Correspondence
Rivaroxaban for Thromboprophylaxis
N Engl J Med 2008; 359:2174-2176November 13, 2008
- Article
To the Editor:
The studies by Eriksson et al. and Lassen et al. (June 26 issue)1,2 show the superiority of oral rivaroxaban over a fixed dose of enoxaparin for thromboprophylaxis. In both studies, there was a wide range in the body weights of the patients, with the weights at the low and high ends of the range differing by a factor of more than three. Was there any difference in effectiveness or safety as a function of body weight?
2 ReferencesEdward P. Schuman, M.D.
Holy Redeemer Hospital and Medical Center, Meadowbrook, PA 190461
Eriksson BI ,Borris LC ,Friedman RJ , et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358:2765-2775
Full Text | Web of Science | Medline2
Lassen MR ,Ageno W ,Borris LC , et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008;358:2776-2786
Full Text | Web of Science | Medline
To the Editor:
The administration of rivaroxaban might greatly simplify thromboprophylaxis in patients undergoing orthopedic surgery, but the lack of specific antidotes remains a challenge with new anticoagulant drugs, especially for activated factor X (factor Xa) inhibitors.1,2 For any new anticoagulant drug, specific indications for reversing anticoagulation should be formulated, and a direct inhibitor should be developed.
2 ReferencesGiuseppe Lippi, M.D.
Università di Verona, 37134 Verona, Italy
ulippi@tin.it Massimo Franchini, M.D.
Servizio Immunoematologia e Trasfusione, 43010 Parma, ItalyGiovanni Targher, M.D.
Università di Verona, 37134 Verona, Italy1
Franchini M ,Lippi G . Antagonists of activated factor X and thrombin: innovative antithrombotic agents. Curr Vasc Pharmacol 2007;5:121-128
CrossRef | Web of Science | Medline2
Weitz JI ,Hirsh J ,Samama MM . New antithrombotic drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133:Suppl:234S-256S[Erratum, Chest 2008;134:473.]
CrossRef | Web of Science | Medline
To the Editor:
I am an orthopedic surgeon and a member of a steering committee for a rivaroxaban trial, the Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism (RECORD) 4 trial. Although rivaroxaban, as compared with enoxaparin, has been shown to have superior efficacy and reasonable safety, I would not recommend it for my patients.
The study by Lassen et al. compared the performance of two drugs in reducing deep venous thrombosis after total knee arthroplasty. Like most anticoagulant studies, however, it did not measure the surgical outcomes, such as wound healing, drainage, infection, range of motion, and chronic pain.
The prevalence of fatal pulmonary embolism after total knee arthroplasty is 0.1%. We must balance that risk with the reported 3.0% risk of major and clinically significant bleeding and other, unstudied consequences related to anticoagulant drugs.
Recognizing the bleeding risks, orthopedists have established their own guidelines for the prevention of pulmonary embolism.1 These guidelines have met with considerable resistance from chest physicians.
Paul A. Lotke, M.D.
University of Pennsylvania, Philadelphia, PA 19104
paul.lotke@uphs. upenn. edu Dr. Lotke reports receiving consulting fees from Bayer. No other potential conflict of interest relevant to this letter was reported.
1 References1
American Academy of Orthopaedic Surgeons clinical guideline on prevention of pulmonary embolism in patients undergoing total hip or knee arthroplasty. May 2007. (Accessed October 24, 2008, at http://www.aaos.org/research/guidelines/PE_guideline.pdf.)
To the Editor:
In their editorial accompanying the reports by Eriksson et al. and Lassen et al., Lohrmann and Becker1 bid farewell to the conventional anticoagulant drugs: “Gone are the days of nonselective anticoagulants with unfavorable pharmacokinetics and pharmacodynamics, archaic and highly vulnerable manufacturing processes, and predictably unpredictable off-target effects.” Obviously, many physicians and their patients will welcome new oral drugs when they turn out to be effective and safe. However, we should not yet throw the baby out with the bath water — the “old” vitamin K antagonists and (low-molecular-weight) heparins have been quite safe and effective for decades, and manufacturing accidents have, in general, been extremely rare.2
In addition to the evaluation of new agents for secondary prevention in ongoing trials, the safety of these agents will need to be determined in the usual patient; many such patients are excluded from clinical trials. Furthermore, the lack of laboratory monitoring and antidotes poses potential safety drawbacks. Finally, selective anticoagulants might well have unpredictable off-target effects, given that proteases such as thrombin are involved in complex diseases such as atherosclerosis and cancer.3,4 This will necessitate thorough and long-term clinical monitoring.
4 ReferencesHugo ten Cate, M.D.
Karly Hamulyak, M.D.
Maastricht University Medical Center, 6200MD Maastricht, the Netherlands
h.tencate@bioch. unimaas. nl 1
Lohrmann J ,Becker RC . New anticoagulants -- the path from discovery to clinical practice. N Engl J Med 2008;358:2827-2829
Full Text | Web of Science | Medline2
Kishimoto TK ,Viswanathan K ,Ganguly T , et al. Contaminated heparin associated with adverse clinical events and activation of the contact system. N Engl J Med 2008;358:2457-2467
Full Text | Web of Science | Medline3
Croce K ,Libby P . Intertwining of thrombosis and inflammation in atherosclerosis. Curr Opin Hematol 2007;14:55-61
CrossRef | Web of Science | Medline4
Nierodzik ML ,Karpatkin S . Thrombin induces tumor growth, metastasis, and angiogenesis: evidence for a thrombin-regulated dormant tumor phenotype. Cancer Cell 2006;10:355-362
CrossRef | Web of Science | Medline
Author/Editor Response
Schuman correctly notes that patients enrolled in the RECORD 1 and RECORD 3 trials had a wide weight range and were given the same dose of rivaroxaban or enoxaparin. However, body weight did not significantly affect either efficacy or bleeding for rivaroxaban or enoxaparin. The superiority of rivaroxaban over enoxaparin was shown across the spectrum of patients who weighed 50 to 110 kg (97% of all those who underwent randomization).
For the treatment of venous thromboembolic disease, the doses of traditional anticoagulants vary among patients on the basis of laboratory monitoring of the anticoagulant effect (for intravenous heparin and warfarin) or body weight (for low-molecular-weight heparins). However, when used as primary thromboprophylaxis, fixed doses of heparin, low-molecular-weight heparin, fondaparinux, and rivaroxaban have been shown to be highly effective and safe in a broad spectrum of patients.
My colleagues and I agree with Lippi et al. that strategies for reversal of the anticoagulant effect should be considered for every anticoagulant. However, we do not agree that a specific antidote is required for each new anticoagulant. Specifically reversing the effect of newer anticoagulants with relatively short half-lives, rather than simply waiting for the anticoagulant effect to decrease, is usually not necessary in clinical practice. There is no specific antidote for low-molecular-weight heparins, despite the extensive use of these agents for the treatment and prevention of thromboembolic disorders for more than 20 years.1 If life-threatening bleeding occurs after the administration of one of the new anticoagulants, recombinant activated factor VII (rFVIIa) may be effective.1 Although there is no specific antidote to reverse the effects of rivaroxaban, preclinical studies suggest that rFVIIa or activated prothrombin-complex concentrate (FEIBA) may reverse the effects of high-dose rivaroxaban.2,3 If strategies such as delayed administration of the next dose of rivaroxaban or discontinuation, mechanical compression, surgical intervention, and blood-product transfusion fail to control bleeding, the administration of rFVIIa or FEIBA may be considered. At this time, however, there are no data on the use of these agents in patients receiving rivaroxaban.
3 ReferencesWilliam Geerts, M.D.
Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canadafor the RECORD 1 and RECORD 3 Investigators
1
Hirsh J ,Bauer KA ,Donati MB , et al. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133:Suppl:141S-159S[Erratum, Chest 2008;134:473.]
CrossRef | Web of Science | Medline2
Gruber A ,Marzec UM ,Buetehorn U ,Hanson SR ,Perzborn E . Recombinant factor VIIa reverses the effects of a high dose of rivaroxaban in baboons. Pathophysiol Haemost Thromb 2007;36:Suppl 1:A39-A393
Perzborn E ,Tinel H . FEIBA reverses the effects of a high dose of rivaroxaban in rats. Pathophysiol Haemost Thromb 2007;36:Suppl 1:A40-A40
CrossRef | Web of Science
Author/Editor Response
The RECORD 3 trial was designed to investigate and compare the efficacy and safety of the anticoagulants rivaroxaban and enoxaparin for the prevention of venous thromboembolism in patients undergoing total knee replacement. The trial compared the effects of 10 mg of rivaroxaban per day with 40 mg of enoxaparin per day for 10 to 14 days. The primary outcome, total venous thromboembolism (a composite of any deep venous thrombosis, nonfatal pulmonary embolism, or death from any cause), occurred in significantly fewer of the patients who received rivaroxaban as compared with those who received enoxaparin (P<0.001).
We agree that the risk of fatal pulmonary embolism must be balanced against the risk of bleeding, but the likelihood of fatal bleeding events must also be considered. In the RECORD 3 trial, there were no deaths attributable to bleeding, but there were deaths due to venous thromboembolism. Furthermore, there was a clinically significant reduction in venous thromboembolism including death without increased bleeding, a finding of great interest for clinicians and patients.
The RECORD 3 trial, like other phase 3 trials of anticoagulants, was neither designed nor intended to provide long-term data on the outcomes of knee arthroplasty. However, the study did provide results on end points that can affect long-term outcomes. The rivaroxaban and enoxaparin groups had similar incidences of major bleeding, hemorrhagic wound complications, blood transfusions, and postoperative wound infections. Only long-term studies of patients undergoing total knee replacement can assess the risks and benefits of various anticoagulants in regard to the surgical outcomes.
The RECORD 3 trial was never intended to compare different enoxaparin regimens; rather, the aim of the rivaroxaban clinical trial program was to establish the safest and most effective dose. A number of factors, such as differences in dosage, pharmacologic targets, or the timing of drug administration, can influence safety or efficacy. However, the trial was not designed or intended to address these issues.
Michael R. Lassen, M.D.
Nordsjællands Hospital, DK-2970 Hørsholm, Denmark
mirula@noh.regionh. dk Walter Ageno, M.D.
University of Insubria, 21100 Varese, ItalyAlexander G.G. Turpie, M.D.
McMaster University, Hamilton, ON L8L 2X2, CanadaAuthor/Editor Response
Our comments were written in the context of contemporary drug development, emphasizing the importance of guiding principles for safe and effective compounds.
We agree with Drs. ten Cate and Hamulyak that carefully designed clinical trials, parallel mechanistic studies,1 and stringent postmarketing surveillance will be required to fully characterize drug safety in diverse patient populations. Their point about active reversibility and the promise of antidotes to achieve “stepwise” anticoagulant intensity is well taken.2,3
As the availability of oral, selective, and direct anticoagulants expands, selection of the right drug at the right dose for the right patient will require clinical acumen and in-depth knowledge of each drug's pharmacokinetics, pharmacodynamics, pharmacogenomics, and specific mechanisms of action, as well as familiarity with the applicable coagulation-assessment tools and the pathobiology of disease. In some settings, a vitamin K antagonist may indeed be the preferred anticoagulant.
3 ReferencesJens Lohrmann, M.D.
University of Freiburg, 79106 Freiburg, GermanyRichard C. Becker, M.D.
Duke University School of Medicine, Durham, NC 277051
Becker RC . A rationale for conducting parallel mechanistic studies in clinical trials of pharmacotherapy. J Thromb Thrombolysis 2008;25:300-302
CrossRef | Web of Science | Medline2
Chan MY ,Rusconi CP ,Alexander JH ,Tonkens RM ,Harrington RA ,Becker RC . A randomized, repeat-dose, pharmacodynamic, and safety study of an antidote-controlled factor IXa inhibitor. J Thromb Haemost 2008;6:789-796
CrossRef | Web of Science | Medline3
Chan MY ,Cohen MG ,Dyke CK , et al. Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease. Circulation 2008;117:2865-2874
CrossRef | Web of Science | Medline
- Citing Articles (4)
Citing Articles
1
Emmanuel J. Favaloro, Giuseppe Lippi. (2011) Laboratory testing and/or monitoring of the new oral anticoagulants/antithrombotics: for and against?. Clinical Chemistry and Laboratory Medicine 49:5, 755-757
CrossRef2
R. Guijarro, J. Montes, C. San Román, J. I. Arcelus, G. Barillari, X. Granero, M. Monreal. (2011) Venous thromboembolism and bleeding after total knee and hip arthroplasty. Thrombosis and Haemostasis 105:4, 610-615
CrossRef3
(2009) Dabigatran versus Warfarin in Patients with Atrial Fibrillation. New England Journal of Medicine 361:27, 2671-2675
Full Text4
Umile Giuseppe Longo, Nicola Maffulli, Vincenzo Denaro. (2009) Rivaroxaban versus enoxaparin after total knee arthroplasty. The Lancet 374:9691, 681-682
CrossRef
