Aspirin is an acetylated salicylate, which irreversibly acetylates serine 539 of cyclooxygenase (COX)-1 inhibiting platelet generation of thromboxane A2, resulting in reduced platelet activation and an antithrombotic affect. Aspirin has an identified role in prevention of new cardiovascular events in patient at high risk, or established cardiovascular disease such as acute coronary artery syndromes, acute occlusive stroke, stable coronary artery disease, stable peripheral artery disease, post coronary artery stenting (as part of dual antiplatelet therapy). It’s role in primary prevention has also been established. Aspirin was shown to significantly reduce the incidence of non-fatal MI and all-cause mortality through a large comprehensive meta-analysis (1).Thrombotic event occurrence is influenced by multiple factors, of which platelet activation is one of them, which in turn is triggered through multiple pathways. Thus, an agent working to counteract one of the pathways of platelet activation, is unlikely to inhibit every thrombotic event. Hence, occurrence of ischemic events while being on single antiplatelet agent like aspirin, is expected, and is termed Treatment failure. There is a subset of these patients, in which COX-1 activity remains, even in presence of aspirin, which is termed aspirin resistance, which is only meaningful if it is associated with clinic outcomes. Aspirin resistance has extensively been described since 1990s in through clinical evidence (2) or in-vitro testing (3,4). Variability seems to be arising on genetic level, and a role of multiple Single Nucleotide Polymorphisms (SNPs) have been postulated as a possible mechanism for “aspirin resistance” (5).It’s clinical significance has been demonstrated by various clinical studies. Gum et al (6) described a case series of 326 patients, in aspirin resistance was determined in 5.2% patients, through proper laboratory testing. On a follow up for around 1.9 years, patients with aspirin resistance experienced significantly increased incidence of myocardial infarction (MI), stroke or death. In another case series Chen et al described 151 patients, who were on aspirin and underwent elective percutaneous coronary intervention, for which they also received clopidogrel prior to the procedure and for maintainance. Patients with laboratory defined aspirin resistance were found to have higher chances of finding elevated post-PCI serum creatine kinase MB and cardiac troponin I levels. (7). Chen et al described a study where previously identified stable coronary artery disease patients with aspirin resistance were found to have increased incidence of cardiovascular death, MI, stroke, transient ischemic attack, or unstable angina requiring hospitalization (8).Claim and Reason:To review and conclude the evidence behind aspirin resistance and it’s implication on the cardiovascular health. Such an interesting drug failure need to be highlighted, to be considered in our daily practice and for educational purposes as well. Although a rare reaction, aspirin resistance is a possible game changer for population under risk of adverse cardiovascular reactions. Aspirin is a main pillar in the current standard of care for secondary prevention of cardiovascular events and disease progression. For this reason, we decided to review the available evidence in the literature regarding this underestimated and under-considered phenomenon. More studies are needed to evaluate the need for such resistance screening in selected populations and whether this might change the outcome or not. Methodology:We reviewed the literature for the reported evidence regarding Aspirin resistance. We searched databases like PubMed, Embase, Ovid by midline and Google scholar for published articles and abstracts. Two different trained researchers conducted the search, and the articles were filtered and reviewed to include only the relevant papers.Results: Our systemic search revealed more than 100 articles in relation to aspirin resistance. We selected 40 articles, that were relevant for this review. Most studies were either non-conclusive or needed to be boostered with bigger studies to validate any concluded results. Various mechanism were described with few were very well documented and understood. Discussion:Aspirin, the most used medication on the world (9), is the ace of the secondary prevention of cardiovascular disease through impairing platelet-centered atherothrombo-embolic incidence by irreversible deactivate of platelet cyclooxygenase-1 (COX-1), resulting in inhibit the production of thromboxane A2. Unfortunately, a large number of patients still develop atherothrombo-embolic events despite aspirin therapy, so-called ‘aspirin treatment failure’, and this is in fact is a multifactorial process. However, around 10% of the population does not respond, as it should, to aspirin in a unique phenomenon called the aspirin resistance, and is laboratory assessed by the measurement of serum thromboxane B2 or TXB2, or by assessing the platelet function testing. However, multiple studies reported some bias in sensitivity and specificity of the resistance assays (10).Mechanism of this resistance is variable and we aimed to conclude some important mechanism and it’s implication on population health. Will discuses the simplest mechanism like patient adherence going up to the rarer mechanisms. There is three types of aspirin resistance was suggested by Webber et. al. (11). Type 1 is in-vivo failure of aspirin to inhibit aggregation and TXB2 formation, which could be overcome by the addition of aspirin in vitro. Type 2 is both in vivo and in vitro failure of aspirin to inhibit aggregation and TXB2 formation. Type 3 and also called pseudo-resistance which implies both in vivo and in vitro failure of aspirin to inhibit aggregation despite an appropriate inhibition of TXB2 formation. Of course other types like adherence or industrial medication synthesis failure to be considered as well, although it wasn’t included in Webber et al. classification. Adherence to medications regimen, is an important factor to be considered when we treat any patient with medications. The more medications we provide, the harder it gets for the patient to be follow and stuck for the scheduled regimen. Adherence is a well-known logic cause of any medications failure, simple because the patient never took it. Before digging in the other causes of therapy resistance and failure or applying any changes of medications, we should always consider and evaluate the patient adherence and whether they take the medications in the appropriate way. Some studies (12) assessed the implication of aspirin adherence on mortality post myocardial infarction, with non-adherence to aspirin caused increase mortality and giving a hazard ratio of 1.82 (95% CI 1.09–3.03). Aspirin is the most widely used drug among the broad spectrum of cardiovascular pathology due to it is diverse therapeutic potentials. Furthermore, in the aftermath of increasing rates of percutaneous coronary intervention aspirin use will increase exponentially. However, these benefits don’t come without a concomitant increase in the risk of gastrointestinal bleeding. Therefore, PPIs are often co-prescribed with aspirin to raise the intragastric PH and offer primary or secondary gastroprotective effect. In the view of these facts, many researchers over the last few years tried to assess whether PPIs can attenuate the antiplatelet aspirin activity. Taking into consideration the large number of cardiovascular patients treated simultaneously with the two medications, even a statistically small reduction of aspirin activity due to PPI might be of paramount clinical significance. PPI main pharmacological action is through the inhibition of the parietal cell proton pumps with a subsequent increase in the intragastric PH above the pKa of aspirin (3.5) (13). The resultant shift in the intragastric PH will enhance aspirin transition into a lipophobic form thus, limiting gastric absorption and bioavailability.The volume, quality, and design of the studies which tackled the putative interaction between PPIs and aspirin remains below expectations. On one hand, Wurtz et all in a case-control pharmacodynamic study including 418 patients have demonstrated that PPIs may attenuate the therapeutic response to aspirin as shown by increased ex vivo residual platelet aggregation and platelet activation in patients treated with concomitant non-enteric coated aspirin and PPI compared with non-enteric coated aspirin monotherapy(14) . However, we should take into account that gastric absorption of enteric-coated aspirin has been shown to increase during PPI therapy(15). The findings of Wurtz et all are also concordant with the results of retrospective Danish study followed all aspirin-treated patients surviving 30 days after a first MI. Treatment with a PPIs was associated with an increased risk of the composite endpoint of cardiovascular death, MI, or stroke (hazard ratio HR 1.46, 95% CI 1.33-1.61)(16).On the Other hand, Niazi et al. (17), and Angiolillo et al. (18), both showed no pharmacodynamic interaction between PPI and Aspirin based on acetylsalicylic acid plasma concentrations and Serum thromboxane B2 inhibition respectfully. Subsequently, Niazi et al. (19), also proved bioequivalence between PPI and aspirin given separately or as a single-tablet containing both agents also based on acetylsalicylic acid plasma concentrations. Moreover, several studies have shown that PPIs don’t interfere with and indeed may enhance the antiplatelet effect of aspirin utilizing ex vivo platelet function tests as a surrogate for the effect of aspirin (20-23). Furthermore, a recent large observational study targeting first-time users of ASA for secondary prevention failed to show associated between PPIs use and increased risk of non-fatal MI or coronary death (24). The previous findings were supported by Post-hoc analysis of the CAPRIE trial where concomitant aspirin and PPI use was not associated with an increased risk of the composite endpoint of ischemic stroke, MI, or vascular death (adjusted hazard ratio 1.04, 95 % CI 0.70–1.57) (25). Finally, a recent meta-analysis by Kagolanu et al. assessed three clinical trials about the safety and efficacy of aspirin-omeprazole combined pill (PA32540). The previous systemic review concluded that PA32540 use is associated with lower GI adverse effects and equal effectiveness in secondary cardiovascular prevention when compared with aspirin alone or with a PPI as two separate pills (26). In fact, most of these studies which support PPIs induced decrease in aspirin efficacy are underpowered and inconsistent. Until a large randomized controlled trial is conducted it is premature to change current guidelines (27). Until that time, aspirin-PPI co-therapy remain the recommended and indeed the most effective therapy in aspirin-treated patients at high risk of gastrointestinal bleeding (28, 29).Esterase-mediated aspirin metabolism is another process where the aspirin might be inactivated (30). After aspirin got absorbed to the circulation, theoretically it might be inactivated by hydrolysis by RBC and plasma esterase as well as PH-related autolysis (31). Studies showed variations in this type of esterase activity. Eventually, no enough studies evaluate this theory. However, in one study platelet low responsiveness to in-vitro aspirin treatment was documented in human plasma and could be esterase-related (32).On the other hand, some researchers observed that patients post-coronary artery bypass grafting (CABG) suffer a high incidence of temporary aspirin resistance that is unable to be reversed by higher concentrations of aspirin (33). Studies concluded that aspirin is a substrate to a well-documented protein called MRP-4 (34), that is highly expressed for few days post GABG. In platelets granules members, MRP4 is highly expressed. In fact, MRP-4 inhibitors, like dipyridamole, enhance the aspirin function (35). Around 10 days after GABG, MRP-4 expression reduced and patients were found to be more responsive for aspirin. However, this effect is still debatable and other platelet dysfunctions were documented after surgeries. We think it’s still a worth mentioning mechanism. Other mechanisms of resistance were described in literature like cyclooxygenase-1 polymorphisms, regeneration of platelet cyclooxygenase-1 in case of high platelet turnover and the observed platelet ability of De novo cyclooxygenase-1 synthesis in response to thrombin and fibrinogen (36). On the other hand less understood mechanisms like platelet cyclooxgenase-independent thromboxane A2 production hence the action of aspirin could be effectively bypassed (37,38), non-platelet thromboxane A2 production (39,40) and possible tachyphylaxis were reported in literature but these mechanism are yet to be studied and evaluated to obtain more clarity and understanding.Conclusion:Aspirin resistance is an interesting phenomenon that worth study and discuses, giving the crucial role of aspirin in the secondary cardiovascular prevention. Multiple mechanisms of the phenomenon were described at literature. Awareness of such interaction is variable among medical practitioners. Eventually, further studies and reviews are needed to further study this phenomena and it’s implication on the cardiovascular health, and hence reaching a valid evidence-based conclusion that might change the practice towards any possible need to screen a selected population for Aspirin resistance.