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Efficacy and safety of weight-adjusted heparin prophylaxis for the prevention of acute venous thromboembolism among obese patients undergoing bariatric surgery: A systematic review and meta-analysis
Efficacy and safety of weight-adjusted heparin prophylaxis for the prevention of acute venous thromboembolism among obese patients undergoing bariatric surgery: A systematic review and meta-analysis Rick Ikesaka, Aur´elien Delluc, Gr´egoire Le Gal, Marc Carrier PII: DOI: Reference:
S0049-3848(14)00045-0 doi: 10.1016/j.thromres.2014.01.021 TR 5372
To appear in:
Thrombosis Research
Received date: Revised date: Accepted date:
6 November 2013 8 January 2014 14 January 2014
Please cite this article as: Ikesaka Rick, Delluc Aur´elien, Le Gal Gr´egoire, Carrier Marc, Efficacy and safety of weight-adjusted heparin prophylaxis for the prevention of acute venous thromboembolism among obese patients undergoing bariatric surgery: A systematic review and meta-analysis, Thrombosis Research (2014), doi: 10.1016/j.thromres.2014.01.021
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ACCEPTED MANUSCRIPT Efficacy and safety of weight-adjusted heparin prophylaxis for the prevention of acute venous thromboembolism among obese patients undergoing bariatric surgery: a systematic review and meta-analysis
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Rick Ikesaka MD*, Aurélien Delluc MD, Grégoire Le Gal MD PhD*†§, Marc Carrier MD MSc*†§. *
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Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada. † Clinical Epidemiology Program, The Ottawa Health Research Institute, Ottawa, Ontario Canada. § Thrombosis Program, Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
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Conflict of Interest Disclosure: All authors have fulfilled the conditions required for authorship and no conflicts of interest exist.
Address of correspondence and requests for reprints:
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Dr. Marc Carrier MD MSc Scientist – Ottawa Hospital Research Institute Associate Professor – University of Ottawa Ottawa Hospital – General Campus 501 Smyth Road, Box 201 Ottawa, ON, Canada Phone: 613-737-8899 ext 73034; fax: 613-739-6266 Email: [email protected]
ACCEPTED MANUSCRIPT ABSTRACT
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Background: The bariatric surgical population is a particularly high risk population for VTE. It is unclear if standard (i.e. non-adjusted) thromboprophylaxis doses of low-molecular weight or unfractionated heparin provide adequate protection for obese patients undergoing bariatric surgery, or if higher doses are required. We sought to determine whether a weight based thromboprophylactic dosing regimen is safe and effective in the post-operative period for obese patients undergoing bariatric surgery.
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Methods: A systematic literature search strategy was conducted using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and all EBM Reviews. Pooled proportions for the different outcomes were calculated.
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Results: A total of 6 studies (1 RCT, 4 cohort studies and one quasi experimental trial) containing 1,858 patients were include in the systematic review. Post bariatric surgery patients receiving weight-adjusted prophylactic doses of heparin products, had an in hospital rate of VTE of 0.54% (95% CI: 0.2 to 1.0%) compared to 2.0% (95% CI: 0.1 to 6.4%) for those that did not weight adjust doses. Rates of major bleeding were similar for both groups: 1.6% (95% CI: 0.6 to 3.0%) for patients receiving weight-adjusted dosing compared to 2.3% (95% CI: 1.1% to 3.9%) for those receiving standard doses of heparin products.
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Conclusions: Adjusting the dose of heparin products for thromboprophylaxis post-bariatric surgery seems to be associated with a lower rate of in hospital VTE compared to a strategy of not adjusting the dose, although this did not reach statistical significance. This practice does not lead to an increase in adverse major bleeding events.
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Keywords: Venous thromboembolism; heparin, low-molecular weight; bariatric surgery; Hemorrhage, mortality.
ACCEPTED MANUSCRIPT INTRODUCTION The prevalence of obesity in society is rapidly increasing with the United States leading
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the world with a prevalence of 34% of adults now being classified as obese (1). Obesity and surgery are known risk factors for venous thrombosis (2-4) and therefore, the
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bariatric surgical population is a particularly high risk population for VTE (5).
The data regarding the use of pharmacological thromboprophylaxis in the post-
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operative period following bariatric surgery is scarce. The most recent version of the American College of Chest Physicians guidelines does not report specific
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recommendation for this population (6). More importantly, it is unclear if standard (i.e.
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non-adjusted) thromboprophylaxis doses of low-molecular weight heparin (LMWH) or unfractionated heparin (UFH) provide adequate protection for obese patients
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undergoing bariatric surgery, or if weight-adjusted doses are required. Obese patients
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have several proposed mechanisms of altered drug distribution and metabolism, including, altered renal clearance, metabolic derangements affecting handling of drugs by the liver and changes in the volume of distribution and absorption of medications (7). In pharmacokinetic studies of LMWH actual body weight was inversely correlated with measured Anti-Xa level (8). Therefore it would seem to make sense that a higher dose of LMWH would be required to obtain the same therapeutic effect. Conversely, it must be acknowledged that LMWHs have a low volume of distribution (9) and generally do not distribute well to adipose tissue there are concerns that truly basing doses on weight may result in overdosing of this patient group. To attempt to bridge this important
ACCEPTED MANUSCRIPT knowledge gap, we conducted a systematic review of the literature to determine whether a weight-based thromboprophylactic dosing regimen of heparin products is
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safe and effective in the post-operative period for obese patients undergoing bariatric
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surgery.
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METHODS
A systematic literature search was performed in MEDLINE (1946- July 6, 2012),
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EMBASE (1947-July 6, 2012), the Cochrane Register of Controlled Trials and all EBM Reviews using an OVID interface. We also sought publications through a hand-search
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of potentially relevant journals and International Society of Thrombosis and
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Haemostasis conference proceedings (2003-2011). We also reviewed the references of included studies and previous systematic reviews for additional potential studies. There
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were no restrictions on language, publication type or publication year applied. The
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Medline search strategy is depicted in Appendix 1 (on-line).
Study Selection and Data Extraction Two reviewers (R.I. and M.C.) independently screened all abstracts records using a standardized extraction form to find potential relevant articles. Discrepancies between the reviewers on which studies should be included were resolved by consensus after discussion. The two investigators (R.I. and M.C.) then reviewed potentially relevant articles in full length to ensure that they satisfied these criteria: 1) patients undergoing
ACCEPTED MANUSCRIPT bariatric surgery; 2) patients received post-operative pharmacological thromboprophylaxis using LMWH, unfractionated heparin (UFH) or fondaparinux; and 3)
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outcome measures available. Studies were excluded if they included pregnant or
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pediatric patients.
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The primary outcome measures were VTE and major bleeding events. Venous
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thromboembolism was defined as symptomatic proximal lower limbs (popliteal vein or more proximal) deep vein thrombosis or objectively diagnosed pulmonary embolism.
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Weight-adjusted thromboprophylactic LMWH dosing was defined as the use of a higher than standard recommended dose set as enoxaparin 30mg subcutaneously q12 hr or
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equivalent. Weight-adjusted UFH was defied as doses higher than 5000 IU
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subcutaneously q8hr or as the use of a subcutaneously UFH protocol that adjusted the dose based on weight and the level of anticoagulation (anti-Xa). Major bleeding was
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defined as clinically overt bleeding associated with one or more of the requirements for
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hospitalization; transfusion of at least 2 units of packed red blood cells; intracranial or retroperitoneal bleeding or bleeding involving a body cavity; bleeding related death; or as defined by the individual studies (10). Outcome measures were independently extracted by each of the reviewers using a standard data extraction form. We attempted to contact authors but failed to retrieve any additional information. Corresponding author of manuscript were contacted if primary or secondary outcomes could not be extracted from the original manuscript.
Quality Assessment
ACCEPTED MANUSCRIPT Observational study quality was assessed using the Newcastle Ottawa Quality Assessment Scale for observational studies. Randomized controlled trials were
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assessed using the Risk of Bias Assessment Tool from the Cochrane Handbook(11).
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Data Synthesis and Statistical Analysis
Pooled proportions using random effect model were calculated for the different outcome
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measure. Ninety-five percent confidence intervals (95% CI) were calculated for each
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proportion using the averaged, inverse variance-weighted estimates from each study. (Stats Direct software, version 2.7.9). I2 was calculated to assess heterogeneity among
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the pooled estimates. It was set that an I2 value of less than 25% was low-level heterogeneity, 25 to 50% was considered moderate and greater than 50% was a high
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RESULTS
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degree of heterogeneity (12) .
A total of 6 studies (1 randomized controlled trial, 4 cohort studies and 1 quasiexperimental trial) containing 1,858 patients met the inclusion criteria and were included in the analysis. Baseline characteristics of the included studies are depicted in Table 1. A wide range of prophylaxis regimens are used by the studies the most aggressive of which was that used in the study by Borkgren-Okonek of up to enoxaparin 60mg subcutaneous q12hours. Other studies used either an alternative regimen of enoxaparin
ACCEPTED MANUSCRIPT (30-40mg q12), nadroparin(5700units vs 9500units) or a unfractionated heparin prophylaxis protocol.
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Of the included studies, the Scholten study is the only one demonstrating superiority of a weight based regimen and the Kalfarentzos study is the only study to demonstrate a
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signal for possible harm of a higher dosing regimen.
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A total of 1428 patients received weight-adjusted prophylactic doses of heparin products whereas 430 patients did not. Placebo patients from the Cossu study were not included
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within the analyses. Post bariatric surgery patients receiving weight-adjusted prophylactic doses of heparin products, had an in hospital rate of VTE of 0.54% (95%
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CI: 0.2 to 1.0%) I2=0% (0% to 64.1%). The rate of VTE was 2.0% (95% CI: 0.1 to 6.4%) I2=71.8% (0% to 89.5%) for those that did not weight adjust doses (Figure 2). Rates of
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major bleeding were for both groups: 1.6% (95% CI: 0.6 to 3.0%) I2=63.3% (0% to
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84.0%) for patients receiving weight-adjusted dosing compared to 2.3% (95% CI: 1.1%
(Figure 2).
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to 3.9%) I2=0% (0% to 72.9%) for those receiving standard doses of heparin products
The quality of the included studies is depicted in Appendix 2 and 3 (on-line). All cohort studies were adequately representative. Follow up duration was deemed to be adequate for all cohort studies with the exception of one study (13) for which follow up was not able to be determined from the paper (Appendix 2). The included randomized controlled trial did not report the procedures for sequence generation, allocation concealment and blinding (Appendix 3) limiting bias assessment (Appendix 3).
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DISCUSSION
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According to the results of the pooled data of our systematic review, weight adjusted thromboprophylaxis after bariatric surgery shows a non-significant trend towards a lower
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rate of inpatient VTE complication without an increased rate of major bleeding.
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Our reported rate of in-hospital VTE in patients receiving weight adjusted thromboprophylaxis is similar to those previously reported in the literature for non
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surgical obese patients which are theoretically a lower risk population (14). This may suggest that a more aggressive thromboprophylaxis dosing strategy would be more
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effective at preventing thrombosis. Similarly, our rates of major bleeding episodes are
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similar to those previously reported. A recently published study assessing the use of non dose adjusted thromboprophylaxis for 2 weeks post bariatric surgery reported a 1%
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rate of bleeding requiring cessation of therapy (15) and another study found a 30 day rate of major bleeding between 1.65-1.86% (16) which are similar to our weight adjusted group and suggestive that the practice of weight adjusting heparin prophylaxis in this patient population does not lead to an increase in adverse bleeding outcomes. Finally, the clinical outcomes in our systematic review are supported by the pharmacokinetic study by Frederiksen(8) as his analysis suggests that higher doses of LMWH are needed to obtain the same pharmacologic activity in obese patients. However, future trials are needed to confirm the efficacy and safety of weight-adjusted parenteral thromboprophylaxis following bariatric surgery.
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There are several limitations to interpretation of the results of this study. First, the low to
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moderate quality of the studies may have introduced bias into the review. Given that the primary outcome is objectively confirmed, it is likely that the bias was minimized,
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however, patient level data was not available and the diagnosis of PE was dependent on the confirmation from the investigators within the individual studies. Second, some
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pooled proportions had moderate to high heterogeneity. This is likely due to the types of
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bariatric surgery (Roux en Y, laparoscopic procedures, etc) or thromboprophylaxis regimens (UFH, LMWH) included within the analysis. These variations from one study
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to the other could lead to variation in rate of VTE between studies. Unfortunately, the number of included studies is too small to perform subgroup analysis establishing rates
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according to the type of surgery or thromboprophylaxis regimen. Fourth, planned
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assessment of publication bias could not be performed due to the small number of included studies. Fifth, being a systematic review, we did not have access to the patient
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level data of the included studies and therefore we could not control for variations in the length of stay in hospital of the duration of therapy of the included studies or for preexisting risk factors (e.g. prior history of VTE, severity of illness, etc) of the enrolled patients. It is possible that a more rapid discharge could have reduced the captured rate of VTE by the early discharge lowering thrombotic risk by earlier ambulation or by increasing the number of VTE events occurring outside the hospital. Sixth, obtaining diagnostic confirmation of VTE might be more challenging in obese patients (e.g. technical limitations, reduced echogenicity, etc) and could have led to imprecision in assessing our primary outcome measure. However, this should not lead to a differential
ACCEPTED MANUSCRIPT bias as it would affect all the patients included within our review. Finally, the studies included in this review primarily looked at in hospital VTE. Many VTEs occur in the post
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discharge period after surgery and further study assessing extended duration
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thromboprophylaxis are needed (17).
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Acknowledging the above limitations, adjusting the dose of heparin products for thromboprophylaxis post-bariatric surgery seems to possibly be associated with a lower
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rate of VTE compared to a strategy of not adjusting the dose but this difference was not
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significant. This practice does not lead to an increase in adverse major bleeding events. Future studies assessing the efficacy and safety of weight adjusted dosing of bariatric
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surgical patients are needed to confirm these findings.
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Conflict of Interest Disclosure Statement
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The authors have no conflicts of interest to disclose.
ACCEPTED MANUSCRIPT REFERENCES
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1. Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999-2008. JAMA. 2010;303(3):235-41. 2. Stein PD. Obesity as a risk factor in venous thromboembolism. Am J Med. 2005;118(9):978-80. 3. Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). United States: American College of Chest Physicians; 2008 [cited 133 (Geerts) Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada]; 6 SUPPL. 6:[381S-453S]. Available from: http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed8&NEWS=N&AN=2008310003. 4. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton LJ, 3rd. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med. 2000 Mar 27;160(6):809-15. 5. Stein PD, Matta F. Pulmonary embolism and deep venous thrombosis following bariatric surgery. Obes Surg. 2013 May;23(5):663-8. 6. Gould MK, Garcia DA, Wren SM, Karanicolas PJ, Arcelus JI, Heit JA, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e227S-77S. 7. Jain R, Chung SM, Jain L, Khurana M, Lau SW, Lee JE, et al. Implications of obesity for drug therapy: limitations and challenges. Clin Pharmacol Ther. 2011 Jul;90(1):77-89. 8. Frederiksen SG, Hedenbro JL, Norgren L. Enoxaparin effect depends on body-weight and current doses may be inadequate in obese patients. United Kingdom: John Wiley and Sons Ltd; 2003 [cited 90 (Frederiksen, Hedenbro) Department of Surgery, Lund University Hospital, Lund, Sweden]; 5:[547-8]. Available from: http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed6&NEWS=N&AN=2003200136. 9. Fareed J, Hoppensteadt D, Walenga J, Iqbal O, Ma Q, Jeske W, et al. Pharmacodynamic and pharmacokinetic properties of enoxaparin : implications for clinical practice. Clin Pharmacokinet. 2003;42(12):1043-57. 10. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. 11. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. 12. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002 Jun 15;21(11):1539-58. 13. Shepherd MF, Rosborough TK, Schwartz ML. Heparin thromboprophylaxis in gastric bypass surgery. United States: FD Communications Inc.; 2003 [cited 13 (Shepherd, Rosborough) Medical Education Department, Abbott Northwestern Hospital, Minneapolis, MN, United States]; 2:[249-53]. Available from: http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed6&NEWS=N&AN=2003210895. 14. Kucher N, Leizorovicz A, Vaitkus PT, Cohen AT, Turpie AGG, Olsson CG, et al. Efficacy and safety of fixed low-dose dalteparin in preventing venous thromboembolism among obese or elderly hospitalized patients: A subgroup analysis of the PREVENT trial. United States: American Medical Association; 2005 [cited 165 (Vaitkus) Pharmacia Corp.]; 3:[341-5]. Available from: http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed7&NEWS=N&AN=2005072188. 15. Woo HD, Kim YJ. Prevention of venous thromboembolism with enoxaparin in bariatirc surgery. J Korean Surg Soc. 2013 May;84(5):298-303.
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16. Birkmeyer NJ, Finks JF, Carlin AM, Chengelis DL, Krause KR, Hawasli AA, et al. Comparative effectiveness of unfractionated and low-molecular-weight heparin for prevention of venous thromboembolism following bariatric surgery. Arch Surg. 2012 Nov 1;147(11):994-8. 17. Nilsson PE, Bergqvist D, Benoni G, Bjorgell O, Fredin H, Hedlund U, et al. The post-discharge prophylactic management of the orthopedic patient with low-molecular-weight heparin: enoxaparin. Orthopedics. 1997 Feb;20 Suppl:22-5.
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Figure 1. Flow diagram
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Table 1. Baseline Characteristics of the Included Studies Design
N
Intervention
Dosing
Nadroparin prophylaxis once pre-operatively and then given once daily post-operatively until discharge.
Nadroparin 9500 sc daily
Treatmen t Duration (days)
389 (W) Scholten, 2002
QuasiTreatment experimen 92 (S) tal trial
Control
Cohort
700 (W)
Minor Bleeding (%)
0
6.7
0
10.0
0
0
0
Enoxaparin 40mg sc q12hr
3.81
0.51
0.26
0
Enoxaparin 30mg sc q12hr
5.67
5.43
1.09
0
Not Reported
0.43
1.0
2.85
10
0.45
2.24
2.24
28
1.16
2.33
0
Nadroparin 5700 sc daily
The goal anti-factor Xa level of the protocol, measured 4 hours after each morning dose, was 0.11-0.25 units/mL
Q12hr heparin dosing determined by equation: (71.34 X weight) (kg) + (83.75 X height) (inches) – 3,467.59 With APTT monitoring
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Shepherd, 2003
LMWH was administered 2 hours prior to surgery and continued q 12 hours until the patient was fully ambulatory or at hospital discharge
CR
30 (S) Control
In Major Hospital Bleeding VTE (%) (%)
9.4
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RCT
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Kalfarentzos, 2001
30 (W) Treatment
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Study
Cossu 2007
Raftopoulous, 2008
Cohort
Cohort
223 (W)
86 UFH (W) protocol
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Cohort
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BorkgrenOkonek, 2007
Enoxaparin 40 mg (BMI Enoxaparin prophylaxis q12 <50) or 60 mg (BMI >50) hours during hospitalization and q12hr Adjustments made for once daily for 10 days after Anti Xa levels outside discharge prophylactic range Only pooled data reported UFH subcutaneous prophylaxis Actual dose given based on 4-5 days pre-op then 8-9 days aPTT monitoring (exact post OR and 15 days of post d/c values not reported) heparin
65 (N) Placebo
Dose x 1 at time of anesthesia
2500 to 5000 IU of UFH
---
3.08
0
0
176 (S) (Group A)
Enoxaparin 1 hour prior to surgery followed by enoxaparin 30 mg subcutaneously twice a day starting 12 hr after surgery until discharge from hospital
Enoxaparin 30 mg sc q12hr.
2.5
1.14
5.3
10.6
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0.57
15.34
IP
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12.5
CR
No pre-op heparin, then enoxaparin 30 mg Enoxaprin 30mg sc q12hr in subcutaneously twice a day hospital followed by starting 12 hr after surgery for 132 (S) the duration of hospital stay (Group B) followed by a 10-day course of Enoxaparin 40mg sc daily x enoxaparin 40 mg sc once a day 10 days post d/c at home after hospital discharge.
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The group in which the group of patients was analyzed is denoted by a letter after the patient number. Weight Adjusted (W) N=1428 , Standard dosing (S) N= 430 or Not analyzed (N) N=65
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Figure 2. Rates of In-hospital VTE and Major Bleeding Events in Bariatric Surgery Patients
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Appendix 1 – Medline Search Strategies obesity/ or obesity, morbid/
2
(obese or obesity).tw.
3
bmi > 30.tw.
4
(high body mass index or high bmi).tw.
5
Bariatric Surgery/
6
(bariatric adj2 patient$).tw.
7
(enoxaparin or lovenox).af.
8
(dalteparin or fragmin).af.
9
(tinzaparin or innohep).af.
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1
heparin/ or heparin, low-molecular-weight/
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Anticoagulants/
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(heparin or low molecular weight heparin$ or lmwh).tw.
13
Venous Thrombosis/ or Venous Thromboembolism/ or vte.tw.
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10
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14 Thromboembolism/ or (thromboembolism or thromboembolic or thromboprophylaxis or phlebothrombosis).tw (vein thrombos$ or venous thrombos$ or dvt).tw.
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Pulmonary Embolism/ or pulmonary embol$.tw.
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Appendix 2. Quality Assessment using the Using the Newcastle/Ottawa Scale for Cohort Studies.
*
*
*
Cossu, 2007
*
*
*
Miller, 2004
*
0
*
Raftopoulous, 2008
*
*
*
Shepherd, 2003
*
0
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BorkgrenOkonek, 2007
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*
IP CR
Outcome Selection non Ascertainment not present exposed of Exposure at start
Design
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Representativeness
Comparability Outcome
T
Selection Criteria
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Cohort Studies
Assessment Length follow Adequacy of outcome up sufficient of follow up
*
**
*
*
*
0
*
0
*
0
0
0
*
*
*
0
**
*
*
*
*
*
*
0
*
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A study can receive a maximum of 1 asterisk for each numbered item within the selection and outcome categories. A maximum of 2 asterisks can be given for comparability.
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Scholten 2002
High Risk
No- serial enrollment High Risk
Incomplete outcome data
Selective Reporting
Low Risk
Clinically important outcomes reportedLow Risk
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Not Reported
Allocation concealment
Blinding of outcome assessors
Blinding of outcome assessors
Not Reported
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Random Sequence Generation No- patients enrolled serially into 2 groups with first 92 being group 1 and next 389 being group 2
Not Reported
Clinically important outcomes reportedLow Risk
Blinding of participants and personnel
Allocation concealment
Blinding of participants and personnel Not Reported but based on randomization protocol it would be easy to find out what the treatment was
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QuasiExperimental Trials
Not Reported
All enrolled accounted for – Low Risk
Detection bias
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Kalfarentzos 2001
Random Sequence Generation
Attrition bias Incomplete outcome data
Performance bias
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Randomized Controlled Trials
CR
Selection bias
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Appendix 3. Quality Assessment Using the Tool from Cochrane Handbook.
High Risk
Probable as radiologists reading scans would not have access to pharmacy data Low Risk
Reporting Other Bias Bias
Selective Reporting
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CR
IP
Size of Treatment effect
Yes
Yes
Yes
No difference between the Objective 0.6 and 1.0 measure nadro groups
Precision
small N=60 study not precise
Benefits Can we of tx apply to our Treatment outweigh populations Feasible harms
Yes
Yes
Yes
Scholten D 2002
No
Can't Tell
Groups tx Were all equally minus accounted Measures interested for/losses objective variable acceptable vs blinding
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QuasiRandomizatio Experimental n
Groups Similar @ Start
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Kalfarentzos F 2001
Unclear protocol. Unknown if random sequence allocation used
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Randomized Randomizatio Control Trials n
Groups Similar @ Start
Groups tx Were all equally minus accounted Measures interested for/losses objective variable acceptable vs blinding
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Yes
Yes
Size of Treatment effect
Precision
Semiobjective Large decline Stats/confiden measures, in VTE events ce intervals not no blinding in 2nd group listed
Benefits Can we of tx apply to our Treatment outweigh populations Feasible harms
Yes
Yes
Yes
S0049-3848(14)00045-0 doi: 10.1016/j.thromres.2014.01.021 TR 5372
To appear in:
Thrombosis Research
Received date: Revised date: Accepted date:
6 November 2013 8 January 2014 14 January 2014
Please cite this article as: Ikesaka Rick, Delluc Aur´elien, Le Gal Gr´egoire, Carrier Marc, Efficacy and safety of weight-adjusted heparin prophylaxis for the prevention of acute venous thromboembolism among obese patients undergoing bariatric surgery: A systematic review and meta-analysis, Thrombosis Research (2014), doi: 10.1016/j.thromres.2014.01.021
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Efficacy and safety of weight-adjusted heparin prophylaxis for the prevention of acute venous thromboembolism among obese patients undergoing bariatric surgery: a systematic review and meta-analysis
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Rick Ikesaka MD*, Aurélien Delluc MD, Grégoire Le Gal MD PhD*†§, Marc Carrier MD MSc*†§. *
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Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada. † Clinical Epidemiology Program, The Ottawa Health Research Institute, Ottawa, Ontario Canada. § Thrombosis Program, Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
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Characters, Title: 113 Word count, total: 1,776
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Conflict of Interest Disclosure: All authors have fulfilled the conditions required for authorship and no conflicts of interest exist.
Address of correspondence and requests for reprints:
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Dr. Marc Carrier MD MSc Scientist – Ottawa Hospital Research Institute Associate Professor – University of Ottawa Ottawa Hospital – General Campus 501 Smyth Road, Box 201 Ottawa, ON, Canada Phone: 613-737-8899 ext 73034; fax: 613-739-6266 Email: [email protected]
ACCEPTED MANUSCRIPT ABSTRACT
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Background: The bariatric surgical population is a particularly high risk population for VTE. It is unclear if standard (i.e. non-adjusted) thromboprophylaxis doses of low-molecular weight or unfractionated heparin provide adequate protection for obese patients undergoing bariatric surgery, or if higher doses are required. We sought to determine whether a weight based thromboprophylactic dosing regimen is safe and effective in the post-operative period for obese patients undergoing bariatric surgery.
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Methods: A systematic literature search strategy was conducted using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and all EBM Reviews. Pooled proportions for the different outcomes were calculated.
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Results: A total of 6 studies (1 RCT, 4 cohort studies and one quasi experimental trial) containing 1,858 patients were include in the systematic review. Post bariatric surgery patients receiving weight-adjusted prophylactic doses of heparin products, had an in hospital rate of VTE of 0.54% (95% CI: 0.2 to 1.0%) compared to 2.0% (95% CI: 0.1 to 6.4%) for those that did not weight adjust doses. Rates of major bleeding were similar for both groups: 1.6% (95% CI: 0.6 to 3.0%) for patients receiving weight-adjusted dosing compared to 2.3% (95% CI: 1.1% to 3.9%) for those receiving standard doses of heparin products.
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Conclusions: Adjusting the dose of heparin products for thromboprophylaxis post-bariatric surgery seems to be associated with a lower rate of in hospital VTE compared to a strategy of not adjusting the dose, although this did not reach statistical significance. This practice does not lead to an increase in adverse major bleeding events.
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Keywords: Venous thromboembolism; heparin, low-molecular weight; bariatric surgery; Hemorrhage, mortality.
ACCEPTED MANUSCRIPT INTRODUCTION The prevalence of obesity in society is rapidly increasing with the United States leading
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the world with a prevalence of 34% of adults now being classified as obese (1). Obesity and surgery are known risk factors for venous thrombosis (2-4) and therefore, the
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bariatric surgical population is a particularly high risk population for VTE (5).
The data regarding the use of pharmacological thromboprophylaxis in the post-
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operative period following bariatric surgery is scarce. The most recent version of the American College of Chest Physicians guidelines does not report specific
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recommendation for this population (6). More importantly, it is unclear if standard (i.e.
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non-adjusted) thromboprophylaxis doses of low-molecular weight heparin (LMWH) or unfractionated heparin (UFH) provide adequate protection for obese patients
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undergoing bariatric surgery, or if weight-adjusted doses are required. Obese patients
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have several proposed mechanisms of altered drug distribution and metabolism, including, altered renal clearance, metabolic derangements affecting handling of drugs by the liver and changes in the volume of distribution and absorption of medications (7). In pharmacokinetic studies of LMWH actual body weight was inversely correlated with measured Anti-Xa level (8). Therefore it would seem to make sense that a higher dose of LMWH would be required to obtain the same therapeutic effect. Conversely, it must be acknowledged that LMWHs have a low volume of distribution (9) and generally do not distribute well to adipose tissue there are concerns that truly basing doses on weight may result in overdosing of this patient group. To attempt to bridge this important
ACCEPTED MANUSCRIPT knowledge gap, we conducted a systematic review of the literature to determine whether a weight-based thromboprophylactic dosing regimen of heparin products is
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safe and effective in the post-operative period for obese patients undergoing bariatric
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surgery.
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METHODS
A systematic literature search was performed in MEDLINE (1946- July 6, 2012),
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EMBASE (1947-July 6, 2012), the Cochrane Register of Controlled Trials and all EBM Reviews using an OVID interface. We also sought publications through a hand-search
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of potentially relevant journals and International Society of Thrombosis and
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Haemostasis conference proceedings (2003-2011). We also reviewed the references of included studies and previous systematic reviews for additional potential studies. There
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were no restrictions on language, publication type or publication year applied. The
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Medline search strategy is depicted in Appendix 1 (on-line).
Study Selection and Data Extraction Two reviewers (R.I. and M.C.) independently screened all abstracts records using a standardized extraction form to find potential relevant articles. Discrepancies between the reviewers on which studies should be included were resolved by consensus after discussion. The two investigators (R.I. and M.C.) then reviewed potentially relevant articles in full length to ensure that they satisfied these criteria: 1) patients undergoing
ACCEPTED MANUSCRIPT bariatric surgery; 2) patients received post-operative pharmacological thromboprophylaxis using LMWH, unfractionated heparin (UFH) or fondaparinux; and 3)
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outcome measures available. Studies were excluded if they included pregnant or
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pediatric patients.
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The primary outcome measures were VTE and major bleeding events. Venous
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thromboembolism was defined as symptomatic proximal lower limbs (popliteal vein or more proximal) deep vein thrombosis or objectively diagnosed pulmonary embolism.
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Weight-adjusted thromboprophylactic LMWH dosing was defined as the use of a higher than standard recommended dose set as enoxaparin 30mg subcutaneously q12 hr or
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equivalent. Weight-adjusted UFH was defied as doses higher than 5000 IU
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subcutaneously q8hr or as the use of a subcutaneously UFH protocol that adjusted the dose based on weight and the level of anticoagulation (anti-Xa). Major bleeding was
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defined as clinically overt bleeding associated with one or more of the requirements for
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hospitalization; transfusion of at least 2 units of packed red blood cells; intracranial or retroperitoneal bleeding or bleeding involving a body cavity; bleeding related death; or as defined by the individual studies (10). Outcome measures were independently extracted by each of the reviewers using a standard data extraction form. We attempted to contact authors but failed to retrieve any additional information. Corresponding author of manuscript were contacted if primary or secondary outcomes could not be extracted from the original manuscript.
Quality Assessment
ACCEPTED MANUSCRIPT Observational study quality was assessed using the Newcastle Ottawa Quality Assessment Scale for observational studies. Randomized controlled trials were
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assessed using the Risk of Bias Assessment Tool from the Cochrane Handbook(11).
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Data Synthesis and Statistical Analysis
Pooled proportions using random effect model were calculated for the different outcome
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measure. Ninety-five percent confidence intervals (95% CI) were calculated for each
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proportion using the averaged, inverse variance-weighted estimates from each study. (Stats Direct software, version 2.7.9). I2 was calculated to assess heterogeneity among
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the pooled estimates. It was set that an I2 value of less than 25% was low-level heterogeneity, 25 to 50% was considered moderate and greater than 50% was a high
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RESULTS
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degree of heterogeneity (12) .
A total of 6 studies (1 randomized controlled trial, 4 cohort studies and 1 quasiexperimental trial) containing 1,858 patients met the inclusion criteria and were included in the analysis. Baseline characteristics of the included studies are depicted in Table 1. A wide range of prophylaxis regimens are used by the studies the most aggressive of which was that used in the study by Borkgren-Okonek of up to enoxaparin 60mg subcutaneous q12hours. Other studies used either an alternative regimen of enoxaparin
ACCEPTED MANUSCRIPT (30-40mg q12), nadroparin(5700units vs 9500units) or a unfractionated heparin prophylaxis protocol.
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Of the included studies, the Scholten study is the only one demonstrating superiority of a weight based regimen and the Kalfarentzos study is the only study to demonstrate a
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signal for possible harm of a higher dosing regimen.
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A total of 1428 patients received weight-adjusted prophylactic doses of heparin products whereas 430 patients did not. Placebo patients from the Cossu study were not included
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within the analyses. Post bariatric surgery patients receiving weight-adjusted prophylactic doses of heparin products, had an in hospital rate of VTE of 0.54% (95%
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CI: 0.2 to 1.0%) I2=0% (0% to 64.1%). The rate of VTE was 2.0% (95% CI: 0.1 to 6.4%) I2=71.8% (0% to 89.5%) for those that did not weight adjust doses (Figure 2). Rates of
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major bleeding were for both groups: 1.6% (95% CI: 0.6 to 3.0%) I2=63.3% (0% to
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84.0%) for patients receiving weight-adjusted dosing compared to 2.3% (95% CI: 1.1%
(Figure 2).
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to 3.9%) I2=0% (0% to 72.9%) for those receiving standard doses of heparin products
The quality of the included studies is depicted in Appendix 2 and 3 (on-line). All cohort studies were adequately representative. Follow up duration was deemed to be adequate for all cohort studies with the exception of one study (13) for which follow up was not able to be determined from the paper (Appendix 2). The included randomized controlled trial did not report the procedures for sequence generation, allocation concealment and blinding (Appendix 3) limiting bias assessment (Appendix 3).
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DISCUSSION
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According to the results of the pooled data of our systematic review, weight adjusted thromboprophylaxis after bariatric surgery shows a non-significant trend towards a lower
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rate of inpatient VTE complication without an increased rate of major bleeding.
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Our reported rate of in-hospital VTE in patients receiving weight adjusted thromboprophylaxis is similar to those previously reported in the literature for non
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surgical obese patients which are theoretically a lower risk population (14). This may suggest that a more aggressive thromboprophylaxis dosing strategy would be more
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effective at preventing thrombosis. Similarly, our rates of major bleeding episodes are
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similar to those previously reported. A recently published study assessing the use of non dose adjusted thromboprophylaxis for 2 weeks post bariatric surgery reported a 1%
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rate of bleeding requiring cessation of therapy (15) and another study found a 30 day rate of major bleeding between 1.65-1.86% (16) which are similar to our weight adjusted group and suggestive that the practice of weight adjusting heparin prophylaxis in this patient population does not lead to an increase in adverse bleeding outcomes. Finally, the clinical outcomes in our systematic review are supported by the pharmacokinetic study by Frederiksen(8) as his analysis suggests that higher doses of LMWH are needed to obtain the same pharmacologic activity in obese patients. However, future trials are needed to confirm the efficacy and safety of weight-adjusted parenteral thromboprophylaxis following bariatric surgery.
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There are several limitations to interpretation of the results of this study. First, the low to
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moderate quality of the studies may have introduced bias into the review. Given that the primary outcome is objectively confirmed, it is likely that the bias was minimized,
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however, patient level data was not available and the diagnosis of PE was dependent on the confirmation from the investigators within the individual studies. Second, some
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pooled proportions had moderate to high heterogeneity. This is likely due to the types of
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bariatric surgery (Roux en Y, laparoscopic procedures, etc) or thromboprophylaxis regimens (UFH, LMWH) included within the analysis. These variations from one study
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to the other could lead to variation in rate of VTE between studies. Unfortunately, the number of included studies is too small to perform subgroup analysis establishing rates
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according to the type of surgery or thromboprophylaxis regimen. Fourth, planned
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assessment of publication bias could not be performed due to the small number of included studies. Fifth, being a systematic review, we did not have access to the patient
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level data of the included studies and therefore we could not control for variations in the length of stay in hospital of the duration of therapy of the included studies or for preexisting risk factors (e.g. prior history of VTE, severity of illness, etc) of the enrolled patients. It is possible that a more rapid discharge could have reduced the captured rate of VTE by the early discharge lowering thrombotic risk by earlier ambulation or by increasing the number of VTE events occurring outside the hospital. Sixth, obtaining diagnostic confirmation of VTE might be more challenging in obese patients (e.g. technical limitations, reduced echogenicity, etc) and could have led to imprecision in assessing our primary outcome measure. However, this should not lead to a differential
ACCEPTED MANUSCRIPT bias as it would affect all the patients included within our review. Finally, the studies included in this review primarily looked at in hospital VTE. Many VTEs occur in the post
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discharge period after surgery and further study assessing extended duration
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thromboprophylaxis are needed (17).
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Acknowledging the above limitations, adjusting the dose of heparin products for thromboprophylaxis post-bariatric surgery seems to possibly be associated with a lower
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rate of VTE compared to a strategy of not adjusting the dose but this difference was not
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significant. This practice does not lead to an increase in adverse major bleeding events. Future studies assessing the efficacy and safety of weight adjusted dosing of bariatric
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surgical patients are needed to confirm these findings.
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Conflict of Interest Disclosure Statement
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The authors have no conflicts of interest to disclose.
ACCEPTED MANUSCRIPT REFERENCES
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1. Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999-2008. JAMA. 2010;303(3):235-41. 2. Stein PD. Obesity as a risk factor in venous thromboembolism. Am J Med. 2005;118(9):978-80. 3. Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). United States: American College of Chest Physicians; 2008 [cited 133 (Geerts) Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada]; 6 SUPPL. 6:[381S-453S]. Available from: http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed8&NEWS=N&AN=2008310003. 4. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton LJ, 3rd. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med. 2000 Mar 27;160(6):809-15. 5. Stein PD, Matta F. Pulmonary embolism and deep venous thrombosis following bariatric surgery. Obes Surg. 2013 May;23(5):663-8. 6. Gould MK, Garcia DA, Wren SM, Karanicolas PJ, Arcelus JI, Heit JA, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e227S-77S. 7. Jain R, Chung SM, Jain L, Khurana M, Lau SW, Lee JE, et al. Implications of obesity for drug therapy: limitations and challenges. Clin Pharmacol Ther. 2011 Jul;90(1):77-89. 8. Frederiksen SG, Hedenbro JL, Norgren L. Enoxaparin effect depends on body-weight and current doses may be inadequate in obese patients. United Kingdom: John Wiley and Sons Ltd; 2003 [cited 90 (Frederiksen, Hedenbro) Department of Surgery, Lund University Hospital, Lund, Sweden]; 5:[547-8]. Available from: http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed6&NEWS=N&AN=2003200136. 9. Fareed J, Hoppensteadt D, Walenga J, Iqbal O, Ma Q, Jeske W, et al. Pharmacodynamic and pharmacokinetic properties of enoxaparin : implications for clinical practice. Clin Pharmacokinet. 2003;42(12):1043-57. 10. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. 11. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. 12. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002 Jun 15;21(11):1539-58. 13. Shepherd MF, Rosborough TK, Schwartz ML. Heparin thromboprophylaxis in gastric bypass surgery. United States: FD Communications Inc.; 2003 [cited 13 (Shepherd, Rosborough) Medical Education Department, Abbott Northwestern Hospital, Minneapolis, MN, United States]; 2:[249-53]. Available from: http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed6&NEWS=N&AN=2003210895. 14. Kucher N, Leizorovicz A, Vaitkus PT, Cohen AT, Turpie AGG, Olsson CG, et al. Efficacy and safety of fixed low-dose dalteparin in preventing venous thromboembolism among obese or elderly hospitalized patients: A subgroup analysis of the PREVENT trial. United States: American Medical Association; 2005 [cited 165 (Vaitkus) Pharmacia Corp.]; 3:[341-5]. Available from: http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed7&NEWS=N&AN=2005072188. 15. Woo HD, Kim YJ. Prevention of venous thromboembolism with enoxaparin in bariatirc surgery. J Korean Surg Soc. 2013 May;84(5):298-303.
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16. Birkmeyer NJ, Finks JF, Carlin AM, Chengelis DL, Krause KR, Hawasli AA, et al. Comparative effectiveness of unfractionated and low-molecular-weight heparin for prevention of venous thromboembolism following bariatric surgery. Arch Surg. 2012 Nov 1;147(11):994-8. 17. Nilsson PE, Bergqvist D, Benoni G, Bjorgell O, Fredin H, Hedlund U, et al. The post-discharge prophylactic management of the orthopedic patient with low-molecular-weight heparin: enoxaparin. Orthopedics. 1997 Feb;20 Suppl:22-5.
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Figure 1. Flow diagram
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Table 1. Baseline Characteristics of the Included Studies Design
N
Intervention
Dosing
Nadroparin prophylaxis once pre-operatively and then given once daily post-operatively until discharge.
Nadroparin 9500 sc daily
Treatmen t Duration (days)
389 (W) Scholten, 2002
QuasiTreatment experimen 92 (S) tal trial
Control
Cohort
700 (W)
Minor Bleeding (%)
0
6.7
0
10.0
0
0
0
Enoxaparin 40mg sc q12hr
3.81
0.51
0.26
0
Enoxaparin 30mg sc q12hr
5.67
5.43
1.09
0
Not Reported
0.43
1.0
2.85
10
0.45
2.24
2.24
28
1.16
2.33
0
Nadroparin 5700 sc daily
The goal anti-factor Xa level of the protocol, measured 4 hours after each morning dose, was 0.11-0.25 units/mL
Q12hr heparin dosing determined by equation: (71.34 X weight) (kg) + (83.75 X height) (inches) – 3,467.59 With APTT monitoring
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LMWH was administered 2 hours prior to surgery and continued q 12 hours until the patient was fully ambulatory or at hospital discharge
CR
30 (S) Control
In Major Hospital Bleeding VTE (%) (%)
9.4
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RCT
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Kalfarentzos, 2001
30 (W) Treatment
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Study
Cossu 2007
Raftopoulous, 2008
Cohort
Cohort
223 (W)
86 UFH (W) protocol
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Cohort
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BorkgrenOkonek, 2007
Enoxaparin 40 mg (BMI Enoxaparin prophylaxis q12 <50) or 60 mg (BMI >50) hours during hospitalization and q12hr Adjustments made for once daily for 10 days after Anti Xa levels outside discharge prophylactic range Only pooled data reported UFH subcutaneous prophylaxis Actual dose given based on 4-5 days pre-op then 8-9 days aPTT monitoring (exact post OR and 15 days of post d/c values not reported) heparin
65 (N) Placebo
Dose x 1 at time of anesthesia
2500 to 5000 IU of UFH
---
3.08
0
0
176 (S) (Group A)
Enoxaparin 1 hour prior to surgery followed by enoxaparin 30 mg subcutaneously twice a day starting 12 hr after surgery until discharge from hospital
Enoxaparin 30 mg sc q12hr.
2.5
1.14
5.3
10.6
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0.57
15.34
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12.5
CR
No pre-op heparin, then enoxaparin 30 mg Enoxaprin 30mg sc q12hr in subcutaneously twice a day hospital followed by starting 12 hr after surgery for 132 (S) the duration of hospital stay (Group B) followed by a 10-day course of Enoxaparin 40mg sc daily x enoxaparin 40 mg sc once a day 10 days post d/c at home after hospital discharge.
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The group in which the group of patients was analyzed is denoted by a letter after the patient number. Weight Adjusted (W) N=1428 , Standard dosing (S) N= 430 or Not analyzed (N) N=65
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Figure 2. Rates of In-hospital VTE and Major Bleeding Events in Bariatric Surgery Patients
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Appendix 1 – Medline Search Strategies obesity/ or obesity, morbid/
2
(obese or obesity).tw.
3
bmi > 30.tw.
4
(high body mass index or high bmi).tw.
5
Bariatric Surgery/
6
(bariatric adj2 patient$).tw.
7
(enoxaparin or lovenox).af.
8
(dalteparin or fragmin).af.
9
(tinzaparin or innohep).af.
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1
heparin/ or heparin, low-molecular-weight/
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Anticoagulants/
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(heparin or low molecular weight heparin$ or lmwh).tw.
13
Venous Thrombosis/ or Venous Thromboembolism/ or vte.tw.
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10
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14 Thromboembolism/ or (thromboembolism or thromboembolic or thromboprophylaxis or phlebothrombosis).tw (vein thrombos$ or venous thrombos$ or dvt).tw.
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Pulmonary Embolism/ or pulmonary embol$.tw.
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Appendix 2. Quality Assessment using the Using the Newcastle/Ottawa Scale for Cohort Studies.
*
*
*
Cossu, 2007
*
*
*
Miller, 2004
*
0
*
Raftopoulous, 2008
*
*
*
Shepherd, 2003
*
0
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BorkgrenOkonek, 2007
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*
IP CR
Outcome Selection non Ascertainment not present exposed of Exposure at start
Design
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Representativeness
Comparability Outcome
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Selection Criteria
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Cohort Studies
Assessment Length follow Adequacy of outcome up sufficient of follow up
*
**
*
*
*
0
*
0
*
0
0
0
*
*
*
0
**
*
*
*
*
*
*
0
*
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A study can receive a maximum of 1 asterisk for each numbered item within the selection and outcome categories. A maximum of 2 asterisks can be given for comparability.
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Scholten 2002
High Risk
No- serial enrollment High Risk
Incomplete outcome data
Selective Reporting
Low Risk
Clinically important outcomes reportedLow Risk
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Not Reported
Allocation concealment
Blinding of outcome assessors
Blinding of outcome assessors
Not Reported
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Random Sequence Generation No- patients enrolled serially into 2 groups with first 92 being group 1 and next 389 being group 2
Not Reported
Clinically important outcomes reportedLow Risk
Blinding of participants and personnel
Allocation concealment
Blinding of participants and personnel Not Reported but based on randomization protocol it would be easy to find out what the treatment was
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QuasiExperimental Trials
Not Reported
All enrolled accounted for – Low Risk
Detection bias
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Kalfarentzos 2001
Random Sequence Generation
Attrition bias Incomplete outcome data
Performance bias
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Randomized Controlled Trials
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Selection bias
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Appendix 3. Quality Assessment Using the Tool from Cochrane Handbook.
High Risk
Probable as radiologists reading scans would not have access to pharmacy data Low Risk
Reporting Other Bias Bias
Selective Reporting
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CR
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Size of Treatment effect
Yes
Yes
Yes
No difference between the Objective 0.6 and 1.0 measure nadro groups
Precision
small N=60 study not precise
Benefits Can we of tx apply to our Treatment outweigh populations Feasible harms
Yes
Yes
Yes
Scholten D 2002
No
Can't Tell
Groups tx Were all equally minus accounted Measures interested for/losses objective variable acceptable vs blinding
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QuasiRandomizatio Experimental n
Groups Similar @ Start
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Kalfarentzos F 2001
Unclear protocol. Unknown if random sequence allocation used
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Randomized Randomizatio Control Trials n
Groups Similar @ Start
Groups tx Were all equally minus accounted Measures interested for/losses objective variable acceptable vs blinding
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Yes
Yes
Size of Treatment effect
Precision
Semiobjective Large decline Stats/confiden measures, in VTE events ce intervals not no blinding in 2nd group listed
Benefits Can we of tx apply to our Treatment outweigh populations Feasible harms
Yes
Yes
Yes