Prevention Of Venous Thromboembolism In The Cancer Surgical Patient A K Kakkar Barts and the London School of Medicine and Thrombosis Research Institute, London UK

Incidence Of VTE In Cancer Surgical Patients Surgical procedure VTE no malignancy (%) VTE malignancy (%)* Neurosurgery0.5–2.32.0–3.6 Head and neck0.1–0.20.2–1.4 Gastrointestinal0.2–1.60.9–2.6 Urological0.3–1.00.4–3.7 Gynaecological0.31.2–2.3 Orthopaedic0.2–2.40.9–3.1 Adapted from White et al. Thromb Haemost. 2003;90: *Symptomatic VTE at 91 days in patients after surgery.

Impact Of Cancer On PE Frequency Adapted from Huber et al. Arch Surg 1992;127: Cancer No CancerOR Surgical (%) Non surgical (%) Total

Prognostic Risk Factors For VTE In Cancer VariableEffect No. of patients VTE / non-VTE OR95 % CI Age ≥ 60 vs < 60 years ≥ 60 yrs: 42 / 1,516 < 60 yrs: 8 / –5.7 Previous VTE Yes vs no Yes: 5 / 36 No: 45 / 2, –16.8 Anaesthesia ≥ 2 vs < 2 hours ≥ 2 hours: 48 / 1,762 < 2 hours: 2 / –19.0 Stage Advanced vs not advanced Advanced: 38 / 1,078 Non advanced: 12 / 1, –5.2 Bedrest ≥ 4 vs < 4 days ≥ 4 days: 25 / 346 < 4 days: 25 / 1, –7.8 Adapted from Agnelli et al. Ann Surg 2006; 243:89-95.

Prophylaxis Against Fatal PE With Low-dose UFH International Multicenter Trial  4121 patients undergoing major surgery  Primary end point: fatal PE  Randomized: control or UFH (5000 IU 2 hours before surgery and every 8 hours postoperatively for 7 days)  180 patients died during the postoperative period: 100 in the control group and 80 in the UFH group  Rate of autopsy was 72 % in control group and 66% in the heparin group Adapted from Kakkar et al. Lancet 1975;2:45-51.

Number of patients with fatal PE P<0.005 Prophylaxis Against Fatal PE With Low-dose UFH ControlUFH Adapted from Kakkar et al., Lancet 1975;2:45-51.

Fatal Post-operative PE In Patients With Cancer Patients with PE, %  23% (n = 953) underwent operation with malignant disease Adapted from Kakkar et al. Lancet 1975;2:45-51.

Heparin Prevents Death After Surgery  21% reduction in total surgical mortality  68% reduction in fatal PE  67% reduction in asymptomatic DVT Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin Adapted from Collins et al. New Engl J Med 1988;318:

(1.7%) 109 (0.3%) 7 (0.9%) 191 (3.0%) 6 PE Fatal bleeds “Other” deaths Death From PE But Not From Bleeding Adapted from Collins et al. N Engl J Med 1988;318:

Canadian Colorectal DVT Prophylaxis Trial 13.9% 1.5% 2.7% 16.9% N=234 N=241 Adapted from McLeod et al. Ann Surg 2001;233: P=0.05 Incidence of Outcome Event VTE Major Bleeding (Cancer) (All) N=653 N=643 Low Dose vs. LMW Heparin

Thromboprophylaxis In Cancer Surgery  Prospective, randomized, double- blind multicenter trial  LMWH once daily –Dalteparin 2500 IU vs 5000 IU daily –Total duration 7 days  Therapy commenced preoperatively  2070 patients randomized  67% (1303/1957) malignancy P= Adapted from Bergqvist et al. Br J Surg. 1995;82: Bleeding complications in patients operated on for malignant disease occurred in 3.6% of those receiving dalteparin 2500 IU and 4.6% of those receiving dalteparin 5000 IU (P=NS). DVT in Patients With Malignancy (%)

Adapted from Mismetti et al. Br J Surg 2001;88:913–30. Clinical thromboembolismCancer Major hemorrhage Asymptomatic DVT Clinical PE Death Total hemorrhage Wound hematoma Transfusion Non-cancer LMWH better UFH better Thromboprophylaxis In The Cancer Surgical Patient

(a) Compression (monotherapy) Graduated957/665133/627– % (10) compression stockings(8.6%)(21.2%) Intermittent19112/ /1147– % (7) pneumatic compression(10.1%)(23.4%) Footpump211/6134/65– % (19) (18.0%)(52.3%) 30180/ /1839– % (6) (9.8%)(23.7%)2 p < No. ofDeep venousStratifiedOdds ratio and% odds trials thrombosis statisticsconfidence intervalreduction Category with data Compression ControlO–E Variance(compression : control)(SE) Effects Of Compression Methods of Thromboprophylaxis On DVT 99% or95% confidence intervals Compression betterworse Treatment effect 2 p < Adapted from Roderick et al. Health Technology Assessment 2005; Vol. 9: No. 49.

(a) Compression (monotherapy) Graduated30/1234/90– compression stockings(0.0%)(4.4%) Intermittent814/59018/618– pneumatic compression(2.4%)(2.9%) Footpump10/280/32 (0.0%)(0.0%) 1214/74122/740– % (28) (1.9%)(3.0%)2 p > 0.1; NS No. ofDeep venousStratifiedOdds ratio and% odds trials thrombosis statisticsconfidence intervalreduction Category with data Compression ControlO–E Variance(compression : control)(SE) Effects Of Compression Methods of Thromboprophylaxis On PE 99% or95% confidence intervals Compression betterworse Treatment effect 2 p = Adapted from Roderick et al. Health Technology Assessment 2005; Vol. 9: No. 49.

83 (18)35 (%) DVT n (%) 6 studies LDH (n=451) LDH+GCS (n=439) RR (95%CI) Combined Mechanical and Pharmacological Prophylaxis Intervention Adapted from IUA Consensus statement Int Angiol 2006.

Prevention Of Fatal PE In Surgical Patients Adapted from Haas et al. Thromb Haem. 2005;94: Low-dose heparin t.i.d. LMWH o.d. P =NS

192 (3.1) 20 (0.33) 5 (0.08) 120 (0.7) 15 (0.09) 4 (0.02) Death (%) Fatal PE (%) Nonfatal PE (%) All Patients* Cancer (n=6,124) No Cancer (n=16,954) P Value Cancer Patients Are At Higher Risk For PE Adapted from Kakkar et al. Thromb Haemost. 2005;94: *Receiving UFH or LMWH. Surgical Population

PE Occurs After Hospital Discharge Adapted from Huber et al. Arch Surg 1992;127: Days In-hospital PE (n=80) After-discharge PE (n=24)

ENOXACAN II: Design Bilateral venography Major abdominal surgery 7 Days 21 Days Enoxaparin (40mg sc od)* Enoxaparin (40mg sc od) n= 165 Placebo n=167 ® Adapted from Bergqvist et al., New Engl J Med 2002;346:975  80. * Pre-op dose

Placebo (n=167) Enoxaparin (n=165) Incidence of DVT (% patients) 12.0% 4.8% 13.8% 5.5% RRR, 60%; P=0.02 RRR, 60%; P= month Day 30 Follow-up ENOXACAN II: Results  332 patients undergoing surgery for abdominal or pelvic tumours received enoxaparin (40 mg daily) for 1 week followed by enoxaparin or placebo for another 21 days  Venography was performed at 30- day and 3-month follow-up  At each follow-up, prolonged TP was associated with a 60% risk reduction for DVT Adapted from Bergqvist et al., N Engl J Med 2002;346:975  80.

FAME: Design Major abdominal surgery Bilateral venography (assessor-blinded) 7 Days 21 Days Dalteparin (5000 IU sc od)* + TED Dalteparin (5000 IU sc od) No further prophylaxis ® *Pre-Op dose TED: graduated compression stockings Adapted from Rasmussen et al., J Thromb Haemost : 2384–90.

FAME: Results  The ITT population consisted of 178 patients in the short-term prophylaxis group and 165 in the prolonged prophylaxis group  Venography was performed on day 28  Prolonged TP was associated with a 55% risk reduction for VTE and 77% risk reduction for proximal DVT Dalteparin 1 week 4 weeks Incidence (% patients) 16.3% 7.3% 8.0% 1.8% RRR, 55% P=0.012 RRR, 77%; P=0.009 Proximal DVT VTE Adapted from Rasmussen et al., J Thromb Haemost : 2384–90.

Extended Thromboprophylaxis: Meta Analysis  4 studies: 2 double-blind and 2 open  1,037 patients  Bilateral venography Adapted from Rasmussen et al. J Thromb Haemost 2005; 3 Suppl 1:P –10 days 4–5 weeks p DVT 15% 6.5% < Proximal DVT 5% 1% < 0.01 Symptomatic DVT 1% 0.3% 0.27

ESMO Clinical Recommendations 1.Prophylaxis with LMWH ( U once daily) or UFH (5000 U three times daily) is recommended. [I, A]*. 2.Cancer patients undergoing elective major abdominal or pelvic surgery should receive post-discharge prophylaxis with LMWH for up to 1 month after surgery [I, A]*. * Levels of evidence [I–V] and grades of recommendation [A–D] as used by the American Society of Clinical Oncology. Should Patients With Cancer Undergoing Surgery Receive Thromboprophylaxis?

ASCO VTE Guideline 1.All patients undergoing major surgical intervention for cancer should be considered for thromboprophylaxis. 2.Patients undergoing laparotomy, laparoscopy, thoracotomy lasting greater than 30 minutes should receive pharmacological thromboprophylaxis with UFH or LMWH unless contraindicated. 3.Commenced preoperatively. Should Patients With Cancer Undergoing Surgery Receive Thromboprophylaxis?

4.Mechanical methods may be added to pharmacological methods but should not be used as monotherapy for VTE prevention unless pharmacological methods are contraindicated because of active bleeding 5.Combined pharmacological and mechanical prophylaxis may improve efficacy especially in the highest risk patients 6.Prophylaxis should be continued for at least days postoperatively. Prolonged prophylaxis for up to 4 weeks after major abdominal and pelvic surgery in patients with high risk features such as residual disease, obesity, and previous history of VTE ASCO VTE Guideline

Conclusions  VTE common after cancer surgery.  Prophylaxis with LMWH effective and safe.  Extended prophylaxis should be considered for highest risk populations.