Aspirin Resistance in Patients With Type 2 DM
The Concept of Aspirin Resistance
Platelet inhibition with aspirin has long been a cornerstone in the treatment and prevention of cardiovascular disease.1,2 In patients at high risk for cardiovascular events, antiplatelet therapy reduces the risk of serious events and death from cardiovascular causes.3 However, a significant number of patients experience a recurrent ischemic event while on aspirin. Although part of this residual risk can be attributed to poor compliance and the multiple pathways of platelet activation,4 variable platelet inhibition during aspirin treatment has also been demonstrated.5 A suboptimal biochemical response to aspirin, popularly designated aspirin resistance, is further associated with recurrent ischemic events,6,7 but estimates of its prevalence differ widely due to distinct drug doses, definitions, and platelet function tests.8 Increased platelet activation and aspirin resistance may be particularly common among patients with greater weight and impaired glucose metabolism.9-11
Measurement of Aspirin Response
Aspirin irreversibly inhibits the cyclooxygenase-1 (COX-1) enzyme, which catalyzes the rate-limiting step in the biosynthesis of thromboxane A2 (TXA2) by mature platelets. This decreases platelet activation and aggregation, and, because platelets cannot synthesize new cyclooxygenase, the inhibitory effect of aspirin lasts for their entire lifespans.12 The degree to which COX-1 is inhibited is often measured through serum concentrations of thromboxane B2 (TXB2), a biologically inert metabolite formed by non-enzymatic hydrolysis of TXA2.13 TXB2 is highly specific for platelets, and its levels are sensitive to antiplatelet therapy. Aspirin (acetylsalicylic acid and the main active metabolite, salicylic acid) concentrations can also be directly measured. Finally, platelet activation and aggregation can be assessed through a wide variety of tests of platelet function, each with its own strengths and limitations.14
Potential Influence of Aspirin Formulation
Inadequate absorption is a potential cause of aspirin nonresponsiveness.4 For example, delayed and reduced absorption may be more common, and platelet inhibitory response more variable, for enteric-coated (EC) aspirin than for immediate-release aspirin (plain aspirin).15 A modified-release lipid-based aspirin formulation (PL2200 aspirin) was approved for cardiovascular disease prevention by the U.S Food and Drug Administration in 2016. But until now, its pharmacological properties had not been compared with those of plain aspirin and EC aspirin.
Aspirin Formulation, Bioavailability, and Response
The association between aspirin response and its oral bioavailability, for three different aspirin formulations, was recently examined in a pharmacokinetic/pharmacodynamic trial.16 Forty obese patients (body mass index = 30-40 kg/m2) with type 2 diabetes, but without cardiovascular disease, were randomized in a single-blind (study staff), triple-crossover fashion to receive a plain aspirin tablet, the PL2200 aspirin capsule, and a delayed-release EC aspirin caplet, each at a dose of 325 mg for 3 consecutive days. The washout period between each stage was 14 days. Various serial measurements were made, of which the time to complete (≥99% from baseline) suppression of serum TXB2 was the primary endpoint. Based on prior studies, nonresponsiveness to aspirin was defined as <99.0% inhibition of serum TXB2 or a serum TXB2 concentration >3.1 ng/mL within the first 72 hours.17,18 Plasma concentrations of aspirin were also determined.
Thirty-five patients completed all crossover stages. Complete aspirin response was achieved significantly more quickly with PL2200 aspirin and plain aspirin versus EC aspirin (p < 0.001 for both comparisons), whereas there was no significant difference between PL2200 aspirin and plain aspirin (p = 0.41) (Figure 1). Per the <99% serum TXB2 inhibition criterion, rates of incomplete aspirin response were similar between PL2200 aspirin (8.1%) and plain aspirin (15.8%; p = 0.30 for difference) but were significantly greater with EC aspirin (52.8%; p < 0.001 for both comparisons). Comparable results were obtained with the serum TXB2 concentration >3.1 ng/mL criterion, and the two definitions were well-correlated. The areas under the curve for aspirin concentration from time = 0 to the last time measured were similar for PL2200 aspirin and plain aspirin (p = 0.14) but were significantly lower for EC aspirin (p < 0.001). Of note, insufficient response on EC aspirin was significantly associated with lower plasma aspirin levels (p = 0.03). Only two individuals did not adequately respond to any aspirin formulation (i.e., the rate of aspirin resistance per se was low).
Figure 1: Time to 99% Inhibition of Serum TXB2 Concentration
Gastrointestinal Complications of Aspirin
Aspirin treatment is frequently complicated by gastrointestinal complications, such as gastric and duodenal ulcers and bleeding. EC aspirin appeared to reduce mucosal damage in early studies.19,20 However, a subsequent large case-control study found no difference in the risk of endoscopically confirmed major upper gastrointestinal bleeding with plain aspirin versus EC aspirin.21 Recently, a randomized 7-day study demonstrated a potential protective effect of PL2200 aspirin on gastroduodenal erosion and ulceration when compared with plain aspirin.22
Optimizing Cardiovascular Protection With Aspirin
The recent aspirin pharmacokinetic/pharmacodynamic study, albeit small and short-term, showed favorable pharmacological characteristics of plain aspirin and PL2200 aspirin over EC aspirin, at a daily dose of 325 mg.16 Patients with low response to EC aspirin also had lower levels of plasma aspirin, indicating decreased absorption as the main underlying cause. Although these results cannot be directly extrapolated to clinical events, they do indicate that use of EC aspirin among individuals at high a priori risk for suboptimal aspirin response should be reconsidered. This may be particularly important in subjects with diabetes because they are intrinsically more prone to atherothrombotic events.23 Furthermore, the classic assumption that EC aspirin conveys gastrointestinal protection does not seem to hold, whereas PL2200 aspirin may be beneficial, though more work is necessary to confirm that finding.22
Given the short duration of the study, these findings may be most important for those needing a relatively rapid antiplatelet response, though for patients with acute myocardial infarction or patients undergoing primary percutaneous coronary intervention, 325 mg of plain aspirin chewed and swallowed appears best. Generalizability to patients without diabetes or in those with a previous cardiovascular event is likely but needs to be established with further studies. Another potential shortcoming is the use of the 325 mg aspirin dose because lower maintenance doses are usually recommended for prevention of recurrent ischemic events.24 However, because low-dose aspirin may be an independent risk factor for aspirin nonresponsiveness, it is likely that its use would only have augmented the obtained results.25 Certainly, long-term study of PL2200 aspirin in terms of both cardiovascular efficacy and gastrointestinal safety is warranted.
In conclusion, despite the controversies associated with aspirin nonresponsiveness, a simple and common explanation may be a formulation-dependent impairment in absorption. Future studies are needed to clarify more precisely the role of the lipid-based aspirin formulation and how to overcome true aspirin resistance.
- Lewis HD Jr, Davis JW, Archibald DG, et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med 1983;309:396-403.
- Cairns JA, Gent M, Singer J, et al. Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial. N Engl J Med 1985;313:1369-75.
- Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86.
- Bhatt DL. Aspirin resistance: more than just a laboratory curiosity. J Am Coll Cardiol 2004;43:1127-9.
- Maree AO, Fitzgerald DJ. Variable platelet response to aspirin and clopidogrel in atherothrombotic disease. Circulation 2007;115:2196-207.
- Eikelboom JW, Hirsh J, Weitz JI, Johnston M, Yi Q, Yusuf S. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation 2002;105:1650-5.
- Gum PA, Kottke-Marchant K, Welsh PA, White J, Topol EJ. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll Cardiol 2003;41:961-5.
- Hovens MM, Snoep JD, Eikenboom JC, van der Bom JG, Mertens BJ, Huisman MV. Prevalence of persistent platelet reactivity despite use of aspirin: a systematic review. Am Heart J 2007;153:175-81.
- Smith JP, Haddad EV, Taylor MB, et al. Suboptimal inhibition of platelet cyclooxygenase-1 by aspirin in metabolic syndrome. Hypertension 2012;59:719-25.
- DiChiara J, Bliden KP, Tantry US, et al. The effect of aspirin dosing on platelet function in diabetic and nondiabetic patients: an analysis from the aspirin-induced platelet effect (ASPECT) study. Diabetes 2007;56:3014-9.
- Bhatt DL. What makes platelets angry: diabetes, fibrinogen, obesity, and impaired response to antiplatelet therapy? J Am Coll Cardiol 2008;52:1060-1.
- Patrono C, Garcia Rodriguez LA, Landolfi R, Baigent C. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005;353:2373-83.
- Patrono C, Ciabattoni G, Pinca E, et al. Low dose aspirin and inhibition of thromboxane B2 production in healthy subjects. Thromb Res 1980;17:317-27.
- Grove EL. Antiplatelet effect of aspirin in patients with coronary artery disease. Dan Med J 2012;59:B4506.
- Grosser T, Fries S, Lawson JA, Kapoor SC, Grant GR, FitzGerald GA. Drug resistance and pseudoresistance: an unintended consequence of enteric coating aspirin. Circulation 2013;127:377-85.
- Bhatt DL, Grosser T, Dong JF, et al. Enteric Coating and Aspirin Nonresponsiveness in Patients With Type 2 Diabetes Mellitus. J Am Coll Cardiol 2017;69:603-12.
- Cox D, Maree AO, Dooley M, Conroy R, Byrne MF, Fitzgerald DJ. Effect of enteric coating on antiplatelet activity of low-dose aspirin in healthy volunteers. Stroke 2006;37:2153-8.
- Frelinger AL 3rd, Li Y, Linden MD, et al. Association of cyclooxygenase-1-dependent and -independent platelet function assays with adverse clinical outcomes in aspirin-treated patients presenting for cardiac catheterization. Circulation 2009;120:2586-96.
- Lanza FL, Royer GL Jr, Nelson RS. Endoscopic evaluation of the effects of aspirin, buffered aspirin, and enteric-coated aspirin on gastric and duodenal mucosa. N Engl J Med 1980;303:136-8.
- Hoftiezer JW, Silvoso GR, Burks M, Ivey KJ. Comparison of the effects of regular and enteric-coated aspirin on gastroduodenal mucosa of man. Lancet 1980;2:609-12.
- Kelly JP, Kaufman DW, Jurgelon JM, Sheehan J, Koff RS, Shapiro S. Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product. Lancet 1996;348:1413-6.
- Cryer B, Bhatt DL, Lanza FL, Dong JF, Lichtenberger LM, Marathi UK. Low-dose aspirin-induced ulceration is attenuated by aspirin-phosphatidylcholine: a randomized clinical trial. Am J Gastroenterol 2011;106:272-7.
- Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229-34.
- Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;64:e139-228.
- Ertugrul DT, Tutal E, Yildiz M, et al. Aspirin resistance is associated with glycemic control, the dose of aspirin, and obesity in type 2 diabetes mellitus. J Clin Endocrinol Metab 2010;95:2897-901.
Clinical Topics: Acute Coronary Syndromes, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Stable Ischemic Heart Disease, Lipid Metabolism, Interventions and ACS, Chronic Angina
Keywords: Acute Coronary Syndrome, Angina, Stable, Aspirin, Blood Platelets, Body Mass Index, Cardiovascular Diseases, Cyclooxygenase 1, Diabetes Mellitus, Type 2, Duodenal Ulcer, Glucose, Hydrolysis, Metabolic Syndrome X, Myocardial Infarction, Percutaneous Coronary Intervention, Platelet Activation, Platelet Aggregation Inhibitors, Platelet Function Tests, Primary Prevention, Prostaglandin-Endoperoxide Synthases, Risk Factors, Thromboxanes, Salicylic Acid
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