Antiplatelet agents for intermittent claudication

Peng F Wong; Lee Yee Chong; Dimitris P Mikhailidis; Peter Robless; Gerard Stansby

doi:10.1002/14651858.CD001272.pub2

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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 Antiplatelet agent versus placebo, Outcome 1 All cause mortality.

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Analysis 1.2

Comparison 1 Antiplatelet agent versus placebo, Outcome 2 Cardiovascular mortality (fatal stroke or MI).

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Analysis 1.3

Comparison 1 Antiplatelet agent versus placebo, Outcome 3 Cardiovascular event (fatal and non‐fatal MI or stroke).

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Analysis 1.4

Comparison 1 Antiplatelet agent versus placebo, Outcome 4 Myocardial infarction (fatal and non‐fatal).

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Analysis 1.5

Comparison 1 Antiplatelet agent versus placebo, Outcome 5 Myocardial infarction (fatal).

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Analysis 1.6

Comparison 1 Antiplatelet agent versus placebo, Outcome 6 Myocardial infarction (non‐fatal).

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Analysis 1.7

Comparison 1 Antiplatelet agent versus placebo, Outcome 7 Stroke (fatal and non‐fatal).

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Analysis 1.8

Comparison 1 Antiplatelet agent versus placebo, Outcome 8 Stroke (fatal).

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Analysis 1.9

Comparison 1 Antiplatelet agent versus placebo, Outcome 9 Stroke (non‐fatal).

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Analysis 1.10

Comparison 1 Antiplatelet agent versus placebo, Outcome 10 Major bleeding.

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Analysis 1.11

Comparison 1 Antiplatelet agent versus placebo, Outcome 11 GI symptoms (dyspepsia).

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Analysis 1.12

Comparison 1 Antiplatelet agent versus placebo, Outcome 12 Early cessation of treatment.

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Analysis 1.13

Comparison 1 Antiplatelet agent versus placebo, Outcome 13 Pain Free Walking Distance.

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Analysis 1.14

Comparison 1 Antiplatelet agent versus placebo, Outcome 14 Revascularisation.

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Analysis 1.15

Comparison 1 Antiplatelet agent versus placebo, Outcome 15 Limb amputations.

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Analysis 2.1

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 1 All cause mortality.

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Analysis 2.2

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 2 Cardiovascular mortality (fatal stroke or MI).

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Analysis 2.3

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 3 Cardiovascular event (fatal and non‐fatal MI or stroke).

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Analysis 2.4

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 4 Myocardial infarction (fatal and non‐fatal).

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Analysis 2.5

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 5 Myocardial infarction (fatal).

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Analysis 2.6

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 6 Myocardial infarction (non‐fatal).

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Analysis 2.7

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 7 Stroke (fatal and non‐fatal).

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Analysis 2.8

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 8 Stroke (fatal).

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Analysis 2.9

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 9 Stroke (non‐fatal).

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Analysis 2.10

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 10 Major bleeding.

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Analysis 2.11

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 11 GI symptoms (dyspepsia).

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Analysis 2.12

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 12 Early cessation of treatment.

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Analysis 2.13

Comparison 2 Antiplatelet agent(s) versus aspirin, Outcome 13 Amputation.

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Comparison 1. Antiplatelet agent versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All cause mortality Show forest plot	5	3926	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.60, 0.98]

1.1 picotamide	1	2304	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.50, 1.66]
1.2 ticlopidine	4	1622	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.56, 0.96]
2 Cardiovascular mortality (fatal stroke or MI) Show forest plot	4	1622	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.32, 0.93]

2.1 ticlopidine	4	1622	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.32, 0.93]
3 Cardiovascular event (fatal and non‐fatal MI or stroke) Show forest plot	5	3926	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.63, 1.01]

3.1 picotamide	1	2304	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.47, 1.50]
3.2 ticlopidine	4	1622	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.61, 1.02]
4 Myocardial infarction (fatal and non‐fatal) Show forest plot	5	3926	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.63, 1.12]

4.1 picotamide	1	2304	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.39, 1.69]
4.2 ticlopidine	4	1622	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.62, 1.16]
5 Myocardial infarction (fatal) Show forest plot	4	1622	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.31, 1.05]

5.1 ticlopidine	4	1622	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.31, 1.05]
6 Myocardial infarction (non‐fatal) Show forest plot	4	1622	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.69, 1.48]

6.1 ticlopidine	4	1622	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.69, 1.48]
7 Stroke (fatal and non‐fatal) Show forest plot	5	3926	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.45, 1.13]

7.1 picotamide	1	2304	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.35, 2.30]
7.2 ticlopidine	4	1622	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.39, 1.12]
8 Stroke (fatal) Show forest plot	4	1622	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.07, 1.64]

8.1 ticlopidine	4	1622	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.07, 1.64]
9 Stroke (non‐fatal) Show forest plot	4	1622	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.42, 1.30]

9.1 ticlopidine	4	1622	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.42, 1.30]
10 Major bleeding Show forest plot	2	838	Risk Ratio (M‐H, Fixed, 95% CI)	1.73 [0.51, 5.83]

10.1 ticlopidine	2	838	Risk Ratio (M‐H, Fixed, 95% CI)	1.73 [0.51, 5.83]
11 GI symptoms (dyspepsia) Show forest plot	9	3818	Risk Ratio (M‐H, Random, 95% CI)	2.11 [1.23, 3.61]

11.1 indobufen	2	352	Risk Ratio (M‐H, Random, 95% CI)	3.29 [1.17, 9.27]
11.2 picotamide	2	2344	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.75, 1.18]
11.3 ticlopidine	4	1000	Risk Ratio (M‐H, Random, 95% CI)	2.40 [1.82, 3.17]
11.4 trifusal	1	122	Risk Ratio (M‐H, Random, 95% CI)	6.41 [0.79, 51.64]
12 Early cessation of treatment Show forest plot	8	4388	Risk Ratio (M‐H, Fixed, 95% CI)	2.05 [1.53, 2.75]

12.1 indobufen	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	1.46 [0.47, 4.49]
12.2 picotamide	2	2344	Risk Ratio (M‐H, Fixed, 95% CI)	1.45 [0.73, 2.84]
12.3 ticlopidine	4	1622	Risk Ratio (M‐H, Fixed, 95% CI)	2.35 [1.66, 3.31]
12.4 trifusal	1	122	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.07, 16.69]
13 Pain Free Walking Distance Show forest plot	3	329	Mean Difference (IV, Random, 95% CI)	78.09 [12.24, 143.95]

13.1 indobufen	2	294	Mean Difference (IV, Random, 95% CI)	196.87 [‐85.58, 479.32]
13.2 picotamide	1	35	Mean Difference (IV, Random, 95% CI)	38.70 [2.68, 74.72]
14 Revascularisation Show forest plot	5	3304	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.43, 0.97]

14.1 picotamide	1	2304	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.50, 1.23]
14.2 ticlopidine	4	1000	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.13, 0.84]
15 Limb amputations Show forest plot	2	2991	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.38, 1.86]

15.1 picotamide	1	2304	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.22, 2.98]
15.2 ticlopidine	1	687	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.32, 2.35]

Comparison 1. Antiplatelet agent versus placebo

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Comparison 2. Antiplatelet agent(s) versus aspirin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All cause mortality Show forest plot	2	7661	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.58, 0.93]

1.1 clopidogrel vs aspirin	1	6452	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.60, 1.02]
1.2 picotamide vs aspirin	1	1209	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.31, 0.98]
2 Cardiovascular mortality (fatal stroke or MI) Show forest plot	2	7661	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.48, 1.15]

2.1 clopidogrel vs aspirin	1	6452	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.51, 1.35]
2.2 picotamide vs aspirin	1	1209	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.16, 1.31]
3 Cardiovascular event (fatal and non‐fatal MI or stroke) Show forest plot	2	7661	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.67, 0.98]

3.1 clopidogrel vs aspirin	1	6452	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.64, 0.97]
3.2 picotamide vs aspirin	1	1209	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.57, 1.54]
4 Myocardial infarction (fatal and non‐fatal) Show forest plot	2	7661	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.50, 0.86]

4.1 clopidogrel vs aspirin	1	6452	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.47, 0.85]
4.2 picotamide vs aspirin	1	1209	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.41, 1.55]
5 Myocardial infarction (fatal) Show forest plot	2	7661	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.40, 1.15]

5.1 clopidogrel vs aspirin	1	6452	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.37, 1.21]
5.2 picotamide vs aspirin	1	1209	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.23, 2.25]
6 Myocardial infarction (non‐fatal) Show forest plot	2	7661	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.47, 0.89]

6.1 clopidogrel vs aspirin	1	6452	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.44, 0.88]
6.2 picotamide vs aspirin	1	1209	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.36, 1.92]
7 Stroke (fatal and non‐fatal) Show forest plot	2	7661	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.76, 1.34]

7.1 clopidogrel vs aspirin	1	6452	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.73, 1.34]
7.2 picotamide vs aspirin	1	1209	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.55, 2.51]
8 Stroke (fatal) Show forest plot	2	7661	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.05, 6.44]

8.1 clopidogrel vs aspirin	1	6452	Risk Ratio (M‐H, Random, 95% CI)	1.38 [0.55, 3.42]
8.2 picotamide vs aspirin	1	1209	Risk Ratio (M‐H, Random, 95% CI)	0.11 [0.01, 2.07]
9 Stroke (non‐fatal) Show forest plot	2	7661	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.76, 1.39]

9.1 picotamide vs aspirin	1	1209	Risk Ratio (M‐H, Fixed, 95% CI)	1.76 [0.74, 4.16]
9.2 clopidogrel vs aspirin	1	6452	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.69, 1.31]
10 Major bleeding Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

10.1 picotamide vs aspirin	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
11 GI symptoms (dyspepsia) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

11.1 picotamide vs aspirin	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
12 Early cessation of treatment Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

12.1 picotamide vs aspirin	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
13 Amputation Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

13.1 picotamide vs aspirin	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 2. Antiplatelet agent(s) versus aspirin

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