Milvexian for the Prevention of Venous Thromboembolism.

BACKGROUND: Factor XIa inhibitors for the prevention and treatment of venous and arterial thromboembolism may be more effective and result in less bleeding than conventional anticoagulants. Additional data are needed regarding the efficacy and safety of milvexian, an oral factor XIa inhibitor. METHODS: In this parallel-group, phase 2 trial, we randomly assigned 1242 patients undergoing knee arthroplasty to receive one of seven postoperative regimens of milvexian (25 mg, 50 mg, 100 mg, or 200 mg twice daily or 25 mg, 50 mg, or 200 mg once daily) or enoxaparin (40 mg once daily). The primary efficacy outcome was venous thromboembolism (which was a composite of asymptomatic deep-vein thrombosis, confirmed symptomatic venous thromboembolism, or death from any cause). The principal safety outcome was bleeding. RESULTS: Among the patients receiving milvexian twice daily, venous thromboembolism developed in 27 of 129 (21%) taking 25 mg, in 14 of 124 (11%) taking 50 mg, in 12 of 134 (9%) taking 100 mg, and in 10 of 131 (8%) taking 200 mg. Among those receiving milvexian once daily, venous thromboembolism developed in 7 of 28 (25%) taking 25 mg, in 30 of 127 (24%) taking 50 mg, and in 8 of 123 (7%) taking 200 mg, as compared with 54 of 252 patients (21%) taking enoxaparin. The dose-response relationship with twice-daily milvexian was significant (one-sided P<0.001), and the 12% incidence of venous thromboembolism with twice-daily milvexian was significantly lower than the prespecified benchmark of 30% (one-sided P<0.001). Bleeding of any severity occurred in 38 of 923 patients (4%) taking milvexian and in 12 of 296 patients (4%) taking enoxaparin; major or clinically relevant nonmajor bleeding occurred in 1% and 2%, respectively; and serious adverse events were reported in 2% and 4%, respectively. CONCLUSIONS: Postoperative factor XIa inhibition with oral milvexian in patients undergoing knee arthroplasty was effective for the prevention of venous thromboembolism and was associated with a low risk of bleeding. (Funded by Bristol Myers Squibb and Janssen Research and Development; AXIOMATIC-TKR ClinicalTrials.gov number, NCT03891524.).

Clinical and radiographic outcomes following anatomic total shoulder arthroplasty utilizing an inset glenoid component at 2-year minimum follow-up: a dual center study.

BACKGROUND: Anatomic total shoulder arthroplasty (aTSA) is a successful and reproducible treatment for patients with painful glenohumeral arthritis. However, long-term outcomes using traditional onlay glenoid components have been tempered by glenoid loosening. Inset components have been proposed to minimize glenoid loosening by reducing edge-loading and opposite-edge lift-off forces with humeral translation. Successful short- and long-term outcomes have been reported while using inset glenoid implants. The current study is the largest study presenting a minimum of 2-year follow-up data following aTSA with an all-polyethylene inset glenoid component (Shoulder Innovations, Holland, MI, USA). METHODS: A dual center, retrospective review of patients undergoing aTSA using an Inset glenoid component by 2 fellowship-trained shoulder surgeons at 2 separate institutions from August, 2016, to August, 2019, was performed. Minimum follow-up was 2 years. Range of motion (ROM), visual analog scale (VAS) pain scores, Single Assessment Numeric Evaluation (SANE), and American Shoulder and Elbow Surgeons (ASES) scores were obtained. Radiographic outcomes, including central peg lucency and glenoid loosening, were assessed by 3 independent reviewers on the postoperative Grashey and axillary radiographs obtained at the final follow-up. RESULTS: Seventy-five shoulders were included for the final analysis. The mean age of the entire cohort was 64 (±11.4) years. Twenty-one (28%) glenoids were type A1, 10 (13.3%) were type A2, 13 (17.3%) were type B1, 22 (29.3%) were type B2, 6 (8%) were type B3, and 3 (4%) were type D. At a minimum follow-up of 24 months (mean: 28.7 months), a significant improvement in ROM in all planes was observed. Significant improvements in VAS (5.1-0.9, P < .001), SANE (39.5-91.2, P < .001), and ASES (43.7-86.6, P < .001) scores were observed. There were 4 (5.3%) cases of central peg lucency about the inset glenoid component and one (1.3%) case of glenoid loosening. No revisions were performed for glenoid loosening. CONCLUSION: At a minimum of 2 years postoperatively, there were significant improvements in ROM, VAS, SANE, and ASES scores with very low rates of central peg lucency and glenoid loosening in patients undergoing aTSA with an inset glenoid component. Further work is needed to determine the long-term benefit of this novel implant.

Patients who have undergone total shoulder arthroplasty prefer greater surgeon involvement in shared decision making.

BACKGROUND: There has been a shift in medical decision making from a paternalist model to a shared decision-making (SDM) approach, described as a patient-physician relationship where both parties collaborate to arrive on an evidence-based treatment regimen that best suits the patient's needs and values. However, there is a scarcity in evidence regarding SDM in shoulder arthroplasty. The purpose of this study was to evaluate overall patient preference for SDM and determine demographic and socioeconomic factors related to SDM preference in those undergoing shoulder arthroplasty. METHODS: Patients aged 40-89 years who had undergone a total shoulder arthroplasty were enrolled. Two-part questionnaires were administered collecting patient demographic information and SDM subscale scores postoperatively. Bivariate and multivariate regression models were used to determine factors associated with SDM Total and subscale scores. RESULTS: A total of 125 patients (53 male; mean age, 69.5 ± 10.4 years) who had undergone primary total shoulder arthroplasty were included. The mean Total SDM score was -2.24 ± 1.9 and the Preoperative, Operative, and Postoperative SDM subscale scores were -1.54 ± 2.0, -2.59 ± 2.2, and -2.48 ± 2.1, respectively, indicating a preference for SDM in the Preoperative subscale and surgeon-driven decision making in the total score and other 2 subscales. Multivariate regression models demonstrated a preference for surgeon decision making at both the 4-12-week postoperative period for the Preoperative subscale (odds ratio [OR] -1.03, 95% CI -2.0, -0.1, P = .039) and the 2-4-week postoperative period for the Operative subscale (OR -1.74, 95% CI -3.4, -0.1, P = .038) when compared to patients at the 2-week postoperative period. No other variables were significantly associated with any of the SDM subscale scores or Total SDM score. CONCLUSION: Patients reported a more passive role in the decision-making process with an overall preference for a surgeon-led approach in primary total shoulder arthroplasty. Patients preferred a shared decision-making approach in regard to preoperative considerations but indicated a significant preference for surgeon-led decision making regarding day of surgery decisions. There were no correlations between SDM scores and age, sex, race, income, education level, insurance type, or treating surgeon. Overall, patients demonstrated a predilection for an SDM approach for preoperative considerations, contrary to those decisions associated with the day of surgery and postoperative care.

Validation of the Artificial Floor Technique in First Metatarsophalangeal Joint Arthrodesis.

BACKGROUND: Patient function after arthrodesis of the first metatarsophalangeal joint (MTPJ) relies on proper positioning of the first MTPJ. To maximize the likelihood of good postoperative function, the dorsiflexion angle, referred to as the fusion sagittal angle, should range between 20° and 30°, corresponding to 10° to 15° of dorsiflexion off the weightbearing axis. However, achieving appropriate sagittal alignment intraoperatively is challenging. The artificial floor technique (AFT) uses a rigid, flat surface to simulate the weightbearing position of the foot intraoperatively to accurately position the first MTPJ without fluoroscopy. This technique has been previously described and is commonly used but, to our knowledge, it has never been validated. QUESTIONS/PURPOSES: (1) Is the AFT a valid and repeatable technique for positioning the fusion sagittal angle between 20° and 30° of dorsiflexion from the first metatarsal? (2) Does the fusion sagittal angle obtained using the AFT vary with foot size? METHODS: In this retrospective study, a search was performed using Current Procedural Terminology codes for patients undergoing first MTPJ arthrodesis by one surgeon between June 2012 and June 2020. The surgical technique used during this time did not vary and consisted of the use of a rigid, flat, sterile surface. The entire foot was placed flat on the surface, simulating the weightbearing position and allowing for an evaluation of the fusion sagittal angle of the first MTPJ. The target sagittal alignment was achieved when the soft tissue of the plantar surface at the distal-most aspect of the proximal phalanx was measured (using a sterile ruler) as 1 cm off the artificial floor. The recommended fusion sagittal angle falls within a range of 20° to 30°, which allows for 1-mm to 2-mm variations in measuring the elevation of the proximal phalanx off the artificial floor. Fixation was achieved with two 2.8-mm threaded, double-pointed Steinmann pins placed through the intramedullary canal of the proximal and distal phalanges and into the first metatarsal. Once fixation was achieved, the fusion sagittal angle was confirmed with the AFT without using fluoroscopy. Postoperatively, patients were allowed to bear weight fully on their heels in a postoperative, rigid-soled shoe. During the study period, 117 patients (135 feet) underwent first MTPJ arthrodesis utilizing the AFT for either first MTPJ arthritis/hallux rigidus, hallux valgus, or inflammatory arthropathy. Of those, we considered patients with preoperative AP and lateral weightbearing radiographs and patients with AP and lateral weightbearing radiographs at 3 months postoperatively after the removal of the internal fixation construct as eligible for analysis. Based on these criteria, 84% (113 of 135) of feet were included in the final radiographic analysis. Sixteen percent (22 of 135) of the feet were excluded because postoperative radiographs demonstrating the removal of the internal fixation construct were absent from the Picture Archiving and Communication System (PACS) in these cases. The length of the whole foot, first metatarsal, and proximal phalanx were measured on preoperative weightbearing radiographs. In addition, fusion sagittal angles were measured on weightbearing radiographs after removal of internal fixation construct at a minimum of 3 months postoperatively (mean 3.5 ± 2.2 months). No patients were lost to follow-up before obtaining those radiographs. Two qualified reviewers independently evaluated each radiograph. We ascertained inter- and intraobserver reliability using intraclass correlation coefficients (ICCs). We determined whether the fusion sagittal angle obtained using the AFT varied with foot size by using a multiple linear regression model. RESULTS: In the entire study group, the mean fusion sagittal angle using the AFT was 27° ± 4°. The interobserver ICC of the fusion sagittal angle measurements was 0.92 (95% confidence interval [CI] 0.56 to 0.97; p < 0.001). The intraobserver ICC for reviewer 1 was 0.95 (95% CI 0.92 to 0.97; p < 0.001) and the intraobserver ICC for reviewer 2 was 0.97 (95% CI 0.88 to 0.98; p < 0.001). Ninety-one percent (103 of 113) of the study group fell within the acceptable range of 20° to 30° ± 2°. The multiple linear regression analyses demonstrated that the preoperative lengths of the whole foot (ß =-0.05 [95% CI -0.12 to 0.02]; p = 0.16), proximal phalanx (ß =-0.13 [95% CI -0.46 to 0.20]; p = 0.44), and first metatarsal (ß = 0.13 [95% CI -0.10 to 0.35]; p = 0.27) were not independently associated with the postoperative fusion sagittal angle. CONCLUSION: The AFT allows for accurate and reproducible positioning of the first MTPJ within the appropriate functional range of dorsiflexion, regardless of foot size. Additionally, this technique can be performed without fluoroscopy and so avoids radiation exposure to the patient and the surgical team. LEVEL OF EVIDENCE: Level III, therapeutic study.

Restoration of the native humeral anatomy during stemless anatomic total shoulder arthroplasty: a radiographic comparison of intramedullary versus freehand resection.

BACKGROUND: During anatomic total shoulder arthroplasty (aTSA), the humeral head can be resected with or without the use of an intramedullary cutting guide, the former referred to as intramedullary (IM) resection and the latter referred to as freehand (FH) resection. Outcomes following aTSA are predicated upon the restoration of the native humeral anatomy, which can be more challenging with stemless implants. To date, no studies have determined which method of humeral head resection is superior in restoring native anatomy. Our purpose was to determine whether FH or IM resection was superior in restoring native anatomy during aTSA with stemless implants. METHODS: A review of all patients who underwent aTSA using the stemless Tornier Simpliciti Shoulder System at two academic institutions by two separate surgeons between January 2017 and June 2020 was performed. One surgeon at one institution performed stemless aTSA using the IM resection technique, while the second surgeon utilized the FH resection technique. Patients were excluded if they underwent surgery for an indication other than glenohumeral osteoarthritis, if they received a short-stem or standard-stem implant, or if they lacked adequate preoperative and postoperative Grashey radiographs. One hundred eleven patients across both institutions (51 IM, 60 FH) were included for the final radiographic assessment. The humeral head height (HH) and neck-shaft angle (NSA) were measured on preoperative and postoperative Grashey radiographs. The centers of rotation (CORs) were measured on postoperative Grashey radiographs. Patients were classified as having acceptable restoration of their native anatomy if the change (Δ) in COR or HH was ≤3 mm and ≤ 5 mm, respectively, or if the postoperative NSA was ≥130°. RESULTS: IM resection had the greatest acceptable restoration of COR (90.2% IM versus 70% FH, P = .009), HH (96.1% IM vs. 63.3% FH, P < .001), and NSA (96.1% IM vs. 78.3% FH, P = .006) relative to FH resection. The mean postoperative NSAs for the IM and FH cohorts were 134.4° (±2.1°) and 133.8° (±5.4°), respectively (P = .208). The mean ΔCORs for the IM and FH groups were 1.2 (±1.5) and 2.3 (±1.2) mm, respectively (P < .001). Finally, the mean ΔHHs for the IM and FH cohorts were 1.7 (±1.4) and 4.4 (±2.9) mm, respectively (P < .001). CONCLUSIONS: Restoration of the native humeral anatomy following stemless aTSA occurred at a significantly higher rate when using IM vs. FH resection.

Effects of opioid-limiting legislation on postoperative opioid use in shoulder arthroplasty in an epidemic epicenter.

BACKGROUND: The current opioid epidemic in the United States has become a public health crisis with an estimated 150 daily deaths and nearly 47,000 opioid-related deaths in the United States in 2017 alone. Sensible prescriber practice changes have been a focus of policymakers to decrease the total number of narcotic pain medications in circulation. In the state of Ohio, opioid prescription limits for acute pain were enacted in August 2017. However, given the association of acute opioid exposure with long-term use and lack of assessment of these policies, there is an unmet need to evaluate the effects of similar legislation in Ohio on postoperative opioid dosing after shoulder arthroplasty. This study evaluates the effects of opioid prescription-limiting legislation in Ohio on postoperative opioid dosing in shoulder arthroplasty and assesses risk factors related to long-term opioid use. METHODS: All patients undergoing primary and revision shoulder arthroplasty over a 5-year period performed by a single surgeon were included. The pre-legislation (PRE) and post-legislation (POST) groups were defined as patients undergoing shoulder arthroplasty before August 31, 2017 and on or after August 31, 2017, respectively. The Ohio Automated Rx Reporting System was queried for controlled-substance prescriptions from 30 days preoperatively to 90 days postoperatively. Patients were designated as opioid tolerant if they had filled an opioid prescription within 30 days of surgery. A binary logistic regression analysis was applied to assess factors related to long-term opioid use. RESULTS: A total of 334 patients were categorized into 2 cohorts: PRE (n = 99) and POST (n = 235). Accounting for legislative effects, we observed significant reductions in cumulative morphine milligram equivalent (MME) dosing in the opioid-naive patients in the 7-day and 30-day postoperative periods (450.0 MMEs in PRE group vs. 210.0 MMEs in POST group, P < .001) and in the opioid-tolerant patients in the 7-day postoperative period (450.0 MMEs in PRE group vs. 250.0 MMEs in POST group, P = .001). Among the opioid-naive patients, the POST group had a significant MME reduction in the 90-day postoperative period relative to the PRE cohort (P < .001). Preoperative opioid tolerance and benzodiazepine tolerance were independent risk factors for increased MME dosing at 90 days postoperatively (P < .001 and P = .02, respectively). CONCLUSION: Opioid prescription-limiting legislation for acute pain in the state of Ohio is associated with a notable reduction in opioid MME dosing in the 90-day postoperative period after shoulder arthroplasty, particularly in opioid-naive patients in the first 30 days postoperatively. Preoperative opioid tolerance is correlated with significantly higher MME dosing postoperatively after shoulder arthroplasty.

Worse Outcomes Are Associated With Proximal Femoral Replacement Following Periprosthetic Joint Infection.

BACKGROUND: Proximal femoral replacements (PFRs) are often used in the setting of severe bone loss. As osteolysis has become less common, PFR may be used to address other causes of bone loss such as infection or periprosthetic fracture. The aim of this study is to investigate the clinical outcomes of PFR for non-neoplastic conditions. METHODS: A retrospective review of 46 patients undergoing PFR at a single institution was performed. The electronic records were reviewed to extract relevant information including the reason for use of PFR, surgical variables, follow-up, and complications. Survivorship curves were generated and differences in survivorship were evaluated using the log-rank test. Radiographic evaluation was also performed. RESULTS: Using revision as an endpoint, the Kaplan-Meier analysis of the entire cohort demonstrated a survival rate of 74% at 1 year and 67% at 5 years. Patients with a preoperative diagnosis of periprosthetic joint infection demonstrated the lowest survivorship with a failure rate of 47%. Furthermore, a high dislocation rate at 17.4% (n = 8) was observed. The use of dual-mobility articulation was effective in reducing dislocation. CONCLUSION: PFR is a valuable reconstructive option for patients with massive proximal femoral bone loss. This study demonstrates that patients with periprosthetic joint infection who undergo PFR reconstruction are at very high risk of subsequent failure, most commonly from reinfection and instability. The use of a dual-mobility articulation in association with PFR appears to help mitigate risk of subsequent dislocation.

Diagnostic delay and characterization of the clinical prodrome in AL amyloidosis among 1523 US adults diagnosed between 2001 and 2019.

Light-chain (AL) amyloidosis is a multisystem disorder with a high early mortality and diagnostic delays of >1 year from symptom onset. This retrospective observational study sought to characterize the clinical prodrome and diagnostic delay to inform early detection. We identified 1523 adults with newly diagnosed AL amyloidosis in the Optum de-identified Clinformatics® Datamart US healthcare claims database as those with ≥2 new diagnosis codes for AL or other amyloidosis in 90 days with ≥1 multiple myeloma treatment within 730 days, excluding patients with prior hereditary or secondary amyloidosis and Familial Mediterranean Fever. We considered 34 signs/symptoms using diagnosis codes in all observable time on or before AL amyloidosis diagnosis. Sign/symptom prevalence was compared to that of 1:4 matched population controls. The overlap and sequence of signs/symptoms and the median time from first sign/symptom to AL amyloidosis diagnosis were explored. Healthcare utilization was summarized. The most common individual AL amyloidosis signs/symptoms were malaise/fatigue (61%) and dyspnea (59%). Cardiac signs/symptoms were observed in 77% of patients, followed by renal (62%) and neurologic (59%) signs/symptoms. Multisystem involvement (≥3 systems) was present in 54%. Monoclonal gammopathy was detected in 29% before diagnosis. Median time from symptom onset to AL amyloidosis diagnosis was 2.7 years. Healthcare utilization was high between first AL amyloidosis signs/symptoms and diagnosis, with 50% visiting ≥5 physician types. AL amyloidosis patients have a lengthy and complex clinical prodrome. Novel approaches to early diagnosis are needed to improve outcomes.

Evaluating the role of graft integrity on outcomes: clinical and imaging results following superior capsular reconstruction.

BACKGROUND: Superior capsular reconstruction (SCR) addresses massive, irreparable rotator cuff tears in young patients. The purpose of this study was to retrospectively evaluate clinical outcomes and graft integrity in patients following SCR. METHODS: Thirty-four consecutive patients undergoing SCR by 2 surgeons with minimum 2-year follow-up were identified. Functional outcomes were obtained, including Simple Shoulder Test (SST), American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES), visual analog scale (VAS), and Single Assessment Numeric Evaluation (SANE) scores. Graft integrity was evaluated on magnetic resonance images (MRIs). RESULTS: Thirty-five shoulders in 34 patients were identified. Four patients underwent subsequent surgery. The mean preoperative scores were SST 21.6 ± 17.6, ASES 28.3 ± 10.1, SANE 50.6 ± 22.1, and VAS 6.6 ± 1.7. The mean postoperative outcomes were SST 79.1 ± 19.6, ASES 79.9 ± 17.4, SANE 74.3 ± 18.7, and VAS 1.5 ± 2.2. There was statistically significant improvement in SST, ASES, and VAS following SCR. MRI revealed graft failure in 62% (n = 13 of 21) of shoulders. Radiographic evidence of graft healing did not have any effect on SST, ASES, SANE, or VAS scores. CONCLUSION: Given the high rate of graft failure without a significant difference in clinical outcomes, graft healing after SCR might not be an independent predictor of success. The improved clinical improvement in patients undergoing SCR may be due to other known beneficial aspects of the procedure, including partial rotator cuff repair, débridement, and biceps management.

Distal Femoral Replacement and Periprosthetic Joint Infection After Non-Oncological Reconstruction: A Retrospective Analysis.

BACKGROUND: Distal femoral replacement (DFR) is commonly used to manage massive bone loss around the knee arising from aseptic loosening, periprosthetic joint infection (PJI), and distal femoral fractures. A number of studies report the outcome of DFR with considerable variation in long-term survivorship. This study investigated the outcome of DFR for patients with aseptic failures, fractures, and PJI. METHODS: A retrospective review of 182 patients who underwent DFR for non-oncological indications between 2002 and 2018 was conducted. Data collected included the following: indication, postoperative complications, reoperation, revision, and follow-up. Implant survivorship with Kaplan-Meier curves along with a log-rank test for different preoperative indications was performed. A Cox regression model was used to evaluate the risk of revision. RESULTS: The overall postoperative complication rate was very high at 36%. The most common complication was PJI (17%). The rate of reoperation for any cause was 29.7%, and the revision rate was 13.7%. The most common cause of re-revision was PJI (7.1%). Revision-free survivorship of the DFR implant was 91.6% at 1 year, 87.9% at 2 years, 82.5% at 5 years, and 73.4% at 10 years. Patients who had a prior-PJI had the lowest survivorship compared to patients undergoing DFR for management of periprosthetic fracture and mechanical loosening. Additionally, the prior-PJI group was at a fourfold increased risk of postoperative PJI compared to the aseptic group. CONCLUSION: DFR is a valuable reconstructive option for patients with massive bone loss around the knee. However, patients undergoing DFR are at high risk of complications, reoperations, and failure.

Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial.

BACKGROUND: Dual antiplatelet therapy (DAPT), aspirin plus a P2Y12 inhibitor, is the standard antithrombotic treatment following acute coronary syndromes. The factor Xa inhibitor rivaroxaban reduced mortality and ischaemic events when added to DAPT, but caused increased bleeding. The safety of a dual pathway antithrombotic therapy approach combining low-dose rivaroxaban (in place of aspirin) with a P2Y12 inhibitor has not been assesssed in acute coronary syndromes. We aimed to assess rivaroxaban 2·5 mg twice daily versus aspirin 100 mg daily, in addition to clopidogrel or ticagrelor (chosen at investigator discretion before randomisation), for patients with acute coronary syndromes started within 10 days after presentation and continued for 6-12 months. METHODS: In this double-blind, multicentre, randomised trial (GEMINI-ACS-1) done at 371 clinical centres in 21 countries, eligible patients were older than 18 years with unstable angina, non-ST segment elevation myocardial infarction (NSTEMI) or ST segment elevation myocardial infarction (STEMI), with positive cardiac biomarkers and either ischaemic electrocardiographic changes or an atherosclerotic culprit lesion identified during angiography. Participants were randomly assigned (1:1) within 10 days after admission for the index acute coronary syndromes event to either aspirin or rivaroxaban based on a computer-generated randomisation schedule. Randomisation was balanced by using randomly permuted blocks with size of four and was stratified based on the background P2Y12 inhibitor (clopidogrel or ticagrelor) intended to be used at the time of randomisation. Investigators and patients were masked to treatment assignment. Patients received a minimum of 180 days of double-blind treatment with rivaroxaban 2·5 mg twice daily or aspirin 100 mg daily. The choice of clopidogrel or ticagrelor during trial conduct was not randomised and was based on investigator preference. The primary endpoint was thrombolysis in myocardial infarction (TIMI) clinically significant bleeding not related to coronary artery bypass grafting (CABG; major, minor, or requiring medical attention) up to day 390. Primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02293395. FINDINGS: Between April 22, 2015, and Oct 14, 2016, 3037 patients with acute coronary syndromes were randomly assigned; 1518 to receive aspirin and 1519 to receive rivaroxaban. 1704 patients (56%) were in the ticagrelor and 1333 (44%) in the clopidogrel strata. Median duration of treatment was 291 days (IQR 239-354). TIMI non-CABG clinically significant bleeding was similar with rivaroxaban versus aspirin therapy (total 154 patients [5%]; 80 participants [5%] of 1519 vs 74 participants [5%] of 1518; HR 1·09 [95% CI 0·80-1·50]; p=0·5840). INTERPRETATION: A dual pathway antithrombotic therapy approach combining low-dose rivaroxaban with a P2Y12 inhibitor for the treatment of patients with acute coronary syndromes had similar risk of clinically significant bleeding as aspirin and a P2Y12 inhibitor. A larger, adequately powered trial would be required to definitively assess the efficacy and safety of this approach. FUNDING: Janssen Research & Development and Bayer AG.

Effect of age on efficacy and safety of vorapaxar in patients with non-ST-segment elevation acute coronary syndrome: Insights from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial.

BACKGROUND: Antithrombotic therapy plays an important role in the treatment of non-ST-segment elevation acute coronary syndromes (NSTE ACS) but is associated with bleeding risk. Advanced age may modify the relationship between efficacy and safety. METHODS: Efficacy and safety of vorapaxar (a protease-activated receptor 1 antagonist) was analyzed across ages as a continuous and a categorical variable in the 12,944 patients with NSTE ACS enrolled in the TRACER trial. To evaluate the effect of age, Cox regression models were developed to estimate hazard ratios (HRs) with the adjustment of other baseline characteristics and randomized treatment for the primary efficacy composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization, and the primary safety composite of moderate or severe Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) bleeding. RESULTS: The median age of the population was 64years (25th, 75th percentiles = 58, 71). Also, 1,791 patients (13.8%) were ≤54years of age, 4,968 (38.4%) were between 55 and 64 years, 3,979 (30.7%) were between 65 and 74 years, and 2,206 (17.1%) were 75years or older. Older patients had higher rates of hypertension, renal insufficiency, and previous stroke and worse Killip class. The oldest age group (≥75years) had substantially higher 2-year rates of the composite ischemic end point and moderate or severe GUSTO bleeding compared with the youngest age group (≤54years). The relationships between treatment assignment (vorapaxar vs placebo) and efficacy outcomes did not vary by age. For the primary efficacy end point, the HRs (95% CIs) comparing vorapaxar and placebo in the 4 age groups were as follows: 1.12 (0.88-1.43), 0.88 (0.76-1.02), 0.89 (0.76-1.04), and 0.88 (0.74-1.06), respectively (P value for interaction = .435). Similar to what was observed for efficacy outcomes, we did not observe any interaction between vorapaxar and age on bleeding outcomes. For the composite of moderate or severe bleeding according to the GUSTO classification, the HRs (95% CIs) comparing vorapaxar and placebo in the 4 age groups were 1.73 (0.89-3.34), 1.39 (1.04-1.86), 1.10 (0.85-1.42), and 1.73 (1.29-2.33), respectively (P value for interaction = .574). CONCLUSION: Older patients had a greater risk for ischemic and bleeding events; however, the efficacy and safety of vorapaxar in NSTE ACS were not significantly influenced by age.

Arterial access site and outcomes in patients undergoing percutaneous coronary intervention with and without vorapaxar.

OBJECTIVES: We evaluated outcomes associated with transradial vs. transfemoral approaches and vorapaxar in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) in the TRACER trial. BACKGROUND: Vorapaxar reduces ischemic events but increases the risk of major bleeding. METHODS: We compared 30-day and 2-year major adverse cardiac events (MACE: cardiovascular death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization) and noncoronary artery bypass graft (CABG)-related bleedings in 2,192 transradial and 4,880 transfemoral patients undergoing PCI after adjusting for confounding variables, including propensity for transradial access. RESULTS: Overall, 30-day GUSTO moderate/severe and non-CABG TIMI major/minor bleeding occurred less frequently in transradial (0.9% vs. 2.0%, P = 0.001) vs. transfemoral (1.1% vs. 2.5%, P = 0.005) patients. A similar reduction was seen at 2 years (3.3% vs. 4.7%, P = 0.008; 3.3% vs. 4.9%, P < 0.001, respectively). Transradial was associated with an increased risk of ischemic events at 30 days (OR 1.38, 95% CI 1.11-1.72; P = 0.004), driven primarily by increased periprocedural myocardial infarctions. At 2 years, rates of MACE were comparable (HR 1.14, 95% CI 0.98-1.33; P = 0.096). Although bleeding rates were higher with vorapaxar in transfemoral vs. transradial patients, there was no significant treatment interaction. Also, the access site did not modulate the association between vorapaxar and MACE. CONCLUSIONS: Transradial access was associated with lower bleeding rates and similar long-term ischemic outcomes, suggesting transradial access is safer than transfemoral access among ACS patients receiving potent antiplatelet therapies. Because of the nonrandomized allocation of arterial access, these results should be considered exploratory. © 2015 Wiley Periodicals, Inc.

Vorapaxar in the secondary prevention of atherothrombotic events.

BACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS: At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS: Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.).

Thrombin-receptor antagonist vorapaxar in acute coronary syndromes.

BACKGROUND: Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation. METHODS: In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. RESULTS: Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P=0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups. CONCLUSIONS: In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.).

Vorapaxar in patients with peripheral artery disease and acute coronary syndrome: insights from Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER).

BACKGROUND: In the TRACER trial, vorapaxar, a protease-activated receptor-1 antagonist, plus standard care in non-ST-segment elevation acute coronary syndrome (NSTE ACS) patients did not significantly reduce the primary composite end point but reduced a key secondary end point and significantly increased bleeding. History of peripheral artery disease (PAD) was a risk-enrichment inclusion criterion. We investigated the efficacy and safety of vorapaxar in NSTE ACS patients with documented PAD. METHODS: TRACER was a double-blind, randomized trial comparing vorapaxar with placebo in 12,944 patients with NSTE ACS. RESULTS: In total, 936 (7.2%) patients had a history of PAD. Ischemic events occurred more frequently among patients with PAD (25.3%) versus no PAD (12.2%, P < .001), and Global Use of Strategies to Open Occluded Coronary Arteries moderate/severe bleeding was more common in PAD (9.1%) versus no PAD (5.0%, P = .004). Similar rates of the composite end point (cardiovascular death, myocardial infarction, or stroke) occurred in patients with PAD treated with vorapaxar and placebo (21.7% vs 24.8%, P interaction = .787). Patients with PAD treated with vorapaxar, when compared with placebo, also had a numerical reduction in peripheral revascularization procedures (8.1% vs 9.0%, P = .158) and a lower extremity amputation rate (0.9% vs 1.5%, P = .107). Vorapaxar increased Global Use of Strategies to Open Occluded Coronary Arteries moderate/severe bleeding similarly in patients with PAD (hazard ratio 1.47, 95% CI 0.89-2.45) and without (hazard ratio 1.48, 95% CI 1.22-1.79; P interaction = .921). CONCLUSIONS: Patients with NSTE ACS and PAD were at increased risk for ischemic events. Lower rates of ischemic end points, peripheral revascularization, and amputation with vorapaxar did not reach statistical significance but warrant further investigation. Vorapaxar increased bleeding in both patients with and without PAD at a similar magnitude of risk.

Vorapaxar with or without clopidogrel after non-ST-segment elevation acute coronary syndromes: results from the thrombin receptor antagonist for clinical event reduction in acute coronary syndrome trial.

BACKGROUND: Protease-activated receptor 1 antagonism with vorapaxar represents a novel strategy for platelet inhibition. In TRACER, vorapaxar was compared with placebo plus standard of care among 12,944 patients with non-ST-segment elevation acute coronary syndromes. We anticipated that most patients would have received clopidogrel as part of standard care. We investigated the modification of vorapaxar's effect associated with clopidogrel use over time. METHODS: The marginal structural model method was used to estimate causal modification of vorapaxar effect by use of clopidogrel over time. The primary outcomes were the composite of cardiovascular death, myocardial infarction, or stroke and Global Use of Strategies to Open Occluded Coronary Arteries moderate or severe bleeding. The event accrual period excluded the time during which clopidogrel was clinically warranted. RESULTS: Among 12,887 patients who received study medication, 11,117 (86.3%) received clopidogrel before randomization, of whom 38.5% stopped later in the trial (median time to stoppage 200 days with placebo; interquartile range [IQR] 14-367) (186 days with vorapaxar; IQR 17-366). In total, 1,770 (13.7%) patients were not on clopidogrel at randomization, of whom 47.8% started afterward (median time to start 2 days; IQR 2-4). During the period of event accrual, vorapaxar was associated with a 26% reduction in the composite of cardiovascular death, myocardial infarction, or stroke when used with clopidogrel (hazard ratio [HR] 0.74; 95% CI 0.60-0.91) and a 24% reduction when used without clopidogrel (HR 0.76; 95% CI 0.56-1.02) (interaction; P = .89). The hazard of Global Use of Strategies to Open Occluded Coronary Arteries bleeding with vorapaxar was not significantly different without clopidogrel (HR 1.33; 95% CI 0.81-2.20) or with clopidogrel (HR 1.09; 95% CI 0.76-1.56) (interaction; P = .53). CONCLUSIONS: We observed no interaction between vorapaxar and clopidogrel after non-ST-segment elevation acute coronary syndromes on efficacy or safety outcomes, supporting a complementary role of protease-activated receptor 1 and P2Y12 antagonism.

Effect of vorapaxar on myocardial infarction in the thrombin receptor antagonist for clinical event reduction in acute coronary syndrome (TRA·CER) trial.

AIMS: The TRA·CER trial compared vorapaxar, a novel platelet protease-activated receptor (PAR)-1 antagonist, with placebo in 12 944 patients with high-risk non-ST-segment elevation acute coronary syndromes (NSTE ACS). In this analysis, we explored the effect of vorapaxar on myocardial infarction (MI). METHODS AND RESULTS: A blinded, independent central endpoint adjudication committee prospectively defined and classified MI according to the universal MI definition, including peak cardiac marker value (creatine kinase-MB [CK-MB] and/or troponin). Because the trial failed to meet its primary endpoint, these analyses are considered exploratory. During a median follow-up of 502 days, 1580 MIs occurred in 1319 patients. The majority (n = 1025, 64.9%) were type 1 (spontaneous) MI, followed by type 4a [percutaneous coronary intervention (PCI)-related] MI (n = 352; 22.3%). Compared with placebo, vorapaxar reduced the hazard of a first MI of any type by 12% [hazard ratio (HR), 0.88; 95% confidence interval (CI), 0.79-0.98; P = 0.021] and the hazard of total number of MIs (first and subsequent) by 14% (HR, 0.86; 95% CI, 0.77-0.97; P = 0.014), an effect that was sustained over time. Vorapaxar reduced type 1 MI by 17% (HR, 0.83; 95% CI, 0.73-0.95; P = 0.007). Type 4a MIs were not significantly reduced by vorapaxar (HR, 0.90; 95% CI, 0.73-1.12; P = 0.35). Vorapaxar effect was consistent across MI sizes defined by peak cardiac marker elevations and across key clinical subgroups; however, in patients not treated with thienopyridine at baseline (HR, 0.65; 95% CI, 0.46-0.92) compared with patients who received thienopyridine (HR, 0.91; 95% CI, 0.81-1.02), there was a trend towards a higher effect (Pint = 0.077). CONCLUSION: The PAR-1 antagonist vorapaxar was associated with a reduction of MI, including total number of infarctions. This reduction was sustained over time and was mostly evident in type 1 MI, the most common type of MI observed.

The Effect of High-Normal Preoperative International Normalized Ratios on Outcomes and Complications After Anterior Cervical Spine Surgery.

Hematoma after anterior cervical spine surgery can result in neurologic and airway compromise. Current guidelines recommend an international normalized ratio (INR) <1.5 before elective spine surgery because of increased complications. The risk associated with an INR of 1.25 is not well studied. The purpose of this study was to determine the risk of complications associated with a preoperative INR >1.25 and ≤1.5 in patients undergoing elective anterior cervical spine surgery. The American College of Surgeons National Surgical Quality Improvement Program database was queried. Patients undergoing elective anterior cervical spine surgery from 2012 to 2016 who had an INR recorded within 24 hours of surgery were included. Outcomes of interest included postoperative hematoma requiring surgery, 30-day mortality, and 30-day readmissions and reoperations. A total of 2949 patients were included. The incidence of a postoperative hematoma that required surgical management was 0.2%, 0.6%, and 4.5% in the INR≤1, 11.25 and ≤1.5 before elective anterior cervical spine surgery is associated with significantly higher rates of postoperative hematoma formation as well as 30-day readmission and reoperation; there was a trend toward significance in mortality rate. [Orthopedics. 2024;47(1):e26-e32.].

Proximal humerus fractures: Postoperative protocols and factors affecting treatment decisions among shoulder and elbow and orthopedic trauma surgeons.

Background: Proximal humerus fractures (PHFs) can lead to functional decline in geriatric and polytraumatized patients. Treatment of PHFs is an area of much debate and much variability between practitioners. Objectives: We surveyed orthopedic trauma (OT) and shoulder and elbow (SE) surgeons to evaluate differences in postoperative protocols when treating acute PHFs with open reduction internal fixation (ORIF), intramedullary nailing (IMN), or hemi or reverse shoulder arthroplasty (rTSA). Materials and methods: We distributed a web-based survey to three OT and SE associations between August 2018-April 2019. Questions included practice characteristics, standard postoperative protocols for weight-bearing, lifting, and range of motion (ROM) by treatment modality, and factors affecting modality and postoperative protocol decisions. We compared the subspecialties. Results: 239 surgeons [100 (42.2 %) OT, 118 (49.8 %) SE] completed the survey. OT were more likely to allow immediate ROM, lifting, and weight bearing following intramedullary nailing (IMN), open reduction internal fixation with a locking plate (ORIF), or arthroplasty (all p < 0.025), and to allow earlier unrestricted use of the extremity following IMN and arthroplasty (p = 0.001, p = 0.021 respectively). OT were more likely to consider operating on a PHF if there was contralateral upper extremity injury or need of the injured arm for work or activities of daily living (all p < 0.026). The subspecialties did not differ significantly on factors affecting their postoperative protocols. OT preferred IMN and SE surgeons preferred rTSA for allowing immediate unrestricted postoperative weight bearing, ROM, or lifting (all p < 0.001). Conclusion: There are significant differences in postoperative protocols between trauma and SE surgeons when treating PHFs. Postoperative protocols should be further studied to balance surgical outcomes and the risks of functional decline when treating patients with PHFs.