2-Hour Accelerated Diagnostic Protocol to Assess Patients With Chest Pain Symptoms Using Contemporary Troponins as the Only Biomarker The ADAPT Trial

ORAL ANTICOAGULANTS

DR SHALINI GARG SR CARDIOLOGYLPS, CARDIOLOGY, KANPUR

HEMOSTATIC SYSTEM

In Brief.

WHEN DOES BLOOD COAGULATE ?

Injury to blood vessel. eg: Plaque rupureBlood stasis. eg: AFProcoagulants > Anticoagulants. eg: Coagulation disorders

OVERVIEW FROM ENDOTHELIAL DAMAGE TO THROMBOSIS

BLOOD COAGULATION PATHWAYS

aPTT

PT/INR

Figure. Classification of established anticoagulants and new anticoagulants that were recently licensed for use or are in advanced stages of clinical development. fIXa indicates factor IXa. *Indirectly inhibit coagulation by interacting with antithrombin. AVE5026 is an ultralow-molecular-weight heparin that primarily inhibits fXa and has minimal activity against thrombin.

Eikelboom J W , and Weitz J I Circulation. 2010;121:1523-1532Copyright American Heart Association, Inc. All rights reserved.

Figure. Classification of established anticoagulants and new anticoagulants that were recently licensed for use or are in advanced stages of clinical development. fIXa indicates factor IXa. *Indirectly inhibit coagulation by interacting with antithrombin. AVE5026 is an ultralow-molecular-weight heparin that primarily inhibits fXa and has minimal activity against thrombin.

CLASSIFICATION OF ORAL ANTICOAGULANTSCoumarin Derivatives e.g. Warfarin, Acenocoumarol (Acitrom)Indandione Derivatives e.g. Phenindione, AnisindioneNewer anticoagulantsDirect thrombin inhibitors Dabigatran etexilate (Pradaxa)Direct factor Xa inhibitors Rivaroxaban (Xarelto) Apixaban Edoxaban (DU-176b) Betrixaban

WARFARIN almost 70 years old and still causing problems

Still we have to stick with it

HISTORY

In the 1920s cattle in the Northern USA and Canada were afflicted by an outbreak of an unusual disease characterized by fatal bleeding, either spontaneously or from minor injuries. Mouldy silage made from sweet clover ( Melilotus alba and M. officinalis ) was implicated, and L M Roderick in North Dakota showed that it contained a haemorrhagic factor that reduced the activity of prothrombin. However, it was not until 1940 that Karl Link and his student Harold Campbell in Wisconsin discovered that the anticoagulant in sweet clover was 3,3methylenebis (4-hydroxy coumarin). Further work by Link led in 1948 to the synthesis of warfarin, which was initially approved as a rodenticide in the USA in 1952, and then for human use in 1954.The name warfarin is derived from WARF (Wisconsin Alumni Research Foundation) and arin from coumarin.

WARFARINMost widely used anticoagulant in the worldCoumarin derivative, water soluble vit K antagonistLow cost and highly effective, if given in right way.

Vitamin K-dependent clotting factors(FII, FVII, FIX, FX, Protein C/S/Z)

EpoxideReductase

-Carboxylase(GGCX)MECHANISM OF ACTION: Warfarin inhibits the vitamin K cycle

WarfarinInactivation

CYP2C9PharmacokineticPost translational modification

PLASMA HALF-LIVES OF VITAMIN K-DEPENDENT PROTEINS

Factor II72hFactor VII6hFactor IX24hFactor X36h

Peak anticoagulant effect may be delayed by 72 to 96 hours

PHARMACOLOGYRecemic micture of R and S isomers (S more active)Rapidly and completely absorbed from GI tractBlood level peaks about 90 min of administration90% of circulating warfarin is bound to albuminPlasma t1/2 is 36-42 hrsOnly small fraction of unbound warfarin is biologically activeWarfarin is accumulates in liver, where it undergoes CYP2C9 mediated oxidative metabolism.Inactive metabolites are excreted in urine and stools.

CYP2C9 SNPs alter warfarin metabolism: CYP2C9*1 (WT) normal activity CYP2C9*2 (Arg144Cys) - low/intermediate activity CYP2C9*3 (Ile359Leu) - low activityTwo relatively common variants, CYP2C9*2 and CYP2C9*3, encode an enzyme with reduced activity. requiring lower maintenance doses of warfarin.Approximately 25% of whites have at least one variant allele of CYP2C9*2 or CYP2C9*3, whereas these variant alleles are less common in blacks and AsiansWarfarin dose reduction requires as follow:Heterozygosity for CYP2C9*2 or CYP2C9*3 allele : 20%-30%Homozygosity for the CYP2C9*2 or CYP2C9*3 allele : 50%-70%

Effect of CYP2C9 Genotype on Anticoagulation

Effect of CYP2C9 Genotype on Anticoagulation-Related Outcomes(Higashi et al., JAMA 2002)

N 127 28 4 18 3 5

mg warfarin/day

VKORC1: New Target Protein for Warfarin

EpoxideReductase

-Carboxylase(GGCX)Clotting Factors(FII, FVII, FIX, FX, Protein C/S/Z) Rost et al. & Li, et al., Nature (2004)

(VKORC1)

5 kb - chr 16

17And encoded for the gene now named VKORC1. In this work by Rost et al that should the overt warfarin resistance was due to non-synonymous mutation in VKORC1 - that is patients needing doses at 25-50 mg/d had clear predisposing mutations. Interestingly, NO nonsynomymous mutations were found in control chromosomes.

Effect of VKORC1 Genotype on AnticoagulationThree polymorphic variants of VKORC1Non-A,Non-A : wild type Requiring more warfarin doseNon-A/A : Heterozygous Requiring 25% dose reductionA/A : Homozygous - Requiring 50% dose reductionMeans wild type having more resistance to warfarin while homozygous is more sensitive.Asians have the highest prevalence of VKORC1 variants, followed by whites and blacksPolymorphisms in VKORC1 likely explain 30% of the variability in warfarin dose requirements.VKORC1 variants are more prevalent than variants of CYP2C9 Genotype Freq in Asians (%) Dose reductionNon-A,Non-A : wild type 7 --Non-A/A : Heterozygous 30 26A/A : Homozygous 63 50

These findings prompted the U.S. Food and Drug Administration (FDA) to amend the prescribing information for warfarin to indicate that lower initiation doses should be considered for patients with CYP2C9 and VKORC1 genetic variants.

DOSINGUsual dose is 5 mg/day (1-20 mg)Lower doses require inElderlyPt on increased risk of bleeding eg. Pt on aspirinHeart failureLiver diseaseRenal impairmentMalnutritionThyrotoxicosis (Opposite in Myxedema)Asian patients: Explained by genetic variation in hepatic enzymes (CYP3C9 & VKORC1 Polymorphism)High intake dietary Vit-K (green vegetables e.g. broccoli) reduces the efficacy of Warfarin.Practically best time to give warfarin is ~ 6 PM.

Caution with VITAMIN K containing food Health Canada recommends a daily intake of 90 120 micrograms (g) of vitamin K. The total amount of vitamin K from day to day may be higher or lower than the recommended amount. It is okay to eat food with different levels of vitamin K, but because vitamin K can interfere with blood-thinning effects of warfarin, it is important to eat the same amount from day to day. Do not eat a lot one day and none the next

Why to add concomitant parenteral anticoagulation ?Because of delayed onset of action, concomitant parenteral anticoagulant should be given in pts with established thrombosis or high risk for thrombosis until INR has been in therapeutic range for at least 2 days.Warfarin monotherapy decreases the levels of two endogenous anticoagulants, proteins C and S, thus increasing thrombogenic potential. Overlapping warfarin for at least 5 days with an immediately effective parenteral anticoagulant counteracts the procoagulant effect of unopposed warfarin. Usually a minimum 5 days of concomitant parenteral anticoagulation is recommended.

Commencement of oral anticoagulant therapy If the baseline INR1.3 the patient will receive 5mg of warfarin once daily on days 1 and 2. The INR is checked on day 3 and 4 and the warfarin dose is adjusted according to the schedule.

MonitoringB/z of narrow therapeutic window of warfarin Standard procedure is to check the PT-INR as follows: INR daily until it is in therapeutic range

3 times weekly for 2 weeks

Once stable & warfarin dose is known

INR every 3-4 weeks or more frequently if introduction of any new medications

What is PT-INRWarfarin therapy is most often monitored using the prothrombin time, a test sensitive to reductions in the levels of prothrombin, factor VII, and factor X.This test involved addition of thromboplastin (a reagent containing TF, phospholipid & Ca++) to citrated plasma and determining the time to clot formation.Thromboplastins vary in their sensitivity to reductions in the levels of the vitamin Kdependent clotting factors INR represent the PT according to international reference thromboplastin, as approved by WHO.

INTERNATIONAL NORMALISED RATIO (INR)

INR = [PTpt] ISI [PTRef]PTpt prothrombin time of patientPTRef prothrombin time of normal pooled sampleISI International Sensitivity Index

Highly sensitive thromboplastins have an ISI of 1.0 Most current thromboplastins have ISI values that range from 1.0 to 1.4

IndicationsAtrial fibrillationProsthetic heart valveVenous thromboembolismPrimary pulmonary hypertensionRarely after Acute MI (If associated with high risk of thromboembolism e.g. AF, mobile or pedunculated mural thrombus or prior venous thromboembolism)

Warfarin in AF CLASS I For patients with nonvalvular AF with prior stroke, transient ischemic attack (TIA), or a CHA2DS2-VASc score of 2 or greater, oral anticoagulants are recommended. Options include: warfarin (INR 2.0 to 3.0) (Level of Evidence: A), dabigatran (Level of Evidence: B), rivaroxaban (Level of Evidence: B), or apixaban (Level of Evidence: B)

Heart valve prostheses

The risk of systemic embolism from prosthetic heart valves depends on the type of valve, its position and other factors that contribute to the patients risk of developing thrombosis, such as cardiac rhythm and dilatation.

Warfarin in Venous thromboembolismWarfarin should be initated concurrently with parenteral heparin.For VTE patients, the usual target INR range is between 2.0 and 3.0.After 5 days, warfarin alone should be continued for at least 3 monthsOptimal duration of anticoagulation depends on clinical settings

Optimal duration of anticoagulationCLINICAL SETTINGRECOMMENDATION1st provoked PE/proximal leg DVT3 to 6 months1st provoked upper extremity DVT or isolated calf DVT3 months2nd provoked VTE Uncertain3rd VTEIndefinite duration

Cancer and VTEConsider indefinite duration or until cancer is resolved

Unprovoked PE/proximal leg DVTConsider indefinite duration

1st unprovoked calf DVT3 months

2nd unprovoked calf DVTUncertain

WARFARIN IN STEMI 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction:Class I1. Anticoagulant therapy with a vitamin K antagonistshould be provided to patients with STEMI and AFwith CHADS2 score greater than or equal to 2, mechanicalheart valves, venous thromboembolism, or hypercoagulable disorder. (Level of Evidence: C)2. The duration of triple antithrombotic therapy with avitamin K antagonist, aspirin, and a P2Y12 receptorinhibitor should be minimized to the extent possibleto limit the risk of bleeding. (Level of Evidence: C)

Class IIa 1. Anticoagulant therapy with a vitamin K antagonist isreasonable for patients with STEMI and asymptomaticLV mural thrombi. (Level of Evidence: C)Duration of treatment is 3 months. Class IIb1. Anticoagulant therapy may be considered for patientswith STEMI and anterior apical akinesis ordyskinesis. (Level of Evidence: C)2. Targeting vitamin K antagonist therapy to a lowerinternational normalized ratio (eg, 2.0 to 2.5) mightbe considered in patients with STEMI who are receivingDAPT. (Level of Evidence: C)

Side effects of WarfarinBleeding Skin necrosisPurple toe syndromeTeratogenicityOsteoporosisOthers: Agranulocytosis, leukopenia, diarrhoea, nausea, anorexia.

BleedingMost common complicationIn form ofMild: epistaxis, hematuriaSevere: Retroperotoneal or gastrointestinal bleedingLife-threatening : Intracranial bleedRate of major bleeding (defined as any visit to hospital for hemorrhage) is 1- 3% per person-year Half of the complications occurs because INR exceeds therapeutic rangeCan be minimized by keeping INR in therapeutic range

Interventions according to INR/symptoms Asymptomatic pts with raised INR

INR INTERVENTION 3.5 - 4.5Withhold warfarin until in therapeutic rangeDecrease the dose of warfarin > 4.5Low dose sublingual/oral Vit K (not routinely) 4.5 9.0Vit k 1 mg > 9.0Vit k 2-3 mg

Higher doses of vitamin K (up to 10 mg) can be administered if more rapid reversal of the INR is required

Although vitamin K administration results in a more rapid reduction in the INR, there is no evidence that it reduces the risk of hemorrhage

Symptomatic pts with raised INR

SYMPTOMS INTERVENTIONMild bleedingWithhold warfarinSevere bleedingVit k 10 mg slow i/v infusion FFP (15 ml/kg)Life threatening bleeding or pt cant tolerate volume overloadProthrombin complex concentrate (II,IX & X)Prosthetic valves ptsVit K should be strictly avoided, unless there is life threatening intracranial bleed (Valve thrombosis)

Subcutaneous Vit K gives variable results and should be avoided

SKIN NECROSISRare but very serious complication of warfarin (prevalence of 0.01-0.1 %)Occurs 2 to 5 days after initiation of warfarinUsually occurs after high dose of warfarinTypical presentation is : Well-demarcated erythematous lesions form on the thighs, buttocks, breasts, or toes. Typically, the center of the lesion becomes progressively necrotic. Examination of skin biopsies taken from the borders of these lesions reveals thrombi in the microvasculature

Warfarin (Coumadin)induced skin necrosis on the lower abdomen & breast

Mechanism : Not well understood but a precipitous fall in plasma protein C or S levels (natural anticoagulants) before warfarin exert anticoagulant effect, results in procoagulant state triggering thrombosis of adipose tissue microvasculatures.

Treatment : Discontinuation of warfarin and reversal with vitamin K, if needed An alternative anticoagulant, such as heparin or LMWH, should be given to patients with thrombosis Protein C concentrates or recombinant activated protein C may accelerate healing of the skin lesions in protein C deficient patients Frozen plasma may be useful for those with protein S deficiency Occasionally, skin grafting is necessary when there is extensive skin loss.

Prevention : Start with low dose warfarin in pts with known Protein C or S deficiencyOverlapping with a parenteral anticoagulant when initiating warfarin therapy

Purple toes syndromeExtremely uncommon cutaneous complicationCharacterized by the sudden appearance of bilateral, painful, purple nonhemorrhagic lesions on the toes and sides of the feet that blanch with pressureUsually develops 3-8 weeks after the start of warfarin therapyMechanism: release of atheromatous plaque emboli Discontinue COUMADIN therapy if such phenomena are observed. Consider alternative drugs if continued anticoagulation therapy is necessary.

Pharmacotherapy. 2003 May;23(5):674-7

TeratogenicityOccurs in 3.5 6 %Depends on time of gestation and dose of warfarin givenUsually in first trimester of pregnancyIt causes characteristic embryopathy consist of :Nasal hypoplasia and Chondrodysplasia punctata (epiphyseal and vertebral bonestippling)Cleft lip and (or) palateChoanal stenosis/atresiaCentral nervous system abnormalitiesCoarctation of aorta (Rare malformations described following first trimester exposure to warfarin)Occurs especially if warfarin dose is > 5 mg/day

Lateral view X-ray showing calcifications and irregular ossification of lumbar and sacral vertebrae, consistent with warfarin embryopathy

OSTEOPOROSISLong- term use of warfarin (> 1 yr)More common in males60% increased risk of osteoporosis-related fracture in menMechanism: combination of reduced intake of vitamin K, which is necessary for bone health, and inhibition by warfarin of vitamin K-mediated carboxylation of certain bone proteins, rendering them nonfunctionalBeta-adrenergic antagonists may protect against osteoporotic fractures

Warfarin in special conditions

PregnancyIt causesFetal abnormalities (Teratogenic)- in first trimisterChances of intracranial bleeding in baby while passage through birth canal in third trimisterBecause of this, warfarin is contraindicated in 1st (first 12 weeks) & 3rd trimsters (last 2 weeks)Warfarin does not passes in breast milk & is safe for nursing mothers.

Warfarin modification before surgeryPt on long term anticoagulation with warfarin should stop it 5 days in prior to elective surgery to allow INR to return to normal levelThose at high risk of thromboembolism can be bridged with once or twice daily s/c LMWH once the INR fall below 2. For pragmatic purposes, to save monitoring the INR as an out-patient, bridging therapy can be instituted with therapeutic dose LMWH 2-3 days after warfarin is stopped i.e. on the morning after two doses have been omitted. The last dose of LMWH should be given 12 or 24 hrs before depending on bd or od dose respectively

In patients who are receiving bridging anticoagulation with therapeutic dose UFH, the heparin should be stopped 4 - 6 hours before surgery. If possible the INR should be determined the day before surgery. This allows the administration of oral vitamin K (2 or 2.5 mg) if the INR is 1.5 so reducing the risk of cancellation. The INR should be checked on the day of surgery. Heparin should be resumed approximately 24 hours after the procedure if there is adequate haemostasis but should not be started until at least 48 hours after surgery in high bleeding risk surgeries Warfarin can be resumed, at the normal maintenance dose, the evening of surgery or the next morning if there is adequate haemostasis.

Dentistry in anticoagulated patients

The risk of significant bleeding in patients on oral anticoagulants and with an INR of 4.0 is small and the risk of thrombosis may be increased in patients in whom oral anticoagulants are temporarily discontinued. Oral anticoagulants should not be discontinued in the majority of patients requiring out-patient dental surgery including dental extraction. The risk of bleeding may be minimised by: The use of oxidised cellulose (Surgicel) or collagen sponges and sutures. 5% tranexamic acid mouthwashes can be used four times a day for 2 days . For patients stably anticoagulated on warfarin, a check INR is recommended 72 hours prior to dental surgery. Patients on warfarin should not be prescribed NSAIDs as analgesia following dental surgery.

Endoscopy in anticoagulated patients

In general, low risk diagnostic procedures including mucosal biopsy can be performed when the INR is up to 2.5, without altering anticoagulation. For therapeutic procedures the risk of post-procedure bleeding is higher and it is better to adjust anticoagulation.

ACENOCOUMAROL (acitrom) Same as warfarin with following differences: Shorter half life 10-16 hrsMore rapid onset of action on PTShorter duration of action (2 days)Causes GI disturbances, oral ulcerations and dermatitis4 mg on day one, 4-8 mg on the day 2nd then maintenance dose 1-8 mg according to response by PT test

THE OVERALL ANTICOAGULATION QUALITY IS SIGNIFICANTLY BETTER WITH WARFARIN AS COMPARED TO ACENOCOUMAROL

72%

67%

64%66%68%70%72%% Responders

WarfarinAcenocoumarolThrombosis And Haemostasis 1994; 71(2): 188-191

Newer Oral Anticoagulants

Why we need alternatives to warfarin ???

Whats wrong with warfarin?Narrow therapeutic rangeSlow onset of actionSlow offset of action (long duration of action, long elimination half life)Multiple drug and dietary interactionsMonitoring required to maintain in therapeutic rangeDifficult to manage for invasive proceduresUnder-use of therapy due to fear of adverse events and complexity of management

8. Efficacy is dependent upon infrastructureTime in therapeutic range (TTR) is associated with improved safety and efficacy TTR is greater in countries with more sophisticated health care infrastructure.

What are the attributes of the ideal anticoagulant?Oral administrationRapid onset of action/rapid offset of actionWide therapeutic rangePredictable therapeutic effect with fixed or weight-based dosingNo food or drug-drug interactionsNo monitoring required (but the ability to monitor if desired)Well defined pharmacokinetics in presence of renal or hepatic diseaseEasily reversibleCost effective

Newer oral anticoagulants

ClassificationDirect thrombin (IIa) inhibitorDabigatran (Pradaxa)Factor Xa inhibitorsRivaroxaban (Xarelto)Apixaban

Dabigatran etexilate (Pradaxa)Oral Direct thrombin (factor IIa) inhibitorIt is a prodrug & does not exhibit any pharmacological activityInitially recommended by FDA on October 19, 2010 for Non-valvular AF

Mechanism of Action

Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.

Pharmacokinetics

Dabigatran etexilate mesylate is absorbed as the dabigatran etexilate ester. The ester is then hydrolyzed, forming dabigatran, the active moiety. The t1/2 is 15 to 17 hrs. 90% is excreted unchanged in urine.

Absorption The absolute bioavailability of dabigatran following oral administration of dabigatran etexilate is approximately 3 to 7% . Cmax occurs at 1 hour post-administration in the fasted state. Coadministration of PRADAXA with a high-fat meal delays the time to Cmax by approximately 2 hours but has no effect on the bioavailability of dabigatran; PRADAXA may be administered with or without food.

Minimal metabolism of dabigatran by CYP3A4 enzymes is clinically insignificantNo dose modification required in hepatic impairmentDabigatran is also a substrate for P- glycoprotein ( a trans-membrane pump expelling drugs out of cell). So P- glycoprotein inhibitors (e.g. amiodarone, verapamil & clarithromycin) can increase whereas inducers (e.g. rifampicin, st. johns wart) may reduce dabigatran level in plasma.

Pharmacodynamics Dabigatran prolongs aptt which targets intrinsic pathway of coagulation; thrombin clotting time (TT), which directly assesses the activity of thrombin in a plasma sample; and the ecarin clotting time, which is a specific assay for thrombin generation. However, at clinically relevant plasma concentrations, dabigatran has relatively little effect on the prothrombin time and INR, which targets the extrinsic coagulation pathway. The TT assay is the most sensitive to prolongation by dabigatran, followed by the ecarin clotting time and aPTT.

The relationship between plasma concentrations of dabigatran and the TT, and ecarin clotting time is linear (ie, dabigatran prolongs the TT, and ecarin clotting time in a concentration dependent fashion over therapeutic concentrations), whereas the aPTT concentration-response curve is curvilinear and flattens at higher concentrations (200 ng/mL).

A dilute thrombin time assay (Hemoclot test, Hyphen Biomed, France) has been certified in Europe since late 2010 for the quantitative determination of dabigatran plasma levels. It can be calibrated with dabigatran standards.

INDICATIONS AND USAGE

Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial FibrillationTreatment of Deep Venous Thrombosis and Pulmonary Embolism Pradaxa is indicated for the treatment of deep venous thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5-10 days.Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism

Recommended dose

SOME SPECIAL POINTS TO MENTION.

If a dose of PRADAXA is not taken at the scheduled time, the dose should be taken as soon as possible on the same day; the missed dose should be skipped if it cannot be taken at least 6 hours before the next scheduled dose. The dose of PRADAXA should not be doubled to make up for a missed dose.

Dabigatran hydrolyze over time when exposed to humidity, causing a breakdown of active ingredient, and rendering the medication less effective

Converting pts from or to WarfarinFrom warfarin to dabigatranStop warfarin & start dabigatran once INR fall below 2From dabigatran to warfarinAdjust the starting time of warfarin based on creatinine clearance CrCL (ml/min)Days before stopping dabigatran> 503 days50 - 302 days30 - 151 day< 15 or dialysisnot recommended

Converting pts from or to parenteral anticoagulantsFrom parenteral anticoagulants to dabigatranIntermittent parenteral anticoagulantStart dabigatran 0-2 hrs before next doseContinuous parenteral anticoagulant (e.g. UFH)Start dabigatran at the time of stopping parenteral anticoagulantFrom dabigatran to parenteral anticoagulants Wait for 12 hrs (CrCl> 30 ml/min) or 24 hrs (CrCl< 30 ml/min) after last dose of dabigatran before starting parenteral anticoagulant

Dabigatran in pts planned for elective surgeryIf possible, stop dabigatran 1-2 days before (CrCl> 50 ml/min) or 3-5 days before (CrCl< 50 ml/min) invasive or surgical procedures.Longer periods may be considered if pt undergoingMajor surgerySpinal puncturePlacement of spinal or epidural catheter or port

Dabigatran in pts planned for emergency surgery

Because specific antidote is not available, options areEither have to wait until the anticoagulant effect has spontaneously diminished OrUndergo their procedure with the knowledge that they have a increased risk of bleeding

Postoperative managementIt depends almost exclusively on the postoperative risk of bleedingProcedures with with good hemostasis shortly after the end of the procedure, resumption on same evening can be done (i.e. minimum of 4 to 6 hours after surgery) starting with a half dose (75 mg) for the rst dose, and thereafter the usual maintenance dose.For major abdominal surgery or urologic surgery with incomplete hemostasis, resumption should be delayed until there is no drainage or other evidence of active bleeding

BLEEDING ON DABIGATRAN TREATMENT

Monitoring anticoagulant effect of dabigatranNeed not to assess regularly (ex. In the setting of emergency surgery)In emergency most accessible tests areTCTaPTTIf the TCT is normal, it is safe to assume that the level of dabigatran is very low and that the patients risk of bleeding development is similar to that of other patients undergoing the procedure

AntidoteSpecific agent not availableThough limited data, following agents may be usedActivated prothrombin complex concentrateRecombinant factor VIIaConcentrate of coagulant factors II, IX and XHemodialysis (because only 35% of dabigatran is bound to plasma proteins) Protamine sulfate and Vit-K are not helpful

Adverse effectsBleeding increases with ageGI eventsDyspepsia (12%)Abdominal painGastritis including GERD, esophagitis, erosive gastritis, gastric hemorrhage and GI ulcersHypersensitivity reaction ( 0.05)Major bleeding: 1.6% vs. 1.9%; Major + clinically relevant bleeding: 5.6% vs. 8.8.% (p = 0.002)Trial design: Evaluated the safety and efficacy of dabigatran 150 mg twice daily (n 1274) vs. warfarin (n 1265) for the treatment of acute VTE. Patients were followed for 6 months. Results Dabigatran(n = 1,274)

Dabigatran 150 mg twice daily is noninferior to warfarin for the treatment of acute VTE, with a slightly better bleeding profileComplements other studies showing safety and efficacy of dabigatran, as compared with warfarin in other settings, such as AF2.42.1%04

(p < 0.001*)ConclusionsWarfarin(n = 1,265) 123Primary endpointMajor bleeding%

(p = 0.38)1.61.9Schulman S, et al. N Engl J Med 2009;361:2342-525* For noninferiority041235

99

Factor Xa inhibitorsRivaroxabanApixaban

Rivaroxaban (Xarelto)

Rivaroxaban (Xarelto)Direct factor Xa inhibitorHalf life: 7 - 9 hoursPeak plasma concentration 0.5 3 hours after administrationHave excellent bio-availability of 80-100%2/3rd of rivaroxaban is metabolized by CYP3A4 system in liver1/3rd of rivaroxaban excreted unchanged in urine while of the metabolized excreted renally while other half via fecal route.

In contrast, bleeding from gastrointestinal sites, including upper, lower, and rectal sites, occurred more frequently in the rivaroxaban group, as did bleeding that led to a drop in the hemoglobin level or bleeding that required transfusion

Conclusion of ROCKET-AF trial In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism with no significant difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group.

Trial design: Patients with recent ACS(