Jay Montgomery 3/13/12

From a surgical discharge summary at the VA: "On July 16 the patient was consented for guillotine amputation. The operation was discussed at length and he agreed that it was his best option."

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

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

73 F with DM II, RA, and paroxysmal atrial fib s/p AV node ablation with pacemaker implantation presented to outpatient clinic with worsening fatigue for last several months that she states is due to daily episodes of atrial fib. She also reports some intermittent hematuria, large bruises, and bleeding gums. Some loose stools over this time.

PMH:
Parox AF DM RA HTN

Social History:
Married. Retired. No tobacco or ETOH. Rare caffeine.

Meds:
Warfarin KCl Chlorthalidone Sotalol (recently increased from 80 to 120 BID) Losartan Amlodipine Sertraline Zolpidem Metformin

Family History:
MCHF at age 83 FAccidental death BrotherOpen heart surgery x 2 SisterUnknown cardiac problems

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. No rash.

EKG:

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

4.1 24

187

136 4.4

103 28

11 1.0

91 9.8

MCV 75 Retic 2.4

Iron 22 Ferritin 17 TIBC 380 Fibrinogen 224 Smear: no schistocytes

Prot 7.4 Alb 4.2 AST 43 ALT 36 Alk P 108

TSH 3.1 INR 4.4 UA nl

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 source of bleeding

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

*=part of CHADS2 score

* * * * *

Lip et al. Chest. 2010 Feb;137(2):26372. Epub 2009 Sep 17.

Decision was made to restart anticoagulation with a new medication

Dabigatran (Pradaxa)
Direct thrombin inhibitor

Relative risk reduction of stroke ~60%

Absolute increase risk of bleeding to at least 1%/yr

Brouwer, Verheugt. Circulation. 2002.

Olsen et al. Lancet. 2003.

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

*=part of CHADS2 score

* * * * *

Lip et al. Chest. 2010 Feb;137(2):26372. Epub 2009 Sep 17.

Dicoumarol discovered in 1939 at Wisconsin University

First hinted at by cattle hemorrhaging after eating spoiled hay

Modified slightly to make Warfarin in 1948

More potent

Originally used a rodenticide Used in humans in 50s

The WARF

INR 1.0

10

Therapeutic window

Risk of thrombosis too high

Risk of bleeding is prohibitive

Hylek et al. NEJM. 2003.

isolated Vitamin K from leeches Antagonists Warfarin Xa inhibitor, antistatin, was 1987: First factor

Drug ClassHirudin, first thrombin inhibitor Oral Parenteral 1950s:

isolated from Mexican leech Factor Xa Heparin, fondaparinux, 1990: Tick anticoagulant peptide (TAP, another inhibitors + enoxaparin, dalteparin Xa inhibitor) isolated Direct Xa 2001: inhibitors Approval of Fondaparinux, indirect (Antistatin, TAP) parenteral Factor Xa inhibitor Argatroban,

IIa Factor Potentiates antithrombin effect on Xa bivalirudin, lepirudin, inhibitors hirudin

Perzborn et al.

Comparison

Stroke Odds ratio, p value 95% CI

Major bleeding Odds ratio, 95 percent CI 1.88 (0.88 to 4.0)

p value 0.10

Conventional 0.31 (0.19 to dose warfarin <0.001 0.50) versus placebo Aspirin versus placebo 0.68 (0.46 to 0.06 1.02) 0.66 (0.45 to 0.04 0.99)

0.82 (0.37 to 1.78) >0.2 1.61 (0.75 to 3.44) >0.2

Conventional dose warfarin versus aspirin

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

Risk-adjusted registryin those with high thromboembolic risk hazard ratios for thromboembolism (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) 0.93 (ASA; 0.890.97) 1.64 (VKA+ASA; 1.551.74) 0.84 (no treatment; 0.810.88)

Bleeding:

Olesen et al. Thromb Haemost 2011; 106: 739749

More basic= stronger inhibitor

Less basic= increased oral bioavailability

Factor Xa inhibitor candidate found through high throughput screening

Rivaroxaban

Drug Class

Oral

Parenteral

Vitamin K Antagonists Warfarin

Factor Xa inhibitors + Direct Xa inhibitors Factor IIa inhibitors Rivaroxaban, apixaban, edoxaban Dabigatran, ximelagatran* Argatroban, bivalirudin, lepirudin, hirudin Heparin, fondaparinux, enoxaparin, dalteparin

Drug RE-LY

Year

Warfarin TTR*

Dabigatran 9/2009

ROCKET AF Rivaroxaban 9/2011 ARISTOTLE Apixaban 9/2011

Death HR 0.88 64% (0.77-1.00) 0.92 55% (0.82-1.03) 0.89 62% (0.80-0.99)*

Stroke HR 0.66 (0.53-0.82)* 1.16 (1.00-1.34) 1.32 (0.80-2.17) 0.79 (0.66-0.96)* 1.04 (0.90-1.20) 0.67 (0.47-0.93)* 0.79 (0.66-0.95)* 0.69 (0.60-0.80)* 0.51 (0.35-0.75)*

Major Bleeding Intracranial HR Hemorrhage HR

Efficacy and Safety Hazard Ratios vs Warfarin

1.4 1.2 1 0.8 0.6 0.4 0.2 0

* *

Warfarin=1.0

* *

Dabigatran

Rivaroxaban Apixaban

Death

Stroke

Major Bleeding

Intracranial Hemorrhage

*statistically significant

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

Cutoff= $50,000/QALY

Dawood Darbar, MD Associate Professor of Medicine Division of Cardiology

Granger C B , Armaganijan L V Circulation 2012;125:159-164