The ALPHA phase 1 study: pulmonary ArteriaL hypertension treated with CardiosPHere-Derived allogeneic stem cells.

BACKGROUND: Pulmonary Arterial Hypertension (PAH) is a progressive condition with no cure. Even with pharmacologic advances, survival remains poor. Lung pathology on PAH therapies still shows impressive occlusive arteriolar remodelling and plexiform lesions. Cardiosphere-derived cells (CDCs) are heart-derived progenitor cells exhibiting anti-inflammatory and immunomodulatory effects, are anti -fibrotic, anti-oxidative and anti-apoptotic to potentially impact several aspects of PAH pathobiology. In preclinical trials CDCs reduced right ventricular (RV) systolic pressure, RV hypertrophy, pulmonary arteriolar wall thickness and inflammation. METHODS: The ALPHA study was a Phase 1a/b study in which CDCs were infused into patients with Idiopathic (I)PAH, Heritable (H) HPAH, PAH-connective tissue disease (CTD) and PAH-human immunodeficiency virus (HIV). The study was IRB approved and DSMB monitored. Phase 1a, was an open label study (n = 6). Phase 1b was a double-blind placebo-controlled study (n = 20) in which half received 100 million CDCs (the maximum feasible dose from manufacturing perspective) and half placebo (PLAC) infusions. Right heart catheterization (RHC) and cardiac MR imaging (cMR) were performed at baseline and at 4 months post infusion. Patients were followed over a year. FINDINGS: No short-term clinical safety adverse events (AE) were related to the IP, the primary outcome measure. There were no adverse hemodynamic, gas exchange, rhythm or other clinical events following infusion and in the 1st 23 h monitored in hospital. There were no long-term AEs over 12 months noted, including unrelated limited hospitalizations. No immunologic short or long-term AEs were noted. We examined exploratory outcomes across multiple domains to determine encouraging signals to motivate future advanced phase testing. Phase 1a data showed encouraging observations for both 50 and 100 million CDC doses. Several encouraging findings favouring CDCs (n = 16) compared to placebo (n = 10) were noted. On cMR, the RV end diastolic volume (RVEDV) and index (RVEDVI) decreased with CDCs with a rise in the PLAC group. The 6-min walk distance was increased 2 months post infusion in the CDC group compared with PLAC. With PLAC, diffusing capacity (DLCO) decreased at 4 months but was unchanged with CDCs. Serum creatinine decreased with CDCs at 4 months. Encouraging observations favouring CDCs were also noted for RV fractional area change on echo and RV ejection fraction (RVEF) on cMR at 4 months. No differences were observed for mean pulmonary artery pressures or pulmonary vascular resistance. Review of long-term data to 12 months showed continued decline in DLCO for the PLAC cohort at 6 months with no change through 12 months. By contrast, CDC subjects showed an unchanged DLCO over 12-months. For parameters exhibiting early encouraging exploratory findings in CDC subjects, no further improvement was noted in long-term follow up through 12 months. INTERPRETATION: Intravenous CDCs were safe in both the short and long term in PAH subjects and thus may be safe in larger cohorts, in line with our extensive track record of safety in clinical trials for other conditions. Further, CDCs exhibited encouraging exploratory findings across several domains. Repeat dosing (quarterly, over one year) of intravenous CDCs has been reported to yield highly significant sustained disease-modifying bioactivity in subjects with advanced Duchenne muscular dystrophy. Because only single CDC doses were used here, the findings represent a lower limit estimate of CDC's potential in PAH. Upcoming phase 2 studies would logically use a repeat dosing paradigm. FUNDING: California Institute for Regenerative Medicine (CIRM). Project Number: CLIN2-09444.

Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19. METHODS: We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 µg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475. FINDINGS: Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87-1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3-7%) in the interferon beta-1a plus remdesivir group and 3% (2-6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69-2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group. INTERPRETATION: Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo. FUNDING: The National Institute of Allergy and Infectious Diseases (USA).

Chronic Thromboembolic Pulmonary Hypertension: the Bedside.

PURPOSE OF REVIEW: Chronic thromboembolic pulmonary hypertension (CTEPH), included in group 4 PH, is an uncommon complication of acute pulmonary embolism (PE), in which emboli in the pulmonary vasculature do not resolve but rather form into an organized scar-like obstruction which can result in right ventricular (RV) failure. Here we provide an overview of current diagnosis and management of CTEPH. RECENT FINDINGS: CTEPH management is complex with treatments that range from surgery, percutaneous interventions, to medical therapies. Current CTEPH medical therapies have largely been repurposed from pulmonary arterial hypertension (PAH). The diagnosis of CTEPH can be challenging, requiring a multimodality approach to differentiate from disease mimics. While these treatments improve symptoms, they may not reverse the underlying pathology of CTEPH.

Results From the United States Chronic Thromboembolic Pulmonary Hypertension Registry: Enrollment Characteristics and 1-Year Follow-up.

BACKGROUND: The United States Chronic Thromboembolic Pulmonary Hypertension Registry (US-CTEPH-R) was designed to characterize the demographic characteristics, evaluation, clinical course, and outcomes of surgical and nonsurgical therapies for patients with chronic thromboembolic pulmonary hypertension. RESEARCH QUESTION: What are the differences in baseline characteristics and 1-year outcomes between operated and nonoperated subjects? STUDY DESIGN AND METHODS: This study describes a multicenter, prospective, longitudinal, observational registry of patients newly diagnosed (< 6 months) with CTEPH. Inclusion criteria required a mean pulmonary artery pressure ≥ 25 mm Hg documented by right heart catheterization and radiologic confirmation of CTEPH. Between 2015 and 2018, a total of 750 patients were enrolled and followed up biannually until 2019. RESULTS: Most patients with CTEPH (87.9%) reported a history of acute pulmonary embolism. CTEPH diagnosis delays were frequent (median, 10 months), and most patients reported World Health Organization functional class 3 status at enrollment with a median mean pulmonary artery pressure of 44 mm Hg. The registry cohort was subdivided into Operable patients undergoing pulmonary thromboendarterectomy (PTE) surgery (n = 566), Operable patients who did not undergo surgery (n = 88), and those who were Inoperable (n = 96). Inoperable patients were older than Operated patients; less likely to be obese; have a DVT history, non-type O blood group, or thrombophilia; and more likely to have COPD or a history of cancer. PTE resulted in a median pulmonary vascular resistance decline from 6.9 to 2.6 Wood units (P < .001) with a 3.9% in-hospital mortality. At 1-year follow-up, Operated patients were less likely treated with oxygen, diuretics, or pulmonary hypertension-targeted therapy compared with Inoperable patients. A larger percentage of Operated patients were World Health Organization functional class 1 or 2 at 1 year (82.9%) compared with the Inoperable (48.2%) and Operable/No Surgery (56%) groups (P < .001). INTERPRETATION: Differences exist in the clinical characteristics between patients who exhibited operable CTEPH and those who were inoperable, with the most favorable 1-year outcomes in those who underwent PTE surgery. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02429284; URL: www.clinicaltrials.gov.

Radiologic mimics of pulmonary embolism.

The diagnosis of pulmonary embolism (PE) is often made more challenging by the presence of diseases that can mimic thromboembolic disease. There is no specific or sensitive constellation of clinical signs or symptoms that can be used to diagnose PE. Ventilation/perfusion scans can have false-positive findings related to mediastinal conditions that can compress the pulmonary arteries, and pulmonary hemorrhage can resemble PE on V/Q scanning with potentially devastating consequences if anticoagulation is started. CT-scan related issues l eading to potential false-positive diagnoses range from inadequate imaging technique, to systemic-pulmonary shunting, to non-thrombotic occlusion of pulmonary arteries by tumor, septic emboli, and emboli of fat, air, and foreign material, as well as vasculitic processes. Careful assessment of the patient and consideration of these potential mimickers is imperative to correct diagnosis of this potentially life-threatening condition.

COVID-19 and Its Implications for Thrombosis and Anticoagulation.

Venous thromboembolism, occlusion of dialysis catheters, circuit thrombosis in extracorporeal membrane oxygenation (ECMO) devices, acute limb ischemia, and isolated strokes, all in the face of prophylactic and even therapeutic anticoagulation, are features of novel coronavirus disease 2019 (COVID-19) coagulopathy. It seems well established at this time that a COVID-19 patient deemed sick enough to be hospitalized, should receive at least prophylactic dose anticoagulation. However, should some hospitalized patients have dosage escalation to intermediate dose? Should some be considered for full-dose anticoagulation without a measurable thromboembolic event and how should that anticoagulation be monitored? Should patients receive postdischarge anticoagulation and with what medication and for how long? What thrombotic issues are related to the various medications being used to treat this coagulopathy? Is antiphospholipid antibody part of this syndrome? What is the significance of isolated ischemic stroke and limb ischemia in this disorder and how does this interface with the rest of the clinical and laboratory features of this disorder? The aims of this article are to explore these questions and interpret the available data based on the current evidence.

A Prospective, Single-Arm, Multicenter Trial of Catheter-Directed Mechanical Thrombectomy for Intermediate-Risk Acute Pulmonary Embolism: The FLARE Study.

OBJECTIVES: The aim of this study was to evaluate the safety and effectiveness of percutaneous mechanical thrombectomy using the FlowTriever System (Inari Medical, Irvine, California) in a prospective trial of patients with acute intermediate-risk pulmonary embolism (PE). BACKGROUND: Catheter-directed thrombolysis has been shown to improve right ventricular (RV) function in patients with PE. However, catheter-directed thrombolysis increases bleeding risk and many patients with PE have relative and absolute contraindications to thrombolysis. METHODS: Patients with symptomatic, computed tomography-documented PE and RV/left ventricular (LV) ratios ≥0.9 were eligible for enrollment. The primary effectiveness endpoint was core laboratory-assessed change in RV/LV ratio. The primary safety endpoint comprised device-related death, major bleeding, treatment-related clinical deterioration, pulmonary vascular injury, or cardiac injury within 48 h of thrombectomy. RESULTS: From April 2016 to October 2017, 106 patients were treated with the FlowTriever System at 18 U.S. sites. Two patients (1.9%) received adjunctive thrombolytics and were analyzed separately. Mean procedural time was 94 min; mean intensive care unit stay was 1.5 days. Forty-three patients (41.3%) did not require any intensive care unit stay. At 48 h post-procedure, average RV/LV ratio reduction was 0.38 (25.1%; p < 0.0001). Four patients (3.8%) experienced 6 major adverse events, with 1 patient (1.0%) experiencing major bleeding. One patient (1.0%) died, of undiagnosed breast cancer, through 30-day follow-up. CONCLUSIONS: Percutaneous mechanical thrombectomy with the FlowTriever System appears safe and effective in patients with acute intermediate-risk PE, with significant improvement in RV/LV ratio and minimal major bleeding. Potential advantages include immediate thrombus removal, absence of thrombolytic complications, and reduced need for post-procedural critical care.

Clinical Features and Outcomes of Patients with Sarcoidosis-associated Pulmonary Hypertension.

The presence of pulmonary hypertension (PH) significantly worsens outcomes in patients with advanced sarcoidosis, but its optimal management is unknown. We aimed to characterize a large sarcoidosis-associated pulmonary hypertension (SAPH) cohort to better understand patient characteristics, clinical outcomes, and management strategies including treatment with PH therapies. Patients at Duke University Medical Center with biopsy-proven sarcoidosis and SAPH confirmed by right heart catheterization (RHC) were identified from 1990-2010. Subjects were followed for up to 11 years and assessed for differences by treatment strategy for their SAPH, including those who were not treated with PH-specific therapies. Our primary outcomes of interest were change in 6-minute walk distance (6MWD) and change in N-terminal pro-brain natriuretic peptide (NT-proBNP) by after therapy. We included 95 patients (76% women, 86% African American) with SAPH. Overall, 70% of patients had stage IV pulmonary sarcoidosis, and 77% had functional class III/IV symptoms. Median NT-proBNP value was elevated (910 pg/mL), and right ventricular dysfunction was moderate/severe in 55% of patients. Median values for mean pulmonary artery pressure (49 mmHg) and pulmonary vascular resistance (8.5 Woods units) were consistent with severe pulmonary hypertension. The mortality rate over median 3-year follow-up was 32%. Those who experienced a clinical event and those who did not had similar overall echocardiographic findings, hemodynamics, 6MWD and NT-proBNP at baseline, and unadjusted analysis showed that only follow-up NT-proBNP was associated with all-cause hospitalization or mortality. A sign test to evaluate the difference between NT-Pro-BNP before and after PH therapy produced evidence that a significant difference existed between the median pre- and post-NT-Pro-BNP (-387.0 (IQR: -1373.0-109), p = 0.0495). Use of PH-specific therapy may be helpful in selected patients with SAPH and pre-capillary pulmonary vascular disease. Prospective trials are needed to characterize responses to PH-specific therapy in this subset of patients with SAPH.

Massive Pulmonary Embolism: Extracorporeal Membrane Oxygenation and Surgical Pulmonary Embolectomy.

Massive pulmonary embolism (PE) refers to large emboli that cause hemodynamic instability, right ventricular failure, and circulatory collapse. According to the 2016 ACCP Antithrombotic Guidelines, therapy for massive PE should include systemic thrombolytic therapy in conjunction with anticoagulation and supportive care. However, in patients with a contraindication to systemic thrombolytics or in those who fail the above interventions, extracorporeal membrane oxygenation (ECMO) and/or surgical embolectomy may be used to improve oxygenation, achieve hemodynamic stability, and successfully treat massive PE. Randomized controlled human trials evaluating ECMO in this context have not been done, and its role has not been well-defined. The European Society of Cardiology 2014 acute PE guidelines briefly mention that ECMO can be used for massive PE as a method for hemodynamic support and as an adjunct to surgical embolectomy. The 2016 CHEST Antithrombotic Therapy for venous thromboembolism Disease guidelines do not mention ECMO in the management of massive PE. However, multiple case reports and small series cited benefit with ECMO for massive PE. Further, ECMO may facilitate stabilization for surgical embolectomy. Unfortunately, ECMO requires full anticoagulation to maintain the functionality of the system; hence, significant bleeding complicates its use in 35% of patients. Contraindications to ECMO include high bleeding risk, recent surgery or hemorrhagic stroke, poor baseline functional status, advanced age, neurologic dysfunction, morbid obesity, unrecoverable condition, renal failure, and prolonged cardiopulmonary resuscitation without adequate perfusion of end organs. In this review, we discuss management of massive PE, with an emphasis on the potential role for ECMO and/or surgical embolectomy.

Clinical and echocardiographic predictors of mortality in acute pulmonary embolism.

PURPOSE: The aim of this study was to evaluate the utility of adding quantitative assessments of cardiac function from echocardiography to clinical factors in predicting the outcome of patients with acute pulmonary embolism (PE). METHODS: Patients with a diagnosis of acute PE, based on a positive ventilation perfusion scan or computed tomography (CT) chest angiogram, were identified using the Duke University Hospital Database. Of these, 69 had echocardiograms within 24-48 h of the diagnosis that were suitable for offline analysis. Clinical features that were analyzed included age, gender, body mass index, vital signs and comorbidities. Echocardiographic parameters that were analyzed included left ventricular (LV) ejection fraction (EF), regional, free wall and global RV speckle-tracking strain, RV fraction area change (RVFAC), Tricuspid Annular Plane Systolic Excursion (TAPSE), pulmonary artery acceleration time (PAAT) and RV myocardial performance (Tei) index. Univariable and multivariable regression statistical analysis models were used. RESULTS: Out of 69 patients with acute PE, the median age was 55 and 48 % were female. The median body mass index (BMI) was 27 kg/m2. Twenty-nine percent of the cohort had a history of cancer, with a significant increase in cancer prevalence in non-survivors (57 % vs 29 %, p = 0.02). Clinical parameters including heart rate, respiratory rate, troponin T level, active malignancy, hypertension and COPD were higher among non-survivors when compared to survivors (p ≤ 0.05). Using univariable analysis, NYHA class III symptoms, hypoxemia on presentation, tachycardia, tachypnea, elevation in Troponin T, absence of hypertension, active malignancy and chronic obstructive pulmonary disease (COPD) were increased in non-survivors compared to survivors (p ≤ 0.05). In multivariable models, RV Tei Index, global and free (lateral) wall RVLS were found to be negatively associated with survival probability after adjusting for age, gender and systolic blood pressure (p ≤ 0.05). CONCLUSION: The addition of echocardiographic assessment of RV function to clinical parameters improved the prediction of outcomes for patients with acute PE. Larger studies are needed to validate these findings.

Treatment goals of pulmonary hypertension.

With significant therapeutic advances in the field of pulmonary arterial hypertension, the need to identify clinically relevant treatment goals that correlate with long-term outcome has emerged as 1 of the most critical tasks. Current goals include achieving modified New York Heart Association functional class I or II, 6-min walk distance >380 m, normalization of right ventricular size and function on echocardiograph, a decreasing or normalization of B-type natriuretic peptide (BNP), and hemodynamics with right atrial pressure <8 mm Hg and cardiac index >2.5 mg/kg/min(2). However, to more effectively prognosticate in the current era of complex treatments, it is becoming clear that the "bar" needs to be set higher, with more robust and clearer delineations aimed at parameters that correlate with long-term outcome; namely, exercise capacity and right heart function. Specifically, tests that accurately and noninvasively determine right ventricular function, such as cardiac magnetic resonance imaging and BNP/N-terminal pro-B-type natriuretic peptide, are emerging as promising indicators to serve as baseline predictors and treatment targets. Furthermore, studies focusing on outcomes have shown that no single test can reliably serve as a long-term prognostic marker and that composite treatment goals are more predictive of long-term outcome. It has been proposed that treatment goals be revised to include the following: modified New York Heart Association functional class I or II, 6-min walk distance ≥ 380 to 440 m, cardiopulmonary exercise test-measured peak oxygen consumption >15 ml/min/kg and ventilatory equivalent for carbon dioxide <45 l/min/l/min, BNP level toward "normal," echocardiograph and/or cardiac magnetic resonance imaging demonstrating normal/near-normal right ventricular size and function, and hemodynamics showing normalization of right ventricular function with right atrial pressure <8 mm Hg and cardiac index >2.5 to 3.0 l/min/m(2).

Incidence of thrombocytopenia among patients receiving heparin venous thromboembolism prophylaxis.

BACKGROUND: Heparin is commonly used for venous thromboembolism prophylaxis; however, the incidence of acquired thrombocytopenia in this setting has not been well described. METHODS: The Complications After Thrombocytopenia Caused by Heparin (CATCH) Registry was designed to evaluate the risk of thrombocytopenia among patients receiving heparin in diverse clinical settings. We examined the incidence, management, and outcomes of thrombocytopenia (platelet count decrease ≥50% or to nadir <150×10(9)/L) among patients with normal admission platelet counts (≥150×10(9)/L) who received ≥72 hours of heparin venous thromboembolism prophylaxis. RESULTS: Among 1017 patients receiving heparin venous thromboembolism prophylaxis, 190 (19%) developed thrombocytopenia. Factors significantly associated with the development of thrombocytopenia include higher admission platelet count, ventilator use, prolonged heparin exposure, unfractionated heparin use, lower admission blood pressure, and cardiac surgery. For thrombocytopenic patients, only 5% received serologic testing for heparin-induced thrombocytopenia, and a hematology consult was obtained in 3%, but none were switched to a direct thrombin inhibitor. Acquired thrombocytopenia was not associated with increased in-hospital risk of mortality or thromboembolic events (adjusted odds ratio 1.06; 95% confidence interval, 0.57-1.95); however, it was associated with increased Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) moderate or severe bleeding risk (adjusted odds ratio 4.49; 95% confidence interval, 2.24-9.02). CONCLUSION: Thrombocytopenia occurs frequently in patients on heparin venous thromboembolism prophylaxis, yet its diagnosis has minimal impact on downstream management. The development of thrombocytopenia is associated with increased bleeding risk.

American Thoracic Society documents: an official American Thoracic Society/Society of Thoracic Radiology Clinical Practice Guideline--Evaluation of Suspected Pulmonary Embolism in Pregnancy.

BACKGROUND: Pulmonary embolism (PE) is a leading cause of maternal mortality in the developed world. Along with appropriate prophylaxis and therapy, prevention of death from PE in pregnancy requires a high index of clinical suspicion followed by a timely and accurate diagnostic approach. METHODS: To provide guidance on this important health issue, a multidisciplinary panel of major medical stakeholders was convened to develop evidence-based guidelines for evaluation of suspected pulmonary embolism in pregnancy using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system. In formulation of the recommended diagnostic algorithm, the important outcomes were defined to be diagnostic accuracy and diagnostic yield; the panel placed a high value on minimizing cumulative radiation dose when determining the recommended sequence of tests. RESULTS: Overall, the quality of the underlying evidence for all recommendations was rated as very low or low with some of the evidence considered for recommendations extrapolated from studies of the general population. Despite the low quality evidence, strong recommendations were made for three specific scenarios: performance of chest radiography (CXR) as the first radiation-associated procedure; use of lung scintigraphy as the preferred test in the setting of a normal CXR; and performance of computed-tomographic pulmonary angiography (CTPA) rather than digital subtraction angiography (DSA) in a pregnant woman with a nondiagnostic ventilation-perfusion (V/Q) result. DISCUSSION: The recommendations presented in this guideline are based upon the currently available evidence; availability of new clinical research data and development and dissemination of new technologies will necessitate a revision and update.

An official American Thoracic Society/Society of Thoracic Radiology clinical practice guideline: evaluation of suspected pulmonary embolism in pregnancy.

BACKGROUND: Pulmonary embolism (PE) is a leading cause of maternal mortality in the developed world. Along with appropriate prophylaxis and therapy, prevention of death from PE in pregnancy requires a high index of clinical suspicion followed by a timely and accurate diagnostic approach. METHODS: To provide guidance on this important health issue, a multidisciplinary panel of major medical stakeholders was convened to develop evidence-based guidelines for evaluation of suspected pulmonary embolism in pregnancy using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system. In formulation of the recommended diagnostic algorithm, the important outcomes were defined to be diagnostic accuracy and diagnostic yield; the panel placed a high value on minimizing cumulative radiation dose when determining the recommended sequence of tests. RESULTS: Overall, the quality of the underlying evidence for all recommendations was rated as very low or low, with some of the evidence considered for recommendations extrapolated from studies of the general population. Despite the low-quality evidence, strong recommendations were made for three specific scenarios: performance of chest radiography (CXR) as the first radiation-associated procedure; use of lung scintigraphy as the preferred test in the setting of a normal CXR; and performance of computed-tomographic pulmonary angiography (CTPA) rather than digital subtraction angiography (DSA) in a pregnant woman with a nondiagnostic ventilation-perfusion (V/Q) result. DISCUSSION: The recommendations presented in this guideline are based upon the currently available evidence; availability of new clinical research data and development and dissemination of new technologies will necessitate a revision and update.

[Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): results obtained in France]. / Risque thromboembolique veineux et pratique de prévention hospitalière : résultats obtenus en France de l'étude internationale ENDORSE.

AIM: Information about the variation in the risk for venous thromboembolism (VTE) and in prophylaxis practices in France and around the world is scarce. METHODS: The Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting (ENDORSE) study is a multinational cross-sectional survey designed to assess the prevalence of VTE risk in the acute hospital care setting, and to determine the proportion of at-risk patients who receive effective prophylaxis, in accordance with the 2004 American College of Chest Physicians (ACCP) guidelines. This paper gives the results of the ENDORSE study in the French centres in comparison with the global worldwide results of the ENDORSE study and with other Western Europe countries. RESULTS: In France, 18 randomized hospitals participated to the study between august 2006 and January 2007. 2844 patients were evaluated (917 from chirurgical wards and 1927 from medical wards). One thousand four hundred and nineteen patients (49.9%) were at VTE risk (78.3% in chirurgical wards and 36.4% in medical wards). Of the 1419 patients at VTE risk, 62.4% received ACCP-recommended VTE prophylaxis (71.2% in chirurgical wards and 53.5% in medical wards). VTE Prophylaxis in France (62.4%) is more frequent than worldwide in the international ENDORSE study (50.2%) and similar to the majority of the other western European countries and the USA. It is also more used in university hospitals (66.9%) than in other hospitals (58.9%). Prophylaxis in patients at risk for VTE was presented in 43% patients with acute heart failure, 53% with non-infectious acute respiratory failure, 57% in patients with pulmonary infection, 56% in patients with stroke, 55% in patients with active cancer and 48% in patients with non-pulmonary sepsis. CONCLUSIONS: The ENDORSE study has shown a high level of patients at risk for VTE in the population of hospitalized patients in France. The rate of prophylaxis for VTE remained low, in particular in Medicine wards. Our data reinforced the rationale for the use of hospital-wide strategies to assess patients' VTE risk and to implement measures that ensure that at-risk patients receive appropriate prophylaxis, in particularly in medical patients.

Crew resource management and VTE prophylaxis in surgery: a quality improvement initiative.

Despite the availability of safe and effective prophylaxis, appropriate use of venous thromboembolism (VTE) prophylaxis in surgical patients remains suboptimal. Multifaceted quality improvement (QI) activities are needed for sustained improvement at the individual institution level. This work describes a QI initiative for VTE prophylaxis in surgery that combined clinical education with Crew Resource Management (CRM)--a set of principles and techniques for communication, teamwork, and error avoidance used in the aviation industry. Surveys of clinicians participating in the initiative demonstrated immediate and retained confidence and increased knowledge in identifying process-related factors leading to errors, applying CRM to patient care, and identifying VTE prophylaxis candidates and guideline-recommended prophylaxis regimens. Reviews of patient charts preinitiative and postinitiative demonstrated performance improvement in meeting guideline recommendations for the timing, inpatient duration, and use of VTE prophylaxis beyond discharge. This new model joins continuing medical education with CRM to improve the appropriate use of VTE prophylaxis in surgery.

Prophylaxis for venous thromboembolism: guidelines translated for the clinician.

Venous thromboembolism is a major cause of morbidity and mortality worldwide and most often affects hospitalized postoperative surgical and medical patients. Venous thromboembolism prophylaxis undoubtedly improves the care of these patients, as demonstrated by the current literature and guidelines. Failure to prescribe prophylaxis when indicated, however, remains a vital health care concern. The American College of Chest Physicians (ACCP) published their most recent guidelines regarding venous thromboembolism prophylaxis in 2008. In this review, we aim to summarize the most recent ACCP prophylaxis guidelines with practical application and interpretation for the practicing physician. Here we present the most practical information from these guidelines and summarize essential recommendations in key tables. We will briefly review the grading system used in the guidelines for the level of evidence and the strength of the recommendation. We will then discuss the recommendations for prophylaxis in the various patient populations described in these guidelines including general and orthopedic surgery, gynecologic surgery, urologic surgery, thoracic surgery, neurosurgery, trauma, medical conditions, cancer patients, and critical care. In addition, we will discuss recent clinical trials regarding novel anticoagulants for venous thromboembolism prophylaxis and share some conclusions.

Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators.

BACKGROUND: Acutely ill, hospitalized medical patients are at risk of VTE. Despite guidelines for VTE prevention, prophylaxis use in these patients is still poor, possibly because of fear of bleeding risk. We used data from the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) to assess in-hospital bleeding incidence and to identify risk factors at admission associated with in-hospital bleeding risk in acutely ill medical patients. METHODS: IMPROVE is a multinational, observational study that enrolled 15,156 medical patients. The in-hospital bleeding incidence was estimated by Kaplan-Meier analysis. A multiple regression model analysis was performed to identify risk factors at admission associated with bleeding. RESULTS: The cumulative incidence of major and nonmajor in-hospital bleeding within 14 days of admission was 3.2%. Active gastroduodenal ulcer (OR, 4.15; 95% CI, 2.21-7.77), prior bleeding (OR, 3.64; 95% CI, 2.21-5.99), and low platelet count (OR, 3.37; 95% CI, 1.84-6.18) were the strongest independent risk factors at admission for bleeding. Other bleeding risk factors were increased age, hepatic or renal failure, ICU stay, central venous catheter, rheumatic disease, cancer, and male sex. Using these bleeding risk factors, a risk score was developed to estimate bleeding risk. CONCLUSIONS: We assessed the incidence of major and clinically relevant bleeding in a large population of hospitalized medical patients and identified risk factors at admission associated with in-hospital bleeding. This information may assist physicians in deciding whether to use mechanical or pharmacologic VTE prophylaxis.