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VTE: It’s still a killer in Canada

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Presentation on theme: "VTE: It’s still a killer in Canada"— Presentation transcript:

1 VTE: It’s still a killer in Canada
Sam Schulman, MD, PhD Dept. of Medicine McMaster University

2 Faculty/Presenter Disclosure
Faculty: Dr. Sam Schulman Program: 51st Annual Scientific Assembly Relationships with commercial interests: Grants/Research Support: N/A Speakers Bureau/Honoraria: Boehringer Ingelheim and Bayer Healthcare for work in study-related committees Consulting Fees: N/A Other: N/A

3 Disclosure of Commercial Support
This program has received financial support from Boehringer Ingelheim and Bayer Healthcare in the form of Honorarium. This program has received in-kind support from N/A Potential for conflict(s) of interest: Dr. Sam Schulman has received Honorarium from Bayer Healthcare and Boehringer Ingelheim whose products are being discussed in this program. Bayer Healthcare and Boehringer Ingelheim sell products that will be discussed in this program: rivaroxaban and dabigatran.

4 Mitigating Potential Bias
All treatment alternatives are discussed

5 Contents Case discussion Epidemiological data
Who is at the highest risk Extended prophylaxis – when? Diagnosis – missing and overinterpreting Treatment – a lot easier now How long after VTE – a dilemma

6 Unfortunate case 65 y.o. male, fell from ladder.
X-rays normal except for L4 burst # on CT No bleeding, Hgb stable Sharp back pain, remains bedridden in hospital. On day 3 urinary problems and weakness in one leg  scheduled for decompression laminectomy next day. SaO % all the time Surgery Day 4 in late afternoon. Suspected MI in recovery  arrest. CPR unsuccessful – large PE

7 PE - mortality 10% succumb within 1 h
Usually before arrival at the hospital PE – 3rd leading cause of cardiovascular death

8 Risk factors for VTE Surgery Trauma Immobility, paresis Malignancy
Cancer therapy Previous VTE Increasing age Pregnancy / postpartum Estrogens Selective estrogen receptor modulators Acute medical illness Heart or respiratory failure Inflam. bowel disease Nephrotic syndrome Myeloprolif disorders PNH Obesity Smoking Varicose veins Central venous catheter Thrombophilic defect ACCP Guidelines on Antithrombotic and Thrombolytic Therapy

9 Cancellation of Sx day after day – not an uncommon phenomenon
Waiting time for hip# Sx often 3 days Typical order: ”NPO for surgery in a.m.”, ”Hold heparin” Heparin or LMWH evening before does not increase bleeding. These patients have to receive LMWH qHS Even neuraxial anesthesia next morning is OK (10-12 h after last dose) American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines, 3rd ed., 2010

10 Postop VTE prophylaxis
Necessary if patient not mobilizing within 24 h Bleeding risk – use mechanical devices Otherwise ”chemoprophylaxis” – usually until discharge. Consider extension if patient not mobilizing at that time point Use a risk assessment score, e.g. Caprini Gould MK et al. ACCP Guidelines. CHEST 2012; 141 Suppl:

11 Data on incidence of VTE
Worcester, MA – all medical records 1999 with VTE diagnosis: 104 per 100,0001 Olmsted County, MN – medical records of all residents with VTE , incl PE on autopsy: 117 per 100,0002 Sweden – Men born 1913, followed from age 50: 387 per 100,0003 Bretagne, France – Diagnosis data: 184/100,0004 Spencer FA. J Gen Intern Med 2006 Silverstein MD. Arch Intern Med 1998 Hansson PO. Arch Intern Med 1997 Oger E and EPI-GETBO. Thromb Haemost 2000

12 Survival after VTE Olmsted County inception cohort
7-day 30-day 1-year DVT 96.2% 94.5% 85.4% PE ±DVT 59.1% 55.6% 47.7% VTE 74.8% 72.0% 63.6% Olmsted County inception cohort Followed , n=2218 Risk factors for death PE Age BMI Patient onset Malignancy CHF More risk factors Neurologic disease Chronic lung disease Recent Sx Hormone Rx Smoking tobacco Chron renal disease Heit JA et al. Arch Intern Med 1999;159:445-53

13 Survival after VTE >1/3 of deaths were on day of onset/unrecognized VTE Heit JA et al. Arch Intern Med 1999;159:445-53

14 Effect of age White, R. H. Circulation 2003;107:I-4-I-8
Annual incidence of VTE among residents of Worcester MA 1986, by age and sex White, R. H. Circulation 2003;107:I-4-I-8 Copyright ©2003 American Heart Association 14 14

15 Prevalence of VTE is predicted to double by 2050
Adults 18 years and older with VTE in USA (millions) 0.5 1 1.5 2 2002 2003 2004 2005 2006 2008 2010 2015 2020 2025 2030 2035 2040 2045 2050 VTE cases per : Year 2002 2003 2004 2005 2006 2008 2010 2015 2020 2025 2030 2035 2040 2045 2050 317 341 371 401 422 426 432 453 478 505 527 544 556 563 567 VTE = venous thromboembolism Deitelzweig SB et al. Am J Haematol 2011;86:217–20 15

16 Patients at highest risk
Recent VTE Malignancy Spinal cord injury Heparin-induced thrombocytopenia

17 Increased prophylactic dose
Spinal cord injury Burn injury Bariatric surgery

18 Bariatric surgery >100,000 procedures in the US
Consecutive patients Early ambulation & mechanical proph. Group 1: enoxaparin 30 mg bid (n=92) DVT 5.4% Group 2: enoxaparin 40 mg bid (n=389) DVT 0.6% Scholten DJ et al. Obes Surg 2002;12:19-24 >100,000 procedures in the US Incidence of reported VTE 0.1% - 1%, fatal PE 0.2% Mainly after discharge 95% of US surgeons give prophylaxis LMWH, UFH tid or fondaparinux: May add mechanical. Higher doses than standard

19 Extended postop prophylaxis, i.e. up to 1 month instead of 1 week
High risk of VTE + pelvic/abdominal Sx for cancer (Grade 1B) Results in 13 fewer non-fatal events per 1000 without significant increase in bleeding Major orthopedic surgery (THR, TKR, HFS) – minimum d (Grade 1B) and suggest up to 35 d (Grade 2B) Results in 9 fewer non-fatal events per 1000 without significant increase in bleeding ACCP Guidelines. CHEST 2012; 141 Suppl

20 Spinal cord injury In case of paraplegia:
Very high risk at least first month Continued increased risk 3 months Then normalization

21 Logistics not an excuse now
LMWH/fondaparinux are parenteral. Rivaroxaban 10 mg or dabigatran 150/220 mg once daily or apixaban 2.5 mg twice daily are available and approved for THR and TKR Effective and safe, cost-effective vs LMWH

22 The Primary Outcomes – Ortho Sx
D a b i R i v a A p i x a RE-MODEL TKR Non-inferior RE-MOBILIZE TKR Inferior RE-NOVATE THR Non-inferior RE-NOVATE II THR Non-inferior RECORD 1 THR Superior RECORD 2 THR Superior RECORD 3 TKR Superior RECORD 4 TKR Superior ADVANCE 1 TKR Non-inferiority not met ADVANCE 2 TKR Superior ADVANCE 3 THR Superior

23 Suspected DVT / PE

24 Typical case 36 y.o. lady with pain in the R calf x 3d
Previously healthy Went for a long walk last weekend Was on COC for 10 years, stopped at age 28, restarted 3 months ago. Physical: Tender calf, no edema or SOB


26 Reduction of imaging diagnostics
Active cancer Paralysis, recent immob 1 Recently bedridden >2 d 1 Localized tenderness 1 Calf swelling >3 cm 1 Unilat pitting edema 1 Collateral superf. veins 1 Previous documented DVT 1 Alt. Dx at least as likely -2 <2 p – unlikely >2 p - likely Use Wells’ score and D-dimer – Only if low score + neg D-dimer will result in No imaging D-dimer: Not useful In generally ill patients Shortly after surgery Differential vs cellulitis Very elderly (>80) Long duration of symptoms

27 Ultrasound pitfalls Very difficult to tell new from old if no comparison If proximal swelling – ask for iliac and inferior v cava veins Should do both legs even if unilat spt

28 Do we have to treat distal DVT?
Analysis of 5 studies of sympt calf DVT without treatment (Rhigini et al 2006): Progression proximally in 25 of 353 (7%) RCT (N=196): VKA alone UFH 5,000 x2 UFH 12,000 x1 Placebo 11% 7% 78% 2.3% 0% 25% Rhigini: progression in 7% on venography or US. Progression 0-8 w 9-24 w (ultrasound) Belcaro G et al. Minerva Med 1997;88:507-14

29 Calf DVT: Risk factors for progression
Positive D-dimer Extensive calf DVT or close to proximal Unprovoked or persistent risk factor Active cancer History of VTE Hospitalized patient Kearon C et al. ACCP Guidelines. CHEST 2012; 141 Suppl

30 Practical approach Treat if very symptomatic or risk factors for extension (Grade 2C) With increasing risk of bleeding – consider not treating – but do serial ultrasound. (Grade 2C) Progression is most common first 2 w. Kearon C et al. ACCP Guidelines. CHEST 2012; 141 Suppl


32 Suspected PE Wells’ clinical prediction score for PE
Previous PE or DVT +1.5 Heart rate > 100/min +1.5 Recent surgery or immobilization +1.5 Clinical signs of DVT +3 Alternative diagnosis less likely than PE +3 Hemoptysis +1 Cancer +1 Dichotomized rule Unlikely < 4 Likely > 4 Wells PS et al. Thromb Haemost. 2000;83:416-20


34 Can my PE-patient in ER go home?
Pulmonary Embolism Severity Index (PESI) Age 1 p / yr SBP < p Male sex 10 p Pulse > p Cancer 30 p RR>30 20 p CHF 10 p Temp <36 20 p Chron lung dis. 10 p SaO2 <90% 20 p  mental status 60 p 85 p or less = low risk of fatal PE – NPV = 99% Aujesky D et al. Am J Resp Crit Care Med 2005;172:1041–6 External validation in: J Intern Med 2007;261:

35 Simplified PESI Retrospective analysis of RIETE registry
Age >80 1 p History of Cancer 1 p Chron cardiopulmonary dis. 1 p Pulse > p CHF 1 p SBP < p SaO2 <90% 1 p 0 = low risk, 1 or more = high risk Jiménez D et al. Arch Intern Med. 2010;170:1383-9

36 Simplified PESI result
Jiménez D et al. Arch Intern Med. 2010;170:1383-9

37 Initial standard anticoagulation
Generally same treatment for DVT and PE (=VTE): UFH iv – weight adjusted (bolus 80 U/kg, infusion at 18 U/kg/h)* UFH s.c. 250 U/kg bid * UFH s.c. 17,500 U bid * UFH s.c. 333 U/kg 1st dose, then 250 U/kg bid without monitoring LMWH s.c. without monitoring Fondaparinux s.c. 7.5 ±2.5 mg daily Rivaroxaban 15 mg p.o. BID x 3 w, then 20 mg q.d. – LU-code 444 * Monitored to keep anti-Xa at IU/mL – at 6 h for s.c. 1B

38 Clinical Outcomes During the Study Period
UFH 250 U/kg bid vs LMWH 100 IU/kg bid FIDO-Study Clinical Outcomes During the Study Period Event UFH LMWH Recurrence 3.8% 3.4% Maj Bleed 1.7% 3.4% Any Bleed 8.3% 8.5% Death 5.2% 6.3% Kearon, C. et al. JAMA 2006;296: Copyright restrictions may apply.

39 UFH sc in renal failure Increased risk of bleeding with any anticoagulant – NOACS, warfarin, LMWH, heparin Lack of good studies but reduce dose for NOACS, LMWH and UFH UFH sc Hamilton for CrCl <30 1st dose 250 IU per kg Then 200 IU per kg q 12 h.

40 Oral Factor Xa inhibitor, rivaroxaban: EINSTEIN-DVT/PE
Objectively confirmed DVT without symptomatic PE Randomisation Predefined treatment period of 3, 6, 12 months Eligible patients Rivaroxaban 15 mg twice daily N~2900 Rivaroxaban 20mg once daily R EINSTEIN-PE Objectively confirmed PE with or without symptomatic DVT N~3300 Enoxaparin twice daily for at least 5 days, plus VKA target INR 2.5 (INR range 2–3) Day 1 Day 21 Day 30 after last dose DVT=deep vein thrombosis; INR=international normalised ratio; LMWH=low molecular weight heparin PE=pulmonary embolism; VKA=vitamin K antagonist 40

41 Rivaroxaban – a new option Einstein DVT
Major or clinically relevant bleeding in 8.1% per group Bauersachs R et al.NEJM 2010; 363:

42 Rivaroxaban – a new option Einstein PE
Major or clinically relevant bleeding in 10.3% (riva) vs % (standard Rx) Büller HR et al. NEJM 2012

43 Caveats for rivaroxaban
Not for severe renal dysfunction (calc CrCl <30 mL/min) Few of the study patients hade extensive DVT or large PE. These patients might benefit from intial parenteral Rx. Dose change at 3 weeks (15 mg BID  20 mg q.d.) Dose with food – more reliable absorption

44 Standard duration of anticoagulation is now 3 m.
6 months? 27 months? Schulman S et al. N Engl J Med 1995; 332: Kearon C et al. N Engl J Med 1999; 340: 901-6 1A

45 WODIT Agnelli et al. NEJM 2001

46 Recurrent DVT after stopping
Patients with unprovoked DVT 3 months Rx – 10% first year after (WODIT) 6 months Rx – 10% first year after (DURAC) 12 months Rx – 10% first year after (WODIT) 24 months Rx – 10% first year after (LAFIT) No difference 3 vs 6 months in patients with proximal DVT or PE in DOTAVK Pinede et al: Circulation; May 27, 2001 (DOTAVK)

47 A meta-analysis on individual data N=2474
PE as a risk factor A meta-analysis on individual data N=2474 Pinede et al. ASH 2003

48 Decision on long-term at 3 m
Long-term treatment for Unprovoked VTE Second episode Cancer Unless bleeding risk or adequate monitoring unavailable 1B

49 Suggestions for duration of VKA
Proximal DVT and permanent risk or PE Bleeding, Poor compliance Old age Needs ASA Female? Mild thrombophilic defect / Second VTE Third VTE or more, Severe thrombophilia, Severe venous insuff., Pulmonary hypertension 3 m m m m Indefinitely Patient preferences

50 Or … Provoked and small DVT or small PE: 3 m Unprovoked small DVT: 3 m
Unprovoked extensive DVT: 6 m Unprovoked extensive PE: 1 y

51 Elevated D-dimer

52 Management strategy – unprovoked VTE
D-dimer Dx m m Pos Neg Pos 8.9%/yr Neg Neg 3.5%/yr Verhovsek M. Ann Intern Med. 2008;149:481-90

53 D-dimer in males Several studies indicate that males have despite normalization of D-dimer a higher risk of recurrence.

54 Conclusions Several risk scores and risk stratification tools are available and should be used Diagnostic algorithm for DVT/PE is helpful Many options for treatment of VTE exist Decide at 3-6 months regarding stopping or indefinite anticoagulation Extended postoperative prophylaxis after THR, TKR, HFS and abdominal/pelvic Sx for cancer

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