2.1 Search Strategy

A systematic review of the literature was conducted using PubMed Central (PMC) and EMBASE databases. The search employed the keywords “antiplatelet drug,” “drug–drug interaction,” “Major Adverse Cardiovascular Events,” and “Bleeding events.” Articles published up to October 2024 were included in the analysis.

The review adhered to the Cochrane Handbook for Systematic Reviews of Interventions and followed the guidelines outlined in the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P).

2.2 Study Selection

The inclusion and exclusion criteria for study selection were as follows:

In cases where studies contained duplicate or overlapping data, the study with the larger sample size and more comprehensive data was selected. One reviewer independently performed the study selection, and any disagreements were resolved through discussion with a second reviewer. The detailed screening process is illustrated in Figure 1.

2.3 Data Extraction

Data extraction was conducted by one author (XQ-H) and subsequently validated by another author (D-Z). Extracted data included the name of the first author, year of publication, country of origin, research design and subject characteristics, antiplatelet drugs studied and concomitant medications, and main findings.

2.4 Outcomes

The primary outcomes analyzed in this review were the rate of cardiovascular and cerebrovascular events or platelet activation rates and the incidence of bleeding events.

2.5 Results

A total of 58 studies met the inclusion criteria, comprising 50 clinical studies, 3 meta-analyses, 3 in vitro studies, and 2 animal experiments. The specific screening process is shown in Figure 1, and detailed characteristics of the included studies are provided in Table 1.

3.1 Antiplatelet Mechanisms of Aspirin

Aspirin (acetylsalicylic acid) is one of the most widely used treatments for ASVD and has been recognized for its antiplatelet properties since the 1950s [7-9]. During the acute phase of ASVD, arachidonic acid (AA) is released from vascular endothelial cells and metabolized by cyclooxygenase enzymes (COX-1 and COX-2) to form prostaglandins (PGG2 and PGH2). These intermediates are further converted into thromboxane A2 (TxA2) by thromboxane synthase in platelets and into other prostaglandins (PGD2, PGE2, and PGI2) by prostaglandin synthase in endothelial tissues (Figure 2) [10, 11].

Aspirin irreversibly inhibits COX-1 activity, reducing serum TxA2 levels and thereby preventing platelet aggregation [12]. Additionally, aspirin has direct inhibitory effects on platelet aggregation through mechanisms independent of COX inhibition, further enhancing its antiplatelet action.

3.2 Platelet Function Tests

Significant variations in aspirin pharmacodynamics were first noted in the 1990s with the identification of aspirin resistance (AR) —a phenomenon characterized by high residual platelet reactivity despite aspirin therapy [13]. AR is typically detected using platelet function tests, which have since evolved to assess aspirin responsiveness accurately (Table 2). Research indicates that the prevalence of AR varies with laboratory methodologies, aspirin dosage, and administration frequency [14, 15]. For instance, patients receiving daily doses of ≥ 300 mg exhibit a lower incidence of AR compared to those on ≤ 100 mg. Furthermore, methods such as platelet function analyzer (PFA)-100 and platelet function analyzer (RPFA) report higher AR prevalence compared to other laboratory techniques [16].

3.3 Drug Interactions Between Aspirin and Anticoagulants

Aspirin is frequently coadministered with anticoagulants in patients with conditions such as atrial fibrillation, acute coronary syndrome, and cardiogenic stroke [17-20].

When combined with warfarin, a widely used oral anticoagulant that inhibits vitamin K regeneration to reduce clotting factor synthesis [21, 22], aspirin increases the risk of bleeding without providing significant additional efficacy in reducing ASVD events [23-26]. This interaction arises because aspirin displaces warfarin from plasma protein binding sites, thereby elevating free warfarin levels and amplifying its anticoagulant effect [23]. Additionally, studies have shown that this combination may prolong warfarin's time in the therapeutic range (TTR), further heightening bleeding risks [27].

Similarly, novel oral anticoagulants (NOACs), such as apixaban, dabigatran, edoxaban, and rivaroxaban, which inhibit thrombin or factor Xa, have been associated with increased bleeding and hospitalization rates when used concurrently with aspirin, without a corresponding reduction in ASVD incidence [28, 29]. The exact mechanisms underlying the interaction between aspirin and DOACs remain unclear, necessitating further investigation.

3.4 Drug Interactions Between Aspirin and Other NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce aspirin's antiplatelet efficacy by preventing its irreversible inhibition of platelet COX-1 activity (Figure 2) [30].

Key factors influencing this interaction include the doses and timing of aspirin and NSAIDs (e.g., low-dose ibuprofen or single-dose naproxen) administration [31-33]. Higher aspirin doses and more frequent administration have been shown to mitigate this effect; for instance, a daily dose of 300 mg enhances platelet inhibition in patients with type 2 diabetes mellitus (T2DM) compared to a 100 mg dose [34]. Similarly, administering 100 mg aspirin twice daily achieves better platelet inhibition than a single 200 mg daily dose [35]. Among NSAIDs, celecoxib is considered safer when combined with aspirin, as it is associated with fewer gastrointestinal and renal adverse events compared to ibuprofen or naproxen. However, the addition of aspirin diminishes the safety advantage of celecoxib [36]. To maximize aspirin's antiplatelet efficacy in preventing ASVD, it is recommended to administer aspirin prior to NSAID use [37].

3.5 Drug Interactions Between Aspirin and Other Drugs

Aspirin interacts with various medications and natural compounds, potentially altering its pharmacokinetics and efficacy. Amoxicillin, for example, has been shown to slow the gut metabolism of aspirin's active metabolite, salicylic acid, thereby modifying its pharmacokinetic profile [38]. Natural medicines such as Ginkgo biloba extract (GBE) can influence platelet aggregation and increase bleeding risk when combined with aspirin [39].

Furthermore, selective serotonin reuptake inhibitors (SSRIs), widely used as antidepressants, have been found to elevate bleeding risk when coadministered with aspirin. This effect is likely mediated by the antiplatelet properties of SSRIs and their protective influence on the endothelium [40-43].

4.1 Antiplatelet Mechanisms of Clopidogrel

Clopidogrel, a second-generation thienopyridine, is the most commonly used ADP receptor antagonist for antiplatelet therapy [44]. The majority of clopidogrel is metabolized by hepatic carboxylesterase 1 into inactive metabolites (SR-26334), which are excreted through the gut. Only a small fraction undergoes a two-step bioactivation via hepatic cytochrome P450 (CYP) isoenzymes to produce its active metabolites (SR-2552), which binds to the P2Y12 receptor, effectively inhibiting platelet activation and aggregation (Figure 3) [45].

4.2 Drug Interactions Between Clopidogrel and Anticoagulants

While clopidogrel and anticoagulants theoretically increase bleeding risk when coadministered, evidence suggests no significant drug interaction between clopidogrel and warfarin [46]. However, NOACs may alter clopidogrel's antiplatelet activity. P-glycoprotein (P-gp) plays a key role in the metabolism of NOACs, and modulators of P-gp can affect NOAC plasma concentrations [47]. Ji et al. [48] demonstrated in mice that reduced P-gp activity correlates with enhanced production of clopidogrel's active metabolite H4, potentially impacting its clinical efficacy. Additionally, phenprocoumon may reduce clopidogrel's antiplatelet effect due to shared metabolic pathways involving CYP2C19 and CYP3A4 [49].

4.3 Drug Interactions Between Clopidogrel and Calcium Channel Blockers

Calcium channel blockers (CCBs), commonly prescribed for hypertension and heart rate control, can influence clopidogrel's antiplatelet efficacy by inhibiting CYP3A4, thereby reducing the production of its active metabolites (Figure 3) [50, 51]. Studies suggest that the CCB-clopidogrel interaction may also involve single nucleotide polymorphisms (SNPs) in CYP3A5, rather than CYP2C19 [52, 53]. The accumulation of CYP3A4 (IVS10+12G>A) A-alleles may intensify these interactions [54]. Among CCBs, dihydropyridine agents like amlodipine have a variable impact, as they do not inhibit P-glycoprotein [55]. Cilostazol has been shown to counteract this interaction and restore clopidogrel's activity [56]. However, a large observational study has not conclusively demonstrated that CCBs significantly reduce clopidogrel's efficacy, indicating the need for further clinical investigation [57].

4.4 Drug Interactions Between Clopidogrel and Proton Pump Inhibitors

Proton pump inhibitors (PPIs) irreversibly inhibit gastric acid secretion and are commonly coprescribed with clopidogrel to reduce gastrointestinal bleeding risks [58, 59]. However, emerging evidence indicates that combining PPIs with clopidogrel in patients with ASVD may increase the risk of major cardiovascular events and recurrence of ASVD [60-63]. This adverse interaction is thought to arise from PPIs interfering with clopidogrel absorption (Figure 3) and metabolism, contributing to clopidogrel resistance (CR). PPIs such as omeprazole and esomeprazole, which have a high affinity for CYP2C19, can significantly inhibit the formation of clopidogrel's active metabolites compared to pantoprazole or rabeprazole (Figure 3) [64-66]. Omeprazole, in particular, has been shown to exert time-dependent inhibitory effects on the generation of clopidogrel's active metabolites, thereby diminishing its antiplatelet efficacy [64].

This interaction is further modulated by CYP2C19 genotypes. Rapid metabolizers (RMs, *1/*1) appear to experience suppressed platelet aggregation when coadministered omeprazole or rabeprazole, while decreased metabolizers (DMs, *2/*3 carriers) are less affected [67]. Evidence suggests that alternative strategies, such as using H₂-receptor antagonists like famotidine, may mitigate these interactions and better preserve clopidogrel's efficacy [68].

4.5 Drug Interactions Between Clopidogrel and Statins

Statins, essential for reducing morbidity and mortality in cardiovascular diseases, are known to stabilize atherosclerotic plaques and modulate inflammatory pathways [69].

However, potential interactions between statins and clopidogrel arise because both are metabolized by CYP3A4, leading to competition within this enzymatic pathway (Figure 3). Despite theoretical concerns, most clinical studies have reported no significant reduction in clopidogrel's antiplatelet activity when coadministered with CYP3A4-metabolized statins [70, 71].

Nevertheless, genetic predispositions such as the presence of CYP2C19*2 alleles may heighten the susceptibility to these interactions [72]. Lau et al. [73] demonstrated a dose-dependent attenuation of clopidogrel's inhibition of platelet aggregation (IPA) by atorvastatin in patients undergoing coronary artery stent implantation. Similarly, in vitro studies suggest that simvastatin may inhibit CES1-catalyzed absorption of clopidogrel and its active metabolite [74]. The clinical impact of these interactions appears dose-dependent [73, 75].

4.6 Drug Interactions Between Clopidogrel and Other Drugs

The metabolism of clopidogrel is highly susceptible to interactions with various drugs that act on liver P450 enzymes. For instance, ketoconazole, a CYP3A4 inhibitor, reduces clopidogrel's antiplatelet activity by interfering with the production of its active metabolites (Figure 3) [76]. Conversely, rifampicin, a CYP3A4 inducer, significantly enhances clopidogrel's IPA by stimulating enzyme activity and enhancing P2Y12 receptor blockade [77]. St. John's wort, another CYP3A4 inducer, has been shown to boost the production of clopidogrel's active metabolite, although this may increase bleeding risks [78]. Smoking, a well-known inducer of CYP1A2, enhances clopidogrel's platelet inhibition, resulting in shorter ischemic times but also an elevated risk of bleeding compared to nonsmokers (Figure 3) [79-81]. The non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirenz inhibits both CYP 2C19 and CYP 2C9, which in turn reduces the bioactivity of clopidogrel [82]. Certain drugs act directly on the P2Y12 receptor or indirectly influence clopidogrel's activity. For example, cangrelor, a direct P2Y12 receptor antagonist, synergistically enhances platelet inhibition when used alongside clopidogrel (Figure 3) [83]. Cilostazol and caffeine, which elevate intracellular cAMP levels, indirectly potentiate clopidogrel's inhibition of platelet activity by antagonizing P2Y12 receptor signaling (Figure 3) [84, 85]. These interactions highlight the complexity of managing clopidogrel therapy in patients on multiple medications and underscore the need for individualized treatment plans.

4.7 Drug Interactions of Prasugrel

Prasugrel, a third-generation thienopyridine, undergoes rapid absorption in the intestinal lumen, where it is hydrolyzed by esterase CES2 into its thiolactone metabolite R-95913 [86, 87]. Unlike clopidogrel, prasugrel's pharmacokinetics and pharmacodynamics are relatively unaffected by CYP3A4 inhibitors (e.g., ketoconazole or ritonavir) or inducers (e.g., rifampin) [76, 88, 89]. This makes prasugrel a viable alternative in scenarios where coadministration of CYP3A4-modulating drugs is unavoidable. However, potential interactions between prasugrel and PPIs remain a topic of debate. The PRINCIPLE-TIMI trial observed a reduction in prasugrel's active metabolite concentration with lansoprazole coadministration [90]. Contrarily, other observational studies and randomized controlled trials (RCTs) reported no significant impact of PPI coprescription on prasugrel's efficacy [91-94]. These conflicting findings highlight the need for further research to clarify the clinical implications of these interactions, particularly in patients at high risk for gastrointestinal complications.

5.1 Antiplatelet Mechanisms of Ticagrelor

Ticagrelor, a reversible inhibitor of the P2Y12 ADP receptor, has demonstrated superior efficacy in reducing thrombotic events compared to clopidogrel [95]. The PLATO trial confirmed ticagrelor's significant reduction in vascular death, myocardial infarction, and stroke among patients with acute coronary syndrome, establishing it as a preferred option for managing ASVD [96].

Unlike clopidogrel, ticagrelor does not require metabolic activation by the liver, making its pharmacokinetics unaffected byCYP2C19 polymorphisms. This characteristic is particularly advantageous in populations with a high prevalence of CYP2C19 loss-of-function alleles, such as Han Chinese patients, for whom ticagrelor has been shown to be more effective than clopidogrel in stroke prevention [97].

5.2 Drug Interactions of Ticagrelor

Ticagrelor is rapidly absorbed in the gastrointestinal tract and inactivated by CYP3A4 in the liver (Figure 4) [98]. Consequently, drugs that inhibit or induce CYP3A4 can significantly influence its pharmacokinetics. CYP3A4 inhibitors such as ketoconazole and diltiazem can slow the metabolism of ticagrelor, leading to elevated plasma concentrations and enhanced antiplatelet effects [99]. Conversely, CYP3A4 inducers like rifampin decrease ticagrelor's efficacy by reducing the levels of its active metabolites (Figure 4) [100]. Recent findings also highlight potential interactions with other drugs; for example, dronedarone significantly increased ticagrelor exposure in a rat model, although human studies are currently lacking (Figure 4) [101]. Similarly, ticagrelor coadministration with antiretroviral drugs like ribavirin has been associated with an increased risk of cardiovascular adverse events in HIV-infected individuals [102], while carbamazepine has been shown to impair ticagrelor's antiplatelet activity by inducing CYP3A4 metabolism [103]. Beyond metabolic interactions, ticagrelor's absorption can be influenced by drugs affecting gastrointestinal motility. Morphine delays gastric emptying, prolonging the time to reach peak ticagrelor plasma levels and thus delaying its antiplatelet effect (Figure 4) [104, 105]. Interestingly, this mechanism does not affect prasugrel, highlighting the distinct pharmacodynamic profiles of these antiplatelet agents. These findings underscore the importance of careful monitoring and potential dose adjustments when ticagrelor is coadministered with drugs that can influence its metabolism or absorption, particularly in complex clinical settings.

7.1 Classification of Clinical Settings for DDIs

Antiplatelet drug interactions vary significantly depending on the clinical setting, requiring tailored strategies for each scenario.

7.2 Personalized Medication Related to Drug Interactions

A nuanced approach to personalized medication is essential in mitigating DDIs that may cause resistance to antiplatelet therapy. For example, modifications to aspirin dosing and frequency can address NSAID-related AR [35], while administering a loading dose rather than a maintenance dose of clopidogrel has shown efficacy in counteracting atorvastatin-induced CR [120].

Comprehensive assessment of patients' medication histories is critical to identifying potential DDIs and optimizing therapy.

Key recommendations include: (1) Monitor efficacy: Frequent evaluation of antiplatelet therapy's effectiveness is vital. For instance, AA-induced platelet aggregation should be monitored in patients on aspirin or indobufen, while ADP-induced aggregation should be checked in those receiving clopidogrel or ticagrelor. (2) Tailoring medication: Treatment should align with individual patient characteristics, such as age, comorbidities, and renal or hepatic function, to balance therapeutic benefits and risks. (3) Patient education: Empowering patients through education on medication adherence and potential DDIs, including the risks of over-the-counter drugs and herbal remedies, enhances safety and compliance. (4) Genetic testing: Testing for genetic polymorphisms, particularly those affecting CYP2C19, is increasingly utilized in clinical settings to guide antiplatelet therapy. For instance, CYP2C19*2 and 3 alleles are associated with reduced efficacy of clopidogrel, especially in Asian populations, where the prevalence of these polymorphisms is higher [121, 122]. Carriers of CYP2C1917, on the other hand, may benefit from enhanced clopidogrel activity [123, 124]. CR may also be influenced by alleles such as A, GA, AA, and GG+GA within the CYP2C19*2 polymorphism [125]. A recent retrospective study highlighted a potential correlation between AR and CR [126]. Furthermore, CYP2C19 polymorphism plays a predictive role in the interaction effects of atorvastatin and PPIs on clopidogrel's antiplatelet activity [64, 72].

The intricate interplay between genetic variants and drug interactions underscores the importance of personalized approaches to antiplatelet therapy. Table 3 outlines other polymorphisms associated with antiplatelet drug resistance, yet further research is essential to comprehensively understand the broader genetic determinants influencing efficacy and resistance in antiplatelet therapy.

7.3 Large Clinical Trials

Large clinical trials are crucial for advancing our understanding of DDIs and their impact on antiplatelet therapy. However, several challenges remain. First, observational studies provide valuable insights into potential correlations but often fail to establish causality. RCTs, although more rigorous, may still be affected by unmeasured confounders and are frequently constrained by high costs and logistical barriers. Additionally, outcomes such as noncardiogenic deaths or vascular interventions, which are unrelated to platelet function, may confound endpoint analyses in these trials. Another significant limitation is individual variability in drug response. Factors such as genetic polymorphisms, age, sex, and medication adherence contribute to highly variable outcomes, making it challenging to develop universal recommendations. Addressing these gaps requires a combination of innovative trial designs, such as adaptive trials, and the integration of real-world evidence to complement traditional RCT data.

7.4 Development of Novel Antiplatelet Drugs

The development of new antiplatelet agents offers promising avenues for improving outcomes in ASVD. Tirofiban, a glycoprotein IIb/IIIa inhibitor, has demonstrated efficacy in preventing platelet aggregation during acute phases of ASVD [127]. Additionally, cilostazol, a phosphodiesterase inhibitor with anti-atherosclerotic and vasodilatory properties, has been shown to reduce atherosclerosis progression without increasing bleeding risk, as highlighted in a recent meta-analysis [128]. While these agents provide novel mechanisms of action, their interactions with existing medications have not been thoroughly studied. For instance, potential DDIs involving newer agents and standard antiplatelet drugs remain unexplored, underscoring the need for further preclinical and clinical studies. Confirming the safety, efficacy, and compatibility of these drugs in combination regimens will be essential for their broader adoption in clinical practice.