**1. Background**

Acetylsalicylic acid, the active principle of aspirin, irreversibly inhibits the activity of platelet cyclo-oxygenase-1 (COX-1), thereby inhibiting the platelet production of the pro-aggregatory and vasoconstrictor molecule thromboxane A2 (TxA2) [1,2]. Due to its inhibitory effect on platelet function, aspirin is widely used as an antithrombotic drug for the treatment of acute coronary syndromes and cerebrovascular accidents and for their secondary prevention; its role in the primary prevention of these disorders is less well established [3]. A common complication of chronic treatment with aspirin is the increased risk of gastrointestinal (GI) discomfort, mucosal erosions/ulcerations and bleeding, which are frequently observed despite the fact that prevention of thrombosis can be obtained by administering low-dose aspirin (75–100 mg o.d.) [2]. A placebo-controlled study showed that the incidence of bleeding peptic ulcers in subjects on cardiovascular prophylaxis with low-dose aspirin was 40–80% higher than in placebo-treated subjects [4], while a Danish cohort study of 27,694 individuals showed that the standardized incidence rate ratio of upper GI bleeding (UGIB) was 2.6 among users of low-dose aspirin [5]. A meta-analysis of 24 randomized clinical trials (RCTs) on the risk of GI hemorrhage with long-term use (at least 1 year) of aspirin as an antiplatelet agent compared to placebo or no

**Citation:** Clerici, B.; Cattaneo, M. Pharmacological Efficacy and Gastrointestinal Safety of Different Aspirin Formulations for Cardiovascular Prevention: A Narrative Review. *J. Cardiovasc. Dev. Dis.* **2023**, *10*, 137. https://doi.org/ 10.3390/jcdd10040137

Academic Editor: Krzysztof J. Filipiak

Received: 23 February 2023 Revised: 18 March 2023 Accepted: 20 March 2023 Published: 23 March 2023

**Copyright:** © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

treatment showed that the pooled odds ratio for GI bleeding in 65,987 participants was 1.68 (95% CI, 1.51–1.88) [6]. As GI bleeding in survivors of myocardial infarction is independently associated with increased risk of death [adjusted hazard ratio 2.54 (95% CI, 1.66–3.89)] [7] its prevention is of outmost importance. Moreover, it is important to emphasize that chronic use of aspirin is associated not only with gastric complications but also with a variety of lesions in the small bowel, including multiple petechiae, loss of villi, erosions, and round, irregular, or punched-out ulcers [8]. With the aim of decreasing GI toxicity, different formulations of aspirin have been developed, including enteric-coated (EC) aspirin (tablets coated with cellulose, silicon, or other inactive ingredients) [9], buffered aspirin (tablets added with buffering agents) [10], and, more recently, PL2200 (a modified-release lipid-based aspirin) [11]. Among these formulations, EC aspirin has been thoroughly studied in terms of pharmacokinetics (PK) and pharmacodynamics (PD) and is the most widely used formulation for the prevention of arterial thrombotic events. Coating aspirin tablets prevents aspirin absorption in the stomach, thus hypothetically decreasing its GI toxicity, which was mostly attributed to the local effects of the drug. However, clear evidence that EC aspirin is safer than non-EC aspirin (which we will refer to as "plain aspirin" in the rest of the manuscript) in terms of incidence of gastric discomfort and bleeding is lacking. In addition to its dubious advantages in terms of GI safety, it must be emphasized that many reports indicate that EC aspirin is inefficiently absorbed by the intestine in some subjects and, consequently, is unable to inhibit platelet function adequately.

Herein, we will review the PK, pharmacological and clinical efficacy, and GI safety of EC aspirin as well as, when available, other formulations, compared to plain aspirin.

#### **2. Pharmacokinetics of Different Aspirin Formulations**

Plain aspirin is absorbed in the stomach, where the low pH favors its absorption and protects the active principle from inactivation. EC aspirin, on the other hand, reaches the small intestine, where the higher pH favors drug deacetylation rather than its absorption [12]. A lower bioavailability of EC aspirin compared with plain aspirin can thus be expected. Aspirin is rapidly hydrolyzed to its metabolite salicylic acid by intestinal, plasma, and hepatic esterases [13], and has therefore a systemic bioavailability of only approximately 50% [14], with a Cmax and an AUC0–24 h that are much lower than those of salicylic acid [15]. After oral administration of 100 mg tablets to healthy subjects, Tmax is about 0.5 h for plain aspirin [16–18] and about 4–5 h for EC aspirin [15,17,18], while Cmax and AUC are slightly lower with EC aspirin [17,18]. After its absorption, aspirin acetylates platelet COX-1 in the pre-systemic circulation [14], as demonstrated by the fact that inhibition of TxB2 (the stable metabolite of TxA2) production [14] and the appearance of acetylated COX-1 in platelets [15] are detectable before the active principle is measurable in the systemic circulation. Maximal inhibition of TxB2 production in healthy subjects was observed 1–1.5 h after oral dosing with 100 mg plain aspirin [18] and 6–8 h after oral dosing with 100 mg EC aspirin [15,18].

At high doses, buffered aspirin [19,20] and PL2200 [21] displayed PK and PD bioequivalence with plain aspirin, while the bioequivalence of low doses (81–100 mg), which are commonly used in cardiovascular disease (CVD) prophylaxis, has not yet been assessed.

The PK and PD properties of plain aspirin, EC aspirin, buffered aspirin, and PL2200 are summarised in Table 1.


**Table 1.** Pharmacokinetics and pharmacodynamics of plain aspirin, enteric-coated aspirin, buffered aspirin, and PL2200 after oral administration to healthy subjects.

\* Calcium carbonate, magnesium oxide, magnesium carbonate; abbreviations: EC, enteric coated.

#### **3. Pharmacological and Clinical Efficacy of Different Aspirin Formulations**

At the beginning of the 21st century, several studies reported a high prevalence of poor pharmacological response to aspirin in treated patients, which was often referred to as "aspirin resistance" [22]. However, a careful analysis of the published studies revealed major flaws in the evaluation of the pharmacological response to aspirin, which was studied using inappropriate and unspecific tests of platelet function [22]. In fact, most attempts to evaluate the efficacy of aspirin using in vivo and in vitro platelet function tests, such as the bleeding time, platelet aggregation assays, and the PFA-100 system, failed to provide consistent data that may be used when discussing the matter of aspirin resistance because of the poor specificity, accuracy, reproducibility, and standardization of the aforementioned tests [22]. The most accurate method to study aspirin resistance is to measure the degree of inhibition of TxA2 formation after drug administration by dosing its stable analogue TxB2 in serum under controlled conditions [23]. The inhibition of at least 95% of serum TxB2 formation has long been considered necessary to prevent thromboxane-dependent platelet activation [24]. Some studies that accurately addressed the issue of aspirin response by measuring serum TxB2 showed inadequate pharmacological inhibition almost exclusively in subjects treated with EC aspirin, as summarized in the following paragraphs.

#### *3.1. Studies of Healthy Subjects or Patients on Chronic Treatment for Stable Coronary Artery Disease*

In the year 2005, Maree et al. measured serum TxB2 levels in 131 stable coronary artery disease (CAD) patients with a median age of 63 years on chronic low-dose (75 mg o.d.) EC aspirin treatment [25]. In this study population, a suboptimal inhibition of TxB2 formation was found in as many as 44% of the patients. In the same patients, the effects of EC aspirin on platelet aggregation were also studied. Although platelet aggregation tests are less accurate and precise than TxB2 measurement to test the pharmacologic efficacy of aspirin, the authors used arachidonic acid (AA), instead of other platelet agonists as in other studies, which is the specific platelet agonist triggering the COX1/TxA2 pathway of platelet aggregation. As expected, inadequate inhibition of AA-induced platelet aggregation was observed more frequently among patients with high serum TxB2 levels. The in vitro addition of aspirin to patients' platelet-rich plasma (PRP) samples abolished the residual AA-induced platelet aggregation, thus implying that insufficient bioavailability of aspirin after oral EC aspirin administration was responsible for the inadequate pharmacological response that had been observed in these patients. A very interesting finding of this study was that predictors of poor response to EC aspirin included young age and high body weight. In the following year, the same group of investigators showed that equivalent doses of EC aspirin are less effective than plain aspirin in inhibiting serum TxB2 formation in 71 healthy subjects aged 20 to 50 years [12]. However, in this study, poor pharmacological response to EC aspirin was observed more frequently among subjects with high body weight. The inverse relationship between pharmacological response to EC aspirin and body weight was again confirmed by a study of 148 CAD patients on chronic treatment

with 75 mg o.d. EC aspirin for at least three months [26]. Finally, very high percentages of poor responders, defined as <95% inhibition of TxA2 production, were observed among healthy subjects 4 h (39/146, 29%) or 8 h (14/199, 7%) after ingestion of 100 mg EC aspirin, versus none among 40 healthy subjects after ingestion of plain aspirin [27]. Even within the class of EC aspirin, there is variability in the ability to inhibit platelet production of TxA2, as shown by Cox et al., who compared two EC aspirin preparations with plain aspirin: both EC preparations were less effective than plain aspirin in inhibiting TxA2 production, but there was no bioequivalence between the two EC preparations [28].
