Effect of extended-duration thromboprophylaxis on venous thromboembolism and major bleeding among acutely ill hospitalized medical patients: a bivariate analysis.

Essentials Anticoagulants prevent venous thromboembolism but may be associated with greater bleeding risks. Bivariate analysis assumes a non-linear relationship between efficacy and safety outcomes. Extended full-dose betrixaban is favorable over standard enoxaparin in bivariate endpoint. Clinicians must weigh efficacy and safety outcomes in decision-making on thromboprophylaxis. SUMMARY: Background Among acutely ill hospitalized medical patients, extended-duration thromboprophylaxis reduces the risk of venous thromboembolism (VTE), but some pharmacologic strategies have been associated with greater risks of major bleeding, thereby offsetting the net clinical benefit (NCB). Methods To assess the risk-benefit profile of anticoagulation regimens, a previously described bivariate method that does not assume a linear risk-benefit tradeoff and can accommodate different margins for efficacy and safety was performed to simultaneously assess efficacy (symptomatic VTE) and safety (major bleeding) on the basis of data from four randomized controlled trials of extended-duration (30-46 days) versus standard-duration (6-14 days) thromboprophylaxis among 28 227 patients (EXCLAIM, ADOPT, MAGELLAN and APEX trials). Results Extended thromboprophylaxis with full-dose betrixaban (80 mg once daily) was superior in efficacy and non-inferior in safety to standard-duration enoxaparin, and showed a significantly favorable NCB, with a risk difference of - 0.51% (- 0.89% to - 0.10%) in the bivariate outcome. Extended enoxaparin was superior in efficacy and inferior in safety (bivariate outcome: 0.03% [- 0.37% to 0.43%]), whereas apixaban and rivaroxaban were non-inferior in efficacy and inferior in safety (- 0.20% [- 0.49% to 0.17%] and 0.23% [- 0.16% to 0.69%], respectively). Reduced-dose betrixaban did not show a significant difference in either efficacy or safety (0.41% [- 0.85% to 1.94%]). Conclusions In a bivariate analysis that assumes non-linear risk-benefit tradeoffs, extended prophylaxis with full-dose betrixaban was superior to standard-duration enoxaparin, whereas other regimens failed to simultaneously achieve both superiority and non-inferiority with respect to symptomatic VTE and major bleeding in the management of acutely ill hospitalized medical patients.

Multicenter randomized controlled trial on Duration of Therapy for Thrombosis in Children and Young Adults (the Kids-DOTT trial): pilot/feasibility phase findings.

BACKGROUND: Randomized controlled trials (RCTs) on pediatric venous thromboembolism (VTE) treatment have been challenged by unsubstantiated design assumptions and/or poor accrual. Pilot/feasibility (P/F) studies are critical to future RCT success. METHODS: The Kids-DOTT trial is a multicenter RCT investigating non-inferiority of a 6-week (shortened) versus 3-month (conventional) duration of anticoagulation in patients aged < 21 years with provoked venous thrombosis. Primary efficacy and safety endpoints are symptomatic recurrent VTE at 1 year and anticoagulant-related, clinically relevant bleeding. In the P/F phase, 100 participants were enrolled in an open, blinded-endpoint, parallel-cohort RCT design. RESULTS: No eligibility violations or randomization errors occurred. Of the enrolled patients, 69% were randomized, 3% missed the randomization window, and 28% were followed in prespecified observational cohorts for completely occlusive thrombosis or persistent antiphospholipid antibodies. Retention at 1 year was 82%. Interobserver agreement between local and blinded central determination of venous occlusion by imaging at 6 weeks after diagnosis was strong (k-statistic = 0.75; 95% confidence interval [CI] 0.48-1.0). The primary efficacy and safety event rates were 3.3% (95% CI 0.3-11.5%) and 1.4% (95% CI 0.03-7.4%). CONCLUSIONS: The P/F phase of the Kids-DOTT trial has demonstrated the validity of vascular imaging findings of occlusion as a randomization criterion, and defined randomization, retention and endpoint rates to inform the fully powered RCT.

Balancing risk and benefit in venous thromboembolism trials: concept for a bivariate endpoint trial design and analytic approach.

Antithrombotic trials in venous thromboembolism treatment and prevention, including those evaluating the new oral anticoagulants, have typically evaluated thromboembolism risk as an efficacy endpoint and bleeding risk as a separate safety endpoint. Findings often occur in opposition (i.e. decreased thromboembolism accompanied by increased bleeding, or vice-versa), leading to variable interpretation of the results, which may ultimately be judged as equivocal. In this paper, we offer an alternative to traditional designs based on the concept of a bivariate primary endpoint that accounts for simultaneous effects on antithrombotic efficacy and harm due to bleeding. We suggest a bivariate endpoint as a general approach to the assessment of 'net clinical benefit' in recently published trials and to the design of future trials. Lastly, we illustrate the bivariate endpoint design using two examples: a recently published superiority trial of rivaroxaban (RECORD1) and an ongoing non-inferiority trial of the duration of anticoagulant therapy in children with venous thrombosis (Kids-DOTT).

Extended venous thromboembolism prophylaxis in patients undergoing hip fracture surgery - the SAVE-HIP3 study.

There is currently limited information available on the benefits and risks of extended thromboprophylaxis after hip fracture surgery. SAVE-HIP3 was a randomised, double-blind study conducted to evaluate the efficacy and safety of extended thromboprophylaxis with the ultra-low molecular-weight heparin semuloparin compared with placebo in patients undergoing hip fracture surgery. After a seven- to ten-day open-label run-in phase with semuloparin (20 mg once daily subcutaneously, initiated post-operatively), patients were randomised to once-daily semuloparin (20 mg subcutaneously) or placebo for 19 to 23 additional days. The primary efficacy endpoint was a composite of any venous thromboembolism (VTE; any deep-vein thrombosis and non-fatal pulmonary embolism) or all-cause death until day 24 of the double-blind period. Safety parameters included major and clinically relevant non-major bleeding, laboratory data, and treatment-emergent adverse events (TEAEs). Extended thromboprophylaxis with semuloparin demonstrated a relative risk reduction of 79% in the rate of any VTE or all-cause death compared with placebo (3.9% vs 18.6%, respectively; odds ratio 0.18 (95% confidence interval 0.07 to 0.45), p < 0.001). Two patients in the semuloparin group and none in the placebo group experienced clinically relevant bleeding. TEAE rates were similar in both groups. In conclusion, the SAVE-HIP3 study results demonstrate that patients undergoing hip fracture surgery benefit from extended thromboprophylaxis.

The effects of rivaroxaban on the complications of surgery after total hip or knee replacement: results from the RECORD programme.

Post-operative complications after total hip or knee replacement can delay recovery, prolong hospitalisation, increase rates of re-admission and, in the most severe cases, lead to long-term disability or even death. In this analysis of pooled data from four large, randomised, phase III clinical trials that compared the oral, direct Factor Xa inhibitor rivaroxaban with subcutaneous enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement (n = 12,729), the incidence of complications, including bleeding and adverse events related to surgery (such as wound infection, wound dehiscence and haemarthrosis) are reported. Interventions and procedures relating to surgery are also compared between the groups. Bleeding events, including excessive wound haematoma and surgical-site bleeding, occurred at similar rates in the rivaroxaban and enoxaparin groups. Over the total study duration, adverse surgical events occurred at a similar rate in the rivaroxaban group compared with the enoxaparin group after total knee replacement (2.26% vs. 2.69%, respectively) and total hip replacement (1.48% vs. 1.65%, respectively). Blood loss, wound drainage and transfusion requirements were also similar between the two groups. This analysis shows that the incidence of adverse surgical events with rivaroxaban was similar to enoxaparin.

Semuloparin for prevention of venous thromboembolism after major orthopedic surgery: results from three randomized clinical trials, SAVE-HIP1, SAVE-HIP2 and SAVE-KNEE.

BACKGROUND: Semuloparin is a novel ultra-low-molecular-weight heparin under development for venous thromboembolism (VTE) prevention in patients at increased risk, such as surgical and cancer patients. OBJECTIVES: Three Phase III studies compared semuloparin and enoxaparin after major orthopedic surgery: elective knee replacement (SAVE-KNEE), elective hip replacement (SAVE-HIP1) and hip fracture surgery (SAVE-HIP2). PATIENTS/METHODS: All studies were multinational, randomized and double-blind. Semuloparin and enoxaparin were administered for 7-10 days after surgery. Mandatory bilateral venography was to be performed between days 7 and 11. The primary efficacy endpoint was a composite of any deep vein thrombosis, non-fatal pulmonary embolism or all-cause death. Safety outcomes included major bleeding, clinically relevant non-major (CRNM) bleeding, and any clinically relevant bleeding (major bleeding plus CRNM). RESULTS: In total, 1150, 2326 and 1003 patients were randomized in SAVE-KNEE, SAVE-HIP1 and SAVE-HIP2, respectively. In all studies, the incidences of the primary efficacy endpoint were numerically lower in the semuloparin group vs. the enoxaparin group, but the difference was statistically significant only in SAVE-HIP1. In SAVE-HIP1, clinically relevant bleeding and major bleeding were significantly lower in the semuloparin vs. the enoxaparin group. In SAVE-KNEE and SAVE-HIP2, clinically relevant bleeding tended to be higher in the semuloparin group, but rates of major bleeding were similar in the two groups. Other safety parameters were generally similar between treatment groups. CONCLUSIONS: Semuloparin was superior to enoxaparin for VTE prevention after hip replacement surgery, but failed to demonstrate superiority after knee replacement surgery and hip fracture surgery. Semuloparin and enoxaparin exhibited generally similar safety profiles.

Thromboxane Antagonism with terutroban in Peripheral Arterial Disease: the TAIPAD study.

BACKGROUND: Terutroban is a selective prostaglandin endoperoxide (TP) receptor antagonist with antithrombotic, antivasoconstrictive and antiatherosclerotic properties and is currently in development for long-term cardiovascular secondary prevention. OBJECTIVES: TAIPAD is an international, double-blind, randomized controlled study comparing the effects of five dosages of oral terutroban vs. aspirin and placebo on platelet aggregation in peripheral arterial disease (PAD) patients. PATIENTS/METHODS: After 10 day's placebo run-in, included patients (n = 435; ankle-brachial pressure index, 0.7 ± 0.1) were randomly allocated to aspirin 75 mg day(-1), terutroban 1, 2.5, 5, 10 or 30 mg day(-1) or placebo. On day 5, the placebo group was reallocated to one of the terutroban groups for the rest of the study (day 83). Ex vivo platelet aggregation induced by the thromboxane analog U46619 (7 µm) was measured 24 h after dosing, as well as platelet aggregation induced by arachidonic acid (AA), collagen and ADP. RESULTS: Terutroban dose-dependently inhibited U46619-induced platelet aggregation at days 5 and 83. At day 5, the inhibition was significant vs. placebo for all terutroban dosages (P < 0.001). Terutroban (5, 10 and 30 mg day(-1)) was at least as effective as aspirin in inhibiting platelet aggregation induced by arachidonic acid (AA), collagen and adenosine diphosphate (ADP). Terutroban was well tolerated, with a safety profile similar to aspirin. CONCLUSIONS: In PAD patients, terutroban dose-dependently inhibited platelet aggregation 24 h after dosing, and was at least as effective as aspirin at 5, 10 and 30 mg day(-1). Terutroban was well tolerated.

Prevention of venous thromboembolism with an oral factor Xa inhibitor, YM150, after total hip arthroplasty. A dose finding study (ONYX-2).

BACKGROUND: Anticoagulant prophylaxis substantially reduces the risk of venous thromboembolism (VTE) after major orthopedic surgery. The direct factor Xa inhibitor YM150 is currently under investigation for the prevention of VTE, stroke and ischemic vascular events in patients after orthopedic surgery, with atrial fibrillation and with acute coronary syndrome, respectively. OBJECTIVES: To investigate the efficacy and safety of YM150 for the prevention of VTE following elective total hip arthroplasty. PATIENTS/METHODS: Patients were randomized to postoperative, once-daily, oral YM150 (5, 10, 30, 60 or 120 mg) (double-blind) or preoperative subcutaneous (open label) enoxaparin (40 mg) for 5 weeks. The primary efficacy endpoint comprised VTE diagnosed by mandatory bilateral venography or verified symptomatic deep vein thrombosis (DVT) plus all deaths up to 9 days after surgery. The primary safety outcome was major bleeding up to 9 days after surgery. RESULTS: Primary efficacy endpoint: of 1017 patients randomized, 960 patients were evaluable for safety and 729 patients for efficacy. A dose-related decrease in VTE incidence from YM150 5 to 60 mg (P = 0.0005) and from 5 to 120 mg (P = 0.0002) was found. The VTE incidence was 27.4%, 31.7%, 19.3%, 13.3% and 14.5% for 5, 10, 30, 60 and 120 mg YM150, respectively, and 18.9% for enoxaparin. Primary safety endpoint: there was one major bleed with YM150 (60 mg) and one with enoxaparin. CONCLUSIONS: The oral direct FXa inhibitor YM150 demonstrated a significant dose response regarding efficacy. Doses from 30 to 120 mg had comparable efficacy to enoxaparin, without compromising safety regarding major bleeding events.

Oral rivaroxaban for the prevention of symptomatic venous thromboembolism after elective hip and knee replacement.

A once-daily dose of rivaroxaban 10 mg, an oral, direct Factor Xa inhibitor, was compared with enoxaparin 40 mg subcutaneously once daily for prevention of venous thromboembolism in three studies of patients undergoing elective hip and knee replacement (RECORD programme). A pooled analysis of data from these studies (n = 9581) showed that rivaroxaban was more effective than enoxaparin in reducing the incidence of the composite of symptomatic venous thromboembolism and all-cause mortality at two weeks (0.4% vs 0.8%, respectively, odds ratio 0.44; 95% confidence interval 0.23 to 0.79; p = 0.005), and at the end of the planned medication period (0.5% vs 1.3%, respectively; odds ratio 0.38; 95% confidence interval 0.22 to 0.62; p < 0.001). The rate of major bleeding was similar at two weeks (0.2% for both) and at the end of the planned medication period (0.3% vs 0.2%). Rivaroxaban started six to eight hours after surgery was more effective than enoxaparin started the previous evening in preventing symptomatic venous thromboembolism and all-cause mortality, without increasing major bleeding.

AVE5026, a new hemisynthetic ultra-low-molecular-weight heparin for the prevention of venous thromboembolism in patients after total knee replacement surgery--TREK: a dose-ranging study.

BACKGROUND: AVE5026 is a new hemisynthetic ultra-low-molecular-weight heparin, with a novel anti-thrombotic profile resulting from high anti-factor (F)Xa activity and residual anti-FIIa activity. AVE5026 is in clinical development for venous thromboembolism (VTE) prevention, a frequent complication after total knee replacement (TKR) surgery. OBJECTIVES: This study evaluated the dose-response of AVE5026 for the prevention of VTE in patients undergoing TKR surgery. PATIENTS/METHODS: In this parallel-group, double-blind, double-dummy study, 690 patients were randomized, and 678 treated with once-daily doses of AVE5026 (5, 10, 20, 40, or 60 mg) or enoxaparin 40 mg in the calibrator arm. The primary efficacy end point was VTE until post-operative day 11, defined as deep vein thrombosis (DVT) detected by bilateral venography, symptomatic DVT, non-fatal pulmonary embolism (PE) and VTE-related death. The primary safety outcome was the incidence of major bleeding. RESULTS: The primary efficacy outcome was assessed in 464 patients. There was a significant dose-response across the five AVE5026 groups for VTE prevention (P<0.0001), with the incidence of VTE ranging from 5.3% to 44.1% compared with 35.8% in the enoxaparin group and for proximal DVT (P=0.0002). Also, a significant dose-response for AVE5026 was seen for major bleeding (P=0.0231) and any bleeding (P=0.0003). Six patients in the AVE5026 groups, four in the 60 mg group, experienced major bleeding; none did in the enoxaparin group. CONCLUSIONS: The safety and efficacy results of this study suggest that a AVE5026 dose of between 20 and 40 mg presents an adequate benefit-to-risk ratio.

Partial factor IXa inhibition with TTP889 for prevention of venous thromboembolism: an exploratory study.

BACKGROUND: Inhibitors of factor (F) IXa show potent antithrombotic activity with a low risk of bleeding in preclinical models. We investigated the anticoagulant potential of oral TTP889, a small molecule that inhibits up to 90% of FIXa activity at therapeutic doses, using a clinical model of extended prophylaxis in hip fracture surgery (HFS). METHODS: In this multicenter, randomized, double-blind study, 261 patients received oral TTP889 (300 mg once daily) or placebo starting 6-10 days after HFS, and standard thromboprophylaxis for 5-9 days. Treatment was continued for 3 weeks and all patients then underwent mandatory bilateral venography. The primary efficacy outcome was venous thromboembolism (VTE; venographic or symptomatic deep vein thrombosis or pulmonary embolism) during treatment, and it was evaluated centrally by an independent adjudication panel. The main safety outcome was bleeding (major, clinically relevant non-major, and minor events). RESULTS: Two hundred and twelve patients with an evaluable venogram were included in the efficacy analysis. The primary efficacy outcome occurred in 32.1% (35/109) of patients who had been allocated TTP889, and 28.2% (29/103) of patients on placebo (P = 0.58). There were no major bleeding events, and only two clinically relevant non-major bleeding events with TTP889. CONCLUSION: Partial FIXa inhibition with TTP889 300 mg daily was not effective for extended prevention of VTE after standard prophylaxis for up to 9 days. Coupled with the low incidence of bleeding episodes, this suggests a lack of antithrombotic potential. Further investigation of TTP889 in different clinical settings is needed. (Clinical trial registration information URL: http://www.clinicaltrials.gov. Unique identifier: NCT00119457).

Fondaparinux combined with intermittent pneumatic compression vs. intermittent pneumatic compression alone for prevention of venous thromboembolism after abdominal surgery: a randomized, double-blind comparison.

BACKGROUND: The benefit of combined mechanical and pharmacologic methods for venous thromboembolism prevention after abdominal surgery has not been clearly established. OBJECTIVES: To compare the efficacy and safety of fondaparinux in conjunction with intermittent pneumatic compression vs. intermittent pneumatic compression alone in this context. PATIENTS AND METHODS: This was a randomized, double-blind, placebo-controlled superiority trial. Patients aged at least 40 years undergoing abdominal surgery were randomized to receive either fondaparinux 2.5 mg or placebo s.c. for 5-9 days, starting 6-8 h postoperatively. All patients received intermittent pneumatic compression. The primary efficacy outcome was venous thromboembolism up to day 10. The main safety outcomes were major bleeding and all-cause mortality. Follow-up lasted 32 days. RESULTS: Of the 1309 patients randomized, 842 (64.3%) were evaluable for efficacy. The venous thromboembolism rate was 1.7% (7/424) in the fondaparinux-treated patients and 5.3% (22/418) in the placebo-treated patients (odds ratio reduction 69.8%; 95% confidence interval 27.9-87.3; P = 0.004). Fondaparinux significantly reduced the proximal deep vein thrombosis rate from 1.7% (7/417) to 0.2% (1/424; P = 0.037). Major bleeds occurred in 1.6% (10/635) and 0.2% (1/650) of fondaparinux-treated and placebo-treated patients, respectively (P = 0.006), none being fatal or involving a critical organ. By day 32, eight patients (1.3%) receiving fondaparinux and five (0.8%) receiving placebo had died. CONCLUSIONS: In patients undergoing abdominal surgery and receiving intermittent pneumatic compression, fondaparinux 2.5 mg reduced the venous thromboembolism rate by 69.8% as compared to pneumatic compression alone, with a low bleeding risk as compared to placebo.

Bridging therapy in patients on long-term oral anticoagulants who require surgery: the Prospective Peri-operative Enoxaparin Cohort Trial (PROSPECT).

BACKGROUND: The peri-operative management of patients on oral anticoagulants (OACs) is a common clinical problem. Our aim was to determine the incidence of major bleeding during peri-operative administration of treatment-dose enoxaparin and the impact of the extensiveness of the procedure on the risk of bleeding. METHODS: We performed a prospective cohort study of 260 patients at 24 North American sites on OACs for atrial fibrillation or a history of deep vein thrombosis (DVT) requiring invasive or surgical procedures whose treating physician felt that bridging therapy was required. Warfarin was withheld, and once-daily s.c. enoxaparin (1.5 mg kg(-1)) was given peri-operatively. Patients were followed for 28 days after OAC was therapeutic. RESULTS: Major bleeding was observed in nine of 260 patients (3.5%, 95% CI: 1.6-6.5). The bleeding risk varied markedly by extensiveness of procedure: the incidence of major bleeding for invasive procedures, minor surgery and major surgery was 0.7% (95% CI: 0.02-3.7), 0% (95% CI: 0-5.0), and 20.0% (95% CI: 9.1-35.7), respectively. There were five thromboembolic events in total (1.9%, 95% CI: 0.6-4.4). There were four arterial events (2.3%, 95% CI: 0.6-5.7) in 176 patients with atrial fibrillation, and one venous event (1.0%, 95% ci: 0.03-5.7) in 96 patients with prior DVT/ CONCLUSIONS: Bridging therapy with once-daily therapeutic-dose enoxaparin administered primarily in an outpatient setting has a low incidence of major bleeding for patients undergoing invasive procedures and minor surgery. Further studies are needed to optimize the bridging strategy for patients undergoing major surgery.

A dose escalation study of YM150, an oral direct factor Xa inhibitor, in the prevention of venous thromboembolism in elective primary hip replacement surgery.

BACKGROUND: YM150, a new oral direct factor Xa inhibitor is used as prophylaxis for venous thromboembolism (VTE), a well-known risk after orthopaedic surgery. OBJECTIVES: To assess the safety and efficacy of thromboprophylaxis with YM150 in a dose escalation study. PATIENTS/METHODS: Patients (174) undergoing hip replacement surgery were randomized per cohort to oral once daily YM150 or subcutaneous enoxaparin (40 mg daily) in a 4:1 ratio for 7-10 days treatment. The YM150 doses were 3, 10, 30 and 60 mg by sequential four-dose escalation cohorts. The primary endpoint was major and/or clinically relevant non-major bleeding. The incidence of VTE was defined as a composite of verified symptomatic events and/or positive findings at bilateral venography on the last treatment day. An independent adjudication committee evaluated blindly the outcomes of the open-label study. RESULTS: No major and three clinically relevant non-major bleeds were reported, 1 (2.9%; 95% CI, 0.1-15.1) in the 3 mg and 2 (5.7%; 95% CI, 1.0-18.8) in the 10 mg YM150 dose groups. Of 147 patients (84%) with an evaluable venogram, VTE was observed in 51.9% (95% CI, 31.9-71.4), 38.7% (95% CI, 22.6-57.0), 22.6% (95% CI, 9.7-39.4), and 18.5% (95% CI, 7.5-36.5) in the YM150 dose groups 3, 10, 30 and 60 mg, respectively. A significant YM150 dose-related trend in VTE incidence was found (P=0.006). VTE with enoxaparin was 38.7% (95% CI, 22.6-57.0). CONCLUSIONS: YM150, 10-60 mg daily, starting 6-10 h after primary hip replacement, was shown to be safe, well tolerated and effective.

Ultrasound screening for asymptomatic deep vein thrombosis after major orthopaedic surgery: the VENUS study.

BACKGROUND: Venography is currently used to assess the incidence of deep vein thrombosis (DVT) in dose-finding and confirmatory trials of new antithrombotic agents. Centrally adjudicated, complete compression ultrasound (CCUS) could be a non-invasive alternative to venography. OBJECTIVES: A substudy of two, similarly designed, phase IIb trials of a novel, oral anticoagulant for the prevention of venous thromboembolism after elective hip or knee arthroplasty was undertaken to validate CCUS against venography. PATIENTS/METHODS: Patients received study drugs until mandatory, bilateral venography was performed 7 +/- 2 days after surgery. CCUS was performed within 24 h after venography by sonographers blinded to the venography result. Sonographers were trained and certified for the standardized examination and documentation procedure. Venograms and sonograms were adjudicated centrally at different sites by two independent readers; discrepancies between readers were resolved by consensus. RESULTS: A total of 1104 matching pairs of evaluable venograms and sonograms were obtained from the participants of the two trials (n = 1435): 19% of venograms and 20% of sonograms were not evaluable. The observed frequency of any DVT was 18.9% with venography and 11.5% with CCUS. Sensitivity of CCUS compared with venography was 31.1% for any DVT (95% confidence interval 23.4, 38.9), 21.0% (2.7, 39.4) for proximal DVT, and 30.8% (23.1, 38.6) for distal DVT. The figures for specificity were 93.0% (91.0, 95.1), 98.7% (98.0, 99.5), and 93.3% (91.5, 95.3), respectively. CONCLUSIONS: Based on these results, centrally adjudicated CCUS will be unable to replace venography for DVT screening early after major orthopaedic surgery in studies evaluating anticoagulant drugs.

Extended duration of thromboprophylaxis in acutely ill medical patients: optimizing therapy?

Summary. Patients who are hospitalized for an acute medical illness are at risk of venous thromboembolism (VTE). Current evidence-based guidelines recommend prophylaxis with unfractionated heparin or low-molecular-weight heparin in acutely ill medical patients who are admitted to hospital with congestive heart failure, severe respiratory disease, or who are bedridden with an additional VTE risk factor. The need for thromboprophylaxis is therefore clear in this patient population; however, the optimal duration of prophylaxis in these patients is less clear. In patients undergoing orthopedic or cancer surgery, extended-duration prophylaxis has been shown to be superior to placebo. To date, however, no large-scale clinical trials have assessed the benefits of extended-duration prophylaxis in acutely ill medical patients. This review therefore focuses on the VTE risk profile of acutely ill medical patients, examines the currently available literature for evidence of a potential benefit of extended-duration prophylaxis in these patients, and provides a rationale for the testing of such a hypothesis in a randomized clinical trial.

Clinical outcomes with unfractionated heparin or low-molecular-weight heparin as bridging therapy in patients on long-term oral anticoagulants: the REGIMEN registry.

BACKGROUND: Patients who receive long-term oral anticoagulant (OAC) therapy often require interruption of OAC for an elective surgical or an invasive procedure. Heparin bridging therapy has been used in these situations, although the optimal method has not been established. No large prospective studies have compared unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for the perioperative management of patients at risk of thromboembolism requiring temporary interruption of long-term OAC therapy. PATIENTS/METHODS: This multicenter, observational, prospective registry conducted in North America enrolled 901 eligible patients on long-term OAC who required heparin bridging therapy for an elective surgical or invasive procedure. Practice patterns and clinical outcomes were compared between patients who received either UFH alone (n = 180) or LMWH alone (n = 721). RESULTS: Overall, the majority of patients (74.5%) requiring heparin bridging therapy had arterial indications for OAC. LMWH, in mostly twice-daily treatment doses, represented approximately 80% of the study population. LMWH-bridged patients had significantly fewer arterial indications for OAC, a lower mean Charlson comorbidity score, and were less likely to undergo major or cardiothoracic surgery, receive intraprocedural anticoagulants or thrombolytics, or receive general anesthesia than UFH-bridged patients (all P < 0.05). The LMWH group had significantly more bridging therapy completed in an outpatient setting or with a < 24-h hospital stay vs. the UFH group (63.6% vs. 6.1%, P < 0.001). In the LMWH and UFH groups, similar rates of overall adverse events (16.2% vs. 17.1%, respectively, P = 0.81), major composite adverse events (arterial/venous thromboembolism, major bleed, and death; 4.2% vs. 7.9%, respectively, P = 0.07) and major bleeds (3.3% vs. 5.5%, respectively, P = 0.25) were observed. The thromboembolic event rates were 2.4% for UFH and 0.9% for LMWH. Logistic regression analysis revealed that for postoperative heparin use a Charlson comorbidity score > 1 was an independent predictor of a major bleed and that vascular, general, and major surgery were associated with non-significant trends towards an increased risk of major bleed. CONCLUSIONS: Treatment-dose LMWH, mostly in the outpatient setting, is used substantially more often than UFH as bridging therapy in patients with predominately arterial indications for OAC. Overall adverse events, including thromboembolism and bleeding, are similar for patients treated with LMWH or UFH. Postoperative heparin bridging should be used with caution in patients with multiple comorbidities and those undergoing vascular, general, and major surgery. These findings need to be confirmed using large randomized trials for specific patient groups undergoing specific procedures.

Significant variation in mortality and functional outcome after acute ischaemic stroke between Western countries: data from the tinzaparin in acute ischaemic stroke trial (TAIST).

BACKGROUND: The medical care of patients with acute stroke varies considerably between countries. This could lead to measurable differences in mortality and functional outcome. OBJECTIVE: To compare case mix, clinical management, and functional outcome in stroke between 11 countries. METHODS: All 1484 patients from 11 countries who were enrolled into the tinzaparin in acute ischaemic stroke trial (TAIST) were included in this substudy. Information collected prospectively on demographics, risk factors, clinical features, measures of service quality (for example, admission to a stroke unit), and outcome were assessed. Outcomes were adjusted for treatment assignment, case mix, and service relative to the British Isles. RESULTS: Differences in case mix (mostly minor) and clinical service (many of prognostic relevance) were present between the countries. Significant differences in outcome were present between the countries. When assessed by geographical region, death or dependency were lower in North America (odds ratio (OR) adjusted for treatment group only = 0.52 (95% confidence interval, 0.39 to 0.71) and north west Europe (OR = 0.54 (0.37 to 0.78)) relative to the British Isles; similar reductions were found when adjustments were made for 11 case mix variables and five service quality measures. Similarly, case fatality rates were lower in North America (OR = 0.44 (0.30 to 0.66)) and Scandinavia (OR = 0.50 (0.33 to 0.74)) relative to the British Isles, whether crude or adjusted for case mix and service quality. CONCLUSIONS: Both functional outcome and case fatality vary considerably between countries, even when adjusted for prognostic case mix variables and measures of good stroke care. Differing health care systems and the management of patients with acute stroke may contribute to these findings.

Deep-vein thrombosis rates after major orthopedic surgery in Asia. An epidemiological study based on postoperative screening with centrally adjudicated bilateral venography.

BACKGROUND: The incidence of postsurgical venous thromboembolism is thought to be low in Asian ethnic populations. OBJECTIVE: We studied the incidence of deep-vein thrombosis (DVT) in Asian patients undergoing major orthopedic surgery of the lower limbs. PATIENTS/METHODS: We performed a prospective epidemiological study in 19 centers across Asia (China, Indonesia, South Korea, Malaysia, Philippines, Taiwan, and Thailand) in patients undergoing elective total hip replacement (THR), total knee replacement (TKR) or hip fracture surgery (HFS) without pharmacological thromboprophylaxis. The primary endpoint was the rate of DVT of the lower limbs documented objectively with bilateral ascending venography performed 6-10 days after surgery using a standardized technique and evaluated by a central adjudication committee unaware of local interpretation. RESULTS: Overall, of 837 Asian patients screened for this survey, 407 (48.6%, aged 20-99 years) undergoing THR (n = 175), TKR (n = 136) or HFS (n = 96) were recruited in 19 centers. DVT was diagnosed in 121 of 295 evaluable patients [41.0%, (95% confidence interval (CI): 35.4-46.7)]. Proximal DVT was found in 30 patients [10.2% (7.0-14.2)]. Total DVT and proximal DVT rates were highest in TKR patients (58.1% and 17.1%, respectively), followed by HFS patients (42.0% and 7.2%, respectively), then THR patients (25.6% and 5.8%, respectively). DVT was more frequent in female patients aged at least 65 years. Pulmonary embolism was clinically suspected in 10 of 407 patients (2.5%) and objectively confirmed in two (0.5%). CONCLUSIONS: The rate of venographic thrombosis in the absence of thromboprophylaxis after major joint surgery in Asian patients is similar to that previously reported in patients in Western countries.