Benefit-to-harm ratio of thromboprophylaxis for patients undergoing major orthopaedic surgery

2014 ◽  
Vol 111 (02) ◽  
pp. 199-212 ◽  
Author(s):  
Jane Liang ◽  
David Bergqvist ◽  
Roger Yusen ◽  
Russell Hull
Keyword(s):  
Major Bleeding ◽  
Orthopaedic Surgery ◽  
Bleeding Event ◽  
Phase Iii ◽  
Number Needed To Treat ◽  
Vte Prophylaxis ◽  
Major Orthopaedic Surgery ◽  
Definition Of ◽  
Newer Anticoagulants ◽  
Number Needed To Harm

SummarySurgeons consider the benefit-to-harm ratio when making decisions regarding the use of anticoagulant venous thromboembolism (VTE) prophylaxis. We evaluated the benefit-to-harm ratio of the use of newer anticoagulants as thromboprophylaxis in patients undergoing major orthopaedic surgery using the likelihood of being helped or harmed (LHH), and assessed the effects of variation in the definition of major bleeding on the results. A systematic literature search was performed to identify phase II and phase III studies that compared regulatory authority-approved newer anticoagulants to the low-molecularweight heparin enoxaparin in patients undergoing major orthopaedic surgery. Analysis of outcomes data estimated the clinical benefit (number-needed-to-treat [NNT] to prevent one symptomatic VTE) and clinical harm (number-needed-to-harm [NNH] or the NNT to cause one major bleeding event) of therapies. We estimated each trial’s benefitto-harm ratio from NNT and NNH values, and expressed this as LHH = (1/NNT)/(1/NNH) = NNH/NNT. Based on reporting of efficacy and safety outcomes, most studies favoured enoxaparin over fondaparinux, and rivaroxaban over enoxaparin. However, when using the LHH metric, most trials favoured enoxaparin over both fondaparinux and rivaroxaban when they included surgical-site bleeding that did not require reoperation in the definition of major bleeding. The exclusion of bleeding at surgical site which did not require reoperation shifted the benefit-to-harm ratio in favour of the newer agents. Variations in the definitions of major bleeding may change the benefit-to-harm ratio and subsequently affect its interpretation. Clinical trials should attempt to improve the consistency of major bleeding reporting.

Efficacy and Safety of VTE Prophylaxis with Oral Rivaroxaban Compared to Fondaparinux or Low-Molecular Weight Heparin In a Large Cohort of Consecutive Patients Undergoing Major Orthopaedic Surgery

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 210-210
Author(s):  
Jan Beyer-Westendorf ◽  
Lars Donath ◽  
Jörg Lützner ◽  
Sebastian Werth ◽  
Oliver Radke ◽  
...  
Keyword(s):  
Orthopaedic Surgery ◽  
Low Molecular Weight Heparin ◽  
Phase Iii ◽  
Bleeding Complications ◽  
Low Molecular Weight ◽  
Severe Bleeding ◽  
Efficacy And Safety ◽  
Vte Prophylaxis ◽  
Superior Efficacy ◽  
Major Orthopaedic Surgery

Abstract Abstract 210 Efficacy and safety of VTE prophylaxis with oral rivaroxaban compared to fondaparinux or low-molecular weight heparin in a large cohort of consecutive patients undergoing major orthopaedic surgery. Aim: Patients undergoing major orthopaedic surgery (MOS) have a high risk of postoperative venous thromboembolism (VTE). Several types of pharmacological thromboprophylaxis are approved for this indication. In phase III VTE prevention trials in MOS, the new oral facor Xa inhibitor rivaroxaban proved superior efficacy over LMWH in preventing VTE without increasing bleeding complications. However, study populations consist of selected patients screened for strict exclusion criteria before randomisation. Little is known about efficacy and safety of rivaroxaban prophylaxis in large unselected cohorts of patients undergoing MOS in daily practice. Method: We retrospectively evaluated 5346 consecutive patients undergoing MOS at our centre between January 2005 and June 2011 for the rate of VTE events, bleeding complications and surgical revisions by review of patient charts, complication and transfusion databases and autopsy reports. All events were analyzed according to the type of thromboprophylaxis used. Results: Of the 5346 patients, 1055 patients received thromboprophylaxis with rivaroxaban (R; hospital standard since 2010), 1683 patients received LMWH (hospital standard 2005–2007), 2069 received fondaparinux (F; hospital standard 2007–2009) and 539 patients received other prophylaxis. Symptomatic VTE event rates for patients receiving R, F or LMWH were 2.5%, 5.5% and 3.9%, respectively (table 1). R was significantly more effective to prevent symptomatic VTE compared to F or LMWH, mostly due to significantly lower rates of distal VTE. Overall, the safety of VTE prophylaxis with R was superior over F or LMWH with significantly lower rates of surgical revisions (1.1%, 1.8% and 4.7%, respectively) and lower rates of severe bleeding complications (7.4%, 11.1% and 14.9%, respectively, which also was statistically significant. Conclusion: VTE prophylaxis with rivaroxaban is superior over prophylaxis with fondaparinux or LMWH with regard to the prevention of symptomatic VTE complications. Furthermore, rivaroxaban prophylaxis was also safer with regard to severe bleeding complications and surgical complications compared to fondaparinux or LMWH, which is in contrast to the results of large phase III trials and the current opinion, that superior efficacy of prophylaxis has the downside of higher bleeding complications. We conclude that real world patients undergoing MOS are different from study populations and may especially benefit from rivaroxaban prophylaxis with regard to both efficacy and safety. Disclosures: Beyer-Westendorf: Bayer Healthcare: Research Funding, Speakers Bureau.

A Pooled Analysis of Four Pivotal Studies of Rivaroxaban for the Prevention of Venous Thromboembolism after Orthopaedic Surgery: Effect on Symptomatic Venous Thromboembolism, Death, and Bleeding

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 36-36 ◽  
Author(s):  
Alexander GG Turpie ◽  
Michael Rud Lassen ◽  
Ajay K Kakkar ◽  
Bengt Eriksson ◽  
Frank Misselwitz ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Major Bleeding ◽  
Active Treatment ◽  
Orthopaedic Surgery ◽  
Pooled Analysis ◽  
Study Medication ◽  
Double Blind ◽  
Study Duration ◽  
Major Orthopaedic Surgery

Abstract Four multinational, randomized, double-blind, double-dummy phase III studies (RECORD1, 2, 3 and 4) investigated the oral, direct Factor Xa inhibitor rivaroxaban for the prevention of venous thromboembolism (VTE) in patients undergoing major orthopaedic surgery. A total of 12,729 patients were randomized to receive oral rivaroxaban 10 mg once daily (od) starting 6–8 hours after surgery, or subcutaneous enoxaparin 40 mg od starting the evening before surgery (RECORD1–3), or 30 mg bid starting 12–24 hours after wound closure or adequate hemostasis (RECORD4). In both RECORD1 and 2, patients undergoing total hip replacement (THR) were given rivaroxaban for 31–39 days. Enoxaparin was given for 31–39 days in RECORD1 or 10–14 days in RECORD2. In RECORD3 and 4, patients undergoing total knee replacement (TKR) received prophylaxis for 10–14 days. All patients were followed up for 30–35 days after the last dose of study medication. All outcomes, including symptomatic outcomes, were adjudicated by the same independent, blinded committees for all four studies. In each of the studies, the rivaroxaban regimens tested significantly reduced the incidence of the primary efficacy outcome (total VTE; the composite of any deep vein thrombosis [DVT], non-fatal pulmonary embolism [PE], and all-cause mortality) compared with enoxaparin regimens tested, with similar rates of bleeding in both groups. The rivaroxaban regimens also consistently reduced the incidence of major VTE (the composite of proximal DVT, non-fatal PE, and VTE-related death) in all four trials compared with the enoxaparin regimens tested. This pre-specified pooled analysis was performed on all randomized patients who received at least one dose of double-blind study medication to evaluate the effect of rivaroxaban on the composite of symptomatic VTE (comprising DVT or PE) and death, and bleeding. These primary outcomes were analyzed at day 12±2 in the active treatment pool (i.e. during the enoxaparin-controlled period common to all studies, to allow for unbiased comparison with enoxaparin), and for the total study duration pool (planned treatment period and 30–35 days follow-up). The results are shown in the table. Rivaroxaban significantly reduced the incidence of symptomatic VTE and death compared with enoxaparin regimens at day 12±2 (0.47% vs 0.97%; p=0.001) and for the total study duration (0.81% vs 1.63%; p<0.001). Rivaroxaban was not associated with a statistically significant increased risk of major bleeding (Table). These data demonstrate that in the regimens tested, rivaroxaban reduced the composite of major clinical outcomes compared with enoxaparin regimens, with no significant increase in the risk of major bleeding in patients undergoing major orthopaedic surgery. Rivaroxaban n=6183 n (%) Enoxaparin n=6200 n (%) p-value *Total study duration pool: active study drug period and 30–35 days follow-up including the placebo phase in RECORD2. †Bleeding after initiation of study medication, regardless of onset after last dose of study medication. ‡Post hoc analysis. p-values refer to Cox regression with treatment and study as covariates (two-sided Wald-test). Symptomatic VTE and death (primary outcome) 29 (0.5) 60 (1.0) 0.001 Day 12±2 active treatment pool 50 (0.8) 101 (1.6) <0.001 Total study duration pool* Death 6 (0.1) 10 (0.2) 0.320 Day 12±2 active treatment pool 13 (0.2) 25 (0.4) 0.055 Total study duration pool* PE or death 12 (0.2) 24 (0.4) 0.049 Day 12±2 active treatment pool 29 (0.5) 47 (0.8) 0.039 Total study duration pool* Major bleeding 21 (0.3) 13 (0.2) 0.175 Day 12±2 active treatment pool 27 (0.4) 17 (0.3) 0.135 Total study duration pool† Any bleeding 409 (6.6) 384 (6.2) 0.376 Day 12±2 active treatment pool 452 (7.3) 415 (6.7) 0.207 Total study duration pool† Composite of major clinical outcomes (death, myocardial infarction, stroke, symptomatic VTE, and major bleeding)*‡ 96 (1.6) 139 (2.2) 0.004

Indirect comparison meta-analysis of two enoxaparin regimens in patients undergoing major orthopaedic surgery

2014 ◽  
Vol 112 (09) ◽  
pp. 503-510 ◽  
Author(s):  
Céline Chapelle ◽  
Laurent Bertoletti ◽  
Jean-Christophe Lega ◽  
Michel Cucherat ◽  
Paul Zufferey ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Major Bleeding ◽  
Orthopaedic Surgery ◽  
Meta Analysis ◽  
Indirect Comparison ◽  
Thromboembolism Prophylaxis ◽  
Double Blind ◽  
Once Daily ◽  
Increased Risk ◽  
Major Orthopaedic Surgery

SummaryTwo enoxaparin dosage regimens are used as comparators to evaluate new anticoagulants for thromboprophylaxis in patients undergoing major orthopaedic surgery, but so far no satisfactory direct comparison between them has been published. Our objective was to compare the efficacy and safety of enoxaparin 3,000 anti-Xa IU twice daily and enoxaparin 4,000 anti-Xa IU once daily in this clinical setting by indirect comparison meta-analysis, using Bucher’s method. We selected randomised controlled trials comparing another anticoagulant, placebo (or no treatment) with either enoxaparin regimen for venous thromboembolism prophylaxis after hip or knee replacement or hip fracture surgery, provided that the second regimen was assessed elsewhere versus the same comparator. Two authors independently evaluated study eligibility, extracted the data, and assessed the risk of bias. The primary efficacy outcome was the incidence of venous thomboembolism. The main safety outcome was the incidence of major bleeding. Overall, 44 randomised comparisons in 56,423 patients were selected, 35 being double-blind (54,117 patients). Compared with enoxaparin 4,000 anti-Xa IU once daily, enoxaparin 3,000 anti-Xa IU twice daily was associated with a reduced risk of venous thromboembolism (relative risk [RR]: 0.53, 95% confidence interval [CI]: 0.40 to 0.69), but an increased risk of major bleeding (RR: 2.01, 95% CI: 1.23 to 3.29). In conclusion, when interpreting the benefit-risk ratio of new anticoagulant drugs versus enoxaparin for thromboprophylaxis after major orthopaedic surgery, the apparently greater efficacy but higher bleeding risk of the twice-daily 3,000 anti-Xa IU enoxaparin regimen compared to the once-daily 4,000 anti-Xa IU regimen should be taken into account.

Alignment to ACCP Prophylaxis Guidelines and VTE Outcomes in THR and TKR Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 170-170 ◽  
Author(s):  
Bijan Borah ◽  
Heather McDonald ◽  
Joe Henk ◽  
Mark A. Crowther ◽  
Rita Selby ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Health Plan ◽  
Bleeding Event ◽  
Routine Practice ◽  
Multivariate Logistic Regression ◽  
Specific Patient ◽  
Vte Prophylaxis ◽  
Vein Thrombosis ◽  
Final Study ◽  
Major Orthopaedic Surgery

Abstract Introduction: Venous thromboembolism (VTE) is a serious and sometimes fatal condition, encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE). Evidence suggests that major orthopaedic surgery, such as total hip replacement (THR) and total knee replacement (TKR), is associated with a high risk of postoperative VTE. Because of this risk, the American College of Chest Physicians (ACCP) guidelines recommend that these patients receive prophylaxis with anticoagulant therapy. However, the degree to which these guidelines are followed in routine practice is variable. In addition, few studies have documented the relationship between the variability in guideline alignment and VTE rates. Therefore, a retrospective database analysis was conducted to determine the extent to which the ACCP guidelines for VTE prophylaxis are followed after THR/TKR and evaluate the incidence of VTE of those who received ACCP recommended prophylaxis according to the guidelines (‘ACCP’) and those who did not (‘non-ACCP’). Methods: In order to fully evaluate VTE prophylaxis patterns and outcomes, patients should be followed from the time of surgery through to hospital discharge and subsequently to care in the community. To our knowledge, a single database that captures this information for a specific patient in these three phases is not yet available. Therefore, a claims database associated with a large US health plan was linked to the Premier database, which provides details of inpatient medication use. Patients age ≥18 years undergoing TKR/THR between April 1, 2004 and December 31, 2007 and enrolled in the health plan 90 days prior to and 90 days following discharge from index hospitalization (or until death) were included in the analysis. Patients were considered to have received ACCP-guideline prophylaxis if they: initiated prophylaxis in hospital with LMWH, fondaparinux, or VKA initiated prophylaxis within one day of surgery (for THR patients) and were prescribed prophylaxis for a minimum of ten days, or until the occurrence of a bleeding event, a VTE-related event, or death. In addition, the number of DVTs and PEs occurring in ACCP and non-ACCP patients was recorded. Multivariate logistic regression was used to assess whether there was a significant relationship between ACCP guideline prophylaxis and the probability of a DVT or PE following THR/TKR. Results: Of the 30,644 eligible patients from the health plan, 3,497 patients could be linked to the inpatient database. Except for geographic indicators, there were no significant differences in patient demographics or baseline co-morbidities between those included and excluded from the final study sample. Of the 3,497 linked patients, 1,395 received ACCP guideline prophylaxis (40%). The number of DVTs occurring in the ACCP and non-ACCP groups were 27 and 62, respectively. Thus, 2.01% of ACCP and 3.76% of non-ACCP patients have a DVT following surgery and up to the end of 90-day followup (p=0.0521), suggesting that non-ACCP patients were almost twice as likely as ACCP patients to have a DVT. The number of PEs occurring in the ACCP and non-ACCP groups were 2 and 25, respectively. Thus, 0.14% of ACCP and 1.19% of non-ACCP patients experienced a PE following the date of surgery and up to the end of 90-day follow-up (p<0.0001), suggesting that non-ACCP patients were more than eight times more likely than ACCP patients to experience a PE. Multivariate logistic regression indicated that the probability of DVT and PE were significantly lower in patients receiving ACCP guideline prophylaxis (p=0.008 and p=0.03, respectively) Conclusions: By following patients from surgery through to care in the community, this study offers a unique perspective on ‘real-world’ prophylaxis patterns and clinical outcomes related to such patterns in THR and TKR patients. It suggests that: only 40% of THR/TKR patients receive prophylaxis that is in alignment with ACCP guidelines and that patients receiving prophylaxis according to the ACCP guidelines were less likely to have a DVT or PE than those not receiving ACCP guideline prophylaxis, the latter were almost twice as likely to have a DVT and more than eight times as likely to experience a PE.

Randomized, Parallel Group, Multicenter, Multinational Study Evaluating Safety of DU-176b Compared with Warfarin in Subjects with Non-Valvular Atrial Fibrillation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 33-33 ◽  
Author(s):  
Jeffrey I. Weitz ◽  
Stuart J. Connolly ◽  
Satoshi Kunitada ◽  
James Jin ◽  
Indravadan Patel
Keyword(s):  
Atrial Fibrillation ◽  
Major Bleeding ◽  
Bleeding Event ◽  
Phase Iii ◽  
Fixed Dose ◽  
Bleeding Events ◽  
Treatment Groups ◽  
Parallel Group ◽  
Elevated Liver Enzymes ◽  
Major Bleeding Events

Abstract Introduction : The primary objective of this phase II study was to assess the safety of different dose regimens of DU-176b, an oral direct factor Xa inhibitor, in patients with non-valvular atrial fibrillation (AF). Methods : This was a randomized, parallel group, multicenter, multinational, double-blind DU-176b and open-label warfarin safety study in patients with AF (CHADS2 index ≥ 2). Patients were randomly assigned to receive either one of four fixed dose regimens of DU-176b (30 mg qd, 30 mg bid, 60 mg qd or 60 mg bid) or warfarin dose-adjusted to a target international normalized ratio (INR) of 2.0–3.0. for 12 weeks. Investigators, sponsor and study subjects were blinded to DU-176b dose but not to the identity of DU-176b vs. warfarin. Investigators adjusted warfarin doses based on INR values obtained in local laboratories. The INR was determined weekly for 4 weeks and every two weeks thereafter. The primary outcomes were the occurrence of centrally adjudicated major and/or clinically relevant non-major bleeding event, and elevated liver enzymes and/or bilirubin. Secondary outcomes included major adverse cardiovascular events (MACE), a composite of stroke, systemic embolism, acute myocardial infarction, hospitalizations due to cardiovascular condition or cardiovascular death, as well as all other adverse events, including all bleeding events. Results : A total of 1,146 patients were randomized. There were no clinically relevant differences between treatment groups with respect to the demographic data and baseline characteristics. Mean age was 65±8.7 years, 63.3% of patients had a CHADS2 index of 2 and 64.40% were warfarin naïve. The DU-176b 60 mg bid treatment arm was prematurely terminated during the study based on a recommendation by the Independent Data Monitoring Committee (DMC). A total of 180 patients were randomized to this group at the time. The incidence of major and clinically relevant non-major bleeding events was significantly higher in both the DU-176b 60 mg bid and 30 mg bid groups than in those given warfarin. The incidence of major and clinically relevant non-major bleeding events in the DU-176b 30 mg qd and 60 mg qd groups was similar to that in warfarin-treated patients. The time in therapeutic range (TTR) for warfarin-experienced patients was 50.1% and for warfarin naïve patients was 41.8%. There were no significant differences in the number (%) of subjects with persistently elevated ALT, AST, or bilirubin values across the treatment groups. The incidence of stroke was similar across treatment groups (Table). DU-176b 30 mg qd N=235 DU-176b 60 mg qd N=234 DU-176b 30 mg bid N=244 DU-176b 60 mg bid N=180 Warfarin qd N=250 Bleeding, n (%) (95% CI) Major+CR non-major 7 (3.0) (1.2–6.0) 11 (4.7) (2.4–8.3) 19 (7.8) (4.8–11.9)a 19 (10.6) (6.5–16.0)b 8 (3.2) (1.4–6.2) Major 0 (0) (0–1.6) 1 (0.4) (0–2.4) 5 (2.0) (0.7–4.7) 6 (3.3) (1.2–7.1)a 1 (0.4) (0–2.2) All 13 (5.5) (3.0–9.3) 19 (8.1) (5.0–12.4) 32 (13.1) (9.1–18.0) 33 (18.3) (13.0–24.8)b 20 (8.0) (5.0–12.1) Stroke, n (%) (95% CI) 1 (0.4) (0–2.3) 1 (0.4) (0–2.4) 2 (0.8) (0.1–2.9) 2 (1.1) (0.1–4.0) 4 (1.6) (0.4–4.0) Conclusions : DU-176b 30 mg qd and 60 mg qd dose regimens had a safety profile similar to warfarin in patients with AF. Patients treated with the DU-176b 30 mg bid or 60 mg bid regimens had more bleeding events than occurred with warfarin. These results suggest that the DU-176b 30 mg qd or 60 mg qd regimens are safe and well tolerated. A Phase III trial is needed to determine whether DU-176b will provide a suitable replacement for warfarin in AF patients. CR, clinically relevant. aP<0.05, bP=0.002 to warfarin.

scholarly journals Thromboprophylactic Efficacy and Safety of Anticoagulants After Arthroscopic Knee Surgery: A Systematic Review and Meta-Analysis

2019 ◽  
Vol 25 ◽  
pp. 107602961988140
Author(s):  
Yang Yu ◽  
Shitao Lu ◽  
Jinpeng Sun ◽  
Wei Zhou ◽  
Hongjian Liu
Keyword(s):  
Major Bleeding ◽  
Bleeding Event ◽  
Control Group ◽  
Controlled Trials ◽  
Number Needed To Treat ◽  
Cochrane Central Register ◽  
Efficacy And Safety ◽  
Bleeding Events ◽  
Increased Risk ◽  
Significant Difference

To examine the efficacy and safety of anticoagulants after knee arthroscopy (KA), PubMed, EMBASE, databases of Cochrane Central Register of Controlled Trials, and Chinese National Knowledge Infrastructure were searched up to August 2019 for randomized controlled trials (RCT). Seven RCTs including 4097 patients were demonstrated eligible according to the inclusion and exclusion criteria. The efficacy and safety of thromboprophylaxis were assessed and expressed using relative risk (RR) and 95% confidence intervals (95% CIs). The analysis of pooled data showed that anticoagulants group exhibited significant lower overall incidence of symptomatic and asymptomatic venous thromboembolism (VTE; RR = 0.35, 95% CIs: 0.22-0.55, P < .00001), significant higher incidence of all bleeding events (RR = 1.42, 95% CIs: 1.08-1.86, P = .01) compared to control group. However, no significant difference was found in terms of incidence of symptomatic VTE (RR = 0.43, 95% CIs: 0.15-1.21, P = .11) and incidence of major bleeding events (RR = 1.87, 95% CIs: 0.40-8.67, P = .42). The pooled number needed to treat to prevent one symptomatic or asymptomatic VTE was 26, while the pooled number needed to harm to cause one major bleeding event was 869. These results show that anticoagulants can effectively reduce the overall risk of VTE after KA; however, the increased risk of bleeding should be fully considered. Further studies are required to address the risk–benefit calculus and cost-effectiveness of anticoagulants after KA.

Evaluation of the Acute Coronary Syndrome Safety Profile of Dabigatran Etexilate in Patients Undergoing Major Orthopaedic Surgery: Findings From Four Phase III Trials

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2309-2309
Author(s):  
Bengt I Eriksson ◽  
John J Smith ◽  
Joseph Caprini ◽  
Stefan Hantel ◽  
Andreas Clemens ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Adverse Events ◽  
Orthopaedic Surgery ◽  
Dabigatran Etexilate ◽  
Phase Iii ◽  
Coronary Syndrome ◽  
Phase Iii Trials ◽  
Acute Mi ◽  
Major Orthopaedic Surgery ◽  
Event Rates

Abstract Abstract 2309 Introduction: We have previously investigated the incidence of acute coronary syndrome (ACS) events in patients treated with the new oral, reversible, direct thrombin inhibitor, dabigatran etexilate (DE) compared with enoxaparin in the treatment and post-treatment periods in patients undergoing major orthopaedic surgery in three phase III trials (RE-MODEL™, RE-NOVATE® and RE-MOBILIZE®). Whether identified through local investigator reporting or blinded central event adjudication, no significant differences in ACS event rates were detected among orthopaedic surgery patients treated with DE compared with enoxaparin during or after treatment. Overall event rates were low, consistent between investigator and centrally adjudicated assessments, and without evidence for a ‘rebound’ effect for either agent in this post-surgical population. In a pooling with a fourth trial (RE-NOVATE® II), we have now conducted an analysis of investigator-reported adverse events possibly related to ACS from 10,148 treated patients. Methods: Patients in the RE-MODEL™, RE-NOVATE®, RE-NOVATE® II and RE-MOBILIZE® trials were randomized to receive oral DE 150 mg (n = 2737) or 220 mg (n = 3692) once daily, or subcutaneous enoxaparin (n = 3719) for 6–35 days, and were followed for 90 days post-surgery. Potential ACS events during treatment were identified based on investigator-reported adverse events classified using pre-specified Standard Medical Dictionary for Regulatory Authorities (MedDRA) Queries (SMQs). This list included terms relating to locally diagnosed ACS as well as broader MedDRA terms that could reflect undiagnosed ACS. Results: In all four trials, adverse events included in the SMQ ‘ischaemic heart disease’ (sub-terms myocardial infarction [MI], acute MI, angina pectoris, myocardial ischaemia, ACS, unstable angina, coronary artery disease, coronary artery occlusion, cardiac enzymes increased, electrocardiogram ST segment depression, electrocardiogram T wave abnormal, ischaemic cardiomyopathy and troponin increased) were reported by the investigator in 16 (0.4%) and 32 (1.2%) patients in the DE 220 mg and DE 150 mg groups, respectively, compared to 25 (0.7%) in the enoxaparin group during treatment. The incidence of individual adverse event terms possibly related to ACS in the respective treatment groups (DE 220 mg, DE 150 mg and enoxaparin) was as follows: MI 3 (0.1%), 11 (0.4%) and 9 (0.2%); acute MI 1 (0.0%), 3 (0.1%) and 1 (0.0%); ACS 1 (0.0%), 0 (0.0%) and 0 (0.0%); unstable angina 1 (0.0%), 0 (0.0%) and 0 (0.0%). Conclusions: The analysis of > 10,000 patients showed no significant differences in investigator-reported ACS-related adverse event rates among orthopaedic surgery patients during treatment, comparing DE with enoxaparin. This is in agreement with, and supports previous findings of, investigator-related and centrally adjudicated ACS events from three trials. Disclosures: Eriksson: Bristol-Myers Squibb: Consultancy; Bayer: Consultancy; Astellas: Consultancy. Smith:Boehringer Ingelheim: Employment. Caprini:ESAI: Consultancy; Pfizer: Consultancy; GSK: Consultancy; Sanofi: Consultancy; Boehringer Ingelheim: Consultancy; Covidien: Consultancy. Hantel:Boehringer Ingelheim: Employment. Clemens:Boehringer Ingelheim: Employment. Feuring:Boehringer Ingelheim: Employment.

scholarly journals Role of new anticoagulants for the prevention of venous thromboembolism after major orthopaedic surgery and in hospitalised acutely ill medical patients

2012 ◽  
Vol 107 (06) ◽  
pp. 1027-1034 ◽  
Author(s):  
Walter Ageno ◽  
Alex Spyropoulos ◽  
Alexander Turpie
Keyword(s):  
Venous Thromboembolism ◽  
Orthopaedic Surgery ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Anticoagulation Therapy ◽  
Phase Iii ◽  
Fixed Dose ◽  
Medical Patients ◽  
Venous Thromboembolic Events ◽  
Major Orthopaedic Surgery

SummaryAnticoagulation therapy for the prevention of venous thromboembolic events is indicated in patients after major orthopaedic surgery and in hospitalised acutely ill medical patients, who have a high or moderate risk of venous thromboembolism (VTE), respectively. Clinical trials have clearly demonstrated that short-term anticoagulation reduces the risk of VTE in these patient groups and that longer-term anticoagulation is beneficial for some indications. Evidence-based guidelines for throm-boprophylaxis have been developed based on these studies. However, despite these guidelines, thromboprophylaxis is still underused, or used suboptimally, in many patients. This is, in part, because of the limitations of traditional anticoagulants such as unfractionated heparin, lowmolecular-weight heparin, synthetic pentasaccharides, and vitamin K antagonists. Newer oral anticoagulants, such as rivaroxaban, apixaban, and dabigatran etexilate, have certain advantages over traditional agents. They can be administered orally at a fixed dose without routine coagulation monitoring and have minimal food and drug interactions. These characteristics may result in better adherence to guidelines and improved patient outcomes. This review provides an overview of phase III clinical trial data for these newer anticoagulants in major orthopaedic surgery and in hospitalised acutely ill medical patients, and discusses their potential for extended use in the post-hospital discharge setting. All three newer oral anticoagulants are approved in many countries for the prevention of VTE after hip replacement or knee replacement surgery in adult patients, and it is likely that these drugs will contribute considerably towards reducing the substantial healthcare burden associated with VTE.

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