Statin therapy in venous thromboembolism: How far from primary and secondary prevention?

Statin therapy is highly recommended for the primary and secondary prevention of arterial thrombosis diseases, including coronary and cerebral atherosclerosis.¹ Several studies also indicate the beneficial effect of statins on venous thrombus, namely venous thromboembolism (VTE) and pulmonary embolism (PE), regardless of healthy people or patients.^2-5 A randomized trial demonstrated rosuvastatin significantly reduced the incidence of VTE, beyond its influence on arterial thrombosis.³ In addition, statins may moderately lower the risk of recurrent VTE among patients with a provoked first VTE (hazard ratio: 0.64, 95% confidence interval (CI): 0.27–1.58). However, so far there is little evidence showing that statin therapy can reduce the risk of fatal PE. Therefore, Can the reduced recurrence risk of VTE caused by statin bring more benefit for reduced the risk of death of acute PE?

Siniscalchi et al. have addressed this interesting question and reported statin use is associated with a lower short-term mortality in patients with acute symptomatic PE.⁶ They used the Registro Informatizado de Pacientes con Enfermedad TromboEmbólica (RIETE) registry, a large multicenter, ongoing, international registry of patients with objectively confirmed, acute VTE (ClinicalTrials.gov identifier: NCT02832245), to assess the correlation between statin therapy and short-term mortality. Among 31 169 patients with acute symptomatic PE enrolled between 2009 and 2021, 5520 (18%) were using statins: 829 at low intensity, 3636 at intermediate intensity, and 1055 at high intensity. Compared to non-users, statin users were 10 years older and prone to have hypertension, diabetes, chronic heart or renal failure, prior myocardial infarction, prior stroke, or peripheral artery disease. They were also more likely to use antiplatelet drugs and had lower serum levels of low density lipoprotein (LDL) cholesterol than non-users. Despite similar proportion of initial PE and hypotension, statin users were more likely to have hypoxemia, raised troponin levels, and worse scored PE severity score than non-users. Compared to non-users, statin users had similar anticoagulant therapy; the odd ratios (ORs) of all-cause death and fatal PE among statin users were 0.65 (95% CI: 0.56–0.76) and 0.42 (95% CI: 0.28–0.62) after multiple adjustment, respectively, which suggests statin use exerts beneficial effects on short-term mortality of acute PE. The mortality rate was lower than those of another two studies, which also used the data from the RIETE registry and found statin users at baseline had a significant decreased 177- or 192-day all-cause mortality compared to non-statin users (4.7%, 9.9%, 8.3%, respectively).^{6, 7} This study indicates a protective effect of statin in outcomes of PE. Interestingly, the authors also compare the effect of three different statin intensities and show an obvious benefit of all three intensities on the all-cause death compared to the non-users, while patients using low- or moderate-intensity statins were at a lower risk of fatal PE, compared to those using high-intensity statins and non-users.

Why would statins affect the short-term mortality of acute PE? Statins can act through several mechanisms to repress the occurrence of VTE. On the one hand, statins lower LDL cholesterol, and reduce the risk factors for hyperlipidemia in VTE. The lower effect may be due to a healthier lifestyle and/or a lower risk condition in people receiving statins. Statins are known to reduce mortality, especially cardiovascular death, in patients with a history of cardiovascular disease (CVD).⁸ However, some studies have suggested that lipids are not associated with recurrence in patients with unprovoked first events.⁹ The lower effect was consistent both in the presence or absence of VTE-related clinical risk factors, such as hyperlipidemia.^{10, 11} On the other hand, statins can affect the blood coagulation system to reduce risk of VTE. They can reduce tissue factor expression and thrombin generation, attenuate fibrinogen cleavage, and increase the activity of the transcription factor Kruppel-like factor 2, thereby promoting thrombomodulin expression on endothelial cells, which enhances the activity of the protein C anticoagulant pathway.¹² Ramberg et al.¹³ demonstrated that statin treatment caused a substantial decreased activity of plasma procoagulant phospholipids (PPL), and then attenuated a PPL-dependent coagulation activation, which may also contribute to a reduced VTE risk following statin treatment.

It is known to all that statin therapy is recommended for primary and secondary prevention of CVD and is cost effective.¹⁴ Nevertheless, statin utility in the primary prevention of VTE will be low, because the small absolute benefit of statin treatment may be counteracted by side effects, such as liver function injury, rhabdomyolysis, or incident diabetes.¹⁵ Nonetheless, statins seem not to have an effect on recurrence in patients with an unprovoked first event.⁴ On one hand, there is opposite evidence of the association of VTE with levels of high-density lipoprotein, LDL, or total cholesterol,^{3, 16} but on the other hand, although rosuvastatin significantly reduced the incidence of symptomatic VTE in a randomized trial in apparently healthy individuals, the recommendation of statins for primary prevention still needs to be confirmed by more high-quality studies.³ Statin therapy can reduce the risk of recurrent VTE and mortality. In addition, statin therapy can help to reduce all-cause mortality and CVD.^{6, 7, 17} Therefore, the net benefit of statins may be higher in high-risk VTE patients, especially those with cardiovascular risk, and potentially be useful in secondary prevention of VTE. However, whether statins can be an attractive anticoagulant replacement therapy during long-term treatment of VTE needs confirmation via randomized trials.

Today, there is little evidence on statin dosage and type. Rosuvastatin 20 mg daily is “royal” in RCT trials,^{3, 13} while in most cohort studies, statin type ranges from simvastatin to lovastatin without comparisons among statin types and dosages.^{4, 5} In another study, Siniscalchi et al.⁷ compared different types of statins and all-cause mortality of patients with VTE during anticoagulation. Compared to non-statin users, patients on simvastatin or other statins had a lower mortality rate, but there was no significant difference in mortality among among patients on atorvastatin or rosuvastatin. Recently, Siniscalchi et al.¹⁸ assessed the strength of associations across the strata of intensities of statin therapy on mortality. Considering the diversity of statins, it may be more beneficial to compare statin intensities. It should be noted that although low and medium doses of statins can decrease the prevalence of fatal PE, there is no significant difference at high doses. Although the authors do not elaborate on this phenomenon in detail, safety of statins requires our attention.

In summary, the study by Siniscalchi et al. adds to the growing body of evidence that statins have a protective effect against short-term mortality in acute symptomatic PE. The effect appears to be of clinical relevance and supported by statin intensities. Large prospective randomized trials of statins, notably statin type and intensity, are warranted to confirm the potential benefits in fatal PE.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

AUTHOR CONTRIBUTIONS

All authors conceived and designed the article, performed analysis and interpretation of the data, revised the manuscript critically for important intellectual content, and gave final approval of the manuscript submitted.