Primary VTE Thromboprophylaxis

Primary VTE Thromboprophylaxis Controversies in Hematology 53 rd Annual Meeting of Thai Society of Hematology Bundarika Suwanawiboon, MD Division of Hematology Department of Medicine Faculty of Medicine Siriraj Hospital

Primary VTE Thromboprophylaxis Bleeding HIT Osteoporosis Allergic reaction Cost Prevention of VTE and VTE-related death https://idealhealthandwellness.wordpress.com

Why Controversies? Lack of generalizable data Recommendation was based on the estimated baseline risk Uncertainty of the outcome Reduction of symptomatic vs asymptomatic VTE? The relative importance of symptomatic VTE reduction and risk of bleeding to the patient, to the physician, and to the health-care system 1 Guyatt GH et al. Chest 2012;141:e185S-e194S

Comparing Apples and Oranges? http://theconversation.com, https://slideplayer.com/slide/2558077

% Low Incidence of Post-op Symptomatic VTE Without Thromboprophylaxis in Asian Population 70 60 Symptomatic DVT: 0.9% Symptomatic PE: 0.3%-0.6% 50 40 30 20 10 0 SMART venography AIDA Sakon Samama Leclerc Agnelli Ockelford Asymptomatic Total DVT Asymptomatic Proximal DVT Angchaisuksiri P. Thromb Haemost. 2011;106:585-590

Lack of Consistency in the Relationship Between Asymptomatic DVT Detected by Venography and Symptomatic VTE in Thromboprophylaxis Trials A consistent relationship between asymptomatic DVT and symptomatic VTE was examined in the systematic review of high quality VTE prevention trials 26 RCTs: 19 orthopedic trials, 5 general surgery trials, 2 general medical patient trials Overall median rates for asymptomatic DVT and symptomatic VTE 9.11% (0.75-54.87%) and 0.49%(0.00-3.10%) Median ratio of asymptomatic DVT to symptomatic VTE: 14.53 (2.75-103.86) Wide variability of the ratios precludes judging the trade-off between thrombotic and bleeding events on the basis of outcomes by venographic DVT Chan NC et al. Thromb Haemost. 2015;114:1049-57

DVT diagnosed by venography or duplex ultrasonography Surgery: hip fracture surgery, total hip and knee arthroplasty n=2454 Participants were mainly from East Asian and South-East Asian countries Thai 12.8% Kanchanabat et al. Br J Surg.2011;98:1356-64

% Incidence of Asymptomatic Post-op VTE Without Thromboprophylaxis in Asia 35 30 31.7 Symptomatic DVT: 4.5% (95%CI 1.9-8.1) 25 20 22.5 18.8 All-site Proximal Distal Symptomatic PE: 0.6% (95%CI 0.3-1.0) No death from PE 15 Isolated distal 10 8.9 9.4 5 5.9 5.9 5.8 0 Venography Ultrasonography Kanchanabat et al. Br J Surg.2011;98:1356-64

% Incidence of Asymptomatic Post-op VTE Without Thromboprophylaxis in Asia 35 30 25 20 15 31.7 22.5 18.8 All-site Proximal Distal Isolated distal Although the possible trend towards increasing incidence, and the ethnic variation, require further consideration, the lack of any reported death from VTE questions the potential benefit of routine thromboprophylaxis in these orthopaedic patients. 10 8.9 9.4 5 5.9 5.9 5.8 0 Venography Ultrasonography Kanchanabat et al. Br J Surg.2011;98:1356-64

DOACs: Acute DVT and PE Treatment DOACs N Dose Comparator Primary end point Dabigatran RE-COVER I&II 5,107 Heparin + 150 mg bid Rivaroxaban EINSTEIN acute DVT EINSTEIN PE 3,449 4,832 15 mg bid x 3 weeks then 20 mg od Apixaban AMPLIFY 5,395 10 mg bid x 7 d then 5 mg bid Edoxaban Hokusai-VTE 8,292 Heparin + 60 mg od (30 mg od if CrCl 30-50 ml/min, BW <60 kg) Heparin + warfarin INR 2-3 Enoxaparin + warfarin INR 2-3 Enoxaparin + warfarin INR 2-3 Heparin + warfarin INR 2-3 Recurrent symptomatic VTE and related-death Recurrent symptomatic VTE and related-death Recurrent symptomatic VTE and related-death Recurrent symptomatic VTE and related-death Schulman S. N Engl J Med. 2009;361:2342-52, EINSTEIN investigators N Engl J Med. 2010;363:2499-2510, N Engl J Med. 2012;366:1287-97, Agnelli G. N Engl J Med. 2013;369:799-808, The Hokusai-VTE Investigators. N Engl J Med. 2013;369:1406-15

DOACs and Thromboprophylaxis after Total Hip or Knee Arthroplasty Dabigatran Rivaroxaban Apixaban Edoxaban RE-NOVATE (THR) RE-MODEL (TKR) RE-MOBILIZE (TKR) RE-NOVATE II (THR) RECORD 1 (THR) RECORD 2 (THR) RECORD 3 (TKR) RECORD 4 (TKR) PROOF OF CONCEPT (THR) ODIXA KNEE (TKR) ODIXA HIP(THR) ADVANCE-1 (TKR) ADVANCE-2 (TKR) ADVANCE-3 (THR) STARS E-3 (TKR) Primary outcome: Symptomatic venous thromboembolism

Estimating Risk of VTE The use of asymptomatic, screening-detected thrombosis as an outcome may lead to over-estimates the clinical benefit of pharmacological prophylaxis ACCP Guideline 2012 Symptomatic VTE rather than asymptomatic VTE is used for estimates of VTE incidence and calculations of prophylaxis benefit For asymptomatic patients following major orthopedic surgery, we recommend against Doppler (or duplex) ultrasound screening before hospital discharge (1B) Kotaska A Thromb J. 2018;16:25, Guyatt GH et al. Chest. 2012;141:7S-47S, Falck-Ytter et al. 2012;141:e278S-e325S

ACCP Estimation of Baseline Risk in ACCP 2012 Guideline Major orthopedic surgery Day 0-14 Day 0-35 VTE rates without prophylaxis 2.8% 4.3% VTE rates with LMWH 1.15% 1.8% Bleeding rate Not avialable Not available We did not find any bleeding risk assessment that have been sufficiently validated in the orthopedic surgery population Falck-Ytter et al. Chest 2012;41;e278S-e325S

ACCP Estimation of Baseline Risk in ACCP 2012 Guideline Major orthopedic surgery Day 0-14 Day 0-35 VTE rates without prophylaxis 2.8% 4.3% VTE rates with LMWH 1.15% 1.8% Bleeding rate Not avialable Not available On We balance, did not it find was any believed bleeding that risk the adverse assessment consequences that have been of a major sufficiently postoperative validated bleeding the event were approximately orthopedic equal surgery to those population of symptomatic VTE Falck-Ytter et al. Chest 2012;41;e278S-e325S

ACCP Estimation of Baseline Risk in ACCP 2012 Guideline AT9 VTE risk category General surgery (GI, Urological, Vascular, breast, Thyroid) Caprini score Observed VTE risk, % Plastic and reconstructive surgery Caprini score Observed VTE risk, % Very low 0 0 0-2 Not available Estimated Baseline risk in the absence of pharmacologic or mechanical prophylaxis, % Low 1-2 0.7 3-4 0.6 1.5 Moderate 3-4 1.0 5-6 1.3 3.0 High 5 1.9 7-8 2.7 6.0 <0.5 Pharmacologic prophylaxis was suggested in patients at moderate risk for VTE (2B) and was recommended in those at high VTE risk (1B) if the patients are not at high bleeding risk. Gould M et al. Chest 2012;41;e227S-e277S

Bleeding Risk Associated with Pharmacologic Prophylaxis in Non-orthopedic Surgery: Data from meta-analysis studies Low dose UFH (10,000-15,000 units/d) vs no prophylaxis LDUH was associated with an 47% reduction in the odds of fatal PE LDUH was associated with a 57% increase in the odds of nonfatal major bleeding LMWH vs no prophylaxis LMWH was associated with a possible reduction in the risk of death from any cause (risk ratio (RR), 0.54; 95%CI, 0.27-1.10) LMWH led to increased risk of major bleeding (RR, 2.03; 95%CI, 1.37-3.01) and wound hematoma (RR, 1.88; 95%CI, 1.54-2.28) Post-operative VTE risk should be at least 3% to justify LMWH prophylaxis Gould M et al. Chest 2012;41;e227S-e277S, Mismetti et al. Br J Surg. 2001;88:913-930, Collins et al. N Engl J Med. 1988;318:1162-1173

Apples vs Asian Fruits http://theconversation.com, https://slideplayer.com/slide/2558077

Incidence of Post-op Symptomatic VTE With and Without Thromboprophylaxis in Total Hip or Knee arthroplasty Retrospective study USA 95% thromboprophylaxis Taiwan No thromboprophylaxis THR TKR THR TKR No. of patients 19,586 24,059 61,460 52,566 Symptomatic VTE, n (%) PE DVT 556 (2.8) 202 (1.1) 357 (1.8) 508 (2.1) 182 (0.8) 326 (1.4) 163 (0.27) 26 (0.04) 137 (0.22) 335 (0.64) 35 (0.07) 300 (0.57) Arch Intern Med. 1998;158 (14);1525-31, Thromb Res. 2014, J Vasc Surg. 1998;1:67-73

Low Incidence of Symptomatic VTE Without Thromboprophylaxis after Hip and Knee Arthroplasty at Siriraj Hospital Prospective observational study n = 896/1200 Inclusion criteria: adult 18 years old who underwent hip or knee arthroplasty between 2013-2014 Exclusion criteria: Concurrent antithrombotic drug use Presence of condition or underlying disease affecting normal hemostasis Intervention Patient education Daily measurement of leg circumference by the patients or relatives Calf muscle exercise Telephone follow-up at 6 and 12 weeks post-op Follow-up period: up to 3 months post-op Wongprasert C and Chinthammitr Y et al.

n=896 Age, years (range) 68 (21-94) Female, n (%) 741 (82.7) Type of surgery, n (%) Knee arthroplasty Hip arthroplasty Pre-op thrombotic risk, n (%) Cancer Estrogen use Prior history of VTE Obesity Congestive heart failure Varicose veins Baseline Characteristics 714 (79.7) 182 (20.3) 32 (3.6) 4 (0.4) 2 (0.2) 163 (18.2) 6 (0.7) 14 (1.6) Median day of post-op immobilization, day (range) 2 (0-74) Tranexamic acid use (pre- and/or post-op) 617 (68.9) Mean operation time, hours (range) 1.5 ± 0.6 (0.5-5.5) Calf muscle exercise, n (%) 896 (100) Wongprasert C and Chinthammitr Y et al.

Results Symptomatic DVT occurred in 2/896 (0.22%) patients (95%CI 0.04-0.90) A 67-year-old woman at 45 days after TKR surgery An 89-year-old woman at 16 days after surgery Both cases had no thrombotic risk No pulmonary embolism Three deaths in 3 months Metastatic CA DRESS syndrome with acute liver injury Septic shock with DIC and respiratory failure Wongprasert C and Chinthammitr Y et al.

Comparison of Results with Prior Studies in Orthopedic Surgery in Asian Patients Without Thromboprophylaxis VTE event n (%) Kanchanabat et al. 2011 Wongprasert and Chinthammitr et al. 2014 DVT in THR 541 (3.9) 1 (0.5) DVT in TKR 714 (2.7) 1 (0.1) PE in THR 633 (0.3) 0 PE in TKR 1053 (0.5) 0 Adapted slide courtesy of Wongprasert C. and Chinthammitr Y, Kanchanabat B. et al. Br J Surg.2011;98:1356-64

Comparison of Duration of Surgery and Immobilization Duration of surgery, median, min (range) Duration of immobilization, median, day (range) Leizorovicz et al. SMART venography Study 2007 THR TKR All 130 (55-420) 5 (1-87) 142 (55-405) 4 (1-29) 139 (55-420) 4 (1-87) DOAC studies Wongprasert and Chinthammitr et al. 2014 79-100 110 (45-350) 2 (1-30) Adapted slide courtesy of Wongprasert C and Chinthammitr Y, Leizorovicz et al. Haematologica. 2007;92:1194-1200

Comparison of Symptomatic VTE Following Hip and Knee Arthroplasty With Thromboprophylaxis Symptomatic VTE in Hip arthroplasty Symptomatic VTE in Knee arthroplasty n Rate (%) n Rate (%) Total 21,369 0.53 23,475 1.09 Time, day <14 14 Missing Prophylaxis LMWH Direct IIa, Xa inhibitor Indirect IIa, Xa inhibitor Wongprasert and Chinthammitr et al. (without VTE prophylaxis) 4,981 4,567 4,821 14,783 4,216 2,370 0.72 0.25 0.40 0.58 0.31 0.62 8,089 14,101 1,285 12,177 10,781 517 1.22 0.92 2.23 1.42 0.81 0.77 182 0.55 714 0.14 Adapted slide courtesy of Wongprasert C and Chinthammitr Y, JAMA.2012;307:294-303

THAI RCT RCT (sealed envelopes), n=50 (no description regarding sample size calculation) Intervention: enoxaparin 40 mg SC OD starting at 24 h post-op x 7-10 days Follow-up: 3-6 months post-surgery No tranexamic acid use Primary outcome: the incidence of DVT detected by US on D6-D10 by 2 radiologists were blinded to the allocation of subjects), PE and major bleeding event Results: Asymptomatic distal DVT occurred in only 1 patient in the control group (4%) and none in the enoxaparin group(0%), p=0.31 No PE 1 patient in the enoxaparin group had a minor bleeding (4%) and wound complication Intiyanaravut et al. J Med Assoc Thai. 2017;100:42-49

Cost Thromboprophylaxis post-orthopedic surgery for up to 35 days n = 896 Enoxaparin 40 mg/d = THB 7,683,200 Rivaroxaban 10 mg OD = THB 3,575,040 Dabigatran 220 mg OD = THB 4,014,080 Apixaban 2.5 mg BID: THB 3,825,920 https://efirstbankblog.com

A cost-utility analysis using societal and healthcare payer s perspectives to simulate relevant cost and health outcomes covering a 3-month time horizon Costs were adjusted to year 2014 The willingness-to-pay threshold of THB 160,000 (USD 4,926) was used Dabigatran and enoxaparin after THR and TKR surgery incurred higher costs and increased quality adjusted life years (QALYs) Dabigatran and enoxaparin are not cost-effective compared to no thromboprophylaxis Kotirum S et al. J Thromb Thrombolysis. 2017;43:252-262

Multicenter, double-blinded, RCT 3424 patients undergoing TKA or THA All patients received rivaroxaban 10 mg OD until post-op D5 then randomized to Rivaroxaban 10 mg OD x 9 d in TKA or 30 d in THA ASA 81 mg x 9 d in TKA or 30 d in THA Primary outcome: symptomatic VTE Tranexamic acid used in 54.3% Outcome Symptomatic VTE PE Proximal DVT PE and proximal DVT Rivaroxaban n=1717 n (%) 12 (0.7) 6 (0.35) 4 (0.23) 2 (0.12) ASA n=1707 n (%) 11 (0.64) 5 (0.29) 4 (0.23) 2 (0.12) P Value 0.84* Major bleeding, n (%) 5 (0.29) 8 (0.47) 0.42 Any bleeding, n (%) 17 (0.99) 22 (1.29) 0.43 Extended prophylaxis with ASA was not significantly * P<0.001 different for noninferiority from rivaroxaban in the prevention of symptomatic VTE Anderson DR et al. N Engl J Med. 2018;378:699-70

Prospective study included adult patients admitted to medical wards, ICU and the stroke unit beyond 3 days n=7126 Primary physician education and fast-tract diagnostic imaging program were implemented Incidence of symptomatic VTE: 42/7126 (0.59%, 95% CI 0.41-0.77) Aniwan and Rojnuckarin Blood Coagul Fibrinolysis. 2010;21:334-338

Characteristics and Risk Factors of VTE Diagnosed During Medical Hospitalization Type of thrombosis DVT alone PE without DVT PE and DVT Characteristics n = 42 Risk factors Complete immobilization Active cancer Severe respiratory disease using assisted ventilation Obesity (BMI >25 kg/m 2 ) Antiphospholipid antibody Arthritis of lower extremities Congestive heart failure Causes of death PE Bleeding complications from anticoagulants Underlying diseases n (%) 19 (45) 19 (45) 4 (10) 31 (74) 22 (52) 5 (12) 5 (12) 3 (7) 2 (5) 1 (2) 9 2 10 Aniwan and Rojnuckarin Blood Coagul Fibrinolysis. 2010;21:334-338

VTE Prophylaxis in Acutely ill Medical Patients ACCP Guideline 2012 Recommendation was made according to the Padua Prediction Score Clinical risk of VTE in high-risk group ( 4): 11% Clinical risk of VTE in low-risk group (<4): 0.3% RCTs demonstrated a baseline VTE risk of 1% or less in general medical patients Risk Factor Points Active cancer 3 Previous VTE 3 Reduced mobility 3 Thrombophilia 3 Recent trauma/ surgery ( 1 mo) 2 Elderly age ( 70 y) 1 Heart and/or resp. failure 1 Acute MI or ischemic stroke 1 Acute infection and/or rheumatologic disorder Obesity (BMI 30) 1 Ongoing hormonal treatment 1 1 Khan S et al. Chest 2012;141;e195s-e226s, Barbar et al. J Thromb Haemost. 2010;8:2450-2457

Heparin vs Placebo or No treatment for the Prevention of VTE in Acutely ill Medical Patients (excluding Stroke and MI) Outcome No. of patients Odds Ratio 95% CI DVT 5,511 0.41 0.25-0.67 Combined non-fatal and/or fatal PE 27,971 0.66 0.43-1.02 All cause mortality 27,786 0.97 0.87-1.08 Major bleeding 13,804 1.65 1.01-2.71 Minor bleeding 13,434 1.61 1.26-2.08 Thrombocytopenia 13,349 1.05 0.64-1.74 16 RCTs: 34,369 participants (heparin vs placebo/no treatment; LMWH vs UFH) A reduction in the risk of DVT needs to be balanced against an increased risk of bleeding associated with thromboprophylaxis Alikhan et al. Cochrange Database Syst Rev. 2014;5:CD003747

Balancing the Bleeding Risks and the Benefits of VTE Prophylaxis: IMPROVE Bleeding Risk Assessment Model Risk Factors at admission Moderate renal failure GFR 30-59 vs 60 ml/min/m 2 Severe renal failure GFR <30 vs 60 ml/min/m 2 Points 1 2.5 Age 40-84 vs <40 1.5 Age 85 vs <40 3.5 Male vs Female 1 *The only bleed risk assessment model in hospitalized medical patients Risk Factors at admission Points Current cancer 2 Rheumatic disease 2 Central venous catheter 2 ICU/CCU stay 2.5 Hepatic failure (INR >1.5) 2.5 Platelet count <50 x 10 9 4 Bleeding in the 3 months before admission Active gastroduodenal ulcer 4 4.5 Rosenberg D et al. Thromb Haemost. 2016;116:530-536

External Validation of the IMPROVE Bleeding Risk Assessment Model in Medical Patients 12,082 subjects VTE prophylaxis use in 82% of subjects Overall rate of any bleed within 14 d: 2.6% Rate of any bleed A score < 7: 2.12% A score 7: 4.68% [OR 2.3, 95%CI 1.8-2.9] Rate of major bleeding A score < 7: 1.5% A score 7: 3.2% [OR 2.2, 95%CI 1.6-2.9] Derivation (%) Validation (%) Sensitivity for predicting any bleed 35.9 34 Specificity for predicting any bleed 90.9 81.5 PPV for predicting any bleed 2.6 4.7 NPV for predicting any bleed 98.2 97.9 Sensitivity for predicting major bleed 51 33.3 Specificity for predicting major bleed 90 81.3 PPV for predicting major bleed 4 3.2 NPV for predicting major bleed 99 98.5 Rosenberg D et al. Thromb Haemost. 2016;116:530-536

Conclusion Liberal pharmacologic prophylaxis of VTE based on the inaccurate estimates of baseline risk of VTE and risk of bleeding can cause more harm than benefits Individualized risk stratification is mandatory prior to the initiation of VTE prophylaxis Real data from specific (Thai) population, rather than the extrapolation of results from previous studies from different patient background, is immensely necessary prior to the establishment of the national policy regarding the primary VTE prophylaxis in Thai population