newer anticoagulants

73
Newer anti- coagulants 13.10.11

Upload: aravazhi

Post on 07-May-2015

4.111 views

Category:

Health & Medicine


0 download

TRANSCRIPT

Page 1: Newer anticoagulants

Newer anti-coagulants

13.10.11

Page 2: Newer anticoagulants

• 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

Page 3: Newer anticoagulants

Hemostatic system

The major components of the hemostatic system are:– Vascular endothelium– Platelets– Coagulation system – Fibrinolytic system.

Page 4: Newer anticoagulants

Coagulation occurs through the action of discrete enzyme complexes, which are composed of a vitamin K–dependent enzyme and a nonenzyme cofactor.

Page 5: Newer anticoagulants

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.

Page 6: Newer anticoagulants

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.

Page 7: Newer anticoagulants
Page 8: Newer anticoagulants

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

Page 9: Newer anticoagulants
Page 10: Newer anticoagulants
Page 11: Newer anticoagulants

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

Page 12: Newer anticoagulants

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

Page 13: Newer anticoagulants

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

Page 14: Newer anticoagulants

Mechanism of action of heparin, LMWH, and fondaparinux

Page 15: Newer anticoagulants

Side effects of heparin

• Bleeding - the most common side effect• Thrombocytopenia• Osteoporosis• Elevated levels of transaminases.

Page 16: Newer anticoagulants

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

Page 17: Newer anticoagulants

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

Page 18: Newer anticoagulants

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

Page 19: Newer anticoagulants

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

Page 20: Newer anticoagulants

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

Page 21: Newer anticoagulants

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

Page 22: Newer anticoagulants

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

Page 23: Newer anticoagulants

Direct thrombin inhibitors – mechanism of action

Active site

Thrombin

Exosite 1(fibrin bindingsite)Argatroban

ormelagatran

Page 24: Newer anticoagulants

Direct thrombin inhibitors – mechanism of action

Active site

Thrombin

Exosite 1(fibrin bindingsite)

Hirudin and bivalirudin

Page 25: Newer anticoagulants

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

Page 26: Newer anticoagulants

• 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

Page 27: Newer anticoagulants

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

Page 28: Newer anticoagulants

Oral Anticoagulants - Vitamin K antagonists

Warfarin SodiumDicoumarol Phenprocoumon

Acenocoumarol Anisindione

Page 29: Newer anticoagulants

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

Page 30: Newer anticoagulants

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

Page 31: Newer anticoagulants

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

Page 32: Newer anticoagulants

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

Page 33: Newer anticoagulants
Page 34: Newer anticoagulants

Comparison of Pharmacological Characteristics of AVE5026, Idrabiotaparinux, Otamixaban,

and RB006

Page 35: Newer anticoagulants

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

Page 36: Newer anticoagulants

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

Page 37: Newer anticoagulants

• 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

Page 38: Newer anticoagulants

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

Page 39: Newer anticoagulants

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

Page 40: Newer anticoagulants
Page 41: Newer anticoagulants

ORAL THROMBIN INHIBITORS

Page 42: Newer anticoagulants

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

Page 43: Newer anticoagulants

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

Page 44: Newer anticoagulants

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.

Page 45: Newer anticoagulants

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

Page 46: Newer anticoagulants

Oral fXa Inhibitors: Rivaroxaban, apixaban and edoxaban

Page 47: Newer anticoagulants

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

Page 48: Newer anticoagulants

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

Page 49: Newer anticoagulants

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.

Page 50: Newer anticoagulants

 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

Page 51: Newer anticoagulants

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

Page 52: Newer anticoagulants

•  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

Page 53: Newer anticoagulants

AVERROES

Page 54: Newer anticoagulants
Page 55: Newer anticoagulants

ARISTOTLE study

Page 56: Newer anticoagulants

ARISTOTLE study

Page 57: Newer anticoagulants

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

Page 58: Newer anticoagulants

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

Page 59: Newer anticoagulants

Other oral fXa inhibitors under development include

• betrixaban (15-hour half-life and extrarenal clearance)

• YM150

• TAK442

Page 60: Newer anticoagulants

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

Page 61: Newer anticoagulants

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

Page 62: Newer anticoagulants
Page 63: Newer anticoagulants
Page 64: Newer anticoagulants

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).

Page 65: Newer anticoagulants

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

Page 66: Newer anticoagulants

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.

Page 67: Newer anticoagulants

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

Page 68: Newer anticoagulants

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

Page 69: Newer anticoagulants

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

Page 70: Newer anticoagulants

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

Page 71: Newer anticoagulants

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

Page 72: Newer anticoagulants

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

Page 73: Newer anticoagulants

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