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

Vishal Sehgal1, Sukhminder Jit Singh Bajwa2, Anurag Bajaj3,  
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

Correspondence Address:
Vishal Sehgal
Commonwealth Health - Regional Hospital of Scranton, Clinical Assistant Professor of Medicine, The Commonwealth Medical College, Scranton, PA 18510


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.

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

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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 2020 Sep 25 ];16:193-200
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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

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}

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}{Table 2}

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}


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.


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