Effect and safety of antithrombotic therapies for secondary prevention after acute coronary syndrome: a network meta-analysis

Figures & data

Figure 1 The flowchart of search results.

Abbreviations: ACS, acute coronary syndrome; RCT, randomized controlled trial.

Figure 2 The comparison network for network meta-analysis.

Table 1 Study characteristics

Study	Phase of trial	Intervention	Comparison	Sample	Definition of bleeding	Definition of MACE	Male (%)	Age (Y)	DM (%)	Hypertension	Previous MI (%)
ATLAS ACS-TIMI 46	II	Rivaroxaban + aspirin + clopidogrel	Aspirin + clopidogrel	3,491	TIMI	1,3,4,5	77.2	57.5	19	57.2	21.1
ATLAS ACS 2-TIMI 51	III	Rivaroxaban + aspirin	Aspirin	15,526	TIMI	2,3,4	74.7	61.7	32.0	67.4	26.9
		Rivaroxaban + aspirin + clopidogrel	Aspirin + clopidogrel
CURE	III	Aspirin + clopidogrel	Aspirin	12,562	Clinical	2,3,4	61.5	64.2	22.6	58.8	32.2
COMMIT	III	Aspirin + clopidogrel	Aspirin	45,852	Clinical	1,3,4	72.1	61.3	NA	43.3	8.3
CLARITY-TIMI 28	III	Aspirin + clopidogrel	Aspirin	3,491	TIMI	1,3,6	80.3	57.5	16.5	43.4	9.1
CHARISMA	III	Aspirin + clopidogrel	Aspirin	9,478	GUSTO	1,3,4	72.9	64	31	69.1	NA
GEMINI-ACS-1	II	Rivaroxaban + clopidogrel	Aspirin + clopidogrel	3,037	TIMI	2,3,4,9	74.9	62	29.8	73.2	21.7
		Rivaroxaban + new P2Y12 inhibitor	Aspirin + new P2Y12
TOPIC	III	Aspirin + new P2Y12 inhibitor/clopidogrel	Aspirin + new P2Y12	646	BARC	2,4,7,8	82	60	27	48	NA
PEGASUS-TIMI 54	III	Aspirin + new P2Y12 inhibitor	Aspirin	21,162	TIMI	2,3,4	76.1	65.3	32.1	77.5	16.5
PLATO	III	Aspirin + new P2Y12 inhibitor	Aspirin + clopidogrel	18,624	PLATO, TIMI	2,3,4	71.6	62	25	65.4	20.5
DISPERSE-2	II	Aspirin + new P2Y12 inhibitor	Aspirin + clopidogrel	990	Clinical	2,3,4	63.8	63	24.3	NA	25.2
PHILO	III	Aspirin + new P2Y12 inhibitor	Aspirin + clopidogrel	801	PLATO, TIMI	2,3,4	76.5	67.5	34.7	74.3	7.9
TRITON-TIMI 38	III	Aspirin + new P2Y12 inhibitor	Aspirin + clopidogrel	13,608	TIMI	2,3,4	74	61	23	64	18
TRILOGY ACS	III	Aspirin + new P2Y12 inhibitor	Aspirin + clopidogrel	9,326	GUSTO, TIMI	2,3,4	60.9	66	38	81.2	43.1
PRASFIT-ACS	III	Aspirin + new P2Y12 inhibitor	Aspirin + clopidogrel	1,363	TIMI	2,3,4	78.8	65.2	35.7	72.3	5.1

Notes: 1 = death; 2 = cardiovascular death; 3 = MI; 4 = stroke; 5 = severe recurrent ischemic requiring revascularization; 6 = occluded infarct-related artery; 7 = urgent revascularization; 8 = BARC >2 bleeding; 9 = stent thrombosis.

Abbreviations: DM, diabetes mellitus; MACE, major cardiovascular events; MI, myocardial infarction.

Figure 3 Risk-of-bias assessment of the randomized controlled trials.

Table 2 Estimated relative treatment effects of clinical significant bleeding events as ORs and its corresponding 95% CIs based on the network meta-analysis

Interventions	Comparisons
	Aspirin	Aspirin + clopidogrel	Aspirin + newer P2Y12 blocker	Rivaroxaban + aspirin	Rivaroxaban + aspirin + clopidogrel	Rivaroxaban + clopidogrel	Rivaroxaban + newer P2Y12 blockers	Asipirin + newer P2Y12 blockers/clopidogrel
Aspirin	1	1.58 (1.19, 2.18)	2.16 (1.54, 3.18)	2.46 (1.22, 5.10)	6.02 (3.58, 10.79)	1.28 (0.60, 2.80)	2.78 (1.42, 5.69)	0.66 (0.24, 1.78)
Aspirin + clopidogrel	0.63 (0.46, 0.84)	1	1.36 (1.07, 1.77)	1.55 (0.8, 3.03)	3.81 (2.36, 6.29)	0.81 (0.39, 1.65)	1.76 (0.94, 3.34)	0.41 (0.15, 1.07)
Asipirin + newer P2Y12 blockers	0.46 (0.31, 0.65)	0.73 (0.57, 0.93)	1	1.13 (0.56, 2.3)	2.79 (1.62, 4.87)	0.59 (0.29, 1.20)	1.28 (0.69, 2.40)	0.30 (0.12, 0.75)
Rivaroxaban + aspirin	0.41 (0.20, 0.82)	0.65 (0.33, 1.25)	0.88 (0.43, 1.78)	1	2.46 (1.32, 4.7)	0.52 (0.20, 1.35)	1.14 (0.45, 2.81)	0.27 (0.08, 0.84)
Rivaroxaban + aspirin + clopidogrel	0.17 (0.09, 0.28)	0.26 (0.16, 0.42)	0.36 (0.21, 0.62)	0.41 (0.21, 0.76)	1	0.21 (0.09, 0.50)	0.46 (0.21, 1.02)	0.11 (0.04, 0.32)
Rivaroxaban + clopidogrel	0.78 (0.36, 1.67)	1.23 (0.61, 2.55)	1.68 (0.84, 3.50)	1.92 (0.74, 5.06)	4.71 (2.00, 11.28)	1	2.16 (1.00, 4.76)	0.51 (0.15, 1.64)
Rivaroxaban + newer	0.36 (0.18, 0.7)	0.57 (0.30, 1.06)	0.78 (0.42, 1.44)	0.88 (0.36, 2.21)	2.17 (0.98, 4.79)	0.46 (0.21, 1.00)	1	0.24 (0.08, 0.71)
P2Y12 blocker
Asipirin + newer P2Y12 blockers/clopidogrel	1.52 (0.56, 4.18)	2.41 (0.93, 6.51)	3.30 (1.32, 8.67)	3.74 (1.19, 12.51)	9.20 (3.17, 28.00)	1.96 (0.61, 6.50)	4.23 (1.40, 13.21)	1

Notes: Comparisons should be read from left to right. The estimate is located at the intersection of the treatments in the column heads and the treatments in the row heads. An OR value >1 favors the column-defining regimen. An OR value <1 favors the row-defining regimen.

Table 3 Estimated relative treatment effects of major bleeding risk as ORs and its corresponding 95% CIs based on the network meta-analysis

Interventions	Comparisons
	Aspirin	Aspirin + clopidogrel	Aspirin + newer P2Y12 blocker	Rivaroxaban + aspirin	Rivaroxaban + aspirin + clopidogrel	Rivaroxaban + clopidogrel	Rivaroxaban + newer P2Y12 blockers	Asipirin + newer P2Y12 blockers/clopidogrel
Aspirin	1	1.21 (0.9, 1.69)	1.57 (1.10, 2.41)	4.12 (1.60, 11.16)	6.38 (3.21, 15.00)	2.05 (0.53, 7.79)	1.60 (0.41, 6.18)	0.30 (0.01, 2.70)
Aspirin + clopidogrel	0.82 (0.59, 1.11)	1	1.29 (0.98, 1.75)	3.40 (1.33, 8.89)	5.27 (2.77, 11.66)	1.73 (0.45, 6.2)	1.32 (0.35, 4.8)	0.24 (0.01, 2.20)
Aspirin + newer P2Y12 blockers	0.64 (0.42, 0.91)	0.77 (0.57, 1.02)	1	2.63 (1.00, 7.02)	4.08 (2.03, 9.36)	1.33 (0.35, 4.74)	1.02 (0.27, 3.64)	0.18 (0.01, 1.68)
Rivaroxaban + aspirin	0.24 (0.09, 0.63)	0.29 (0.11, 0.75)	0.38 (0.14, 1.00)	1	1.56 (0.71, 3.74)	0.50 (0.1, 2.39)	0.39 (0.08, 1.86)	0.07 (0, 0.78)
Rivaroxaban + aspirin + clopidogrel	0.16 (0.07, 0.31)	0.19 (0.09, 0.36)	0.25 (0.11, 0.49)	0.64 (0.27, 1.41)	1	0.32 (0.07, 1.32)	0.25 (0.05, 1.02)	0.04 (0, 0.46)
Rivaroxaban + clopidogrel	0.48 (0.13, 1.90)	0.58 (0.16, 2.24)	0.75 (0.21, 2.89)	1.98 (0.42, 10.27)	3.1 (0.76, 14.25)	1	0.77 (0.18, 3.32)	0.13 (0, 1.86)
Rivaroxaban + new P2Y12 blocker	0.62 (0.16, 2.40)	0.76 (0.21, 2.85)	0.98 (0.27, 3.68)	2.57 (0.54, 13.08)	4.01 (0.98, 18.78)	1.29 (0.3, 5.65)	1	0.17 (0.01, 2.44)
Aspirin + new P2Y12 blockers/clopidogrel	3.48 (0.37, 99.65)	4.24 (0.45, 120.51)	5.46 (0.6, 155.03)	14.61 (1.27, 461.53)	22.9 (2.20, 709.15)	7.45 (0.54, 256.79)	5.74 (0.41, 198.65)	1

Notes: Comparisons should be read from left to right. The estimate is located at the intersection of the treatments in the column heads and the treatments in the row heads. An OR value >1 favors the column-defining regimen. An OR value <1 favors the row-defining regimen.

Table 4 Estimated relative treatment effects of major cardiovascular events as ORs and its corresponding 95% CIs based on the network meta-analysis

Interventions	Comparisons
	Aspirin	Aspirin + clopidogrel	Aspirin + newer P2Y12 blocker	Rivaroxaban + aspirin	Rivaroxaban + aspirin + clopidogrel	Rivaroxaban + clopidogrel	Rivaroxaban + newer P2Y12 blockers	Asipirin + newer P2Y12 blockers/clopidogrel
Aspirin	1	0.76 (0.61, 0.89)	0.69 (0.53, 0.87)	0.81 (0.53, 1.18)	0.56 (0.37, 0.76)	0.82 (0.44, 1.45)	0.71 (0.39, 1.25)	0.29 (0.15, 0.55)
Aspirin + clopidogrel	1.32 (1.12, 1.65)	1	0.91 (0.76, 1.11)	1.07 (0.72, 1.56)	0.74 (0.51, 1.01)	1.08 (0.61, 1.91)	0.94 (0.54, 1.63)	0.39 (0.21, 0.73)
Aspirin + newer P2Y12 blockers	1.45 (1.15, 1.90)	1.1 (0.9, 1.32)	1	1.17 (0.76, 1.77)	0.81 (0.53, 1.15)	1.19 (0.66, 2.09)	1.02 (0.59, 1.77)	0.43 (0.24, 0.77)
Rivaroxaban + aspirin	1.24 (0.85, 1.89)	0.94 (0.64, 1.38)	0.85 (0.56, 1.32)	1	0.69 (0.45, 1.03)	1.01 (0.51, 2.03)	0.88 (0.45, 1.72)	0.36 (0.18, 0.76)
Rivaroxaban + aspirin + clopidogrel	1.79 (1.31, 2.68)	1.36 (0.99, 1.95)	1.24 (0.87, 1.87)	1.45 (0.97, 2.22)	1	1.47 (0.77, 2.89)	1.27 (0.68, 2.47)	0.53 (0.27, 1.09)
Rivaroxaban + clopidogrel	1.22 (0.69, 2.27)	0.92 (0.52, 1.64)	0.84 (0.48, 1.51)	0.99 (0.49, 1.96)	0.68 (0.35, 1.3)	1	0.86 (0.46, 1.64)	0.36 (0.16, 0.83)
Rivaroxaban + new P2Y12 blocker	1.42 (0.80, 2.56)	1.07 (0.61, 1.86)	0.98 (0.56, 1.70)	1.14 (0.58, 2.23)	0.79 (0.4, 1.47)	1.16 (0.61, 2.19)	1	0.42 (0.19, 0.94)
Aspirin + new P2Y12 blockers/clopidogrel	3.40 (1.82, 6.56)	2.57 (1.37, 4.76)	2.34 (1.30, 4.23)	2.74 (1.32, 5.67)	1.88 (0.91, 3.75)	2.78 (1.21, 6.34)	2.41 (1.06, 5.36)	1

Notes: Comparisons should be read from left to right. The estimate is located at the intersection of the treatments in the column heads and the treatments in the row heads. An OR value <1 favors the column-defining regimen. An OR value <1 favors the row-defining regimen.

Table 5 Estimated relative treatment effects of death as ORs and its corresponding 95% CIs based on the network meta-analysis

Interventions	Comparisons
	Aspirin	Aspirin + clopidogrel	Aspirin + newer P2Y12 blockers	Rivaroxaban + clopidogrel	Rivaroxaban + new P2Y12 blocker
Aspirin	1	0.94 (0.89, 1.00)	0.86 (0.79, 0.93)	0.86 (0.38, 1.92)	0.93 (0.38, 2.29)
Aspirin + clopidogrel	1.06 (1.00, 1.12)	1	0.91 (0.84, 0.98)	0.91 (0.41, 2.03)	0.99 (0.40, 2.42)
Aspirin + new P2Y12 blockers	1.17 (1.07, 1.27)	1.10 (1.02, 1.19)	1	1.00 (0.45, 2.26)	1.09 (0.44, 2.68)
Rivaroxaban + clopidogrel	1.17 (0.52, 2.61)	1.10 (0.49, 2.46)	1.00 (0.44, 2.25)	1	1.08 (0.32, 3.61)
Rivaroxaban + new	1.07 (0.44, 2.65)	1.01 (0.41, 2.50)	0.92 (0.37, 2.28)	0.92 (0.28, 3.09)	1
P2Y12 blocker

Notes: Comparisons should be read from left to right. The estimate is located at the intersection of the treatments in the column heads and the treatments in the row heads. An OR value >1 favors the column-defining regimen. An OR value <1 favors the row-defining regimen.

Table 6 Estimated relative treatment effects of cardiac death as ORs and its corresponding 95% CIs based on the network meta-analysis

Interventions	Comparisons
	Aspirin	Aspirin + clopidogrel	Aspirin + new P2Y12 blockers	Rivaroxaban + clopidogrel	Rivaroxaban + new P2Y12 blocker	Aspirin + new P2Y12 blockers/clopidogrel
Aspirin	1	0.92 (0.81, 1.03)	0.79 (0.68, 0.91)	1.01 (0.42, 2.46)	1.05 (0.37, 3.05)	0.15 (0.01, 1.20)
Aspirin + clopidogrel	1.09 (0.97, 1.23)	1	0.86 (0.79, 0.93)	1.10 (0.46, 2.68)	1.15 (0.40, 3.29)	0.16 (0.01, 1.31)
Aspirin + newer P2Y12 blockers	1.27 (1.10, 1.47)	1.16 (1.07, 1.27)	1	1.28 (0.53, 3.13)	1.34 (0.47, 3.85)	0.19 (0.01, 1.52)
Rivaroxaban + clopidogrel	0.99 (0.41, 2.41)	0.91 (0.37, 2.19)	0.78 (0.32, 1.89)	1	1.04 (0.27, 4.12)	0.14 (0, 1.44)
Rivaroxaban + newer P2Y12 blocker	0.95 (0.33, 2.73)	0.87 (0.30, 2.48)	0.75 (0.26, 2.14)	0.96 (0.24, 3.72)	1	0.14 (0, 1.51)
Aspirin + new P2Y12 blockers/ clopidogrel	6.73 (0.83, 192.28)	6.16 (0.76, 175.18)	5.29 (0.66, 149.65)	6.92 (0.69, 213.43)	7.28 (0.68, 226.38)	1

Notes: Comparisons should be read from left to right. The estimate is located at the intersection of the treatments in the column heads and the treatments in the row heads. An OR value >1 favors the column-defining regimen. An OR value <1 favors the row-defining regimen.

Table 7 Estimated relative treatment effects of myocardial infarction risk as ORs and its corresponding 95% CIs based on the network meta-analysis

Interventions	Comparisons
	Aspirin	Aspirin + clopidogrel	Aspirin + new P2Y12 blockers	Rivaroxaban + clopidogrel	Rivaroxaban + new P2Y12 blocker	Aspirin + new P2Y12 blockers/clopidogrel
Aspirin	1	0.80 (0.67, 0.92)	0.67 (0.55, 0.84)	0.70 (0.36, 1.32)	1.16 (0.62, 2.15)	0.55 (0.39, 0.79)
Aspirin + clopidogrel	1.25 (1.08, 1.48)	1	0.84 (0.74, 0.99)	0.88 (0.46, 1.63)	1.46 (0.81, 2.64)	0.69 (0.52, 0.97)
Aspirin + newer P2Y12 blockers	1.48 (1.20, 1.83)	1.18 (1.01, 1.34)	1	1.03 (0.54, 1.94)	1.72 (0.93, 3.17)	0.82 (0.62, 1.09)
Rivaroxaban + clopidogrel	1.44 (0.76, 2.75)	1.14 (0.61, 2.15)	0.97 (0.51, 1.86)	1	1.66 (0.71, 3.90)	0.80 (0.40, 1.63)
Rivaroxaban + new P2Y12 blocker	0.86 (0.47, 1.61)	0.69 (0.38, 1.24)	0.58 (0.32, 1.07)	0.60 (0.26, 1.42)	1	0.48 (0.25, 0.94)
Aspirin + new P2Y12 blockers/ clopidogrel	1.80 (1.26, 2.55)	1.44 (1.03, 1.94)	1.22 (0.91, 1.62)	1.25 (0.61, 2.49)	2.09 (1.00, 4.05)	1

Notes: Comparisons should be read from left to right. The estimate is located at the intersection of the treatments in the column heads and the treatments in the row heads. An OR value >1 favors the column-defining regimen. An OR value <1 favors the row-defining regimen.