Low molecular weight heparin (LMWH) for primary thrombo-prophylaxis in patients with solid malignancies – systematic review and meta-analysis

Figures & data

Figure 1. Randomized controlled trials search and selection.

Table I. Characteristics of studies included in the meta-analysis.

First Author, Year [Ref]	Design	LMWH, Schedule	Duration of Treatment	Number of Patients	Cancer type	Disease Stage	Concomitant therapy
Altinbas, 2004 [17]	RCT Open label	(5000 IU sc, od) Control = no Dalteprin	18 weeks	42 LMWH 42 Control	Small cell lung carcinoma	Metastatic or LA	Chemotherapy
Kakkar 2004 [18]	Prospective, multicenter RCT	Dalteparin (5000 IU sc, od) Control = placebo	1 year	196 LMWH 189 Control	Breast, lung, gastrointestinal, pancreas, liver, genitourinary, ovary, or uterus	Metastatic or LA	Chemotherapy and/or radiotherapy
Klerk 2005 [19]	RCT	Nadroparin received body weight–adjusted therapeutic doses of subcutaneous nadroparin for 2 weeks (< 50 kg, 3,800 IU twice daily; 50–70 kg, 11 400 IU once daily;> 70 kg, 15 200 IU once daily) followed by half-therapeutic doses for an additional 4 weeks (< 50 kg, 3,800 IU once daily; 50–70 kg, 5,700 IU once daily;> 70 kg, 7,600 IU once daily)	6 weeks	148 LMWH 154 Control	Solid cancers	Metastatic or LA	Chemotherapy and/or radiotherapy
Sideras 2006 [20]	RCT	Dalteparin (5000 IU sc, od) Control = placebo	18 weeks or up to disease progression	71 LMWH 70 Control	Breast cancer, prostate cancer, lung cancer, colorectal cancer	Metastatic	Chemotherapy and/or radiotherapy
Agnelli 2009 [PROTECHT; 21]	Prospective, multicenter RCT	Nadroparin (3800 IU sc, od) Control = placebo	Duration of chemotherapy or up to a maximum of 120 days	779 LMWH 387 Control	Gastrointestinal, pancreatic, breast, ovarian, or head and neck cancer	Metastatic or LA	Chemotherapy
Riess 2010 [CONKO004; 22]	RCT Open label	Enoxaparin (1mg/kg, sc, od) Control = no Enoxaparin	12 weeks	160 LMWH 152 Control	Pancreatic cancer	Metastatic or LA	Chemotherapy
Van Doormaal 2011 [23]	RCT	Nadroparin: received body weight–adjusted subcutaneous therapeutic doses for 2 weeks (< 50 kg, 3,800 IU twice daily; 50–70 kg, 11 400 IU once daily;> 70 kg, 15 200 IU once daily) followed by half-therapeutic doses for an additional 4 weeks (< 50 kg, 3,800 IU once daily; 50–70 kg, 5,700 IU once daily;> 70 kg, 7,600 IU once daily)	12 weeks	244 LMWH 259 Control	Prostate cancer, lung cancer, pancreatic cancer	Metastatic or LA	Chemotherapy
Agnelli 2012 [SAVE ONCO; 24]	RCT	Semuloparin, 20 mg, sc, od)	3.5 months (median) Until change of chemotherapy	1608 LMWH 1604 Control	Lung cancer, pancreatic cancer, gastric cancer, colorectal cancer, bladder cancer, ovarian cancer	Metastatic or LA	Chemotherapy
Maraveyas 2012 [25]	RCT	Dalteparin 200 IU/kg sc, od for 4 weeks followed by a step down to 150 IU/kg for a further 8 weeks) Control = no Dalteparin	12 week	63 LMWH 60 Control	Pancreatic cancer	Metastatic or LA	Chemotherapy
Haas 2012 [TOPIC 1; 26,27]	RCT	Certoparin (3000 IU sc, od) Control = placebo	6 months	174 LMWH 177 Control	Breast cancer	LA	Chemotherapy
Hass 2012 [TOPIC 2; 26,27]	RCT	Certoparin (3000 IU sc, od) Control = placebo	6 months	273 LMWH 274 Control	Lung cancer	Metastatic or LA	Chemotherapy

Abbreviations: IU, international units; SC, subcutaneous; LA, locally advanced; OD, once daily; RCT, randomized controlled trials.

Figure 2. Forest plot of risk ratios (RRs) comparing (A) Symptomatic venous thromboembolism (VTE) (B) Deep vein thrombosis symptomatic (DVT) and (C) pulmonary embolism for patients who received LMWH in addition to standard therapy versus those who received standard therapy only. Risk ratios for each trial are represented by the squares, the size of the square represents the weight of the trial in the meta-analysis, and the horizontal line crossing the square represents the 95% confidence interval (CI). The diamonds represent the estimated overall effect based on the meta-analysis random effects of all trials.

Figure 3. Forest plot of risk ratios (RRs) comparing (A) venous thromboembolism (VTE) in lung cancer patients and (B) in pancreatic cancer patients who received LMWH in addition to standard therapy versus those who received standard therapy only. Risk ratios for each trial are represented by the squares, the size of the square represents the weight of the trial in the meta-analysis, and the horizontal line crossing the square represents the 95% confidence interval (CI). The diamonds represent the estimated overall effect based on the meta-analysis random effects of all trials.

Figure 4. Forest plot of risk ratios (RRs) comparing (A) mortality at 6 months or (B) 12 months for patients who received LMWH in addition to standard therapy versus those who received standard therapy only. Risk ratios for each trial are represented by the squares, the size of the square represents the weight of the trial in the meta-analysis, and the horizontal line crossing the square represents the 95% confidence interval (CI). The diamonds represent the estimated overall effect based on the meta-analysis random effect of all trials.

Altinbas M, Coskun HS, Er O, Ozkan M, Eser B, Unal A, et al. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost 2004;2:1266–71.

 PubMed Web of Science ®Google Scholar

Kakkar AK, Levine MN, Kadziola Z, Lemoine NR, Low V, Patel HK, et al. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: The fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol 2004;22:1944–8.

 PubMed Web of Science ®Google Scholar

Klerk CPW, Smorenburg SM, Otten HM, Lensing AW, Prins MH, Piovella F, et al. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol 2005;23:2130–5.

 PubMed Web of Science ®Google Scholar

Sideras K, Schaefer PL, Okuno SH, Sloan JA, Kutteh L, Fitch TR, et al. Low-molecular-weight heparin in patients with advanced cancer: A phase 3 clinical trial. Mayo Clin Proc 2006;81:758–67.

 PubMed Web of Science ®Google Scholar

van Doormaal FF, Di Nisio M, Otten HM, Richel DJ, Prins M, Buller HR. Randomized trial of the effect of the low molecular weight heparin nadroparin on survival in patients with cancer. J Clin Oncol 2011;29:2071–6.

 PubMed Web of Science ®Google Scholar

Maraveyas A, Waters J, Roy R, Fyfe D, Propper D, Lofts F, et al. Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. Eur J Cancer 2012; 48:1283–92.

 PubMed Web of Science ®Google Scholar