Preventing VTE in gynaecological surgery

Rt Hon. Professor the Lord Kakkar PC Thrombosis Research Institute and

University College London UK

Disclosures for Ajay Kakkar

Research support/principal investigator: Bayer

Consultant/Advisory Board/Honoraria: Bayer HealthCare, sanofi-aventis, Boehringer Ingelheim, Daiichi Sankyo, Janssen

My talk today

Burden of disease

Rationale for thromboprophylaxis

Mechanical methods

Extended thromboprophylaxis

Adaptation of the Caprini model by ACCP 2012

Gould MK, et al. Chest 2012; 141 (Suppl):e227s–77s.

Patient population

Patients undergoing major general thoracic or vascular

surgery

Patients undergoing general surgery, including GI, urological, vascular, breast

and thyroid procedures Patients undergoing plastic and

reconstructive surgery

Other surgical populations in risk category

AT9 VTE risk category

Rogers score

Observed risk of symptomatic VTE, %

Caprini score

Observed risk of symptomatic VTE, %

Caprini score

Observed risk of VTE, %

Very low < 7 0.1 0 0 0–2 NA Most outpatient or same-day surgery

Low 7–10 0.4 1–2 0.7 3–4 0.6 Spinal surgery for non-malignant disease

Moderate > 10 1.5 3–4 1.0 5–6 1.3 Gynaecological non-cancer surgery Cardiac surgery

Most thoracic surgery Spinal surgery for malignant disease

High NA NA ≥ 5 1.9 7–8 2.7 Bariatric surgery Gynaecological cancer surgery

Pneumonectomy Craniotomy

Traumatic brain injury Spinal cord injury

Other major trauma

VTE risk assessment scores: gynaecological oncology

17,713 National Surgical Quality Improvement Program cervical, ovarian, uterine, vaginal, vulvar cancers between 2008 and

2013 Caprini and Rogers scores were calculated for each patient 30 day VTE rate 1.8%

Barber EL et al. Am J Obstet Gynecol 2016;215:445.e1‒9

Caprini Rogers Low risk 0% Low risk 0.2% Moderate 0.1% Medium 36.9% High 3.0% High (>10) 63.0% Highest (≥5) 96.9%

VTE: type of gynaecologic malignancy

National Surgical Quality Improvement Program database 104,368 gynaecologic surgeries: 11,427 for malignancy

Ovarian: 2.7% (n=2800); uterine: 6.8% (n=7114); cervical: 1.0% (n=1026); vulvar: 0.5% (n=487)

VTE rate: 1.8% (202/11,427)

Ovarian cancer :OR 1.5 (95% CI, 1.10‒2.16) VTE 64% lower: MIS vs open surgery VTE higher disseminated vs early cancer (OR, 5.96; p=0.027)

Graul A et al. Int J Gynecol Cancer 2017;27:581‒587

VTE: abdominal vs minimally invasive hysterectomy

Hysterectomy for benign conditions between 2010 and 2012

National Surgical Quality Improvement

44,167 patients included

2,733 (28.8%) open

22,559 (51.1%) laparoscopic

8875 (20.1%) vaginal

Barber EL et al. Am J Obstet Gynecol 2015;212:609.e1‒7

Open Minimally invasive 0.6% 81 / 12,733 0.2% 73 / 31,434

p

VTE: laparoscopic surgery for malignancy

2219 NSQIP patients: uterine, ovarian or cervical cancer

VTE rate: 0.7% (15/2219) median time 6 days

No difference in rate of VTE between cancer types

VTE predictive of higher 30-day mortality OR, 26.0; 95% CI, 2.2‒306.9; p=0.01

Mahdi H et al. J Minim Invasive Gynecol 2016;23:1057‒1062

Impact of VTE on mortality after surgery for different malignant tumours

Trinh VQ, et al. JAMA Surgery 2014; 149:43–9. OR = odds ratio; VTE = venous thromboembolism.

Mortality

Cancer type Overall, % Without VTE, % With VTE, % OR (95%) P-value

Overall 2.0 1.9 12.0 5.30 (4.88–5.76) < 0.001

Colectomy 3.1 2.9 11.3 3.74 (3.34–4.19) < 0.001

Cystectomy 2.5 2.3 9.6 4.58 (3.22–6.51) < 0.001

Oesophagectomy 7.2 6.9 13.6 2.01 (1.13–3.56) 0.02

Gastrectomy 5.7 5.5 14.7 2.81 (2.12–3.73) < 0.001

Hysterectomy 0.4 0.3 5.2 10.93 (6.85–17.45) < 0.001

Lung resection 2.9 2.6 19.8 8.73 (7.39–10.31) < 0.001

Pancreatectomy 4.9 4.7 13.2 3.08 (2.05–4.61) < 0.001

Prostatectomy 0.1 0.1 3.9 56.42 (30.54–104.25) < 0.001

Venous thromboembolism: Long-term complications and burden

• Post-thrombotic syndrome • Frequency of PTS 20–50% • Severe PTS in 5–10%

• Incidence of sympto-

matic pulmonary hypertension after PE • 1.0% at 6 months • 3.1% at 1 year • 3.8% at 2 years

Pengo V., Lensing A.W.A., Prins M.H., et al. N Engl J Med 2004; 350:2257 - 2264

4

9

26 132 postoperative patients

40

92 normal

Natural history of postoperative DVT

Kakkar VV, et al. Lancet. 1969;2:230-232.

Efficacy of low-dose unfractionated heparin (UFH) in prevention of DVT after major surgery

42

8

05

1015202530354045

Control Low-dose UFH

– s.c. low-dose UFH: pre-operative and b.i.d. post-operative

– 78 ‘high-risk’ patients

s.c., subcutaneous; b.i.d., twice a day Kakkar et al. Lancet 1972;2:101–6

Pharmacological Prevention of Thrombosis

Num

ber o

f pat

ient

s w

ith fa

tal P

E

P < 0.005

Prophylaxis of fatal, postoperative PE with low-dose UFH (2)

16

2

0 2 4 6 8

10 12 14 16 18

Control UFH

Low-dose UFH saves 7 lives for every 1000 operated patients. Kakkar VV et al, Lancet. 1975;2:45-51.

Bleeding complications

Control Heparin P

Excessive blood loss 126 182 NS

Wound hematoma 117 158 < 0.01

Mean transfusion requirements (mL) 1285 1316 0.34

Mean Hb fall (g/100 mL) 0.7 1.0 0.23

NS = not significant. Kakkar vv et al, Lancet. 1975;2:45-51.

Thromboprophylaxis in cancer surgery: dose of LMWH

Prospective, randomized, double-blind multicentre trial

LMWH once daily

dalteparin 2,500 IU versus 5,000 IU daily

total duration 7 days

Therapy commenced pre-operatively

2,070 patients randomized

67% malignancy (1,303/1,957)

p = 0.001

Bergqvist D, et al. Br J Surg. 1995;82:496-501.

Bleeding complications in patients operated on for malignant disease occurred in 3.6% of those receiving dalteparin 2,500 IU and 4.6% of those receiving dalteparin 5,000 IU (p = NS).

DV

T in

pat

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s w

ith m

alig

nanc

y (%

)

Chart1

Dalteparin 2,500 IU

Dalteparin 5,000 IU

% DVT

14.9

8.5

Sheet1

Dalteparin 2,500 IUDalteparin 5,000 IU

% DVT14.98.5

LMWH for thromboprophylaxis in benign gynaecologic surgery

Bemiparin 3500 IU n=387 vs. or no intervention n=387

Clinical DVT, PE and fatal PE within 30 days

Immobility OR 7.1; 95% CI, 1.3‒36.2

Varicose veins OR 16.8; 95% CI, 3.1‒76.2

Thrombophilia OR 39.3; 95% CI, 1.5‒1006.7

No major bleeding events or side effects related to bemiparin Alalaf SK et al. J Thromb Haemost 2015;13:2161‒2167

Bemiparin Control 0% 0 / 377 3.2% 12 / 380

95% CI, 0.002-0.6

(a) Compression (monotherapy) Graduated 9 57/665 133/627 –39.7 37.2 66% (10) compression stockings (8.6%) (21.2%) Intermittent 19 112/1108 268/1147 –76.3 71.0 66% (7) pneumatic compression (10.1%) (23.4%) Footpump 2 11/61 34/65 –10.7 7.3 77% (19) (18.0%) (52.3%)

30 180/1834 435/1839 –126.7 115.5 67% (6)

(9.8%) (23.7%) 2p < 0.00001

No. of Deep venous Stratified Odds ratio and % odds trials thrombosis statistics confidence interval reduction Category with data Compression Control O–E Variance (compression : control) (SE)

Effects of compression methods of thromboprophylaxis on DVT

99% or 95% confidence intervals 0.0 0.5 1.0 1.5 2.0

Compression Compression better worse Treatment effect 2p < 0.00001

Roderick P, et al. Health Technology Assessment 2005; Vol. 9: No. 49.

(a) Compression (monotherapy) (a) Orthopaedic 8 66/460 172/502 –49.3 38.9 72% (9)

(14.3%) (34.3%) (b) General surgery 11 60/654 150/673 –44.7 40.7 67% (10)

(9.2%) (22.3%) (c) Neurosurgery/spinal 6 27/357 69/354 –21.1 20.8 64% (14)

(7.6%) (19.5%) (d) Gynaecological 3 19/267 32/254 –6.8 11.0 46% (22)

(7.1%) (12.6%) (e) Mixed surgery 1 1/31 5/24 –2.4 1.3 84% (40)

(3.2%) (20.8%) (f) Medical/unknown 1 7/65 7/32 –2.4 2.7 (10.8%) (21.9%) 30 180/1834 435/1839 –126.7 115.4 67% (6)

(9.8%) (23.7%) 2p < 0.00001

No. of Deep venous Stratified Odds ratio and % odds trials thrombosis statistics confidence interval reduction Category with data Compression Control O–E Variance (compression : control) (SE)

Effects of compression methods on DVT among different types of patients

99% or 95% confidence intervals 0.0 0.5 1.0 1.5 2.0

Compression Compression better worse Treatment effect 2p < 0.00001

Roderick P, et al. Health Technology Assessment 2005; Vol. 9: No. 49.

(a) Compression (monotherapy) Graduated 3 0/123 4/90 –1.8 0.9 compression stockings (0.0%) (4.4%) Intermittent 8 14/590 18/618 –1.6 7.6 pneumatic compression (2.4%) (2.9%) Footpump 1 0/28 0/32 (0.0%) (0.0%) 12 14/741 22/740 –3.4 8.5 33% (28) (1.9%) (3.0%) 2p > 0.1; NS

No. of Deep venous Stratified Odds ratio and % odds trials thrombosis statistics confidence interval reduction Category with data Compression Control O–E Variance (compression : control) (SE)

Effects of compression methods of thromboprophylaxis on PE

99% or 95% confidence intervals 0.0 0.5 1.0 1.5 2.0

Compression Compression better worse Treatment effect 2p = 0.006

Roderick P, et al. Health Technology Assessment 2005; Vol. 9: No. 49.

VTE: mechanical vs pharmacological prophylaxis

Robotic (n=739) or laparoscopic hysterectomy (n=674) for endometrial carcinoma or

complex hyperplasia with atypia

All patients received mechanical prophylaxis; 61% received additional pharmacologic prophylaxis

Incidence of VTE was 0.35% (5/1413)

Freeman AH et al. Gynecol Oncol 2016;142:267‒272

Pharmacologic Mechanical 0.23% 2 / 865 0.55% 3 / 548

p=0.38

@RISTOS: VTE risk persists in cancer surgery patients

Agnelli G, et al. Ann Surg. 2006;243:89-95.

Days post-surgery

0

2

4

6

8

10

12

14

1–5 6–10 11–15 16–20 21–25 26–30 > 30

Num

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f VTE

eve

nts

40% of VTEs were observed more than 21 days after cancer surgery

RIETE: Time course and clinical presentation of post-operative VTE

Arcelus, et al. Thromb Haemost 2008;99:546–51

19%

55% of VTEs were diagnosed after prophylaxis was discontinued

77%

PE Proximal DVT Distal DVT

1 2 7 15 30 60

Clinically overt PE 22 (2.8%) 41 (5.2%) 149 (19%) 376 (48%) 608 (77%) 787 (100%)

Proximal DVT 9 (1.4%) 21 (3.3%) 91 (14%) 248 (39%) 432 (68%) 633 (100%)

Distal DVT 2 (1.1%) 5 (2.7%) 34 (19%) 98 (54%) 145 (80%) 182 (100%)

Days

Cum

ulat

ive

inci

denc

e

Extended thromboprophylaxis after cancer surgery

All VTE

Proximal DVT

Rasmussen MS, et al. Cochrane Database. 2009:CD004318.

9th ACCP recommendations on prophylaxis after non-orthopedic surgery

VTE risk categories: very low, low, moderate, and high

For general and abdomino-pelvic surgery at very low risk (Caprini score 0): no specific pharmacologic prophylaxis (1B) or mechanical (2C) other than early ambulation

For general surgery patients at low risk (Caprini score 1-2) suggest mechanical prophylaxis (IPC) over no prophylaxis (2C)

For general surgery patients at moderate risk (Caprini score 3-4) who are not at high risk for major bleeding: suggest LMWH (2B), LDUH (2B), or mechanical prophylaxis with IPC (2C) over no prophylaxis Remark: 3 of 7 authors favored a strong recommendation in favor of LMWH or LDU over no prophylaxis

Gould MK , et al. Chest. 2012; 141 (2) (Suppl): e227s-e277s

9th ACCP recommendations on prophylaxis after non-orthopedic surgery (II)

For moderate-risk patients undergoing general surgery who are at high risk for major bleeding suggest mecanical prophylaxis, preferably with IPC over no prophylaxis (2C)

For general surgery patients at high-risk for VTE (Caprini score >4) who are not at high risk for bleeding recommend LMWH (1B) or LDUH (1B) over no prophylaxis. We suggest that mechanical prophylaxis with stockings or IPC should be added (2C)

For patients at high risk for VTE undergoing abdominal or pelvic surgery for cancer without high risk for bleeding, we recommend extending pharmacological prophylaxis with LMWH four weeks over limited-duration prophylaxis (1B)

Gould MK , et al. Chest. 2012; 141 (2) (Suppl): e227s-e277s

Preventing VTE in gynaecological surgeryDisclosures for Ajay KakkarMy talk todayAdaptation of the Caprini model by�ACCP 2012VTE risk assessment scores: gynaecological oncology VTE: type of gynaecologic �malignancyVTE: abdominal vs minimally invasive hysterectomy VTE: laparoscopic surgery �for malignancyImpact of VTE on mortality after surgery for different malignant tumoursVenous thromboembolism: �Long-term complications and burdenNatural history of postoperative DVT Pharmacological Prevention of ThrombosisProphylaxis of fatal, postoperative �PE with low-dose UFH (2)Bleeding complicationsThromboprophylaxis in cancer surgery: dose of LMWH LMWH for thromboprophylaxis �in benign gynaecologic surgeryEffects of compression methods of thromboprophylaxis on DVTEffects of compression methods on DVT �among different types of patientsEffects of compression methods of thromboprophylaxis on PE VTE: mechanical vs pharmacological prophylaxis@RISTOS: VTE risk persists in cancer surgery patientsRIETE: Time course and clinical presentation of post-operative VTESlide Number 309th ACCP recommendations on prophylaxis after non-orthopedic surgery9th ACCP recommendations on prophylaxis after non-orthopedic surgery (II)