Lung cancer Thorax: first published as 10.1136/thoraxjnl-2012-202592 on 15 January 2013. Downloaded from ORIGINAL ARTICLE Efficacy and safety of adjunctive anticoagulation in patients with lung cancer without indication for anticoagulants: a systematic review and meta-analysis Jing Zhang,1 Yue-Li Zhang,2 Kai-Xiang Ma,3 Jie-Ming Qu2 ▸ Additional material is ABSTRACT published online only. To view Background Patients with lung cancer are at high risk Key messages please visit the journal online (http://dx.doi.org/10.1136/ of venous thromboembolism (VTE), and VTE predicts a thoraxjnl-2012-202592). poor prognosis. Anticoagulation therefore might be beneficial for these patients. It is not clear whether 1Department of Pulmonary What is the key question? Medicine, Zhongshan Hospital, anticoagulants could improve survival and other ▸ Can anticoagulants improve survival and other Shanghai Medical College, outcomes in patients with lung cancer with no indication outcomes in patients with lung cancer without Fudan University, Shanghai, for anticoagulation. indication for anticoagulation? China Methods We searched the Web of Science, Medline, 2Department of Pulmonary What is the bottom line? Medicine, Huadong Hospital, EMBASE and Cochrane databases for relevant studies. Two reviewers evaluated the studies and extracted data ▸ This meta-analysis revealed a long-term Shanghai Medical College, fi Fudan University, Shanghai, independently. The primary outcomes were 1-year survival bene t in addition to reduced China survival and incidence of VTE. Pooled risk ratios (RR) incidence of venous thromboembolism from 3Department of Pulmonary anticoagulation treatment in patients with lung ’ were calculated using control as a reference group and Medicine, Fuyuan People s fi cancer who have no clinical indication for Hospital, Yunnan Province, signi cance was determined by the Z test. China Results Nine eligible studies with 2185 participants anticoagulants. fi were included. Anticoagulation showed signi cant Why read on? Correspondence to improvement in survival at 1 year (RR 1.18, 95% CI Professor Jie-Ming Qu, ▸ Patients with small cell lung cancer or Department of Pulmonary 1.06 to 1.32; p=0.004) and at 2 years (RR 1.27, 95% prolonged life expectancy might benefit most Medicine, Huadong Hospital, CI 1.04 to 1.56; p=0.02), but not at 6 months. from adjunctive anticoagulation. Shanghai Medical College, fi Subgroup analysis showed a survival bene t for patients http://thorax.bmj.com/ Fudan University, 221 West with small cell lung cancer (SCLC) and those with non- ’ Yan an Road, Shanghai advanced/limited cancer. The incidence of VTE 200040, China; (RR=0.55, 95% CI 0.31 to 0.97; p=0.04) and [email protected] Activation of coagulation can predict a poor thromboembolic events (RR=0.48, 95% CI 0.28 to 0.82; prognosis in patients with lung cancer. Previous JZ and Y-LZ contributed p=0.008) was reduced with anticoagulation. Both studies showed that elevated plasma levels of equally to this paper. vitamin K antagonist (VKA) and subcutaneous heparin thrombin–antithrombin complex and D-dimer increased the risk of haemorrhage, but heparin did not Received 19 August 2012 were associated with increased mortality.78The increase the incidence of major bleeding. on September 25, 2021 by guest. Protected copyright. Revised 2 December 2012 presence of VTE is also a significant independent Accepted 18 December 2012 Conclusions Anticoagulation showed a survival predictor of death.3 Danish registry data indicate Published Online First benefit, especially for those with SCLC and prolonged that 1-year survival in cancer patients with VTE is 15 January 2013 life expectancy, and reduced the risk of VTE in lung three times less than in those without VTE.9 cancer patients with no indication for anticoagulants. A more recent study by Huang et al5 reported that Subcutaneous heparin is superior to VKA because of a lung cancer patients with VTE had a twofold potentially smaller risk of major bleeding. shorter time to death. Anticoagulants have potential antitumour effects by mechanisms of regulating growth, apoptosis and INTRODUCTION differentiation of neoplastic cells, inhibiting angio- It is well-known that malignancy is a common risk genesis and modulating metastatic processes in add- factor for venous thromboembolism (VTE).12The ition to their antithrombotic effect.10 Some incidence of VTE in patients with cancer has been small-scale studies have suggested that concomitant reported to be increased by >20-fold compared with treatment with heparin may improve the response the general population,23and this risk seems to rate to chemotherapy and prolong progression-free increase further by 20–30% in patients with survival in patients with small cell lung cancer – advanced cancer who receive chemotherapy.45Lung (SCLC).11 14 Putting these facts together, it is cancer is among the malignant diseases showing the rational to consider using anticoagulants in patients highest incidence of VTE.16Many patients with lung with lung cancer to achieve a better outcome. To cite: Zhang J, Zhang Y-L, cancer have a history of smoking and thus are more However, individual studies on the survival Ma K-X, et al. Thorax likely to have comorbidities which may further benefit and safety of anticoagulation in patients – 2013;68:442 450. increase the risk of thromboembolic events. with lung cancer were of limited sample size and 442 Zhang J, et al. Thorax 2013;68:442–450. doi:10.1136/thoraxjnl-2012-202592 Lung cancer Thorax: first published as 10.1136/thoraxjnl-2012-202592 on 15 January 2013. Downloaded from there has been a lack of consistency between various studies due of relevant publications were manually searched for to heterogeneity. We therefore performed a systematic literature additional studies. Ethical approval was not required for this review and meta-analysis to investigate the impact of anticoagu- meta-analysis. lants on survival in patients with lung cancer. The impact on the incidence of thromboembolic events and adverse events such as bleeding was also evaluated. Study eligibility Two reviewers independently screened the abstracts of papers METHODS generated by the literature search, retrieved potentially relevant Literature search studies and determined study eligibility. Included studies had to A literature search was performed using the Web of Knowledge be randomised controlled trials (RCTs) with at least two com- (1990–July 2012) via the library of Fudan University and parison groups (ie, anticoagulation treatment and controls) and Medline (1990–July 2012) by PubMed search engines, with the survival data reported. Anticoagulation therapy could be oral databases being last accessed on 15 August 2012. The Cochrane VKA or heparin. In case of studies containing the same datasets Central database and EMBASE were also searched for relevant as studies that had been published before, only the study with studies published up to July 2012. No language restriction was the largest sample size was included. Data published only in imposed. The search strategies were as follows: (lung cancer OR abstract form or from website materials were excluded because SCLC OR non-SCLC (NSCLC)) AND (coagulant* OR anti- these studies had not been peer reviewed and their inclusion coagulant* OR coagulation OR heparin OR warfarin OR might introduce bias into the meta-analysis. Case reports, low-molecular-weight heparin (LMWH) OR vitamin K antagon- review articles and textbook chapters were also excluded from ist (VKA) OR low molecular weight heparin). The reference lists the analysis. http://thorax.bmj.com/ on September 25, 2021 by guest. Protected copyright. Figure 1 Flow of study selection. Zhang J, et al. Thorax 2013;68:442–450. doi:10.1136/thoraxjnl-2012-202592 443 Lung cancer Thorax: first published as 10.1136/thoraxjnl-2012-202592 on 15 January 2013. Downloaded from Table 1 Characteristics of studies included in the meta-analysis No. of Quality Study (year) Population Interventions patients score Agnelli (2009) Subjects extracted from the study with metastatic or Intervention: subcutaneous nadroparin 3800 IU anti-Xa once 199/80 5 locally advanced lung cancer undergoing CT daily. Control: placebo Altinbas (2004) Patients with SCLC undergoing chemotherapy Intervention: dalteparin 5000 IU once daily during 18 weeks of 42/42 2 CT. Control: no intervention Altinbas-1 Subjects extracted from the study: limited SCLC 23/25 (2004) Altinbas-2 Subjects extracted from the study: extensive SCLC 19/17 (2004) Chahinian Patients with extensive SCLC undergoing CT Intervention: VKA (PT 1.5–2). Control: no intervention 103/85 2 (1989) Haas (2012) Subjects extracted from the study with stage III/IV NSCLC Intervention: certoparin 3000 IU subcutaneously once daily for 273/273 5 undergoing CT 6 months. Control: placebo Lebeau (1994) Patients with limited or extensive SCLC undergoing CT Intervention: subcutaneous heparin for 5 weeks. Control: no 138/139 3 intervention Lebeau-1 Subjects extracted from the study: limited SCLC 64/57 (1994) Lebeau-2 Subjects extracted from the study: extensive SCLC 74/82 (1994) Maurer (1997) Patients with limited SCLC undergoing CT and Intervention: VKA (PT 1.4–1.6) started with CT and continued 178/169 3 radiotherapy; minimum life expectancy 2 months for 3 weeks after last cycle of CT. Control: no intervention Stanford (1979) Patients with stage III or more SCLC undergoing CT Intervention: VKA following heparin. Control: no intervention 12/12 2 van Doormaal Subjects extracted from the study with stage