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.
References
Turpie AGG, Levine MN, Hirsh J, et al. A randomized controlled trial of a low-molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery. N Engl J Med 1986;315:925-929. [Abstract]
Jørgensen LN, Wille-Jørgensen P, Hauch O. Prophylaxis of postoperative thromboembolism with low molecular weight heparins. Br J Surg 1993;80:689-704. [Medline]
Paiement GD, Schutzer SF, Wessinger SJ, Harris WH. Influence of prophylaxis on proximal venous thrombus formation after total hip arthroplasty. J Arthroplasty 1992;7:471-475. [Medline]
Mohr DN, Silverstein MD, Murtaugh PA, Harrison JM. Prophylactic agents for venous thrombosis in elective hip surgery: meta-analysis of studies using venographic assessment. Arch Intern Med 1993;153:2221-2228. [Free Full Text]
Leizorovicz A, Haugh MC, Chapuis F-R, Samama MM, Boissel J-P. Low molecular weight heparin in prevention of perioperative thrombosis. BMJ 1992;305:913-920.
Nurmohamed MT, Rosendaal FR, Büller HR, et al. Low molecular weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis. Lancet 1992;340:152-156. [CrossRef][Medline]
Anderson DR, O'Brien BJ, Levine MN, Roberts R, Wells PS, Hirsh J. Efficacy and cost of low-molecular-weight heparin compared with standard heparin for the prevention of deep vein thrombosis after total hip arthroplasty. Ann Intern Med 1993;119:1105-1112. [Free Full Text]
Borris LC, Lassen MR, Jensen HP, Andersen BS, Poulsen KS. Perioperative thrombosis prophylaxis with low molecular weight heparins in elective hip surgery: clinical and economic considerations. Int J Clin Pharmacol Ther 1994;32:262-268. [Medline]
Bergqvist D, Lindgren B, Mätzsch T. Cost-effectiveness of preventing postoperative deep vein thrombosis. In: Hull R, Pineo G, eds. Disorders of thrombosis. Philadelphia: W.B. Saunders, 1996:228-33.
Hampson WGJ, Harris FC, Lucas HK, et al. Failure of low-dose heparin to prevent deep-vein thrombosis after hip-replacement arthroplasty. Lancet 1974;2:795-797. [Medline]
Mannucci PM, Citterio LE, Panajotopoulos N. Low-dose heparin and deep-vein thrombosis after total hip replacement. Thromb Haemost 1976;36:157-164. [Medline]
Stamatakis JD, Kakkar VV, Sagar S, Lawrence D, Nairn D, Bentley PG. Femoral vein thrombosis and total hip replacement. BMJ 1977;2:223-225.
Planes A, Vochelle N, Fagola M. Total hip replacement and deep vein thrombosis: a venographic and necropsy study. J Bone Joint Surg Br 1990;72:9-13.
McNally MA, Mollan RAB. Total hip replacement, lower limb blood flow and venous thrombogenesis. J Bone Joint Surg Br 1993;75:640-644. [Medline]
Scurr JH, Coleridge-Smith PD, Hasty JH. Deep venous thrombosis: a continuing problem. BMJ 1988;297:28-28.
Trowbridge A, Boese CK, Woodruff B, Brindley HH Sr, Lowry WE, Spiro TE. Incidence of posthospitalization proximal deep venous thrombosis after total hip arthroplasty: a pilot study. Clin Orthop 1994;299:203-208.
Bergqvist D, Lindblad B. A 30-year survey of pulmonary embolism verified at autopsy: an analysis of 1274 surgical patients. Br J Surg 1985;72:105-108. [Medline]
Huber O, Bounameaux H, Borst F, Rohner A. Postoperative pulmonary embolism after hospital discharge: an underestimated risk. Arch Surg 1992;127:310-313. [Free Full Text]
Sevitt S, Gallagher N. Venous thrombosis and pulmonary embolism: a clinico-pathological study in injured and burned patients. Br J Surg 1961;48:475-489. [Medline]
Bergqvist D, Fredin H. Pulmonary embolism and mortality in patients with fractured hips -- a prospective consecutive series. Eur J Surg 1991;157:571-574. [Medline]
Schrøder HM, Andreassen M. Autopsy-verified major pulmonary embolism after hip fracture. Clin Orthop 1993;293:196-203.
Nicolaides A, Arcelus J, Belcaro G, et al. Prevention of venous thromboembolism. Int Angiol 1992;11:151-159. [Medline]
Planes A, Vochelle N, Mazas F, et al. Prevention of postoperative venous thrombosis: a randomized trial comparing unfractionated heparin with low molecular weight heparin in patients undergoing total hip replacement. Thromb Haemost 1988;60:407-410. [Medline]
Eriksson BI, Zachrisson BE, Teger-Nilsson AC, Risberg B. Thrombosis prophylaxis with low molecular weight heparin in total hip replacement. Br J Surg 1988;75:1053-1057. [Medline]
Leyvraz PF, Bachmann F, Hoek J, et al. Prevention of deep vein thrombosis after hip replacement: randomised comparison between unfractionated heparin and low molecular weight heparin. BMJ 1991;303:543-548. [Erratum, BMJ 1991;303:1243.]
Bergqvist D, Lindblad B, Mätzsch T. Low molecular weight heparin for thromboprophylaxis and epidural/spinal anaesthesia -- is there a risk? Acta Anaesthesiol Scand 1992;36:605-609. [Medline]
Vandermeulen EP, Van Aken H, Vermylen J. Anticoagulants and spinal-epidural anesthesia. Anesth Analg 1994;79:1165-1177. [Free Full Text]
Ginsberg JS, Caco CC, Brill-Edwards PA, et al. Venous thrombosis in patients who have undergone major hip or knee surgery: detection with compression US and impedance plethysmography. Radiology 1991;181:651-654. [Free Full Text]
Agnelli G, Volpato R, Radicchia S, et al. Detection of asymptomatic deep vein thrombosis by real-time B-mode ultrasonography in hip surgery patients. Thromb Haemost 1992;68:257-260. [Medline]
Wells PS, Lensing AW, Davidson BL, Prins MH, Hirsh J. Accuracy of ultrasound for the diagnosis of deep venous thrombosis in asymptomatic patients after orthopedic surgery: a meta-analysis. Ann Intern Med 1995;122:47-53. [Free Full Text]
Kristiansen P, Bergentz S-E, Bergqvist D, Nylander G. Thrombosis after elective phlebography as demonstrated with the 125I-fibrinogen test. Acta Radiol Diagn (Stockh) 1981;22:577-580. [Medline]
Dahl OE, Andreassen G, Müller C, et al. The effect of prolonged thromboprophylaxis with dalteparin on the frequency of deep vein thrombosis (DVT) and pulmonary embolism (PE) 35 days after hip replacement surgery (HRS). Thromb Haemost 1995;73:1094-1094.abstract
Planes A, Vochelle N, Fagola M, et al. Persistence of the risk of deep venous thrombosis after hospital discharge in patients undergoing total hip replacement. Lancet (in press).
Warwick D, Williams MH, Bannister GC. Death and thromboembolic disease after total hip replacement: a series of 1162 cases with no routine chemical prophylaxis. J Bone Joint Surg Br 1995;77:6-10.
Eriksson, B. I., Borris, L. C., Friedman, R. J., Haas, S., Huisman, M. V., Kakkar, A. K., Bandel, T. J., Beckmann, H., Muehlhofer, E., Misselwitz, F., Geerts, W., the RECORD1 Study Group,
(2008). Rivaroxaban versus Enoxaparin for Thromboprophylaxis after Hip Arthroplasty. NEJM
358: 2765-2775
[Abstract][Full Text]
Geerts, W. H., Bergqvist, D., Pineo, G. F., Heit, J. A., Samama, C. M., Lassen, M. R., Colwell, C. W.
(2008). Prevention of Venous Thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest
133: 381S-453S
[Abstract][Full Text]
Singelyn, F. J., Verheyen, C. C.P.M., Piovella, F., Van Aken, H. K., Rosencher, N., for the EXPERT Study Investigators,
(2007). The Safety and Efficacy of Extended Thromboprophylaxis With Fondaparinux After Major Orthopedic Surgery of the Lower Limb With or Without a Neuraxial or Deep Peripheral Nerve Catheter: The EXPERT Study. Anesth. Analg.
105: 1540-1547
[Abstract][Full Text]
Skedgel, C., Goeree, R., Pleasance, S., Thompson, K., O'Brien, B., Anderson, D.
(2007). The Cost-Effectiveness of Extended-Duration Antithrombotic Prophylaxis After Total Hip Arthroplasty. JBJS
89: 819-828
[Abstract][Full Text]
Friedman, R. J.
(2007). Optimal Duration of Prophylaxis for Venous Thromboembolism Following Total Hip Arthroplasty and Total Knee Arthroplasty. J Am Acad Orthop Surg
15: 148-155
[Abstract][Full Text]
Dhupar, S., Iorio, R., Healy, W. L., Dhimitri, K.
(2006). A Comparison of Discharge and Two-Week Duplex Ultrasound Screening Protocols for Deep Venous Thrombosis Detection Following Primary Total Joint Arthroplasty. JBJS
88: 2380-2385
[Abstract][Full Text]
Nutescu, E. A, Wittkowsky, A. K, Dobesh, P. P, Hawkins, D. W, Dager, W. E
(2006). Choosing the Appropriate Antithrombotic Agent for the Prevention and Treatment of VTE: A Case-Based Approach. The Annals of Pharmacotherapy
40: 1558-1570
[Abstract][Full Text]
Bjornara, B. T., Gudmundsen, T. E., Dahl, O. E.
(2006). Frequency and timing of clinical venous thromboembolism after major joint surgery. J Bone Joint Surg Br
88-B: 386-391
[Abstract][Full Text]
Thabut, G., Estellat, C., Boutron, I., Samama, C. M., Ravaud, P.
(2006). Methodological issues in trials assessing primary prophylaxis of venous thrombo-embolism. Eur Heart J
27: 227-236
[Abstract][Full Text]
Watts, A. C., Howie, C. R., Simpson, A. H. R. W.
(2006). Assessment of a self-administration protocol for extended subcutaneous thromboprophylaxis in lower limb arthroplasty. J Bone Joint Surg Br
88-B: 107-110
[Abstract][Full Text]
Tapson, V. F., Hyers, T. M., Waldo, A. L., Ballard, D. J., Becker, R. C., Caprini, J. A., Khetan, R., Wittkowsky, A. K., Colgan, K. J., Shillington, A. C., for the NABOR (National Anticoagulation Benchmark,
(2005). Antithrombotic Therapy Practices in US Hospitals in an Era of Practice Guidelines. Arch Intern Med
165: 1458-1464
[Abstract][Full Text]
Enyart, J. J, Jones, R. J
(2005). Low-Dose Warfarin for Prevention of Symptomatic Thromboembolism After Orthopedic Surgery. The Annals of Pharmacotherapy
39: 1002-1007
[Abstract][Full Text]
Rowlingson, J. C., Hanson, P. B.
(2005). Neuraxial Anesthesia and Low-Molecular-Weight Heparin Prophylaxis in Major Orthopedic Surgery in the Wake of the Latest American Society of Regional Anesthesia Guidelines. Anesth. Analg.
100: 1482-1488
[Abstract][Full Text]
Dager, W. E, Vondracek, T. G, McIntosh, B. A, Nutescu, E. A
(2004). Ximelagatran: An Oral Direct Thrombin Inhibitor. The Annals of Pharmacotherapy
38: 1881-1897
[Abstract][Full Text]
McGuire, M., Dobesh, P. P.
(2004). Therapeutic Update on the Prevention and Treatment of Venous Thromboembolism. Journal of Pharmacy Practice
17: 289-307
[Abstract]
Geerts, W. H., Pineo, G. F., Heit, J. A., Bergqvist, D., Lassen, M. R., Colwell, C. W., Ray, J. G.
(2004). Prevention of Venous Thromboembolism: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest
126: 338S-400S
[Abstract][Full Text]
Thalava, R., Radl, R., Windhager, R.
(2004). Venous Thrombosis After Hallux Valgus Surgery * R. Radl and R. Windhager reply:. JBJS
86: 872-872
[Full Text]
Radl, R., Kastner, N., Aigner, C., Portugaller, H., Schreyer, H., Windhager, R.
(2003). Venous Thrombosis After Hallux Valgus Surgery. JBJS
85: 1204-1208
[Abstract][Full Text]
Anderson, F. A. Jr., Spencer, F. A.
(2003). Risk Factors for Venous Thromboembolism. Circulation
107: I-9-16
[Abstract][Full Text]
Eriksson, B. I., Lassen, M. R.
(2003). Duration of Prophylaxis Against Venous Thromboembolism With Fondaparinux After Hip Fracture Surgery: A Multicenter, Randomized, Placebo-Controlled, Double-blind Study. Arch Intern Med
163: 1337-1342
[Abstract][Full Text]
O'Donnell, M., Linkins, L.-A., Kearon, C., Julian, J., Hirsh, J.
(2003). Reduction of Out-of-Hospital Symptomatic Venous Thromboembolism by Extended Thromboprophylaxis With Low-Molecular-Weight Heparin Following Elective Hip Arthroplasty: A Systematic Review. Arch Intern Med
163: 1362-1366
[Abstract][Full Text]
Phillips, C. B., Barrett, J. A., Losina, E., Mahomed, N. N., Lingard, E. A., Guadagnoli, E., Baron, J. A., Harris, W. H., Poss, R., Katz, J. N.
(2003). Incidence Rates of Dislocation, Pulmonary Embolism, and Deep Infection During the First Six Months After Elective Total Hip Replacement. JBJS
85: 20-26
[Abstract][Full Text]
Westrich, G. H., Weksler, B. B., Glueck, C. J., Blumenthal, B. F., Salvati, E. A.
(2002). Correlation of Thrombophilia and Hypofibrinolysis with Pulmonary Embolism Following Total Hip Arthroplasty: An Analysis of Genetic Factors. JBJS
84: 2161-2167
[Abstract][Full Text]
Samama, C. M., Vray, M., Barre, J., Fiessinger, J.-N., Rosencher, N., Lecompte, T., Potron, G., Basile, J., Hull, R., Desmichels, D., for the SACRE Study Investigators,
(2002). Extended Venous Thromboembolism Prophylaxis After Total Hip Replacement: A Comparison of Low-Molecular-Weight Heparin With Oral Anticoagulant. Arch Intern Med
162: 2191-2196
[Abstract][Full Text]
Prandoni, P., Bruchi, O., Sabbion, P., Tanduo, C., Scudeller, A., Sardella, C., Errigo, G., Pietrobelli, F., Maso, G., Girolami, A.
(2002). Prolonged Thromboprophylaxis With Oral Anticoagulants After Total Hip Arthroplasty: A Prospective Controlled Randomized Study. Arch Intern Med
162: 1966-1971
[Abstract][Full Text]
Lassen, M. R., Borris, L. C., Nakov, R. L.
(2002). Use of the Low-Molecular-Weight Heparin Reviparin to Prevent Deep-Vein Thrombosis after Leg Injury Requiring Immobilization. NEJM
347: 726-730
[Abstract][Full Text]
Strebel, N., Prins, M., Agnelli, G., Buller, H. R.
(2002). Preoperative or Postoperative Start of Prophylaxis for Venous Thromboembolism With Low-Molecular-Weight Heparin in Elective Hip Surgery?. Arch Intern Med
162: 1451-1456
[Abstract][Full Text]
Douketis, J. D., Eikelboom, J. W., Quinlan, D. J., Willan, A. R., Crowther, M. A.
(2002). Short-Duration Prophylaxis Against Venous Thromboembolism After Total Hip or Knee Replacement: A Meta-analysis of Prospective Studies Investigating Symptomatic Outcomes. Arch Intern Med
162: 1465-1471
[Abstract][Full Text]
Alikhan, R., Zaw, H. M., Comp, P. C., Spiro, T. E., Friedman, R. J., Whitsett, T. L., Johnson, G. J., Gardiner, G. A. Jr.
(2002). Thromboprophylaxis in Hip Arthroplasty. JBJS
84: 876-877
[Full Text]
Grion, A. M., Gallo, U., Bano, F., Ragazzi, M., Cestrone, A., Orsini, A., Salomoni, M., Gaion, R. M., Pengot, V.
(2002). Difference in Mortality After Hip Fracture is Associated with Postdischarge Prescription of Antithrombotic Prophylaxis: A Case-Control Study. CLIN APPL THROMB HEMOST
8: 143-146
[Abstract]
Bergqvist, D., Agnelli, G., Cohen, A. T., Eldor, A., Nilsson, P. E., Le Moigne-Amrani, A., Dietrich-Neto, F., the ENOXACAN II Investigators,
(2002). Duration of Prophylaxis against Venous Thromboembolism with Enoxaparin after Surgery for Cancer. NEJM
346: 975-980
[Abstract][Full Text]
Sculco, T. P., Colwell, C. W. Jr., Pellegrini, V. D. Jr., Westrich, G. H., Bottner, F.
(2002). Prophylaxis Against Venous Thromboembolic Disease in Patients Having a Total Hip or Knee Arthroplasty. JBJS
84: 466-477
[Full Text]
Pitto, R. P., Hamer, H., Fabiani, R., Radespiel-Troeger, M., Koessler, M.
(2002). Prophylaxis Against Fat and Bone-Marrow Embolism During Total Hip Arthroplasty Reduces the Incidence of Postoperative Deep-Vein Thrombosis : A Controlled, Randomized Clinical Trial. JBJS
84: 39-48
[Abstract][Full Text]
Hull, R. D., Pineo, G. F., Stein, P. D., Mah, A. F., MacIsaac, S. M., Dahl, O. E., Butcher, M., Brant, R. F., Ghali, W. A., Bergqvist, D., Raskob, G. E.
(2001). Extended Out-of-Hospital Low-Molecular-Weight Heparin Prophylaxis against Deep Venous Thrombosis in Patients after Elective Hip Arthroplasty: A Systematic Review. ANN INTERN MED
135: 858-869
[Abstract][Full Text]
Kher, A., Samama, M.M.
(2001). Low-Molecular-Weight Heparins: Weeks or Months Instead of Days of Treatment. CLIN APPL THROMB HEMOST
7: 314-320
[Abstract]
NURMOHAMED, M T, DIJKMANS, B A C
(2001). Prevention of post-discharge venous thromboembolism in patients with rheumatoid arthritis undergoing knee or hip arthroplasty: a continuing matter of debate. Ann Rheum Dis
60: 905-907
[Full Text]
Hull, R. D., Pineo, G. F., Stein, P. D., Mah, A. F., MacIsaac, S. M., Dahl, O. E., Ghali, W. A., Butcher, M. S., Brant, R. F., Bergqvist, D., Hamulyak, K., Francis, C. W., Marder, V. J., Raskob, G. E.
(2001). Timing of Initial Administration of Low-Molecular-Weight Heparin Prophylaxis Against Deep Vein Thrombosis in Patients Following Elective Hip Arthroplasty: A Systematic Review. Arch Intern Med
161: 1952-1960
[Abstract][Full Text]
Thomas, D. P
(2001). Thromboprophylaxis after replacement arthroplasty. BMJ
322: 686-687
[Full Text]
Comp, P. C., Spiro, T. E., Friedman, R. J., Whitsett, T. L., Johnson, G. J., Gardiner, G. A., Landon, G. C., Jové, M.
(2001). Prolonged Enoxaparin Therapy to Prevent Venous Thromboembolism After Primary Hip or Knee Replacement. JBJS
83: 336-336
[Abstract][Full Text]
Weitz, J. I., Hirsh, J.
(2001). New Anticoagulant Drugs. Chest
119
: 95S-107S
[Full Text]
Geerts, W. H., Heit, J. A., Clagett, G. P., Pineo, G. F., Colwell, C. W., Anderson, F. A. Jr., Wheeler, H. B.
(2001). Prevention of Venous Thromboembolism. Chest
119
: 132S-175S
[Full Text]
White, R. H., Gettner, S., Newman, J. M., Trauner, K. B., Romano, P. S.
(2000). Predictors of Rehospitalization for Symptomatic Venous Thromboembolism after Total Hip Arthroplasty. NEJM
343: 1758-1764
[Abstract][Full Text]
Noda, K., Wada, H., Yamada, N., Noda, N., Gabazza, E. C., Kumeda, K., Okugawa, T., Yanoh, K., Ito, M., Nakano, T., Shiku, H., Nobori, T., Kato, H., Toyoda, N.
(2000). Changes of Hemostatic Molecular Markers After Gynecological Surgery. CLIN APPL THROMB HEMOST
6: 197-201
[Abstract]
Hull, R. D., Pineo, G. F., Francis, C., Bergqvist, D., Fellenius, C., Soderberg, K., Holmqvist, A., Mant, M., Dear, R., Baylis, B., Mah, A., Brant, R., for the North American Fragmin Trial Investigators,
(2000). Low-Molecular-Weight Heparin Prophylaxis Using Dalteparin in Close Proximity to Surgery vs Warfarin in Hip Arthroplasty Patients: A Double-blind, Randomized Comparison. Arch Intern Med
160: 2199-2207
[Abstract][Full Text]
Hull, R. D., Pineo, G. F., Francis, C., Bergqvist, D., Fellenius, C., Soderberg, K., Holmqvist, A., Mant, M., Dear, R., Baylis, B., Mah, A., Brant, R., for the North American Fragmin Trial Investigators,
(2000). Low-Molecular-Weight Heparin Prophylaxis Using Dalteparin Extended Out-of-Hospital vs In-Hospital Warfarin/Out-of-Hospital Placebo in Hip Arthroplasty Patients: A Double-blind, Randomized Comparison. Arch Intern Med
160: 2208-2215
[Abstract][Full Text]
Heit, J. A., Elliott, C. G., Trowbridge, A. A., Morrey, B. F., Gent, M., Hirsh, J., for the Ardeparin Arthroplasty Study Group*,
(2000). Ardeparin Sodium for Extended Out-of-Hospital Prophylaxis against Venous Thromboembolism after Total Hip or Knee Replacement: A Randomized, Double-Blind, Placebo-Controlled Trial. ANN INTERN MED
132: 853-861
[Abstract][Full Text]
Davidson, B. L., Lensing, A. W.A.
(2000). Prolonged Prophylaxis after Joint Replacement: Another Step Sideways?. ANN INTERN MED
132: 914-915
[Full Text]
Bjorgell, O., Nilsson, P. E., Jarenros, H., Bjorgell, O.
(2000). Nonfilling of Contrast in Deep Leg Vein Isolated Nonfilling of Contrast in Deep Leg Vein Segments Seen on Phlebography, and a Comparison with Color Doppler Ultrasound, to Assess the Incidence of Deep Leg Vein Thrombosis. ANGIOLOGY
51: 451-461
[Abstract]
Ginsberg, J. S., Gent, M., Turkstra, F., Buller, H. R., MacKinnon, B., Magier, D., Hirsh, J.
(2000). Postthrombotic Syndrome After Hip or Knee Arthroplasty: A Cross-sectional Study. Arch Intern Med
160: 669-672
[Abstract][Full Text]
Ansell, J. E., Weitz, J. I., Comerota, A. J.
(2000). Advances in Therapy and the Management of Antithrombotic Drugs for Venous Thromboembolism. ASH Education Book
2000: 266-284
[Abstract][Full Text]
Samama, M. M., Cohen, A. T., Darmon, J.-Y., Desjardins, L., Eldor, A., Janbon, C., Leizorovicz, A., Nguyen, H., Olsson, C.-G., Turpie, A. G., Weisslinger, N., The Prophylaxis in Medical Patients with Enoxapari,
(1999). A Comparison of Enoxaparin with Placebo for the Prevention of Venous Thromboembolism in Acutely Ill Medical Patients. NEJM
341: 793-800
[Abstract][Full Text]
COLWELL, C. W., COLLIS, D. K., PAULSON, R., McCUTCHEN, J. W., BIGLER, G. T., LUTZ, S., HARDWICK, M. E.
(1999). Comparison of Enoxaparin and Warfarin for the Prevention of Venous Thromboembolic Disease After Total Hip Arthroplasty. Evaluation During Hospitalization and Three Months After Discharge. JBJS
81: 932-40
[Abstract][Full Text]
NURMOHAMED, M T, LEMS, W F, DIJKMANS, B A C
(1999). Risk of post-discharge venous thromboembolism in patients with rheumatoid arthritis undergoing knee or hip arthroplasty. Is prolonged thromboprophylaxis warranted or dangerous?. Ann Rheum Dis
58: 392-395
[Full Text]
Bjorgell, O., Nilsson, P. E., Svensson, P. J., Bergqvist, D., Bjorgell, O.
(1999). A New Scoring System for the Detailed Description of the Distribution and Thrombotic Burden in Deep Leg Vein Thrombosis. ANGIOLOGY
50: 179-187
[Abstract]
SARMIENTO, A., GOSWAMI, A. D. K.
(1999). Thromboembolic Prophylaxis with Use of Aspirin, Exercise, and Graded Elastic Stockings or Intermittent Compression Devices in Patients Managed with Total Hip Arthroplasty. JBJS
81: 339-46
[Abstract][Full Text]
WARWICK, D., HARRISON, J., GLEW, D., MITCHELMORE, A., PETERS, T. J., DONOVAN, J.
(1998). Comparison of the Use of a Foot Pump with the Use of Low-Molecular-Weight Heparin for the Prevention of Deep-Vein Thrombosis after Total Hip Replacement. A Prospective, Randomized Trial. JBJS
80: 1158-66
[Abstract][Full Text]
White, R. H., Romano, P. S., Zhou, H., Rodrigo, J., Bargar, W.
(1998). Incidence and Time Course of Thromboembolic Outcomes Following Total Hip or Knee Arthroplasty. Arch Intern Med
158: 1525-1531
[Abstract][Full Text]
Goldhaber, S. Z.
(1998). Pulmonary Embolism. NEJM
339: 93-104
[Full Text]
Dixon, D. J., Ricci, M. A., Reid, J. G., Possidente, C., Incavo, S. J., Howe, J. G.
(1998). Is Impedance Plethysmography a Safe Test After Total Joint Replacement?. VASC ENDOVASCULAR SURG
32: 255-260
[Abstract]
Leclerc, J. R., Gent, M., Hirsh, J., Geerts, W. H., Ginsberg, J. S., for the Canadian Collaborative Group,
(1998). The Incidence of Symptomatic Venous Thromboembolism During and After Prophylaxis With Enoxaparin: A Multi-institutional Cohort Study of Patients Who Underwent Hip or Knee Arthroplasty. Arch Intern Med
158: 873-878
[Abstract][Full Text]
Hull, R. D., Pineo, G. F.
(1998). Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism: Current Recommendations. CLIN APPL THROMB HEMOST
4: 96-104
[Abstract]
Bounameaux, H.
(1998). Unfractionated versus low-molecular-weight heparin in the treatment of venous thromboembolism. Vasc Med
3: 41-46
[Abstract]
Agnelli, G.
(1998). Postdischarge prophylaxis for venous thromboembolism among high-risk surgery patients. Vasc Med
3: 51-56
[Abstract]
FRANCIS, C. W., PELLEGRINI, V. D. JR., TOTTERMAN, S., BOYD, A. D. JR., MARDER, V. J., LIEBERT, K. M., STULBERG, B. N., AYERS, D. C., ROSENBERG, A., KESSLER, C., JOHANSON, N. A.
(1997). Prevention of Deep-Vein Thrombosis after Total Hip Arthroplasty. Comparison of Warfarin and Dalteparin. JBJS
79: 1365-72
[Abstract][Full Text]
Anderson, D. R., Gross, M., Robinson, K. S., Wells, P. S., Pedell, L., Bergqvist, D.
(1997). Enoxaparin as Prophylaxis against Thromboembolism after Total Hip Replacement. NEJM
336: 585-586
[Full Text]
(1996). Low-Molecular-Weight Heparin After Total Hip Replacement . .. Journal Watch Cardiology
1996: 26-26
[Full Text]
(1996). LOW-MOLECULAR-WEIGHT HEPARIN AFTER TOTAL HIP REPLACEMENT.... JWatch General
1996: 1-1
[Full Text]
Previous
