Combination anticoagulant or P2Y12 inhibitor with low-dose aspirin versus low-dose aspirin alone in patients at risk or with documented coronary and/or peripheral artery disease

Figures & data

Table 1. Study characteristics.

Trial	Population	Follow-up	Interventions	N	Age†, y	Female	CAD*	PAD	CVD	MI	Diabetes
Charisma 2006^4	CAD, PAD, and/or CVD or multiple risk factors	28 months (median)	Clopidogrel + ASA	7802	64.0 (39.0–95.0)	29.7%	47.7%	22.6%	24.9%	34.2%	42.3%
			ASA alone	7801	64.0 (45.0–93.0)	29.8%	48.3%	22.7%	24.3%	34.9%	41.7%
Compass 2017^3	CAD and/or PAD	23 months (mean)	Rivaroxaban + ASA	9152	68.3 (7.9)	22.5%	90.8%	27.2%	3.8%	61.8%	37.7%
			ASA alone	9126	68.2 (8.0)	21.8%	90.5%	27.4%	3.7%	62.7%	38.1%

Abbreviations. ASA, Acetylsalicylic acid; CAD, Coronary artery disease; CHARISMA, Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; COMPASS, Cardiovascular Outcomes for People Using Anticoagulation Strategies; CVD, Cerebrovascular disease; MI, Myocardial infarction; PAD, Peripheral artery disease; y, Years.

*Charisma reported proportion of study participants with documented coronary disease.

†Charisma reported age as median (range) while COMPASS reported age as mean (standard deviation).

Figure 1. Flowchart of included citations. Abbreviations. ASA, Acetylsalicylic acid; CAD, Coronary artery disease; PAD, Peripheral artery disease; RCT, Randomized controlled trial.

Figure 2. Diagram of the indirect treatment comparison. Abbreviations. CHARISMA, Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; COMPASS, Cardiovascular Outcomes for People Using Anticoagulation Strategies; ITC, Indirect treatment comparison.

Figure 3. RoB assessment. Abbreviations. R, Risk arising from the randomization process; D, Bias due to deviations from intended interventions; Mi, Bias due to missing outcome data; Me, Bias in measurement of the outcome; S, Bias in selection of the reported result; O, Overall risk of bias; CHARISMA, Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; COMPASS, Cardiovascular Outcomes for People Using Anticoagulation Strategies; RoB, Risk of bias.

Figure 4. Results of efficacy outcomes for the indirect treatment comparison. Abbreviations. CI, Confidence interval; CV, Cardiovascular; HR, Hazard ratio; ICH, Intracranial hemorrhage; MACE, Major adverse cardiovascular event; MI, Myocardial infarction; RR, Risk ratio.

Table 2. Results of efficacy outcomes for the indirect treatment comparison.

Outcome	Rivaroxaban + ASA vs. ASA alone HR/RR (95% CI) Incidence, %	Clopidogrel + ASA vs. ASA alone HR/RR (95% CI) Incidence, %	Rivaroxaban + ASA vs. clopidogrel + ASA per ITC HR/RR (95% CI)	p value Rivaroxaban + ASA vs. clopidogrel + ASA per ITC
MACE	0.76 (0.66–0.86)	0.93 (0.83–1.05)	0.82 (0.68–0.98)	.03
	4.1 vs. 5.4	6.8 vs. 7.3
CV death	0.78 (0.64–0.96)	1.04 (0.87–1.25)	0.75 (0.57–0.98)	.04
	1.7 vs. 2.2	3.1 vs. 2.9
Stroke	0.59 (0.45–0.77)	0.87 (0.73–1.05)^a	0.67 (0.49–0.93)	.02
	0.9 vs. 1.6	2.6 vs. 3.0
Ischemic stroke	0.52 (0.39–0.69)	0.86 (0.71–1.05)^c	0.60 (0.42–0.86)	.004
	0.7 vs. 1.4	2.3 vs. 2.7
MI	0.87 (0.71–1.06)	0.93 (0.77–1.14)^b	0.93 (0.70–1.23)	.64
	1.9 vs. 2.2	2.4 vs. 2.6
All-cause mortality	0.82 (0.71–0.96)	0.99 (0.86–1.14)	0.83 (0.67–1.02)	.07
	3.4 vs. 4.1	4.8 vs. 4.8

Abbreviations. ASA, Acetylsalicylic acid; CI, Confidence interval; CV, Cardiovascular; HR, Hazard ratio; ICH, Intracranial hemorrhage; ITC, Indirect treatment comparison; MACE, Major adverse cardiovascular event; MI, Myocardial infarction; RR, Risk ratio.

^aRR calculated from Berger et al., Figure 5 ¹⁸.

^bRR calculated from Berger et al., Figure 4 ¹⁸.

^cRR calculated as difference in stroke from Berger et al., Figure 5¹⁸ minus ICH from Bhatt et al., Table 4 ⁴.

Figure 5. Results of safety outcomes for the indirect treatment comparison. Abbreviations. CI, Confidence interval; CV, Cardiovascular; HR, Hazard ratio; ICH, Intracranial hemorrhage; MACE, Major adverse cardiovascular event; MI, Myocardial infarction; RR, Risk ratio. *Calculated using moderate/severe bleeding per clinician evaluation collected from Eikelboom et al., Table 3¹⁷.

Table 3. Results of safety outcomes for the indirect treatment comparison.

Outcome	Rivaroxaban + ASA vs. ASA alone HR/RR (95% CI) Incidence, %	Clopidogrel + ASA vs. ASA alone HR/RR (95% CI) Incidence, %	Rivaroxaban + ASA vs. clopidogrel + ASA per ITC HR/RR (95% CI)	p value Rivaroxaban + ASA vs. clopidogrel + ASA per ITC
Moderate-to-severe bleeding	1.70 (1.40–2.05)^b	1.48 (1.24–1.78)^a	1.15 (0.81–1.62)	.30
	3.1 vs. 1.9	3.7 vs. 2.5
Moderate-to-severe bleeding (alternate definition)	1.73 (1.46–2.05)^c	1.46 (1.22–1.74)^a	1.19 (0.93–1.52)	.18
	4.0 vs. 2.3	3.7 vs. 2.5
Fatal bleeding	1.49 (0.67–3.33)	1.53 (0.83–2.82)	0.97 (0.36–2.67)	.96
	0.2 vs. 0.1	0.3 vs. 0.2
ICH	1.16 (0.67–2.00)	0.96 (0.56–1.65)	1.21 (0.56–2.61)	.63
	0.3 vs. 0.3	0.3 vs. 0.3

Abbreviations. ASA, Acetylsalicylic acid; CI, Confidence interval; HR, Hazard ratio; ICH, Intracranial hemorrhage; ITC, Indirect treatment comparison; RR, Risk ratio.

^aHR collected from Berger et al., Figure 1A (severe/moderate bleed)¹⁶.

^bUsing a modified International Society on Thrombosis and Haemostasis definition³.

^cRR calculated using moderate/severe bleeding per clinician evaluation collected from Eikelboom et al., Table 3¹⁷.

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