77)
T80: Telmisartan 80 mg qd (n=77)
Exercise duration: ↑ in all groups; NSD between baseline and follow-up for any group; NSD between any T group and El

NYHA classification: NSD for any group

Death: 2 on T20; 1 on T40; 1 on T80; 2 on E20

Quality of life (Minnesota Living with Heart Failure): NSD between or within groups
Total withdrawals: 11
Withdrawals due to AEs: 3 (all telmisartan)

Any AE: 54% overall; similar across treatment groups
Telmisartan compared with ramipril
The ONTARGET Investigators 200831

40 countries
ONTARGET: The Ongoing Telmisartan
Alone and in combination with Ramipril Global Endpoint Trial

Good
RCT, parallel group, noninferiority study of AIIRA compared with ACE; superiority of combination to ramipril

Follow-up median 56 months

CVD or diabetes with end-organ damage
R: to 10 mg qd (n=8576)

T: Telmisartan 80mg qd (n=8542)

R+T: ramipril + telmisartan (n=8502)
Composite, primary outcome (death from CVD causes, MI, stroke, hospitalization for HF): R 16.5%; T 16.7%; R+T 16.3%; RR, T vs. R 1.01 (95% CI, 0.94 to 1.09); RR, R+T vs. R 0.99 (95% CI, 0.92 to 1.07)T < RStudy drug discontinuation: R 23.7%; T 21.0%; R+T 22.7% (both drugs), 6.7% (1 drug)

Cough: T < R (P<0.0001)
Angioedema: T < R (P=0.01)
Hypotension: T > R (P<0.001); T+R > R (P<0.001)
Renal dysfunction: T+R > R (P<0.001)
Valsartan compared with captopril
Pfeffer MA 200313
Reed SD 200546
Prisant LM 200845
Anavekar NS, 200843
Anavekar NS, 200442 (NEJM)
White HD, 200547
Anderson RE, 200844

International (24 countries)

VALIANT
Valsartan in Acute
Myocardial Infarction trial

Good
RCT

Median follow-up: 24.7 months

Post MI with HF or LVSD
All dosages titrated up to goal dosage:

V: Valsartan 160 mg bid (n=4909)

V+C: Valsartan 80 mg bid + 50 mg captopril tid (n=4885)

C: Captopril 50 mg tid (n=4909)
Hazard ratio death (97.5% CI)
V vs. C: 1.00 (0.90 to 1.11)
V+C vs. C: 0.98 (0.89 to 1.09)

Hazard ratio for death from CV cause, or MI, or HF hospitalization:
V vs. C: 0.95 (97.5% CI, 0.88 to 1.03)
V+C vs. C: 0.97 (97.5% CI, 0.89 to 1.05)

V not inferior to C for mortality by prespecified criteria

Quality of life: NSD among treatment groups
Total withdrawals (%): V: 29.5, V+C: 23.4, C: 21.6
Withdrawals due to AEs (%): V: 5.8, V+C: 9.0, C: 7.7

AEs resulting in permanent discontinuation of treatment (%):
Hypotension: V: 1.4 (vs. C, P<0.05), V+C: 1.9 (vs. C, P=0.05), C: 0.8
Renal causes: V: 1.1, V+C: 1.3 (vs. C, P<0.05), C: 0.8
Hyperkalemia: V: 0.1, V+C: 0.2, C: 0.1
Angioedema: V: 0.2, C+V: 0.2, C: 0.3
Valsartan compared with enalapril
Willenheimer R 200236

Sweden

HEAVEN Study (Heart Failure Exercise Capacity Evaluation)

Fair
RCT, parallel group, non-inferiority of valsartan to enalapril

Follow-up: 12 weeks

HF
V: Valsartan: to 160 mg qd (n=70)

E: Enalapril: to 10 mg bid (n=71)
Change in 6-min walk test distance (ITT population): least squares means treatment difference (V-E): 1.12 m (95% CI, −21.89 to +24.12). P<0.001 for noninferiority; superiority P=0.462

NSD between groups in the dyspnea-fatigue index and the Minnesota Living with HF Questionnaire
Total withdrawals: V 9/71; E 14/71
Withdrawals due to AEs: V 2/70; E 3/71

Any AE (%): V 50, E 63 (P>0.05)
Deaths: V 1.4%, E 7.6%
Worsening CHF: V 5.7%, E 1.4%

Serious AEs: V 9%, E 16% (not defined, included deaths)

Abbreviations: AE, adverse event; bid, twice daily; CHD, coronary heart disease; CVD, cardiovascular disease; EF, ejection fraction; HF, heart failure; ITT, intention to treat; LVSD, left ventricular systolic dysfunction; MI, myocardial infarction; NSD, no significant difference; NYHA, New York Heart Association; RCT, randomized controlled trial; tid, 3 times daily; qd, once daily; RR, relative risk.

From: Results

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.

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