Primary VTE Thromboprophylaxis VTE... · Why Controversies? Lack of generalizable data Recommendation was based on the estimated baseline risk Uncertainty of the outcome Reduction

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

http://theconversation.com/

Comparing Apples and Oranges?



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


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


“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


“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


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



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


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


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

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

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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