Prevention of Venous Thromboembolism in Gynecological Cancer Patients Undergoing Major Abdominopelvic Surgery

Prevention of venous thromboembolism in gynecological cancer patients undergoing major abdominopelvic surgery: A systematic review and network meta-analysis Insin, P., Vitoopinyoparb, K., Thadanipon, K., Charakorn, C., Attia, J., McKay, G. J., & Thakkinstian, A. (2021). Prevention of venous thromboembolism in gynecological cancer patients undergoing major abdominopelvic surgery: A systematic review and network meta-analysis. Gynecologic Oncology. https://doi.org/10.1016/j.ygyno.2021.01.027 Published in: Gynecologic Oncology

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Download date:25. Sep. 2021 YGYNO-978311; No. of pages: 10; 4C: Gynecologic Oncology xxx (xxxx) xxx

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Gynecologic Oncology

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Review Article Prevention of venous thromboembolism in gynecological cancer patients undergoing major abdominopelvic surgery: A systematic review and network meta-analysis

Putsarat Insin a,b, Kasidin Vitoopinyoparb a,c, Kunlawat Thadanipon a, Chuenkamon Charakorn a,d,⁎, John Attia e, Gareth J. McKay f, Ammarin Thakkinstian a a Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 270 Rama VI road, Thung Phaya Thai, Ratchathewi District, Bangkok 10400, Thailand b Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Rajavithi Hospital, 2 Phayathai Road, Ratchathewi Districts, Bangkok 10400, Thailand c Department of Surgery, Rajavithi Hospital, 2 Phayathai Road, Ratchathewi Districts, Bangkok, 10400, Thailand d Department of Clinical Epidemiology and Biostatistics, and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Faculty of Medicine Ramathibodi Hospital, Mahidol Uni- versity, 270 Rama VI Road, Thung Phaya Thai, Khet Ratchathewi, Bangkok, 10400, Thailand e Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, University Dr, Callaghan, NSW 2308, Australia f Centre for Public Health, Queen’s University Belfast, Institute of Clinical Science, Block A, Royal Victoria Hospital, Belfast BT12 6BA, United Kingdom

HIGHLIGHTS

• Choice of perioperative VTE prophylactic measures in cancer patients is debatable. • The effects of these measures in gynecological cancer patients were compared. • Graduated compression stockings plus LMWH had highest probability to prevent VTE. • Sequential compression devices (SCD) gave lowest bleeding among active measures. • SCD plus LMWH seemed to be optimally balanced between risks for VTE and bleeding.

article info abstract

Article history: Objective. Although thromboprophylaxis is recommended to reduce death and disability from venous throm- Received 8 November 2020 boembolism (VTE), it remains underused due to a perceived risk of bleeding, especially in major abdominopelvic Accepted 20 January 2021 surgical patients. Available online xxxx Methods. We conducted a systematic literature review to identify all eligible randomized controlled trials (RCTs), searching MEDLINE and Scopus databases through November 25, 2020. RCTs published in any lan- Keywords: guage were eligible if they studied in gynecological cancer patients undergoing major abdominopelvic surgery Gynecological Cancer fi fi Major abdominopelvic surgery and assessed ef cacy of mechanical and pharmacological interventions. Studies with insuf cient data for Network meta-analysis pooling or those comparing different doses/schedules of interventions were excluded. Outcomes of interest Venous thromboembolism were composite VTE (ie, deep vein thrombosis or pulmonary embolism) and major bleeding. Relevant data were extracted for direct and network meta-analyses. Risk ratios (RR) and 95% confidence interval (CI) were estimated and the best intervention probability calculated for each outcome. This study was registered with PROSPERO (CRD42019145508). Results. We identified 1990 studies; 20 RCTs (4970 patients) were eligible. The overall risk of bias was of some concern. In direct meta-analyses, antithrombins were superior to unfractionated heparin in preventing composite VTE (RR 0.69; 95% CI 0.48–0.99), with no difference detected in the rate of major bleeding for any pairwise comparison. In network meta-analyses, graduated compression stockings plus low-molecular-weight heparin (LMWH) was top-ranked for prevention of composite VTE, whereas sequential compression devices (SCD) ranked second, after no treatment, for major bleeding. In a clustered ranking plot, SCD plus LMWH provided optimal balance between efficacy and safety.

⁎ Corresponding author at: Department of Clinical Epidemiology and Biostatistics, and Division of Gyneocologic Oncology, Department of Obstetrics and Gynecology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 270 Rama VI Road, Thung Phaya Thai, Khet Ratchathewi, Bangkok 10400, Thailand. E-mail address: [email protected] (C. Charakorn).

https://doi.org/10.1016/j.ygyno.2021.01.027 0090-8258/© 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article as: P. Insin, K. Vitoopinyoparb, K. Thadanipon, et al., Prevention of venous thromboembolism in gynecological cancer patients undergoing major abdominopelvi..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2021.01.027 P. Insin, K. Vitoopinyoparb, K. Thadanipon et al. Gynecologic Oncology xxx (xxxx) xxx

Conclusions. SCD plus LMWH might be safe and effective in VTE prevention following gynecological cancer surgery. However, the patient's bleeding risk should be considered to balance the risk and beneﬁt of treatment. © 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Contents

1. Introduction...... 0 2. Methods...... 0 2.1. Searchstrategyandselectioncriteria...... 0 2.2. Dataextractionandchecking...... 0 2.3. Statisticalanalysis...... 0 3. Results...... 0 3.1. Directmeta-analysis...... 0 3.2. Networkmeta-analysis...... 0 3.2.1. Venousthromboembolism...... 0 3.2.2. Majorbleedingoutcome...... 0 3.2.3. Treatmentranking...... 0 4. Discussion...... 0 Funding...... 0 DeclarationofCompetingInterest...... 0 Acknowledgement...... 0 AppendixA. Supplementarydata...... 0 References...... 0

1. Introduction classified as high risk, clinical practice guidelines by the American Soci- ety of Clinical Oncology (ASCO) [15] and the National Comprehensive Venous thromboembolism (VTE), including deep vein thrombosis Cancer Network (NCCN) [16] recommend that all cancer patients un- (DVT) and pulmonary embolism (PE), represents a serious complication dergoing major surgical intervention should receive pharmacologic following major abdominopelvic surgery, doubling the risk of morbidity thromboprophylaxis with either UH or LMWH unless there is contrain- and mortality and is the second leading cause of death in cancer patients dication of high bleeding risk. These measures should begin before sur- [1]. Risk of VTE is 4 to 7 times higher in cancer patients than the general gery and continue for at least 7–10 days, including extending up to population. In absolute terms, approximately 20% of cancer patients 28 days in patients at high-risk [15]. Despite strong recommendations present with VTE [2]. The incidence of VTE varies by cancer type and for VTE prophylaxis, many physicians still underuse these agents [17]. tumor burden, and is particularly high in patients with mucin- To date, only two systematic reviews have evaluated VTE prophy- secreting adenocarcinoma of the ovary, pancreas, stomach, and colon, laxis in gynecological cancers; one review in 2007 [8]useddirect as well as brain tumors [3,4]. Patients with gynecological cancers are meta-analysis (DMA) to evaluate the effects of only a few therapeutic at higher risk, not only from the malignancy itself and the consequent methods (i.e., UH vs LMWH and UH vs no prophylaxis) on VTE. The abdominopelvic surgery, but also from additional risk factors including other systematic review in 2011 [13] included 9 studies with advanced age, high body mass index (BMI), comorbidities, immobility, gynegological cancers, but they failed to apply DMA due to insufficient hormonal therapy, venous obstruction, thrombin formation, and treat- data. Neither study considered the risk of bleeding. Given the wide ment modalities (eg, long operative time, chemotherapy, and targeted range of prophylactic interventions currently available, an updated sys- therapy) [5,6]. tematic review and network meta-analysis (NMA) to evaluate all evi- A previous study estimated that VTE risk was approximately 14-fold dence of thromboprophylaxis in gynecological cancer patients higher in patients with gynecological cancer than those without cancer, undergoing major abdominopelvic surgery would identify the most ef- reporting DVT and PE incidence ranging from 17% to 40% and 1% to 2.6%, fective and safest prophylaxis for perioperative and postoperative VTE respectively [7–9]. The 28-day case fatality rate was 11% after the first in these patients. VTE event, with survivors experiencing an impaired quality of life despite treatment [10,11]. As such, VTE prophylaxis should be considered 2. Methods as a high priority in these patients. The three factors predisposing to venous thrombosis comprise the 2.1. Search strategy and selection criteria Virchow's triad of endothelial injury, venous stasis or blood flow turbu- lence, and hypercoagulable state [12]. Many prophylactic strategies This study followed the Preferred Reporting Items for Systematic Re- have been developed to mitigate these factors. Two types of VTE pro- views and Meta-Analyses (PRISMA) statement extension for network phylaxis are available in surgical patients, ie, mechanical and pharmaco- meta-analysis and was prospectively registered with PROSPERO (regis- logical methods. The former (ie, graduated compression stockings tration number: CRD42019145508) [18]. [GCS], and sequential compression devices [SCD] or intermittent pneu- We identified relevant studies published in any language in matic compression [IPC] devices) help reduce venous stasis and may MEDLINE via PubMed and Scopus through November 25th, 2020. The promote endogenous fibrinolysis, while pharmacological intervention search strategy is reported in Supplementary Table S1. Reference lists (eg, unfractionated heparin [UH] [13], low-molecular-weight heparin of articles were also explored for additional relevant studies. [LMWH]), prevent clot formation by impairing the clotting cascade [14]. Two reviewers (PI and KV) independently selected studies. Dis- Prophylactic interventions initiated before gynecological procedures agreements were resolved through discussion and consensus with a se- can reduce VTE incidence by 50–70% [8]. Given all cancer patients are nior author (KT). Titles and abstracts were screened, and full texts

2 P. Insin, K. Vitoopinyoparb, K. Thadanipon et al. Gynecologic Oncology xxx (xxxx) xxx reviewed. Randomized controlled trials (RCTs) published in any lan- the SUCRAs of composite VTE occurrence and major bleeding was con- guage were eligible if they met the following criteria: a) included gyne- structed to simultaneously reflect the benefit from lowering VTE and cological cancer patients who underwent major abdominopelvic major bleeding. The consistency assumption was checked using a surgery; b) compared any pair of interventions: GCS, SCD/IPC, UH, design-by-treatment interaction model [21,22]. Potential for small- LMWH, antithrombins, combined treatment, and no treatment/usual study effects, seen as a proxy for publication bias, was assessed using a care/placebo; and c) reported any VTE occurrence (ie, DVT, PE, or VTE) comparison-adjusted funnel plot. or major bleeding events. Studies were excluded if they compared Kappa statistics were applied to estimate disagreements in study se- the same drugs with different dosages or formulations. For duplicate lections and data extractions between reviewers. Stata software pack- publications, the most complete was included in the analysis. Non- age, version 16.1 (StataCorp. 2019. College Station, TX, USA) was used English studies were translated by using Google Translate service to perform statistical analysis. A p < 0.05 was considered statistically (https://translate.google.com/). significant for all analyses, except for Cochran's Q test, which used a The interventions of interest were no treatment/usual care/placebo, p <0.1. mechanical methods (ie, GCS and SCD/IPC), pharmacological methods (ie, UH, LMWH, and antithrombins which include dermatan sulfate 3. Results [DS] and defibrotide [DF]), and combined treatment (ie, GCS plus LMWH, SCD plus LMWH, and UH plus dihydroergotamine [UHDHE]). A total of 20 RCTs [23–42], 3 of which [30,32,41] were non-English, Two main outcomes wereconsidered:composite VTEoccurrence and met the inclusion criteria from 1990 articles identified (Fig. 1). Agree- major bleeding. CompositeVTE occurrence comprisedeitherDVT or PE. If ment for study eligibility between both reviewers was 94.5% (kappa co- RCT reported DVT and PE, but not for VTE, the maximum number of efficient 0.68). The RCTs published between 1983 and 2015 were events among these 2 outcomes was used as the number of composite mainly conducted in the USA, Italy, and France with sample sizes rang- VTE. DVT included both symptomatic and asymptomatic DVT that was ing between 30 and 885, totalling 4970 participants. Characteristics of confirmed by radioiodine fibrinogen uptake test, venography, duplex included studies are summarized in Table 1.Ofthese,14RCTs (Doppler) ultrasound, computed tomography (CT) scan or impedance [24–28,30–32,34,35,38,40–42] included only gynecologic cancer pa- plethysmography. PE was confirmed by CT scan (spiral or with contrast), tients, whereas the rest [23,29,33,36,37,39] included mixed patients pulmonaryangiogramorventilation/perfusionscanincludingechocardi- with percentage of cancer patients ranging from 63.9% to 93.9%. Per- ography. Major bleedingwas defined as the presence of at least oneof the centage of ovarian cancer patients was reported in only 9 RCTs following conditions as per the International Society of Thrombosis and [23,24,34,35,37,38,40–42], which ranged from 7.5% to 100% with a me- Haematosis: fatal bleeding, symptomatic bleeding (ie, intracranial, dian of 28%. Mean age ranged from 46.7 to 69.9 years. Seven studies intraspinal, pericardial, intraocular, or retroperitoneal), extra-surgical [27,30,31,39–42] reported mean BMI which varied from 22.3 to site bleeding causing a fall in hemoglobin level of ≥2 g/dL, or leading to 27.5 kg/m2, 4 of which [30,31,39,40] had mean BMI ≥25 kg/m2. Two- transfusion of ≥2 units of blood, surgical site bleeding that requires a sec- thirds of the RCTs included patients who underwent total abdominal ond intervention, or unexpected and prolonged and/or sufficiently large hysterectomy without lymphadenectomy. The mean operative time bleeding to cause hemodynamic instability [19]. varied from 72.9 to 482.2 with a median of 199 min. VTE was investi- gated and diagnosed 7 to 42 days after operation with a median of ap- 2.2. Data extraction and checking proximately 10 days. Nine VTE prophylactic methods were evaluated in the 20 RCTs, ie, no Two reviewers (PI and KV) independently extracted data including treatment (6 RCTs), GCS (2 RCTs), SCD (4 RCTs), UH (14 RCTs), LMWH general data (study design, year of publication), participants' character- (7 RCTs), antithrombins (4 RCTs), GCS plus LMWH (1 RCT), SCD plus istics (mean age, weight, BMI, underlying disease, cancer type, cancer LMWH (1 RCT), and UHDHE (1 RCT). Their regimens, dosages, and stage, operative procedure, operative time), treatment (intervention treatment schedules are summarized in Supplementary Table S2. type, dosage, and duration), and outcomes (ie, DVT, PE, VTE, and Most of the studies included clinically diagnosed DVT and PE major bleeding). Potential risk of bias was also assessed independently (Table 1). Nineteen RCTs [23,24,26–42] reported DVT, PE, or VTE events by the same reviewers using Risk of Bias in randomized trials tool with time of diagnosis between seven and 42 days; Ten RCTs (RoB2) [20]. Disagreements between reviewers were resolved by dis- [27,28,31,32,34,37–40,42] reported major bleeding, see Supplementary cussion and consensus with a senior reviewer (KT). Table S3. Out of 19 VTEs, 12 RCTs provided VTE data, whereas 3 RCTs provided only DVT, and 4 RCTs provided both DVT and PE data. Agree- 2.3. Statistical analysis ment between reviewers regarding data extraction was 86% (kappa coefficient 0.85). Intention-to-treat analysis was carried out for the entire quantitative The risk of bias for individual studies is provided in Supplementary synthesis. DMA was performed by pooling risk ratios (RR) if there were Figs. S1A and S1B. Over 94% (18 RCTs) of included RCTs were of some at least three studies with similar interventions and outcomes. concerns because they provided no details of randomization. In addi- Cochran's Q test and Higgins I2 statistics were applied to assess hetero- tion, blinding was not possible in these surgical studies owing to the na- geneity. A random-effects model (DerSimonian and Laird) was chosen ture of the interventions. The agreement between both reviewers was for pooling RRs if heterogeneity was present (p < 0.1 or I2 ≥ 25%). Oth- 93.8% with a kappa coefficient of 0.84. erwise, a fixed-effect model using the inverse-variance method was chosen. Sources of heterogeneity (ie, setting, participants, and treat- 3.1. Direct meta-analysis ments) were subsequently explored by fitting each factor in a meta- regression; a subgroup analysis was performed accordingly. Publication There were two DMAs among three treatments on each outcome. bias was assessed using Egger's test and funnel plots. The results of the DMAs are presented in Supplementary Tables S4 A network map was constructed to display head-to-head compari- and S5 and Fig. 2. In brief, antithrombins had significantly lower com- sons in all included RCTs. A NMA consistency model was constructed posite VTE occurrence risk compared to UH with pooled RR (95% CI) to indirectly compare the treatment effects among all treatment regi- of 0.69 (0.48, 0.99) with no heterogeneity observed; whereas LMWH mens using a two-stage approach. Treatments were then ranked using and UH were not significantly different. Likewise, none of the treat- the surface under the cumulative ranking curve (SUCRA) method. A ments showed a significant difference in the major bleeding outcome. higher SUCRA value corresponds to a higher level of efficiency and Funnel plots indicated no obvious evidence of asymmetry, consistent safety indicating better treatments. A clustered ranking plot to illustrate with the Egger's test (Supplementary Figs. S2A and S2B).

3 P. Insin, K. Vitoopinyoparb, K. Thadanipon et al. Gynecologic Oncology xxx (xxxx) xxx

Fig. 1. Flowchart showing selection and inclusion of randomized controlled trials in systematic review and network meta-analysis.

3.2. Network meta-analysis tonotreatment, althoughnonewassigniﬁcant (Table2). UH,LMWH,and SCD demonstrated 7 to 8 times higher risk of VTE than GCS, but none was Treatment comparisons were mapped for both VTE and bleeding signiﬁcant. Adding LMWH to GCS or SCD lowered the composite VTE oc- outcomes (Fig. 3). Results of NMAs are as follows: currence relative to monotherapy with each agent, with pooled RRs of 0.20(0.01,4.61)and0.18(0.02,1.54), respectively. Thetop-ranked treatments in lowering composite VTE occurrence by SUCRA were GCS plus 3.2.1. Venous thromboembolism LMWH, SCD plus LMWH, and GCS with the SUCRAs of 91.0%, 76.6%, and Data from 19 RCTs (4692 patients) consisting of direct comparisons 75.4%, respectively (Supplementary Fig. S3). between nine treatments were pooled for composite VTE occurrence. Among single agent prophylaxis options, the three most effective treatments in lowering composite VTE occurrence were GCS, antithrombins, 3.2.2. Major bleeding outcome and LMWH or UH with pooled RRs (95% CI) of 0.10 (0.00, 2.01), 0.51 Ten RCT (2697 patients) consisting of 6 and 15 direct and indirect com- (0.18, 1.42), 0.71 (0.35, 1.44), and 0.71 (0.39, 1.30), respectively, relative parisons were pooled for the major bleeding outcome. All 5 monotherapy

4 P. Insin, K. Vitoopinyoparb, K. Thadanipon et al. Gynecologic Oncology xxx (xxxx) xxx

Table 1 Characteristics of included studies.

Author, Year Country Treatment Total patients Center Mean age Mean BMI %Varicose vein %Prior VTE Obesity %Cancer

(years) (kg/m2)

Clarke-Pearson D [23] USA UH vs No treatment 185 Single 69.9 NR 31.9 5.4 NR 84.3 Clarke-Pearson D [24] USA SCD vs No treatment 194 Single 69.0 NR 30.0 3.0 NR 100.0 Clarke-Pearson D [25] USA UH vs No treatment 182 Single 53.0 NR NR NR NR 100.0 Turner GM [26] England GCS vs No treatment 196 Single 46.7 NR NR NR NR 100.0 Fricker JP [27] France LMWH vs UH 80 Single 57.6 24.8 43.7 13.7 NR 100.0 Samama M [28] France LMWH vs UH 885 Multiple 56.7 NR NR NR NR 100.0 Clarke-Pearson D [29] USA UH vs No treatment 304 Single 60.6 NR 18.1 3.6 NR 86.4 Dindelli M [30] Italy Antithrombin vs UH 50 Single 58.7 26.1 NR NR NR 100.0 Ferrari A [31] Italy Antithrombin vs UH 60 Single 57.5 26.1 NR NR NR 100.0 Fontanelli A [32] Italy Antithrombin vs UH 81 Single 59.0 NR NR NR NR 100.0 Clarke-Pearson D [33] USA UH vs SCD 208 Single 56.0 NR 17.8 1.9 NR 63.9 Urlep-Sallinovic V [34] Slovenia UH + DHE vs UH 155 Single 54.5 NR 24.5 7.7 44.5% 100.0 Von Tempelhoff GF [35] Germany LMWH vs UH 60 Single 58.0 NR NR NR NR 100.0 Ward B [36] Australia LMWH vs UH 566 Single 55.0 NR NR NR NR 81.4 Di Carlo V [37] Italy Antithrombin vs UH 842 Multiple 63.0 NR NR NR NR 93.7 Baykal C [38] Turkey LMWH vs UH 102 Single 57.4 NR NR NR 10.8% 100.0 Maxwell GL [39] USA LMWH vs SCD 211 Single 69.0 27.5 42.2 4.7 NR 79.6 Bergqvist D [40] Europe LMWH vs No treatment 332 Multiple 65.5 25.0 12.3 2.7 13.5% 100.0 Zheng H [41] China GCS + LMWH vs GCS 247 Single 50.7 24.8 NR NR NR 100.0 Nagata C [42] Japan SCD + LMWH vs SCD 30 Multiple 57.1 22.3 NR NR 20.0% 100.0

Author, Year Treatment Total Ovarian % Operative Time since Reported Method of VTE diagnosis patients cancer LND time surgery to VTE outcomes diagnosis

(min) (days)

Clarke-Pearson D [23]UHvsNo 185 27.0 27.0 NR 42 DVT, PE, VTE Signs/symptoms, I125, venography, treatment plethysmography, V/Q, PA Clarke-Pearson D [24] SCD vs No 194 23.0 29.9 233.0 42 DVT, PE, VTE Signs/symptoms, I125, venography, treatment plethysmography, V/Q, PA Clarke-Pearson D [25]UHvsNo 182 NR 26.9 231.1 NR NR NR treatment Turner GM [26] GCS vs No 196 NR NR 72.9 7 DVT, PE Signs/symptoms, I125 treatment Fricker JP [27] LMWH vs UH 80 NR 48.7 216.5 10 DVT, PE, VTE, Signs/symptoms, I125, venography, Major bleeding plethysmography, V/Q, PA Samama M [28] LMWH vs UH 885 NR NR 158.6 7 DVT, PE, VTE, Signs/symptoms, I125, V/Q, PA Major bleeding Clarke-Pearson D [29]UHvsNo 304 NR 32.6 189.2 30 DVT, PE, VTE Signs/symptoms, I125, venography, treatment plethysmography, V/Q, PA Dindelli M [30] Antithrombin 50 NR 56.0 NR 7 DVT Signs/symptoms, plethysmography, vs UH radio-isotopic phlebography Ferrari A [31] Antithrombin 60 NR NR NR 7 DVT Signs/symptoms, plethysmography vs UH Fontanelli A [32] Antithrombin 81 NR NR NR 7 DVT, Major Doppler vs UH bleeding Clarke-Pearson D [33] UH vs SCD 208 NR 13.9 232.4 30 DVT, PE, VTE Signs/symptoms, I125, Doppler, venography, plethysmography, V/Q, PA Urlep-Sallinovic V [34] UH + DHE vs 155 23.2 NR 149.0 10 DVT, PE, VTE, Signs/symptoms, I125, radio-isotopic UH Major bleeding phlebography, V/Q Von Tempelhoff GF [35] LMWH vs UH 60 100.0 NR NR 7 DVT, PE, VTE Signs/symptoms, venography, plethysmography, V/Q Ward B [36] LMWH vs UH 566 NR NR NR 42 DVT, PE Signs/symptoms, Doppler, venography, V/Q Di Carlo V [37] Antithrombin 842 7.5 NR 197.5 28 DVT, PE, VTE, Signs/symptoms, venography, V/Q, PA vs UH Major bleeding Baykal C [38] LMWH vs UH 102 46.1 100.0 148.3 NR DVT, PE, Major Signs/symptoms, Doppler, V/Q, PA bleeding Maxwell GL [39] LMWH vs SCD 332 NR NR 482.2 30 DVT, PE, Major Signs/symptoms, Doppler, venography, V/Q, bleeding PA Bergqvist D [40] LMWH vs No 211 28.0 20.4 198.0 30 DVT, PE, VTE, Signs/symptoms, Doppler treatment Major bleeding Zheng H [41] GCS + LMWH 247 33.6 NR 199.4 7 PE, VTE Signs/symptoms, Doppler, CTA vs GCS Nagata C [42] SCD + LMWH 30 40.0 80.0 238.0 11 DVT, PE, VTE, Signs/symptoms, CT with contrast vs SCD Major bleeding

Abbreviation: BMI, body mass index; DHE, dihydroergotamine; GCS, graduated compression stockings; kg, kilograms; LMWH, low molecular weight heparin; m, meters; NR, not reported; SCD, sequential compression device; UH, unfractionated heparin; VTE, venous thromboembolism; BMI, body mass index; CT scan, computerized tomography scan; CTA, computerized tomography angiography; DHE, dihydroergotamine; DVT, deep vein thrombosis; GCS, graduated compression stockings; I125 Fibrinogen, iodine 125-labeled ﬁbrinogen scanning; kg, kilograms; LND, lymphadenectomy; LMWH, low molecular weight heparin; m, meter; NR, not reported; PA, pulmonary arteriography; PE, pulmonary embolism; SCD, sequential compression device; UH, unfractionated heparin; V/Q, ventilation-perfusion scan; VTE, venous thromboembolism.

5 P. Insin, K. Vitoopinyoparb, K. Thadanipon et al. Gynecologic Oncology xxx (xxxx) xxx

Fig. 2. Forest plots of composite VTE occurrence and major bleeding outcomes

a) composite VTE occurrence outcome comparing between LMWH and UH, b) composite VTE occurrence outcome comparing between antithrombin and UH, c) major bleeding outcome comparing between LMWH and UH, and d) major bleeding outcome comparing between antithrombin and UH

options, ie, UHDHE, UH, antithrombins, LMWH, and SCD, had higher 3.2.3. Treatment ranking risk of major bleeding when compared with no treatment with pooled Risk of major bleeding and benefit from prevention of composite RRs of 5.04 (0.05, 496.48), 4.72 (0.43, 51.46), 4.16 (0.36, 47.76), 2.93 VTE occurrence were simultaneously considered using cluster plots of (0.30, 28.63), and 2.18 (0.14, 33.49) respectively, although none were SUCRAs of lowering composite VTE occurrence on the y-axis and significant (Table 2). SCD was 0.43 (0.01, 30.71), 0.46 (0.09, 2.45), major bleeding on the x-axis (Fig. 4). Seven treatments with data avail- and 0.52 (0.09, 3.00) times less likely to have major bleeding than able for VTE occurrence and major bleeding were considered. The plot UHDHE, UH, and antithrombins, respectively, but none were signifi- was divided into 4 quadrants: the upper right reflected the best treat- cant. The top three active treatments in lowering major bleeding ment and the lower left reflected the worst treatment. The clustering were SCD, SCD plus LMWH, and LMWH with SUCRAs of 60.2%, 56.8%, identified only SCD plus LMWH as the best treatment option for lower- and 54.8%, respectively (Supplementary Fig. S4). ing VTE occurrence and major bleeding.

Fig. 3. Network map of a) composite VTE occurrence and b) major bleeding.

6 P. Insin, K. Vitoopinyoparb, K. Thadanipon et al. Gynecologic Oncology xxx (xxxx) xxx

All analyses met the consistency assumption demonstrating agreement between direct and indirect sources of evidence within this re- 89)

.37) view (Supplementary Table S6). Publication bias was assessed using a 3.32) comparison-adjusted funnel plot, which indicated no evidence of asymmetry (Supplementary Fig. S5). 6 (0.24,2.43) .4, 0.4 49 (0.41,5.44) UHDHE 4. Discussion

) 7.69 (0.30,195.20) We conducted a systematic review, DMA, and NMA to provide a comprehensive assessmentof VTE prophylaxis interventionsand identify the most effective modality with the least side effects for gynecological can-

, 19.7 4.92 (0.38,64.22) cer patients undergoing major abdominopelvic surgery. Nineteen RCTs

SCD plus LMWH 1.92 (0.02,219.76)0.88 (0.02,42.38)0.41 5.04 (0.01,27.60) (0.05,496.48) 0.66 (0.01,41.80) 2.31 (0.03,163.93) 0.46 (0.01,32.27) 1.07 (0.02,53.78) 56.8, 29.3 1.72 (0.03,92.43) 0.38 (0.00,120.96) 1.21 (0.02,63.07) 36.7, 14.5 2.62 (0.01,829.39) (9 interventions, 4692 patients) and 10 RCTs (7 interventions, 2696 patients) were considered in the composite VTE occurrence and the major bleedingnetworks,respectively.OurNMAﬁndingssuggestedthatacom- bination of GCS plus LMWH was best at lowering composite VTE occurrence, while SCD was the safest for major bleeding. However, a , 71.1 0.75 (0.06,1080.50) 38.14 (0.42,3436.41) combination of SCD plus LMWH provided the optimal balance between

LMWH – – – – – – – composite VTE occurrence and major bleeding. In our DMA, antithrombins, either DS or DF, were more effective for VTE prevention. DS is a glycosaminoglycan effective on both free and ﬁbrin-bound thrombin which inhibits thrombus formation, while DF is a drug characterized by its antithrombotic and proﬁbrinolytic activity.

e treatment along left-hand column. Each diagonal cell contains SUCRA; percentage prob- Both drugs have proven effective in the prevention of postoperative

ency model. DVT in general and following orthopedic surgery with a low rate of hemorrhagic complications [43,44]. Unfortunately, the results of DMA were inconsistent with NMA, therefore, this pooling should be further updated when more studies are published. To our knowledge, only two systematic reviews [8,13] have previ- ously evaluated VTE prophylaxis in gynecological cancer patients. The firstreviewin2007[8] considered only effects of pharmacological methods, ie, UH vs LMWH (N = 5) and UH vs no prophylaxis (N =3). They found that UH could significantly prevent DVT by 42% relative to no prophylaxis, but it was not significantly different from LMWH. The later review in 2011 [13] described evidence from 9 studies in which the overall incidence of clinical VTE prophylaxis in gynecological cancers ranged from 0 to 14.8% and it was as high as 34.6% in non- prophylaxis. Neither VTE prevention nor bleeding between prophylactic methods was compared. Our study represents the most recent and comprehensive synthesis of evidence from 20 RCTs to evaluate not only the efficacy in prevention of VTE, but also safety from bleeding for VTE prophylaxis strategies. This synthesis incorporated more interventions (ie, 9 pharmacological and non-pharmacological methods including no treatment, GCS, SCD, UH, LMWH, antithrombins, GCS plus LMWH, SCD plus LMWH, and UHDHE) than previous reviews. Effects of all currently available interventions on VTE prophylaxis and bleeding following gy- 2.18 (0.14,33.49)60.2, 8.00.46 (0.09,2.45) 4.720.74 (0.43,51.46) (0.16,3.36)0.52 (0.09,3.00)1.13 (0.02,54.43) 26.0, 0.0 2.93 (0.30,28.63)0.43 (0.01,30.71) 1.61 (0.79,3.30) 2.17 (0.41,11.52) 1.14 (0.68,1.88) 2.46 (0.04,166.60) 4.16 (0.36,47.76) 0.94 (0.02,47.34) 54.8, 1.35 1.5 (0.30,6.08) 1.53 (0.02,97.28) 0.70 (0.29,1.69) 0.62 (0.30,1.27)necological 0.58 (0.01,31.37) 1.91 (0.33,10.92) 2.16 (0.03,151.19) 36.4, 1.4 0.88 (0.53,1.46) 0.83 (0.02,43.09) 1.42 (0.59,3.40) cancer surgery, but not for non-surgery, were considered in our NMA. The most recent clinical practice guidelines by the ASCO [15] and the NCCN[16]recommendedpharmacologicthromboprophylaxiswitheither UHorLMWHforallcancerpatientsundergoingmajorsurgery.Thesephar-

E occurrence and major bleeding) of each treatment. macologic treatments, particularly UH, require prothrombin time moni-

– – – – – – – toring, which is inconvenient and costly. Mechanical methods are also recommended in addition to pharmacologic thromboprophylaxis, but not as monotherapy unless pharmacologic methods are contraindicated. The ASCO guideline does not specify the choice of mechanical thromboprophylaxis, but the NCCN recommends IPC or SCD. However, patient's compliance with SCD varied because it was commonly associated with discomfort, heat, skin bullae, and itching from the compression pad,

No treatment GCS SCDand lack of mobility. UH Despite being LMWH rare, some Antithrombin serious complications GCS plus LMWH SCD plus LMWH UHDHE may also include compartment syndrome and skin necrosis [45]. Although SCD was considered as the safest option, this method's efﬁcacy in the re- duction of VTE events was not high, as shown by its poor ranking in the composite VTE occurrence outcome. As such, the use of SCD alone as a pri- mary intervention is questionable and does not represent the best option Comparatorsa) No Composite treatment VTE occurrence: risk ratiosNo (95%CIs) treatmentGCSSCD 16.0, 0.0UH GCSLMWHAntithrombinGCS plus LMWH 10.16 (0.50,207.46)SCD plus 1.97 LMWH (0.70,5.52) 1.14 (0.48,2.70) 50.40 (0.65,3893.23)UHDHE 0.10 1.40 (0.00,2.01) 75.4, (0.69,2.83) 6.50 7.8 1.41 (0.63,67.62)b) (0.77,2.58) Major 4.96 bleeding: SCD (0.22,113.48) risk ratios (95%CIs) 0.19 (0.01,4.60) 0.88 0.11 44.28No (0.37,2.09) (0.00,2.58) (0.53,3724.50) treatment 0.64 (0.01,29.15) 0.14SCD (0.01,3.05) 0.14 (0.01,3.01) 1.32 (0.41,4.24) 35.76 (0.44,2881.04)UH 1.73 (0.49,6.13) 26.1, 0.0 79.1, 8.93 5.71 45.3 (0.39,205.81) (0.65,50.36)LMWH 0.71 35.98 1.23 (0.39,1.30) (0.44,2941.45) (0.45,3.36) 1.24 (0.49,3.14)Antithrombin 0.13 25.56 (0.01,3.30) (0.29,2227.65)SCD 7.21 plus (0.33,156.35) 1.40 LMWH (0.61,3.20) UH 4.61 (0.43,49.23)UHDHE 0.24 91.0 0.71 (0.02,2.76) 0.46 0.99 (0.35,1.44) (0.03,7.05) 0.52 (0.57,1.74) 38.7, (0.00,59.43) 0.0 1.16 (0.30,4.54) 7.25 0.34 (0.33,160.62) (0.03,3.33) 0.21 (0.02,2.31) 0.81 (0.32,2.05) 4.64 (0.42,51.00) 1.41 (0.52,3.82) 0.51 37.7, 5.15 (0.18,1.42) 0.1 (0.21,124.88) 0.20 0.94 (0.00,19.58) (0.35,2.54) 3.30 0.81 (0.27,40.86) (0.30,2.22) 53.2, 0.9 0.20 (0.01,4.61) 1.01 (0.58,1.76) LMWH 0.02 (0.00,1.53) 0.94 (0.30,2.96) 0.13 (0.00,17.99) 1.56 (0.03,71.15 0.58 (0.16,2.04) 0.15 (0.01,1.60) 0.71 76.6 (0.26,1.93) 0.71 (0.31,1.63) 0.67 (0.18,2.45) 0.04 0.7 (0.00,3.41) 0.02 (0.00,1.90) 0.03 Antithrombin (0.00,2.27) 0.03 (0.00,2.25) 0.30 (0.02,3.75) 0.18 (0.02,1.54) 0.03 (0.00,2.36) 0.22 (0.02,2.37) 0.22 (0.02,2.31) 0.20 (0.02,2.65) 1. GCS 0.86 plus (0.22,3 1.06 (0.34, 1.07 (0.39,2. 35 Effect of an intervention in rowability was of compared being to best effect treatment of an (lower intervention composite in VT column. Risk ratio (RR) < 1 favors the treatment along top and RR > 1 favors th Table 2 Results of network meta-analyses of composite VTE occurrence and major bleeding outcomes for all treatments relative to each other under the consist for the prevention of VTE.

7 P. Insin, K. Vitoopinyoparb, K. Thadanipon et al. Gynecologic Oncology xxx (xxxx) xxx

Fig. 4. Clustered ranking plot based on cluster analysis of SUCRA values for having lowest composite VTE occurrence versus lowest major bleeding.

SCD plus LMWH was noticeably superior to LMWH alone in terms of Our study had several strengths. Our NMA included the most recent efficacy and safety as indicated by clustered ranking analysis placing it published RCTs and more recently available treatments not considered in fourth in terms of composite VTE occurrence and major bleeding. How- previous reviews [8,13]. We also included non-English language searches ever, the mechanisms that lead to a lower rate of major bleeding follow- to retrieve all available relevant evidence because negative results tend to ing SCD with LMWH intervention compared to LMWH alone have yet to be published in native language journals. This analysis identified no evi- be fully elucidated. Previous studies have reported higher risk of bleed- dence of heterogeneity in all pairwise comparisons and no discrepancy being with a daily dose of 5000 antiXaIU LMWH but not with a daily dose tween direct and indirect treatment evidence in NMA, indicating that of 2500 antiXaIU LMWH when compared with 5000 heparin units twice despite methodological and clinical differences, the main findings were ro- daily [46,47]. The lower LMWH dosage combined with SCD may lead to bust. Furthermore, the risk of bias assessed was not high. Although the pa- reduced bleeding complications compared to the higher LMWH dosage tients were not blinded in most studies, the measurement bias remained (4000 antiXaIU versus 6000 antiXaIU) as recommended in both small because all outcomes of interest evaluated were objective. guidelines. However, the results of this analysis should be carefully considered. This NMAs confirms the effectiveness of combination interventions First, many studies were not recent with most published between 1983 that use both mechanical and pharmacological methods for the preven- and 2000 and only five published post 2000. Patient characteristics, VTE tion of VTE. These results highlight the necessity for consideration of prophylactic methods, and modalities of cancer treatment have both efficacy and safety of pharmacological prophylactic approaches, changed considerably over this period and evaluation of the efficacy of especially if those with better efficacy for VTE prevention were more VTE prevention may have changed. Secondly, only a small number of likely to increase risk of bleeding. As such, the benefit-risk balance re- studies were available for inclusion in both DMA and NMA, and both requires careful consideration for clinical prescribing decisions. Neverthe- sults were inconsistent and the precision of treatment effects might be less, this evidence was based on a relatively small number of studies and questionable. For instance, results of DMA for antithrombins in lowering additional studies to investigate combination interventions including composite VTE was marginally significant relative to UH, but it was not GCS with or SCD with LMWH would provide an opportunity for more in the NMA when the sample size of UH group was increased by bor- robust and meaningful conclusions. rowing data from other comparisons. Likewise, for LMWH vs UH, esti- In addition, decision analysis of high-risk gynecological cancer pa- mation of treatment effects from both DMA and NMA were still tients also identified the dual prophylaxis strategy combining SCD imprecise due to a small number of included studies. In addition, the with LMWH as cost-effective and a reasonable use of healthcare re- sample size for each RCT was quite small, which resulted in zero num- sources [48]. Although the addition of LMWH to SCD offered a marginal ber of bleeding outcome for most studies. Although we could estimate improvement in the risk associated with VTE occurrence, the interven- RRs by applying continuity correction, filling the zero cells with a tion was considered costly, exceeding $50,000 per life-year saved in pa- small value, the estimated treatment effects on bleeding were impre- tients considered high-risk for the development of perioperative and cise. Therefore, caution should be exercised when interpreting and ap- postoperative VTE. In contrast, consideration of long-term disability plying the results. Thirdly, although the majority of the participants and costs associated with post-thrombotic syndrome would increase had gynecological cancer who underwent abdominopelvic surgery, the cost-effectiveness of VTE prophylaxis. Future studies with a full eco- the study population also included a minority of patients with other nomic evaluation for all available VTE prophylactic methods are needed cancers or benign gynecological conditions. Our results should not to verify the most cost-effective option and take account of reduced hos- be applied to those patients who did not have surgery. Fourthly, pital stay, rehabilitation, mortality, and long-term complications, such the included RCTs in our review had insufficient description of risk as pulmonary hypertension and post-thrombotic syndrome. factors for VTE occurrence: operative procedure (ie, laparotomy or

8 P. Insin, K. Vitoopinyoparb, K. Thadanipon et al. Gynecologic Oncology xxx (xxxx) xxx laparoscopy), cancer type (ie, ovarian, uterine, cervical, or vulvar can- [14] E.L. Barber, D.L. Clarke-Pearson, Prevention of venous thromboembolism in gynecologic oncology surgery, Gynecol. Oncol. 144 (2017) 420–427. cer), cancer stage (ie, early, advanced, or recurrent), BMI, and anesthesia [15] N.S. Key, A.A. Khorana, N.M. Kuderer, K. Bohlke, A.Y. Lee, J.I. Arcelus, et al., Venous type (ie, with or without epidural anesthesia). Sub-group analysis could thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical not be performed to identify any specific group of patients such as obe- practice guideline update, J. Clin. Oncol. 38 (2020) 496–520. sity who might gain more benefit than general patients. 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