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2013 Update on Venous Thromboembolism Stephan Moll, MD University of North Carolina Chapel Hill, NC Advocate Lutheran General Hospital; Park Ride, IL,

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Presentation on theme: "2013 Update on Venous Thromboembolism Stephan Moll, MD University of North Carolina Chapel Hill, NC Advocate Lutheran General Hospital; Park Ride, IL,"— Presentation transcript:

1 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,

2 Disclosures Consultant: Janssen, Boehringer-Ingelheim, Daiichi Speaker bureau: none

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

4 Q1: Outpatient or inpatient? Diagnosis few days later 3 moany time Patient

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

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

7 A.Outpatient? B.Admit? How to manage this patient? Question – Outpatient vs. Inpatient? Unprovoked PE. VTE risk factors: (a) obesity. Diagnosis

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

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 dx’d 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]

10 PESI = Pulmonary Embolism Severity Index [Aujesky D et al. Am J Respir Crit Care Med 2005;15;172(8):1041-6]

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

12 Q1: Outpatient or inpatient? Q2: Thrombolytics? Diagnosis few days later 3 moany time Patient

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?

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; ]

15 Thrombolytics? [http://clinicaltrials.gov/ct2/show/NCT ?term=peitho&rank=1] [http://clinicaltrials.gov/ct2/show/NCT ?term=ATTRACT&rank=1] PEITHO trial: 1,006 patients with RV stain PLUS pos. troponin: thrombolytics versus placebo; results spring ATTRACT trial 392/692 patients enrolled as of Jan 8 th, 2013.

16 Q1: Outpatient or inpatient? Q2: Thrombolytics? Q3: LMWH/warfarin or rivaroxaban? Diagnosis few days later 3 moany time Patient

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

18 [Garcia D et al. Blood Jan 7;115(1): Review] DabigatranRivaroxabanApixaban tmax hrs2 - 4 hrs1 - 3 hrs Half life hrs 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)

19 Rivaroxaban in Acute DVT and PE [Bueller H et al. NEJM 2010;363: ] A. DVT study [Bueller H et al. NEJM 2012;366: ] B. PE study

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: ] [Bueller H et al. NEJM 2012;366: ] Nov 2012

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?

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 doesn’t like idea of “no known reversal agent/strategy”.

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. John’s wort F/u with you in 3 weeks and in 3 months, then yearly. Things to consider when starting rivaroxaban

24 Rivaroxaban Acute or previous VTE: Rivaroxaban is a possible treatment option. Teaching point #2

25 Other Drug Approvals in 2012

26 Apixaban in Atrial Fibrillation [Granger CB et al. N Engl J Med 2011;365:981-92]

27 Apixaban in Atrial Fibrillation Apixaban… a) is MORE effective than warfarin b) leads to LESS major bleeding. Dec 2012

28 Hospital Guide for New Oral Anticoagulants Dabigatran : Rivaroxaban : Apixaban : %20Updated% pdf Comprehensive management documents: : UNC and rivaroxaban Teaching Point #3

29 New Oral Anticoagulants: Cost Per day: $ 9.20 to $ (ca. $ /day) Per month: $ to (ca. $ /mo) [personal communciations: evaluation of Average Wholesale Price (AWP) and inquiry from 3 national pharmacy chains; Jan 28, 2013]

30 VTE Brochure [http://files.www.clotconnect.org/DVT_and_PE.pdf]

31 VTE Brochure Teaching point #4

32 Q1: Outpatient or inpatient? Q2: Thrombolytics? Q3: LMWH/warfarin or rivaroxaban? Q4: Compression stockings? Diagnosis few days later 3 moany time Patient

33 Compression stockings probably/possibly do not prevent PTS. Teaching point #5 [Kahn SR;ASH 2012;abstract 393] Compression Stockings? SOX trial

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

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?

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]

37 VTE Recurrence – Risk Assessment Scores HERDOO-2 score DASH score [Rodger M et al; CMAJ 2008;179: ] [Tosetto A et al. J Thromb Haemost 2012 Jun;10(6): ]

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: ] How Long to Treat With Warfarin? - HERDOO-2 Women

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): ]

40 Patient‘s Preference 0 10 “Coumadin hate factor”

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:

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

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

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

45 Rivaroxaban in VTE, Secondary Prophylaxis [Bueller H et al. NEJM 2010;363: ] VTE extension study

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

47 Aspirin and VTE Prevention placebo aspirin HR % CI 0.36 to 0.93 p= 0.02 A. WARFASA study [Becattini C et al; NEJM 2012; 366: ]

48 [Brighton TA, et al. N Engl J Med Nov 22;367(21): ] B. ASPIRE study Aspirin and VTE Prevention

49 [Brighton TA, et al. N Engl J Med Nov 22;367(21): ] C. Meta-analysis Aspirin and VTE Prevention – Meta-Analysis

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

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

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]

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

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

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]

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

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

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.

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.

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