Blood pressure lowering efficacy of partial agonist beta blocker monotherapy for primary hypertension

Gavin WK Wong; Heidi N Boyda; James M Wright

doi:10.1002/14651858.CD007450.pub2

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Figure 1

Study flow diagram

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Figure 2

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

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Analysis 1.1

Comparison 1 Acebutolol vs Placebo, Outcome 1 SBP.

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Analysis 1.2

Comparison 1 Acebutolol vs Placebo, Outcome 2 DBP.

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Analysis 1.3

Comparison 1 Acebutolol vs Placebo, Outcome 3 Heart rate.

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Analysis 1.4

Comparison 1 Acebutolol vs Placebo, Outcome 4 Pulse pressure.

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Analysis 2.1

Comparison 2 Pindolol vs Placebo, Outcome 1 SBP.

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Analysis 2.2

Comparison 2 Pindolol vs Placebo, Outcome 2 DBP.

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Analysis 2.3

Comparison 2 Pindolol vs Placebo, Outcome 3 Heart rate.

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Analysis 2.4

Comparison 2 Pindolol vs Placebo, Outcome 4 Pulse pressure.

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Analysis 3.1

Comparison 3 Celiprolol vs Placebo, Outcome 1 SBP.

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Analysis 3.2

Comparison 3 Celiprolol vs Placebo, Outcome 2 DBP.

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Analysis 3.3

Comparison 3 Celiprolol vs Placebo, Outcome 3 Heart rate.

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Analysis 3.4

Comparison 3 Celiprolol vs Placebo, Outcome 4 Pulse pressure.

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Analysis 3.5

Comparison 3 Celiprolol vs Placebo, Outcome 5 SBP dose comparison.

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Analysis 3.6

Comparison 3 Celiprolol vs Placebo, Outcome 6 DBP dose comparison.

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Analysis 4.1

Comparison 4 Alprenolol vs Placebo, Outcome 1 SBP.

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Analysis 4.2

Comparison 4 Alprenolol vs Placebo, Outcome 2 DBP.

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Analysis 4.3

Comparison 4 Alprenolol vs Placebo, Outcome 3 Heart rate.

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Analysis 4.4

Comparison 4 Alprenolol vs Placebo, Outcome 4 Pulse pressure.

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Analysis 5.1

Comparison 5 Bopindolol vs Placebo, Outcome 1 SBP.

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Analysis 5.2

Comparison 5 Bopindolol vs Placebo, Outcome 2 DBP.

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Analysis 5.3

Comparison 5 Bopindolol vs Placebo, Outcome 3 Heart rate.

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Analysis 5.4

Comparison 5 Bopindolol vs Placebo, Outcome 4 Pulse pressure.

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Analysis 5.5

Comparison 5 Bopindolol vs Placebo, Outcome 5 WDAE.

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Analysis 6.1

Comparison 6 Oxprenolol vs Placebo, Outcome 1 SBP.

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Analysis 6.2

Comparison 6 Oxprenolol vs Placebo, Outcome 2 DBP.

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Analysis 6.3

Comparison 6 Oxprenolol vs Placebo, Outcome 3 Pulse pressure.

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Analysis 7.1

Comparison 7 Pooled partial agonist effects, Outcome 1 SBP.

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Analysis 7.2

Comparison 7 Pooled partial agonist effects, Outcome 2 DBP.

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Analysis 7.3

Comparison 7 Pooled partial agonist effects, Outcome 3 Heart rate.

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Analysis 7.4

Comparison 7 Pooled partial agonist effects, Outcome 4 Pulse Pressure.

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Analysis 7.5

Comparison 7 Pooled partial agonist effects, Outcome 5 WDAE.

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Analysis 7.6

Comparison 7 Pooled partial agonist effects, Outcome 6 Combined starting and twice the starting dose.

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Blood pressure lowering effects of partial agonists compared with placebo for primary hypertension
Patient or population: Adults with primary hypertension Intervention: Partial agonists Comparison: Placebo
Outcomes	Mean estimates of 1x and 2x starting dose (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)
Decrease in systolic blood pressure	‐8.1 [‐10.1 to ‐6.1]^1,2,3,4	490 (10)	Very low^5,6,7
Decrease in diastolic blood pressure	‐4.0 [‐5.1 to ‐2.9]^1,2,3,4	490 (10)	Very low^5,6,7
Decrease in heart rate	‐4.9 [‐6.2 to ‐3.7]^2,3	256 (7)	Very low^5,6,7
Decrease in pulse pressure	‐3.6 [‐5.3 to ‐1.9]^1,2	490 (10)	Very low^5,6,7,8
Withdrawal due to adverse effect	RR [95%CI]: 0.72 [0.07 to 7.67]⁹	117 (1)	Very low^5,6,10
95% CI: 95% confidence interval; RR: relative risk
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
Test for subgroup differences showed that 1x and 2x starting dose subgroups were not significantly different from each other. The recommended starting and 2x starting contained most of the data for this class. Combining them provided the best estimate of the overall subclass effect. BP was measured at peak hours. Weighted mean baseline BP of included studies was 175/107 mmHg. Quality of evidence was downgraded by one level due to small sample size and wide confidence intervals. Quality of evidence was downgraded by one level due to high or unknown risk of detection bias caused by loss of blinding. Quality of evidence was downgraded by one level due to high risk of publication bias. None of the studies included reported pulse pressure. Pulse pressure was calculated by subtracting DBP from SBP. Withdrawal due to adverse effect was estimated based on one trial from bopindolol. Quality of evidence was downgraded by one level due to high risk of reporting bias.

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Comparison 1. Acebutolol vs Placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SBP Show forest plot	3		Mean Difference (Fixed, 95% CI)	Subtotals only

1.1 (starting dose) 400mg/day	3	85	Mean Difference (Fixed, 95% CI)	‐5.12 [‐8.85, ‐1.40]
2 DBP Show forest plot	3		Mean Difference (Fixed, 95% CI)	Subtotals only

2.1 (starting dose) 400mg/day	3	85	Mean Difference (Fixed, 95% CI)	‐1.77 [‐3.88, 0.34]
3 Heart rate Show forest plot	3		Mean Difference (Fixed, 95% CI)	Subtotals only

3.1 (starting dose) 400mg/day	3	85	Mean Difference (Fixed, 95% CI)	‐8.68 [‐10.85, ‐6.51]
4 Pulse pressure Show forest plot	3		Mean Difference (Fixed, 95% CI)	Subtotals only

4.1 (starting dose) 400 mg/day	3	85	Mean Difference (Fixed, 95% CI)	‐2.40 [‐5.39, 0.59]

Comparison 1. Acebutolol vs Placebo

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Comparison 2. Pindolol vs Placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SBP Show forest plot	3		Mean Difference (Fixed, 95% CI)	Subtotals only

1.1 (starting dose) 10 mg/day	2	29	Mean Difference (Fixed, 95% CI)	‐14.46 [‐19.84, ‐9.08]
1.2 (4x starting) 30 mg/day	1	16	Mean Difference (Fixed, 95% CI)	‐12.5 [‐20.16, ‐4.84]
2 DBP Show forest plot	3		Mean Difference (Fixed, 95% CI)	Subtotals only

2.1 (starting dose) 10 mg/day	2	29	Mean Difference (Fixed, 95% CI)	‐6.88 [‐10.15, ‐3.61]
2.2 (4x starting) 30 mg/day	1	16	Mean Difference (Fixed, 95% CI)	‐8.8 [‐14.80, ‐2.80]
3 Heart rate Show forest plot	2		Mean Difference (Fixed, 95% CI)	Subtotals only

3.1 (starting dose) 10 mg/day	2	29	Mean Difference (Fixed, 95% CI)	‐5.91 [‐9.50, ‐2.32]
4 Pulse pressure Show forest plot	3		Mean Difference (Fixed, 95% CI)	Subtotals only

4.1 (starting dose)10 mg/day	2	29	Mean Difference (Fixed, 95% CI)	‐8.01 [‐12.74, ‐3.29]
4.2 (4x starting) 30 mg/day	1	16	Mean Difference (Fixed, 95% CI)	‐3.70 [‐10.34, 2.94]

Comparison 2. Pindolol vs Placebo

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Comparison 3. Celiprolol vs Placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SBP Show forest plot	3		Mean Difference (Fixed, 95% CI)	Subtotals only

1.1 (starting dose) 200 mg/day	3	171	Mean Difference (Fixed, 95% CI)	‐7.86 [‐11.88, ‐3.84]
1.2 (2x starting) 400 mg/day	2	120	Mean Difference (Fixed, 95% CI)	‐8.59 [‐13.41, ‐3.77]
1.3 (4x starting) 600 mg/day	1	90	Mean Difference (Fixed, 95% CI)	‐10.0 [‐16.47, ‐3.53]
2 DBP Show forest plot	3		Mean Difference (Fixed, 95% CI)	Subtotals only

2.1 (starting dose) 200 mg/day	3	171	Mean Difference (Fixed, 95% CI)	‐4.57 [‐6.62, ‐2.53]
2.2 (2x starting) 400 mg/day	2	120	Mean Difference (Fixed, 95% CI)	‐4.88 [‐7.25, ‐2.52]
2.3 (4x starting) 600 mg/day	1	90	Mean Difference (Fixed, 95% CI)	‐6.0 [‐9.49, ‐2.51]
3 Heart rate Show forest plot	1		Mean Difference (Fixed, 95% CI)	Subtotals only

3.1 (starting dose) 200 mg/day	1	26	Mean Difference (Fixed, 95% CI)	‐2.4 [‐4.93, 0.13]
3.2 (2x starting) 400 mg/day	1	26	Mean Difference (Fixed, 95% CI)	‐0.6 [‐3.36, 2.16]
4 Pulse pressure Show forest plot	3		Mean Difference (Fixed, 95% CI)	Subtotals only

4.1 (starting dose) 200 mg/day	3	171	Mean Difference (Fixed, 95% CI)	‐3.76 [‐7.26, ‐0.25]
4.2 (2x starting) 400 mg/day	2	120	Mean Difference (Fixed, 95% CI)	‐3.89 [‐8.09, 0.32]
4.3 (4x starting) 600 mg/day	1	90	Mean Difference (Fixed, 95% CI)	‐4.0 [‐9.59, 1.59]
5 SBP dose comparison Show forest plot	2		Mean Difference (Fixed, 95% CI)	Subtotals only

5.1 200 mg/day	2	80	Mean Difference (Fixed, 95% CI)	‐7.42 [‐12.15, ‐2.69]
5.2 400 mg/day	2	85	Mean Difference (Fixed, 95% CI)	‐8.59 [‐13.41, ‐3.77]
6 DBP dose comparison Show forest plot	2		Mean Difference (Fixed, 95% CI)	Subtotals only

6.1 200 mg/day	2	80	Mean Difference (Fixed, 95% CI)	‐5.09 [‐7.34, ‐2.85]
6.2 400 mg/day	2	85	Mean Difference (Fixed, 95% CI)	‐4.88 [‐7.25, ‐2.52]

Comparison 3. Celiprolol vs Placebo

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Comparison 4. Alprenolol 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

1.1 400 mg/day	2	27	Mean Difference (Fixed, 95% CI)	‐16.94 [‐23.86, ‐10.01]
2 DBP Show forest plot	2		Mean Difference (Fixed, 95% CI)	Subtotals only

2.1 400 mg/day	2	27	Mean Difference (Fixed, 95% CI)	‐6.73 [‐10.06, ‐3.39]
3 Heart rate Show forest plot	1		Mean Difference (Fixed, 95% CI)	Subtotals only

3.1 400 mg/day	1	16	Mean Difference (Fixed, 95% CI)	‐8.0 [‐15.45, ‐0.55]
4 Pulse pressure Show forest plot	2		Mean Difference (Fixed, 95% CI)	Subtotals only

4.1 400 mg/day	2	27	Mean Difference (Fixed, 95% CI)	‐8.71 [‐14.77, ‐2.65]

Comparison 4. Alprenolol vs Placebo

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Comparison 5. Bopindolol 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 0.5 mg/day	1	55	Mean Difference (IV, Fixed, 95% CI)	‐5.90 [‐15.77, 3.97]
1.2 1 mg/day	1	60	Mean Difference (IV, Fixed, 95% CI)	‐6.10 [‐15.58, 3.38]
1.3 2 mg/day	1	60	Mean Difference (IV, Fixed, 95% CI)	‐5.80 [‐14.64, 3.04]
2 DBP Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

2.1 0.5 mg/day	1	55	Mean Difference (IV, Fixed, 95% CI)	‐1.5 [‐6.84, 3.84]
2.2 1 mg/day	1	60	Mean Difference (IV, Fixed, 95% CI)	‐4.0 [‐9.05, 1.05]
2.3 2 mg/day	1	60	Mean Difference (IV, Fixed, 95% CI)	‐2.40 [‐7.24, 2.44]
3 Heart rate Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

3.1 0.5 mg/day	1	55	Mean Difference (IV, Fixed, 95% CI)	‐2.23 [‐7.33, 2.87]
3.2 1 mg/day	1	60	Mean Difference (IV, Fixed, 95% CI)	‐5.57 [‐10.13, ‐1.01]
3.3 2 mg/day	1	60	Mean Difference (IV, Fixed, 95% CI)	‐6.06 [‐10.21, ‐1.91]
4 Pulse pressure Show forest plot	1		Mean Difference (Fixed, 95% CI)	Subtotals only

4.1 0.5 mg/day	1	55	Mean Difference (Fixed, 95% CI)	‐4.8 [‐13.35, 3.75]
4.2 1 mg/day	1	60	Mean Difference (Fixed, 95% CI)	‐2.1 [‐10.39, 6.19]
4.3 2 mg/day	1	60	Mean Difference (Fixed, 95% CI)	‐3.4 [‐11.06, 4.26]
5 WDAE Show forest plot	1	117	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.07, 7.67]

Comparison 5. Bopindolol vs Placebo

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Comparison 6. Oxprenolol 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 (0.25x starting) 20 mg/day	1	26	Mean Difference (IV, Fixed, 95% CI)	3.40 [‐8.57, 15.37]
1.2 (0.5x starting) 40 mg/day	1	27	Mean Difference (IV, Fixed, 95% CI)	‐6.20 [‐17.93, 5.53]
1.3 (starting dose) 60 & 80 mg/day	1	39	Mean Difference (IV, Fixed, 95% CI)	‐11.50 [‐21.60, ‐1.40]
2 DBP Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

2.1 (0.25x starting) 20 mg/day	1	26	Mean Difference (IV, Fixed, 95% CI)	4.2 [‐2.33, 10.73]
2.2 (0.5x starting) 40 mg/day	1	27	Mean Difference (IV, Fixed, 95% CI)	0.40 [‐6.02, 6.82]
2.3 (starting dose) 60 & 80 mg/day	1	39	Mean Difference (IV, Fixed, 95% CI)	‐3.30 [‐8.94, 2.34]
3 Pulse pressure Show forest plot	1		Mean Difference (Fixed, 95% CI)	Subtotals only

3.1 (0.25x starting) 20 mg/day	1	26	Mean Difference (Fixed, 95% CI)	5.3 [‐5.11, 15.71]
3.2 (0.5x starting) 40 mg/day	1	27	Mean Difference (Fixed, 95% CI)	0.7 [‐9.51, 10.91]
3.3 (starting dose) 60 & 80 mg/day	1	39	Mean Difference (Fixed, 95% CI)	2.7 [‐7.71, 13.11]

Comparison 6. Oxprenolol vs Placebo

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Comparison 7. Pooled partial agonist effects

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SBP Show forest plot	11		Mean Difference (Fixed, 95% CI)	Subtotals only

1.1 0.25x starting dose	1	26	Mean Difference (Fixed, 95% CI)	3.4 [‐8.58, 15.38]
1.2 0.5x starting dose	2	82	Mean Difference (Fixed, 95% CI)	‐6.12 [‐11.36, ‐0.87]
1.3 starting dose	10	384	Mean Difference (Fixed, 95% CI)	‐8.11 [‐10.41, ‐5.81]
1.4 2x starting dose	3	180	Mean Difference (Fixed, 95% CI)	‐7.95 [‐12.18, ‐3.72]
1.5 4x starting dose	2	106	Mean Difference (Fixed, 95% CI)	‐11.04 [‐15.98, ‐6.10]
2 DBP Show forest plot	11	778	Mean Difference (Fixed, 95% CI)	‐3.89 [‐4.87, ‐2.91]

2.1 0.25x starting dose	1	26	Mean Difference (Fixed, 95% CI)	4.2 [‐2.33, 10.73]
2.2 0.5x starting dose	2	82	Mean Difference (Fixed, 95% CI)	‐0.73 [‐4.83, 3.38]
2.3 starting dose	10	384	Mean Difference (Fixed, 95% CI)	‐3.81 [‐5.08, ‐2.55]
2.4 2x starting dose	3	180	Mean Difference (Fixed, 95% CI)	‐4.41 [‐6.53, ‐2.28]
2.5 4x starting dose	2	106	Mean Difference (Fixed, 95% CI)	‐6.71 [‐9.72, ‐3.69]
3 Heart rate Show forest plot	7		Mean Difference (Fixed, 95% CI)	Subtotals only

3.1 0.5x starting dose	1	55	Mean Difference (Fixed, 95% CI)	‐2.23 [‐7.33, 2.87]
3.2 1x starting dose	7	200	Mean Difference (Fixed, 95% CI)	‐5.96 [‐7.38, ‐4.53]
3.3 2x starting dose	2	86	Mean Difference (Fixed, 95% CI)	‐2.27 [‐4.58, 0.03]
4 Pulse Pressure Show forest plot	11	765	Mean Difference (Fixed, 95% CI)	‐3.40 [‐4.94, ‐1.87]

4.1 0.25x starting dose	1	26	Mean Difference (Fixed, 95% CI)	5.3 [‐5.11, 15.71]
4.2 0.5x starting dose	2	82	Mean Difference (Fixed, 95% CI)	‐2.53 [‐9.09, 4.02]
4.3 1x starting dose	10	371	Mean Difference (Fixed, 95% CI)	‐3.58 [‐5.54, ‐1.63]
4.4 2x starting dose	3	180	Mean Difference (Fixed, 95% CI)	‐3.76 [‐7.39, ‐0.14]
4.5 4x starting dose	2	106	Mean Difference (Fixed, 95% CI)	‐3.88 [‐8.15, 0.40]
5 WDAE Show forest plot	1	117	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.07, 7.67]

6 Combined starting and twice the starting dose Show forest plot	10		Mean Difference (Fixed, 95% CI)	Subtotals only

6.1 SBP	10	564	Mean Difference (Fixed, 95% CI)	‐8.07 [‐10.09, ‐6.05]
6.2 DBP	10	564	Mean Difference (Fixed, 95% CI)	‐3.97 [‐5.05, ‐2.88]
6.3 Heart rate	7	286	Mean Difference (Fixed, 95% CI)	‐4.94 [‐6.15, ‐3.73]
6.4 Pulse pressure	10	551	Mean Difference (Fixed, 95% CI)	‐3.62 [‐5.34, ‐1.90]

Comparison 7. Pooled partial agonist effects

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