Risk of recurrent venous thromboembolism after discontinuation of vitamin K antagonist treatment: a nested case–control study

Martínez, Carlos; Katholing, Anja; Folkerts, Kerstin; Cohen, Alexander T.

doi:10.1111/jth.13337

Cited by 16 publications

(13 citation statements)

References 25 publications

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“…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 . As both thrombin generation and D‐dimer are markers of hypercoagulability , 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 . Preventing such a rebound hypercoagulability may be a further benefit to patients with previous VTE in whom anticoagulation is withdrawn.…”

Section: Discussionsupporting

confidence: 91%

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: 91%

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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“…11 After withdrawal of anticoagulant treatment, D-dimer levels normally increase, which is called the rebound phenomenon. 33,34 D-dimer levels are the result of the amount of available fibrin and the fibrinolytic potential. Rosuvastatin is expected to lower fibrin levels by reducing clotting factors and by its anti-inflammatory effects, and to increase the fibrinolytic potential.…”

Section: Discussionmentioning

confidence: 99%

Rosuvastatin use increases plasma fibrinolytic potential: a randomised clinical trial

et al. 2020

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We conducted a study to assess the effect of rosuvastatin use on fibrinolysis in patients with previous venous thromboembolism (VTE). This was a post hoc analysis within the STAtins Reduce Thrombophilia (START) study (NCT01613794). Plasma fibrinolytic potential, fibrinogen, plasmin inhibitor, plasminogen activator inhibitor‐1 (PAI‐1) and thrombin‐activatable fibrinolysis inhibitor (TAFI) were measured before and after four weeks of rosuvastatin or no treatment in participants with prior confirmed VTE, after ending anticoagulant therapy. In the non‐rosuvastatin group (n = 121), plasma fibrinolytic potential and individual fibrinolysis parameters did not change at the end of the study versus the baseline, whereas in the rosuvastatin group (n = 126), plasma fibrinolytic potential increased: the mean clot lysis time decreased by 8·75 min (95% CI −13·8 to −3·72), and plasmin inhibitor levels and TAFI activity were lower at the end of the study (−0·05 U/ml; 95% CI −0·07 to −0·02 and −4·77%; 95% CI −6·81 to −2·73, respectively). PAI‐1 levels did not change and fibrinogen levels were 0·17 g/l (95% CI 0·04–0·29) higher. In participants with prior VTE, rosuvastatin use led to an increased fibrinolytic potential compared with non‐statin use. Our findings support the need for further studies on the possible role for statins in the secondary prevention of VTE.

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“…In addition, blood sampling was done 3 months after discontinuation, which is fundamentally different from the original models (Vienna and DASH), where blood is drawn 1 month after discontinuation. This may have led to underestimation of risks, as some studies have suggested a rebound phenomenon in which several markers of coagulation, including D‐dimer levels, increase shortly after anticoagulant treatment is withheld and because the risk of recurrence is highest shortly after anticoagulation withdrawal . Of note, 52 patients had a recurrent event before D‐dimer testing and were not included in the analyses as this could lead to immortal time bias.…”

Section: Discussionmentioning

confidence: 99%

Risk prediction of recurrent venous thrombosis; where are we now and what can we add?

Timp

Lijfering

Rosendaal

et al. 2019

Journal of Thrombosis and Haemostasis

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BackgroundSeveral models are available to predict recurrent venous thrombosis (VT) in patients with unprovoked first events.ObjectivesTo validate these prediction models externally.MethodsWithin the MEGA follow‐up study (n = 3750), we externally validated the Vienna and DASH score. These models were validated (a) by using the original study's criteria for patients with unprovoked VT and (b) by using our own criteria for unprovoked VT. In addition, absolute recurrence risks based on individual VT risk factors were calculated.ResultsThe recurrence rate was 5.2 (95% CI, 4.6‐5.9) per 100 patient‐years in those who had a first unprovoked VT according to our definition. For the Vienna model it was 3.4 per 100 patient‐years and for DASH 3.8 per 100 patient‐years. The C‐statistic was 0.62 for Vienna and 0.65 for DASH. The C‐statistic declined to 0.58 for both Vienna and DASH when we used our own definition of “unprovoked VT.” Within the provoked group a strong gradient in risk was found dependent on the presence of traditional risk factors or biomarkers in a patient.ConclusionsThe ability to distinguish patients’ recurrence risks is lower than proposed in the original prediction model studies and dependent on the definition that is used for an unprovoked first event. Furthermore, our results suggest that a more‐refined risk estimation is possible, also in patients with a provoked first event, who are currently all classified as low risk.

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Risk of recurrent venous thromboembolism after discontinuation of vitamin K antagonist treatment: a nested case–control study

Cited by 16 publications

References 25 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

Rosuvastatin use increases plasma fibrinolytic potential: a randomised clinical trial

Risk prediction of recurrent venous thrombosis; where are we now and what can we add?

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