Statins but not aspirin reduce thrombotic risk assessed by thrombin generation in diabetic patients without cardiovascular events: the RATIONAL trial

Alejandro Macchia, Nicolás Laffaye, Pablo D Comignani, Elena Cornejo Pucci, Cecilia Igarzabal, Alejandra S Scazziota, Lourdes Herrera, Javier A Mariani, Julio C Bragagnolo, Hugo Catalano, Gianni Tognoni, Antonio Nicolucci, Alejandro Macchia, Nicolás Laffaye, Pablo D Comignani, Elena Cornejo Pucci, Cecilia Igarzabal, Alejandra S Scazziota, Lourdes Herrera, Javier A Mariani, Julio C Bragagnolo, Hugo Catalano, Gianni Tognoni, Antonio Nicolucci

Abstract

Background: The systematic use of aspirin and statins in patients with diabetes and no previous cardiovascular events is controversial. We sought to assess the effects of aspirin and statins on the thrombotic risk assessed by thrombin generation (TG) among patients with type II diabetes mellitus and no previous cardiovascular events.

Methodology/principal findings: Prospective, randomized, open, blinded to events evaluation, controlled, 2×2 factorial clinical trial including 30 patients randomly allocated to aspirin 100 mg/d, atorvastatin 40 mg/d, both or none. Outcome measurements included changes in TG levels after treatment (8 to 10 weeks), assessed by a calibrated automated thrombogram. At baseline all groups had similar clinical and biochemical profiles, including TG levels. There was no interaction between aspirin and atorvastatin. Atorvastatin significantly reduced TG measured as peak TG with saline (85.09±55.34 nmol vs 153.26±75.55 nmol for atorvastatin and control groups, respectively; p = 0.018). On the other hand, aspirin had no effect on TG (121.51±81.83 nmol vs 116.85±67.66 nmol, for aspirin and control groups, respectively; p = 0.716). The effects of treatments on measurements of TG using other agonists were consistent.

Conclusions/significance: While waiting for data from ongoing large clinical randomized trials to definitively outline the role of aspirin in primary prevention, our study shows that among diabetic patients without previous vascular events, statins but not aspirin reduce thrombotic risk assessed by TG.

Trial registration: ClinicalTrials.gov NCT00793754.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Study flowchart.
Figure 1. Study flowchart.

References

    1. Haffner SM. Coronary heart disease in patients with diabetes. N Engl J Med. 2000;342:1040–1042.
    1. Haffner SM, Lehto S, Ronnemaa T, Pyorala 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;339:229–234.
    1. American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care. 2005;28(Suppl 1):S4–S36.
    1. 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.
    1. De Berardis G, Sacco M, Strippoli GF, Pellegrini F, Graziano G, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials. BMJ. 2009;339:b4531.
    1. Zhang C, Sun A, Zhang P, Wu C, Zhang S, et al. Aspirin for primary prevention of cardiovascular events in patients with diabetes: A meta-analysis. Diabetes Res Clin Pract. 2010;87:211–8.
    1. Belch J, MacCuish A, Campbell I, Cobbe S, Taylor R, et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ. 2008;337:a1840.
    1. Ogawa H, Nakayama M, Morimoto T, Uemura S, Kanauchi M, et al. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA. 2008;300:2134–41.
    1. Bruno A, Grassi G, Dani F, Degiovanni M, Maghenzani G, et al. Use of antiplatelet therapy in a diabetic outpatient service of a large urban public hospital. Nutr Metab Cardiovasc Dis. 2005;15:42–46.
    1. Costa J, Borges M, David C, Vaz Carneiro A. Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. BMJ. 2006;332:1115–24.
    1. Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;2008;371:117–25.
    1. Nicolucci A, Standl E. Antiplatelet therapy for every diabetic person?. Diabetes Care. 2011;34(Suppl 2):S150–54.
    1. Hron G, Kollars M, Binder BR, Eichinger S, Kyrle PA. Identification of patients at low risk for recurrent venous thromboembolism by measuring thrombin generation. JAMA. 2006;296:397–402.
    1. Ye Z, Liu EH, Higgins JP, Keavney BD, Lowe GD, et al. Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66,155 cases and 91,307 controls. Lancet. 2006;367:651–658.
    1. Hemker HC, Al Dieri R, De Smedt E, Béguin S. Thrombin generation, a function test of the haemostatic-thrombotic system. Thromb Haemost. 2006;96:553–61.
    1. Wegert W, Graff J, Kaiser D, Breddin HK, Klinkhardt U, et al. Effects of antiplatelet agents on platelet-induced thrombin generation. Int J Clin Pharmacol Ther. 2002;40:135–41.
    1. American Diabetes Association. Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2010;33(Suppl. 1):S62–S69.
    1. Altman R, Scazziota AS, Herrera Mde L, Gonzalez C. Thrombin generation by activated factor VII on platelet activated by different agonists. Extending the cell-based model of hemostasis. Thromb J. 2006;4:5.
    1. Hemker HC, Giesen P, Al Dieri R, Regnault V, de Smedt E, et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb. 2003;33:4–15.
    1. De Berardis G, Sacco M, Evangelista V, Filippi A, Giorda CB, et al. Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D): design of a randomized study of the efficacy of low-dose aspirin in the prevention of cardiovascular events in subjects with diabetes mellitus treated with statins. Trials. 2007;8:21.
    1. Current Controlled Trials website. Available: . Accessed 2012 Feb 9.
    1. Evangelista V, Totani L, Rotondo S, Lorenzet R, Tognoni G, et al. Prevention of cardiovascular disease in type-2 diabetes: how to improve the clinical efficacy of aspirin. Thromb Haemost. 2005;93:8–16.
    1. Halushka MK, Halushka PV. Why are some individuals resistant to the cardioprotective effects of aspirin? Circulation. 2002;105:1620–22.
    1. Vinik AI, Erbas T, Park TS, Nolan R, Pittenger GL. Platelet dysfunction in type 2 diabetes. Diabetes Care. 2001;24:1476–85.
    1. Liao JK. Beyond lipid lowering: the role of statins in vascular protection. Int J Cardiol. 2002;86:5–18.
    1. McFarlane SI, Muniyappa R, Francisco R, Sowers JR. Pleiotropic effects of statins: lipid reduction and beyond. J Clin Endocrinol Metab. 2002;87:1451–58.
    1. Undas A, Brummel KE, Musial J, Mann KG, Szczeklik A. Simvastatin Depresses Blood Clotting by Inhibiting Activation of Prothrombin, Factor V, and Factor XIII and by Enhancing Factor Va Inactivation. Circulation. 2001;103:2248–53.
    1. Undas A, Celinska-Löwenhoff M, Brummel-Ziedins KE, Brozek J, Szczeklik A, et al. Simvastatin given for 3 days can inhibit thrombin generation and activation of factor V and enhance factor Va inactivation in hypercholesterolemic patients. Arterioscler Thromb Vasc Biol. 2005;25:1524–25.
    1. Mazzone T, Chait A, Plutzky J. Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies. Lancet. 2008;371:1800–09.
    1. Borissoff JI, Spronk HM, ten Cate H. The hemostatic system as a modulator of atherosclerosis. N Engl J Med. 2011;364:1746–60.
    1. Geisler T, Mueller K, Aichele S, Bigalke B, Stellos K, et al. Impact of inflammatory state and metabolic control on responsiveness to dual antiplatelet therapy in type 2 diabetics after PCI: prognostic relevance of residual platelet aggregability in diabetics undergoing coronary interventions. Clin Res Cardiol. 2010;99:743–52.
    1. Carcaillon L, Alhenc-Gelas M, Bejot Y, Spaft C, Ducimetière P, et al. Increased thrombin generation is associated with acute ischemic stroke but not with coronary heart disease in the elderly: the Three-City cohort study. Arterioscler Thromb Vasc Biol. 2011;31:1445–51.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere