NORMALLY THE ENDOTHELIUM HAS BOTH PRO AND ANTI THROMBOTIC PROPERTIES….IT SECRETES ANTIPLATELETS, ANTICOAGULANTS AD FIBRINOLYTICS AS WELL AS PLATELET AGGREGAMNTS, COAGULATION FACTORS, AND ANTIFIBRINOLYTIC AGNETS…..
We have 13 numbered coa. Factors along with HMWK and kallikreins…..
Explain the intrinsic and extrinsic pathways…
With these learned concepts in mind. Let us now venture into the topic proper-”anticoagualtion”…
An ideal anticoagulant ld prevent pathological thrombus formation, at the same time, preserve the body’s ability to respond to an endothelial injury….but the fact remains that, we still do not have a drug that has NO bleeding risk…all the drugs in our armamentarium have significant bleeding risks though the level of significance variesfrom one drug to the other….
Let us see which of our anticoagulants both contemporary and newer, who can come even close to these……
BUT IN THIS ERA OF EVIDENCE BASED MEDICINE, THE GUIDELINES HAVE BECOME A LOT SRINGENT AND WE NEED TO KNOW WHICH ANTICOAGULANT TO USE and WHEN AS PUT DOWN IN THE GUIDELINES which are formulated AFTER MANY META ANALYSES OF RCTs…..AND IN THIS PRESENTATION WE LL BE ADHERING TO THE LATEST GUIDELINES ISSUED BY THE CONCERNED AUTHORITIES….
The following at our disposal at present….
SO AS WE SEE HERE, WE DEFINITELY HAVE A BIGGER SPECTRUM OF ANTICOAGULANTS TO CHOOSE FROM...
LET US CLASSIFY THE…
AS WE HAVE SEEN PREVIOUSLY, THE BEST BET LD BE TO INHIBIT THIS MOECULE” THROMBIN”…..HMWH OR UFH HAS EQUAL THROMBIN INHIBITING AND FACTOR XA INHIBITING PROPERTIES….WHEREAS LMWH HAS LESSER OF THIS THROMBIN INHIBITION AND MORE OF FACTOR XA INHIBITION…WE LL SEE HOW….
AS WE HAVE SEEN PREVIOUSLY, THE BEST BET LD BE TO INHIBIT THIS MOLECULE” THROMBIN”…..HMWH OR UFH HAS EQUAL THROMBIN INHIBITING AND FACTOR XA INHIBITING PROPERTIES….WHEREAS LMWH HAS LESSER OF THIS THROMBIN INHIBITION AND MORE OF FACTOR XA INHIBITION…WE LL SEE HOW….
LET US CLASSIFY THE…
The following at our disposal at present….
The following at our disposal at present….THIS GROUP OF NEWER ORAL ANTICOAGULANTS HAS BEEN THE AREA OF INTENSE RESEARCH…..
KNOWING THIS IS IMPORTANT COS THESE DISADVANTAGES FORM THE BASIS FOR THE CONTINUOUS SEARCH OF THE NEWER ANITCOAGULANTS…
Long chain inclues the high affinity pentasaccharaide sequence…
WITH THESE BASICS, LETS SEE THE SIDE EFFECTS OF UNFARCTIONATED HEPARIN AND SEE GHOW LMWH SCORES BETTER THAN IT….
Warfarin acts as an anticoagulant by blocking the ability of Vitamin K to carboxylate the Vitamin K dependent clotting factors, thereby reducing their coagulant activity.
The indications and where each of these anitcoagualnts are approved to use will be dealt shortly….
Was a very atrractive option when introduced, but, Failed to prove superiorty over LMHW and bleeding risks were higher….
Potent selective inhibitor of factor Xa. Absorption: well absorbed from GI tract with Bioavail > 80% The terminal t1/2 is ~ 5-9 hrs in young individual and 11-13 hrs in the elderly Dual mechanism of excretion. 66% in the kidneys and the remainder in the feces 30-40% excreted unchanged in the urine and excreted via a combination of glomerular filtration and tubular secretion and the remainder reflects metabolites. Use in caution for pts with renal insufficiency. Intestinal excretion of rivaroxaban appears to be mediated, by P-glyp (transport protein) The drug is contraindicated in pts with severe liver dx b/c of metabolic inactivation may be impaired. Also caution should be used in patients receiving tratment with potent inhibitors of both CYP3A$ and P-glyp (ketoconazole/ritonovir) Reduced fecal and renal clearance of rivaroxaban by these drugs can cause exaggerated anticoagulant effect Rivaroxaban prolongs the PT and aPTT, with the PT being more sensitive than the aPTT depending on the reagents used for testing. The effect of the drug on these tests is short-lived with prolongation only seen at peak drug levels. Factor Xa inhibition is the best test to monitor drug concentrations in plasma.
Regulation of Coagulation in major Orthopedic surgery reducing the Risk of DVT and PE (RECORD) RECORD 1 and 2: THR surgery RECORD1: Rivaroxaban 10mg once daily (Primary endpoint: 1.1% vs. 3.7%; p <0.001 Major bleeds: 0.3% vs 0.1%) -RECORD2: Rivaroxaban 10 mg once daily (Primary enpoint: 2.0% vs 9.3%; p<0.001 Major bleeds: 0.1% vs. 0.1%) Results showed an impressive 50% reduction in DVT, nonfatal PE, and all-cause mortality favoring the once daily rivaroxaban treated group over enoxaparin. Also an equally impressive 60% statistically significant risk reduction, again favoring rivaroxaban over enoxaparin for major VTE. Appeared to be no differences in major bleeding or any severity of bleeding between groups.
Rivaroxaban 10mg once daily vs. FDA approved Enoxaparin 30 mg SC BID RRR of 31% in primary endpoint (reduction in total VTE events) for rivaroxaban (6.9% vs. 10.1% p = 0.012) There was a trend towards more major bleeding events with rivaroxaban compared with enox, despite use of a 50% higher dose of enoxaparin than in RECORD 1,2, or 3 but the difference was not statistically significant (0.7% vs. 0.3%; P> 0.05)
EINSTEIN DVT and PE (Phase II) EINSTEIN Extension: focused on once daily dosing Other studies: ODIXa – HIP (Phase II) vs. Enox ODIXa – HIP2 (Phase II) vs. Enox ODIXa – Knee (Phase II) vs. Enox ODIXa – OD – HIP (Phase II) vs. Enox - ODIXa-DVT (Phase II) vs. Enox and warfarin
Absorption: Bioavailability = 50% - 81% Peak Plasma levels = 3 hrs t ½ = 9-14 hrs = Long – especially in the elderly may be prolonged Metabolized: in the liver via CYP3A4 and CYP independent mechanisms Excretion: Dual mechanism – 25% kidneys / 75% = biliary/feces Monitoring: using a factor Xa inhibition assay or a dilute prothrombin time **Apixiban prolongs PTT and INR in a concentration-dependent fashion – however effect on these tests is minimal at therapeutic concentrations. - Followup drug to Razaxaban (halted due to high bleeding) = similar characteristics
N (TOTAL) = 1238 Phase II Double Blind Randomized study of 1238 pts undergoing TKR. Apixaban 1/6 doses, open label warfarin, or enoxaparin 30 mg BID Followup at day 42 The composite of VTE and mortality were lower with all apixaban doses vs. enoxaparin and warfarin, although apixaban dose-dependency did not achieve significance P = 0.09) When looking at the overall riskk-benefit profile, apixaban 2.5mg twice daily or 5mg once daily appeared the most promising dose regimen for further phase three considerations.
Bleeding Rates were significantly dose-dependent with the once (P= 0.01) and twice daily (P=0.02) apixaban regimens
So when we have a superior ORAL drug with the the safety profile as a parenteral drug, then why not go for it !!!
The main advantages over present strategies are highlighted in bold italics.
REVOLUTION TRIAL PROGRAM = phase 3 program that will be enrolling over 27,000 patients worldwide and includes REMODEl, REMOBILIZE, and RENOVATE studies in primary VTE prevention in ortho patients REMOBILIZE: Dabigatran with enoxaparin dose 30mg BID started post-procedurally in pts undergoing TKA. The 150mg and 22mg daily dose did not meet the non-inferiority design compared with enoxaparin. OTHER STUDIES RESOLVE, RECOVER, REMEDY = VTE treatment and secondary thromboprophylaxis RELY - Dabigatran 110 mg = similar rates of stroke and systemic embolization and lower rates of major hemorrhage Dabigatran 150 mg = lower rates of stroke and systemic embolism but with similar rate of major hemorrhage **Rate of MI was higher with both doses of dabigatran than with warfarin** **Did not find liver toxicity with dabigatran in RE-LY pts**
Dabigatran 110 mg = similar rates of stroke and systemic embolization and lower rates of major hemorrhage Dabigatran 150 mg = lower rates of stroke and systemic embolism but with similar rate of major hemorrhage **Rate of MI was higher with both doses of dabigatran than with warfarin**
Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). There was a definite advantage of the 150 mg group in terms of superiority over warfarin
Warfarin was associated with less ICH vs fixed dose warfarin + ASA or dual antiplatelet treatment. Here in RELY, there is a significant reduction even beyond that. This is significant for clinical practice in that fear of ICH should now be a minimal concern when taken in balance with stroke prevention.
Published trials in order of year of major publication. ACTIVE-W Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events; AFASAK Atrial Fibrillation, ASpirin, AntiKoagulation; ATAFS Antithrombotic Therapy in Atrial Fibrillation Study; BAATAF Boston Area Anticoagulation Trial for Atrial Fibrillation; CAFA Canadian Atrial Fibrillation Anticoagulation; EAFT European Atrial Fibrillation Trial; ESPS European Stroke Prevention Study; FFAACS Fluindione Fibrillation Auriculaire Aspirin et Contraste Spontane´; JAST Japan Atrial fibrillation Stroke Trial; JNAFESP Japanese Nonvalvular Atrial Fibrillation Embolism Secondary Prevention; LASAF Low-dose Aspirin, Stroke, Atrial Fibrillation; MWNAF Minidose Warfarin in Nonrheumatic Atrial Fibrillation; NASPEAF NAtional Study for Prevention of Embolism in Atrial Fibrillation; PATAF Prevention of Arterial Thromboembolism in Atrial Fibrillation; PETRO Prevention of Embolic and ThROmbotic events; SAFT Swedish Atrial Fibrillation Trial; SIFA Studio Italiano Fibrillazione Atriale; SPAF Stroke Prevention in Atrial Fibrillation; SPINAF Stroke Prevention in Nonrheumatic Atrial Fibrillation; SPORTIF Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation; UK-TIA United Kingdom Transient Ischaemic Attack; WASPO Warfarin vs. Aspirin for Stroke Prevention in Octogenarians.
The decision to test two doses of dabigatran in a large phase II trial was taken because the identification of the correct dose was considered critical to ensure the optimum balance of efficacy and safety. The 150 mg bid dose had been tested in the phase II PETRO study, whereas 110 mg bid had not been directly tested. The choice of this lower dose was based on interpolations of phase II data, considering the time course and the peak of the anticoagulant effect of dabigatran, and on the observation that a total daily dose of 220 mg was effective for the prevention of deep-vein thrombosis in patients undergoing orthopedic surgery. The two-dose approach used in RE‑LY ® may also allow the opportunity to tailor dabigatran dosing to individual patient characteristics in order to maximize the benefit/risk ratio.
Only dabigatran is presently approved for SPAF in the following countries: Canada, Colombia, Israel, Namibia, New Zealand, Philippines, USA, Japan, Australia, Indonesia, Singapore, Korea, Malaysia. References: NCT00412984. www.clinicalTrials.gov. Accessed September 9, 2010. Lopes RD, et al. Am Heart J. 2010;159:331-339. NCT00496769. www.clinicalTrials.gov. Accessed September 9, 2010. Eikelboom JW, et al. Am Heart J. 2010;159:348-533. NCT00403767. www.clinicalTrials.gov. Accessed September 9, 2010. ROCKET-AF Study Investigators. Am Heart J. 2010;159:340-477. NCT00781391. www.ClinicalTrials.gov. Accessed September 9, 2010.
Cos in HIT protein c and s is also consumed keading to their deficiency…
PCI has been the standard of acre now a days…..need to perform PCI at the earliest need not be overemphasised now….spo inorder to faciolitate…
Antidote : SSR 126517 (Factor Xa Inhibitor) is the only new anticoagulant being studied that has an antidote. Neutralization of Direct Factor Xa Inhibitors: plasma derived or recombinant factor Xa modified to lack catalytic and membrane binding activities, can neutralize the effects of small molecular factor Xa and LMWH Dialysis is likely to clear the direct factor Xa or Thrombin inhibitors = all of which are small molecules
NEWER ANTICOAGULANTS-Dr.Deep Chandh Raja(as on Feb’2013)
SYNOPSIS• OVERVIEW OF COAGULATION CASCADE• CONTEMPORARY ANTICOAGULANTS & THEIRDISADVANTAGES• “IDEAL” ANTICOAGULANT• SPECTRUM OF NEWER ANTICOAGULANTS• PRESENT INDICATIONS OF NEWERANTICOAGULANTS• FUTURE OF ANTICOAGULATION
• COAGULATION-“A DEFENCE MECHANISM of the body”ANTI-COAGULANTSCOAGULANTS
• ‘Fixed’ ‘oral’ dose• No need for dose adjustment• Wide therapeutic range• Acceptable bleeding risks• No need for monitoringAN “IDEAL” ANTI COAGULANT
Indications of Anticoagulant Therapy• Prevention and Treatment of Deep VenousThrombosis• Treatment of Pulmonary Emboli• Prevention of stroke in patients with atrialfibrillation, artificial heart valves, establishedthrombosis (DVT, Cardiac)• Ischaemic heart disease• During procedures such as cardiac catheterisation
Rivaroxaban OngoingClinical TrialsDVTEinstein-DVTRivarox 15mg BID x 3wks then 20mg QdayvsEnox/VKAPEEinstein-PERivarox 15mg BID x 3wks then 20mg QdayvsEnox/VKAMedically IllRivarox 10mg Qday x 35 daysvsEnox 40mg Qday x 10 daysDVT/PEEinstein-ExtensionRivarox 20mg QdayvsPlacebo
Apixaban• Oral tablet• Bioavailability: 50%• Peak Plasma Levels = 3 hrs• Half-life ~ 12 hours• Metabolized in liver viaCYP3A4 and CYPindependent mechanisms• Eliminated via multiplepathways• No laboratorymonitoring required• Has been submitted forapproval by the US FDA
Apixaban EfficacyOutcomes in TKR05101520253035405QDay10QDay20QDayEnox30mg BID(n=152)Warf(n=153)2.5BID5BID10BIDApixaban (mg) (n = 933)Incidence of VTE and all-cause death (%)Duration =10 -14 daysLassen MR, et al. J Thromb Haemost. 2007;5:2368 – 2375.
Apixaban SafetyOutcomes in TKR0246810121416185QDay10QDay20QDayEnox30mg BID(n=152)2.5BID5BID10BIDApixaban (mg) (n = 933)Warf(n=153)Incidence of bleeding events (%)
Summary of ADVANCE – 2 TRIAL• Apixaban 2.5mg BID vs. Enoxaparin 40mg QD• Superior for:– Primary endpoint of ANY DVT/PE/All-Cause Death– Secondary endpoint for Major VTE• Lower observed bleeding rates– Major– Clinically relevant non-major• Similar overall safety profile
Ximelagatran• First target-specific oral anticoagulant in trials• Ximelagatran is the oral prodrug of Melagatran• Hepatatoxicity– Did not receive FDA approval in 2004– On the market in Europe but pulled in 2006• ‘proof of principle’– “efficacious” as warfarin– Wider therapeutic index– Little dosage adjustment/ no monitoring
Dabigatran Etexilate• Potent and reversible oral Direct Thrombin Inhibitor• Inhibiting both clot bound and free thrombin• Predictable and consistent PK profile-Rapid onset/offset ofaction (Peak plasma levels within 2 hours)• Anticoagulation monitoring—Not required• Half-life 12–17 hours (twice-daily dosing)• Low drug–drug interactions (not metabolised by CYP450enzymes) However, P glycoprotein inhibitors Amiodarone,verapamil and quinidine may increase its plasma level• No food–drug interactions reported• Dosing independent of meals or dietary restrictions• 65% bioavailability, ~80% renal excretion
TRIALS IN PREVENTION OF DVT• RE-MOBILISE• RE-NOVATE• RE-MODEL“Dabigatran was non inferior to enoxaparin interms of efficacy and bleeding risks”
What about RE-LY?Dabigatran versus Warfarin in Patients withAtrial Fibrillation• Non-inferiority trial• Over 18,000 patients• Followup = 2 yearsDabigatran 110 mg and 150mgDabigatran 110 mg and 150mgvs.vs.Adjusted dose warfarinAdjusted dose warfarin
PREVENTION OF DVTPrinciples of treatment• HMWH• LMWH• WarfarinNEWER• Fondaparinux• Dabigatran 220 mg bd(Post THR, TKR)• Rivaroxaban 10 mg qd(Post THR, TKR)• In critically illpatients• Post THR, TKR• Orthopedic &other surgeries• Medicalconditions likepost MI, StrokeCONTEMPORARY
TREATMENT OF DVTPrinciples of treatment• HMWH80 U/kg STAT f/b18 U/kg/hrinfusion• LMWHNEWER• Fondaparinux• Dabigatran awaitsapproval by US FDA• Anti thrombotics-a must• Decision to betaken reg. IVCfilters• 2nd VTE,unprovoked VTE &cancer associatedVTE-indefiniteduration• Else- 3-6 monthsdurationCONTEMPORARY
TREATMENT OF PULMONARY EMBOLISMPrinciples of treatment• HMWH80 U/kg stat f/b18 U/kg/hrinfusion• LMWHNEWER• Fondaparinux• Other trials areongoing….• Presence of RVdysfunction /hemodynamicinstabilityThrombolysis• Small tomoderate PE-antithrombotics• Well’s criteria> 3-antithromboticsCONTEMPORARY
Why do we need long termanticoagulation ?• Atrial fibrillation (AF) is responsible for one-third of all strokesand is the leading cause of embolic stroke• Stroke is the most serious complication of AF• There is 5 foldand 17 foldincrease in the risk of stroke due tonon-valvular AF (NVAF) and valvular AF respectively• About one in four people at age 55 years will go on to developAF (24% of men and 22% of women)• 1 in 20 (5%) AF patients can have a stroke if not prevented• In excess of 7% per year can be attributed to rate of brainischemia due to transient ischemic attacks and clinically ‘silent’strokes, associated with Non valvular Atrial Fibrillation
PREVENTION OF STROKEIN ATRIAL FIBRILLATION• CLASS 1 INDICATIONS:1.Presence of cardiac thrombus / DVT2.In AF due to valvular causes3.In AF due to non valvular causes(as per CHADS2 score)
Choice In AF due to non valvular causes(as per CHADS2 score)• 1= aspirin /anticoagulant• >1=anticoagulant
PREVENTION OF STROKEPrinciples of treatment• HMWH• LMWHNEWER• FONDAPARINUX• DABIGATRAN110/150 mg BD• RIVAROXABAN20 mg QD• APIXABAN awaitsapproval by US FDA• In AF• Mechanical heartvalves• Incardiomyopathies• Inheritedcoagulopathies• DVTCONTEMPORARY
150 mg OR 110 mg DABIGATRAN ?150 mg 110 mg< 75 years1, 2≥ 75 years1, 2with risk factors:(i) Higher risk for bleed*(ii)Pharmacodynamic interactions**(iii)Factors increasing dabigatran plasmalevels***1, 2Superior vs warfarin for stroke1, 2Noninferior vs warfarin for stroke1, 2Noninferior vs warfarin for risk of majorbleed1, 2 –Superior vs warfarin for ICHSuperior vs warfarin for risk of major bleed1, 2Superior vs warfarin for ICH*1. Congenital or acquired coagulation disorders, 2.Thrombocytopenia or functional platelet defects, 3.Active ulcerative gastrointestinal(GI) disease, 4.Recent GI bleeding, 5.Recent biopsy or major trauma, 6.Recent intracranial hemorrhage, 7.Brain, spinal or ophthalmicsurgery, 8.Bacterial endocarditis**Acetylsalicylic acid, NSAID, Clopidogrel***Moderate renal impairment (30-50ml/min CrCL), P- glycoprotein-inhibitor comedication
Prevention of Atrial Fibrillation-Related Stroke
76The Newer Anticoagulants on theHorizonTrial Drug Dose Comparator NCHADS2scoreRE-LY Dabigatran150 mg and110 mg*BIDWarfarin(INR 2.0–3.0)18,113 >0ROCKET-AF5,6Rivaroxaban20 mg*ODWarfarin(INR 2.0–3.0)14,264 ≥2AVERROES3,4Apixaban5 mgBIDAspirin(81–324 mg OD)6000 ≥1ARISTOTLE1,2Apixaban5 mgBIDWarfarin(INR 2.0–3.0)18,201 ≥1ENGAGE-AF TIMI487Edoxaban30 mg OD60 mg ODWarfarin(INR 2.0–3.0)>20,000 ≥2*Adjusted based on renal function. BID, twice daily; INR, international normalised ratio; OD, once daily
PREVENTION OF STROKEIN NON CARDIOEMBOLIC EVENTS“No evidence that warfarin is superior toaspirin in stroke prevention”Evidence based on the following landmark trials-•WATCH- low ef CHF•APASS- APLS syndrome pts.•PICSS- Patent foramen ovale pts.•WARSS trials
IN H.I.T SyndromesWithdraw heparin and initiate one of thefollowing:•Lepirudin – preferred over Argatroban in hepaticdiseases•Argatroban- preferred over lepirudin andfondaparinux in renal diseases•Fondaparinux“Warfarin NOT TO BE USED IMMEDIATELY postHMWH/LMWH”
Pre Cardiac catherisation (PCI)• LMWH / Bivaluridin preferred post MI
Potential Limitations of NewAnticoagulants• Antidotes– None of the newer agents has a specific antidote• Monitoring• Adverse Drug Events• Compliance• Cost• Clinical Trials vs. Actual Clinical Practice• Patient populations not even studied (i.e. Cancer)