Blood pressure lowering efficacy of beta‐1 selective beta blockers for primary hypertension

Gavin WK Wong; Heidi N Boyda; James M Wright

doi:10.1002/14651858.CD007451.pub2

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Figure 1

PRISMA 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 nebivolol 5 mg to 20 mg (SBP)

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Figure 4

Funnel plot of nebivolol 5 mg to 20 mg (DBP)

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Analysis 1.1

Comparison 1 Nebivolol vs Placebo, Outcome 1 SBP.

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Analysis 1.2

Comparison 1 Nebivolol vs Placebo, Outcome 2 DBP.

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Analysis 1.3

Comparison 1 Nebivolol vs Placebo, Outcome 3 Heart rate.

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Analysis 1.4

Comparison 1 Nebivolol vs Placebo, Outcome 4 Pulse Pressure.

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Analysis 1.5

Comparison 1 Nebivolol vs Placebo, Outcome 5 Peak vs Trough SBP.

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Analysis 1.6

Comparison 1 Nebivolol vs Placebo, Outcome 6 Peak vs Trough DBP.

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Analysis 2.1

Comparison 2 Atenolol vs Placebo, Outcome 1 SBP.

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Analysis 2.2

Comparison 2 Atenolol vs Placebo, Outcome 2 DBP.

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Analysis 2.3

Comparison 2 Atenolol vs Placebo, Outcome 3 Heart rate.

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Analysis 2.4

Comparison 2 Atenolol vs Placebo, Outcome 4 Pulse pressure.

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Analysis 3.1

Comparison 3 Metoprolol vs Placebo, Outcome 1 SBP.

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Analysis 3.2

Comparison 3 Metoprolol vs Placebo, Outcome 2 DBP.

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Analysis 3.3

Comparison 3 Metoprolol vs Placebo, Outcome 3 Heart rate.

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Analysis 3.4

Comparison 3 Metoprolol vs Placebo, Outcome 4 Pulse pressure.

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Analysis 4.1

Comparison 4 Bisoprolol vs placebo, Outcome 1 SBP.

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Analysis 4.2

Comparison 4 Bisoprolol vs placebo, Outcome 2 DBP.

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Analysis 4.3

Comparison 4 Bisoprolol vs placebo, Outcome 3 Heart rate.

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Analysis 4.4

Comparison 4 Bisoprolol vs placebo, Outcome 4 Pulse pressure.

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Analysis 5.1

Comparison 5 Betaxolol vs Placebo, Outcome 1 SBP.

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Analysis 5.2

Comparison 5 Betaxolol vs Placebo, Outcome 2 DBP.

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Analysis 5.3

Comparison 5 Betaxolol vs Placebo, Outcome 3 Heart rate.

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Analysis 5.4

Comparison 5 Betaxolol vs Placebo, Outcome 4 Pulse pressure.

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Analysis 6.1

Comparison 6 Bevantolol vs Placebo, Outcome 1 SBP.

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Analysis 6.2

Comparison 6 Bevantolol vs Placebo, Outcome 2 DBP.

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Analysis 6.3

Comparison 6 Bevantolol vs Placebo, Outcome 3 Heart rate.

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Analysis 6.4

Comparison 6 Bevantolol vs Placebo, Outcome 4 Pulse pressure.

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Analysis 7.1

Comparison 7 Pafenolol vs Placebo, Outcome 1 SBP.

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Analysis 7.2

Comparison 7 Pafenolol vs Placebo, Outcome 2 DBP.

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Analysis 7.3

Comparison 7 Pafenolol vs Placebo, Outcome 3 Heart rate.

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Analysis 7.4

Comparison 7 Pafenolol vs Placebo, Outcome 4 Pulse pressure.

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Analysis 8.1

Comparison 8 Practolol vs Placebo, Outcome 1 SBP.

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Analysis 8.2

Comparison 8 Practolol vs Placebo, Outcome 2 DBP.

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Analysis 8.3

Comparison 8 Practolol vs Placebo, Outcome 3 Heart rate.

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Analysis 8.4

Comparison 8 Practolol vs Placebo, Outcome 4 Pulse pressure.

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Analysis 9.1

Comparison 9 Pooled overall effect, Outcome 1 SBP.

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Analysis 9.2

Comparison 9 Pooled overall effect, Outcome 2 DBP.

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Analysis 9.3

Comparison 9 Pooled overall effect, Outcome 3 Heart rate.

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Analysis 9.4

Comparison 9 Pooled overall effect, Outcome 4 Pulse pressure.

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Analysis 9.5

Comparison 9 Pooled overall effect, Outcome 5 WDAE.

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Analysis 9.6

Comparison 9 Pooled overall effect, Outcome 6 SBP combined starting dose and 2 x starting dose.

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Analysis 9.7

Comparison 9 Pooled overall effect, Outcome 7 DBP combined starting dose and 2 x starting dose.

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Analysis 9.8

Comparison 9 Pooled overall effect, Outcome 8 Heart rate combined starting dose and 2 x starting dose.

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Analysis 9.9

Comparison 9 Pooled overall effect, Outcome 9 Pulse pressure combined starting dose and 2 x starting dose.

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Analysis 9.10

Comparison 9 Pooled overall effect, Outcome 10 SBP test for 2 x starting dose subgroup difference.

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Analysis 9.11

Comparison 9 Pooled overall effect, Outcome 11 DBP test for 2 x starting dose subgroup difference.

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Analysis 9.12

Comparison 9 Pooled overall effect, Outcome 12 Heart rate test for 2 x starting dose subgroup difference.

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Blood pressure lowering effects of beta‐1 blockers compared with placebo for primary hypertension
Patient or population: People with primary hypertension Intervention: Beta‐1 selective blockers Comparison: Placebo
Outcomes	mean estimates of combining 1x and 2x starting dose (95% CI)	No of Participants (No. of RCT)	Quality of the evidence (GRADE)
Systolic blood pressure	‐10.4 (‐11.1, ‐9.7)^1,2,3	5246 (47)	Low^4,5
Diastolic blood pressure	‐8.3 (‐8.7, ‐7.8)^1,2,3	5316 (48)	Low^4,5
Heart rate	‐10.9 (‐11.5, ‐10.4)^1,2	3407 (33)	Low^4,5
Pulse pressure	‐1.8 [‐2.3, ‐1.2]^1,2	5246 (47)	Very low^4,5,6
WDAE	0.9 (0.5, 1.5)	2618 (3)	Low^7,8
95% CI: 95% confident interval; WDAE: Withdrawal due to adverse effect.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
Footnotes
The data for this analysis is from recommended starting and 2x the starting dose. Combining them provides the best estimate of the subclass effect. Half of measurements at peak hours and the other half at trough hours. The mean baseline BP was 156/101 mmHg. Downgraded due to publication bias, extreme outliers causing significant heterogeneity within some subgroups. Downgraded due to high risk of detection bias caused by loss of blinding. Downgraded due to indirectness, none of the studies reported pulse pressure. Pulse pressure was calculated by subtracting DBP from SBP. Downgraded due to imprecision. Downgraded due to selective reporting bias.

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Comparison 1. Nebivolol vs Placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SBP Show forest plot	13		Mean Difference (Fixed, 95% CI)	Subtotals only

1.1 (0.25 x starting dose) 1.0 & 1.25 mg/day	3	366	Mean Difference (Fixed, 95% CI)	‐4.49 [‐7.15, ‐1.83]
1.2 (0.5 x starting dose) 2.5 mg/day	3	415	Mean Difference (Fixed, 95% CI)	‐4.96 [‐7.66, ‐2.26]
1.3 (starting dose) 5 mg/day	12	1280	Mean Difference (Fixed, 95% CI)	‐8.81 [‐10.23, ‐7.40]
1.4 (2 x starting dose) 10 mg/day	6	1684	Mean Difference (Fixed, 95% CI)	‐6.04 [‐7.47, ‐4.60]
1.5 (4 x starting dose) 20 mg/day	3	652	Mean Difference (Fixed, 95% CI)	‐6.95 [‐9.26, ‐4.63]
1.6 (8 x starting dose) 30, 40 mg/day	3	1155	Mean Difference (Fixed, 95% CI)	‐8.10 [‐9.84, ‐6.36]
2 DBP Show forest plot	13		Mean Difference (Fixed, 95% CI)	Subtotals only

2.1 (0.25 x starting dose) 1.0 & 1.25 mg/day	3	366	Mean Difference (Fixed, 95% CI)	‐3.55 [‐5.17, ‐1.93]
2.2 (0.5 x starting dose) 2.5 mg/day	3	415	Mean Difference (Fixed, 95% CI)	‐4.23 [‐5.76, ‐2.70]
2.3 (starting dose) 5 mg/day	12	1280	Mean Difference (Fixed, 95% CI)	‐6.67 [‐7.54, ‐5.80]
2.4 (2 x starting dose) 10 mg/day	6	1684	Mean Difference (Fixed, 95% CI)	‐5.90 [‐6.78, ‐5.01]
2.5 (4 x starting dose) 20 mg/day	3	652	Mean Difference (Fixed, 95% CI)	‐5.81 [‐7.21, ‐4.41]
2.6 (8 x starting dose) 30, 40 mg/day	3	1155	Mean Difference (Fixed, 95% CI)	‐7.70 [‐8.80, ‐6.61]
3 Heart rate Show forest plot	8		Mean Difference (Fixed, 95% CI)	Subtotals only

3.1 (0.25 x starting dose) 1.25 mg/day	1	136	Mean Difference (Fixed, 95% CI)	‐2.9 [‐5.86, 0.06]
3.2 (0.5 x starting dose) 2.5 mg/day	2	218	Mean Difference (Fixed, 95% CI)	‐3.89 [‐6.18, ‐1.61]
3.3 (starting dose) 5 mg/day	7	487	Mean Difference (Fixed, 95% CI)	‐8.21 [‐9.66, ‐6.76]
3.4 (2 x starting dose) 10 mg/day	3	1120	Mean Difference (Fixed, 95% CI)	‐7.23 [‐8.48, ‐5.99]
3.5 (4 x starting dose) 20 mg/day	2	298	Mean Difference (Fixed, 95% CI)	‐8.43 [‐10.48, ‐6.38]
3.6 (8 x starting dose) 30, 40 mg/day	3	1155	Mean Difference (Fixed, 95% CI)	‐10.94 [‐12.18, ‐9.71]
4 Pulse Pressure Show forest plot	13		Mean Difference (Fixed, 95% CI)	Subtotals only

4.1 (0.25 x starting dose) 1.0 & 1.25 mg/day	3	366	Mean Difference (Fixed, 95% CI)	‐0.88 [‐3.21, 1.45]
4.2 (0.5 x starting dose) 2.5 mg/day	3	415	Mean Difference (Fixed, 95% CI)	‐0.95 [‐3.32, 1.41]
4.3 (starting dose) 5 mg/day	12	1314	Mean Difference (Fixed, 95% CI)	‐1.62 [‐2.83, ‐0.41]
4.4 (2 x starting dose) 10 mg/day	6	1684	Mean Difference (Fixed, 95% CI)	‐0.19 [‐1.47, 1.08]
4.5 (4 x starting dose) 20 mg/day	3	652	Mean Difference (Fixed, 95% CI)	‐1.25 [‐3.38, 0.89]
4.6 (8 x starting dose) 30, 40 mg/day	3	1155	Mean Difference (Fixed, 95% CI)	‐0.37 [‐1.94, 1.20]
5 Peak vs Trough SBP Show forest plot	4		Mean Difference (Fixed, 95% CI)	Subtotals only

5.1 (0.25 x starting dose) 1.0 & 1.25 mg/day	2	335	Mean Difference (Fixed, 95% CI)	0.30 [‐1.90, 2.49]
5.2 (0.5 x starting dose) 2.5 mg/day	3	415	Mean Difference (Fixed, 95% CI)	‐1.24 [‐3.28, 0.81]
5.3 (starting dose) 5 mg/day	4	817	Mean Difference (Fixed, 95% CI)	1.40 [0.14, 2.66]
5.4 (2 x starting dose) 10 mg/day	4	822	Mean Difference (Fixed, 95% CI)	‐0.17 [‐1.42, 1.08]
5.5 (4 x starting dose) 20 mg/day	3	652	Mean Difference (Fixed, 95% CI)	1.17 [‐0.27, 2.61]
5.6 (8 x starting dose) 30, 40 mg/day	2	331	Mean Difference (Fixed, 95% CI)	‐1.20 [‐3.19, 0.78]
6 Peak vs Trough DBP Show forest plot	4	3372	Mean Difference (Fixed, 95% CI)	‐1.53 [‐1.95, ‐1.11]

6.1 (0.25 x starting dose) 1.0 & 1.25 mg/day	2	335	Mean Difference (Fixed, 95% CI)	‐0.95 [‐2.38, 0.48]
6.2 (0.5 x starting dose) 2.5 mg/day	3	415	Mean Difference (Fixed, 95% CI)	‐1.88 [‐3.12, ‐0.64]
6.3 (starting dose) 5 mg/day	4	817	Mean Difference (Fixed, 95% CI)	‐1.54 [‐2.52, ‐0.57]
6.4 (2 x starting dose) 10 mg/day	4	822	Mean Difference (Fixed, 95% CI)	‐1.06 [‐1.86, ‐0.26]
6.5 (4 x starting dose) 20 mg/day	3	652	Mean Difference (Fixed, 95% CI)	‐1.53 [‐2.41, ‐0.65]
6.6 (8 x starting dose) 30, 40 mg/day	2	331	Mean Difference (Fixed, 95% CI)	‐2.73 [‐3.98, ‐1.49]

Comparison 1. Nebivolol vs Placebo

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Comparison 2. Atenolol vs Placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SBP Show forest plot	22		Mean Difference (Fixed, 95% CI)	Subtotals only

1.1 (0.5 x starting dose) 25 mg/day	1	87	Mean Difference (Fixed, 95% CI)	‐7.0 [‐12.55, ‐1.45]
1.2 (starting dose) 50 mg/day	11	669	Mean Difference (Fixed, 95% CI)	‐10.28 [‐11.94, ‐8.62]
1.3 (2 x starting dose) 100 mg/day	12	495	Mean Difference (Fixed, 95% CI)	‐15.34 [‐16.86, ‐13.82]
1.4 (4 x starting dose) 150 & 200 mg/day	3	121	Mean Difference (Fixed, 95% CI)	‐11.29 [‐14.03, ‐8.55]
2 DBP Show forest plot	22		Mean Difference (Fixed, 95% CI)	Subtotals only

2.1 (0.5 x starting dose) 25 mg/day	1	87	Mean Difference (Fixed, 95% CI)	‐4.0 [‐6.76, ‐1.24]
2.2 (starting dose) 50 mg/day	11	657	Mean Difference (Fixed, 95% CI)	‐7.78 [‐8.80, ‐6.76]
2.3 (2 x starting dose) 100 mg/day	12	495	Mean Difference (Fixed, 95% CI)	‐12.91 [‐13.89, ‐11.93]
2.4 (4 x starting dose) 150, 200 mg/day	3	121	Mean Difference (Fixed, 95% CI)	‐8.76 [‐10.56, ‐6.95]
3 Heart rate Show forest plot	17		Mean Difference (Fixed, 95% CI)	Subtotals only

3.1 (0.5 x starting dose) 25 mg/day	1	87	Mean Difference (Fixed, 95% CI)	‐4.0 [‐9.55, 1.55]
3.2 (starting dose) 50 mg/day	7	470	Mean Difference (Fixed, 95% CI)	‐12.04 [‐13.39, ‐10.68]
3.3 (2 x starting dose) 100 mg/day	10	413	Mean Difference (Fixed, 95% CI)	‐13.70 [‐14.83, ‐12.56]
3.4 (4 x starting dose) 150, 200 mg/day	4	129	Mean Difference (Fixed, 95% CI)	‐18.33 [‐20.26, ‐16.41]
4 Pulse pressure Show forest plot	22		Mean Difference (Fixed, 95% CI)	Subtotals only

4.1 (0.5 x starting dose) 25 mg/day	1	87	Mean Difference (Fixed, 95% CI)	‐3.0 [‐7.80, 1.80]
4.2 (starting dose) 50 mg/day	11	669	Mean Difference (Fixed, 95% CI)	‐2.30 [‐3.71, ‐0.90]
4.3 (2 x starting dose) 100 mg/day	12	495	Mean Difference (Fixed, 95% CI)	‐2.01 [‐3.24, ‐0.77]
4.4 (4 x starting dose) 150, 200 mg/day	3	121	Mean Difference (Fixed, 95% CI)	‐2.62 [‐4.82, ‐0.42]

Comparison 2. Atenolol vs Placebo

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Comparison 3. Metoprolol vs Placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SBP Show forest plot	9		Mean Difference (Fixed, 95% CI)	Subtotals only

1.1 (0.25 x starting dose) 25 mg/day	2	424	Mean Difference (Fixed, 95% CI)	‐6.33 [‐9.22, ‐3.44]
1.2 (0.5 x starting dose) 50 mg/day	2	339	Mean Difference (Fixed, 95% CI)	‐6.30 [‐9.47, ‐3.13]
1.3 (starting dose) 100 mg/day	3	410	Mean Difference (Fixed, 95% CI)	‐5.35 [‐8.12, ‐2.58]
1.4 (2 x starting dose) 200 mg/day	5	284	Mean Difference (Fixed, 95% CI)	‐11.54 [‐14.37, ‐8.71]
1.5 (4 x starting dose) 400 mg/day	2	193	Mean Difference (Fixed, 95% CI)	‐10.91 [‐15.42, ‐6.40]
2 DBP Show forest plot	9		Mean Difference (Fixed, 95% CI)	Subtotals only

2.1 (0.25 x starting dose) 25 mg/day	2	424	Mean Difference (Fixed, 95% CI)	‐3.64 [‐5.44, ‐1.85]
2.2 (0.5 x starting dose) 50 mg/day	2	339	Mean Difference (Fixed, 95% CI)	‐4.56 [‐6.42, ‐2.70]
2.3 (starting dose) 100 & 120 mg/day	3	410	Mean Difference (Fixed, 95% CI)	‐4.74 [‐6.50, ‐2.98]
2.4 (2 x starting dose) 200 mg/day	5	284	Mean Difference (Fixed, 95% CI)	‐10.25 [‐11.99, ‐8.51]
2.5 (4 x starting dose) 400 mg/day	2	193	Mean Difference (Fixed, 95% CI)	‐7.71 [‐10.72, ‐4.69]
3 Heart rate Show forest plot	5		Mean Difference (Fixed, 95% CI)	Subtotals only

3.1 (0.5 x starting dose) 50 mg/day	1	94	Mean Difference (Fixed, 95% CI)	‐5.6 [‐10.03, ‐1.17]
3.2 (starting dose) 100 & 120 mg/day	1	24	Mean Difference (Fixed, 95% CI)	‐15.0 [‐18.92, ‐11.08]
3.3 (2 x starting dose) 200 mg/day	2	40	Mean Difference (Fixed, 95% CI)	‐13.25 [‐17.04, ‐9.46]
3.4 (4 x starting dose) 400 mg/day	1	8	Mean Difference (Fixed, 95% CI)	‐20.00 [‐25.88, ‐14.12]
4 Pulse pressure Show forest plot	9		Mean Difference (Fixed, 95% CI)	Subtotals only

4.1 (0.25 x starting dose) 25 mg/day	2	424	Mean Difference (Fixed, 95% CI)	‐2.70 [‐5.23, ‐0.17]
4.2 (0.5 x starting dose) 50 mg/day	2	339	Mean Difference (Fixed, 95% CI)	‐1.74 [‐4.52, 1.04]
4.3 (starting dose) 100 mg/day	3	410	Mean Difference (Fixed, 95% CI)	‐0.58 [‐3.01, 1.85]
4.4 (2 x starting dose) 200 mg/day	5	284	Mean Difference (Fixed, 95% CI)	‐1.22 [‐3.62, 1.18]
4.5 (4 x starting dose) 400 mg/day	2	193	Mean Difference (Fixed, 95% CI)	‐3.30 [‐7.29, 0.69]

Comparison 3. Metoprolol vs Placebo

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Comparison 4. Bisoprolol vs placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SBP Show forest plot	6		Mean Difference (Fixed, 95% CI)	Subtotals only

1.1 (starting dose) 5 mg/day	5	422	Mean Difference (Fixed, 95% CI)	‐11.40 [‐13.67, ‐9.13]
1.2 (2 x starting dose) 10 mg/day	2	134	Mean Difference (Fixed, 95% CI)	‐7.03 [‐11.07, ‐2.99]
1.3 (4 x starting dose) 20 mg/day	1	121	Mean Difference (Fixed, 95% CI)	‐7.6 [‐12.60, ‐2.60]
2 DBP Show forest plot	7		Mean Difference (Fixed, 95% CI)	Subtotals only

2.1 (starting dose) 5 mg/day	6	462	Mean Difference (Fixed, 95% CI)	‐8.16 [‐9.49, ‐6.84]
2.2 (2 x starting dose) 10 mg/day	3	173	Mean Difference (Fixed, 95% CI)	‐7.44 [‐9.88, ‐5.01]
2.3 (4 x starting dose) 20 mg/day	1	121	Mean Difference (Fixed, 95% CI)	‐8.5 [‐11.56, ‐5.44]
3 Heart rate Show forest plot	6		Mean Difference (Fixed, 95% CI)	Subtotals only

3.1 (starting dose) 5 mg/day	5	236	Mean Difference (Fixed, 95% CI)	‐6.91 [‐8.82, ‐4.99]
3.2 (2 x starting dose) 10 mg/day	3	173	Mean Difference (Fixed, 95% CI)	‐10.19 [‐12.87, ‐7.52]
3.3 (4 x starting dose) 20 mg/day	1	121	Mean Difference (Fixed, 95% CI)	‐11.1 [‐14.98, ‐7.22]
4 Pulse pressure Show forest plot	6		Mean Difference (Fixed, 95% CI)	Subtotals only

4.1 (starting dose) 5 mg/day	5	422	Mean Difference (Fixed, 95% CI)	‐3.35 [‐5.32, ‐1.38]
4.2 (2 x starting dose) 10 mg/day	2	134	Mean Difference (Fixed, 95% CI)	1.65 [‐1.96, 5.26]
4.3 (4 x starting dose) 20 mg/day	1	121	Mean Difference (Fixed, 95% CI)	0.9 [‐3.45, 5.25]

Comparison 4. Bisoprolol vs placebo

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Comparison 5. Betaxolol vs Placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SBP Show forest plot	2		Mean Difference (Fixed, 95% CI)	Subtotals only

1.1 (0.5 x starting dose) 5 mg/day	1	148	Mean Difference (Fixed, 95% CI)	‐5.81 [‐10.55, ‐1.07]
1.2 (starting dose) 10 mg/day	1	146	Mean Difference (Fixed, 95% CI)	‐8.2 [‐12.94, ‐3.46]
1.3 (2 x starting dose) 20 mg/day	2	477	Mean Difference (Fixed, 95% CI)	‐11.25 [‐13.21, ‐9.29]
2 DBP Show forest plot	2		Mean Difference (Fixed, 95% CI)	Subtotals only

2.1 (0.5 x starting dose) 5 mg/day	1	148	Mean Difference (Fixed, 95% CI)	‐3.8 [‐6.54, ‐1.06]
2.2 (starting dose) 10 mg/day	1	146	Mean Difference (Fixed, 95% CI)	‐6.5 [‐9.24, ‐3.76]
2.3 (2 x starting dose) 20 mg/day	2	477	Mean Difference (Fixed, 95% CI)	‐7.94 [‐9.17, ‐6.71]
3 Heart rate Show forest plot	2		Mean Difference (Fixed, 95% CI)	Subtotals only

3.1 (0.5 x starting dose) 5 mg/day	1	148	Mean Difference (Fixed, 95% CI)	‐7.4 [‐10.34, ‐4.46]
3.2 (starting dose) 10 mg/day	1	146	Mean Difference (Fixed, 95% CI)	‐8.2 [‐11.14, ‐5.26]
3.3 (2 x starting dose) 20 mg/day	2	477	Mean Difference (Fixed, 95% CI)	‐13.40 [‐15.03, ‐11.77]
4 Pulse pressure Show forest plot	2		Mean Difference (Fixed, 95% CI)	Subtotals only

4.1 (0.5x starting dose) 5 mg/day	1	148	Mean Difference (Fixed, 95% CI)	‐1.1 [‐5.24, 3.04]
4.2 (starting dose) 10 mg/day	1	146	Mean Difference (Fixed, 95% CI)	‐1.7 [‐5.84, 2.44]
4.3 (2 x starting dose) 20 mg/day	2	477	Mean Difference (Fixed, 95% CI)	‐3.26 [‐5.00, ‐1.52]

Comparison 5. Betaxolol vs Placebo

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Comparison 6. Bevantolol vs Placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SBP Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.1 Bevantolol 100mg/day	1	35	Mean Difference (IV, Fixed, 95% CI)	‐13.0 [‐29.57, 3.57]
1.2 Bevantolol 200mg/day	1	35	Mean Difference (IV, Fixed, 95% CI)	‐9.0 [‐25.57, 7.57]
1.3 Bevantolol 300mg/day	1	35	Mean Difference (IV, Fixed, 95% CI)	‐7.0 [‐23.57, 9.57]
1.4 Bevantolol 400mg/day	1	35	Mean Difference (IV, Fixed, 95% CI)	‐8.0 [‐24.57, 8.57]
2 DBP Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

2.1 Bevantolol 100mg/day	1	35	Mean Difference (IV, Fixed, 95% CI)	‐5.0 [‐15.52, 5.52]
2.2 Bevantolol 200mg/day	1	35	Mean Difference (IV, Fixed, 95% CI)	‐9.0 [‐19.52, 1.52]
2.3 Bevantolol 300mg/day	1	35	Mean Difference (IV, Fixed, 95% CI)	‐9.0 [‐19.52, 1.52]
2.4 Bevantolol 400mg/day	1	35	Mean Difference (IV, Fixed, 95% CI)	‐10.0 [‐20.52, 0.52]
3 Heart rate Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

3.1 Bevantolol 100mg/day	1	35	Mean Difference (IV, Fixed, 95% CI)	‐13.0 [‐29.57, 3.57]
3.2 Bevantolol 200mg/day	1	35	Mean Difference (IV, Fixed, 95% CI)	‐9.0 [‐25.57, 7.57]
3.3 Bevantolol 300mg/day	1	35	Mean Difference (IV, Fixed, 95% CI)	‐7.0 [‐23.57, 9.57]
3.4 Bevantolol 400mg/day	1	35	Mean Difference (IV, Fixed, 95% CI)	‐8.0 [‐24.57, 8.57]
4 Pulse pressure Show forest plot	1		Mean Difference (Fixed, 95% CI)	Subtotals only

4.1 Bevantolol 100mg/day	1		Mean Difference (Fixed, 95% CI)	‐8.0 [‐22.52, 6.52]
4.2 Bevantolol 200mg/day	1		Mean Difference (Fixed, 95% CI)	0.0 [‐14.52, 14.52]
4.3 Bevantolol 300mg/day	1		Mean Difference (Fixed, 95% CI)	2.0 [‐12.56, 16.56]
4.4 Bevantolol 400mg/day	1		Mean Difference (Fixed, 95% CI)	2.0 [‐12.52, 16.52]

Comparison 6. Bevantolol vs Placebo

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Comparison 7. Pafenolol vs Placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SBP Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.1 25 mg/day	1	21	Mean Difference (IV, Fixed, 95% CI)	3.0 [‐11.79, 17.79]
1.2 50 mg/day	2	33	Mean Difference (IV, Fixed, 95% CI)	‐5.94 [‐17.57, 5.68]
1.3 100 mg/day	1	14	Mean Difference (IV, Fixed, 95% CI)	‐6.0 [‐22.94, 10.94]
2 DBP Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

2.1 25 mg/day	1	21	Mean Difference (IV, Fixed, 95% CI)	‐8.0 [‐16.73, 0.73]
2.2 50 mg/day	2	33	Mean Difference (IV, Fixed, 95% CI)	‐4.41 [‐11.22, 2.40]
2.3 100 mg/day	1	14	Mean Difference (IV, Fixed, 95% CI)	‐2.0 [‐12.75, 8.75]
3 Heart rate Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

3.1 25 mg/day	1	21	Mean Difference (IV, Fixed, 95% CI)	‐3.0 [‐12.93, 6.93]
3.2 50 mg/day	2	33	Mean Difference (IV, Fixed, 95% CI)	‐8.14 [‐15.91, ‐0.36]
3.3 100 mg/day	1	14	Mean Difference (IV, Fixed, 95% CI)	‐20.0 [‐32.60, ‐7.40]
4 Pulse pressure Show forest plot	2		Mean Difference (Fixed, 95% CI)	Subtotals only

4.1 25 mg/day	1	21	Mean Difference (Fixed, 95% CI)	11.0 [‐1.82, 23.82]
4.2 50 mg/day	2	33	Mean Difference (Fixed, 95% CI)	‐1.75 [‐11.86, 8.37]
4.3 100 mg/day	1	14	Mean Difference (Fixed, 95% CI)	‐4.0 [‐18.86, 10.86]

Comparison 7. Pafenolol vs Placebo

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Comparison 8. Practolol vs Placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SBP Show forest plot	1	24	Mean Difference (Fixed, 95% CI)	‐21.2 [‐29.31, ‐13.09]

1.1 Practolol 600mg/day	1	24	Mean Difference (Fixed, 95% CI)	‐21.2 [‐29.31, ‐13.09]
2 DBP Show forest plot	1	24	Mean Difference (Fixed, 95% CI)	‐13.9 [‐17.00, ‐8.80]

2.1 Practolol 600mg/day	1	24	Mean Difference (Fixed, 95% CI)	‐13.9 [‐17.00, ‐8.80]
3 Heart rate Show forest plot	1	24	Mean Difference (Fixed, 95% CI)	‐14.0 [‐21.45, ‐6.55]

3.1 Practolol 600mg/day	1	24	Mean Difference (Fixed, 95% CI)	‐14.0 [‐21.45, ‐6.55]
4 Pulse pressure Show forest plot	1	24	Mean Difference (Fixed, 95% CI)	‐7.30 [‐14.41, ‐0.19]

4.1 Practolol 600mg/day	1	24	Mean Difference (Fixed, 95% CI)	‐7.30 [‐14.41, ‐0.19]

Comparison 8. Practolol vs Placebo

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Comparison 9. Pooled overall effect

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SBP Show forest plot	50		Mean Difference (Fixed, 95% CI)	Subtotals only

1.1 0.25 x starting dose	5	790	Mean Difference (Fixed, 95% CI)	‐5.34 [‐7.29, ‐3.38]
1.2 0.5 x starting dose	7	941	Mean Difference (Fixed, 95% CI)	‐5.71 [‐7.59, ‐3.82]
1.3 starting dose	30	2879	Mean Difference (Fixed, 95% CI)	‐9.29 [‐10.21, ‐8.38]
1.4 2 x starting dose	27	3026	Mean Difference (Fixed, 95% CI)	‐10.58 [‐11.45, ‐9.71]
1.5 4 x starting dose	9	1087	Mean Difference (Fixed, 95% CI)	‐8.90 [‐10.47, ‐7.34]
1.6 8 x starting dose	2	331	Mean Difference (Fixed, 95% CI)	‐8.29 [‐11.24, ‐5.35]
2 DBP Show forest plot	51		Mean Difference (Fixed, 95% CI)	Subtotals only

2.1 0.25 x starting dose	5	790	Mean Difference (Fixed, 95% CI)	‐3.59 [‐4.79, ‐2.39]
2.2 0.5 x starting dose	7	941	Mean Difference (Fixed, 95% CI)	‐4.27 [‐5.31, ‐3.22]
2.3 starting dose	31	2907	Mean Difference (Fixed, 95% CI)	‐7.06 [‐7.62, ‐6.51]
2.4 2 x starting dose	28	3065	Mean Difference (Fixed, 95% CI)	‐8.92 [‐9.47, ‐8.38]
2.5 4 x starting dose	9	1087	Mean Difference (Fixed, 95% CI)	‐7.17 [‐8.15, ‐6.18]
2.6 8 x starting dose	2	331	Mean Difference (Fixed, 95% CI)	‐7.20 [‐8.99, ‐5.40]
3 Heart rate Show forest plot	37		Mean Difference (Fixed, 95% CI)	Subtotals only

3.1 0.25 x starting dose	1	136	Mean Difference (Fixed, 95% CI)	‐2.9 [‐5.86, 0.06]
3.2 0.5 x starting dose	5	499	Mean Difference (Fixed, 95% CI)	‐4.34 [‐6.21, ‐2.47]
3.3 starting dose	20	1315	Mean Difference (Fixed, 95% CI)	‐9.80 [‐10.65, ‐8.94]
3.4 2 x starting dose	20	2175	Mean Difference (Fixed, 95% CI)	‐11.33 [‐12.06, ‐10.61]
3.5 4 x starting dose	8	556	Mean Difference (Fixed, 95% CI)	‐13.71 [‐15.00, ‐12.43]
3.6 8 x starting dose	2	331	Mean Difference (Fixed, 95% CI)	‐9.19 [‐11.21, ‐7.18]
4 Pulse pressure Show forest plot	50		Mean Difference (Fixed, 95% CI)	Subtotals only

4.1 0.25 x starting dose	5	790	Mean Difference (Fixed, 95% CI)	‐1.72 [‐3.43, ‐0.00]
4.2 0.5 x starting dose	7	941	Mean Difference (Fixed, 95% CI)	‐1.48 [‐3.13, 0.17]
4.3 starting dose	30	2913	Mean Difference (Fixed, 95% CI)	0.00 [‐2.78, ‐1.22]
4.4 2 x starting dose	27	3026	Mean Difference (Fixed, 95% CI)	‐1.39 [‐2.14, ‐0.65]
4.5 4 x starting dose	9	1087	Mean Difference (Fixed, 95% CI)	‐1.80 [‐3.16, ‐0.44]
4.6 8 x starting dose	2	331	Mean Difference (Fixed, 95% CI)	‐1.04 [‐3.67, 1.60]
5 WDAE Show forest plot	3	2618	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.50, 1.45]

6 SBP combined starting dose and 2 x starting dose Show forest plot	47	5246	Mean Difference (Fixed, 95% CI)	‐10.42 [‐11.11, ‐9.72]

6.1 starting dose	30	2509	Mean Difference (Fixed, 95% CI)	‐9.71 [‐10.75, ‐8.67]
6.2 2 x starting dose	27	2737	Mean Difference (Fixed, 95% CI)	‐10.99 [‐11.93, ‐10.06]
7 DBP combined starting dose and 2 x starting dose Show forest plot	48	5316	Mean Difference (Fixed, 95% CI)	‐8.27 [‐8.69, ‐7.84]

7.1 starting dose	31	2540	Mean Difference (Fixed, 95% CI)	‐7.23 [‐7.85, ‐6.60]
7.2 2x starting dose	28	2776	Mean Difference (Fixed, 95% CI)	‐9.16 [‐9.74, ‐8.58]
8 Heart rate combined starting dose and 2 x starting dose Show forest plot	33	3407	Mean Difference (Fixed, 95% CI)	‐10.93 [‐11.48, ‐10.37]

8.1 starting dose	20	1268	Mean Difference (Fixed, 95% CI)	‐10.03 [‐10.90, ‐9.17]
8.2 2 x starting dose	20	2139	Mean Difference (Fixed, 95% CI)	‐11.57 [‐12.30, ‐10.84]
9 Pulse pressure combined starting dose and 2 x starting dose Show forest plot	47	5246	Mean Difference (Fixed, 95% CI)	‐1.76 [‐2.34, ‐1.19]

9.1 starting dose	30	2509	Mean Difference (Fixed, 95% CI)	‐2.09 [‐2.94, ‐1.23]
9.2 2 x starting dose	27	2737	Mean Difference (Fixed, 95% CI)	‐1.49 [‐2.27, ‐0.71]
10 SBP test for 2 x starting dose subgroup difference Show forest plot	26	2197	Mean Difference (Fixed, 95% CI)	‐11.27 [‐12.22, ‐10.32]

10.1 Atenolol	12	495	Mean Difference (Fixed, 95% CI)	‐15.34 [‐16.86, ‐13.82]
10.2 Nebivolol	5	855	Mean Difference (Fixed, 95% CI)	‐5.26 [‐7.19, ‐3.34]
10.3 Metoprolol	5	284	Mean Difference (Fixed, 95% CI)	‐11.54 [‐14.37, ‐8.71]
10.4 Bisoprolol	2	134	Mean Difference (Fixed, 95% CI)	‐7.03 [‐11.07, ‐2.99]
10.5 Betaxolol	2	429	Mean Difference (Fixed, 95% CI)	‐11.63 [‐13.73, ‐9.53]
11 DBP test for 2 x starting dose subgroup difference Show forest plot	27	2236	Mean Difference (Fixed, 95% CI)	‐9.47 [‐10.06, ‐8.88]

11.1 Atenolol	12	495	Mean Difference (Fixed, 95% CI)	‐12.91 [‐13.89, ‐11.93]
11.2 Nebivolol	5	855	Mean Difference (Fixed, 95% CI)	‐5.82 [‐6.99, ‐4.65]
11.3 Metoprolol	5	284	Mean Difference (Fixed, 95% CI)	‐10.25 [‐11.99, ‐8.51]
11.4 Bisoprolol	3	173	Mean Difference (Fixed, 95% CI)	‐7.44 [‐9.88, ‐5.01]
11.5 Betaxolol	2	429	Mean Difference (Fixed, 95% CI)	‐8.08 [‐9.39, ‐6.77]
12 Heart rate test for 2 x starting dose subgroup difference Show forest plot	19	1346	Mean Difference (Fixed, 95% CI)	‐12.24 [‐13.05, ‐11.42]

12.1 Atenolol	10	413	Mean Difference (Fixed, 95% CI)	‐13.70 [‐14.83, ‐12.56]
12.2 Nebivolol	2	291	Mean Difference (Fixed, 95% CI)	‐5.94 [‐7.98, ‐3.90]
12.3 Metoprolol	2	40	Mean Difference (Fixed, 95% CI)	‐13.25 [‐17.04, ‐9.46]
12.4 Bisoprolol	3	173	Mean Difference (Fixed, 95% CI)	‐10.19 [‐12.87, ‐7.52]
12.5 Betaxolol	2	429	Mean Difference (Fixed, 95% CI)	‐14.43 [‐16.35, ‐12.51]

Comparison 9. Pooled overall effect

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