Anticoagulanti Orali Diretti
Rivaroxaban is an oral direct reversibile and competitive inhibitor of activated factor X (Factor Xa).
It binds to both free and clot-bound factor Xa. Rivaroxaban was studied in 4 clinical trials (RECORD trials) for thromboprophylaxis in patients who have undergone a total knee or a total hip arthroplasty and the results in the rivaroxaban group were favorable.
Rivaroxaban was also studied in one trial,ROCKET-AF trial,(1) (NEJM 2011 vol. 365 pp. 883-891) for the prevention of stroke or systemic embolism in patients with non valvular atrial fibrillation, in 2 trials, EINSTEIN-DVT (2) (NEJM 2010 vol. 363 pp. 2499-2510) and EINSTEIN-EXTENSION (2) (NEJM 2010 vol. 363 pp. 2499-2510) trials,for treatment and secondary prevention of symptomatic deep vein thrombosis (DVT) and for prevention of recurrent venous thromboembolism in patients who had already completed 6 to 12 months of treatment for venous thromboembolism respectively, and in one trial, EINSTEIN-PE trial, (3) (NEJM 2012 vol. 366 pp. 1287-1297) was studied for treatment of symptomatic pulmonary embolism and for prevention of recurrent venous thromboembolism. In another clinical trial, ATLAS ACS 2-TIMI 51,(4) (NEJM 2012 vol. 366 pp. 9-19) rivaroxaban was compared to placebo in patients with a recent acute coronary syndrome. (For the results of these trials, and for diseases in which the therapeutic use of rivaroxaban has been approved by regulatory agencies, see section on "Indications") All these trials were funded by rivaroxaban manufacturer. As for dabigatran, also for rivaroxaban we do not have a specific antidote to neutralize its anticoagulant effect but, differently from dabigatran,in case of rivaroxaban bleedings,we can use Prothrombin Complex Concentrates (PCC) with a certain efficacy. Although there are less drug interactions than vitamin k antagonists such as warfarin,some important drug interactions are present with rivaroxaban.
This drug is both a CYP3A4 and P-glycoprotein (P-gp) substrate and its elimination is partially dependent on normal renal function. Concomitant use of rivaroxaban with strong inhibitors of CYP3A4 and P-glycoprotein (P-gp) as ketoconazol, ritonavir,chloramphenicol etc. must be avoided because AUC (area under the curve) that is a method of measurement of the bioavailability of a drug based on a plot of blood concentrations sampled at frequent intervals, and the Cmax,that is the maximum peak concentration that a drug achieves, are increased.
Also use with strong inducers of CYP3A4 and P-gp as carbamazepine, phenytoin, dexamethasone, rifampicin etc. must be avoided because in this case the average rivaroxaban AUC and Cmax are reduced. In this review, in the section “indications”, we will examine the results of the numerous clinical trials in which rivaroxaban was studied. Comments on these studies will be discussed at the end, in the section “ Conclusions “.
At the moment rivaroxaban has been approved by the European Medical Agency (EMA) for a) venous thromboprophylaxis in patients undergoing hip or knee replacement surgery, b) to prevent stroke or systemic embolism in patients with Nonvalvular Atrial Fibrillation, c) to treat Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE), d) to prevent recurrent DVT and PE, e) to prevent atherothrombotic events in patients who have had an Acute Coronary Syndrome (ACS) with elevated biomarkers. It has been approved for the same first four indications by the Food and Drug Administration (FDA) and in Canada, but not to prevent atherothrombotic events in patients with an Acute Coronary Syndrome (ACS). In fact on february 14 2014, the U.S. FDA has rejected rivaroxaban as a treatment for patients with acute coronary syndrome (ACS). This is the third time the agency has denied the supplemental new drug application (sNDA) based on data from the ATLAS-ACS 2 TIMI-51 trial for the rivaroxaban ACS indication. In January, the Cardiovascular and Renal Drugs Advisory Committee voted almost unanimously against approving rivaroxaban as a treatment in ACS patients. In addition to denying the sNDA for rivaroxaban in ACS to reduce the risk of MI, stroke, or death, the FDA also denied an expanded indication for rivaroxaban in ACS patients to reduce the risk of stent thrombosis. (5) (www.medscape.com/viewarticle/820651) Just recently, in November 2014 the New England Journal of Medicine published a letter. The authors write that PER977 (Aripazine), developed by Perosphere, a small synthetic, water-soluble, cationic molecule that is designed to bind specifically to unfractioned heparin (UF) and low molecular weight heparin (LMWH) through non-covalent hydrogen bonding and charge-charge interactions, binds in a similar way to the new oral factor Xa inhibitors, edoxaban, rivaroxaban and apixaban, and to the oral thrombin inhibitor dabigatran. (6) (New England Journal of Medicine 2014 vol. 371 pp. 2141-2142) Andexanet alfa, a modified recombinant protein derived from human coagulation factor X, is a new agent which can be used in antagonizing the anticoagulant effect of direct factor Xa inhibitors such as rivaroxaban, apixaban and edoxaban. However at the moment is not commercially available. (7) (Nature Medicine 2013 vol. 19 pp. 446-451) (for details, see section on "adverse reactions") In January 2014,Turpie and collegues published a study of 17,701 patients enrolled from 252 centres in 37 countries, emphasizing the favourable benefit-risk profile of rivaroxaban compared with standard-of-care for thromboprophylaxis after major orthopaedic surgery. Also this study as all the large studies involving DOAs was sponsored by the drug manufacturer, in this case Bayer Heathcare Pharmaceuticals with support from Janssen Research and Development. Primary hip and knee replacement surgery accounted for more than 90% of all surgical operations. It is important to note that standard-of-care in this study included, LMWHs, Unfractioned Heparin (UF), fondaparinux, dabigatran etexilate, acetylsalicylic acid and vitamin K antagonists. The type, duration and dose of pharmacological agents were determined by the attending physician before the patients enrollement into the study. it is clear that considering as standard-of-care all these agents, the results of the study might have a relevant bias because in Europe and North America the most used drugs for thromboprophylaxis in case of hip or knee replacement surgery are LMWHs. In any case also if we analyze the published results of this study is evident that there is not any important advantage of rivaroxaban compared with the standard-of- care treatment. In fact, the results (Table 2, page 98) showed only a slight reduced incidence of thromboembolic events in the rivaroxaban group, balanced by an increased incidence of major and minor bleeding events in the rivaroxaban group compared with the standard-of-care group. The number of deaths was exactly the same in the two groups (7 vs 7). Five authors of the study have been consultants for Bayer HeathCare, the rivaroxaban manufacturer, and other pharmaceutical companies, one author has been paid for educational presentation from Bayer HeathCare, the other four authors are employees of Bayer HealthCare. (8) (Thrombosis and Haemostasis 2014 vol. 111 (1) pp. 94-102) I do not see any reason to use rivaroxaban in these cases when we can use LMWH that we know very well and that we have been using since many years, although the dosage used in Europe, Enoxaparin 40 mg once daily, (the most used LMWH) is different from the dosage used in the US, Enoxaparin 30 mg twice daily. As many drugs, about 1/3 of rivaroxaban is metabolized by the cytochrome P 450 enzymes CYP3A4/5 and CYP2J2. Rivaroxaban is also a substrate of the efflux transporter proteins P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).
For this it should not be administered with strong inhibitors of P-gp/CYP3A4 such as azoles and protease inhibitors and coadministration with moderate inhibitors such as erythromycin should be exercised with caution to avoid a dangerous increased concentration of the active drug. Rivaroxaban should also not be administered with strong inducers of CYP3A4/P-gp such as rifampicin to avoid a dangerous decrease of its active concentration. (for details see sections on "Absorption and metabolism" and on "Dosage and drug interactions"). In addition, because clinically relevant polymorphisms exist for genes encoding CYP3A4/5, P-gp, and BCRP, these genetic variations play an important role in determinig rivaroxaban exposure. (for details see section on "Absorption and metabolism") At this point I report exactly the words used by Gong and collegues as conclusions of their interesting paper because any attempt to change these words would result in a loss of their efficacy. "As the clinical use of NOACs increases, surveillance using therapeutic monitoring (measurement of plasma drug concentration or anticoagulation response) throughout the treatment period might be evaluable in minimizing the risk of bleeding and lack of efficacy. Finally, because of the extent of interindividual variation in the metabolism and clearance of NOACs, it is likely that a greater range of NOACs doses will be needed to more precisely treat our patients". (9) (Canadian Journal of Cardiology 2013 vol. 29 pp. S24-S33) For other details, see abstracts of reviews on Dabigatran and Apixaban. In the X-VERT study Cappato and collegues used rivaroxaban for the prevention of cardiovascular events in patients with nonvalvular atrial fibrillation scheduled for cardioversion and oral rivaroxaban appears to be an effective and safe alternative to VKA and may allow prompter cardioversion. see section on "Indications" . (10) (European Heart Journal 2014 vol. 35 pp. 3346-3355) The most statistically efficient randomization ratio is 1:1 because it maximizes statistical power for a given total sample size. On the contrary, in this study,randomization of patients in a 2:1 ratio causes in any case a loss of statistical power, although modest.This randomization is acceptable when may be more economically efficient to randomize fewer patients to the expensive treatment and more to the cheaper one, or when for ethical reasons as for example in the oncology trials, it is necessary to allocate more patients in the arm of the treatment which probably will prolong the survival time and less patients in the placebo/medical care that will not prolong much their survival time. On the contrary in this study, the authors randomized more patients in the rivaroxaban arm, and this drug is much more expensive than warfarin, and in addition rivaroxaban was never used in this indication and for this, for ethical reasons, would have been more reasonable to allocate more patients in the warfarin group than in the rivaroxaban group. This study was supported by Bayer HealthCare Pharmaceuticals and Janssen Scientific Affairs LLC and the long list of conflicts of interests of the authors at the end of the paper is really impressive. See section on "Indications". (10) (European Heart Journal 2014 vol. 35 pp. 3346-3355) The authors caution that the trial was "underpowered to provide statistically rigorous results and was thus exploratory in nature", but in the same time Dr. Cappato, the principal author of the study, said to "Heartwire" that X-VERT provides a high level of "solid, methodologically sound evidence" for those clinicians who are already using NOACs in this setting instead of VKA. (11) (Medscape September 02, 2014) Safety and efficacy of well managed warfarin compared with DOACs is demonstrated in a recent paper published in 2015, in the June number of Thrombosis and Haemostasis.The study was a retrospective, registry-based study, including 77423 patients treated with warfarin in the Swedish national anticoagulation register Auricula from January 1, 2006 to December 31, 2011. Atrial fibrillation was the most common indication (68%). The mean time in therapeutic range of INR was 76.5%. The annual incidence of severe bleeding was 2.24% and of thromboembolism was 2.65%. The incidence of intracranial bleeding was 0.37% per treatment year in the whole population, and 0.38% among patients with atrial fibrillation. The authors affirm that limiting their analysis to patients with atrial fibrillation as indication for warfarin treatment, and not including the other types of patients, did not change their conclusions. This study is the demonstration that is possible to achieve efficient warfarin therapy with a mean TTR of 76.5% in routine clinical care, in the so called "real word", without exclusion of any patient groups and with very few serious bleeding complications. In fact, bleeding complications were fewer than what reported in the large randomised trials where warfarin was compared with DOACs because the TTR in this study (76.5%) was far higher than the mean TTR levels of 55-64% in the pivotal DOACs trials. In addition, a very important characteristic which strengthens the results of this study is that all warfarin treated patients were included, which means that there were more elderly patients and patients with multiple concomitant diseases than in DOACs clinical trials with inclusion and exclusion criteria. Intracranial bleeding, the most severe adverse event, associated with high mortality, occurred at an annual rate of 0.37% per treatment year in the whole group, and of 0.38% in patients with AF. This was far lower than in the DOACs trials where the warfarin treated patients had intracranial bleeds at a rate of 0.70 to 0.80% annually. It was even lower than with rivaroxaban (0.50%), and not much higher than with apixaban (0.33%), dabigatran 150 mg (0.30%) and dabigatran 110 mg (0.23%). In addition, in patients with atrial fibrillation, stroke, TIA or systemic emboli occurred at an annual rate of 1.54% per treatment year which is considerably lower than the 1.74% and 2.42% found in the warfarin arms in the pivotal studies for dabigatran and rivaroxaban respectively, despite of an unselected patient population with no inclusion or exclusion criteria. Patients with heart valve disease had more bleeding complications than other patients, probably because many of these patients had treatment with higher therapeutic range of INR 2.5-3.5 instead of the more common INR 2.0-3.0. The inclusion of patients with higher INR goals than 2.0-3.0 means that this study showed a larger risk of bleeding than for the patients with lower goals, and could therefore better reflect clinical reality. The authors conclude that "efficient warfarin therapy with a mean TTR of 76.5% is possible to achieve in routine clinical care with unselected patients, and should not be ruled out in favour of DOACs". (12) (Thrombosis and Haemostasis 2015 vol. 113 (6) pp. 1370-1377) Recently has been published ahead of print on May 21, 2015 in the journal Thrombosis and Haemostasis the design of a multicentre, randomised, double-blind, active controlled, event-driven study, the EINSTEIN CHOICE study, in which will be evaluated the efficacy and safety of two once-daily doses of rivaroxaban (20 and 10 mg) with aspirin (100 mg daily) for the prevention of recurrent VTE in patients who completed 6-12 months of anticoagulant therapy for their index acute VTE event. All treatments will be given for 12 months. (13) (Thrombosis and Haemostasis 2015, vol. 114 (3) pp.645-650) In this study the enrollement criterion of patients is unacceptable because in daily clinical practice, clinicians must decide to continue or not to continue the oral anticoagulant treatment on a case by case basis, evaluating the bleeding risk and the thrombotic risk of every patient and must not to switch to aspirin treatment just because they or their patients have "concerns about bleeding and frequent laboratory monitoring". In case the patient refuses the continuation of the oral anticoagulant treatment considered necessary by the clinician expert in thrombosis and haemostasis, the patient should be told to be treated elsewhere. Aspirin must be used only in patients with a high bleeding risk and consequently cannot continue the oral anticoagulant treatment, and cannot be used just because the "treating physician is uncertain about the need for continued anticoagulant therapy". In addition to affirm that rivaroxaban does not need laboratory monitoring is not correct. (9) (Canadian Journal of Cardiology 2013 vol. 29 pp. S24-S33);(14) (Blood Coagulation and Fibrinolysis 2015 vol. 26 pp. 925-933); (15) (Thrombosis Research 2016 vol. 137 pp. 178-183) (see above, section on "Conclusions", and review on "Dabigatran") and let the enrolled patients believe this, is simply unacceptable. At the end of the EINSTEIN-CHOICE study paper (13) (Thrombosis and Haemostasis 2015 vol. 114 (3) pp.645-650), the list of conflict of interests of the authors is so long that is really impressive. In addition two authors of the study are employees of Bayer Heathcare, the rivaroxaban manufacturer. The health and the life of patients cannot be considered secondary to the economic interests of pharmaceutical companies, of healthcare institutions and of "key opinion leaders" physicians.
Just recently, the British Medical Journal found that in the ROCKET AF trial a defective point of care device was used to measure INR in its comparator arm of patients taking warfarin. For this reason, may be that warfarin results looked worse than they otherwise would seem. This point of care device was subject to a recall. In December 2014 a recall notice said that certain INRatio devices could deliver INR results that were clinically significantly lower than a laboratory INR method. It said that Alere, the manufacturer of the device, had received 18924 reports of malfunctions, including 14 serious injuries. (16) (British Medical Journal 2015 vol. 351 pp. h6431) In a letter submitted to the New England Journal of Medicine (as yet unpublished) and shown to the BMJ, former FDA cardiovascular and renal drug reviewer, Thomas Marcinicak, says : "The care for the warfarin control arm patients in the ROCKET AF trial appears to have been compromised". (17) (British Medical Journal 2016 vol. 352 pp. i575) The authors of this trial made another analysis of 5294 (37%) patients who had a recall condition and now affirm that the results obtained by this analysis, indicate that possible malfunction of the point-of-care device used for INR measurement that potentially led to lower INR values than would be obtained by laboratory testing, did not have any significant clinical effect on the primary efficacy and safety outcomes in the ROCKET AF trial. (18) (New England Journal of Medicine 2016 vol. 374 pp. 785-788) However, a recent article published in The New England Journal of Medicine of March 1, 2016 has revealed that lawyers for patients suing Johnson & Johnson and Bayer over the safety of the drug Xarelto claimed that the letter published in the NEJM left out critical laboratory data. In fact investigators in the ROCKET AF trial compared the device readings with test results that were done at a central laboratory at two points in the trial, drawing blood from more than 5,000 of the patients who took warfarin and sending the samples for testing. The blood was taken 12 and 24 weeks after patients enrolled in the trial. But the Duke researchers made no mention of these lab data in their letter. Dr. Steve Nissen, a cardiologist at the Cleveland Clinic, who served on the FDA advisoty panel that voted to approve Xarelto in 2011, and who was one of the two members who voted against the drug said : "Given the fact that the device was inaccurate, there is no way anybody can tell you what would have happened in the trial ". (19) (The New York Times March 1, 2016) (for details see section on "Conclusions") Siegal and collegues recently reported the results of two randomized, double-blind, placebo-controlled studies of adexanet alfa, a novel antidote to Factor Xa inhibitors, to antagonize the anticoagulant effects of apixaban (ANNEXA-A) and of rivaroxaban (ANNEXA-R). The study was performed in healthy volunteers with an age range of 50 to 75 years and although andexanet alfa seems to effectively neutralize the anticoagulant effect of apixaban and rivaroxaban without adverse events and thrombotic complications, it is unknown whether andexanet use would improve outcomes for patients with major bleeding. For this reason, the ongoing ANNEXA-4 phase 3b-4 study (ClinicalTrials.gov.number, NCT02329327) is evaluating the efficacy and safety of andexanet in patients with factor Xa inhibitor-associated acute major bleeding. Interestingly the dosage used to antagonize rivaroxaban was twice of that used to neutralize the anticoagulant effect of apixaban. (20) (New England Journal of Medicine 2015 vol. 373 pp. 2413-2424); (21) (New England Journal of Medicine 2015 vol. 373 pp. 2471-2472) For details, see the last section on "Conclusions".
1 ) Patel Manesh R., Mahaffey Kenneth W., Garg Jyotsna et al. : Rivaroxaban versus warfarin in non valvular atrial fibrillation. New England Journal of Medicine 2010; 365 : 883-891
2 ) The EINSTEIN Investigators : Oral rivaroxaban for symptomatic venous thromboembolism. New England Journal of Medicine 2010; 363 : 2499-2510
3 ) The EINSTEIN-PE Investigators : Oral rivaroxaban for symptomatic venous thromboembolism. New England Journal of Medicine 2012; 366 : 1287-1297
4 ) Mega Jessica L., Braunwald Eugene, Wiviott Stephen D. et al. : Rivaroxaban in patients with a recent acute coronary syndrome. New England Journal of Medicine 2012; 366 : 9-19
5 ) O'Riordan Michael : FDA again denies rivaroxaban ACS indication.
February 14, 2014 www.medscape.com/viewarticle/820651
6 ) Ansell Jack E., Bakhru Sasha H., Grosso Michael et al. : Use of PER977 to reverse the anticoagulant effect of edoxaban. New England Journal of Medicine 2014; 371 : 2141-2142
7 ) Lu Genmin, DeGuzman Francis R., Hollenbach Stanley J. et al. : A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nature Medicine 2013 vol. 19 pp. 446-451
8 ) Turpie Alexander G.G., Haas Sylvia, Kreutz Reinhold et al. : A non-interventional comparison of rivaroxaban with standard of care for thromboprophylaxis after major orthopaedic surgery in 17,701 patients with propensity score adjustment. Thrombosis and Haemostasis 2014; 111 (1) : 94-102
9 ) Gong Inna Y. and Kim Richard B. : Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban. Canadian Journal of Cardiology 2013; 29 : S24-S33
10 ) Cappato Riccardo, Ezekowitz Michael D., Klein Allan L. et al. : Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation. European Heart Journal 2014; 35 : 3346-3355
11 ) Steve Stiles : X-VERT : Rivaroxaban (Xarelto) a warfarin alternative in AF cardioversion, without the INR. www.medscape.com/viewarticle/830760_print
12 ) Sjogren Vilhelm, Grzymala-Lubanski Bartosz, Renlund Henrik et al. : Safety and efficacy of well managed warfarin. A report from the Swedish quality register Auricula. Thrombosis and Haemostasis 2015; 113 (6) : 1370-1377
13 ) Weitz JL, Bauersachs R.,Beyer-Westendorf J. et al. : Two doses of rivaroxaban versus aspirin for prevention of recurrent venous thromboembolism. Rationale for and design of the EINSTEIN CHOICE study. Thrombosis and Haemostasis 2015; 114 (3) : 645-650
14 ) Freyburger Geneviève, Macouillard Gérard, Khennoufa Karim et al. : Rivaroxaban and apixaban in orthopaedics : is there a difference in their plasma concentration and anticoagulant effects? Blood Coagulation and Fibrinolysis 2015; 26 : 925-933
15 ) Testa Sophie, Tripodi Armando, Legnani Cristina et al. : Plasma levels of direct oral anticoagulants in real life patients with atrial fibrillation : Results observed in four anticoagulation clinics. Thrombosis Research 2016; 137 : 178-183
16 ) Cohen Deborah : Data on trial of anticoagulant is to be reanalyzed after discovery that investigators used faulty device. British Medical Journal 2015; 351 : h6431
17 ) Cohen Deborah : Rivaroxaban : can we trust the evidence ? British Medical Journal 2016; 352 : i575
18 ) Patel Manesh R., Hellkamp Anne S., Fox Keith A.A. et al. : Point-of-care warfarin monitoring in the ROCKET AF trial. New England Journal of Medicine 2016; 374 : 785-788
19 ) Thomas Katie : Document claims drug makers deceived a top medical journal. The New York Times March 1, 2016
20 ) Siegal Deborah M., Curnutte John T., Connolly Stuart J. et al. : Andexanet alfa for the reversal of factor Xa inhibitor activity. New England Journal of Medicine 2015; 373 : 2413-2424
21 ) Connors Jean M. : Antidote for Factor Xa anticoagulants. New England Journal of Medicine 2015; 373 : 2471-2472