Comparative Efficacy and Safety of Ticagrelor and Prasugrel in Acute Coronary Syndrome: A Meta-Analysis of Randomized controlled trials

Comparative Efficacy and Safety of Ticagrelor and Prasugrel in Acute Coronary Syndrome: A Meta-Analysis of Randomized controlled trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Comparative Efficacy and Safety of Ticagrelor and Prasugrel in Acute Coronary Syndrome: A Meta-Analysis of Randomized controlled trials Shaheer bin shafiq This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9389696/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Acute coronary syndrome (ACS) remains a leading cause of morbidity and mortality worldwide despite advances in percutaneous coronary intervention (PCI) and pharmacotherapy. Methods We searched PubMed, Web of Science, and Cochrane CENTRAL for RCTs comparing prasugrel with ticagrelor in adults with ACS undergoing PCI. The primary outcome was all-cause mortality. Secondary outcomes included cardiovascular death, myocardial infarction, composite ischemic events, stent thrombosis, stroke, and bleeding events. Results Four randomized controlled trials selected comprising 10,480 patients. All-cause mortality was similar between prasugrel and ticagrelor [RR 0.95 (95% CI: 0.75, 1.20); P = 0.66; I² = 20%]. Prasugrel and ticagrelor also showed comparable risks of cardiovascular death [RR 1.00 (95% CI: 0.80, 1.26); P = 0.98; I² = 0%], myocardial infarction [RR 0.94 (95% CI: 0.64, 1.39); P = 0.77; I² = 67%], composite ischemic events [RR 1.01 (95% CI: 0.73, 1.41); P = 0.94; I² = 80%], stent thrombosis [RR 0.93 (95% CI: 0.52, 1.65); P = 0.80; I² = 59%], and stroke [RR 1.04 (95% CI: 0.67, 1.61); P = 0.86; I² = 0%]. Major bleeding [RR 0.99 (95% CI: 0.77, 1.27); P = 0.91; I² = 20%] and minor bleeding [RR 0.95 (95% CI: 0.76, 1.19); P = 0.67; I² = 64%] were also comparable between groups. Conclusion Prasugrel and ticagrelor demonstrated similar efficacy and safety in patients with ACS undergoing PCI. These findings support an individualized approach to P2Y12 inhibitor selection based on patient characteristics, contraindications, tolerability, and adherence considerations rather than a preference for either agent. Cardiac & Cardiovascular Systems Acute Coronary Syndrome Ticagrelor Prasugrel Percutaneous Coronary Intervention Dual Antiplatelet Therapy Mortality Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction Acute coronary syndrome (ACS), comprising ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina, remains a major cause of morbidity and mortality worldwide ( 1 – 3 ). The management of ACS has evolved substantially over the past decades, with percutaneous coronary intervention (PCI) emerging as the cornerstone of treatment for patients presenting with ACS, particularly those with STEMI and high-risk NSTEMI. Timely coronary revascularization has significantly improved clinical outcomes by reducing mortality and reinfarction ( 4 ). Despite advances in PCI, patients remain vulnerable to thrombotic complications such as stent thrombosis, which is associated with an increased risk of recurrent myocardial infarction and cardiovascular death ( 5 – 7 ). To address these complications, the 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Acute Coronary Syndromes recommends dual antiplatelet therapy (DAPT) with aspirin and an oral P2Y12 inhibitor for at least 12 months as the default strategy in patients with ACS who are not at high bleeding risk ( 8 ). Among patients undergoing PCI, potent P2Y12 inhibitors Ticagrelor and Prasugrel are recommended in preference to clopidogrel due to their superior and more consistent platelet inhibition, resulting in improved ischemic outcomes( 8 ) . Large randomized controlled trials (RCTs) have demonstrated the superiority of both agents over clopidogrel in reducing major adverse cardiovascular events in patients with ACS, thereby establishing their role in contemporary guideline-directed therapy ( 9 , 10 ). However, the comparative effectiveness and safety of ticagrelor versus prasugrel remain uncertain. The landmark ISAR-REACT 5 trial demonstrated that among 4,018 patients with ACS undergoing PCI, prasugrel was associated with a significantly lower incidence of death, myocardial infarction, or stroke compared with ticagrelor ( 11 ). Conversely, the recent TUXEDO-2 trial reported numerically higher, though statistically non-significant, rates of death, myocardial infarction, stroke with ticagrelor compared with prasugrel. These divergent findings highlight the heterogeneity of available evidence and the ongoing uncertainty regarding the optimal P2Y12 inhibitor in ACS patients undergoing PCI ( 12 ). Given these inconsistencies, we conducted a systematic review and meta-analysis of randomized controlled trials comparing prasugrel and ticagrelor in patients with ACS undergoing PCI. By incorporating the most contemporary evidence, our study aims to provide more precise and robust findings of comparative efficacy and safety, thereby informing clinical decision-making and guideline implementation. 2. Methods 2.1 Study design and reporting guidelines: This systematic review and meta-analysis was conducted to evaluate the comparative efficacy and safety of prasugrel versus ticagrelor in patients with ACS undergoing PCI. The study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines ( 13 ). Institutional review board approval was not needed because this is not individual patient-level data. This meta-analysis incorporates newly available randomized controlled trial (RCT) data while restricting inclusion exclusively to randomized trials to enhance internal validity and minimize confounding and selection bias associated with observational studies. The protocol for this study was registered on PROSPERO (ID: CRD420261338833) 2.2 Data Sources and Search Strategy: A comprehensive and systematic literature search was conducted in the following electronic databases: PubMed/MEDLINE, Web of Science and Cochrane Central Register of Controlled Trials (CENTRAL). The search strategy was designed using Medical Subject Headings (MeSH) terms and keyword combinations related to PCI, ticagrelor, and prasugrel. Major keywords: “ticagrelor,” “prasugrel,” and “myocardial infarction” were used. The complete search string used is listed in Supplemental Table 1 . Manual screening of reference lists of included studies was performed to identify eligible studies. Through this systematic search, 4 randomized controlled trials meeting eligibility criteria were identified and included in the present analysis. 2.3 Eligibility criteria Studies were included based on predefined eligibility criteria using the Population, Intervention, Comparison, Outcomes, and Study design (PICOS) framework. Randomized controlled trials (RCTs) were eligible if they included adult patients (≥ 18 years) with ACS undergoing PCI and directly compared prasugrel with ticagrelor as part of dual antiplatelet therapy. Trials were required to report at least one prespecified clinical outcome, including the primary outcome of all-cause mortality or secondary outcomes such as bleeding events, myocardial infarction, cardiovascular mortality, non-cardiovascular mortality, stent thrombosis, or stroke, with sufficient binary data to calculate relative risks. The primary composite ischemic endpoint was generally defined as the occurrence of death, myocardial infarction, or stroke, though the specific criteria such as the inclusion of all-cause versus cardiovascular mortality—varied across the included trials. The clinical criteria used to define major bleeding and minor bleeding varied across the included trials. A detailed breakdown of the specific endpoint definitions utilized by each individual study is provided in Supplementary Table 2 . Only trials reporting binary clinical outcomes or sufficient data to calculate relative risks were included. Studies were excluded if they were observational in design, did not involve PCI-treated ACS patients, did not directly compare prasugrel and ticagrelor, included pediatric populations, or reported irrelevant outcomes. 2.4 Study selection Two independent reviewers screened all identified records by title and abstract (K.T.M and T.A). Full texts of potentially eligible studies were retrieved and assessed according to predefined inclusion and exclusion criteria. Disagreements between reviewers were resolved through discussion and consensus. If consensus could not be reached, a third reviewer was consulted (M.M). The PRISMA flow diagram is depicted in Fig. 1 . 2.5 Data extraction Data were systematically extracted by two independent authors using a standardized data extraction form (G.T.K and M.A). Extracted information included study characteristics such as study design, sample size, duration of follow-up, and patient demographics and baseline clinical characteristics where available. Details of the intervention and comparison groups, including prasugrel and ticagrelor treatment regimens, were also recorded. The primary outcome extracted was all-cause mortality. Secondary outcomes included myocardial infarction, cardiovascular mortality, non-cardiovascular mortality, stent thrombosis, and stroke. Composite ischemic endpoints and trial-specific composite primary outcomes reported by individual trials were also extracted where available. Safety outcomes included bleeding events as defined by individual trials, including major and minor bleeding classified according to standardized criteria such as TIMI or BARC where available. Additionally, effect size measures including relative risks, hazard ratios, odds ratios, and corresponding 95% confidence intervals were extracted, along with raw event data when necessary to calculate relative risks. Any discrepancies in data extraction were resolved through discussion and consensus between the reviewers. 2.6 Quality Assessment The methodological quality of included trials was assessed independently by the two independent reviewers using the Cochrane Risk Of Bias 2.0 tool, which examined the bias arising from randomization, deviation from intended intervention, missing outcome data, outcome measurement and selective reporting (A.M and A.S) ( 14 ). Each trial was categorized to have low; some concern or high risk of bias. Disagreements were resolved by discussion with a third author (S.B.S). Additionally, the certainty of evidence for each outcome was assessed using the GRADE approach ( 15 ) . 2.7 Statistical analysis Meta-analysis was performed using relative risk (RR) as the primary effect measure for all binary outcomes. Pooled effect estimates were calculated with corresponding 95% confidence intervals (CI) using a random-effects model to account for potential inter-study variability. Statistical heterogeneity among included studies was assessed using the I² statistic, with values of 0–25% considered low heterogeneity, 26–50% considered moderate heterogeneity, and greater than 50% considered substantial heterogeneity ( 16 ). For all analyses and visualizations, we used Review Manager (RevMan version 5.4; Copenhagen: The Nordic Cochrane Centre, 2014). Relative risks were calculated using extracted event data where necessary. Relative risks were calculated using raw event data when available, while reported hazard ratios and odds ratios were extracted and used for qualitative comparison where appropriate. A sensitivity analysis, particularly the leave one out analysis, was conducted if the heterogeneity was greater than 50%. Furthermore, in order to investigate potential sources of heterogeneity among studies, meta-regression analyses were performed using R software (R Core Team. R: a language and environment for statistical computing. Vienna (AT): R Foundation for Statistical Computing; 2024), considering baseline characteristics as potential moderators of treatment effect. 3. Results A visual summary of the study design, key efficacy and safety outcomes, and overall clinical interpretation is provided in the Graphical Abstract. 3.1 Study selection: A total of 710 records were identified through systematic database searches across PubMed, Web of Science and Cochrane CENTRAL. After removing duplicates, 641 records were selected for screening based on the title and abstract. Of these, 634 studies were excluded based on title and abstract review, following which 7 potentially relevant articles were reviewed based on full text. Ultimately, 4 studies met our inclusion criteria. The study selection process is summarized in the PRISMA flow diagram Fig. 1 . 3.2 Study characteristics and baseline profile: A total of 10,480 patients with ACS undergoing PCI were included across four studies ( 11 , 12 , 17 , 18 ), of whom 4,783 received prasugrel and 5,697 received ticagrelor. Follow-up was 12 months across the included trials. Participants were predominantly male (approximately 71%–85%), and the mean age, reported in three studies, ranged from 60 to 65 years. Traditional cardiovascular risk factors, including hypertension and current smoking, were common, whereas prior CABG was infrequently reported. ACS presentation varied across studies, with differing proportions of STEMI, NSTEMI, and unstable angina. Further details regarding study design and baseline characteristics are summarized in Table 1 . Table 1 Characteristics of Clinical Trials Comparative Efficacy and Safety of Ticagrelor and Prasugrel in ACS Study Motovska (2017) Schupke (2019) Welsh (2019) TUXEDO-2 (2026) Drug TICA PRA TICA PRA TICA PRA TICA PRA Total Patients (n) 596 634 2012 2006 2188 1244 901 899 Male (n) 439 489 1534 1528 1704 1054 636 660 Age (mean) 61.8 61.8 64.5 64.6 NA 60.5 60.1 HTN (n) 211 212 1432/2008 1384/2003 962 560 534 550 Systolic Blood Pressure (mm Hg) NA 144 ± 25 143 ± 24 130 ± 23 131 ± 22 126 ± 17 126 ± 16 Diatolic Blood Pressure (mm Hg) NA 82 ± 15 82 ± 14 80 ± 16 81 ± 15 77 ± 10 77 ± 10 Hypercholesterolemia (n) 205 224 1178/2007 1163/2003 NA 749 748 Smokers (n) 392 406 682/2002 667/1999 945 603 140 146 Diabetes (n) 108 119 463/2011 429/2005 332 253 901 899 Prior PCI (n) 45 42 1679/2009 1701/2005 188 148 31 43 Prior MI (n) 55 47 311/2010 320/2005 817 521 183 204 Prior CABG (n) 9 12 47/2009 36/2005 NA NA Prior Stroke (n) 15 19 NA 48 9 11 8 STEMI n (%) 533 (89.4) 568 (89.6) 833 (41.4) 820 (40.9) 2188 (100) 1244 (100) 220 (24.4) 232 (25.8) NSTEMI n (%) 34 (5.7) 33 (5.2) 930 (46.2) 925 (46.1) NA 308 (34.2) 299 (33.3) UA (n) NA 249 261 NA 189 172 Atrial Fibrillation (n) NA NA NA 41 37 Follow up (months) 12 12 12 12 n= Number; NA = Not available; Tic= Ticagrelor; Pra= Prasugrel; HTN= Hypertension; PCI= Percutaneous coronary intervention; UA= Unstable angina CABG= Coronary artery bypass graft; STEMI = ST-elevation myocardial infarction; NSTEMI = Non-STEMI. Graphical Abstract. Comparative efficacy and safety of ticagrelor versus prasugrel in acute coronary syndrome undergoing percutaneous coronary intervention: overview of study design, pooled outcomes, and clinical interpretation. 3.3 Risk of bias assessment: Among the four included randomized trials, overall risk of bias was low in two studies and raised some concerns in two studies. Schupke et al. and TUXEDO-2 were judged overall low risk, whereas Motovska et al. and Welsh et al. raised some concerns, mainly due to issues in outcome measurement and deviations from intended interventions. Overall, the included evidence was methodologically robust, with only limited study-specific concerns Supplementary Table 3. 3.4 Outcomes: 3.4.1 Primary outcome: All-cause mortality All-cause mortality occurred in 169/4,783 (3.53%) patients receiving prasugrel and 201/5,697 (3.53%) receiving ticagrelor. The pooled analysis showed no evidence of a difference between strategies (RR 0.95, 95% CI 0.75–1.20; p = 0.66), with low heterogeneity (I² = 20%, heterogeneity p = 0.29) Fig. 2 . 3.4.2 Secondary outcomes: 3.4.2.1 Cardiovascular death Cardiovascular death was observed in 136/4,783 (2.84%) patients in the prasugrel group and 153/5,697 (2.69%) in the ticagrelor group. The pooled estimate indicated comparable risk (RR 1.00, 95% CI 0.80–1.26; p = 0.98) with no between-study heterogeneity (I² = 0%, heterogeneity p = 0.59) Fig. 3 . 3.4.2.2 Composite ischemic event Composite ischemic events occurred in 325/4,783 (6.79%) with prasugrel versus 388/5,697 (6.81%) with ticagrelor. The pooled effect was neutral overall (RR 1.01, 95% CI 0.73–1.41; p = 0.94); however, results demonstrated substantial heterogeneity across studies (I² = 80%, heterogeneity p = 0.002) Fig. 4 . On leave-one-out sensitivity analysis, exclusion of Welsh et al. attenuated heterogeneity and did not materially alter the overall finding, with the association remaining non-significant (RR 0.85, 95% CI 0.68–1.06; p = 0.15; I² = 39%) Supplementary Fig. 5 . 3.4.2.3 Major bleeding Major bleeding occurred in 156/4,550 (3.43%) patients receiving prasugrel and 182/5,674 (3.21%) receiving ticagrelor. The pooled analysis did not demonstrate a between-group difference (RR 0.99, 95% CI 0.77–1.27; p = 0.91) and heterogeneity was low (I² = 20%, heterogeneity p = 0.29) Fig. 5 . 3.4.2.4 Minor bleeding Across three contributing studies, minor bleeding occurred in 461/3,884 (11.87%) with prasugrel and 545/4,796 (11.36%) with ticagrelor. The pooled estimate remained non-significant (RR 0.95, 95% CI 0.76–1.19; p = 0.67) with moderate-to-substantial heterogeneity (I² = 64%, heterogeneity p = 0.06) Supplementary Fig. 1 . Sensitivity analysis excluding Welsh et al. significantly reduced heterogeneity and confirmed the non-significant association for minor bleeding (RR = 1.07 [0.94, 1.23]; P = 0.32; I² = 0%) Supplementary Fig. 6. 3.4.2.5 Myocardial infarction Myocardial infarction occurred in 153/4,783 (3.20%) patients allocated to prasugrel and 197/5,697 (3.46%) allocated to ticagrelor. The pooled result did not indicate a significant difference (RR 0.94, 95% CI 0.64–1.39; p = 0.77), with moderate heterogeneity (I² = 67%, heterogeneity p = 0.03) Supplementary Fig. 2 . Leave-one-out sensitivity analysis excluding Schupke et al. reduced heterogeneity and confirmed the persistence of a non-significant association for myocardial infarction (RR = 1.10 [0.81, 1.51]; P = 0.54; I² = 18%) Supplementary Fig. 7 . 3.4.2.6 Stent thrombosis Stent thrombosis was reported in 61/4,783 (1.28%) patients receiving prasugrel and 74/5,697 (1.30%) receiving ticagrelor. The pooled estimate suggested similar risk (RR 0.93, 95% CI 0.52–1.65; p = 0.80) with moderate heterogeneity (I² = 59%, heterogeneity p = 0.06) Supplementary Fig. 3 . 3.4.2.7 Stroke Stroke occurred in 40/4,783 (0.84%) patients in the prasugrel arm and 44/5,697 (0.77%) in the ticagrelor arm. There was no measurable difference between groups (RR 1.04, 95% CI 0.67–1.61; p = 0.86), and heterogeneity was absent (I² = 0%, heterogeneity p = 0.75) Supplementary Fig. 4 . Leave-one-out sensitivity analysis excluding Welsh et al. confirmed the persistence of a non-significant association (RR 0.71, 95% CI 0.45–1.11; p = 0.13; I² = 0%) Supplementary Fig. 8 . 3.5 Meta Regression: Meta-regression analysis was performed to assess whether study-level covariates influenced treatment effects across outcomes. No significant associations were identified for ACOM, cardiovascular death, major bleeding, myocardial infarction, or stroke, although borderline associations were observed for hypertension in ACOM and myocardial infarction, and for smoking and hypertension in major bleeding. For composite ischemic events, hypertension was the only significant predictor and was inversely associated with effect size (coefficient: −0.05, 95% CI: −0.07 to − 0.02; p = 0.00). For minor bleeding, male sex was associated with a lower effect estimate (coefficient: −0.06, 95% CI: −0.12 to − 0.01; p = 0.02), whereas hypertension (coefficient: 0.02, 95% CI: 0.00 to 0.05; p = 0.02) and diabetes (coefficient: 0.07, 95% CI: 0.01 to 0.12; p = 0.02) were associated with higher effect estimates. For stent thrombosis, significant associations were observed for male sex (coefficient: 0.16, 95% CI: 0.04 to 0.27; p = 0.01), hypertension (coefficient: −0.07, 95% CI: −0.12 to − 0.02; p = 0.01), and prior MI (coefficient: 0.03, 95% CI: 0.01 to 0.06; p = 0.02).Overall, most study-level covariates did not materially influence the pooled estimates, with significant associations observed only for selected covariates in composite ischemic events, minor bleeding, and stent thrombosis. Detailed results of all meta-regression analyses are provided in Supplementary Tables 4–12 and Supplementary Figs. 9–16 . 3.6 Certainty of Evidence: The certainty of evidence for each outcome was evaluated using the GRADE approach. The certainty of evidence was rated as low for all-cause mortality, major or severe bleeding, cardiovascular death, and stroke, primarily due to concerns related to risk of bias and imprecision. In contrast, the certainty of evidence was judged to be very low for composite ischemic events, myocardial infarction, minor bleeding, and stent thrombosis due to imprecision. Overall, these findings indicate that confidence in the pooled estimates ranged from low to very low across all assessed outcomes. The detailed summary of findings is provided in Supplementary Table 13. 4. Discussion Across four randomized controlled trials including 10,480 patients with ACS treated with PCI and followed for 12 months, this RCT-only meta-analysis provides a focused comparison of two potent P2Y12 inhibitors used in contemporary dual antiplatelet therapy ( 11 , 12 , 18 ), The aggregate randomized evidence indicates that prasugrel and ticagrelor yield comparable protection against post-PCI ischemic events and do not demonstrate a consistent separation in bleeding outcomes. Because randomization balances baseline risk and reduces confounding by indication, the overall neutrality across outcomes supports an interpretive shift away from a universal hierarchy and toward patient-level selection guided by adherence, tolerability, contraindications, and pragmatic treatment considerations. With respect to ischemic endpoints, pooled randomized comparisons suggest that prasugrel and ticagrelor are broadly similar in preventing clinically important post-PCI complications in ACS, including death, recurrent myocardial infarction, stent thrombosis, and stroke. This finding is consistent with the broader therapeutic context in which both agents were developed to provide rapid and consistent inhibition of ADP-mediated platelet activation relative to clopidogrel, and each demonstrated superiority versus clopidogrel in large ACS outcome programs. Ticagrelor reduced major ischemic events compared with clopidogrel in a large ACS program, and prasugrel reduced ischemic events including myocardial infarction and stent thrombosis compared with clopidogrel in ACS patients undergoing PCI ( 9 ). When both comparators have already demonstrated high-potency benefit against an older standard, incremental head-to-head differences in modern PCI settings may be modest and sensitive to trial design, endpoint definitions, and clinical implementation. This interpretation aligns with guideline framing in which contemporary European and American recommendations endorse a potent P2Y12 inhibitor, prasugrel or ticagrelor, as the preferred partner to aspirin after ACS treated with PCI, emphasizing potency at the class level rather than a consistent “winner” ( 19 ). A similar pattern is observed when pooled comparisons beyond the included trials are considered. Earlier meta-analyses restricted to randomized comparisons of prasugrel versus ticagrelor generally reported no reproducible difference in major ischemic outcomes and bleeding when estimates were aggregated ( 20 ). This recurring neutral signal supports a clinically pragmatic inference that, for the typical ACS-PCI population, any differences in hard outcomes are likely to be small, context-dependent, or influenced by implementation factors rather than reflecting a stable pharmacologic superiority of one agent. Divergence in individual datasets remains possible, but lack of reproducibility across populations and endpoint frameworks suggests that observed differences may reflect profound clinical and methodological heterogeneity rather than true pharmacological divergence. For instance, the included trials represent vastly different baseline ACS case-mixes: the TOTAL trial exclusively enrolled patients with ST-segment elevation myocardial infarction (STEMI), TUXEDO-2 targeted a highly specific high-risk cohort with diabetes and multivessel disease, while ISAR-REACT 5 included the entire ACS spectrum. Furthermore, differences in trial execution significantly contribute to heterogeneity. The open-label design of trials like ISAR-REACT 5 and PRAGUE-18 inherently introduces performance and detection bias, particularly regarding the reporting of subjective adverse effects or minor bleeding. Additionally, economic realities drove substantial medication crossover; in PRAGUE-18, over 34% of patients transitioned to clopidogrel at discharge due to out-of-pocket costs, heavily diluting the intention-to-treat efficacy and safety signals., definitions of periprocedural myocardial infarction, composite construction, switching patterns, and discontinuation behavior. In contemporary PCI, outcomes are also shaped by multiple standardized determinants that can attenuate incremental drug-level differences, including stent design, intraprocedural anticoagulation, vascular access strategy, intensity of secondary prevention, and competing risks such as heart failure, arrhythmia, and infection. The overall neutrality is also biologically plausible. Prasugrel and ticagrelor differ in pharmacologic class, with prasugrel functioning as an irreversible thienopyridine prodrug and ticagrelor acting as a direct, reversible P2Y12 receptor antagonist, yet both achieve rapid and substantial P2Y12 receptor inhibition after loading, which is the mechanistic target for reducing early platelet-driven coronary thrombosis after plaque rupture and stent implantation ( 21 , 22 ). Ticagrelor has additional pharmacology beyond P2Y12 antagonism, most notably inhibition of cellular adenosine uptake via equilibrative nucleoside transporters ENT1 and ENT2, increasing extracellular adenosine ( 23 ). This pathway is frequently discussed in relation to dyspnea and other physiological effects, and focused syntheses of ticagrelor-associated dyspnea describe adenosine-mediated mechanisms as a plausible contributor ( 24 ). However, additional biology does not necessarily translate into superior clinical outcomes in direct comparisons when both agents already achieve similarly high levels of platelet inhibition. Apparent between-study differences can also arise from treatment implementation features such as early discontinuation, structured or unstructured switching, timing of loading relative to angiography and PCI, and heterogeneity in endpoint definitions, particularly periprocedural myocardial infarction, each of which can shift event rates without establishing a robust drug hierarchy. Bleeding outcomes in this synthesis follow the same conceptual logic. Major and minor bleeding were comparable between prasugrel and ticagrelor, consistent with the expectation that agents producing similar degrees of platelet inhibition will often demonstrate similar bleeding liability when co-therapies and procedural strategies are balanced. External pooled randomized comparisons have likewise not demonstrated a consistent difference in bleeding when estimates are aggregated ( 20 ). Clinically, this argues against selecting one agent on the presumption of an inherent and consistent bleeding safety advantage in the average ACS-PCI patient. Instead, individualized selection becomes central because real-world effectiveness may be driven by persistence, tolerability, and contraindications when efficacy and major bleeding risk appear closely aligned. Ticagrelor requires twice-daily administration and has a recognized dyspnea signal that can precipitate discontinuation or switching in routine care, with clinical implications summarized in Krakowiak, “Ticagrelor-Related Severe Dyspnoea” ( 24 ). Prasugrel carries explicit restrictions in patients with prior stroke or transient ischemic attack ( 25 ). In practice, these constraints may exert greater influence on net clinical benefit than small pharmacodynamic distinctions, particularly when interruptions, switching, or nonadherence erode protection more than any theoretical incremental efficacy advantage. This individualized approach is congruent with guideline recommendations that position prasugrel or ticagrelor as preferred potent options after ACS-PCI ( 8 ). A central rationale for restricting the present synthesis to randomized trials is that much of the existing comparative literature combines randomized and observational evidence ( 26 ). Observational cohorts can inform patterns of use and outcomes in practice, but they cannot fully eliminate confounding because clinicians do not prescribe these drugs randomly and treatment selection is influenced by perceived ischemic risk, bleeding risk, age, comorbidities, and local practice. The Shah et al. meta-analysis, for example, incorporated both RCTs and observational studies and applied propensity matching because the ticagrelor group was larger, while also acknowledging that combining study designs can accumulate bias and increase heterogeneity ( 26 ). While the Shah et al. synthesis was restricted to individual hard endpoints, the present analysis expands the comparative framework by evaluating composite ischemic events and minor bleeding. Furthermore, this study utilizes meta-regression to identify specific trial-level predictors. By limiting inclusion to RCTs, the present analysis reduces confounding by indication and offers a cleaner estimate of comparative effects between prasugrel and ticagrelor in ACS patients undergoing PCI. while also incorporating the most recent randomized evidence available to provide an updated estimate aligned with contemporary PCI practice. Implications for future research follow directly from the finding of overall equivalence. If two potent P2Y12 inhibitors provide comparable ischemic protection without consistent bleeding separation in randomized evidence, future work is likely to be more informative when focused on strategy questions rather than generalized superiority claims. These include identifying patient phenotypes most likely to benefit from one agent based on contraindications, tolerability and adherence profiles, optimizing management of side effects to improve long-term persistence, clarifying when structured de-escalation is appropriate, and defining optimal pathways for transition to monotherapy in selected patients. Additional priorities include improving harmonization of endpoint definitions, particularly for periprocedural myocardial infarction, and generating stronger evidence in populations often underrepresented in trials, including very elderly patients, advanced chronic kidney disease, frailty, and those requiring concomitant oral anticoagulation. Limitations : The limitations of this analysis should be interpreted within this framework. The relatively small number of included studies and the limited overall pooled sample size restrict the statistical power of this synthesis, meaning small differences in infrequent individual endpoints cannot be excluded with certainty. The synthesis relies on trial-level rather than individual patient-level data, limiting the ability to conduct time-to-event modeling and to explore granular subgroup interactions. Heterogeneity was observed for certain nonfatal ischemic endpoints, plausibly reflecting differences in trial design including open-label elements, variation in baseline ACS case-mix across studies, and heterogeneity in outcome definitions, particularly periprocedural myocardial infarction and composite endpoint construction. Some individual endpoints were infrequent, so small differences cannot be excluded with certainty. Nonetheless, the overall randomized signal remains consistent. Finally, the follow-up duration across the studies is largely restricted to one year, leaving the comparative long-term clinical outcomes unclear. Nonetheless, the overall randomized signal remains consistent and clinically actionable 5. Conclusion ACS patients undergoing PCI with 12-month follow-up, prasugrel and ticagrelor demonstrated comparable efficacy for major ischemic outcomes and a similar overall bleeding profile. The absence of a consistent randomized advantage supports a patient-centered approach to agent selection, prioritizing contraindications, dosing feasibility, symptom tolerance, and strategies that maximize persistence on therapy over the intended treatment duration. Future investigations are best directed toward optimizing implementation, de-escalation and monotherapy pathways, and generating robust evidence in underrepresented high-risk groups, rather than expecting a stable, universal clinical superiority of one potent P2Y12 inhibitor over the other. Declarations Disclosures/Competing interests: All the authors have no conflicts of interest to declare. Ethics Approval: Not applicable. Funding: The authors received no funds, grants, or financial support for this study. Availability of data and materials: The data supporting the findings of this study were obtained from published studies. The data and material used were publicly available. References Singh A, Museedi AS, Grossman SA Acute Coronary Syndrome. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 [cited 2026 Mar 13]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK459157/ PubMed PMID: 29083796 Effects of Percutaneous Coronary Intervention on Death and Myocardial Infarction Stratified by Stable and Unstable Coronary Artery Disease | Circulation: Cardiovascular Quality and Outcomes [Internet]. [cited 2026 Mar 13]. 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JAMA 293(17):2126–2130. 10.1001/jama.293.17.2126 PubMed PMID: 15870416 Lasala JM, Cox DA, Dobies D, Baran K, Bachinsky WB, Rogers EW et al (2009) Drug-eluting stent thrombosis in routine clinical practice: two-year outcomes and predictors from the TAXUS ARRIVE registries. Circ Cardiovasc Interv 2(4):285–293. 10.1161/CIRCINTERVENTIONS.109.852178.109.852178 PubMed PMID: 20031730 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines | Circulation [Internet]. [cited 2026 Mar 13]. Available from: https://www.ahajournals.org/doi/ 10.1161/CIR.0000000000001309 Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes | New England Journal of Medicine [Internet]. [cited 2026 Mar 13]. Available from: https://www.nejm.org/doi/full/ 10.1056/NEJMoa0904327 Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes | New England Journal of Medicine [Internet]. [cited 2026 Mar 13]. Available from: https://www.nejm.org/doi/full/ 10.1056/NEJMoa0706482 Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes | New England Journal of Medicine [Internet]. [cited 2026 Mar 13]. Available from: https://www.nejm.org/doi/full/ 10.1056/NEJMoa1908973 Ticagrelor vs Prasugrel in Patients With Diabetes and Multivessel Coronary Artery Disease The TUXEDO-2 Randomized Clinical Trial | Diabetes | JAMA Cardiology | JAMA Network [Internet]. [cited 2026 Mar 13]. Available from: https://jamanetwork.com/journals/jamacardiology/article-abstract/2844869 The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration - PubMed [Internet]. [cited 2026 Mar 13]. Available from: https://pubmed.ncbi.nlm.nih.gov/19621070/ Jørgensen L, Paludan-Müller AS, Laursen DRT, Savović J, Boutron I, Sterne JAC et al (2016) Evaluation of the Cochrane tool for assessing risk of bias in randomized clinical trials: overview of published comments and analysis of user practice in Cochrane and non-Cochrane reviews. Syst Rev 5:80. 10.1186/s13643-016-0259-8 PubMed PMID: 27160280; PubMed Central PMCID: PMC4862216 GRADE | Cochrane [Internet] [cited 2026 Mar 16]. Available from: https://www.cochrane.org/learn/courses-and-resources/cochrane-methodology/grade Higgins JPT, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560. 10.1136/bmj.327 .7414.557 PubMed PMID: 12958120; PubMed Central PMCID: PMC192859 Welsh RC, Sidhu RS, Cairns JA, Lavi S, Kedev S, Moreno R et al (2019) Outcomes Among Clopidogrel, Prasugrel, and Ticagrelor in ST-Elevation Myocardial Infarction Patients Who Underwent Primary Percutaneous Coronary Intervention From the TOTAL Trial. Can J Cardiol 35(10):1377–1385. 10.1016/j.cjca.2019.04 .026 PubMed PMID: 31492492 American College of Cardiology [Internet] [cited 2026 Mar 13]. Comparison of Prasugrel and Ticagrelor in the Treatment of Acute Myocardial Infarction. Available from: https://www.acc.org/latest-in-cardiology/clinical-trials/2016/08/29/05/46/http%3a%2f%2fwww.acc.org%2flatest-in-cardiology%2fclinical-trials%2f2016%2f08%2f29%2f05%2f46%2fprague-18 (2023) Acute Coronary Syndromes [Internet]. [cited 2026 Mar 13]. Available from: https://www.escardio.org/guidelines/clinical-practice-guidelines/all-esc-practice-guidelines/acute-coronary-syndromes-acs-guidelines Bundhun PK, Shi JX, Huang F (2017) Head to head comparison of Prasugrel versus Ticagrelor in patients with acute coronary syndrome: a systematic review and meta-analysis of randomized trials. BMC Pharmacol Toxicol 18:80. 10.1186/s40360-017-0189-7 PubMed PMID: 29233189; PubMed Central PMCID: PMC5727970 Sampat PJ, Wadhwa R Prasugrel. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 [cited 2026 Mar 13]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK557427/ PubMed PMID: 32491359 Dobesh PP, Oestreich JH (2014) Ticagrelor: Pharmacokinetics, Pharmacodynamics, Clinical Efficacy, and Safety. Pharmacotherapy 34(10):1077–1090. 10.1002/phar.1477 PubMed PMID: 25164528; PubMed Central PMCID: PMC4282310 Adenosine-Mediated Effects of Ticagrelor Evidence and Potential Clinical Relevance | JACC [Internet]. [cited 2026 Mar 13]. Available from: https://www.jacc.org/doi/ 10.1016/j.jacc.2014.03.031 Krakowiak A, Kuleta J, Plech I, Zarębiński M, Wojciechowska M, Wretowski D et al (2020) Ticagrelor-Related Severe Dyspnoea: Mechanisms, Characteristic Features, Differential Diagnosis and Treatment. Clin Med Insights Case Rep 13:1179547620956634 doi:10.1177/1179547620956634 PubMed PMID: 33100831; PubMed Central PMCID: PMC7550933 Drugs.com [Internet] [cited 2026 Mar 13]. Prasugrel Disease Interactions. Available from: https://www.drugs.com/disease-interactions/prasugrel.html Shah RP, Shafiq A, Hamza M, Maniya MT, Duhan S, Keisham B et al (2023) Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome: A Systematic Review and Meta-Analysis. Am J Cardiol 207:206–214 .117 PubMed PMID: 37751668 Additional Declarations The authors declare no competing interests. Supplementary Files image1.png Graphical Abstract. Comparative efficacy and safety of ticagrelor versus prasugrel in acute coronary syndrome undergoing percutaneous coronary intervention: overview of study design, pooled outcomes, and clinical interpretation. Supplementarymaterialticvspsg.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9389696","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":621494787,"identity":"da0771d9-24e8-461d-881d-3a017abeb7c3","order_by":0,"name":"Shaheer bin shafiq","email":"data:image/png;base64,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","orcid":"","institution":"dow university of health sciences","correspondingAuthor":true,"prefix":"","firstName":"Shaheer","middleName":"bin","lastName":"shafiq","suffix":""}],"badges":[],"createdAt":"2026-04-11 17:22:34","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9389696/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9389696/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106903504,"identity":"08cecdfc-2e84-4f6d-bce8-41f0ffb4a8dd","added_by":"auto","created_at":"2026-04-14 15:11:54","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":65183,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flow diagram of the study selection process.\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-9389696/v1/111579d05613559db17c8e3c.png"},{"id":106903525,"identity":"d0f55bf1-321d-4b49-9be4-c687468d7675","added_by":"auto","created_at":"2026-04-14 15:11:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":9434,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot showing the All-Cause Mortality (ACM).\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-9389696/v1/2d5837a059759629e39da9ba.png"},{"id":106903508,"identity":"1b17946a-b9a5-4785-add2-ed0574d29c6f","added_by":"auto","created_at":"2026-04-14 15:11:54","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":9495,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot showing the Cardiovascular mortality.\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-9389696/v1/8422153204383eb215848395.png"},{"id":106903513,"identity":"c1acf6e3-e7f4-46dc-a23b-7fa3085d628a","added_by":"auto","created_at":"2026-04-14 15:11:55","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":9496,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot showing the Composite Ischemic Event.\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-9389696/v1/1df6f0a3a6d9979ec501611d.png"},{"id":106903578,"identity":"331532b1-a8bf-4e96-9ed0-1e96ac993853","added_by":"auto","created_at":"2026-04-14 15:12:06","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":9503,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot showing the Major Bleeding outcomes.\u003c/p\u003e","description":"","filename":"image6.png","url":"https://assets-eu.researchsquare.com/files/rs-9389696/v1/dedb838af5bc1a8c34840c2f.png"},{"id":106961189,"identity":"cd36396e-4be2-4646-a6ea-3a26b6339bf5","added_by":"auto","created_at":"2026-04-15 09:24:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1206379,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9389696/v1/b815ee21-bace-41c0-b60b-25b9c1959cfb.pdf"},{"id":106903502,"identity":"694cd190-d0fa-4528-b861-1747d838cbff","added_by":"auto","created_at":"2026-04-14 15:11:54","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":2268995,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGraphical Abstract.\u003c/strong\u003e Comparative efficacy and safety of ticagrelor versus prasugrel in acute coronary syndrome undergoing percutaneous coronary intervention: overview of study design, pooled outcomes, and clinical interpretation.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-9389696/v1/c83a69f64e2b0dc8a5081231.png"},{"id":106903527,"identity":"47fd94bc-8475-4e37-ac57-d8cb2133e88e","added_by":"auto","created_at":"2026-04-14 15:11:58","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1046371,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterialticvspsg.docx","url":"https://assets-eu.researchsquare.com/files/rs-9389696/v1/c72e57cc7cf6d08ba85e0cc8.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eComparative Efficacy and Safety of Ticagrelor and Prasugrel in Acute Coronary Syndrome: A Meta-Analysis of Randomized controlled trials\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eAcute coronary syndrome (ACS), comprising ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina, remains a major cause of morbidity and mortality worldwide (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The management of ACS has evolved substantially over the past decades, with percutaneous coronary intervention (PCI) emerging as the cornerstone of treatment for patients presenting with ACS, particularly those with STEMI and high-risk NSTEMI. Timely coronary revascularization has significantly improved clinical outcomes by reducing mortality and reinfarction (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Despite advances in PCI, patients remain vulnerable to thrombotic complications such as stent thrombosis, which is associated with an increased risk of recurrent myocardial infarction and cardiovascular death (\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTo address these complications, the 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Acute Coronary Syndromes recommends dual antiplatelet therapy (DAPT) with aspirin and an oral P2Y12 inhibitor for at least 12 months as the default strategy in patients with ACS who are not at high bleeding risk (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Among patients undergoing PCI, potent P2Y12 inhibitors Ticagrelor and Prasugrel are recommended in preference to clopidogrel due to their superior and more consistent platelet inhibition, resulting in improved ischemic outcomes(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) .\u003c/p\u003e \u003cp\u003eLarge randomized controlled trials (RCTs) have demonstrated the superiority of both agents over clopidogrel in reducing major adverse cardiovascular events in patients with ACS, thereby establishing their role in contemporary guideline-directed therapy (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). However, the comparative effectiveness and safety of ticagrelor versus prasugrel remain uncertain. The landmark ISAR-REACT 5 trial demonstrated that among 4,018 patients with ACS undergoing PCI, prasugrel was associated with a significantly lower incidence of death, myocardial infarction, or stroke compared with ticagrelor (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Conversely, the recent TUXEDO-2 trial reported numerically higher, though statistically non-significant, rates of death, myocardial infarction, stroke with ticagrelor compared with prasugrel. These divergent findings highlight the heterogeneity of available evidence and the ongoing uncertainty regarding the optimal P2Y12 inhibitor in ACS patients undergoing PCI (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eGiven these inconsistencies, we conducted a systematic review and meta-analysis of randomized controlled trials comparing prasugrel and ticagrelor in patients with ACS undergoing PCI. By incorporating the most contemporary evidence, our study aims to provide more precise and robust findings of comparative efficacy and safety, thereby informing clinical decision-making and guideline implementation.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study design and reporting guidelines:\u003c/h2\u003e \u003cp\u003eThis systematic review and meta-analysis was conducted to evaluate the comparative efficacy and safety of prasugrel versus ticagrelor in patients with ACS undergoing PCI. The study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Institutional review board approval was not needed because this is not individual patient-level data. This meta-analysis incorporates newly available randomized controlled trial (RCT) data while restricting inclusion exclusively to randomized trials to enhance internal validity and minimize confounding and selection bias associated with observational studies. The protocol for this study was registered on PROSPERO (ID: CRD420261338833)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Data Sources and Search Strategy:\u003c/h2\u003e \u003cp\u003eA comprehensive and systematic literature search was conducted in the following electronic databases: PubMed/MEDLINE, Web of Science and Cochrane Central Register of Controlled Trials (CENTRAL). The search strategy was designed using Medical Subject Headings (MeSH) terms and keyword combinations related to PCI, ticagrelor, and prasugrel. Major keywords: \u0026ldquo;ticagrelor,\u0026rdquo; \u0026ldquo;prasugrel,\u0026rdquo; and \u0026ldquo;myocardial infarction\u0026rdquo; were used. The complete search string used is listed in \u003cb\u003eSupplemental Table\u0026nbsp;1\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eManual screening of reference lists of included studies was performed to identify eligible studies. Through this systematic search, 4 randomized controlled trials meeting eligibility criteria were identified and included in the present analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Eligibility criteria\u003c/h2\u003e \u003cp\u003eStudies were included based on predefined eligibility criteria using the Population, Intervention, Comparison, Outcomes, and Study design (PICOS) framework.\u003c/p\u003e \u003cp\u003eRandomized controlled trials (RCTs) were eligible if they included adult patients (\u0026ge;\u0026thinsp;18 years) with ACS undergoing PCI and directly compared prasugrel with ticagrelor as part of dual antiplatelet therapy. Trials were required to report at least one prespecified clinical outcome, including the primary outcome of all-cause mortality or secondary outcomes such as bleeding events, myocardial infarction, cardiovascular mortality, non-cardiovascular mortality, stent thrombosis, or stroke, with sufficient binary data to calculate relative risks. The primary composite ischemic endpoint was generally defined as the occurrence of death, myocardial infarction, or stroke, though the specific criteria such as the inclusion of all-cause versus cardiovascular mortality\u0026mdash;varied across the included trials. The clinical criteria used to define major bleeding and minor bleeding varied across the included trials. A detailed breakdown of the specific endpoint definitions utilized by each individual study is provided in \u003cb\u003eSupplementary Table\u0026nbsp;2\u003c/b\u003e. Only trials reporting binary clinical outcomes or sufficient data to calculate relative risks were included. Studies were excluded if they were observational in design, did not involve PCI-treated ACS patients, did not directly compare prasugrel and ticagrelor, included pediatric populations, or reported irrelevant outcomes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Study selection\u003c/h2\u003e \u003cp\u003eTwo independent reviewers screened all identified records by title and abstract (K.T.M and T.A). Full texts of potentially eligible studies were retrieved and assessed according to predefined inclusion and exclusion criteria. Disagreements between reviewers were resolved through discussion and consensus. If consensus could not be reached, a third reviewer was consulted (M.M). The PRISMA flow diagram is depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Data extraction\u003c/h2\u003e \u003cp\u003eData were systematically extracted by two independent authors using a standardized data extraction form (G.T.K and M.A). Extracted information included study characteristics such as study design, sample size, duration of follow-up, and patient demographics and baseline clinical characteristics where available. Details of the intervention and comparison groups, including prasugrel and ticagrelor treatment regimens, were also recorded. The primary outcome extracted was all-cause mortality. Secondary outcomes included myocardial infarction, cardiovascular mortality, non-cardiovascular mortality, stent thrombosis, and stroke. Composite ischemic endpoints and trial-specific composite primary outcomes reported by individual trials were also extracted where available. Safety outcomes included bleeding events as defined by individual trials, including major and minor bleeding classified according to standardized criteria such as TIMI or BARC where available. Additionally, effect size measures including relative risks, hazard ratios, odds ratios, and corresponding 95% confidence intervals were extracted, along with raw event data when necessary to calculate relative risks. Any discrepancies in data extraction were resolved through discussion and consensus between the reviewers.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Quality Assessment\u003c/h2\u003e \u003cp\u003eThe methodological quality of included trials was assessed independently by the two independent reviewers using the Cochrane Risk Of Bias 2.0 tool, which examined the bias arising from randomization, deviation from intended intervention, missing outcome data, outcome measurement and selective reporting (A.M and A.S) (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Each trial was categorized to have low; some concern or high risk of bias. Disagreements were resolved by discussion with a third author (S.B.S). Additionally, the certainty of evidence for each outcome was assessed using the GRADE approach (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) .\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.7 Statistical analysis\u003c/h2\u003e \u003cp\u003eMeta-analysis was performed using relative risk (RR) as the primary effect measure for all binary outcomes. Pooled effect estimates were calculated with corresponding 95% confidence intervals (CI) using a random-effects model to account for potential inter-study variability. Statistical heterogeneity among included studies was assessed using the I\u0026sup2; statistic, with values of 0\u0026ndash;25% considered low heterogeneity, 26\u0026ndash;50% considered moderate heterogeneity, and greater than 50% considered substantial heterogeneity (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). For all analyses and visualizations, we used Review Manager (RevMan version 5.4; Copenhagen: The Nordic Cochrane Centre, 2014). Relative risks were calculated using extracted event data where necessary. Relative risks were calculated using raw event data when available, while reported hazard ratios and odds ratios were extracted and used for qualitative comparison where appropriate.\u003c/p\u003e \u003cp\u003eA sensitivity analysis, particularly the leave one out analysis, was conducted if the heterogeneity was greater than 50%. Furthermore, in order to investigate potential sources of heterogeneity among studies, meta-regression analyses were performed using R software (R Core Team. R: a language and environment for statistical computing. Vienna (AT): R Foundation for Statistical Computing; 2024), considering baseline characteristics as potential moderators of treatment effect.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eA visual summary of the study design, key efficacy and safety outcomes, and overall clinical interpretation is provided in the \u003cb\u003eGraphical Abstract.\u003c/b\u003e\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Study selection:\u003c/h2\u003e \u003cp\u003eA total of 710 records were identified through systematic database searches across PubMed, Web of Science and Cochrane CENTRAL. After removing duplicates, 641 records were selected for screening based on the title and abstract. Of these, 634 studies were excluded based on title and abstract review, following which 7 potentially relevant articles were reviewed based on full text. Ultimately, 4 studies met our inclusion criteria. The study selection process is summarized in the PRISMA flow diagram Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Study characteristics and baseline profile:\u003c/h2\u003e \u003cp\u003eA total of 10,480 patients with ACS undergoing PCI were included across four studies (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e), of whom 4,783 received prasugrel and 5,697 received ticagrelor. Follow-up was 12 months across the included trials. Participants were predominantly male (approximately 71%\u0026ndash;85%), and the mean age, reported in three studies, ranged from 60 to 65 years. Traditional cardiovascular risk factors, including hypertension and current smoking, were common, whereas prior CABG was infrequently reported. ACS presentation varied across studies, with differing proportions of STEMI, NSTEMI, and unstable angina. Further details regarding study design and baseline characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of Clinical Trials Comparative Efficacy and Safety of Ticagrelor and Prasugrel in ACS\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eMotovska (2017)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eSchupke (2019)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eWelsh (2019)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eTUXEDO-2 (2026)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrug\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTICA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePRA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTICA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePRA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTICA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePRA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eTICA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePRA\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal Patients (n)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e596\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e634\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2188\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1244\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e901\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e899\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMale (n)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e439\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e489\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1534\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1528\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1704\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1054\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e636\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e660\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (mean)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e64.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e64.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e60.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e60.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHTN (n)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e211\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e212\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1432/2008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1384/2003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e962\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e560\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e534\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e550\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSystolic Blood\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003ePressure (mm Hg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e144\u0026thinsp;\u0026plusmn;\u0026thinsp;25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e143\u0026thinsp;\u0026plusmn;\u0026thinsp;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e130\u0026thinsp;\u0026plusmn;\u0026thinsp;23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e131\u0026thinsp;\u0026plusmn;\u0026thinsp;22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e126\u0026thinsp;\u0026plusmn;\u0026thinsp;17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e126\u0026thinsp;\u0026plusmn;\u0026thinsp;16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiatolic Blood\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003ePressure (mm Hg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e82\u0026thinsp;\u0026plusmn;\u0026thinsp;15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e82\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e80\u0026thinsp;\u0026plusmn;\u0026thinsp;16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e81\u0026thinsp;\u0026plusmn;\u0026thinsp;15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e77\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e77\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHypercholesterolemia (n)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e205\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e224\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1178/2007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1163/2003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e749\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e748\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSmokers (n)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e392\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e406\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e682/2002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e667/1999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e945\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e603\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e140\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e146\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiabetes (n)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e108\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e119\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e463/2011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e429/2005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e332\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e253\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e901\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e899\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrior PCI (n)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1679/2009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1701/2005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e188\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e148\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrior MI (n)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e311/2010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e320/2005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e817\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e521\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e183\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e204\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrior CABG (n)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47/2009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e36/2005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrior Stroke (n)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSTEMI n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e533 (89.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e568 (89.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e833 (41.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e820 (40.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2188 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1244 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e220 (24.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e232 (25.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNSTEMI n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (5.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (5.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e930 (46.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e925 (46.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e308 (34.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e299 (33.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUA (n)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e249\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e261\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e189\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e172\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAtrial Fibrillation (n)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFollow up (months)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003en= Number; NA\u0026thinsp;=\u0026thinsp;Not available; Tic= Ticagrelor; Pra= Prasugrel; HTN= Hypertension; PCI= Percutaneous coronary intervention; UA= Unstable angina\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eCABG= Coronary artery bypass graft; STEMI\u0026thinsp;=\u0026thinsp;ST-elevation myocardial infarction; NSTEMI\u0026thinsp;=\u0026thinsp;Non-STEMI.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003cb\u003eGraphical Abstract.\u003c/b\u003e Comparative efficacy and safety of ticagrelor versus prasugrel in acute coronary syndrome undergoing percutaneous coronary intervention: overview of study design, pooled outcomes, and clinical interpretation. \u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Risk of bias assessment:\u003c/h2\u003e \u003cp\u003eAmong the four included randomized trials, overall risk of bias was low in two studies and raised some concerns in two studies. Schupke et al. and TUXEDO-2 were judged overall low risk, whereas Motovska et al. and Welsh et al. raised some concerns, mainly due to issues in outcome measurement and deviations from intended interventions. Overall, the included evidence was methodologically robust, with only limited study-specific concerns \u003cb\u003eSupplementary Table\u0026nbsp;3.\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Outcomes:\u003c/h2\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003e3.4.1 Primary outcome:\u003c/h2\u003e \u003cp\u003e \u003cb\u003eAll-cause mortality\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAll-cause mortality occurred in 169/4,783 (3.53%) patients receiving prasugrel and 201/5,697 (3.53%) receiving ticagrelor. The pooled analysis showed no evidence of a difference between strategies (RR 0.95, 95% CI 0.75\u0026ndash;1.20; p\u0026thinsp;=\u0026thinsp;0.66), with low heterogeneity (I\u0026sup2; = 20%, heterogeneity \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.29) Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section3\"\u003e \u003ch2\u003e3.4.2 Secondary outcomes:\u003c/h2\u003e \u003cdiv id=\"Sec17\" class=\"Section4\"\u003e \u003ch2\u003e3.4.2.1 Cardiovascular death\u003c/h2\u003e \u003cp\u003eCardiovascular death was observed in 136/4,783 (2.84%) patients in the prasugrel group and 153/5,697 (2.69%) in the ticagrelor group. The pooled estimate indicated comparable risk (RR 1.00, 95% CI 0.80\u0026ndash;1.26; p\u0026thinsp;=\u0026thinsp;0.98) with no between-study heterogeneity (I\u0026sup2; = 0%, heterogeneity \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.59) Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section4\"\u003e \u003ch2\u003e3.4.2.2 Composite ischemic event\u003c/h2\u003e \u003cp\u003eComposite ischemic events occurred in 325/4,783 (6.79%) with prasugrel versus 388/5,697 (6.81%) with ticagrelor. The pooled effect was neutral overall (RR 1.01, 95% CI 0.73\u0026ndash;1.41; p\u0026thinsp;=\u0026thinsp;0.94); however, results demonstrated substantial heterogeneity across studies (I\u0026sup2; = 80%, heterogeneity \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002) Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. On leave-one-out sensitivity analysis, exclusion of Welsh et al. attenuated heterogeneity and did not materially alter the overall finding, with the association remaining non-significant (RR 0.85, 95% CI 0.68\u0026ndash;1.06; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.15; I\u0026sup2; = 39%) \u003cb\u003eSupplementary Fig.\u0026nbsp;5\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section4\"\u003e \u003ch2\u003e3.4.2.3 Major bleeding\u003c/h2\u003e \u003cp\u003eMajor bleeding occurred in 156/4,550 (3.43%) patients receiving prasugrel and 182/5,674 (3.21%) receiving ticagrelor. The pooled analysis did not demonstrate a between-group difference (RR 0.99, 95% CI 0.77\u0026ndash;1.27; p\u0026thinsp;=\u0026thinsp;0.91) and heterogeneity was low (I\u0026sup2; = 20%, heterogeneity \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.29) Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section4\"\u003e \u003ch2\u003e3.4.2.4 Minor bleeding\u003c/h2\u003e \u003cp\u003eAcross three contributing studies, minor bleeding occurred in 461/3,884 (11.87%) with prasugrel and 545/4,796 (11.36%) with ticagrelor. The pooled estimate remained non-significant (RR 0.95, 95% CI 0.76\u0026ndash;1.19; p\u0026thinsp;=\u0026thinsp;0.67) with moderate-to-substantial heterogeneity (I\u0026sup2; = 64%, heterogeneity \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.06) \u003cb\u003eSupplementary Fig.\u0026nbsp;1\u003c/b\u003e. Sensitivity analysis excluding Welsh et al. significantly reduced heterogeneity and confirmed the non-significant association for minor bleeding (RR\u0026thinsp;=\u0026thinsp;1.07 [0.94, 1.23]; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.32; I\u0026sup2; = 0%) \u003cb\u003eSupplementary Fig.\u0026nbsp;6.\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section4\"\u003e \u003ch2\u003e3.4.2.5 Myocardial infarction\u003c/h2\u003e \u003cp\u003eMyocardial infarction occurred in 153/4,783 (3.20%) patients allocated to prasugrel and 197/5,697 (3.46%) allocated to ticagrelor. The pooled result did not indicate a significant difference (RR 0.94, 95% CI 0.64\u0026ndash;1.39; p\u0026thinsp;=\u0026thinsp;0.77), with moderate heterogeneity (I\u0026sup2; = 67%, heterogeneity \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03) \u003cb\u003eSupplementary Fig.\u0026nbsp;2\u003c/b\u003e. Leave-one-out sensitivity analysis excluding Schupke et al. reduced heterogeneity and confirmed the persistence of a non-significant association for myocardial infarction (RR\u0026thinsp;=\u0026thinsp;1.10 [0.81, 1.51]; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.54; I\u0026sup2; = 18%) \u003cb\u003eSupplementary Fig.\u0026nbsp;7\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section4\"\u003e \u003ch2\u003e3.4.2.6 Stent thrombosis\u003c/h2\u003e \u003cp\u003eStent thrombosis was reported in 61/4,783 (1.28%) patients receiving prasugrel and 74/5,697 (1.30%) receiving ticagrelor. The pooled estimate suggested similar risk (RR 0.93, 95% CI 0.52\u0026ndash;1.65; p\u0026thinsp;=\u0026thinsp;0.80) with moderate heterogeneity (I\u0026sup2; = 59%, heterogeneity \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.06) \u003cb\u003eSupplementary Fig.\u0026nbsp;3\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec23\" class=\"Section4\"\u003e \u003ch2\u003e3.4.2.7 Stroke\u003c/h2\u003e \u003cp\u003eStroke occurred in 40/4,783 (0.84%) patients in the prasugrel arm and 44/5,697 (0.77%) in the ticagrelor arm. There was no measurable difference between groups (RR 1.04, 95% CI 0.67\u0026ndash;1.61; p\u0026thinsp;=\u0026thinsp;0.86), and heterogeneity was absent (I\u0026sup2; = 0%, heterogeneity \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.75) \u003cb\u003eSupplementary Fig.\u0026nbsp;4\u003c/b\u003e. Leave-one-out sensitivity analysis excluding Welsh et al. confirmed the persistence of a non-significant association (RR 0.71, 95% CI 0.45\u0026ndash;1.11; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.13; I\u0026sup2; = 0%) \u003cb\u003eSupplementary Fig.\u0026nbsp;8\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Meta Regression:\u003c/h2\u003e \u003cp\u003eMeta-regression analysis was performed to assess whether study-level covariates influenced treatment effects across outcomes. No significant associations were identified for ACOM, cardiovascular death, major bleeding, myocardial infarction, or stroke, although borderline associations were observed for hypertension in ACOM and myocardial infarction, and for smoking and hypertension in major bleeding. For composite ischemic events, hypertension was the only significant predictor and was inversely associated with effect size (coefficient: \u0026minus;0.05, 95% CI: \u0026minus;0.07 to \u0026minus;\u0026thinsp;0.02; p\u0026thinsp;=\u0026thinsp;0.00). For minor bleeding, male sex was associated with a lower effect estimate (coefficient: \u0026minus;0.06, 95% CI: \u0026minus;0.12 to \u0026minus;\u0026thinsp;0.01; p\u0026thinsp;=\u0026thinsp;0.02), whereas hypertension (coefficient: 0.02, 95% CI: 0.00 to 0.05; p\u0026thinsp;=\u0026thinsp;0.02) and diabetes (coefficient: 0.07, 95% CI: 0.01 to 0.12; p\u0026thinsp;=\u0026thinsp;0.02) were associated with higher effect estimates. For stent thrombosis, significant associations were observed for male sex (coefficient: 0.16, 95% CI: 0.04 to 0.27; p\u0026thinsp;=\u0026thinsp;0.01), hypertension (coefficient: \u0026minus;0.07, 95% CI: \u0026minus;0.12 to \u0026minus;\u0026thinsp;0.02; p\u0026thinsp;=\u0026thinsp;0.01), and prior MI (coefficient: 0.03, 95% CI: 0.01 to 0.06; p\u0026thinsp;=\u0026thinsp;0.02).Overall, most study-level covariates did not materially influence the pooled estimates, with significant associations observed only for selected covariates in composite ischemic events, minor bleeding, and stent thrombosis. Detailed results of all meta-regression analyses are provided in \u003cb\u003eSupplementary Tables\u0026nbsp;4\u0026ndash;12 and Supplementary Figs.\u0026nbsp;9\u0026ndash;16\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec25\" class=\"Section2\"\u003e \u003ch2\u003e3.6 Certainty of Evidence:\u003c/h2\u003e \u003cp\u003eThe certainty of evidence for each outcome was evaluated using the GRADE approach. The certainty of evidence was rated as low for all-cause mortality, major or severe bleeding, cardiovascular death, and stroke, primarily due to concerns related to risk of bias and imprecision. In contrast, the certainty of evidence was judged to be very low for composite ischemic events, myocardial infarction, minor bleeding, and stent thrombosis due to imprecision. Overall, these findings indicate that confidence in the pooled estimates ranged from low to very low across all assessed outcomes. The detailed summary of findings is provided in \u003cb\u003eSupplementary Table\u0026nbsp;13.\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eAcross four randomized controlled trials including 10,480 patients with ACS treated with PCI and followed for 12 months, this RCT-only meta-analysis provides a focused comparison of two potent P2Y12 inhibitors used in contemporary dual antiplatelet therapy (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e), The aggregate randomized evidence indicates that prasugrel and ticagrelor yield comparable protection against post-PCI ischemic events and do not demonstrate a consistent separation in bleeding outcomes. Because randomization balances baseline risk and reduces confounding by indication, the overall neutrality across outcomes supports an interpretive shift away from a universal hierarchy and toward patient-level selection guided by adherence, tolerability, contraindications, and pragmatic treatment considerations.\u003c/p\u003e \u003cp\u003eWith respect to ischemic endpoints, pooled randomized comparisons suggest that prasugrel and ticagrelor are broadly similar in preventing clinically important post-PCI complications in ACS, including death, recurrent myocardial infarction, stent thrombosis, and stroke. This finding is consistent with the broader therapeutic context in which both agents were developed to provide rapid and consistent inhibition of ADP-mediated platelet activation relative to clopidogrel, and each demonstrated superiority versus clopidogrel in large ACS outcome programs. Ticagrelor reduced major ischemic events compared with clopidogrel in a large ACS program, and prasugrel reduced ischemic events including myocardial infarction and stent thrombosis compared with clopidogrel in ACS patients undergoing PCI (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). When both comparators have already demonstrated high-potency benefit against an older standard, incremental head-to-head differences in modern PCI settings may be modest and sensitive to trial design, endpoint definitions, and clinical implementation. This interpretation aligns with guideline framing in which contemporary European and American recommendations endorse a potent P2Y12 inhibitor, prasugrel or ticagrelor, as the preferred partner to aspirin after ACS treated with PCI, emphasizing potency at the class level rather than a consistent \u0026ldquo;winner\u0026rdquo; (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA similar pattern is observed when pooled comparisons beyond the included trials are considered. Earlier meta-analyses restricted to randomized comparisons of prasugrel versus ticagrelor generally reported no reproducible difference in major ischemic outcomes and bleeding when estimates were aggregated (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). This recurring neutral signal supports a clinically pragmatic inference that, for the typical ACS-PCI population, any differences in hard outcomes are likely to be small, context-dependent, or influenced by implementation factors rather than reflecting a stable pharmacologic superiority of one agent. Divergence in individual datasets remains possible, but lack of reproducibility across populations and endpoint frameworks suggests that observed differences may reflect profound clinical and methodological heterogeneity rather than true pharmacological divergence. For instance, the included trials represent vastly different baseline ACS case-mixes: the TOTAL trial exclusively enrolled patients with ST-segment elevation myocardial infarction (STEMI), TUXEDO-2 targeted a highly specific high-risk cohort with diabetes and multivessel disease, while ISAR-REACT 5 included the entire ACS spectrum. Furthermore, differences in trial execution significantly contribute to heterogeneity. The open-label design of trials like ISAR-REACT 5 and PRAGUE-18 inherently introduces performance and detection bias, particularly regarding the reporting of subjective adverse effects or minor bleeding. Additionally, economic realities drove substantial medication crossover; in PRAGUE-18, over 34% of patients transitioned to clopidogrel at discharge due to out-of-pocket costs, heavily diluting the intention-to-treat efficacy and safety signals., definitions of periprocedural myocardial infarction, composite construction, switching patterns, and discontinuation behavior. In contemporary PCI, outcomes are also shaped by multiple standardized determinants that can attenuate incremental drug-level differences, including stent design, intraprocedural anticoagulation, vascular access strategy, intensity of secondary prevention, and competing risks such as heart failure, arrhythmia, and infection.\u003c/p\u003e \u003cp\u003eThe overall neutrality is also biologically plausible. Prasugrel and ticagrelor differ in pharmacologic class, with prasugrel functioning as an irreversible thienopyridine prodrug and ticagrelor acting as a direct, reversible P2Y12 receptor antagonist, yet both achieve rapid and substantial P2Y12 receptor inhibition after loading, which is the mechanistic target for reducing early platelet-driven coronary thrombosis after plaque rupture and stent implantation (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Ticagrelor has additional pharmacology beyond P2Y12 antagonism, most notably inhibition of cellular adenosine uptake via equilibrative nucleoside transporters ENT1 and ENT2, increasing extracellular adenosine (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). This pathway is frequently discussed in relation to dyspnea and other physiological effects, and focused syntheses of ticagrelor-associated dyspnea describe adenosine-mediated mechanisms as a plausible contributor (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). However, additional biology does not necessarily translate into superior clinical outcomes in direct comparisons when both agents already achieve similarly high levels of platelet inhibition. Apparent between-study differences can also arise from treatment implementation features such as early discontinuation, structured or unstructured switching, timing of loading relative to angiography and PCI, and heterogeneity in endpoint definitions, particularly periprocedural myocardial infarction, each of which can shift event rates without establishing a robust drug hierarchy.\u003c/p\u003e \u003cp\u003eBleeding outcomes in this synthesis follow the same conceptual logic. Major and minor bleeding were comparable between prasugrel and ticagrelor, consistent with the expectation that agents producing similar degrees of platelet inhibition will often demonstrate similar bleeding liability when co-therapies and procedural strategies are balanced. External pooled randomized comparisons have likewise not demonstrated a consistent difference in bleeding when estimates are aggregated (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Clinically, this argues against selecting one agent on the presumption of an inherent and consistent bleeding safety advantage in the average ACS-PCI patient. Instead, individualized selection becomes central because real-world effectiveness may be driven by persistence, tolerability, and contraindications when efficacy and major bleeding risk appear closely aligned. Ticagrelor requires twice-daily administration and has a recognized dyspnea signal that can precipitate discontinuation or switching in routine care, with clinical implications summarized in Krakowiak, \u0026ldquo;Ticagrelor-Related Severe Dyspnoea\u0026rdquo; (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Prasugrel carries explicit restrictions in patients with prior stroke or transient ischemic attack (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). In practice, these constraints may exert greater influence on net clinical benefit than small pharmacodynamic distinctions, particularly when interruptions, switching, or nonadherence erode protection more than any theoretical incremental efficacy advantage. This individualized approach is congruent with guideline recommendations that position prasugrel or ticagrelor as preferred potent options after ACS-PCI (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA central rationale for restricting the present synthesis to randomized trials is that much of the existing comparative literature combines randomized and observational evidence (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Observational cohorts can inform patterns of use and outcomes in practice, but they cannot fully eliminate confounding because clinicians do not prescribe these drugs randomly and treatment selection is influenced by perceived ischemic risk, bleeding risk, age, comorbidities, and local practice. The Shah et al. meta-analysis, for example, incorporated both RCTs and observational studies and applied propensity matching because the ticagrelor group was larger, while also acknowledging that combining study designs can accumulate bias and increase heterogeneity (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). While the Shah et al. synthesis was restricted to individual hard endpoints, the present analysis expands the comparative framework by evaluating composite ischemic events and minor bleeding. Furthermore, this study utilizes meta-regression to identify specific trial-level predictors. By limiting inclusion to RCTs, the present analysis reduces confounding by indication and offers a cleaner estimate of comparative effects between prasugrel and ticagrelor in ACS patients undergoing PCI. while also incorporating the most recent randomized evidence available to provide an updated estimate aligned with contemporary PCI practice.\u003c/p\u003e \u003cp\u003eImplications for future research follow directly from the finding of overall equivalence. If two potent P2Y12 inhibitors provide comparable ischemic protection without consistent bleeding separation in randomized evidence, future work is likely to be more informative when focused on strategy questions rather than generalized superiority claims. These include identifying patient phenotypes most likely to benefit from one agent based on contraindications, tolerability and adherence profiles, optimizing management of side effects to improve long-term persistence, clarifying when structured de-escalation is appropriate, and defining optimal pathways for transition to monotherapy in selected patients. Additional priorities include improving harmonization of endpoint definitions, particularly for periprocedural myocardial infarction, and generating stronger evidence in populations often underrepresented in trials, including very elderly patients, advanced chronic kidney disease, frailty, and those requiring concomitant oral anticoagulation.\u003c/p\u003e \u003cp\u003e \u003cb\u003eLimitations\u003c/b\u003e:\u003c/p\u003e \u003cp\u003eThe limitations of this analysis should be interpreted within this framework. The relatively small number of included studies and the limited overall pooled sample size restrict the statistical power of this synthesis, meaning small differences in infrequent individual endpoints cannot be excluded with certainty. The synthesis relies on trial-level rather than individual patient-level data, limiting the ability to conduct time-to-event modeling and to explore granular subgroup interactions. Heterogeneity was observed for certain nonfatal ischemic endpoints, plausibly reflecting differences in trial design including open-label elements, variation in baseline ACS case-mix across studies, and heterogeneity in outcome definitions, particularly periprocedural myocardial infarction and composite endpoint construction. Some individual endpoints were infrequent, so small differences cannot be excluded with certainty. Nonetheless, the overall randomized signal remains consistent. Finally, the follow-up duration across the studies is largely restricted to one year, leaving the comparative long-term clinical outcomes unclear. Nonetheless, the overall randomized signal remains consistent and clinically actionable\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eACS patients undergoing PCI with 12-month follow-up, prasugrel and ticagrelor demonstrated comparable efficacy for major ischemic outcomes and a similar overall bleeding profile. The absence of a consistent randomized advantage supports a patient-centered approach to agent selection, prioritizing contraindications, dosing feasibility, symptom tolerance, and strategies that maximize persistence on therapy over the intended treatment duration. Future investigations are best directed toward optimizing implementation, de-escalation and monotherapy pathways, and generating robust evidence in underrepresented high-risk groups, rather than expecting a stable, universal clinical superiority of one potent P2Y12 inhibitor over the other.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDisclosures/Competing interests:\u003c/strong\u003e All the authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003ch2\u003eEthics Approval:\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eFunding:\u003c/h2\u003e\n\u003cp\u003eThe authors received no funds, grants, or financial support for this study.\u003c/p\u003e\n\u003ch2\u003eAvailability of data and materials:\u003c/h2\u003e\n\u003cp\u003eThe data supporting the findings of this study were obtained from published studies. 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Am J Cardiol 207:206\u0026ndash;214 .117 PubMed PMID: 37751668\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Dow University of Health Sciences","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Acute Coronary Syndrome, Ticagrelor, Prasugrel, Percutaneous Coronary Intervention, Dual Antiplatelet Therapy, Mortality","lastPublishedDoi":"10.21203/rs.3.rs-9389696/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9389696/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAcute coronary syndrome (ACS) remains a leading cause of morbidity and mortality worldwide despite advances in percutaneous coronary intervention (PCI) and pharmacotherapy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe searched PubMed, Web of Science, and Cochrane CENTRAL for RCTs comparing prasugrel with ticagrelor in adults with ACS undergoing PCI. The primary outcome was all-cause mortality. Secondary outcomes included cardiovascular death, myocardial infarction, composite ischemic events, stent thrombosis, stroke, and bleeding events.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFour randomized controlled trials selected comprising 10,480 patients. All-cause mortality was similar between prasugrel and ticagrelor [RR 0.95 (95% CI: 0.75, 1.20); P\u0026thinsp;=\u0026thinsp;0.66; I\u0026sup2; = 20%]. Prasugrel and ticagrelor also showed comparable risks of cardiovascular death [RR 1.00 (95% CI: 0.80, 1.26); P\u0026thinsp;=\u0026thinsp;0.98; I\u0026sup2; = 0%], myocardial infarction [RR 0.94 (95% CI: 0.64, 1.39); P\u0026thinsp;=\u0026thinsp;0.77; I\u0026sup2; = 67%], composite ischemic events [RR 1.01 (95% CI: 0.73, 1.41); P\u0026thinsp;=\u0026thinsp;0.94; I\u0026sup2; = 80%], stent thrombosis [RR 0.93 (95% CI: 0.52, 1.65); P\u0026thinsp;=\u0026thinsp;0.80; I\u0026sup2; = 59%], and stroke [RR 1.04 (95% CI: 0.67, 1.61); P\u0026thinsp;=\u0026thinsp;0.86; I\u0026sup2; = 0%]. Major bleeding [RR 0.99 (95% CI: 0.77, 1.27); P\u0026thinsp;=\u0026thinsp;0.91; I\u0026sup2; = 20%] and minor bleeding [RR 0.95 (95% CI: 0.76, 1.19); P\u0026thinsp;=\u0026thinsp;0.67; I\u0026sup2; = 64%] were also comparable between groups.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003ePrasugrel and ticagrelor demonstrated similar efficacy and safety in patients with ACS undergoing PCI. These findings support an individualized approach to P2Y12 inhibitor selection based on patient characteristics, contraindications, tolerability, and adherence considerations rather than a preference for either agent.\u003c/p\u003e","manuscriptTitle":"Comparative Efficacy and Safety of Ticagrelor and Prasugrel in Acute Coronary Syndrome: A Meta-Analysis of Randomized controlled trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-14 15:10:45","doi":"10.21203/rs.3.rs-9389696/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c28896ea-0b97-4ccc-9631-a95e7442ee89","owner":[],"postedDate":"April 14th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":66141476,"name":"Cardiac \u0026 Cardiovascular Systems"}],"tags":[],"updatedAt":"2026-04-14T15:10:48+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-14 15:10:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9389696","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9389696","identity":"rs-9389696","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}