Low-Molecular-Weight Heparin (Enoxaparin) as Prophylaxis against Venous Thromboembolism after Total Hip Replacement
David Bergqvist, Ph.D., Göran Benoni, M.D., Ola Björgell, M.D., Hans Fredin, Ph.D., Urban Hedlundh, M.D., Sylvain Nicolas, Ph.D., Paul Nilsson, Ph.D., and Göran Nylander, Ph.D.
Background The risk of venous thromboembolism in patients undergoingtotal hip replacement is known to be high. However, the optimalduration of prophylaxis with anticoagulant agents after thisprocedure is unknown. We sought to determine whether one monthof anticoagulant therapy with the low-molecular-weight heparinenoxaparin is more effective than enoxaparin therapy given onlyduring the hospitalization for surgery.
Methods Two hundred sixty-two patients undergoing total hipreplacement received enoxaparin during their hospitalizations(average stay, 10 to 11 days). They were then randomly assignedto receive enoxaparin or placebo (131 patients each). Blindedoutpatient therapy (or placebo) was continued long enough thatthe total treatment period, inpatient plus outpatient, was onemonth for each patient. Bilateral ascending phlebography wasperformed 19 to 23 days after discharge, with deep-vein thrombosisas the primary end point. Distal and proximal thrombosis, pulmonaryembolism, and hemorrhage were also recorded, as were deaths.
Results Venography was adequate in 116 patients in the placebogroup and 117 in the enoxaparin group. We observed 43 episodesof deep-vein thrombosis and 2 episodes of pulmonary embolismin the placebo group, but only 21 episodes of deep-vein thrombosisand no episodes of pulmonary embolism in the enoxaparin group(incidence of thromboembolism, 39 percent and 18 percent, respectively;P<0.001). The difference in the incidence of proximal deep-veinthrombosis was also significant (24 percent and 7 percent inthe placebo and enoxaparin groups, respectively; P<0.001).Six patients in the enoxaparin group and one patient in theplacebo group had hematomas at their injection sites. No patientsdied or had major complications.
Conclusions There were significantly fewer venous thromboemboliccomplications in patients undergoing elective hip replacementwhen prophylaxis with enoxaparin was given for a total of onemonth, rather than only during the hospitalization.
Without prophylactic anticoagulation, the frequency of deep-veinthrombosis after total hip replacement is high, in the rangeof 50 to 60 percent.1,2 With various methods of anticoagulanttherapy, this frequency can be substantially reduced,3,4 thebest option at present being low-molecular-weight heparin,1,2,4,5,6which is also cost effective.7,8,9
In addition to the high risk of deep-vein thrombosis, hip surgeryhas certain special characteristics. The risk of deep-vein thrombosisis more protracted after hip surgery than after general surgery,when it usually develops during the first few postoperativedays.10,11 The surgical technique, which kinks the femoral vein,seems to stimulate proximal deep-vein thrombosis in the legthat is operated on,12,13 whereas calf-vein thrombosis is morelikely to develop in either leg. Another result of surgery canbe the impairment of venous hemodynamics, which may last severalweeks, in the leg that is operated on.14 In a study of patientsundergoing general abdominal surgery, Scurr et al.15 found thatdeep-vein thrombosis continued to be a problem after the patientshad left the hospital. During the first month, the conditiondeveloped in about 25 percent of those without thrombosis atdischarge.
A recent study of patients undergoing total hip arthroplastyshowed a 10.5 percent incidence of deep-vein thrombosis duringthe first six weeks after surgery.16 Thus, the thrombogenicperiod may be prolonged in some patients, and the risk of fatalpulmonary embolism continues for at least one month after surgery.17,18In patients with trauma, the risk may last even longer.19,20,21For these reasons, the question of providing extended prophylacticanticoagulant therapy has been raised and was said to be ofkey importance in the European Consensus Statement.22
We therefore attempted to determine whether enoxaparin, a low-molecular-weightheparin, prevented thrombosis better if it was given only duringthe hospitalization for surgery (according to the usual practice)or if it was continued for a full month postoperatively.
Methods
Study Design
This was a prospective, randomized, double-blind study conductedat a single center. Patients undergoing primary elective hiparthroplasty were included in the study if they were more than39 years old and weighed more than 60 kg. They were excludedfrom the study if they had renal insufficiency; hypersensitivityto contrast medium, heparin, or low-molecular-weight heparin;a past or present risk of hemorrhage; endocarditis, severe liverdisease, or untreated hypertension; or venous thromboembolismwithin the preceding three months; if they had received treatmentwith heparin, low-molecular-weight heparin, oral anticoagulants,or nonsteroidal antiinflammatory drugs within the five daysbefore surgery; or if they had undergone ipsilateral hip surgerywithin the preceding six months; if they were pregnant or lactating;or if they did not give informed consent.
During the hospitalization (which was scheduled to last 9 days;anticipated range, 7 to 11 days), all the patients receivedprophylaxis against thrombosis with 40 mg (0.4 ml) of enoxaparin(Klexane, Rhône–Poulenc Rorer) injected subcutaneouslyinto the abdominal wall once daily, with the first dose giventhe evening before surgery (according to the schedule, 12 hoursbeforehand; range, 10 to 14). At the end of the hospitalization,the patients were randomly assigned to continue receiving enoxaparin(40 mg once daily) or to receive placebo (0.4 ml of saline)once daily.
The first injection after the hospitalization was given theday after discharge. The post-discharge prophylaxis was givenby study nurses who visited the patients daily in their homes.The outpatient prophylaxis was scheduled to last 21 days (range,19 to 23), or until the time of phlebography. To enter the double-blindphase of the trial, patients could not have undergone a reoperationor have had clinical venous thromboembolism or major hemorrhage.They also had to have received prophylaxis with enoxaparin startingthe evening before their surgery, as stated in the protocol.
Hip surgery was performed through a lateral incision, with orwithout osteotomy, with the patient supine.
Assessment of Outcome
On day 21 (range, 19 to 23) after hospital discharge, the protocolcalled for bilateral ascending phlebography of the legs to screenfor deep-vein thrombosis. During this procedure, the patientwas seated with the lower leg in a vertical position. Fiftymilliliters of contrast medium (Hexabrix [with 160 mg of iodineper milliliter] or Omnipaque [180 mg of iodine per milliliter])was injected into a dorsal foot vein. Frontal and lateral filmsof the lower leg were obtained. The patient was then placedin a supine position, and a tourniquet was applied to the uppermostpart of the thigh to occlude the great saphenous vein. An additional50 ml of contrast medium was injected into the same vein thathad been used in the lower leg, and frontal films of the popliteal,femoral, iliac, and inferior caval veins were obtained. Withthis technique, even bedridden patients who had just undergonesurgery could be examined adequately.
When thrombosis was suspected for clinical reasons before thetime of the scheduled phlebography, the procedure was performedon an emergency basis. If deep-vein thrombosis was found, nofurther phlebography was performed. If the study was negative,the planned bilateral phlebography was performed according toprotocol.
Each phlebogram was examined by a committee of three radiologistsunaware of the patients' group assignments. All the interpretationsand classifications were made before the randomization codewas broken. Each film was interpreted independently by eachradiologist. If there were discrepancies in diagnoses, the committeemembers discussed the case further and reached a consensus.
A thrombus was considered to be present when there was a fillingdefect surrounded by contrast medium, or the consistent nonvisualizationof a deep vein, caused by increased subfascial pressure or totalobliteration. Collateral flow through the superficial leg veinswas seen when there was increased subfascial pressure or totalobliteration. In the latter case, the tip of the thrombus wasoften visible. Only thrombi in venous segments located withinthe deep fascia were considered to be deep-vein thrombi.
The results of phlebography were considered inadequate if theamount of contrast medium injected was too small and the resultingphlebograms were uninterpretable. The thrombi were classifiedaccording to whether they occurred in the leg that was operatedon or the contralateral leg and according to whether the thrombosiswas proximal, distal, or both proximal and distal (involvingthe whole leg). The border between proximal and distal thromboseswas the knee joint. In the case of clinically suspected pulmonaryembolism, ventilation–perfusion lung scanning or pulmonaryangiography was performed.
Follow-up was performed three months postoperatively to determinethe patients' vital status.
Hemorrhagic Complications
The anesthetist estimated the amount of blood lost intraoperativelyby examining swabs and suction bottles. The volume of blooddrained postoperatively was recorded, as were the transfusionrequirements and all instances of postoperative hemorrhage,wound hematoma, and reoperation. Hemorrhages were classifiedas minor or major. Major hemorrhage was defined as clinicallyovert bleeding that was associated with a decrease in the hemoglobinlevel of 2 g per deciliter or more, requiring the transfusionof two or more units of blood products; bleeding that was retroperitonealor intracranial in location; or bleeding that necessitated reoperation.Hemorrhage that did not meet any of these criteria was classifiedas minor.
Statistical Analysis
The analysis of thromboembolic events (both deep-vein thrombosisand pulmonary embolism) included 233 patients who had adequatevenography (116 in the placebo group and 117 in the enoxaparingroup). The analysis of hemorrhagic complications included onlythe patients who were actually treated. Most of the data wereexpressed in terms of descriptive statistics or 95 percent confidenceintervals. In the analysis of efficacy, two-tailed chi-squaretests and odds ratios derived from a logistic-regression analysiswere used. In the analysis of safety, two-tailed Fisher's exacttests were used. The study was approved by the ethics committeeof the University of Lund, Sweden. All the patients providedwitnessed informed consent.
Results
Two hundred eighty-eight patients were enrolled in the study,262 of whom underwent randomization for outpatient prophylaxis.The results for the hospital period (before randomization) andthe period from discharge to the time of phlebography (the double-blindperiod) are presented separately here.
Hospital Period
During the hospital period, all the patients received prophylaxiswith enoxaparin. The patients later assigned to enoxaparin andthose later assigned to placebo were well matched with regardto demographic variables, surgical procedures, and variablespertaining to the hospital course after surgery (Table 1). Themedian time from the preoperative dose of enoxaparin to thestart of surgery was 12.3 hours (range, 9.6 to 33.5) in theplacebo group and 12.2 hours (range, 9.0 to 15.9) in the enoxaparingroup. There was no difference between the groups in the sideof the body on which the surgery was performed, the surgicalapproach (Hardinge or Charnley), the type of prosthesis used(cemented or uncemented), or intraoperative blood loss (medianin both groups, 700 ml). In the majority of operations (95 percent),epidural anesthesia was used. The median duration of surgerywas 1.9 hours (range, 1.0 to 5.0) in the placebo group and 1.7hours (range, 1.1 to 5.2) in the enoxaparin group. The amountof blood lost through drainage, the amount given in transfusion,and the decrease in hemoglobin did not differ between the groups.The open-label period lasted 11 days (range, 7 to 12) in theplacebo group and 10 days (range, 6 to 11) in the enoxaparingroup. Five patients had hemorrhagic complications: three inthe enoxaparin group and two in the placebo group. All weredue to bleeding from the surgical wound. There were no clinicalepisodes of thromboembolism during hospitalization.
Table 1. Demographic Characteristics and Risk Factors in 262 Patients Who Underwent Total Hip Replacement, According to Study Group.
Post-Discharge Period
Of the 288 patients initially enrolled, 262 were randomized,131 to each study group. Twenty-six patients were not randomized:eight withdrew their consent, the condition of five was deteriorating,four had violations of the study protocol, two had intercurrentevents, one died (acute myocardial infarction was suspected,but no autopsy was performed), one was excluded for administrativereasons, and five were not randomized for various other reasons.After randomization, no patients were excluded from the analysisof patients who were actually treated.
Phlebography could not be performed at all in four patientsand was performed in only one leg in an additional five. In20 cases, the phlebography was considered inadequate. The mediantime from discharge to phlebography was 18 days (range, 1 to23) in the placebo group and 19 days (range, 1 to 23) in theenoxaparin group.
Thromboembolic Complications
Of the 233 patients who could be evaluated, 66 had deep-veinthrombosis or pulmonary embolism (28 percent). Table 2 showsthe frequencies of these conditions. The reduction in the frequencyof venous thromboembolic disease with enoxaparin treatment wassignificant, especially in the case of proximal deep-vein thrombosis.There were two pulmonary emboli in the placebo group, one diagnosedby pulmonary angiography and the other by scintigraphy.
Table 2. Incidence of Thromboembolic Events in the Patients with Adequate Venography, with Odds Ratios and 95 Percent Confidence Intervals (CI).
Table 3 shows the location of thrombi in the patients undergoingunilateral hip replacement who could be evaluated, accordingto whether the thrombi occurred in the leg that was operatedon, the contralateral leg, or both legs. In 34 patients (18percent) the thrombi occurred exclusively in the leg that wasoperated on, in 4 (2 percent) only in the contralateral leg,and in the remaining 12 (6 percent) in both legs.
Table 3. Deep-Vein Thrombosis in the Study Patients Undergoing Unilateral Hip Replacement Who Could Be Evaluated, According to the Location of the Thrombosis.
Rehospitalization because of deep-vein thrombosis was judgednecessary for 32 patients in the placebo group and 11 patientsin the enoxaparin group, for totals of 269 and 99 days, respectively(median duration of rehospitalization in the placebo group,8.4 days [range, 4 to 29]; in the enoxaparin group, 9.0 days[range, 1 to 21]). The majority of patients (80 percent) weretreated with low-molecular-weight heparin and warfarin. Theremaining patients, who had small thrombi in muscular veins,were treated with elastic compression stockings, antiphlogisticagents, or both, without rehospitalization.
Clinical symptoms or signs of venous thromboembolism developedin 12 patients (included in Table 2) during the outpatient phase.Ten of these patients (eight with deep-vein thrombosis and twowith pulmonary embolism) were in the placebo group, and two(both with deep-vein thrombosis) were in the enoxaparin group.The thrombi were all verified objectively. No further episodesof symptomatic thromboembolism occurred. No patients died duringthe post-discharge period.
Hemorrhagic Complications
Hematomas were seen at the injection site in one patient inthe placebo group (1 percent) and six patients in the enoxaparingroup (5 percent). Four patients in the placebo group and twopatients in the enoxaparin group had decreases in hemoglobinof at least 2 g per deciliter; no patient had an absolute hemoglobinlevel below 8 g per deciliter. An increase in alanine aminotransferaseto more than three times the upper limit of normal was foundin one patient in the enoxaparin group. One patient in the enoxaparingroup and none in the placebo group had mild thrombocytopenia(defined as a platelet count of 100,000 to 125,000 cells percubic millimeter). This patient, a man 78 years old, had a preoperativeplatelet count of 263,000 per cubic millimeter. The count waslowest on postoperative day 23, at 121,000, and was 161,000three days later. The patient's treatment was continued.
Other Adverse Events
There were no rehospitalizations for nonthrombotic, nonhemorrhagiccauses. The incidence of adverse events leading to a discontinuationof the study medication, except for those related to venousthromboembolism, was similar in the two study groups. No patientsdied during the three months after randomization.
Discussion
In several studies, a beneficial effect of low-molecular-weightheparin in the prevention of postoperative thrombosis has beenfound.1,23,24,25 In our study, enoxaparin was used for routineprophylaxis during hospitalization in all patients. This prophylaxiswas well tolerated, and there were no problems that could havebeen attributed to the administration of enoxaparin. It shouldbe noted that the first dose was given about 12 hours beforesurgery, that the majority of patients (95 percent) receivedepidural or spinal anesthesia, and that in keeping with previousobservations, no complications were observed in patients receivingenoxaparin and epidural anesthesia.26,27
The design of our study could be criticized in that patientsin whom deep-vein thrombosis developed during the period ofopen-label therapy with enoxaparin were not identified and excludedbefore randomization. There were several reasons for the designwe used. Ultrasonography is not optimal for the detection ofthrombi in asymptomatic patients, especially distal and smallproximal thrombi.28,29,30 Moreover, ultrasonography was notavailable at the time the study started. At least theoretically,phlebography performed at the time of discharge could have induceddeep-vein thrombosis in some patients, although such a resultis uncommon with the technique used in our hospital.31 Diagnosticsurveillance is not routinely performed at hospital dischargein this population of patients. The frequency of deep-vein thrombosisat discharge is therefore unknown, but it was 11 percent atthe same point in the study by Turpie et al.1 In our study,the 18 percent incidence of deep-vein thrombosis in the groupgiven enoxaparin for one month may mean that there is a periodof continued risk after hospital discharge even with extendedprophylaxis, but that without such prophylaxis the risk is significantlyhigher.
In studies of patients undergoing hip-replacement surgery, bilateralphlebography must be used to diagnose deep-vein thrombosis.Ultrasonography lacks sensitivity as a screening instrumentin asymptomatic patients.30 In our study, the use of a strictstudy protocol implemented by a few investigators made it possibleto obtain adequate phlebograms in the vast majority of patients.Moreover, there was high compliance with the treatment protocol.
The main outcome was that prolonged prophylaxis with enoxaparinsignificantly reduced the incidence of venous thromboembolism;in addition, the frequency of proximal thrombi was significantlyreduced. An important question is whether these findings haveeconomic implications, but answering that question requiresa formal economic analysis.9 The prophylactic effect at onemonth was in keeping with recently abstracted data32 and studyfindings.33 The frequency of clinical thromboembolism in theplacebo group was equivalent to that recently reported in astudy of total hip replacement in which there was no routinepharmacologic prophylaxis.34
Another important question is whether the beneficial resultsseen in this study can be reproduced in a routine clinical setting.Compliance was guaranteed in this trial because the study nursesadministered the injections of the study drug. However, ourclinical impression is that most patients, when motivated, areable to give themselves injections of the medication withoutdifficulty.
In conclusion, patients receiving prophylaxis with enoxaparinfor a full month after surgery had significantly less venousthromboembolic disease (most of which was asymptomatic), includingproximal deep-vein thrombosis, than patients receiving enoxaparinprophylaxis only during their hospitalizations. In addition,there was a significant reduction in the incidence of symptomaticthromboembolic events.
Supported by a grant (00759) from the Swedish Medical ResearchCouncil, by the Swedish Heart and Lung Foundation, and by Rhône–PoulencRorer.
We are indebted to the project nurses, Christine Persson andLill Borgström, for their efforts and contributions; tothe following members of the research staff at Rhône–PoulencRorer for important contributions: Alistair Bone, Jean Bouthier,Sophie Combe, Jarl Molin, Ghislaine Pisapia, Björn Rubin,and Theodore Spiro; and to the following members of the researchteam for their dedication: Anne Guerriero, Mary Keiser, AnnMaher, Jennifer Rohr, Mary Jane Seipp, Susan Snyder, and MaryJ. Sparks.
Source Information
From the Department of Surgery, Academic Hospital, Uppsala, Sweden (D.B.); the Departments of Orthopedic Surgery (G.B., H.F., U.H.) and Diagnostic Radiology (O.B., P.N., G.N.), Malmö University Hospital, Malmö, Sweden; and the Department of Research and Development, Rhône–Poulenc Rorer, Paris (S.N.).
Address reprint requests to Dr. Bergqvist at Academic Hospital, Department of Surgery, S-751 85 Uppsala, Sweden.
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