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Background: The accuracy of gadolinium-enhanced magnetic resonance pulmonary angiography and magnetic resonance venography for diagnosing pulmonary embolism has not been determined conclusively.Objective: To investigate performance characteristics of magnetic resonance angiography, with or without magnetic resonance venography, for diagnosing pulmonary embolism.Design: Prospective, multicenter study from 10 April 2006 to 30 September 2008.Setting: 7 hospitals and their emergency services.Patients: 371 adults with diagnosed or excluded pulmonary embolism.Measurements: Sensitivity, specificity, and likelihood ratios were measured by comparing independently read magnetic resonance imaging with the reference standard for diagnosing pulmonary embolism. Reference standard diagnosis or exclusion was made by using various tests, including computed tomographic angiography and venography, ventilation-perfusion lung scan, venous ultrasonography, d-dimer assay, and clinical assessment.Results: Magnetic resonance angiography, averaged across centers, was technically inadequate in 25% of patients (92 of 371). The proportion of technically inadequate images ranged from 11% to 52% at various centers. Including patients with technically inadequate images, magnetic resonance angiography identified 57% (59 of 104) with pulmonary embolism. Technically adequate magnetic resonance angiography had a sensitivity of 78% and a specificity of 99%. Technically adequate magnetic resonance angiography and venography had a sensitivity of 92% and a specificity of 96%, but 52% of patients (194 of 370) had technically inadequate results.Limitation: A high proportion of patients with suspected embolism was not eligible or declined to participate.Conclusion: Magnetic resonance pulmonary angiography should be considered only at centers that routinely perform it well and only for patients for whom standard tests are contraindicated. Magnetic resonance pulmonary angiography and magnetic resonance venography combined have a higher sensitivity than magnetic resonance pulmonary angiography alone in patients with technically adequate images, but it is more difficult to obtain technically adequate images with the 2 procedures. [ABSTRACT FROM AUTHOR]

Background: The accuracy of multidetector computed tomographic angiography (CTA) for the diagnosis of acute pulmonary embolism has not been determined conclusively. Methods: The Prospective Investigation of Pulmonary Embolism Diagnosis II trial was a prospective, multicenter investigation of the accuracy of multidetector CTA alone and combined with venous-phase imaging (CTA-CTV) for the diagnosis of acute pulmonary embolism. We used a composite reference test to confirm or rule out the diagnosis of pulmonary embolism. Results: Among 824 patients with a reference diagnosis and a completed CT study, CTA was inconclusive in 51 because of poor image quality. Excluding such inconclusive studies, the sensitivity of CTA was 83 percent and the specificity was 96 percent. Positive predictive values were 96 percent with a concordantly high or low probability on clinical assessment, 92 percent with an intermediate probability on clinical assessment, and nondiagnostic if clinical probability was discordant. CTA-CTV was inconclusive in 87 of 824 patients because the image quality of either CTA or CTV was poor. The sensitivity of CTA-CTV for pulmonary embolism was 90 percent, and specificity was 95 percent. CTA-CTV was also nondiagnostic with a discordant clinical probability. Conclusions: In patients with suspected pulmonary embolism, multidetector CTA-CTV has a higher diagnostic sensitivity than does CTA alone, with similar specificity. The predictive value of either CTA or CTA-CTV is high with a concordant clinical assessment, but additional testing is necessary when the clinical probability is inconsistent with the imaging results. [ABSTRACT FROM AUTHOR]

Background: Despite extensive literature, the diagnostic role of d-dimer for deep venous thrombosis (DVT) or pulmonary embolism (PE) remains unclear, reflecting multiple d-dimer assays and concerns about differing sensitivities and variability.Purpose: To systematically review trials that assessed sensitivity, specificity, likelihood ratios, and variability among d-dimer assays.Data Sources: Studies in all languages were identified by searching PubMed from 1983 to January 2003 and EMBASE from 1988 to January 2003.Study Selection: The researchers selected prospective studies that compared d-dimer with a reference standard. Studies of high methodologic quality were included in the primary analyses; sensitivity analysis included additional weaker studies.Data Extraction: Two authors collected data on study-level factors: d-dimer assay used, cutoff value, and whether patients had suspected DVT or PE.Data Synthesis: For DVT, the enzyme-linked immunosorbent assay (ELISA) and quantitative rapid ELISA dominate the rank order for these values: sensitivity, 0.96 (95% confidence limit [CL], 0.91 to 1.00), and negative likelihood ratio, 0.12 (CL, 0.04 to 0.33); and sensitivity, 0.96 (CL, 0.90 to 1.00), and negative likelihood ratio, 0.09 (CL, 0.02 to 0.41), respectively. For PE, the ELISA and quantitative rapid ELISA also dominate the rank order for these values: sensitivity, 0.95 (CL, 0.85 to 1.00), and negative likelihood ratio, 0.13 (CL, 0.03 to 0.58); and sensitivity, 0.95 (CL, 0.83 to 1.00), and negative likelihood ratio, 0.13 (CL, 0.02 to 0.84), respectively. The ELISA and quantitative rapid ELISA have negative likelihood ratios that yield a high certainty for excluding DVT or PE. The positive likelihood values, which are in the general range of 1.5 to 2.5, do not greatly increase the certainty of diagnosis. Sensitivity analyses do not affect these findings.Limitations: Although many studies evaluated multiple d-dimer assays, findings are based largely on indirect comparisons of test performance characteristics across studies.Conclusion: The ELISAs in general dominate the comparative ranking among the d-dimer assays for sensitivity and negative likelihood ratio. For excluding PE or DVT, a negative result on quantitative rapid ELISA is as diagnostically useful as a normal lung scan or negative duplex ultrasonography finding. [ABSTRACT FROM AUTHOR]

Study Objective: To review the published experience with gadolinium-enhanced magnetic resonance angiography (MRA) for the detection of acute pulmonary embolism (PE) in order to test the hypothesis that gadolinium-enhanced MRA may be potentially sensitive and specific enough to include it among diagnostic alternatives in the evaluation of patients with suspected PE.Methods: Studies were identified by searching MEDLINE for trials that used gadolinium-enhanced MRA to diagnose acute PE based on the visualization of an intraluminal filling defect or a cutoff vessel, using pulmonary angiography as a reference standard.Results: Twenty-eight investigations were identified in which MRA was used to diagnose PE. Only three studies, however, met the criteria for inclusion in the analysis. In these three case series, the sensitivity of gadolinium-enhanced MRA ranged from 77 to 100%, and the specificity ranged from 95 to 98%.Conclusion: Gadolinium-enhanced MRA may be a useful diagnostic alternative in some patients with suspected acute PE, particularly if they have an elevated creatinine level, have an allergy to radiographic contrast material, or should, if possible, avoid exposure to ionizing radiation. [ABSTRACT FROM AUTHOR]

Objective: To assess the relative risks for bleeding with thrombolytic therapy in patients who are managed using pulmonary angiograms compared with those managed using noninvasive tests, primarily the ventilation-perfusion lung scan.Design: A decision analysis based on data from other studies.Methods: The risk for major bleeding in patients with pulmonary embolism who receive thrombolytic therapy after a noninvasive diagnosis was assessed from complications of thrombolytic therapy in patients with myocardial infarction, assuming that the same risk ratio for major bleeding when comparing an invasive with a noninvasive approach applied to patients with pulmonary embolism. The risk ratio was 3.3 (95% CI, 1.5 to 9.8) for major bleeding in patients with myocardial infarction. One or more major complications of pulmonary angiography occurred in 1.3% of patients (CI, 0.6% to 1.9%).Results: The average reported risk was 14% (18 of 129 patients) (CI, 7.9% to 20.1%) for major bleeding in patients who had pulmonary angiography before receiving tissue plasminogen activator (tPA). The estimated risk was 4.2% (estimated CI, 1.4% to 9.3%) for major bleeding with tPA after a noninvasive diagnosis of pulmonary embolism. Assuming a risk of 1.3% for major complications from pulmonary angiography, a risk for major hemorrhage of 14.0% for an invasive diagnosis, and a risk of 4.2% for a noninvasive diagnosis, fewer complications would occur with noninvasive management if the prevalence of pulmonary embolism exceeded 21%.Conclusion: Among patients with suspected pulmonary embolism who are candidates for thrombolytic therapy, it is safer to use noninvasive diagnostic tests in many patients. [ABSTRACT FROM AUTHOR]

Objective: To assess the benefit of exercise training in patients with heart failure caused by left ventricular systolic dysfunction and to further describe the physiologic changes associated with exercise training in these patients.Design: Randomized, controlled trial.Setting: Urban outpatient clinic.Patients: 40 men with compensated heart failure who were receiving standard medical therapy were randomly assigned to an exercise-training group or to a control group that did not exercise. Fifteen of the 21 patients assigned to exercise training and 14 of the 19 patients assigned to the control group completed the study.Intervention: Patients assigned to exercise training participated in a program of three exercise sessions per week for 24 weeks.Measurements: Symptom-limited exercise tests with gas exchange analysis done just before randomization, at week 12, and at week 24.Results: At week 24, the following changes (mean +/- SE) were seen in patients in the exercise group and patients in the control group, respectively; exercise duration, 2.8 +/- 0.6 minutes and 0.5 +/- 0.5 minutes; peak oxygen consumption (VO2), 231 +/- 54 L/min and 58 +/- 38 L/min; peak ventilation, 12 +/- 3 L/min and -4 +/- 3 L/min; peak heart rate, 10 +/- 4 beats/min and -2 +/- 4 beats/min; and peak power output, 20 +/- 6 W and 2 +/- 5 W. Differences between the increases occurring in the exercise group and the changes occurring in the control group were significant (P < 0.05). Among patients in the exercise group, 85% of the increase in peak VO2 occurred by week 12, and 46% of the increase in peak VO2 was caused by the increase in peak heart rate.Conclusion: Exercise training does not appear to be contraindicated in patients with compensated heart failure. Exercise training improved exercise tolerance, as measured by increases in peak VO2, exercise duration, and power output. This improved exercise tolerance was caused in part by an increase in peak heart rate. [ABSTRACT FROM AUTHOR]

This chapter about prevention of coronary artery bypass occlusion is part of the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients' values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S-187S). Among the key recommendations in this chapter are the following: For patients undergoing coronary artery bypass grafting (CABG), we recommend aspirin, 75 to 162 mg/d, starting 6 h after operation over preoperative aspirin (Grade 1A). In patients in whom postoperative bleeding prevents the administration of aspirin at 6 h after CABG, we recommend starting aspirin as soon as possible thereafter (Grade 1C). For patients undergoing CABG, we recommend against addition of dipyridamole to aspirin therapy (Grade 1A). For patients with coronary artery disease undergoing CABG who are allergic to aspirin, we recommend clopidogrel, 300 mg, as a loading dose 6 h after operation followed by 75 mg/d p.o. (Grade 1C+). In patients who undergo CABG for non-ST-segment elevation acute coronary syndrome (ACS), we recommend clopidogrel, 75 mg/d for 9 to 12 months following the procedure in addition to treatment with aspirin (Grade 1A). For patients who have received clopidogrel for ACS and are scheduled for CABG, we recommend discontinuing clopidogrel for 5 days prior to the scheduled surgery (Grade 2A). For patients undergoing CABG who have no other indication for vitamin K antagonists (VKAs), we suggest clinicians to not administer VKAs (Grade 2B). For patients undergoing CABG in whom oral anticoagulants are indicated, such as those with heart valve replacement, we suggest clinicians administer VKA in addition to aspirin (Grade 2C). For all patients with coronary artery disease who undergo internal mammary artery (IMA) bypass grafting, we recommend aspirin, 75 to 162 mg/d, indefinitely (Grade 1A). For all patients undergoing IMA bypass grafting without other indication for VKA, we suggest clinicians not use VKA (Grade 2C). [ABSTRACT FROM AUTHOR]

This chapter about antithrombotic therapy in native and prosthetic valvular heart disease is part of the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients' values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S-187S). Among the key recommendations in this chapter are the following: For patients with rheumatic mitral valve disease and atrial fibrillation (AF), or a history of previous systemic embolism, we recommend long-term oral anticoagulant (OAC) therapy (target international normalized ratio [INR], 2.5; range, 2.0 to 3.0) [Grade 1C+]. For patients with rheumatic mitral valve disease with AF or a history of systemic embolism who suffer systemic embolism while receiving OACs at a therapeutic INR, we recommend adding aspirin, 75 to 100 mg/d (Grade 1C). For those patients unable to take aspirin, we recommend adding dipyridamole, 400 mg/d, or clopidogrel (Grade 1C). In people with mitral valve prolapse (MVP) without history of systemic embolism, unexplained transient ischemic attacks (TIAs), or AF, we recommended against any antithrombotic therapy (Grade 1C). In patients with MVP and documented but unexplained TIAs, we recommend long-term aspirin therapy, 50 to 162 mg/d (Grade 1A). For all patients with mechanical prosthetic heart valves, we recommend vitamin K antagonists (Grade 1C+). For patients with a St. Jude Medical (St. Paul, MN) bileaflet valve in the aortic position, we recommend a target INR of 2.5 (range, 2.0 to 3.0) [Grade 1A]. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, we recommend a target INR of 3.0 (range, 2.5 to 3.5) [Grade 1C+]. For patients with caged ball or caged disk valves, we suggest a target INR of 3.0 (range, 2.5 to 3.5) in combination with aspirin, 75 to 100 mg/d (Grade 2A). For patients with bioprosthetic valves, we recommend vitamin K antagonists with a target INR of 2.5 (range, 2.0 to 3.0) for the first 3 months after valve insertion in the mitral position (Grade 1C+) and in the aortic position (Grade 2C). For patients with bioprosthetic valves who are in sinus rhythm and do not have AF, we recommend long-term (> 3 months) therapy with aspirin, 75 to 100 mg/d (Grade 1C+). [ABSTRACT FROM AUTHOR]

In this investigation we explore whether assessment of the risk of mortality can be refined by stratifying high-risk patients with pulmonary embolism (PE) according to whether they had cardiac arrest. We stratified high-risk patients according to whether they had shock but no cardiac arrest, or cardiac arrest diagnosed in the emergency department (ED). This was a retrospective cohort study based on administrative data from the Nationwide Emergency Department Sample (NEDS), 2016. Included patients were 274,227 who were admitted to the same hospital as the ED or died in the ED. This was 77% of 354,616 patients with pulmonary embolism seen in the ED in 2016. Patients were identified based on International Classification of Diseases, 10th Edition, Clinical Modification (ICD-10-CM) Codes. High-risk with no cardiac arrest were 4,317 of 274,227 (1.6%) and high-risk with cardiac arrest were 1,027 of 274,227 (0.4%). Mortality of high-risk patients who did not have cardiac arrest was 1,753 of 4,317 (41%). Mortality of high-risk patients who had cardiac arrest was 754 of 1027 (74%). Mortality increased with age in high-risk patients who did not have cardiac arrest, but mortality was not age-related in high-risk patients with cardiac arrest. In conclusion, high-risk patients with PE are a heterogeneous group and stratification according to whether they had cardiac arrest refines risk assessment., (Copyright © 2021. Published by Elsevier Inc.)

Background: Several advanced treatments of high-risk patients with pulmonary embolism have been used in recent decades. We assessed the 19-year national trend in mortality of high-risk patients with pulmonary embolism to determine what impact, if any, advanced therapy might have had on mortality., Methods: Mortality (case fatality rate) was assessed in patients with a primary (first-listed) diagnosis of high-risk pulmonary embolism who were hospitalized during the period from 1999 to 2014 and in 2016 and 2017. High-risk was defined as patients with pulmonary embolism who were in shock or suffered cardiac arrest. International Classification of Diseases, 9th revision, Clinical Modification codes were used for data on the period from 1999 to 2014, and version 10 codes were used for data on the years 2016 and 2017. Trends in mortality were assessed according to treatment., Results: From 1999 to 2017 (excluding 2015), 58,784 patients were hospitalized in United States with a primary diagnosis of pulmonary embolism that was high risk. Mortality in all high-risk patients decreased from 72.7% in 1999 to 49.8% in 2017 (P < .0001). Most high-risk patients (60.3%) were treated with anticoagulants alone and did not receive an inferior vena cava filter. Mortality in these patients decreased from 79.0% in 1999 to 55.7% in 2017 (P < .0001). Thrombolytic therapy was administered to 16.1% of high-risk patients, open pulmonary embolectomy alone was used in 4.3%, and extracorporeal membrane oxygenation was used in 0.4%., Conclusions: Mortality of high-risk patients with pulmonary embolism has decreased. This decrease can be attributed to improved treatment of patients with shock and with cardiac arrest, and does not reflect advances in therapy for pulmonary embolism., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Whether deep venous thrombosis involving the pelvic veins or inferior vena cava is associated with higher in-hospital mortality or higher prevalence of in-hospital pulmonary embolism than proximal or distal lower extremity deep venous thrombosis is not known., Methods: This was a retrospective cohort study based on administrative data from the Nationwide Inpatient Sample, 2016, 2017. Patients hospitalized with a primary diagnosis of deep venous thrombosis at known locations were identified by International Classification of Diseases-10-Clinical Modification codes., Results: In-hospital all-cause mortality with deep venous thrombosis involving the inferior vena cava in patients treated only with anticoagulants was 2.2% versus 0.8% with pelvic vein deep venous thrombosis (p<0.0001), 0.7% with proximal deep venous thrombosis (p<0.0001) and 0.2% with distal deep venous thrombosis (p<0.0001).  Mortality with anticoagulants was similar with pelvic vein deep venous thrombosis compared with proximal lower extremity deep venous thrombosis, 0.8% versus 0.7% (p=0.39). Lower mortality was shown with pelvic vein deep venous thrombosis treated with thrombolytics than with anticoagulants, 0% versus 0.8% (p<0.0001). In-hospital pulmonary embolism occurred in 11% to 23%, irrespective of the site of deep venous thrombosis., Conclusion: Patients with deep venous thrombosis involving the inferior vena cava had higher in-hospital mortality than patients with deep venous thrombosis at other locations. Pelvic vein deep venous thrombosis did not result in higher mortality or more in-hospital pulmonary embolism than proximal lower extremity deep venous thrombosis.  The incidence of in-hospital pulmonary embolism was considerable with deep venous thrombosis at all sites., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The incidence of pulmonary embolism has been increasing. It has been suggested that this may reflect overdiagnosis due to widespread use of computed tomographic pulmonary angiography. The purpose of the present investigation is to further evaluate whether the increasing incidence of pulmonary embolism represents overdiagnosis., Methods: This was a retrospective cohort study based on administrative data from the National (Nationwide) Inpatient Sample 1999-2014. International Classification of Diseases, Ninth Revision, Clinical Modification codes were used. The population of the United States according to year was determined from the Centers for Disease Control and Prevention., Results: The incidence of pulmonary embolism increased from 65/100,000 population in 1999 to 137/100,000 population in 2014 (P < .0001). High-risk pulmonary embolism increased from 2.2/100,000 population to 9.9/100,000 population (P < .0001). The incidence of primary pulmonary embolism increased from 40/100,000 population in 1999 to 73/100,000 population in 2014 (P < .0001). High-risk pulmonary embolism in patients with a primary diagnosis of pulmonary embolism increased from 0.8/100,000 population in 1999 to 2.3/100,000 population in 2014 (P < .0001). Among patients with pulmonary embolism, the incidence of high-risk pulmonary embolism increased from 1999-2014 (P = .0025). In-hospital all-cause mortality in high-risk patients was 102,402 of 195,909 (52.2%)., Conclusions: The incidence of high-risk pulmonary embolism has increased concordantly with the increasing incidence of all pulmonary embolism. Increasing proportions of patients with potentially lethal pulmonary embolism are being diagnosed., (Copyright © 2020. Published by Elsevier Inc.)

Despite apparent advantages of home treatment of deep venous thrombosis (DVT) based upon results of randomized controlled trials, physicians maintain a conservative approach, and a large proportion of patients with DVT are hospitalized. In the present investigation we assess whether selection of patients for hospitalization for acute DVT was related to the site of the DVT or to age. This was a retrospective cohort study based on administrative data from the Nationwide Emergency Department Sample, 2016. Patients were identified by International Classification of Diseases-10-Clinical Modification codes. Most, 87,436 of 133,414 (66%), had proximal DVT. A minority of patients with isolated distal DVT were hospitalized, 10,621 of 37,592 (28%). However, hospitalization was selected for 47,459 of 87,436 (54%) with proximal DVT; 4,867 of 7,599 (64%) with pelvic vein DVT; and 611 of 788 (78%) with DVT involving the inferior vena cava. Hospitalization for patients with distal DVT, proximal DVT, and pelvic vein DVT was age-dependent. In conclusion, both the site of acute DVT and age were factors affecting the clinical decision of emergency department physicians to select patients for hospital treatment., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We performed this investigation to determine the effects on mortality of thrombolytic therapy in low-risk patients with pulmonary embolism (PE). This was a retrospective cohort study based on administrative data from the Nationwide Inpatient Sample, 2016 and 2017. Patients with a primary (first-listed) diagnosis of acute PE who were not in shock and not on a ventilator who did not have acute cor pulmonale were defined as low-risk. Patients were identified by International Classification of Diseases-10-Clinical Modification Codes. Mortality was assessed according to treatment with catheter-directed thrombolysis, intravenous thrombolytic therapy, or anticoagulants alone. Mortality with inferior vena cava (IVC) filters was also assessed. Mortality was lowest in low-risk patients treated with anticoagulants alone, 6,765 of 331,430 (2.0%). Mortality was somewhat higher with catheter-directed thrombolysis, 195 of 6915 (2.8%; p <0.0001), and highest with intravenous thrombolysis 510 of 5,200 (9.8%; p <0.0001). Matched patients showed similar results. IVC filters did not reduce mortality in patients treated with anticoagulants alone. Mortality was only 0.5% higher in patients treated with anticoagulants who had saddle PE than in patients with nonsaddle PE, 450 of 17,935 (2.5%) versus 6,315 of 313,495 (2.0%; p <0.0001). However, a larger proportion of low-risk patients with saddle PE received catheter-directed thrombolysis than patients who had nonsaddle PE, 2,330 of 21,760 (11%) versus 4,585 of 321,785 (1.4%; p <0.0001). Similarly, a larger proportion of patients with saddle PE received intravenous thrombolytic therapy than patients with nonsaddle PE, 1,495 of 21,760 (6.9%) versus 3,705 of 321,785 (1.2%; p <0.0001). In conclusion, low-risk patients with PE did not have lower mortality with catheter-directed thrombolysis or intravenous thrombolytic therapy than with anticoagulants alone, and IVC filters did not reduce mortality with anticoagulants alone., (Copyright © 2020. Published by Elsevier Inc.)

Treatment of submassive (intermediate-risk) pulmonary embolism (PE), defined as hemodynamically stable with right ventricular (RV) dysfunction, showed lower in-hospital all-cause mortality with intravenous thrombolytic therapy than with anticoagulants, but at an increased risk of major bleeding. The present investigation was performed to test whether catheter-directed thrombolysis reduces mortality without increasing bleeding in submassive PE. This was a retrospective cohort study based on administrative data from the Nationwide Inpatient Sample. In 2016, 13,130 patients were hospitalized with PE and acute cor pulmonale, were stable, and treated with catheter-directed thrombolysis in 1,500 (11%) or anticoagulants alone in 11,630 (89%). Mortality was lower with catheter-directed thrombolysis than with anticoagulants in unmatched patients, 35 of 1,500 (2.3%) compared with 755 of 11,630 (6.5%; p <0.0001) and in matched patients, 30 of 1,260 (2.4%) compared with 440 of 6,910 (6.4%; p <0.0001). Time-dependent analysis showed catheter-directed thrombolysis reduced mortality if administered within the first 3 days. Patients with saddle PE treated with anticoagulants had lower mortality than non-saddle PE, 75 of 1,730 (4.3%) compared with 680 of 9,900 (6.9%; p < 0.0001) in unmatched patients and 45 of 1,305 (3.4%) compared with 395 of 5,605 (7.0%; p < 0.0001) in matched patients. Mortality was not lower with inferior vena cava filters either in those who received catheter-directed thrombolysis or those treated with anticoagulants. There were no fatal or nonfatal adverse events associated with catheter-directed thrombolysis. In conclusion, patients with submassive PE appear to have lower in-hospital all-cause mortality with catheter-directed thrombolysis administered within 3 days than with anticoagulants, and risks are low., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Mortality with adjunctive therapy in patients with unstable pulmonary embolism, defined as those in shock or on ventilator support, is sparsely studied and requires further investigation. This was a retrospective cohort study based on administrative data from the Nationwide Inpatient Sample, 2016. In-hospital all-cause mortality in unstable patients with acute pulmonary embolism was assessed according to treatment. Patients were identified by International Classification of Diseases-10-Clinical Modification Codes. Most unstable patients, 85%, received only anticoagulants. Their mortality was 3,080 of 6,635 (46%) without an inferior vena cava (IVC) filter, and mortality was much less with an IVC filter, 285 of 1,185 (24%) (p <0.0001). Mortality with catheter-directed thrombolysis alone, 70 of 235 (30%), did not differ significantly from mortality with anticoagulants plus an IVC filter, p = 0.07, although a trend favored the latter. Intravenous thrombolytic therapy without an IVC filter showed a mortality of 295 of 695 (42%) which tended to be lower than mortality with anticoagulants alone (p = 0.06). The addition of an IVC filter to intravenous thrombolytic therapy resulted in a mortality of 20 of 165 (12%), which was the lowest mortality with any combination of adjunctive treatments. Intravenous thrombolytic therapy, however, was associated with more adverse effects of therapy than catheter-directed thrombolysis or anticoagulants., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In the absence of a randomized controlled trial, it is important to obtain as much evidence as possible by other methods on whether inferior vena cava (IVC) filters reduce mortality in patients who undergo pulmonary embolectomy. Therefore, this retrospective cohort study based data from the National Inpatient Sample 2009 to 2014 was undertaken. We assessed in-hospital all-cause mortality in stable and unstable (in shock or on ventilator support) patients with acute pulmonary embolism who underwent pulmonary embolectomy. International Classification of Diseases-9-Clinical Modification (ICD-9-CM) codes were used to identify patients. Co-morbidities were assessed by the updated Charlson co-morbidity index. A time-dependent analysis was performed to control for immortal time bias. In stable patients who underwent pulmonary embolectomy, mortality with an IVC filter was 50 of 1,212 (4.1%) compared with 202 of 755 (27%) with no IVC filter (p <0.0001). In unstable patients, mortality with an IVC filter was 108 of 598 (18%) compared with 179 of 358 (50%) with no IVC filter (p <0.0001). Mortality was reduced with IVC filters only if the filters were inserted in the first 4 or 5 days. Co-morbid conditions and immortal time bias could not explain these results. We conclude that both stable and unstable patients who underwent pulmonary embolectomy had a lower mortality with IVC filters if inserted in the first 4 or 5 days., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Trends in the use of inferior vena cava (IVC) filters in patients with pulmonary embolism (PE) who are stratified according to whether they are stable or unstable (in shock or ventilator dependent) may show where improvements of management could be made according to the best evidence that we now have., Methods: This was a retrospective cohort study based on administrative data, 1999-2014, from the National (Nationwide) Inpatient Sample., Results: In-hospital all-cause mortality in unstable patients who received an IVC filter was lower in each year of investigation and in all age groups. Mortality from 1999 to 2014 was 10,140 of 35,230 (28.8%) with an IVC filter compared with 54,018 of 116,642 (46.3%) without a filter (P <0.0001). In stable patients from 1999 to 2014, mortality with an IVC filter was 31,909 of 546,858 (5.8%) with an IVC filter compared with 220,443 of 3,367,783 (6.5%) without a filter (P <0.0001). In patients ages > 80 years, mortality in stable patients with an IVC filter was 7,438 of 114,457 (6.5%) with an IVC filter compared with 64,113 of 567,348 (11.3%) without an IVC filter (P <0.0001). The number of stable patients who received an IVC filter decreased from 2010 to 2014, but even in those years the largest number of IVC filters was inserted in stable patients, 194,502 of 212,611 (91.5%)., Conclusions: Mortality is markedly reduced in unstable patients who receive an IVC filter. Despite this, the proportion of unstable patients who receive an IVC filter is decreasing. The largest number of IVC filters continues to be inserted in stable patients, although there is no evidence of a clinically meaningful reduced mortality with IVC filters in stable patients unless age >80 years., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The purpose of the present investigation is to determine the response to the evidence and recommendations against the use of inferior vena cava (IVC) filters in patients with deep venous thrombosis (DVT). This was a retrospective cohort study based on administrative data from the National Hospital Discharge Survey 1979 to 2006 and from the National (Nationwide) Inpatient Sample 2007 to 2014. The number of IVC filters inserted in patients with lone DVT peaked in 2009 and then decreased from 2009 to 2014. The proportion of patients with lone DVT who received an IVC filter peaked in 2010 and then decreased from 2010 to 2014. Both the number of IVC filters inserted yearly and the proportion of patients who received an IVC filter remained higher than in 1998 when a randomized controlled trial showed no reduced mortality with permanent IVC filters in patients with DVT. In conclusion, large numbers of patients with lone DVT continue to receive IVC filters despite a randomized controlled trial that showed no reduced mortality with IVC filters in patients with DVT and despite clinical guideline recommendations against the use of IVC filters in such patients., (Copyright © 2019. Published by Elsevier Inc.)

Mortality according to the use inferior vena cava (IVC) filters in patients with pulmonary embolism (PE) and heart failure (HF) has been sparsely studied. In the present investigation, we assess whether IVC filters in stable patients with PE and HF reduce mortality. This is a retrospective cohort study of administrative data from the Premier Healthcare Database, 2009 through 2015. Patients aged ≥18 years hospitalized with a primary diagnosis of PE and a discharge diagnosis of HF were identified by International Classification of Diseases-Ninth Revision-Clinical Modification codes. Exclusions were unstable patients (in shock or on a ventilator), patients who underwent pulmonary embolectomy, and patients with co-morbidities. In-hospital all-cause mortality was 102 of 2,423 (4.2%) with an IVC filter compared with 686 of 14,063 (4.9%) without an IVC filter (p = 0.16). Only patients aged >80 years showed a lower in-hospital all-cause mortality with IVC filters, 38 of 933 (4.1%) with an IVC filter compared with 307 of 4,486 (6.8%) without an IVC filter (p = 0.0012). In conclusion, stable patients with PE and HF, if aged >80 years, showed a reduced in-hospital all-cause mortality with IVC filters., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Retrospective cohort studies using administrative data from national databases or a registry suggest that there are subcategories of stable patients with acute pulmonary embolism who would show a reduced mortality with an inferior vena cava (IVC) filter in addition to anticoagulants. These subcategories are those who underwent pulmonary embolectomy, receiving thrombolytic therapy, suffering recurrent pulmonary embolism while on treatment, hospitalized with solid malignant tumors if aged >60 years, hospitalized with chronic obstructive pulmonary disease (COPD) if aged >50 years, and very elderly (aged >80 years). The following is a review of these studies. It is important to be circumspect in inferring a lower mortality with IVC filters based on comparative effectiveness research that uses national observational data. On the other hand, the likelihood of a randomized controlled trial in any of these subcategories of stable patients is remote. Whether patients are better served by inserting an IVC filter on the basis of retrospective cohort studies, or by withholding IVC filters until a randomized controlled trial can be obtained is a matter for consideration., (Copyright © 2019 Elsevier Inc. All rights reserved.)

There are no randomized controlled trials of thrombolytic therapy, pulmonary embolectomy, or inferior vena cava (IVC) filters in patients with unstable pulmonary embolism (those in shock or on ventilator support). Yet, there are many investigations of these treatments based on retrospective cohort studies using administrative data from large government and commercial databases. Extensive data from these cohort studies showed that thrombolytic therapy resulted in the lowest in-hospital all-cause mortality. The results of thrombolytic therapy were greatly improved if IVC filters were added. In fact, IVC filters decreased in-hospital all-cause mortality with anticoagulants alone or with pulmonary embolectomy as well as thrombolytic therapy in adults of all ages with unstable pulmonary embolism. The IVC filters reduced mortality only if inserted on the day of admission or the next day, while the patients were unstable and in a fragile condition. We conclude that the best treatment for patients with unstable pulmonary embolism is thrombolytic therapy combined with an IVC filter inserted during the period of fragility, while the patient is unstable, and this treatment is indicated in all unstable patients irrespective of age., (Copyright © 2018. Published by Elsevier Inc.)

Background: There are sparse data to support the recommendation for inferior vena cava (IVC) filters in patients with recurrent pulmonary embolism while on anticoagulant therapy., Methods: This was a retrospective cohort study of administrative data from the Premier Healthcare Database, 2009-2014. All-cause mortality according to the use of IVC filters was evaluated in patients who suffered a recurrent pulmonary embolism within 3 months of an index pulmonary embolism. Patients were identified by International Classification of Disease, 9th Clinical Modification codes. A time-dependent analysis controlled for immortal time bias., Results: An IVC filter was inserted in 603 of 814 (74.1%) of patients hospitalized for recurrent pulmonary embolism within 3 months of an index pulmonary embolism. Mortality with an IVC filter was 18 of 603 (3.0%) vs 83 of 211 (39.3%) (P < .0001) without a filter. Among patients with recurrent pulmonary embolism who were stable and did not receive thrombolytic therapy or undergo pulmonary embolectomy, mortality with an IVC filter was 15 of 572 (2.6%) vs 72 of 169 (42.6%) (P < .0001) without a filter., Conclusion: In the United States, usual practice was to insert an IVC filter in patients with early recurrent pulmonary embolism. Mortality was lower in those who received an IVC filter. Even stable patients with early recurrent pulmonary embolism showed a decreased mortality with IVC filters, even though in other circumstances, IVC filters do not reduce mortality in stable patients. Additional cohort studies would be useful in the absence of a randomized controlled trial., (Copyright © 2019. Published by Elsevier Inc.)

Synthesis and structure-activity relationships (SAR) of a novel series of benzodiazepinedione-based inhibitors of Clostridium difficile toxin B (TcdB) are described. Compounds demonstrating low nanomolar affinity for TcdB, and which possess improved stability in mouse plasma vs. earlier compounds from this series, have been identified. Optimized compound 11d demonstrates a good pharmacokinetic (PK) profile in mouse and hamster and is efficacious in a hamster survival model of Clostridium difficile infection., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Immortal time bias is a possible confounding factor in cohort studies. In this investigation, we assessed mortality with inferior vena cava (IVC) filters in unstable patients with pulmonary embolism using a design to control for immortal time bias., Methods: Data were from the Premier Healthcare Database, 2010-2014. International Classification of Diseases-Ninth Revision-Clinical Modification codes were used. Unstable patients with pulmonary embolism and an admitting diagnosis of pulmonary embolism, as well as a primary diagnosis of pulmonary embolism, were included. A time-dependent analysis was used according to the day of insertion of the IVC filter to control for immortal time bias., Results: Among all unstable patients, irrespective of the use of thrombolytic therapy, in-hospital all-cause mortality was 35 of 180 (19.4%) in those who received an IVC filter vs 122 of 299 (40.8%) with no filter (P < .0001). Mortality was lower in patients in whom the IVC filter was inserted on days 1 or 2 (on day 1, 21.4% compared with 40.8%, P = .017, and on day 2, 14.8% compared with 29.2%, P = .023), but it was not lower in those in whom the filter was inserted on subsequent days., Conclusions: Mortality in unstable patients with pulmonary embolism appeared to be reduced with IVC filters only when the filter was inserted on the first or second day of admission. The design used for these analyses controlled for immortal time bias as a cause of the lower mortality with IVC filters., (Copyright © 2018. Published by Elsevier Inc.)

Clostridium difficile infection (CDI) is the leading cause of hospital-acquired infectious diarrhea, with significant morbidity, mortality, and associated health care costs. The major risk factor for CDI is antimicrobial therapy, which disrupts the normal gut microbiota and allows C. difficile to flourish. Treatment of CDI with antimicrobials is generally effective in the short term, but recurrent infections are frequent and problematic, indicating that improved treatment options are necessary. Symptoms of disease are largely due to two homologous toxins, TcdA and TcdB, which are glucosyltransferases that inhibit host Rho GTPases. As the normal gut microbiota is an important component of resistance to CDI, our goal was to develop an effective nonantimicrobial therapy. Here, we report a highly potent small-molecule inhibitor (VB-82252) of TcdA and TcdB. This compound inhibits the UDP-glucose hydrolysis activity of TcdB and protects cells from intoxication after challenge with either toxin. Oral dosing of the inhibitor prevented inflammation in a murine intrarectal toxin challenge model. In a murine model of recurrent CDI, the inhibitor reduced weight loss and gut inflammation during acute disease and did not cause the recurrent disease that was observed with vancomycin treatment. Lastly, the inhibitor demonstrated efficacy similar to that of vancomycin in a hamster disease model. Overall, these results demonstrate that small-molecule inhibition of C. difficile toxin UDP-glucose hydrolysis activity is a promising nonantimicrobial approach to the treatment of CDI., (Copyright © 2018 American Society for Microbiology.)

Background: Which patients with fractures, if any, have a lower mortality with prophylactic inferior vena cava filters has yet to be established. The purpose of this investigation is to determine if patients with low-risk fractures might benefit from a prophylactic inferior vena cava filter., Methods: Administrative data was analyzed from the National (Nationwide) Inpatient Sample using ICD-9-CM codes. Included patients were aged 18 years or older with a primary diagnosis of non-complex fracture of the pelvis, or fracture of the femuralone, or fracture of the tibia and/or fibula., Results: From 2003-2012, 1,479,039 patients were hospitalized with low-risk fracture. The vast majority of patients with fracture, 1,461,378 of 1,479,039 (98.8%) did not receive an inferior vena cava filter. Among those who did not receive a filter, 1,446,489 of 1,461,378 (99.0%) did not develop deep venous thrombosis or pulmonary embolism. Pulmonary embolism without a filter occurred in 7207 of 1,461,378 (0.5%) and deep venous thrombosis occurred in 7682 of 1,461,378 (0.5%). Total in-hospital all-cause mortality in those who did not receive a filter was 15,683 of 1,461,378 (1.1%). An inferior vena cava filter was inserted in 17,661 of 1,479,039 (1.2%) of patients with fractures. Most of those who received an inferior vena cava filter, 12,025 of 17,661 (68.1%) did not develop pulmonary embolism or deep venous thrombosis. Total in-hospital all-cause mortality in all patients with an inferior vena cava filter was 516 of 17,661 (2.9%)., Conclusion: The evidence is against the use of a prophylactic inferior cava vena filter in patients with a non-complex pelvic fracture or single fracture of the femur or fracture of the tibia and/or fibula.

Background: Administrative data have shown a lower mortality in hospitalized patients with pulmonary embolism and cancer who receive a vena cava filter. In the absence of a randomized controlled trial of vena cava filters in such patients, further investigation is necessary. Therefore, we performed this investigation using administrative data from a different database than used previously, and we investigate patients hospitalized in more recent years., Methods: We analyzed administrative data from the Premier Healthcare Database, 2010-2014, in patients hospitalized with pulmonary embolism and solid malignant tumors. Patients were identified on the basis of International Classification of Disease, Ninth Revision, Clinical Modification codes., Results: Patients aged >60 years had a lower in-hospital all-cause mortality with vena cava filters than those who did not have filters, 346 of 4648 (7.4%) compared with 2216 of 19,847 (11.2%) (P < .0001) (relative risk 0.67). Among patients aged >60 years who received an inferior vena cava, all-cause mortality within 3 months was 704 of 4648 (15.1%), compared with 3444 of 19,847 (17.4%) among those who did not receive a filter (P < .0001) (relative risk 0.86)., Conclusion: Elderly patients with pulmonary embolism and cancer may be a special population in whom inferior vena cava filters reduce in-hospital and 3-month all-cause mortality. Further investigation is needed, particularly in younger patients., (Copyright © 2018. Published by Elsevier Inc.)