Roger D. Yusen

Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism.

BACKGROUND The Pulmonary Embolism Severity Index (PESI) estimates the risk of 30-day mortality in patients with acute pulmonary embolism (PE). We constructed a simplified version of the PESI. METHODS The study retrospectively developed a simplified PESI clinical prediction rule for estimating the risk of 30-day mortality in a derivation cohort of Spanish outpatients. Simplified and original PESI performances were compared in the derivation cohort. The simplified PESI underwent retrospective external validation in an independent multinational cohort (Registro Informatizado de la Enfermedad Tromboembólica [RIETE] cohort) of outpatients. RESULTS In the derivation data set, univariate logistic regression of the original 11 PESI variables led to the removal of variables that did not reach statistical significance and subsequently produced the simplified PESI that contained the variables of age, cancer, chronic cardiopulmonary disease, heart rate, systolic blood pressure, and oxyhemoglobin saturation levels. The prognostic accuracy of the original and simplified PESI scores did not differ (area under the curve, 0.75 [95% confidence interval (CI), 0.69-0.80]). The 305 of 995 patients (30.7%) who were classified as low risk by the simplified PESI had a 30-day mortality of 1.0% (95% CI, 0.0%-2.1%) compared with 10.9% (8.5%-13.2%) in the high-risk group. In the RIETE validation cohort, 2569 of 7106 patients (36.2%) who were classified as low risk by the simplified PESI had a 30-day mortality of 1.1% (95% CI, 0.7%-1.5%) compared with 8.9% (8.1%-9.8%) in the high-risk group. CONCLUSION The simplified PESI has similar prognostic accuracy and clinical utility and greater ease of use compared with the original PESI.

Results of 150 consecutive bilateral lung volume reduction procedures in patients with severe emphysema

Between January 1993 and February 1996, we performed 150 bilateral lung volume reduction procedures for patients with severe emphysema. Patients were selected on the basis of severe dyspnea, increased lung capacity, and a pattern of emphysema that included regions of severe destruction, hyperinflation, and poor perfusion. Twenty percent to 30% of the volume of each lung was excised with the use of a linear stapler and bovine pericardial strips attached to buttress the staple line. Patients were between 36 and 77 years old, with an average 1-second forced expiratory volume of 25% of predicted, total lung capacity of 142% of predicted, and residual volume of 283% of predicted. Ninety-three percent of patients required supplemental oxygen, continuously or with exertion. All patients but one were extubated at the end of the procedure. The 90-day mortality was 4%. Hospital stay progressively decreased with experience, and for the last 50 patients the median hospital stay was 7 days. Prolonged air leakage was the major complication. Results at 6 months show a 51% increase in the 1-second forced expiratory volume and a 28% reduction in the residual volume. The Pao2 increased by an average of 8 mm Hg, and 70% of the patients who had previously required continuous supplemental oxygen no longer had this requirement. The improvements in measured pulmonary function were paralleled by a significant reduction in dyspnea and an improvement in the quality of life. Reevaluation at 1 year and 2 years after operation showed the benefit to be well maintained. We conclude that lung volume reduction offers benefits not achievable by any means other than lung transplantation for highly selected patients with severe emphysema.

The Registry of the International Society for Heart and Lung Transplantation: Thirty-first Official Adult Heart Transplant Report—2014; Focus Theme: Retransplantation

Data are submitted to the International Society for Heart and Lung Transplantation (ISHLT) Registry by national and multinational organ and data exchange organizations or by participating individual centers. Since the Registry inception, 416 heart transplant centers, 241 lung transplant centers, and 168 heart-lung transplant centers have reported data to the registry. We estimate that data submission to the Registry represents approximately 66% of worldwide thoracic transplant activity. This report used standard statistical methodology for analyses and reporting. Where appropriate, a more detailed explanation about the analytic methodology accompanies the Web site slides (in the “Notes Page” view). To assess time-to-event rates (e.g., survival), this report used the

The Registry of the International Society for Heart and Lung Transplantation: Thirtieth Official Adult Heart Transplant Report—2013; Focus Theme: Age

This 30th adult heart transplant report is based on data submitted on 110,486 heart transplants in recipients of all ages (including 99,008 adults) by 407 centers worldwide since 1982 through June 30, 2012, with follow-up until June 30, 2012. Summary data are provided for the entire cohort of patients, whereas a number of additional analyses focus on cohorts who received transplants more recently. Detailed data analyses can be viewed in the International Society for Heart and Lung Transplantation (ISHLT) Registry slide sets available online (www.ishlt.org/registries). The report is divided into several sections:

The Registry of the International Society for Heart and Lung Transplantation: Thirtieth Adult Lung and Heart-Lung Transplant Report—2013; Focus Theme: Age

This section of the 30th official Registry report of 2013 summarizes data from 43,428 adult lung and 3,703 adult heart-lung transplant recipients and their donors for transplants that occurred through June 30, 2012. This report describes donor and recipient characteristics, transplant type, and recipient outcomes data. The full Registry slide set available online (www.ishlt.org/registries) provides more detail, additional analyses, and other information not included in this printed report. For the first time, the Registry report focuses on an overall theme of recipient and donor age and incorporates new age-related analyses into its annual update.

Subcutaneous Enoxaparin Once or Twice Daily Compared with Intravenous Unfractionated Heparin for Treatment of Venous Thromboembolic Disease

Venous thromboembolic disease causes significant morbidity and mortality in both hospitalized and nonhospitalized patients. The mean annual incidence in the United States is 48 per 100 000 for deep venous thrombosis and 23 per 100 000 for pulmonary embolism, according to an epidemiologic study conducted in Massachusetts (1). A similar study in Sweden showed an annual incidence of 160 new cases of deep venous thrombosis per 100 000 inhabitants (2). Five to 10 days of unfractionated heparin is a common recommended initial treatment for deep venous thrombosis. This treatment maintains the activated partial thromboplastin time above 1.5 times its control value (3, 4), as calibrated by protamine titration or an antifactor Xa assay. Another recommended initial treatment is 5 to 10 days of weight-adjusted low-molecular-weight heparin followed by at least 3 months of oral anticoagulant therapy (3-7). Low-molecular-weight heparins are now frequently being used in place of unfractionated heparin for both prevention and treatment of venous thromboembolism (3, 8). Randomized trials and meta-analyses have shown subcutaneously administered low-molecular-weight heparins to have antithrombotic efficacy equal to (9-12) or greater than (13-16) that of continuously infused unfractionated heparin in the initial treatment of deep venous thrombosis and equal to that of unfractionated heparin in the treatment of pulmonary embolism (17, 18). However, many of these studies enrolled small numbers of patients (9-13, 15, 16), used primarily venographic plethysmographic or scintigraphic end points (9-11, 13, 16), and sometimes excluded patients with pulmonary embolism (11, 15). Most trials of twice-daily low-molecular-weight heparin adjusted treatment regimens according to patient weight without laboratory monitoring. However, several studies suggest that once-daily weight-adjusted dosage of a low-molecular-weight heparin is as effective in the treatment of proximal deep venous thrombosis as adjusted dosages of intravenous unfractionated heparin (14, 19) or twice-daily low-molecular-weight heparin (20). Since low-molecular-weight heparins differ in their physicochemical and pharmacologic characteristics, study results that apply to one cannot be extended to another (21, 22). We conducted the present study to determine whether enoxaparin administered subcutaneously once or twice per day is as effective as continuously infused unfractionated heparin in the treatment of patients with acute, symptomatic venous thromboembolic disease. Methods Study Description This parallel-group, randomized, partially blinded, international, multicenter clinical trial compared continuously infused unfractionated heparin (adjusted to maintain activated partial thromboplastin time within a defined range) with two weight-adjusted dosages of enoxaparin administered subcutaneously once or twice daily. The study was conducted in 74 hospitals in 16 countries, including the United States, several European countries, Australia, and Israel, and was approved by the institutional review board or ethics committees at each location. Written informed consent was obtained from each patient. Four committees participated in this study: an Advisory Committee; an Outcome Adjudication Committee, which provided blinded outcome assignments for incidence of recurrent venous thromboembolic disease, major or minor hemorrhage, immune thrombocytopenia, and cause of death; an independent Safety Committee; and a Vascular Imaging Committee, which reviewed all baseline venograms and all vascular imaging studies in a blinded manner to determine whether deep venous thrombosis was present at baseline and whether objective evidence of recurrence existed. Patient Characteristics Patients were required to be at least 18 years of age and willing to remain hospitalized during randomized therapy. The primary inclusion criteria were symptomatic lower-extremity deep venous thrombosis confirmed by venography or ultrasonography (if venography was inconclusive), symptomatic pulmonary embolism confirmed by high-probability ventilationperfusion scanning, or positive pulmonary angiography with confirmation of lower-extremity deep venous thrombosis. All eligible patients underwent baseline lung scanning or angiography. Exclusion criteria were more than 24 hours of previous treatment with heparin or warfarin; need for thrombolytic therapy; known hemorrhagic risk, including active hemorrhage, active intestinal ulcerative disease, known angiodysplasia, or eye, spinal, or central nervous system surgery within the previous month; renal insufficiency (serum creatinine concentration>180 mol/L [2.03 mg/dL]); severe hepatic insufficiency; allergy to heparin, protamine, porcine products (both heparin and enoxaparin are derived from pork intestinal mucosa), iodine, or contrast media; history of heparin-associated thrombocytopenia or heparin- or warfarin-associated skin necrosis; treatment with other investigational therapeutic agents within the previous 4 weeks; inferior vena cava interruption; or known pregnancy or lactation. Treatments Within each center, consecutive eligible patients were randomly assigned sequentially to one of three treatment groups. Randomization was done without stratification in blocks of six, according to ascending randomization number. The numbers were affixed to sealed treatment kits that contained study medication and were provided by the study sponsor. Patients assigned to enoxaparin received a weight-adjusted subcutaneous dose. Two blinded regimens were tested: 1.0 mg/kg of body weight twice daily or 1.5 mg/kg once daily. Several clinical trials have shown the twice-daily regimen to be effective and safe (16, 23, 24). The once-daily dosage was chosen on the basis of results of pharmacokinetic studies that showed it to have a suitable pharmacokinetic profile in healthy volunteers and to be well tolerated in the treatment of patients with venous thromboembolism (25, 26). In these previous studies, therapeutic antifactor Xa levels were present for up to 18 hours in both volunteers and patients, and measurable levels were present for up to 24 hours. A total of three injections, study drug and placebo, were given each day to maintain blinding for volume of solutions and frequency of administration. Patients assigned to the nonblinded unfractionated heparin group received an intravenous bolus dose and infusion on the basis of an approved institution-specific nomogram. In most cases, administration was as follows: Six hours after the initial bolus, the activated partial thromboplastin time was measured and the dose was adjusted to maintain the specified value, which was between 55 and 80 seconds in most centers (4-7). Activated partial thromboplastin time was measured at least daily during unfractionated heparin treatment. Enoxaparin and heparin treatments were continued for at least 5 days, and warfarin was started within 72 hours of initial study drug administration. Forty-three patients received phenprocoumon in place of warfarin sodium. Prothrombin time was measured daily, and patients could be discharged from the hospital after the international normalized ratio was found to be between 2.0 and 3.0 on 2 consecutive days. Oral anticoagulation was continued for at least 3 months. Study Assessments Observers who were aware of treatment assignment assessed patients daily and monthly during the 3-month follow-up for worsening or recurrence of deep venous thrombosis or pulmonary embolism, hemorrhage, adverse events, changes in concomitant medications and adequacy of warfarin use, and warfarin adherence. For patients receiving unfractionated heparin, adherence was defined as an activated partial thromboplastin time within or above the therapeutic range on the second day of treatment. For patients receiving enoxaparin, adherence was defined as at least 10 doses of study medication given with no dosing errors. Adherence to warfarin therapy was defined as having at least one international normalized ratio value greater than or equal to 2.0 between day 4 and the last dose of study treatment during the initial treatment period. These definitions of treatment adherence were established before the analysis of the study outcomes. Efficacy Analysis The efficacy analysis was performed on two study samples: all treated patients, who received at least one dose of study medication, and evaluable patients, which excluded all patients who met at least one of the criteria for nonevaluability. These criteria were no confirmed deep venous thrombosis at baseline, insufficient study therapy, placement of an inferior vena cava filter, two random assignments, and no 3-month follow-up. Insufficient study therapy was defined as one or more missed enoxaparin doses among at least eight consecutive enoxaparin doses or less than 4 consecutive days of heparin infusion. The definition of insufficient study therapy was established before analysis of study outcomes. These two study samples were analyzed to strengthen the conclusion of equivalence among the treatment groups. The homogeneity of the results of the two analyses is considered to be more supportive of the conclusion of equivalence than the results of either analysis alone. Primary clinical end points were recurrent deep venous thrombosis or pulmonary embolism within 3 months of randomization. Patients with symptoms of recurrent thrombosis underwent confirmatory testing with venography, ultrasonography, or both. Patients presenting with signs or symptoms of pulmonary embolism underwent lung perfusion scanning, pulmonary angiography, or both. Clinical symptoms and supportive findings on objective tests; extension of existing thrombi or new thrombi for venography, angiography, or ultrasonography; or high-probability defect patterns on perfusion scans were required to confirm recurrent thrombosis. Prespecified subgroup analyses were performed on the basis of patient demog

The Registry of the International Society for Heart and Lung Transplantation: Thirty-second Official Adult Lung and Heart-Lung Transplantation Report—2015; Focus Theme: Early Graft Failure

This section of the 32nd official International Society for Heart and Lung Transplantation (ISHLT) Registry Report of 2015 summarizes data from 51,440 adult lung and 3,820 adult heart-lung transplants that occurred through June 30, 2014. This publication reports data for donor and recipient characteristics, transplant events, and recipient treatments and outcomes. This Registry Report focuses on an overall theme of recipient early graft failure. The Registry’s online full slide set provides more detail, additional analyses, and other information not included in this publication.

The Registry of the International Society for Heart and Lung Transplantation: Thirty-first Adult Lung and Heart–Lung Transplant Report—2014; Focus Theme: Retransplantation

This section of the 31st official International Society for Heart and Lung Transplantation (ISHLT) Registry Report 2014 summarizes data from 47,647 adult lung and 3,772 adult heart–lung transplants that occurred through June 30, 2013. We report findings for donor and recipient characteristics, transplant types and recipient outcomes. This report focuses on the overall theme of recipient retransplantation and incorporates new retransplantation-related analyses into its annual update. The full Registry slide set available online (www.ishlt.org/registries) provides more detail, additional analyses and other information not included herein.

Extended-Duration Venous Thromboembolism Prophylaxis in Acutely Ill Medical Patients With Recently Reduced Mobility: A Randomized Trial

BACKGROUND Extended-duration low-molecular-weight heparin has been shown to prevent venous thromboembolism (VTE) in high-risk surgical patients. OBJECTIVE To evaluate the efficacy and safety of extended-duration enoxaparin thromboprophylaxis in acutely ill medical patients. DESIGN Randomized, parallel, placebo-controlled trial. Randomization was computer-generated. Allocation was centralized. Patients, caregivers, and outcome assessors were blinded to group assignment. (ClinicalTrials.gov registration number: NCT00077753) SETTING: 370 sites in 20 countries across North and South America, Europe, and Asia. PATIENTS Acutely ill medical patients 40 years or older with recently reduced mobility (bed rest or sedentary without [level 1] or with [level 2] bathroom privileges). Eligibility criteria for patients with level 2 immobility were amended to include only those who had additional VTE risk factors (age >75 years, history of VTE, or active or previous cancer) after interim analyses suggested lower-than-expected VTE rates. INTERVENTION Enoxaparin, 40 mg/d subcutaneously (2975 patients), or placebo (2988 patients), for 28 +/- 4 days after receiving open-label enoxaparin for an initial 10 +/- 4 days. MEASUREMENTS Incidence of VTE up to day 28 and of major bleeding events up to 48 hours after the last study treatment dose. RESULTS Extended-duration enoxaparin reduced VTE incidence compared with placebo (2.5% vs. 4%; absolute risk difference favoring enoxaparin, -1.53% [95.8% CI, -2.54% to -0.52%]). Enoxaparin increased major bleeding events (0.8% vs. 0.3%; absolute risk difference favoring placebo, 0.51% [95% CI, 0.12% to 0.89%]). The benefits of extended-duration enoxaparin seemed to be restricted to women, patients older than 75 years, and those with level 1 immobility. LIMITATION Estimates of efficacy and safety for the overall trial population are difficult to interpret because of the change in eligibility criteria during the trial. CONCLUSION Use of extended-duration enoxaparin reduces VTE more than it increases major bleeding events in acutely ill medical patients with level 1 immobility, those older than 75 years, and women. PRIMARY FUNDING SOURCE Sanofi-aventis.

The Registry of the International Society for Heart and Lung Transplantation: Thirty-second Official Adult Heart Transplantation Report - 2015; Focus Theme: Early Graft Failure

Data are submitted to the ISHLT Registry by national and multinational organ/data exchange organizations and individual centers. Since the Registry’s inception, 418 heart transplant centers, 242 lung transplant centers and 174 heart–lung transplant centers have reported data. The Registry website (www.ishlt.org/registries) provides spread sheets that show data elements collected in the Registry. The online slide set (http://www.ishlt.org/registries/slides.asp? slides=heartLungRegistry) provides POWERPOINT slides of figures and tables that support this study. The site contains additional slides for this report and slide sets from the previous annual reports.