Dabigatran versus Warfarin after Mechanical Mitral Valve Replacement in the Swine Model

Schomburg, John; Medina, Eduardo; Lahti, Matthew T.; Bianco, Richard W.

doi:10.3109/08941939.2011.616256

Cited by 24 publications

(17 citation statements)

References 14 publications

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“…In an experimental swine model with a heart valve grafted onto the descending aorta, dabigatran administered post implantation for 30 days vs. LMWH significantly reduced valve thrombus and platelet deposition (McKellar et al, 2011). In a separate study, swine underwent mitral valve replacement and received dabigatran or warfarin for 90 days (Schomburg et al, 2012). Valve thrombus was observed in all groups; however there was decreased incidence of bleeding and a significant mortality benefit in the dabigatran-treated group vs. warfarin.…”

Section: Clinical Studies and Indicationsmentioning

confidence: 99%

The Discovery of Dabigatran Etexilate

Ryn¹,

Goss²,

Hauel³

et al. 2013

Front. Pharmacol.

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Thromboembolic disease is a major cause of mortality and morbidity in the developed world and is caused by an excessive stimulation of coagulation. Thrombin is a key serine protease in the coagulation cascade and numerous efforts have been made to develop safe and effective orally active direct thrombin inhibitors (DTIs). Current anticoagulant therapy includes the use of indirect thrombin inhibitors (e.g., heparins, low-molecular-weight-heparins) and vitamin K antagonists such as warfarin. However there are several caveats in the clinical use of these agents including narrow therapeutic window, parenteral delivery, and food- and drug–drug interactions. Dabigatran is a synthetic, reversible DTI with high affinity and specificity for its target binding both free and clot-bound thrombin, and offers a favorable pharmacokinetic profile. Large randomized clinical trials have demonstrated that dabigatran provides comparable or superior thromboprophylaxis in multiple thromboembolic disease indications compared to standard of care. This minireview will highlight the discovery and development of dabigatran, the first in a class of new oral anticoagulant agents to be licensed worldwide for the prevention of thromboembolism in the setting of orthopedic surgery and stroke prevent in atrial fibrillation.

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Section: Clinical Studies and Indicationsmentioning

confidence: 99%

The Discovery of Dabigatran Etexilate

Ryn¹,

Goss²,

Hauel³

et al. 2013

Front. Pharmacol.

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“…In recent studies in swine [55] and rabbit [56] even higher dosages were used. However, the dosage should not be elevated in this experiment due to the efficacy in 2 sheep and the increased possibility of bleeding complications.…”

Section: Discussionmentioning

confidence: 99%

New aspects on efficient anticoagulation and antiplatelet strategies in sheep

et al. 2013

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BackgroundAfter addressing fundamental questions in preclinical models in vitro or in small animals in vivo, the translation into large animal models has become a prerequisite before transferring new findings to human medicine. Especially in cardiovascular, orthopaedic and reconstructive surgery, the sheep is an important in vivo model for testing innovative therapies or medical devices prior to clinical application. For a wide variety of sheep model based research projects, an optimal anticoagulation and antiplatelet therapy is mandatory. However, no standardised scheme for this model has been developed so far. Thus the efficacy of antiplatelet (acetylsalicylic acid, clopidogrel, ticagrelor) and anticoagulant (sodium enoxaparin, dabigatran etexilate) strategies was evaluated through aggregometry, anti-factor Xa activity and plasma thrombin inhibitor levels in sheep of different ages.ResultsResponses to antiplatelet and anticoagulant drugs in different concentrations were studied in the sheep. First, a baseline for the measurement of platelet aggregation was assessed in 20 sheep. The effectiveness of 225 mg clopidogrel twice daily (bid) in 2/5 sheep and 150 mg bid in 3/5 lambs could be demonstrated, while clopidogrel and its metabolite carboxylic acid were detected in every plasma sample. High dose ticagrelor (375 mg bid) resulted in sufficient inhibition of platelet aggregation in 1/5 sheep, while acetylsalicylic acid did not show any antiplatelet effect. Therapeutic anti-factor Xa levels were achieved with age-dependent dosages of sodium enoxaparin (sheep 3 mg/kg bid, lambs 5 mg/kg bid). Administration of dabigatran etexilate resulted in plasma concentrations similar to human ranges in 2/5 sheep, despite receiving quadruple dosages (600 mg bid).ConclusionHigh dosages of clopidogrel inhibited platelet aggregation merely in a low number of sheep despite sufficient absorption. Ticagrelor and acetylsalicylic acid cannot be recommended for platelet inhibition in sheep. Efficient anticoagulation can be ensured using sodium enoxaparin rather than dabigatran etexilate in age-dependent dosages. The findings of this study significantly contribute to the improvement of a safe and reliable prophylaxis for thromboembolic events in sheep. Applying these results in future translational experimental studies may help to avoid early dropouts due to thromboembolic events and associated unnecessary high animal numbers.

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“…Developments in anticoagulation strategies may further influence surgical decision making in favour of mechanical prostheses. However, despite encouraging large animal data for thromboembolic prophylaxis with dabigatran in the setting of mechanical heart valve replacement,25 26 recent data from a randomised phase 2 study has associated dabigatran with increased rates of thromboembolic and bleeding complications compared to warfarin 27. Conversely, the development of mitral valve-in-valve transcatheter implantation techniques28 may lead to an increase in the implantation of bioprostheses.…”

Section: Discussionmentioning

confidence: 99%

Mitral valve prosthesis choice for patients aged 65 years and over in the UK. Are the guidelines being followed and does it matter?

Dimarakis

Grant

Hickey

et al. 2013

Heart

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Objective Current guidelines recommend that most patients aged ≥65 years should undergo mitral valve replacement (MVR) using a biological prosthesis. The objectives of this study were to assess whether these guidelines are being followed in UK practice, and to investigate whether the guidelines are appropriate based on in-hospital mortality and mid-term survival. Methods Data from the National Institute for Cardiovascular Outcomes Research Adult Cardiac Surgery Audit database from all National Health Service (NHS) hospitals and some private hospitals performing adult cardiac surgery in the UK between April 2001 and March 2011 were analysed. The overall cohort included 3862 patients aged ≥65 years who underwent first-time MVR. Propensity score matching and regression adjustment were used to compare outcomes between prosthesis groups. Results The mean age was 73.0 years (SD 4.9) with 50% of patients having surgery with a mechanical prosthesis. This proportion decreased over the study period and with increasing patient age with marked variation between hospitals. In the propensity-matched cohort, in-hospital mortality in the biological group was 6.9%, and in the mechanical group it was 5.9% giving an unadjusted OR of 1.17 (95% CI 0.84 to 1.63). There was no significant difference in mid-term survival between the matched groups with an unadjusted HR for biological prosthesis of 1.08 (95% CI 0.93 to 1.24). Similar results were found when using regression adjustment on unmatched data. Conclusions Current guidelines concerning age and mitral valve prosthesis choice are not being followed for patients aged ≥65 years. With regards to in-hospital and mid-term mortality, this study demonstrates that there is no difference between prosthesis types.

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Dabigatran versus Warfarin after Mechanical Mitral Valve Replacement in the Swine Model

Cited by 24 publications

References 14 publications

The Discovery of Dabigatran Etexilate

The Discovery of Dabigatran Etexilate

New aspects on efficient anticoagulation and antiplatelet strategies in sheep

Mitral valve prosthesis choice for patients aged 65 years and over in the UK. Are the guidelines being followed and does it matter?

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