Dabigatran, rivaroxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replacement: systematic review, meta-analysis, and indirect treatment comparisons.
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ABSTRACT: Objective
To analyse clinical outcomes with new oral anticoagulants for prophylaxis against venous thromboembolism after total hip or knee replacement.Design
Systematic review, meta-analysis, and indirect treatment comparisons.Data sources
Medline and CENTRAL (up to April 2011), clinical trials registers, conference proceedings, and websites of regulatory agencies.Study selection
Randomised controlled trials of rivaroxaban, dabigatran, or apixaban compared with enoxaparin for prophylaxis against venous thromboembolism after total hip or knee replacement. Two investigators independently extracted data. Relative risks of symptomatic venous thromboembolism, clinically relevant bleeding, deaths, and a net clinical endpoint (composite of symptomatic venous thromboembolism, major bleeding, and death) were estimated using a random effect meta-analysis. RevMan and ITC software were used for direct and indirect comparisons, respectively.Results
16 trials in 38,747 patients were included. Compared with enoxaparin, the risk of symptomatic venous thromboembolism was lower with rivaroxaban (relative risk 0.48, 95% confidence interval 0.31 to 0.75) and similar with dabigatran (0.71, 0.23 to 2.12) and apixaban (0.82, 0.41 to 1.64). Compared with enoxaparin, the relative risk of clinically relevant bleeding was higher with rivaroxaban (1.25, 1.05 to 1.49), similar with dabigatran (1.12, 0.94 to 1.35), and lower with apixaban (0.82, 0.69 to 0.98). The treatments did not differ on the net clinical endpoint in direct or indirect comparisons.Conclusions
A higher efficacy of new anticoagulants was generally associated with a higher bleeding tendency. The new anticoagulants did not differ significantly for efficacy and safety.
SUBMITTER: Gomez-Outes A
PROVIDER: S-EPMC3375207 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Thromboprophylaxis is recommended for patients undergoing total hip or total knee replacement (THR, TKR). An international, open-label, prospective, observational, single-arm study in a routine clinical setting was performed to assess the safety and efficacy of dabigatran etexilate 220 mg once daily in patients undergoing THR or TKR, and in subgroups of patients with potentially increased risk of bleeding or venous thromboembolism (VTE). MATERIALS AND METHODS:Patients were ?18 years and required to be eligible to receive dabigatran 220 mg once daily (first dose 110 mg 1-4 h after THR/TKR surgery) according to the European Summary of Product Characteristics. The primary safety and efficacy outcomes were incidence of major bleeding events (MBEs), and the composite incidence of symptomatic VTE events and all-cause mortality, respectively. RESULTS:In total, 5292 patients (median age 64 years) were enrolled and received dabigatran (2734 THR and 2558 TKR). Median drug exposure was 31 days (THR 34 days; TKR 27 days). Overall incidence of MBEs was 0.72 % (95 % confidence interval [CI] 0.51, 0.98), and this rate was comparable between types of surgery and was not significantly affected by protocol-defined risk factors. The overall incidence of symptomatic VTE and all-cause mortality was 1.04 % (95 % CI 0.78, 1.35); the only significant risk factor was history of VTE events (odds ratio 5.59; 95 % CI 2.53, 11.08). A post-hoc analysis showed that the incidence of MBEs in this observational study was similar to or lower than those reported in previous phase 3 trials. CONCLUSIONS:Results from this observational study of dabigatran etexilate administered to patients undergoing THR or TKR surgery are reassuring and supportive of those obtained in dabigatran phase 3 trials. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT00846807.
| S-EPMC4818472 | biostudies-literature
Project description:AimsThere are concerns regarding increased risk of acute coronary syndrome with dabigatran. We aimed to assess whether alternative treatment options such as rivaroxaban or apixaban carry a similar risk as compared with dabigatran.MethodsWe searched MEDLINE and EMBASE for randomized controlled trials of apixaban, dabigatran or rivaroxaban against control (placebo, heparin or vitamin K antagonist). We pooled odds ratios (OR) for adverse coronary events (acute coronary syndrome or myocardial infarction) using fixed effect meta-analysis and assessed heterogeneity with I(2) . We conducted adjusted indirect comparisons to compare risk of adverse coronary events with apixaban or rivaroxaban vs. dabigatran.ResultsTwenty-seven randomized controlled trials met the inclusion criteria. Dabigatran was associated with a significantly increased risk of adverse coronary events in pooled analysis of nine trials (OR 1.45, 95% CI 1.14, 1.86). There was no signal for coronary risk with apixaban from nine trials (pooled OR 0.89, 95% CI 0.78, 1.03) or rivaroxaban from nine trials (pooled OR 0.81, 95% CI 0.72, 0.93). Overall, adjusted indirect comparison suggested that both apixaban (OR 0.61, 95% CI 0.44, 0.85) and rivaroxaban (OR 0.54; 95% CI 0.39, 0.76) were associated with lower coronary risk than dabigatran. Restricting the indirect comparison to a vitamin K antagonist as a common control, yielded similar findings, OR 0.57 (95% CI 0.39, 0.85) for apixaban vs. dabigatran and 0.53 (95% CI 0.37, 0.77) for rivaroxaban vs. dabigatran.ConclusionsThere are significant differences in the comparative safety of apixaban, rivaroxaban and dabigatran with regards to acute coronary adverse events.
| S-EPMC4239965 | biostudies-literature
Project description:BackgroundPatients undergoing hip or knee replacement are at high risk of developing a postoperative venous thromboembolism even after discharge from hospital. We sought to identify hospital and patient characteristics associated with receiving thromboprophylaxis after discharge and to compare the risk of short-term mortality among those who did or did not receive thromboprophylaxis.MethodsWe conducted a retrospective cohort study using system-wide hospital discharge summary records, physician billing information, medication reimbursement claims and demographic records. We included patients aged 65 years and older who received a hip or knee replacement and who were discharged home after surgery.ResultsIn total we included 10 744 patients. Of these, 7058 patients who received a hip replacement and 3686 who received a knee replacement. The mean age was 75.4 (standard deviation [SD] 6.8) years and 38% of patients were men. In total, 2059 (19%) patients received thomboprophylaxis at discharge. Patients discharged from university teaching hospitals were less likely than those discharged from community hospitals to received thromboprophylaxis after discharge (odds ratio [OR] 0.89, 95% confidence interval [CI] 0.80-1.00). Patients were less likely to receive thromboprophylaxis after discharge if they had a longer hospital stay (15-30 days v. 1-7 days, OR 0.69, 95% CI 0.59-0.81). Patients were more likely to receive thromboprophylaxis if they had hip (v. knee) replacement, osteoarthritis, heart failure, atrial fibrillation or hypertension, higher (v. lower) income or if they were treated at medium-volume hospitals (69-116 hip and knee replacements per year). In total, 223 patients (2%) died in the 3-month period after discharge. The risk of short-term mortality was lower among those who received thromboprophylaxis after discharge (hazard ratio [HR] 0.34, 95% CI 0.20-0.57).InterpretationFewer than 1 in 5 elderly patients discharged home after a hip-or knee-replacement surgery received postdischarge thromboprophylaxis. Those prescribed these medications had a lower risk of short-term mortality. The benefits of and barriers to thromboprophylaxis therapy after discharge in this population requires further study.
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Project description:BACKGROUND:Apixaban, a novel oral anticoagulant, is also used for deep vein thrombosis (DVT) prophylaxis. In this study, we sought to critically evaluate the differences in the rates of symptomatic DVT and bleeding, and analyze the rates of pulmonary embolism (PE) in subgroups of patients from ADVANCE I and II trials given their similar indication and design. METHODS:Studies were identified through electronic literature searches of MEDLINE, clinicaltrial.gov, SCOPUS, and EMBASE up to January 2014. Phase III RCTs involving use of apixaban and enoxaparin for thromboprophylaxis in patients undergoing total knee or hip replacement were included. Study-specific odds ratios were calculated and between-study heterogeneity was assessed using the I (2) statistics. RESULTS:In three studies involving 11,659 patients, the risk of symptomatic DVT (pooled OR 0.38, 95% CI 0.16-0.90, I (2)=0%, p=0.03) and bleeding (pooled OR 0.87, 95% CI 0.77-0.99, I (2)=0%, p=0.03) was less in apixaban group compared to the enoxaparin group. However, it was interesting to note that on subgroup analysis, the risk of PE was higher with apixaban when used for thromboprophylaxis in knee replacement surgery (pooled OR 2.58, 95% CI 1.10-6.04, I (2)=0%, p=0.03). CONCLUSION:Apixaban was found to be associated with lower risk of symptomatic DVT and bleeding compared to enoxaparin when used for thromboprophylaxis in patients undergoing knee and hip replacement surgeries. However, it was associated with higher risk of PE in patients undergoing knee replacement.
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Project description:Background:Despite long clinical experience some authorities recommend against the use of aspirin for perioperative VTE prophylaxis and favour alternatives such as dabigatran. A change from Dabigatran to an Aspirin based protocol in a British district general hospital created the conditions of a natural experiment. Methods:We conducted a single centre, retrospective study of 6-months using a dabigatran based protocol (THA n?=?191, TKA n?=?155) and 6-months using and aspirin based protocol (THA n?=?165, TKA n?=?136). Outcomes addressed include: VTE used, VTE events within 90-days, 30-day return to theatre (RTT) rates, and 90-day mortality. Results:Pre-intervention, the dabigatran prescription rate was 73% (n?=?139) and 78% (n?=?123) with aspirin prescription post-intervention in 67% (n?=?110) and 70% (n?=?90) for THA and TKA respectively. We found a similar VTE rate when comparing dabigatran and aspirin groups for THA (2.2% vs. 0%, p?=?0.17) and TKA (0.64% vs. 0%, p?=?0.32). Similarly, no difference in the RTT rate was seen for THA (0.7% vs.2.7%, p?=?0.23) or TKA (1.6% vs. 3.2%, p?=?0.38). Conclusion:No significant differences in safety were found comparing aspirin to dabigatran for VTE prophylaxis for lower limb arthroplasty which, has not been previously reported and represents significant cost saving implications.
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Project description:ObjectivesFor the non-vitamin-K oral anticoagulants, data on bleeding when used for 42 days as thromboprophylaxis after total knee arthroplasty (TKA) are scarce. This pilot study assessed feasibility of a multicentre randomised clinical trial to evaluate major and clinically relevant non-major bleeding during 42-day use of dabigatran, nadroparin and rivaroxaban after TKA.Patients and methodsIn 70 weeks, between July 2012 and November 2013, 198 TKA patients were screened for eligibility in the Martini Hospital (Groningen, the Netherlands). Patients were randomly assigned to dabigatran (n=45), nadroparin (n=45) or rivaroxaban (n=48). The primary outcome was the combined endpoint of major bleeding and clinically relevant non-major bleeding. Secondary endpoints of this study were the occurrence of clinical venous thromboembolism (VTE) (pulmonary embolism or deep venous thrombosis), compliance, duration of hospital stay, rehospitalisation, adverse events and Knee Injury and Osteoarthritis Outcome Score (KOOS).ResultsThe primary outcome was observed in 33.3% (95% CI 20.0% to 49.0%), 24.4% (95% CI 12.9% to 39.5%) and 27.1% (95% CI 15.3% to 41.8%) of patients who received dabigatran, nadroparin or rivaroxaban, respectively (p=0.67). Major bleeding was found in two patients who received nadroparin (p=0.21). Clinically relevant non-major bleeding was observed in 33.3% (95% CI 20.0% to 49.0%), 22.2% (95% CI 11.2% to 37.1%) and 27.1% (95% CI 15.3% to 41.8%) for dabigatran, nadroparin and rivaroxaban, respectively (p=0.51). Wound haematoma was the most observed bleeding event. VTE was found in one patient who received dabigatran (p=0.65). The presurgery and postsurgery KOOS qQuestionnaires were available for 32 (71%), 35 (77%) and 35 (73%) patients for dabigatran, nadroparin and rivaroxaban, respectively. KOOS was highly variable, and no significant difference between treatment groups in mean improvement was observed.ConclusionsA multicentre clinical trial may be feasible. However, investments will be substantial. No differences in major and clinically relevant non-major bleeding events were found between dabigatran, nadroparin and rivaroxaban during 42 days after TKA. KOOS may not be suitable to detect functional loss due to bleeding.Trial registration numberNCT01431456.
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Project description:BackgroundAtrial fibrillation is a major risk factor for stroke, which causes thousands of deaths and sequelae. It is recommended that atrial fibrillation patients at medium or high risk of stroke use an oral anticoagulant to reduce the risk of stroke. In the past few years, three new oral anticoagulants (NOACs), dabigatran, rivaroxaban, and apixaban, have been introduced in competition to the older oral anticoagulant warfarin.ObjectiveThe objective of this study was to evaluate the relative cost effectiveness of warfarin, dabigatran, rivaroxaban, and apixaban in a Norwegian setting.MethodsWe created a probabilistic decision-analytic Markov model to simulate the life of patients with atrial fibrillation. We performed several scenario analyses, including changing the switching age for dabigatran from 80 to 75 years old.ResultsAssuming the European Society of Cardiology guidance, sequential dabigatran (2 × 150 mg daily until 80 years old, 2 × 110 mg thereafter) seems to be the most cost-effective alternative for high-risk AF patients. For medium-risk patients, apixaban (2 × 5 mg daily) seems to be somewhat more effective than dabigatran, but dabigatran is still marginally the most cost-effective alternative. In scenario analyses reducing dabigatran from 2 × 150 mg to 2 × 110 mg at the age of 75 years (instead of at age 80), apixaban (2 × 5 mg daily) becomes the most cost-effective alternative for both risk groups.ConclusionWe have found apixaban or sequential dabigatran to be the alternatives most likely to be considered cost effective, depending on the switching age for dabigatran. These conclusions are highly sensitive to assumptions made in the analysis.
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Project description:Venous thromboembolism (VTE) is the most widespread severe complication after total hip arthroplasty (THA) and total knee arthroplasty (TKA). We conducted this meta-analysis to further validate the benefits and harms of rivaroxaban use for thromboprophylaxis after THA or TKA. We thoroughly searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. Trial sequential analysis (TSA) was applied to test the robustness of our findings and to obtain a more conservative estimation. Of 316 articles screened, nine studies were included. Compared with enoxaparin, rivaroxaban significantly reduced symptomatic VTE (P = 0.0001) and symptomatic deep vein thrombosis (DVT; P = 0.0001) but not symptomatic pulmonary embolism (P = 0.57). Furthermore, rivaroxaban was not associated with an increase in all-cause mortality, clinically relevant non-major bleeding and postoperative wound infection. However, the findings were accompanied by an increase in major bleeding (P = 0.02). The TSA demonstrated that the cumulative z-curve crossed the traditional boundary but not the trial sequential monitoring boundary and did not reach the required information size for major bleeding. Rivaroxaban was more beneficial than enoxaparin for preventing symptomatic DVT but increased the risk of major bleeding. According to the TSA results, more evidence is needed to verify the risk of major bleeding with rivaroxaban.
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Project description:Non-vitamin K antagonist oral anticoagulants (NOACs) are widely used for prevention of stroke secondary to nonvalvular atrial fibrillation (NVAF). Increased use of NOACs is partially a result of simplified regimens compared with warfarin, which has been associated with poor adherence and persistence to therapy. Few studies have assessed adherence to NOACs, especially using contemporary data now that multiple NOACs are available.To evaluate adherence to NOACs in a cohort of newly diagnosed NVAF patients who are commercially insured.Incident, treatment-naïve NVAF patients were identified in 2013 from a large claims database. Patients were included who initiated rivaroxaban, dabigatran, or apixaban within 30 days after diagnosis. Subjects were required to have 12 months of pre-index information to assess demographic and clinical characteristics (comorbidities, CHA2 DS2-VASc, and HAS-BLED scores). Adherence to the index medication and adherence to any oral anticoagulant was assessed using proportion of days covered (PDC) at 3, 6, and 9 months. The number of switches and gaps in therapy were also evaluated. Analyses were stratified by stroke risk scores, and a logistic regression model was used to control for factors that may predict high adherence (PDC ? 0.80).A total of 3,455 rivaroxaban, 1,264 dabigatran, and 504 apixaban users were included with no major clinical or demographic differences between groups. At 3, 6, and 9 months of follow-up, dabigatran had lower adherence (PDC = 0.77, 0.67, and 0.62) compared with rivaroxaban (PDC = 0.84, 0.75, and 0.70; P < 0.001) and apixaban (PDC = 0.82, 0.75, and 0.71; P < 0.001), as well as nearly twice the number of switches to either other anticoagulants or antiplatelet therapy. At 9 months, 55.0% of rivaroxaban initiators had PDC ? 0.80, which was comparable with 56.8% for apixaban and significantly greater than 46.7% for dabigatran (P < 0.001). Adherence was higher overall as stroke risk increased and showed dabigatran had consistently lower adherence compared with the other NOACs. Overall adherence to any oral anticoagulants, allowing for switches to another NOAC or warfarin, was not dependent on the index medication (9-month PDC = 0.74, 0.71, and 0.74 for rivaroxaban, dabigatran, and apixaban initiators). Adjusted analyses showed that increasing age and comorbid hypertension and diabetes were associated with higher adherence. Compared with rivaroxaban, dabigatran initiators had nearly 30% lower odds of being adherent to their index medication, and no differences were observed between apixaban and rivaroxaban. At 9 months, there were no differences between NOACs for overall adherence to oral anticoagulants.In this real-world analysis of adherence to NOACs, rivaroxaban and apixaban had favorable profiles compared with dabigatran, and rivaroxaban appeared to have higher overall adherence among the NOACs. Clinicians and managed care organizations should consider the implications of lower adherence on clinical outcomes as well as quality assessment.The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number UL1TR000117. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Brown reports receiving a training fellowship from Human and Pfizer. Study concept and design were contributed by Brown and Shewale. Talbert took the lead in data collection, along with Brown, and data interpretation was primarily performed by Brown, along with Shewale. The manuscript was written primarily by Brown, along with Shewale, and revised by all the authors.
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