10/21/14

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 erythrocytes (red blood cells) + ++ Ions /electrolytes (K Cl- Ca ) leukocytes (white blood cells) plasma proteins (Fibrinogen) platelets transported substances

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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

Intrinsic XII

XI TF Extrinsic IX VIII VII X

V II

Fibrinogen

Fibrin Clot

The Balance

Bleeding Clotting

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Anti-Platelet Therapy

Aspirin Pharmacology

• 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

• 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

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Aspirin blunts but does not eliminate circadian variation of AMI Physicians’ Health Study; N = 22,071 men

Placebo Aspirin

30 30

20 20

10 10

0 0 0 12 24 0 12 24 Hour of day Hour of day

Ridker PM et al. Circulation. 1990;82:897-902.

Clopidogrel:

• 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

CURE: Patients continue to have recurrent CV events despite dual antiplatelet therapy N = 12,562 with NSTE-ACS; all patients received ASA; Primary outcome = CV death, MI, stroke

0.14

0.12 Placebo 0.10

Clopidogrel Cumulative 0.08 hazard rate 0.06 for primary outcome 0.04 P < 0.001

0.02

0.00 0 3 6 9 12 Follow-up (months)

CURE = Clopidogrel in Unstable CURE Trial Investigators. N Engl J Med. Angina to Prevent Recurrent Events 2001;345:494-502.

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Prasugrel

• 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)

Ticagrelor

• 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

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 Bare-metal Drug-eluting Without stent or Stent group Stent group PTCA alone

ASA 162-325 mg/d ASA 162-325mg/d for for ≥1mo then at least 3 mo for SES, ASA 162-325 mg/d 75-100mg/d indefinitely 6mo for PES, then indefinitely + 75-100mg/d indefinitely + Clodpidogrel 75mg/d or + Clodpidogrel 75mg/d Prasugrel 10mg/d or Clodpidogrel 75mg/d or or ? Prasugrel Ticagrelor 90mg BID Prasugrel 10mg/d or or ?Ticagrelor for at 6-12 months Ticagrelor 90mg BID for at least 1 mo (class for at 6-12 months 1A) & up to 12 months Shorter duration if Shorter duration if bleeding risk >benefit 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 Score CVA CHADS2-VASc Score Score CVA (%/Yr) (%/Yr) CHF 1 CHF 1 0 1.9% 0 0% Hypertension 1 Hypertension 1 1 2.8 % 1 1.3% Age>75 2 Age >75 1 2 4.0% 2 2.2% DM 1 DM 1 3 5.9% 3 3.2% 4 8.5% CVA/TIA 2 4 4.0% CVA or TIA 2 5 12.5% Vascular Ds 1 5 6.7% (MI, PAD) Total 6 6 18.2% 6 9.8% Aged 65-74 1 7 9.6% Female 1 8 6.7% Total 9 9 15.2%

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Anticoagulants

• CURRENT DRUGS TARGETED FACTOR – Unfractionated Heparin______Antithrombin (indirectly Xa and IIa) – Low Molecular Weight Heparin______Antithrombin (indirectly Xa and IIa) – Lepirudin (DTI)______Thrombin (IIa) – Bivalirudin (DTI) ______Thrombin (IIa) – Argatroban(DTI)______Thrombin (IIa) – Danaparoid______Antithrombin – Drotrecogin Alfa______Va, VIIIa – Vitamin K antagonists (Warfarin)______Prothrombin (II), VII, IX, X • NEW/ in DEVELOPMENT DRUGS – Fondaparinux______Xa – Idraparinux______Xa – SSR 126517______Xa – Rivaroxaban______Xa – Apixaban______Xa – LY517717______Xa – YM150______Xa – DU-176b______Xa – Betrixaban______Xa – Ximelagatran*______Thrombin (IIa) – Dabigatran etexilate______Thrombin (IIa)

*taken off the market Italics are Oral Drugs

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

Intrinsic XII Extrinsic

XI Tissue Factor IX VIII VII Direct Xa Inhibitors AT X “-xaban” V Direct warfarin II Thrombin Inhibitors Fibrinogen “-gatran” Fibrin Clot

Dicoumarol Phenprocoumon

Vitamin K antagonists:

Warfarin Sodium

Acenocoumarol Anisindione

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Vitamin K antagonists 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

Anticoagulation for nonvalvular AF Pooled data from AFASAK, SPAF, and BAATAF

For every 1000 patients with nonvalvular AF in clinical trials treated with warfarin for 1 year: Benefit Risk 31 fewer thromboembolic events* 1 more intracranial or major bleed*

*Compared with control 35 more minor bleeds occurred with warfarin Intention-to-treat analysis Adapted from Albers GW et al. Ann Neurol. 1991;30:511-8.

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Warfarin risk/benefit balance

20

15

Odds ratio 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.

Vitamin K antagonists Problems with Warfarin

• Food and drug interactions

dosage adjustments & • Genetic variation in metabolism freq. monitor with INR

• narrow therapeutic window

• slow onset of action

overlap with parenteral drugs

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

Intrinsic XII Extrinsic

XI Tissue Factor IX VIII VII Direct Xa Inhibitors AT X “-xaban” V Direct warfarin II Thrombin Inhibitors Fibrinogen “-gatran” Fibrin Clot

Direct Thrombin Inhibitors

Intrinsic XII Extrinsic XI TF IX VIII VII X

V Direct Thrombin Inhibitors II “-gatran” Fibrinogen

Fibrin Clot

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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.

Direct Thrombin Inhibitors

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

Dabigatran

Currently, Pradaxa is the only direct thrombin inhibitor (DTI) that is approved for stroke prevention in atrial fibrillation.

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Dabigatran

• Oral capsule • No dietary/food • Rapid onset of action interactions • Half-life 12-17 hours • Brand name Pradaxa® • Renal elimination • Boehringer-Ingelheim • 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)

% Total VTE & Death % Adverse Events 41 n=1541 patients 12 treated 6-10 days, 40 followed for 3 10 months post- 39 surgery 8 6 38 4 37 2 36 0 35 150 mg 220 mg Enox 40 Qday Qday Qday 34 Dabigatran 150 mg 220 mg Enox 40 Qday Qday Qday Major Bleeding Minor Bleeding Dabigatran LFT > 3xULN

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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

1.0 0.05

0.04 ↓34% 0.8 P < 0.001 0.03

0.6 0.02 Cumulative hazard rate 0.01 0.4 0.00 0 6 12 18 24 30 0.2

0.0 0 6 12 18 24 30 Months

Warfarin Dabigatran 110 Dabigatran 150

Connolly SJ et al. N Engl J Med. 2009;361:1139-51.

Dabigatran (Pradaxa) Advantages & Disadvantages

Advantage Disadvantage

• Stroke vs warfarin ⇓ Ø Twice-daily dosing – Effect on • ICH vs warfarin ⇓ compliance? • No INR monitoring Ø Irreversibility Convenient Ø Renal dosing Inability to assess efficacy Ø Dyspepsia (11-12%) • Rapid onset of effect

Direct Factor Xa Inhibitors

Intrinsic XII Extrinsic XI TF IX VIII VII Direct Xa Inhibitors X “-xaban” V II

Fibrinogen

Fibrin Clot

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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®, § Primarily renal Bayer elimination • Oral tablet § No laboratory monitoring • High oral bioavailability required (>80%) § No dosage adjustment for • Onset of action 2-4 hours gender, age, extreme • Half-life 9-12 hours body weight § Approved by Europe and • No observed effects on Canadian agencies, and agonist-induced platelet under FDA review aggregation currently

Rivaroxaban in VTE Prevention: RECORD 3 - TKA 2531 patients

% % 6 20 No Difference 18 5 16 RRR 4 14 62% RRR 12 3 10 49% 8 2 6 4 1 2 0 0 Rivarox 10 Enox 40 Qday Rivarox 10 Enox 40 Qday Qday x 14 d x 14 days Qday Composite Major VTE Major Bleed Any Bleed

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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% § Eliminated via § Peak Plasma Levels = multiple pathways 3 hrs § No laboratory § Half-life ~ 12 hours monitoring required § Metabolized in liver § Manufactured by via CYP3A4 and CYP Bristol-Myers Squibb/ independent Pfizer mechanisms

Apixaban Efficacy Outcomes in TKR (Phase II) Incidence of VTE and all-cause death (%)

Duration = 10 -14 days

5 2.5 10 5 20 10 Enox Warf QDay BID QDay BID QDay BID 30mg BID Apixaban (mg) (n = 933) (n=152) (n=153)

Lassen MR, et al. J Thromb Haemost. 2007;5:2368 – 2375.

Apixaban Safety Outcomes in TKR (Phase II) Incidence of bleeding events (%)

5 2.5 10 5 20 10 Enox Warf QDa BID QDa BID QDa BID 30mg BID y Apixabany (mg) (n = 933)y (n=152(n=153 ) )

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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?

Factor Xa Inhibitors 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

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