Association between statin use and plasma D-dimer levels

Summary

D-dimers, specific breakdown fragments of cross-linked fibrin, are generally used as circulating markers of activated coagulation. Statins influence haemostatic factors, but their effect on plasma D-dimer levels is controversial. Therefore, the aim of this meta-analysis was to evaluate the association between statin therapy and plasma D-dimer levels. We searched PubMed, Web of Science, Cochrane Library, Scopus and EMBASE (up to September 25, 2014) to identify randomised controlled trials (RCTs) investigating the impact of statin therapy on plasma D-dimer levels. Two independent reviewers extracted data on study characteristics, methods and outcomes. Meta-analysis of data from nine RCTs with 1,165 participants showed a significant effect of statin therapy in reducing plasma D-dimer levels (standardised mean difference [SMD]: –0.988 µg/ml, 95 % confidence interval [CI]: –1.590 – –0.385, p=0.001). The effect size was robust in sensitivity analysis and omission of no single study significantly changed the overall estimated effect size. In the subgroup analysis, the effect of statins on plasma D-dimer levels was significant only in the subsets of studies with treatment duration ≥ 12 weeks (SMD: –0.761 µg/ml, 95 %CI: –1.163– –0.360; p< 0.001), and for lipophilic statins (atorvastatin and simvastatin) (SMD: –1.364 µg/ml, 95 % CI: –2.202– –0.526; p=0.001). Hydrophilic statins (pravastatin and rosuvastatin) did not significantly reduce plasma D-dimer levels (SMD: –0.237 µg/ml, 95 %CI: –1.140–0.665, p=0.606). This meta-analysis of RCTs suggests a decrease of plasma D-dimer levels after three months of statin therapy, and especially after treatment with lipophilic statins. Well-designed trials are required to validate these results.

Note: The review process for this paper was fully handled by Christian Weber, Editor in Chief.

Keywords

D-dimer - statin - coagulation - fibrinolysis

^# Drs Sahebkar and Serban contributed equally to this meta-analysis.

• References

• 1 Halaby R, Popma CJ, Cohen A. et al. D-Dimer elevation and adverse outcomes. J Thromb Thrombol 2015; 39: 55-59.
• 2 Fowkes F, Housley E, Rattray A. et al. Cross-linked fibrin degradation products, progression of peripheral arterial disease, and risk of coronary heart disease. Lancet 1993; 342: 84-86.
• 3 Smith F, Rumley A, Lee A. et al. Haemostatic factors and prediction of ischaemic heart disease and stroke in claudicants. Br J Haematol 1998; 100: 758-763.
• 4 Lowe GD. Fibrin D-dimer and cardiovascular risk. Semin Vasc Med. 2005 pp. 387-398.
• 5 Lee AJ, Fowkes GR, Lowe GD. et al. Determinants of fibrin D-dimer in the Edinburgh Artery Study. Arterioscl Thromb Vasc Biol 1995; 15: 1094-1097.
• 6 Schwartz RS, Borissoff JI, Spronk HM. et al. The hemostatic system as a modulator of atherosclerosis. N Engl J Med 2011; 364: 1746-1760.
• 7 Willeit P, Thompson A, Aspelund T. et al. Hemostatic factors and risk of coronary heart disease in general populations: new prospective study and updated meta-analyses. PloS one 2013; 08: e55175.
• 8 Cervellin G, Bonfanti L, Picanza A. et al. Relation of d-Dimer and Troponin I in Patients With New-Onset Atrial Fibrillation. Am J Cardiol 2014; 114: 1129-1130.
• 9 Davis SJ, Kessler CM. Disseminated Intravascular Coagulation: Diagnosis and Management. Hemost Thromb 2014; 151.
• 10 Stockley CJ, Reed MJ, Newby DE. et al. The utility of routine D-dimer measurement in syncope. Eur J Emerg Med 2009; 16: 256-260.
• 11 Goldhaber SZ, Vaughan DE, Tumeh SS. et al. Utility of cross-linked fibrin degradation products in the diagnosis of pulmonary embolism. Am Heart J 1988; 116: 505-508.
• 12 Stott DJ, Robertson M, Rumley A. et al. Activation of hemostasis and decline in cognitive function in older people. Arterioscl Thromb Vasc Biol 2010; 30: 605-611.
• 13 Wilson CJ, Cohen HJ, Pieper CF. Cross-Linked Fibrin Degradation Products (D-Dimer), Plasma Cytokines, and Cognitive Decline in Community-Dwelling Elderly Persons. J Am Geriat Soc 2003; 51: 1374-1381.
• 14 Yucel Y, Tanriverdi H, Arikanoglu A. et al. Increased fibrinogen, D-dimer and galectin-3 levels in patients with migraine. Neurol Sci 2014; 35: 545-549.
• 15 Durczynski A, Kumor A, Hogendorf P. et al. D-dimers Revisited: A New Marker of Pancreatic Cancer. Am J Clin Oncol 2014; 37: 642.
• 16 Inal T, Anar C, Polat G. et al. The prognostic value of D-dimer in lung cancer. Clin Resp J 2015; 09: 305-313.
• 17 Ma X, Li Y, Zhang J. et al. Prognostic role of D-dimer in patients with lung cancer: a meta-analysis. Tumour Biol 2014; 35: 2103-2109.
• 18 Edwards CM, Warren J, Armstrong L. et al. D-dimer: a useful marker of disease stage in surgery for colorectal cancer. Br J Surg 1993; 80: 1404-1405.
• 19 Khangarot SS, Gupta N, Goswami B. et al. Correlation of D dimer and factor VIII levels with histopathology in patients with breast carcinoma. Cancer Biomarkers Section A 2010; 07: 305-314.
• 20 Mitter CG, Zielinski CC. Plasma levels of D-dimer: a crosslinked fibrin-degradation product in female breast cancer. J Cancer Res Clin Oncol 1991; 117: 259-262.
• 21 Banach M, Mikhailidis DP, Kjeldsen SE. et al. Time for new indications for sta-tins?. Medical Sci Monitor 2009; 15: MS1-5.
• 22 Banach M, Malodobra-Mazur M, Gluba A. et al. Statin therapy and new-onset diabetes: molecular mechanisms and clinical relevance. Curr Pharmaceut Design 2013; 19: 4904-4912.
• 23 Violi F, Calvieri C, Ferro D. et al. Statins as antithrombotic drugs. Circulation 2013; 127: 251-257.
• 24 Phillip Owens III A, Mackman N. The Antithrombotic Effects of Statins. Ann Rev Med 2014; 65: 433-445.
• 25 Undas A, Brummel-Ziedins KE, Mann KG. Statins and blood coagulation. Arterioscler Thromb Vasc Biol 2005; 25: 287-294.
• 26 Margaritis M, Channon KM, Antoniades C. Statins as regulators of redox state in the vascular endothelium: beyond lipid lowering. Antioxid Redox Signal 2014; 20: 1198-1215.
• 27 Antoniades C, Channon KM. Statins: pleiotropic regulators of cardiovascular redox state. Antioxid Redox Signal 2014; 20: 1195-1197.
• 28 Krysiak R, Okopien B, Herman Z. Effects of HMG-CoA reductase inhibitors on coagulation and fibrinolysis processes. Drugs 2003; 63: 1821-1854.
• 29 Zhou Q, Liao JK. Pleiotropic effects of statins. – Basic research and clinical perspectives. Circulation J 2010; 74: 818-826.
• 30 Moher D, Liberati A, Tetzlaff J. et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Br Med J 2009; 339: b2535.
• 31 Jadad AR, Moore RA, Carroll D. et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Control Clin Trials 1996; 17: 1-12.
• 32 Moher D, Cook D, Jadad A. et al. Assessing the quality of reports of randomised trials: implications for the conduct of meta-analyses. Health Technol Assessm 1998; 03: i-iv 1–98.
• 33 Borenstein M, Hedges L, Higgins J. et al. Comprehensive meta-analysis version 2. Englewood: NJ: Biostat; 2005: 104.
• 34 Sutton AJ, Abrams KR, Jones DR. et al. Methods for meta-analysis in medical research. J. Wiley; 2000
• 35 Sahebkar A. Does PPAR 2 gene Pro12Ala polymorphism affect nonalcoholic fatty liver disease risk? Evidence from a meta-analysis. DNA Cell Biol 2013; 32: 188-198.
• 36 Sahebkar A. Are Curcuminoids Effective C-Reactive Protein-Lowering Agents in Clinical Practice? Evidence from a Meta-Analysis. Phytotherapy Res 2014; 28: 633-642.
• 37 Song F, Altman DG, Glenny A-M. et al. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. Br Med J 2003; 326: 472.
• 38 Bucher HC, Guyatt GH, Griffith LE. et al. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol 1997; 50: 683-691.
• 39 Duval S, Tweedie R. Trim and fill: a simple funnel-plot–based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000; 56: 455-463.
• 40 Chang JW, Yang WS, Min WK. et al. Effects of simvastatin on high-sensitivity C-reactive protein and serum albumin in hemodialysis patients. Am J Kidney Dis 2002; 39: 1213-1217.
• 41 Dangas G, Badimon JJ, Smith DA. et al. Pravastatin therapy in hyperlipidemia: effects on thrombus formation and the systemic hemostatic profile. J Am Coll Cardiol 1999; 33: 1294-1304.
• 42 Eckard AR, Jiang Y, Debanne SM. et al. Effect of 24 weeks of statin therapy on systemic and vascular inflammation in HIV-infected subjects receiving anti-retroviral therapy. J Infect Dis 2014; 209: 1156-1164.
• 43 Kinlay S, Schwartz GG, Olsson AG. et al. Endogenous tissue plasminogen activator and risk of recurrent cardiac events after an acute coronary syndrome in the MIRACL study. Atherosclerosis 2009; 206: 551-555.
• 44 Min L, Shao S, Wu X. et al. Anti-inflammatory and anti-thrombogenic effects of atorvastatin in acute ischemic stroke. Neural Regen Res 2013; 08: 2144.
• 45 Sommeijer DW, MacGillavry MR, Meijers JC. et al. Anti-inflammatory and anticoagulant effects of pravastatin in patients with type 2 diabetes. Diabetes Care 2004; 27: 468-473.
• 46 Undas A, Kaczmarek P, Sladek K. et al. Fibrin clot properties are altered in patients with chronic obstructive pulmonary disease. Thromb Haemost 2009; 102: 1176-1182.
• 47 Van De Ree M, De Maat M, Kluft C. et al. Decrease of hemostatic cardiovascular risk factors by aggressive vs. conventional atorvastatin treatment in patients with Type 2 diabetes mellitus. J Thromb Haemost 2003; 01: 1753-1757.
• 48 Szabo S, Suselbeck T, Borggrefe M. et al. Effect of Atorvastatin on Haemostasis, Fibrinolysis and Inflammation in Normocholesterolaemic Patients with Coronary Artery Disease. Clin Drug Invest 2010; 30: 453-460.
• 49 Bruinstroop E, Van de Ree M, Huisman M. The use of D-dimer in specific clinical conditions: a narrative review. Eur J Intern Med 2009; 20: 441-446.
• 50 Margetic S. Inflammation and hemostasis. Biochemia Medica 2012; 22: 49-62.
• 51 Phipps RP, Blumberg N. Statin islands and PPAR ligands in platelets. Arterioscl Thromb Vasc Biol 2009; 29: 620-621.
• 52 Puccetti L, Sawamura T, Pasqui A. et al. Atorvastatin reduces platelet-oxidized-LDL receptor expression in hypercholesterolaemic patients. Eur J Clin Invest 2005; 35: 47-51.
• 53 Moraes LA, Vaiyapuri S, Sasikumar P. et al. Antithrombotic actions of statins involve PECAM-1 signalling. Blood 2013; 122: 3188-3196.
• 54 Kaneider NC, Egger P, Dunzendorfer S. et al. Reversal of thrombin-induced deactivation of CD39/ATPDase in endothelial cells by HMG-CoA reductase inhibition effects on Rho-GTPase and adenosine nucleotide metabolism. Arterioscl Thromb Vasc Biol 2002; 22: 894-900.
• 55 Antoniades C, Bakogiannis C, Leeson P. et al. Rapid, direct effects of statin treatment on arterial redox state and nitric oxide bioavailability in human atherosclerosis via tetrahydrobiopterin-mediated endothelial nitric oxide synthase coupling. Circulation 2011; 124: 335-345.
• 56 Antoniades C, Bakogiannis C, Tousoulis D. et al. Preoperative atorvastatin treatment in CABG patients rapidly improves vein graft redox state by inhibition of Rac1 and NADPH-oxidase activity. Circulation 2010; 122 (11) (Suppl. 01) S66-S73.
• 57 Obi C, Wysokinski W, Karnicki K. et al. Inhibition of platelet-rich arterial thrombus in vivo acute antithrombotic effect of intravenous HMG-CoA Reductase therapy. Arterioscl Thromb Vasc Biol 2009; 29: 1271-1276.
• 58 Antonopoulos AS, Margaritis M, Lee R. et al. Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials. Curr Pharmaceut Design 2012; 18: 1519.
• 59 Jonsdottir LS, Sigfusson N, Gunason V. et al. Do lipids, blood pressure, diabetes, and smoking confer equal risk of myocardial infarction in women as in men? The Reykjavik Study. Eur J Cardiovasc Risk 2002; 09: 67-76.
• 60 Lowe G, Danesh J, Lewington S. et al. Tissue plasminogen activator antigen and coronary heart disease Prospective study and meta-analysis. Eur Heart J 2004; 25: 252-259.
• 61 Folsom AR, Aleksic N, Park E. et al. Prospective Study of Fibrinolytic Factors and Incident Coronary Heart Disease The Atherosclerosis Risk in Communities (ARIC) Study. Arterioscl Thromb Vasc Biol 2001; 21: 611-617.
• 62 Danesh J, Whincup P, Walker M. et al. Fibrin D-dimer and coronary heart disease prospective study and meta-analysis. Circulation 2001; 103: 2323-2327.
• 63 Bladbjerg E, De Maat M, Christensen K. et al. Genetic influence on thrombotic risk markers in the elderly–a Danish twin study. J Thromb Haemost 2006; 04: 599-607.
• 64 Ariëns RA, de Lange M, Snieder H. et al. Activation markers of coagulation and fibrinolysis in twins: heritability of the prethrombotic state. Lancet 2002; 359: 667-671.
• 65 Smith NL, Huffman JE, Strachan DP. et al. Genetic predictors of fibrin D-dimer levels in healthy adults. Circulation 2011; 123: 1864-1872.
• 66 Rudnicka AR, Rumley A, Lowe GD. et al. Diurnal, seasonal, and blood-processing patterns in levels of circulating fibrinogen, fibrin D-dimer, C-reactive protein, tissue plasminogen activator, and von Willebrand factor in a 45-year-old population. Circulation 2007; 115: 996-1003.
• 67 Tabassum F, Kumari M, Rumley A. et al. Lifecourse social position and D-dimer; findings from the 1958 British birth cohort. PLoS One 2014; 09: e93277.