By Seema Gupta, MD, MSPH

Clinical Assistant Professor, Department of Family and Community Health, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV

Dr. Gupta reports no financial relationships relevant to this field of study.

SYNOPSIS: A large-scale systematic review and meta-analysis found a 15-25% reduction in relative risk for venous thromboembolism in those who used statins vs. those who did not.

SOURCE: Kunutsor SK, Seidu S, Khunti K. Statins and primary prevention of venous thromboembolism: A systematic review and meta-analysis. Lancet Haematol 2017;4:e83-e93.

Venous thromboembolism (VTE), which consists of deep venous thrombosis (DVT) and pulmonary embolism (PE), is a common public health issue that requires early diagnosis and treatment because of its association with high mortality and morbidity. Although the precise number of people affected by DVT and PE is unknown, up to 900,000 Americans could be affected each year, with a significant number of cases leading to hospitalization, resulting in a high number of fatalities from this preventable illness.1 The most common inherited etiology for hypercoagulable states include factor V Leiden mutation, prothrombin gene mutation, and defects in protein S, protein C, and antithrombin. Acquired risk factors include a prior thrombotic event, recent major surgery or major medical illness, trauma, immobilization, malignancy, presence of a central venous line, pregnancy, the use of oral contraceptives, myeloproliferative disorders, and antiphospholipid syndrome.

A large body of literature demonstrates that the incidence of VTE can be reduced in the medically ill and surgical populations. Pharmacological prophylaxis may be recommended for patients considered to have an increased risk for VTE and a low risk for bleeding, while mechanical compression and/or early ambulation are otherwise recommended for patients considered to be low risk for VTE or high risk for bleeding. Statins are well established as a standard of care for primary and secondary prevention of cardiovascular disease because of their lipid-lowering properties. Statins also are known to exhibit pleiotropic effects on coagulation and inflammation without increasing the risk of bleeding. The effect of statins on DVT prevention was first studied in a 2009 randomized, controlled trial (RCT), which demonstrated that the rate of DVT was decreased significantly in patients treated with rosuvastatin vs. controls.2 However, a subsequent analysis of pooled studies did not find a significant reduction in VTE with statin use.3 Since then, there have been a number of newer, more robust studies published on the matter, and there is a need to establish whether the association of statin use with VTE primary prevention exists.

Kunutsor et al conducted a systematic review and meta-analysis of the existing observational cohort studies and RCTs using a predefined protocol. Included were 36 eligible studies published prior to July 18, 2016, that involved more than 3.2 million participants and assessed the association of statin use with VTE in adults, as well as studies that evaluated the effects of statins compared with a placebo or no treatment for VTE outcomes.

Researchers found that in observational studies, there was a 25% reduction in relative risk (RR) for VTE (RR, 0.75; 95% confidence interval [CI], 0.65-0.87; P < 0.0001) when statin use was compared with no statin use. In RCTs, there was a 15% reduction in RR for VTE (RR, 0.85; 95% CI, 0.73-0.99; P = 0.038) when statin therapy was compared with placebo or no treatment. In the subgroup analyses, significant differences in the effect of statins by type of statin were found, with rosuvastatin demonstrating the lowest risk of VTE compared with other statins (RR, 0.57; 95% CI, 0.42-0.75; P = 0.015).

COMMENTARY

The findings from this large, well-conducted systematic review and meta-analysis suggests a role for statins in the primary prevention of VTE. The vasoprotective effects of statins may be related to their antithrombotic and anti-inflammatory properties. Increasing evidence suggests that statins modulate the blood coagulation cascade at multiple levels, leading to reduced thrombogenicity and inhibited platelet aggregation while maintaining a beneficial balance between prothrombotic and fibrinolytic processes. Several mechanisms have been proposed for the reduction in thrombosis in patients treated with statins, including decreased tissue factor, plasminogen activator inhibitor-1 decreased platelet aggregation, increased thrombomodulin expression, and increased tissue plasminogen activator expression.4 There also are decades of data on statins that demonstrate no bleeding side effects, making them a potential adjunctive therapy for VTE.

Interestingly, studies have found that some statins, specifically rosuvastatin, may be more effective than others as a prevention therapy for VTE.5 Whether VTE reduction is a class effect of statins is uncertain. That raises an important point: Although an extensive body of evidence on the clinical benefit of statins in the occurrence of VTE has been developed, some questions remain unanswered, including the effect of statins on prevention of DVT and PE specifically, the type and dose of statins used, and the benefits of such therapy in patients with normal cholesterol levels. There still exists a need to conduct future intervention research with VTE outcomes prespecified as primary outcomes before guidelines for statin use are expanded to include prevention of VTE. Until then, it is important to keep in mind that the statin we prescribe may play a role in preventing the next thromboembolic event in our patients.

REFERENCES

  1. Raskob GE, Silverstein R, Bratzler DW, et al. Surveillance for deep vein thrombosis and pulmonary embolism: Recommendations from a national workshop. Am J Prev Med 2010; 38(4 Suppl):S502-09.
  2. Glynn RJ, Danielson E, Fonseca FA, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med 2009;360:1851-1861.
  3. Squizzato A, Galli M, Romualdi E, et al. Statins, fibrates, and venous thromboembolism: A meta-analysis. Eur Heart J 2010;31:1248-1256.
  4. Rodriguez AL, Wojcik BM, Wrobleski SK, et al. Statins, inflammation and deep vein thrombosis: A systematic review. J Thromb Thrombolysis 2012;33:371-382.
  5. Li L, Zhang P, Tian JH, Yang K. Statins for primary prevention of venous thromboembolism. Cochrane Database Syst Rev 2014;(12):CD008203.