10/21/14 1 Coagulation and New Anticoagulants Maureen E. Mays, MD, MS, FACC Director ~ Portland Preventive Cardiology Diplomate, American Board of Clinical Lipidology www.portlandpreventivecardiology.com October 2014 Overview • Blood and blood clotting • Anti-platelet medications • Anticoagulants – Heparins – Warfarin – New Drugs • direct thrombin inhibitor(s) • Factor Xa inhibitors Blood Composition connective tissue with cells suspended in plasma Plasma (55%) Cellular Elements (45%) water Ions /electrolytes (K + Cl- Ca ++ ) plasma proteins (Fibrinogen) transported substances erythrocytes (red blood cells) leukocytes (white blood cells) platelets
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Coagulation 2014 PA State Lecture Presentations/… · Aspirin Pharmacology! ... Parenteral Anticoagulants! Basics of Heparin! • Derived from mucosal tissues of slaughtered meat
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10/21/14
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Coagulation and New Anticoagulants
Maureen E. Mays, MD, MS, FACC Director ~ Portland Preventive Cardiology
Diplomate, American Board of Clinical Lipidology
www.portlandpreventivecardiology.com
October 2014
Overview
• Blood and blood clotting • Anti-platelet medications • Anticoagulants
– Heparins – Warfarin – New Drugs
• direct thrombin inhibitor(s) • Factor Xa inhibitors
Blood Composition connective tissue with cells suspended in plasma
Plasma (55%) Cellular Elements (45%)
water
Ions /electrolytes (K+ Cl- Ca++)
plasma proteins (Fibrinogen)
transported substances
erythrocytes (red blood cells)
leukocytes (white blood cells)
platelets
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How blood clots
• Damage to endothelium • Platelet plug • Coagulation Factors from plasma, platelets & damaged cells Leading to: • Activated Fibrin
– fibers woven into a patch
The Coagulation Cascade
Fibrin Clot
XII
VII VIII
IX
XI
Fibrinogen
II
V
X
TF
Intrinsic Extrinsic
The Balance
Bleeding Clotting
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Anti-Platelet Therapy
• Prodrug: metabolized to salicylate • Absorption: affected by food, antacid
buffer, enteric coating, chewing • Irreversible COX-1, COX-2 inhibition • Effect within minutes, peak in 1-2 hours
Aspirin Pharmacology
• Beneficial in PTCA (cath) • 77% reduction in ischemic complications • Maintenance dose 81-162 mg • Low dose has similar efficacy but decreased
bleeding than with higher doses
Aspirin
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Aspirin blunts but does not eliminate circadian variation of AMI
Ridker PM et al. Circulation. 1990;82:897-902.
Physicians’ Health Study; N = 22,071 men
30
20
10
00 12 24 0 12 24
30
20
10
0
Placebo Aspirin
Hour of day Hour of day
• Absorption: Not affected by food or antacids, however,
inactivated by some PPI’s • Prodrug – converted by liver to active metabolites • Elimination half life = 8 hours • Irreversible binding: biologic effects = platelet life
Clopidogrel:
CURE: Patients continue to have recurrent CV events despite dual antiplatelet therapyN = 12,562 with NSTE-ACS; all patients received ASA; Primary outcome = CV death, MI, stroke
CURE Trial Investigators. N Engl J Med.2001;345:494-502.
CURE = Clopidogrel in Unstable Angina to Prevent Recurrent Events
Cumulative hazard rate for primary
outcome
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.000 3 6 9 12
P < 0.001
Clopidogrel
Placebo
Follow-up (months)
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• Absorption: may be taken with food/antacids, although absorption decreased after fatty meal
• Prodrug: intestinal/liver conversion to active • Elimination half-life = 7hours • Irreversible binding to P2Y12 receptor: biologic
effects = platelet life (5-10days)
Prasugrel
• Absorption: not affected by food or antacids • Non-Prodrug: Onset of action within 1-2 hours • Elimination half-life = 8 hours • Reversible binding: biologic t1/2 = 6 hours
• NEW/ in DEVELOPMENT DRUGS – Fondaparinux_____________________ – Idraparinux_______________________ – SSR 126517______________________ – Rivaroxaban______________________ – Apixaban_________________________ – LY517717________________________ – YM150__________________________ – DU-176b_________________________ – Betrixaban________________________ – Ximelagatran*_____________________ – Dabigatran etexilate________________
*taken off the market Italics are Oral Drugs
TARGETED FACTOR Antithrombin (indirectly Xa and IIa) Antithrombin (indirectly Xa and IIa) Thrombin (IIa) Thrombin (IIa) Thrombin (IIa) Antithrombin Va, VIIIa Prothrombin (II), VII, IX, X Xa Xa Xa Xa Xa Xa Xa Xa Xa Thrombin (IIa) Thrombin (IIa)
Heparin
and other current Parenteral Anticoagulants
Basics of Heparin
• Derived from mucosal tissues of slaughtered meat animals. • Increases Antithrombin activity. (Indirect inhibition of IIa
& Xa) • Usually intravenous adminstration • Low molecular weight heparin: different composition; more
predictable; subcutaneous injection twice daily; use preferred over unfractionated heparin
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More about Heparin
• Fast action intravenously or sub-Q • peak after injection 2 - 4 hr • half life 1 - 5 hr • Few drug-drug interactions • Toxicities: Bleeding & Heparin-Induced Thrombocytopenia
Other Parenteral Anticoagulants
• Lepirudin (DTI) derived from hirudin from leech salivary glands
• Bivalirudin (DTI) approved for use during heparin-induced thrombocytopenia (HIT) & percutaneous coronary interventions
• Argatroban (DTI) can be used in patients with risk of (HIT) • Danaparoid no longer available in the U.S. • Drotrecogin Alfa used in patients with sepsis; recombinant
form of activated protein C that inhibits f Va and f VIIIa
DTI = direct thrombin inhibitor; HIT = heparin induced thrombocytopenia
Oral Anticoagulants
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Site of Action for Oral ���Anticoagulants
Fibrin Clot
Intrinsic Extrinsic XII
VII VIII
IX XI
Fibrinogen
II
V
Tissue Factor
X Direct Xa Inhibitors
“-xaban” AT
Direct Thrombin Inhibitors
“-gatran”
warfarin
Vitamin K antagonists: ���
Warfarin Sodium
Dicoumarol Phenprocoumon
Acenocoumarol Anisindione
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History of Warfarin
• 1930s: cows hemorrhage after eating spoiled sweet clover silage
• 1939: bishydroxycoumarin (dicoumarol) identified • 1948: potent form as rodenticide
– Called Warfarin (Wisconsin Alumni Research Foundation)
Anticoagulant in humans? No, too toxic!? • 1951: Army inductee’s failed attempt at suicide
with high dose of warfarin rodenticide • Clinical use for over 60 years
Vitamin K antagonists
Warfarin
• Adminstered orally, intravenously, or rectally • Absorption dampered by food • Binds to albumin 99% of time • Can cross placental barrier • Half-life: 25 - 60 hours; Excreted in urine and stool • Food-drug & drug-drug interactions: extensive!! • Toxicities: bleeding, fetal bone abnormalities
Vitamin K antagonists
Anticoagulation for nonvalvular AF
*Compared with control 35 more minor bleeds occurred with warfarin Intention-to-treat analysis
Pooled data from AFASAK, SPAF, and BAATAF
Benefit Risk31 fewer thromboembolic events* 1 more intracranial or major bleed*
Adapted from Albers GW et al. Ann Neurol. 1991;30:511-8.
For every 1000 patients with nonvalvular AF in clinical trials treated with warfarin for 1 year:
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Warfarin risk/benefit balance
Odds ratio
20
15
10
5
1
1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0
International normalized ratio
Ischemic stroke Intracranial bleeding
Fuster V et al. Circulation. 2006;114:e257-e354.
Problems with Warfarin • Food and drug interactions
• Genetic variation in metabolism
• narrow therapeutic window
• slow onset of action
overlap with parenteral drugs
dosage adjustments & freq. monitor with INR
Vitamin K antagonists
Newer Anticoagulants
Targeting specific factors
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Background
• Until recently, vitamin K antagonists (VKAs) were the only available orally active anticoagulants.
• VKAs have numerous limitations, which complicate their use.
• These limitations have prompted the introduction of new oral anticoagulants that target thrombin and factor (F) Xa, key enzymes in the coagulation pathway.
Advancement
• The new oral anticoagulants, which can be given in fixed doses without routine coagulation monitoring, overcome many of the problems associated with VKAs.
• More effective and safer when compared to warfarin.
• No monitoring, no food interactions, more predictable.
Mechanism
These agents inhibit a single step in coagulation, at major variance from VKAs,
which block multiple steps because they reduce the synthesis of the vitamin K–
dependent coagulation factors.
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Current “Novel Anticoagulants”
• Direct Thrombin Inhibitor – dabigatran (Pradaxa)
• The direct thrombin inhibitors (DTI) (gatrans) bind to thrombin and block its capacity to convert fibrinogen to fibrin.
• In contrast to indirect thrombin inhibitors, such as heparin, DTIs not only inhibit free thrombin, but also inhibit thrombin bound to fibrin.
Ximelagatran
• First target-specific oral anticoagulant in trials • Hepatatoxicity
– Did not receive FDA approval in 2004 – On the market in Europe but pulled in 2006
• ‘proof of principle’ – as “efficacious” as warfarin – Wider therapeutic index – Little dosage adjustment/ no monitoring
Direct Thrombin Inhibitors
Dabigatran
Currently, Pradaxa is the only direct thrombin inhibitor (DTI) that is approved for stroke prevention in atrial fibrillation.
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Dabigatran
• No dietary/food interactions
• Brand name Pradaxa® • Boehringer-Ingelheim
• Oral capsule • Rapid onset of action • Half-life 12-17 hours • Renal elimination • No routine monitoring
required
Dabigatran etexilate.
� Synthetic low molecular weight peptidomimetic that binds directly and reversibly to the catalytic site of thrombin.
� Has 6% bioavailability after oral administration.
� Pharmacokinetic data in healthy volunteers show peak plasma levels 2-3 h after oral administration.
Dabigatran in total knee replacement:���RE-MODEL (Phase II)
34
35
36
37
38
39
40
41
150 mg
Qday
220 mg
Qday
Enox 40
Qday
0
2
4
6
8
10
12
150 mg
Qday
220 mg
Qday
Enox 40
Qday
Major Bleeding Minor Bleeding
LFT > 3xULN
% Total VTE & Death
n=1541 patients treated 6-10 days,
followed for 3 months post-
surgery
% Adverse Events
Dabigatran
Dabigatran
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Dabigatran etexilate.
• Eliminated unchanged primarily by the kidneys.
• Plasma concentrations are increased in patients with moderately impaired renal function (creatinine clearance [CrCl]< 50 ml/min).
• No dose adjustment is necessary for patients with mild renal impairment (CrCl of 50 to 80 ml/min).
Dabigatran etexilate.
• 150mg BID for patients with CrCl>50ml/min.
• For patients with a high risk of bleeding, including patients 75 to 80 years of age, a dose reduction to 220 mg taken as one 110-mg capsule twice daily should be considered.
• The lower dose is mandatory for patients older than 80 years of age.
Dabigatran etexilate.
� There is currently no specific reversal agent or antidote for dabigatran.
• The largest family of new anticoagulants for long-term use is the Factor Xa inhibitors.
• Parenteral synthetic pentasaccharides mediate
indirect, antithrombin-dependent inhibition of Factor Xa. The prototype of such drugs, fondaparinux, has been in clinical use for the treatment of acute coronary syndromes.
Rivaroxaban
• Brand name Xarelto®, Bayer
• Oral tablet • High oral bioavailability
(>80%) • Onset of action 2-4 hours • Half-life 9-12 hours • No observed effects on
agonist-induced platelet aggregation
§ Primarily renal elimination
§ No laboratory monitoring required
§ No dosage adjustment for gender, age, extreme body weight
§ Approved by Europe and Canadian agencies, and under FDA review currently
Rivaroxaban in VTE Prevention:���RECORD 3 - TKA
0
2
4
6
8
10
12
14
16
18
20
Rivarox 10
Qday x 14 d
Enox 40 Qday
x 14 days
Composite Major VTE
0
1
2
3
4
5
6
Rivarox 10
Qday
Enox 40 Qday
Major Bleed Any Bleed
%
RRR 49%
RRR 62%
% No Difference
2531 patients
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Rivaroxaban
• Rivaroxaban is a highly selective, reversible direct oral FXa inhibitor.
• Rapidly absorbed after oral administration with a maximum concentration after 2 to 4 h.
• Bioavailability of rivaroxaban at a dose of 20 mg in the fasting state is approximately 66% (Increases with food).
Rivaroxaban
� About one-third of the drug is excreted renally
� CrCl of 15 to 29 ml/min, exposure is 1.5-fold higher than that with values >80 ml/min.
� The half-life of the drug is 5 to 13 h. � Has been administered once daily (20mg)
for atrial fibrillation and twice daily in the setting of acute coronary syndromes, mostly in combination with antiplatelet drugs.
Rivaroxaban
• There is currently no specific reversal agent or antidote for rivaroxaban.
• Charcoal. • Hemodialysis is unlikely to be helpful because
rivaroxaban is highly protein bound. • Fresh frozen plasma, prothrombin complex
concentrates, or activated Factor VII may reverse its effects.
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Rivaroxaban. The ROCKET-AF (Rivaroxaban Once���Daily Oral Direct Factor Xa Inhibition Compared With ���
Vitamin K Antagonism for Prevention of Stroke and ���Embolism Trial in Atrial Fibrillation)
• Included patients with nonvalvular atrial fibrillation at high risk of stroke, as evidenced by a CHADS2 score of >2.
• Randomized 14,264 patients to double-blind treatment with rivaroxaban 20 mg Q.D. (15 mg daily for CrCl of 30 to 49 ml/min) or warfarin.
• mean CHADS2 score of 3.5.
ROCKET-AF
� 55% had a history of stroke, transient ischemic attack, or systemic embolism.
� The warfarin treatment aimed at an INR level between 2.0 and 3.0. However, the mean TTR was 55% (median 58%), which is lower than in other randomized trials.
� Primary objective was to demonstrate noninferiority of rivaroxaban versus warfarin for the occurrence of stroke or systemic embolism.