Reduction In Symptomatic Venous Thromboembolism Research Articles

Thromboembolic Events During Weightbearing vs Nonweightbearing Accelerated Rehabilitation Protocols for Complete Achilles Tendon Ruptures.

Achilles tendon rupture can be treated nonoperatively with functional rehabilitation. However, prolonged immobilization has associated risk of venous thromboembolism (VTE). Early weightbearing may reduce VTE risk, and this was introduced to our rehabilitation protocol. We investigated the prevalence of symptomatic VTE events before and after the introduction of the early weightbearing protocol. Adults with ultrasonography-confirmed complete tendo-Achilles ruptures between January 2017 and June 2020 were included. Preprotocol, patients were instructed to not weightbear for 4 weeks. In 2018, immediate weightbearing was introduced to the treatment protocol. All patients in both cohorts were given low-molecular-weight heparin for 4 weeks. Patients with symptomatic VTE events were investigated with duplex ultrasonographic scan or chest computed tomography. Two independent anonymized examiners collected data from electronic records. Rates of symptomatic VTEs were compared. A total of 296 patients were included. Sixty-nine patients were managed with the nonweightbearing protocol, and 227 patients were managed with the early-weightbearing protocol. Two patients in each group developed deep vein thrombosis and 1 developed pulmonary embolism in the early-weightbearing group. Rates of VTEs were lower in the early-weightbearing group (1.3% vs 2.9%) but did not reach statistical significance (P = .33). In this cohort we found that symptomatic VTE after nonoperatively treated Achilles tendon rupture was uncommon. We did not demonstrate a reduction in symptomatic VTE between our early weightbearing and nonweightbearing rehabilitation protocols. We believe a larger study may help clarify whether early weightbearing is beneficial in VTE reduction. Level III, retrospective cohort study.

Effect of Pharmacologic Prophylaxis on Venous Thromboembolism After Radical Prostatectomy: The PREVENTER Randomized Clinical Trial

BackgroundDirect high-quality evidence is lacking evaluating perioperative pharmacologic prophylaxis (PP) after radical prostatectomy (RP) to prevent venous thromboembolism (VTE) leading to significant practice variation. ObjectiveTo study the impact of in-hospital PP on symptomatic VTE incidence and adverse events after RP at 30 d, with the secondary objective of evaluating overall VTE in a screening subcohort. Design, setting, and participantsA prospective, phase 4, single-center, randomized trial of men with prostate cancer undergoing open or robotic-assisted laparoscopic RP was conducted (July 2017–November 2018). InterventionPP (subcutaneous heparin) plus routine care versus routine care alone. The screening subcohort was offered lower extremity duplex ultrasound at 30 d. Outcomes measurements and statistical analysisThe primary efficacy outcome was symptomatic VTE incidence (pulmonary embolism [PE] or deep venous thrombosis [DVT]). Primary safety outcomes included the incidence of symptomatic lymphocele, hematoma, or bleeding after surgery. Secondary outcomes were overall VTE, estimated blood loss, total surgical drain output, complications, and surveillance imaging bias. Fisher’s exact test and modified Poisson regression were performed. Results and limitationsA total of 501 patients (75% robotic) were randomized and >99% (500/501) completed follow-up. At second interim analysis (N = 445), the symptomatic VTE rate was 2.3% (four PE + DVT and one DVT) for routine care versus 0.9% (one PE + DVT and one DVT) for PP (relative risk 0.40 [95% confidence interval 0.08–2.03], p = 0.3) meeting a futility threshold for early stopping. In the screening subcohort, the overall VTE rate was 3.3% versus 2.4% (p = 0.7). Results were similar at the final analysis (symptomatic VTE: 2.0% vs 0.8%, p = 0.3; overall VTE: 2.9% vs 2.8%, p = 1). No differences were observed in safety or secondary outcomes. All VTE events (seven symptomatic and three asymptomatic) occurred in patients undergoing pelvic lymph node dissection. ConclusionsThis study was not able to demonstrate a statistically significant reduction in symptomatic VTE associated with PP. There was no increase in the development of symptomatic lymphoceles, bleeding, or other adverse events. Given that the event rate was lower than powered for, further research is needed among high-risk patients (Caprini score ≥8) or patients receiving pelvic lymph node dissection. Patient summaryIn this report, we randomized patients undergoing radical prostatectomy to perioperative pharmacologic prophylaxis or routine care alone. We found that pharmacologic prophylaxis did not reduce postoperative symptomatic venous thromboembolism significantly for men at routine risk. Importantly, pharmacologic prophylaxis did not increase adverse events, such as formation of lymphoceles or bleeding, and can safely be implemented when indicated for patients with risk factors undergoing radical prostatectomy.

Use of Fondaparinux Following Elective Lumbar Spine Surgery Is Associated With a Reduction in Symptomatic Venous Thromboembolism

Study Design:Retrospective cohort study.Objective:To assess the impact of fondaparinux on venous thromboembolism (VTE) following elective lumbar spine surgery in high-risk patients.Methods:Matched patient cohorts who did or did not receive inpatient fondaparinux starting postoperative day 2 following elective lumbar spine surgery were compared. All patients received 1 month of acetyl salicylic acid 325 mg following discharge. The primary outcome was a symptomatic DVT (deep vein thrombosis) or PE (pulmonary embolus) within 30 days of surgery. Secondary outcomes included prolonged wound drainage, epidural hematoma, and transfusion.Results:A significantly higher number of DVTs were diagnosed in the group that did not receive inpatient VTE prophylaxis (3/102, 2.9%) compared with the fondaparinux group (0/275, 0%, P = .02). Increased wound drainage was seen in 18.5% of patients administered fondaparinux, compared with 25.5% of untreated patients (P = .15). Deep infections were equivalent (2.2% with fondaparinux vs 4.9% control, P = .18). No epidural hematomas were noted, and the number of transfusions after postoperative day 2 and 90-day return to operating room rates were equivalent.Conclusions:Patients receiving fondaparinux had lower rates of symptomatic DVT and PE and a favorable complication profile when compared with matched controls. The retrospective nature of this work limits the safety and efficacy claims that can be made about the use of fondaparinux to prevent VTE in elective lumbar spine surgery patients. Importantly, this work highlights the potential safety of this regimen, permitting future high-quality trials.

Potent Anticoagulation Does Not Reduce Venous Thromboembolism in High-Risk Patients.

Based on current guidelines from the American Academy of Orthopaedic Surgeons (AAOS), a number of prophylactic modalities for the prevention of venous thromboembolism in total joint arthroplasty may be used. It is common practice that more potent prophylactic agents are used for patients at higher risk of venous thromboembolism. However, we are aware of no studies that have investigated the efficacy of potent anticoagulation in higher-risk individuals. Therefore, the purpose of our study was to test the hypothesis that low-molecular-weight heparin and warfarin result in a reduction in venous thromboembolism events in high-risk patients. A retrospective, multi-institutional study of 60,467 primary and revision total joint arthroplasties from 2000 to 2015 was performed. Identified medications were classified as aspirin, low-molecular-weight heparin, or warfarin. Patients with unavailable venous thromboembolism prophylaxis information or those not receiving the aforementioned prophylaxis were excluded. Information pertinent to the objective of this study was collected and a venous thromboembolism risk score was calculated based on 26 variables. Treatment outcomes assessed included 90-day rate of symptomatic venous thromboembolism and periprosthetic joint infection. Propensity score matching was performed (1:1), as well as logistic regression analysis on the total sample. Aspirin prophylaxis demonstrated a lower rate of deep vein thrombosis, pulmonary embolism, and venous thromboembolism than warfarin and low-molecular-weight heparin alone throughout all risk scores. In the matched propensity score analysis, low-molecular-weight heparin and warfarin demonstrated increased odds of venous thromboembolism for both standard-risk and high-risk patients undergoing total knee arthroplasties compared with aspirin. For primary total hip arthroplasty, warfarin demonstrated an increased risk for high-risk patients and low-molecular-weight heparin demonstrated an increased risk for standard-risk patients. The prevalence of periprosthetic joint infection was higher in patients receiving warfarin (p < 0.001 for both comparisons of warfarin with aspirin and low-molecular-weight heparin). The results of this multi-institutional study demonstrate that the use of warfarin and low-molecular-weight heparin in higher-risk patients does not necessarily result in a reduction in symptomatic venous thromboembolism. Aspirin administered to higher-risk patients seems to be as effective as potent anticoagulation and more effective than warfarin. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Interventions for implementation of thromboprophylaxis in hospitalized patients at risk for venous thromboembolism.

Background Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in hospitalized patients. While numerous randomized controlled trials (RCTs) have shown that the appropriate use of thromboprophylaxis in hospitalized patients at risk for VTE is safe, effective, and cost‐effective, thromboprophylaxis remains underused or inappropriately used. Our previous review suggested that system‐wide interventions, such as education, alerts, and multifaceted interventions were more effective at improving the prescribing of thromboprophylaxis than relying on individual providers’ behaviors. However, 47 of the 55 included studies in our previous review were observational in design. Thus, an update to our systematic review, focused on the higher level of evidence of RCTs only, was warranted.

Treatment for superficial thrombophlebitis of the leg.

The optimal treatment of superficial thrombophlebitis (ST) of the legs remains poorly defined. While improving or relieving the local painful symptoms, treatment should aim at preventing venous thromboembolism (VTE), which might complicate the natural history of ST. This is the third update of a review first published in 2007. To assess the efficacy and safety of topical, medical, and surgical treatments for ST of the leg in improving local symptoms and decreasing thromboembolic complications. For this update, the Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register (March 2017), CENTRAL (2017, Issue 2), and trials registries (March 2017). We handsearched the reference lists of relevant papers and conference proceedings. Randomised controlled trials (RCTs) evaluating topical, medical, and surgical treatments for ST of the legs that included people with a clinical diagnosis of ST of the legs or objective diagnosis of a thrombus in a superficial vein. Two authors assessed the trials for inclusion in the review, extracted the data, and assessed the quality of the studies. Data were independently extracted from the included studies and any disagreements resolved by consensus. We assessed the quality of the evidence using the GRADE approach. We identified three additional trials (613 participants), therefore this update considered 33 studies involving 7296 people with ST of the legs. Treatment included fondaparinux; rivaroxaban; low molecular weight heparin (LMWH); unfractionated heparin (UFH); non-steroidal anti-inflammatory drugs (NSAIDs); compression stockings; and topical, intramuscular, or intravenous treatment to surgical interventions such as thrombectomy or ligation. Only a minority of trials compared treatment with placebo rather than an alternative treatment and many studies were small and of poor quality. Pooling of the data was possible for few outcomes, and none were part of a placebo-controlled trial. In one large, placebo-controlled RCT of 3002 participants, subcutaneous fondaparinux was associated with a significant reduction in symptomatic VTE (risk ratio (RR) 0.15, 95% confidence interval (CI) 0.04 to 0.50; moderate-quality evidence), ST extension (RR 0.08, 95% CI 0.03 to 0.22; moderate-quality evidence), and ST recurrence (RR 0.21, 95% CI 0.08 to 0.54; moderate-quality evidence) relative to placebo. Major bleeding was infrequent in both groups with very wide CIs around risk estimate (RR 0.99, 95% CI 0.06 to 15.86; moderate-quality evidence). In one RCT on 472 high-risk participants with ST, fondaparinux was associated with a non-significant reduction of symptomatic VTE compared to rivaroxaban 10 mg (RR 0.33, 95% CI 0.03 to 3.18; low-quality evidence). There were no major bleeding events in either group (low-quality evidence). In another placebo-controlled trial, both prophylactic and therapeutic doses of LMWH (prophylactic: RR 0.44, 95% CI 0.26 to 0.74; therapeutic: RR 0.46, 95% CI 0.27 to 0.77) and NSAIDs (RR 0.46, 95% CI 0.27 to 0.78) reduced the extension (low-quality evidence) and recurrence of ST (low-quality evidence) in comparison to placebo, with no significant effects on symptomatic VTE (low-quality evidence) or major bleeding (low-quality evidence). Overall, topical treatments improved local symptoms compared with placebo, but no data were provided on the effects on VTE and ST extension. Surgical treatment combined with elastic stockings was associated with a lower VTE rate and ST progression compared with elastic stockings alone. However, the majority of studies that compared different oral treatments, topical treatments, or surgery did not report VTE, ST progression, adverse events, or treatment adverse effects. Prophylactic dose fondaparinux given for 45 days appears to be a valid therapeutic option for ST of the legs for most people. The evidence on topical treatment or surgery is too limited and does not inform clinical practice about the effects of these treatments in terms of VTE. Further research is needed to assess the role of rivaroxaban and other direct oral factor-X or thrombin inhibitors, LMWH, and NSAIDs; the optimal doses and duration of treatment in people at various risk of recurrence; and whether a combination therapy may be more effective than single treatment. Adequately designed and conducted studies are required to clarify the role of topical and surgical treatments.

A Systematic Review and Meta-Analysis of Randomized Trials Examining Extended Thromboprophylaxis with Direct Oral Anticoagulants in Hospitalized Medical Patients

▪INTRODUCTION:Thromboprophylaxisduring hospitalization is an accepted intervention to prevent hospital related venous thromboembolism (VTE), however VTE still occurs post discharge. Recently, several randomized trials have compared extended prophylaxis with a direct oral anticoagulant (DOAC) for a prolonged period after hospital discharge to standard short-course prophylaxis with low molecular weight heparin (LMWH) in acutely-ill medical patients. While DOACs offer a convenient means to prevent post-hospitalization VTE, it remains unclear if this intervention has a positive risk-benefit ratio in the overall population of acutely hospitalized medical patients. To better answer this, we performed the following systematic review and meta-analysis.METHODS:We performed a systematic literature search in Medline using PUBMED in an attempt to identify all relevant randomized clinical trials comparing extended prophylaxis with any DOAC to standard course prophylaxis in hospitalized medical (non-surgical) patients. We extracted data on study design and characteristics, total VTE, symptomatic VTE, total bleeding, and major bleeding. Pooled relative risk (RR) was calculated with a corresponding 95% confidence interval (CI) using a Mantel-Haneszelrandom-effects model. Absolute risk differences and the number needed to treat (NNT) or number needed to harm (NNH) were generated along with Forest plots.RESULTS:Our search identified 338 individual publications, of which 313 were excluded on initial screening by title and abstract. Full text were obtained of the remaining 25 studies and independently reviewed by two physicians, of which 22 were excluded for the following reasons: Comments on other articles (12), Study Protocol (1), Review article (8), Data unavailable (1).A total of three trials, enrolling 22,142 patients, were included. Apixaban, rivaroxaban, andbetrixabanwere each evaluated by one study. Among the studies, 11,064 patients were randomized to extended DOAC prophylaxis, while 11,078 were randomized to standard course LMWH prophylaxis.In pooled analysis, VTE (including screened asymptomatic VTE) occurred in 4.30% of the patients receiving extended DOAC prophylaxis and 5.61% of patients treated with standard course LMWH (RR 0.76 [95% CI, 0.67-0.87], P = <0.0001, I2 = 0%). The NNT was 76. Symptomatic VTE occurred in 1.11% of patients treated with extended course DOACs and 1.68% patients treated with standard course LMWH. DOAC extended prophylaxis was associated with a significant reduction in symptomatic VTE (RR 0.66 [95% CI, 0.51-0.86], P = 0.002, I2 = 0%). The pooled absolute risk reduction was 0.57%, with a NNT of 176.A bleeding event occurred in 4.82% of patients receiving extended course DOACs compared to 3.16% of patients receiving standard course LMWH. The pooled analysis demonstrates a statistically relevant increase in bleeding (RR 1.74 [95% CI, 1.05-2.90], P < 0.001, I2 = 92%), with an absolute risk difference of 1.67% and a NNH of 60. A major bleeding event occurred in 0.59% of patients treated with extended course DOACs and 0.35% of patients treated with standard course LMWH. DOAC extended prophylaxis was associated with a significantly increased rate of major bleeding (RR 1.71 [95% CI, 1.07-2.75], P = 0.03, I2 = 23%). The pooled absolute risk difference is 0.24% with a NNH of 417.CONCLUSIONS:In this pooled analysis, extendedthromboprophylaxiswith DOACs was associated with a significant decrease in total and symptomatic VTEin medical patientsas compared to standard course LMWH. However, the low rate of symptomatic VTE, low absolute risk reduction, and significantly increased rate of bleeding with extended prophylaxis calls into questions if this intervention should be used. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy.

Venous thromboembolism (VTE) often complicates the clinical course of cancer. The risk is further increased by chemotherapy, but the trade-off between safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain. This is the second update of a review first published in February 2012. To assess the efficacy and safety of primary thromboprophylaxis for VTE in ambulatory cancer patients receiving chemotherapy compared with placebo or no thromboprophylaxis. For this update the Cochrane Vascular Information Specialist searched the Cochrane Vascular Group Specialised Register (June 2016). In addition, the Information Specialist searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 5). Clinical trials registries were searched up to June 2016. Randomised controlled trials comparing any oral or parenteral anticoagulant or mechanical intervention to no thromboprophylaxis or placebo, or comparing two different anticoagulants. We extracted data on methodological quality, participant characteristics, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively. We identified five additional randomised controlled trials (2491 participants) in the updated search, considering in this update 26 trials with a total of 12,352 participants, all evaluating pharmacological interventions and performed mainly in people with locally advanced or metastatic cancer. The quality of the evidence ranged from high to very low across the different outcomes and comparisons. The main limiting factors were imprecision and risk of bias. One large trial of 3212 participants found a 64% (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.22 to 0.60) reduction of symptomatic VTE with the ultra-low molecular weight heparin (uLMWH) semuloparin relative to placebo, with no apparent difference in major bleeding (RR 1.05, 95% CI 0.55 to 2.00). When compared with no thromboprophylaxis, LMWH significantly reduced the incidence of symptomatic VTE (RR 0.54, 95% CI 0.38 to 0.75; no heterogeneity, Tau2 = 0.00%) with a non-statistically significant 44% higher risk of major bleeding events (RR 1.44, 95% CI 0.98 to 2.11). In participants with multiple myeloma, LMWH was associated with a significant reduction in symptomatic VTE compared with the vitamin K antagonist warfarin (RR 0.33, 95% CI 0.14 to 0.83), while the difference between LMWH and aspirin was not statistically significant (RR 0.51, 95% CI 0.22 to 1.17). Major bleeding was observed in none of the participants treated with LMWH or warfarin and in less than 1% of those treated with aspirin. Only one study evaluated unfractionated heparin against no thromboprophylaxis but did not report on VTE or major bleeding. When compared with placebo, warfarin was associated with a non-statistically significant reduction of symptomatic VTE (RR 0.15, 95% CI 0.02 to 1.20). Antithrombin, evaluated in one study involving paediatric patients, had no significant effect on VTE or on major bleeding when compared with no antithrombin. The direct oral factor Xa inhibitor apixaban was evaluated in a phase II dose-finding study that suggested a low rate of major bleeding (2.1% versus 3.4%) and symptomatic VTE (1.1% versus 13.8%) in comparison with placebo. In this second update, we confirmed that primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy. In addition, the uLMWH semuloparin, which is not commercially available, significantly reduced the incidence of symptomatic VTE. The risk of major bleeding associated with LMWH, while not reaching statistical significance, suggest caution and mandate additional studies to determine the risk-to-benefit ratio of LMWH in this setting. Despite the encouraging results of this review, routine prophylaxis in ambulatory cancer patients cannot be recommended before safety issues are adequately addressed. We need additional studies investigating targeted primary prophylaxis in people with specific types or stages of cancer associated with a higher risk of VTE.

Effectiveness and safety of expanded perioperative thromboprophylaxis in complex gynecologic surgery

ObjectiveTo determine the effectiveness and safety of an expanded perioperative venous thromboembolism (VTE) prophylaxis strategy in women undergoing complex gynecologic surgery. MethodsWe performed a cohort study of 527 patients undergoing major surgery at a single institution over a thirty-month interval during which the gynecologic oncology service implemented an expanded approach to VTE prophylaxis. We compared rates of VTE pre- and post-intervention as well as bleeding and infectious complications. ResultsPrior to the intervention, there were 23 VTE events in 345 patients (rate of 6.67%): 8 deep vein thromboses (DVTs) and 15 pulmonary emboli (PEs). Post-intervention, there were 5 VTE events in 182 patients (2.7%): 3 DVTs and 2 PEs (RR=0.4, p=0.056). Time-to-event analysis showed a significantly higher incidence of VTE events in the pre-intervention time frame compared to the post-intervention period (p=0.049). There were no significant differences in bleeding or infection complications between groups. ConclusionsImplementation of a perioperative VTE prophylaxis protocol was safe, feasible and resulted in a clinically significant reduction in symptomatic VTE. Preoperative single-dose unfractionated heparin for all patients, combined with two weeks of thromboprophylaxis in gynecologic cancer patients, may decrease VTE events without increasing bleeding or infection.

Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy.

Venous thromboembolism (VTE) often complicates the clinical course of cancer. The risk is further increased by chemotherapy, but the safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain. This is an update of a review first published in February 2012. To assess the efficacy and safety of primary thromboprophylaxis for VTE in ambulatory cancer patients receiving chemotherapy compared with placebo or no thromboprophylaxis. For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched May 2013), CENTRAL (2013, Issue 5), and clinical trials registries (up to June 2013). Randomised controlled trials (RCTs) comparing any oral or parenteral anticoagulant or mechanical intervention to no intervention or placebo, or comparing two different anticoagulants. Data were extracted on methodological quality, patients, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively. We identified 12 additional RCTs (6323 patients) in the updated search so that this update considered 21 trials with a total of 9861 patients, all evaluating pharmacological interventions and performed mainly in patients with advanced cancer. Overall, the risk of bias varied from low to high. One large trial of 3212 patients found a 64% (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.22 to 0.60) reduction of symptomatic VTE with the ultra-low molecular weight heparin (uLMWH) semuloparin relative to placebo, with no apparent difference in major bleeding (RR 1.05, 95% CI 0.55 to 2.00). LMWH, when compared with inactive control, significantly reduced the incidence of symptomatic VTE (RR 0.53, 95% CI 0.38 to 0.75; no heterogeneity, Tau(2) = 0%) with similar rates of major bleeding events (RR 1.30, 95% CI 0.75 to 2.23). In patients with multiple myeloma, LMWH was associated with a significant reduction in symptomatic VTE when compared with the vitamin K antagonist warfarin (RR 0.33, 95% CI 0.14 to 0.83), while the difference between LMWH and aspirin was not statistically significant (RR 0.51, 95% CI 0.22 to 1.17). No major bleeding was observed in the patients treated with LMWH or warfarin and in less than 1% of those treated with aspirin. Only one study evaluated unfractionated heparin against inactive control and found an incidence of major bleeding of 1% in both study groups while not reporting on VTE. When compared with placebo, warfarin was associated with a statistically insignificant reduction of symptomatic VTE (RR 0.15, 95% CI 0.02 to 1.20). Antithrombin, evaluated in one study involving paediatric patients, had no significant effect on VTE nor major bleeding when compared with inactive control. The new oral factor Xa inhibitor apixaban was evaluated in a phase-II dose finding study that suggested a promising low rate of major bleeding (2.1% versus 3.3%) and symptomatic VTE (1.1% versus 10%) in comparison with placebo. In this update, we confirmed that primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy. In addition, the uLMWH semuloparin significantly reduced the incidence of symptomatic VTE. However, the broad confidence intervals around the estimates for major bleeding suggest caution in the use of anticoagulation and mandate additional studies to determine the risk to benefit ratio of anticoagulants in this setting. Despite the encouraging results of this review, routine prophylaxis in ambulatory cancer patients cannot be recommended before safety issues are adequately addressed.

Treatment for superficial thrombophlebitis of the leg.

The optimal treatment of superficial thrombophlebitis (ST) of the legs remains poorly defined. While improving or relieving the local painful symptoms, treatment should aim at preventing venous thromboembolism (VTE), which might complicate the natural history of ST. This is the second update of a review first published in 2007. To assess the efficacy and safety of topical, medical, and surgical treatments in patients presenting with ST of the legs. For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched November 2012) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 11). We handsearched the reference lists of relevant papers and conference proceedings. Randomised controlled trials (RCTs) evaluating topical, medical, and surgical treatments for ST of the legs that included participants with a clinical diagnosis of ST of the legs or an objective diagnosis of a thrombus in a superficial vein. Two authors assessed the trials for inclusion in the review, extracted the data, and assessed the quality of the studies. Data were independently extracted from the included studies and any disagreements resolved by consensus. We identified four additional trials (986 patients), so this update considered 30 studies involving 6507 participants with ST of the legs.Treatment ranged from fondaparinux, low molecular weight heparin (LMWH), unfractionated heparin (UFH), non-steroidal anti-inflammatory agents (NSAIDs), topical treatment, oral treatment, intramuscular treatment, and intravenous treatment to surgery. Only a minority of trials compared treatment with placebo rather than an alternative treatment, none evaluated the same treatment comparisons on the same study outcomes (which precluded meta-analysis), and many of the studies were small and of poor quality. In one large, placebo-controlled RCT of about 3000 patients, subcutaneous fondaparinux was associated with a significant reduction in symptomatic VTE (RR 0.15; 95% CI 0.04 to 0.50), ST extension (RR 0.08; 95% CI 0.03 to 0.22), and ST recurrence (RR 0.21; 95% CI 0.08 to 0.54) with comparable rates of major bleeding (RR 0.99; 95% CI 0.06 to 15.86) relative to placebo. In a further placebo-controlled trial, both prophylactic and therapeutic doses of LMWH (RR 0.40; 95% CI 0.22 to 0.72 and RR 0.42; 95% CI 0.23 to 0.75, respectively) and NSAIDs (RR 0.41; 95% CI 0.23 to 0.75) reduced the extension and recurrence of ST in comparison to placebo, with no significant effects on symptomatic VTE nor major bleeding. Overall, topical treatments improved local symptoms compared with placebo but no data were provided on the effects on VTE and ST extension. Surgical treatment combined with elastic stockings was associated with a lower VTE rate and ST progression compared with elastic stockings alone. However, the majority of studies that compared different oral treatment, topical treatment, or surgery did not report VTE, ST progression, adverse events, or treatment side effects. Prophylactic dose fondaparinux given for six weeks appears to be a valid therapeutic option for ST of the legs. The evidence on oral treatments, topical treatment, or surgery is too limited and does not inform clinical practice about the effects of these treatments in terms of VTE and ST progression. Further research is needed to assess the role of the new oral direct thrombin and activated factor-X inhibitors, LMWH, and NSAIDs; the optimal doses and duration of treatment; and whether a combination therapy may be more effective than single treatment. Adequately designed and conducted studies are required to clarify the role of topical and surgical treatments.

Venous thromboembolism prophylaxis: do trial results enable clinicians and patients to evaluate whether the benefits justify the risk? proceedings of an ad hoc working group meeting

Venous thromboembolism prophylaxis: do trial results enable clinicians and patients to evaluate whether the benefits justify the risk? proceedings of an ad hoc working group meeting

Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty

Four phase III studies compared oral rivaroxaban with subcutaneous enoxaparin for the prevention of venous thromboembolism (VTE) after total hip or knee arthroplasty (THA or TKA). A pooled analysis of these studies compared the effect of rivaroxaban with enoxaparin on symptomatic VTE plus all-cause mortality and bleeding events, and determined whether these effects were consistent in patient subgroups. Patients (N=12,729) aged ≥18 years and scheduled for elective THA or TKA received rivaroxaban 10 mg once daily or enoxaparin 40 mg once daily or 30 mg every 12 hours. The composite of symptomatic VTE and all-cause mortality, the prespecified primary efficacy endpoint and adjudicated bleeding events were analysed in the day 12± 2 active treatment pool. Subgroup analyses of these outcomes were performed over the total treatment period. In the day 12± 2 pool, the primary efficacy endpoint occurred in 29/6,183 patients receiving rivaroxaban (0.5%) versus 60/6,200 patients receiving enoxaparin (1.0%; p=0.001). Major bleeding occurred in 21 (0.3%) versus 13(0.2%) patients, p=0.23; major plus non-major clinically relevant bleeding in 176(2.8%) versus 152 (2.5%) patients, p=0.19; and any bleeding in 409 (6.6%) versus 384 (6.2%) patients, p=0.38, respectively. The reduction of symptomatic VTE plus all-cause mortality was consistent across prespecified subgroups (age, gender, body weight, creatinine clearance) in the total treatment period. Compared with enoxaparin regimens, rivaroxaban reduces the composite of symptomatic VTE and all-cause mortality after elective THA or TKA, with a small increase in bleeding, no signs of compromised liver safety and fewer serious adverse events.

Rivaroxaban for Prevention of Venous Thromboembolism after Total Knee Replacement: Impact on Healthcare Costs Based on the RECORD4 Study.

Introduction: Rivaroxaban is a novel, oral, direct Factor Xa inhibitor in development for the prevention of venous thromboembolism (VTE) after major orthopaedic surgery. Two large, phase III, randomized controlled trials compared rivaroxaban with subcutaneous (sc) enoxaparin following total knee replacement (TKR). In the recently published RECORD3 trial, rivaroxaban, 10 mg once daily (od), showed superior efficacy to an enoxaparin regimen of 40 mg od. However, enoxaparin 30 mg twice daily (bid) is the more widely used regimen in North America for VTE prophylaxis following TKR. The RECORD4 trial compared rivaroxaban 10 mg od versus enoxaparin 30 mg bid (both for 12 ± 2 days), for prevention of VTE following TKA. In the modified intent to treat population, the primary outcome (deep vein thrombosis [DVT], pulmonary embolism [PE], and all-cause mortality) occurred in 6.9% of rivaroxaban patients and 10.1% of enoxaparin patients (RRR 32%; p<0.012). Symptomatic VTE was observed in 0.7% of rivaroxaban patients and 1.2% of enoxaparin patients, although this difference was not statistically significant. There was no difference in major bleeding between rivaroxaban and enoxaparin. This analysis was designed to show the impact of the efficacy improvement with rivaroxaban and of oral vs. subcutaneous administration on US healthcare costs from a payer's perspective.Methods: The impact of rivaroxaban was assessed using the efficacy data from RECORD4, and the reduced administration cost associated with oral therapy. The treatment cost of symptomatic VTE and major bleeding were taken from published managed care data in the US. For costing purposes, the duration of hospitalization for TKR (4 days) was obtained from a published US orthopaedic registry. It was assumed that asymptomatic events had no impact on healthcare costs, and conservatively assumed that nurses spend three minutes per day administering enoxaparin and training patients to self-inject for outpatient use while patients are in the hospital. This is likely to be an underestimate in light of other studies and clinical experience of VTE post TKR in the US clinical practice, so a sensitivity analysis included incremental costs associated with home nurse visits to administer sc injections. The duration of prophylaxis was assumed to be for 14 days. As rivaroxaban is not yet approved and available in the US, the analysis assumed similar drug acquisition costs to enoxaparin 40 mg, which is less expensive than enoxaparin 30mg bid.Results: The total cost associated with healthcare resource use in the US for the duration of treatment was $469 per patient with enoxaparin 30 mg bid injection and $307 with oral rivaroxaban 10 mg od. This implies a saving of $162 per patient. This improvement was driven primarily by the reduced drug acquisition relative to enoxaparin 30 mg bid, and monitoring costs. In addition, published data suggest home nurse visits during post-hospital prophylaxis period cost an average of $100 for enoxaparin; suggesting that potential savings with rivaroxaban could rise to $262 per patient. This analysis excludes any treatment benefits from a reduction in symptomatic events or the impact of post-thrombotic syndrome. However, pooled data from all phase III rivaroxaban trials (RECORD1, 2, 3, 4) vs. enoxaparin showed a significant reduction in symptomatic VTE and death until day 12±2 (P<0.001). Estimated US costs for the treatment for symptomatic VTE range from $9,805 to $14,146 per event. Given the reduced incidence of symptomatic events with rivaroxaban, there may be even further savings in healthcare costs associated with rivaroxaban.Conclusions: The improved efficacy of rivaroxaban over enoxaparin 30 mg BID for VTE prevention after TKR and reduced administration and acquisition costs are expected to result in savings to healthcare resources. With more than 300,000 US patients having TKR annually, these potential cost savings are significant.

Evidence for extended prophylaxis in the setting of orthopedic surgery.

Patients undergoing orthopedic surgery represent one of the highest risk groups for the development of venous thromboembolism (VTE). Evidence shows that this risk extends beyond the period in which the patient is hospitalized, especially for patients undergoing hip surgery. Clinical trials have shown that extended prophylaxis with the low-molecular-weight heparins is effective in reducing the rate of total VTE, and a meta-analysis demonstrated a reduction in symptomatic VTE with extended prophylaxis after total hip replacement surgery. Based on these results, the American College of Chest Physicians gives a grade 2A recommendation for the use of extended prophylaxis after orthopedic surgery. Until recently, data evaluating the role of prophylaxis in patients undergoing hip fracture surgery were limited. Subsequently, a novel anticoagulant, fondaparinux, demonstrated significant benefit in these patients and has become the first and only agent approved by the United States Food and Drug Administration (FDA) for use in patients undergoing hip fracture surgery Despite the limitations of the older trials, their findings supported the need to evaluate extended prophylaxis in patients undergoing hip fracture surgery. In the first well-conducted trial of extended prophylaxis for hip fracture surgery, fondaparinux provided impressive results in reducing total and symptomatic VTE. The results of this trial have once again led to fondaparinux being the first and only agent to be granted FDA approval for the indication of extended prophylaxis in patients undergoing hip fracture surgery.

Reduction of out-of-hospital symptomatic venous thromboembolism by extended thromboprophylaxis with low-molecular-weight heparin following elective hip arthroplasty: a systematic review.

Numerous trials and meta-analyses have shown that extended out-of-hospital prophylaxis with low-molecular-weight heparin reduces asymptomatic and symptomatic venous thromboembolism after total hip arthroplasty. We hypothesized that knowledge of the results of screening tests may have resulted in overdiagnosis of symptomatic venous thromboembolism in many of these studies. The purpose of this analysis was to obtain an accurate estimate of the absolute risk reduction (ARR) of symptomatic venous thromboembolism after discharge from hospital in controlled studies that avoided this potential bias for overdiagnosis. Articles were identified using MEDLINE, EMBASE, and the Cochrane Library databases (January 1980-April 2002). Studies were eligible if the assessment of symptomatic venous thromboembolism was standardized and performed independently of mandatory objective testing. Two studies (907 patients) were eligible for assessment of symptomatic venous thromboembolism, 5 studies (1917 patients) for symptomatic pulmonary embolism, and 7 studies (2425 patients) for fatal pulmonary embolism. In controls vs extended treatment groups, after hospital discharge, the frequency of symptomatic venous thromboembolism was 2.7% vs 1.1% (ARR, 1.56%; 95% confidence interval [CI], -0.21% to 3.3%; number needed to treat, 64); symptomatic pulmonary embolism was 0.36% vs 0% (ARR, 0.36%; 95% CI, -0.3% to 1.36%; number needed to treat, 278); and fatal pulmonary embolism was 0.09% vs 0% (ARR, 0.09%; 95% CI, -0.08% to 0.27%; number needed to treat, 1093). The absolute reduction in symptomatic venous thromboembolism attributed to extended prophylaxis in some studies and meta-analyses seems to have been overestimated.

Low molecular weight heparin versus aspirin for acute ischemic stroke: A systematic review

Aspirin is the standard treatment for acute ischemic stroke, although heparins are widely prescribed. We performed a systematic review of randomized controlled trials to compare the safety and efficacy of low molecular weight heparins (LMWH) with aspirin in acute ischemic stroke. Two completed randomized controlled trials involving 1,933 patients were identified; 1 trial only included patients with presumed cardioembolic stroke. As compared with aspirin, treatment with heparin was associated with a significant reduction in symptomatic venous thromboembolism (odds ratio [OR] - 0.29, 95% confidence interval [CI] - 0.12-0.66) and an increase in major extracranial hemorrhage (OR - 2.57, 95% CI - 1.01-6.52). Nonsignificant increases in end-of-treatment case fatality (OR - 1.35, 95% CI - 0.87-2.08) and symptomatic intracranial haemorrhage (OR - 1.82, 95% CI - 0.68-4.87) were seen; symptomatic intracranial haemorrhage was significantly raised (OR - 4.26, 95% CI - 1.04-17.4) with heparin in patients treated within 24 hours of stroke onset. Stroke recurrence (OR - 1.24, 95% CI - 0.79-1.94) and deterioration (OR - 1.13, 95% CI - 0.85-1.50) during treatment and end-of-trial death (OR - 1.00, 95% CI - 0.77-1.30) or dependency and case fatality (OR - 1.03, 95% CI - 0.85-1.25) did not differ between the 2 treatments. No benefit of LMWH over aspirin was seen in patients with presumed cardioembolic stroke. Low molecular weight heparin should not replace aspirin in the routine management of patients with ischemic stroke, including those with presumed cardioembolic stroke. Copyright © 2002 by National Stroke Association