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Differential effect of statin use on coagulation markers: an active comparative analysis in the NEO study

Thrombosis Journal volume 19, Article number: 45 (2021) Cite this article

Abstract

Background

Statins are a potential treatment for venous thromboembolism (VTE) prophylaxis complementary to conventional anticoagulants without associated bleeding complications. This study aimed to compare pro-thrombotic activities of different classes of lipid-lowering drugs in an active comparator design and determine whether there is a relation between statin versus fibrate/niacin use and pro-coagulant factor outcomes.

Methods

This is a cross-sectional analysis of participants from the Netherlands Epidemiology of Obesity study using any class of lipid-lowering drugs, including any types of statins, niacin, and fibrates. We performed linear regression analyses to determine fibrinogen, factor (F) VIII, FIX, and FXI activity in statins versus fibrate/niacin users and adjusted for age, sex, tobacco smoking, body mass index (BMI), hypertension, diabetes, and prevalent cardiovascular disease.

Results

Among 1043 participants, the mean age was 58.4 ± 5.2 years, 61% were men, and the mean BMI was 31.3 ± 4.5 kg/m2. Clinical characteristics were balanced between statin and fibrate/niacin users. Statin users had lower mean FXI (18.3 IU/dL, 95% confidence interval (CI) 9.4 to 27.3) levels compared to fibrate/niacin users. The level of FVIII (15.8 IU/dL, 95% CI − 0.003 to 31.6), and FIX (11.3 IU/dL, 95% CI − 0.4 to 23.2) were lower in statin users than fibrate/niacin users with marginal statistical significance.

Conclusion

Current statin use was associated with lower plasma levels of FXI than fibrate/niacin use. The effects on coagulation factors may, in part, explain the benefit of statin therapy rendered in primary and secondary prevention of VTE.

Introduction

Venous thromboembolism (VTE) has an estimated annual incidence rate of 1–2 per 1000 person-years among people of European ancestry [1]. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, the so-called statins, are a class of lipid-lowering drugs widely used to prevent arterial atherosclerotic disease [2].

A growing body of evidence indicates that statins are a promising treatment for VTE prophylaxis complementary to anticoagulants without associated bleeding complications [3,4,5,6,7,8,9].

Statins have anti-inflammatory and anti-oxidant properties besides their lipid-lowering effects [10, 11]. Moreover, it has been postulated by mainly in-vitro studies and observational studies that they may have beneficial effects on the vessel wall and anti-thrombotic properties [12, 13]. These include decreased tissue factor expression and thrombin generation, impairment of pro-coagulant reactions catalyzed by thrombin including fibrinogen cleavage and factor (F) V and FXIII activation, reduction of FVII and FVIII activity, enhanced endothelial thrombomodulin expression, and upregulation of fibrinolytic activity manifested by decreased plasminogen activator inhibitor (PAI)-1 and increased tissue plasminogen activator (tPA) expression [14, 15]. In addition, it has also been postulated to have antiplatelet effects by immediate and delayed inhibition of platelet activation, adhesion, and aggregation, although a previous trial could not confirm these findings in vitro [15, 16].

A randomized trial recently showed that 1 month of treatment with rosuvastatin 20 mg/day leads to an improved coagulation profile, most notably decreased FVIII, in patients with prior VTE compared to non-statin users [17]. Given that the effects of drugs are not necessarily class effects, the reduction of pro-coagulant factors by rosuvastatin may not be generalized to other statins currently on the market. It is known that different types of statins show different reducing effects on low-density lipoprotein, atherosclerosis, and inflammation. This reduction is the least strong in pravastatin users, followed by simvastatin and atorvastatin users, and is strongest in rosuvastatin users [16, 18, 19]. A meta-analysis of randomized clinical trials suggested a dose-response relation where rosuvastatin, which is most related to halting or regression of atherosclerosis, dyslipidemia, and inflammation, also provided the most substantial risk reduction in the occurrence of venous thrombosis [20].

We aimed to examine whether there is a relation between statin use and pro-coagulant factor outcomes in individuals participating in the Netherlands Epidemiology of Obesity (NEO) study [21].

Materials and methods

We performed a cross-sectional analysis of baseline measurements of participants from the NEO study who used a class-specific lipid-lowering drug (statin or fibrate/niacin) and compared their pro-thrombotic activities in an active comparator design.

The NEO study is a cohort study in 6671 individuals aged 45–65 years living in the Leiden area (West of the Netherlands). The majority of the participants have a self-reported body mass index (BMI) of 27 kg/m2 or higher. At the baseline visit, blood samples were drawn into tubes containing 0.106 M trisodium citrate (Sarstedt, Numbrecht, Germany) after an overnight fast. Plasma was obtained by centrifugation at 2500×g for 10 min at room temperature and stored in aliquots at − 80° C until testing. Fibrinogen activity was measured according to the method of Clauss. In addition, the activity of FVIII:C, FIX:C, FXI:C, was measured with a mechanical clot detection method on an ACL TOP 700 analyzer (Werfen, Barcelona, Spain). All assays were performed by laboratory technicians who were unaware of the status of the samples.

Since comparisons between statin-users and non-statin users are likely to be confounded, we selected participants who were using any class of lipid-lowering drugs (self-reported), including statins, niacin, and fibrates. The European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) guidelines for the management of dyslipidemias recommend that statins are always tried first, and niacin/fibrates are prescribed when statins are not tolerated [22], making niacin/fibrates a better comparator since side effects from statins are expected to be random. In total, 1043 cases were included in the active comparator analysis.

Statistical analysis

The participants’ general characteristics were reported as means (± standard deviation) or numbers (with percentages). As niacin/fibrates are not associated with anti-thrombotic properties [23], participants who used this class of drugs were regarded as the reference group. The mean of coagulation factors in participants using any statins were compared with the reference group using linear regression and reported as mean difference. The effect size was shown with 95% confidence intervals (CI).

One assumption is that there is no preference in prescribing a lipid-lowering drug to a specific patient and that the clinical characteristics should be distributed evenly over the participants. Given that this assumption might be too strong, we included age, sex, tobacco smoking, BMI, hypertension, diabetes, and prevalent cardiovascular disease (myocardial infarction, angina pectoris, congestive heart failure) as potential confounding factors to the regression analyses. All statistical analyses were computed in SPSS version 22.0.

Results

The general characteristics of participants (n = 1043) who used lipid-lowering medication at baseline are shown in Table 1. The majority of them used five different classes of statins. A small subgroup (n = 22) used niacin/fibrates as the lipid-lowering drug. More than two-thirds of the participants reported to smoke (past or current), and nearly half of them were hypertensive (systolic blood pressure (BP) ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg). About one-third of the patients were diabetic (self-reported diabetes mellitus on medication or fasting plasma glucose > 7 mmol/L) or had impaired fasting glucose (6.1–7 mmol/L).

Table 1 General characteristics of the study population
Full size table

The crude analysis revealed that all coagulation factors were lower in statin users than in fibrate/niacin users except fibrinogen, which was higher in the statin groups (Table 2). The difference was most notable in FXI:C, which showed almost 17 IU/dL lower levels in statin users than fibrate/niacin users (mean difference − 17.1 IU/dL, 95% CI) -30.0 to − 4.3). Adjustment for potential confounding factors did not change the results (mean difference − 18.3 IU/dL, 95% CI − 27.3 to − 9.4). Additionally, current statin users had lower FIX and FVIII (adjusted mean difference − 11.3 IU/dL, 95% CI − 23.2 to 0.4), and − 15.8 IU/dL, 95% CI − 31.6 to 0.003, respectively) with borderline statistical significance. Rosuvastatin users appeared to have lower levels of FVIII and FIX, than users of other types of statins, though these analyses were hampered by small numbers (Table 3).

Table 2 Mean difference of coagulation factors among different lipid-lowering drugs users
Full size table
Table 3 Comparative results of mean difference in coagulation profile among individuals using different lipid-lowering drugs
Full size table

Discussion

We found that current users of statins had lower plasma levels of FXI:C than fibrate/niacin users. The results of our study confirm findings of the STAtins Reduce Thrombophilia (START) trial, which concluded that one-month treatment with rosuvastatin 20 mg daily in patients with prior VTE reduced the plasma levels of coagulation factors VII:C, FVIII:C, FXI:C and von Willebrand factor (vWF):Ag in comparison with non-statin users [17]. We also showed that current statin users had 18.3 IU/dL (9.4 to 27.3) lower FXI:C and 15.8 IU/dL (− 0.003 to 31.6) lower FVIII:C than individuals who used fibrates/niacin as their lipid-lowering drugs. The observed difference seems to be mostly related to rosuvastatin use than other types of statins as they consistently showed almost 18 IU/dL lower levels of FVIII:C and FXI:C and about 15 IU/dL less FIX:C compared to non-statin users (Table 3).

The effects of statins on coagulation factor levels were previously noted in different studies. In the Multi-Ethnic Study of Atherosclerosis (MESA) cohort consisting of people free of cardiovascular disease or active cancer, statin users had lower adjusted D-dimer and FVIII levels than non-statin users [14]. Treatment with simvastatin in patients with impaired glucose tolerance and hypercholesterolemia reduced plasma levels of fibrinogen, FX:C, vWF:Ag, PAI-1, and FVII activity. It also led to prolongation of the prothrombin time and activated partial thromboplastin time. Co-administration of ezetimibe with simvastatin showed a synergistic effect on the coagulation profile [24, 25]. Additionally, it was reported that ezetimibe might increase and stabilize the anticoagulant effects of warfarin, particularly when added to statins [26]. Similarly, rosuvastatin but not pitavastatin increased the international normalized ratio (INR) in healthy volunteers on steady-state warfarin [27]. A Dutch study that assessed the immediate and long-term effects of new statin use on the dosage of vitamin K antagonist (VKA) showed that statin users needed lower doses of VKA to achieve the target INR, with the most substantial effect seen with simvastatin and rosuvastatin [28]. Pravastatin was also noted to potentiate the anticoagulant effects of dalteparin [29].

On the other hand, co-administration of rosuvastatin and warfarin in a small number of healthy subjects did not affect warfarin’s steady-state pharmacodynamics [30]. It was also reported that rosuvastatin did not inhibit thromboxane-mediated platelet aggregation in patients with a previous history of VTE [31]. Moreover, one-year treatment with atorvastatin or simvastatin in patients with coronary heart disease had no significant effect on the measured coagulation variables, though they were accompanied by an improved fibrinolytic profile in the treated patients [32]. There have also been reports suggesting that statins do not affect FVII and FVIII levels or activity [33,34,35,36,37].

While the observed differences in coagulation profile, particularly FVIII and FIX, between statin-users and fibrate/niacin-users in our study cohort, were seemingly more attributed to rosuvastatin, we could not detect a difference between rosuvastatin and other types of statin probably because of small numbers. It is believed that the side effects of drugs are not necessarily class effects, especially when the primary mechanism of the drug and the mechanism of side effects are different [38]. Therefore, it makes sense to expect that statins’ anti-thrombotic properties may be limited to some statins. In most observational studies and randomized controlled trials, it was concluded that rosuvastatin use was associated with the strongest (nearly 40%) reduced risk of VTE compared to non-statin users [20, 39,40,41,42]. Furthermore, in a Dutch cohort of patients with prior history of pulmonary emboli (PE), highly potent statins with regards to lipid-lowering effects (e.g., rosuvastatin) had the most substantial effect in preventing PE recurrence (hazard ratio (HR) 0.29, 95% CI 0.07–1.16) followed by statins of moderate potency (e.g., atorvastatin; HR 0.44, 95% CI 0.3–0.65) and low potency (e.g., pravastatin; HR 0.88, 95% CI 0.5–1.54) [43]. Despite these findings, several reports emphasize no difference between the type of statin and the risk of first or recurrent VTE [7, 44, 45].

Finally, we showed that contrary to other measured coagulation factors, fibrinogen level was higher in statin users than fibrate/niacin users, though the difference was statistically insignificant. Since fibrinogen is associated with pro-inflammatory and pro-coagulants effects [46], one would expect that statins will decrease fibrinogen levels. A previous study reported that the fibrinogen level reduced after 12 weeks of treatment with simvastatin 20 mg daily in individuals with impaired fasting glucose and hypercholesterolemia [24]. However, in a meta-analysis of 14 other studies, including patients with high serum cholesterol or stable coronary disease, no effect of statins on fibrinogen was found [47]. In a population-based study with 1000 statin users, fibrinogen levels were significantly higher in statin users than in non-users after adjusting for cardiovascular risk factors [14, 47]. We recently confirmed in the START randomized trial [17] that rosuvastatin users had higher fibrinogen levels than non-statin users [48]. It is presently unknown why statins can increase fibrinogen levels, but the timing of plasma fibrinogen level measurement and the type of statin used in different studies may explain such variability.

Our study was conducted with an active comparator design to minimize potential confounding and help us to make treatment groups with similar treatment indications. We compared different statin users with fibrates/niacin users as the reference group. Such a study design was previously explored in the control subjects of the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study, which showed statin users had a less hypercoagulable profile than fibrate users. Among the studied statins, rosuvastatin users had the lowest levels of FII, FVII, FVIII, vWF: Ag, FIX, FX, and FXI [38]. However, the latter study was conducted with a small number of participants (n = 361), which made the authors warn that the finding should be interpreted cautiously [30]. Therefore, we included a much larger population (n = 1043) to overcome this shortcoming and mainly found similar results in MEGA.

Besides, in a cohort of Japanese subjects who were LDL-cholesterol matched at baseline and were treated either with statins or fibrates, the overall mean LDL cholesterol level was lower by 27.3 mg/dl in statin users than in fibrate users (P < 0.001) [49]. Furthermore, a meta-analysis of fourteen studies revealed that statin use significantly reduced VTE risk (OR, 0.81; 95% CI, 0.66–0.99, random-effect model), while the use of fibrates was associated with a significant increase in the risk of VTE (OR, 1.58; 95% CI, 1.23–2.02), and niacin did not change the risk of VTE [50]. Thus, it seems that statins are more potent drugs than fibrates in lowering LDL-cholesterol, reducing the risk of atherosclerosis, and reducing coagulation factors, which may ultimately lead to a lower risk of first or recurrent VTE.

Our study was limited by the small numbers of niacin/fibrate users as the reference group. Though we used an active comparator design to minimize confounding, residual confounding might have remained since those prescribed fibrates/niacin may differ from those who received a statin prescription. Besides, we cannot exclude the possibility of adherence bias affecting our results since we included prevalent statins users. Additionally, since the analyses were cross-sectional, causal inferences cannot be made. Setting up a randomized controlled trial is advised to attenuate the possibility of adherence bias, and it is comforting to see that our results are in line with findings from the START trial.

Conclusion

Current statin use is associated with lower plasma levels of FXI. The type of statin may matter, though it needs further randomized control trials with much larger sample sizes.

Availability of data and materials

The data used during the current study are available from the corresponding author on reasonable request.

Abbreviations

VTE:

Venous thromboembolism

F:

Factor

BMI:

Body mass index

CI:

Confidence interval

tPA:

Tissue plasminogen activator

NEO:

The Netherlands Epidemiology of Obesity

ESC:

The European Society of Cardiology

EAS:

The European Atherosclerosis Society

BP:

Blood pressure

START:

STAtins Reduce Thrombophilia

vWF:

Von Willebrand factor

MESA:

Multi-Ethnic Study of Atherosclerosis

INR:

International normalized ratio

VKA:

Vitamin K antagonist

PE:

Pulmonary emboli

HR:

Hazard ratio

MEGA:

The Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis

References

  1. Heit JA, Spencer FA, White RH. The epidemiology of venous thromboembolism. J Thromb Thrombolysis. 2016;41(1):3–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Pastori D, Farcomeni A, Milanese A, Del Sole F, Menichelli D, Hiatt WR, et al. Statins and major adverse limb events in patients with peripheral artery disease: a systematic review and meta-analysis. Thromb Haemost. 2020;120(5):866–75.

    Article  PubMed  Google Scholar 

  3. Braekkan SK, Caram-Deelder C, Siegerink B, van Hylckama VA, le Cessie S, Rosendaal FR, et al. Statin use and risk of recurrent venous thrombosis: results from the MEGA follow-up study. Res Pract Thromb Haemostasis. 2017;1(1):112–9.

    Article  CAS  Google Scholar 

  4. Kunutsor SK, Seidu S, Khunti K. Statins and secondary prevention of venous thromboembolism: pooled analysis of published observational cohort studies. Eur Heart J. 2017;38(20):1608–12.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Li L, Zhang P, Tian JH, Yang K. Statins for primary prevention of venous thromboembolism. Cochrane Database Syst Rev. 2014;12:Cd008203.

    Google Scholar 

  6. Schmidt M, Cannegieter SC, Johannesdottir SA, Dekkers OM, Horvath-Puho E, Sorensen HT. Statin use and venous thromboembolism recurrence: a combined nationwide cohort and nested case-control study. J Thromb Haemostasis. 2014;12(8):1207–15.

    Article  CAS  Google Scholar 

  7. Smith NL, Harrington LB, Blondon M, Wiggins KL, Floyd JS, Sitlani CM, et al. The association of statin therapy with the risk of recurrent venous thrombosis. J Thromb Haemostasis. 2016;14(7):1384–92.

    Article  CAS  Google Scholar 

  8. Tagalakis V, Eberg M, Kahn S, Azoulay L. Use of statins and reduced risk of recurrence of VTE in an older population. A population-based cohort study. Thromb Haemost. 2016;115(6):1220–8.

    Article  PubMed  Google Scholar 

  9. Lassila R, Jula A, Pitkaniemi J, Haukka J. The association of statin use with reduced incidence of venous thromboembolism: a population-based cohort study. BMJ Open. 2014;4(11):e005862.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Gaertner S, Cordeanu EM, Nouri S, Mirea C, Stephan D. Statins and prevention of venous thromboembolism: myth or reality? Arch Cardiovasc Dis. 2016;109(3):216–22.

    Article  PubMed  Google Scholar 

  11. Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol. 2001;21(11):1712–9.

    Article  CAS  PubMed  Google Scholar 

  12. Pignatelli P, Carnevale R, Pastori D, Cangemi R, Napoleone L, Bartimoccia S, et al. Immediate antioxidant and antiplatelet effect of atorvastatin via inhibition of Nox2. Circulation. 2012;126(1):92–103.

    Article  CAS  PubMed  Google Scholar 

  13. Chaffey P, Thompson M, Pai AD, Tafreshi AR, Tafreshi J, Pai RG. Usefulness of statins for prevention of venous thromboembolism. Am J Cardiol. 2018;121(11):1436–40.

    Article  CAS  PubMed  Google Scholar 

  14. Adams NB, Lutsey PL, Folsom AR, Herrington DH, Sibley CT, Zakai NA, et al. Statin therapy and levels of hemostatic factors in a healthy population: the multi-ethnic study of atherosclerosis. J Thromb Haemostasis. 2013;11(6):1078–84.

    Article  CAS  Google Scholar 

  15. Bianconi V, Sahebkar A, Banach M, Pirro M. Statins, haemostatic factors and thrombotic risk. Curr Opin Cardiol. 2017;32(4):460–6.

    Article  PubMed  Google Scholar 

  16. Oikonomou E, Leopoulou M, Theofilis P, Antonopoulos AS, Siasos G, Latsios G, et al. A link between inflammation and thrombosis in atherosclerotic cardiovascular diseases: clinical and therapeutic implications. Atherosclerosis. 2020;309:16–26.

    Article  CAS  PubMed  Google Scholar 

  17. Biedermann JS, Kruip M, van der Meer FJ, Rosendaal FR, Leebeek FWG, Cannegieter SC, et al. Rosuvastatin use improves measures of coagulation in patients with venous thrombosis. Eur Heart J. 2018;39(19):1740–7.

    Article  CAS  PubMed  Google Scholar 

  18. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ (Clinical research ed). 2003;326(7404):1423.

    Article  CAS  Google Scholar 

  19. Sipahi I, Nicholls SJ, Tuzcu EM, Nissen SE. Coronary atherosclerosis can regress with very intensive statin therapy. Cleve Clin J Med. 2006;73(10):937–44.

    Article  PubMed  Google Scholar 

  20. Rahimi K, Bhala N, Kamphuisen P, Emberson J, Biere-Rafi S, Krane V, et al. Effect of statins on venous thromboembolic events: a meta-analysis of published and unpublished evidence from randomised controlled trials. PLoS Med. 2012;9(9):e1001310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. de Mutsert R, den Heijer M, Rabelink TJ, Smit JW, Romijn JA, Jukema JW, et al. The Netherlands epidemiology of obesity (NEO) study: study design and data collection. Eur J Epidemiol. 2013;28(6):513–23.

    Article  PubMed  Google Scholar 

  22. Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, et al. ESC/EAS guidelines for the management of dyslipidaemias: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European atherosclerosis society (EAS). Eur Heart J. 2011;32(14):1769–818.

    Article  PubMed  Google Scholar 

  23. Ramcharan AS, Van Stralen KJ, Snoep JD, Mantel-Teeuwisse AK, Rosendaal FR, Doggen CJ. HMG-CoA reductase inhibitors, other lipid-lowering medication, antiplatelet therapy, and the risk of venous thrombosis. J Thromb Haemostasis. 2009;7(4):514–20.

    Article  CAS  Google Scholar 

  24. Krysiak R, Okopien B. Haemostatic effects of simvastatin in subjects with impaired glucose tolerance. Intern Med J. 2011;41(6):473–81.

    Article  CAS  PubMed  Google Scholar 

  25. Krysiak R, Zmuda W, Okopien B. The effect of ezetimibe and simvastatin on hemostasis in patients with isolated hypercholesterolemia. Fundam Clin Pharmacol. 2012;26(3):424–31.

    Article  CAS  PubMed  Google Scholar 

  26. Hashikata T, Yamaoka-Tojo M, Kakizaki R, Nemoto T, Fujiyoshi K, Namba S, et al. Ezetimibe enhances and stabilizes anticoagulant effect of warfarin. Heart Vessel. 2017;32(1):47–54.

    Article  Google Scholar 

  27. Yu CY, Campbell SE, Zhu B, Knadler MP, Small DS, Sponseller CA, et al. Effect of pitavastatin vs. rosuvastatin on international normalized ratio in healthy volunteers on steady-state warfarin. Curr Med Res Opin. 2012;28(2):187–94.

    Article  CAS  PubMed  Google Scholar 

  28. van Rein N, Biedermann JS, Bonafacio SM, Kruip MJ, van der Meer FJ, Lijfering WM. Statin use decreases coagulation in users of vitamin K antagonists. Eur J Clin Pharmacol. 2016;72(12):1441–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Zimmer JE, Spillert CR, Puppala S, Zamecki K, Bhatt BA, Arora RR. Pravastatin potentiates the anticoagulant effects of low molecular weight heparin. Thromb Res. 2004;113(6):407–10.

    Article  CAS  PubMed  Google Scholar 

  30. Jindal D, Tandon M, Sharma S, Pillai KK. Pharmacodynamic evaluation of warfarin and rosuvastatin co-administration in healthy subjects. Eur J Clin Pharmacol. 2005;61(9):621–5.

    Article  CAS  PubMed  Google Scholar 

  31. Biedermann JS, Cannegieter SC, Roest M, van der Meer FJ, Reitsma PH, Kruip MJ, et al. Platelet reactivity in patients with venous thrombosis who use rosuvastatin: a randomized controlled clinical trial. J Thromb Haemostasis. 2016;14(7):1404–9.

    Article  CAS  Google Scholar 

  32. Seljeflot I, Tonstad S, Hjermann I, Arnesen H. Improved fibrinolysis after 1-year treatment with HMG CoA reductase inhibitors in patients with coronary heart disease. Thromb Res. 2002;105(4):285–90.

    Article  CAS  PubMed  Google Scholar 

  33. Joukhadar C, Klein N, Prinz M, Schrolnberger C, Vukovich T, Wolzt M, et al. Similar effects of atorvastatin, simvastatin and pravastatin on thrombogenic and inflammatory parameters in patients with hypercholesterolemia. Thromb Haemost. 2001;85(1):47–51.

    Article  CAS  PubMed  Google Scholar 

  34. Dangas G, Badimon JJ, Smith DA, Unger AH, Levine D, Shao JH, et al. Pravastatin therapy in hyperlipidemia: effects on thrombus formation and the systemic hemostatic profile. J Am Coll Cardiol. 1999;33(5):1294–304.

    Article  CAS  PubMed  Google Scholar 

  35. Gottsater A, Anwaar I, Lind P, Mattiasson I, Lindgarde F. Increasing plasma fibrinogen, but unchanged levels of intraplatelet cyclic nucleotides, plasma endothelin-1, factor VII, and neopterin during cholesterol lowering with fluvastatin. Blood Coagul Fibrinolysis. 1999;10(3):133–40.

    Article  CAS  PubMed  Google Scholar 

  36. Sbarouni E, Melissari E, Kyriakides ZS, Kremastinos DT. Effects of simvastatin or hormone replacement therapy, or both, on fibrinogen, factor VII, and plasminogen activator inhibitor levels in postmenopausal women with proven coronary artery disease. Am J Cardiol. 2000;86(1):80–3.

    Article  CAS  PubMed  Google Scholar 

  37. Ambrosi P, Aillaud MF, Habib G, Kreitmann B, Metras D, Luccioni R, et al. Fluvastatin decreases soluble thrombomodulin in cardiac transplant recipients. Thromb Haemost. 2000;83(1):46–8.

    Article  CAS  PubMed  Google Scholar 

  38. Lijfering WM, Biedermann JS, Kruip MJ, Leebeek FW, Rosendaal FR, Cannegieter SC. Can we prevent venous thrombosis with statins: an epidemiologic review into mechanism and clinical utility. Expert Rev Hematol. 2016;9(11):1023–30.

    Article  CAS  PubMed  Google Scholar 

  39. Kunutsor SK, Seidu S, Khunti K. Statins and primary prevention of venous thromboembolism: a systematic review and meta-analysis. Lancet Haematol. 2017;4(2):e83–93.

    Article  PubMed  Google Scholar 

  40. Glynn RJ, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med. 2009;360(18):1851–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ (Clinical research ed). 2010;340:c2197.

    Article  Google Scholar 

  42. Rosendaal FR. Statins and venous thrombosis: a story too good to be true? PLoS Med. 2012;9(9):e1001311.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Biere-Rafi S, Hutten BA, Squizzato A, Ageno W, Souverein PC, de Boer A, et al. Statin treatment and the risk of recurrent pulmonary embolism. Eur Heart J. 2013;34(24):1800–6.

    Article  CAS  PubMed  Google Scholar 

  44. Agarwal V, Phung OJ, Tongbram V, Bhardwaj A, Coleman CI. Statin use and the prevention of venous thromboembolism: a meta-analysis. Int J Clin Pract. 2010;64(10):1375–83.

    Article  CAS  PubMed  Google Scholar 

  45. El-Refai SM, Black EP, Adams VR, Talbert JC, Brown JD. Statin use and venous thromboembolism in cancer: a large, active comparator, propensity score matched cohort study. Thromb Res. 2017;158:49–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Davalos D, Akassoglou K. Fibrinogen as a key regulator of inflammation in disease. Seminars in immunopathology; 2012.

    Google Scholar 

  47. Balk EM, Lau J, Goudas LC, Jordan HS, Kupelnick B, Kim LU, et al. Effects of statins on nonlipid serum markers associated with cardiovascular disease: a systematic review. Ann Intern Med. 2003;139(8):670–82.

    Article  CAS  PubMed  Google Scholar 

  48. Schol-Gelok S, de Maat MPM, Biedermann JS, van Gelder T, Leebeek FWG, Lijfering WM, et al. Rosuvastatin use increases plasma fibrinolytic potential: a randomised clinical trial. Br J Haematol. 2020;190:916.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Takeuchi S, Takahashi Y, Asai S. Comparison of pleiotropic effects of statins vs fibrates on laboratory parameters in patients with dyslipidemia: a retrospective cohort study. Medicine. 2020;99(50):e23427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Squizzato A, Galli M, Romualdi E, Dentali F, Kamphuisen PW, Guasti L, et al. Statins, fibrates, and venous thromboembolism: a meta-analysis. Eur Heart J. 2010;31(10):1248–56.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We acknowledge S. Parand for her kind help in preparing and submitting the manuscript.

Funding

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Authors and Affiliations

  1. Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Mohammadreza Bordbar

  2. Department of Clinical Epidemiology, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands

    Renée de Mutsert, Melike Cevval, Frits R. Rosendaal & Willem M. Lijfering

  3. Department of Cardiology, Leiden University Medical Centre, Leiden, the Netherlands

    J. Wouter Jukema

Authors
  1. Mohammadreza Bordbar
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  2. Renée de Mutsert
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  3. Melike Cevval
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  4. Frits R. Rosendaal
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  5. J. Wouter Jukema
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  6. Willem M. Lijfering
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Contributions

FRR and WML have contributed to the concept and design of the study. MB and MC gathered the data. MB, MC, and WML performed statistical analysis. RM, JWJ, FRR, and WML interpreted the data. MB wrote the initial draft. All the authors reviewed the drafts, provided critical comments, and approved the final manuscript.

Corresponding author

Correspondence to Willem M. Lijfering.

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Ethics approval and consent to participate

The study was approved by the medical ethical committee of the Leiden University Medical Center (LUMC). Participants have given written informed consent for participation in the study and obtained medical records and information on vital status during follow-up. They also gave consent that the data can be used for research purposes.

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Not applicable.

Competing interests

The authors have no competing interests.

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Bordbar, M., de Mutsert, R., Cevval, M. et al. Differential effect of statin use on coagulation markers: an active comparative analysis in the NEO study. Thrombosis J 19, 45 (2021). https://doi.org/10.1186/s12959-021-00299-2

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  • DOI: https://doi.org/10.1186/s12959-021-00299-2

Keywords

  • Statins
  • Venous thromboembolism
  • Coagulation factors
  • Niacin
  • Fibrates

Thrombosis Journal

ISSN: 1477-9560

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