OBJECTIVE: In the Re-NOVATE II study, oral dabigatran provided thromboprophylaxis after total hip arthroplasty and improved compliance postdischarge in a global population. This article aims to identify trends (if any) in the Indian population.
METHODS: In this prospective, double-blind, double-dummy study, patients scheduled for primary, unilateral, elective total hip arthroplasty were randomized to 220 mg oral dabigatran once daily, starting with a 110 mg half-dose, 1-4 hours after surgery, or subcutaneous enoxaparin 40 mg once daily, starting the evening before surgery. Each group received a placebo of the other study drug. The primary efficacy outcome was the composite of total venous thromboembolism (VTE) and all-cause mortality. Secondary outcome measures were composite of major VTE and VTE-related mortality during the treatment period. The major safety outcome was incidence of bleeding events.
RESULTS: Of the 179 Indian patients randomized, 91 received oral dabigatran and 88 received subcutaneous enoxaparin for 28-35 days. Total VTE and all-cause mortality occurred in 18.7% of patients in the dabigatran group and 13.7% in the enoxaparin group [odds ratio = 1.4 (95% confidence interval 0.6, 3.5)]. Major VTE and VTE-related mortality was numerically lower in the dabigatran group (7.9%) compared with the enoxaparin group (9.9%). Safety outcomes were comparable between both groups.
CONCLUSION: Dabigatran is an effective oral alternative to enoxaparin for thromboprophylaxis as demonstrated by the RE-NOVATE II study global results. Data analyzed in Indian patients indicate comparable effects of dabigatran etexilate for major efficacy and safety outcomes.
This prospective study was conducted to report the effect of oral factor Xa inhibitor and low-molecular-weight heparin (LMWH) on surgical complications following total hip arthroplasty (THA). The patients with an age < 60 years were randomly assigned to three groups (rivaroxaban, enoxaparin, and placebo) and the patients with an age ≥ 60 years were assigned to two groups (rivaroxaban and enoxaparin). All drug regimens started at 12 hours postoperatively and continued for two weeks after surgery. Primary measure outcome was major surgical wound complications defined as haematoma requiring any intervention, superficial wound infection, deep periprosthetic infection, and increased wound bleeding. Secondary measured outcome included minor surgical complications (swelling, drainage, erythema, and oozing), organ bleeding, and venous thromboembolic (VTE) events. A total of 184 patients aged < 60 years and 167 patients aged ≥ 60 years were included as the analysis population per group. Up to 14 days after surgery, the overall incidence of major surgical complications associated with thromboprophylaxis was 6.5 % (58/886). There were no significant differences in the rate of major surgical complications among all the three groups of the patients aged < 60 years and between two groups of the patients aged ≥ 60 years. For the patients aged < 60 years, wound oozing continued significantly longer in the pharmacological group than in the placebo group, but wound infection did not occur in any case. The VTE events were similar in all the groups.
BACKGROUND: Thromboprophylaxis for at least 10 days and for up to 4–5 weeks is recommended after total hip arthroplasty (THA). Rivaroxaban is an oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. RECORD1 was a phase III, multinational, randomized, double-blind, double-dummy trial, conducted to determine the efficacy and safety of oral rivaroxaban, compared with subcutaneous enoxaparin, for 5 weeks of thromboprophylaxis in patients undergoing THA. METHODS: Patients received rivaroxaban 10 mg beginning 6–8 hours after surgery and once daily (od) thereafter, or enoxaparin 40 mg od, beginning the evening before surgery (restarting 6–8 hours after surgery). Therapy continued for 35±4 days and mandatory, bilateral venography was conducted the next day. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality. The primary efficacy analysis was a test for non-inferiority in the per-protocol (PP) population, followed by a test for superiority in the modified intention-to-treat (mITT) population. The main secondary efficacy endpoint was major venous thromboembolism (VTE): the composite of proximal DVT, non-fatal PE and VTE-related death. Major and non-major bleeding during the active treatment period were the primary and secondary safety endpoints, respectively. RESULTS: A total of 4541 patients were randomized; 4433 were eligible for the safety population, 3153 for the mITT population, and 3029 for the PP population. The criteria for non-inferiority were met and testing for superiority was performed. Rivaroxaban significantly reduced the incidence of the primary efficacy endpoint (p<0.001) and major VTE (p<0.001), compared with enoxaparin, in the mITT population (Table). The incidence of major and non-major bleeding events was similar in both groups (Table). CONCLUSIONS: Rivaroxaban was significantly more effective than enoxaparin for extended prophylaxis after THA, with a similar safety profile. This is the first pivotal trial to demonstrate the efficacy and safety of a fixed, unmonitored dose of an oral, direct Factor Xa inhibitor - rivaroxaban - for extended thromboprophylaxis after THA.
BACKGROUND: Deep vein thrombosis (DVT) and pulmonary emboli (PE), known together as venous thromboembolic (VTE) disease remain major complications following elective hip and knee surgery. This study compares three chemoprophylactic regimens for VTE following elective primary unilateral hip or knee replacement, one of which was designed to minimize risk of post-operative bleeding. METHODS: Patients were randomized and stratified for hip vs. knee to receive A: variable dose warfarin (first dose on the night preceding surgery with subsequent target INR 2.0-2.5), B: 2.5 mg fondaparinux daily starting 6-18 h postoperatively, or C: fixed 1.0 mg dose warfarin daily starting 7 days preoperatively. All treatments continued until bilateral leg venous ultrasound day 28 ± 2 or earlier upon a VTE event. The study examined primary endpoints including leg DVT, PE or death due to VTE and secondary endpoints including effects on D-dimer, estimated blood loss (EBL) at surgery and hemorrhagic complications. RESULTS: Three hundred fifty-five patients were randomized. None was lost to follow-up. Taking 1.0 mg warfarin for seven days preoperatively did not prolong the prothrombin time (PT). Two patients in Arm C had asymptomatic distal DVT. One major bleed occurred in Arm B and one in Arm C (ischemic colitis). Elevated d-dimer did not predict delayed VTE for one year. CONCLUSIONS: Fixed low dose warfarin started preoperatively is equivalent to two other standards of care under study (95 % CI: -0.0428, 0.0067 for both) as VTE prophylaxis for the patients having elective major joint replacement surgery.
BACKGROUND: Thromboembolic disease (TED) after knee arthroplasty occurs infrequently in Iran. The aim of this study was to examine the incidence of TED in patients with osteo-arthritis undergoing knee replacement in Southern Iran while on prophylaxis. Materials & methods: In a case series study from January to December 2012,100 consecutive total knee arthroplasty (TKA) candidates were evaluated for TED by clinical evaluation and Doppler sonography preoperatively and 2 months postoperatively and by clinical evaluation one year after surgery. The patients in this study randomly received either warfarin or enoxaparin prophylactically. RESULTS: A total of 77 women and 23 men with mean age of 67 years (52-82 years) entered the study. The average hemoglobin drop of 2.7 g with warfarin and 3.3 with enoxaparin was observed. No case of TED, pulmonary embolus (PE), major bleeding, post-thrombotic syndrome, or hemarthrosis was observed. CONCLUSION: No clinically significant DVT was found using either enoxaparin or warfarin prophylaxis after TKA in Southern Iran. Relatively excessive postoperative bleeding was observed, particularly with enoxaparin.
Background: In the absence of thromboprophylaxis, patients undergoing total hip arthroplasty (THA) are at increased risk for venous thromboembolism (VTE). The objective of this study was to compare the efficacy and safety of edoxaban with enoxaparin for the prevention of VTE after THA in Japan. Methods: This was a phase 3, double-blind, double-dummy, noninferiority study. Patients undergoing elective, unilateral primary THA were randomized to receive edoxaban 30 mg once daily (n = 307) or enoxaparin 2000 IU (equivalent to 20 mg) twice daily (n = 303) for 11 to 14 days. The primary efficacy endpoint was the incidence of VTE. Safety endpoints included the incidence of major or clinically relevant nonmajor (CRNM) bleeding. Results: The incidence of VTE, based on venography and clinical surveillance, was 2.4 % in the edoxaban group and 6.9 % in the enoxaparin group (P <0.001). The absolute difference in the incidence of VTE was -4.5 % (95 % confidence interval [CI]: -8.6, -0.9), which was within the noninferiority margin set at 8 % for the difference and established the noninferiority of edoxaban to enoxaparin. Since the upper limit of the 95 % CI of the absolute difference was less than 0 %, the superiority of edoxaban over enoxaparin was demonstrated. The incidence of major or CRNM bleeding was 2.6 % in the edoxaban group and 3.7 % in the enoxaparin group (P = 0.475). Conclusions: Oral edoxaban 30 mg once daily was superior to subcutaneous enoxaparin 2000 IU twice daily in the prevention of VTE following THA without increasing the risk for major or CRNM bleeding.
Thromboprophylaxis after joint replacement surgery is evidence-based standard care. Usually, when thromboprophylaxis regimens with new anticoagulants have been more effective than existing standard practice they have also caused increased bleeding. Apixaban, a novel orally administered factor Xa inhibitor, has been evaluated in three phase 3 randomized, double-blind, double-dummy clinical trials (the ADVANCE studies) for the prevention of venous thromboembolism (VTE) after hip or knee replacement. A pre-specified aim of this program, in order to provide more precise estimates of the incidences of major VTE, bleeding, and the additional safety outcomes of myocardial infarction, stroke, and liver function, was to combine data from the two trials comparing apixaban 2.5 mg twice daily with the same enoxaparin regimen of 40 mg once daily (ADVANCE-2 and 3). Major VTE was defined a priori as the composite of adjudicated symptomatic or asymptomatic proximal deep-vein thrombosis (popliteal, femoral, or iliac vein thrombosis), non-fatal pulmonary embolism, and VTE-related death, counted if they occurred during the intended treatment period for each trial or within 2 days after the last dose of study medication, whichever was longer. The bleeding outcomes of major bleeding (adapted from ISTH criteria), clinically relevant non-major bleeding, and the composite of major and clinically relevant non-major bleeding, were counted if they occurred during the treatment period or within 2 days after the last dose of study medication. In both studies, subcutaneous enoxaparin (or placebo) was started 12±3 hours before operation, and resumed after surgery according to the investigator's standard of care, and oral apixaban (or placebo) was initiated 12 to 24 hours after wound closure (typically on the morning after surgery). Study medications were continued for 10 to 14 days after knee arthroplasty in ADVANCE- 2, and for 32 to 38 days after hip replacement in ADVANCE- 3. In both studies, mandatory bilateral venography was done at the end of the intended treatment period to assess the presence or absence of asymptomatic deep-vein thrombosis, and clinically suspected VTE was confirmed or excluded by objective testing. Patients were followed-up 30±5 and 60±5 days after the last dose of study medication. All venograms and all episodes of suspected VTE, bleeding, myocardial infarction, stroke, or death were adjudicated without knowledge of assigned treatment by an independent central adjudication committee. The site of bleeding was analysed as reported by the investigator. The pooled analysis was stratified by the type of joint replacement (hip or knee) for statistical calculations. A total of 8,564 patients were randomized in the ADVANCE-2 and 3 trials. Major VTE occurred in 23 of 3,394 evaluable patients (0.68%) in the apixaban group and in 51 of 3,394 (1.50%) evaluable patients in the enoxaparin group (absolute risk difference, -0.76%, 95% CI, -1.23% to -0.30%). Major bleeding occurred in 31 of 4,174 patients (0.74%) who received apixaban (18 occurred before the first dose) and in 32 of 4,167 patients (0.77%) given enoxaparin (absolute risk difference -0.02%, 95% CI, -0.40% to 0.35%). Major bleeding at the surgical site occurred in 26 apixaban and 27 enoxaparin patients (absolute risk difference -0.02%, 95% CI, -0.37% to 0.32%). The composite of major or clinically relevant non-major bleeding occurred in 182 patients (4.36%) given apixaban, compared with 206 patients (4.94%) given enoxaparin (absolute risk difference -0.58%, 95% CI, -1.49% to 0.32%); these bleeding events occurred at the surgical site in 135 (3.23%) apixaban patients, and in 155 (3.72%) enoxaparin patients (absolute risk difference -0.49%, 95% CI, -1.27% to 0.30%). Myocardial infarction or stroke during treatment or follow-up occurred in 13 patients (0.31%) in the apixaban group and in 10 patients (0.24%) in the enoxaparin group (absolute risk difference 0.07%, 95% CI, -0.15% to 0.30%). Elevated levels (>3 times upper normal limit) of enzymes ALT or AST occurred in 2.2% and 2.8% of apixaban patients respectively, and in 3.0% and 2.8% of enoxaparin patients respectively. The apixaban regimen was more effective than enoxaparin 40 mg once daily for preventing major VTE, without increased bleeding, and has the clinical advantages of oral administration and later initiation 12 to 24 hours post-operatively.
<b>BACKGROUND: </b>There is currently little evidence defining the clinical importance of detecting and treating isolated distal DVT (IDDVT). International guidelines vary regarding diagnostic and therapeutic advice. The potential benefits of anticoagulation are unquantified. We sought to evaluate the feasibility of a randomized controlled study within a modern framework and provide a primary outcome point estimate.<b>METHODS: </b>In this open-label, external pilot randomized controlled trial, consecutive, symptomatic, ambulatory patients with IDDVT were approached for inclusion. Participants were allocated to receive either therapeutic anticoagulation or conservative management. Patients underwent blinded color-duplex imaging at 7 and 21 days and follow-up at 3 months. Principal feasibility outcomes included recruitment rate and attrition. The principal clinical outcome was a composite including proximal propagation, pulmonary embolism, death attributable to VTE disease, or major bleeding. Analysis was by intention to treat.<b>RESULTS: </b>In total, 93 patients with IDDVT were screened, and 70 of those eligible (88.6%) were recruited. All patients but one were followed-up by direct contact after 90 days. Allocation crossover occurred in 15 patients (21.4%). The principal clinical outcome occurred in four of 35 of those conservatively treated (11.4%) and zero of 35 in the anticoagulated group (absolute risk reduction, 11.4%; 95% CI, -1.5 to 26.7, P = .11, number needed to treat of nine). There were no major bleeding episodes.<b>CONCLUSIONS: </b>We have established the feasibility of definitive study regarding the value of therapeutic anticoagulation in IDDVT and provide an approximate point estimate for serious complications with a contemporary conservative strategy.<b>Trial Registry: </b>Current Controlled Trials; No.: ISRCTN75175695; URL: www.controlled-trials.com.
AIM: No study of strong methodology could be found to resolve the controversy of optimal treatment of distal deep venous thrombosis (DDVT). Some inconclusive evidence exists on two approaches to care: anticoagulants and compression therapy or compression therapy and Duplex scanning monitoring. Different studies report propagation to popliteal vein in 8% of patients without anticoagulant treatment, while a complete thrombus resolution within 4 weeks occurred in 20% of patients. We report data of a study conducted in patients affected by DDVT and treated with nadroparin administered once daily in association with compression therapy.
METHODS: One hundred and ten patients with DDVT of the gastrocnemius or tibial veins, assessed by Duplex scanning, were enrolled in 8 clinical centres of the Lazio Region. At baseline, patient demographics, medical history (including risk factors for DDVT), circumferences of both calves and ankles, and a VAS-pain scale were recorded. At 7 and 28 days from baseline, patients were re-assessed by Duplex scanning, calves and ankles circumferences and VAS-pain were measured, and the patients were asked about possible side effects.
RESULTS: At the end of the study period, no propagation to the popliteal vein was observed, and no side effects were reported. Overall, the calf circumference in the affected leg significantly decreased from baseline (38.1 cm) to week 1 (37.1 cm), and to week 4 (35.7 cm). Also the VAS-pain scores significantly decreased during the study - the observed means were 58.4, 30.7, and 12.7 at the three visits, respectively. The percentage of partial recanalization of tibial DVT at 7 days was lower than gastrocnemius DVT (31.6% vs. 59.8%) whereas the percentage of total recanalization at 28 days was comparable (52.6% vs. 59.8%). Complete recanalization occurred in 56.4% of all patients.
CONCLUSION: Our study suggests that anticoagulant treatment, associated with compression therapy, is safe and causes clinical improvement (as assessed by calf measurements) and pain relief. Overall complete resolution (56.4%) is significantly higher than in untreated patients (20%). Such results, together with the already reported higher satisfaction of patients for the once-daily administration regimen, should be considered as a viable option for the treatment of DDVT.
OBJECTIVE: To compare the effects of short-term and long-term thromboprophylaxis after total hip replacement on coagulation indicators in plasma sampled before and 1, 7 and 35 days post-operation.
METHODS: A total of 40 patients scheduled for elective total hip replacement were randomly assigned into the short-term (n = 20) or long-term (n = 20) thromboprophylaxis groups on oral rivaroxaban 10 mg once daily for 7 or 35 days. The primary efficacy hemostatic variables included thrombin-antithrombin complexes (TAT), prothrombin fragment 1+2 (F1t2), D-dimer and fibrinogen (Fib) preoperatively and at Days 1, 7 and 35 postoperatively. And ultrasonography was performed on all patients preoperatively and at days 7 and 35 postoperatively to exclude deep vein thrombosis of lower extremities.
RESULTS: None of them had deep vein thrombosis (DVT) of lower extremities. Among them, TAT, F1+2, D-dimer and Fib post-operation were higher than those preoperative baseline values. TAT and D-dimer peaked at day 1 postoperatively while the peaks of F1+2 and Fib appeared at day 7 postoperatively. At Day 35 post-operation, the levels of TAT and F1+2 in the long-term thromboprophylaxis group were significantly lower than those of the short-term thromboprophylaxis group (P < 0.05).
CONCLUSION: The status of hypercoagulability may sustain at least 35 days after total hip replacement. Though not completely eliminated, it can still be reduced by prolonged thromboprophylaxis. However, according to ultrasonography, the effects of short-term and long-term thromboprophylaxis on the incidence rate of DVT remain to be further explored.
In the Re-NOVATE II study, oral dabigatran provided thromboprophylaxis after total hip arthroplasty and improved compliance postdischarge in a global population. This article aims to identify trends (if any) in the Indian population.
METHODS:
In this prospective, double-blind, double-dummy study, patients scheduled for primary, unilateral, elective total hip arthroplasty were randomized to 220 mg oral dabigatran once daily, starting with a 110 mg half-dose, 1-4 hours after surgery, or subcutaneous enoxaparin 40 mg once daily, starting the evening before surgery. Each group received a placebo of the other study drug. The primary efficacy outcome was the composite of total venous thromboembolism (VTE) and all-cause mortality. Secondary outcome measures were composite of major VTE and VTE-related mortality during the treatment period. The major safety outcome was incidence of bleeding events.
RESULTS:
Of the 179 Indian patients randomized, 91 received oral dabigatran and 88 received subcutaneous enoxaparin for 28-35 days. Total VTE and all-cause mortality occurred in 18.7% of patients in the dabigatran group and 13.7% in the enoxaparin group [odds ratio = 1.4 (95% confidence interval 0.6, 3.5)]. Major VTE and VTE-related mortality was numerically lower in the dabigatran group (7.9%) compared with the enoxaparin group (9.9%). Safety outcomes were comparable between both groups.
CONCLUSION:
Dabigatran is an effective oral alternative to enoxaparin for thromboprophylaxis as demonstrated by the RE-NOVATE II study global results. Data analyzed in Indian patients indicate comparable effects of dabigatran etexilate for major efficacy and safety outcomes.
