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

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

doi:10.1002/14651858.CD012721.pub3

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Figure 1

Study flow diagram

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Figure 2

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

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Figure 3

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

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Analysis 1.1

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

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Analysis 1.2

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

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Analysis 1.3

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

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Analysis 1.4

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

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Analysis 1.5

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

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Analysis 2.1

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

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Analysis 2.2

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

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Analysis 2.3

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

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Analysis 2.4

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

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Analysis 2.5

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

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Analysis 2.6

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

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Analysis 2.7

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

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Analysis 2.8

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

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Analysis 2.9

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

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Analysis 3.1

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

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Analysis 3.2

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

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Analysis 3.3

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

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Analysis 3.4

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

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Analysis 3.5

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

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Analysis 3.6

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

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Analysis 4.1

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

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Analysis 4.2

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

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Analysis 4.3

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

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Analysis 4.4

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

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Analysis 4.5

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

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Analysis 4.6

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

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Analysis 4.7

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

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Analysis 4.8

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

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Analysis 4.9

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

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Analysis 5.1

Comparison 5: ARNI versus usual care, Outcome 1: Cardiovascular mortality (RR)

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Analysis 5.2

Comparison 5: ARNI versus usual care, Outcome 2: Heart failure hospitalisation, first (RR)

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Analysis 5.3

Comparison 5: ARNI versus usual care, Outcome 3: Heart failure hospitalisation (HR)

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Analysis 5.4

Comparison 5: ARNI versus usual care, Outcome 4: Hyperkalaemia

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Analysis 5.5

Comparison 5: ARNI versus usual care, Outcome 5: All‐cause mortality (RR)

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Analysis 5.6

Comparison 5: ARNI versus usual care, Outcome 6: Withdrawal due to adverse event

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Summary of findings 1. Beta‐blockers compared to placebo or no treatment for chronic heart failure with preserved ejection fraction

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Beta‐blockers compared to placebo or no treatment for chronic heart failure with preserved ejection fraction
Patient or population: patients with chronic heart failure with preserved ejection fraction Setting: secondary care Intervention: beta‐blockers Comparison: placebo or no treatment
Outcomes	Risk with placebo or no treatment	Risk with beta‐blockers	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
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)	RR 0.78 (0.62 to 0.99)	1046 (3 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}
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}	Follow‐up unclear for SWEDIC. ELANDD reported that no hospitalisation due to heart failure occurred
	117 per 1000	86 per 1000 (55 to 133)	RR 0.73 (0.47 to 1.13)	449 (4 RCTs)	⊕⊝⊝⊝ VERY LOW ^{1 3}
Hyperkalaemia follow‐up: mean 3.2 years				245 (1 RCT)	⊕⊝⊝⊝ VERY LOW^{1 6}	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)	RR 0.82 (0.67 to 1.00)	1105 (4 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}
Quality of life (MLHFQ): from 0 to 105 follow‐up: mean 6 months	Mean quality of life (MLHFQ) was 24	MD 1 lower (9.05 lower to 7.05 higher)	‐	93 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{4 5}	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; MD: Mean difference; MLHFQ: Minnesota Living with Heart Failure Questionnaire; RCT: Randomised controlled trial; 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
¹Downgraded by one level due to study limitations (unclear selection bias in most studies). ²Downgraded by one level due to imprecision (concerns about the smaller study being more precise than the larger study). ³Downgraded by two levels due to imprecision (few events and wide CI). ⁴Downgraded by two levels due to imprecision (very small sample size). ⁵Downgraded by one level due to suspected publication bias (this is a patient‐relevant outcome that is not reported in most studies). ⁶Downgraded by two levels due to suspected publication bias (incomplete reporting).

Summary of findings 1. Beta‐blockers compared to placebo or no treatment for chronic heart failure with preserved ejection fraction

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Summary of findings 2. Mineralocorticoid receptor antagonists (MRAs) compared to placebo or no treatment for chronic heart failure with preserved ejection fraction

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
MRAs compared to placebo or no treatment for chronic heart failure with preserved ejection fraction
Patient or population: patients with chronic heart failure with preserved ejection fraction Setting: secondary care Intervention: MRAs Comparison: placebo or no treatment
Outcomes	Risk with placebo or no treatment	Risk with MRAs	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
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)	RR 0.90 (0.74 to 1.11)	4070 (3 RCTs)	⊕⊕⊕⊝ MODERATE ¹
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)	RR 0.82 (0.69 to 0.98)	3714 (3 RCTs)	⊕⊕⊕⊝ MODERATE ¹
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
Hyperkalaemia follow‐up: range 24 weeks to 3.3 years	83 per 1000	175 per 1000 (146 to 208)	RR 2.11 (1.77 to 2.52)	4291 (6 RCTs)	⊕⊕⊕⊕ HIGH	Two trials defined hyperkalaemia ≥ 5.5 mEg/L
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
All‐cause mortality follow‐up: range 9 months to 3.3 years	133 per 1000	121 per 1000 (104 to 141)	RR 0.91 (0.78 to 1.06)	4207 (5 RCTs)	⊕⊕⊕⊝ MODERATE ¹
Quality of life (MLHFQ): from 0 to 105 follow‐up: range 9 months to 12 months	Mean quality of life (MLHFQ) 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; MD: Mean difference; MLHFQ: Minnesota Living with Heart Failure Questionnaire; MRAs: Mineralocorticoid receptor antagonists; RCT: Randomised controlled trial; 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
¹Downgraded by one level due to imprecision. ²Downgraded by one level due to study limitations (one trial was open label). ³Downgraded by one level due to imprecision (small sample size).

Summary of findings 2. Mineralocorticoid receptor antagonists (MRAs) compared to placebo or no treatment for chronic heart failure with preserved ejection fraction

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Summary of findings 3. Angiotensin‐converting enzyme inhibitors (ACEIs) compared to placebo or no treatment for chronic heart failure with preserved ejection fraction

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
ACEIs compared to placebo or no treatment for chronic heart failure with preserved ejection fraction
Patient or population: patients with chronic heart failure with preserved ejection fraction Setting: secondary care Intervention: ACEIs Comparison: placebo or no treatment
Outcomes	Risk with placebo/no treatment	Risk with ACEI	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
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)	RR 0.93 (0.61 to 1.42)	945 (2 RCTs)	⊕⊕⊕⊝ MODERATE ¹
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)	RR 0.86 (0.64 to 1.15)	1019 (3 RCTs)	⊕⊕⊕⊝ MODERATE ¹
Hyperkalaemia follow‐up: 6 months				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 1.04 (0.75 to 1.45)	1187 (5 RCTs)	⊕⊕⊕⊝ MODERATE ¹	One additional trial (Kitzman 2010) reported that no deaths occurred
	102 per 1000	106 per 1000 (77 to 148)	RR 1.04 (0.75 to 1.45)	1187 (5 RCTs)	⊕⊕⊕⊝ MODERATE ¹
Quality of life (MLHFQ): from 0 to 105 follow‐up: mean 12 months	Mean quality of life (MLHFQ) 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). ACEIs: Angiotensin‐converting enzyme inhibitors; CI: Confidence interval; MD: Mean difference; MLHFQ: Minnesota Living with Heart Failure Questionnaire; RCT: Randomised controlled trial; 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
¹Downgraded by one level due to imprecision (wide CI). ²Downgraded by one level due to study limitations (risk of bias (open label)). ³Downgraded by one level due to imprecision (low sample size). ⁴Downgraded by one level due to study limitations (unclear selection bias).

Summary of findings 3. Angiotensin‐converting enzyme inhibitors (ACEIs) compared to placebo or no treatment for chronic heart failure with preserved ejection fraction

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Summary of findings 4. Angiotensin receptor blockers (ARBs) compared to placebo or no treatment for chronic heart failure with preserved ejection fraction

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
ARBs compared to placebo or no treatment for chronic heart failure with preserved ejection fraction
Patient or population: patients with chronic heart failure with preserved ejection fraction Setting: secondary care Intervention: ARBs Comparison: placebo or no treatment
Outcomes	Risk with placebo or no treatment	Risk with ARBs	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
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)	RR 1.02 (0.90 to 1.14)	7254 (3 RCTs)	⊕⊕⊕⊕ HIGH
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)	RR 0.92 (0.83 to 1.02)	7254 (3 RCTs)	⊕⊕⊕⊕ HIGH
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
Hyperkalaemia follow‐up: range 36.6 months to 49.5 months	3 per 1,000	5 per 1,000 (3 to 8)	RR 1.88 (1.07 to 3.33)	7148 (2 RCTs)	⊕⊕⊕⊕ HIGH
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)	RR 1.01 (0.92 to 1.11)	7964 (4 RCTs)	⊕⊕⊕⊕ HIGH
Quality of life (MLHFQ): from 0 to 105 follow‐up: range mean 13.8 weeks to mean 49.5 months	Mean quality of life (MLHFQ) 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). ARBs: Angiotensin receptor blockers; CI: Confidence interval; MD: Mean difference; MLHFQ: Minnesota Living with Heart Failure Questionnaire; RCT: Randomised controlled trial; 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

Summary of findings 4. Angiotensin receptor blockers (ARBs) compared to placebo or no treatment for chronic heart failure with preserved ejection fraction

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Summary of findings 5. Angiotensin receptor neprilysin inhibitors (ARNIs) compared to usual care for chronic heart failure with preserved ejection fraction

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
ARNIs compared to usual care for chronic heart failure with preserved ejection fraction
Patient or population: patients with chronic heart failure with preserved ejection fraction Setting: secondary care Intervention: ARNI (sacubitril‐valsartan) Comparison: ARB (valsartan)
Outcomes	Risk with usual care	Risk with ARNI	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Cardiovascular mortality (RR) Median follow‐up: 35 months	Study population		RR 0.96 (0.79 to 1.15)	4796 (1 study)	⊕⊕⊕⊝ MODERATE¹
Cardiovascular mortality (RR) Median follow‐up: 35 months	89 per 1,000	85 per 1,000 (70 to 102)	RR 0.96 (0.79 to 1.15)	4796 (1 study)	⊕⊕⊕⊝ MODERATE¹
Heart failure hospitalisation, first (RR) Range of follow‐up: 24 weeks to 35 months	Study population		RR 0.89 (0.80 to 1.00)	7362 (2 studies)	⊕⊕⊕⊝ MODERATE¹
	142 per 1,000	126 per 1,000 (113 to 142)	RR 0.89 (0.80 to 1.00)	7362 (2 studies)	⊕⊕⊕⊝ MODERATE¹
Hyperkalaemia Range of follow‐up: 36 weeks to 35 months	Study population		RR 0.88 (0.77 to 1.01)	5054 (2 studies)	⊕⊕⊕⊝ MODERATE¹
Hyperkalaemia Range of follow‐up: 36 weeks to 35 months	147 per 1,000	129 per 1,000 (113 to 148)	RR 0.88 (0.77 to 1.01)	5054 (2 studies)	⊕⊕⊕⊝ MODERATE¹
All‐cause mortality (RR) Range of follow‐up: 36 weeks to 35 months	Study population		(RR 0.97 CI 0.84 to 1.11)	7663 (3 studies)	⊕⊕⊕⊕ HIGH
	138 per 1,000	134 per 1,000 (117 to 153)	(RR 0.97 CI 0.84 to 1.11)	7663 (3 studies)	⊕⊕⊕⊕ HIGH
Quality of life Range of follow‐up: 36 weeks to 35 months	PARAMOUNT reported change from baseline for the KCCQ overall summary score for the intervention arm (n =118) as 11.25 (2.185) and the control arm (n = 116) as 11.31 (2.183) and summarised the findings as "no difference in KCCQ score between treatment groups". PARAGON‐HF reported a difference of the clinical summary score KCCQ between treatment arms as 1.0 (0.0 to 2.1). PARALLAX reported "KCCQ improved in both treatment groups, with an early benefit of S/V that was no longer significant after 24 week".				⊕⊕⊕⊕ HIGH
*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). ARB: Angiotensin receptor blocker; ARNIs: Angiotensin receptor neprilysin inhibitors; CI: Confidence interval; KCCQ: Kansas City Cardiomyopathy Questionnaire; MD: Mean difference; RCT: Randomised controlled trial; 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
¹Downgraded by one level due to imprecision.

Summary of findings 5. Angiotensin receptor neprilysin inhibitors (ARNIs) compared to usual care for chronic heart failure with preserved ejection fraction

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Comparison 1. Beta‐blockers versus placebo or no treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Cardiovascular mortality (RR) Show forest plot	3	1046	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.62, 0.99]

1.2 Heart failure hospitalisation (RR) Show forest plot	4	449	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.47, 1.13]

1.3 All‐cause mortality (RR) Show forest plot	4	1105	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.67, 1.00]

1.4 Quality of life (Minnesota) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.5 Withdrawal due to adverse event Show forest plot	2	338	Risk Ratio (M‐H, Fixed, 95% CI)	18.07 [2.45, 133.04]

Comparison 1. Beta‐blockers versus placebo or no treatment

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Comparison 2. Mineralocorticoid receptor antagonists versus placebo or no treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Cardiovascular mortality (RR) Show forest plot	3	4070	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.74, 1.11]

2.2 Heart failure hospitalisation (RR) Show forest plot	3	3714	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.69, 0.98]

2.3 Heart failure hospitalisation (HR) Show forest plot	2	3670	Hazard Ratio (IV, Fixed, 95% CI)	0.82 [0.69, 0.98]

2.4 Hyperkalaemia Show forest plot	6	4291	Risk Ratio (M‐H, Fixed, 95% CI)	2.11 [1.77, 2.51]

2.5 All‐cause mortality (RR) Show forest plot	5	4207	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.78, 1.06]

2.6 Quality of life Show forest plot	5	603	Std. Mean Difference (IV, Random, 95% CI)	0.05 [‐0.23, 0.34]

2.7 Quality of life (KCCQ) Show forest plot	2	92	Mean Difference (IV, Random, 95% CI)	‐0.78 [‐28.02, 26.46]

2.8 Quality of life (Minnesota) Show forest plot	3	511	Mean Difference (IV, Random, 95% CI)	0.84 [‐2.30, 3.98]

2.9 Withdrawal due to adverse event Show forest plot	5	4037	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [1.00, 1.21]

Comparison 2. Mineralocorticoid receptor antagonists versus placebo or no treatment

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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
3.1 Cardiovascular mortality (RR) Show forest plot	2	945	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.61, 1.42]

3.2 Heart failure hospitalisation (RR) Show forest plot	3	1019	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.64, 1.15]

3.3 Hyperkalaemia Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.4 All‐cause mortality (RR) Show forest plot	5	1187	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.75, 1.45]

3.5 Quality of life (Minnesota) Show forest plot	2	154	Mean Difference (IV, Fixed, 95% CI)	‐0.09 [‐3.66, 3.48]

3.6 Withdrawal due to adverse event Show forest plot	4	1127	Risk Ratio (M‐H, Random, 95% CI)	2.52 [0.49, 12.87]

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

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Comparison 4. Angiotensin receptor blockers versus placebo or no treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Cardiovascular mortality (RR) Show forest plot	3	7254	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.90, 1.14]

4.2 Cardiovascular mortality (HR) Show forest plot	2	7148	Hazard Ratio (IV, Fixed, 95% CI)	1.00 [0.89, 1.13]

4.3 Heart failure hospitalisation (RR) Show forest plot	3	7254	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.83, 1.02]

4.4 Heart failure hospitalisation (HR) Show forest plot	2	7148	Hazard Ratio (IV, Fixed, 95% CI)	0.90 [0.80, 1.01]

4.5 Hyperkalaemia Show forest plot	2	7148	Risk Ratio (M‐H, Fixed, 95% CI)	1.88 [1.07, 3.33]

4.6 All‐cause mortality (RR) Show forest plot	4	7964	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.92, 1.11]

4.7 All‐cause mortality (HR) Show forest plot	2	4838	Hazard Ratio (IV, Fixed, 95% CI)	0.99 [0.88, 1.12]

4.8 Quality of life (Minnesota) Show forest plot	3	3117	Mean Difference (IV, Fixed, 95% CI)	0.41 [‐0.86, 1.67]

4.9 Withdrawal due to adverse event Show forest plot	4	7406	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [1.09, 1.36]

Comparison 4. Angiotensin receptor blockers versus placebo or no treatment

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Comparison 5. ARNI versus usual care

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Cardiovascular mortality (RR) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5.2 Heart failure hospitalisation, first (RR) Show forest plot	2	7362	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.80, 1.00]

5.3 Heart failure hospitalisation (HR) Show forest plot	2	7362	Hazard Ratio (IV, Fixed, 95% CI)	0.87 [0.76, 0.99]

5.4 Hyperkalaemia Show forest plot	2	5054	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.77, 1.01]

5.5 All‐cause mortality (RR) Show forest plot	3	7663	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.84, 1.11]

5.6 Withdrawal due to adverse event Show forest plot	3	7663	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.91, 1.14]

Comparison 5. ARNI versus usual care

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