Basic & Clinical Pharmacology & Toxicology, 2015, 116, 212–215

Doi: 10.1111/bcpt.12362

MiniReview

Enteric Coating Can Lead to Reduced Antiplatelet Effect of Low-Dose Acetylsalicylic Acid Peter Fentz Haastrup1, Thor Grønlykke2 and Dorte Ejg Jarbøl1 Research Unit of General Practice, Department of Public Health, University of Southern Denmark, Odense C, Denmark and 2Institute for Rational Pharmacotherapy, Danish Health and Medicines Authority, Kobenhavn, Denmark

1

(Received 30 September 2014; Accepted 25 November 2014) Abstract: Low-dose acetylsalicylic acid (ASA) is widely used as antithrombotic prophylaxis. Enteric-coated ASA has been developed to decrease the risk of gastrointestinal side effects. The consequences of enteric coating on pharmacokinetics and antiplatelet effect of ASA have not systematically been assessed. This MiniReview demonstrates that data from clinical trials indicate that enteric coating can reduce the antiplatelet effect of ASA compared to plain ASA. This is possibly due to decreased bioavailability of ASA caused by prolonged solvation and absorption of the enteric-coated formulations. Therefore, low-dose entericcoated ASA might not be bioequivalent to plain ASA, entailing the risk of insufficient cardiovascular prophylaxis.

Low-dose acetylsalicylic acid (ASA) is effective both as primary and secondary prophylaxis of thromboembolism [1]. ASA inhibits platelet aggregation by irreversible acetylation and inactivation of the enzyme cyclooxygenase (COX). This disables platelets and endothelia to convert arachidonic acid to prostaglandins and platelet-activating thromboxane (TX) [2]. ASA is known to cause gastrointestinal side effects, primarily dyspepsia or peptic ulcer [3]. Enteric-coated formulations of ASA have been designed to resist disintegration in the stomach, releasing ASA in the proximal small intestine, anticipating that this could decrease the harmful effects of ASA on gastric mucosa. It has been shown that enteric-coated ASA causes significantly fewer asymptomatic minor gastrointestinal lesions compared to plain ASA as evaluated by endoscopy after short-term treatment [4]. Nevertheless, there is questionable evidence as to whether enteric coating of low-dose ASA truly reduces gastrointestinal side effects such as incident dyspepsia [4–6] or gastrointestinal bleeding of clinical relevance [7]. This supports that injury severe enough to induce bleeding is thought to reflect the systemic rather than the topical harmful effects of ASA [8]. However, it is unknown whether enteric coating can have negative consequences for solubility, absorption and antiplatelet effect of ASA. Therefore, we carried out a review of the literature to evaluate the effect of enteric coating on pharmacokinetics and antiplatelet effect of ASA.

Author for correspondence: Peter Fentz Haastrup, Research Unit of General Practice, Institute of Public Health, University of Southern Denmark. J.B. Winsløws Vej 9a, DK-5000 Odense C, Denmark (e-mail [email protected]).

Materials and Methods The databases PubMed and EMBASE were searched in October 2014 for relevant studies with the search terms enteric coating, enterocoating, acetylsalicylic acid, aspirin, bioavailability, absorption, effect, response, resistance, antiplatelet and pharmacokinetics. The search terms were used both singularly and combined. Only papers written in English or Scandinavian languages and based on adult patients (aged 18 years or above) were included. Concurrent hand searching of relevant journals and articles was undertaken for other possible references and to pursue references of references. Each unique abstract was scrutinized by the first author to determine relevancy. Any doubts regarding eligibility of a study were resolved through consensus among the authors. Data extraction were performed by the first author and afterwards controlled by the author group. Any disagreements were solved through consensus. Clinical studies investigating consequences of enteric coating on pharmacokinetics and antiplatelet function of ASA were included.

Results We found seven articles meeting the inclusion criteria. Characteristics of the studies and their main findings are summarized in table 1. Grosser et al. [9] examined the degree of inhibition of COX after giving either 325 mg plain ASA or enteric-coated ASA to 400 healthy individuals. In the first part of the study, 40 persons were allocated to plain ASA and 360 persons to enteric-coated ASA. Baseline COX activity was measured for all individuals. The enteric-coated ASA group was split, so COX activity was measured in 210 of 360 individuals 8 hr after the medicine was given and measured in 150 of 360 patients 4 hr after consumption of trial medication. The COX activity was measured after 8 hr in all 40 individuals given plain ASA.

© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)

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Table 1. Characteristics and main findings of the studies included. Reference

Year

Grosser et al.

2013

400 Healthy individuals

>60% reduction in COX activity

Cox et al.

2006

>95% TXA2 inhibition

Peace et al.

2010

Maree et al.

2005

Ridker et al. Bochner et al. Patrignani et al.

1996

71 Healthy individuals 236 Patients with stable CVD 131 Patients with stable CVD 22 Healthy individuals 12 Healthy individuals 24 Healthy individuals

1991 2014

Individuals

Outcome

TXB2 < 10 ng/ml

Main results 83% sufficient response after single-dose 325 mg EC-ASA versus 100% after single-dose 325 mg ASA given 8 hr prior to measurement After 1 week of treatment, 98% sufficient response in individuals not responding to single-dose treatment 100% sufficient response after 2 weeks of treatment with 75 mg ASA versus 87% after 2 weeks of treatment with EC-ASA 4.2% with insufficient response. All treated with 75 mg EC-ASA. After switch to ASA 70% adequate response

TXB2 < 2.2 ng/ml

44% had insufficient response to treatment with 75 mg EC-ASA

Decrease in thromboxane and prostacyclin Time to maximum plasma concentration of ASA Acetylation of COX and decrease in thromboxane

After 2 weeks of treatment, no differences in outcome between individuals treated with 100 mg EC-ASA or 100 mg ASA Prolonged solution and absorption of 100 mg EC-ASA compared to 100 mg ASA Insufficient acetylation of COX after single dosing of 100 mg EC-ASA Sufficient response after 6 days of treatment Suggests cumulative COX inhibition is achievable upon repeated daily dosing

ASA, acetylsalicylic acid; EC-ASA, enteric-coated acetylsalicylic acid; TX, thromboxane; COX, cyclooxygenase; CVD, cardiovascular disease.

All 40 of these persons given plain ASA had sufficient inhibition of COX defined as more than a 60% decrease in COX activity. A total of 175 of 210 (83%) of the individuals given enteric-coated ASA had sufficient effect after 8 hr. Among those having COX activity measured 4 hr after consumption of enteric-coated ASA, 76 of 150 (51%) had more than a 60% reduction of COX activity. In the second part of the study, the procedure was repeated. Here, the authors found that 120 persons had responded sufficiently in both rounds, 95 individuals had responded sufficiently in one of the rounds and 42 individuals had not responded sufficiently in any of the rounds. A total of 45 of the individuals, who had responded sufficiently in both rounds, were matched by gender, age and ethnicity with the 42 persons who had not responded sufficiently in any of the rounds. They all received 1-week treatment with either 81 mg enteric-coated ASA or 75 mg clopidogrel in a cross-over design, meaning that each apparently ASA-resistant person was exposed to 1-week treatment with enteric-coated ASA and after a 14-day wash-out period to 1-week treatment with clopidogrel or the other way around. Among these apparently ASA-resistant persons, 41 of 42 (98%) had sufficient decrease in COX activity after 1-week treatment with enteric-coated ASA. An explanation for this could be that enteric coating reduces the absorption and thereby the effect of ASA and that regular and repeated dosing is necessary to achieve sufficient absorption and antiplatelet effect. Cox et al. [10] tested in a cross-over design three manufacturers’ 75 mg enteric-coated ASA, 75 mg plain ASA and a combination drug with 200 mg dipyridamole and 25 mg ASA, the latter given twice daily. A total of 71 healthy individuals aged 20–50 years took part in the study. All had COX activity measured prior to treatment and after 2 weeks of treatment. After a 2-weeks

wash-out period, the trial was repeated with one of the other antiplatelet drugs for each individual. Primary outcome was inhibition of TXA2 after 2 weeks of treatment. Treatment failure, defined as 10 ng/ml) as a sign of insufficient antiplatelet effect. To rule out non-compliance, 20 of the patients who had increased levels of TXB2 in repeated analyses were given their medication supervised. Afterwards, 10 patients still had too high levels of TXB2. These patients were all treated with 75 mg enteric-coated ASA. The treatment was changed to 75 mg plain ASA, and after 2 weeks of treatment, 7 of 10 (70%) had adequate response. The three patients still having insufficient response had an average weight of 120 kg, and after the dosage had been increased to 150 mg plain ASA, all three had adequate decrease in COX activity. The authors concluded that there can be insufficient antiplatelet effect of enteric-coated ASA, even after repeated regular dosing. This may be due to poorer absorption, because the majority had sufficient response when given plain ASA. Furthermore, the results indicate that greater doses of ASA might be necessary in obese patient due to increased distribution volume. Maree et al. [12] examined 131 stable patients with known cardiovascular disease who were all treated with 75 mg entericcoated ASA. Increased COX activity (TXB2 > 2.2 ng/ml) was

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found in 58 of 131 (44%) as a sign of insufficient antiplatelet effect. The authors found inadequate decrease in COX activity to be significantly associated with young age, high weight and previous myocardial infarction. Ridker et al. [13] randomized 22 healthy individuals to either 100 mg plain ASA or 100 mg enteric-coated ASA. The medicine was given every other day. After 2 weeks of treatment, there was no statistically significant difference between antiplatelet responses in the two groups. This was interpreted as a sign of equivalence of enteric-coated and plain ASA, when given as repeated regular doses. However, the study is limited by its modest study size. Bochner et al. [14] examined the pharmacokinetic properties of 100 mg enteric-coated ASA and plain ASA given to 12 healthy individuals. The individuals were six males and six females at the age of 19–38 years. They did not take any other medication, and their weight ranged from 51 to 71 kg. In a crossover design, they received alternately a single dose of 100 mg plain ASA and 100 mg enteric-coated ASA with a wash-out period of 4–14 days. Every dose was given with 100 ml water after a night of fasting. Plasma concentrations of ASA were measured up to 14 times evenly distributed over up to 16 hr after consumption of the drug. The individuals all received standardized meals. The experiment showed significant differences in the time to maximum plasma concentration between plain ASA and enteric-coated ASA, 0.35–0.48 and 3.73–6.48 hr, respectively. Among the enteric-coated ASA, a faster effect was seen in those given enteric-coated granules in a capsule compared to enteric-coated tablets. The plasma concentration of ASA decreased to below 5 lg/ l, 7 hr after administration of plain ASA. The plasma concentration decreased to the same level for those treated with enteric-coated ASA after 16 hr. This suggests a prolonged solution and absorption of enteric-coated ASA. However, the study is limited by its modest study size. Patrignani et al. [15] compared traditional indirect markers of action of ASA, that is serum TX and urinary excretion of TXb2, and a novel proteomic strategy for absolute protein quantification (termed AQUA) to evaluate the effects on the extent and duration of platelet COX acetylation. The study included 24 healthy individuals who received a daily dose of 100 mg enteric-coated ASA. The authors found acetylation of COX to be detectable 2 hr after dosing (before ASA was detectable in the systemic circulation) and maximal inhibition of TXA2 8 hr after dosing. The degree of acetylated COX did not reach a maximal value after the first dose. At 24 hr, after the sixth dose, the level of inactivated COX was significantly higher than measured at 24 hr after the first dose, indicating that cumulative COX inhibition is achievable upon repeated daily dosing. Furthermore, the study suggests a saturation effect, given that the extent of acetylated COX 24 hr after the seventh dose was comparable to the value 24 hr after the sixth dose. Discussion We found seven studies evaluating the consequences of enteric coating on antiplatelet effect of ASA. In five of the

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studies, enteric-coated ASA did not meet pre-defined criteria for sufficient antiplatelet response or had insufficient or decreased antiplatelet effect compared to plain ASA. However, in two of the studies, the difference did not persist after 1 week of treatment, just like in the fifth study where there was no difference after 2 weeks of treatment. Why this difference in antiplatelet effect diminishes over time is uncertain, but it might reflect that enteric-coated ASA is absorbed more incompletely and with greater variation than plain ASA. It is important to keep this time difference in mind in situations where quick absorption and immediate effect is wanted (e.g. myocardial infarction) [16]. ASA is partly absorbed from the stomach, where the low pH value counteracts deacetylation and keeps ASA in the non-ionized form which facilitates absorption. Enteric-coated ASA is dissolved in the small intestine, where the more alkaline environment may impede absorption [17]. Inhibition of TXA2 and acetylation of COX is measurable before ASA can be detected in the systemic circulation, which might reflect the fact that a part of the antiplatelet effect of ASA is executed already in the portal circulation [15,18]. ASA is deacetylated to inactive salicylic acid in several sites of the body, for example intestines and liver [19]. Firstpass metabolism of the liver is relatively high, while the capacity of first-pass metabolism of intestinal mucosa is uncertain. It is plausible that deacetylation displays saturation kinetics during absorption to the portal circulation, even in low-dose treatment. The part of enteric-coated ASA absorbed while saturation kinetics is displayed may be less than for plain ASA, because enteric-coated ASA is released more slowly and thereby is absorbed at lower concentrations over a longer time period. This can lead to lower bioavailability of ASA in the portal circulation, which can explain the decreased antiplatelet effect of enteric-coated ASA compared to plain ASA. This potential pharmacokinetic pseudo-resistance mechanism can make it necessary to administer enteric-coated ASA in higher doses than plain ASA and over longer time to achieve sufficient and comparable antiplatelet effect. This is also reflected in the included studies, where two of the studies found equivalent antiplatelet effect after minimum a week of treatment and in higher doses (81 and 100 mg) than the 75 mg recommended low dose [20]. The included studies have different definitions of insufficient antiplatelet effect. The study by Cox et al. has the strictest definition of treatment failure, namely

Enteric coating can lead to reduced antiplatelet effect of low-dose acetylsalicylic acid.

Low-dose acetylsalicylic acid (ASA) is widely used as antithrombotic prophylaxis. Enteric-coated ASA has been developed to decrease the risk of gastro...
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