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Newer anti-coagulants
13.10.11
• Coagulation system• Available anticoagulants:
– Heparin ,LMWH ,fondaparinux, Direct thrombin inhibitors, Warfarin
• Limitations of established parenteral and oral anticoagulants
• Potential advantages of the new agents• Pharmacology and clinical trial results with new
anticoagulants• Conclusions and Future Directions
Hemostatic system
The major components of the hemostatic system are:– Vascular endothelium– Platelets– Coagulation system – Fibrinolytic system.
Coagulation occurs through the action of discrete enzyme complexes, which are composed of a vitamin K–dependent enzyme and a nonenzyme cofactor.
XII
Contact (Eg: with glass)
XIIa
XI XIa
IX IXa
X Xa
VIIIa
PL
Ca++
Intrinsic Pathway (APTT)
• Factors VIII, IX, XI, and XII.• Activated on surface of exposed
endothelium.• Complexes form on platelet
phospholipids.
Tissue factor (TF)
VII VIIa- TF
IX IXa
X Xa
XIa
VIIIa
Extrinsic PathwayExtrinsic Pathway: (PT)
• Factors VII, IX, X• Activated by Tissue phospholipids
(Tissue Factor or Tissue thromboplastin) released into blood as a result of tissue damage.
Anticoagulants – historical development
1916 1924 1936 1940 1950s 20061970s 1976 1980s 1990s 2001
Oral
Injection
Spoiled sweet clover
Dicoumaroldiscovered
Warfarinclinical use
Warfarin / Vitamin Kmechanism
High / low doseWarfarin / INR
Warfarinclinical trials
Heparindiscovered
Heparinclinical use
Continous heparininfusion/
aPTT
LMWHdiscovered
LMWHclinical trials
Pentasaccharideclinical trials
Ximelagatranclinical trials
DabigatranRivaroxabanApixaban AZD0837
Features of an ideal anticoagulant
High efficacy to safety index
Predictable dose response
Administration by parenteral and oral routes
Rapid onset of action
Availability of a safe antidote
Freedom from side effects
Minimal interactions
Heparin
• Parenteral Anticoagulant• A sulfated polysaccharide• Most commercial heparin is derived
from porcine intestinal mucosa • Polymer of alternating d-glucuronic
acid and N-acetyl-d-glucosamine residues
Mechanism of Action
• Activates antithrombin and accelerates the rate at which it inhibits clotting enzymes, particularly thrombin and factor Xa
• Heparin binds to the serpin via a unique pentasaccharide sequence found on one third of the chains of commercial heparin
Mechanism of action of heparin, LMWH, and fondaparinux
Side effects of heparin
• Bleeding - the most common side effect• Thrombocytopenia• Osteoporosis• Elevated levels of transaminases.
Pharmacokinetic and Biophysical Limitations of Heparin
LIMITATION MECHANISM
Poor bioavailability Limited absorption of long heparin chains
Dose-dependent clearance Binds to endothelial cells
Variable anticoagulant responseBinds to plasma proteins; levels vary from
patient to patient
Reduced activity in the vicinity of platelet-rich thrombi
Neutralized by platelet factor 4 released from activated platelets
Limited activity against factor Xa incorporated into the prothrombinase complex and thrombin bound to fibrin
Reduced capacity of heparin-antithrombin complex to inhibit factor Xa bound to
activated platelets and thrombin bound to fibrin
Low-Molecular-Weight Heparin
• Consists of smaller fragments of heparin
• LMWH is prepared from unfractionated heparin by controlled enzymatic or chemical depolymerization.
• The mean molecular weight of LMWH is about 5000, one third the mean molecular weight of unfractionated heparin
• Shorter heparin chains bind less avidly to endothelial cells, macrophages, and heparin-binding plasma proteins
• The clearance of LMWH is dose-independent and its plasma half-life is longer
• Situations that may require LMWH monitoring include renal insufficiency , pregnancy and obesity
Fondaparinux
• A synthetic analogue of the antithrombin-binding pentasaccharide sequence
• Fondaparinux catalyzes factor Xa inhibition by antithrombin and does not enhance the rate of thrombin inhibition
• Recombinant activated factor VII reverses the anticoagulant effects of fondaparinux
Comparison of the Features of Heparin, Low-Molecular-Weight Heparin, and
Fondaparinux
FEATURE HEPARIN LMWH FONDAPARINUX
Source Biologic Biologic Synthetic
Molecular weight 15,000 5000 1728
Target Xa and IIa Xa and IIa Xa
Bioavailability (%) 30 90 100
Half-life (hr) 1 4 17
Renal excretion No Yes Yes
Antidote Complete Partial No
HIT <5% <1% Never
Advantages of Low-Molecular-Weight Heparin and Fondaparinux over Heparin
ADVANTAGE CONSEQUENCE
Better bioavailability and longer half-life after
subcutaneous injection
Can be given subcutaneously once or twice daily for both prophylaxis and treatment
Dose-independent clearance Simplified dosing
Predictable anticoagulant response
Coagulation monitoring unnecessary for most patients
Lower risk of heparin-induced thrombocytopenia
Safer than heparin for short- or long-term administration
Lower risk of osteoporosisSafer than heparin for long-
term administration
Direct thrombin inhibitors
· Derived from leech (Hirudo medicinalis)
Hirudin Recombinant proteins
· Recombinant hirudin (MW 6979.5 Da)
· Bivalirudin (MW 2180 Da)
Synthetic molecules
· Argatroban (MW 527 Da)
· Melagatran
· Dabigatran
· AZD0837
· Polypeptide (65 amino acids)
· MW 7000 Da
• Do not require a plasma cofactor• Bind directly to thrombin and block its interaction with its substrates
Why thrombin is an excellent target?
• Forms & stabilizes the clot
• Furthers generation of thrombin
• Stimulates thrombus- activated fibrinolysis inhibitor (TAFI) resulting in inhibition of fibrinolysis
• Activates platelets
Direct thrombin inhibitors – mechanism of action
Active site
Thrombin
Exosite 1(fibrin bindingsite)Argatroban
ormelagatran
Direct thrombin inhibitors – mechanism of action
Active site
Thrombin
Exosite 1(fibrin bindingsite)
Hirudin and bivalirudin
Parenteral Direct Thrombin Inhibitors
PARAMETER HIRUDIN BIVALIRUDIN ARGATROBAN
Molecular mass 7000 1980 527
Site(s) of interaction with
thrombin
Active site and exosite 1
Active site and exosite 1
Active site
Renal clearance Yes No No
Hepatic metabolism
No No Yes
Plasma half-life (min)
60 25 45
• Lepirudin and argatroban are approved for the treatment of patients with HIT
• Bivalirudin is approved as an alternative to heparin in patients undergoing PCI, including those with HIT
Limitations of Existing Parenteral Anticoagulants
• The need for daily subcutaneous injection limits the long-term use of LMWH or fondaparinux.
• Potential for accumulation in patients with renal impairment
• The lack of an antidote• Risk of catheter thrombosis when these agents are
used as the sole anticoagulant in patients undergoing PCI
Oral Anticoagulants - Vitamin K antagonists
Warfarin SodiumDicoumarol Phenprocoumon
Acenocoumarol Anisindione
Mechanism of Action
• Some clotting factors need a carboxyl group added to their carboxyl-terminal glutamates after synthesis in the liver
• This γ-carboxylation reaction requires reduced Vitamin K• Vitamin K epoxide is then converted back to its reduced form
via the enzyme vitamin K epoxide reductase and NADH• The Vitamin K antagonists inhibit the action of the reductase
enzyme
Effect on Coagulation Vitamin K dependent clotting factors: Factors II, VII, IX, and X
XIIXIIa
XIa XI
IXa IX
VIIIa
VIIaTF
X XaVa
II (prothrombin) IIa (thrombin)
Fibrinogen Fibrin Stabilized Fibrin
XIII XIIIa
Extrinsic pathway
Intrinsic pathway
Common pathway
Warfarin• Bioavailabily nearly complete; absorption dampered by
food• Peak concentration 2 - 8 hr• Binds to albumin 99% of time• Can cross placental barrier• Racemic mixture: S form by CYP2C9; R by CYP1A2,
minor pathway CYP2C19, and minor pathway CYP3A4• half-life: 25 - 60 hr; Excreted in urine and stool
• Food-drug & drug-drug interactions: extensive!!• Toxicities: bleeding, fetal bone abnormalities, skin
necrosis
Problems with Warfarin• Food and drug interactions
• Genetic variation in metabolism
• narrow therapeutic window
• slow onset of actionoverlap with parenteral drugs
dosage adjustments & freq. monitor with INR
Comparison of Pharmacological Characteristics of AVE5026, Idrabiotaparinux, Otamixaban,
and RB006
AVE5026
• Ultralow-molecular-weight heparin with a mean molecular weight of 2400
• Primarily targets fXa • Given subcutaneously, the half-life is 16 to 20 hours, enabling
once-daily administration. • Excreted renally• Anticoagulant effects are not neutralized by protamine sulfate• Phase III program comparing AVE5026 with enoxaparin for
VTE prevention in 9000 patients undergoing hip, knee, or abdominal surgery and in 3200 cancer patients receiving chemotherapy is ongoing(SAVE-HIP2 , SAVE-ABDO, SAVE-KNEE , SAVE-HIP3 , SAVE-ONCO
Idrabiotaparinux
• Hypermethylated derivative of fondaparinux
• Binds antithrombin with high affinity
• Has a half-life of 130 hours; idrabiotaparinux is given subcutaneously on a once-weekly basis.
• Excreted unchanged by the kidneys.
• Differs from idraparinux in that it contains a biotin moiety that enables reversal with intravenous avidin
• The Van Gogh deep vein thrombosis (DVT) trial compared 3 to 6 months of idraparinux with conventional anticoagulant therapy in 2904 patients with acute DVT.
• At 3 months, the incidence of recurrent VTE (nonfatal or fatal) was similar in the 2 treatment groups
• Idraparinux was associated with significantly fewer major plus clinically relevant nonmajor bleeds than conventional therapy
• The AMADEUS trial compared idraparinux with a VKA for prevention of thromboembolism in patients with AF.
• The trial was stopped early because of an excess of clinically relevant bleeds with idraparinux compared with a VKA
• EQUINOX bioequivalence study suggested that idrabiotaparinux and idraparinux are similarly effective for DVT treatment
• CASSIOPEA trial is comparing 3 to 6 months of idrabiotaparinux with conventional anticoagulation therapy for prevention of recurrent VTE
Otamixaban• A parenteral direct fXa inhibitor• Has a rapid onset of action• produces a predictable anticoagulant effect• Has a short half-life• 25% of the drug is cleared by the kidneys.• These features render otamixaban an attractive candidate to
replace heparin in patients with ACS• SEPIA-ACS 1(TIMI) 42, a phase II dose-finding study that
compared 5 different doses of otamixaban with the combination of heparin plus eptifibatide in 3241 patients with non–ST-segment elevation ACS
RB006• An RNA aptamer that targets factor IXa with high affinity and specificity, • When given intravenously, produces a rapid and dose-proportional
anticoagulant effect • Immediately reversed by intravenous administration of RB007, the
complementary oligonucleotide antidote.• RB006 is not cleared renally• does not appear to be immunogenic• has the potential to inhibit the activation of coagulation induced by
exposure of blood to artificial surfaces, such as stents or cardiac bypass circuits
• potential to replace heparin and protamine sulfate in patients undergoing cardiopulmonary bypass surgery.
• May also be useful for patients at high risk of bleeding and for those with renal impairment
• Phase II REVERSAL-PCI study, the efficacy and safety of RB006/RB007 are being compared with those of heparin in 26 patients undergoing elective PCI
ORAL THROMBIN INHIBITORS
Dabigatran Etexilate• a prodrug of dabigatran, which reversibly inhibits the
active site of thrombin• has an oral bioavailability of 6%• Plasma levels of dabigatran peak 2 hours after drug
administration. • Dabigatran has a half-life of 14 to 17 hours, which
permits once- or twice-daily administration• 80% of the drug is excreted unchanged by the
kidneys• Coadministration of dabigatran etexilate and
amiodarone, a weak P-gp inhibitor, increases dabigatran levels by 50% without significantly affecting those of amiodarone
Dabigatran etexilate in VTE
• Dabigatran etexilate is approved for VTE prevention after elective hip or knee arthroplasty.
• 220-mg dose of dabigatran etexilate is recommended for the majority of patients
• 150-mg dose is reserved for patients also taking amiodarone and for those at higher risk for bleeding
• RECOVER-1 in acute VTE– dabigatran etexilate or warfarin
for 6 months after initial treatment with a parenteral anticoagulant.
– recurrent symptomatic VTE and VTE-related death, were 2.4% and 2.1% in dabigatran and warfarin groups, respectively
– Rates of major bleeding were 1.6% and 1.9% in the dabigatran and warfarin groups, respectively
Dabigatran etexilate in AF
• The RE-LY trial randomized 18 113 patients with AF and at least 1 additional risk factor for stroke to receive dabigatran etexilate (at doses of 110 or 150 mg twice daily) or warfarin
• Dabigatran110 mg b.i.d. was non-inferior to VKA for the prevention of stroke and systemic embolism with lower rates of major bleeding
• Dabigatran 150 mg b.i.d. was associated with lower rates of stroke and systemic embolism with similar rates of major haemorrhage, compared with VKA.
Dabigatran etexilate in ACS
• Dabigatran etexilate has also been evaluated in the phase II RE-DEEM study in ACS to determine whether it reduces the risk of recurrent ischemia when given in conjunction with antiplatelet drugs
Oral fXa Inhibitors: Rivaroxaban, apixaban and edoxaban
Rivaroxaban
• An active compound with an oral bioavailability of 80%
• Has a rapid onset of action and a half-life of 7 to11 hours.
• Has a dual mode of elimination• concomitant administration of potent inhibitors or both
P-gp and CYP3A4 is contraindicated• On the basis of the results of RECORD trials,
rivaroxaban is approved for the prevention of VTE in patients undergoing elective hip or knee arthroplasty
Primary Efficacy OutcomeStroke and non-CNS Embolism
Event Rates are per 100 patient-yearsBased on Protocol Compliant on Treatment Population
No. at risk:Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655
Warfarin
HR (95% CI): 0.79 (0.66, 0.96)
P-value Non-Inferiority: <0.001
Days from Randomization
Cum
ulat
ive
even
t ra
te (
%)
Rivaroxaban
Rivaroxaban Warfarin
Event Rate 1.71 2.16
ROCKET AF
Summary ROCKET AF
• Efficacy:
– Rivaroxaban was non-inferior to warfarin for prevention of stroke and non-CNS embolism.
– Rivaroxaban was superior to warfarin while patients were taking study drug.
– By intention-to-treat, rivaroxaban was non-inferior to warfarin but did not achieve superiority.
• Safety:
– Similar rates of bleeding and adverse events.– Less ICH and fatal bleeding with rivaroxaban.
• Conclusion:
– Rivaroxaban is a proven alternative to warfarin for moderate or high risk patients with AF.
Rivaroxaban in ACS
• phase-3 ATLAS-ACS 2 TIMI 51 clinical trial of rivaroxaban ACS patients has met its primary efficacy end point
• statistically significant reduction in the primary composite end point of cardiovascular death, MI, and stroke vs placebo.
• significant increase in the primary safety end point: major bleeding events not associated with coronary artery bypass surgery
• The ATLAS-ACS 2 TIMI 51 results will be presented as a late-breaking clinical trial at the American Heart Association 2011 Scientific Sessions in Orlando
Apixaban
• An active drug• absorbed rapidly• Maximal plasma concentrations are achieved 3 hours after oral
administration.• half-life of 8 to14 hours. • eliminated via multiple pathways• Concomitant treatment with potent inhibitors of CYP3A4 is
contraindicated
• Pooled data from the ADVANCE clinical-trial program showed that apixaban is more effective than enoxaparin for the prevention of major VTE in patients undergoing hip- or knee-replacement surgery
AVERROES
ARISTOTLE study
ARISTOTLE study
APPRAISE-2 ACS trial
• the phase 3 APPRAISE-2 trial of apixaban in high-risk patients with recent acute coronary syndrome discontinued after it became clear that the increase in bleeding risk in patients randomized to apixaban would not be offset by reductions in ischemic events
Edoxaban
• active drug • rapidly absorbed• half-life of 9 to 11 hours • dual mechanism of elimination• ENGAGE-AF-TIMI 48 trial is comparing
2 doses of edoxaban (30 or 60 mg once daily) with warfarin in 16 500 patients with AF
Other oral fXa inhibitors under development include
• betrixaban (15-hour half-life and extrarenal clearance)
• YM150
• TAK442
Conclusions and Future Directions
• the unmet needs for parenteral anticoagulants have diminished with LMWH and fondaparinux,
• some problems persist. – severe renal impairment– The lack of an antidote
• New synthetic parenteral anticoagulants that are – eliminated extrarenally – can be reversed readily and – do not cause thrombocytopenia
may be advantageous• Anticoagulant aptamer/antidote pairs, such as
RB007/RB008, possess all of these desirable features
Conclusions and Future Directions
• The favorable results of the RE-LY trial are likely to revolutionize our approach to long-term anticoagulant therapy
• The availability of simple, fixed-dose, unmonitored therapy should increase the use of anticoagulant therapy in patients with AF at risk for stroke
• Streamlining oral therapy will increase the uptake of anticoagulant prophylaxis in patients with AF, thereby decreasing death and disability from stroke.
• The search for replacements for VKAs appears to be nearing completion
Prothrombin Time: PT• PT reagent contains Calcium ions and
Thromboplastin from brain tissue (Rabbit).• Thromboplastin (Tissue Factor) protein-lipid
complex found in tissues outside blood vessels.
• Measures the function of the Extrinsic Pathway.
• Sensitive to Factors IV, V, VII, X.• Provided as a lyophilized reagent.• Used to monitor oral anticoagulant therapy
(Warfarin / Coumadin).
PT Reagent Calibration• Reagents are calibrated against standard PT reagent
established by the WHO.• ISI = International Sensitivity Index.• ISI is assigned by the manufacturer for each lot of
reagent using reference material traceable to WHO.• The lower the ISI the more sensitive the Reagent
– ISI of 1.8 to 2.4 = Low sensitivity (North American Standard PT)
– ISI of 1.4 to 1.8 = Average sensitivity – ISI 1.0 to 1.4 = High Sensitivity
PT: INR Values
• INR = International Normalised Ratio.• MNP = Mean Normal Plasma.• INR = (PT / MNP)ISI
• An INR of 1.0 means that the patient PT is normal.
• An INR greater then 1.0 means the clotting time is elevated.
Performing a PT test
• Pre-warm PT reagent and sample to 37 oC
• Add 100 L sample to cuvette• Add 200 L of PT reagent to cuvette• Start timer• Record time to clot in seconds• Calculate INR• see product insert for PT
Activated Partial Thromboplastin Time
• APTT or PTT• Reagent contains phospholipids and a ‘surface
activator’; (Ellagic Acid, Micronized Silica)• Calcium Chloride reagent added to start the
reaction.• APTT reagent mimics the surface of a platelet.• Measures activity of clotting factors in the
Intrinsic Pathway, factors VIII, IX, XI and XII• No WHO calibration standard
Performing an APTT Test
• Pre-warm Calcium Chloride reagent to 37 oC.• Add 100 L of sample to cuvette.• Add 100 L of APTT to cuvette and incubate
for 3 minutes.• Add 100 L of Calcium Chloride reagent and
start timer.• Record the time to clot in seconds.• See APTT product Insert
Activated Clotting Time (ACT)
• Clotting time of whole blood in the presence of silica based activator.
• Normal clotting times = 90 to 170 sec.• Used to monitor heparin doses from 1 to 10 U/mL
(APTT is sensitive to heparin at 0.2 to 1 U/mL).• Used with invasive procedures that require on-
site adjustment of heparin and protamine dosage. (ex. Cardiopulmonary bypass surgery).
• Not amenable for use with an optical instrument, too cloudy.
• Also called HMT, Heparin Management Test
Heparin monitoring
• Variable anticoagulant response• Binds to plasma proteins; levels vary
from patient to patient• Coagulation monitoring is essential to
ensure the response is therapeutic• The aPTT, ACT or anti–factor Xa level is
used to monitor heparin
HIT
• Heparin-induced thrombocytopenia (HIT) is an antibody-mediated process triggered by antibodies against neoantigens on PF4 that are exposed when heparin binds to this protein
Features of Heparin-Induced Thrombocytopenia
FEATURE DETAILS
ThrombocytopeniaPlatelet count of 100,000/µL or less or decrease in platelet count of
50% or more from baseline
Timing Platelet count falls 5-10 days after starting heparin
Type of heparin More common with unfractionated heparin than with LMWH
Type of patientMore common in surgical patients than medical patients; more
common in women than in men
Thrombosis Venous thrombosis more common than arterial thrombosis