© Schattauer 2015 Thrombosis and Haemostasis 114.3/2015 1 Association between statin use and plasma D-dimer levels A systematic review and meta-analysis of randomised controlled trials Amirhossein Sahebkar 1,2# ; Corina Serban 3# ; Dimitri P. Mikhailidis 4 ; Anetta Undas 5 ; Gregory Y. H. Lip 6 ; Paul Muntner 7 ; Vera Bittner 8 ; Kausik K. Ray 9 ; Gerald F. Watts 10 ; G. Kees Hovingh 11 ; Jacek Rysz 12 ; John J. P. Kastelein 11 ; Maciej Banach 12 ; Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group 1 Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; 2 Metabolic Research Centre, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia; 3 Department of Functional Sciences, Discipline of Pathophysiology, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania; 4 Department of Clinical Biochemistry, Royal Free Campus, University College London Medical School, University College London (UCL), London, UK; 5 Institute of Cardiology, Jagiellonian University Medical College, and John Paul II Hospital, Krakow, Poland; 6 University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK; 7 Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA; 8 Division of Cardiovascular Disease, Preventive Cardiology Section, University of Alabama at Birmingham, Birmingham, Alabama, USA; 9 Cardiovascular Sciences Research Centre, St George’s University of London, London, UK; 10 Lipid Disorders Clinic, Cardiovascular Medicine, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia; 11 Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands; 12 Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, Poland 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 lev- els 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, Sco- pus 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 esti- mated 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 de- crease 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. Keywords D-dimer, statin, coagulation, fibrinolysis Correspondence to: Prof. Maciej Banach, MD, PhD, FNLA, FAHA, FESC; FASA Department of Hypertension, WAM University Hospital in Lodz Medical University of Lodz Zeromskiego 113; 90–549 Lodz, Poland Tel.: +48 42 639 37 71, Fax: +48 42 639 37 71 E-mail: maciejbanach@aol.co.uk Received: November 15, 2014 Accepted after major revision: March 29, 2015 Epub ahead of print: ■■■ ((not until forms received)) http://dx.doi.org/10.1160/TH14-11-0937 Thromb Haemost 2015; 114: ■■■ # Drs Sahebkar and Serban contributed equally to this meta-analysis. Note: The review process for this paper was fully handled by Christian Weber, Editor in Chief. Blood Coagulation, Fibrinolysis and Cellular Haemostasis Introduction In clinical practice, D-dimers (cross-linked fibrin degradation products) are “the gold standard” that represent activation of both coagulation and fibrinolysis (1). In 1993, for the first time, Fowkes et al. evaluated the value of D-dimer as an independent predictor of arterial thrombotic events (2). After six years, Smith et al. con- firmed these results from the extended follow-up for the same in- dividuals (3). Today, plasma levels of D-dimer are mainly used to rule out the diagnosis of venous thrombembolism (VTE) (4). Fur- thermore, it was speculated that a high fibrin turnover may repre- sent not just a prothrombotic state, but also accelerated athero- sclerosis, since coagulation and atherosclerosis may be interrelated processes (5, 6). Available experimental and clinical studies have observed an association between circulating D-dimers and coron- ary heart disease (CHD) (7), atrial fibrillation (8), disseminated intravascular coagulation (DIC) (9), syncope (10), pulmonary em- bolism (11), cognitive decline (12, 13), migraine (14), pancreatic