Posts Tagged ‘Dabigatran’

Advantages and Disadvantages of Novel Oral Anticoagulants (NOACs)


Reporter: Aviva Lev-Ari, PhD, RN



UPDATED ON 2/1/2019

NOACs Usually Preferable to Warfarin in Atrial Fibrillation: Guideline Update

READ ALL GUIDELINES at the sources listed below.

Here we post only,

Triple vs Double Antithrombotic Therapy

The update provides a warning about the extra bleeding risk associated with OAC in patients with AF who have undergone percutaneous coronary intervention (PCI) for ACS, who otherwise would also receive dual antiplatelet therapy (DAPT). Such “triple therapy” is usually best avoided, it emphasizes.

In patients with increased stroke risk (based on a CHA2DS2-VASc ≥2) who’ve had PCI for ACS, the update states, “double therapy” with P2Y12 inhibitor antiplatelets plus a dose-adjusted vitamin-K antagonist, low-dose rivaroxaban, or 150 mg bid dabigatran “is reasonable to reduce the risk of bleeding compared with triple therapy.” The recommendations are IIa, level of evidence B-R.

“The guideline acknowledges that if there’s a need to put them on triple therapy, it should only be for a short period of time: 4 to 6 weeks, for example,” January said. Following that early post-PCI period in which stent thrombosis is most likely, the patient should preferably be transitioned to double therapy.

“DAPT alone may be considered for patients with ACS who have AF and a CHA2DS2-VASc score of 0 to 1, with reconsideration of the indications for anticoagulation over time,” the new document says.

January reported no conflicts. Disclosure information for all writing committee members and reviewers is in the report and tabulated separately online.

Original Publications:
  • Circulation. Published online January 28, 2019. Report
  • J Am Coll Cardiol. Published online January 28, 2019. Report
  • Heart Rhythm. Published online January 28, 2019. Report





In the past four years, three novel oral anticoagulant (NOAC) medications have become available:

  • apixaban (Eliquis®),
  • dabigatran (Pradaxa®), and
  • rivaroxaban (Xarelto®). A fourth NOAC,
  • edoxaban (Savaysa™), has been submitted for approval by the US Food and Drug Administration …

Two small to moderate size trials have shown similar bleeding risk with other NOACs (VENTURE-AF with rivaroxaban [Xarelto] and RE-CIRCUIT with dabigatran [Pradaxa]) compared with vitamin K antagonists. In a non-formal “eyeball” meta-analysis with AXAFA-AFNET 5, combined death, stroke or transient ischemic attack, and major bleeding risk appeared to trend lower with a NOAC than vitamin K antagonist.

However, “differences in populations and procedures may well explain the different outcomes in bleeding rates and silent strokes with NOAC versus vitamin K antagonists,” suggested Blomstrom-Lundqvist.

Increased Bleeding is Main Issue With Newer Agents

Regardless of which agent is used, clinical practice and research has shifted focus to decreasing the risk of bleeding for patients on oral anticoagulants and antithrombotics. While the newer agents might be better than warfarin on several points, the more effective ability to prevent clotting also results in the unwanted consequence of increased bleeding. This sentiment was echoed multiple times by speakers at ACC.16. The most common bleeding complication with NOACs compared to warfarin is gastrointestinal (GI) bleeding.  The results of the Ruff meta-analysis favored warfarin over NOACs for rates of GI bleeds (whether results from dabigatran trials were included or not).

“Major bleeds, as well as minor bleeds, may be a problem because patients stop their treatments — not only their antithrombotic treatment, but also the ACE inhibitors, statins and all other life-saving therapies,” explained Freek Verheugt, M.D., FESC, FACC, FAHA, professor of cardiology, Heart-Lung Centre of the University Medical Centre of Nijmegen and chairman of the Department of Cardiology at Onze Lieve Vrouwe Gasthuis, The Netherlands.

Evolution of the Anticoagulant Nomenclature 

The approval of dabigatran (Pradaxa) in 2010 lead to the creation of the term new oral anticoagulants (NOACs). This term was changed to novel oral anticoagulants (NOACs) when rivaroxaban (Xarelto) came to the market in 2011. After apixaban (Eliquis) and edoxaban (Savaysa) were cleared, the name changed to direct oral anticoagulants (DOACs) and is the term used by the International Society of Thrombosis and Haemostasis. Alternative names for these agents are target-specific oral anticoagulants (TSOACs) and non-vitamin K oral anticoagulants (NOACs), the term used by the American College of Chest Physicians and the FDA. All of these acronyms refer to the same agents.



Warfarin Use May Not Bring Long-Term Stability for Atrial Fibrillation

Registry study finds INR values fluctuate over 18 months, even in patients considered “stable”

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Apixaban (Eliquis): Mechanism of Action, Drug Comparison and Additional Indications

Curator: Aviva Lev-Ari, PhD, RN

WC 5

WordCloud by Zach Day; Article Title: Apixaban (Eliquis): Mechanism of Action, Drug Comparison and Additional Indications

During the past 20 years, the approval of anticoagulants such as low-molecular-weight heparins (LMWHs), indirect factor Xa inhibitors (eg, fondaparinux), and direct thrombin inhibitors (eg, argatroban, bivalirudin, lepirudin, and desirudin) has signaled a growing interest in antithrombotic compounds that have relatively discrete targets within the coagulation pathway. Although these medications offer several potential advantages over unfractionated heparin, they all require parenteral administration and are substantially more expensive than oral vitamin K antagonists (VKAs). Thus VKAs, despite disadvantages such as variability in dose response, a narrow therapeutic index, and numerous drug and dietary interactions, are the only option for most patients requiring chronic anticoagulation.


Eliquis Approval History

Eliquis (apixaban) is a factor Xa inhibitor anticoagulant indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, and for the prophylaxis of deep vein thrombosis (DVT) in patients who have undergone hip or knee replacement surgery.

FDA Approval History for Eliquis

Date Article
Mar 18, 2014 Approval FDA Approves Eliquis to Reduce Risk of Blood Clots Following Hip Or Knee Replacement Surgery
Jul 11, 2013 Approval FDA Accepts Eliquis (apixaban) Supplemental New Drug Application for Review for Prophylaxis of Deep Vein Thrombosis Following Hip Or Knee Replacement Surgery
Dec 28, 2012 Approval FDA Approves Eliquis to Reduce the Risk of Stroke, Blood Clots in Patients with Non-Valvular Atrial Fibrillation
Sep 26, 2012 FDA Acknowledges Receipt of Resubmission of the Eliquis (apixaban) New Drug Application to Reduce the Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation
Jun 25, 2012 Bristol-Myers Squibb and Pfizer Receive Complete Response Letter From U.S. Food and Drug Administration for Eliquis (Apixaban)
Mar  1, 2012 U.S. Food and Drug Administration Extends Action Date for Eliquis (apixaban) by Three Months
Nov 29, 2011 FDA Accepts Eliquis (apixaban) New Drug Application for Review for the Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation


Indirect Comparisons of New Oral Anticoagulant Drugs for Efficacy and Safety When Used for Stroke Prevention in Atrial Fibrillation

Gregory Y.H. Lip, MD?; Torben Bjerregaard Larsen, MD, PhD; Flemming Skjøth, PhD; Lars Hvilsted Rasmussen, MD, PhD

Results  There was a significantly lower risk of stroke and systemic embolism (by 26%) for dabigatran (150 mg BID) compared with rivaroxaban, as well as hemorrhagic stroke and nondisabling stroke. There were no significant differences for apixaban versus dabigatran (both doses) or rivaroxaban; or rivaroxaban versus dabigatran 110 mg BID in preventing stroke and systemic embolism. For ischemic stroke, there were no significant differences between the new OACs. Major bleeding was significantly lower with apixaban compared with dabigatran 150 mg BID (by 26%) and rivaroxaban (by 34%), but not significantly different from dabigatran 110 mg BID. There were no significant differences between apixaban and dabigatran 110 mg BID in safety endpoints. Apixaban also had lower major or clinically relevant bleeding (by 34%) compared with rivaroxaban. When compared with rivaroxaban, dabigatran 110 mg BID was associated with less major bleeding (by 23%) and intracranial bleeding (by 54%). There were no significant differences in myocardial infarction events between the dabigatran (both doses) and apixaban.

Conclusions  Notwithstanding the limitations of an indirect comparison study, we found no profound significant differences in efficacy between apixaban and dabigatran etexilate (both doses) or rivaroxaban. Dabigatran 150 mg BID was superior to rivaroxaban for some efficacy endpoints, whereas major bleeding was significantly lower with dabigatran 110 mg BID or apixaban. Only a head-to-head direct comparison of the different new OACs would fully answer the question of efficacy/safety differences between the new drugs for stroke prevention in AF.


Clinical trials with new oral anticoagulants

Journal: Hämostaseologie
ISSN: 0720-9355
Topic: 57. Jahrestagung der Gesellschaft für Hämostase- und Thromboseforschung e.V.
DOI: http://dx.doi.org/10.5482/HAMO-12-11-0021
Issue: Issues of 2013 (Vol. 33): Issue 1 2013 (1-76)
Pages: 62-70

New Eliquis® (apixaban) Post-hoc Subanalysis of the Phase III ARISTOTLE trial Demonstrated that within 30 Days of a Procedure, Stroke or Systemic Embolism and Major Bleeding were Uncommon –


The ARISTOTLE study was designed to demonstrate the efficacy and safety of Eliquis versus warfarin for the prevention of stroke or systemic embolism. In ARISTOTLE, 18,201 patients were randomized (9,120 patients to Eliquis and 9,081 to warfarin). ARISTOTLE was an active-controlled, randomized, double-blind, multi-national trial in patients with nonvalvular atrial fibrillation or atrial flutter, and at least one additional risk factor for stroke. Patients were randomized to treatment with Eliquis 5 mg orally twice daily (or 2.5 mg twice daily in selected patients, representing 4.7 percent of all patients) or warfarin (target INR range 2.0-3.0), and followed for a median of 1.8 years.

Results presented today at the ESC Congress 2013

“For NVAF patients for whom interruption of anticoagulation for a procedure is required, these findings suggest that using apixaban instead of warfarin, which is more challenging to stop and restart, may simplify the management of peri-operative anticoagulation in NVAF patients.”

The new oral anticoagulants

  1. David Garcia1,
  2. Edward Libby1, and
  3. Mark A. Crowther2
    1. 1University of New Mexico, Albuquerque; and

    2. 2McMaster University, Hamilton, ON


Phase 2 data for apixaban in the prevention and treatment of venous thromboembolism (VTE) suggested that this compound may be a safe and effective anticoagulant over a wide range of doses.16,17 The first phase 3 orthopedic prophylaxis trial (ADVANCE-1) randomized 3195 patients, in double-blind fashion, to either apixaban (2.5 mg orally twice a day) or enoxaparin (30 mg subcutaneously every 12 hours). In both arms, treatments were begun 12 to 24 hours after surgery; all patients underwent venography approximately 2 weeks later. The proportion of patients who reached the primary endpoint (VTE, both symptomatic and venographically detected, or death from any cause) was similar for the apixaban (8.99%) and enoxaparin (8.85%) arms; however, the predetermined noninferiority endpoint was not met.7 It is unclear whether the failure to prove noninferiority can be explained by inaccurately low prestudy estimates of event rates, the dose/timing of apixaban, or some other cause. In any case, the comparable event rates (neither regimen was found superior to the other), along with less clinically relevant bleeding in the apixaban arm, strongly suggest that apixaban is an effective anticoagulant. Results from ADVANCE-2, a randomized double-blind multicenter trial comparing apixaban 2.5 mg orally twice a day with enoxaparin 40 mg subcutaneously once daily for preventing VTE after total knee replacement were presented at the congress of the International Society of Thrombosis and Hemostasis in July 2009. The primary efficacy outcome (all VTE) occurred in 147 of 976 evaluable patients (15.1%) in the apixaban group and 243 of 997 evaluable patients (24.4%) in the enoxaparin group (relative risk = 0.62; 95% confidence interval, 0.51-0.74, 1-sidedP < .001). A nonsignificant trend toward less clinically relevant bleeding also favored apixaban (53 patients, 3.5% vs 72 patients, 4.8%; P = .09).

A phase 3 study (AMPLIFY) of patients with acute VTE (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]) will compare apixaban (10 mg twice daily for 7 days, followed by apixaban 5 mg, twice daily for 6 months) to a standard strategy using enoxaparin followed by VKA. A phase 3 “extension” study will enroll patients for whom there is clinical uncertainty about whether to continue oral anticoagulation after 6 months of routine treatment with a VKA. Participants will be randomly assigned to receive 1 of 3 possible interventions for 12 months: placebo, apixaban 2.5 mg twice daily, or apixaban 5 mg twice daily. In both trials, the primary outcome measure will be a composite of symptomatic, objectively confirmed recurrent VTE or death during the treatment period.

The APPRAISE trial was a phase 2 dose-finding study in which 1700 patients were randomized to receive placebo or 1 of 4 apixaban doses for the 6 months after standard acute therapy for acute coronary syndrome.18 For patients receiving the 2 highest doses of apixaban, the trial was terminated prematurely because of excess bleeding. In this population of patients receiving one or more concomitant antiplatelet agents, the 2 lower-dose apixaban arms had higher rates of the primary endpoint (major bleeding plus clinically relevant nonmajor bleeding) than did the placebo group. The trial was not powered to detect a statistically significant difference in the rates in the composite efficacy endpoint of cardiovascular death, nonfatal heart attack, severe recurrent ischemia, and nonhemorrhagic stroke but showed trends favoring apixaban over placebo for these endpoints. A phase 3 trial (APPRAISE-2) comparing apixaban 5 mg twice daily versus placebo in this clinical setting is under way.

Finally, apixaban is being studied as a stroke prevention strategy for patients with atrial fibrillation (AF). When completed, the ARISTOTLE trial will randomize approximately 18 000 patients with chronic nonvalvular AF to apixaban 5 mg orally twice daily or warfarin, target international normalized ratio (INR) 2.0 to 3.0. This event-driven, double-blind, parallel arm study is designed to show that apixaban is noninferior to well-managed warfarin in the prevention of stroke or systemic embolism. In a different randomized, double-blind study (AVERROES), apixaban (5 mg orally twice daily) is being compared with aspirin (81-324 mg daily) among AF patients who have failed or are unsuitable for VKA treatment. This trial will include 5000 to 6000 patients; follow-up will be up to 36 months.


Clinical Studies

Reduction Of Risk Of Stroke And Systemic Embolism In Nonvalvular Atrial Fibrillation


Evidence for the efficacy and safety of ELIQUIS was derived from ARISTOTLE, a multinational, double-blind study in patients with nonvalvular AF comparing the effects of ELIQUIS and warfarin on the risk of stroke and non-central nervous system (CNS) systemic embolism. In ARISTOTLE, patients were randomized to ELIQUIS 5 mg orally twice daily (or 2.5 mg twice daily in subjects with at least 2 of the following characteristics: age ≥ 80 years, body weight ≤ 60 kg, or serum creatinine ≥ 1.5 mg/dL) or to warfarin (targeted to an INR range of 2.0–3.0). Patients had to have one or more of the following additional risk factors for stroke:

The primary objective of ARISTOTLE was to determine whether ELIQUIS 5 mg twice daily (or 2.5 mg twice daily) was effective (noninferior to warfarin) in reducing the risk of stroke (ischemic or hemorrhagic) and systemic embolism. Superiority of ELIQUIS to warfarin was also examined for the primary endpoint (rate of stroke and systemic embolism), major bleeding, and death from any cause.

A total of 18,201 patients were randomized and followed on study treatment for a median of 89 weeks. Forty-three percent of patients were vitamin Kantagonist (VKA) “naive,” defined as having received ≤ 30 consecutive days of treatment with warfarin or another VKA before entering the study. The mean age was 69 years and the mean CHADS2 score (a scale from 0 to 6 used to estimate risk of stroke, with higher scores predicting greater risk) was 2.1. The population was 65% male, 83% Caucasian, 14% Asian, and 1% Black. There was a history of stroke, TIA, or non-CNS systemic embolism in 19% of patients. Concomitant diseases of patients in this study included hypertension 88%, diabetes 25%, congestive heart failure (or left ventricular ejection fraction ≤ 40%) 35%, and prior myocardial infarction14%. Patients treated with warfarin in ARISTOTLE had a mean percentage of time in therapeutic range (INR 2.0–3.0) of 62%.

ELIQUIS was superior to warfarin for the primary endpoint of reducing the risk of stroke and systemic embolism (Table 5 and Figure 4). Superiority to warfarin was primarily attributable to a reduction in hemorrhagic stroke and ischemic strokes with hemorrhagic conversion compared to warfarin. Purely ischemic strokes occurred with similar rates on both drugs.

ELIQUIS also showed significantly fewer major bleeds than warfarin [seeADVERSE REACTIONS].

Table 5: Key Efficacy Outcomes in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE (Intent-to-Treat Analysis)

N (%/YEAR)
N (%/YEAR)
Stroke or systemic embolism 212 (1.27) 265 (1.60) 0.79 (0.66, 0.95) 0.01
  Stroke 199 (1.19) 250 (1.51) 0.79 (0.65, 0.95)
    Ischemic without hemorrhage 140 (0.83) 136 (0.82) 1.02 (0.81, 1.29)
    Ischemic with hemorrhagic conversion 12 (0.07) 20 (0.12) 0.60 (0.29, 1.23)
    Hemorrhagic 40 (0.24) 78 (0.47) 0.51 (0.35, 0.75)
    Unknown 14 (0.08) 21 (0.13) 0.65 (0.33, 1.29)
  Systemic embolism 15 (0.09) 17 (0.10) 0.87 (0.44, 1.75)
The primary endpoint was based on the time to first event (one per subject). Component counts are for subjects with any event, not necessarily the first.

Figure 4: Kaplan-Meier Estimate of Time to First Stroke or Systemic Embolism in ARISTOTLE (Intent-to-Treat Population)


Apixaban, a direct factor Xa inhibitor, inhibits tissue-factor induced human platelet aggregation in vitro : Comparison with direct inhibitors of factor VIIa, XIa and thrombin

P. C. Wong (1), X. Jiang (1)

(1) Thrombosis Research, Bristol-Myers Squibb Company, Pennington, New Jersey, USA


Tissue factor, platelet aggregation, rivaroxaban, direct factor Xa inhibitor, dabigatran, Apixaban


Apixaban is an oral, direct and highly selective factor Xa (FXa) inhibitor in late-stage clinical development. This study evaluated the in vitro effect of apixaban on human platelet aggregation induced by thrombin derived via the extrinsic pathway. Direct inhibitors of FXa (rivaroxaban), FVIIa (BMS-593214), thrombin (dabigatran, argatroban) and FXIa (BMS-262084) were included for comparison. Citrated human platelets-rich plasma (PRP) was treated with 50 mg/ml corn trypsin inhibitor (to block the contact factor pathway) and 3 mM H-Gly-Pro-Arg-Pro-OH-AcOH (to prevent fibrin polymerisation). Human tissue factor (TF) (Innovin®; dilution 1:1,000 to 1:1,500) plus 7.5 mM CaCl2 was added to PRP pre-incubated with vehicle or increasing concentrations of inhibitors. The TF-induced platelet aggregation was measured by optical aggregometry. TF produced 85 ± 3% aggregation of human platelets in the vehicle-treated group (n=10). Apixaban and other factor inhibitors, except the FXIa inhibitor, inhibited TF-induced platelet aggregation with IC50 (nM) values as follows: 4 ± 1 (apixaban), 8 ± 2 (rivaroxaban), 13 ± 1 (BMS-593214), 46 ± 1 (dabigatran) and 79 ± 1 (argatroban). BMS-262084 (IC50 = 2.8 nM vs. human FXIa) had no effect on TF-induced platelet aggregation at 10 μM. These inhibitors at 10 μM had no effect on platelet aggregation induced by ADP and collagen, as expected from their mechanism of action. This study demonstrates that inhibition of thrombin generation by blocking upstream proteases (FVIIa and FXa) in the blood coagulation cascade is as effective as direct thrombin inhibition in preventing TF-induced platelet aggregation. Under these experimental conditions, a FXIa inhibitor did not prevent TF-induced platelet aggregation.


Mechanism Of Action

Apixaban is a selective inhibitor of FXa. It does not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound FXa, and prothrombinase activity. Apixaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, apixaban decreases thrombin generation and thrombusdevelopment.


As a result of FXa inhibition, apixaban prolongs clotting tests such asprothrombin time (PT), INR, and activated partial thromboplastin time (aPTT). Changes observed in these clotting tests at the expected therapeutic dose, however, are small, subject to a high degree of variability, and not useful in monitoring the anticoagulation effect of apixaban.

The Rotachrom® Heparin chromogenic assay was used to measure the effect of apixaban on FXa activity in humans during the apixaban development program. A concentration-dependent increase in anti-FXa activity was observed in the dose range tested and was similar in healthy subjects and patients with AF.

This test is not recommended for assessing the anticoagulant effect of apixaban.

Pharmacodynamic Drug Interaction Studies

Pharmacodynamic drug interaction studies with aspirin, clopidogrel, aspirin and clopidogrel, prasugrel, enoxaparin, and naproxen were conducted. No pharmacodynamic interactions were observed with aspirin, clopidogrel, or prasugrel [see WARNINGS AND PRECAUTIONS]. A 50% to 60% increase in anti-FXa activity was observed when apixaban was coadministered with enoxaparin or naproxen.

Specific Populations

Renal impairment: Anti-FXa activity adjusted for exposure to apixaban was similar across renal function categories.

Hepatic impairment: Changes in anti-FXa activity were similar in patients with mild-tomoderate hepatic impairment and healthy subjects. However, in patients with moderate hepatic impairment, there is no clear understanding of the impact of this degree of hepatic function impairment on the coagulation cascade and its relationship to efficacy and bleeding. Patients with severe hepatic impairment were not studied.

Cardiac Electrophysiology

Apixaban has no effect on the QTc interval in humans at doses up to 50 mg.


Apixaban demonstrates linear pharmacokinetics with dose-proportional increases in exposure for oral doses up to 10 mg.

The LancetVolume 383, Issue 9921, Pages 955 – 962, 15 March 2014
doi:10.1016/S0140-6736(13)62343-0Cite or Link Using DOI
This article can be found in the following collections: Cardiology & Vascular Medicine (Ischaemic heart diseasePericardial & endocardial disease); Neurology (Cerebrovascular diseaseNeurology-other)
Published Online: 04 December 2013

Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials

Dr Christian T Ruff MD a Corresponding AuthorEmail AddressRobert P Giugliano MD aProf Eugene Braunwald MD aElaine B Hoffman PhD aNaveen Deenadayalu MPH aProf Michael D Ezekowitz MBChB b cProf A John Camm MD dProf Jeffrey I Weitz MD eProf Basil S LewisMD fProf Alexander Parkhomenko MD gProf Takeshi Yamashita MD hProf Elliott M Antman MD a

a Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
b Jefferson Medical College, Philadelphia, PA, USA
c Cardiovascular Research Foundation, New York, NY, USA
d St George’s University, London, UK
e McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada
f Lady Davis Carmel Medical Center, Haifa, Israel
g Institute of Cardiology, Kiev, Ukraine
h The Cardiovascular Institute, Tokyo, Japan
Corresponding Author Information Correspondence to: Dr Christian T Ruff, Thrombolysis in Myocardial Infarction (TIMI) Study Group, 350 Longwood Avenue, 1st Floor Offices, Boston, MA 02115, USA


Four new oral anticoagulants compare favourably with warfarin for stroke prevention in patients with atrial fibrillation; however, the balance between efficacy and safety in subgroups needs better definition. We aimed to assess the relative benefit of new oral anticoagulants in key subgroups, and the effects on important secondary outcomes.


We searched Medline from Jan 1, 2009, to Nov 19, 2013, limiting searches to phase 3, randomised trials of patients with atrial fibrillation who were randomised to receive new oral anticoagulants or warfarin, and trials in which both efficacy and safety outcomes were reported. We did a prespecified meta-analysis of all 71 683 participants included in the RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF—TIMI 48 trials. The main outcomes were stroke and systemic embolic events, ischaemic stroke, haemorrhagic stroke, all-cause mortality, myocardial infarction, major bleeding, intracranial haemorrhage, and gastrointestinal bleeding. We calculated relative risks (RRs) and 95% CIs for each outcome. We did subgroup analyses to assess whether differences in patient and trial characteristics affected outcomes. We used a random-effects model to compare pooled outcomes and tested for heterogeneity.


42 411 participants received a new oral anticoagulant and 29 272 participants received warfarin. New oral anticoagulants significantly reduced stroke or systemic embolic events by 19% compared with warfarin (RR 0·81, 95% CI 0·73—0·91; p<0·0001), mainly driven by a reduction in haemorrhagic stroke (0·49, 0·38—0·64; p<0·0001). New oral anticoagulants also significantly reduced all-cause mortality (0·90, 0·85—0·95; p=0·0003) and intracranial haemorrhage (0·48, 0·39—0·59; p<0·0001), but increased gastrointestinal bleeding (1·25, 1·01—1·55; p=0·04). We noted no heterogeneity for stroke or systemic embolic events in important subgroups, but there was a greater relative reduction in major bleeding with new oral anticoagulants when the centre-based time in therapeutic range was less than 66% than when it was 66% or more (0·69, 0·59—0·81 vs 0·93, 0·76—1·13; p for interaction 0·022). Low-dose new oral anticoagulant regimens showed similar overall reductions in stroke or systemic embolic events to warfarin (1·03, 0·84—1·27; p=0·74), and a more favourable bleeding profile (0·65, 0·43—1·00; p=0·05), but significantly more ischaemic strokes (1·28, 1·02—1·60; p=0·045).


This meta-analysis is the first to include data for all four new oral anticoagulants studied in the pivotal phase 3 clinical trials for stroke prevention or systemic embolic events in patients with atrial fibrillation. New oral anticoagulants had a favourable risk—benefit profile, with significant reductions in stroke, intracranial haemorrhage, and mortality, and with similar major bleeding as for warfarin, but increased gastrointestinal bleeding. The relative efficacy and safety of new oral anticoagulants was consistent across a wide range of patients. Our findings offer clinicians a more comprehensive picture of the new oral anticoagulants as a therapeutic option to reduce the risk of stroke in this patient population.




HSR Proc Intensive Care Cardiovasc Anesth. 2013; 5(1): 40–54.
PMCID: PMC3670724

Comparative effectiveness of novel oral anticoagulants for atrial fibrillation: evidence from pair-wise and warfarin-controlled network meta-analyses

Table 1

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Novel oral anticoagulants have been tested against warfarin for atrial fibrillation, yet no direct comparison is available. We thus aimed to perform pair-wise (direct) and warfarin-adjusted network (i.e. indirect) meta-analyses of novel oral anticoagulants for atrial fibrillation.


Databases were searched for randomized warfarin-controlled trials of novel anticoagulants for non-valvular atrial fibrillation. The primary end-point was long-term stroke/systemic embolism. Odds ratios (95% intervals) were computed with RevMan and WinBUGS.


Seven trials (52701 patients) were included, focusing on apixaban, dabigatran, edoxaban and rivaroxaban. Pair-wise meta-analysis showed that after a weighted average of 23 months these novel anticoagulants lead to significant reductions in the risk of stroke/systemic embolism (odds ratio=0.81 [0.71-0.92], I2=23%) and all cause death (odds ratio=0.88 [0.82-0.95], I2=0%) in comparison to warfarin. Network meta-analysis showed that apixaban and dabigatran proved similarly superior to warfarin in preventing stroke/systemic embolism (odds ratio=0.78 [0.62-0.96] for apixaban vs warfarin; odds ratio=0.66 [0.52-0.84] for high-dose dabigatran vs warfarin; odds ratio for apixaban vs high-dose dabigatran=1.17 [0.85-1.63]), but apixaban was associated with fewer major bleedings (odds ratio=0.73 [0.57-0.93]) and drug discontinuations (odds ratio=0.64 [0.52-0.78]) than dabigatran. Rivaroxaban did not reduce stroke/systemic embolism (odds ratio=0.87 [0.71-1.07]) or major bleedings in comparison to warfarin (odds ratio=0.87 [0.71-1.07]) and was associated with more major bleedings in comparison to apixaban (odds ratio=1.52 [1.19-1.92]). Data for edoxaban were inconclusive.


Novel oral anticoagulants appear as a very promising treatment option for atrial fibrillation.

Keywords: apixaban, atrial fibrillation, dabigatran, meta-analysis, rivaroxaban, systematic review, warfarin


Source: Google images

aSource: Google images

Drugs along CoagulationCascade

SOURCE: Google Images

reverse druggingdrugs on Factoe Xa


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Eliquis - 1



Additive value of indirect comparisons (network meta-analyses)

Free download of English version

J. Harenberg (1), C. Weiss (2), S. Marx (1), S. Zolfaghari (1)

Phlebologie 2013 42 3: 139-148



An indirect comparison analysis

Online Supplementary Material

F. Skjøth (1, 2), T. B. Larsen (1, 2), L. H. Rasmussen (1, 2), G. Y. H. Lip (1, 3)

Thromb Haemost 2014 111 5: 981-988



Ready to be replaced?

J. Steffel (1), T. F. Luscher (1)

Hämostaseologie 2012 32 4: 249-257


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  26. Harenberg J, Marx S, Wehling M. Head-to-head or indirect comparisons of the novel oral anticoagulants in atrial fibrillation: what’s next? Thromb Haemost 2012; 108: 407-409. DOI:10.1160/TH12-07-0463
  27. Schneeweiss S, Gagne JJ, Patrick AR et al. Comparative efficacy and safety of new oral anticoagulants in patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes 2012; 5: 480-486.DOI:10.1161/CIRCOUTCOMES.112.965988
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  29. You JJ, Singer DE, Howard PA et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 2012; 141: e531S-575S. DOI:10.1378/chest.11-2304
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Read Full Post »

Do Novel Anticoagulants Affect the PT/INR? The Cases of  XARELTO (rivaroxaban) or PRADAXA (dabigatran)

Curators: Vivek Lal, MBBS, MD, FCIR, Justin D Pearlman, MD, PhD, FACC


Article Curator: Aviva Lev-Ari, PhD, RN

WC 3

WordCloud by Zach Day; Article Title: Do Novel Anticoagulants Affect the PT/INR? The Cases of XARELTO (rivaroxaban) and PRADAXA (dabigatran)

UPDATED on 7/16/2019

More of Xarelto’s scripts came from Medicare Part D patients in Q2 of this year compared with last, according to J&J’s earnings presentation. And J&J was on the hook for a bigger share of patient costs in Medicare Part D’s donut hole. Congress implemented the donut hole change last year, forcing drugmakers to pay more to move patients out of the coverage gap.

Once J&J gets a few quarters ahead of those changes, Xarelto should start turning in more impressive growth percentages, Duato said. How? J&J plans to grow Xarelto’s market share and volume in existing uses, plus focus on launches in new indications, Duato said, though he didn’t specify exactly how it’ll pump up that volume.

Bristol-Myers Squibb and Pfizer’s rival drug Eliquis is surely facing some of the same issues—the donut hole provision, for instance—but its sales look much healthier. While BMS hasn’t yet released second-quarter results, it did report a 36% boost to U.S. Eliquis sales in the first quarter, to $1.2 billion. For comparison, J&J’s Xarelto posted a 6.3% decrease to $542 million for the same period in the U.S.


J&J execs have plenty to brag about in pharma. Why downplay Xarelto, Zytiga woes?


UPDATED ON 7/21/2016

Xarelto Lawsuits

The blood-thinner Xarelto can cause uncontrolled bleeding — a dangerous and possibly fatal side effect for which there is no antidote. Plaintiffs who say they were harmed by the drug and family members who lost loved ones to severe bleeding filed lawsuits against Bayer, the drug’s maker. They claim Bayer failed to warn them and manufactured a faulty drug.



UPDATED on 8/4/2014

A cost-analysis model for anticoagulant treatment in the hospital setting

Journal of Medical Economics

July 2014, Vol. 17, No. 7 , Pages 492-498 (doi:10.3111/13696998.2014.914032)

aJanssen Scientific Affairs, LLC,

Raritan, NJ


bAnalysis Group, Inc.,

Boston, MA


cGroupe d’analyse, Ltée,

Montréal, Québec


dJanssen Scientific Affairs, LLC,

Raritan, NJ


Address for correspondence: 

Lynn Huynh, Associate

Analysis Group, Inc.,

111 Huntington Ave. Tenth Floor, Boston, MA 02199

USA. Tel.: 617-425-8189; Fax: 617-425-8001




Rivaroxaban is the first oral factor Xa inhibitor approved in the US to reduce the risk of stroke and blood clots among people with non-valvular atrial fibrillation, treat deep vein thrombosis (DVT), treat pulmonary embolism (PE), reduce the risk of recurrence of DVT and PE, and prevent DVT and PE after knee or hip replacement surgery. The objective of this study was to evaluate the costs from a hospital perspective of treating patients with rivaroxaban vs other anticoagulant agents across these five populations.


An economic model was developed using treatment regimens from the ROCKET-AF, EINSTEIN-DVT and PE, and RECORD1-3 randomized clinical trials. The distribution of hospital admissions used in the model across the different populations was derived from the 2010 Healthcare Cost and Utilization Project database. The model compared total costs of anticoagulant treatment, monitoring, inpatient stay, and administration for patients receiving rivaroxaban vs other anticoagulant agents. The length of inpatient stay (LOS) was determined from the literature.


Across all populations, rivaroxaban was associated with an overall mean cost savings of $1520 per patient. The largest cost savings associated with rivaroxaban was observed in patients with DVT or PE ($6205 and $2742 per patient, respectively). The main driver of the cost savings resulted from the reduction in LOS associated with rivaroxaban, contributing to ∼90% of the total savings. Furthermore, the overall mean anticoagulant treatment cost was lower for rivaroxaban vs the reference groups.


The distribution of patients across indications used in the model may not be generalizable to all hospitals, where practice patterns may vary, and average LOS cost may not reflect the actual reimbursements that hospitals received.


From a hospital perspective, the use of rivaroxaban may be associated with cost savings when compared to other anticoagulant treatments due to lower drug cost and shorter LOS associated with rivaroxaban.




Justin D Pearlman, MD, PhD, FACC

The classic medication for chronic anti-coagulation is coumadin, but it is problematic. Coumadin impedes the production of coagulation proteins that depend on vitamin K (factors 7, 9, 10, and 2, in order of half-lifes, which range 2-72 hours). Consequently, a change in dose today does not have full impact for 2-3 days. Physicians and pharmacists have difficulties adjusting the dose to its target effect on the biomarker test International Normalized Ratio (INR). The therapeutic range is very narrow. A change in intake of leafy green vegetables can have profound impact (by changing intake of vitamin K). A change in virtually any medication or vitamin that can bind to albumin can also profoundly change the INR to a life-threatening level, because 80% of coumadin is inactivated by binding to albumin, and displacement of coumadin by other agents can boost the effective circulating amount. Those limitations, and the need for testing each month and each medication change have stimulated the development of alternatives. For example, rivaroxaban is a new anticogulant that focuses on factor 10 (factor X), deemed as good as coumadin without the need for the blood tests. In fact, INR test for rivaroxaban is misleading, as values may range as high at 7 (“DANGER”) at normal therapeutic dosing. The following reviews some of the data on that unexpected issue. Physicians not aware of this “false positive” have demanded stoppage of therapy due to the inapplicable spuriously high INR values.

UPDATED on 9/25

Dabigatran versus Warfarin in Patients with Mechanical Heart Valves

Dabigatran is an oral direct thrombin inhibitor that has been shown to be an effective alternative to warfarin in patients with atrial fibrillation. We evaluated the use of dabigatran in patients with mechanical heart valves.


The trial was terminated prematurely after the enrollment of 252 patients because of an excess of thromboembolic and bleeding events among patients in the dabigatran group. In the as-treated analysis, dose adjustment or discontinuation of dabigatran was required in 52 of 162 patients (32%). Ischemic or unspecified stroke occurred in 9 patients (5%) in the dabigatran group and in no patients in the warfarin group; major bleeding occurred in 7 patients (4%) and 2 patients (2%), respectively. All patients with major bleeding had pericardial bleeding.


The use of dabigatran in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications, as compared with warfarin, thus showing no benefit and an excess risk. (Funded by Boehringer Ingelheim; ClinicalTrials.gov numbers, NCT01452347 and NCT01505881.)


N Engl J Med 2013; 369:1206-1214 September 26, 2013 DOI: 10.1056/NEJMoa1300615

UPDATED on 9/23

ESC: Edoxaban Bests Warfarin on Safety in VTE

By Peggy Peck, Editor-in-Chief, MedPage Today
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner
Action Points

AMSTERDAM — Edoxaban, a novel factor Xa inhibitor, met its primary endpoints in a trial that pitted it against warfarin for treatment of symptomatic venous thromboembolism (VTE).

Among more than 8,000 patients with deep-vein thrombosis (DVT) or pulmonary embolism (PE), 130 (3.2%) of the patients treated with edoxaban had a recurrent, symptomatic VTE versus 146 (3.5%) warfarin-treated patients, a hazard ratio of 0.89 (95% CI 0.70-1.13, P<0.004 for non-inferiority), Harry R. Büller, MD, of the Academic Medical Center, Amsterdam, reported in a Hot Line session at theEuropean Society of Cardiology meeting here.

The safety endpoint was bleeding (major or clinically relevant non-major bleeding), and in that analysis edoxaban was superior to warfarin, as 8.5% of the edoxaban patients had bleeding events versus 10.3% of the patients in the warfarin group (P=0.004 for superiority).

Moreover, edoxaban appeared to work best in the highest-risk patients — 938 patients with pulmonary embolism and right ventricular dysfunction assessed by N-terminal pro-brain natriuretic peptide levels. In those patients, the recurrent VTE rate was 3.3% in the edoxaban group versus 6.2% in the warfarin group, Büller said.

Based on the results in that very high risk population, Büller predicted that clinicians treating those patients will consider that efficacy profile when selecting an oral Factor Xa inhibitor.

The study, from the Hokusai VTE Investigators, was simultaneously published online by the New England Journal of Medicine.

In the highly competitive oral anticoagulant group, those numbers look good, but at first blush the two already approved Factor Xa inhibitors, rivaroxaban (Xarelto) and apixaban (Eliquis) looked better when they were studied in VTE.

In EINSTEIN-VTE, rivaroxaban had a recurrent symptomatic VTE rate of 2.1%, and 8.1% of patients met the safety endpoint.

Likewise, in another VTE trial — AMPLIFY-EXT — apixaban (2.5 mg or 5 mg twice a day) had a recurrent or VTE-related death rate of 1.7%, and 3.2% of the patients who received low-dose apixaban reached the safety endpoint, as did 4.3% of patients treated with 5 mg of apixaban.

Patrick T. O’Gara, MD, American College of Cardiology president-elect, praised the design of the trial, but he agreed that “for mortality benefit, apixaban does appear to have the edge.”

That apixaban benefit, O’Gara said, is militated by the fact that patients need to take the drug twice daily, while “edoxaban is once a day, as is rivaroxaban.”

Asked if there was a specific population that might benefit from edoxaban versus rivaroxaban or apixaban, O’Gara, who is director of clinical cardiology at Brigham and Women’s Hospital and a professor at Harvard Medical School, said the findings from the Hokusai researchers did not provide that answer.

The attempt at a cross-trial comparison drew harsh criticism from Elliott Antman, MD, principal investigator in a trial of edoxaban for prevention of stroke in patients with atrial fibrillation (ENGAGE-AF).

Antman, who like O’Gara is a Harvard professor, said that comparing the edoxaban VTE results to EINSTEIN-VTE or AMPLIFY-EXT would only lead to false conclusions. “You could repeat the rivaroxaban trial 100 times and still not achieve data that can be compared.”

Stavros V. Konstantinides MD, PhD, of the Medical University in Mainz, Germany, who was the ESC discussant for the paper, said that, despite the advantage of once-daily dosing of edoxaban, “apixaban has the best safety profile so far.”

Moreover, unlike the VTE studies of apixaban and rivaroxaban, all patients in the Hokusai trial received heparin for 5 days. After that heparin run-in, patients were randomized to edoxaban or to warfarin. The median duration of heparin after randomization was 7 days.

Antman said that design best replicated real-world clinical practice, in which heparin is usually started before warfarin.

Buller noted that he was an investigator for the EINSTEIN-VTE study, “and after that the thinking was maybe we don’t need low molecular weight heparin, but now I think we need to reconsider that assumption.”

The Hokusai-VTE trial recruited 4,921 patients with DVT and 3,319 patients with PE. Patients initially were treated with heparin, and then were randomized to edoxaban (60 mg or 30 mg) or warfarin. There was an overlap of the heparin therapy when warfarin was started.

During a press conference, Keith Fox, MBChB, chair of the ESC scientific program, asked Buller if that overlap could have increased bleeding risk in the warfarin arm, thus introducing bias, but Buller said the overlap merely allowed warfarin to reach therapeutic range.

The edoxaban regimen “may be less handy, especially for early-discharge patients… [though] some doctors may feel more comfortable starting with low molecular weight heparin and then switching to edoxaban for the one-third of patients with severe PE,” Konstantinides said.

He added, “The NOACs [new oral anticoagulants] have shown efficacy and safety. Now, the test under real life conditions begins. They have to prove efficacy and safety there. I expect that. And they now must justify the high cost by showing … an improvement in patient treatment satisfaction and quality of life and, hopefully, a reduction in healthcare costs … with lower hospitalizations.”

The average age of patients in the Hokusai study was 56-57, and just over half were men.

Patients were enrolled from January 2011 through October 2012 at 439 centers in 37 countries.

About 40% of patients were treated for a year, and 80% of the edoxaban group was adherent to study treatment. Among the warfarin patients, average time in therapeutic range was 63.5%.

The study was supported by Daiichi-Sankyo, which is developing edoxaban.

Buller reported personal fees from Daichi Sankyo during the study, as well as grant support and personal fees from Bayer Health Care and Pfizer. He also received personnal fees from Boehringer Ingelheim, Bristol-Myers Squibb, Isis Pharmaceuticals, and ThromboGenics outside the submitted work.

Antman has a research grant from Daiichi-Sankyo through Brigham and Women’s Hospital. O’Gara said he had no financial disclosures.





Author: Vivek Lal, MBBS, MD, FCIR

Pathological thromboembolism, as seen in Myocardial Infarction or stroke, led to the use of low dose aspirin as an-antiplatelet drug, as a prophylaxis for subsequent intravascular thrombotic episodes.  Aspirin, an irreversible Cyclo-oxygenase inhibitor, resulted in a reduction of the production of Thromboxane A2, which in itself is a powerful vaso-constrictor and a platelet aggregator.   Certain limitation with the use of aspirin necessitated the search for newer anti-platelet drugs, with a quicker onset of action, quick termination of action on cessation of treatment, and minimal side effects like bleeding.  ADP inhibitors like Clopidogrel, which inhibits the ADP dependent activation of Glycoprotein IIb/IIIa receptors, was the next in the armamentarium of these drugs.  Later, oral anti-coagulants like coumadin (warfarin sodium) were added to anti-platelet approach, to tackle the overactive coagulation cascade in pathological intravascular thrombosis.  Warfarin is a drug which counters the effects of Vit-K on the synthesis of coagulation factors in the liver.  Thus, all green leafy vegetables, which contain high amounts of Vit-K, will interfere with the action of Warfarin.   Moreover, warfarin is extremely prone to drug interations, owing to its biotransformation by hepatic microsomal enzymes, which are also metabolizing many other drugs.  Thus, a therapeutic drug monitoring of warfarin action is mandatory, which, is a big limitation to its use.  The quest for pharmacologically superior oral anticoagulants, as compared to Warfarin, reached an important milestone with the discovery of two major drugs, Dabigatran and Rivaroxaban.  Both these drugs are Direct Thrombin Inhibitors, though the indications and adverse events are somewhat different.  This post will discuss Rivaroxaban pharmacology in brief, and address certain clinical issues.

Question: Does rivaroxaban or dabigatran affect the PT or INR? Can either be monitored using the PT or INR?

Response from Jenny A. Van Amburgh, PharmD, CDE

Assistant Dean of Academic Affairs and Associate Clinical Professor, School of Pharmacy, Northeastern University; Director of the Clinical Pharmacy Team and Residency Program Director, Harbor Health Services, Inc., Boston, Massachusetts

Warfarin is the most commonly used anticoagulant for the prevention of thrombosis or stroke. Because of a narrow therapeutic window, it requires regular coagulation monitoring of the prothrombin time (PT)/international normalized ratio (INR).[1] As such, the inconvenience of frequent blood draws remains a major burden. For the first time in over 50 years, 2 new oral anticoagulants, dabigatran, a direct thrombin inhibitor, and rivaroxaban, a factor Xa inhibitor, were approved by the US Food and Drug Administration. While these anticoagulants carry similar side effects to warfarin, such as risk for gastrointestinal bleeding and intracranial hemorrhage, INR and PT monitoring are not required. How then are providers to gauge the safety and efficacy of the medication in a patient? Can clinicians monitor these medications with the conventional coagulation assays, or are they rendered useless?[1]

The effect of both dabigatran and rivaroxaban on commonly used coagulation assays has been evaluated in the literature, both in vitro and in vivo. The usefulness of these tests relates directly to the medications’ mechanisms of action. For both agents, the use of an INR to determine the effectiveness and safety is meaningless because INR is calibrated for use with vitamin K antagonists (such as warfarin) only.[1] Although use may be associated with an increase in INR, this increase does not relate to the effectiveness of therapy or provide a linear correlation of concentration and effect that is seen when measuring warfarin levels.[2,3] In some instances, point-of-care INR measurements have been drawn on patients using dabigatran; however, the results have failed to correlate to appropriateness in therapy and have varied greatly case by case.[4]

As dabigatran directly inhibits thrombin, PT measures lack the sensitivity to detect therapeutic levels.[1,5] Often, if this assay is measured in patients taking dabigatran, a subtherapeutic level is noted, regardless of concentration of dabigatran.[6] More appropriate assays for dabigatran may be activated partial thromboplastin time (aPTT), diluted thrombin time (TT), or ecarin clotting time (ECT). These tests are better able to capture changes throughout the clotting cascade. Using aPTT may underestimate high levels and could be used more as a qualitative assessment of activity instead of a quantitative assessment.[7] Where available and if desired, monitoring via the diluted TT or ECT has proved a more useful measure for dabigatran.[1]

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Unlike dabigatran, studies have demonstrated a correlation between the levels of rivaroxaban and PT through inhibition of factor Xa, but not to the same extent as warfarin.[8] In some instances, the use of PT monitoring for this medication may be useful. A linear response between PT and rivaroxaban can be seen; however, the accuracy of the test improves when concentrations of rivaroxaban are higher. Additionally, the use of PT for monitoring rivaroxaban can be difficult because the measurement differs greatly depending on the reagent used to determine PT. Calibrating PT assays to assess rivaroxaban appropriately is an option currently being evaluated.[8]

In conclusion, the INR is not a viable option when assessing the use of dabigatran or rivaroxaban. Additionally, PT is not a viable option when monitoring a patient on dabigatran. However, PT may be an option for monitoring select patients on rivaroxaban until more reliable standardized tests are developed. Methods of measuring the effectiveness of these agents are currently being developed and tested; however, until they are made available, the existing tests may be adapted to be used in a more effective manner.

The author wishes to acknowledge the assistance of Jacqueline M. Kraft, PharmD, Ngoc Diem Nguyen, PharmD, and Phillipa Scheele, PharmD, PGY1 Residents, and Michael P. Conley, PharmD, and Nga T. Pham, PharmD, CDE, AE-C, Assistant Clinical Professors at Northeastern University — School of Pharmacy and Harbor Health Services, Inc., Boston, Massachusetts.


  1. Favaloro EJ, Lippi G. The new oral anticoagulants and the future of haemostasis laboratory testing. Biochem Med (Zagreb). 2012;22:329-341.
  2. Dager WE, Gosselin RC, Kitchen S, Dwyre D. Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen: a multicenter, in vitro study. Ann Pharmacother. 2012;46:1627-1636. Abstract
  3. Samama MM, Martinoli JL, LeFlem L, et al. Assessment of laboratory assays to measure rivaroxaban — an oral, direct factor Xa inhibitor. Thromb Haemost. 2010;103:815-825. Abstract
  4. O’Riordan M. Falsely elevated point-of-care INR values in dabigatran-treated patients. Heartwire. July 7, 2011.http://www.theheart.org/article/1251461.do. Accessed January 11, 2013.
  5. Halbmayer WM, Weigel G, Quehenberger P, et al. Interference of the new oral anticoagulant dabigatran with frequently used coagulation tests. Clin Chem Lab Med. 2012;50:1601-1605. Abstract
  6. Lindahl TL, Baghaei F, Blixter IF, et al. Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays. Thromb Haemost. 2011;105:371-378. Abstract
  7. Freyburger G, Macouillard G, Labrouche S, Sztark F. Coagulation parameters in patients receiving dabigatran etexilate or rivaroxaban: two observational studies in patients undergoing total hip or total knee replacement. Thromb Res. 2011;127:457-465. Abstract
  8. Hillarp A, Baghaei F, Fagerberg Blixter I, et al. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost. 2011;9:133-139. Abstract



PRADAXA (dabigatran)


PRADAXA represents progress in helping to reduce the risk of stroke due to atrial fibrillation (AFib) not caused by a heart valve problem.

Review the chart below to compare PRADAXA and warfarin (also known as Coumadin® or Jantoven®). And find out why your doctor may choose PRADAXA. Remember, only your doctor can decide which treatment may be right for you.

Medication type:
Both PRADAXA and warfarin are anticoagulants. These blood-thinning medicines help to stop clots by targeting factors your blood needs to form clots.PRADAXA and warfarin work differently to help reduce the risk of stroke due to AFib not caused by a heart valve problem.
PRADAXA is a direct thrombin inhibitor that helps to stop clots from forming by working directly on thrombin.PRADAXA is not for use in people with artificial (prosthetic) heart valves Warfarin is a vitamin K antagonist that helps to stop clots from forming by interfering with vitamin K—a vitamin your body needs to form clots.
Stroke risk reduction:
PRADAXA and warfarin help to stop clots by targeting factors your blood needs to form clots.
In a clinical trial of more than 18,000 people, PRADAXA 150 mg capsules was proven superior to warfarin at reducing the risk of stroke. Warfarin has been extensively studied and prescribed by doctors to help reduce the risk of stroke in people with AFib since 1954.
How you take the medication: PRADAXA is taken by mouth 2 times each day. Warfarin is taken by mouth once every day.
Dosing options: PRADAXA comes in 75 mg and 150 mg strengths.Your doctor will decide which dose is right for you based on a simple kidney function test. Warfarin comes in 1 mg, 2 mg, 2-1/2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7-1/2 mg, and 10 mg strengths.Your doctor will decide which dose is right for you. He or she will adjust your dose based on the results ofregular blood tests.Based on these tests, your doctor will determine your dose and adjust it, if necessary.
Monitoring: No need for regular blood tests.PRADAXA has been clinically proven to help reduce the risk of stroke in people with AFib not caused by a heart valve problem. And, unlike warfarin, there is no need for regular blood tests to see if your blood-thinning level is in the right range.
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Requires regular blood test.Warfarin has also been proven to be an effective blood thinner. When you take warfarin, you need to have a regular blood test to measure International Normalized Ratio (INR) to determine the time it takes for your blood to clot.
Dietary restrictions: No dietary restrictionsPRADAXA requires no changes to your diet. Dietary restrictions requiredWhen you take warfarin, you need to limit foods high in vitamin K, such as large amounts of leafy green vegetables and some vegetable oils. This is because Vitamin K can affect the way warfarin works in your body.You may also need to limit alcohol, cranberry juice, and products containing cranberries.



 XARELTO (rivaroxaban)


XARELTO® is a prescription medicine used to reduce the risk of stroke and blood clots in people with atrial fibrillation, not caused by a heart valve problem. For patients currently well managed on warfarin, there is limited information on how XARELTO® and warfarin compare in reducing the risk of stroke.

XARELTO® is also a prescription medicine used to treat deep vein thrombosis and pulmonary embolism, and to help reduce the risk of these conditions occurring again.

XARELTO® is also a prescription medicine used to reduce the risk of forming a blood clot in the legs and lungs of people who have just had knee or hip replacement surgery.



  • For people taking XARELTO® for atrial fibrillation:
  • People with atrial fibrillation (an irregular heart beat) are at an increased risk of forming a blood clot in the heart, which can travel to the brain, causing a stroke, or to other parts of the body. XARELTO® lowers your chance of having a stroke by helping to prevent clots from forming. If you stop taking XARELTO®, you may have increased risk of forming a clot in your blood.
  • Do not stop taking XARELTO® without talking to the doctor who prescribes it for you. Stopping XARELTO® increases your risk of having a stroke.
  • If you have to stop taking XARELTO®, your doctor may prescribe another blood thinner medicine to prevent a blood clot from forming.
  • XARELTO® can cause bleeding, which can be serious, and rarely may lead to death. This is because XARELTO® is a blood thinner medicine that reduces blood clotting. While you take XARELTO® you are likely to bruise more easily and it may take longer for bleeding to stop.

You may have a higher risk of bleeding if you take XARELTO® and take other medicines that increase your risk of bleeding, including:

  • Aspirin or aspirin-containing products
  • Non-steroidal anti-inflammatory drugs (NSAIDs)
  • Warfarin sodium (Coumadin®, Jantoven®)
  • Any medicine that contains heparin
  • Clopidogrel (Plavix®)
  • Other medicines to prevent or treat blood clots

Tell your doctor if you take any of these medicines. Ask your doctor or pharmacist if you are not sure if your medicine is one listed above.

Call your doctor or get medical help right away if you develop any of these signs or symptoms of bleeding:

  • Unexpected bleeding or bleeding that lasts a long time, such as:
    • Nosebleeds that happen often
    • Unusual bleeding from gums
    • Menstrual bleeding that is heavier than normal, or vaginal bleeding
  • Bleeding that is severe or that you cannot control
  • Red, pink, or brown urine
  • Bright red or black stools (looks like tar)
  • Cough up blood or blood clots
  • Vomit blood or your vomit looks like “coffee grounds”
  • Headaches, feeling dizzy or weak
  • Pain, swelling, or new drainage at wound sites

Spinal or epidural blood clots (hematoma): People who take a blood thinner medicine (anticoagulant) like XARELTO®, and have medicine injected into their spinal and epidural area, or have a spinal puncture, have a risk of forming a blood clot that can cause long-term or permanent loss of the ability to move (paralysis). Your risk of developing a spinal or epidural blood clot is higher if:

  • A thin tube called an epidural catheter is placed in your back to give you certain medicine
  • You take NSAIDs or a medicine to prevent blood from clotting
  • You have a history of difficult or repeated epidural or spinal punctures
  • You have a history of problems with your spine or have had surgery on your spine

If you take XARELTO® and receive spinal anesthesia or have a spinal puncture, your doctor should watch you closely for symptoms of spinal or epidural blood clots. Tell your doctor right away if you have tingling, numbness, or muscle weakness, especially in your legs and feet.

XARELTO® is not for patients with artificial heart valves.


Do not take XARELTO® if you:

  • Currently have certain types of abnormal bleeding. Talk to your doctor before taking XARELTO® if you currently have unusual bleeding.
  • Are allergic to rivaroxaban or any of the ingredients of XARELTO®.


Before taking XARELTO®, tell your doctor if you:

  • Have ever had bleeding problems
  • Have liver or kidney problems
  • Have any other medical condition
  • Are pregnant or plan to become pregnant. It is not known if XARELTO® will harm your unborn baby. Tell your doctor right away if you become pregnant while taking XARELTO®. If you take XARELTO® during pregnancy, tell your doctor right away if you have bleeding or symptoms of blood loss.
  • Are breastfeeding or plan to breastfeed. It is not known if XARELTO® passes into your breast milk. You and your doctor should decide if you will take XARELTO® or breastfeed.

Tell all of your doctors and dentists that you are taking XARELTO®. They should talk to the doctor who prescribed XARELTO® for you before you have any surgery, medical or dental procedure.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some of your other medicines may affect the way XARELTO® works. Certain medicines may increase your risk of bleeding. See “What is the most important information I should know about XARELTO®?”

Especially tell your doctor if you take:

  • Ketoconazole (Nizoral®)
  • Itraconazole (Onmel™, Sporanox®)
  • Ritonavir (Norvir®)
  • Lopinavir/ritonavir (Kaletra®)
  • Indinavir (Crixivan®)
  • Carbamazepine (Carbatrol®, Equetro®, Tegretol®, Tegretol®-XR, Teril™, Epitol®)
  • Phenytoin (Dilantin-125®, Dilantin®)
  • Phenobarbital (Solfoton™)
  • Rifampin (Rifater®, Rifamate®, Rimactane®, Rifadin®)
  • St. John’s wort (Hypericum perforatum)

Ask your doctor if you are not sure if your medicine is one listed above. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.


Take XARELTO® exactly as prescribed by your doctor.

Do not change your dose or stop taking XARELTO® unless your doctor tells you to.

    • Your doctor will tell you how much XARELTO® to take and when to take it.
    • Your doctor may change your dose if needed.

If you take XARELTO® for:

    • Atrial Fibrillation: Take XARELTO® 1 time a day with your evening meal. If you miss a dose of XARELTO®, take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time.
    • Blood clots in the veins of your legs or lungs:
      • Take XARELTO® once or twice a day as prescribed by your doctor.
      • Take XARELTO® with food at the same time each day.
      • If you miss a dose of XARELTO®:
        • and take XARELTO® 2 times a day: Take XARELTO® as soon as you remember on the same day. You may take 2 doses at the same time to make up for the missed dose. Take your next dose at your regularly scheduled time.
        • and take XARELTO® 1 time a day: Take XARELTO® as soon as you remember on the same day. Take your next dose at your regularly scheduled time.
    • Hip or knee replacement surgery: Take XARELTO® 1 time a day with or without food. If you miss a dose of XARELTO®, take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time.
  • If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take XARELTO®.
  • Your doctor will decide how long you should take XARELTO®. Do not stop taking XARELTO® without talking to your doctor first.
  • Your doctor may stop XARELTO® for a short time before any surgery, medical or dental procedure. Your doctor will tell you when to start taking XARELTO®again after your surgery or procedure.
  • Do not run out of XARELTO®. Refill your prescription for XARELTO® before you run out. When leaving the hospital following a hip or knee replacement, be sure that you have XARELTO® available to avoid missing any doses.
  • If you take too much XARELTO®, go to the nearest hospital emergency room or call your doctor right away.


Please see “What is the most important information I should know about XARELTO®?”

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You are also encouraged to report side effects to the FDA: visit http://www.fda.gov/medwatch or call 1-800-FDA-1088. You may also report side effects to Janssen Pharmaceuticals, Inc., at 1-800-JANSSEN (1-800-526-7736).

Please see full Prescribing Information, including Boxed Warnings, and Medication Guide.



Figure-1 : Targets for anti-coagulant drugs in the coagulation cascade

Targets for anticoagulant drugs in the coagulation cascade

Pharmacology of Rivaroxaban 

Rivaroxaban, chemically an oxazolidinone derivative, is a directly acting Coagulation factor Xa inhibitor, acting on both free Factor Xa as well as that bound to the Prothrombinase complex.  It has a good oral bioavailability (~ 80-100%) and a rapid onset of action, with peak plasma concentrations being achieved in about 2-4 hours of oral intake.  It is about 95% plasma protein bound, with an aVd of about 50L.  It is partly metabolized in liver and excreted both unchanged as well as inactive metabolites in the urine, so also in the feces.  Strong CYP3A4 inhibitors like Ketoconazole, Ritonavir, Clarithromycin, Conivaptan etc can increase the pharmacodynamic effects of Rivaroxaban by a gross reduction in its metabolism.   Weaker CYP3A4 inhibitors like Amiodarone, Azithromycin, Diltiazem, Dronaderone, Erythromycin, Felodipine, Quinidine, Ranolazine, Verapamil maybe used with Rivaroxaban except in renal impairment.  Similarly, enzyme inducers like Rifampicin can decrease the plasma concentrations of Rivaroxaban.

Indications : Prophylaxis of stroke and systemic embolism in patients of atrial fibrillation, treatment and prevention of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE).

Dosage : 10-20 mg with or without food, depending on the indication.

Adverse Effects : As with any other anticoagulant, an increased risk of bleeding. An increased risk of stroke after discontinuation of the drug in atrial fibrillation, and spinal and epidural hematomas.

Therapeutic monitoring : Both Dabigatran and Rivaroxaban do not mandate a therapeutic monitoring clinically, as in the case of Warfarin.  Moreover, both Prothrombin Time (PT) as well as the International Normalized Ratio (INR) are not suitable to measure the pharmacodynamic profile of Rivaroxaban for various reasons1.  Development of novel methods of assays, for instance Anti Factor Xa assay which utilizes rivaroxaban containing plasma calibrators, may provide optimal therapeutic monitoring modalities for Rivaroxaban in the future.

Figure – 2 : PT and aPTT dependent on plasma concentration of anticoagulant drugs.

(A) rivaroxaban (experimental data from internal studies);

(B) DX-9065a (experimental data from the literature, and

(C) ximelagatran (experimental data for PT and aPTT from the literature. aPTT, activated partial thromboplastin time; INR, international normalized ratio; PT, prothrombin time.



There is some concern regarding a spurious rise in the INR values if a patient stabilized on warfarin is switched over to Rivaroxaban.  This concern is ill-founded since it is already mentioned above that INR is not a suitable  investigation to give an indication of Rivaroxaban pharmacodynamics.   Moreover, no suitable litrerature is available which can explain the rise in INR values on Rivaroxaban administration.  It may require some additional clinical studies to throw some light on this clinical anomaly.

Figure-3 : Annualized Incidence of Complications of Rivaroxaban



  1. Lindhoff-Last et al. Assays for measuring Rivaroxaban : Their suitability and Limitations. Ther Drug Monitoring Dec 2010 (32, Issue 6): 673-79.


Burghaus R, Coboeken K, Gaub T, Kuepfer L, et al. (2011) Evaluation of the Efficacy and Safety of Rivaroxaban Using a Computer Model for Blood Coagulation. PLoS ONE 6(4): e17626. doi:10.1371/journal.pone.0017626



Copyright © McGraw-Hill Education, LLC.  All rights reserved.
Hurst’s The Heart
 > Part 6. Rhythm and Conduction Disorders > Chapter 40. Atrial Fibrillation, Atrial Flutter, and Atrial Tachycardia > Atrial Fibrillation > Treatment > Anticoagulation > Antithrombotic Agents >


Burghaus R, Coboeken K, Gaub T, Kuepfer L, et al. (2011) Evaluation of the Efficacy and Safety of Rivaroxaban Using a Computer Model for Blood Coagulation. PLoS ONE 6(4): e17626. doi:10.1371/journal.pone.0017626


Other articles published on this Open Access Online Scientific Journal include the following:

Xarelto (Rivaroxaban): Anticoagulant Therapy gains FDA New Indications and Risk Reduction for: (DVT) and (PE), while in use for Atrial fibrillation increase in Gastrointestinal (GI) Bleeding Reported

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