Anti Coagulation

8/2/2019 Anti Coagulation

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Jay Montgomery

3/13/12


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From a surgical discharge summary at theVA: "On July 16 the patient was consented forguillotine amputation. The operation was

discussed at length and he agreed that it washis best option."


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Me: "In addition to her abdominal infection, itlooks like she has also infarcted her left lobe ofher transplanted liver.

Social Worker: "I hope it's not anything moreserious."


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73 F with DM II, RA, and paroxysmal atrial fibs/p AV node ablation with pacemakerimplantation presented to outpatient clinic

with worsening fatigue for last several monthsthat she states is due to daily episodes of atrialfib. She also reports some intermittenthematuria, large bruises, and bleeding gums.

Some loose stools over this time.


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PMH:Parox AF

DMRAHTN

Meds:

WarfarinKClChlorthalidoneSotalol (recently increasedfrom 80 to 120 BID)LosartanAmlodipineSertralineZolpidem

Metformin

Family History:MCHF at age 83FAccidental deathBrotherOpen heart

surgery x 2SisterUnknown cardiacproblems

Social History:Married. Retired. No

tobacco or ETOH. Rarecaffeine.


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T 98.1 F, HR 60 BP 128/54, RR 16, SaO2 96% on RA

Gen: Awake, alert, NAD

HEENT: Clear OP. Mild conjunctival pallor.

Neck: No JVD. No LAD.

Lungs: CTAB

CV: NR, RR, no M/R/G.

Abd: Soft. NT. ND.

Neuro: Non-focal.

Skin: Ecchymoses on both dorsal forearms and hands. Norash.


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EKG:

PM interrogation: normal PM function. 16episodes of AF in last 8 months; longest 5hours.


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4.1

24

187136 103 11

4.4 28 1.0

91

9.8

Prot 7.4

Alb 4.2AST 43ALT 36Alk P 108

MCV 75

Retic 2.4

TSH 3.1

INR 4.4

UA nl

Iron 22

Ferritin 17TIBC 380Fibrinogen224Smear: noschistocytes


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INR history, recent

1.6, 1.6, 2.9, 4.4, 1.8, 3.2, 3.4, 1.4, 1.1, 1.9, 2.4, 2.3, 3.8,5.1, 2.1, 1.3, 1.5, 3.7

Stools dark, borderline melanic

Colonoscopy without identified discrete sourceof bleeding


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Coumadin stopped

CHADS2 revisited: 2 (~4.0% risk of stroke/yr)

*=part ofCHADS2score

Lip et al. Chest. 2010 Feb;137(2):263-72. Epub 2009 Sep 17.

*****


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Decision was made to restart anticoagulationwith a new medication

Dabigatran (Pradaxa)

Direct thrombin inhibitor


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Relative risk

reduction ofstroke ~60%

Absolute increase

risk of bleeding toat least 1%/yr

Olsen et al. Lancet. 2003.Brouwer, Verheugt.Circulation. 2002.


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Coumadin stopped

CHADS2 revisited: 2 (~4.0% risk of stroke/yr)

*=part ofCHADS2score

Lip et al. Chest. 2010 Feb;137(2):263-72. Epub 2009 Sep 17.

****

*


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Dicoumarol discovered in 1939 at WisconsinUniversity First hinted at by cattle hemorrhaging after eating spoiled

hay

Modified slightly to make Warfarin in 1948 More potent

The WARF

Originally used arodenticide

Used in humansin 50s


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Risk ofthrombosistoo high

T

herapeuticwindo

w

Risk ofbleeding isprohibitive

INR 1.0 2 3 5 10

Hylek et al. NEJM. 2003.


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1950s: Hirudin, first thrombin inhibitorisolated from leeches

1987: First factor Xa inhibitor, antistatin, was

isolated from Mexican leech 1990: Tick anticoagulant peptide (TAP, another

Xa inhibitor) isolated

2001: Approval of Fondaparinux, indirectparenteral Factor Xa inhibitor

Potentiates antithrombin effect on Xa

Perzborn et al.

Drug Class Oral ParenteralVitamin KAntagonists WarfarinFactor Xainhibitors + Heparin, fondaparinux,enoxaparin, dalteparinDirect Xa

inhibitors (Antistatin, TAP)Factor IIainhibitors

Argatroban,bivalirudin, lepirudin,hirudin


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Comparison

Stroke Major bleeding

Odds ratio,

95% CI

p valueOdds ratio, 95

percent CI

p value

Conventionaldose warfarinversus placebo

0.31 (0.19 to0.50)

0.2

Conventionaldose warfarinversus aspirin

0.66 (0.45 to0.99)

0.04 1.61 (0.75 to 3.44) >0.2

McNamara, RL, Tamariz, LJ, Segal, JB, Bass, EB, Ann InternMed 2004; 139:1018.


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Risk-adjusted registryin those with highthromboembolic risk hazard ratios forthromboembolism (Coumadin=1.0)

1.81 with ASA (1.73-1.90) 1.14 for coumadin + ASA (1.06-1.23)

1.86 if no treatment (1.78-1.95)

Bleeding:

0.93 (ASA; 0.890.97)

1.64 (VKA+ASA; 1.551.74)

0.84 (no treatment; 0.810.88)

Olesen et al. Thromb Haemost 2011; 106: 739749


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More basic=

strongerinhibitor

Less basic=

increased oralbioavailability


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Rivaroxaban

Factor Xa inhibitor candidate found throughhigh throughput screening


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Drug Class Oral ParenteralVitamin KAntagonists WarfarinFactor Xainhibitors + Heparin, fondaparinux,enoxaparin, dalteparinDirect Xa

inhibitorsFactor IIainhibitors

Argatroban,bivalirudin, lepirudin,hirudin

Rivaroxaban,apixaban,

edoxabanDabigatran,ximelagatran*


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Drug Year

Warfarin

TTR* Death HR Stroke HR

Major Bleeding

HR

Intracranial

Hemorrhage HR

RE-LY Dabigatran 9/2009 64%

0.88

(0.77-1.00)

0.66

(0.53-0.82)* 1.16 (1.00-1.34) 1.32 (0.80-2.17)

ROCKET AF Rivaroxaban 9/2011 55%

0.92

(0.82-1.03)

0.79

(0.66-0.96)* 1.04 (0.90-1.20) 0.67 (0.47-0.93)*

ARISTOTLE Apixaban 9/2011 62%

0.89

(0.80-0.99)*

0.79

(0.66-0.95)* 0.69 (0.60-0.80)* 0.51 (0.35-0.75)*


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0

0.2

0.4

0.6

0.8

1

1.2

1.4

Death Stroke Major Bleeding IntracranialHemorrhage

Dabigatran

Rivaroxaban

Apixaban

Efficacy and Safety Hazard Ratios vs Warfarin

Warfarin=1.0

**

* **

**

*statistically significant


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Eerenberg E S et al. Circulation 2011;124:1573-1579


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Cutoff=$50,000/QALY


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Dawood Darbar, MD

Associate Professor of Medicine

Division of Cardiology


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Anti Coagulation