Research Opportunities in Stroke Prevention for Atrial Fibrillation: A Report From a National Heart, Lung, and Blood Institute Virtual Workshop.

Atrial fibrillation (AF) is one of the strongest risk factors for ischemic stroke, which is a leading cause of disability and death. Given the aging population, increasing prevalence of AF risk factors, and improved survival in those with cardiovascular disease, the number of individuals affected by AF will continue increasing over time. While multiple proven stroke prevention therapies exist, important questions remain about the optimal approach to stroke prevention at the population and individual patient levels. Our report summarizes the National Heart, Lung, and Blood Institute virtual workshop focused on identifying key research opportunities related to stroke prevention in AF. The workshop reviewed major knowledge gaps and identified targeted research opportunities to advance stroke prevention in AF in the following areas: (1) improving risk stratification tools for stroke and intracranial hemorrhage; (2) addressing challenges with oral anticoagulants; and (3) delineating the optimal roles of percutaneous left atrial appendage occlusion and surgical left atrial appendage closure/excision. This report aims to promote innovative, impactful research that will lead to more personalized, effective use of stroke prevention strategies in people with AF.

Predictors of long-term opioid use and opioid use disorder among construction workers: Analysis of claims data.

BACKGROUND: Construction workers have high rates of work-related musculoskeletal disorders, which lead to frequent opioid use and opioid use disorder (OUD). This paper quantified the incidence of opioid use and OUD among construction workers with and without musculoskeletal disorders. METHODS: We conducted a retrospective study using union health claims from January 2015 to June 2018 from 19,909 construction workers. Claims for diagnoses of chronic musculoskeletal disorders, acute musculoskeletal injuries, musculoskeletal surgery, and other conditions were linked to new opioid prescriptions. We examined the effects of high doses (≥50 morphine mg equivalents per day), large supply (more than 7 days per fill), long-term opioid use (60 or more days supplied within a calendar quarter), and musculoskeletal disorders, on the odds of a future OUD. RESULTS: There were high rates (42.8% per year) of chronic musculoskeletal disorders among workers, of whom 24.1% received new opioid prescriptions and 6.3% received long-term opioid prescriptions per year. Workers receiving opioids for chronic musculoskeletal disorders had the highest odds of future OUD: 4.71 (95% confidence interval 3.09-7.37); workers prescribed long-term opioids in any calendar quarter had a nearly 10-fold odds of developing an OUD. CONCLUSIONS: Among construction workers, opioids initiated for musculoskeletal pain were strongly associated with incident long-term opioid use and OUD. Musculoskeletal pain from physically demanding work is likely one driver of the opioid epidemic in occupations like construction. Prevention of work injuries and alternative pain management are needed for workers at risk for musculoskeletal injuries.

Lung transplant outcomes are influenced by severity of neutropenia and granulocyte colony-stimulating factor treatment.

Although neutropenia is a common complication after lung transplant, its relationship with recipient outcomes remains understudied. We evaluated a retrospective cohort of 228 adult lung transplant recipients between 2008 and 2013 to assess the association of neutropenia and granulocyte colony-stimulating factor (GCSF) treatment with outcomes. Neutropenia was categorized as mild (absolute neutrophil count 1000-1499), moderate (500-999), or severe (<500) and as a time-varying continuous variable. Associations with survival, acute rejection, and chronic lung allograft dysfunction (CLAD) were assessed with the use of Cox proportional hazards regression. GCSF therapy impact on survival, CLAD, and acute rejection development was analyzed by propensity score matching. Of 228 patients, 101 (42.1%) developed neutropenia. Recipients with severe neutropenia had higher mortality rates than those of recipients with no (adjusted hazard ratio [aHR] 2.97, 95% confidence interval [CI] 1.05-8.41, P = .040), mild (aHR 14.508, 95% CI 1.58-13.34, P = .018), or moderate (aHR 3.27, 95% CI 0.89-12.01, P = .074) neutropenia. Surprisingly, GCSF treatment was associated with a higher risk for CLAD in mildly neutropenic patients (aHR 3.49, 95% CI 0.93-13.04, P = .063), although it did decrease death risk in severely neutropenic patients (aHR 0.24, 95% CI 0.07-0.88, P = .031). Taken together, our data point to an important relationship between neutropenia severity and GCSF treatment in lung transplant outcomes.

Derivation and Validation of a Risk Assessment Model for Immunomodulatory Drug-Associated Thrombosis Among Patients With Multiple Myeloma.

BACKGROUND: Although venous thromboembolism (VTE) is a significant complication for patients with multiple myeloma (MM) receiving immunomodulatory drugs (IMiDs), no validated clinical model predicts VTE in this population. This study aimed to derive and validate a new risk assessment model (RAM) for IMiD-associated VTE. METHODS: Patients with newly diagnosed MM receiving IMiDs were selected from the SEER-Medicare database (n=2,397) to derive a RAM and then data from the Veterans Health Administration database (n=1,251) were used to externally validate the model. A multivariable cause-specific Cox regression model was used for model development. RESULTS: The final RAM, named the "SAVED" score, included 5 clinical variables: prior surgery, Asian race, VTE history, age ≥80 years, and dexamethasone dose. The model stratified approximately 30% of patients in both the derivation and the validation cohorts as high-risk. Hazard ratios (HRs) were 1.85 (P<.01) and 1.98 (P<.01) for high- versus low-risk groups in the derivation and validation cohorts, respectively. In contrast, the method of stratification recommended in the current NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease had HRs of 1.21 (P=.17) and 1.41 (P=.07) for the corresponding risk groups in the 2 datasets. CONCLUSIONS: The SAVED score outperformed the current NCCN Guidelines in risk-stratification of patients with MM receiving IMiD therapy. This clinical model can help inform providers and patients of VTE risk before IMiD initiation and provides a simplified clinical backbone for further prognostic biomarker development in this population.

Predicting venous thromboembolism in multiple myeloma: development and validation of the IMPEDE VTE score.

Venous thromboembolism (VTE) is a common cause of morbidity and mortality among patients with multiple myeloma (MM). The International Myeloma Working Group (IMWG) developed guidelines recommending primary thromboprophylaxis, in those identified at high-risk of VTE by the presence of risk factors. The National Comprehensive Cancer Network (NCCN) has adopted these guidelines; however, they lack validation. We sought to develop and validate a risk prediction score for VTE in MM and to evaluate the performance of the current IMWG/NCCN guidelines. Using 4446 patients within the Veterans Administration Central Cancer Registry, we used time-to-event analyses to develop a risk score for VTE in patients with newly diagnosed MM starting chemotherapy. We externally validated the score using the Surveillance, Epidemiology, End Results (SEER)-Medicare database (N = 4256). After identifying independent predictors of VTE, we combined the variables to develop the IMPEDE VTE score (Immunomodulatory agent; Body Mass Index ≥25 kg/m2 ; Pelvic, hip or femur fracture; Erythropoietin stimulating agent; Dexamethasone/Doxorubicin; Asian Ethnicity/Race; VTE history; Tunneled line/central venous catheter; Existing thromboprophylaxis). The score showed satisfactory discrimination in the derivation cohort, c-statistic = 0.66. Risk of VTE significantly increased as score increased (hazard ratio 1.20, P = <.0001). Within the external validation cohort, IMPEDE VTE had a c-statistic of 0.64. For comparison, when evaluating the performance of the IMWG/NCCN guidelines, the c-statistic was 0.55. In summary, the IMPEDE VTE score outperformed the current IMWG/NCCN guidelines and could be considered as the new standard risk stratification for VTE in MM.

Assessment of ICD-10-CM code assignment validity for case finding of outpatient anticoagulant-related bleeding among Medicare beneficiaries.

PURPOSE: To assess performance of International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) code assignments for identifying bleeding events resulting in emergency department visits and hospitalizations among outpatient Medicare beneficiaries prescribed anticoagulants. METHODS: Performance of 206 ICD-10-CM code assignments indicative of bleeding, five anticoagulant adverse effect/poisoning codes, and five coagulopathy codes (according to Medicare Parts A and B claims) as assessed among Medicare fee-for-service beneficiaries prescribed anticoagulants between October 1, 2015 and September 30, 2016 (according to Part D claims). Structured medical record review was the gold standard for validating the presence of anticoagulant-related bleeding. Sensitivity was adjusted to correct for partial verification bias due to sampling design. RESULTS: Based on the study sample of 1166 records (583 cases, 583 controls), 57 of 206 codes yielded the optimal performance for anticoagulant-related bleeding (diagnostic odds ratio, 51; positive predictive value (PPV), 75.7% [95% CI, 72.0%-79.1%]; adjusted sensitivity, 70.0% [95% CI, 63.2%-77.7%]). Codes for intracranial bleeding demonstrated the highest PPV (85.0%) and adjusted sensitivity (91.0%). Bleeding codes in the primary position demonstrated high PPV (86.9%), but low adjusted sensitivity (36.0%). The adjusted sensitivity improved to 69.5% when codes in a secondary position were added. Only one adverse effect/poisoning code was used, appearing in 7.8% of cases and controls (PPV, 71.4% and adjusted sensitivity, 6.8%). CONCLUSIONS: Performance of ICD-10-CM code assignments for bleeding among patients prescribed anticoagulants varied by bleed type and code position. Adverse effect/poisoning codes were not commonly used and would have missed over 90% of anticoagulant-related bleeding cases.

Effect of Low-Intensity vs Standard-Intensity Warfarin Prophylaxis on Venous Thromboembolism or Death Among Patients Undergoing Hip or Knee Arthroplasty: A Randomized Clinical Trial.

Importance: The optimal international normalized ratio (INR) to prevent venous thromboembolism (VTE) in warfarin-treated patients with recent arthroplasty is unknown. Objective: To determine the safety and efficacy of a target INR of 1.8 vs 2.5 for VTE prophylaxis after orthopedic surgery. Design, Setting, and Participants: The randomized Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis enrolled 1650 patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016. Interventions: In a 2 × 2 factorial design, participants were randomized to a target INR of 1.8 (n = 823) or 2.5 (n = 827) and to either genotype-guided or clinically guided warfarin dosing. For the first 11 days of therapy, open-label warfarin dosing was guided by a web application. Main Outcomes and Measures: The primary outcome was the composite of VTE (within 60 days) or death (within 30 days). Participants underwent screening duplex ultrasound postoperatively. The hypothesis was that an INR target of 1.8 would be noninferior to an INR target of 2.5, using a noninferiority margin of 3% for the absolute risk of VTE. Secondary end points were bleeding and INR values of 4 or more. Results: Among 1650 patients who were randomized (mean age, 72.1 years; 1049 women [63.6%]; 1502 white [91.0%]), 1597 (96.8%) received at least 1 dose of warfarin and were included in the primary analysis. The rate of the primary composite outcome of VTE or death was 5.1% (41 of 804) in the low-intensity-warfarin group (INR target, 1.8) vs 3.8% (30 of 793) in the standard-treatment-warfarin group (INR target, 2.5), for a difference of 1.3% (1-sided 95% CI, -∞ to 3.05%, P = .06 for noninferiority). Major bleeding occurred in 0.4% of patients in the low-intensity group and 0.9% of patients in the standard-intensity group, for a difference of -0.5% (95% CI, -1.6% to 0.4%). The INR values of 4 or more occurred in 4.5% of patients in the low-intensity group and 12.2% of the standard-intensity group, for a difference of -7.8% (95% CI, -10.5% to -5.1%). Conclusions and Relevance: Among older patients undergoing hip or knee arthroplasty and receiving warfarin prophylaxis, an international normalized ratio goal of 1.8 compared with 2.5 did not meet the criterion for noninferiority for risk of the composite outcome of VTE or death. However, the trial may have been underpowered to meet this criterion and further research may be warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT01006733.

High-Sensitivity Cardiac Troponin T Improves the Diagnosis of Perioperative MI.

BACKGROUND: The diagnosis of myocardial infarction (MI) after noncardiac surgery has traditionally relied on using relatively insensitive contemporary cardiac troponin (cTn) assays. We hypothesized that using a recently introduced novel high-sensitivity cTnT (hscTnT) assay would increase the detection rate of perioperative MI. METHODS: In this ancillary study of the Vitamins in Nitrous Oxide trial, readjudicated incidence rates of myocardial injury (new isolated cTn elevation) and MI were compared when diagnosed by contemporary cTnI versus hscTnT. We probed various relative (eg, >50%) or absolute (eg, +5 ng/L) hscTnT change metrics. Inclusion criteria for this ancillary study were the presence of a baseline and at least 1 postoperative hscTnT value. RESULTS: Among 605 patients, 70 patients (12%) had electrocardiogram changes consistent with myocardial ischemia; 82 patients (14%) had myocardial injury diagnosed by contemporary cTnI, 31 (5.1%) of which had an adjudicated MI. After readjudication, 67 patients (11%) were diagnosed with MI when using hscTnT, a 2-fold increase. Incidence rates of postoperative myocardial injury ranged from 12% (n = 73) to 65% (n = 393) depending on the hscTnT metric used. Incidence rates of MI using various hscTnT change metrics and the presence of ischemic electrocardiogram changes, but without event adjudication, ranged from 3.6% (n = 22) to 12% (n = 74), a >3-fold difference. New postoperative hscTnT elevation, either by absolute or relative hscTnT change metric, was associated with an up to 5-fold increase in 6-month mortality. CONCLUSIONS: The use of hscTnT compared to contemporary cTnI increases the detection rate of perioperative MI by a factor of 2. Using different absolute or relative hscTnT change metrics may lead to under- or overdiagnosis of perioperative MI.

Improving Prediction of Postoperative Myocardial Infarction With High-Sensitivity Cardiac Troponin T and NT-proBNP.

BACKGROUND: This study sought to determine whether preoperatively measured high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) improve cardiac risk prediction in patients undergoing major noncardiac surgery compared with the standard risk indices. METHODS: In this ancillary study to the Vitamins in Nitrous Oxide trial, patients were included who had preoperative hs-cTnT and NT-proBNP measured (n = 572). Study outcome was the incidence of postoperative myocardial infarction (MI) within the first 3 postoperative days. hs-cTnT was considered elevated if >14 ng/L and NT-proBNP if >300 ng/L. Additional cutoff values were investigated on the basis of receiver operating characteristic statistics. Biomarker risk prediction was compared with Lee's Revised Cardiac Risk Index (RCRI) with the use of standard methods and net reclassification index. RESULTS: The addition of hs-cTnT (>14 ng/L) and NT-proBNP (>300 ng/L) to RCRI significantly improved the prediction of postoperative MI (event rate 30/572 [5.2%], Area under the receiver operating characteristic curve increased from 0.590 to 0.716 with a 0.66 net reclassification index [95% confidence interval 0.32-0.99], P < .001). The use of 108 ng/L as a cutoff for NT-proBNP improved sensitivity compared with 300 ng/L (0.87 vs 0.53). Sensitivity, specificity, positive, and negative predictive value for hs-cTnT were 0.70, 0.60, 0.09, and 0.97 and for NT-proBNP were 0.53, 0.68, 0.08, and 0.96. CONCLUSIONS: The addition of cardiac biomarkers hs-cTnT and NT-proBNP to RCRI improves the prediction of adverse cardiac events in the immediate postoperative period after major noncardiac surgery. The high negative predictive value of preoperative hs-cTnT and NT-proBNP suggest usefulness as a "rule-out" test to confirm low risk of postoperative MI.

Safety and Efficacy of New Anticoagulants for the Prevention of Venous Thromboembolism After Hip and Knee Arthroplasty: A Meta-Analysis.

BACKGROUND: Venous thromboembolism (VTE) is a common and potentially fatal complication of arthroplasty. METHODS: We reviewed randomized trials to determine which anticoagulant has the best safety and efficacy in hip and knee arthroplasty patients. We searched PubMed, MEDLINE, and EMBASE through January 2016. RESULTS: Compared to enoxaparin (most commonly dosed 40 mg once daily), the relative risk (RR) of VTE was lowest for edoxaban 30 mg once daily (0.49; 95% confidence interval [CI], 0.32-0.75), fondaparinux 2.5 mg once daily (0.53; 95% CI, 0.45-0.63), and rivaroxaban 10 mg once daily (0.55; 95% CI, 0.46-0.66), and highest for dabigatran 150 mg once daily (1.19; 95% CI; 0.98-1.44). The RR of major/clinically relevant bleeding was lowest for apixaban 2.5 mg twice daily (0.84; 95% CI; 0.70-0.99) and highest for rivaroxaban (1.27; 95% CI, 1.01-1.59) and fondaparinux (1.64; 95% CI, 0.24-11.35). Fondaparinux was the only agent that was more effective than enoxaparin 30 mg twice daily (VTE RR = 0.58; 95% CI, 0.43-0.76). CONCLUSION: With the possible exception of apixaban, newer anticoagulants that lower the risk of postoperative VTE increase bleeding.

Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty: The GIFT Randomized Clinical Trial.

Importance: Warfarin use accounts for more medication-related emergency department visits among older patients than any other drug. Whether genotype-guided warfarin dosing can prevent these adverse events is unknown. Objective: To determine whether genotype-guided dosing improves the safety of warfarin initiation. Design, Setting, and Patients: The randomized clinical Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis included patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty and was conducted at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016. Interventions: Patients were genotyped for the following polymorphisms: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. In a 2 × 2 factorial design, patients were randomized to genotype-guided (n = 831) or clinically guided (n = 819) warfarin dosing on days 1 through 11 of therapy and to a target international normalized ratio (INR) of either 1.8 or 2.5. The recommended doses of warfarin were open label, but the patients and clinicians were blinded to study group assignment. Main Outcomes and Measures: The primary end point was the composite of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Patients underwent a screening lower-extremity duplex ultrasound approximately 1 month after arthroplasty. Results: Among 1650 randomized patients (mean age, 72.1 years [SD, 5.4 years]; 63.6% women; 91.0% white), 1597 (96.8%) received at least 1 dose of warfarin therapy and completed the trial (n = 808 in genotype-guided group vs n = 789 in clinically guided group). A total of 87 patients (10.8%) in the genotype-guided group vs 116 patients (14.7%) in the clinically guided warfarin dosing group met at least 1 of the end points (absolute difference, 3.9% [95% CI, 0.7%-7.2%], P = .02; relative rate [RR], 0.73 [95% CI, 0.56-0.95]). The numbers of individual events in the genotype-guided group vs the clinically guided group were 2 vs 8 for major bleeding (RR, 0.24; 95% CI, 0.05-1.15), 56 vs 77 for INR of 4 or greater (RR, 0.71; 95% CI, 0.51-0.99), 33 vs 38 for venous thromboembolism (RR, 0.85; 95% CI, 0.54-1.34), and there were no deaths. Conclusions and Relevance: Among patients undergoing elective hip or knee arthroplasty and treated with perioperative warfarin, genotype-guided warfarin dosing, compared with clinically guided dosing, reduced the combined risk of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Further research is needed to determine the cost-effectiveness of personalized warfarin dosing. Trial Registration: clinicaltrials.gov Identifier: NCT01006733.

A systematic analysis and comparison of warfarin initiation strategies.

OBJECTIVE: Randomized trials have reported inconsistent evidence on the effectiveness of algorithms that use genotypes to initiate warfarin therapy. The Clarification of Optimal Anticoagulation through Genetics (COAG) trial initiated therapy on the basis of predicted maintenance doses, with a pharmacogenetic-guided algorithm in one study group and a clinically guided algorithm in the other. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) consortium initiated therapy on the basis of loading doses, with an algorithm-based prediction in one study group and a fixed-dose regimen in the other. To understand the differences between these trials, we compared the initial doses between alternative dosing algorithms (the pharmacogenetic-guided and clinically guided algorithms developed by Gage and colleagues and those developed by the International Warfarin Pharmacogenetics Consortium) and between the COAG and EU-PACT dose-initiation strategies. METHODS: This was a secondary analysis of the COAG trial - a double-blind, randomized-controlled trial (2009-2013) - conducted at 18 clinical centers in the USA, which included 1010 adults initiating warfarin therapy, of whom 719 achieved maintenance dose. RESULTS: Among COAG participants, the distribution of initial doses differed between algorithms, but showed similar prediction accuracy for maintenance dose. However, had the COAG trial implemented the EU-PACT strategy, the 3-day initial dose would have been 4.8 mg greater among participants randomized to pharmacogenetic-guided dosing, but only 2.5 mg greater among participants randomized to clinically guided dosing (P<0.001). CONCLUSION: Compared with the COAG trial, the EU-PACT trial used systematically larger loading doses in the pharmacogenetic-guided group and might have inadequately adjusted for clinical variability in warfarin dose requirements in the fixed-dose group.

A pharmacogenetic versus a clinical algorithm for warfarin dosing.

BACKGROUND: The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. METHODS: We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy. RESULTS: At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], -0.2; 95% confidence interval, -3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy. CONCLUSIONS: Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. (Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657.).

Trends in antithrombotic therapy for atrial fibrillation: Data from the Veterans Health Administration Health System.

BACKGROUND: Although controversial, several prior studies have suggested that oral anticoagulants (OACs) are underused in the US atrial fibrillation (AF) population. Appropriate use of OACs is essential because they significantly reduce the risk of stroke in those with AF. In the >2 million Americans with AF, OACs are recommended when the risk of stroke is moderate or high but not when the risk of stroke is low. To quantify trends and guideline adherence, we evaluated OAC use (either warfarin or dabigatran) in a 10-year period in patients with new AF in the Veterans Health Administration. METHODS: New AF was defined as at least 2 clinical encounters documenting AF within 120 days of each other and no previous AF diagnosis (N = 297,611). Congestive Heart Failure, Hypertension, Age > 75, Diabetes, and Stroke (CHADS2) scores were determined using age and diagnoses of hypertension, diabetes, heart failure, and stroke or transient ischemic attack during the 12 months before AF diagnosis. Receipt of an OAC within 90 days of a new diagnosis of AF was evaluated using VA pharmacy data. RESULTS: Overall, initiation of an OAC fell from 51.3% in 2002 to 43.1% in 2011. For patients with CHADS2 score of 0, 1, 2, 3, 4, and 5-6, the proportions of patients prescribed an OAC showed a relative decrease of 26%, 23%, 14%, 12%, 9%, and 13%, respectively (P < .001). Clopidogrel use was stable at 10% of the AF population. CONCLUSIONS: Among US veterans with new AF and additional risk factors for stroke, only about half receive OAC, and the proportion is declining.

Risk model for estimating the 1-year risk of deferred lesion intervention following deferred revascularization after fractional flow reserve assessment.

AIMS: Although lesions deferred revascularization following fractional flow reserve (FFR) assessment have a low risk of adverse cardiac events, variability in risk for deferred lesion intervention (DLI) has not been previously evaluated. The aim of this study was to develop a prediction model to estimate 1-year risk of DLI for coronary lesions where revascularization was not performed following FFR assessment. METHODS AND RESULTS: A prediction model for DLI was developed from a cohort of 721 patients with 882 coronary lesions where revascularization was deferred based on FFR between 10/2002 and 7/2010. Deferred lesion intervention was defined as any revascularization of a lesion previously deferred following FFR. The final DLI model was developed using stepwise Cox regression and validated using bootstrapping techniques. An algorithm was constructed to predict the 1-year risk of DLI. During a mean (±SD) follow-up period of 4.0 ± 2.3 years, 18% of lesions deferred after FFR underwent DLI; the 1-year incidence of DLI was 5.3%, while the predicted risk of DLI varied from 1 to 40%. The final Cox model included the FFR value, age, current or former smoking, history of coronary artery disease (CAD) or prior percutaneous coronary intervention, multi-vessel CAD, and serum creatinine. The c statistic for the DLI prediction model was 0.66 (95% confidence interval, CI: 0.61-0.70). CONCLUSION: Patients deferred revascularization based on FFR have variation in their risk for DLI. A clinical prediction model consisting of five clinical variables and the FFR value can help predict the risk of DLI in the first year following FFR assessment.

Accuracy of Wearable Cameras to Track Social Interactions in Stroke Survivors.

BACKGROUND: Social isolation after a stroke is related to poor outcomes. However, a full study of social networks on stroke outcomes is limited by the current metrics available. Typical measures of social networks rely on self-report, which is vulnerable to response bias and measurement error. We aimed to test the accuracy of an objective measure-wearable cameras-to capture face-to-face social interactions in stroke survivors. If accurate and usable in real-world settings, this technology would allow improved examination of social factors on stroke outcomes. METHODS: In this prospective study, 10 stroke survivors each wore 2 wearable cameras: Autographer (OMG Life Limited, Oxford, United Kingdom) and Narrative Clip (Narrative, Linköping, Sweden). Each camera automatically took a picture every 20-30 seconds. Patients mingled with healthy controls for 5 minutes of 1-on-1 interactions followed by 5 minutes of no interaction for 2 hours. After the event, 2 blinded judges assessed whether photograph sequences identified interactions or noninteractions. Diagnostic accuracy statistics were calculated. RESULTS: A total of 8776 photographs were taken and adjudicated. In distinguishing interactions, the Autographer's sensitivity was 1.00 and specificity was .98. The Narrative Clip's sensitivity was .58 and specificity was 1.00. The receiver operating characteristic curves of the 2 devices were statistically different (Z = 8.26, P < .001). CONCLUSIONS: Wearable cameras can accurately detect social interactions of stroke survivors. Likely because of its large field of view, the Autographer was more sensitive than the Narrative Clip for this purpose.

Clinical Benefit of American College of Chest Physicians versus European Society of Cardiology Guidelines for Stroke Prophylaxis in Atrial Fibrillation.

BACKGROUND: Guidelines for anticoagulant therapy in patients with atrial fibrillation (AF) conflict with each other. The American College of Chest Physicians (ACCP) guidelines suggest no anticoagulant therapy for patients with a CHADS2 score of 0. The European Society of Cardiology (ESC) prefer anticoagulant therapy for patients with a CHA2DS2-VASc of 1, which includes 65-74-year-olds with a CHADS2 score of 0. Resolving this conflicting advice is important, because these guidelines have potential to change anticoagulant therapy in 10 % of the AF population. METHODS: Using the National Registry of Atrial Fibrillation (NRAF) II data set, we compared these guidelines using stroke equivalents. Based on structured review of 23,657 patient records, we identified 65-74-year-old patients with a CHADS2 stroke score of 0 and no contraindication to warfarin. We used Medicare claims data to ascertain rates of ischemic stroke, intracranial hemorrhage, and other hemorrhage. We calculated net stroke equivalents for these (N = 478) patients using a weight of 1.5 for intracranial hemorrhages (ICH) and 1.0 for ischemic stroke. In a multivariate analysis, we used 14,466 records with documented atrial fibrillation and adjusted for CHADS2 and HEMORR2 HAGES score. RESULTS: In 65-74-year-old patients with a CHADS2 stroke score of 0, the stroke equivalents per 100 patient-years was 2.6 with warfarin and 2.9 without warfarin; the difference between these two strategies was not significant (0.3 stroke equivalents, 95 % CI -3.2 to 3.7). However, rates of hemorrhage per 100 patient-years were nearly tripled (hazard ratio 2.9; 95 % CI 1.5-5.4; p = 0.0011) with warfarin (21.1) versus without it (7.4). The most common site for major hemorrhage was gastrointestinal (ICD-9 code 578.9). CONCLUSIONS: By expanding warfarin use to 65--74-year-olds with a CHADS2 score of 0, rates of hemorrhages would rise without a significant reduction in stroke equivalents.

Effectiveness and safety of expanded perioperative thromboprophylaxis in complex gynecologic surgery.

OBJECTIVE: To determine the effectiveness and safety of an expanded perioperative venous thromboembolism (VTE) prophylaxis strategy in women undergoing complex gynecologic surgery. METHODS: We performed a cohort study of 527 patients undergoing major surgery at a single institution over a thirty-month interval during which the gynecologic oncology service implemented an expanded approach to VTE prophylaxis. We compared rates of VTE pre- and post-intervention as well as bleeding and infectious complications. RESULTS: Prior to the intervention, there were 23 VTE events in 345 patients (rate of 6.67%): 8 deep vein thromboses (DVTs) and 15 pulmonary emboli (PEs). Post-intervention, there were 5 VTE events in 182 patients (2.7%): 3 DVTs and 2 PEs (RR=0.4, p=0.056). Time-to-event analysis showed a significantly higher incidence of VTE events in the pre-intervention time frame compared to the post-intervention period (p=0.049). There were no significant differences in bleeding or infection complications between groups. CONCLUSIONS: Implementation of a perioperative VTE prophylaxis protocol was safe, feasible and resulted in a clinically significant reduction in symptomatic VTE. Preoperative single-dose unfractionated heparin for all patients, combined with two weeks of thromboprophylaxis in gynecologic cancer patients, may decrease VTE events without increasing bleeding or infection.

Predictors of Non-Variceal Hemorrhage in a National Cohort of Patients With Chronic Liver Disease.

Background: Non-variceal hemorrhage in patients with chronic liver disease (CLD) increases morbidity, mortality, and healthcare costs. There are limited data on risk factors for non-variceal hemorrhage in the CLD population. The aim of this study was to assess the predictive value of various clinical and laboratory parameters for non-variceal hemorrhage in CLD patients. Methods: We conducted a retrospective cohort study of US veterans diagnosed with CLD between 2002 and 2018 within the Veterans Health Administration database. We derived candidate variables from existing risk prediction models for hemorrhage, risk calculators for severity of liver disease, Charlson index of prognostic comorbidities, and prior literature. We used a competing risk analysis to study the relationship between putative risk factors and incidence of non-variceal hemorrhage in patients with CLD. Results: Of 15,183 CLD patients with no history of cancer or anticoagulation use, 674 experienced non-variceal hemorrhage within 1 year of CLD diagnosis. In multivariable analysis, 11 of the 26 candidate variables independently predicted non-variceal hemorrhage: race, international normalized ratio (INR) > 1.5, bilirubin ≥ 2 mg/dL, albumin ≤ 3.5 g/dL, anemia, alcohol abuse, antiplatelet therapy, chronic kidney disease, dementia, proton pump inhibitor prescription, and recent infection. Conclusions: In this study of almost 15,000 veterans, risk factors for non-variceal bleeding within the first year after diagnosis of CLD included non-Caucasian race, laboratory parameters indicating severe liver disease and recent infection in addition to the risk factors for bleeding observed in a general non-CLD population.

Effects of phosphodiesterase type 5 inhibition on systemic and pulmonary hemodynamics and ventricular function in patients with severe symptomatic aortic stenosis.

BACKGROUND: Pressure overload resulting from aortic stenosis causes maladaptive ventricular and vascular remodeling that can lead to pulmonary hypertension, heart failure symptoms, and adverse outcomes. Retarding or reversing this maladaptive remodeling and its unfavorable hemodynamic consequences has the potential to improve morbidity and mortality. Preclinical models of pressure overload have shown that phosphodiesterase type 5 inhibition is beneficial; however, the use of phosphodiesterase type 5 inhibitors in patients with aortic stenosis is controversial because of concerns about vasodilation and hypotension. METHODS AND RESULTS: We evaluated the safety and hemodynamic response of 20 subjects with severe symptomatic aortic stenosis (mean aortic valve area, 0.7 ± 0.2 cm(2); ejection fraction, 60 ± 14%) who received a single oral dose of sildenafil (40 or 80 mg). Compared with baseline, after 60 minutes, sildenafil reduced systemic (-12%; P<0.001) and pulmonary (-29%; P=0.002) vascular resistance, mean pulmonary artery (-25%; P<0.001) and wedge (-17%; P<0.001) pressures, and increased systemic (13%; P<0.001) and pulmonary (45%; P<0.001) vascular compliance and stroke volume index (8%; P=0.01). These changes were not dose dependent. Sildenafil caused a modest decrease in mean systemic arterial pressure (-11%; P<0.001) but was well tolerated with no episodes of symptomatic hypotension. CONCLUSIONS: This study shows for the first time that a single dose of a phosphodiesterase type 5 inhibitor is safe and well tolerated in patients with severe aortic stenosis and is associated with improvements in pulmonary and systemic hemodynamics resulting in biventricular unloading. These findings support the need for longer-term studies to evaluate the role of phosphodiesterase type 5 inhibition as adjunctive medical therapy in patients with aortic stenosis.