DR RAKESH JAIN SR CARDIOLOGY MEDICAL COLLEGE, CALICUT

HEMOSTATIC SYSTEM In Brief.

WHEN DOES BLOOD COAGULATE ? Injury to blood vessel. Ex: Plaque rupure Blood stasis. Ex: AF Procoagulants > Anticoagulants. Ex: Coagulation disorders

OVERVIEW FROM ENDOTHELIAL DAMAGE TO THROMBOSIS

BLOOD COAGULATION PATHWAYS aPTT PT/ INR

CLASSIFICATION OF ANTICOAGULANTS Coumarin Derivatves e.g. Warfarin, Acenocoumarol (Acitrom) Indandione Derivatves e.g. Phenindione, Anisindione Newer anticaogulants Direct 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 3,3 methylenebis (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.

WARFARIN Most widely used anticoagulant in the world Coumarin derivative, water soluble vit K antagonist Low cost and highly effective, if given in right way.

Vitamin K-dependent clotting factors (FII, FVII, FIX, FX, Protein C/S/Z) Epoxide Reductase -Carboxylase (GGCX) MECHANISM OF ACTION: Warfarin inhibits the vitamin K cycle Warfarin Inactivation CYP2C9 Pharmacokinetic Post translational modification

PLASMA HALF-LIVES OF VITAMIN K-DEPENDENT PROTEINS Factor II72h Factor VII6h Factor IX24h Factor X36h Peak anticoagulant effect may be delayed by 72 to 96 hours

PHARMACOLOGY Recemic micture of R and S isomers (S more active) Rapidly and completely absorbed from GI tract Blood level peaks about 90 min of administration 90% of circulating warfarin is bound to albumin Plasma t1/2 is 36-42 hrs Only small fraction of unbound warfarin is biologically active Warfarin 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 activity Two 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 Asians Warfarin dose reduction requires as follow: Heterozygosity for CYP2C9*2 or CYP2C9*3 allele : 20%-30% Homozygosity for the CYP2C9*2 or CYP2C9*3 allele : 5 0%-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 Epoxide Reductase -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

Effect of VKORC1 Genotype on Anticoagulation Three polymorphic variants of VKORC1 Non-A,Non-A : wild type Requiring more warfarin dose Non-A/A : Heterozygous Requiring 25% dose reduction A/A : Homozygous - Requiring 50% dose reduction Means wild type having more resistance to warfarin while homozygous is more sensitive. Asians have the highest prevalence of VKORC1 variants, followed by whites and blacks Polymorphisms 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 reduction Non-A,Non-A : wild type 7 -- Non-A/A : Heterozygous 30 26 A/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.

DOSING Usual dose is 5 mg/day (1-20 mg) Lower doses require in Elderly Pt on increased risk of bleeding Ex. Pt on aspirin Heart failure Liver disease Renal impairment Malnutrision Thyrotoxicosis (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.

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 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.

Monitoring B/c 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-INR Warfarin 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 = [PT pt ] ISI [PT Ref ] [PT Ref ] PT pt prothrombin time of patient PT Ref prothrombin time of normal pooled sample ISI 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

Indication INR Prophylaxis of venous thromboembolism 2.0-3.0 2.0-3.0 Treatment of venous thromboembolism 2.0-3.0 2.0-3.0 Atrial fibrillation 2.0-3.0 2.0-3.0 Heart valve replacement Bioprosthetic valve Mechanical valve 2.0-3.0 2.0-3.0 2.5-3.5 2.5-3.5 OPTIMAL THERAPEUTIC RANGE

Indications Atrial fibrillation Prosthetic heart valve Venous thromboembolism Primary pulmonary hypertension Rarely 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 AF in the presence of heart disease is strongly associated with thromboembolism and the benefits of warfarin far exceed than risk of hemorrhage. Only clear indication for withholding warfarin are: 1. Lone AF in younger pts 2. Bleeding diathesis 3. Elderly pts with frequent falls

Warfarin in MS/MR Warfarin is indicated if associated with AF (Persistent or paroxysmal) Previous embolic episodes (Even if in sinus rhythm) May be considered if Marked LA enlargement (Diameter > 55 mm) Spontaneous contrast on echocardiography Warfarin is not indicated in pts with MS/MR with sinus rhythm.

Warfarin in Mechanical Prosthetic heart valve Class I indication Warfarin should begin about 2 days after operation INR should be in the range of 2.0 to 3.0 - bileaflet disc & Medtronic-Hall valve in aortic position. 2.5 and 3.5 - higher risk for thrombosis (e.g., AF, previous thromboembolism) or for other mechanical valves in aortic position & for all valves in the mitral position Aspirin 75 - 100 mg daily should be given to all patients with prosthetic valves pts on warfarin for adequte protection from thromboembolism (Class I indication)

Warfarin in Bio-Prosthetic heart valve Warfarin mandatory only for first 6-12 weeks when risk of thromboembolism is highest. Thereafter Aspirin alone is required.

Warfarin in Venous thromboembolism Warfarin 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 months Optimal duration of anticoagulation depends on clinical settings

Optimal duration of anticoagulation CLINICAL SETTINGRECOMMENDATION 1 st provoked PE/proximal leg DVT3 to 6 months 1 st provoked upper extremity DVT or isolated calf DVT 3 months 2 nd provoked VTEUncertain 3rd VTEIndefinite duration Cancer and VTEConsider indefinite duration or until cancer is resolved Unprovoked PE/proximal leg DVTConsider indefinite duration 1 st unprovoked calf DVT3 months 2 nd unprovoked calf DVTUncertain

Warfarin in Idiopathic PAH Widely recommended & supported by numerous studies implicating thrombus as contributing to disease progression. Significant survival advantage in warfarin treated pts Current recommendation is to use relatively low dose of warfarin to maintain INR between 2-3.

Side effects of Warfarin Bleeding Skin necrosis Purple toe syndrome Teratogenicity Osteoporosis Others: Agranulocytosis, leukopenia, diarrhoea, nausea, anorexia. nausea, anorexia.

Bleeding Most common complication In form of Mild: epistaxis, hematuria Severe: Retroperotoneal or gastrointestinal bleeding Life-threatening : Intracranial bleed Rate of major bleeding (defined as any visit to hospital for hemorrhage) is 1- 3% per person-year [CMAJ on November 26, 2012] Half of the complications occurs because INR exceeds therapeutic range Can 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 range > 4.5Low dose sublingual/oral Vit K 4.9 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 INTERVENTION Mild bleedingWithhold warfarin Severe bleedingVit k 10 mg slow i/v infusion FFP (15 ml/kg) Life threatening bleeding or pt cant tolerate volume overload Prothrombin 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 NECROSIS Rare but very serious complication of warfarin (prevalence of 0.01-0.1 %) Br J Surg. 2000 Mar;87(3):266-72 Br J Surg. Occurs 2 to 5 days after initiation of warfarin Usually occurs after high dose of warfarin Typical 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 deficiency Overlapping with a parenteral anticoagulant when initiating warfarin therapy

Purple toes syndrome Extremely uncommon cutaneous complication Characterized by the sudden appearance of bilateral, painful, purple nonhemorrhagic lesions on the toes and sides of the feet that blanch with pressure Usually develops 3-8 weeks after the start of warfarin therapy Mechanism: 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 Pharmacotherapy.

Teratogenicity Occurs in 3.5 6 % Depends on time of gestation and dose of warfarin given Usually in first trimester of pregnancy It causes characteristic embryopathy consist of : Nasal hypoplasia and Chondrodysplasia punctata (epiphyseal and vertebral bone stippling) Cleft lip and (or) palate Choanal stenosis/atresia Central nervous system abnormalities Coarctation of aorta (Rare malformations described following first trimester exposure to warfarin) Occurs especially if warfarin dose is > 5 mg/day J Am Coll Cardiol 1999;33:1637 41

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

OSTEOPOROSIS Long- term use of warfarin (> 1 yr) More common in males 60% increased risk of osteoporosis-related fracture in men Mechanism: 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 nonfunctional Beta-adrenergic antagonists may protect against osteoporotic fractures Arch Intern Med. 2006 Jan 23;166(2):241-6 Arch Intern Med.

Drug interaction- with Warfarin Drugs that Increase Warfarin Activity Decrease binding to Albumin Inhibit Degradation Decrease synthesis of Clotting Factors Aspirin, Sulfonamides Cimetidine, Disulfiram Antibiotics (oral) Category Mechanism Representative Drugs

Drug interaction with Warfarin Drugs that promote bleeding Inhibition of plateletsAspirin Inhibition of clotting heparin Factors antimetabolites Drugs that decrease Warfarin activity Induction of metabolizingBarbiturates EnzymesPhenytoin Promote clotting factorVitamin K Synthesis Reduced absorptioncholestyramine colestipol

Warfarin in special conditions

Pregnancy It causes Fetal abnormalities (Teratogenic)- in first trimister Chances of intracranial bleeding in baby while passage through birth canal in third trimister Because of this, warfarin is contraindicated in 1 st (first 12 weeks) & 3 rd trimsters (last 2 weeks) Warfarin does not passes in breast milk & is safe for nursing mothers.

Anticoagulant approach in pregnancy Should be First 12 weeks12 to 38 weeks38 weeks to 12 hrs before delivery Postpartum period UFH/LMWH WarfarinUFH or LMWHWarfarin+ UFH/LMWH (4-5 days) Warfarin < 5 mg/day throughout pregnancy (Best, because of its good antithrombotic effect)

Warfarin modification before surgery Pt on long term anticoagulation with warfarin should stop it 5 days in prior to elective surgery to allow INR to return to normal level Those at high risk of thromboembolism can be bridged with once or twice daily s/c LMWH once the INR fall below 2. The last dose of LMWH should be given 12 or 24 hrs before depending on bd or od dose respectively

ACENOCOUMAROL (acitrom) Same as warfarin with following differences: Shoter half life 10-16 hrs More rapid onset of action on PT Shorter duration of action (2 days) Causes GI disturbances, oral ulcerations and dematitis 4 mg on day one, 4-8 mg on the day 2 nd 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 WarfarinAcenocoumarol Thrombosis And Haemostasis 1994; 71(2): 188-191

Newer Oral Anticoagulants

Why we need alternatives to warfarin ???

Whats wrong with warfarin? 1. Narrow therapeutic range 2. Slow onset of action 3. Slow offset of action (long duration of action, long elimination half life) 4. Multiple drug and dietary interactions 5. Monitoring required to maintain in therapeutic range 6. Difficult to manage for invasive procedures 7. Under-use of therapy due to fear of adverse events and complexity of management

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

What are the attributes of the ideal anticoagulant? 1. Oral administration 2. Rapid onset of action/rapid offset of action 3. Wide therapeutic range 4. Predictable therapeutic effect with fixed or weight-based dosing 5. No food or drug-drug interactions 6. No monitoring required (but the ability to monitor if desired) 7. Well defined pharmacokinetics in presence of renal or hepatic disease 8. Easily reversible 9. Cost effective

Newer oral anticoagulants

Classification Direct thrombin (IIa) inhibitor Dabigatran (Pradaxa) Factor Xa inhibitors Rivaroxaban (Xarelto) Apixaban

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

Pharmacokinetics: After oral administration, dabigatran etexilate is rapidly absorbed. It get rapidly & completely converted to dabigatran (active form in plasma) Peak plasma concentration reached in 0.5 2 hrs T1/2 is 15-17 hours 90% of excreted unchanged in urine. So dose reduction required in moderate renal impairment & is contraindicated in severe renal impairment.

Minimal metabolism of dabigatran by CYP3A4 enzymes is clinically insignificant No dose modification required in hepatic impairment Dabigatran 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.

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

So, Pradaxa is packaged in a 30-day supply bottle with a desiccant cap or in unit-of-use blister packaging to minimize product breakdown from moisture. (Use within 4 months of opening and keep in original container)

RE-COVER Primary outcome (recurrent VTE or death due to VTE): 2.4% vs. 2.1% Mortality: 1.6% vs. 1.7% (p > 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 profile Complements other studies showing safety and efficacy of dabigatran, as compared with warfarin in other settings, such as AF 2.4 2.1 % 0 4 (p < 0.001*) Conclusions Warfarin (n = 1,265) 1 2 3 Primary endpointMajor bleeding % (p = 0.38) 1.6 1.9 Schulman S, et al. N Engl J Med 2009;361:2342-52 5 * For noninferiority 0 4 1 2 3 5

Indications of dabigatran Useful alternative to warfarin- To prevent stroke & blood clots in pts with either paroxysmal or permanent AF in the absence of prosthetic heart valve, significant heart valve disease or severe renal impairment (i.e. non valvular AF) Treatment of DVT & Pulmonary embolism Prophylaxis of venous thromboembolism after orthopedic surgery

Dose of Dabigatran Depends on renal function i.e. creatinine clearance GFR (ml/min) Dabigatran dose > 30150 mg 1BD 30 - 1575 mg 1BD < 15 or dialysis not recommended Dabigtran should be discontinued in pts who develop ARF while on dabigatran and alternative anticoagulant should be considered.

Prophylaxis of venous thromboembolism after orthopedic surgery is 220 mg once daily against venous thromboembolism in post operative period Against stroke in AF pts Dose reduction by 50 % in Moderate renal impairement Older than 75 years of age No dose adjustment is required for pts weight Use without regard to meal AJR:199,September 2012

Converting pts from or to Warfarin From warfarin to dabigatran Stop warfarin & start dabigatran once INR fall below 2 From dabigatran to warfarin Adjust the starting time of warfarin based on creatinine clearance CrCL (ml/min)Days before stopping dabigatran > 503 days 50 - 302 days 30 - 151 day < 15 or dialysisnot recommended

Converting pts from or to parenteral anticoagulants From parenteral anticoagulants to dabigatran Intermittent parenteral anticoagulant Start dabigatran 0-2 hrs before next dose Continuous parenteral anticoagulant (e.g. UFH) Start dabigatran at the time of stopping parenteral anticoagulant From 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 surgery If 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 undergoing 1. Major surgery 2. Spinal puncture 3. Placement of spinal or epidural catheter or port

Dabigatran in pts planned for emergency surgery Because specific antidote is not available, options are Either have to wait until the anticoagulant effect has spontaneously diminished Or Undergo their procedure with the knowledge that they have a increased risk of bleeding

Postoperative management It depends almost exclusively on the postoperative risk of bleeding Procedures 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

Monitoring anticoagulant effect of dabigatran Need not to assess regularly (ex. In the setting of emergency surgery) In emergency most accessible tests are 1. TCT 2. aPTT If 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

Antidote Specific agent not available Though limited data, following agents may be used Activated prothrombin complex concentrate Recombinant factor VIIa Concentrate of coagulant factors II, IX and X Hemodialysis (because only 35% of dabigatran is bound to plasma proteins) Protamine sulfate and Vit-K are not helpful

Adverse effects Bleeding increases with age GI events Dyspepsia (12%) Abdominal pain Gastritis including GERD, esophagitis, erosive gastritis, gastric hemorrhage and GI ulcers Hypersensitivity reaction (

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DR RAKESH JAIN SR CARDIOLOGY MEDICAL COLLEGE, CALICUT