Rosuvastatin use improves measures of coagulation in patients with venous thrombosis

Biedermann, Joseph S.; Kruip, Marieke J.H.A.; Meer, F J van der; Rosendaal, Frits R.; Leebeek, Frank W.G.; Cannegieter, Suzanne C.; Lijfering, Willem M.

doi:10.1093/eurheartj/ehy014

Cited by 56 publications

(65 citation statements)

References 48 publications

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“…We also observed that the relative treatment effect of rosuvastatin on ETP was mainly driven by the absence of an increase in this parameter among rosuvastatin users, in contrast to a significant increase in ETP in patients not using statins. This is consistent with a previous observation from this trial demonstrating that the difference in D-dimer levels between the treatment groups was driven by the absence of an increase in D-dimer following rosuvastatin use [12]. As both thrombin generation and D-dimer are markers of hypercoagulability [25,26], the current results provide further evidence that rosuvastatin may prevent a rebound phenomenon; that is, a shift to a more procoagulant profile along with increased risk of a recurrence of VTE after the sudden withdrawal of anticoagulant treatment [40,41].…”

Section: Discussionsupporting

confidence: 93%

“…Additionally, these findings are consistent with previous results from the START trial, in which rosuvastatin treatment was shown to decrease the plasma factor VIII levels by 6% (adjusted mean difference in change between treatments, À8.2 IU dL À1 ; 95% CI, À13.6 to À2.9) and those of FXI by 4% (adjusted mean difference in change between treatments, À4.9 IU dL À1 ; 95% CI, 9.9 to À0.1), coinciding with a decrease in D-dimer by 3% and factor VII levels by 4% [12]. The results from the START trial point to the same direction of an effect of rosuvastatin on the individual coagulation profile, but the observed decrease in thrombin generation potential was only partially mediated by factor VII and by D-dimer, factor VIII or XI.…”

Section: Discussionmentioning

confidence: 91%

“…The differences in the change in lag time, time to peak or velocity index were considered secondary endpoints. The study was originally powered on factor VIII . Nevertheless, we observed in the non‐statin users that the mean ETP was 1245 m m *min (SD 322) at randomization.…”

Section: Methodsmentioning

confidence: 93%

“…First, the trial was not blind to the participants and physicians involved; however, it was considered unlikely that knowledge of the treatment could affect a surrogate laboratory outcome. Second, we previously noticed that the distribution of sex and age after randomization was different between the groups, and we a priori decided to adjust the analysis for these potential confounding factors . These adjustments did not influence our results.…”

Section: Discussionmentioning

confidence: 98%

“…Recently, we have shown in the STAtins Reduce Thrombophilia (START) trial that 1 month of treatment with rosuvastatin at 20 mg day À1 led to an improved coagulation profile as compared with non-statin users in patients with prior VTE, most notably by reducing factor VIII plasma levels [12]. These observations from the START trial were the first randomized evidence indicating that rosuvastatin reduces coagulation factor levels in patients with prior VTE and confirmed similar findings previously observed for other statins [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

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

Orsi

Biedermann

Kruip

et al. 2019

Journal of Thrombosis and Haemostasis

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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.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 91%

Section: Methodsmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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

Orsi

Biedermann

Kruip

et al. 2019

Journal of Thrombosis and Haemostasis

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Production of tert‐butyl (3R,5S)‐6‐chloro‐3,5‐dihydroxyhexanoate using carbonyl reductase coupled with glucose dehydrogenase with high space–time yield

Zhang

Zheng

et al. 2019

Biotechnology Progress

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tert-Butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate ((3R,5S)-CDHH) is an important chiral intermediate for the synthesis of rosuvastatin. The biotechnological production of (3R,5S)-CDHH is catalyzed from tert-butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate ((S)-CHOH) by a carbonyl reductase, and this synthetic pathway is becoming a primary route for (3R,5S)-CDHH production due to its high enantioselectivity, mild reaction conditions, low cost, process safety, and environmental friendship. However, the requirement of the pyridine nucleotide cofactors, reduced nicotinamide adenine dinucleotide (NADH) or reduced nicotinamide adenine dinucleotide phosphate (NADPH) limits its economic flexibility. In the present study, a recombinant Escherichia coli strain harboring carbonyl reductase R9M and glucose dehydrogenase (GDH) was constructed with high carbonyl reduction activity and cofactor regeneration efficiency. The recombinant E. coli cells were applied for the efficient production of (3R,5S)-CDHH with a substrate conversion of 98.8%, a yield of 95.6% and an enantiomeric excess (e.e.) of >99.0% under 350 g/L of (S)-CHOH after 12 hr reaction. A substrate fed-batch strategy was further employed to increase the substrate concentration to 400 g/L resulting in an enhanced product yield to 98.5% after 12 hr reaction in a 1 L bioreactor. Meanwhile, the space-time yield was 1,182.3 g L −1 day −1 , which was the highest value ever reported by a coupled system of carbonyl reductase and glucose dehydrogenase. K E Y W O R D Scarbonyl reductase, co-expression, glucose dehydrogenase, tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate

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Significant decrease in plasmad‐dimer levels and mean platelet volume after a 3‐month treatment with rosuvastatin in patients with venous thromboembolism

Alirezaei

Sattari

Irilouzadian

2022

Clinical Cardiology

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Background Inflammation has been considered as a possible mechanism for the initiation and recurrence of venous thromboembolism (VTE). Statins have anti‐inflammatory and potential immune‐modulatory effects, but their effect on plasma d ‐dimer levels is controversial. Hypothesis In this study, we aimed to evaluate the impact of rosuvastatin on D‐dimer and other inflammatory serum markers in VTE patients. Methods We conducted a prospective, randomized study on 228 patients with VTE. Control group received conventional treatment (warfarin or rivaroxaban), whereas rosuvastatin‐intervention group received rosuvastatin 10 mg daily, in addition to their conventional treatment for 3 months. Serum markers were extracted from both groups at the baseline and 3 months after the beginning of treatment. Results After 3 months, in patients of the intervention group, there was a statistically significant decrease in levels of d ‐dimer and mean platelet volume (MPV) but no significant change in neutrophil‐to‐lymphocyte ratio and platelet‐to‐lymphocyte ratio. Conclusions Our results showed that a 3‐month treatment with 10 mg rosuvastatin daily can significantly decrease the plasma levels of d ‐dimer and MPV, which would support a potential role of statins to reduce activated systemic inflammation among VTE patients. Such effects can be used to reduce the rate of recurrent VTE in these patients.

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Rosuvastatin use improves measures of coagulation in patients with venous thrombosis

Abstract: Rosuvastatin 20 mg/day substantially improved the coagulation profile among patients with prior VT. These results suggest that statin therapy might be beneficial in patients at risk of recurrent VT.

Cited by 56 publications

References 48 publications

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

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

Production of tert‐butyl (3R,5S)‐6‐chloro‐3,5‐dihydroxyhexanoate using carbonyl reductase coupled with glucose dehydrogenase with high space–time yield

Significant decrease in plasmad‐dimer levels and mean platelet volume after a 3‐month treatment with rosuvastatin in patients with venous thromboembolism

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