10.3, 2 studies, 111 patients) (observe <strong>in</strong>verse analysis)) with aPeto Odds ratio at 4.17 (95% Confidence Interval 1.37-12.70).The data on PE alone as outcome parameter were too sparse todraw any conclusions.D I S C U S S I O NDur<strong>in</strong>g the per<strong>for</strong>mance of this review, the primary protocol wasviolated several times due to unexpected distribution of <strong>and</strong> limitedaccess to data. The violations were:- doppler-ultrasound was permitted as screen<strong>in</strong>g parameter, as itwas considered that the limited sensitivity of this type of <strong>in</strong>vestigation<strong>in</strong> asymptomatic patients (Mantoni 1997, Dauzat 1997)was equally distributed among the r<strong>and</strong>omised groups.- neiher analysis of total mortality <strong>and</strong>/or fatal PE nor <strong>in</strong>tentionto treat analyses were per<strong>for</strong>med due to lack of data.- some non-bl<strong>in</strong>ded studies were <strong>in</strong>cluded.No analyses of bleed<strong>in</strong>g complications due to heterogeneity betweenthe method of comput<strong>in</strong>g <strong>and</strong> the fact, that the data wereunaccessible <strong>for</strong> colorectal patients <strong>in</strong> most studies, thus loos<strong>in</strong>gthe ability to balance between efficacy <strong>and</strong> safety.These violations of the protocol might <strong>in</strong>validate this review. Somestudies not fulfill<strong>in</strong>g the orig<strong>in</strong>al selection criteria were <strong>in</strong>cluded,as the overall scientific methodology were judged to be reasonablefree of bias, <strong>and</strong> the results were considered to important to leaveout. If we have followed the orig<strong>in</strong>al crieteria <strong>for</strong> selection only 10studies had been <strong>in</strong>cluded, but the overall results <strong>and</strong> conclusionswould not have been altered.When evaluat<strong>in</strong>g the efficacy of <strong>thromboprophylaxis</strong> it has beena methodological dem<strong>and</strong> to screen all patients with an objectivemethod as most postoperative TE are asymptomatic. One couldargue, that this is evaluat<strong>in</strong>g a treatment with a surrogate parameters,as the <strong>in</strong>dividual patient do not care, whether he/she experiencean asymptomatic TE. The most relevant endpo<strong>in</strong>t wouldbe symptomatic DVT <strong>and</strong>/or PE, perhaps even fatal PE <strong>and</strong>/ortotal mortality. This would dem<strong>and</strong> very large trials (up to 50,000<strong>in</strong> each treatment arm), but feasible <strong>in</strong> a multi centre setup. Thelargest thromboprophylactic trial ever per<strong>for</strong>med is to our knowledgeGerman <strong>and</strong> showed that the <strong>in</strong>cidence of fatal PE <strong>and</strong> totalmortality was the same after prophylaxis with either unfractionatedhepar<strong>in</strong> or LMWH (Haas 1999). There is although a proportionalitybetween the <strong>in</strong>cidence of fatal PE <strong>and</strong> asymptomaticTE (Wille-Jørgensen 1991), <strong>and</strong> it is shown that venous functionoften is impaired after even asymptomatic DVT, giv<strong>in</strong>g riseto chronic venous <strong>in</strong>sufficiency (Siragusa 1997, Andersen 1991).Although not optimal, studies us<strong>in</strong>g sensitive screen<strong>in</strong>g <strong>methods</strong>can <strong>in</strong> our op<strong>in</strong>ion be used <strong>in</strong> evaluat<strong>in</strong>g the efficacy of variousprophylactic <strong>methods</strong>.There was no significant statistical heterogeneity among the studies,but the meta-analysis per<strong>for</strong>med on all hepar<strong>in</strong>s versus notreatment or placebo (comparison 07) should be taken with somereserve, due to methodological heterogeneity between the studies.Also one should account <strong>for</strong> the different drugs <strong>and</strong> controlgroups be<strong>in</strong>g used <strong>in</strong> this analysis. As 10 out of 11 studies po<strong>in</strong>t <strong>in</strong>the same direction the conclusion that hepar<strong>in</strong> works is althoughconsidered valid.The analyses are <strong>in</strong>validated by the many miss<strong>in</strong>g data, as we wereunable to retrieve data of colorectal patients from the primary authorsbut the results obta<strong>in</strong>ed are <strong>in</strong> agreement with other reviewsdeal<strong>in</strong>g with general surgery as a whole (Wille-Jørgensen 1991)except <strong>for</strong> one po<strong>in</strong>t. We were not able to f<strong>in</strong>d any differencebetween LMWH <strong>and</strong> LDH. Nurmohammed (Nurmohammed1992) found LMWH to be more effective <strong>in</strong> orthopaedic surgerybut not conv<strong>in</strong>c<strong>in</strong>gly <strong>in</strong> general surgery a comprehensive metaanalysis.This analysis is although to be taken with care due tosevere heterogeneity. In a systematic review where meta-analysiswas omitted due to the heterogeneity (Jørgensen 1993), it wasconcluded that the two treatments do not differ substantially. Theef<strong>for</strong>ts <strong>in</strong> retriev<strong>in</strong>g the <strong>in</strong>accessible data will cont<strong>in</strong>ue <strong>and</strong> thisreview will be updated whenever new data on colorectal patientsare at h<strong>and</strong>.In the <strong>in</strong>vestigations with the comb<strong>in</strong>ation regimens (Wille-Jørgensen 1986, Wille-Jorgensen 1991) unfractionated hepar<strong>in</strong>was used. There are no <strong>in</strong>vestigations <strong>in</strong> general surgery wherethe comb<strong>in</strong>ation of LMWH <strong>and</strong> stock<strong>in</strong>gs has been <strong>in</strong>vestigated,but there is no reason to believe that different results would beobta<strong>in</strong>ed, if the unfractionated hepar<strong>in</strong> was replaced by LMWH<strong>in</strong> the comb<strong>in</strong>ation regimens. The comb<strong>in</strong>ation regimen seems tobe the best, but there are limited data available <strong>and</strong> the data allcome the same author. An <strong>in</strong>vestigation <strong>in</strong> general surgery us<strong>in</strong>ga paired design with stock<strong>in</strong>gs on one leg only (r<strong>and</strong>omised toleft or right), thus compar<strong>in</strong>g legs <strong>and</strong> not persons also showeda significant better effect of the comb<strong>in</strong>ation as compared withunfractionated hepar<strong>in</strong> alone (Törngren 1980). Due to the designthis study was not <strong>in</strong>cluded <strong>in</strong> the analysis, but the result supportsour conclusion. Two of the studies await<strong>in</strong>g assessment <strong>in</strong>vestigatesthe comb<strong>in</strong>ation therapy (Borow 1983, Moser 1976). Thefirst f<strong>in</strong>d a significant better effect of the comb<strong>in</strong>ation as comparedto hepar<strong>in</strong> alone <strong>and</strong> the latter could not show any significance<strong>in</strong> a small sample size. Although these miss<strong>in</strong>g data comprise apublication bias, this is not considered to alter the conclusion.There are other ways to prevent postoperative DVT <strong>and</strong>/or PEthan hepar<strong>in</strong>s <strong>and</strong> stock<strong>in</strong>gs. Aspir<strong>in</strong> has dur<strong>in</strong>g the last couple ofyears been shown to be somewhat effective (Collaborative 1994),but seem<strong>in</strong>gly not as effective as hepar<strong>in</strong>s. No valid comparisonshave to our knowledge been made between aspir<strong>in</strong> <strong>and</strong> hepar<strong>in</strong>s.<strong>Hepar<strong>in</strong>s</strong> <strong>and</strong> <strong>mechanical</strong> <strong>methods</strong> <strong>for</strong> <strong>thromboprophylaxis</strong> <strong>in</strong> colorectal surgery (Review)Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd5
A U T H O R S ’Implications <strong>for</strong> practiceC O N C L U S I O N SBoth unfractionated hepar<strong>in</strong> <strong>and</strong> low molecular weight hepar<strong>in</strong>can be used as effective prophylaxis aga<strong>in</strong>st postoperative thromboemboliccomplications after colorectal surgery. The optimalprophylaxis <strong>in</strong> colorectal surgery seems to be the comb<strong>in</strong>ation ofgraded compression stock<strong>in</strong>gs <strong>and</strong> low-dose unfractionated hepar<strong>in</strong>.The unfractionated hepar<strong>in</strong> can likely be replaced with lowmolecular weight hepar<strong>in</strong>.Implications <strong>for</strong> researchFurther ef<strong>for</strong>t to retrieve colorectal results from the many studieson general surgery should be cont<strong>in</strong>ued. Large r<strong>and</strong>omised trialsevaluat<strong>in</strong>g the use of the comb<strong>in</strong>ation regime versus monotherapywith fatal pulmonary embolism as outcome should be per<strong>for</strong>med.P O T E N T I A L C O N F L I C T O FI N T E R E S TOne of the reviewers (Morten Schnack Rasmussen) was part timedur<strong>in</strong>g the review process work<strong>in</strong>g as a research fellow on longtermthrombosis prophylaxis. His salary was partly paid <strong>for</strong> by Pharmacia/Upjohn- a company which produces one of the compounds,which potentially occur <strong>in</strong> this review. The current review has noconnection to his work as a research fellow, despite be<strong>in</strong>g <strong>in</strong> thesame scientific area. The company had no <strong>in</strong>fluence on the review.No conflict of <strong>in</strong>terest is considered to exist <strong>in</strong> this respect.The three other reviewers have no economical connection to thepharmaceutical <strong>in</strong>dustry with respect to this review, thus no conflictof <strong>in</strong>terest exists.The primary reviewer has two papers <strong>in</strong>cluded <strong>in</strong> the analyses.A C K N O W L E D G E M E N T SThe few primary authors (Maressi 1993, Onarheim 1986) whosupplied us with orig<strong>in</strong>al data are greatly acknowledged.S O U R C E S O F S U P P O R TExternal sources of support• No sources of support suppliedInternal sources of support• H:S Central Research Fund DENMARKR E F E R E N C E SReferences to studies <strong>in</strong>cluded <strong>in</strong> this reviewButson 1981 {published data only}Butson AR. Intermittent pneumatic calf compression <strong>for</strong> preventionof deep venous thrombosis <strong>in</strong> general abdom<strong>in</strong>al surgery. Am J Surg1981;142(2):525–7. 82021671.Covey 1975 {published data only}∗ Covey TH, Sherman L, Baue AE. Low-dose hepar<strong>in</strong> <strong>in</strong> postoperativepatients: a prospective, coded study. Arch Surg 1975;110:1021–1026.Fricker 1988 {published data only}∗ Fricker JP, Vergnes Y, Schach R, Heitz A, Eber M, Grunebaum L,et al. Low dose hepar<strong>in</strong> versus low molecular weight hepar<strong>in</strong> (Kabi2165, Fragm<strong>in</strong>) <strong>in</strong> the prophylaxis of thromboembolic complicationsof abdom<strong>in</strong>al oncological surgery. Eur J Cl<strong>in</strong> Invest 1988;18(6):561–567. 89137198.Gallus 1976 {published data only}∗ Gallus AS, Hirsh J, O’Brien SE, McBride JA, Tuttle RJ, Gent M.Prevention of venous thrombosis with small, subcutaneous doses ofhepar<strong>in</strong>. JAMA 1976;235:1980–1982.Ho 1999 {published data only}Ho YH, Seow-Choen F, Leong A, Eu KW, Nyam D, Teoh MK.R<strong>and</strong>omized, controlled trial of low molecular weight hepar<strong>in</strong> vs. nodeep ve<strong>in</strong> thrombosis prophylaxis <strong>for</strong> major colon <strong>and</strong> rectal surgery<strong>in</strong> Asian patients. Dis Colon Rectum 1999;42:196–203.Joffe 1976 {published data only}∗ Joffe S. Drug prevention of postoperative deep ve<strong>in</strong> thrombosis.A compararative study of calcium hepar<strong>in</strong>ate <strong>and</strong> sodium pentosanpolysulfate. Arch Surg 1976;111:37–40.Koppenhagen 1992 {published data only}Koppenhagen K, Adolf J, Matthes M, Troster E, Roder JD, Hass S,et al. Low molecular weight hepar<strong>in</strong> <strong>and</strong> prevention of postoperativethrombosis <strong>in</strong> abdom<strong>in</strong>al surgery. Thromb Haemost 1992;67(6):627–30. 92376750.Kosir 1996 {published data only}∗ Kosir MA, Kozol RA, Perales A, McGee K, Beleski K, Lange P, etal. Is DVT prophylaxis overemphasized? A r<strong>and</strong>omized prospectivestudy. J-Surg-Res 1996;60:289–92. CN-00006333 - CCTR. MED-LINE 96173505 EMBASE 96068622.Lahnborg 1974 {published data only}∗ Lahnborg G, Bergstrom K, Friman L, Lagergren H. Effect of lowdosehepar<strong>in</strong> on <strong>in</strong>cidence of postoperative pulmonary embolismdetected by photoscann<strong>in</strong>g. Lancet 1974;1:329–331.Maressi 1993 {published <strong>and</strong> unpublished data}∗ Maressi A, Balzano G, Mari G, D´ Angelo SV, Valle PD, Di Carlo V,et al. Prevention of Postoperative Deep Ve<strong>in</strong> Thrombosis <strong>in</strong> CancerPatients. A R<strong>and</strong>omized Trial with Low Molecular Weight Hepar<strong>in</strong>(CY 216). Int Surg 1993;78:166–70.<strong>Hepar<strong>in</strong>s</strong> <strong>and</strong> <strong>mechanical</strong> <strong>methods</strong> <strong>for</strong> <strong>thromboprophylaxis</strong> <strong>in</strong> colorectal surgery (Review)Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd6
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