Download - 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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