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1.
Injury ; 51(4): 887-891, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32145902

ABSTRACT

INTRODUCTION: The purpose of this study was to investigate the prevalence of illicit drug use among patients admitted with traumatic orthopaedic injuries and to determine its effect on hospital length of stay (LOS). We hypothesized that patients with pre-injury drug use would have a longer hospital LOS compared to those who do not use drugs. METHODS: We conducted a retrospective cohort study at our level 1 urban trauma center of patients admitted with traumatic orthopaedic injuries between 2013 and 2015 with urine toxicology screening. We collected demographic and hospital LOS data from chart review. RESULTS: Of 611 patients, over half (55%) had a positive drug screen: marijuana (41%), amphetamine (19%), cocaine (7%), and/or PCP (2%). The highest incidence of drug use was in males under 19 years of age (81%). Patients with any drug use had a longer hospital LOS compared to those who did not use drugs (8.3 vs. 6.3 days; p = 0.03). Patients who used amphetamines had a longer hospital LOS than those patients who did not (9.5 vs. 6.9 days; p = 0.01). CONCLUSION: Compared to the orthopaedic trauma population two decades ago, the current population using illicit drugs is younger (<30 years) with an increased preference for amphetamine and marijuana and a decreased preference for cocaine. Pre-injury drug use was associated with a longer hospital LOS in patients with a traumatic orthopaedic injury. Knowledge of the current trends in illicit drug use amongst orthopaedic trauma patients could facilitate medical decision-making regarding clinical care and optimizing resource utilization in this complex population of individuals.


Subject(s)
Amphetamine-Related Disorders/epidemiology , Illicit Drugs/adverse effects , Length of Stay/statistics & numerical data , Marijuana Abuse/epidemiology , Wounds and Injuries/epidemiology , Adolescent , Adult , Aged , Aged, 80 and over , California/epidemiology , Cocaine-Related Disorders/epidemiology , Female , Humans , Incidence , Injury Severity Score , Male , Middle Aged , Orthopedics , Regression Analysis , Retrospective Studies , Trauma Centers , Young Adult
2.
Curr Med Res Opin ; 33(9): 1717-1723, 2017 09.
Article in English | MEDLINE | ID: mdl-28678604

ABSTRACT

BACKGROUND: Rivaroxaban is a novel oral anticoagulant indicated for prophylaxis against deep vein thrombosis and pulmonary embolism in patients undergoing total hip replacement (THR) or total knee replacement (TKR) surgery. OBJECTIVE: To evaluate major bleeding (MB) in THR/TKR patients receiving post-operative rivaroxaban. METHODS: Electronic medical records of nearly 10 million US Department of Defense (DoD) beneficiaries were queried from 1 January 2013 through 30 June 2015. Using the validated Cunningham case-finding algorithm, post-surgical MB events in rivaroxaban users were identified and analyzed. The incidence of MB was determined, and descriptive statistics were used to compare patient characteristics and other covariates in those with and without MB. Two additional methods were used to explore and identify bleeding cases that were not considered MB events per the study case-finding algorithm. RESULTS: A total of 12,429 patients received THR and/or TKR surgery, and were post-operatively prescribed rivaroxaban. Nine patients had MB, yielding an incidence proportion of 0.07% (95% CI 0.02-0.13). The alternative case-finding methods found bleeding incidences of 0.46% and 0.21%, though it is not clear whether these are clinical MB cases, since the alternative methods were not validated. CONCLUSIONS: The incidence of MB in this retrospective analysis is lower than that observed in the clinical trials of rivaroxaban. Whether this is due to lower real-world MB rates or challenges with case-finding algorithms is unclear.


Subject(s)
Anticoagulants/therapeutic use , Hemorrhage/epidemiology , Rivaroxaban/therapeutic use , Aged , Anticoagulants/adverse effects , Arthroplasty, Replacement, Hip/methods , Arthroplasty, Replacement, Knee/methods , Electronic Health Records , Female , Humans , Incidence , Male , Middle Aged , Pulmonary Embolism/etiology , Pulmonary Embolism/prevention & control , Retrospective Studies , Rivaroxaban/adverse effects , Venous Thrombosis/prevention & control
3.
Hematol Oncol Clin North Am ; 30(5): 1007-18, 2016 10.
Article in English | MEDLINE | ID: mdl-27637304

ABSTRACT

Elective total hip or knee arthroplasty places patients at risk for venous thromboembolism (VTE). As our understanding of the pathophysiology of VTE after joint arthroplasty has increased, pharmacologic strategies have been developed to target different aspects of the coagulation cascade. Various approaches have been used as risk reduction strategies. In 2011 and 2014 the Food and Drug Administration approved rivaroxaban and apixaban as new oral antithrombotic agents. Although controversies remain with regard to the ideal VTE pharmacoprophylactic agent, this class of novel oral anticoagulants has been demonstrated to be safe and to be more effective than enoxaparin.


Subject(s)
Anticoagulants/therapeutic use , Arthroplasty, Replacement, Knee/adverse effects , Arthroplasty, Replacement/adverse effects , Postoperative Complications/prevention & control , Thromboembolism/prevention & control , Administration, Oral , Anticoagulants/adverse effects , Humans , Postoperative Complications/blood , Thromboembolism/blood , Thromboembolism/etiology
4.
Postgrad Med ; 128(1): 76-84, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26631936

ABSTRACT

Opioid abuse is a healthcare and societal problem that burdens individuals, their families and the healthcare professionals who care for them. Restricting access to opioid analgesics is one option to deter abuse, but this may prevent pain patients in need from obtaining effective analgesics. Therefore, strategies that mitigate the risk of opioid abuse while maintaining access are being pursued by several stakeholders including federal agencies, state governments, payors, researchers, the pharmaceutical industry and clinicians. Federal agency efforts have included required licensure and documentation for prescribing opioids, implementation of risk evaluation and mitigation strategies, and guidance on assessment and labeling of opioid abuse-deterrent formulations. In addition, state governments and payors have enacted monitoring programs, and pharmaceutical companies continue to develop abuse-deterrent opioid formulations. Strategies for clinicians to mitigate opioid abuse include comprehensive patient assessment and universal precautions (e.g. use of multimodal analgesia and abuse-deterrent opioid formulations, urine toxicology screening, participation in prescription drug monitoring and risk evaluation and mitigation strategy programs).


Subject(s)
Acute Pain/drug therapy , Analgesics, Opioid/therapeutic use , Opioid-Related Disorders/prevention & control , Physician's Role , Drug Monitoring , Drug and Narcotic Control , Guideline Adherence , Humans , Opioid-Related Disorders/diagnosis , Opioid-Related Disorders/etiology , Pharmacovigilance , Practice Guidelines as Topic , Risk Assessment , United States
5.
Clin Pharmacol ; 5: 143-8, 2013.
Article in English | MEDLINE | ID: mdl-23946671

ABSTRACT

Routine thromboprophylaxis represents the current standard of care in the management of patients following total hip or knee replacement. Legacy agents used to address the issue of risk of venous thromboembolism present barriers to use, either by the need for monitoring and dose adjustment (warfarin) or the need for injection (low molecular weight heparins and fondaparinux), or pose a risk of upper gastrointestinal bleeding (acetylsalicylic acid and all antithrombotic agents). The introduction of new pharmacologic agents in recent years has sought to address the issues of not only efficacy, but also safety, ease of use, and patient compliance. New orally administered agents, ie, apixaban, dabigatran, and rivaroxaban, have demonstrated various degrees of efficacy over enoxaparin while preserving safety. Indirect comparisons of the relative efficacies of apixaban, dabigatran, and rivaroxaban have shown rivaroxaban to be more efficacious than dabigatran and apixaban in reducing symptomatic and total venous thromboembolism following total hip or knee replacement surgery. A pooled analysis of the four RECORD (Regulation of Coagulation in Orthopedic Surgery to Prevent deep vein thrombosis and pulmonary embolism) trials (two in total hip replacement and two in total knee replacement) demonstrated rivaroxaban to be the first and only antithrombotic agent ever to demonstrate superiority in reducing symptomatic venous thromboembolism and all-cause mortality compared with another antithrombotic agent (enoxaparin). New oral antithrombotic agents have demonstrated efficacy in prophylaxis against venous thromboembolism following total hip or knee replacement surgery while preserving safety, with increased ease of administration of thromboprophylaxis for both the patient and the physician, which may contribute to improved compliance.

7.
Ann Pharmacother ; 46(9): 1232-8, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22932305

ABSTRACT

OBJECTIVE: To evaluate potential drug-drug interactions with rivaroxaban in patients undergoing total hip replacement (THR) and total knee replacement (TKR) surgeries. DATA SOURCES: PubMed; January 2009-April 2012 abstract databases of major congresses for hematology and cardiovascular medicine. STUDY SELECTION AND DATA EXTRACTION: Searches were performed using the key words rivaroxaban and drug interaction. Studies were included if they evaluated interactions with drugs that are commonly used in patients undergoing THR or TKR, based on our clinical experience. DATA SYNTHESIS: A Phase 1 study found that coadministration of rivaroxaban and the nonsteroidal antiinflammatory drug (NSAID) naproxen significantly increased bleeding time. However, in a retrospective analysis of 4 large trials evaluating rivaroxaban in patients undergoing THR or TKR, the difference between major and clinically relevant nonmajor bleeding was not significantly different between NSAID users and nonusers. In addition, proton pump inhibitors, which are frequently coadministered with NSAIDs to prevent gastrointestinal toxicity, have not been demonstrated to cause any appreciable changes in rivaroxaban pharmacokinetics or pharmacodynamics. A Phase 2 study that evaluated several doses and administration intervals of rivaroxaban in combination with aspirin or both aspirin and clopidogrel in patients with acute coronary syndrome found that clinically significant bleeding events occurred in patients receiving rivaroxaban 10 mg daily (the dose approved for the orthopedic indication). However, this risk was not great enough to end the trial early. CONCLUSIONS: Phase 1 drug-drug interaction studies in healthy humans provided little insight into the pharmacodynamic drug interactions between rivaroxaban and NSAIDs or antiplatelet agents. A pooled analysis of the RECORD (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Vein Thrombosis and Pulmonary Embolism) trials and data from other large trials provides clinical evidence that these agents can be coadministered with rivaroxaban, as long as proper monitoring is instituted.


Subject(s)
Anticoagulants/therapeutic use , Arthroplasty, Replacement, Hip , Arthroplasty, Replacement, Knee , Morpholines/therapeutic use , Thiophenes/therapeutic use , Drug Interactions , Factor Xa Inhibitors , Humans , Rivaroxaban , Venous Thromboembolism/prevention & control
8.
Orthopedics ; 35(6): e932-8;discussion e939, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22691670

ABSTRACT

Patients undergoing major orthopedic surgery, including total hip arthroplasty (THA) and total knee arthroplasty (TKA), are at high risk for developing venous thromboembolism (VTE). Although largely a preventable complication, VTE develops in a significant proportion of patients, highlighting the need for improved methods of VTE prevention. Current thromboprophylactic options are limited by unpredictable pharmacokinetics and pharmacodynamics (vitamin K antagonists), parenteral/subcutaneous administration (heparin and low-molecular-weight heparins), complicated dosing, and increased risk of bleeding.Rivaroxaban is an oral, direct Factor Xa inhibitor that has recently received marketing authorization in the United States for prophylaxis of deep vein thrombosis in patients undergoing hip or knee replacement surgery. The clinical pharmacology of rivaroxaban supports a convenient, oral, once-daily dosing regimen without the need for routine coagulation monitoring after THA or TKA. A comprehensive phase II and III study program supports its safety and efficacy for VTE prevention after THA or TKA. Phase III results have demonstrated the superior efficacy of rivaroxaban regimens compared with enoxaparin regimens, with similar rates of major bleeding. This article provides an overview of the phase II and III results that support the use of this agent for the prevention of VTE after elective total hip or knee replacement.


Subject(s)
Factor Xa Inhibitors , Morpholines/administration & dosage , Postoperative Complications/prevention & control , Thiophenes/administration & dosage , Venous Thromboembolism/prevention & control , Administration, Oral , Dose-Response Relationship, Drug , Humans , Rivaroxaban , Treatment Outcome
9.
Expert Opin Pharmacother ; 13(3): 333-44, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22220855

ABSTRACT

INTRODUCTION: Concerns regarding risk versus benefit, that is, the possible impact of surgical-site bleeding on post-operative joint infections, have contributed to a continuing debate over recommendations for venous thromboembolism (VTE) prophylaxis in post-surgical orthopedic patients undergoing total hip and knee arthroplasty (THA/TKA). AREAS COVERED: A comprehensive literature search using MEDLINE covering the period 2004-2009 was conducted, and published studies that focused on THA and TKA and contained data applicable to thromboprophylaxis, post-surgical wound infection and bleeding are reviewed in this paper. The search strategy included various combinations of terms related to lower limb joint arthroplasty, anticoagulant drugs, post-operative bleeding and prosthetic joint infection (wound infection). Methodological constraints included failure in some studies to define an infection, variations among the studies in the definitions of bleeding and differences in the follow-up time for capturing infection and bleeding events. Despite this, this comprehensive review identified observational, 'real-world' data that can contribute in important ways to the existing evidence base. EXPERT OPINION: There are insufficient data to either confirm or refute the hypothesis that post-operative bleeding is a mediating pathophysiologic factor linking pharmacologic VTE prophylaxis to an increased risk for wound infection. Studies specifically designed to examine the interrelationship between thromboprophylaxis, bleeding and wound infections following THA/TKA are warranted.


Subject(s)
Anticoagulants/adverse effects , Arthroplasty, Replacement, Hip/adverse effects , Arthroplasty, Replacement, Knee/adverse effects , Hip Prosthesis/adverse effects , Knee Prosthesis/adverse effects , Postoperative Hemorrhage/chemically induced , Prosthesis-Related Infections/etiology , Venous Thromboembolism/prevention & control , Arthroplasty, Replacement, Hip/instrumentation , Arthroplasty, Replacement, Knee/instrumentation , Evidence-Based Medicine , Humans , Postoperative Hemorrhage/complications , Risk Assessment , Risk Factors , Treatment Outcome , Venous Thromboembolism/etiology
10.
J Arthroplasty ; 27(5): 659-66.e5, 2012 May.
Article in English | MEDLINE | ID: mdl-22035977

ABSTRACT

A survey was mailed to a representative sample of US orthopedic surgeons to assess protocols for the prevention of venous thromboembolism after lower extremity total joint arthroplasty. Practices were examined by type of operation, annual surgical volume, and opinions of consensus guidelines issued by the American Academy of Orthopaedic Surgeons and the American College of Chest Physicians. Although there was near-unanimous agreement that routine thromboprophylaxis should be the standard practice for patients who undergo hip or knee arthroplasty, surgeons were divided as to the exact management approach.


Subject(s)
Arthroplasty, Replacement, Hip/statistics & numerical data , Arthroplasty, Replacement, Knee/statistics & numerical data , Orthopedics/statistics & numerical data , Practice Patterns, Physicians'/statistics & numerical data , Venous Thromboembolism/epidemiology , Venous Thromboembolism/prevention & control , Anticoagulants/therapeutic use , Arthroplasty, Replacement, Hip/adverse effects , Arthroplasty, Replacement, Knee/adverse effects , Aspirin/therapeutic use , Drug Monitoring/statistics & numerical data , Humans , Orthopedics/education , Population Surveillance , Practice Guidelines as Topic , Societies, Medical/statistics & numerical data , Stockings, Compression/statistics & numerical data , United States/epidemiology , Venous Thromboembolism/etiology , Warfarin/therapeutic use
11.
Vasc Health Risk Manag ; 7: 461-6, 2011.
Article in English | MEDLINE | ID: mdl-21822393

ABSTRACT

Rivaroxaban (Bayer AG, Leverkusen, Germany) is a highly selective direct inhibitor of factor Xa. It has completed Phase III clinical trials evaluating its efficacy and safety against enoxaparin in the prophylaxis against venous thromboembolism (VTE) in orthopedic patients following primary total hip and total knee arthroplasty. Rivaroxaban has been extensively studied worldwide in 12,729 patients in the Regulation of Coagulation in Major Orthopedic Surgery Reducing the Risk of DVT and PE (RECORD) program. Pivotal clinical trials have demonstrated the superior efficacy in reducing total VTE in comparison with both the North American and European regimens of enoxaparin. Safety of the drug was found to be excellent, with no demonstrable cardiovascular or hepatic effects and no statistically significant increase in major bleeding. A pooled analysis of data collected on the patients from the four RECORD trials revealed rivaroxaban to be the first antithrombotic agent to demonstrate superiority over another antithrombotic (enoxaparin) in reducing symptomatic VTE and all-cause mortality. While there was a significant difference in the composite safety endpoint of major and clinically relevant nonmajor bleeding in the pooled analysis with the use of rivaroxaban compared with enoxaparin, there was no significant difference in major bleeding or in any other bleeding.


Subject(s)
Anticoagulants/therapeutic use , Arthroplasty, Replacement, Hip , Arthroplasty, Replacement, Knee , Clinical Trials as Topic , Fibrinolytic Agents/therapeutic use , Morpholines/therapeutic use , Thiophenes/therapeutic use , Venous Thromboembolism/prevention & control , Anticoagulants/adverse effects , Arthroplasty, Replacement, Hip/adverse effects , Arthroplasty, Replacement, Hip/mortality , Arthroplasty, Replacement, Knee/adverse effects , Arthroplasty, Replacement, Knee/mortality , Evidence-Based Medicine , Fibrinolytic Agents/adverse effects , Hemorrhage/chemically induced , Humans , Morpholines/adverse effects , Risk Assessment , Rivaroxaban , Thiophenes/adverse effects , Treatment Outcome , Venous Thromboembolism/etiology , Venous Thromboembolism/mortality
12.
Am J Manag Care ; 17(1 Suppl): S22-6, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21517652

ABSTRACT

Venous thromboembolism (VTE) following joint replacement surgery represents an economic as well as a clinical burden; however, the risk of thromboembolic events is greatly reduced by appropriate anticoagulation. Rivaroxaban, a Factor Xa inhibitor currently in phase III development, was compared with the low molecular weight heparin enoxaparin in 4 clinical trials, collectively called the RECORD program (REgulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism). In a pooled analysis of data from the RECORD trials, rivaroxaban was superior to enoxaparin regimens in reducing the composite end point of symptomatic venous thromboembolism and all-cause mortality in patients following elective primary total hip or total knee arthroplasty (THA or TKA), with a comparable incidence of major bleeding events. In cost-effectiveness analyses, compared with enoxaparin, rivaroxaban showed the potential to reduce costs associated with the prophylaxis and treatment of thromboembolic events in a post-orthopedic surgery/arthroplasty population.


Subject(s)
Anticoagulants/therapeutic use , Arthroplasty, Replacement, Hip/adverse effects , Arthroplasty, Replacement, Knee/adverse effects , Enoxaparin/therapeutic use , Morpholines/therapeutic use , Thiophenes/therapeutic use , Venous Thromboembolism/prevention & control , Anticoagulants/economics , Cost-Benefit Analysis , Enoxaparin/economics , Factor Xa Inhibitors , Humans , Morpholines/economics , Rivaroxaban , Thiophenes/economics , United States , Venous Thromboembolism/economics , Venous Thromboembolism/etiology
14.
Am J Manag Care ; 16(11): 857-63, 2010 Nov.
Article in English | MEDLINE | ID: mdl-21348557

ABSTRACT

BACKGROUND: Venous thromboembolism (VTE) following total hip replacement (THR) and total knee replacement (TKR) surgery imposes significant health and economic burden. OBJECTIVE: To examine the impact of thromboprophylaxis duration on deep vein thrombosis (DVT), pulmonary embolism (PE), total VTE (DVT and PE), and bleeding events among THR/TKR patients. METHODS: A retrospective study (April 1, 2004, to December 31, 2006) was conducted using a US health plan claims database linked to an inpatient database containing medication use. Outcomes were compared using χ2 tests; predictors of outcomes were analyzed using multivariate logistic regression. RESULTS: Of 3497 patients, 3195 (91%) received thromboprophylaxis for =1 day postsurgery. Most patients (67%) received short-duration (1-14 days) rather than extended-duration (>14 days) thromboprophylaxis. The incidence of thromboembolic and bleeding events was higher in those who received short-duration thromboprophylaxis: DVT (2.84% vs 1.24%; P = .0038), PE (1.12% vs 0.19%; P = .0052), total VTE (3.96% vs 1.43%; P <.0001), and major bleeding (1.68% vs 0.38%; P = .0011). Multivariate logistic regressions (adjusted for observed demographic and clinical characteristics) revealed similar results. Baseline comorbidity score was significantly associated with major bleeding; most of the bleeding events in those who received short-duration thromboprophylaxis occurred within the first 14 days. CONCLUSIONS: In this database analysis of patients who had undergone THR/TKR surgery, a large proportion of patients did not receive the minimum duration of thromboprophylaxis recommended by the guidelines. Extended-duration thromboprophylaxis was associated with a significantly lower risk of DVT, PE, and VTE compared with short-duration thromboprophylaxis.


Subject(s)
Arthroplasty, Replacement, Hip/methods , Arthroplasty, Replacement, Knee/methods , Orthopedics , Venous Thromboembolism/prevention & control , Anticoagulants/therapeutic use , Humans , Insurance Claim Review , Multivariate Analysis , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/therapeutic use , Pulmonary Embolism/prevention & control , Retrospective Studies , Risk Factors , Time Factors , Treatment Outcome , Venous Thrombosis/prevention & control
15.
Lancet ; 373(9676): 1673-80, 2009 05 16.
Article in English | MEDLINE | ID: mdl-19411100

ABSTRACT

BACKGROUND: Prophylaxis for venous thromboembolism is recommended for at least 10 days after total knee arthroplasty; oral regimens could enable shorter hospital stays. We aimed to test the efficacy and safety of oral rivaroxaban for the prevention of venous thromboembolism after total knee arthroplasty. METHODS: In a randomised, double-blind, phase III study, 3148 patients undergoing knee arthroplasty received either oral rivaroxaban 10 mg once daily, beginning 6-8 h after surgery, or subcutaneous enoxaparin 30 mg every 12 h, starting 12-24 h after surgery. Patients had mandatory bilateral venography between days 11 and 15. The primary efficacy outcome was the composite of any deep-vein thrombosis, non-fatal pulmonary embolism, or death from any cause up to day 17 after surgery. Efficacy was assessed as non-inferiority of rivaroxaban compared with enoxaparin in the per-protocol population (absolute non-inferiority limit -4%); if non-inferiority was shown, we assessed whether rivaroxaban had superior efficacy in the modified intention-to-treat population. The primary safety outcome was major bleeding. This trial is registered with ClinicalTrials.gov, number NCT00362232. FINDINGS: The primary efficacy outcome occurred in 67 (6.9%) of 965 patients given rivaroxaban and in 97 (10.1%) of 959 given enoxaparin (absolute risk reduction 3.19%, 95% CI 0.71-5.67; p=0.0118). Ten (0.7%) of 1526 patients given rivaroxaban and four (0.3%) of 1508 given enoxaparin had major bleeding (p=0.1096). INTERPRETATION: Oral rivaroxaban 10 mg once daily for 10-14 days was significantly superior to subcutaneous enoxaparin 30 mg given every 12 h for the prevention of venous thromboembolism after total knee arthroplasty. FUNDING: Bayer Schering Pharma AG, Johnson & Johnson Pharmaceutical Research & Development.


Subject(s)
Arthroplasty, Replacement, Knee/adverse effects , Morpholines/therapeutic use , Thiophenes/therapeutic use , Venous Thrombosis/prevention & control , Administration, Oral , Aged , Analysis of Variance , Anticoagulants/therapeutic use , Double-Blind Method , Enoxaparin/therapeutic use , Female , Follow-Up Studies , Hemorrhage/chemically induced , Hemorrhage/epidemiology , Humans , Incidence , Male , Middle Aged , Morpholines/adverse effects , Phlebography , Risk Reduction Behavior , Rivaroxaban , Sensitivity and Specificity , Thiophenes/adverse effects , Treatment Outcome , Venous Thrombosis/diagnostic imaging , Venous Thrombosis/epidemiology , Venous Thrombosis/etiology
16.
J Arthroplasty ; 23(6 Suppl 1): 25-30, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18722300

ABSTRACT

The use of outpatient anticoagulation after major orthopedic surgery with oral or injectable anticoagulants is recommended by national guidelines. A retrospective analysis of medical and pharmacy claims data using the PharMetrics Patient-Centric Database Inc, Watertown, Mass, was conducted. After adjusting for covariates, patients receiving warfarin were approximately 30% more likely to experience a venous thromboembolism than those receiving an injectable anticoagulant (6.3% vs 4.8%; adjusted odds ratio, 1.3; 95% confidence interval, 1.1-1.5) by 30 days. The data at 90 days showed similar results. No significant differences in the incidence of major bleeding events between the cohorts were observed (incidence of major bleed <0.4%). These findings support the randomized controlled studies and expand the data to the real-world perspective. Clinicians should evaluate these data alongside the clinical trial data when selecting the safest and most effective prophylactic therapy for postdischarge anticoagulation.


Subject(s)
Anticoagulants/administration & dosage , Orthopedic Procedures , Venous Thromboembolism/prevention & control , Administration, Oral , Arthroplasty , Female , Hemorrhage/chemically induced , Humans , Injections , Male , Middle Aged , Patient Discharge , Postoperative Complications/prevention & control , Pulmonary Embolism/prevention & control , Retrospective Studies , Warfarin/administration & dosage
17.
Clin Pharmacokinet ; 47(3): 203-16, 2008.
Article in English | MEDLINE | ID: mdl-18307374

ABSTRACT

BACKGROUND: There is a clinical need for novel oral anticoagulants with predictable pharmacokinetics and pharmacodynamics. Rivaroxaban is an oral direct Factor Xa (FXa) inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. This analysis was performed to characterize the population pharmacokinetics and pharmacodynamics of rivaroxaban in patients participating in two phase II, double-blind, randomized, active-comparator-controlled studies of twice-daily rivaroxaban for the prevention of venous thromboembolism after total hip- or knee-replacement surgery. METHODS: Sparse blood samples were taken from all patients participating in the studies (n = 1009). In addition, a subset of patients in the hip study (n = 36) underwent full profiling. Rivaroxaban plasma concentrations, FXa activity and the prothrombin time were determined. Nonlinear mixed-effects modelling was used to model the population pharmacokinetics and pharmacodynamics of rivaroxaban. RESULTS: An oral one-compartment model described the population pharmacokinetics of rivaroxaban well. On the first postoperative day only, categorization of patients as slow or fast absorbers as a tool to address variability in absorption improved the fit of the model. Clearance of rivaroxaban was lower and more variable on the first postoperative day, and so time was factored into the model. Overall, the only major difference between the models for the hip study and the knee study was that clearance was 26% lower in the knee study, resulting in approximately 30% higher exposure. Residual variability in the models was moderate (37% and 34% in the hip and knee studies, respectively). Plasma concentrations of rivaroxaban increased dose dependently. Pharmacokinetic parameters that were estimated using the models agreed closely with results from full-profile patients in the hip study, demonstrating that rivaroxaban pharmacokinetics are predictable. The pharmacokinetics of rivaroxaban were affected by expected covariates: age affected clearance in the hip study only, haematocrit (on the first postoperative day only) and gender affected clearance in the knee study only, and renal function affected clearance in both studies. Bodyweight affected the volume of distribution in both studies. However, the effects of covariates on the pharmacokinetics of rivaroxaban were generally small, and predictions of 'extreme' case scenarios suggested that fixed dosing of rivaroxaban was likely to be possible. FXa activity and the prothrombin time were both affected by surgery, probably because of perioperative bleeding and intravenous administration of fluids; therefore, time was included in the pharmacodynamic models. In both studies, FXa activity correlated with rivaroxaban plasma concentrations following a maximum effect model, whereas prothrombin time prolongation correlated following a linear model with intercept. The slope of the prothrombin time prolongation correlation was 3.2 seconds/(100 microg/L) in the hip study and 4.2 seconds/(100 microg/L) in the knee study. Both pharmacodynamic models in both studies demonstrated low residual variability of approximately 10%. CONCLUSION: This population analysis in patients undergoing major orthopaedic surgery demonstrated that rivaroxaban has predictable, dose-dependent pharmacokinetics that were well described by an oral one-compartment model and affected by expected covariates. Rivaroxaban exposure could be assessed using the prothrombin time, if necessary, but not the international normalized ratio. The findings suggested that fixed dosing of rivaroxaban may be possible in patients undergoing major orthopaedic surgery.


Subject(s)
Factor Xa Inhibitors , Morpholines/pharmacology , Morpholines/pharmacokinetics , Thiophenes/pharmacology , Thiophenes/pharmacokinetics , Venous Thromboembolism/prevention & control , Adult , Age Factors , Aged , Aged, 80 and over , Arthroplasty, Replacement, Hip , Arthroplasty, Replacement, Knee , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Male , Middle Aged , Models, Biological , Morpholines/administration & dosage , Nonlinear Dynamics , Prothrombin Time , Rivaroxaban , Sex Factors , Thiophenes/administration & dosage , Time Factors , Tissue Distribution
18.
Thromb Haemost ; 97(6): 931-7, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17549294

ABSTRACT

Rivaroxaban (BAY 59-7939) is an oral, direct factor Xa inhibitor in clinical development for the prevention and treatment of venous thromboembolism (VTE). This analysis of pooled results from two phase II studies of rivaroxaban for VTE prevention after major orthopaedic surgery aimed to strengthen the conclusions of the individual studies. One study was conducted in patients undergoing total hip replacement (THR; N = 722), and one in patients undergoing total knee replacement (TKR; N = 621). In both studies, patients were randomized, doubleblind, to oral, twice-daily (bid) rivaroxaban beginning after surgery, or subcutaneous enoxaparin (40 mg once daily beginning before THR, and 30 mg bid beginning after TKR). Treatment continued until mandatory bilateral venography was performed 5-9 days after surgery. Total VTE (deep vein thrombosis, pulmonary embolism, and all-cause mortality) occurred in 16.1-24.4% of per-protocol patients receiving rivaroxaban 5-60 mg, and 27.8% receiving enoxaparin (n = 914). There was a flat dose response relationship between rivaroxaban and total VTE (p = 0.39). Major bleeding (safety population, n = 1,317) increased dose-dependently with rivaroxaban (p < 0.001), occurring in 0.9%, 1.3%, 2.1%, 3.9%, and 7.0% of patients receiving rivaroxaban total daily doses of 5, 10, 20, 40, and 60 mg, respectively, versus 1.7% of patients receiving enoxaparin. No routine coagulation monitoring was performed, and there were no significant differences between dose response relationships with rivaroxaban after THR and TKR. Overall, rivaroxaban total daily doses of 5-20 mg had the most favorable balance of efficacy and safety, relative to enoxaparin, for the prevention of VTE after major orthopaedic surgery.


Subject(s)
Arthroplasty, Replacement, Hip/adverse effects , Arthroplasty, Replacement, Knee/adverse effects , Enoxaparin/therapeutic use , Fibrinolytic Agents/therapeutic use , Morpholines/therapeutic use , Pulmonary Embolism/prevention & control , Thiophenes/therapeutic use , Venous Thrombosis/prevention & control , Adult , Aged , Aged, 80 and over , Dose-Response Relationship, Drug , Enoxaparin/adverse effects , Female , Fibrinolytic Agents/adverse effects , Hemorrhage/chemically induced , Humans , Incidence , Male , Middle Aged , Morpholines/adverse effects , Phlebography , Pulmonary Embolism/diagnostic imaging , Pulmonary Embolism/etiology , Pulmonary Embolism/mortality , Rivaroxaban , Thiophenes/adverse effects , Treatment Outcome , Venous Thrombosis/diagnostic imaging , Venous Thrombosis/etiology , Venous Thrombosis/mortality
19.
Thromb Res ; 121(1): 17-24, 2007.
Article in English | MEDLINE | ID: mdl-17449088

ABSTRACT

INTRODUCTION: Venous thromboembolism (VTE) is an important cause of morbidity and mortality following major orthopedic surgeries. In clinical trials, fondaparinux and low molecular weight heparins have been shown to be more effective than unfractionated heparin (UFH) in preventing VTE. We retrospectively analyzed a large hospital discharge database to assess the occurrence of clinically detected VTE as a function of the injectable antithrombotic agent used for VTE prophylaxis in orthopedic surgery. METHODS: The Premier's Perspective database, representing over 500 hospitals across the US, was utilized to identify patients receiving dalteparin, enoxaparin, fondaparinux, or UFH following hip or knee replacement or hip fracture surgery between January 2003 and March 2005. The primary outcome was the proportion of patients in each cohort with a VTE, while secondary outcomes included VTE occurrence during index hospitalization, and proportion of patients with a VTE-associated hospital readmission. RESULTS: A total of 144,806 patients were included in the study. Significantly fewer fondaparinux patients experienced a VTE event (1.5%) compared to enoxaparin (2.3%), dalteparin (2.1%), and UFH (4.2%). After controlling for baseline covariates, the odds of experiencing a VTE was significantly higher for other treatments when compared to fondaparinux (odds ratios: dalteparin=1.22 [95% CI: 1.01 to 1.46] p=0.0370; enoxaparin=1.39 [1.19 to 1.62], p<0.0001; UFH=1.98 [1.67 to 2.34], p<0.0001). Significantly fewer fondaparinux-treated patients experienced an event during the index hospitalization or were readmitted for a VTE compared to other treatments. CONCLUSIONS: Similar to clinical trial findings, patients receiving fondaparinux in this study experienced fewer VTE events following orthopedic surgeries.


Subject(s)
Heparin/therapeutic use , Orthopedic Procedures/adverse effects , Polysaccharides/therapeutic use , Postoperative Complications/prevention & control , Premedication/methods , Venous Thromboembolism/prevention & control , Aged , Chemoprevention/methods , Cohort Studies , Dalteparin/therapeutic use , Data Collection , Enoxaparin/therapeutic use , Female , Fondaparinux , Humans , Male , Retrospective Studies , Venous Thromboembolism/etiology
20.
J Arthroplasty ; 20(4 Suppl 2): 12-4, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15991121

ABSTRACT

Venous thromboembolism is a recognized complication of total hip arthroplasty, knee arthroplasty, and hip fracture surgery. Various pharmacological agents have been introduced in orthopedic surgery in an attempt to reduce the mortality as well as the short-term and long-term morbidity associated with the development of deep vein thrombosis and pulmonary embolism. Clinical trials demonstrate the increasing thromboprophylactic efficacy of newer generations of drugs. The most current guidelines of the American College of Chest Physicians regarding thromboprophylaxis after total hip arthroplasty, total knee arthroplasty, and hip fracture surgery give the highest recommendations in support of the use of low-molecular-weight heparin, warfarin, or fondaparinux. Their highest recommendation is also given against the use of aspirin due to its lack of demonstrated efficacy.


Subject(s)
Anticoagulants/therapeutic use , Arthroplasty, Replacement , Postoperative Complications/prevention & control , Venous Thrombosis/prevention & control , Anticoagulants/administration & dosage , Arthroplasty, Replacement, Hip , Arthroplasty, Replacement, Knee , Aspirin/administration & dosage , Aspirin/therapeutic use , Heparin, Low-Molecular-Weight/administration & dosage , Heparin, Low-Molecular-Weight/therapeutic use , Humans
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