2013 Update on Venous Thromboembolism Stephan Moll, MD
University of North Carolina Chapel Hill, NC Advocate Lutheran
General Hospital; Park Ride, IL, March 2 nd, 2013 12345 Slide 2
Disclosures Consultant: Janssen, Boehringer-Ingelheim, Daiichi
Speaker bureau: none Slide 3 The 3 Major Developments in 2012
Approval of Apixaban for atrial fibrillation III Publication of
ACCP Guidelines 2012 I Approval of Rivaroxaban for VTE II Slide 4
Q1: Outpatient or inpatient? Diagnosis few days later 3 moany time
Patient Slide 5 Case - PE 63 year old man, quite healthy 4 days h/o
moderate CP + SOB; now SOB with 1 flight of stairs. No leg symptoms
No preceding trauma, immobility, surgery, long-distance travel HPI
Arthroscopic knee surg 2 yrs ago HTN; Obesity (BMI 32.3) No h/o
cancer; no h/o bleeding PMH Negative for VTE FH Slide 6 BP 135/87;
P 92 / min RR at rest 16 min, not SOB when talking; O 2 on RA 93 %
BMI 32.3; lungs clear; legs R=L Physical Exam CTA chest Case RUL
segmental PE, L UL and LL subsegmental PE Slide 7 A.Outpatient?
B.Admit? How to manage this patient? Question Outpatient vs.
Inpatient? Unprovoked PE. VTE risk factors: (a) obesity. Diagnosis
Slide 8 ACCP 2012 [Kearon C et al. Chest
2012;141(2)(Suppl):e419S-e494S] Recommend home treatment for DVT
(1B) and early d/c for low-risk PE. (2B). Acute Treatment Slide 9
Outpatient vs. Inpatient HESTIA Criteria [Zondag W et al. J Thromb
Haemost 2013(Jan 6 th )ePub] 1. Hemodynamically unstable? 2.
Thrombolysis or embolectomy needed? 3. Active bleeding or high risk
of bleeding? 4. Oxygen needed to keep O 2 saturation > 90 % for
> 24 hrs? 5. PE dxd during anticoagulant therapy? 6. iv pain
meds for > 24 hrs? 7. Medical or social reason for admission? 8.
GFR < 30 ml/min? 9. Severe liver impairment? 10. Pregnant? 11.
Documented h/o HIT? [Zondag W et al. J Thromb Haemost
2011;9:1500-7] Slide 10 PESI = Pulmonary Embolism Severity Index
[Aujesky D et al. Am J Respir Crit Care Med 2005;15;172(8):1041-6]
Slide 11 Outpatient vs. Inpatient HESTIA Score Outpatient PE
management Suitable for, may be, 50 % of PE patients; HESTIA
criteria can be useful for decision making. Teaching point #1 Slide
12 Q1: Outpatient or inpatient? Q2: Thrombolytics? Diagnosis few
days later 3 moany time Patient Slide 13 [Kearon C et al. Chest
2012;141(2)(Suppl):e419S-e494S] For PE, with hypotension or high
risk for hypotension: suggest thrombolytics, systemically. 2C For
DVT, suggest anticoagulant therapy alone over thrombolysis
(catheter-directed or systemic). 2C Thrombolytics? Slide 14 PE:
Indicators of Poor Outcome ESC criteria (based on consensus; lack
of validation) Criteriamortality High riskCardiovascular shock or
persistent hypotension > 30 % Intermediate riskLab (troponin,
BNP) or RV dysfunction 1-30 % Low risknl labs (troponin, BNP); nl
RV function < 1 % [Torbicki A et al. Eur Heart J 2008;2276-315]
Slide 15 Thrombolytics?
[http://clinicaltrials.gov/ct2/show/NCT00639743?term=peitho&rank=1]
[http://clinicaltrials.gov/ct2/show/NCT00790335?term=ATTRACT&rank=1]
PEITHO trial: 1,006 patients with RV stain PLUS pos. troponin:
thrombolytics versus placebo; results spring 2013. ATTRACT trial
392/692 patients enrolled as of Jan 8 th, 2013. Slide 16 Q1:
Outpatient or inpatient? Q2: Thrombolytics? Q3: LMWH/warfarin or
rivaroxaban? Diagnosis few days later 3 moany time Patient Slide 17
A.LMWH or fondaparinux / warfarin B.Rivaroxaban (Xarelto)
C.Dabigatran (Pradaxa) D.Apixaban (Eliquis) Outpatient management
is chosen. CBC, PT, aPTT normal; Creatinine 0.95; liver enzymes
normal. How would you treat? Question Anticoagulant Choice Slide 18
[Garcia D et al. Blood. 2010 Jan 7;115(1):15-20. Review]
DabigatranRivaroxabanApixaban tmax1.5 - 3 hrs2 - 4 hrs1 - 3 hrs
Half life12 - 14hrs9 - 13 hrs8 - 15hrs Renal excretion 80%66 %ca.
25 % FDA approval A. fib VTE prevention VTE treatment A. fib New
Oral Anticoagulants In clinical development: Edoxaban, Betrixaban
(not FDA approved) Slide 19 Rivaroxaban in Acute DVT and PE
[Bueller H et al. NEJM 2010;363:2499-510] A. DVT study [Bueller H
et al. NEJM 2012;366:1287-97] B. PE study Slide 20 Rivaroxaban
Clinically relevant bleeding (composite of major and clinically
relevant non-major bleeding): Same. Major bleeding: Same (DVT
study) or less (PE study). BLEEDING [Bueller H et al. NEJM
2010;363:2499-510] [Bueller H et al. NEJM 2012;366:1287-97] Nov
2012 Slide 21 Rivaroxaban a)Acute DVT or PE All patients treated as
outpatients Mild to moderate DVT; HESTIA criteria for PE b)On
long-term warfarin I discuss it with all patients Fluctuating INRs,
high warfarin hate factor In which patient do I consider
rivaroxaban? Slide 22 Rivaroxaban In which patient would I NOT use
rivaroxaban? Renal impairment: GFR < 30 ml/min (or 40; buffer
zone) by Cockroft-Gault Liver disease Increased bleeding risk;
particularly GI bleeding Acute cerebral vein thrombosis BMI > 40
or low body weight Cancer Patient who doesnt like idea of no known
reversal agent/strategy. Slide 23 Rivaroxaban LABS: CBC,
creatinine, AST, ALT, t. bili GFR > 30 ml/min Check with
insurance carrier ($ 335 / month) 15 mg bid for 3 weeks, then 20 mg
qd Take with food (AM or PM) Drug interactions: HIV meds,
antifungal, sz drugs, St. Johns wort F/u with you in 3 weeks and in
3 months, then yearly. Things to consider when starting rivaroxaban
Slide 24 Rivaroxaban Acute or previous VTE: Rivaroxaban is a
possible treatment option. Teaching point #2 Slide 25 Other Drug
Approvals in 2012 Slide 26 Apixaban in Atrial Fibrillation [Granger
CB et al. N Engl J Med 2011;365:981-92] Slide 27 Apixaban in Atrial
Fibrillation Apixaban a) is MORE effective than warfarin b) leads
to LESS major bleeding. Dec 2012 Slide 28 Hospital Guide for New
Oral Anticoagulants Dabigatran : Rivaroxaban : Apixaban :
http://professionalsblog.clotconnect.org/wp-content/uploads/2012/05/UNC-Xarelto-2012.pdf
http://www.med.unc.edu/im/staff/clinic/files/Dabigatran%20Management%20-%20PDF%20-
%20Updated%20201111.pdf
http://patientblog.clotconnect.org/wp-content/uploads/2013/02/Apixaban-UNC-2-2013.pdf
Comprehensive management documents: : UNC and rivaroxaban Teaching
Point #3 Slide 29 New Oral Anticoagulants: Cost Per day: $ 9.20 to
$ 11.20 (ca. $ 10.00 /day) Per month: $ 276.00 to 336.00 (ca. $
300.00 /mo) [personal communciations: evaluation of Average
Wholesale Price (AWP) and inquiry from 3 national pharmacy chains;
Jan 28, 2013] Slide 30 VTE Brochure
[http://files.www.clotconnect.org/DVT_and_PE.pdf] Slide 31 VTE
Brochure www.clotconnect.org Teaching point #4 Slide 32 Q1:
Outpatient or inpatient? Q2: Thrombolytics? Q3: LMWH/warfarin or
rivaroxaban? Q4: Compression stockings? Diagnosis few days later 3
moany time Patient Slide 33 Compression stockings probably/possibly
do not prevent PTS. Teaching point #5 [Kahn SR;ASH 2012;abstract
393] Compression Stockings? SOX trial Slide 34 Q1: Outpatient or
inpatient? Q2: Thrombolytics? Q3: LMWH/warfarin or rivaroxaban? Q4:
Compression stockings? Q5: D/c anticoag or long-term? Diagnosis few
days later 3 moany time Patient Slide 35 VTE due to transient risk
factor Man with PE Man with DVT Woman with PE Woman with DVT, not
hormones Woman with DVT or PE, hormones Long-term 3 months Other
considerations: Bleeding, fluctuating INRs, lifestyle impact, pt
preference Other risk factors for recurrence: Obesity?; age? -
D-dimer + Strong Thrombophilia How Long To Treat With
Anticoagulation? Slide 36 How Long to Treat with Anticoagulation?
[Verhovsek M et al. Systematic review on D-dimer to predict
recurrent VTE. Ann Int Med 2008;149(7):481 490] [Palareti G et al.
NEJM 2006;355:1780-9] Slide 37 VTE Recurrence Risk Assessment
Scores HERDOO-2 score DASH score [Rodger M et al; CMAJ
2008;179:417-426] [Tosetto A et al. J Thromb Haemost 2012
Jun;10(6):1019-25] Slide 38 Conclusion: Women 1 d/c
anticoagulation. Men, no matter what the score, need to continue
anticoagulation. HERDOO-2 rule HER = Hyperpigmentation or Edema or
Redness D = D-dimer positivity (on warfarin) O= obesity, BMI 30 O =
Older age, 65 yrs 2 = score of 2: continue warfarin [Rodger M et
al; CMAJ 2008;179:417-426] How Long to Treat With Warfarin? -
HERDOO-2 Women Slide 39 Conclusion: Score 1: d/c anticoagulation
DASH score D = D-dimer pos (off warfarin) + 2 A = age < 50 years
+ 1 S = sex (male) + 1 H = hormone use - 2 How Long to Treat With
Warfarin? - DASH Annual VTE recurrence rate: 1: 3.1 % 2: 6.4 % 3:
12.3 % [Tosetto A et al. J Thromb Haemost 2012 Jun;10(6):1019-25]
Slide 40 Patients Preference 0 10 Coumadin hate factor Slide 41 3.
Patient preference Coumadin hate factor 2. Risk of Bleeding (a).,
(b)., (c) .. 1. Risk of recurrent VTE (a)., (b)., (c) .. VTE:
Length of Anticoagulation Conglomerate decision of: Slide 42 ACCP
2012 Guidelines: Highlights [Kearon C et al. Chest
2012;141(2)(Suppl):e419S-e494S] Surgery-associated DVT/PE:
recommend 3 months. (1B) Non-surgical transient risk factor:
recommend 3 months over 6 or more months. (1B) Unprovoked DVT/PE
and low/intermediate risk for bleeding: suggest extended
anticoagulation (2B). High bleeding risk: 3 months (1B). Cancer
patient with DVT/PE: recommend/suggest extended therapy. LMWH
rather than VKA (2C). Treatment beyond Acute Period Slide 43 VTE:
Length of Anticoagulation How long to treat with anticoagulation?
Risk factors for VTE: (a)., (b).., (c) Risk factors for bleeding:
(a)., (b).., (c) Patient preference Teaching point #6 Slide 44 Q1:
Outpatient or inpatient? Q2: Thrombolytics? Q3: LMWH/warfarin or
rivaroxaban? Q4: Compression stockings? Q5: D/c anticoag or
long-term? Q6: Warfarin or rivaroxaban? Diagnosis few days later 3
moany time Patient Slide 45 Rivaroxaban in VTE, Secondary
Prophylaxis [Bueller H et al. NEJM 2010;363:2499-510] VTE extension
study Slide 46 Patient Q1: Outpatient or inpatient? Q2:
Thrombolytics? Q3: LMWH/warfarin or rivaroxaban? Q4: Compression
stockings? Q5: D/c anticoag or long-term? Q6: Warfarin or
rivaroxaban? Q7: Aspirin vs anticoagulant? Diagnosis few days later
3 moany time Slide 47 Aspirin and VTE Prevention placebo aspirin HR
0.58 95% CI 0.36 to 0.93 p= 0.02 A. WARFASA study [Becattini C et
al; NEJM 2012; 366:1959-1967] Slide 48 [Brighton TA, et al. N Engl
J Med. 2012 Nov 22;367(21):1979-87] B. ASPIRE study Aspirin and VTE
Prevention Slide 49 [Brighton TA, et al. N Engl J Med. 2012 Nov
22;367(21):1979-87] C. Meta-analysis Aspirin and VTE Prevention
Meta-Analysis Slide 50 ASA and VTE Not clear whether Aspirin
prevents recurrent VTE. But it does lead to a net vascular benefit
(arterial and venous together). Teaching point #7 Slide 51 Q1:
Outpatient or inpatient? Q2: Thrombolytics? Q3: LMWH/warfarin or
rivaroxaban? Q4: Compression stockings? Q5: D/c anticoag or
long-term? Q6: Warfarin or rivaroxaban? Q7: Aspirin vs
anticoagulant? Q8: Surgery Diagnosis few days later 3 moany time
Patient Slide 52 When to d/c at Times of Surgery Renal function
[CrCl, mL/min] Half-life [hours] When to stop drug before surgery
(after last drug dose) Standard bleeding risk High bleeding risk
Dabigatran > 8013 (11-22)24 hrs2-4 d > 50 to 8015 (12-34)24
hrs2-4 d > 30 to 5018 (13-23) 2 d4 d 3027 (22-35)2-5 d> 5 d
Rivaroxaban >3012 (11-13)24 hrs2 d < 30 mL/minUnknown2 d4 d
[UNC 2013 treatment guidelines] Slide 53 When to d/c at Times of
Surgery No published data exist on optimal perioperative management
d/c 24 h or 48 h prior standard / high risk procedures Apixaban For
all new oral anticoagulants: D/c before surgery: 24 hrs for
standard risk surgery; 2-4 d for high risk. Consider renal fx.
Teaching point #8 Slide 54 Q1: Outpatient or inpatient? Q2:
Thrombolytics? Q3: LMWH/warfarin or rivaroxaban? Q4: Compression
stockings? Q5: D/c anticoag or long-term? Q6: Warfarin or
rivaroxaban? Q7: Aspirin vs anticoagulant? Q8: Surgery Diagnosis
few days later 3 moany time Q9: Major bleed Patient Slide 55 Major
Bleeding Reversal, Management? Problem with existing data: NO
meaningful patient data published Animals: Mice and rat tails Human
volunteers: reversal of coagulation tests Ex vivo plasma spiking
tests: reversal of coagulation tests Mice intracranial bleeding
model Best strategy not known [Zhou W et al. Stroke 2013:44:ePub]
Slide 56 Major Bleeding 1.Supportive care! Treatment Options 4.No
clotting factor therapy 2.Activated charcoal 3.Hemodialysis for
Dabigatran, not for Rivaroxaban or Apixaban Slide 57 Major Bleeding
5.Non-activated PCC (prothrombin complex concentrate) 6.Activated
PCC 7.Recombinant factor VIIa 8.FFP 9.Anti-fibrinolytic drugs
(aminocaproic acid, tranexamic acid) Treatment Options Slide 58
Summary 1.Outpatient VTE management Suitable for, may be, 50 % of
PE patients; HESTIA criteria for PE risk can be useful for decision
making. 2.Rivaroxaban for VTE (acute; previous): possible treatment
option. 3.New oral anticoagulants Starting the drugs; D/c before
surgery (24 h for standard risk; 2-4 d for high risk; Major
bleeding management. Slide 59 Summary 4.VTE Patient brochure
available 5.Compression stockings probably/possibly do not prevent
PTS. 6.How long to treat with anticoagulation? Risk factors for
VTE: (a)., (b).., (c) Risk factors for bleeding: (a)., (b).., (c)
7. Aspirin: Not clear whether it prevents recurrent VTE. I do
encourage the use. Slide 60
