For patients with non–ST-segment elevation acute coronary syndrome (NSTE-ACS), prasugrel was recommended over ticagrelor in a recent randomized controlled trial, although more data are needed on the rationale. Here, the effects of P2Y12 inhibitors on ischemic and bleeding events in patients with NSTE-ACS were investigated.
Clinical trials that enrolled patients with NSTE-ACS were included, relevant data were extracted, and a network meta-analysis was performed.
This study included 37,268 patients with NSTE-ACS from 11 studies. There was no significant difference between prasugrel and ticagrelor for any end point, although prasugrel had a higher likelihood of event reduction than ticagrelor for all end points except cardiovascular death. Compared with clopidogrel, prasugrel was associated with decreased risks of major adverse cardiovascular events (MACE) (hazard ratio [HR], 0.84; 95% CI, 0.71–0.99) and myocardial infarction (HR, 0.82; 95% CI, 0.68–0.99) but not an increased risk of major bleeding (HR, 1.30; 95% CI, 0.97–1.74). Similarly, compared with clopidogrel, ticagrelor was associated with a reduced risk of cardiovascular death (HR, 0.79; 95% CI, 0.66–0.94) and an increased risk of major bleeding (HR, 1.33; 95% CI, 1.00–1.77; P = .049). For the primary efficacy end point (MACE), prasugrel showed the highest likelihood of event reduction (P = .97) and was superior to ticagrelor (P = .29) and clopidogrel (P = .24).
Prasugrel and ticagrelor had comparable risks for every end point, although prasugrel had the highest probability of being the best treatment for reducing the primary efficacy end point. This study highlights the need for further studies to investigate optimal P2Y12 inhibitor selection in patients with NSTE-ACS.
Abbreviations and Acronyms
acute coronary syndrome
dual antiplatelet therapy
major adverse cardiovascular events
non–ST-segment elevation acute coronary syndrome
non–ST-segment elevation myocardial infarction
percutaneous coronary intervention
Preferred Reporting Items for Systematic Reviews and Meta-Analyses
Randomized controlled trial
ST-segment elevation myocardial infarction
Thrombolysis in Myocardial Infarction
Dual antiplatelet therapy (DAPT), consisting of aspirin in combination with a P2Y12 inhibitor, is a crucial treatment for the prevention of thrombotic events. Current guidelines recommend DAPT in patients with acute coronary syndrome (ACS).1–4 Non–ST-segment elevation myocardial infarction (NSTEMI) and unstable angina are collectively referred to as non–ST-segment elevation ACS (NSTE-ACS).5,6 Previous landmark studies recommended a more potent P2Y12 inhibitor (prasugrel or ticagrelor) over clopidogrel for patients with STEMI or NSTE-ACS.1,2,6–10 A recent randomized control trial (RCT) of a head-to-head comparison of prasugrel and ticagrelor demonstrated that the former significantly reduced the composite outcome of death, MI, or stroke among patients with NSTE-ACS.11,12 Based on that single RCT, the current European Society of Cardiology guidelines, updated in 2020, give a class IIA recommendation for prasugrel as the preferred agent over ticagrelor for patients with NSTE-ACS who require percutaneous coronary intervention (PCI).13 The level of evidence is limited, however, and a recent large-scale retrospective study demonstrated that prasugrel and ticagrelor had similar efficacy and safety in real-world patients with ACS.14 The current systematic review and meta-analysis investigated the effect of P2Y12 inhibitors on ischemic and bleeding events in patients with NSTE-ACS.
This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement standards.15 The study protocol was registered in International Prospective Register of Systematic Reviews (registration No. CRD42021235922). No patient or public entity was involved in the study.
The eligibility criteria were as follows: (1) the study was published in a peer-reviewed journal, (2) the study was an RCT or subgroup analysis of an RCT of patients with NSTE-ACS that examined at least 2 different P2Y12 inhibitors, and (3) the study reported outcomes of interest.
Information Sources and Search
All studies investigating the effect of P2Y12 inhibitors in patients with NSTE-ACS were searched using the following strategy. First, the PubMed, Embase, and CENTRAL databases were searched on November 26, 2020. The search terms included PCI; acute coronary syndrome; antiplatelet OR aspirin OR prasugrel OR clopidogrel OR ticagrelor OR p2y12; and randomized OR randomly OR random. The authors did not apply any language restrictions.
Study Selection and Data-Collection Process
Relevant studies were identified through a manual search of secondary sources, including references to the initially identified articles, reviews, and commentaries. All references were downloaded for consolidation, elimination of duplicates, and further analysis. Two independent, blinded authors (T.F. and T.K.16 ) reviewed the search results and selected studies based on the inclusion and exclusion criteria. If these 2 authors could not reach consensus, a third author (H.T.17 ) was consulted to reach a decision. Any disagreements were resolved by consensus.
Data were collected according to the PICOS framework:
P (Population): Patients with NSTE-ACS
I (Intervention): Potent P2Y12 inhibitors (prasugrel and ticagrelor)
C (Comparison): Other P2Y12 inhibitors
O (Outcome): Major adverse cardiovascular events (MACE), all-cause mortality, cardiovascular (CV) death, MI, stroke, or major bleeding
S (Study type): RCT
Study quality was assessed by using version 2 of the Cochrane risk-of-bias tool for randomized trials.18 Two investigators (T.F. and T.K.) reviewed the studies and judged the selection, comparability, and outcomes independently.
The primary end point was the occurrence of MACE. Trial-defined MACE included any of the following: composite of CV death, MI, and stroke; composite of death, MI, and stroke; or composite of death, MI, stroke, and rehospitalization for CV causes or bleeding. Secondary end points included all-cause mortality, CV death, MI, stroke, and trial-defined major bleeding. Major bleeding events were defined in various ways in included studies as Thrombolysis in Myocardial Infarction (TIMI) major bleeding; non–coronary artery bypass graft–related TIMI major bleeding; and Bleeding Academic Research Consortium grade 3, 4, or 5 bleeding. The hazard ratios (HRs) and risk ratios were calculated for each study. If the HR or risk ratio was not described in a study, only the risk ratio was calculated from the event and patient numbers.
A network meta-analysis was performed using the net-meta 3.6.2 package (R Foundation for Statistical Computing) to calculate the pooled HRs with 95% CIs for all outcomes comparing each P2Y12 inhibitor.19 Statistical significance was defined as P < .05. If a specific P2Y12 inhibitor was used in more than 90% of the patients in a group, the group was classified into a specific P2Y12 inhibitor group. Within the framework, I2 and Q statistics, which represent the proportion of total variation in study estimates resulting from heterogeneity, were used to quantify heterogeneity.20,21 The Q statistic is the sum of a statistic for heterogeneity and a statistic for inconsistency and represents the variability of treatment effect between direct and indirect comparisons at the meta-analytical level.22 The P-score metric was used to rank the treatments' comparative hierarchy of efficacy and safety; P-scores ranged from 0 to 1, with a higher value indicating a higher likelihood of a treatment being more effective or safe and a lower value indicating that the treatment was ineffective.
For the sensitivity analysis, ReviewManager, version 5.4 (The Cochrane Collaboration) was used to calculate the pooled HRs with 95% CIs for all outcomes by comparing the potent P2Y12 inhibitors with clopidogrel. A random-effects model was used regardless of interstudy heterogeneity because it allows a more conservative assessment of the pooled effect size. Significant heterogeneity was considered to be present when the I2 index was greater than 50% or P < .05 for heterogeneity. Publication bias was assessed by using funnel plots.
This study identified 11 eligible RCTs (Fig. 1), for a total of 37,268 patients from analyses of the DISPERSE-2,23 TRITON-TIMI 38,9,24 PLATO,10,25 TRILOGY ACS,26 PRASFIT-ACS,27 PHILO,28 PRAGUE-18,29 Elderly ACS II,30 ISAR-REACT 5,11,12 TICAKOREA,31 and POPular AGE trials.32 Four trials compared prasugrel and clopidogrel, 4 trials compared ticagrelor and clopidogrel, 2 trials compared prasugrel and ticagrelor, and 1 trial compared clopidogrel with other potent P2Y12 inhibitors (prasugrel, 5%; ticagrelor, 95%). The median follow-up period of the included studies ranged from 3 to 30 months.
Patients' Baseline Characteristics
The demographics of the patients with NSTE-ACS in each trial are summarized in Table I.9–12,23–32 The median age ranged from 61 to 77 years, and the percentage of men ranged from 60% to 75%. A reduced maintenance dose of prasugrel (3.75–5 mg daily) was administered to patients who were 75 years of age or older or weighed less than 60 kg in the TRILOGY ACS, PRAGUE-18, ISAR-REACT 5, and POPular AGE trials. Details of the baseline demographics of patients with NSTE-ACS in the PRASFIT ACS, PHILO, PRAGUE-18, and TICAKOREA trials were not available. The baseline characteristics of all patients, including patients with STEMI and not limited to the NSTE-ACS population, in each trial are summarized in Supplemental Table I. The Elderly ACS II and POPular AGE trials mainly included older patients (ie, patients whose mean age was greater than that in other studies). Most patients underwent invasive management for their index events, except for those in the TRILOGY ACS trial, which excluded patients who underwent PCI. Approximately half of the patients received bare-metal stents in 4 trials (DISPERSE-2, TRITON-TIMI 38, PLATO, and PRASFIT ACS). All studies defined MACE as a composite of CV death, MI, and stroke, except for the ISAR-REACT 5 trial (which defined it as a composite of death, MI, and stroke) and Elderly ACS II (which defined it as a composite of death, MI, disabling stroke, and rehospitalization for CV causes or bleeding) (Supplemental Table II). All the studies were considered to have a low risk of bias (Supplemental Fig. 1).
Compared with ticagrelor, prasugrel was not associated with a reduced risk of MACE (HR, 0.83; 95% CI, 0.66–1.04). Prasugrel was associated with a decreased risk of MACE (HR, 0.84; 95% CI, 0.71–0.99; P = .04) compared with clopidogrel. Significant heterogeneity (I2 = 51.4%; P = .07) and inconsistencies (P = .02) were noted (Fig. 2). The P-score analysis confirmed that prasugrel was most likely the best treatment for the primary end point because it had a significantly higher P-score (0.97) than did ticagrelor (P-score = 0.29) or clopidogrel (P-score = 0.24).
There was no significant difference among any P2Y12 inhibitors for the risk of all-cause mortality. Considerable heterogeneity (I2 = 56.7%; P = .33) and inconsistencies (P = .03) were observed (Supplemental Fig. 2). The P-scores were 0.78, 0.47, and 0.25 for prasugrel, ticagrelor, and clopidogrel, respectively.
There was no significant difference in CV death between the prasugrel and ticagrelor groups. Ticagrelor was associated with a reduced risk of CV death compared with clopidogrel (HR, 0.79; 95% CI, 0.66–0.94; P < .01), without significant heterogeneity (I2 = 0%; P = .70) (Supplemental Fig. 3). Ticagrelor was most likely the best treatment (P-score = 0.97), followed by prasugrel (P-score = 0.44) and clopidogrel (P-score = 0.09).
There was no significant difference in MI between prasugrel and ticagrelor. Prasugrel was associated with a decreased risk of MI (HR, 0.82; 95% CI, 0.68–0.99; P = .04) compared with clopidogrel. There was significant heterogeneity (I2 = 52.4%; P = .10) without significant inconsistency (P = .13) (Supplemental Fig. 4). The P-scores were 0.89, 0.50, and 0.11 for prasugrel, ticagrelor, and clopidogrel, respectively.
There was no significant difference among the P2Y12 inhibitors in the risk of stroke, and there was no significant heterogeneity (I2= 0%; P = .54) or inconsistency (P = .95) (Supplemental Fig. 5). The P-scores were 0.60, 0.45, and 0.44 for prasugrel, ticagrelor, and clopidogrel, respectively.
There was no significant difference in major bleeding between the prasugrel and ticagrelor groups. Ticagrelor was associated with an increased risk of major bleeding compared with clopidogrel (HR, 1.33; 95% CI, 1.00–1.77; P = .049). Prasugrel was not associated with an increased risk of major bleeding compared with clopidogrel (HR, 1.30; 95% CI, 0.97–1.74; P = .08). No significant heterogeneity (I2 = 41.1%; P = .09) or inconsistency (P = .68) was noted (Fig. 3). The P-scores were 0.97, 0.30, and 0.23 for clopidogrel, prasugrel, and ticagrelor, respectively.
The use of potent P2Y12 inhibitors was associated with decreased risks of MACE (HR, 0.90; 95% CI, 0.81–1.00; P = .04), CV death (HR, 0.88; 95% CI, 0.79–0.98; P = .02), and MI (HR, 0.86; 95% CI, 0.76–0.96; P < .01) vs clopidogrel. The use of potent P2Y12 inhibitors was associated with an increased risk of major bleeding (HR, 1.31; 95% CI, 1.05–1.65; P = .02). There were no significant differences in the risks of all-cause mortality (HR, 0.87; 95% CI, 0.74–1.03; P = .10) or stroke (HR, 0.98; 95% CI, 0.80–1.20; P = .85) between the potent P2Y12 inhibitors and clopidogrel. There was also no significant heterogeneity in these outcomes among the studies (Supplemental Fig. 6). Funnel plots were used to evaluate publication bias; no significant publication bias was observed for any of the outcomes assessed (Supplemental Fig. 7).
The key findings of this meta-analysis of the efficacy and safety of various P2Y12 inhibitors in patients with NSTE-ACS are as follows: (1) There was no significant difference between prasugrel and ticagrelor in any end point, although the P-score analysis demonstrated that prasugrel had a higher probability of being a better treatment than ticagrelor for all end points, except CV death; (2) prasugrel was associated with a reduced risk of MACE and MI vs clopidogrel; and (3) ticagrelor was associated with a reduced risk of CV death and an increased risk of major bleeding vs clopidogrel.
The ISAR-REACT 5 trial compared prasugrel and ticagrelor in 4,018 patients with ACS (NSTE-ACS and STEMI) for whom invasive management was planned; it demonstrated that prasugrel was superior to ticagrelor at reducing the combined 1-year risk of death, MI, and stroke without increasing the risk of bleeding.12 Fewer MI events in the prasugrel group primarily drove this result. A post hoc subgroup analysis of the ISAR-REACT 5 trial showed the same results in patients with NSTE-ACS.11 In contrast, a small subgroup analysis of 72 patients with NSTEMI in the PRAGUE-18 trial showed no significant differences between prasugrel and ticagrelor for MACE—a composite of CV death, MI, and stroke—and bleeding outcomes during the first year after MI.29 In real-world patients with ACS, a retrospective study using the SWEDEHEART registry demonstrated that prasugrel and ticagrelor had similar efficacy and safety.14 Although studies are limited, the current European Society of Cardiology guidelines recommend prasugrel over ticagrelor for patients with NSTE-ACS who require PCI based on the ISAR-REACT 5 trial findings.13 The current large-scale network meta-analysis provided essential insight into the limited evidence of selecting P2Y12 inhibitors among patients with NSTE-ACS.
This study demonstrates that patients with NSTE-ACS have better outcomes after treatment with potent P2Y12 inhibitors for ischemic events. The rationale for this finding is clear: novel, potent P2Y12 inhibitors have more reliable pharmacologic properties.2 Despite the absence of a statistically significant difference between prasugrel and ticagrelor for each end point, P-score analysis suggested that prasugrel has a greater chance of being the best treatment for all ischemic outcomes, except CV death. Recent studies demonstrated that prasugrel was associated with improved endothelial function and better platelet inhibition than ticagrelor in patients with ACS undergoing PCI.33,34 Furthermore, prasugrel featured irreversible P2Y12 inhibition and better compliance with once-daily dosing. These differences between the 2 potent P2Y12 inhibitors might explain the further reduction in ischemic end points by prasugrel.
Large registries show that STEMI is less common than NSTE-ACS in older adults (≥75 years of age)35,36 and that older age and multiple comorbidities are associated with bleeding events.37 In addition, major bleeding is associated with an increased risk of mortality in patients with NSTE-ACS, similar to ischemic events.38 The previous meta-analysis of patients with STEMI showed no significant difference in 1-year rates of major bleeding among various P2Y12 inhibitors,39 whereas the current meta-analysis of patients with NSTE-ACS demonstrated that the use of potent P2Y12 inhibitors increased major bleeding compared with clopidogrel. Bavishi et al40 previously performed a conventional meta-analysis in patients with NSTE-ACS and reported that bleeding events increased with prasugrel compared with clopidogrel. The current network meta-analysis showed, however, that ticagrelor and prasugrel similarly increased bleeding compared with clopidogrel, although only the ticagrelor vs clopidogrel result showed statistical significance. This discordance may be explained by the inclusion of recent dedicated trials in the current network meta-analysis.
Distinguishing the timing of DAPT administration between NSTE-ACS and STEMI is vital. In patients with STEMI, the use of a potent P2Y12 inhibitor is recommended as early as possible, or at least at the time of primary PCI,7,8 because patients with STEMI have transmural myocardial ischemia with cell damage caused by a greater thrombus burden than patients with NSTE-ACS, in whom the pathophysiology at the myocardial level is limited to subendocardial ischemia with or without cell damage. In patients with NSTE-ACS, based on the findings of landmark trials such as PLATO10 and ACCOAST,41 it has become common practice to perform early loading with ticagrelor at the time of diagnosis or prasugrel administration in catheterization laboratories when the coronary anatomy is known. A large-scale observational study of 64,857 patients with NSTE-ACS, however, demonstrated that pretreatment with P2Y12 antagonists was associated with an increased risk of bleeding without improved efficacy outcomes,42 whereas the ISAR-REACT 5 trial showed the superiority of prasugrel over ticagrelor treatment with a pretreatment strategy.12 The current European Society of Cardiology guidelines recommend against pretreatment with P2Y12 inhibitors for patients with NSTE-ACS in whom the coronary anatomy is unknown and early invasive management is planned.13 In our analysis, the bleeding risks associated with pretreatment may explain the increased risk of major bleeding in the ticagrelor group.
In addition, the dose arrangement available for prasugrel may partially explain the absence of a statistically significant difference in the risk of major bleeding between the prasugrel and clopidogrel groups in our analysis. The TRITON-TIMI 38 trial9,24 showed no net clinical benefit of prasugrel vs clopidogrel in patients 75 years of age or older or those with a lower body weight (<60 kg) because of high rates of bleeding events; therefore, a reduced dosage of prasugrel is recommended for these patients. In contrast, in the PLATO trial,10,25 bleeding complications occurred more frequently with ticagrelor than with clopidogrel in patients 75 years of age or older, but the superiority of ticagrelor in terms of ischemic end points was not age dependent; therefore, dose reduction of ticagrelor is not recommended.
This study has several limitations. First, it was a meta-analysis of trial-level data; thus, differences in trial designs, compared treatment regimens, and individual patient data were not fully accounted for. Second, there were insufficient data to evaluate differences within the P2Y12 inhibitor group. Third, the medication dose used or compliance with each treatment strategy was not considered. Fourth, the definitions of end points (MACE and bleeding events) varied across studies. Finally, despite the high-quality designs of the RCTs included in this analysis, significant heterogeneity and inconsistencies were noted in several end points. This heterogeneity could be the result of interstudy differences in designs, patient populations, and treatment strategies. Therefore, these results should be interpreted with caution. A P-score analysis was used to rank the P2Y12 inhibitors.
The present network meta-analysis demonstrated that prasugrel and ticagrelor had comparable effects in terms of efficacy end points. Nevertheless, prasugrel showed the highest probability of being the best treatment for reducing the primary end point, and no significant difference in bleeding was observed between prasugrel and ticagrelor. These findings align with the current guidelines' rationale but suggest a more neutral stance regarding the preferential use of prasugrel over ticagrelor. This study highlights the need for further studies to investigate optimal P2Y12 inhibitor selection in patients with NSTE-ACS. For instance, more large-scale multiethnic studies and novel trials assessing the efficacy of new DAPT strategies (ie, short DAPT, precision medicine–guided DAPT, P2Y12 inhibitor monotherapy, and P2Y12 inhibitor deescalation) are warranted.
Conflict of Interest/Disclosure: Dr Latib is a consultant and on the advisory board of Medtronic, Abbott, Boston Scientific, and Philips. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Funding/Support: This study was supported by Grants-in-Aid for Scientific Research (No. 23K07479) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
Meeting Presentation: This study was presented at a national conference: Fujisaki T, Kuno T, Briasoulis A, Misumida N, Takagi H, Latib A. P2Y12 inhibitors in patients with non–ST-segment elevation acute coronary syndrome: insights from a systematic review and network meta-analysis of randomized trials. Eur Heart J. 2021;42(suppl 1):ehab724.1213. doi:10.1093/eurheartj/ehab724.1213