novel anticoagulants - american college of physicians

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Novel Anticoagulants Mark T. Reding, MD Associate Professor of Medicine Division of Hematology, Oncology, and Transplantation Director, Center for Bleeding and Clotting Disorders University of Minnesota Medical Center American College of Physicians – Minnesota Chapter Annual Scientific Session Minneapolis, MN November 8, 2013

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Page 1: Novel Anticoagulants - American College of Physicians

Novel Anticoagulants

Mark T. Reding, MD Associate Professor of Medicine

Division of Hematology, Oncology, and Transplantation Director, Center for Bleeding and Clotting Disorders

University of Minnesota Medical Center

American College of Physicians – Minnesota Chapter Annual Scientific Session

Minneapolis, MN November 8, 2013

Page 2: Novel Anticoagulants - American College of Physicians

Disclosures I have served as an advisory board member, consultant, speaker,

and / or received research funding from:

Baxter Bayer

Biogen Idec Novo Nordisk Octapharma

Pfizer

(All activities related to hemophilia)

Off-label use will be mentioned: dabigatran, rivaroxaban, apixaban

Page 3: Novel Anticoagulants - American College of Physicians

Anticoagulant Therapy What are the options ?

1930s – heparin

1950s – warfarin

1990s – low MW heparins

1990s – direct thrombin inhibitors

2000s – factor Xa inhibitor

2010s – new oral anticoagulants

More new drugs are coming . . .

Page 4: Novel Anticoagulants - American College of Physicians

Partial List of Anticoagulant Drugs Under Development

Weitz JI et al. Chest 2012

Page 5: Novel Anticoagulants - American College of Physicians

New Oral Anticoagulants Dabigatran – Pradaxa

(Boehringer Ingelheim) Rivaroxaban – Xarelto

(Janssen)

Apixaban – Eliquis (Bristol-Myers Squibb / Pfizer)

Edoxaban – Lixiana (Daiichi Sankyo)

Approved only in Japan, for VTE prophylaxis

Page 6: Novel Anticoagulants - American College of Physicians

New Oral Anticoagulants Approval History

Dabigatran Rivaroxaban Apixaban

VTE prophylaxis (THA, TKA)

Europe – Mar 2008 Canada – Jun 2008

Europe – Sep 2008 Canada – Sep 2008

USA – July 2011

Europe – May 2011 Canada – Mar 2012

Atrial fibrillation

Canada – Oct 2010 USA – Oct 2010

Europe – Aug 2011

USA – Nov 2011 Europe – Dec 2011 Canada – Jan 2012

Europe – Nov 2012 Canada – Dec 2012

USA – Dec 2012

VTE treatment

Europe – Dec 2011 Canada – Feb 2012

USA – Nov 2012

Acute coronary syndromes

Europe – May 2013

Page 7: Novel Anticoagulants - American College of Physicians

Summary of Major Clinical Trials

VTE prophylaxis VTE treatment Atrial

fibrillation Acute coronary

syndromes

REMODEL REMOBILIZE RENOVATE

RENOVATE 2

RECOVER REMEDY

RESONATE RECOVER 2

RELY RELYABLE

REDEEM

RECORD 1 RECORD 2 RECORD 3 RECORD 4

EINSTEIN-DVT EINSTEIN-EXT EINSTEIN-PE

ROCKET-AF

ATLAS (ACS-TIMI 46)

ATLAS (ACS-TIMI 51)

ADVANCE 1 ADVANCE 2 ADVANCE 3

AMPLIFY AMPLIFY-EXT

ARISTOTLE AVERROES

APPRAISE 1 APPRAISE 2

Dabigatran Rivaroxaban Apixaban

Page 8: Novel Anticoagulants - American College of Physicians

FDA Approved Indications As of October 2013

Dabigatran Rivaroxaban Apixaban

VTE prophylaxis (THA, TKA)

x x Atrial fibrillation VTE treatment x x Acute coronary syndromes x x x

Page 9: Novel Anticoagulants - American College of Physicians

Pharmacokinetics Dabigatran Rivaroxaban Apixaban

Target Thrombin Factor Xa Factor Xa

Peak Effect (h) 2 – 3 3 – 4 3 – 4

Half-life (h) 12 – 17 5 – 13 8 – 15

Dosing Frequency Twice daily Daily* Twice daily

Clearance 80% Renal 20% Biliary

66% Renal 33% Biliary

25% Renal 75% Biliary

* Despite short half-life, once daily dosing possible due to persistence of anti-Xa activity

Harder S, Graff J. Eur J Clin Pharmacol 2013; 69(9):1617-33

Page 10: Novel Anticoagulants - American College of Physicians

Drug Interactions • Dabigatran interacts with drugs that affect the

transporter P-glycoprotein (P-gp)

• Rivaroxaban and apixaban also interact with P-gp drugs, as well as those that affect the microsomal enzyme CYP3A4

• Examples Ketoconazole Rifampicin Cyclosporine Itraconazole Clarithromycin Tacrolimus Amiodarone Protease inhibitors Carbamazepine Verapamil St. John’s wort Phenytoin

• Increased risk of major bleeding seen in studies of all 3 drugs when used with anti-platelet agents

Schulman S, Crowther MA. Blood 2012; 119(13):3016-23 Harder S, Graff J. Eur J Clin Pharmacol 2013; 69(9):1617-33

Page 11: Novel Anticoagulants - American College of Physicians

Laboratory Monitoring

Dabigatran Rivaroxaban Apixaban

PT / INR Increases with dose Very insensitive PT / INR and aPTT are both prolonged, but

to a varying degree, and depend upon the reagents used

aPTT Increases with dose Not linear, plateaus

Thrombin Time

Most sensitive Normal TT = no drug

Too sensitive No effect No effect

Other Ecarin clotting time is the best assay, but is not widely

available

Anti-Xa assay can be used, but must be standardized to

the drug

Anti-Xa assay very similar to LMWH,

and may not need to re-calibrate

Baumann-Kreuziger LM, et al. J Trauma Acute Care Surg 2012

Page 12: Novel Anticoagulants - American College of Physicians

Summary of Clinical Trials

Atrial Fibrillation

VTE Prophylaxis

VTE Treatment

Page 13: Novel Anticoagulants - American College of Physicians

Summary of Clinical Trials Atrial Fibrillation

RE-LY (Connolly SJ et al. NEJM 2009; 361:1139-51)

• N = 18,113

• Dabigatran 150 mg bid vs. warfarin Reduced risk of stroke (1.11% / yr vs. 1.69% / yr) Similar major bleed risk

BUT . . . Warfarin TTR averaged 64%

IF . . . Compare to patients with warfarin TTR > 65% Dabigatran not superior to warfarin

Dabigatran associated with less ICH, but double the risk of major GI bleed

Page 14: Novel Anticoagulants - American College of Physicians

Summary of Clinical Trials Atrial Fibrillation

ROCKET AF (Patel MR et al. NEJM 2011; 365:883-91)

• N = 14,264

• Rivaroxaban 20 mg daily vs. warfarin

• Rivaroxaban was non-inferior to warfarin for prevention of stroke

• No overall difference in major bleeding, however…

• Rivaroxaban associated with less ICH and fatal bleeding, but more GI bleeding

Page 15: Novel Anticoagulants - American College of Physicians

Summary of Clinical Trials Atrial Fibrillation

ARISTOTLE (Granger CB et al. NEJM 2011; 365:981-92)

• N = 18,201

• Apixaban 5 mg bid vs. warfarin

• Apixaban was superior in preventing stroke (1.27% / yr vs. 1.6% / yr), with less overall bleeding (7.7% absolute risk reduction) and lower all cause mortality

• Apixaban associated with less ICH (0.8% / yr vs. 0.33% / yr)

• No increase in GI bleeding

Page 16: Novel Anticoagulants - American College of Physicians

Summary of Clinical Trials VTE Prophylaxis (THA, TKA)

Dabigatran

Rivaroxaban

Apixaban

vs. Low Molecular

Weight Heparin

• Equal or better efficacy

• Similar bleeding risk

• Advantage of oral administration

(Dabigatran and apixaban are not approved in the US for this indication)

Page 17: Novel Anticoagulants - American College of Physicians

Summary of Clinical Trials VTE Treatment

Dabigatran

Rivaroxaban

Apixaban

vs. Warfarin

or Placebo

• Non-inferior to warfarin, with same or less overall bleeding risk and less major bleeding

• Need to carefully look at TTR for warfarin patients • Better than placebo (not a surprise)… with

acceptable bleeding risk • Apixaban had same bleeding risk as placebo?!?

(Dabigatran and apixaban are not approved in the US for this indication)

Time in Therapeutic Range (INR 2.0 – 3.0)

RE-MEDY = 65%

EINSTEIN = 58%

EINSTEIN-PE = 63%

AMPLIFY = 61%

Page 18: Novel Anticoagulants - American College of Physicians

Management of Bleeding

Dabigatran Rivaroxaban Apixaban

Antidote None None None

Activated charcoal* Yes Yes Yes

Dialysis

~35% protein bound

~60% removed in 2 -3 h **

Highly protein bound

Dialysis ineffective

Highly protein bound

Dialysis ineffective

* Activated charcoal indicated within 2 – 3 hours of drug ingestion

** Dabigatran has a very large volume of distribution (60 – 70 L); expect multiple dialysis sessions to be required

Page 19: Novel Anticoagulants - American College of Physicians

Hemostatic Agent Options for Management of Bleeding

Name Category Available in US? Aminocaproic acid antifibrinolytic Yes

Tranexamic acid antifibrinolytic Yes

Profilnine, Bebulin 3 factor PCC Yes

Cofact, Kanokad 4 factor PCC No

Octaplex, Kaskadil 4 factor PCC, + PC, PS No

Beriplex / Kcentra 4 factor PCC, + PC, PS, AT Yes

FEIBA Activated PCC Yes

NovoSeven rfVIIa Yes

(None are approved in the US for this indication)

Page 20: Novel Anticoagulants - American College of Physicians

Use of Hemostatic Agents for Management of Bleeding

Summary of Data Dabigatran Rivaroxaban Apixaban

Animal Human Animal Human Animal Human

3 factor PCC

Case rpt +/-

4 factor PCC

Rat +/- Rabbits +

Mice ICH +

In vitro + In vivo -

Case rpt -

Rats + Rabbits -

In vitro +/- In vivo +

In vitro +

aPCC Rats +/- Mice -

In vitro + Rat +

Primate + In vitro + In vitro +

rfVIIa Rats +/- Mice +/-

Mice ICH -

In vitro + Case rpt +/-

Rat + Rabbits +/- Primate +/-

In vitro +/- In vitro +

+ effective, - not effective, +/- mixed results

Bottom Line: very little human, in vivo, real-world, published experience at this time

Page 21: Novel Anticoagulants - American College of Physicians

Use of Factor Concentrates for Management of Bleeding

• Factor Concentrates are NOT antidotes – They create hypercoagulability, not reversal – Specific reversal agents in early phase trials

• Thrombotic risk is present • Dabigatran

– aPCC (FEIBA) 50 U/kg • Rivaroxaban and Apixaban

– 4-Factor PCC (Kcentra) 50 U/kg Siegal DM, Crowther MA. Eur Heart J 2013; 34(7):489-498b. Schulman S. HTRS 2013 Annual Meeting, oral presentation.

Khoo TL, et al. Int J Lab Hematol 2013; 35(2):222-4. Eerenberg ES et al. Circulation 2011; 124(14):1573-9.

Page 22: Novel Anticoagulants - American College of Physicians

Perioperative Management

Drug Package Insert Recommendations

Dabigatran

For CrCl >50, stop 1 to 2 days prior For CrCl <50, stop 3 to 5 days prior

Consider longer if major surgery, spinal puncture, spinal or epidural catheter

Rivaroxaban Stop at least 24 hours prior

Apixaban

Stop at least 48 hours prior (moderate or high risk procedures)

Stop at least 24 hours prior (low risk procedures)

• Lab testing – If TT (dabigatran) or anti-Xa (rivaroxaban, apixaban) are normal, drug has cleared

• If not normal, there is still drug on board (but cannot quantitate risk)

Page 23: Novel Anticoagulants - American College of Physicians

Advantages • Direct

anticoagulants

• Predictable pharmacokinetics

• No monitoring needed

• Few diet / drug interactions

Disadvantages • Cannot monitor

• Renal / hepatic excretion

• No antidotes

• Limited experience

• Lack of long-term safety data

• Cost

New Oral Anticoagulants

Page 24: Novel Anticoagulants - American College of Physicians

New Oral Anticoagulants To use or not to use ?

• Those already on warfarin, with good INR control, have little to gain by switching

• New agents slightly preferred over warfarin for those newly initiating treatment

• Some evidence suggests an increased risk of MI or ACS related to dabigatran; use with caution in those with CAD

• Watch renal / liver function

Atrial Fibrillation

Page 25: Novel Anticoagulants - American College of Physicians

New Oral Anticoagulants To use or not to use ?

• Dabigatran and apixaban are not approved in the US for this indication

• Rivaroxaban is a good alternative to LMWH / warfarin in this setting

• Approval currently limited to orthopedic surgery

Prevention of VTE

Page 26: Novel Anticoagulants - American College of Physicians

New Oral Anticoagulants To use or not to use ?

• Dabigatran and apixaban are not approved in the US for this indication

• Rivaroxaban was recently approved in the US for this indication (Nov. 2012)

• Rivaroxaban is a good choice for those who need short term treatment

• Long term concerns: safety, cost (to patient), breakthrough clots (?)

Treatment of VTE

Page 27: Novel Anticoagulants - American College of Physicians

• Malignancy

• Pregnancy

• “Severe” thrombophilia (APS, PC, PS, AT, double heterozygotes or homozygotes for FVL / PGM)

• Extremes of body weight

• Impaired renal / hepatic function

• Mechanical heart valves

• Those with more than “low” bleeding risk

• Real-world compliance (not on studies)

New Oral Anticoagulants To use or not to use ?

We need more experience in patients with:

RE-ALIGN Study (NEJM 2013; 369:1206-14)

• Dabigatran vs. warfarin

• Aortic and mitral valves

• Terminated early due to excess thromboembolic and bleeding events in dabigatran group

Page 28: Novel Anticoagulants - American College of Physicians

Take Home Points

The new oral anticoagulants are not necessarily better than warfarin; they are different, and each has advantages and disadvantages

Careful patient selection is crucial for the safe use of new oral anticoagulants

Management of bleeding complications from the new oral anticoagulants is a major clinical challenge; we lack data and “real world” clinical experience

Page 29: Novel Anticoagulants - American College of Physicians