upha anticoagulation therapy update -...

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An)coagula)on Therapy Update

Daniel M. Wi>, PharmD, FCCP, BCPS University of Utah College of Pharmacy

Outline

•  Review of hemostasis & thrombosis •  Overview of available an)coagulants •  What to do following an)coagula)on therapy-‐related bleeding

•  Choosing between available an)coagulants

J Thromb Haemost. 2003 Feb;1(2):227-‐30

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Hemosta)c System

•  Preserves integrity of circulatory system •  A highly complex system

•  Vessel wall (endothelial cells) •  Soluble plasma proteins (cloZng factors) •  Cellular components (platelets) •  Micropar)cles ()ssue factor)

•  Ac)vated by )ssue injury or changes in the endothelial surface

Overview

•  Hemostasis is the arrest of bleeding following blood vessel damage

•  Rapid forma)on of impermeable platelet and fibrin plug at site of injury

•  Localized to site of injury •  Fibrin within clot triggers its own dissolu)on (fibrinolysis)

•  Pathologic thrombus = normal regulatory controls overwhelmed

A Clot is Formed

Red = platelets

Green = )ssue factor

White = platelets + fibrin + )ssue factor

Blue = fibrin

Platelet thrombus and fibrin deposi3on occur at the same 3me

N Engl J Med 2008;359:938-‐49

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Platelet Thrombus Forma)on

•  Dynamic process influenced by shear, flow, turbulence and number of platelets in circula)on

•  Platelet ac)va)on (by collagen or )ssue factor) results in the release of components cri)cal for thrombus forma)on and platelet-‐platelet interac)on

Thromb Haemost 2013; 110: 859–867

Coagula)on Complexes

(An)coagulant complex)

Co-‐factor

Enzyme

Substrate(s)

Blood Cells, Molecules, and Diseases 36 (2006) 108 – 117

Tissue Factor

•  Membrane protein •  Present on many cells/has many func)ons

•  Present in vessel wall •  Can be expressed on monocytes and endothelium •  Present in circula)ng blood (micropar)cles)

•  Blood-‐borne TF captured in thrombus via interac)ons between P-‐selec)n/PSGL-‐1

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•  TF may circulate in ac)ve and inac)ve forms •  Inac)ve TF requires ac)va)on at the site of vascular injury

•  Pathologic micropar)cles may bear ac)ve TF •  Fibrin is the end product of the coagula)on cascade

The Coagula)on Cascade

X

Xa Va

XII HMK PK

VIIa Tissue Factor

IXa VIIIa IX

XI XIa

Prothrombin (II) Thrombin (IIa)

‘Common Pathway’

‘Extrinsic Pathway’

‘Intrinsic Pathway’

Does NOT explain how blood clots in vivo

The Coagula)on Cascade

X

Xa Va

XII HMK PK

VIIa Tissue Factor

IXa VIIIa IX

XI XIa


‘Common Pathway’

‘Extrinsic Pathway’

‘Intrinsic Pathway’ Deficiency results in increased PTT but no bleeding tendency

Deficiency results in increased PTT and

hemophilia

Unable to sustain hemostasis in hemophilia

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Cellular Model of Clot Forma)on

Thromb Haemost 2013; 109: 569–579

Ini)a)on Phase •  Ac)vated )ssue factor is the fuse •  TF/VIIa complex ac)vates small

amounts of IX and X •  Xa then associates with Va to form

prothrombinase complex •  A small amount of thrombin is

produced •  Tissue Factor Pathway Inhibitor

•  Neutralizes Xa •  Feedback inhibi)on on TF/VIIa in

presence of Xa

Thromb Haemost 2013; 109: 569–579

Amplifica)on Phase

•  Low concentra)ons of thrombin ac)vate platelets adhering to injury site

•  Thrombin ac)vates V, VIII, and XI •  Va, VIIIa, and XIa bind to surfaces

of ac)vated platelets

Thromb Haemost 2013; 109: 569–579

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Propaga)on Phase

•  Intrinsic tenase and prothrombinase assemble on surface of ac)vated platelets

•  XIa ac)vates IX to form addi)onal intrinsic tenase

•  Burst of thrombin •  Fibrin generated and stabilized by

XIIIa

Thromb Haemost 2013; 109: 569–579

This is what fibrin looks like…

Thromb Haemost 2010; 104: 1281–1284

Termina)on

•  Coagula)on reac)ons are likely terminated when fibrin deposi)on ‘paves over’ the site of injury

•  Fresh components of coagula)on reac)ons are no longer able to access the site

•  Protein C/S & AT limit thrombus to site of injury

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Modula)on

Prothrombin Thrombin

Fibrinogen Fibrin

FXII

FX

FXI

FIX

FXa

FVIII FV

TFPI

AT

PS PC

FVII

Endogenous An)coagulant Mechanisms

•  An)thrombin •  Inhibits only free enzymes •  Limits coagula)on to site of injury

•  Thrombomodulin •  Ac)vates protein C

•  Protein C •  Modulates ac)vity of FVa & VIIIa (even when part of intrinsic tenase and

prothrombinase complexes) •  Limits coagula)on to site of injury

•  Protein S •  Supports ac)vity of protein C

•  Tissue Factor Pathway Inhibitor (TFPI) •  Inhibits FXa and TF/VIIa complex

Thrombolysis

Fibrinogen (circula3on) Fibrin

(thrombus)

Alpha2 An)plasmin

tPA

Plasmin Plasminogen

Plasminogen Ac)vator Inhibitor (PAI-‐1)

(Binds and inac)vates plasmin)

(Circula)ng inac)ve

precursor)

(Cleaves bonds in fibrin and fibrinogen)

(Binds and inac)vates tPA)

(Physiologic ac)vator of plasminogen)

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UFH/LMWH/Fondaparinux


Fibrinogen Fibrin

FXII

FX

FXI

FIX

FXa

FVIII FV

TFPI

AT

PS PC

FVII

LMWH

Fondaparinux

Xa

1

AT AT

2 3

AT

4

AT Thrombin

Xa

1

AT AT

2 3

AT

4

AT Thrombin

Xa

1

AT AT

2 3

AT

4

AT Thrombin

Unfrac3onated Heparin


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UFH LMWH Fondaparinux

Monitoring aPTT

Platelet count Platelet count Renal func)on

Platelet count Renal func)on

Variability of response Yes Rela)vely low Rela)vely low

Primary Route of Elimina3on

1.  Saturable binding

2.  Renal Renal Renal

Reversal Agent Yes Par)al No

HIT Postop: <1% -‐ 5% Med/OB: <1%

Postop: <1% Med/OB: <0.1%

No

Warfarin


Fibrinogen Fibrin

FXII

FX

FXI

FIX

FXa

FVIII FV

TFPI

AT

PS PC

FVII

Warfarin Pharmacokine)cs

Half-‐life ≈ 36 hrs

Time to steady state ≈

3-‐5 half-‐lives

108-‐180 hrs OR 4.5-‐7.5 days

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Direct Oral An)coagulants

X

Xa Va

XII HMK PK

VIIa Tissue Factor

IXa VIIIa IX

XI XIa


Rivaroxaban Apixaban Edoxaban Betrixaban Darexaban

Dabigatran

Pharmacology of DOACs

CYP = cytochrome P450; Tmax = )me to maximum concentra)on

Apixaban (Eliquis)

Dabigatran (Pradaxa) Rivaroxaban (Xarelto)

Drug class Direct factor Xa inhibitor Direct factor IIa inhibitor Direct factor Xa inhibitor

Bioavailability 50% 3%-‐7% 80%-‐100% for 10-‐mg dose 66% for 20-‐mg dose

Protein binding 84% 35% 92–95%

Tmax 3-‐4 hours 1-‐2 hours 2-‐4 hours

Onset of an3coagulant effect Within 3 hours Within 2 hours Within 4 hours

Renal excre3on 27% 80% 36%

Dialyzable No Yes No

Half-‐life 8-‐15 hours 12-‐17 hours 5-‐9 hours; 11-‐13hrs elderly

Dosage form Tablet Capsule Tablet

Dosing frequency BID BID QD/BID

An3dote No No No

DOACs: Compara)ve Metabolism

Dabigatran Rivaroxaban Apixaban

Ac3va3on

•  prodrug dabigatran etexilate is rapidly converted to ac)ve drug dabigatran via hydrolysis

•  none •  none

Metabolism •  conjuga)on (no CYP involvement)

•  oxida)on (via CYP3A4, CYP3A5 and CYP2J2) and hydrolysis

•  oxida)on (via CYP3A4, CYP3A5) and conjuga)on

Pgp -‐ Substrate YES YES YES

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DOACs: A New Drug Interac)on Mindset

•  Warfarin •  Drug interac)ons can be managed through increased monitoring and dose adjustment

•  Interac)ng drugs are not contraindicated

•  DOACs •  Drug interac)ons are contraindica)ons or precau)ons

•  No ability to monitor and adjust dose based on response

DOACs: Formula)on Issues, Food Effects

Apixaban Dabigatran Rivaroxaban

Formula3on • No informa)on

• Capsules cannot be: crushed (no feeding tube), broken, or chewed

• Expires 4 mo awer bo>le is opened

• May be crushed and mixed with applesauce in a feeding tube (G-‐tube)

Food Effects • Bioavailability not affected by food

•  May be taken with or without food

• 10-‐mg tablet: may be taken with/without food

• 15-‐mg and 20-‐mg tablets: should take with largest meal of the day

Case 1

A 77 year old man receiving warfarin for AF is admi>ed with a bleeding duodenal ulcer. He has a history of HTN and DM. He is discharged on omeprazole 20 mg daily. Should his warfarin be resumed? If yes, when?

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Gastrointestinal tract bleeding

Adjusted HR= 1.18, 95% CI 0.94 – 1.10

Recurrent GI Bleeding

Am J Card 2014;113:662-68

Retrospective cohort study of subjects who developed GIB while on anticoagulation. Time-to-event adjusted analyses were performed to find an association of restarting warfarin and recurrent GIB, arterial thromboembolism, and mortality.


Am J Card 2014;113:662-68

Adjusted HR= 0.71, 95% CI 0.54-0.93

Thromboembolism

Gastrointestinal tract bleeding Overall Mortality

Am J Card 2014;113:662-68

Adjusted HR= 0.67, 95% CI 0.56-0.81

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Adjusted HR=0.31, 95% CI 0.15-0.62

Adjusted HR=1.32, 95% CI 0.5-3.57

Adjusted HR=0.05, 95% CI 0.01-0.58

Arch Intern Med 2012;172:1484-91

Retrospective, cohort study. Kaplan-Meier curves were constructed to estimate the survival function of thrombosis, recurrent GIB, and death between the “resumed warfarin therapy” and “did not resume warfarin therapy” groups. Cox proportional hazards modeling to adjust for potentially confounding factors.

Gastrointestinal tract bleeding •  Timing of resumption

–  Patients who never interrupted therapy or resumed therapy within 14 days experienced no thrombosis

–  Recurrent GIB was significantly increased if warfarin resumed within 7 days

–  Death rate was lowest when warfarin was resumed between 15 and 90 days

•  Resumption less likely in older patients and those in whom the source of GIB was not identified

•  Resumption more likely with mechanical valve indication and in bleeding confined to hemorrhoidal bleeding

Arch Intern Med 2012;172:1484-91

Gastrointestinal tract bleeding •  Evidence from two observational trials (n=1771) supports

reduced thromboembolism and death when warfarin resumed following GIB without increasing risk for recurrent GIB

•  Optimal timing for resumption appears to be around 14 days –  Minimizes risk for recurrent bleeding –  Does not appear to increase TE/death

•  Severity of bleeding event and underlying TE risk should be considered

•  Do these results apply to other extracranial bleeding sites?

39

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Case 1

A 77 year old man receiving warfarin for AF is admi>ed with a bleeding duodenal ulcer. He has a history of HTN and DM. He is discharged on omeprazole 20 mg daily. Should his warfarin be resumed? If yes, when?

Case 2

A 55 year old man taking apixaban for treatment of a DVT sustained following knee replacement surgery 4 months ago is admi>ed with bloody stools and a hematocrit of 27%. He receives 2 units of packed RBCs. No source of bleeding is iden)fied. Should an)coagula)on therapy be resumed following discharge?

Case 3

A 62-year-old man who presents with an intracerebral hemorrhage (ICH) while taking warfarin for atrial fibrillation. His INR is 2.5. His CHADS score is 3. Should warfarin be restarted to decrease the risk of future thromboembolism?

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Intracranial hemorrhage •  The ‘BRAIN’ Study •  Cohort of consecutive patients with warfarin-related ICH (intracerebral

[~1/3 lobar] or subarachnoid) •  Among the 284 patients studied (mean age 74 ±12 years), warfarin was

restarted in-hospital in 91 patients (32%) •  Mortality rates lower in those who restarted warfarin in-hospital: 31.9%

vs 54.4% (30-day, P < 0.001) and 48% vs 61% (1-year, P = 0.04), and bleeding not increased

•  Multivariable predictors of mortality: –  Restarted warfarin in-hospital (30-day OR 0.49, 95% CI 0.26-0.93) –  Intraventricular hemorrhage (30-day OR 2.19, 95% CI 1.09-4.40) –  CNS <7 (more severe stroke) (30-day OR 6.04, 95% CI 3.32-10.97) –  INR >3.0 at presentation (30-day OR 3.28, 95% CI 1.66-6.49)

Can J Card 2012;28:33–39

Intracranial Hemorrhage

Intracranial hemorrhage Factors arguing for and against resuming anticoagulation after ICH FACTOR FOR AGAINST Etiology HTN-related ICH (deep), BP adequately controlled Cerebral amyloid angiopathy (lobar) Microvascular risk Microbleeds on gradient-echo MRI Indication for anticoagulation Secondary prevention Primary prevention Atrial fibrillation, CHADS2 ≥ 4 or CHA2DS2-VASc ≥ 5 Atrial fibrillation, low CHADS2 < 4 or CHA2DS2-VASc < 5 Mechanical heart valve Thrombophilia (protein S/C/antithrombin deficiency; APLA) Anticipated difficulty managing anticoagulation

X X X X X

X X X X X

CCJM 2010;77:791-99

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Case 3

A 62-year-old man who presents with an intracerebral hemorrhage (ICH) while taking warfarin for atrial fibrillation. His INR is 2.5. His CHADS score is 3. Should warfarin be restarted to decrease the risk of future thromboembolism?

Case 4

A 66 year old woman with history of HTN and CAD is diagnosed with symptoma)c atrial fibrilla)on. Her ventricular rate is controlled with verapamil and amiodarone is started for rhythm control. She takes ASA 81 mg daily for her stable CAD. Is an)coagula)on therapy indicated? If yes, which agent should be selected?

Beyond INR-‐based Dose Adjustment

•  Is an)coagulant therapy appropriate for my pa)ent? •  Does the benefit outweigh the bleeding risk? •  Are the financial and lifestyle costs jus)fied?

•  Is my pa)ent on the CORRECT an)coagulant? •  Can I make an)coagulant therapy safer for my pa)ent?

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Atrial Fibrilla)on

•  Assess stroke and bleeding risk •  Withhold/discon)nue AC therapy in the rare pa)ent for whom it would not be beneficial

•  Reduce bleeding risk •  Be familiar with all therapeu)c op)ons

Lew Atrial Appendage (LAA)

CHADS2: Risk of Stroke Na)onal Registry of Atrial Fibrilla)on Par)cipants (NRAF)

Scoring: 1 point: Conges)ve heart failure, HTN, ≥ 75 years, and DM 2 points: Stroke history or transient ischemic a>ack † Expected stroke rate per 100 pt-‐yrs from the exponen)al survival model, assuming aspirin not taken

CHADS2 Score # Pa3ents (n = 1733)

# Strokes (n = 94)

NRAF Crude Stroke Rate per 100 Pa3ent-‐yrs

NRAF Adjusted Stroke Rate (95%

CI)†

0 120 2 1.2 1.9 (1.2-‐3.0)

1 463 17 2.8 2.8 (2.0-‐3.8)

2 523 23 3.6 4.0 (3.1-‐5.1)

3 337 25 6.4 5.9 (4.6-‐7.3)

4 220 19 8.0 8.5 (6.3-‐11.1)

5 65 6 7.7 12.5 (8.2-‐17.5)

6 5 2 44.0 18.2 (10.5-‐27.4)

Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. JAMA. 2001 Jun 13;285(22):2864-‐70. Pub Med PMID: 11401607.

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Risk Factor Score

Conges)ve heart failure/LV dysfunc)on 1

Hypertension 1

Age ≥ 75 years 2

Diabetes mellitus 1

Stroke/TIA/TE 2

Vascular disease (Prior myocardial infarc)on, peripheral artery disease, or aor)c plaque)

1

Age 65-‐74 years 1

Sex category (i.e. female gender)

1

CHA2DS2-‐VASc 2009 Birmingham Schema Expressed as a Point-‐Based Scoring System

LV = leh ventricle; TE = thromboembolism

Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Chest. 2010 Feb;137(2):263-‐72. Pub Med PMID: 19762550.

Bleeding Risk Scores in AF

1.  Hemoglobin <13 g/dl men; <12 g/dl women 2.  Es)mated glomerular filtra)on rate <30 ml/min or

dialysis-‐dependent 3.  Diagnosed hypertension 4.  Systolic blood pressure >160 mmHg 5.  Presence of chronic dialysis or renal transplanta)on or

serum crea)nine ≥200 mmol/L 6.  Chronic hepa)c disease (eg cirrhosis) or biochemical evidence of significant hepa)c derangement (eg bilirubin 2 x upper

limit of normal, in associa)on with aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase >3 x upper limit normal, etc.)

7.  Unstable/high INRs or poor )me in therapeu)c range (eg <60%) 8.  Concomitant use of drugs, such as an)platelet agents, non-‐steroidal an)-‐inflammatory drugs, or alcohol abuse etc. 9.  Cirrhosis, two-‐fold or greater eleva)on of AST or APT, or albumin <3.6 g/dl 10. Platelets <75,000, use of an)platelet therapy (eg daily aspirin) or NSAID therapy; or blood dyscrasia 11. Prior hospitaliza)on for bleeding 12. Most recent hematocrit <30 or hemoglobin <10 g/dl 13. CYP2C9*2 and/or CYP2C9*3 14. Alzheimer's demen)a, Parkinson's disease, schizophrenia, or any condi)on predisposing to repeated falls

ATRIA

Anemia1 3

Severe renal disease2 3

Age ≥ 75 years 2

Any prior hemorrhage 1

Hypertension3 1

HAS-‐BLED

Hypertension4 1

Abnormal renal5 or liver func)on6

1

Stroke 1

Bleeding 1

Labile INR7 1

Elderly (>65 years) 1

Drugs8 or alcohol 1

HEMORR2HAGES

Hepa)c9 or renal disease2 1

Ethanol abuse 1

Malignancy 1

Older age (>75 years) 1

Reduced platelet number or func)on10

1

Rebleeding11 2

Hypertension4 1

Anemia12 1

Gene)c factors13 1

Excessive fall risk14 1

Stroke 1 Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. J Am Coll Cardiol. 2012 Jul 24. [Epub ahead of print] PMID: 22858389

Teaching Points

•  Modify bleeding risk factors •  Stop ASA and/or clopidogrel whenever possible •  Control blood pressure •  Reduce fall risk •  Maximize )me that INR is ‘in range’ or consider DOAC

•  If CHADS2 is low (1 or 2) •  Any AC therapy likely appropriate if 0-‐2 bleeding RFs •  If 3 or more non-‐modifiable bleeding RFs, consider:

•  No AC therapy (especially if creat cl < 50 mL/min)

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Meta-‐analysis of Efficacy and Safety of Direct Oral An)coagulants

Dabigatran, Rivaroxaban, Apixaban, Edoxaban vs. Warfarin in AF pa)ents

All cause stroke/SE

Ruff et al. Epub.December 4, 2013 hlp://dx.doi.org/10.1016/S0140-‐6736(13)62343-‐0


Dabigatran, Rivaroxaban, Apixaban vs. Warfarin in AF pa)ents

Major Bleeding



Dabigatran, Rivaroxaban, Apixaban, Edoxaban vs. Warfarin in AF pa)ents

Secondary Safety and Efficacy Outcomes


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Case 4

A 66 year old woman with history of HTN and CAD is diagnosed with symptoma)c atrial fibrilla)on. Her ventricular rate is controlled with verapamil and amiodarone is started for rhythm control. She takes ASA 81 mg daily for her stable CAD. Is an)coagula)on therapy indicated? If yes, which agent should be selected?

Case 5

A 48 year old man is diagnosed with a popliteal DVT. He recently had reconstruc)ve knee surgery following an injury sustained on his job as a roughneck on an offshore oil pla�orm. He has no other health problems and is on no other medica)ons. What would be the best plan for star)ng an)coagula)on therapy for this pa)ent?

DVT/PE: Goals of Therapy

Acute Phase (≥ 5 days)

Chronic Phase (≥ 3 months)

Relieve symptoms Avoid Recurrence (new clot)

Prevent emboliza)on Minimize risk of post-‐thrombo)c syndrome chronic. Pulm HTN Avoid clot extension/

forma)on

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Tradi)onal/Standard Therapy

•  Warfarin target INR 2-‐3 with 5 day overlap using – Heparin – LMWH – Fondaparinux

Acute VTE Treatment: Summary

Trial Name Drug Year Published

Heparin/ LMWH at start

HR or RR: Recurrent VTE vs. warfarin (95% CI)

HR: Major Bleeding vs. warfarin (95% CI)

RE-‐COVER (DVT and/or PE) dabi 2009 Yes 1.10

(0.65 -‐ 1.84) 0.82

(0.45 -‐ 1.48)

RE-‐COVER II dabi 2013 Yes 1.08 (0.64 -‐ 1.80)

0.69 (0.36 to 1.32)

EINSTEIN DVT riva 2010 No 0.68 (0.44 -‐ 1.04)

0.65 (0.33 -‐ 1.30)

EINSTEIN PE riva 2012 No 1.12 (0.75 -‐ 1.68)

0.49 (0.31 -‐ 0.79)

AMPLIFY apix 2013 No 0.84 (0.60 -‐ 1.18)

0.31 (0.17 -‐ 0.55)

HOKUSAI edox 2013 Yes 0.89 (0.70 – 1.13)

0.84 (0.59 – 1.21)

Op)mal Candidates for DOACs

•  Pa)ents who: •  Have difficulty geZng INR tes)ng or, despite adherence to recommenda)ons, have low ‘)me-‐in-‐range’

•  Can afford (or arrange to get) them •  Are not taking medica)ons known to interact with the new an)coagulants

•  Have normal renal func)on •  Do not have cancer, APS •  Not pregnant

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Case 5

A 48 year old man is diagnosed with a popliteal DVT. He recently had reconstruc)ve knee surgery following an injury sustained on his job as a roughneck on an offshore oil pla�orm. He has no other health problems and is on no other medica)ons. What would be the best plan for star)ng an)coagula)on therapy for this pa)ent?

Ques)ons?

Thank you for a>ending!

upha anticoagulation therapy update -...

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