ACA App
Annals of Cardiac Anaesthesia Annals of Cardiac Anaesthesia Annals of Cardiac Anaesthesia
Home | About us | Editorial Board | Search | Ahead of print | Current Issue | Archives | Submission | Subscribe | Advertise | Contact | Login 
Users online: 719 Small font size Default font size Increase font size Print this article Email this article Bookmark this page
 


 

 
     
    Advanced search
 

 
 
     
  
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Email Alert *
    Add to My List *
* Registration required (free)  


    Abstract
   Introduction
   Conclusion
    References
    Article Figures
    Article Tables

 Article Access Statistics
    Viewed7548    
    Printed230    
    Emailed13    
    PDF Downloaded943    
    Comments [Add]    
    Cited by others 2    

Recommend this journal

 


 
Table of Contents
REVIEW ARTICLE  
Year : 2013  |  Volume : 16  |  Issue : 3  |  Page : 193-200
New orally active anticoagulants in critical care and anesthesia practice: The good, the bad and the ugly


1 Department of Internal Medicine, The Common Wealth Medical College, Scranton, PA 18510, USA
2 Department of Anaesthesiology and Intensive Care Medicine, Gian Sagar Medical College, Banur, Patiala, Punjab, India
3 Department of Internal Medicine, Wright Center, Scranton, PA, USA

Click here for correspondence address and email

Date of Submission20-Feb-2013
Date of Acceptance29-May-2013
Date of Web Publication29-Jun-2013
 

   Abstract 

With the adoption of dabigatran, rivaroxaban, and apixaban into clinical practice, a new era has arrived in the practice of oral anticoagulants. Venous thromboembolism (VTE) has traditionally been underdiagnosed and under treated in Asia. With increasing longevity, the diagnosis and the need for management of atrial fibrillation (AF) and VTE is likely to increase significantly. The new orally active anticoagulants (NOACs) have reasonably filled the lacunae that clinicians traditionally faced when treating patients with vitamin K antagonist (VKA). Unlike VKA, NOACs do not need frequent monitoring. Therefore, more patients are likely to get therapeutic effects of anticoagulation and thus reduce morbidity and mortality associated with VTE and AF. However, the clinicians need to be circumspect and exercise caution in use of these medications. In particular (in geriatric population), the clinicians should look out for drug-drug interactions and underlying renal insufficiency. This would ensure therapeutic efficacy and minimize bleeding complications. Here, it is important to note that the antidote for NOACs is not available and is a major concern if emergency surgical procedure is required in their presence.

Keywords: Apixaban, Atrial fibrillation, Dabigatran, New orally active anticoagulants, Rivaroxaban, Venous thromboembolism

How to cite this article:
Sehgal V, Bajwa SJ, Bajaj A. New orally active anticoagulants in critical care and anesthesia practice: The good, the bad and the ugly. Ann Card Anaesth 2013;16:193-200

How to cite this URL:
Sehgal V, Bajwa SJ, Bajaj A. New orally active anticoagulants in critical care and anesthesia practice: The good, the bad and the ugly. Ann Card Anaesth [serial online] 2013 [cited 2019 Jul 24];16:193-200. Available from: http://www.annals.in/text.asp?2013/16/3/193/114244



   Introduction Top


Dabigatran, rivaroxaban and apixaban are the three new orally active anticoagulants (NOACs) which are likely to displace vitamin K antagonist (VKA) from the clinical practice. [1],[2],[3],[4],[5],[6],[7],[8],[9] As compared to warfarin (VKA), the major bleeding complications, particularly, intracranial bleed is significantly lower with NOACs. [10] Moreover, routine monitoring is not required during their use. All three NOACs have been approved by Food and Drug Administration for use in atrial fibrillation (AF); and rivaroxaban has also been approved for prophylaxis and treatment of venous thromboembolism (VTE).

Baby boomer generation is coming of age in the US. Longevity is increasing even in the developing world. In US alone stroke occurs in about 795,000 patients each year. [11] With aging population we see more and more people with disease pathologies requiring anticoagulation [12] the notable pathologies being AF and VTE. The VTE is not widely diagnosed or managed in Asia. This is secondary to misplaced notion that it is more common in Caucasians. [13] With increasing longevity, clinicians in Asia are likely to come across increasing geriatric population requiring anticoagulation. Furthermore, the dosing of VKA, which has been the gold standard until now, is pretty complex. The introduction of NOACs is likely to change the way oral anticoagulation is practiced. [14] It would be prudent for physicians to be familiar with these medications. [15],[16] Physicians are likely to encounter the bleeding complications associated with these medications. Also, prior to elective surgeries, the NOACs would need to be withheld without jeopardizing anticoagulation for the underlying pathology. These concerns are all the more important for anesthesiologists involved in the care of cardiac surgery patients as these patients often have pathologies requiring anticoagulation and are likely to bleed in the perioperative period. The same would be true for physicians involved in the care of critically ill-patients. These drugs are great as they do not need monitoring like warfarin, but the pitfall being the absence of a known reversal agent. [17] The present review aims to discuss the pros and cons of individual drugs so as to help the clinicians use their judgment in choosing the right drug in the appropriate clinical setting. The review also cautions the clinicians about the pitfalls of these drugs. The search strategies for the manuscript included search for full text articles and ongoing clinical trials related to NOACs. The literature search was performed from PubMed, PubMed central, Science direct, Scopus, Wolters Kluwer, Medscape and Google.com.

Scoring systems to assess the risk of VTE in AF

With increasing longevity and higher life span an increase in AF is known with a word-wide prevalence rate of 1% in the general population. [18] AF is much more common in the elderly. The risk of a stroke may be reduced by about 2/3 rd with the use of VKA and by about 20% with the use of aspirin. [3] Risk of stroke on an average is 4.5%, but may vary from 1% to 20% depending on the risk-factors. Multiple multivariate risk models have been developed for risk stratification in AF patients. [19] CHADS2 scoring system is the most validated scoring system wherein one point each is given for the presence or history of congestive heart failure, hypertension, diabetes and age more than 75 years; and 2 points are given for a history of stroke/transient ischemic attack. A total score of 6 is highest; a score of 0 indicates low-risk; a score of 1 or 2 indicates intermediate risk and a score of > 3 indicates high risk. The 2012 focused update of the European society cardiology guidelines for the management of AF strongly recommends CHADS2-VASc scoring system for risk stratification in AF. [20] This scoring system gives weightage to vascular disease and sex also in addition to CHADS2 score for the risk stratification; history of vascular disease and female gender each is given one point. The age between 65-74 year is given one point whereas age above 75 year is given 2 points; a total score of 9 is highest. It lowers the threshold of initiating anticoagulation. Anticoagulation is strongly recommended with a score of 2 or more; weakly recommended with a score of 1 and not indicated with a score of 0. Anticoagulation is cost-effective if there is a high-risk of stroke. [21] Aspirin was not recommended. Until recently, VKA has been the standard of care. However, VKA has numerous food and drug-drug interactions and requires repeated monitoring. Many times, it is difficult to maintain the VKA in therapeutic range. This is where the NOACs are expected to play a major role and decrease the burden of AF related strokes. [3],[10],[22],[23]

Mechanism of action of NOACs

Rivaroxaban and apixaban reversibly inhibit factor Xa, whereas dabigatran reversibly inhibits both free and fibrin bound thrombin (Factor IIa) [Figure 1]. In contrast, warfarin acts on multiple vitamin K dependent clotting factors namely II, VII, IX and X. Pharmacokinetic and pharmacodynamic characteristics of NOACs is similar to low molecular weight heparins. Their peak plasma levels are achieved in 2-4 h and half-lives are between 7 h and 14 h. The NOACs differ primarily in their renal elimination. [24] Drug discontinuation is usually sufficient to control bleeding in most clinical settings, since their half-life is relatively short in subjects with normal renal function.
Figure 1: Mechanism of action of oral anticoagulants

Click here to view


Factor IIa inhibitors

The NOAC dabigatran is a selective, reversible inhibitor of both free and clot bound thrombin. Time to peak plasma concentration after oral intake is 1.25-1.5 h. Maximum anticoagulant effects are achieved within 1-2 h depending upon food intake with maximum effect in 2 h. [25] To prevent the product breakdown from moisture and loss of potency, dabigatran capsules are stored in the original bottle supplied by the manufacturer. It comes as a pro-drug which is converted to the active compound dabigatran by non-specific esterases in plasma and liver. It then binds directly to thrombin with high affinity and specificity. Dabigatran has a half-life of approximately 12-14 h in adult volunteers with normal renal function. Renal excretion of unchanged drug is the predominant elimination pathway, with about 90% of drug being excreted unchanged in the urine. [26] Dabigatran is not metabolized, induced or inhibited by cytochrome p450 enzyme system. It has a low protein binding (30%) and is potentially dialyzable. However, because of its large volume of distribution there is usually a rebound in the drug level; therefore, dialysis as a means of removing the drug from the body is impractical. [27] It can be dialyzed in patients with renal impairment, with about 60% drug being removed after 2-3 h of dialysis. A randomized evaluation of long-term anticoagulation therapy (RE-LY) comparing dabigatran with warfarin using its two doses, 150 mg or 110 mg twice a day, showed fewer strokes with 150 mg dose, but similar major bleeds. With 110 mg dose, there were a similar number of strokes but lesser major bleeds. The findings has been similar in different clinical settings. [28] In the RE-LY trial most common non-bleeding adverse effect with dabigatran was gastro-esophageal-reflux-disease like symptoms with dyspepsia [29] and it was the most common non-bleeding cause for discontinuation of the medication. [30] Routine monitoring of the extent of anticoagulation is not recommended for patients taking dabigatran. Thrombin clotting time and ecarin clotting time are sensitive for quantitating anticoagulation effect of dabigatran. [25] Activated partial thromboplastin time (aPPT) is prolonged, but not in a dose dependent manner. The aPPT may serve as qualitative test, but it is less sensitive to supratherapeutic concentration of dabigatran. There is no antidote for dabigatran. This should be taken into account before initiating the drug. It would be appropriate to start reversible parenteral anticoagulants like intravenous heparin or enoxaparin prior to starting NOACs. Furthermore, it needs to be kept in mind that dabigatran is predominantly excreted renally and its elimination in patients with underlying acute and chronic kidney disease (CKD) is likely to be slower. This is especially true in the peri-operative settings in cardiac surgery. For control of active bleeding supportive care and activated charcoal may be given if the patient is seen within 2 h of ingestion of dabigatran. [31] Prothrombin complex concentrate (PCC) and high dose fresh frozen plasma have been suggested as possible reversal agents. [32] The dose of PCC needs to be titrated clinically. [33]

Factor Xa inhibitors

Rivaroxaban is a selective, reversible and direct inhibitor of factor Xa. It has bioavailability of 80 percent and its peak plasma concentrations occur within 2.5-4 h after oral administration. The half-life of the drug is 3-9 h. [34] It is metabolized by CYP3A4 in CYP450 system. It is predominantly excreted through kidney and roughly 36% of the drug is excreted unchanged and 30% is excreted as inactive metabolites, the remaining drug is eliminated in feces. [35] It does interact with CYP450 system with a specific interaction with CYP3A4 and CYP2J2. [36] It is a substrate for p-glycoprotein (p-gp) and thus affected by drugs, which interfere with p-gp. Morbid obesity, age or gender does not significantly change the pharmacodynamics of the drug. The ROCKET-AF clinical trial evaluated the efficacy of rivaroxaban in the management of AF. Rivaroxaban was associated with 12% reduction in the incidence of stroke compared with warfarin. [37] With rivaroxaban, the patients remained in the therapeutic range for only 55% of the time, which is less than RE-LY (64%) and ARISTOTLE (66%). This is the main criticism for the ROCKET-AF trial. [38] Rivaroxaban was slightly less effective than dabigatran for prevention of stroke in AF, but there was no difference in all causes mortality. [39],[40] However, such indirect comparisons need to be studied in randomized controlled clinical trials. Warfarin (VKA) reduces the incidence of AF related strokes by two-thirds. [41] These drugs are likely to further increase the optimally anticoagulated patients and reduce the risk of stroke related to AF. [22],[42],[43] There is no specific antidote for rivaroxaban. This is important especially in critical care settings where invasive procedures might be needed. In such situations, if possible sufficient time should be given for spontaneous reversal of anticoagulant effect prior to invasive procedures. In perioperative settings, no bridging is necessary because of short half-life.

Apixaban is a selective, reversible and direct inhibitor of factor Xa. Food does not interfere significantly with its absorption. Its half-life is 12 h. [44],[45] Time to reach maximum plasma concentration is 0.5 h to 2 h. It is metabolized by the CYP3A4 in the CYP450 system. Apixaban is approximately 87% protein bound; therefore, difficult to dialyze. Renal excretion of the active drug is 25%. [45],[46] Slower excretion is expected in the setting of CKD. There is concern for cumulative toxicity in renal insufficiency; however, it has been used successfully with no major increase in bleeding complications in CKD stage III patients. [47] Apixaban has minimal impact on INR and aPPT in therapeutic concentrations. Factor Xa inhibition is a sensitive marker to detect its presence. Apixaban is superior to warfarin for prevention of stroke in AF. [48] It has been studied extensively in the AVERROES and ARISTOTLE trials. In AVERROES as compared with aspirin it has been shown to reduce the incidence of VTE. [49],[50] It had similar relative risk of bleeding compared with aspirin. [51] In ARISTOTLE, it showed lower gastrointestinal and major bleeds and decreased overall mortality. It was shown to be superior to VKA in preventing VTE. [48],[50],[52],[53],[54] For deep vein thrombosis (DVT) prophylaxis in ADVANCE 2 TRIAL after total hip replacement (THR), it was shown to be non-inferior to enoxaparin 40 mg daily. The dose of apixaban used in the trial was 2.5 mg twice daily. In ADVANCE 1 when 2.5 mg daily dose was compared with 30 mg twice daily dosing of enoxaparin it did not meet the non-inferiority criteria. [55],[56] Among the NOACs, apixaban has the best pharmacokinetic and pharmacodynamic profile. It is minimally excreted through kidneys and is likely to have a rapid reversal. Meta-analysis and indirect comparisons for the safety and efficacy of the three anticoagulants showed apixaban safer than others secondary to less major bleeds. [57] Extended treatment with prophylactic or therapeutic doses of apixaban has been shown to reduce recurrent VTE when there is clinical equipoise regarding continuation of anticoagulation. [58] However, increased incidence of major bleed is a concern as it is with VKA. This is especially important when used concomitantly with antiplatelet therapy. [59],[60] These drugs May be used with caution in patients with higher risk for intracranial bleed such as patients with a prior history of cerebral infarction, micro bleeds on magnetic resonance imaging or concomitant use of antiplatelets. [61]

Drug interactions

The NOACs have no major interaction with food but do have limited drug-drug interaction. Apixaban and rivaroxaban are metabolized through CYP3A4 a subset of the cytochrome p450 system. [62] Dabigatran is neither a substrate nor an inhibitor or an inducer of CYP450 enzyme system and is not affected by them. The p-gp (glycoproteins) prevent absorption and increase secretions of certain drugs known as p-gp substrates. All the NOACs serve as a substrate for the p-gp transport system. Amiodarone, verapamil macrolides and even commonly used pain medication naproxen inhibit p-gp and therefore increase bioavailability of NOACs [Table 1]. It is very important to be aware of this interaction for safe and effective anticoagulation. Amiodarone when used with dabigatran have been shown to increase chances of bleeding. Dose reduction or stopping the drug should be considered in these scenarios. Atorvastatin is a substrate for CYP3A4 and p-gp, but does not affect the NOACs in a clinically significant way. [63] Digoxin is a p-gp substrate, but does not affect dabigatran in a clinically significant way. The RECORD trial in joint replacement surgery showed minimal increase in bleeding when rivaroxaban was used with statins compared with enoxaparin with statin. [64] Ranitidine is a weak CYP3A4 inhibitor, but has no clinically significant effect on NOACs, [65] human immunodeficiency virus - protease inhibitors and azoles are strong inhibitors of both CYP3A4 and p-gp. Rivaroxaban is contraindicated with these medications. [64] Cytochrome CYP3A4 inducers [Table 2] are likely to decrease the bioavailability of rivaroxaban and apixaban and thus decrease the efficacy. These drug interactions are especially important in elderly patients where underlying CKD may lead to inappropriate use of NOACs. In Beers criteria NOACs figure as potentially inappropriate medications in patients with age > 75 years.
Table 1: Moderate to Strong P-gp Inhibitors and inducers

Click here to view
Table 2: Selected inducers, inhibitors of CYP3A4

Click here to view


NOACs in Perioperative settings

NOACs are required to be stopped before elective surgery. The timing of discontinuation depends upon the risk of bleeding with the surgical procedure and underlying renal insufficiency. [66] Factor Xa inhibitors need to be stopped 48 h before surgical procedures carrying high-risk for bleeding and 24 h before surgical procedures with low-risk for bleeding. Holding time needs to be longer in patients with underlying renal insufficiency. Antifactor Xa activity can give an idea of anticoagulant activity of Xa inhibitors. [66] With dabigatran if glomerular filtration rate (GFR) is > 50 ml/min it is recommended to stop it 24-48 h before surgery. If GFR is < 50 ml/min it is recommended to stop it 3-5 days before surgery. [67] Thrombin time may be used to detect the presence of dabigatran before surgery. [66]

All three drugs have been studied extensively in the perioperative settings for DVT prophylaxis. NOACs have similar or improved efficacy for thromboprophylaxis. [15],[68],[69] When used for thromboprophylaxis after hip and knee replacement surgeries apixaban has been associated with lesser bleeds. [70] Dabigatran has been shown to be non-inferior and cost-effective to enoxaparin after TKR and THR surgeries in the dose of 150-220 mg daily. [71] However, concerns regarding bleeding complications, asymptomatic renal disease and drug-drug interactions have limited their use. [72] When compared with coumadin, there is no difference in efficacy or incidence of major bleeds in the perioperative settings during TKR and THR surgery. Chances of increased bleeding remain a concern in patients with renal insufficiency and where drug-drug interactions remain a possibility. [73]

Choice of anti-coagulant: A difficult comparison

There is no head to head comparison among the three NOACs. [74],[75],[76] Dabigatran has been shown to be superior to VKA in 150 mg dose and non-inferior with 110 mg dose. Rivaroxaban has been shown to be non-inferior to VKA and apixaban has been shown to be superior to VKA. However, these results may not be translated into clinical practice as such. [77] The prescriber needs to be aware of potential drug-drug interaction, renal and hepatic insufficiency and most of all need for anticoagulation depending on the risk factors. [78],[79] There is no data for their use in acute stroke and uncontrolled hypertension; although, all three NOACs have proven to cause significantly less intracranial bleeds. [80] Clinicians should consider avoiding dabigatran in patients who have pre-existing dyspepsia as it is one of the major non-bleeding cause of patient non-compliance. These drugs need to be used with caution in patients with CKD. Stage 4 CKD is a contraindication for the use of NOACs. Dabigatran may be used with caution, but at a reduced dose of 75 mg twice daily. Stage 3 CKD is one of the major risk-factor for VTE in patients with AF. The NOACs may be used in patients with stage 3 CKD, but slow renal elimination is expected in the critical care and perioperative settings. [6] In the ARISTOTLE trial, apixaban was associated with decreased rate of major bleed, stroke or death even in patients with CKD. In fact, the benefit was highest in patients with CKD as there were less major bleeds. [81],[82] All NOACs are eliminated variably through the kidneys [Figure 2] and awareness about changing renal profile is important [83],[84],[85],[86] and need to be considered along with close clinical monitoring to minimize any major bleeding. [83],[84],[87],[88] The clinician needs to pick up the drug based on individual patient profile. [89] Lack of availability of reversal agent poses a medical conundrum in the critical care and perioperative settings. If chosen judiciously these drugs are likely to be highly beneficial and an excellent alternative to warfarin for anticoagulation. [90] The decision should depend on the benefit-risk profile and should be individualized. [91],[92],[93],[94] The NOACs are cost effective compared to warfarin and have ushered in a new era in anticoagulation. [95],[96],[97] Further randomized trials are needed to refine the indications further. [98]
Figure 2: Variable renal clearance of new orally active anticoagulants

Click here to view



   Conclusion Top


To conclude the NOACs could be good, the bad or ugly depending on the way physician uses them. They appear as a good alternative to VKA in AF related stroke prophylaxis and VTE. However if drug interactions are not considered when NOACs are prescribed, they could turn bad. Also if renal insufficiency is not taken into consideration along with drug interactions, they could turn ugly. The ramifications of this could be uncontrolled bleeding. Apixaban appears superior because of better pharmacokinetic and pharmacodynamic properties. Its renal excretion is minimal compared with other two NOACs, which is a big benefit in patients who have progressive renal insufficiency. It has been used in CKD stage 3 with excellent results.

 
   References Top

1.Blanco-Molina A. New advances in anticoagulation: Is it time to forget about heparin and vitamin K antagonists? Yes. Rev Clin Esp 2012;212 Suppl 1:3-7.  Back to cited text no. 1
[PUBMED]    
2.Deedwania P, Huang GW. An update on antithrombotic therapy in atrial fibrillation: The role of newer and emergent drugs. Rev Cardiovasc Med 2012;13:e89-104.  Back to cited text no. 2
[PUBMED]    
3.Cairns JA. Prevention of stroke and systemic embolization in atrial fibrillation: A Canadian perspective. Pol Arch Med Wewn 2012;122:428-36.  Back to cited text no. 3
[PUBMED]    
4.Cohen AT. Long-term benefits of preventing venous thromboembolic events. Curr Med Res Opin 2012;28:877-89.  Back to cited text no. 4
[PUBMED]    
5.Diener HC, Eikelboom J, Granger CB, Hacke W. The king is dead (warfarin): Direct thrombin and factor Xa inhibitors: The next Diadochian War? Int J Stroke 2012;7:139-41.  Back to cited text no. 5
[PUBMED]    
6.Hart RG, Eikelboom JW, Ingram AJ, Herzog CA. Anticoagulants in atrial fibrillation patients with chronic kidney disease. Nat Rev Nephrol 2012;8:569-78.  Back to cited text no. 6
[PUBMED]    
7.Mahan C, Spyropoulos AC. Improving prevention and treatment of venous thromboembolism: Clinical trial results. J Med Econ 2012;15:611-22.  Back to cited text no. 7
[PUBMED]    
8.Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol 2012;110:453-60.  Back to cited text no. 8
[PUBMED]    
9.Ranganathan RL, Venkatesh P. Atrial fibrillation and stroke prevention: Is warfarin still an option?-No. J Neural Transm 2012; [Epub ahead of print]  Back to cited text no. 9
    
10.Dentali F, Riva N, Crowther M, Turpie AG, Lip GY, Ageno W. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: A systematic review and meta-analysis of the literature. Circulation 2012;126:2381-91.  Back to cited text no. 10
[PUBMED]    
11.Morales-Vidal S, Schneck MJ, Flaster M, Biller J. Direct thrombin inhibitors and factor Xa inhibitors in patients with cerebrovascular disease. Expert Rev Neurother 2012;12:179-89.  Back to cited text no. 11
[PUBMED]    
12.Liew A, Eikelboom JW, O'Donnell M. Randomized controlled trials of new oral anticoagulants for stroke prevention in atrial fibrillation. Curr Opin Cardiol 2012;27:331-9.  Back to cited text no. 12
[PUBMED]    
13.Liew NC, Chang YH, Choi G, Chu PH, Gao X, Gibbs H, et al. Asian venous thromboembolism guidelines: Prevention of venous thromboembolism. Int Angiol 2012;31:501-16.  Back to cited text no. 13
[PUBMED]    
14.Suárez Ortega S. Dabigatran: Transforming the management of oral anticoagulation. Rev Clin Esp 2012;212 Suppl 2:15-22.  Back to cited text no. 14
    
15.Deitelzweig S. Preventing venous thromboembolic events after total hip arthroplasty: New developments in clinical practice. Hosp Pract (1995) 2012;40:79-87.  Back to cited text no. 15
    
16.Mantha S, Cabral K, Ansell J. New avenues for anticoagulation in atrial fibrillation. Clin Pharmacol Ther 2013;93:68-77.  Back to cited text no. 16
[PUBMED]    
17.Baumann Kreuziger LM, Morton CT, Dries DJ. New anticoagulants: A concise review. J Trauma Acute Care Surg 2012;73:983-92.  Back to cited text no. 17
[PUBMED]    
18.Deftereos S, Tsounis D, Giannopoulos G, Kossyvakis C, Panagopoulou V, Raisakis K, et al. Oral IIa and Xa inhibitors for prevention of stroke in atrial fibrillation: Clinical studies and regulatory considerations. Curr Clin Pharmacol 2012;7:166-74.  Back to cited text no. 18
[PUBMED]    
19.Stroke risk in atrial fibrillation working group. Comparison of 12 risk stratification schemes to predict stroke in patients with nonvalvular atrial fibrillation. Stroke 2008;39:1901-10.  Back to cited text no. 19
[PUBMED]    
20.Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: An update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719-47.  Back to cited text no. 20
[PUBMED]    
21.Pisters R, Lane DA, Marin F, Camm AJ, Lip GY. Stroke and thromboembolism in atrial fibrillation. Circ J 2012;76:2289-304.  Back to cited text no. 21
[PUBMED]    
22.Alberts MJ, Eikelboom JW, Hankey GJ. Antithrombotic therapy for stroke prevention in non-valvular atrial fibrillation. Lancet Neurol 2012;11:1066-81.  Back to cited text no. 22
[PUBMED]    
23.Guo Y, Pisters R, Apostolakis S, Blann AD, Wang H, Zhao X, et al. Stroke risk and suboptimal thromboprophylaxis in Chinese patients with atrial fibrillation: Would the novel oral anticoagulants have an impact? Int J Cardiol 2012 [Epub ahead of print].  Back to cited text no. 23
    
24.Dempfle CE. Pharmacology of the new oral anticoagulants. Herz 2012;37:362-8.  Back to cited text no. 24
[PUBMED]    
25.Stangier J, Rathgen K, Stähle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007;64:292-303.  Back to cited text no. 25
    
26.Stangier J, Stähle H, Rathgen K, Fuhr R. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008;47:47-59.  Back to cited text no. 26
    
27.Chang DN, Dager WE, Chin AI. Removal of dabigatran by hemodialysis. Am J Kidney Dis 2013;61:487-9.  Back to cited text no. 27
[PUBMED]    
28.Barrios V, Escobar C. New evidences for old concerns with oral anticoagulation in atrial fibrillation: Focus on dabigatran. Expert Opin Pharmacother 2012;13:2649-61.  Back to cited text no. 28
[PUBMED]    
29.Bytzer P, Connolly SJ, Yang S, Ezekowitz M, Formella S, Reilly PA, et al. Analysis of upper gastrointestinal adverse events among patients given dabigatran in the RE-LY trial. Clin Gastroenterol Hepatol 2013;11:246-52.e1-5.  Back to cited text no. 29
    
30.Michel J, Mundell D, Boga T, Sasse A. Dabigatran for anticoagulation in atrial fibrillation-early clinical experience in a hospital population and comparison to trial data. Heart Lung Circ 2013;22:50-5.  Back to cited text no. 30
[PUBMED]    
31.Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol 2012;87 Suppl 1:S141-5.  Back to cited text no. 31
[PUBMED]    
32.Dumkow LE, Voss JR, Peters M, Jennings DL. Reversal of dabigatran-induced bleeding with a prothrombin complex concentrate and fresh frozen plasma. Am J Health Syst Pharm 2012;69:1646-50.  Back to cited text no. 32
[PUBMED]    
33.Spannagl M, Bauersachs R, Debus ES, Gawaz M, Gerlach H, Haas S, et al. Dabigatran therapy: Perioperative management and interpretation of coagulation tests. Hamostaseologie 2012;32:294-305.  Back to cited text no. 33
[PUBMED]    
34.Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939: An oral, direct Factor Xa inhibitor: After multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005;61:873-80.  Back to cited text no. 34
[PUBMED]    
35.Weinz C, Schwarz T, Kubitza D, Mueck W, Lang D. Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug Metab Dispos 2009;37:1056-64.  Back to cited text no. 35
[PUBMED]    
36.Ufer M. Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development. Thromb Haemost 2010;103:572-85.  Back to cited text no. 36
[PUBMED]    
37.Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91.  Back to cited text no. 37
[PUBMED]    
38.Giorgi MA, Miguel LS. Rivaroxaban in atrial fibrillation. Vasc Health Risk Manag 2012;8:525-31.  Back to cited text no. 38
[PUBMED]    
39.Harenberg J, Marx S, Diener HC, Lip GY, Marder VJ, Wehling M, et al. Comparison of efficacy and safety of dabigatran, rivaroxaban and apixaban in patients with atrial fibrillation using network meta-analysis. Int Angiol 2012;31:330-9.  Back to cited text no. 39
[PUBMED]    
40.Mantha S, Ansell J. An indirect comparison of dabigatran, rivaroxaban and apixaban for atrial fibrillation. Thromb Haemost 2012;108:476-84.  Back to cited text no. 40
[PUBMED]    
41.Becattini C, Vedovati MC, Agnelli G. Old and new oral anticoagulants for venous thromboembolism and atrial fibrillation: A review of the literature. Thromb Res 2012;129:392-400.  Back to cited text no. 41
[PUBMED]    
42.Banerjee A, Lane DA, Torp-Pedersen C, Lip GY. Net clinical benefit of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus no treatment in a 'real world' atrial fibrillation population: A modelling analysis based on a nationwide cohort study. Thromb Haemost 2012;107:584-9.  Back to cited text no. 42
[PUBMED]    
43.Bommer WJ. Current and future alternatives to warfarin for the prevention of stroke in atrial fibrillation. Crit Pathw Cardiol 2012;11:45-54.  Back to cited text no. 43
[PUBMED]    
44.Frost C, Wang J, Nepal S, Schuster A, Barrett YC, Mosqueda-Garcia R, et al. Apixaban, an oral, direct factor Xa inhibitor: Single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects. Br J Clin Pharmacol 2013;75:476-87.  Back to cited text no. 44
[PUBMED]    
45.Raghavan N, Frost CE, Yu Z, He K, Zhang H, Humphreys WG, et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos 2009;37:74-81.  Back to cited text no. 45
[PUBMED]    
46.Schellong SM, Haas S. Novel oral anticoagulants and their use in the perioperative setting. Anasthesiol Intensivmed Notfallmed Schmerzther 2012;47:266-72.  Back to cited text no. 46
[PUBMED]    
47.Eikelboom JW, Connolly SJ, Gao P, Paolasso E, De Caterina R, Husted S, et al. Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease. J Stroke Cerebrovasc Dis 2012;21:429-35.  Back to cited text no. 47
[PUBMED]    
48.Littrell R, Flaker G. Apixaban for the prevention of stroke in atrial fibrillation. Expert Rev Cardiovasc Ther 2012;10:143-9.  Back to cited text no. 48
[PUBMED]    
49.Diener HC, Eikelboom J, Connolly SJ, Joyner CD, Hart RG, Lip GY, et al. Apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: A predefined subgroup analysis from AVERROES, a randomised trial. Lancet Neurol 2012;11:225-31.  Back to cited text no. 49
[PUBMED]    
50.Doggrell SA. More light at the end of the tunnel-apixaban in atrial fibrillation. Expert Opin Investig Drugs 2012;21:1235-9.  Back to cited text no. 50
[PUBMED]    
51.Flaker GC, Eikelboom JW, Shestakovska O, Connolly SJ, Kaatz S, Budaj A, et al. Bleeding during treatment with aspirin versus apixaban in patients with atrial fibrillation unsuitable for warfarin: The apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment (AVERROES) trial. Stroke 2012;43:3291-7.  Back to cited text no. 51
    
52.Deedwania P, Huang GW. An evidence-based review of apixaban and its potential in the prevention of stroke in patients with atrial fibrillation. Core Evid 2012;7:49-5.  Back to cited text no. 52
[PUBMED]    
53.Easton JD, Lopes RD, Bahit MC, Wojdyla DM, Granger CB, Wallentin L, et al. Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: A subgroup analysis of the ARISTOTLE trial. Lancet Neurol 2012;11:503-11.  Back to cited text no. 53
[PUBMED]    
54.Lopes RD, Al-Khatib SM, Wallentin L, Yang H, Ansell J, Bahit MC, et al. Efficacy and safety of apixaban compared with warfarin according to patient risk of stroke and of bleeding in atrial fibrillation: A secondary analysis of a randomised controlled trial. Lancet 2012;380:1749-58.  Back to cited text no. 54
[PUBMED]    
55.Deeks ED. Apixaban: A review of its use in the prevention of venous thromboembolism after knee or hip replacement surgery. Drugs 2012;72:1271-91.  Back to cited text no. 55
[PUBMED]    
56.Imberti D, Gallerani M, Manfredini R. Therapeutic potential of apixaban in the prevention of venous thromboembolism in patients undergoing total knee replacement surgery. J Thromb Thrombolysis 2012;34:208-13.  Back to cited text no. 56
[PUBMED]    
57.Schneeweiss S, Gagne JJ, Patrick AR, Choudhry NK, Avorn J. Comparative efficacy and safety of new oral anticoagulants in patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes 2012;5:480-6.  Back to cited text no. 57
[PUBMED]    
58.Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368:699-708.  Back to cited text no. 58
[PUBMED]    
59.De Caterina R, Husted S, Wallentin L, Andreotti F, Arnesen H, Bachmann F, et al. New oral anticoagulants in atrial fibrillation and acute coronary syndromes: ESC working group on thrombosis-task force on anticoagulants in heart disease position paper. J Am Coll Cardiol 2012;59:1413-25.  Back to cited text no. 59
[PUBMED]    
60.Hart RG, Benavente O, Pearce LA. Increased risk of intracranial hemorrhage when aspirin is combined with warfarin: A meta-analysis and hypothesis. Cerebrovasc Dis 1999;9:215-7.  Back to cited text no. 60
    
61.Yasaka M, Okada Y. Management of intracranial hemorrhage during anticoagulant therapy with warfarin or novel anticoagulants. Rinsho Shinkeigaku 2012;52:1113-6.  Back to cited text no. 61
[PUBMED]    
62.Merli GJ. The new oral anticoagulants: A challenge for hospital formularies. Hosp Pract (1995) 2012;40:126-8.  Back to cited text no. 62
    
63.Stangier J, Rathgen K, Stähle H, Reseski K, Körnicke T, Roth W. Coadministration of dabigatran etexilate and atorvastatin: Assessment of potential impact on pharmacokinetics and pharmacodynamics. Am J Cardiovasc Drugs 2009;9:59-68.  Back to cited text no. 63
    
64.Walenga JM, Adiguzel C. Drug and dietary interactions of the new and emerging oral anticoagulants. Int J Clin Pract 2010;64:956-67.  Back to cited text no. 64
[PUBMED]    
65.Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Effect of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY 59-7939 (rivaroxaban), an oral, direct factor Xa inhibitor, in healthy subjects. J Clin Pharmacol 2006;46:549-58.  Back to cited text no. 65
[PUBMED]    
66.van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, et al. Dabigatran etexilate: A novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010;103:1116-27.  Back to cited text no. 66
[PUBMED]    
67.Wysokinski WE, McBane RD 2 nd . Periprocedural bridging management of anticoagulation. Circulation 2012;126:486-90.  Back to cited text no. 67
    
68.Bozzato S, Galli L, Ageno W. Thromboprophylaxis in surgical and medical patients. Semin Respir Crit Care Med 2012;33:163-75.  Back to cited text no. 68
[PUBMED]    
69.Cohen A, Drost P, Marchant N, Mitchell S, Orme M, Rublee D, et al. The efficacy and safety of pharmacological prophylaxis of venous thromboembolism following elective knee or hip replacement: Systematic review and network meta-analysis. Clin Appl Thromb Hemost 2012;18:611-27.  Back to cited text no. 69
[PUBMED]    
70.Alves C, Batel-Marques F, Macedo AF. Apixaban and rivaroxaban safety after hip and knee arthroplasty: A meta-analysis. J Cardiovasc Pharmacol Ther 2012;17:266-76.  Back to cited text no. 70
[PUBMED]    
71.Burness CB, McKeage K. Dabigatran etexilate: A review of its use for the prevention of venous thromboembolism after total hip or knee replacement surgery. Drugs 2012;72:963-86.  Back to cited text no. 71
[PUBMED]    
72.Welle MK. Understanding the new emerging oral anticoagulants for venous thromboembolism prophylaxis. Orthop Nurs 2012;31:265-78; quiz 279.  Back to cited text no. 72
[PUBMED]    
73.Apixaban. After hip or knee replacement: LMWH remains the standard treatment. Prescrire Int 2012;21:201-2, 204.  Back to cited text no. 73
[PUBMED]    
74.Brand B, Graf L. New anticoagulants-direct thrombin inhibitors. Ther Umsch 2012;69:643-9.  Back to cited text no. 74
[PUBMED]    
75.Rasmussen LH, Larsen TB, Graungaard T, Skjøth F, Lip GY. Primary and secondary prevention with new oral anticoagulant drugs for stroke prevention in atrial fibrillation: Indirect comparison analysis. BMJ 2012;345:e7097.  Back to cited text no. 75
    
76.Lip GY, Larsen TB, Skjøth F, Rasmussen LH. Indirect comparisons of new oral anticoagulant drugs for efficacy and safety when used for stroke prevention in atrial fibrillation. J Am Coll Cardiol 2012;60:738-46.  Back to cited text no. 76
    
77.Coccheri S, Orlando D. New oral anticoagulants in atrial fibrillation: A reappraisal of trial results looking at absolute figures. Intern Emerg Med 2013;8:115-22.  Back to cited text no. 77
[PUBMED]    
78.Carter KL, Streiff MB, Ross PA, Wellman JC, Thomas ML, Kraus PS, et al. Analysis of the projected utility of dabigatran, rivaroxaban, and apixaban and their future impact on existing Hematology and Cardiology Anticoagulation Clinics at The Johns Hopkins Hospital. J Thromb Thrombolysis 2012;34:437-45.  Back to cited text no. 78
[PUBMED]    
79.Haschke M. Clinical pharmacological aspects of new oral anticoagulants. Ther Umsch 2012;69:657-60.  Back to cited text no. 79
[PUBMED]    
80.van Dijk EJ, Koudstaal PJ, Roos YB, Brouwers PJ, Kappelle LJ. New oral anticoagulants for atrial fibrillation: A neurologist's view. Ned Tijdschr Geneeskd 2012;156:A5283.  Back to cited text no. 80
[PUBMED]    
81.Hohnloser SH, Hijazi Z, Thomas L, Alexander JH, Amerena J, Hanna M, et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: Insights from the ARISTOTLE trial. Eur Heart J 2012;33:2821-30.  Back to cited text no. 81
[PUBMED]    
82.Jones MM. ACP Journal Club. Apixaban reduced stroke or systemic embolism more than warfarin in AF regardless of renal function. Ann Intern Med 2012;157:JC6-7.  Back to cited text no. 82
    
83.Le Heuzey JY. Antithrombotic treatment of atrial fibrillation: New insights. Thromb Res 2012;130 Suppl 1:S59-60.  Back to cited text no. 83
[PUBMED]    
84.Ru San T, Chan MY, Wee Siong T, Kok Foo T, Kheng Siang N, Lee SH, et al. Stroke prevention in atrial fibrillation: Understanding the new oral anticoagulants dabigatran, rivaroxaban, and apixaban. Thrombosis 2012;2012:108983.  Back to cited text no. 84
[PUBMED]    
85.Ruiz-Giménez Arrieta N.[Scope of the latest RE-LY substudies: Clinical implications]. Rev Clin Esp 2012;212 Suppl 2:4-14.  Back to cited text no. 85
    
86.Hankey GJ. Anticoagulant therapy for patients with ischaemic stroke. Nat Rev Neurol 2012;8:319-28.  Back to cited text no. 86
[PUBMED]    
87.Táborský M, Heinc P, Hrèková Y. Dabigatran etexilate in clinical practice for prevention of thromboembolic events in patients with atrial fibrillation. Vnitr Lek 2012;58:769-77.  Back to cited text no. 87
    
88.Salmela B, Joutsi-Korhonen L, Armstrong E, Lassila R. Active online assessment of patients using new oral anticoagulants: Bleeding risk, compliance, and coagulation analysis. Semin Thromb Hemost 2012;38:23-30.  Back to cited text no. 88
[PUBMED]    
89.Cabral KP, Ansell J. Oral direct factor Xa inhibitors for stroke prevention in atrial fibrillation. Nat Rev Cardiol 2012;9:385-91.  Back to cited text no. 89
[PUBMED]    
90.Wooten JM. Comparing new anticoagulants. South Med J 2012;105:665-9.  Back to cited text no. 90
[PUBMED]    
91.Rosenberg DJ, Ansell J. Target-specific oral anticoagulants for stroke prevention in patients with atrial fibrillation: Real-world considerations. Hosp Pract (1995) 2012;40:50-7.  Back to cited text no. 91
    
92.Arquizan C. Atrial fibrillation in elderly. Rev Prat 2012;62:1229-33.  Back to cited text no. 92
[PUBMED]    
93.Le Gal G, Mottier D. New anticoagulants in the treatment of VTE. Semin Respir Crit Care Med 2012;33:191-8.  Back to cited text no. 93
[PUBMED]    
94.Haas S, Spannagl M, Schellong SM. Novel oral anticoagulants: Key messages for the angiologist. Vasa 2012;41:177-91.  Back to cited text no. 94
[PUBMED]    
95.Kamel H, Easton JD, Johnston SC, Kim AS. Cost-effectiveness of apixaban vs. warfarin for secondary stroke prevention in atrial fibrillation. Neurology 2012;79:1428-34.  Back to cited text no. 95
[PUBMED]    
96.Lee S, Mullin R, Blazawski J, Coleman CI. Cost-effectiveness of apixaban compared with warfarin for stroke prevention in atrial fibrillation. PLoS One 2012;7:e47473.  Back to cited text no. 96
[PUBMED]    
97.Deitelzweig S, Amin A, Jing Y, Makenbaeva D, Wiederkehr D, Lin J, et al. Medical cost reductions associated with the usage of novel oral anticoagulants vs warfarin among atrial fibrillation patients, based on the RE-LY, ROCKET-AF, and ARISTOTLE trials. J Med Econ 2012;15:776-85.  Back to cited text no. 97
[PUBMED]    
98.Augoustides JG. Breakthroughs in anticoagulation: Advent of the oral direct factor Xa inhibitors. J Cardiothorac Vasc Anesth 2012;26:740-5.  Back to cited text no. 98
[PUBMED]    

Top
Correspondence Address:
Vishal Sehgal
Commonwealth Health - Regional Hospital of Scranton, Clinical Assistant Professor of Medicine, The Commonwealth Medical College, Scranton, PA 18510
USA
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0971-9784.114244

Rights and Permissions


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]

This article has been cited by
1 Warfarin and Aspirin Use for Stroke Prevention Among Patients With Atrial Fibrillation
Amir Goren,Xianchen Liu,Shaloo Gupta,Teresa A. Simon,Hemant Phatak
American Journal of Therapeutics. 2015; 22(4): 248
[Pubmed] | [DOI]
2 Haemostatic challenges in the cancer patient: focus on the peri-operative period
Kate Burbury
Best Practice & Research Clinical Anaesthesiology. 2013;
[Pubmed] | [DOI]



 

Top