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When to Start Lovenox Again Postoperatively

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Original Commodity

Duration of Prophylaxis against Venous Thromboembolism with Enoxaparin later Surgery for Cancer

List of authors.
  • David Bergqvist, One thousand.D., Ph.D.,
  • Giancarlo Agnelli, Grand.D.,
  • Alexander T. Cohen, Thou.D.,
  • Amiram Eldor, One thousand.D.,
  • Paul Due east. Nilsson, M.D., Ph.D.,
  • Anne Le Moigne-Amrani, M.Southward.,
  • and Flavia Dietrich-Neto, M.D.
  • for the ENOXACAN 2 Investigators*

Abstract

Background

Abdominal surgery for cancer carries a loftier run a risk of venous thromboembolism, only the optimal duration of postoperative thromboprophylaxis is unknown.

Methods

Nosotros conducted a double-blind, multicenter trial in which patients undergoing planned curative open surgery for abdominal or pelvic cancer received enoxaparin (twoscore mg subcutaneously) daily for 6 to 10 days and were then randomly assigned to receive either enoxaparin or placebo for another 21 days. Bilateral venography was performed between days 25 and 31, or sooner if symptoms of venous thromboembolism occurred. The primary terminate indicate with respect to efficacy was the incidence of venous thromboembolism between days 25 and 31. The primary safety finish signal was bleeding during the three-week period later randomization. The patients were followed for three months.

Results

The intention-to-treat analysis of efficacy included 332 patients. The rates of venous thromboembolism at the finish of the double-blind phase were 12.0 percent in the placebo group and four.8 percent in the enoxaparin group (P=0.02). This difference persisted at three months (13.8 per centum vs. v.5 percent, P=0.01). Iii patients in the enoxaparin group and 6 in the placebo group died inside three months after surgery. There were no significant differences in the rates of bleeding or other complications during the double-blind or follow-up periods.

Conclusions

Enoxaparin prophylaxis for four weeks after surgery for abdominal or pelvic cancer is condom and significantly reduces the incidence of venographically demonstrated thrombosis, as compared with enoxaparin prophylaxis for i week.

Introduction

The efficacy of low-molecular-weight heparin in preventing postoperative venous thromboembolism is well documented, but the optimal duration of prophylaxis after surgery for cancer has not been clearly defined.i Prophylaxis is usually limited to the period of hospitalization, but the risk of thromboembolism remains high for several weeks after major surgery.2-7 Six randomized, double-bullheaded trials have shown that prophylaxis with low-molecular-weight heparin for approximately 1 month afterwards orthopedic surgery significantly reduces the frequency of deep-vein thrombosis, every bit compared with low-molecular-weight heparin given but during the start postoperative calendar week.eight-13

Venous thromboembolism is an important crusade of death in patients with cancer,14-16 and intestinal surgery for cancer carries a especially high run a risk of this complexity.17 In a survey of clinical trials of thromboprophylaxis in surgical patients with cancer, the boilerplate incidence of deep-vein thrombosis in untreated patients was 29 percent.1 In the Enoxaparin and Cancer (ENOXACAN) I report, deep-vein thrombosis occurred in 15 percent of patients receiving x days of enoxaparin prophylaxis after abdominal surgery for cancer.xviii We conducted the present ENOXACAN II written report to compare a four-week and a one-week regimen of enoxaparin prophylaxis in terms of safety and efficacy in patients undergoing constituent surgery for abdominal or pelvic cancer.

Methods

Patients

Eligible patients were xl years of age or older, with a life expectancy of at to the lowest degree six months, and were scheduled to undergo open, elective, curative surgery for a cancerous tumor of the alimentary canal (other than the esophagus), genitourinary tract, or female person reproductive organs. Procedures were performed with the patient under general anesthesia and with a planned duration of surgery of more than 45 minutes. The exclusion criteria were renal or hepatic insufficiency; known hypersensitivity to low-molecular-weight heparin or radiographic contrast medium; cognitive thrombosis, cerebral hemorrhage, or neurosurgery within the previous vi months; known cognitive metastases, generalized bleeding disorders, endocarditis, or active peptic ulcer; venous thromboembolism within the previous iii months; uncontrolled arterial hypertension; treatment with heparin compounds or oral anticoagulant agents within five days before surgery; and pregnancy or lactation.

Study Design

This study was a prospective, placebo-controlled, double-bullheaded, randomized trial. All patients received xl mg of enoxaparin (Lovenox or Clexane, Aventis Pharmaceuticals, Paris) once daily, with the starting time dose given 10 to 14 hours preoperatively, for 6 to 10 days. Subsequently this open-treatment menstruum, the patients were randomly assigned to receive 40 mg of subcutaneous enoxaparin or placebo in one case daily for 19 to 21 days, for a total handling flow of 25 to 31 days. Randomization was stratified co-ordinate to the land where the institution was located. All patients randomly assigned to enoxaparin or placebo after the first week of therapy had undergone abdominal or pelvic surgery lasting at to the lowest degree 45 minutes and had received the specified enoxaparin prophylaxis. Patients were excluded from randomization if they had received prohibited medications or had had objectively verified venous thromboembolism or major bleeding. The prohibited medications for the 28-day treatment menstruum were heparin compounds (except enoxaparin given as part of this report), oral anticoagulant agents, and ticlopidine. Graduated compression stockings were immune, but intermittent pneumatic compression and electrical calf-muscle stimulation were not.

During the period of prolonged prophylaxis subsequently the patients had been discharged from the infirmary, competent patients, their caregivers, or district nurses were allowed to administer the injections. The exact amount of study medication dispensed was documented. Compliance was checked past a review of the documentation of the administration of study medication (the mean solar day and time for each injection) and counts of the remaining doses of drug.

The study was performed according to the provisions of the Proclamation of Helsinki and good clinical practice. An ideals committee in each country approved the trial. Written, informed consent was obtained from all patients or their legal guardians.

All the authors had access to the information, took function in the analysis and interpretation, fully controlled the decision whether to publish, and agreed on the final manuscript. The steering committee, in consultation with the sponsors, designed the study and analyzed and interpreted the information. The first typhoon of the manuscript was written by the chairman of the steering committee (Dr. Bergqvist), and the final draft was written past the steering commission together with the sponsor (Aventis Pharmaceuticals). I representative of the sponsor performed the statistical analysis (Ms. Le Moigne-Amrani), and one took part in writing the manuscript (Dr. Dietrich-Neto). All members of the steering commission received fees for their commission duties merely take no equity interests in Aventis Pharmaceuticals. Ms. Le Moigne-Amrani and Dr. Dietrich-Neto are employed by Aventis Pharmaceuticals.

Assessment of Outcome

The master efficacy end point was deep-vein thrombosis verified by venograms read past a central committee that was unaware of the patients' treatment assignments, symptomatic pulmonary embolism confirmed by ventilation–perfusion lung scanning or pulmonary angiography, or both. Venography was performed routinely between days 25 and 31. A clinical suspicion of venous thromboembolism before that time required objective testing and adjudication by a primal commission. The secondary efficacy end point was decease from thromboembolic illness earlier three months, with separate analyses of bloodshed during the three-calendar week double-blind menstruation and the ii-month follow-up period.

The patients returned to the hospital for bilateral ascending venography within three days of the final outpatient injection. If symptoms or signs of deep-vein thrombosis had developed, unilateral venography or ultrasonography was performed within iii days. If this exam was positive and the consequence was confirmed by the adjudication commission, the patient was considered to have reached an end signal. If the test was negative, the patient continued in the trial and underwent venography according to the protocol.

The venographic results were evaluated and agreed on by the venography reading commission (consisting of three radiologists) before the investigators were unblinded. The venographic definition of deep-vein thrombosis was a constant intraluminal filling defect; thrombi in the popliteal vein or higher up were considered proximal. A venogram was considered acceptable if a deep-vein thrombosis was constitute or if the entire deep venous organization was visualized from the dogie veins to the common iliac vein in both legs. Each participating center received guidelines from the venography reading committee. If pulmonary embolism was suspected clinically, ventilation–perfusion lung scanning, pulmonary angiography, or both were performed.

The primary rubber end point was the occurrence of hemorrhage during the period of double-blind treatment. The prophylactic evaluation too examined serious adverse events during the double-blind period and hemorrhage and other serious adverse events during the two-month follow-up period. Hemoglobin measurements and platelet counts were performed at the stop of the open-label menses and again at the end of the double-blind period. Hemorrhages reported during the double-blind period were assessed so classified by the investigator as either major or minor. A hemorrhage was classified as major if it resulted in decease, a decrease in the hemoglobin concentration of 2 g per deciliter or more, or the transfusion of at least ii units of blood; if it was retroperitoneal, intracranial, or intraocular; if it resulted in a serious or life-threatening clinical event; or if surgical or medical intervention was required to stop or control the hemorrhage. Minor hemorrhages were those that were confirmed to be overt and to have some clinically important characteristic, such as epistaxis, ecchymosis, hematoma, or macroscopic hematuria just that did not meet the criteria for major hemorrhage. All major hemorrhages were adjudicated and confirmed by the information monitoring and safety committee.

Patients were followed upwards at iii months (±ten days), and instances of death, venous thromboembolism, and adverse events, including hemorrhagic episodes, were recorded. All deaths were adjudicated and confirmed.

Statistical Analysis

Calculation of sample size was based on the estimated frequency of venographically demonstrated thromboembolism at day 28±three. It was hypothesized that the frequency of thromboembolism in the placebo group would be 28 per centum, and it was considered clinically important to reduce this frequency to xvi percentage. In lodge to find a 12 percentage bespeak subtract with a type I mistake of 5 percent and a power of 80 percent in a two-sided test, 186 patients who could exist evaluated would exist required in each grouping. On the supposition that 25 percent of the patients would not exist able to be evaluated, a total of 496 patients would be required. After the first 216 bilateral venograms had been analyzed, an interim cess of the data was performed by an independent statistician who was not blinded to the treatment assignments. This statistician adamant that although the incidence of venous thromboembolism was lower than had been estimated, the study still had sufficient power to demonstrate a statistically meaning reduction in the incidence of venous thromboembolism, and it was recommended to the steering committee that the sample size not be adjusted.

Chiselled data were compared with use of either a chi-square test or Fisher'south exact test. The reported P values are based on 2-sided tests. For the estimation and estimation of differences between the groups in the rates of venous thromboembolism, 95 percentage confidence intervals were calculated.

The study population for the safety analysis was defined as all patients randomly assigned to treatment who received at least i dose of the assigned study medication during the double-bullheaded period. For the efficacy assay, the intention-to-treat population was defined as all patients who underwent randomization and received at least one dose of the study medication who had likewise been evaluated for deep-vein thrombosis and pulmonary embolism. This population included all patients for whom a readable venogram obtained inside three days of the last double-bullheaded injection was available or in whom confirmed venous thromboembolism occurred between randomization and the solar day of the last double-blind injection (plus three days).

Results

Study Populations

The study was conducted between October 1998 and June 2000 at 37 centers in Denmark, France, Greece, Israel, Italy, Sweden, Switzerland, and the U.k.. Of the 613 patients who were recruited, 609 received open up-label prophylaxis with enoxaparin. Of these, 501 were then randomly assigned to continued enoxaparin prophylaxis (253 patients) or placebo (248 patients) and were treated during the double-blind period; these patients were included in the rubber analysis. The mean elapsing of double-blind therapy was nineteen.5 days in the placebo group and 19.3 days in the enoxaparin grouping.

Venography was not performed or the results could not be evaluated in 81 patients in the placebo group and 88 patients in the enoxaparin group. These patients were therefore excluded from the efficacy assay. Of the remaining 332 patients, 167 had been assigned to placebo and 165 to enoxaparin.

Table 1. Tabular array 1. Demographic Characteristics and Clinical Risk Factors at Base Line. Table 2. Tabular array ii. Surgical Procedures and Related Events.

The patients in the ii groups were well matched at base of operations line with regard to demographic variables, risk factors, and the type and duration of surgery (Table ane and Table 2). Gastrointestinal surgery was the most common procedure (Table 2). The protocol-specified surgery was expected to be curative. However, during the operation, surgery was judged to be palliative in 3.6 percent of the patients assigned to placebo (6 of 167) and 9.7 pct of the patients assigned to enoxaparin (16 of 165) (P=0.02).

Efficacy

Table three. Tabular array 3. Incidence of Venous Thromboembolic Events.

During the double-blind period, the overall incidence of venous thromboembolism was eight.iv percentage (28 of 332). In the group given one week of prophylaxis (placebo group), the incidence was 12.0 percent (20 of 167); in the group given four weeks of prophylaxis, it was 4.8 percent (8 of 165) (P=0.02). This corresponds to a reduction in risk of 60 percent (95 percent confidence interval, 10 to 82 pct). Proximal deep-vein thrombosis was identified in three patients in the placebo group and one in the enoxaparin grouping (Tabular array 3).

Before the scheduled venography, signs and symptoms suggestive of venous thromboembolism developed in six patients. 1 of these cases — a pulmonary embolism occurring in a patient receiving placebo — was confirmed by objective testing. The remaining 27 cases of venous thromboembolism were diagnosed on routine venography. During the follow-upwards period, venous thromboembolism was suspected in v patients; in three of these it was confirmed by objective testing. In 1 patient in the placebo group, an unsuspected pulmonary embolism was identified at autopsy.

Adverse Events

Table 4. Tabular array 4. Incidence of Hemorrhage.

In that location were no pregnant differences between the groups in the incidence of major or pocket-sized bleeding during the double-blind catamenia or the two-month follow-up period (Table 4). There were no cases of thrombocytopenia (defined as fewer than lxx,000 platelets per cubic millimeter). Analysis of other serious adverse events revealed no significant differences between the two treatment groups.

There were no deaths during the double-bullheaded menstruation. Nine patients died during the two-month follow-up period: half dozen (3.half-dozen percent) in the placebo group and three (1.8 percent) in the enoxaparin group. In the placebo group, the causes of expiry were sepsis in ii patients, cancer in three, and pulmonary embolism in one. In the enoxaparin group, 1 patient each died of sepsis, cancer, and myocardial infarction.

Discussion

Our main finding was that prophylaxis with enoxaparin for iv weeks later surgery for intestinal or pelvic cancer significantly reduced the frequency of postoperative venous thromboembolism. The incidence of venous thromboembolism during this catamenia was reduced from 12.0 percent to 4.8 percent, an absolute gamble reduction of 7.2 percent points and a relative gamble reduction of threescore per centum. There was no increment in hemorrhagic complications with enoxaparin. The overall frequency of venous thromboembolism in this study was lower than expected. Nevertheless we were able to demonstrate a significant difference between the effects of the two treatments because the chance reduction achieved was greater than predicted.

The reduction in venous thromboembolism that we observed is similar in magnitude to that seen in a small, open-label study of extended prophylaxis with low-molecular-weight heparin after elective intestinal or thoracic (noncardiac) surgery.19 That study, however, did not have sufficient power to demonstrate a significant issue of treatment. The blueprint of our investigation was like to that of a report of enoxaparin in elective hip surgery, and we found a similar benefit of extended therapy.8

In elective hip surgery, prolonged prophylaxis with enoxaparin (given for one month) has been shown to be cost constructive.20 In our study of patients with cancer, the number needed to treat to avoid i case of deep-vein thrombosis was only fourteen, and in that location was no difference betwixt the groups in the incidence of adverse events that might increase total treatment costs. Yet, although at that place is reason to believe that four weeks of prophylaxis may accept economical benefits in high-run a risk cancer surgery, we did non perform such an assay and we therefore cannot brand such projections.

The clinical relevance of deep-vein thrombosis detected on venography one month after surgery that is non associated with clinical symptoms and signs has been discussed by other investigators.21 In guild for venographically detected deep-vein thrombosis to be a reliable surrogate for clinical venous thromboembolism, there should exist a articulate association between the ii end points. Such an association has been established in a contempo meta-analysis of six randomized studies of prolonged thromboprophylaxis later lower-limb arthroplasty.22 Although no private trial had sufficient power to demonstrate a pregnant reduction in clinical end points, the meta-assay showed a significant fifty pct reduction in the odds of venous thromboembolism with clinical symptoms, similar to that observed for venographically detected deep-vein thrombosis.

Approximately one 3rd of our patients did not undergo venography or had an uninterpretable venogram. This proportion is somewhat higher than that in our written report of patients undergoing hip arthroplasty,viii which was a single-middle written report, merely lower than that in the multicenter ENOXACAN I written report.18 This effigy is reasonable, because we studied patients with cancer who had to return to the hospital for the investigation. What is important is that there was no difference between the groups.

It is sometimes suggested that thromboprophylaxis simply delays venous thromboembolism, rather than preventing it.23 Such a rebound miracle has rarely been observed with enoxaparin; indeed, in this written report the three-month follow-up information showed no indication of delayed venous thromboembolism. In fact, the reduction in take a chance was just every bit robust, with i additional case of deep-vein thrombosis in the enoxaparin group equally compared with three in the placebo group, during follow-up (Table iii).

The results of a recent prospective study showed that patients assigned to low-molecular-weight heparin for thromboprophylaxis later surgery for cancer had longer survival than patients assigned to unfractionated heparin.24 In the present written report, half dozen patients in the placebo group and 3 patients in the enoxaparin group died. The report did not have the statistical ability to evaluate differences in mortality betwixt the groups, but this area claim farther investigation.

Funding and Disclosures

Supported past a grant (00759) from the Swedish Medical Research Quango and by Aventis Pharmaceuticals.

Writer Affiliations

From Academic Hospital, Uppsala, Sweden (D.B.); Università di Perugia, Perugia, Italy (Yard.A.); Guy's, Male monarch's and St. Thomas' School of Medicine, London (A.T.C.); Tel Aviv Sourasky Medical Center, Tel Aviv, State of israel (A.Due east.); Malmö University Infirmary, Malmö, Sweden (P.E.North.); and Aventis Pharmaceuticals, Bridgewater, N.J. (A.L.One thousand.-A., F.D.-N.).

Address reprint requests to Dr. Bergqvist at the Department of Surgery, University Hospital, SE-751 85 Uppsala, Sweden, or at [e-mail protected].

Participants in the Enoxaparin and Cancer (ENOXACAN) II study group are listed in the Appendix.

Appendix

The following participated in the report: Steering Committee — D. Bergqvist, Uppsala, Sweden; G. Agnelli, Perugia, Italia; A.T. Cohen, London; A. Eldor, Tel Aviv, Israel; Venography Reading Committee — P.E. Nilsson, O. Björgell, and G. Nylander, Malmö, Sweden; Data Monitoring and Safety Committee — H. Büller, D. Brandjes, and Martin Prins, Amsterdam; Writing Committee — the members of the steering committee, P.E. Nilsson, Malmö, Sweden, and F. Dietrich-Neto (Aventis Pharmaceuticals); Investigators — Kingdom of denmark: K.Due east.J. Jensen, Esbjerg; P.F. Jensen, Århus; J. Nielsen, Viborg; Due south. Schulze, Glostrup; France: D. Benchimol, Nice; J.-L. Bourgain, Villejuif; P.H. Cugnenc, Paris; J.-P. Favre, Dijon; J. Fusciardi, Tours; J.-C. Gaux, Paris; B. Goubaux, Prissy; G. Janvier, Pessac; P. Lallemant, Mulhouse; A. Lienhart, Paris; Y. Malledant, Rennes; G. Mantion, Besançon; J. Marty, Clichy; Northward. Nathan-Denizot, Limoges; J.-L. Pourriat, Bondy; Grand. Raucoules, Prissy; J.-P. Sales, Le Kremlin-Bicêtre; M. Samama, Bobigny; P. Schoeffler, Clermont-Ferrand; A. Steib, Strasbourg; Greece: G. Androulakis, Athens; A. Kappas, Ioannina; C. Liapis, Athens; T. Mavromatis, Athens; State of israel: A. Eldor, Tel Aviv; G. Lugassy, Ashkelon; Italy: W. Ageno, Varese; A. Bartoli, Perugia; C. Finco, Padua; F. Meduri, Padua; F. Piovella, Pavia; S. Tateo, Pavia; Sweden: L.-E. Hammarström and F. Swahn, Eskilstuna; M. Krog, Gävle; Per Leveau, Ystad; T. Mätzsch, Malmö, B. Pålsson, Lund; A. Törnqvist, Karlstad; Switzerland: P. Gertsch, Bellinzona; Thou. Gillet, Lausanne; R. Grüssner, Zurich; J. Lange, St. Gallen; P. Tschantz, Neuchâtel; United Kingdom: A. Cohen, London; B. Edmondson, Lewisham.

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Source: https://www.nejm.org/doi/full/10.1056/nejmoa012385

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