Acetylsalicylic acid irreversibly inhibits the activity of platelet cyclooxygenase-1 (COX-1), thereby inhibiting the platelet production of thromboxane A2 (TXA2) [17, 18]. By preventing the formation of TXA2, ASA reduces platelet activation and aggregation promoted by TXA2 [19, 20].

ASA is frequently prescribed with meals to alleviate dyspeptic symptoms. EC-ASA is erratically absorbed, and the bioavailability decreases with the ingestion of food. The novel lipid-aspirin complex (PL-ASA) liquid capsule formulation is an immediate-release aspirin with consistent bioavailability that has been specifically designed to attenuate gastrointestinal (GI) effects [6, 21]. There has been a recent paradigm shift in the pharmaceutical development and commercialization of phosphatidylcholine–nonsteroidal anti-inflammatory drugs (PC-NSAIDs), namely Vazalore®, that reduce GI injury, such as ulcers, without compromising therapeutic activity [22, 23]. The PC-NSAID complex (PLxGuard™ delivery platform, PLx Pharma Inc., Sparta, NJ, USA) remains intact in low pH environments, such as the stomach, limiting free aspirin contact with the gastric mucosa [24]. A recent prospective, randomized crossover study demonstrated that LD PL-ASA resulted in faster platelet inhibition compared with EC-ASA, which could not be attributed to ASA formulation [25]. Lipid excipients used in LP-ASA did not impair the pharmacodynamic effects or alter platelet function [26].

Aspirin resistance (AR) describes a phenomenon where patients receiving aspirin therapy respond in a suboptimal manner, evidenced by continued MACE and/or the lack of attenuated platelet reactivity. Studies demonstrate that approximately 25% of patients with vascular disease are resistant to aspirin therapy, conferring an almost fourfold increased risk of MACE [27]. Novel antithrombotic strategies incorporating clopidogrel, ticagrelor, and direct oral anticoagulants such as rivaroxaban improve outcomes in patients with vascular disease [27]. Many investigators postulate that AR is implicated in major adverse cardiovascular and cerebrovascular events (MACCE) [28,29,30,31]. AR is a heterogeneous entity and remains challenging to define clinically or biochemically [32]. Fundamentally, it is the inability of aspirin to attenuate TXA2 production with effects on platelet activation and aggregation. Contributory factors include inappropriate dosage dose, drug–drug interactions, polymorphisms of COX-1 genes regulating thromboxane biosynthesis, upregulation of other sources of thromboxane production, and accentuated platelet turnover [33, 34]. Conditions that influence AR include age, gender, acute coronary syndromes, heart failure, chronic kidney disease, anemia, diabetes mellitus, tobacco use, concomitant NSAID use, malabsorption, and genetic factors [35, 36]. Compliance is also a key factor in the suboptimal response to ASA [28]. Medication compliance is a critical aspect of this phenomenon and potentially contributes to its overreporting. Thus, counseling patients with respect to the benefits of antiplatelet therapy may enhance compliance [37]. Our study did not show any statistically significant association with gender, ethnicity, body mass index, or body surface area. Our participants’ compliance was verified by pill accountability by the consultant cardiologists.

The VerifyNow™ (VN) (Werfen, Bedford, MA, USA) is a bedside, point-of-care platelet function analyzer in which a blood sample is exposed to fibrinogen-coated beads and platelet agonists. Light transmission is accentuated with platelet aggregation, signifying the absence of an antiplatelet effect and suggesting aspirin resistance [33]. VerifyNow™ test results are expressed in aspirin reaction units (ARU), and the cutoff for determination of aspirin resistance was ≥ 550 ARU [14]. The prevalence of aspirin resistance is estimated to be between 5.5 and 60% in patients, contingent on the definition, assessment, and parameters utilized [16]. When the VN-ARU test is used, the prevalence ranges from 7 to 27% [38, 39]. However, using the “gold standard” methodology, optical aggregometry, the prevalence is about 0.4–9%. Our study displayed similar results, with a mean ARU score of 426 and 19.1% of participants having an ARU > 550 on LD EC-ASA. LD PL-ASA derived a mean ARU score of 435, with 14.9% of participants achieving an ARU > 550, of which neither parameter reached statistical significance. There is the caveat that our participants were all healthy volunteers without any pre-existing comorbidity.

Currently, the decision whether to initiate LD ASA use for the primary prevention of CVD in middle-aged adults who have a 10% or greater 10-year CVD risk should be tailored to each individualized, as the net clinical benefit is marginal. The United States Preventive Services Task Force (USPSTF) recommends against the use of LD ASA for the primary prevention of CVD in older adults [40]. However, it is crucial to note that these overarching recommendations are derived from a completely different ethnic profile from that encountered in the Caribbean.

Important information including prospective data demonstrating that AR is detrimental, evidence that alternative antiplatelet therapies and strategies can achieve a clinical effect, and support for a reliable test that can assess AR status and predict outcomes is pivotal in attenuating CVD burden and MACE [41,42,43].

Despite being powered for pharmacodynamic ARU values, this study was not designed for clinical outcomes and, thus, is limited with respect to external validity for the efficacy and safety of aspirin formulations in patients with CAD.

This study was of a prospective, open-label, single-arm crossover design. The study was not randomized or blinded, as there are currently no pharmaceutical division resources for interaction response technology, such as interaction web randomization services in this region. As a result, selection bias during enrolment and inaccurate estimates of the treatment effects of the two aspirin regimens can occur. Currently, there are also no contract research organizations (CROs) that operate within Trinidad and Tobago. Therefore, the study investigators decided to pursue an open-label, pragmatic study for transparency and supervised all other aspects, as there were no third-party entities to specifically coordinate randomization and/or blinding, as would be expected in large-scale trials. Conducting clinical trials, even small pilot studies, in the Caribbean is very difficult as there are limited resources with respect to grant financing, logistical planning, and experienced personnel who are qualified and trained in clinical trial management.

The study showed a predilection for Caribbean South Asian patients (68%), which is strikingly similar to other exploratory pilot studies performed by this group, suggestive of an inherent selection bias [15, 44,45,46].

Unfortunately, the prevalence of AR is contingent on the assay utilized, which has relatively poor inter-test reliability [32]. Comprehensive platelet function testing biochemical and pharmacokinetic data may prove to be more informative; however, due to several logistical issues, these are not currently available in Trinidad.