Twice daily dosing of aspirin improves platelet inhibition in whole blood in patients with type 2 diabetes mellitus and micro- or macrovascular complications

Summary

The efficacy of low-dose aspirin in type 2 diabetes mellitus (T2DM) has been questioned. We tested if twice daily dosing of aspirin would be more effective in T2DM, possibly due to increased platelet turnover. A randomised cross-over study compared 75 mg aspirin OD, 75 mg BID and 320 mg OD (≥2 week treatment periods) in 25 patients with T2DM and micro- or macrovascular complications. Platelet responses were examined by impedance aggregometry (WBA) and the IMPACT-R aspirin test in whole blood, light transmittance aggregometry in plateletrich plasma (LTA), and urinary 11-dehydro-thromboxane B2 (TxM). Aspirin 75 mg BID decreased arachidonic acid (AA)-induced WBA compared to 75 mg OD (9.7 ± 4.5 vs. 12.6 ± 3.5 ohm; p=0.003) or to 320 mg OD (11.5 ± 4.2 Ohms; p=0.049). WBA responses to collagen were similarly attenuated by BID or high dosing (by 12–14%; p=0.02 for both). The IMPACT-R showed a better response to 75 mg BID compared to 75 mg OD (p=0.049), but not to 320 mg OD. AA-induced aggregation by LTA was <6.5% on all occasions, with no differences between aspirin dosages. TxM was reduced after 320 mg OD (p=0.002), but not 75 mg BID (p=0.07). Reticulated platelets were highly correlated with mean platelet volume (MPV; r2=0.74, p<0.0001). Both markers for platelet turnover were correlated with AA-induced WBA, but neither identified patients who benefited from BID dosing dependably. In conclusion, twice daily dosing improved laboratory responses to aspirin in high risk T2DM patients. Studies of whether BID dosing of aspirin can improve clinical outcomes in such patients are of interest.

Keywords

Acetylsalicylic acid - aspirin - diabetes mellitus - dosing - platelet function

• References

• 1 Anti-thrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J 2002; 324: 71-86.
• 2 Baigent C, Blackwell L, Collins R. et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373: 1849-1860.
• 3 Pignone M, Alberts MJ, Colwell JA. et al. Aspirin for Primary Prevention of Cardiovascular Events in People With Diabetes. A Position Statement of the American Diabetes Association, a Scientific Statement of the American Heart Association, and an Expert Consensus Document of the American College of Cardiology Foundation. Circulation 2010; 121: 2694-2701.
• 4 Awtry AH, Loscalzo J. Aspirin. Circulation 2000; 101: 1206-1218.
• 5 Roth G, Hirsh J, Baigent C. et al. Antiplatelet drugs. American College of Chest Physicians (8th Ed. Physicians Evidence Based Practice Guidelines) Chest 2008: S199-S233.
• 6 Reilly IAG, FitzGerald GA. Inhibition of thromboxane formation in vivo and ex vivo: implications for therapy with platelet inhibitory drugs. Blood 1987; 69: 180-186.
• 7 Perneby C, Wallén NH, Rooney C. et al. Dose- and time-dependent antiplatelet effects of aspirin. Thromb Haemost 2006; 95: 652-658.
• 8 DiMinno G, Silver MJ, Cerbone AM, Murphy S. Trial of repeated low-dose aspirin in diabetic angiopathy. Blood 1986; 68: 886-891.
• 9 Guthikonda S, Lev EI, Patel R. et al. Reticulated platelets and unhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin. J Thromb Haemost 2007; 5: 490-496.
• 10 Cesari F, Marcucci R, Caporale R. et al. Relationship between high platelet turnover and platelet function in high-risk patients with coronary artery disease on dual antiplatelet therapy. Thromb Haemost 2008; 99: 930-935.
• 11 Bath PMW, Butterworth RJ. Platelet size: measurement, physiology and vascular disease. Blood Coag Fibrinol 1996; 7: 157-161.
• 12 Shenkman B, Einav Y, Salomon O. et al. Testing agonist-induced platelet aggregation by the Impact-R [Cone and plate(let) analyzer (CPA)]. Platelets 2008; 19: 440-446.
• 13 Spectre G, Brill A, Gural A. et al. A new point-of-care method for monitoring antiplatelet therapy: application of the cone and plate(let) analyzer. Platelets 2005; 16: 293-299.
• 14 Wallén NH, Held C, Rehnqvist N, Hjemdahl P. Impact of treatment with acetylsalicylic acid on the proaggregatory effects of adrenaline in vitro in patients with stable angina pectoris: influence of the anticoagulant. Clin Sci (Lond.) 1993; 85: 577-583.
• 15 Perneby C, Granström E, Beck O. et al. Optimization of an enzyme immunoassay for 11-dehydro-thromboxane B2 in urine: comparison with GC-MS. Thromb Res 1999; 96: 427-436.
• 16 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: 2897-2901.
• 17 Santilli F, Rocca B, De Cristofaro R. et al. Platelet cyclooxygenase inhibition by low-dose aspirin is not reflected consistently by platelet function assays: implications for aspirin „resistance“. J Am Coll Cardiol 2009; 53: 667-677.
• 18 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: 3014-3019.
• 19 Li N, Hu H, Lindqvist M. et al. Platelet-leukocyte crosstalk in whole blood. Arterioscl Thromb Vasc Biol 2000; 20: 2702-2708.
• 20 Hu H, Li N, Yngen M, Östensson C-G. et al. Enhanced leukocyte-platelet crosstalk in type 1 diabetes mellitus: relationship to microangiopathy. J Thromb Haemost 2004; 2: 58-64.
• 21 Sala A, Folco G, Murphy RC. Transcellular biosynthesis of eicosanoids. Pharmacol Rep 2010; 62: 503-510.
• 22 Maclouf JA, Murphy RC. Transcellular metabolism of neutrophil-derived leukotriene A4 by human platelets. A potential cellular source of leukotriene C4. J Biol Chem 1988; 263: 174-181.
• 23 Rocca B, Secchiero P, Ciabattoni G. et al. Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. Proc Natl Acad Sci USA 2002; 99: 7634-7639.
• 24 Santos MT, Valles J, Lago A. et al. Residual platelet thromboxane A₂ and prothrombotic effects of erythrocytes are important determinants of aspirin resistance in patients with vascular disease. J Thromb Haemost 2008; 6: 615-621.
• 25 Eikelboom JW, Hankey GJ, Thom J. et al. Incomplete inhibition of thromboxane biosynthesis by aspirin – determinants and effect on cardiovascular risk. Circulation 2008; 118: 1705-1712.
• 26 Hjemdahl P. Aspirin resistance testing not ready for “prime time“. Heart 2009; 95: 1220-1222.
• 27 Henry P, Vermillet A, Boval B. et al. 24-hour time-dependent aspirin efficacy in patients with stable coronary artery disease. Thromb Haemost 2011; 105: 336-344.
• 28 Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR. Aspirin “resistance“ and the risk of cardiovascular morbidity: systematic review and meta-analysis. Br Med J 2008; 336: 195-198.
• 29 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: 2586-2596.
• 30 Sibbing D, Braun S, Morath T. et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 2009; 53: 849-856.
• 31 Würtz M, Grove EL, Wulff LN. et al. Patients with previous definite stent thrombosis have a reduced antiplatelet effect of aspirin and a larger fraction of immature platelets. J Am Coll Cardiol: Cardiovasc Intervent 2010; 3: 828-835.
• 32 Lordkipanidzé M. Why an aspirin a day no longer keeps the doctor away. Thromb Haemost 2011; 105: 209-210.