Prophylactic and Therapeutic Anticoagulation for Thrombosis in Oncology

Table 1. Characteristics of the Short Term Thromboprophylaxis Studies for Cancer Patients Undergoing Abdominal Surgery
Study	Design	Number of patients	Intervention (I); control (C)	Outcome measured	Primary outcome	Significance
Fricker et al. (1988)^[8]	Open-label RCT	80	I: Dalteparin 5,000 U OD C: UFH 5,000 U TID	Symptomatic VTE or positive fibrinogen uptake test confirmed by venography	I: 0/40 C:2/40	No significant difference
McLeod et al. (2001)^[9]	Double-blind RCT	324	I: Enoxaparin 40 mg OD C: UFH 5,000 U TID	Symptomatic VTE or venographic DVT at days 5 and 9	I: 23/164 (14.0%) C: 27/160 (16.9%)	No significant difference
ENOXACAN (1997)^[10]	Double-blind RCT	631	I: Enoxaparin 40 mg OD C: UFH 5,000 U TID	Symptomatic VTE or venographic DVT at 10 days	I: 58/319 (18.2%) C: 46/312 (14.7%)	No significant difference
Petrov et al. (2007)^[11]	Double-blind RCT	256	I: Enoxaparin 20 mg OD C: UFH 5,000 U TID	Symptomatic VTE or venographic DVT at days 7 and 9	I: 4/130 (3.1%) C: 5/126 (4.0%)	No significant difference

Abbreviations: DVT, deep vein thrombosis; OD, once daily; RCT, randomized controlled trial; TID, three times daily; U: units; UFH: unfractionated heparin; VTE, venous thromboembolic event.

Table 2. Characteristics of the Thromboprophylaxis Studies for Patients Undergoing Neurosurgery
Study	Design	Number of patients	Intervention (I); control (C)	Outcome measured	Primary outcome, n (%)	Significance
Cerrato et al. (1978)^[24]	Open-label RCT	100 (all cancer)	I: UFH 5,000 U TID for ≥7 days C: Nothing	VTE on fibrinogen uptake test	I: 3/50 (6.0) C: 17/50 (34.0)	Significant difference favoring prophylaxis
Melon et al. (1987)^[25]	Double-blind RCT	122 (any neurosurgery)	I: Enoxaparin 20 mg OD for 10 days C: Placebo	Symptomatic VTE or venographic DVT at 10 days	I: 10/64 (15.6) C: 14/58 (24.1)	No significant difference
Nurmohamed et al. (1996)^[26]	Double-blind RCT	345 (about 80% cancer patients)	I: Nadroparin 7,500 U OD for 10 days + CS C: Placebo + CS	Symptomatic VTE or venographic DVT at day 28	I: 31/166 (18.6) C: 47/179 (26.3)	Significant difference favoring LMWH
Agnelli et al. (1998)^[27]	Double-blind RCT	307 (about 80% cancer patients)	I: Enoxaparin 40 mg OD for ≥7 days C: Placebo	Symptomatic VTE or venographic DVT at day 8 ± 1	I: 22/153 (14.4) C: 42/154 (27.3)	Significant difference favoring LMWH
Goldhaber et al. (2002)^[30]	Double-blind RCT	150	I: Enoxaparin 40 mg OD while admitted + ICD C: UFH 5,000 U BID while admitted + ICD	Symptomatic VTE or DVT on duplex US before discharge	I: 11/75 (14.7) C: 16/75 (21.3)	No significant difference
MacDonald et al.(2003)^[31]	Open-label pilot RCT	100	I: Dalteparin 2,500 U OD for 7 days or ambulating + ICD C: UFH 5,000 U BID for 7 days or ambulating + ICD	Symptomatic VTE or DVT on duplex US on day 7	I: 2/51 (3.9) C: 0/49 (0)	No significant difference

Abbreviations: BID, twice daily; CS, compressive stockings; ICD, intermittent compressive devices; OD, once daily; DVT, deep vein thrombosis; LMWH, low-molecular-weight heparin; n, number of patients; RCT, randomized controlled trial; TID, three times daily; U, units; UFH, unfractionated heparin; US, ultrasound; VTE, venous thromboembolic event.

Table 2. Characteristics of the Thromboprophylaxis Studies for Patients Undergoing Neurosurgery
Study	Design	Number of patients	Intervention (I); control (C)	Outcome measured	Primary outcome, n (%)	Significance
Cerrato et al. (1978)^[24]	Open-label RCT	100 (all cancer)	I: UFH 5,000 U TID for ≥7 days C: Nothing	VTE on fibrinogen uptake test	I: 3/50 (6.0) C: 17/50 (34.0)	Significant difference favoring prophylaxis
Melon et al. (1987)^[25]	Double-blind RCT	122 (any neurosurgery)	I: Enoxaparin 20 mg OD for 10 days C: Placebo	Symptomatic VTE or venographic DVT at 10 days	I: 10/64 (15.6) C: 14/58 (24.1)	No significant difference
Nurmohamed et al. (1996)^[26]	Double-blind RCT	345 (about 80% cancer patients)	I: Nadroparin 7,500 U OD for 10 days + CS C: Placebo + CS	Symptomatic VTE or venographic DVT at day 28	I: 31/166 (18.6) C: 47/179 (26.3)	Significant difference favoring LMWH
Agnelli et al. (1998)^[27]	Double-blind RCT	307 (about 80% cancer patients)	I: Enoxaparin 40 mg OD for ≥7 days C: Placebo	Symptomatic VTE or venographic DVT at day 8 ± 1	I: 22/153 (14.4) C: 42/154 (27.3)	Significant difference favoring LMWH
Goldhaber et al. (2002)^[30]	Double-blind RCT	150	I: Enoxaparin 40 mg OD while admitted + ICD C: UFH 5,000 U BID while admitted + ICD	Symptomatic VTE or DVT on duplex US before discharge	I: 11/75 (14.7) C: 16/75 (21.3)	No significant difference
MacDonald et al.(2003)^[31]	Open-label pilot RCT	100	I: Dalteparin 2,500 U OD for 7 days or ambulating + ICD C: UFH 5,000 U BID for 7 days or ambulating + ICD	Symptomatic VTE or DVT on duplex US on day 7	I: 2/51 (3.9) C: 0/49 (0)	No significant difference

Abbreviations: BID, twice daily; CS, compressive stockings; ICD, intermittent compressive devices; OD, once daily; DVT, deep vein thrombosis; LMWH, low-molecular-weight heparin; n, number of patients; RCT, randomized controlled trial; TID, three times daily; U, units; UFH, unfractionated heparin; US, ultrasound; VTE, venous thromboembolic event.

Table 3. Characteristics of the Studies Using Low-molecular-weight Heparin for Outpatient Thromboprophylaxis in Cancer Patients
Study	Type of cancer	Design	Number of patients	Intervention (I); control (C)	Primary outcome, n (%)	Conclusions
Haas et al. (2005)^[52]	Advanced breast cancer	Double-blind RCT	351	I: Certoparin 3,000 U OD C: Placebo	I: 7/174 (4.0) C: 7/177 (3.9)	No difference
	Non-small-cell lung carcinoma		532	I: Certoparin 3,000 U OD C: Placebo	I: 12/268 (4.5) C: 22/264 (8.3)	No difference
Perry et al. (2007)^[32]	Grade III/IV malignant glioma	Double-blind RCT	186	I: Dalteparin 5,000 U OD for 6- 12 months C: Placebo	I: 9/99 (11.0) C: 12/87 (17.0)	No difference
Pelzer et al. (2007)^[53]	Advanced pancreatic cancer	Open-label RCT interim analysis	12 with VTE	I: Enoxaparin (1 mg/kg for 12 weeks) then 40 mg OD C: Nothing	I: 4 patients with VTE C: 8 patients with VTE	Addition of enoxaparin is safe

Abbreviations: n, number of patients; OD, once-daily; RCT, randomized controlled trial; U, units; VTE, venous thromboembolic event.

Table 4. Characteristics of the Thromboprophylaxis Studies for Patients Undergoing Gynecological and/or Pelvic Cancer Surgery
Study	Design	Number of patients	Intervention (I); control (C)	Primary outcome, n (%)	Statistical significance
Clark-Pearson et al. (1983)^[33]	Open-label RCT	185	I: UFH 5,000 U BID for 7 days C: Control	I: 11/88 (12.5) C: 11/97 (11.3)	No significant difference
Clark-Pearson et al. (1990)^[34]	Open-label RCT	304	I: UFH 5,000 U TID for 7 days C: Control	I: 16/201 (8.0) C: 19/103 (18.5)	Significant difference favoring prophylaxis
Fricker et al. (1988)^[8]	Open-label RCT	59	I: Dalteparin 5,000 U OD for 10 days C: UFH 5,000 U TID for 7 days	I: 2/32 (6.25) C: 0/27 (0)	No significant difference
Borstad et al. (1988)^[36]	Double-blind RCT	13	I: Dalteparin 2,500 U OD for 7 days C: UFH 5,000 U BID for 7 days	I: 0/9 (0) C: 0/4 (0)	No significant difference
Kaaja et al. (1992)^[37]	Open-label RCT	12	I: Enoxaparin 20 mg OD for 3 days C: UFH 5,000 U BID for 3 days	I: 0/5 (0) C: 0/7 (0)	No significant difference
von Tempelhoff et al. (2000)^[38]	Double-blind RCT	134	I: Certoparin 3,000 U for 7 days C: UFH 5,000 U BID for 7 days	I: 9/64 (14.1) C: 9/70 (12.9)	No significant difference
Baykal et al. (2001)^[39]	Double-blind RCT	102	I: Enoxaparin 20 mg OD for 7 days C: UFH 5,000 U BID for 7 days	I: 0/47 (0%) C: 0/55 (0%)	No significant difference

Abbreviations: BID, twice daily; n, number of patients; OD: Once daily; RCT: randomized controlled trial; TID: three times daily; U: units; UFH: unfractionated heparin.

Table 4. Characteristics of the Thromboprophylaxis Studies for Patients Undergoing Gynecological and/or Pelvic Cancer Surgery
Study	Design	Number of patients	Intervention (I); control (C)	Primary outcome, n (%)	Statistical significance
Clark-Pearson et al. (1983)^[33]	Open-label RCT	185	I: UFH 5,000 U BID for 7 days C: Control	I: 11/88 (12.5) C: 11/97 (11.3)	No significant difference
Clark-Pearson et al. (1990)^[34]	Open-label RCT	304	I: UFH 5,000 U TID for 7 days C: Control	I: 16/201 (8.0) C: 19/103 (18.5)	Significant difference favoring prophylaxis
Fricker et al. (1988)^[8]	Open-label RCT	59	I: Dalteparin 5,000 U OD for 10 days C: UFH 5,000 U TID for 7 days	I: 2/32 (6.25) C: 0/27 (0)	No significant difference
Borstad et al. (1988)^[36]	Double-blind RCT	13	I: Dalteparin 2,500 U OD for 7 days C: UFH 5,000 U BID for 7 days	I: 0/9 (0) C: 0/4 (0)	No significant difference
Kaaja et al. (1992)^[37]	Open-label RCT	12	I: Enoxaparin 20 mg OD for 3 days C: UFH 5,000 U BID for 3 days	I: 0/5 (0) C: 0/7 (0)	No significant difference
von Tempelhoff et al. (2000)^[38]	Double-blind RCT	134	I: Certoparin 3,000 U for 7 days C: UFH 5,000 U BID for 7 days	I: 9/64 (14.1) C: 9/70 (12.9)	No significant difference
Baykal et al. (2001)^[39]	Double-blind RCT	102	I: Enoxaparin 20 mg OD for 7 days C: UFH 5,000 U BID for 7 days	I: 0/47 (0%) C: 0/55 (0%)	No significant difference

Abbreviations: BID, twice daily; n, number of patients; OD: Once daily; RCT: randomized controlled trial; TID: three times daily; U: units; UFH: unfractionated heparin.

Table 3. Characteristics of the Studies Using Low-molecular-weight Heparin for Outpatient Thromboprophylaxis in Cancer Patients
Study	Type of cancer	Design	Number of patients	Intervention (I); control (C)	Primary outcome, n (%)	Conclusions
Haas et al. (2005)^[52]	Advanced breast cancer	Double-blind RCT	351	I: Certoparin 3,000 U OD C: Placebo	I: 7/174 (4.0) C: 7/177 (3.9)	No difference
	Non-small-cell lung carcinoma		532	I: Certoparin 3,000 U OD C: Placebo	I: 12/268 (4.5) C: 22/264 (8.3)	No difference
Perry et al. (2007)^[32]	Grade III/IV malignant glioma	Double-blind RCT	186	I: Dalteparin 5,000 U OD for 6- 12 months C: Placebo	I: 9/99 (11.0) C: 12/87 (17.0)	No difference
Pelzer et al. (2007)^[53]	Advanced pancreatic cancer	Open-label RCT interim analysis	12 with VTE	I: Enoxaparin (1 mg/kg for 12 weeks) then 40 mg OD C: Nothing	I: 4 patients with VTE C: 8 patients with VTE	Addition of enoxaparin is safe

Abbreviations: n, number of patients; OD, once-daily; RCT, randomized controlled trial; U, units; VTE, venous thromboembolic event.

Table 5. Characteristics of the Studies of Long-term Anticoagulation for the Prevention of Recurrent Venous Thromboembolic Events in Cancer Patients
Study	Design	Number of patients	Intervention (I); control (C)	Outcome measured	Primary outcome, n (%)	Significance
Meyer et al. (2002)^[64]	Open label RCT	146	I: Enoxaparin 1.5 mg/kg for 3 months C: Enoxaparin 1.5 mg/kg for 4 days plus warfarin	Composite: recurrent VTE or major bleeding episode	I: 7/71 (9.9) C: 15/75 (20.0)	No significant difference at 3 months
Lee et al. (2003)^[62]	Open label RCT	676	I: Dalteparin 200 U/kg for 1 month then 75-80% for a total of 6 months C: Dalteparin 200 U/kg for 5 days plus warfarin	Symptomatic, recurrent VTE	I: 27/338 (8.0) C: 53/338 (15.7)	Significant decrease in cumulative risk of VTE recurrence favoring LMWH
Deitcher et al.^a (2006)^[65]	Open label pilot RCT	91	Enoxaparin 1.0 mg/kg every 12 h for 5 days, then: I¹: enoxaparin 1.0 mg/kg OD I²: enoxaparin 1.5 mg/kg OD C: warfarin	Recurrent VTE or symptomatic extension	I¹: 1/29 (3.4) I²: 1/32 (3.1) C: 2/30 (6.7)	No significant difference in safety profile
Hull et al. (2006)^[63]	Open-label RCT	200	I: Tinzaparin 175 U/kg for 3 months C: UFH plus warfarin	Recurrent VTE at 3-month and 12-month follow-up	I: 6/100 (6.0%) at 3 months; 7/100 (7.0%) at 12 months C: 10/100 (10.0%) at 3 months; 16/100 (16.0%) at 12 months	Significant decrease in cumulative risk of recurrence at 12 months

^aThree-arm study: I¹, first intervention; I², second intervention; C, control.
Abbreviations: LMWH, low-molecular-weight-heparin; n, number of patients; OD, once-daily; RCT, randomized controlled trial; U, units; UFH, unfractionated heparin; VTE, venous thromboembolic event.

Table 5. Characteristics of the Studies of Long-term Anticoagulation for the Prevention of Recurrent Venous Thromboembolic Events in Cancer Patients
Study	Design	Number of patients	Intervention (I); control (C)	Outcome measured	Primary outcome, n (%)	Significance
Meyer et al. (2002)^[64]	Open label RCT	146	I: Enoxaparin 1.5 mg/kg for 3 months C: Enoxaparin 1.5 mg/kg for 4 days plus warfarin	Composite: recurrent VTE or major bleeding episode	I: 7/71 (9.9) C: 15/75 (20.0)	No significant difference at 3 months
Lee et al. (2003)^[62]	Open label RCT	676	I: Dalteparin 200 U/kg for 1 month then 75-80% for a total of 6 months C: Dalteparin 200 U/kg for 5 days plus warfarin	Symptomatic, recurrent VTE	I: 27/338 (8.0) C: 53/338 (15.7)	Significant decrease in cumulative risk of VTE recurrence favoring LMWH
Deitcher et al.^a (2006)^[65]	Open label pilot RCT	91	Enoxaparin 1.0 mg/kg every 12 h for 5 days, then: I¹: enoxaparin 1.0 mg/kg OD I²: enoxaparin 1.5 mg/kg OD C: warfarin	Recurrent VTE or symptomatic extension	I¹: 1/29 (3.4) I²: 1/32 (3.1) C: 2/30 (6.7)	No significant difference in safety profile
Hull et al. (2006)^[63]	Open-label RCT	200	I: Tinzaparin 175 U/kg for 3 months C: UFH plus warfarin	Recurrent VTE at 3-month and 12-month follow-up	I: 6/100 (6.0%) at 3 months; 7/100 (7.0%) at 12 months C: 10/100 (10.0%) at 3 months; 16/100 (16.0%) at 12 months	Significant decrease in cumulative risk of recurrence at 12 months

^aThree-arm study: I¹, first intervention; I², second intervention; C, control.
Abbreviations: LMWH, low-molecular-weight-heparin; n, number of patients; OD, once-daily; RCT, randomized controlled trial; U, units; UFH, unfractionated heparin; VTE, venous thromboembolic event.

Table 6. Characteristics of the Survival Studies Using Low-molecular-weight Heparin
Study	Type of cancer	Design	Number of patients	Intervention (I); control (C)	One-year mortality, n (%)	Conclusions
Altinbas et al. (2004)^[74]	Small-cell lung cancer	Open-label RCT	84	I: Dalteparin 5,000 U OD for 18 weeks C: Nothing	I: 20/42 (47.6) C: 30/42 (71.4)	Significant difference favoring LMWH
Kakkar et al. (2004)^[76]	Advanced-stage (III-IV) solid cancer	Double-blind RCT	385	I: Dalteparin 5,000 U OD for 1 year C: Placebo	I: 103/190 (54.2) C: 109/184 (59.2)	No difference
Klerk et al. (2005)^[75]	Advanced curable solid cancer	Double-blind RCT	302	I: Weight-based nadroparin (2,800-7,600 U) BID for 2 weeks then OD for 4 weeks C: Placebo	I: 90/148 (60.8) C: 112/154 (72.7)	Significant difference favoring LMWH
Sideras et al. (2007)^[77]	Advanced incurable solid cancer	Double-blind RCT for 76 patients then open-label	141	I: Dalteparin 5,000 U OD C: Placebo	I: 42/68 (61.8) C: 42/70 (60.0)	No difference

Abbreviations: BID, twice daily; LMWH, low-molecular-weight-heparin; OD, once-daily; RCT, randomized controlled trial; U, units; UFH, unfractionated heparin.

Sidebar: Summary of Recommendations for Prophylactic and Therapeutic Anticoagulation in Cancer Patients

Major Abdominal Surgery

All patients should have thromboprophylaxis using UFH 5,000 U TID or prophylactic doses of LMWH or fondaparinux 2.5 mg for at least 7-10 days postoperatively unless contraindicated.

Prolonged prophylaxis for up to 30 days should be considered in patients with additional risk factors.

Neurosurgery

A combined regimen of pharmacologic (UFH or LMWH) and mechanical prophylaxis, starting after surgery, is recommended for at least 7-10 days in the absence of contraindications.

Routine prophylaxis beyond discharge is not currently recommended.

Gynecological or Pelvic Surgery

All patients should have thromboprophylaxis with UFH 5,000 U TID or prophylactic doses of LMWH for at least 7-10 days.

Hospitalized Medical Patients

All patients with cancer should receive thromboprophylaxis with UFH 5,000 U TID or prophylactic doses of LMWH or fondaparinux 2.5 mg in the absence of contraindications to anticoagulation.

Ambulatory Patients Receiving Chemotherapy

Routine prophylaxis with an antithrombotic agent is currently not recommended.

Initial Treatment of VTE

LMWH is recommended for the initial treatment (5-10 days) of VTE.

Long-term Treatment of VTE

All patients should be treated with a LMWH for minimum of 6 months and for as long as the cancer is 'active' and while the patient is receiving antitumor therapy, in the absence contraindications to LMWH. Warfarin with a targeted INR between 2.0 and 3.0 is an alternative if LMWH is not available.

Abbreviations: LMWH, low-molecular-weight-heparin; TID, three times a day; U, units; UFH, unfractionated heparin; VTE, venous-thromboembolic events.

Prophylactic and Therapeutic Anticoagulation for Thrombosis-Major Issues in Oncology

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Prophylactic and Therapeutic Anticoagulation for Thrombosis-Major Issues in Oncology

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Sidebar: Summary of Recommendations for Prophylactic and Therapeutic Anticoagulation in Cancer Patients

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