Abstract

Introduction

Venous thromboembolism (VTE) comprises deep vein thrombosis (DVT) and pulmonary embolism (PE). In a recent study, the estimated total annual cases of VTE occurring in the United States exceeded 900,000, of which more than 250,000 were fatal [1]. An international study that involved six countries within the European Union, reported 465,715 estimated annual cases of DVT; 295,982 PE events and 370,012 VTE-related deaths [2]. Clinically, DVT is divided into two distinct phases: acute and chronic. It is during the acute phase of DVT that PE, a serious and potentially fatal condition may occur as a result of a dislodged thrombus. In addition, post-thrombotic syndrome (PTS), which is a long-term sequelae of DVT [3–5], affects 23–60% of patients and carries with it a high level of morbidity [6]. Despite the progress in medicine and vascular biology, there has been no decrease in the incidence of VTE in the last 25 years [7]. The standard protocol for a patient presenting with a DVT is initial treatment with heparin, followed by long-term anticoagulation with warfarin in order to reduce the chance of PE, complications of PTS and recurrence of DVT. However, all of these medications are associated with a high risk of bleeding [8]. An overview of bleeding complications demonstrated that the rate of intracranial bleeding was 1.15% per year and the case fatality rate of major bleeding was 13% [8]. Thus, investigation into new treatment options for DVT is warranted.

The effect of statins on DVT was brought to light in 2009 through a clinical randomized controlled trial (RCT) called the JUPITER Trial. In this study, relatively healthy people with high levels of C-reactive protein (CRP) and normal low density lipoprotein cholesterol (LDL-C) levels, were given either a placebo or rosuvastatin [9]. It showed that the rate of DVT was significantly decreased in patients treated with rosuvastatin versus controls, 34 versus 60 patients respectively, with a median follow-up point of 1.9 years [9]. Rosuvastatin, along with other statins, inhibits hydroxymethylglutaryl (HMG)-CoA reductase, and are used as a treatment for hypercholesterolemia.

Several mechanisms have been proposed for the reduction in thrombosis in patients treated with statins, including decreased tissue factor [10, 11], plasminogen activator inhibitor-1 (PAI-1) [11, 12], increased tissue plasminogen activator (tPA) expression, decreased platelet aggregation, and increased thrombomodulin expression [11, 13]. The effect of rosuvastatin on DVT is not clear, and its investigation will provide an important contribution to the field. In addition to their anti-thrombotic/anti-inflammatory potential, statins have years of data that show no bleeding side effects, making them a potential adjunctive therapy for DVT. We have thus conducted a systematic review of the literature regarding the non-lipid effects of statins and the potential link between DVT, inflammation, and statins. We hypothesize that DVT, inflammation and statins are interrelated due to the probable anti-thrombotic and anti-inflammatory properties of statins.

Materials and methods

Search strategy

An English language literature search from 1950 to February 2011 was performed with MEDLINE, EMBASE, and PUBMED databases. The search included the following keywords: “statins”, “HMG-CoA reductase inhibitors”, “venous thromboembolism”, “pulmonary embolism”, “deep vein thrombosis”, and either or “inflammation”. The inclusion and exclusion criteria as well as the results of the search are outlined in Figs. 1 and ​and2.2. A total of 911 manuscripts were initially identified, after removal of duplicates the remaining 877 abstracts [598 anti-coagulation, Fig. 1 + 279 inflammation, Fig. 2] were then reviewed. Two independent reviewers evaluated all abstracts (A.L.R. and J.A.D.) based on the inclusion and exclusion criteria. All relevant review articles generated by the search were analyzed. In addition, articles were added to the final analysis based on evaluation of the references of the articles previously included, and using the same inclusion/exclusion criteria applied for the systematic review (Fig. 3). Disputes between authors on inclusion were reexamined together and only those that were agreed upon by both authors were included in the final analysis.

Open in a separate window

Fig. 1

Open in a separate window

Fig. 2

Open in a separate window

Fig. 3

Results

A total of 29 articles were identified that fit the eligibility criteria, shown in Figs. 1 and ​and2.2. Common investigative topics were identified and articles categorized by subject (Fig. 3). The inflammatory biomarkers and inflammatory events that were reviewed in this work are shown in Table 1.

Discussion

The recent JUPITER trial showed that statins might be beneficial for patients suffering from deep vein thrombosis. The JUPITER trial involved 17,802 non-hyperlipidemic patients with elevated CRP levels where rosuvastatin treatment caused a significant decrease in the rate of DVT [9]. This prompted our review of the literature in order to determine what evidence currently exists in support of or in opposition to this claim.

Multiple inflammatory biomarkers were found to be associated with VTE including IL-6, IL-8, sP-selectin, MCP-1, TNFα, and CRP. However, it is difficult to conclude whether the elevations in these biomarkers are from systemic inflammation or play an integral part in the formation of thrombosis. Direct inhibition of IL-6, TNFα, and P-selectin was found to reduce VTE and its sequelae, PTS [17, 27, 28]. This evidence supports pharmacological therapy targeted at inflammatory mediators to decrease the incidence and recurrence of VTE and may explain the underlying anti-thrombotic effect of statins.

In fact, several studies found that statin use led to decreased levels of inflammatory biomarkers including IL-6, IL-8, MCP-1 and CRP. These inflammatory biomarkers were specifically found to be elevated in patients with VTE and affected the physiology of endothelial cells. Most of the current research involving statins and inflammation focuses on the arterial side of the circulation and while this review aims to discuss mainly the venous side, it is important to look at biomarkers that both have in common. IL-6 was the most common inflammatory biomarker analyzed and is primarily studied because it is a known regulator in the activation of an acute phase response. It is usually analyzed both on an individual basis and also in conjunction with IL-8, MCP-1, and CRP [31, 32, 34]. The study by Arnaud et al. [31] looked at levels of IL-6 induced CRP in which they found them to be decreased by statins. In addition, the study by Jougaski also examined levels of MCP-1, a cytokine that is induced by IL-6. This study found that statins suppressed IL-6 induced MCP-1 expression [33]. One RCT that analyzed plasma inflammatory biomarkers by Millar et al. [34], found no changes in the expression of IL-6, hs-CRP and other inflammatory biomarkers with either the in vivo or ex vivo use of statins. However, the patient population consisted of normolipidemic adults with normal CRP levels, versus the elevated CRP levels in the participants of the JUPITER trial, suggesting baseline CRP levels are an important marker in predicting the efficacy of reducing VTE with statins [9, 34].

Statin therapy was found to reduce VTE in all studies included in this review. While many patient populations were studied, the strong support for effective statin use exists for normolipidemic patients with elevated levels of CRP, indicating increased inflammation. The studies were comprised of various statins including: pravastatin, simvastatin, atorvastatin, rosuvastatin, lovastatin, fluvastatin and cerivastatin. The degree of risk reduction was found to differ between statins. Khemasuwan et al. [37], Ramcharan et al. [40], and Doggen et al. [36] were all in accordance with the beneficial effect of simvastatin in decreasing the rate of DVT, but a discrepancy was seen in regards to the level of benefit conferred by this statin in comparison to others. Khemasuwan et al. [37] found simvastatin led to fewer occurrences of DVT, when compared to atorvastatin. Ramcharan discovered a beneficial preventative effect of DVT with pravastatin, which was higher in comparison to simvastatin. Doggen found that pravastatin showed no benefit in reducing the rate of DVT and the initial protective effect on DVT observed was seen only in those treated with simvastatin [36, 37]. While this observation made by Doggen is in opposition to the conclusion made by Ramcharan, the number of patients in Doggen’s study using simvastatin was approximately three times higher than those treated with pravastatin (simvastatin 16:5 pravastatin). This discrepancy brings into question the reliability of this conclusion. Furthermore, this study was conducted only in postmenopausal women, which decreases the ability to generalize results and accurately compare them to those from the other studies. The remainder of the studies reviewed consisted of both male and female participants in approximately equal ratios [9, 36–41].

In summary, there is overwhelming support that statin therapy has the ability to decrease the incidence and recurrence of VTE. Further work must be done to uncover the mechanism leading to this anti-thrombotic affect and to more clearly define appropriate patient populations. However, our review suggests that the anti-thrombotic effects are likely exhibited through the anti-inflammatory properties of statins. Cytokines that most likely are involved include IL-6, IL-8, CRP, and MCP-1. Specifically, statin therapy reduces the IL-6 induced expression of both CRP and MCP-1, which are elevated in patients with VTE [31–33]. Reduction of IL-6 induced MCP-1 has also been linked to vein wall fibrosis, which would predispose a patient to PTS and recurrent DVT [28]. Collectively, this may explain why anti-inflammatory effects of statins in normolipidemic patients, with elevated CRP levels, appear to lead to the greatest reduction in the incidence and recurrence of VTE and potentially could decrease the incidence of PTS. Given their low risk of bleeding, statins have the potential to serve as a safe adjunctive pharmacological therapy to current treatments in select patients with VTE, however further investigations into this concept are needed and essential.

Acknowledgments

Abbreviations

Contributor Information

April L. Rodriguez, Department of Surgery, Section of Vascular Surgery, Conrad Jobst Vascular Research Laboratories, School of Medicine, University of Michigan, A570A MSRB II, 1150 W. Medical Center Dr., Dock #6, Ann Arbor, MI 48109, USA.

Brandon M. Wojcik, Department of Surgery, Section of Vascular Surgery, Conrad Jobst Vascular Research Laboratories, School of Medicine, University of Michigan, A570A MSRB II, 1150 W. Medical Center Dr., Dock #6, Ann Arbor, MI 48109, USA.

Shirley K. Wrobleski, Department of Surgery, Section of Vascular Surgery, Conrad Jobst Vascular Research Laboratories, School of Medicine, University of Michigan, A570A MSRB II, 1150 W. Medical Center Dr., Dock #6, Ann Arbor, MI 48109, USA.

Daniel D. Myers, Jr., Department of Surgery, Section of Vascular Surgery, Conrad Jobst Vascular Research Laboratories, School of Medicine, University of Michigan, A570A MSRB II, 1150 W. Medical Center Dr., Dock #6, Ann Arbor, MI 48109, USA. Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA.

Thomas W. Wakefield, Department of Surgery, Section of Vascular Surgery, Conrad Jobst Vascular Research Laboratories, School of Medicine, University of Michigan, A570A MSRB II, 1150 W. Medical Center Dr., Dock #6, Ann Arbor, MI 48109, USA.

Jose A. Diaz, Department of Surgery, Section of Vascular Surgery, Conrad Jobst Vascular Research Laboratories, School of Medicine, University of Michigan, A570A MSRB II, 1150 W. Medical Center Dr., Dock #6, Ann Arbor, MI 48109, USA.

References