Association between statin use and plasma D-dimer levels

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Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Association between statin use and plasma D-dimer levels A systematic review and meta-analysis of randomised controlled trials Amirhossein Sahebkar1,2#; Corina Serban3#; Dimitri P. Mikhailidis4; Anetta Undas5; Gregory Y. H. Lip6; Paul Muntner7; Vera Bittner8; Kausik K. Ray9; Gerald F. Watts10; G. Kees Hovingh11; Jacek Rysz12; John J. P. Kastelein11; Maciej Banach12; Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group 1Biotechnology

Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; 2Metabolic Research Centre, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia; 3Department of Functional Sciences, Discipline of Pathophysiology, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania; 4Department of Clinical Biochemistry, Royal Free Campus, University College London Medical School, University College London (UCL), London, UK; 5Institute of Cardiology, Jagiellonian University Medical College, and John Paul II Hospital, Krakow, Poland; 6University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK; 7Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA; 8Division of Cardiovascular Disease, Preventive Cardiology Section, University of Alabama at Birmingham, Birmingham, Alabama, USA; 9Cardiovascular Sciences Research Centre, St George’s University of London, London, UK; 10Lipid Disorders Clinic, Cardiovascular Medicine, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia; 11Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands; 12Department 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 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 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: [email protected]

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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.

Keywords D-dimer, statin, coagulation, fibrinolysis 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.

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. confirmed these results from the extended follow-up for the same individuals (3). Today, plasma levels of D-dimer are mainly used to © Schattauer 2015

rule out the diagnosis of venous thrombembolism (VTE) (4). Furthermore, it was speculated that a high fibrin turnover may represent not just a prothrombotic state, but also accelerated atherosclerosis, since coagulation and atherosclerosis may be interrelated processes (5, 6). Available experimental and clinical studies have observed an association between circulating D-dimers and coronary heart disease (CHD) (7), atrial fibrillation (8), disseminated intravascular coagulation (DIC) (9), syncope (10), pulmonary embolism (11), cognitive decline (12, 13), migraine (14), pancreatic Thrombosis and Haemostasis 114.3/2015

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Sahebkar, Serban et al. Statin use and plasma D-dimer levels

cancer (15), lung cancer (16, 17), colorectal cancer (18) and breast cancer (19, 20) although in some cases the clinical relevance is unclear. Statins are extensively utilised for the treatment of cardiovascular disease (CVD) (21). Statins possess pleiotropic effects beyond inhibition of cholesterol synthesis, such as anti-inflammatory, antithrombotic, atheroma stabilising and endothelium protecting attributes, which could lead to definite clinical benefits (22, 23). Recent experimental and clinical studies have shown that statins decrease thrombosis through inhibition of the expression of protein tissue factor, reduction of platelet activation, increase of the activity of the protein C anticoagulant pathway, inhibition of prenylation of RhoA and various effects on intracellular signalling molecules like nuclear factor (NF)-κB and Krüppel-like factor 2 (KLF2) (24–27). Statin therapy may cause a considerable downregulation of the coagulation cascade at several levels as a consequence of reduced expression of tissue factor that results in diminished production of thrombin (25). Statin therapy also seems to decrease tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) (25, 28, 29), but the impact of statin therapy on plasma D-dimer levels is still unclear. Therefore, we systematically reviewed all published trials on the impact of statin therapy on plasma D-dimer levels.

Methods Data sources This study was designed in conformity with the guidelines of the 2009 Preferred Reporting Items for Systematic Reviews and MetaAnalysis (PRISMA) statement (30). Our search included SCOPUS (http://www.scopus.com), Medline (http://www.ncbi.nlm.nih.gov/ pubmed), Web of Science (http://apps.webofknowledge.com), and Cochrane Library (www.thecochranelibrary.com/) databases and was limited to randomised controlled trials (RCTs) carried out from January 1, 1970 to September 25, 2014, investigating the effect of statins on plasma D-dimers levels. The databases were searched using the following search terms in titles and abstracts (also in combination with MESH terms): (rosuvastatin OR pravastatin OR fluvastatin OR simvastatin OR atorvastatin OR pitavastatin OR lovastatin OR cerivastatin OR “statin therapy” OR statins) AND (D-dimer OR “D dimer” OR Ddimer). The wild-card term ‘‘*’’ was used to increase the sensitivity of the search strategy. No language restriction was used in the literature search. The search was limited to studies in humans. Two reviewers (CS and AS) evaluated each article separately. Disagreements were resolved by agreement and discussion with a third party (MB).

Study selection Original studies were included if they met the following inclusion criteria: i) a randomised controlled trial in either parallel or crossover design, ii) investigating the impact of statin therapy on plasma/serum levels of D-dimer, iii) treatment duration of ≥ 2 weeks, and, iv) presentation of sufficient information on D-dimer conThrombosis and Haemostasis 114.3/2015

centrations at baseline and at the end of study in both the statin and control groups or providing the net changes in each group. Exclusion criteria: the studies were excluded if: i) they were non-clinical studies, ii) they were uncontrolled trials, iii) there was a lack of sufficient information on baseline or follow-up D-dimer levels, iv) we were unable to obtain adequate details of study methodology or results from the article or the investigators, or v) the study was an ongoing trial.

Data extraction Eligible studies were reviewed and the following data were abstracted: i) first author’s name; ii) year of publication; iii) study location; iv) number of participants in the statin and control groups; v) age, gender and body mass index (BMI) of study participants; vi) baseline levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, high-sensitivity C-reactive protein (hsCRP) and glucose; vii) systolic and diastolic blood pressure, and, viii) data regarding baseline and follow-up concentrations of D-dimer. Plasma D-dimer levels were collated in µg/ml. If D-dimer levels were collated in nmol/l they were converted to µg/ml by dividing by 5.476. Quantitative D-dimer assay result might be also reported as fibrinogen-equivalent units (FEUs), which are easily convertible to D-dimer unit (D-DU = µg/ml), since the mass of one unit of FEU equals approximately half of one D-DU: 1 FEU = 2 X D-DU.

Quality assessment The quality of included studies was assessed using the Jadad scale. This scale encompasses randomisation (0–2 points), blinding (0–2 points), and dropouts and withdrawals (0–1 point). The overall score of a study according to this scale ranges between 0–5, with higher scores indicative of a better quality (31). Studies with Jadad scores of ≤ 2 and ≥ 3 were considered as low- and high-quality, respectively (32).

Quantitative data synthesis The meta-analysis was conducted using Comprehensive MetaAnalysis (CMA) V2 software (Biostat, NJ) (33). Standard deviations (SDs) of the mean difference were calculated using the following formula: SD = square root [(SDpre-treatment)2 + (SDpost-treat2 ment) – (2R × SDpre-treatment × SDpost-treatment)], assuming a correlation coefficient (R) = 0.5. In case of reporting SEM, SD was estimated using the following formula: SD = SEM × square root (n), where n is the number of subjects. Net changes in measurements (change scores) were calculated for parallel and cross-over trials, as follows: (measure at end of follow-up in the treatment group – measure at baseline in the treatment group) – (measure at end of follow-up in the control group – measure at baseline in the control group). A random-effects model (using DerSimonian-Laird method) and the generic inverse variance method were used to compensate for the heterogeneity of studies in terms of statin type, statin dose, study design, treatment duration, and the characteristics of popu© Schattauer 2015


lations being studied (34). Effect sizes were expressed as standardised mean difference (SMD) using Cohen’s d as the summary statistic, and 95 % confidence interval (CI). Post-hoc subgroup analyses were carried out to explore the impact of duration (< 12 weeks vs ≥ 12 weeks) of statin therapy and type (lipophilic vs hydrophilic) of statin therapy on plasma D-dimer concentrations. In order to evaluate the influence of each study on the overall effect size, sensitivity analysis was conducted using the one-study remove (leave-one-out) approach (35, 36). In the absence of trials making head-to-head comparison of hydrophilic vs lipophilic statins, the effect of these two types of statins on plasma D-dimer levels were compared using adjusted indirect comparison according to the method proposed by Song et al. (37) and Bucher et al. (38). In this method, treatment effects estimated for each type of statins in the random-effects model could be compared indirectly through common controls.

Meta-regression Random-effects meta-regression was performed using unrestricted maximum likelihood method to evaluate the association between calculated SMD in plasma D-dimer concentrations with dose and duration of statin therapy, as well as baseline D-dimer levels and changes in plasma LDL-C and non-HDL-C concentrations.

Publication bias Potential publication bias was explored using visual inspection of Begg’s funnel plot asymmetry, and Begg’s rank correlation and Egger’s weighted regression tests. Duval & Tweedie “trim and fill” and “fail-safe N” methods were used to adjust the analysis for the effects of publication bias (39).

Results Search results and trial flow The preliminary screening for probable importance omitted the articles in whose titles and/or abstracts were clearly irrelevant. After assessment, nine RCTs achieved the inclusion criteria and were included in the final meta-analysis (40–48). In total, 1,165 participants were randomised; 636 were allocated to statin treatment and 529 were controls. A summary of the study selection process is shown in ▶ Figure 1. Demographic and baseline biochemical variables of the included studies are shown in ▶ Table 1.

Quantitative data synthesis Meta-analysis of data from nine RCTs (comprising 10 treatment arms) showed a significant effect of statin therapy in reducing plasma D-dimer levels (SMD: –0.988 µg/ml, 95 % CI: -1.590-

Figure 1: Flow chart of the number of studies identified and included into the meta-analysis.

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Thrombosis and Haemostasis 114.3/2015

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Sahebkar, Serban et al. Statin use and plasma D-dimer levels Table 1: Demographic characteristics of the included studies.

Jadad score Year Location Design Duration of trial Inclusion criteria Statin regimen

Chang et al. (40)

Dangas et al. (41)

Eckard et al. (42)

Kinlay et al. (43)

3 2002 Korea Randomised open-label parallel-group trial 8 weeks Patients on haemodialysis Simvastatin (20 mg/day) 31

3 1999 USA Randomised double-blind placebocontrolled parallel-group trial 24 weeks Patients with untreated LDL-C > 145 mg/dl Pravastatin (20–40 mg/day) 26

3 2014 USA Randomised double-blind placebo-controlled parallel-group trial 24 weeks HIV-infected subjects on antiretroviral therapy Rosuvastatin (10 mg/day) 72

3 2009 USA Randomised double-blind placebo-controlled parallel-group trial 16 weeks Patients with acute coronary syndrome Atorvastatin (80 mg/day) 197

Participants

Statin

Age (years)

Control 31 Statin 63 ± 11

36 64.7 ± 2.2*

75 45.6 (41.1, 51.4)**

198 NS

Male (%)

Control 60 ± 12 Statin 25.8

59.6 ± 1.9* 35

46.9 (39.2, 53.6)** 81

NS NS

Smoking (%)

Statin Statin

32.3 NS

17 54

76 60

NS

Diabetes (%)

Control NS Statin 48.4

56 19

72 NS

NS NS

Hypertension (%)

Control 45.2 Statin 58.1

17 35

NS 27.8

NS NS

BMI (kg/m2)

Control 64.5 Statin 23.2 ± 2.6

47 NS

25.0 26.6 (23.4, 30.0)**

NS NS

Control 21.8 ± 2.6 Statin 232 ± 25

NS 277.0 ± 7.6*

27.2 (23.5, 30.5)** NS

NS NS

Control 223 ± 20 Statin 162 ± 29

265.5 ± 4.3* 192.8 ± 7.0*

NS 96 (76, 107)**

NS NS


185.1 ± 4.0* 54.2 ± 3.4*

97 (77, 121)** 47 (38, 58)**

NS NS


51.1 ± 2.3* NS

46 (37, 57)** 105 (77, 184)**

NS NS

Control 172 ± 97 Statin -0.06 ± 0.87

NS +0.05 ± 0.30

121 (87, 184)** +0.07 ± 13.13

NS +10.8 ± 39.7

Control -0.03 ± 0.99

+0.03 ± 0.13

+0.22 ± 13.73

NS

Total cholesterol (mg/ dl)

LDL-C (mg/dl)

HDL-C (mg/dl)

Triglycerides (mg/dl)

D-dimer changes (µg/ml)

Values are expressed as mean ± SD. *Values are expressed as mean ± SE **Values are expressed as median (interquartile sity lipoprotein cholesterol; BMI: body mass index; #the value was provided for the total population.


+24.4 ± 38.85 range). aLow-dose

(10 mg/day) atorvastatin group; bHigh

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Min et al. (44)

Sommeijer et al. (45)

Undas et al. (46)

Van de Ree et al. (47)

Walter et al. (48)

3 2013 China Randomised double-blind placebo-controlled parallel-group trial 4 weeks Patients with acute ischaemic stroke Atorvastatin (20 mg/day) 43

3 2004 The Netherlands Randomised open-label cross-over trial 8 weeks Patients with Type 2 Diabetes

3 2003 The Netherlands Randomised double-blind placebo-controlled parallel-group trial 4 weeks Patients with Type 2 Diabetes

Pravastatin (40 mg/day) 50×

3 2009 Poland Randomised open-label parallel-group trial 12 weeks Patients with chronic obstructive pulmonary disease Simvastatin (40 mg/day) 28

3 2010 Germany Randomised double-blind parallel-group trial 8 weeks Normocholesterolaemic patients with coronary artery disease Atorvastatin (30 mg/day) 54

46 67.7 ± 6.9

50y 59 (54–64)**

28 66.1 ± 11.4

65.0 ± 7.7 58.1

50

63.8 ± 8.4 91.1

58.7 NS

24

36.4

NS 19

100

16

20 56

42

50

56 NS

28.9 (26.8–33.1)**

25.2 ± 4.5

NS 231.7±38.6

6.3 (5.7–6.9)**

219.7 ± 53.7

235.5±38.6 139.0±34.7

4.0 (3.6–4.6)**

216.6 ± 40.9 134.0 ±38.2 137.5 ± 30.9

139.0±30.9 42.5± 11.6

1.2 (1.0–1.5)**

55.2 ±12.0 51.0 ± 11.6

42.5 ± 7.7 159.3 ± 61.9

Atorvastatin (10 or 80 mg/day) 69a 66b 61 59.7 ± 7.6 a 60.3 ± 7.8 b 58.6 ± 7.5 62 a 55 b 48

54 60.6 ± 10.4 62.4 ± 9.0 64.8 72.2

NS a NS b NS 100 a 100 b 100 46 a 61 b 53 29.9 ± 3.8 a 30.5 ± 4.4 b 32.2 ± 6.1 227.8 ± 34.7 a 235.5 ± 34.7 b 231.7 ± 30.9

34

142.9 ± 34.7 a 146.7 ± 34.7 b 146.7 ± 30.9

121 ± 22

40.5 ± 10.0 a 40.2 ± 9.3 b 40.5 ± 8.1

47 ± 18

221.2 ± 79.6 a 247.8 ± 97.3 b 230.1 ± 79.6

NS

39 24 20 78 83 NS NS 194 ± 40 195 ± 47

124 ± 25

43 ± 12

150.4 (123.9–247.8)

96.5 ± 93.8

159.3 ± 53.1 -0.4 ± 0.1

+0.27 ± 0.04

150.4 ± 85.0 -0.67 ± 0.47

-0.01 ± 0.01

+0.47 ± 0.17

+0.3 ± 0.1

+0.26 ± 0.03

-0.04 ± 0.59

+0.002 ± 0.01

+0.45 ± 0.18

NS

h-dose (80 mg/day) atorvastatin group; x = statin group; y= control group. BMI: body mass index; NA: not available; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-den-

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Figure 2: Forest plot detailing weighted mean difference and 95 % confidence intervals for the impact of statin therapy on plasma D-dimer concentrations. Meta-analysis was performed using a random-effect model with inverse variance weighting.

Figure 3: Leave-one-out sensitivity analysis of the impact of statin therapy on plasma D-dimer concentrations.

–0.385, p = 0.001) (▶ Figure 2). This effect size was robust in sensitivity analysis and omission of no single study significantly changed the overall estimated effect size (▶ Figure 3). In order to further explore the presence of any heterobaric effect, a separate analysis was performed excluding two studies, which reported the highest magnitude of reduction in plasma D-dimer levels {Min, Thrombosis and Haemostasis 114.3/2015

2013 #364}(44, 46). The pooled estimate was still significant after removing the above-mentioned studies from the meta-analysis (SMD: –0.39 µg/ml, 95 %CI: –0.76– –0.01, p=0.042). In the subgroup analysis, the effect of statins on plasma D-dimer was significant in the subsets of studies with treatment durations ≥ 12 weeks (SMD: –0.761 µg/ml, 95 %CI: –1.163- –0.360, p< 0.001) (41–43, © Schattauer 2015


Figure 4: Forest plot detailing weighted mean difference and 95 % confidence intervals for the impact of statin therapy on plasma D-dimer concentrations in trials with treatment durations of < 12 weeks (above) and > 12 weeks (below). Meta-analysis was performed using a randomeffects model with inverse variance weighting.

46), and marginally significant in the subset of studies with treatment duration < 12 weeks (SMD: -1.554 µg/ml, 95 %CI: -3.339–0.232, p=0.088) (40, 44, 45, 47, 48) (▶ Figure 4).

Adjusted indirect meta-analysis In order to compare the effects of hydrophilic vs lipophilic statins on plasma levels of D-dimer, a subgroup analysis was first conducted to estimate the effect size. In the subgroup analysis, lipophilic (comprising five treatment arms with atorvastatin and two arms with simvastatin) (SMD: –1.364 µg/ml, 95 %CI: -2.202© Schattauer 2015

–0.526, p=0.001) but not hydrophilic (comprising two treatment arms with pravastatin and rosuvastatin) (SMD: –0.237 µg/ml, 95 %CI: -1.140–0.665, p=0.606) statins had a significant effect in lowering plasma D-dimer levels (▶ Figure 5). Superior effect of lipophilic vs hydrophilic statins was also confirmed in the adjusted indirect comparison, where the effect size was estimated to be 1.127 µg/ml, 95 %CI: 0.578–1.676 µg/ml, delta Z = 4.03, p< 0.05 (total studies), and 1.817 µg/ml, 95 %CI: 1.340–2.290; delta Z = 7.51, p< 0.001 (total studies excluding those with haemodialysis [40] and HIV patients [42]). Thrombosis and Haemostasis 114.3/2015

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Figure 5: Forest plot detailing weighted mean difference and 95 % confidence intervals for the impact of statin therapy on plasma D-dimer concentrations in trials hydrophilic (above) and hydrophobic (below) statins. Meta-analysis was performed using a random-effects model with inverse variance weighting.

Meta-regression Meta-regression analysis was conducted to assess the association between changes in plasma D-dimer concentrations with dose and duration of statin therapy as well as baseline D-dimer levels and changes in LDL-C levels as potential moderator variables. The impact of statins on plasma concentrations of D-dimer levels was found to be independent of administered dose (slope: 0.015; 95 %CI: -0.033–0.064; p=0.530), duration of supplementation (slope: 0.055; 95 %CI: –0.069–0.180; p=0.385), baseline D-dimer concentrations (slope: 0.080; 95 % CI: –1.095–1.256; p=0.893), Thrombosis and Haemostasis 114.3/2015

changes in plasma LDL-C levels (slope: 0.061; 95 %CI: –0.038–0.160; p=0.225) and changes in plasma non-HDL-C levels (slope: 0.029; 95 %CI: –0.039–0.097; p=0.404) (▶ Figure 6). These associations remained non-significant after elimination of studies with haemodialysis (40) and HIV patients (42) as potential sources of heterogeneity.

Publication bias The funnel plot of the study precision (inverse standard error) by effect size (SMD) was asymmetric and suggested potential publi© Schattauer 2015


Figure 6: Meta-regression plots of the association between mean changes in plasma D-dimer concentrations and dose of statin therapy, duration of statin therapy, baseline D-dimer levels, and corresponding changes in plasma LDL-C and non-HDL-C concentrations. The size of each circle is inversely proportional to the variance of change.

cation bias. However, this observation was not supported by the results of Begg’s rank correlation (Kendall’s Tau with continuity correction = –0.267, Z = 1.073, two-tailed p = 0.283) and Egger’s linear regression (intercept = -5.98, standard error = 3.42; 95 %CI: -13.87–1.91, t = 1.75, df = 8.00, two-tailed p = 0.119) tests. The observed asymmetry in the funnel plot was imputed using trim-andfill correction. Four potentially missing studies were imputed leading to a corrected effect size that was greater than the initial estimate (-1.83; 95 %CI: -2.70- -0.95). The “fail safe N” method indicated that 272 theoretically missing studies would be required to make the overall estimated effect size non-significant. Funnel plot of the impact of statin therapy on plasma D-dimer levels is illustrated in ▶ Figure 7. © Schattauer 2015

Discussion The results of this meta-analysis of available RCTs indicate for the first time a decrease in plasma D-dimer levels associated with statin therapy. This effect was independent of administered dose, duration of administration, baseline D-dimer concentrations and changes in plasma LDL-C levels. In the subgroup analysis, lipophilic, but not hydrophilic statins, were associated with decreased plasma D-dimer levels. The superior effect of lipophilic compared with hydrophilic statins was also confirmed by adjusted indirect meta-analysis. It is also already known that D-dimer levels might be falsely increased in various conditions (atrial fibrillation, coronary artery disease, syncope, pulmonary embolism, cognitive disThrombosis and Haemostasis 114.3/2015

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Figure 7: Funnel plot detailing publication bias in the studies reporting the impact of statin therapy on plasma D-dimer concentrations. Open circles represent observed published studies; closed circles represent imputed unpublished studies.

orders, migraine, and cancer) and processes (inflammation, infection, pregnancy) (49). Some of these conditions (haemodialysis and HIV patients) were eliminated in the meta-regression analysis, without influence on the final results. However, still many confounding factors may account for these results, therefore, they

What is known about this topic?

• • •

Statins possess pleiotropic effects beyond inhibition of cholesterol synthesis, such as antithrombotic ones. Statins decrease thrombosis through, among others, inhibition of the expression of protein tissue factor, reduction of platelet activation and increase of the activity of the protein C anticoagulant pathway. Statin therapy seems to also decrease tPA and PAI-1, but the impact on plasma D-dimer levels is still unclear.

What does this paper add?

• • •

The meta-analysis showed a significant effect of statin therapy in reducing plasma D-dimer levels. The effect of statins on plasma D-dimer levels was significant only in the subsets of studies with treatment duration ≥12 weeks and for lipophilic statins. The observed effect was not associated with the administered dose, duration of administration, baseline D-dimer concentrations, and changes in plasma LDL-C and non-HDL-C levels.


should be used as a hypothesis generating, and by no mean suggest a direct effect or causal relationship between statin therapy and D-dimer levels. The observation on D-dimer reduction with statin therapy had affirmative effect regarding possible pleiotropic effects of statins without any meaningful or clinical significance. The reason why statins are associated with a reduction of D-dimers levels seems to relate to the substantial interplay between haemostatic and immune system, involving platelets, endothelial cells, coagulation cascade, fibrinolytic activity and anticoagulation pathways (50). The mechanisms by which statins reduce platelets activation are stimulation of PPAR-α and PPAR-γ (51), reduction of CD36 and lectin-like oxidised-LDL receptor-1 on platelet surface (52) and action on platelet endothelial cell adhesion molecule-1 (PECAM-1) (53). Furthermore, statins decrease platelets-endothelium interactions through the maintenance of adenine nucleotide metabolism by alteration of CD39/ATPase expression of endothelial cells via a pathway dependent of Rho-GTPase (54). Statins are capable of changing the intracellular redox state of the endothelial cells through reduction of redox-sensitive transcriptional pathways such as activator protein 1 (AP-1) and nuclear factor kappa B (NF-κB), that control the expression of various proinflammatory genes (55, 56). An experimental study in a porcine model showed that intravenous lovastatin decreases the dimensions of platelet-rich thrombus in the damaged carotid artery by > 50 % (57). However, it has been shown that discontinuation of statins quickly generates a phenomenon of rebound inflammation and introduces a short-term CVD risk, even in the lack of modification of lipid values (58). © Schattauer 2015


In the Reykjavik Study, the authors observed weak associations of tPA antigen, D-dimer and von Willebrand factor (VWF) with the risk of CHD, after adjustment for typical CVD risk factors (59). tPA antigen has been correlated with male sex, blood pressure, BMI, triglycerides, rheological and inflammatory markers (60, 61). In contrast, D-dimer levels were inversely associated with tPA antigen levels and all risk factors (62). This association may be explained by the fact that tPA antigen levels typically indicate tPA/ PAI-1 complexes and increased PAI-1 values decrease endogenous fibrinolysis and consequently D-dimer levels (7). However, it has been recently shown that the heritability of D-dimer values vary from 23 to 65 % in Northern Europeans (63, 64). A meta-analysis that involved > 20,000 healthy European individuals and 2.5 million markers through the genome, identified F3, F5, and FGA genes to be associated with plasma D-dimer levels (65). Therefore, since the within-person variability of D-dimers is higher than expected, it is necessary to assess the role of pharmacogenomics in the changes in plasma D-dimer levels in response to statin therapy (66). A recent study reported that the patients from more disadvantaged social classes had elevated levels of D-dimer compared to patients from less disadvantaged social class (67). The present meta-analysis has various limitations. Most notably, D-dimer levels are associated in the thrombosis/fibrinolysis cascade; however, their use in clinical practice is limited to the deep-vein thrombosis (DVT) and pulmonary embolism (PE) diagnosis (out-of hospital only), and again in a negative manner (only low levels are used to rule out DVT/PE). There were only few eligible RCTs, and most of them had a modest numbers of participants (from 26 to 197 in the statin group). Furthermore, the included studies were heterogeneous concerning the characteristics of patients and study design. Nevertheless, our meta-analysis employed a conservative random-effects model and was robust in the sensitivity analysis, even after excluding the studies with the greatest effect size from the analysis. These results suggest that the observed significant effect of statin therapy in reducing plasma D-dimer levels is actually the combined effect of all included studies. The meta-analysis was also limitted due to the fact that the social classes of participants, an important determinant of D-dimer levels, were not included in this meta-analysis. Some studies included in this meta-analysis were also performed in acute phase of stroke or acute coronary syndromes, and in hypercoagulable states the levels of D-dimers are usually increased. However, as it has been already mentioned, these results should be treated as hypothesis generating, and next well-design studies are necessary to validate these data and establish their clinical relevance. In conclusion, this meta-analysis of available randomized controlled trials suggests an association between the reduction of plasma D-dimer levels and lipophilic statin therapy, independent of administered dose, duration of administration, baseline D-dimer concentrations and changes in plasma LDL-C levels. This effect of statins supports the need for future prospective studies, which should have clinical primary endpoints and, in parallel, D-dimer levels and other markers of thrombosis as secondary endpoints. This may also help to explain the established cardioprotective ef© Schattauer 2015

Abbreviations BMI = body mass index; CAD = coronary artery disease; CI = confidence interval; CV = cardiovascular; CMA = Comprehensive MetaAnalysis; DIC = disseminated intravascular coagulation; HDL-C = high-density lipoprotein cholesterol; hsCRP = high-sensitivity Creactive protein; LDL-C = low-density lipoprotein cholesterol; NA = not available; Non-HDL-C= non-high-density lipoprotein cholesterol; PAI-1 = plasminogen activator inhibitor-1; SD = standard deviation; SMD = standardised mean difference; tPA= tissue plasminogen activator; TNF-α = tumour necrosis factor-alpha; VTE = venous thromboembolism; VWF = von Willebrand factor; WMD = weighed mean difference.

fects of statins and further highlights the importance of statins in reducing atherothrombotic events. Conflicts of interest

None declared.

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