Note: The corresponding author had full access to all data and final responsibility for the decision to submit the manuscript for publication.
Acknowledgment: The authors thank the Catalan Lupus Foundation and all the patients who participated in the trial; the investigators who recruited patients to the study; and the research staff who assisted with patient recruitment, data collection, biomarker measurements, and data management.
Financial Support: From Bayer Hispania.
Disclosures: Drs. Ordi-Ros and Cortés-Hernández report institutional support from Bayer Hispania to conduct the study. Dr. Ortiz-Santamaria reports personal fees and nonfinancial support from Pfizer, Janssen, Lilly, GSK, Novartis, Roche, and Abbott outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at
www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-0291.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Catharine B. Stack, PhD, MS, Deputy Editor, Statistics, reports that she has stock holdings in Pfizer, Johnson & Johnson, and Colgate-Palmolive. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Data Sharing Statement: The following data will be made available with publication: deidentified participant data (available from Dr. Josefina Cortés-Hernández; e-mail,
[email protected]). The following supporting documents will be made available with publication: informed consent form (available from Dr. Josefina Cortés-Hernández; e-mail,
[email protected]). These data will be made available to researchers whose proposed use of the data has been approved for a specified purpose, with investigator support, and with a signed data access agreement (no restrictions).
Corresponding Author: Josefina Cortés-Hernández, MD, PhD, Department of Internal Medicine, Rheumatology Research Group, Vall d'Hebrón University Hospital Research Institute, Passeig Vall d'Hebrón 119-129, 08035, Barcelona, Spain; e-mail,
[email protected].
Current Author Addresses: Drs. Ordi-Ros, Vidal, and Solé: Vall d'Hebrón University Hospital Research Institute, Passeig Vall d'Hebrón 119-129, 08035, Barcelona, Spain.
Drs. Sáez-Comet and Pérez-Conesa: Servicio de Medicina Interna, Hospital Universitario Miguel Servet, Paseo Isabel La Católica 9, 50009, Zaragoza, Spain.
Dr. Riera-Mestre: Internal Medicine Department, L'Hospitalet de Llobrega, Feixa llarga s/n, 08907, Barcelona, Spain.
Dr. Castro-Salomó: Internal Medicine Department, Sant Joan de Reus University Hospital, Sant Joaquim 42 1-3, 43204, Reus, Spain.
Drs. Cuquet-Pedragosa and Ortiz-Sanatmaria: Granollers University Hospital, Avinguda Francesc Ribas s/n, 08402, Granollers, Spain.
Dr. Mauri-Plana: Department of Internal Medicine, Mataro Hospital, Carrer de Cirera, 230, 08304, Mataró, Spain.
Dr. Cortés-Hernández: Department of Internal Medicine, Rheumatology Research Group, Vall d'Hebrón University Hospital Research Institute, Passeig Vall d'Hebrón 119-129, 08035, Barcelona, Spain.
Author Contributions: Conception and design: J. Ordi-Ros, M. Pérez-Conesa, X. Vidal, J. Cortés-Hernández.
Analysis and interpretation of the data: J. Ordi-Ros, X. Vidal, A. Castro-Salomó, C. Solé, J. Cortés-Hernández.
Drafting of the article: J. Ordi-Ros, L. Sáez-Comet, X. Vidal, A. Riera-Mestre, C. Solé, J. Cortés-Hernández.
Critical revision for important intellectual content: J. Ordi-Ros, L. Sáez-Comet, X. Vidal, A. Castro-Salomó, J. Cuquet-Pedragosa, C. Solé, J. Cortés-Hernández.
Final approval of the article: J. Ordi-Ros, L. Sáez-Comet, M. Pérez-Conesa, X. Vidal, A. Riera-Mestre, A. Castro-Salomó, J. Cuquet-Pedragosa, V. Ortiz-Santamaria, M. Mauri-Plana, C. Solé, J. Cortés-Hernández.
Provision of study materials or patients: J. Ordi-Ros, L. Sáez-Comet, M. Pérez-Conesa, A. Castro-Salomó, V. Ortiz-Santamaria, J. Cortés-Hernández.
Statistical expertise: X. Vidal.
Obtaining of funding: J. Ordi-Ros, J. Cortés-Hernández.
Administrative, technical, or logistic support: J. Ordi-Ros, L. Sáez-Comet, J. Cortés-Hernández.
Collection and assembly of data: J. Ordi-Ros, L. Sáez-Comet, M. Pérez-Conesa, X. Vidal, A. Riera-Mestre, A. Castro-Salomó, J. Cuquet-Pedragosa, M. Mauri-Plana, J. Cortés-Hernández.
This article was published at
Annals.org on 15 October 2019.
Rivaroxaban vs VKA in APS
A bias may well have been introduced into the study by Ordi-Ros et al influencing the findings that more thrombotic events occurred in the rivaroxaban treated group than in the vitamin K antagonists (VKA) group, as the study may have favored enrollment of patients who tend to do well on VKAs [ref 1]. It would be important to know (a) how long patients had been on anticoagulation for their previous thrombotic event(s) before they were enrolled and (b) how many of them had previously been treated with a VKA or a direct oral anticoagulant (DOAC). Given the enrollment criteria, I suspect that the anticoagulant used prior to study enrollment had been a VKA in the majority of patients.
VKAs are known to have a substantial failure rate with recurrent thrombosis occurring in up to 11.1 % of patients [ref 2,3]. In clinical practice, such patients are often switched to another anticoagulant and would likely not have been approached for enrollment into the current study given their warfarin failure. Therefore, this study likely enrolled patients who, by their history of having tolerated a VKA well, were expected to continue to do well on a VKA. On the other hand, a number of patients randomized to the rivaroxaban arm were likely rivaroxaban-naïve, thus never before had a chance to prove rivaroxaban failure. This may have led to a bias of the observed lower thrombosis rate in the VKA compared to the rivaroxaban group. The TRAPS study, also did not report the pre-enrollment anticoagulant drug and treatment length details and, therefore, may have been biased in the same way [ref 4].
The only scientifically accurate clinical conclusion that can be drawn from the current study – as well as the TRAPS study - is this: Patients with APS and a history of thrombosis who have done well on a VKA are best continued on a VKA as they have a low VKA failure rate, but a higher rate if switched to rivaroxaban. In patients with newly diagnosed APS, however, it is currently not known whether a VKA or a DOAC is a better choice; either one can lead to anticoagulant failure. The strong statement in the Summary for Patients, that “Rivaroxaban should not be used to prevent blood clots in patients with APS”, is scientifically not solid or justifiable given the limitations discussed above [ref 5].
References
1. Ordi-Ros J, Sáez-Comet L, Pérez-Conesa M, Vidal X, Riera-Mestre A, Castro-Salomó A, Cuquet-Pedragosa J, Ortiz-Santamaria V, Mauri-Plana M, Solé C, Cortés-Hernández J. Rivaroxaban Versus Vitamin K Antagonist in Antiphospholipid Syndrome: A Randomized Noninferiority Trial. Ann Intern Med. 2019 Oct 15. doi: 10.7326/M19-0291. [Epub ahead of print].
2. Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, Laskin C, Fortin P, Anderson D, Kearon C, Clarke A, Geerts W, Forgie M, Green D, Costantini L, Yacura W, Wilson S, Gent M, Kovacs MJ. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003 Sep 18;349(12):1133-8.
3. Finazzi G, Marchioli R, Brancaccio V, Schinco P, Wisloff F, Musial J, Baudo F, Berrettini M, Testa S, D'Angelo A, Tognoni G, Barbui T A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost. 2005 May;3(5):848-53.
4. Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A, Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A, De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S, Barcellona D, Gerosa M, Banzato A. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018 Sep 27;132(13):1365-1371. doi: 10.1182/blood-2018-04-848333. Epub 2018 Jul 12.
5. Summaries for patients. Rivaroxaban versus Vitamin K Antagonist in Antiphospholipid Syndrome. Ann Intern Med Oct 15, 2019.
Disclosures: None
Corticosteroid drug interactions with rivaroxaban
We read with interest this important study by Ordi-Ros and colleagues comparing the efficacy and safety of rivaroxaban versus vitamin K antagonist (VKA) for secondary thromboprophylaxis in patients with antiphospholipid antibody syndrome (APS).(1) Surprisingly, not only was rivaroxaban shown to be not non-inferior to VKA, but there was also a nearly two-fold increase (albeit statistically non-significant) in thrombotic events (rivaroxaban, 11.6% vs. VKA, 6.3%).(1) These results were similar to the Trial on Rivaroxaban in AntiPhospholid Syndrome (TRAPS) study conducted in patients with triple-positive APS.(2) It is unclear why patients receiving rivaroxaban had a higher incidence of thrombotic events and the authors present several sensible potential explanations in their discussion. Expanding on their first hypothesis of subtherapeutic rivaroxaban drug concentrations, we would like to propose an additional potential explanation for the study findings.
Rivaroxaban is a substrate of both CYP3A4 and P-glycoprotein (P-gp) at the level of the gut, liver, and kidney.(3) While patients who were taking CYP3A4 inducers, such as rifampin, phenytoin, phenobarbital and carbamazepine were excluded from the study, 27.4% of patients in the rivaroxaban group were taking corticosteroids.(1) Similarly in the TRAPS study, 19% of patients receiving rivaroxaban were also receiving corticosteroids.(2) Corticosteroids have been demonstrated to induce CYP3A4 and P-gp which would result in reduced bioavailability, increased metabolism and excretion, and ultimately lower, potentially subtherapeutic serum concentrations that would put a patient at increased risk for thrombosis.(3-5) The European Society of Cardiology guidelines recommend avoiding concomitant use of direct oral anticoagulants (DOACs) with corticosteroids; specifically dexamethasone is contraindicated, and caution is advised with prednisone.(3) Without therapeutic drug monitoring, it is impossible to be certain of levels, but given that more than a quarter of the study participants were on corticosteroids, the consequent CYP3A4 and P-gp induction could be a real explanation as to why rivaroxaban failed in this study. All DOACs are subject to this drug interaction with corticosteroids to some degree, and future studies examining DOACs in APS should take this into account.
References:
1. Ordi-Ros J, Saez-Comet L, Perez-Conesa M, et al. Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome: A randomized non-inferiority trial. Ann Intern Med. 15 October 2019. [Epub ahead of print]. doi: 10.7326/M19-0291.
2. Pengo V, Denas G, Zoppellaro G, et al. Rivaroxaban vs. warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018;132:1365-1371.
3. Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018;39:1330-1393.
4. Shimada T, Terada A, Yokogawa K, et al. Lowered blood concentration of tacrolimus and its recovery with changes in expression of CYP3A and P-glycoprotein after high-dose steroid therapy. Transplantation. 2002;74:1419-1424.
5. Usui T, Saitoh Y, Komada F. Induction of CYP3As in HepG2 cells by several drugs – association between induction of CYP3A4 and expression of glucocorticoid receptor. Biol Pharm Bull. 2003;26:510-517.
Authors' Response to Leong
Drug, herbal medicines and foods have many interactions with old and new oral anticoagulants (2). The DOACS are approved for the prevention and treatment of venous thromboembolism and of systemic and cerebral embolism in atrial fibrillation. Their advantages over VKA include a more predictable and stable anticoagulant effect and fewer interactions with foods, herbal supplements or drugs. However, the interactions have been poorly evaluated to date and more studies are needed in order to understand these aspects better. Awareness of drugs that alter the function of the P-gp efflux transporter protein and CYP3A4 enzymes and provide additive effects should enable prescribers to anticipate and avoid potential drug-drug interactions involving the new oral anticoagulants [3]. In new prospective randomized studies, it is important to consider possible pharmacological interactions of DOACs and other drugs that patients receive.
References
1. Ordi-Ros J, Sáez-Comet L, Pérez-Conesa M, Vidal X, Riera-Mestre A, Castro-Salomó A, Cuquet-Pedragosa J, Ortiz-Santamaria V, Mauri-Plana M, Solé C, Cortés-Hernández J. Rivaroxaban versus Vitamin K antagonist in Antiphospholipid síndrome: a randomized Noninferiority Trial. Ann Intern Med 2019 Oc 15.doi: 10.7326/M19-0291 [Epub ahead of print]
2.- Di Minno A, Frigerio B, Spadarella G, Ravani A, Sansaro D, Amato M, Kitzmiller JP, Pepi M, Tremoli E, Baldassarre D. Old and oral anticoagulants: Food, herbal medicines and drug interactions. Blood Reviews 2017;31:193-203
3.- Herink MC, Zhuo YF, Williams CD, DeLoughery TG. Clinical Management of Pharmacokinetic Drug Interactions with Direct Oral Anticoagulants (DOACs). Drugs 2019;79:1625-1634.
Authors Response to Moll
At the time of APS diagnosis, all patients were anticoagulated with VKA, standard INR 2.0 to 3.0. Those patients with recurrent arterial or venous thrombosis despite therapy were treated according standard clinical practice increasing the INR target to 3-4 or adding low dose aspirin (100 mg/day) rather than changing to direct oral anticoagulants (DOAC) [2]. DOACS were not financed by health authorities at the time of the study in APS. Thrombosis recurrence in APS occurs in up to 11.1 % of patients while treated with VKA [ref 3,4]. In response to treatment history, the duration of anticoagulation ranged between 4 to 15 years and there were no differences between VKA and Rivaroxaban groups regarding the period of exposure to VKA prior to enrolment. Median time on VKA in the rivaroxaban-treated group was 7 years (4-15 years) and 6 years (4-12) for the VKA-treated group [1].
In our study, not only patients doing well on VKA were enrolled, but there were also 28 APS patients (14.7%) with a history of recurrent thrombosis despite VKA that at inclusion were requiring high intensity anticoagulation (INR 3.1 to 4.0). As shown in Table 1 [1], the proportion of patients enrolled with a higher target INR (3.1 to 4.0) was similar in both groups (12/95 (12.6%) rivaroxaban vs 16/95 (16.8%) VKA) [1]. Therefore, since there was no selection at inclusion of patients based on their response to VKA, the introduction of a bias is unlikely. Finally, we agree that there is not enough knowledge for comparative VKA and DOAC rates of failure in newly diagnosed APS patients. However, new patients should be evaluated individually and stratified according to their thrombotic risk. Rivaroxaban should not be used in patients with APS with triple aPL positivity and caution needs to be taken with those with migraine, valvulopathy and livedo reticularis [1,5].
References:
1. Ordi-Ros J, Sáez-Comet L, Pérez-Conesa M, Vidal X, Riera-Mestre A, Castro-Salomó A, Cuquet-Pedragosa J, Ortiz-Santamaria V, Mauri-Plana M, Solé C, Cortés-Hernández J. Rivaroxaban versus Vitamin K antagonist in Antiphospholipid síndrome: a randomized Noninferiority Trial. Ann Intern Med 2019 Oc 15.doi: 10.7326/M19-0291 [Epub ahead of print]
2. Tektonidou MG, Andreoli L, Limper M, Amoura Z, Cervera R, Costedoat-Chalumeau N, Cuadrado MJ, Dörner T, Ferrer-Oliveras R, Hambly K, Khamashta MA, King J, Marchiori F, Meroni PL, Mosca M, Pengo V, Raio L, Ruiz-Irastorza G, Shoenfeld Y, Stojanovich L, Svenungsson E, Wahl D, Tincani A, Ward MM. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis. 2019 Oct;78(10):1296-1304. doi: 10.1136/annrheumdis-2019-215213.
3. Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, Laskin C, Fortin P, Anderson D, Kearon C, Clarke A, Geerts W, Forgie M, Green D, Costantini L, Yacura W, Wilson S, Gent M, Kovacs MJ. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003 Sep 18;349(12):1133-8.
4. Finazzi G, Marchioli R, Brancaccio V, Schinco P, Wisloff F, Musial J, Baudo F, Berrettini M, Testa S, D'Angelo A, Tognoni G, Barbui T. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost. 2005 May;3(5):848-53.
5. Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A, Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A, De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S, Barcellona D, Gerosa M, Banzato A. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018 Sep 27;132(13):1365-1371. doi: 10.1182/blood-2018-04-848333. Epub 2018 Jul 12.
Authors' Response
All patients were anticoagulated with an adjusted-dose of VKA since diagnosis. No one received DOACS as they were not financed by health authorities for APS at study time. Duration of VKA anticoagulation prior to enrolment ranged between 4 to 15 years and there was no significant difference between groups. Median time on VKA in the rivaroxaban-treated group was 7 years (4-15 years) and 6 years (4-12) for the VKA-treated group [1]. Finally, we agree that there is not enough knowledge for comparative VKA and DOAC failure rates in newly-diagnosed APS. However, new patients should be evaluated individually and stratified according to their thrombotic risk. Rivaroxaban should not be indicated in APS patients with triple aPL positivity. Caution needs to be taken in those with migraine, valvulopathy and livedo reticularis racemosa [1,2].
Leong et al suggest a possible drug interaction, such as corticosteroids, on the rivaroxaban metabolism as a cause of the observed increased thrombosis. Corticosteroid treatment in APS is rarer than in systemic lupus erythematosus (SLE), although high prednisone doses (>0.5 mg/kg or i.v methylprednisolone pulses) are administered in severe APS complications (e.g pulmonary capillaritis, catastrophic syndrome, severe thrombocytopenia or hemolytic anemia). The influence of steroids in our results seems unlikely since only 32.6% of the rivaroxaban-treated patients and 28.4% of VKA-treated group were receiving prednisone at low doses (mean dose of 2.68±6.5 mg/day and 1.89±5.29 mg/day respectively) (1). SLE flares requiring a steroid increment only occurred in 8 patients in the rivaroxaban group and 3 in the VKA group. Only one in the VKA group with severe membranous lupus glomerulonephritis developed a DVT.
Drugs, herbal medicines and foods have many interactions with old and new oral anticoagulants [3]. The advantages of DOACS over VKA include a more predictable and stable anticoagulant effect and fewer interactions but these have not been extensively studied. Awareness of drugs interacting with the P-gp efflux transporter protein and CYP3A4 enzymes should flag potential drug-drug interactions with new oral anticoagulants [4]. Pharmacological interactions with DOACS should be considered in future studies.
References:
1. Ordi-Ros J, Sáez-Comet L, Pérez-Conesa M, Vidal X, Riera-Mestre A, Castro-Salomó A, Cuquet-Pedragosa J, Ortiz-Santamaria V, Mauri-Plana M, Solé C, Cortés-Hernández J. Rivaroxaban versus Vitamin K antagonist in Antiphospholipid síndrome: a randomized Noninferiority Trial. Ann Intern Med 2019 Oc 15.doi: 10.7326/M19-0291 [Epub ahead of print]
2. Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A, Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A, De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S, Barcellona D, Gerosa M, Banzato A. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018 Sep 27;132(13):1365-1371. doi: 10.1182/blood-2018-04-848333. Epub 2018 Jul 12.
3. Di Minno A, Frigerio B, Spadarella G, Ravani A, Sansaro D, Amato M, Kitzmiller JP, Pepi M, Tremoli E, Baldassarre D. Old and oral anticoagulants: Food, herbal medicines and drug interactions. Blood Reviews 2017;31:193-203
4. Herink MC, Zhuo YF, Williams CD, DeLoughery TG. Clinical Management of Pharmacokinetic Drug Interactions with Direct Oral Anticoagulants (DOACs). Drugs 2019;79:1625-1634.