Table 3.

Summary of key efficacy and safety findings in randomized studies evaluating prolonged (>12 months) dual antiplatelet therapy (not specific to NSTEMI populations)

Trial [reference] ClinicalTrials.gov number	Patient population	Treatment and follow-up	Key efficacy findings	Key safety findings
TRA2°P-TIMI 50 [9] NCT00526474	History of atherothrombosis; an MI within previous 2–52 weeks	Vorapaxar (2.5 mg daily, n = 8898) versus placebo (n = 8881), both groups also received aspirin	Significant reduction in 3-year KM estimates for primary end point (CV death, MI, or stroke): 8.1 versus 9.7 %; HR, 0.80 (95 % CI, 0.72–0.89); p < 0.0001	Significant increase in 3-year KM estimates for moderate or severe bleeding: 3.4 versus 2.1 %; HR, 1.61 (95 % CI, 1.31–1.97); p < 0.0001
		Median follow-up = 2.5 years
CHARISMA [13] NCT00050817	Prior MI, ischemic stroke, or PAD	Clopidogrel (75 mg daily, n = 4735) versus placebo (n = 4743), both groups also received aspirin	Significant reduction in primary end point (CV death, MI, or stroke): 7.3 versus 8.8 %; HR, 0.83 (95 % CI, 0.72–0.96); p = 0.01	No difference in rate of severe bleeding: 1.7 versus 1.5 %; HR, 1.12 (95 % CI, 0.81–1.53); p = 0.50 Significant increase in rate of moderate bleeding: 2.0 versus 1.3 %; HR, 1.60 (95 % CI, 1.16–2.20); p = 0.004
		Median follow-up = 27.6 months
DAPT [46] NCT00977938	Had a coronary stent procedure (drug-eluting stent only)	After 12 months of clopidogrel or prasugrel plus aspirin, patients either continued on the thienopyridine (n = 5020) or received placebo (n = 4941) for another 18 months	Significant reduction in rates of: stent thrombosis (0.4 versus 1.4 %; HR, 0.29 [95 % CI, 0.17–0.48]; p < 0.001); major adverse CV and cerebrovascular events (4.3 versus 5.9 %; HR, 0.71 [95 % CI, 0.59–0.85]; p < 0.001); MI (2.1 versus 4.1 %; HR, 0.47 [95 CI: 0.37–0.61]; p < 0.001) Higher rate of all-cause mortality (2 versus 1.5 %; HR, 1.36 [95 % CI, 1.00–1.85]; p = 0.05)	Significant increase in rate of GUSTO moderate or severe bleeding: 2.5 versus 1.6 %, p = 0.001
DAPT subgroup analysis [47] NCT00977938	Had a coronary stent procedure (drug-eluting or bare-metal stents) following presentation with acute MI (n = 3576) or without evidence of MI (n = 8072)	After 12 months of clopidogrel or prasugrel plus aspirin, patients either continued on the thienopyridine (n = 5862) or received placebo (n = 5786) for another 18 months	Significant reduction in rates of: stent thrombosis (MI group: 0.5 versus 1.9 %; HR, 0.27 [95 % CI, 0.13–0.57]; p < 0.001; no MI group: 0.4 versus 1.1 %; HR, 0.33 [95 % CI, 0.18–0.60]; p < 0.001); major adverse CV and cerebrovascular events (MI group: 3.9 versus 6.8 %; HR, 0.56 [95 % CI, 0.42–0.76]; p < 0.001)	Significant increase in rate of GUSTO moderate or severe bleeding (MI group: 1.9 versus 0.8 %; HR, 2.38 [95 % CI, 1.28–4.43]; p = 0.005; no MI group: 2.6 versus 1.7 %; HR, 1.53 [95 % CI, 1.12–2.08]; p = 0.007)
			No significant reduction in rate of major adverse CV and cerebrovascular events in no MI group (4.4 versus 5.3 %; HR, 0.83 [95 % CI, 0.68–1.02); p = 0.08)
ITALIC/ITALIC+ [49] NCT01476020	Had a coronary stent procedure (drug-eluting stent)	Patients randomized to either 6 months (n = 912) or 24 months (n = 910) of dual antiplatelet therapy post-stent, i.e. aspirin plus clopidogrel (75 mg/day) or prasugrel (60 mg/day) or ticagrelor (90 mg twice daily)	No significant difference in primary end point (death, MI, target lesion revascularization, stroke, and major bleeding at 12 months post-stent): 1.6 versus 1.5 %; HR, 1.072 (95 % CI, 0.517–2.221); p = 0.85 Non-inferiority demonstrated for 6- versus 12-month treatment; absolute risk difference 0.11 % (95 % CI, -1.04–1.26); p for non-inferiority = 0.0002	There were no significant differences in bleeding complications between the 6- and 24-month groups: Major bleeding occurred in only 3 (0.3 %) patients in the 24-month group (0 patients in 6-month group; HR, N/A); minor bleeding (0.5 versus 0.4 %; HR, 1.247 [95 % CI, 0.335–4.643]; p = 0.74
PEGASUS-TIMI 54 [51] NCT01225562	History of MI 1–3 years previously, at least one of the following risk factors: age ≥ 65 years, diabetes, a second prior MI, multivessel CAD that included ≥50 % occlusion in 2 or more coronary arteries, or chronic renal dysfunction	Three groups: ticagrelor (90 mg twice daily [n = 7050], or 60 mg twice daily [n = 7045]) and placebo (n = 7067); all groups also received aspirin	Significant reduction in 3-year KM estimates for primary end point (CV death, MI, or stroke): 7.85 % (90 mg ticagrelor; HR, 0.85 [95 % CI, 0.75–0.96]; p = 0.008), 7.77 % (60 mg ticagrelor; HR, 0.84 [95 % CI, 0.74–0.95]; p = 0.004), and 9.04 % (placebo)	Rates of TIMI major bleeding were higher with ticagrelor (90 mg: 2.60 %; 60 mg: 2.30 %) versus placebo (1.06 %; p < 0.001 for each ticagrelor dose)
	40.3 % of the overall patients had NSTEMI	Median follow-up: 33 months

CAD coronary artery disease, CI confidence interval, CV cardiovascular, GUSTO Global Utilization of Streptokinase and TPA for Occluded Arteries, HR hazard ratio, KM Kaplan–Meier, MI myocardial infarction, N/A not applicable, NSTEMI non-ST-segment elevation myocardial infarction, PAD peripheral arterial disease, TIMI Thrombolysis in Myocardial Infarction