Renin inhibitors versus angiotensin converting enzyme (ACE) inhibitors for primary hypertension

Gan Mi Wang; Liang Jin Li; Wen Lu Tang; James M Wright

doi:10.1002/14651858.CD012569.pub2

Cochrane Database of Systematic Reviews

Renin inhibitors versus angiotensin converting enzyme (ACE) inhibitors for primary hypertension

Information

DOI:

https://doi.org/10.1002/14651858.CD012569.pub2 Copy DOI

Database:

Cochrane Database of Systematic Reviews

Version published:

22 October 2020see what's new

Type:

Intervention

Stage:

Review

Cochrane Editorial Group:

Cochrane Hypertension Group

Copyright:

Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Authors

Gan Mi Wang

Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
Liang Jin Li

Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
Wen Lu Tang

Correspondence to: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China

[email protected]
James M Wright

Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada

Contributions of authors

Wen Lu Tang formulated the idea for the review, developed the basis for the protocol and was responsible for developing the review.

James M Wright offered expert advice, reviewed the protocol, and contributed to the interpretation of the writing of the review.

Gan Mi Wang took the lead role in searching, identifying and assessing studies, in data extraction and analysis, and in writing up the review.

Liang Jin Li took the executive role in identifying and assessing studies, in data extraction and analysis, and in writing up the review.

Sources of support

Internal sources

University of British Columbia, Department of Anesthesiology, Pharmacology & Therapeutics, Canada

infrastructure and salary support
Fudan University, China

infrastructure and salary support

External sources

No sources of support supplied

Declarations of interest

Gan Mi Wang: None known.

Liang Jin Li: None known.

Wen Lu Tang: None known.

James M Wright: None known.

Acknowledgements

We would like to acknowledge the assistance received from the Cochrane Hypertension Group.

We would like to thank Yu Jie Chen, author of the protocol, for assistance in identifying and assessing studies. We would like to thank Douglas Salzwedel, Information Specialist for Cochrane Hypertension, for designing and conducting the searches, and Ciprian Jauca, Managing Editor for Cochrane Hypertension, for his assistance. We would like to express our gratitude to Dr. Vijaya Musini for the editorial advice.

Version history

Published

Title

Stage

Authors

Version

2020 Oct 22

Renin inhibitors versus angiotensin converting enzyme (ACE) inhibitors for primary hypertension

Review

Gan Mi Wang, Liang Jin Li, Wen Lu Tang, James M Wright

https://doi.org/10.1002/14651858.CD012569.pub2

2017 Feb 27

Renin inhibitors versus angiotensin converting enzyme (ACE) inhibitors for primary hypertension

Protocol

Gan Mi Wang, Liang Jin Li, Yu Jie Chen, Wen Lu Tang, James M Wright

https://doi.org/10.1002/14651858.CD012569

Differences between protocol and review

None.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Aged; Female; Humans; Male; Middle Aged;

PICOs

Population

Intervention

Comparison

Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Funnel plot of comparison: 1 Renin inhibitors vs. ACE inhibitors, outcome: 1.6 SBP.

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Figure 4

Funnel plot of comparison: 1 Renin inhibitors vs. ACE inhibitors, outcome: 1.7 DBP.

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Analysis 1.1

Comparison 1: Renin inhibitors vs. ACE inhibitors, Outcome 1: All‐cause mortality

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Analysis 1.2

Comparison 1: Renin inhibitors vs. ACE inhibitors, Outcome 2: Fatal or non‐fatal myocardial infarction

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Analysis 1.3

Comparison 1: Renin inhibitors vs. ACE inhibitors, Outcome 3: Adverse events

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Analysis 1.4

Comparison 1: Renin inhibitors vs. ACE inhibitors, Outcome 4: Fatal or non‐fatal serious adverse events

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Analysis 1.5

Comparison 1: Renin inhibitors vs. ACE inhibitors, Outcome 5: Withdrawal due to adverse effects (WDAE)

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Analysis 1.6

Comparison 1: Renin inhibitors vs. ACE inhibitors, Outcome 6: SBP

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Analysis 1.7

Comparison 1: Renin inhibitors vs. ACE inhibitors, Outcome 7: DBP

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Summary of findings 1. Renin inhibitors compared to ACE inhibitors for primary hypertension

Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Renin inhibitors compared to ACE inhibitors for primary hypertension
Patient or population: people with primary hypertension Setting: ambulatory clinics Intervention: Renin inhibitors Comparison: ACE inhibitors
Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with ACE inhibitors	Risk difference with Renin inhibitors
All‐cause mortality follow‐up: range 4 weeks to 36.6 months	5962 (5 RCTs)	⊕⊕⊝⊝ LOW^a,b	RR 1.05 (0.93 to 1.18)	Study population
All‐cause mortality follow‐up: range 4 weeks to 36.6 months	5962 (5 RCTs)	⊕⊕⊝⊝ LOW^a,b	RR 1.05 (0.93 to 1.18)	131 per 1000	7 more per 1,000 (9 fewer to 24 more)
Fatal or non‐fatal myocardial infarction follow‐up: range 8 weeks to 54 weeks	957 (2 RCTs)	⊕⊝⊝⊝ VERY LOW^a,c	RR 0.86 (0.22 to 3.39)	Study population
	957 (2 RCTs)	⊕⊝⊝⊝ VERY LOW^a,c	RR 0.86 (0.22 to 3.39)	7 per 1000	1 fewer per 1000 (5 fewer to 16 more)
Adverse events follow‐up: range 4 weeks to 54 weeks	6007 (10 RCTs)	⊕⊕⊕⊝ MODERATE^a	RR 0.98 (0.93 to 1.03)	Study population
Adverse events follow‐up: range 4 weeks to 54 weeks	6007 (10 RCTs)	⊕⊕⊕⊝ MODERATE^a	RR 0.98 (0.93 to 1.03)	489 per 1000	10 fewer per 1000 (34 fewer to 15 more)
Fatal or non‐fatal serious adverse events follow‐up: range 4 weeks to 54 weeks	6007 (10 RCTs)	⊕⊕⊝⊝ LOW^a,c	RR 1.21 (0.89 to 1.64)	Study population
	6007 (10 RCTs)	⊕⊕⊝⊝ LOW^a,c	RR 1.21 (0.89 to 1.64)	27 per 1000	6 more per 1000 (3 fewer to 17 more)
Withdrawal due to adverse effects (WDAE) follow‐up: range 4 weeks to 54 weeks	6008 (10 RCTs)	⊕⊕⊝⊝ LOW^a,c	RR 0.85 (0.68 to 1.06)	Study population
	6008 (10 RCTs)	⊕⊕⊝⊝ LOW^a,c	RR 0.85 (0.68 to 1.06)	60 per 1000	9 fewer per 1000 (19 fewer to 4 more)
SBP follow‐up: range 4 weeks to 54 weeks	5001 (9 RCTs)	⊕⊕⊝⊝ LOW^a,d	‐	‐	MD 1.72 mm Hg lower (2.47 lower to 0.97 lower)
DBP follow‐up: range 4 weeks to 54 weeks	5001 (9 RCTs)	⊕⊕⊝⊝ LOW^a,d	‐	‐	MD 1.18 lower (1.65 lower to 0.72 lower)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; DBP: diastolic blood pressure; RR: Risk ratio; SBP: systolic blood pressure
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
^aDowngraded due to high risk of source of funding bias. ^bResults almost entirely from ATMOSPHERE 2016, 60% hypertensive heart‐failure participants at baseline. ^cDowngraded due to wide confidence interval. ^dDowngraded due to risk of publication bias.

Summary of findings 1. Renin inhibitors compared to ACE inhibitors for primary hypertension

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Table 1. Main characteristics of included studies

Study ID	N	Follow‐up (weeks)	Mean Age (years)	Co‐morbidity	Intervention	Add‐on drugs	Baseline SBP/DBP (mm Hg)
AGELESS 2010	901	36	T: 72.0 C: 72.2	Baseline diabetes: aliskiren 21.7%; ramipril 19.6%.	T: Aliskiren 150‐300 mg/day C: Ramipril 5‐10 mg/day	HCTZ 12.5 ‐ 25 mg/day or HCTZ 12.5 ‐ 25 mg/day +amlodipine 5 ‐ 10 mg/day	T: 156.5/85.5 C: 156.6/86.0
ALIAS 2012	506	8	T: 60.1 C: 59.8	NA	T: Aliskiren 150‐300 mg/day C: Ramipril 5‐10 mg/day	None	T: 166.4/89.9 C: 166.3/90.9
Andersen 2008	842	26	T: 53.4 C: 53.1	Baseline diabetes: aliskiren 10%; ramipril 11.6%. Baseline metabolic syndrome: aliskiren 40.7%; ramipril 43.3%.	T: Aliskiren 150 ‐ 300 mg/day C: Ramipril 5 ‐ 10 mg/day	HCTZ 12.5 ‐ 25 mg/day	T: 151.3/98.8 C: 151.4/98.9
ATMOSPHERE 2016	7064	36.6 months	T: 63.3 C1: 63.3 C2: 63.2	Heart failure as inclusion criterion; Baseline diabetes: aliskiren 26.8%; enalapril 27.9%; enalapril + aliskiren 28.4%	T: Aliskiren 150 ‐ 300 mg/day C1: Enalapril 5 ‐ 10 mg/day C2: Enalapril 5 ‐ 10 mg/day + Aliskiren 150 ‐ 300 mg/day	Optimal heart failure therapy, including beta blockers, but with the exception of ACE inhibitors	NA Note: Numbers of hypertensive participants at baseline, n(%): T: 1460 (62.4%) C1: 1425 (61.0%) C2: 1447 (61.8%)
Jones‐Burton 2010	195	4	T1: 52.8 T2: 52.8 C1: 51.5 C2: 53.1	NA	T1:MK‐8141 250 mg/day T2:MK‐8141 500 mg/day C1: Enalapril 20 mg/day C2: Placebo	None	T1: 150.2/93.8 T2: 149.7/94.2 C1: 150.6/95.1 C2: 151.9/93.6
NCT00631917 2011	774	54	T: 59.3 C: 59.3	Baseline diabetes: aliskiren 22.1%; ramipril 25.1%.	T: Aliskiren 150 ‐ 300 mg/day C: Ramipril 5 ‐ 10 mg/day	HCTZ 12.5 ‐ 25 mg/day or HCTZ 12.5 ‐ 25 mg/ay + amlodipine 5 ‐ 10 mg/day	NA
Palatini 2010	654	9	T: 53.5 C1: 53.9 C2: 53.4	NA	T: Aliskiren 150 ‐ 300 mg/day C1: Ramipril 5 ‐ 10 mg/day C2: Irbesartan 150 ‐ 300 mg/day	None	T: 145.5/93 C1:145.8/92.4 C2:145.4/93.0
Strasser 2007	183	8	T: 55.3 C: 55.6	Baseline diabetes: aliskiren 12.0%; lisinopril 13.8%. Baseline metabolic syndrome: aliskiren 52.8%; lisinopril 58.6% Baseline hypercholesterolemia: aliskiren 16.8%; lisinopril 15.5%	T: Aliskiren 150 ‐ 300 mg/day C: Lisinopril 20 ‐ 40 mg/day	HCTZ 25 mg/day	T: 163.4/108.4 C: 161.7/108.0
Uresin 2007	837	8	T: 60.0 C1: 59.9 C2: 59.5	Type 1 or 2 diabetes mellitus as inclusion criteria	T: Aliskiren 150 ‐ 300 mg/day C1: Ramipril 5 ‐ 10 mg/day C2: Aliskiren 150 ‐ 300 mg/day+ Ramipril 5 ‐ 10 mg/day	None	T: 157.4/98.4 C1: 155.9/98.2 C2: 156.5/98.4
Verdecchia 2007	355	8	T1: 73.6 T2: 73.2 T3: 73.0 C: 74.2	Baseline diabetes: aliskiren 75 mg 13.2%; aliskiren 150 mg 11.9%; aliskiren 300 mg 11.7%; lisinopril 7.0% Baseline metabolic syndrome: aliskiren 75 mg 27.5%; aliskiren 150 mg 22.6%; aliskiren 300 mg 24.5%; lisinopril 23.3%	T1: Aliskiren 75 mg/day T2: Aliskiren 150 mg/day T3: Aliskiren 300 mg/day C: Lisinopril 10 mg/day	None	T1: 160.4/88.0 T2: 160.2/89.3 T3: 160.7/90.1 C: 161.4/88.1
Zhu 2012	1316	8	T1: 52.7 T2: 53.3 T3: 53.8 C: 52.9	Baseline diabetes: aliskiren 75 mg 10.5%; aliskiren 150 mg 9.6%; aliskiren 300 mg 10.9%; ramipril 5 mg 15.2%.	T1: Aliskiren 75 mg/day T2: Aliskiren 150 mg/day T3: Aliskiren 300 mg/day C: Ramipril 5 mg/day	None	T1: 147.3/98.9 T2: 146.8/98.5 T3: 148.9/98.9 C1: 148.5/98.8
C: control group; DBP: diastolic blood pressure; HCTZ: hydrochlorothiazide; N: total number of participants randomized in each trial; T: test group; NA: not available; SBP: systolic blood pressure

Table 1. Main characteristics of included studies

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Comparison 1. Renin inhibitors vs. ACE inhibitors

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 All‐cause mortality Show forest plot	5	5962	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.93, 1.18]

1.2 Fatal or non‐fatal myocardial infarction Show forest plot	2	957	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.22, 3.39]

1.3 Adverse events Show forest plot	10	6007	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.93, 1.03]

1.4 Fatal or non‐fatal serious adverse events Show forest plot	10	6007	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.89, 1.64]

1.5 Withdrawal due to adverse effects (WDAE) Show forest plot	10	6008	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.68, 1.06]

1.6 SBP Show forest plot	9	5001	Mean Difference (IV, Fixed, 95% CI)	‐1.72 [‐2.47, ‐0.97]

1.7 DBP Show forest plot	9	5001	Mean Difference (IV, Fixed, 95% CI)	‐1.18 [‐1.65, ‐0.72]

Comparison 1. Renin inhibitors vs. ACE inhibitors

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Renin inhibitors versus angiotensin converting enzyme (ACE) inhibitors for primary hypertension

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