Primary VTE Thromboprophylaxis VTE... · Why Controversies? Lack of generalizable data Recommendation was based on the estimated baseline risk Uncertainty of the outcome Reduction
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Primary VTE ThromboprophylaxisControversies in Hematology
53rd Annual Meeting of Thai Society of Hematology
Bundarika Suwanawiboon, MD
Division of Hematology
Department of Medicine
Faculty of Medicine Siriraj Hospital
Primary VTE Thromboprophylaxis
https://idealhealthandwellness.wordpress.com
Bleeding
HIT
Osteoporosis
Allergic reaction
Cost
Prevention of VTE and
VTE-related death
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 system1
Guyatt GH et al. Chest 2012;141:e185S-e194S
Comparing Apples and Oranges?
http://theconversation.com, https://slideplayer.com/slide/2558077
Comparing Apples and Oranges?
http://theconversation.com, https://slideplayer.com/slide/2558077
0
10
20
30
40
50
60
70
SMARTvenography
AIDA Sakon Samama Leclerc Agnelli Ockelford
%
Asymptomatic Total DVT Asymptomatic Proximal DVT
Angchaisuksiri P. Thromb Haemost. 2011;106:585-590
Symptomatic DVT: 0.9%
Symptomatic PE: 0.3%-0.6%
Low Incidence of Post-op Symptomatic VTE
Without Thromboprophylaxis in Asian Population
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
• Symptomatic DVT: 4.5%
(95%CI 1.9-8.1)
• Symptomatic PE: 0.6%
• (95%CI 0.3-1.0)
• No death from PE
0
5
10
15
20
25
30
35
Venography Ultrasonography
%
All-site
Proximal
Distal
Isolated distal
31.7
9.48.9
5.9 5.9 5.8
22.5
18.8
Kanchanabat et al. Br J Surg.2011;98:1356-64
Incidence of Asymptomatic Post-op VTE
Without Thromboprophylaxis in Asia
0
5
10
15
20
25
30
35
Venography Ultrasonography
%
All-site
Proximal
Distal
Isolated distal
31.7
9.48.9
5.9 5.9 5.8
22.5
18.8
Kanchanabat et al. Br J Surg.2011;98:1356-64
“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.”
DOACs N Dose Comparator Primary end point
DabigatranRE-COVER I&II 5,107 Heparin +
150 mg bid
Heparin + warfarinINR 2-3
Recurrent symptomaticVTE and related-death
Rivaroxaban
EINSTEIN acute DVT
EINSTEIN PE
3,4494,832
15 mg bid x 3 weeks then 20 mg od
Enoxaparin + warfarinINR 2-3
Recurrent symptomatic VTE and related-death
ApixabanAMPLIFY 5,395 10 mg bid x 7 d
then 5 mg bidEnoxaparin + warfarin
INR 2-3Recurrent symptomaticVTE and related-death
EdoxabanHokusai-VTE
8,292 Heparin + 60 mg od
(30 mg od if CrCl
30-50 ml/min, BW <60 kg)
Heparin + warfarinINR 2-3
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: Acute DVT and PE Treatment
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)
DOACs and Thromboprophylaxis
after Total Hip or Knee Arthroplasty
▪ 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
ACCPMajor 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
Estimation of Baseline Risk in ACCP 2012 Guideline
“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
ACCPMajor 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
Estimation of Baseline Risk in ACCP 2012 Guideline
“We did not find any bleeding risk assessment that have been sufficiently validated in the
orthopedic surgery population”
“On balance, it was believed that the adverse consequences of a major postoperative bleeding
event were approximately equal to those of symptomatic VTE”
Falck-Ytter et al. Chest 2012;41;e278S-e325S
ACCPAT9 VTE risk
categoryGeneral surgery (GI,
Urological, Vascular,
breast, Thyroid)
Plastic and
reconstructive surgery
Estimated Baseline
risk in the absence of
pharmacologic or
mechanical
prophylaxis, %Caprini
score
Observed
VTE risk, %
Caprini
score
Observed
VTE risk, %
Very low 0 0 0-2 Not available
<0.5
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
Estimation of Baseline Risk in ACCP 2012 Guideline
Gould M et al. Chest 2012;41;e227S-e277S
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.
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)
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
Post-operative VTE risk should be at least 3% to justify LMWH prophylaxis
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
Wongprasert C and Chinthammitr Y et al.
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
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
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
714 (79.7)
182 (20.3)
Pre-op thrombotic risk, n (%)
Cancer
Estrogen use
Prior history of VTE
Obesity
Congestive heart failure
Varicose veins
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)
Baseline Characteristics
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
Wongprasert C and Chinthammitr Y et al.
No pulmonary embolism
Three deaths in 3 months
Metastatic CA
DRESS syndrome with acute liver
injury
Septic shock with DIC and
respiratory failure
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
Leizorovicz et al.
SMART venography Study
2007
DOAC studies Wongprasert
and
Chinthammitr
et al.
2014THR TKR All
Duration of
surgery, median,
min (range)
130
(55-
420)
142
(55-405)
139
(55-
420)
79-100 110
(45-350)
Duration of
immobilization,
median, day
(range)
5
(1-87)
4
(1-29)
4
(1-87)
2
(1-30)
Adapted slide courtesy of Wongprasert C and Chinthammitr Y, Leizorovicz et al. Haematologica. 2007;92:1194-1200
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
4,981
4,567
4,821
0.72
0.25
0.40
8,089
14,101
1,285
1.22
0.92
2.23
Prophylaxis
LMWH
Direct IIa, Xa inhibitor
Indirect IIa, Xa inhibitor
14,783
4,216
2,370
0.58
0.31
0.62
12,177
10,781
517
1.42
0.81
0.77
Wongprasert and
Chinthammitr et al.
(without VTE prophylaxis)
182 0.55 714 0.14
Comparison of Symptomatic VTE Following Hip and Knee
Arthroplasty With Thromboprophylaxis
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 Rivaroxaban
n=1717
n (%)
ASA
n=1707
n (%)
P Value
Symptomatic VTE
PE
Proximal DVT
PE and proximal DVT
12 (0.7)
6 (0.35)
4 (0.23)
2 (0.12)
11 (0.64)
5 (0.29)
4 (0.23)
2 (0.12)
0.84*
Major bleeding, n (%) 5 (0.29) 8 (0.47) 0.42
Any bleeding, n (%) 17 (0.99) 22 (1.29) 0.43
* P<0.001 for noninferiorityExtended prophylaxis with ASA was not significantly different 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
n = 42
n (%)
Type of thrombosis
DVT alone
PE without DVT
PE and DVT
19 (45)
19 (45)
4 (10)
Risk factors
Complete immobilization
Active cancer
Severe respiratory disease using assisted ventilation
Obesity (BMI >25 kg/m2)
Antiphospholipid antibody
Arthritis of lower extremities
Congestive heart failure
31 (74)
22 (52)
5 (12)
5 (12)
3 (7)
2 (5)
1 (2)
Causes of death
PE
Bleeding complications from anticoagulants
Underlying diseases
9
2
10
Characteristics and Risk Factors of VTE
Diagnosed During Medical Hospitalization
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
1
Obesity (BMI ≥ 30) 1
Ongoing hormonal treatment 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)
▪ 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
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
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
Points
Moderate renal failure
GFR 30-59 vs ≥ 60
ml/min/m2
1
Severe renal failure
GFR <30 vs ≥ 60
ml/min/m2
2.5
Age 40-84 vs <40 1.5
Age ≥ 85 vs <40 3.5
Male vs Female 1
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 109 4
Bleeding in the 3 months
before admission
4
Active gastroduodenal
ulcer
4.5
Rosenberg D et al. Thromb Haemost. 2016;116:530-536
*The only bleed risk assessment model
in hospitalized medical patients
External Validation of the IMPROVE Bleeding Risk
Assessment Model in Medical Patients
Rosenberg D et al. Thromb Haemost. 2016;116:530-536
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
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
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
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