Enteric Coating Can Lead to Reduced Antiplatelet Effect of Low‐Dose

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 1Research 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 (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 enteric- coated ASA might not be bioequivalent to plain ASA, entailing the risk of insufficient cardiovascular prophylaxis.

Low-dose acetylsalicylic acid (ASA) is effective both as pri- Materials and Methods mary and secondary prophylaxis of thromboembolism [1]. ASA inhibits platelet aggregation by irreversible acetylation The databases PubMed and EMBASE were searched in October 2014 and inactivation of the enzyme cyclooxygenase (COX). This for relevant studies with the search terms enteric coating, enterocoat- disables platelets and endothelia to convert arachidonic acid to ing, acetylsalicylic acid, aspirin, bioavailability, absorption, effect, response, resistance, antiplatelet and pharmacokinetics. The search prostaglandins and platelet-activating thromboxane (TX) [2]. terms were used both singularly and combined. Only papers written in ASA is known to cause gastrointestinal side effects, primar- English or Scandinavian languages and based on adult patients (aged ily dyspepsia or peptic ulcer [3]. Enteric-coated formulations 18 years or above) were included. Concurrent hand searching of rele- of ASA have been designed to resist disintegration in the vant journals and articles was undertaken for other possible references stomach, releasing ASA in the proximal small intestine, antic- and to pursue references of references. Each unique abstract was scru- ipating that this could decrease the harmful effects of ASA on tinized by the first author to determine relevancy. Any doubts regard- ing eligibility of a study were resolved through consensus among the gastric mucosa. It has been shown that enteric-coated ASA authors. Data extraction were performed by the first author and after- causes significantly fewer asymptomatic minor gastrointestinal wards controlled by the author group. Any disagreements were solved lesions compared to plain ASA as evaluated by endoscopy through consensus. Clinical studies investigating consequences of after short-term treatment [4]. Nevertheless, there is question- enteric coating on pharmacokinetics and antiplatelet function of ASA able evidence as to whether enteric coating of low-dose ASA were included. truly reduces gastrointestinal side effects such as incident dys- – pepsia [4 6] or gastrointestinal bleeding of clinical relevance Results [7]. This supports that injury severe enough to induce bleeding is thought to reflect the systemic rather than the topical harm- We found seven articles meeting the inclusion criteria. Char- ful effects of ASA [8]. acteristics of the studies and their main findings are summa- However, it is unknown whether enteric coating can have rized in table 1. Grosser et al. [9] examined the degree of negative consequences for solubility, absorption and antiplat- inhibition of COX after giving either 325 mg plain ASA or elet effect of ASA. Therefore, we carried out a review of the enteric-coated ASA to 400 healthy individuals. In the first part literature to evaluate the effect of enteric coating on pharmaco- of the study, 40 persons were allocated to plain ASA and 360 kinetics and antiplatelet effect of ASA. 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 medi- Author for correspondence: Peter Fentz Haastrup, Research Unit of cine was given and measured in 150 of 360 patients 4 hr after General Practice, Institute of Public Health, University of Southern Denmark. J.B. Winsløws Vej 9a, DK-5000 Odense C, Denmark consumption of trial medication. The COX activity was mea- (e-mail [email protected]). sured after 8 hr in all 40 individuals given plain ASA.

Table 1. Characteristics and main findings of the studies included. Reference Year Individuals Outcome Main results Grosser 2013 400 Healthy >60% reduction in COX 83% sufficient response after single-dose 325 mg EC-ASA versus 100% et al. individuals activity 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 Cox et al. 2006 71 Healthy >95% TXA2 inhibition 100% sufficient response after 2 weeks of treatment with 75 mg ASA individuals versus 87% after 2 weeks of treatment with EC-ASA Peace 2010 236 Patients TXB2 < 10 ng/ml 4.2% with insufficient response. All treated with 75 mg EC-ASA. After et al. with stable switch to ASA 70% adequate response CVD Maree 2005 131 Patients TXB2 < 2.2 ng/ml 44% had insufficient response to treatment with 75 mg EC-ASA et al. with stable CVD Ridker 1996 22 Healthy Decrease in thromboxane After 2 weeks of treatment, no differences in outcome between individuals et al. individuals and prostacyclin treated with 100 mg EC-ASA or 100 mg ASA Bochner 1991 12 Healthy Time to maximum plasma Prolonged solution and absorption of 100 mg EC-ASA compared to 100 mg et al. individuals concentration of ASA ASA Patrignani 2014 24 Healthy Acetylation of COX and Insufficient acetylation of COX after single dosing of 100 mg EC-ASA et al. individuals decrease in thromboxane 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 inhi- wash-out period, the trial was repeated with one of the other bition of COX defined as more than a 60% decrease in COX antiplatelet drugs for each individual. Primary outcome was activity. A total of 175 of 210 (83%) of the individuals given inhibition of TXA2 after 2 weeks of treatment. Treatment fail- enteric-coated ASA had sufficient effect after 8 hr. Among ure, defined as <95% inhibition of TXA2, was found in 0% those having COX activity measured 4 hr after consumption [95% confidence interval (CI) 0–13.3%] of those treated with of enteric-coated ASA, 76 of 150 (51%) had more than a 60% plain ASA, in 13% (95% CI 7.8–21.0%) of those treated with reduction of COX activity. enteric-coated ASA and in 8% (95% CI 1.9–27.7%) of those In the second part of the study, the procedure was repeated. treated with the combination drug. Here, the authors found that 120 persons had responded suffi- Peace et al. [11] compared the effect of plain ASA and ciently in both rounds, 95 individuals had responded suffi- enteric-coated ASA on the level of serum-TXB2 in patients ciently in one of the rounds and 42 individuals had not with known cardiovascular disease. The patients had been responded sufficiently in any of the rounds. treated for at least 3 months and stated that they had taken the A total of 45 of the individuals, who had responded suffi- medication within the past 36 hr. ciently in both rounds, were matched by gender, age and eth- In 44 of 236 (19%) individuals, the level of TXB2 was nicity with the 42 persons who had not responded sufficiently found to be too high (>10 ng/ml) as a sign of insufficient anti- in any of the rounds. They all received 1-week treatment with platelet effect. To rule out non-compliance, 20 of the patients either 81 mg enteric-coated ASA or 75 mg clopidogrel in a who had increased levels of TXB2 in repeated analyses were cross-over design, meaning that each apparently ASA-resistant given their medication supervised. Afterwards, 10 patients still person was exposed to 1-week treatment with enteric-coated had too high levels of TXB2. These patients were all treated ASA and after a 14-day wash-out period to 1-week treatment with 75 mg enteric-coated ASA. The treatment was changed with clopidogrel or the other way around. to 75 mg plain ASA, and after 2 weeks of treatment, 7 of 10 Among these apparently ASA-resistant persons, 41 of 42 (70%) had adequate response. The three patients still having (98%) had sufficient decrease in COX activity after 1-week insufficient response had an average weight of 120 kg, and treatment with enteric-coated ASA. An explanation for this after the dosage had been increased to 150 mg plain ASA, all could be that enteric coating reduces the absorption and thereby three had adequate decrease in COX activity. The authors con- the effect of ASA and that regular and repeated dosing is nec- cluded that there can be insufficient antiplatelet effect of essary to achieve sufficient absorption and antiplatelet effect. enteric-coated ASA, even after repeated regular dosing. This Cox et al. [10] tested in a cross-over design three manufac- may be due to poorer absorption, because the majority had turers’ 75 mg enteric-coated ASA, 75 mg plain ASA and a sufficient response when given plain ASA. Furthermore, the combination drug with 200 mg dipyridamole and 25 mg ASA, results indicate that greater doses of ASA might be necessary the latter given twice daily. in obese patient due to increased distribution volume. A total of 71 healthy individuals aged 20–50 years took Maree et al. [12] examined 131 stable patients with known part in the study. All had COX activity measured prior to cardiovascular disease who were all treated with 75 mg enteric- treatment and after 2 weeks of treatment. After a 2-weeks coated ASA. Increased COX activity (TXB2 > 2.2 ng/ml) was

© 2014 Nordic Association for the Publication of2 BCPT (former Nordic Pharmacological Society) 3 214 PETER FENTZ HAASTRUP ET AL. MiniReview found in 58 of 131 (44%) as a sign of insufficient antiplatelet studies, enteric-coated ASA did not meet pre-defined criteria effect. The authors found inadequate decrease in COX activity for sufficient antiplatelet response or had insufficient or to be significantly associated with young age, high weight and decreased antiplatelet effect compared to plain ASA. However, previous myocardial infarction. in two of the studies, the difference did not persist after Ridker et al. [13] randomized 22 healthy individuals to 1 week of treatment, just like in the fifth study where there either 100 mg plain ASA or 100 mg enteric-coated ASA. The was no difference after 2 weeks of treatment. Why this differ- medicine was given every other day. After 2 weeks of treat- ence in antiplatelet effect diminishes over time is uncertain, ment, there was no statistically significant difference between but it might reflect that enteric-coated ASA is absorbed more antiplatelet responses in the two groups. This was interpreted incompletely and with greater variation than plain ASA. It is as a sign of equivalence of enteric-coated and plain ASA, important to keep this time difference in mind in situations when given as repeated regular doses. However, the study is where quick absorption and immediate effect is wanted (e.g. limited by its modest study size. myocardial infarction) [16]. ASA is partly absorbed from the Bochner et al. [14] examined the pharmacokinetic properties stomach, where the low pH value counteracts deacetylation of 100 mg enteric-coated ASA and plain ASA given to 12 and keeps ASA in the non-ionized form which facilitates healthy individuals. The individuals were six males and six absorption. Enteric-coated ASA is dissolved in the small intes- females at the age of 19–38 years. They did not take any other tine, where the more alkaline environment may impede medication, and their weight ranged from 51 to 71 kg. In a cross- absorption [17]. over design, they received alternately a single dose of 100 mg Inhibition of TXA2 and acetylation of COX is measurable plain ASA and 100 mg enteric-coated ASA with a wash-out per- before ASA can be detected in the systemic circulation, which iod of 4–14 days. Every dose was given with 100 ml water after might reflect the fact that a part of the antiplatelet effect of a night of fasting. Plasma concentrations of ASA were measured ASA is executed already in the portal circulation [15,18]. up to 14 times evenly distributed over up to 16 hr after consump- ASA is deacetylated to inactive salicylic acid in several tion of the drug. The individuals all received standardized meals. sites of the body, for example intestines and liver [19]. First- The experiment showed significant differences in the time pass metabolism of the liver is relatively high, while the to maximum plasma concentration between plain ASA and capacity of first-pass metabolism of intestinal mucosa is enteric-coated ASA, 0.35–0.48 and 3.73–6.48 hr, respectively. uncertain. It is plausible that deacetylation displays saturation Among the enteric-coated ASA, a faster effect was seen in kinetics during absorption to the portal circulation, even in those given enteric-coated granules in a capsule compared to low-dose treatment. The part of enteric-coated ASA absorbed enteric-coated tablets. while saturation kinetics is displayed may be less than for The plasma concentration of ASA decreased to below 5 lg/ plain ASA, because enteric-coated ASA is released more l, 7 hr after administration of plain ASA. The plasma concen- slowly and thereby is absorbed at lower concentrations over a tration decreased to the same level for those treated with longer time period. This can lead to lower bioavailability of enteric-coated ASA after 16 hr. This suggests a prolonged ASA in the portal circulation, which can explain the decreased solution and absorption of enteric-coated ASA. However, the antiplatelet effect of enteric-coated ASA compared to plain study is limited by its modest study size. ASA. Patrignani et al. [15] compared traditional indirect markers of This potential pharmacokinetic pseudo-resistance mecha- action of ASA, that is serum TX and urinary excretion of TXb2, nism can make it necessary to administer enteric-coated ASA and a novel proteomic strategy for absolute protein quantifica- in higher doses than plain ASA and over longer time to tion (termed AQUA) to evaluate the effects on the extent and achieve sufficient and comparable antiplatelet effect. This is duration of platelet COX acetylation. The study included 24 also reflected in the included studies, where two of the studies healthy individuals who received a daily dose of 100 mg found equivalent antiplatelet effect after minimum a week of enteric-coated ASA. The authors found acetylation of COX to treatment and in higher doses (81 and 100 mg) than the be detectable 2 hr after dosing (before ASA was detectable in 75 mg recommended low dose [20]. the systemic circulation) and maximal inhibition of TXA2 8 hr The included studies have different definitions of insuffi- after dosing. The degree of acetylated COX did not reach a cient antiplatelet effect. The study by Cox et al. has the strict- maximal value after the first dose. At 24 hr, after the sixth dose, est definition of treatment failure, namely <95% of the TX the level of inactivated COX was significantly higher than mea- production inhibited and incomplete response defined as sured at 24 hr after the first dose, indicating that cumulative <99% inhibited. It is also in this study the greatest difference COX inhibition is achievable upon repeated daily dosing. Fur- between plain and enteric-coated ASA is demonstrated. thermore, the study suggests a saturation effect, given that the In the study by Grosser et al., there just had to be more extent of acetylated COX 24 hr after the seventh dose was com- than 60% inhibition of COX activity to be sufficient response, parable to the value 24 hr after the sixth dose. and they found no difference between plain and enteric-coated ASA after 1 week of treatment. The clinical relevance of incomplete antiplatelet effect is proven, as a higher risk of car- Discussion diovascular events is observed in patients without complete We found seven studies evaluating the consequences of COX inhibition [21,22]. Furthermore, the variation in the stud- enteric coating on antiplatelet effect of ASA. In five of the ies is considered to be less than in daily practice.

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