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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
clinical effect 3-5 days
Ticagrelor
Therapy in ACS is Complex
• Anticoagulants: UFH LMWH
• Antiplatelets: ASA Clopidogrel Prasugrel Ticagrelor
• IV anitplatelets: None Abciximab Eptifibatide/Tirofiban
• Cath strategy: Early Delayed Never
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Long Term Antiplatelet Rx.���Acute & Stable Coronary
Syndrome Medical
Theraphy Without stent or
PTCA alone
Drug-eluting Stent group
Bare-metal Stent group
ASA 162-325 mg/d indefinitely
+ Clodpidogrel 75mg/d
or ? Prasugrel or ?Ticagrelor
for at least 1 mo (class 1A) & up to 12 months
ASA 162-325mg/d for at least 3 mo for SES,
6mo for PES, then 75-100mg/d indefinitely
+ Clodpidogrel 75mg/d or
Prasugrel 10mg/d or Ticagrelor 90mg BID for at 6-12 months
Shorter duration if bleeding risk >benefit
ASA 162-325 mg/d for ≥1mo then
75-100mg/d indefinitely +
Clodpidogrel 75mg/d or Prasugrel 10mg/d or Ticagrelor 90mg BID
for at 6-12 months
Shorter duration if bleeding risk >benefit
Anticoagulation
Thromboembolism in the U.S.
Annually, more individuals may die from DVT complications than from the combination of AIDS, breast cancer, and motor vehicle accidents combined
– 900,000 to 2,000,000 VTE cases per year in U.S. – Estimates of death rates per year vary from 50,000 to
300,000 – 700,000 Strokes per year
• 15% of strokes are in people with Atrial Fibrillation
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New Data on Prevention of Stroke ���in Nonvalvular AF
A-Fib in the USA Approx 5 million people Increase with age Increasing incidence & prevalence in the US
Life time Risk: ∼25% Independent predictor of mortality
Risk of stroke 3-7%/year Increase with age Almost half of all embolic strokes About 100,000 strokes/year
A growing Epidemic Approx 15M by 2050
Stroke Risk Stratification
CHADS2 Risk Score
CHF 1
Hypertension 1
Age >75 1
DM 1
CVA or TIA 2
Total 6
CHADS2-VASc Score
CHF 1
Hypertension 1
Age>75 2
DM 1
CVA/TIA 2
Vascular Ds 1 (MI, PAD) Aged 65-74 1
Female 1
Total 9
Score CVA (%/Yr)
0 1.9%
1 2.8 %
2 4.0%
3 5.9%
4 8.5%
5 12.5%
6 18.2%
Score CVA (%/Yr)
0 0%
1 1.3%
2 2.2%
3 3.2%
4 4.0%
5 6.7%
6 9.8%
7 9.6%
8 6.7%
9 15.2%
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Anticoagulants • CURRENT DRUGS
– Unfractionated Heparin______________ – Low Molecular Weight Heparin________ – Lepirudin (DTI)____________________ – Bivalirudin (DTI) ___________________ – Argatroban(DTI)____________________ – Danaparoid_______________________ – Drotrecogin Alfa____________________ – Vitamin K antagonists (Warfarin)_______
• 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)
• Factor Xa Inhibitors – apixaban (Eliquis) – rivaroxaban (Xarelto) – edoxaban – betrixaban – TAK-442 – darexaban
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
Direct Thrombin Inhibitors
Fibrin Clot
XII
VII VIII IX
XI
Fibrinogen
II V
X
TF
Intrinsic Extrinsic
Direct Thrombin Inhibitors
“-gatran”
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Mechanism of DTI’s
• 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.
� Charcoal � Fresh frozen plasma, prothrombin complex
concentrates may not be wholly effective in reversing its effects.
� In cases of uncontrolled bleeding, unactivated or activated prothrombin complex concentrates or recombinant activated FVII may be helpful.
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RE-LY: Stroke or systemic embolism
Connolly SJ et al. N Engl J Med. 2009;361:1139-51.
↓34% P < 0.001
Dabigatran 150Dabigatran 110Warfarin
Months18 24 301260
0.0
0.2
0.4
0.6
0.8
1.0 0.05
0.04
0.03
0.02
0.01
0.000 6 12 18 24 30
Cumulative hazard rate
Dabigatran (Pradaxa)���Advantages & Disadvantages
• ⇓ Stroke vs warfarin • ⇓ ICH vs warfarin • No INR monitoring
Convenient Inability to assess efficacy
• Rapid onset of effect
Ø Twice-daily dosing – Effect on compliance?
Ø Irreversibility Ø Renal dosing Ø Dyspepsia (11-12%)
Advantage Disadvantage
Direct Factor Xa Inhibitors
Fibrin Clot
XII
VII VIII IX
XI
Fibrinogen
II V
X
TF
Intrinsic Extrinsic
Direct Xa Inhibitors
“-xaban”
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Factor Xa Inhibitors.
• 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.
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Apixaban § Oral tablet § Bioavailability: 50% § Peak Plasma Levels =
3 hrs § Half-life ~ 12 hours § Metabolized in liver
via CYP3A4 and CYP independent mechanisms
§ Eliminated via multiple pathways
§ No laboratory monitoring required
§ Manufactured by Bristol-Myers Squibb/Pfizer
Apixaban Efficacy ���Outcomes in TKR (Phase II)
5 QDay
10 QDay
20 QDay
Enox 30mg BID
(n=152)
Warf���
(n=153)
2.5 BID
5 BID
10 BID
Apixaban (mg) (n = 933)
Incidence of VTE and all-cause death (%)
Duration = ���10 -14 days
Lassen MR, et al. J Thromb Haemost. 2007;5:2368 – 2375.
Apixaban Safety Outcomes in TKR (Phase II)
5 QDa
y
10 QDa
y
20 QDa
y
Enox 30mg BID
(n=152)
2.5 BID
5 BID
10 BID
Apixaban (mg) (n = 933)
Warf
(n=153)
Incidence of bleeding events (%)
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Summary of ADVANCE – 2 Study
§ 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
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Primary Efficacy Endpoints of Stroke ���or Systemic Embolism
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Comparable Primary Safety���Endpoints of Major Bleeding
Stroke risk Reductions ���for current oral anticoagulants
Withholding Factor Xa Inhibitors Before Procedures
Hold med for 24 hours prior to planned minor procedure (no bridge needed)
Hold med for 48 hours prior to planned major* procedure (no bridge needed)
Restart as you would other anticoagulants
or antiplatelet meds * high risk of bleeding or bleeding in an unacceptable area
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Potential Limitations of New Anticoagulants
• 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 yet studied (i.e.
oncology patients)
Future of Anticoagulants
• Clinical trials of novel anticoagulants will continue
• New drugs to be on the market soon but cost will determine how wide spread the use will be
• Parallel development of f Xa inhibitors and direct thrombin inhibitors
• Drugs with other targets (f VIIa - TF, f Va - VIIIa, f IXa) will go to trials
• Utilize crystal structures/docking algorithms
Summary
• Several new oral anticoagulants are available at this time.
• The new medications are expensive but appear to be as safe or more safe than LMWH and warfarin.
• Efficacy in preventing thromboembolism appears to be better than warfarin for A-fib, DVT/PE, and orthopedic surgery.
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Thank you !
Questions?
Rivaroxaban & Apixaban Rivaroxaban Apixaban
Company sponsor Bayer, Johnson & Johnson Bristol-Myers Squibb; Pfizer # clinical trials 21 15
Molecular weight
436 460
Bioavailability 80% 50%
Peak , half-life (hr) 3, 5-9 3, 9-14
metabolism CYP 3A4, CYP2J2, CYP-ind.mech. CYP 3A4, CYP-ind.mech.
excretion 66% kidney, rest in feces 25% kidney, rest in feces
Factor Xa Inhibitors
Recommended
