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Cochrane Database of Systematic Reviews

Beta‐blockers and inhibitors of the renin‐angiotensin aldosterone system for chronic heart failure with preserved ejection fraction

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Information

DOI:
https://doi.org/10.1002/14651858.CD012721.pub2Copy DOI
Database:
  1. Cochrane Database of Systematic Reviews
Version published:
  1. 28 June 2018see what's new
Type:
  1. Intervention
Stage:
  1. Review
Cochrane Editorial Group:
  1. Cochrane Heart Group

Copyright:
  1. Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Authors

  • Nicole Martin

    Farr Institute of Health Informatics Research, University College London, London, UK

  • Karthick Manoharan

    Emergency Department, John Radcliffe Hospital, London, UK

  • James Thomas

    EPPI‐Centre, Social Science Research Unit, UCL Institute of Education, University College London, London, UK

  • Ceri Davies

    Department of Cardiology, Barts Heart Centre, St Bartholomew's Hospital, London, UK

  • R Thomas Lumbers

    Correspondence to: Institute of Health Informatics, University College London, London, UK

    [email protected]

Contributions of authors

NM: selection of studies, data extraction, analysis, GRADE assessment, co‐wrote the manuscript.

KM: selection of studies, GRADE assessment.

JT: contributed to review design, approved the final version.

CD: contributed to review design, GRADE assessment, approved the final version.

TL: guarantor of review, designed the review, data extraction, analysis, GRADE assessment, co‐wrote the manuscript.

Sources of support

Internal sources

  • R Thomas Lumbers, UK.

    NIHR Academic Clinical Lectureship

External sources

  • This project was supported by the National Institute for Health Research via Cochrane Infrastructure and NIHR Incentive funding to Cochrane Heart. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health, UK.

Declarations of interest

NM: none known.

KM: none known.

JT: none known.

CD: has received sponsorship from Servier, Roche and Novartis to attend cardiology conferences, payment from GE Healthcare to give lectures on heart failure, and has served as a paid consultant to Servier and Vifor.

TL: has received research grants from Pfizer and has served as an unpaid consultant to GSK.

Acknowledgements

T.L was supported by an NIHR Clinical Lectureship and, subsequently, a UKRI Health Data Research Fellowship. We are grateful to Marta Battle Lopez, Derya Senturk, Hatoko Sasaki, Lu Chunli, Teresa Cantisani, Liliya Eugenevna Ziganshina, Hanneke Dominicus, Joanna Zajac, Anna Aryee, and Vaclav Papez for their help with the full text assessment of non‐English language papers. We are also grateful to Rui Providencia for assessing and extracting data from non‐English language papers, and to Juan‐Pablo Casas for his guidance in designing this review.

Version history

Published

Title

Stage

Authors

Version

2021 May 22

Beta‐blockers and inhibitors of the renin‐angiotensin aldosterone system for chronic heart failure with preserved ejection fraction

Review

Nicole Martin, Karthick Manoharan, Ceri Davies, R Thomas Lumbers

https://doi.org/10.1002/14651858.CD012721.pub3

2018 Jun 28

Beta‐blockers and inhibitors of the renin‐angiotensin aldosterone system for chronic heart failure with preserved ejection fraction

Review

Nicole Martin, Karthick Manoharan, James Thomas, Ceri Davies, R Thomas Lumbers

https://doi.org/10.1002/14651858.CD012721.pub2

2017 Jul 17

Beta‐blockers and inhibitors of the renin‐angiotensin aldosterone system for chronic heart failure with preserved ejection fraction

Protocol

R Thomas Lumbers, Nicole Martin, Karthick Manoharan, Jonathan Nyong, James Thomas, Juan P Casas, Ceri Davies

https://doi.org/10.1002/14651858.CD012721

Differences between protocol and review

We originally planned to include participants with LVEF ≥ 40% but changed this to LVEF > 40%, since this is a more frequently used cut‐off in clinical trials.

We originally limited our population to symptomatic heart failure (NYHA class > I) at enrolment; however, this criterion was removed to include people with diagnosis of heart failure in whom symptoms had improved the functional class.

We added a clarification regarding the exclusion of cross‐over trials.

We originally planned to include withdrawals due to adverse events in the 'Summary of findings' table. This was changed because this outcome was frequently reported inconsistently, which limits the applicability of a pooled analysis. Instead, we added hyperkalaemia to the 'Summary of findings' table because this adverse event outcome has relevance for clinical decision making. For the same reason, hyperkalaemia was switched from secondary to primary outcomes and withdrawals due to adverse events was switched from primary to secondary outcomes.

We did not pre specify which scale for quality of life we would focus on in the 'Summary of findings' table. To aid comparisons across the 'Summary of findings' tables we chose to include the Minnsota Living with Heart Failure Questionnaire and not the standardised mean difference across two scales which applied only to MRA versus placebo or no treatment comparison.

Keywords

MeSH

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.

Study flow diagram
Figures and Tables -
Figure 1

Study flow diagram

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 3

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

Comparison 1 Beta‐blockers versus placebo or no treatment, Outcome 1 Cardiovascular mortality (RR).
Figures and Tables -
Analysis 1.1

Comparison 1 Beta‐blockers versus placebo or no treatment, Outcome 1 Cardiovascular mortality (RR).

Comparison 1 Beta‐blockers versus placebo or no treatment, Outcome 2 Heart failure hospitalisation (RR).
Figures and Tables -
Analysis 1.2

Comparison 1 Beta‐blockers versus placebo or no treatment, Outcome 2 Heart failure hospitalisation (RR).

Comparison 1 Beta‐blockers versus placebo or no treatment, Outcome 3 All‐cause mortality (RR).
Figures and Tables -
Analysis 1.3

Comparison 1 Beta‐blockers versus placebo or no treatment, Outcome 3 All‐cause mortality (RR).

Comparison 1 Beta‐blockers versus placebo or no treatment, Outcome 4 Quality of life (Minnesota).
Figures and Tables -
Analysis 1.4

Comparison 1 Beta‐blockers versus placebo or no treatment, Outcome 4 Quality of life (Minnesota).

Comparison 1 Beta‐blockers versus placebo or no treatment, Outcome 5 Withdrawal due to adverse event.
Figures and Tables -
Analysis 1.5

Comparison 1 Beta‐blockers versus placebo or no treatment, Outcome 5 Withdrawal due to adverse event.

Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 1 Cardiovascular mortality (RR).
Figures and Tables -
Analysis 2.1

Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 1 Cardiovascular mortality (RR).

Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 2 Heart failure hospitalisation (RR).
Figures and Tables -
Analysis 2.2

Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 2 Heart failure hospitalisation (RR).

Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 3 Heart failure hospitalisation (HR).
Figures and Tables -
Analysis 2.3

Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 3 Heart failure hospitalisation (HR).

Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 4 Hyperkalaemia.
Figures and Tables -
Analysis 2.4

Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 4 Hyperkalaemia.

Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 5 All‐cause mortality (RR).
Figures and Tables -
Analysis 2.5

Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 5 All‐cause mortality (RR).

Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 6 Quality of life.
Figures and Tables -
Analysis 2.6

Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 6 Quality of life.

Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 7 Quality of life (KCCQ).
Figures and Tables -
Analysis 2.7

Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 7 Quality of life (KCCQ).

Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 8 Quality of life (Minnesota).
Figures and Tables -
Analysis 2.8

Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 8 Quality of life (Minnesota).

Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 9 Withdrawal due to adverse event.
Figures and Tables -
Analysis 2.9

Comparison 2 Mineralocorticoid receptor antagonists versus placebo or no treatment, Outcome 9 Withdrawal due to adverse event.

Comparison 3 Angiotensin converting enzyme inhibitors versus placebo or no treatment, Outcome 1 Cardiovascular mortality (RR).
Figures and Tables -
Analysis 3.1

Comparison 3 Angiotensin converting enzyme inhibitors versus placebo or no treatment, Outcome 1 Cardiovascular mortality (RR).

Comparison 3 Angiotensin converting enzyme inhibitors versus placebo or no treatment, Outcome 2 Heart failure hospitalisation (RR).
Figures and Tables -
Analysis 3.2

Comparison 3 Angiotensin converting enzyme inhibitors versus placebo or no treatment, Outcome 2 Heart failure hospitalisation (RR).

Comparison 3 Angiotensin converting enzyme inhibitors versus placebo or no treatment, Outcome 3 Hyperkalaemia.
Figures and Tables -
Analysis 3.3

Comparison 3 Angiotensin converting enzyme inhibitors versus placebo or no treatment, Outcome 3 Hyperkalaemia.

Comparison 3 Angiotensin converting enzyme inhibitors versus placebo or no treatment, Outcome 4 All‐cause mortality (RR).
Figures and Tables -
Analysis 3.4

Comparison 3 Angiotensin converting enzyme inhibitors versus placebo or no treatment, Outcome 4 All‐cause mortality (RR).

Comparison 3 Angiotensin converting enzyme inhibitors versus placebo or no treatment, Outcome 5 Quality of life (Minnesota).
Figures and Tables -
Analysis 3.5

Comparison 3 Angiotensin converting enzyme inhibitors versus placebo or no treatment, Outcome 5 Quality of life (Minnesota).

Comparison 3 Angiotensin converting enzyme inhibitors versus placebo or no treatment, Outcome 6 Withdrawal due to adverse event.
Figures and Tables -
Analysis 3.6

Comparison 3 Angiotensin converting enzyme inhibitors versus placebo or no treatment, Outcome 6 Withdrawal due to adverse event.

Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 1 Cardiovascular mortality (RR).
Figures and Tables -
Analysis 4.1

Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 1 Cardiovascular mortality (RR).

Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 2 Cardiovascular mortality (HR).
Figures and Tables -
Analysis 4.2

Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 2 Cardiovascular mortality (HR).

Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 3 Heart failure hospitalisation (RR).
Figures and Tables -
Analysis 4.3

Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 3 Heart failure hospitalisation (RR).

Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 4 Heart failure hospitalisation (HR).
Figures and Tables -
Analysis 4.4

Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 4 Heart failure hospitalisation (HR).

Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 5 Hyperkalaemia.
Figures and Tables -
Analysis 4.5

Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 5 Hyperkalaemia.

Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 6 All‐cause mortality (RR).
Figures and Tables -
Analysis 4.6

Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 6 All‐cause mortality (RR).

Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 7 All‐cause mortality (HR).
Figures and Tables -
Analysis 4.7

Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 7 All‐cause mortality (HR).

Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 8 Quality of life (Minnesota).
Figures and Tables -
Analysis 4.8

Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 8 Quality of life (Minnesota).

Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 9 Withdrawal due to adverse event.
Figures and Tables -
Analysis 4.9

Comparison 4 Angiotensin receptor blockers versus placebo or no treatment, Outcome 9 Withdrawal due to adverse event.

Summary of findings for the main comparison. Beta‐blockers compared to placebo or no treatment for chronic heart failure with preserved ejection fraction

Beta‐blockers compared to placebo or no treatment for chronic heart failure with preserved ejection fraction

Patient or population: chronic heart failure with preserved ejection fraction
Setting: secondary care
Intervention: beta‐blockers
Comparison: placebo/no treatment

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo/no treatment

Risk with Beta‐blockers

Cardiovascular mortality (RR)
follow‐up: range 21 months to 3.2 years

Study population

RR 0.78
(0.62 to 0.99)

1046
(3 RCTs)

⊕⊕⊝⊝
LOW 1 2

Three additional studies (ELANDD; SWEDIC; Takeda 2004) reported that no deaths occurred

173 per 1000

135 per 1000
(107 to 171)

Heart failure hospitalisation (RR)
follow‐up: range 6 months to 3.2 years

Study population

RR 0.73
(0.47 to 1.13)

449
(4 RCTs)

⊕⊝⊝⊝
VERY LOW 1 3 4

Follow‐up unclear for SWEDIC. ELANDD reported that no hospitalisation due to heart failure occurred

117 per 1000

86 per 1000
(55 to 133)

Hyperkalaemia

245 (1 RCT)

⊕⊝⊝⊝
VERY LOW1 7

J‐DHF reported one participant in the intervention group (N = 120) experienced hyperkalaemia but did not report on this outcome for the control group. No further data were available from any of the other studies.

All‐cause mortality (RR)
follow‐up: range 21 months to 3.2 years

Study population

RR 0.82
(0.67 to 1.00)

1105
(4 RCTs)

⊕⊕⊝⊝
LOW 1 2

Follow‐up unclear for Adamyan 2010. ELANDD, SWEDIC and Takeda 2004 reported that no deaths occurred

243 per 1000

199 per 1000
(163 to 243)

Quality of life (Minnesota)
Scale from: 0 to 105
follow‐up: mean 6 months

Mean quality of life (Minnesota) was 24

MD 1 lower
(9.05 lower to 7.05 higher)

93
(1 RCT)

⊕⊝⊝⊝
VERY LOW 5 6

Lower = better, 5 point difference considered to be clinically meaningful

*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; RR: Risk ratio

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

1 Downgraded by one level due to unclear selection bias in most studies.

2 Downgraded by one level due to concerns about the smaller study being more precise than the larger study.

3 Downgraded by one level due to large variation in size of effect.

4 Downgraded by two levels due to few events and wide CI.

5 Downgraded by two levels due to very small sample size.

6 Suspected publication bias; this is a patient‐relevant outcome that is not reported in most studies.

7 Downgraded by two levels due to incomplete reporting.

Figures and Tables -
Summary of findings for the main comparison. Beta‐blockers compared to placebo or no treatment for chronic heart failure with preserved ejection fraction
Summary of findings 2. MRA compared to placebo or no treatment for chronic heart failure with preserved ejection fraction

MRA compared to placebo or no treatment for chronic heart failure with preserved ejection fraction

Patient or population: chronic heart failure with preserved ejection fraction
Setting: secondary care
Intervention: MRA
Comparison: placebo/no treatment

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo/no treatment

Risk with MRA

Cardiovascular mortality (RR)
follow‐up: range 12 months to 3.3 years

Study population

RR 0.90
(0.74 to 1.11)

4070
(3 RCTs)

⊕⊕⊕⊝
MODERATE 1

Two additional trials (RAAM‐PEF, Kurrelmeyer 2014) reported that no deaths occurred

88 per 1000

79 per 1000
(65 to 97)

Heart failure hospitalisation (RR)
follow‐up: range 24 weeks to 3.3 years

Study population

RR 0.82
(0.69 to 0.98)

3714
(3 RCTs)

⊕⊕⊕⊝
MODERATE 1

Three additional trials (ALDO‐DHF ,Kurrelmeyer 2014, Upadhya 2017) reported that no hospitalisation due to heart failure occurred

136 per 1000

112 per 1000
(94 to 134)

Hyperkalaemia
follow‐up: range 24 weeks to 3.3 years

Study population

RR 2.11
(1.77 to 2.52)

4291
(6 RCTs)

⊕⊕⊕⊕
HIGH

Two trials defined hyperkalaemia ≥ 5.5 mEg/L

83 per 1000

175 per 1000
(146 to 208)

All‐cause mortality
follow‐up: range 9 months to 3.3 years

Study population

RR 0.91
(0.78 to 1.06)

4207
(5 RCTs)

⊕⊕⊕⊝
MODERATE 1

Two additional trials (RAAM‐PEF, Kurrelmeyer 2014) reported that no deaths occurred

133 per 1000

121 per 1000
(104 to 141)

Quality of life (Minnesota)
Scale from: 0 to 105
follow‐up: range 9 months to 12 months

Mean quality of life (Minnesota) ranged from 20 to 25

MD 0.84 higher
(2.30 lower to 3.98 higher)

511
(3 RCTs)

⊕⊕⊝⊝
LOW 2 3

Lower = better, 5 points are considered a clinically significant difference

We did not pre‐specify which QoL scale was to be reported in the 'Summary of findings' table. To aid comparisons among 'Summary of findings' tables we chose to include the Minnesota Living with Heart Failure questionnaire and not the SMD across two scales

*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; RR: Risk ratio

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

1 Downgraded by one level due to imprecision.

2 Downgraded by one level because one trial was open label.

3 Downgraded by one level due to small sample size.

Figures and Tables -
Summary of findings 2. MRA compared to placebo or no treatment for chronic heart failure with preserved ejection fraction
Summary of findings 3. ACEI compared to placebo or no treatment for chronic heart failure with preserved ejection fraction

ACEI compared to placebo or no treatment for chronic heart failure with preserved ejection fraction

Patient or population: chronic heart failure with preserved ejection fraction
Setting: secondary care
Intervention: ACEI
Comparison: placebo/no treatment

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo/no treatment

Risk with ACEI

Cardiovascular mortality (RR)
follow‐up: range mean 12 months to mean 26.2 months

Study population

RR 0.93
(0.61 to 1.42)

945
(2 RCTs)

⊕⊕⊕⊝
MODERATE 1

One additional trial (Kitzman 2010) reported that no deaths occurred

86 per 1000

81 per 1000
(53 to 123)

Heart failure hospitalisation (RR)
follow‐up: range 6 months to 26.2 months

Study population

RR 0.86
(0.64 to 1.15)

1019
(3 RCTs)

⊕⊕⊕⊝
MODERATE 1

13 per 1000

11 per 1000
(8 to 15)

Hyperkalaemia

74 (1 RCTs)

⊕⊝⊝⊝
VERY LOW 1 3 4

One trial (Zi 2003) reported 2 events in the intervention group (N = 36), 0 events in the control group (N = 38) (RR 5.27, 95% CI 0.26 to 106.16)

All‐cause mortality (RR)
follow‐up: range mean 6 months to mean 26.2 months

Study population

RR 0.99
(0.71 to 1.38)

1079
(4 RCTs)

⊕⊕⊕⊝
MODERATE 1

One additional trial (Kitzman 2010) reported that no deaths occurred

119 per 1000

119 per 1000
(84 to 166)

Quality of life (Minnesota)
Scale from: 0 to 105
follow‐up: mean 12 months

Mean quality of life (Minnesota) ranged from 10.9 to 29

MD 0.09 lower
(3.66 lower to 3.48 higher)

154
(2 RCTs)

⊕⊕⊝⊝
LOW 2 3

Scale: 0 to 105, lower = better, 5 point difference considered clinically relevant

One trial (SNEGOVIK) reported mean change from baseline of ‐19.8 for intervention and ‐10.7 for control

*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; RR: Risk ratio;

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

1 Downgraded by one level due to wide CI.

2 Downgraded by one level due to risk of bias (open label).

3 Downgraded by one level due to low sample size.

4 Downgraded by one level due to unclear selection bias.

Figures and Tables -
Summary of findings 3. ACEI compared to placebo or no treatment for chronic heart failure with preserved ejection fraction
Summary of findings 4. ARB compared to placebo or no treatment for chronic heart failure with preserved ejection fraction

ARB compared to placebo or no treatment for chronic heart failure with preserved ejection fraction

Patient or population: chronic heart failure with preserved ejection fraction
Setting: secondary care
Intervention: ARB
Comparison: placebo/no treatment

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo/no treatment

Risk with ARB

Cardiovascular mortality (RR)
follow‐up: range mean 12 months to mean 49.5 months

Study population

RR 1.02
(0.90 to 1.14)

7254
(3 RCTs)

⊕⊕⊕⊕
HIGH

One additional trial (Parthasarathy 2009) reported that no deaths occurred

131 per 1000

133 per 1000
(118 to 149)

Heart failure hospitalisation (RR)
follow‐up: range mean 12 months to mean 49.5 months

Study population

RR 0.92
(0.83 to 1.02)

7254
(3 RCTs)

⊕⊕⊕⊕
HIGH

171 per 1,‐000

157 per 1,‐000
(142 to 174)

Hyperkalaemia
follow‐up: range 36.6 months to 49.5 months

Study population

RR 1.88
(1.07 to 3.33)

7148
(2 RCTs)

⊕⊕⊕⊕
HIGH

3 per 1,000

5 per 1,000
(3 to 8)

All‐cause mortality (RR)
follow up: range 1 years to 4.4 years

Study population

RR 1.01
(0.92 to 1.11)

7964
(4 RCTs)

⊕⊕⊕⊕
HIGH

One additional trial (Parthasarathy 2009) reported that no deaths occurred

72 per 1000

73 per 1,‐000
(66 to 80)

Quality of life (Minnesota)
scale from: 0 to 105
follow‐up: range mean 13.8 weeks to mean 49.5 months

Mean quality of life (Minnesota) ranged from 10.9 to 31.6

MD 0.41 higher
(0.86 lower to 1.67 higher)

3117
(3 RCTs)

⊕⊕⊕⊕
HIGH

Scale: 0 to 105, lower = better, 5 point difference considered clinically relevant

*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; RR: Risk ratio;

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

Figures and Tables -
Summary of findings 4. ARB compared to placebo or no treatment for chronic heart failure with preserved ejection fraction
Comparison 1. Beta‐blockers versus placebo or no treatment

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Cardiovascular mortality (RR) Show forest plot

3

1046

Risk Ratio (M‐H, Fixed, 95% CI)

0.78 [0.62, 0.99]

2 Heart failure hospitalisation (RR) Show forest plot

4

449

Risk Ratio (M‐H, Fixed, 95% CI)

0.73 [0.47, 1.13]

2.1 Follow‐up < 12 months

1

67

Risk Ratio (M‐H, Fixed, 95% CI)

0.31 [0.09, 1.02]

2.2 Follow‐up ≥ 12 months

2

285

Risk Ratio (M‐H, Fixed, 95% CI)

0.79 [0.48, 1.31]

2.3 Follow‐up unknown

1

97

Risk Ratio (M‐H, Fixed, 95% CI)

5.31 [0.26, 107.85]

3 All‐cause mortality (RR) Show forest plot

4

1105

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.67, 1.00]

4 Quality of life (Minnesota) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

5 Withdrawal due to adverse event Show forest plot

2

338

Risk Ratio (M‐H, Fixed, 95% CI)

18.07 [2.45, 133.04]

Figures and Tables -
Comparison 1. Beta‐blockers versus placebo or no treatment
Comparison 2. Mineralocorticoid receptor antagonists versus placebo or no treatment

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Cardiovascular mortality (RR) Show forest plot

3

4070

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.74, 1.11]

2 Heart failure hospitalisation (RR) Show forest plot

3

3714

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.69, 0.98]

2.1 Follow‐up < 12 months

1

44

Risk Ratio (M‐H, Fixed, 95% CI)

0.55 [0.05, 5.61]

2.2 Follow‐up ≥ 12 months

2

3670

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.69, 0.98]

3 Heart failure hospitalisation (HR) Show forest plot

2

3670

Hazard Ratio (Fixed, 95% CI)

0.82 [0.69, 0.98]

4 Hyperkalaemia Show forest plot

6

4291

Risk Ratio (M‐H, Fixed, 95% CI)

2.11 [1.77, 2.51]

5 All‐cause mortality (RR) Show forest plot

5

4207

Risk Ratio (M‐H, Fixed, 95% CI)

0.91 [0.78, 1.06]

6 Quality of life Show forest plot

5

603

Std. Mean Difference (IV, Random, 95% CI)

0.05 [‐0.23, 0.34]

7 Quality of life (KCCQ) Show forest plot

2

92

Mean Difference (IV, Random, 95% CI)

‐0.78 [‐28.02, 26.46]

8 Quality of life (Minnesota) Show forest plot

3

511

Mean Difference (IV, Random, 95% CI)

0.84 [‐2.30, 3.98]

9 Withdrawal due to adverse event Show forest plot

4

3986

Risk Ratio (M‐H, Fixed, 95% CI)

1.10 [1.00, 1.21]

Figures and Tables -
Comparison 2. Mineralocorticoid receptor antagonists versus placebo or no treatment
Comparison 3. Angiotensin converting enzyme inhibitors versus placebo or no treatment

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Cardiovascular mortality (RR) Show forest plot

2

945

Risk Ratio (M‐H, Fixed, 95% CI)

0.93 [0.61, 1.42]

2 Heart failure hospitalisation (RR) Show forest plot

3

1019

Risk Ratio (M‐H, Fixed, 95% CI)

0.86 [0.64, 1.15]

2.1 Follow‐up < 12 months

1

74

Risk Ratio (M‐H, Fixed, 95% CI)

0.42 [0.09, 2.04]

2.2 Follow‐up ≥ 12 months

2

945

Risk Ratio (M‐H, Fixed, 95% CI)

0.88 [0.66, 1.19]

3 Hyperkalaemia Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

4 All‐cause mortality (RR) Show forest plot

4

1079

Risk Ratio (M‐H, Fixed, 95% CI)

0.99 [0.71, 1.38]

5 Quality of life (Minnesota) Show forest plot

2

154

Mean Difference (IV, Fixed, 95% CI)

‐0.09 [‐3.66, 3.48]

6 Withdrawal due to adverse event Show forest plot

3

1019

Risk Ratio (M‐H, Random, 95% CI)

1.53 [0.26, 9.00]

Figures and Tables -
Comparison 3. Angiotensin converting enzyme inhibitors versus placebo or no treatment
Comparison 4. Angiotensin receptor blockers versus placebo or no treatment

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Cardiovascular mortality (RR) Show forest plot

3

7254

Risk Ratio (M‐H, Fixed, 95% CI)

1.02 [0.90, 1.14]

2 Cardiovascular mortality (HR) Show forest plot

2

5087

Hazard Ratio (Fixed, 95% CI)

1.00 [0.89, 1.13]

3 Heart failure hospitalisation (RR) Show forest plot

3

7254

Risk Ratio (M‐H, Fixed, 95% CI)

0.92 [0.83, 1.02]

4 Heart failure hospitalisation (HR) Show forest plot

2

7148

Hazard Ratio (Fixed, 95% CI)

0.90 [0.80, 1.01]

5 Hyperkalaemia Show forest plot

2

7148

Risk Ratio (M‐H, Fixed, 95% CI)

1.88 [1.07, 3.33]

6 All‐cause mortality (RR) Show forest plot

4

7964

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.92, 1.11]

7 All‐cause mortality (HR) Show forest plot

2

4838

Hazard Ratio (Fixed, 95% CI)

0.99 [0.88, 1.12]

8 Quality of life (Minnesota) Show forest plot

3

3117

Mean Difference (IV, Fixed, 95% CI)

0.41 [‐0.86, 1.67]

9 Withdrawal due to adverse event Show forest plot

4

7406

Risk Ratio (M‐H, Fixed, 95% CI)

1.22 [1.09, 1.36]

Figures and Tables -
Comparison 4. Angiotensin receptor blockers versus placebo or no treatment