Rosuvastatin use reduces thrombin generation potential in patients with venous thromboembolism: a randomized controlled trial

Abstract

Essentials The role of statins in hemostasis and venous thromboembolism (VTE) prophylaxis is not clear.This trial assessed whether rosuvastatin use affects thrombin generation in patients with VTE.Endogenous thrombin potential and peak were decreased by 10% and 5% with rosuvastatin therapy.These results provide basis for trials on the efficacy of statins in reducing recurrent VTE risk. SummaryBackgroundStatin therapy could form an alternative prophylactic treatment for venous thromboembolism (VTE) if statins are proven to downregulate hemostasis and prevent recurrent VTE, without increasing bleeding risk.ObjectivesThe STAtins Reduce Thrombophilia (START) trial investigated whether statin affects coagulation in patients with prior VTE.Patients/methodsAfter anticoagulation withdrawal, patients were randomized to rosuvastatin 20 mg day−1 for 4 weeks or no intervention. Plasma samples taken at baseline and at the end of the study were analyzed employing thrombin generation assay.Results and conclusionsThe study comprised 126 rosuvastatin users and 119 non‐users. Mean age was 58 years, 61% were men, 49% had unprovoked VTE and 75% had cardiovascular (CV) risk factors. Endogenous thrombin potential (ETP) increased from baseline to end of study in non‐statin users (mean 97.22 nm*min; 95% CI, 40.92–153.53) and decreased in rosuvastatin users (mean −24.94 nm*min; 95% CI, −71.81 to 21.93). The mean difference in ETP change between treatments was −120.24 nm*min (95% CI, −192.97 to −47.51), yielding a 10.4% ETP reduction by rosuvastatin. The thrombin peak increased in both non‐statin (mean 20.69 nm; 95% CI, 9.80–31.58) and rosuvastatin users (mean 8.41 nm; 95% CI −0.86 to 17.69). The mean difference in peak change between treatments was −11.88 nm (95% CI, −26.11 to 2.35), yielding a 5% peak reduction by rosuvastatin. Other thrombin generation parameters did not change substantially. The reduction in ETP and peak by rosuvastatin was more pronounced in the subgroups of participants with CV risk factors and with unprovoked VTE. We conclude that rosuvastatin reduces thrombin generation potential in patients who had VTE.

Different Types of Statins and All-Cause Mortality during Anticoagulation for Venous Thromboembolism: Validation Study from RIETE Registry

“…First, the observed lower mortality rate is not due to the effect of statins on LDL-C or total cholesterol levels, but rather to other "pleiotropic" mechanisms, such as platelet inhibition, reduction of inflammation, reduction of C-reactive protein, increased production of nitric oxide, or downregulation of the coagulation cascade. 6,21 This is supported by meta-analysis and metaregression of randomized controlled trials 8 and randomized clinical trial (START) 9 and several clinical studies demonstrating that statin therapy either with rosuvastatin, 21 simvastatin, 22 atorvastatin, 23,24 or cerivastatin 25 affects coagulation factors and thrombin generation. In our study, no differences in levels of total or LDL cholesterol at baseline were observed and this can be in line with this hypothesis.…”

Investigating pleiotropic effects of statins on ischemic heart disease in the UK Biobank using Mendelian randomisation

“…Mechanisms by which androgens might cause IHD have not been extensively investigated, but likely involve coagulation and red blood cell attributes. Several haemostatic and thrombotic factors, such as thromboxane A 2 [44,45], endothelin-1 [46][47][48], nitric oxide [44,49] and possibly thrombin [50,51], may be driven by androgens and likely play a role in IHD [52][53][54]. Von Willebrand factor [55] and asymmetric dimethylarginine [56] are also modulated by statins and may cause IHD [4,57], whether they are driven by testosterone is unknown.…”

“…Mechanisms by which androgens might cause IHD have not been extensively investigated, but likely involve coagulation and red blood cell attributes. Several haemostatic and thrombotic factors, such as thromboxane A 2 ( Pignatelli et al, 2012 ; Ajayi and Halushka, 2005 ), endothelin-1 ( Polderman et al, 1993 ; van Kesteren et al, 1998 ; Sahebkar et al, 2015 ), nitric oxide ( Pignatelli et al, 2012 ; Rosselli et al, 1998 ) and possibly thrombin ( Orsi et al, 2019 ; Ferenchick et al, 1995 ), may be driven by androgens and likely play a role in IHD ( Schooling et al, 2018b ; Zhao, 2018 ; Nikpay et al, 2015 ). Von Willebrand factor ( Sahebkar et al, 2016 ) and asymmetric dimethylarginine ( Serban et al, 2015 ) are also modulated by statins and may cause IHD ( Aday and Ridker, 2018 ; Au Yeung et al, 2016 ), whether they are driven by testosterone is unknown.…”

A Pilot Randomized Study of Atorvastatin As Adjunct Therapy in Patients with Acute Venous Thromboembolism

“…The START (The STAtins Reduce Thrombophilia) trial published in 2019 randomized 245 patients with a history of VTE (48.6% unprovoked) who have completed a course of anticoagulation to rosuvastatin 20 mg daily or no statin for 4 weeks (29). All patients stopped vitamin K antagonists for one month prior to enrollment.…”