Time for Aspirin

Cover Page
The handle http://hdl.handle.net/1887/29692 holds various files of this Leiden University
dissertation
Author: Bonten, Tobias N.
Title: Time for aspirin : blood pressure and reactivity
Issue Date: 2014-11-13
Appendices
Appendices
Chapter 3, appendix table 1
Appendix table 1. Mean 24-hour, day- and night ambulatory blood pressure values (mmHg) according to time of aspirin administration in the secondary analysis population (n=150)
Aspirin on
awakening
Aspirin at bedtime
Mean difference
(bedtime – awakening)
[95% CI]*
24-hour SBP
125 ± 10
125 ± 9
0.0 [-1.1 to 1.1]
24-hour DBP
78 ± 8
77 ± 8
-0.4 [-1.2 to 0.3]
Day SBP
129 ± 10
129 ± 10
0.1 [-1.2 to 1.3]
Day DBP
81 ± 9
80 ± 8
-0.5 [-1.3 to 0.2]
Night SBP
115 ± 12
115 ± 12
0.0 [-1.5 to 1.5]
Night DBP
68 ± 10
68 ± 9
-0.2 [-1.2 to 0.7]
*Mean difference and 95% CI obtained with paired t-tests. Values are mean ± standard deviation.
SBP: systolic blood pressure; DBP: diastolic blood pressure; CI: confidence interval
115
116
Appendices
Chapter 3, appendix table 2
Appendix table 2. Side effects and relation with timing of aspirin intake of subjects that did not
complete study follow-up (n=26)
Patient code
Period of
drop-out
Timing of Aspirin
intake at drop-out
Reason drop-out
Related to
side effect
of aspirin
105
1
At bedtime
Stopped aspirin use after advise
cardiologist
No
113
1
On awakening
Stomach pain after switch from
evening intake to intake on
awakening
Yes
132
1
At bedtime
Study participation too aggravating
No
151
1
On awakening
Withdrawal of consent to participate
in other clinical trial
No
173
1
At bedtime
Study participation too aggravating
No
180
1
At bedtime
Study participation too aggravating
No
250
1
On awakening
Stomach pain after switch from
evening intake to intake on
awakening
Yes
251
1
At bedtime
Study participation too aggravating
No
327
1
On awakening
Study participation too aggravating
No
329
1
At bedtime
Stopped aspirin use after head
trauma; advise of first aid physician
No
365
1
At bedtime
Study participation too aggravating
No
436
1
On awakening
Study participation too aggravating
No
447
1
On awakening
Study participation too aggravating
No
455
1
At bedtime
Study participation too aggravating
No
462
1
At bedtime
Study participation too aggravating
No
203
2
At bedtime
Study participation too aggravating
No
271
2
At bedtime
Study participation too aggravating
No
334
2
On awakening
Stopped aspirin use after advise
cardiologist
No
344
2
On awakening
Study participation too aggravating
No
366
2
On awakening
Switch to vitamin k antagonist instead
of aspirin after advise cardiologist
No
368
2
On awakening
Switch to vitamin k antagonist instead
of aspirin after advise cardiologist
No
387
2
At bedtime
Switch to vitamin k antagonist instead
of aspirin after advise cardiologist
No
405
2
At bedtime
Did not want to take aspirin at
bedtime due to practical reasons
No
417
2
On awakening
Study participation too aggravating
No
465
2
At bedtime
Headache after switch from morning
intake to intake at bedtime
Possible
437
2
On awakening
Study participation too aggravating
No
Appendices
Chapter 3, appendix table 3
Appendix table 3. Self-reported side effects of randomized study subjects at baseline and
subjects who completed study follow-up
At Baseline
(n=290), n (%)
Dyspepsia
15 (5.2)
During study follow-up
(n=264), n (%)
Aspirin
on awakening
Aspirin
at bedtime
p-value*
12 (4.5)
12 (4.5)
1.00
Nausea
8 (2.8)
4 (1.5)
9 (3.4)
0.18
Heartburn
27 (9.3)
16 (6.1)
20 (7.6)
0.50
Nose bleeding
13 (4.5)
9 (3.4)
6 (2.3)
0.55
Bruises
45 (15.5)
32 (12.1)
35 (13.3)
0.75
Bloody stool
4 (1.4)
5 (1.9)
5 (1.9)
1.00
*P-value obtained by McNemar’s test
117
4.4
(2.8)
Morning peak,
Mean (SD)
4.3
(3.0)
9.6
(5.1)
448.6
(66.6)
4.4
(2.8)
10.9
(4.9)
445.1
(63.3)
892.1
(34.5)
438.2
(54.3)
4394.7
(436.4)
2.6
(1.3)
5.2
(2.0)
421.7
(60.9)
851.1
(105.0)
429.6
(58.8)
4300.4
(454.2)
Intention
to treat
Bedtime
2.6
(1.4)
5.2
(2.3)
424.8
(65.4)
858.2
(112.5)
433.9
(62.5)
4343.2
(479.4)
2.5
(1.1)
5.4
(2.1)
415
(51.9)
840.3
(31.9)
428.2
(56.8)
4289.8
(526.9)
Per protocol Sensitivity
-1.8
(-2.8;-0.8)
-4.7
(-6.9;-2.5)
-23.4
(-50.7;3.9)
-31.3
(-88.2;25.6)
-8.5
(-21.3;4.3)
-79.4
(-229.4;70.4)
Intention
to treat
PMA
TRAP
ADP
Awakening
50.5
(16.6)
25.1
(8.3)
Morning peak,
Mean (SD)
55.5
(6.0)
Morning peak,
Mean (SD)
Morning peak,
AUC (SD)
110.2
(12.0)
15.2
(6.3)
Morning peak,
Mean (SD)
Morning peak,
AUC (SD)
30.5
(12.8)
Morning peak,
AUC (SD)
26.5
(7.6)
53.1
(15.3)
56.2
(5.8)
111.5
(11.5)
16.6
(5.5)
33.3
(11.3)
24.0
(9.0)
48.5
(18.3)
55.3
(5.6)
109.5
(11.5)
16.1
(6.5)
32.3
(13.2)
Intention Per protocol Sensitivity
to treat
22.1
(7.7)
44.6
(15.0)
56.0
(6.6)
112.1
(13.0)
16.0
(8.1)
31.6
(15.1)
Intention
to treat
Bedtime
23.3
(7.7)
46.9
(15.1)
56.4
(6.6)
112.9
(13.1)
16.9
(8.3)
33.5
(15.3)
21.4
(7.5)
42.7
(14.7)
56.7
(6.9)
113.2
(13.7)
16.9
(8.4)
33.4
(15.6)
Per protocol Sensitivity
-1.9
(-2.9;-0.9)
-5.6
(-8.2;-2.9)
-29.5
(-55.7;-3.2)
-51.8
(-105.4;1.8)
-10.0
(-22.6;2.6)
-104.9
(-320.8;110.9)
Sensitivity
-3.0
(-7.3;1.2)
-5.9
(-13.8;2.0)
0.5
(-1.9;2.9)
1.9
(-2.5;6.4)
-0.8
(-1.8;3.3)
1.1
(-3.2;5.3)
Intention
to treat
-3.2
(-7.8;1.4)
-6.2
(-14.8;2.4)
0.1
(-2.7;2.9)
1.4
(-3.8;6.6)
0.3
(-2.7;3.2)
0.2
(-4.7;5.1)
Per protocol
-2.6
(-7.2;2.0)
-5.7
(-14.0;2.6)
1.4
(-1.1;3.9)
3.7
(-0.9;8.2)
0.8
(-2.5;4.0)
1.0
(-4.4;6.4)
Sensitivity
Difference, Bedtime – Awakening* (95% CI)
-1.7
(-2.8;-0.6)
-4.5
(-7.2;-1.7)
-23.8
(-55.3;7.6)
-26.7
(-96.4;37.0)
-7.5
(-22.0;7.0)
-69.4
(-237.4;98.6)
Per protocol
Difference, Bedtime – Awakening* (95% CI)
Cox-1-independent assays – Surface CD62 (P-selectin) expression
9.9
(4.6)
445.1
(63.3)
Morning peak,
Mean (SD)
Morning peak,
AUC (SD)
882.4
(107.3)
Morning peak,
AUC (SD)
STxB2
(ng/ml)
441.4
(56.1)
438.1
(54.1)
Whole day,
Mean (SD)
887.9
(113.4)
4412.6
(398.9)
VerifyNow Whole day, AUC 4379.9
(ARU)
(SD)
(385.3)
Intention Per protocol Sensitivity
to treat
Awakening
Cox-1-dependent assays
Supplemental Table 1. Effect of aspirin intake on awakening or at bedtime on Cox-1 dependent and non-Cox-1 dependent platelet reactivity.
118
Appendices
Chapter 4, appendix table
19.6
(9.2)
9.6
(5.0)
Morning peak,
Mean (SD)
23.5
(4.7)
Morning peak,
Mean (SD)
Morning peak,
AUC (SD)
47.4
(7.9)
25.1
(3.6)
Morning peak,
Mean (SD)
Morning peak,
AUC (SD)
49.9
(6.4)
Morning peak,
AUC (SD)
22.5
(4.9)
42.4
(12.1)
9.9
(5.3)
20.1
(9.7)
23.2
(4.9)
46.8
(8.1)
25.0
(3.9)
49.6
(6.8)
22.8
(5.2)
43.6
(12.5)
10.8
(4.4)
21.6
(8.5)
24.7
(3.7)
49.2
(7.0)
26.0
(2.7)
51.5
(5.3)
22.5
(4.8)
40.8
(13.0)
10.4
(4.7)
20.2
(8.7)
25.4
(3.8)
50.4
(6.7)
26.6
(3.9)
52.7
(6.7)
22.7
(4.1)
42.5
(10.4)
Intention
to treat
Bedtime
9.8
(4.8)
19.8
(9.3)
25.2
(3.9)
50.3
(6.6)
25.9
(2.9)
51.7
(5.1)
22.4
(3.2)
43.1
(9.3)
10.6
(5.1)
20.4
(9.6)
25.0
(4.2)
49.8
(7.4)
26.5
(4.2)
52.5
(7.2)
22.3
(4.4)
41.5
(10.3)
Per protocol Sensitivity
0.8
(-2.7;4.3)
0.6
(-5.3;6.6)
1.9
(-1.8;5.6)
2.9
(-3.3;9.2)
1.5
(-1.6;4.7)
2.8
(-2.5;8.1)
0.1
(-3.4;3.7)
0.1
(-8.6;8.8)
Intention
to treat
-0.1
(-3.8;3.5)
-0.3
(-7.0;6.3)
2.0
(-2.0;6.0)
3.5
(-3.2;10.1)
0.9
(-2.2;4.0)
2.1
(-3.1;7.4)
-0.4
(-3.9;3.1)
-0.5
(-9.2;8.1)
Per protocol
-0.2
(-4.5;4.2)
-1.3
(-8.5;5.9)
0.4
(-3.2;3.9)
0.6
(-6.0;7.2)
0.5
(-2.7;3.7)
1.0
(-4.7;6.7)
-0.2
(-4.2;3.7)
0.7
(-10.1;11.5)
Sensitivity
Difference, Bedtime – Awakening* (95% CI)
*Difference (Bedtime – Awakening): for AUC estimated by paired t-tests; Mean differences estimated by linear mixed model analysis. ARU: aspirin
reaction units; AUC: area under the curve; STxB2: serum thromboxane B2; ADP: adenosine diphosphate; TRAP: Thrombin receptor agonist peptide;
PMA: phorbol 12-myristate 13-acetate; FCA: flow cytometry based aggregation.
PMA
ADP
TRAP
Morning peak,
Mean (SD)
Ristocetin Morning peak,
AUC (SD)
Intention Per protocol Sensitivity
to treat
Awakening
Cox-1-independent assays – Flow cytometry based aggregation (FCA)
Appendices
119
120
Appendices
Chapter 6, Appendix Methods 1
Overview of the complete search strategy per database. Results for search on June
1st 2013:
Pubmed search strategy (331 hits)
(“Platelet
function
Tests”[Mesh]
OR
“Platelet
function
Tests”[ti]
OR
“VerifyNow”[tiab] OR “PFA-100”[tiab] OR “multiple electrode aggregometry”[tiab]
OR “light transmission aggregometry”[tiab] OR “serum thromboxane”[tiab] OR
“Platelet Aggregation”[Majr] OR “Platelet Aggregation”[ti] OR “Platelet Aggregation Inhibitors”[Majr] OR “antiplatelet”[ti] OR “Platelet Adhesiveness”[Majr]
OR “Platelet Adhesiveness”[ti] OR “Platelet Antiaggregant”[ti] OR “Platelet
Antiaggregants”[ti]) AND (“adrenergic beta-antagonists”[Majr] OR “adrenergic beta-antagonists”[ti] OR “beta blockers”[ti] OR “beta-blockers”[ti] OR
“betablockers”[ti] OR “beta blocker”[ti] OR “beta-blocker”[ti] OR “betablocker”[ti]
OR “adrenergic beta-antagonists”[Pharmacological Action] OR “β blocker”[ti]
OR “β-blocker”[ti] OR “β blockers”[ti] OR “β-blockers”[ti] OR “beta-Adrenergic
Blocking”[ti])
Embase search strategy (734 hits)
(“platelet function test*”.ti,ab. OR “platelet aggregation” .ti,ab. OR exp thrombocyte aggregation/ OR “VerifyNow”.ti,ab. OR “PFA-100”.ti,ab. OR “multiple
electrode aggregometry”.ti,ab. OR “light transmission aggregometry”.ti,ab. OR
“serum thromboxane”.ti,ab. OR “platelet adhesion”.ti,ab. OR exp thrombocyte
adhesion/ OR antiplatelet*.ti,ab. OR “platelet adhesiveness”.ti,ab. OR “platelet
antiaggregant*”.ti,ab.)AND (exp *beta adrenergic receptor blocking agent/ OR
“adrenergic beta-antagonist*”.ti. OR “beta blocker*”.ti. OR “beta-blocker*”.ti.
OR “betablocker*”.ti. OR “beta-Adrenergic Blocking”.ti.)
Chapter
6,
appendix
methods
2222
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121
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𝑁𝑁
𝑆𝑆𝑆𝑆𝑆𝑆
𝑖𝑖
𝑝𝑝
𝑡𝑡𝑡𝑡𝑡𝑡
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
+
�
𝑁𝑁
∗
𝑁𝑁
2(𝑁𝑁
−
2)
𝑁𝑁
∗
𝑁𝑁
2(𝑁𝑁
−
2)
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
𝑆𝑆𝑆𝑆
𝑡𝑡𝑡𝑡𝑡𝑡
+ 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
�
𝑆𝑆𝑆𝑆𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
𝑡𝑡𝑡𝑡𝑡𝑡
𝑁𝑁𝑁𝑁𝑖𝑖𝑖𝑖𝑖𝑖𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
𝑁𝑁𝑁𝑁𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 2(𝑁𝑁
2(𝑁𝑁
−
2)
𝑖𝑖∗∗∗𝑁𝑁
𝑡𝑡𝑡𝑡𝑡𝑡−
𝑡𝑡𝑡𝑡𝑡𝑡
2(𝑁𝑁
−2)
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�𝑡𝑡𝑡𝑡𝑡𝑡
𝑡𝑡𝑡𝑡𝑡𝑡 −
𝑖𝑖 ∗ 𝑁𝑁𝑝𝑝
𝑁𝑁
2(𝑁𝑁
2)
𝑁𝑁𝑖𝑖 ∗ 𝑁𝑁𝑝𝑝 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
2(𝑁𝑁𝑡𝑡𝑡𝑡𝑡𝑡 − 2) 𝑆𝑆𝑆𝑆𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑁𝑁
𝑖𝑖𝑖𝑖𝑖𝑖 ∗ 𝑁𝑁𝑝𝑝𝑝𝑝
𝑡𝑡𝑡𝑡𝑡𝑡
𝑝𝑝
𝑡𝑡𝑡𝑡𝑡𝑡
𝑁𝑁𝑖𝑖 ∗ 𝑁𝑁𝑝𝑝
2(𝑁𝑁𝑡𝑡𝑡𝑡𝑡𝑡 − 2)
Cross-sectional
study
𝑀𝑀
−
𝑀𝑀
Cross-sectional
study
𝑒𝑒 −
𝑛𝑛𝑛𝑛
𝑀𝑀
𝑀𝑀
𝑀𝑀
−
𝑀𝑀
22
Cross-sectional
study
Cross-sectional
study
𝑛𝑛𝑛𝑛
𝑀𝑀
−
𝑀𝑀
𝑛𝑛𝑛𝑛
𝑀𝑀
𝑁𝑁
𝑆𝑆𝑆𝑆𝑆𝑆
Cross-sectional
study
𝑛𝑛𝑛𝑛
𝑀𝑀𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒−
−𝑀𝑀
𝑀𝑀𝑛𝑛𝑛𝑛
𝑀𝑀𝑒𝑒 −
𝑀𝑀
Cross-sectional
𝑡𝑡𝑡𝑡𝑡𝑡
Cross-sectional
study
Cross-sectional study
22
𝑛𝑛𝑛𝑛
𝑛𝑛𝑛𝑛
𝑀𝑀
−
𝑀𝑀
22
𝑁𝑁
𝑆𝑆𝑆𝑆𝑆𝑆
𝑆𝑆𝑆𝑆𝑆𝑆
𝑀𝑀𝑒𝑒 − study
𝑀𝑀
Cross-sectional
study
2
𝑡𝑡𝑡𝑡𝑡𝑡
𝑁𝑁𝑁𝑁
𝑆𝑆𝑆𝑆𝑆𝑆
𝑡𝑡𝑡𝑡𝑡𝑡
𝑛𝑛𝑛𝑛
𝑁𝑁
𝑆𝑆𝑆𝑆𝑆𝑆
𝑒𝑒𝑆𝑆𝑆𝑆𝑛𝑛𝑛𝑛 𝑛𝑛𝑛𝑛
𝑛𝑛𝑛𝑛
�
+
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𝑁𝑁
𝑆𝑆𝑆𝑆𝑆𝑆
𝑁𝑁𝑡𝑡𝑡𝑡𝑡𝑡
𝑆𝑆𝑆𝑆𝑆𝑆 2
2
𝑡𝑡𝑡𝑡𝑡𝑡
2
𝑀𝑀
−
𝑀𝑀
𝑡𝑡𝑡𝑡𝑡𝑡
𝑁𝑁
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Cross-sectional study𝑁𝑁𝑡𝑡𝑡𝑡𝑡𝑡 𝑆𝑆𝑆𝑆
𝑆𝑆𝑆𝑆
𝑆𝑆𝑆𝑆
+
+
𝑒𝑒
𝑛𝑛𝑛𝑛
𝑡𝑡𝑡𝑡𝑡𝑡
�
𝑛𝑛𝑛𝑛
𝑆𝑆𝑆𝑆
𝑛𝑛𝑛𝑛
+
2
�
𝑡𝑡𝑡𝑡𝑡𝑡
+
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∗
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2(𝑁𝑁
−
2)
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+
𝑛𝑛𝑛𝑛
𝑁𝑁
𝑆𝑆𝑆𝑆𝑆𝑆
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𝑛𝑛𝑛𝑛
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𝑛𝑛𝑛𝑛
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+
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∗
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2(𝑁𝑁
−
2)
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∗
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2(𝑁𝑁
−
2)
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𝑆𝑆𝑆𝑆𝑛𝑛𝑛𝑛
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𝑛𝑛𝑛𝑛
𝑡𝑡𝑡𝑡𝑡𝑡
𝑁𝑁𝑁𝑁𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒∗∗∗∗𝑁𝑁
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−
2)
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𝑛𝑛𝑛𝑛
𝑛𝑛𝑛𝑛
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−2)
2)
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� 𝑡𝑡𝑡𝑡𝑡𝑡
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𝑁𝑁
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2)
𝑁𝑁𝑒𝑒 ∗ 𝑁𝑁𝑛𝑛𝑛𝑛
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𝑡𝑡𝑡𝑡𝑡𝑡 − 2) 𝑆𝑆𝑆𝑆𝑛𝑛𝑛𝑛 𝑁𝑁𝑒𝑒
𝑒𝑒
𝑛𝑛𝑛𝑛
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𝑁𝑁𝑡𝑡𝑡𝑡𝑡𝑡
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𝑒𝑒
𝑛𝑛𝑛𝑛
Paired
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Paired One-group trial
𝑀𝑀
−
𝑀𝑀
One-group
trial
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
𝑝𝑝𝑝𝑝𝑝𝑝
𝑀𝑀
−
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𝑀𝑀
−
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22
One-group
trial
One-group
trial
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
𝑝𝑝𝑝𝑝𝑝𝑝
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−
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𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝−
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One-group
trial
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
𝑝𝑝𝑝𝑝𝑝𝑝
One-group
trial
𝑀𝑀𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
−𝑀𝑀
𝑀𝑀𝑝𝑝𝑝𝑝𝑝𝑝
𝑀𝑀𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 −11
𝑀𝑀𝑝𝑝𝑝𝑝𝑝𝑝 𝑆𝑆𝑆𝑆𝑆𝑆
One-group
trial
22
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 −
𝑝𝑝𝑝𝑝𝑝𝑝
𝑀𝑀
𝑀𝑀
22
𝑆𝑆𝑆𝑆𝑆𝑆
1
𝑆𝑆𝑆𝑆𝑆𝑆
𝑀𝑀𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
− 𝑀𝑀𝑝𝑝𝑝𝑝𝑝𝑝 One-group trial 𝑀𝑀
One-group
trial
2
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
𝑝𝑝𝑝𝑝𝑝𝑝
1
𝑆𝑆𝑆𝑆𝑆𝑆
1
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1−
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0.5 ∗ 𝑁𝑁𝑡𝑡𝑡𝑡𝑡𝑡
𝑁𝑁𝑡𝑡𝑡𝑡𝑡𝑡
𝑀𝑀
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Cross-over
trial
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
𝑝𝑝𝑝𝑝𝑝𝑝
Cross-over trial
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−
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𝑀𝑀
−
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22
Cross-over
trial
Cross-over
trial
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𝑝𝑝𝑝𝑝𝑝𝑝
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𝑆𝑆𝑆𝑆𝑆𝑆
Cross-over
trial
2
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𝑝𝑝𝑝𝑝𝑝𝑝
Cross-over
trial
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𝑀𝑀
−
𝑀𝑀
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
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Cross-over
trial
2
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𝑝𝑝𝑝𝑝𝑝𝑝
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 1
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𝑆𝑆𝑆𝑆𝑆𝑆
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− 𝑀𝑀𝑝𝑝𝑝𝑝𝑝𝑝 Cross-over trial 𝑀𝑀𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
Cross-over
trial
11
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𝑆𝑆𝑆𝑆
�
𝑝𝑝𝑝𝑝𝑝𝑝
�2(1
+
×
−
𝜌𝜌)
𝑆𝑆𝑆𝑆
0.5
∗
𝑁𝑁
𝑁𝑁
�2(1
�
�
+
×
−
𝜌𝜌)
𝑝𝑝𝑝𝑝𝑝𝑝
+
× �2(1 − 𝜌𝜌)
𝑆𝑆𝑆𝑆
𝑆𝑆𝑆𝑆
�2(1
𝑝𝑝𝑝𝑝𝑝𝑝
1
𝑆𝑆𝑆𝑆𝑆𝑆
𝑡𝑡𝑡𝑡𝑡𝑡
𝑡𝑡𝑡𝑡𝑡𝑡
�
𝑝𝑝𝑝𝑝𝑝𝑝
+
×
−
𝜌𝜌)
𝑝𝑝𝑝𝑝𝑝𝑝
𝑆𝑆𝑆𝑆
0.5
𝑁𝑁
𝑁𝑁
�2(1
�
0.5
𝑁𝑁
+ 𝑝𝑝𝑝𝑝𝑝𝑝
× �2(1 − 𝜌𝜌)
𝑆𝑆𝑆𝑆𝑝𝑝𝑝𝑝𝑝𝑝
𝑡𝑡𝑡𝑡𝑡𝑡
𝑡𝑡𝑡𝑡𝑡𝑡
0.5
𝑁𝑁𝑁𝑁
𝑁𝑁
𝑡𝑡𝑡𝑡𝑡𝑡
𝑡𝑡𝑡𝑡𝑡𝑡
𝑁𝑁
𝑡𝑡𝑡𝑡𝑡𝑡
𝑡𝑡𝑡𝑡𝑡𝑡
0.5∗∗∗∗∗∗𝑁𝑁
𝑁𝑁𝑡𝑡𝑡𝑡𝑡𝑡
𝑁𝑁𝑡𝑡𝑡𝑡𝑡𝑡
0.5+∗ 𝑁𝑁𝑡𝑡𝑡𝑡𝑡𝑡 ×𝑁𝑁𝑡𝑡𝑡𝑡𝑡𝑡
�
𝑆𝑆𝑆𝑆𝑝𝑝𝑝𝑝𝑝𝑝 0.5
𝑡𝑡𝑡𝑡𝑡𝑡
𝑡𝑡𝑡𝑡𝑡𝑡
�2(1 − 𝜌𝜌)
0.5
𝑁𝑁
𝑁𝑁
0.5 ∗ 𝑁𝑁𝑡𝑡𝑡𝑡𝑡𝑡 𝑝𝑝𝑝𝑝𝑝𝑝
𝑁𝑁𝑡𝑡𝑡𝑡𝑡𝑡
𝑡𝑡𝑡𝑡𝑡𝑡
𝑡𝑡𝑡𝑡𝑡𝑡
𝑡𝑡𝑡𝑡𝑡𝑡
𝑡𝑡𝑡𝑡𝑡𝑡
0.5 ∗ 𝑁𝑁
𝑁𝑁
𝑡𝑡𝑡𝑡𝑡𝑡
𝑡𝑡𝑡𝑡𝑡𝑡
SMD
=
standardized
difference;
MD,i–––pre-test
=
meanin
difference
post
– pre-test in
SMD
===standardized
mean
difference;
M
mean
difference
post
intervention
group;
D,i =
SMD
standardized
mean
difference;
M
===mean
mean
difference
post
pre-test
in
intervention
group;
SMD
standardized
mean
difference;
M
mean
difference
post
pre-test
in
intervention
group;
D,i
D,i=
SMD
standardized
mean
difference;
M
mean
difference
post
pre-test
in
intervention
group;
SMD
standardized
mean
difference;
M
mean
difference
post
in
D,i
SMD=M
standardized
mean
difference;
MD,i
mean
difference
post
pre-test
inintervention
intervention
group; in intervention group;
SMD
= standardized
difference;
M
=–––pre-test
mean
difference
post – group;
pre-test
D,i==in
D,i –
SMD
===mean
standardized
mean
difference;
M
mean
difference
post
pre-test
in
intervention
group;
ference;
difference
post
–group;
pre-test
intervention
group;
D,i
D,i = mean
D,i
M
=
difference
post
–
pre-test
in
placebo
group;
M
=
mean
in
exposed
group;
M
=
mean
in
=
mean
difference
post
–
pre-test
in
placebo
group;
Me =group;
intervention
M
D,p
e
ne
SMD = standardized
mean
difference;
MD,i
====mean
difference
post
– pre-test
in
intervention
D,p
M
===mean
mean
difference
post
pre-test
in
placebo
group;
M
mean
in
exposed
group;
M
===in
mean
in
M
mean
difference
post
––pre-test
pre-test
in
placebo
group;
M
==mean
mean
in
exposed
group;
M
mean
in
D,p
D,p=
ne=
M
mean
difference
post
pre-test
in
placebo
group;
M
mean
in
exposed
group;
M
mean
in
M
difference
post
–=–––mean
in
group;
M
in
M
mean
in
D,p
ne
eeeeemean
MD,p
mean
difference
post
pre-test
inplacebo
placebo
group;
M
mean
inexposed
exposed
group;
Mnene
mean
in group;
M
mean
difference
post
–M
pre-test
in
placebo
group;group;
Me = mean
exposed
Mne = mean in
D,p==in
ne==
D,p
M
mean
difference
post
pre-test
in
placebo
group;
M
=
mean
in
exposed
group;
M
mean
in
– pre-test
placebo
group;
M
=
in
exposed
group;
=
in
D,p
e
ne
e
ne
D,p
e
ne
non-exposed
group;
M
post-test;
===mean
=
mean
in non-exposed
= mean
post-test;
exposed
group;
M
post =
pre
MD,p mean
=M
mean
difference
post M
–M
pre-test
in pre-test.
placebo
group; Me =group;
mean M
in post
exposed
group;
Mne = mean in
non-exposed
group;
==in
mean
post-test;
mean
pre-test.
non-exposed
group;
M
==mean
mean
post-test;
M
mean
pre-test.
post
pre
post=
prene
non-exposed
group;
M
mean
post-test;
M
=
mean
pre-test.
non-exposed
group;
M
mean
post-test;
M
=
mean
pre-test.
post
pre
post
pre
non-exposed
group;
M
mean
post-test;
M
=
mean
pre-test.
non-exposed
group;
M
post-test;
M
=
mean
pre-test.
post
pre= mean pre-test.
pre
Mpost
= meanpre-test.
post-test; Mpost
meannon-exposed
post-test; Mgroup;
pre-test.
pre
pre = mean
post
pre post-test; M (𝑁𝑁𝑁𝑁−1)𝑆𝑆𝑆𝑆𝑖𝑖
2
= mean
Mpre
non-exposed
group; Mpost = mean
= mean222222pre-test.
+(𝑁𝑁𝑁𝑁−1)𝑆𝑆𝑆𝑆𝑆𝑆
pre
(𝑁𝑁𝑁𝑁−1)𝑆𝑆𝑆𝑆𝑖𝑖
(𝑁𝑁𝑁𝑁−1)𝑆𝑆𝑆𝑆𝑖𝑖
+(𝑁𝑁𝑁𝑁−1)𝑆𝑆𝑆𝑆𝑆𝑆
+(𝑁𝑁𝑁𝑁−1)𝑆𝑆𝑆𝑆𝑆𝑆22222
�
(𝑁𝑁𝑁𝑁−1)𝑆𝑆𝑆𝑆𝑖𝑖
+(𝑁𝑁𝑁𝑁−1)𝑆𝑆𝑆𝑆𝑆𝑆
SD
=
pooled
standard
deviation
at
baseline,
calculated
as
(𝑁𝑁𝑁𝑁−1)𝑆𝑆𝑆𝑆𝑖𝑖
2
pooled
(𝑁𝑁𝑁𝑁−1)𝑆𝑆𝑆𝑆𝑖𝑖
2
+(𝑁𝑁𝑁𝑁−1)𝑆𝑆𝑆𝑆𝑆𝑆22 (𝑁𝑁𝑁𝑁−1)𝑆𝑆𝑆𝑆𝑖𝑖2 +(𝑁𝑁𝑁𝑁−1)𝑆𝑆𝑆𝑆𝑆𝑆 2
�
�
2 +(𝑁𝑁𝑁𝑁−1)𝑆𝑆𝑆𝑆𝑆𝑆
2
SD
=
pooled
standard
deviation
at
baseline,
calculated
as
SD
=
pooled
standard
deviation
at
baseline,
calculated
as
(𝑁𝑁𝑁𝑁−1)𝑆𝑆𝑆𝑆𝑖𝑖
+(𝑁𝑁𝑁𝑁−1)𝑆𝑆𝑆𝑆𝑆𝑆
�
(𝑁𝑁𝑁𝑁−1)𝑆𝑆𝑆𝑆𝑖𝑖
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁
pooled
+(𝑁𝑁𝑁𝑁−1)𝑆𝑆𝑆𝑆𝑆𝑆
�
pooled
(𝑁𝑁𝑁𝑁−1)𝑆𝑆𝑆𝑆𝑖𝑖
SD
=
pooled
standard
deviation
at
baseline,
calculated
as
+(𝑁𝑁𝑁𝑁−1)𝑆𝑆𝑆𝑆𝑆𝑆
SD
===pooled
standard
at
calculated
�
pooled
SDpooled
pooled
standard
deviation
atbaseline,
baseline,
calculated
as
SDdeviation
standard
deviationas
at �
baseline,
calculated
as � 2 +(𝑁𝑁𝑁𝑁−1)𝑆𝑆𝑆𝑆𝑆𝑆
2
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁
pooled
pooled
�= pooled
SD
pooled
standard
deviation
at
baseline,
calculated
as
(𝑁𝑁𝑁𝑁−1)𝑆𝑆𝑆𝑆𝑖𝑖
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁
viation
at
baseline,
calculated
as
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁
pooled
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁
pooled
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁
SDpooled
=non-exposed;
pooled
standard
deviation
baseline,
calculated
as �
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁
SDpooled
= pooled
standard
deviation
atat
baseline,
calculated
as
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁
standard
deviation
in
SD
standard
deviation
pre-test.
SD
ne =
pre=
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁
=
standard
deviation
in
non-exposed;
SD
=
standard
deviation
pre-test.
SD
=
standard
deviation
in
non-exposed;
SD
=
standard
deviation
pre-test.
SD
ne
pre
ne=
pre
= standard
standard
deviation
in
non-exposed;
SD
standard
deviation
pre-test.
SD
deviation
in
SD
====standard
deviation
SD
ne
pre
standard
deviation
innon-exposed;
SDpre
standard
deviation
pre-test.
SDnene
=non-exposed;
standard
deviation
in
non-exposed;
SDpre-test.
= standard deviation pre-test.
SDdeviation
ne==standard
pre
ne
pre
in
non-exposed;
SD
standard
deviation
pre-test.
SD
non-exposed;
SD
standard
pre-test.
pre
pre= deviation
presubjects in intervention
NN
total
number
of
subjects
;;;N
number
of
group;
NNNp===number
of
totne=
i=
=
standard
deviation
in
non-exposed;
SD
=
standard
deviation
pre-test.
SD
SD
=
standard
deviation
in
non-exposed;
SD
=
standard
deviation
=
total
number
of
subjects
N
=
number
of
subjects
in
intervention
group;
number
of
N
=
total
number
of
subjects
N
=
number
of
subjects
in
intervention
group;
number
of
ne
pre
tot
i
tot
i
p==intervention
N
=
total
number
of
subjects
;
N
=
number
of
subjects
in
intervention
group;
NNin
number
of
===total
of
;;;NNNii =i=number
subjects
in
intervention
group;
NN
ne
pre subjects
tot
p=
tot
pp
totalnumber
number
ofsubjects
subjects
=number
number
of
subjects
in
intervention
group;
numberof
ofpre-test.
Ntot
= total
ofof
subjects
;N
number of
group; Np= number of
p= number
i=
NN
total
number
of
subjects
number
of
subjects
in
intervention
group;
number
of
s ; NN
=totnumber
of subjects
in
intervention
group;
N
=
number
of
ii
p
i tot
p
tot
p
subjects
in
placebo
group;
N
=number
of
subjects
in
the
exposed
group;
N
=
number
of
subjects
in
e =number
neintervention
N
=
total
number
of
subjects
;
N
=
number
of
subjects
in
group;
Npgroup;
=in
number
subjects
in
placebo
group;
N
of
subjects
in
the
exposed
group;
N
=
number
of
subjects
subjects
in
placebo
group;
N
=number
of
subjects
in
the
exposed
group;
N
=
number
of
subjects
in
=
total
number
of
subjects
;
N
=
number
of
subjects
in
intervention
Np=ofof subjects in
N
tot
i
ee=number
ne
e=number
ne
subjects
in
placebo
group;
N
of
subjects
in
the
exposed
group;
N
=
number
of
subjects
in
subjects
in
placebo
group;
N
of
subjects
in
the
exposed
group;
N
=
number
of
subjects
in
totsubjects
i
ne
e
ne
subjects
in
placebo
group;
N
=number
of
subjects
in
the
exposed
group;
N
=
number
of
subjects
in= number
in
placebo
group;
N
=number
of
subjects
in
the
exposed
group;
N
e=number
ne
e
ne
subjects
in
placebo
group;
N
of
subjects
in
the
exposed
group;
N
=
number
of
subjects
in
=number
of
subjects
in
the
exposed
group;
N
=
number
of
subjects
in
e
ne
ne
e
ne
non-exposed
group.
subjects in placebo
group;inNplacebo
=number
of subjects
in the exposed
group;
Nne=exposed
numbergroup;
of subjects in
non-exposed
group.
non-exposed
group.
of subjects
in the
of subjects
group;
Ne=number
non-exposed
group.
non-exposed
non-exposedgroup.
group.number
non-exposed
group. e
non-exposed
group.
non-exposed group.
of subjects
in non-exposed
group.
Nne= number
2
2
𝑆𝑆𝑆𝑆 22+
22
22− 𝑆𝑆𝑆𝑆
2 𝑆𝑆𝑆𝑆
𝑝𝑝𝑝𝑝𝑝𝑝
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
222
222 −
𝑆𝑆𝑆𝑆
++𝑆𝑆𝑆𝑆
𝑆𝑆𝑆𝑆
𝑆𝑆𝑆𝑆
22+
𝑆𝑆𝑆𝑆𝑝𝑝𝑝𝑝𝑝𝑝
𝑆𝑆𝑆𝑆𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
𝑆𝑆𝑆𝑆𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
2
2 +SD
𝑝𝑝𝑝𝑝𝑝𝑝
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
𝑆𝑆𝑆𝑆
𝑆𝑆𝑆𝑆
−−
𝑆𝑆𝑆𝑆
𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
𝑆𝑆𝑆𝑆
2
of
the
ρρρ2==+=correlation,
calculated
as
2−
𝑝𝑝𝑝𝑝𝑝𝑝
22+
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
2
𝑆𝑆𝑆𝑆
+𝑆𝑆𝑆𝑆
𝑆𝑆𝑆𝑆
−𝑆𝑆𝑆𝑆
𝑆𝑆𝑆𝑆𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
𝑆𝑆𝑆𝑆
−
𝑆𝑆𝑆𝑆𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑2 deviation
𝑝𝑝𝑝𝑝𝑝𝑝
2
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
diff =
2 𝑆𝑆𝑆𝑆with
𝑝𝑝𝑝𝑝𝑝𝑝
𝑝𝑝𝑝𝑝𝑝𝑝
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
𝑆𝑆𝑆𝑆
−
𝑆𝑆𝑆𝑆
with
SD
====standard
standard
deviation
of
the
correlation,
calculated
as
with
SD
standard
deviation
of
the
correlation,
calculated
as
with
standarddeviation
devia- of the
ρ =ρcorrelation,
calculated
as
𝑆𝑆𝑆𝑆𝑝𝑝𝑝𝑝𝑝𝑝
𝑆𝑆𝑆𝑆
𝑆𝑆𝑆𝑆𝑝𝑝𝑝𝑝𝑝𝑝
+𝑆𝑆𝑆𝑆
𝑆𝑆𝑆𝑆
−𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
𝑆𝑆𝑆𝑆𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
∗∗2𝑆𝑆𝑆𝑆
222∗∗+
diff
𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
diff=
with
SD
standard
deviation
of
the
ρρ====correlation,
correlation,
calculated
as
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 − 𝑆𝑆𝑆𝑆𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
2
𝑝𝑝𝑝𝑝𝑝𝑝
2 SD
standard
deviation
ρρ
calculated
as
𝑝𝑝𝑝𝑝𝑝𝑝
2 + 𝑆𝑆𝑆𝑆with
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
diff
𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
diff
diff
with
SD
standard
deviation
ofthe
the
correlation,
calculated
as
with SD
SDof
==
standard
=
correlation,
calculated
as
𝑆𝑆𝑆𝑆
𝑆𝑆𝑆𝑆
∗
𝑆𝑆𝑆𝑆
2
∗
𝑆𝑆𝑆𝑆
diff
𝑆𝑆𝑆𝑆
−
𝑆𝑆𝑆𝑆
diff
with
SD
=
standard
deviation
of
the
correlation, calculated
as
𝑝𝑝𝑝𝑝𝑝𝑝
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
𝑝𝑝𝑝𝑝𝑝𝑝∗∗∗𝑆𝑆𝑆𝑆
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
𝑆𝑆𝑆𝑆
22standard
𝑆𝑆𝑆𝑆
𝑝𝑝𝑝𝑝𝑝𝑝
with
SD
deviation
of
the
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
∗∗∗∗𝑆𝑆𝑆𝑆
diff
𝑝𝑝𝑝𝑝𝑝𝑝
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
diff =22
𝑆𝑆𝑆𝑆
𝑆𝑆𝑆𝑆
∗
𝑆𝑆𝑆𝑆
2
∗
𝑆𝑆𝑆𝑆
𝑝𝑝𝑝𝑝𝑝𝑝
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
diff
𝑝𝑝𝑝𝑝𝑝𝑝∗
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
𝑝𝑝𝑝𝑝𝑝𝑝
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝with SD
𝑆𝑆𝑆𝑆
𝑆𝑆𝑆𝑆
∗
𝑆𝑆𝑆𝑆
2
∗
𝑆𝑆𝑆𝑆
=
standard
deviation
of the
ρ
=
correlation,
calculated
as
𝑝𝑝𝑝𝑝𝑝𝑝
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
∗
𝑆𝑆𝑆𝑆
2
∗
𝑆𝑆𝑆𝑆
𝑝𝑝𝑝𝑝𝑝𝑝
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
diff
tion of the differences.
𝑝𝑝𝑝𝑝𝑝𝑝
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
differences.
2 ∗ 𝑆𝑆𝑆𝑆𝑝𝑝𝑝𝑝𝑝𝑝 ∗ 𝑆𝑆𝑆𝑆𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
differences.
differences.
differences.
differences.
differences.
differences.
differences.
assuming
equal
variances
overthe
treatment
If not SD
reported,
we calculated
SDpreover
IfIfIfnot
reported,
we
calculated
equal
variances
treatment
periods
and
using
pre assuming
differences.
not
reported,
we
calculated
SD
assuming
equal
variances
over
treatment
periods
and
using
the
not
reported,
we
calculated
SD
assuming
equal
variances
over
treatment
periods
and
using
the
pre
preassuming
IfIfnot
not
reported,
we
calculated
SD
assuming
equal
variances
over
treatment
periods
and
using
the
reported,
we
calculated
SD
equal
over
treatment
periods
the
pre
not
reported,
wevariances
calculated
SDpre
assuming
equalvariances
variances
over
treatment
periodsand
andusing
using
the periods and using the
If notover
reported,
we calculated
SDpre
assuming
equal variances
over
treatment
pre
If
not
reported,
we
calculated
SD
assuming
equal
variances
over
treatment
periods
and
using
the
d SDIfpre
assuming
equal
treatment
periods
and
using
the
pre
2
pre
and
using
the mean
of the
other included
paired
studies
(mean
𝑆𝑆𝑆𝑆
If notperiods
reported,
we
calculated
SDprecorrelation
assuming equal
variances
over treatment
and using the 2
𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑periods
22
22
𝑆𝑆𝑆𝑆
𝑆𝑆𝑆𝑆
𝑆𝑆𝑆𝑆
𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
�
𝑆𝑆𝑆𝑆
22
mean
correlation
of
the
other
included
paired
studies
(mean
0.54):
SD
𝑆𝑆𝑆𝑆
𝑆𝑆𝑆𝑆𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
2
𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
pre =
𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
�
�
𝑆𝑆𝑆𝑆
𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑2
𝑆𝑆𝑆𝑆𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑correlation
=
mean
correlation
of
the
other
included
paired
studies
(mean
correlation
0.54):
SD
=
mean
correlation
of
the
other
included
paired
studies
(mean
correlation
0.54):
SD
𝑆𝑆𝑆𝑆
�
2(1−𝜌𝜌)
pre
𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
pre
�
=
mean
correlation
of
the
other
included
paired
studies
(mean
correlation
0.54):
SD
=
correlation
0.54):
SD
=
mean
correlation
of
the
other
included
paired
studies
(mean
correlation
0.54):
SD
�
𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
pre
meancorrelation
correlation
ofthe
the
other
includedpaired
paired
studies
(meancorrelation
correlation
0.54):
SDpre
= 2�
mean
correlation
ofprethestudies
other
included
paired studies
(mean
2(1−𝜌𝜌)
2(1−𝜌𝜌) 0.54): SD
𝑆𝑆𝑆𝑆pre
precorrelation
==�2(1−𝜌𝜌)
mean
of
other
included
(mean
0.54):
SD
2(1−𝜌𝜌)
SD
r included
paired
studies
(mean
correlation
0.54):
𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 2(1−𝜌𝜌)
pre
pre = �
2(1−𝜌𝜌)
pre
2(1−𝜌𝜌)
2(1−𝜌𝜌) studies (mean correlation 0.54):
mean correlation of the other included paired
2(1−𝜌𝜌) SDpre = �
2(1−𝜌𝜌)
Author
Vlachakis
Frishman
Mehta
Mehta
Frishman
Lote study1
Lote study2
Lote study3
Leon
Mehta
Thaulow
study1
Thaulow
study2
Thaulow
study3
Campbell
Markel
Ref
1
2
3
4
5
6
6
6
7
8
9
9
9
10
11
1983
1981
1981
1981
1981
1979
1978
1978
1978
1978
1978
1978
1978
1974
1980
Year
Population
N (%
male)
CAD
CAD
CAD
43 (91)
16 (63)
cross-over
trial
Hypertension 14 (100)
1-group trial Hypertension 8 (ns)
2-group trial Previous MI
2-group trial Healthy
16 (63)
28 (ns)
4 (ns)
Hypertension 4 (100)
Hypertension 4 (100)
2-group trial Healthy
crosssectional
20 (ns)
16 (ns)
18 (ns)
19 (70)
Hypertension 5 (80)
1-group trial Healthy
cross-over
trial
cross-over
trial
cross-over
trial
2-group trial CAD
crosssectional
crosssectional
2-group trial CAD
1-group trial Hypertension 16 (75)
Design
Appendix Table 1 Characteristics of all included studies
42-58
21-63
41-76
23-37
23-37
41-64
34
30-45
30-45
30-45
52
46-64
57
54
54
400
200
5
10
Atenolol
100
Propranolol 320
Timolol
Propranolol 40
Timolol
Propranolol 20
Propranolol 160
Propranolol 80
Labetalol
Labetalol
Propranolol 40
Propranolol 80
Propranolol 80
Propranolol 40
4 wks
4 wks
> 1 yr
once
once
ns
2d
2 wks
2 wks
2 wks
50 wks
ns
ns
4 wks
8 wks
Dose Duration
(mg)*
Propranolol 60
Age mean β-blocker
or range
(yrs)
Coll, ADP, Epi
Thromb
ADP
ADP
ADP
ADP, Epi
Coll, ADP, Epi
Coll, ADP, Epi
Coll, ADP, Epi
Coll, ADP, Epi
ADP
ADP, Epi
ADP, Epi
ADP
ADP
Aggregation
agonist (LTA)
AUC, mg
Threshold
concentration
Threshold
concentration
Threshold
concentration
Threshold
concentration
% platelet aggregation
% light transmittance
% platelet aggregation
% platelet aggregation
% platelet aggregation
Threshold
concentration
% platelet aggregation
% platelet aggregation
Threshold
concentration
Threshold
concentration
Outcome Measure
122
Appendices
Chapter 6, Appendix table
Kirch
Ring
Winther
study1
Winther
study2
Davi
Willich
Gleerup
Pamphilon
Nagakawa
Lin
Ding
Giugliano
Patki
Mugellini
study1
Mugellini
study2
13
14
15
15
16
17
18
19
20
21
22
23
24
25
25
2005
2005
1998
1998
1994
1991
1990
1989
1989
1989
1988
1988
1988
1987
1986
1984
Healthy
9 (100)
CAD
CAD
Healthy
10 (100)
10 (100)
5 (100)
10 (80)
cross-over
trial
cross-over
trial
30 (43)
Hypertension 30 (47)
DM
1-group trial Hypertension 6 (83)
8 (75)
Hypertension 30 (57)
2-group trial DM
cross-over
trial
2-group trial Hypertension 25 (80)
1-group trial Hypertension 11 (27)
8 (ns)
Hypertension 10 (80)
CAD
1-group trial Healthy
cross-over
trial
cross-over
trial
2-group trial Hypertension 12 (ns)
cross-over
trial
cross-over
trial
cross-over
trial
1-group trial Hypertension 9 (ns)
cross-over
trial
74
75
47
53
59
44
69
18-37
54
52-77
>60
60
60
28-32
51
33
100
10
5
600
20
Atenolol
Atenolol
Atenolol
Carvedilol
50
50
50
25
Propranolol 75
Labetalol
Carvedilol
Propranolol 160
Timolol
Metoprolol 200
Propranolol 80
Timolol
Metoprolol 100
Propranolol 40
Atenolol
Metoprolol 100
6 wks
6 wks
1 wks
12 wks
10 wks
4 wks
8 wks
once
2 wks
9d
1 wks
2 wks
2 wks
once
12 wks
3 wks
Threshold
concentration
Threshold
concentration
Threshold
concentration
Threshold
concentration
Threshold
concentration
% platelet aggregation
AUC, cm²/min
Threshold
concentration
% light transmittance
% platelet aggregation
ADP, Coll
ADP, Coll
ADP
ADP
Delta T-max%
Delta T-max%
% platelet inhibition
% platelet aggregation
Coll, ADP, AA, Epi max. amplitude
Coll, ADP, Epi
AA
Coll, ADP, AA, Epi Angle Slope
ADP
ADP, Epi
ADP, Coll, AA
ADP
ADP
ADP, Epi
ADP, Coll
ADP, Thromb,
AA, Epi
CAD: coronary artery disease; DM: diabetes mellitus; MI: myocardial infarction; N: total number of patients; yrs: years; mg: milligrams; wks:
weeks; d: days; yr: years; LTA: light transmission aggregometry; Coll: collagen; ADP: adenosine diphosphate; Epi: epinephrine; AA: arachidonic
acid; Thromb: thrombine; ns: not specified;
* When studies used a run-in period for beta-blocker dosage titration, the final reached dose of the beta-blocker or the mean dose was used.
Cortellaro
12
Appendices
123
124
Appendices
Chapter 6, Appendix figure 1
Risk of bias assessment for clinical trials (n=28)
Random sequence generation
Allocation concealment
Blinding of participants and personnel
Blinding of outcome assessment
Incomplete outcome data
Selective reporting
Reporting on carry−over effects
Presence of carry−over
A
0
20
40
percent
60
80
100
Risk of bias assessment for observational studies (n=3)
Random sequence generation
Allocation concealment
Blinding of participants and personnel
Blinding of outcome assessment
Incomplete outcome data
Selective reporting
Reporting in−and exclusion criteria
Control for confounding factors
B
0
20
40
percent
60
80
Low
High
Unclear
Not applicable
100
Appendix figure 1 – Risk of bias assessment. Methodological quality graphs: review authors’
judgements about each methodological quality item presented across included trials (panel a)
and observational studies (panel b).
Appendices
Chapter 6, Appendix figure 2
Author
Year
Standard
error SMD
SMD, random
effects (95% CI)
Ding
Mugellini_study2
Mugellini_study1
Thaulow_study3
Markel
Vlachakis
Mehta
Nagakawa
Lin
Winther_33_study1
Willich
Gleerup
Kirch
Cortellaro
Pamphilon
Guigliano
Thaulow_study2
Thaulow_study1
Davi
Winther_33_study2
Ring
Patki
Mehta
Frishman
Lote_study1
Mehta
Leon
Lote_study2
Lote_study3
Frishman
Campbell
1994
2005
2005
1981
1983
1980
1979
1990
1991
1988
1989
1989
1986
1984
1989
1998
1981
1981
1988
1988
1987
1998
1978
1974
1978
1978
1978
1978
1978
1978
1981
.25
.26
.27
.31
.34
.38
.4
.41
.42
.45
.45
.46
.49
.5
.51
.51
.52
.52
.58
.59
.6
.62
.63
.64
.7
.72
.73
.77
.91
1.19
2.75
−0.00 (−0.49, 0.49)
−0.03 (−0.38, 0.33)
−0.15 (−0.44, 0.15)
−0.12 (−0.38, 0.14)
−0.11 (−0.35, 0.14)
−0.17 (−0.40, 0.07)
−0.23 (−0.48, 0.01)
−0.21 (−0.43, 0.01)
−0.23 (−0.44, −0.03)
−0.21 (−0.41, −0.01)
−0.20 (−0.40, −0.00)
−0.17 (−0.36, 0.02)
−0.17 (−0.36, 0.02)
−0.17 (−0.35, 0.02)
−0.16 (−0.35, 0.02)
−0.17 (−0.35, 0.01)
−0.18 (−0.36, −0.00)
−0.18 (−0.36, −0.01)
−0.18 (−0.35, −0.01)
−0.15 (−0.32, 0.02)
−0.18 (−0.36, −0.00)
−0.19 (−0.36, −0.02)
−0.24 (−0.44, −0.04)
−0.31 (−0.54, −0.07)
−0.32 (−0.55, −0.09)
−0.39 (−0.65, −0.13)
−0.39 (−0.65, −0.14)
−0.40 (−0.65, −0.15)
−0.41 (−0.66, −0.16)
−0.51 (−0.80, −0.22)
−0.54 (−0.84, −0.24)
−1.5
Decreases
0
1.5
Increases
Platelet aggregation
Appendix figure 2 – Cumulative meta-analysis based on study precision.
125
126
Appendices
Chapter 6, Appendix references
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