Disclosures: Helen Hollingsworth, MD Employee of UpToDate, Inc. April F Eichler, MD, MPH Equity Ownership/Stock Options: Johnson & Johnson [Dementia (galantamine), Epilepsy (topiramate)]. Employment: Employee of UpToDate, Inc. Geraldine Finlay, MD Employee of UpToDate, Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.
Safety of inhaled long-acting beta agonist/glucocorticoid for asthma during pregnancy (February 2015)
An important clinical question for pregnant women with asthma is whether using a combination long-acting beta-agonist (LABA) plus inhaled glucocorticoid confers an increased risk for adverse fetal outcomes, compared with monotherapy using a higher dose of the inhaled glucocorticoid. In a study of 1302 pregnant women with asthma, the risk for a major congenital malformation was not increased when a LABA plus low dose inhaled glucocorticoid was compared with a medium dose inhaled glucocorticoid, or when a LABA plus medium-dose inhaled glucocorticoid was compared with a high-dose inhaled glucocorticoid . (See "Management of asthma during pregnancy", section on 'Long-acting beta-adrenergic agents'.)
Safety of omalizumab for asthma during pregnancy (February 2015)
The safety of omalizumab exposure during pregnancy in humans has not been formally evaluated, but outcomes from an omalizumab registry have been published . There were 169 pregnancies with known outcomes: 156 live births (160 infants), 1 fetal death/stillborn, and 11 spontaneous abortions. The rate of preterm birth was 14 percent, and 11 percent of infants were small for gestational age. Congenital anomalies were present in 13 percent, and 4 percent had a major anomaly. While the sample size is small, these results are similar to findings from other studies of pregnant women with asthma. Further data are needed to more fully characterize outcomes of omalizumab use in pregnancy. (See "Management of asthma during pregnancy", section on 'Anti-immunoglobulin E'.)
Novel glucocorticoid receptor agonist for asthma (February 2015)
The investigational agent AZD5423 is a nonsteroidal compound that binds to the glucocorticoid receptor in a different manner from that of traditional glucocorticoids. It suppresses production of proinflammatory proteins (like traditional glucocorticoids), but with reduced adverse effects in animal models. An inhaled dry powder formulation of AZD5423 was assessed in a trial that randomly assigned 20 subjects with mild allergic asthma to pretreatment with AZD5423, budesonide, or placebo for seven days followed by allergen-bronchoprovocation . AZD5423 attenuated the fall in forced expiratory volume in one second (FEV1) during the late phase asthmatic response compared with budesonide or placebo, but did not affect the early decrease in FEV1. AZD5423 also decreased allergen-induced sputum eosinophilia and allergen-induced airway hyperresponsiveness at 24 hours and was well-tolerated. Additional studies are needed to determine the safety and efficacy of AZD5423 compared with inhaled glucocorticoids. (See "Alternative and experimental agents for the treatment of asthma", section on 'Novel glucocorticoid receptor agonist'.)
Aspirin therapy for aspirin-exacerbated respiratory disease (October 2014)
Aspirin desensitization followed by daily aspirin therapy is used in the treatment of aspirin-exacerbated respiratory disease (AERD). The utility of aspirin therapy in patients who have asthma and chronic polypoid rhinosinusitis but who tolerate aspirin has been unclear. In a small trial, 20 patients with AERD and 14 patients with asthma and CRS with nasal polyposis, but without aspirin intolerance, were randomized to receive aspirin therapy or placebo . Aspirin therapy improved several asthma and rhinitis outcomes and led to lower maintenance doses of inhaled glucocorticoids in patients with aspirin intolerance, but was not beneficial in patients without aspirin intolerance. Although small, the findings of this trial support the clinical impression that aspirin's benefits are limited to patients with intolerance. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Efficacy of aspirin therapy in AERD'.)
Mepolizumab for severe asthma associated with peripheral blood eosinophilia (October 2014)
The anti-interleukin-5 monoclonal antibody mepolizumab has previously been shown to reduce exacerbations in patients with severe asthma and eosinophilic airway inflammation. Two additional trials validate using peripheral blood eosinophil counts to select patients with severe asthma who are likely to respond to mepolizumab, demonstrate comparable effects of intravenous and subcutaneous preparations, and show a glucocorticoid-sparing effect.
●The larger multicenter trial (MEpolizumab as adjunctive therapy iN patients with Severe Asthma, MENSA) evaluated mepolizumab (given either intravenously or subcutaneously every four weeks) in patients with severe asthma and eosinophilic airway inflammation despite high-dose inhaled glucocorticoids . At 32 weeks, exacerbations were reduced by approximately 50 percent for the groups using mepolizumab given by either route, compared with placebo.
●In a group of patients with severe asthma requiring systemic glucocorticoids, the SteroId ReductIon with mepolizUmab Study (SIRIUS) compared subcutaneous mepolizumab, given every four weeks, with placebo . At 20 weeks, mepolizumab allowed a median reduction in the systemic glucocorticoid dose of 50 percent, decreased the number of asthma exacerbations, and improved control of asthma symptoms.
Mepolizumab is not commercially available at present, although it is under review by regulatory agencies. (See "Alternative and experimental agents for the treatment of asthma", section on 'Anti-IL-5 antibodies'.)
Intermittent montelukast for acute wheezing episodes in young children (September 2014)
Several randomized trials have examined the intermittent use of leukotriene receptor antagonists (LTRAs) in preschool children with recurrent wheezing, with mixed results. The most recent trial adds to the data that do not favor this approach in most children, although specific subgroups based upon genotype may benefit. In this trial, over 1300 children aged 10 months to 5 years with a history of two or more wheezing episodes were randomly assigned to intermittent montelukast or placebo at the onset of any subsequent wheezing episode over a 12 month period . No difference between the groups was seen in the frequency of unscheduled medical visits for wheezing episodes, although subgroup analysis suggested the response to montelukast was modified by arachidonate 5-lipoxygenase (ALOX5) genotype. Further study is needed to define and confirm these subpopulations. (See "Treatment of recurrent virus-induced wheezing in young children", section on 'Intermittent leukotriene-receptor antagonists'.)
Combination of varenicline and nicotine patch improves smoking cessation rates (October 2014)
In a randomized trial, 435 smokers were assigned to treatment with varenicline combined with either a nicotine or a placebo patch . Nicotine or placebo patches were started two weeks before the quit day and varenicline was started one week before the quit day. Both patches and varenicline were continued for 12 weeks. Treatment with varenicline and the nicotine patch resulted in a higher rate of continuous abstinence compared with varenicline and the placebo patch (49 versus 33 percent) at six months after the end of drug treatment. Prior studies have also shown higher rates of abstinence with the combination of nicotine replacement therapy (NRT) and bupropion, and with the combination of varenicline and bupropion. We continue to suggest initiating therapy with medication from a single class (eg, varenicline, bupropion, or NRT), given the increased cost and additional side effects with combining therapies, but combining medication classes is a reasonable option for patients who have failed initial therapy. (See "Pharmacotherapy for smoking cessation in adults", section on 'Patients who fail to quit'.)
Bronchoscopic lung volume reduction with nitinol coils in severe emphysema (October 2014)
Bronchoscopic placement of nitinol coils is an experimental method to treat emphysema. When the coils are deployed in areas of emphysema, they resume their coiled shape, collecting and collapsing the surrounding lung tissue and thereby reducing hyperinflation. In a multicenter, observational study, 60 patients with severe heterogeneous emphysema underwent bronchoscopic placement of nitinol coils (55 bilateral, 5 unilateral) with a median of 10 coils per lobe . Serious adverse events included seven COPD exacerbations, four pneumothoraces, and one episode of hemoptysis. The remaining patients experienced modest but sustained improvements in quality of life and lung function at six and 12 months. Randomized trials with a longer duration of follow-up are needed to confirm these findings. (See "Emerging therapies for COPD: Bronchoscopic treatment of emphysema", section on 'Coils'.)
Ketamine in patients with elevated intracranial pressure (February 2015)
The use of ketamine as an induction agent for rapid sequence intubation (RSI) in patients with head trauma has been debated because some observational studies suggest it elevates intracranial pressure (ICP). However, a systematic review of 10 trials involving 953 critically ill patients, all managed with intubation and mechanical ventilation, concluded that the use of intravenous ketamine did not adversely affect patient outcomes, including mortality . Most studies included in the review had methodological limitations, but two randomized, double-blinded controlled trials comparing the effects of prolonged ketamine and sufentanil infusions in patients with traumatic brain injury found no differences in mean daily ICP and cerebral perfusion pressures. The findings of this systematic review support our view that ketamine is an appropriate induction agent for RSI in patients with suspected ICP elevation and normal blood pressure or hypotension. (See "Sedation or induction agents for rapid sequence intubation in adults", section on 'Elevated intracranial pressure'.)
Adjunctive glucocorticoids for hospitalized patients with community-acquired pneumonia (January 2015)
There has been interest in using glucocorticoids as adjunctive therapy to antibiotics in hospitalized patients with community-acquired pneumonia (CAP) in an attempt to reduce the inflammatory response, which is likely to contribute to the morbidity of the disease. There are conflicting data on this approach, but the largest randomized trial suggests a modest benefit. In the trial, which included 785 hospitalized adults with CAP, prednisone 50 mg daily for seven days shortened the time to clinical stability by approximately one day compared with placebo, without an increase in complications . Pending the results of a large trial evaluating mortality rates in severe CAP, we do not favor the routine use of adjunctive glucocorticoids in adults with CAP. (See "Treatment of community-acquired pneumonia in adults who require hospitalization", section on 'Glucocorticoids'.)
Prophylactic antibiotics do not benefit patients with acute liver failure (October 2014)
The role of prophylactic antibiotics in the treatment of patients with acute liver failure is controversial. In a retrospective study of 1551 patients with acute liver failure, antimicrobial prophylaxis did not reduce the incidence of bloodstream infection or mortality . Our approach to antibiotic prophylaxis is to not give patients prophylactic antibiotics, but instead give antibiotics only if there is evidence of active infection, positive surveillance culture results, or clinical deterioration. (See "Acute liver failure in adults: Management and prognosis", section on 'Infection surveillance and prevention'.)
Antibiotic decontamination of the digestive tract in the ICU and antimicrobial resistance (October 2014)
The use of prophylactic antibiotics to decontaminate the oropharyngeal and/or digestive tracts of critically ill patients and reduce the risk of infection confers a modest mortality benefit but is not widely used, in part, because of concern that it can promote antimicrobial resistance. A large multicenter cluster-randomized trial in intensive care units in the Netherlands compared resistance rates with selective oropharyngeal decontamination (SOD; antibiotics applied to the oropharynx only) and selective digestive decontamination (SDD; antibiotics applied to the oropharynx and through a nasogastric tube plus a different intravenous antibiotic) . Rates of rectal colonization with highly resistant bacteria were overall lower with SDD than SOD, but colonization with aminoglycoside-resistant gram-negative bacilli increased more over time with SDD than SOD. Given the very low baseline rate of antimicrobial resistance in the Netherlands and the absence of a control group that received no prophylactic antibiotics, these findings do not sufficiently allay concerns about long-term antimicrobial resistance with antibiotic use for decontamination of the gastrointestinal tract. (See "Epidemiology and prevention of infections and antimicrobial resistance in the intensive care unit", section on 'Decontamination of the digestive tract'.)
Restrictive transfusion threshold safe in septic shock (October 2014)
Blood transfusion using a lower (restrictive) hemoglobin threshold has been adopted in a variety of settings, including hemodynamically stable patients in the intensive care unit. However, debate has remained regarding the safety of this approach in patients with septic shock. A new randomized trial has shown that a restrictive hemoglobin threshold of 7 g/dL can be used in this setting. The Transfusion Requirements in Septic Shock (TRISS) trial randomly assigned 998 patients with septic shock to a restrictive or a liberal transfusion strategy (hemoglobin threshold of 7 or 9 g/dL) . All outcomes were similar between the two groups at 90 days, including mortality, cardiac ischemia, and transfusion reactions. We and other experts agree that for most patients with septic shock, red blood cell transfusion should be reserved for those with a hemoglobin of ≤7 g/dL. (See "Evaluation and management of severe sepsis and septic shock in adults", section on 'Red blood cell transfusions' and "Indications and hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Intensive care unit/septic shock'.)
Enteral versus parenteral nutrition in critically ill patients (October 2014)
In critically ill patients, the benefits of enteral nutrition compared with parenteral nutrition are unclear, with small randomized trials suggesting marginal benefit to enteral nutrition in surgical patients. One large multicenter randomized trial compared enteral nutrition with parenteral nutrition in 2400 critically ill patients, most of whom had medical rather than surgical illnesses . There was no difference in mortality or rates of infections between the groups. These findings support the continued use of enteral nutrition in both medical and surgical patients who are critically ill, when feasible. (See "Nutrition support in critically ill patients: An overview", section on 'Enteral versus parenteral'.)
Immune modulatory enteral feeds in critically ill patients (August 2014)
Small retrospective studies have suggested that high-protein enteral formulas with immune modulating nutrients (IMHP), such as glutamine, selenium, and omega-3 fatty acids, may improve survival and reduce the rate of infections in critically ill patients. The effect of IMHP was examined in a multicenter, randomized, double-blind trial of 301 mechanically ventilated adult patients (MetaPlus) . There was no difference reported in the rate of infections, duration of mechanical ventilation, or length of ICU or hospital stay. Use of IMHP was associated with a higher six-month mortality rate (54 versus 35 percent) in one predefined subpopulation of medical patients, which was not seen in the surgical or trauma patients. These findings are consistent with previous large randomized trials of high-protein formulas supplemented with glutamine or omega-3 fatty acids alone, which also found lack of benefit and possible harmful effects. (See "Nutrition support in critically ill patients: Enteral nutrition", section on 'Immune modulators'.)
PULMONARY VASCULAR DISEASE
Two distinct phenotypes in patients with idiopathic pulmonary artery hypertension (January 2015)
Vasoconstriction and luminal obstruction from plexiform lesions are both thought to play a role in the pathogenesis of idiopathic pulmonary artery hypertension (IPAH). A minority of patients responds to pulmonary vasodilators (responders), suggesting vasoconstriction may be more important in the pathogenesis of the disease in these patients compared with non-responders. Functional capillary surface area (FCSA) is a measurement of the amount of available pulmonary flow (ie, pulmonary reserve) that can be recruited during vasodilatation for improved gas exchange and hemodynamics. In an observational study of 14 patients with IPAH, FSCA response to a vasodilator challenge was compared between responders and non responders. Responders had a higher FCSA which increased during vasodilator testing, supporting the hypothesis that vasoconstriction, rather than luminal obstruction, was the dominant pathogenetic process in this population . Further exploration of this theory with larger numbers of patients is warranted. (See "Pathogenesis of pulmonary hypertension", section on 'Pathophysiology'.)
Negative D-dimer does not predict recurrence risk in unprovoked VTE (January 2015)
Indefinite anticoagulation is preferred in patients with a first episode of unprovoked venous thromboembolism (VTE). The D-dimer assay has been proposed as a test to identify patients in whom anticoagulant therapy may be safely discontinued. However, a prospective study that measured the VTE recurrence rate in 319 patients with a first episode of unprovoked VTE who had two consecutive negative D-dimer levels does not support this indication for d-dimer testing . The first level was drawn following completion of a standard course of anticoagulant therapy and the second after one month off anticoagulation. The two year recurrence rate was 7 percent per patient-year, with higher rates reported in men (10 percent per patient year) compared with women (5 percent per patient year). These rates are sufficiently high that they support the current recommendation of indefinite anticoagulation in this population; D-dimer measurements do not appear to be useful in identifying candidates for more limited treatment. (See "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Elevated D-dimer'.)
Novel anticoagulant strategies with potentially lower bleeding risk (December 2014)
Anticoagulants reduce the risk of thromboembolism, but this benefit is balanced by an increased risk of bleeding. Two new strategies for anticoagulation are in development that may carry a lower risk of bleeding compared with currently available agents. The first uses an antisense oligonucleotide to reduce production of coagulation factor XI (FXI-ASO). In patients undergoing knee replacement, treatment with FXI-ASO was associated with a 3 percent risk of venous thromboembolism, compared with approximately 30 percent with low molecular weight heparin, without increasing bleeding . However, the duration of anticoagulation was long, injection site reactions were common, and no antidote is available. The second strategy targets polyphosphate, a pro-thrombotic substance released from activated platelets or microbes . In preclinical models, polyphosphate inhibitors have shown reduced arterial thrombosis without increased bleeding. Additional studies are awaited to determine the role of these new strategies in clinical practice. (See "Anticoagulation with direct thrombin inhibitors and direct factor Xa inhibitors", section on 'Anticoagulants in development'.)
CPAP therapy for older adults with obstructive sleep apnea (October 2014)
Continuous positive airway pressure (CPAP) is the mainstay of therapy for most adults with obstructive sleep apnea (OSA), but previous clinical trials have enrolled primarily younger adults. In a multicenter trial that included 278 adults ≥65 years of age with newly diagnosed OSA, patients randomized to receive CPAP therapy plus best supportive care had improvement in daytime sleepiness compared with those assigned to best supportive care alone . The benefits of CPAP were present at both three- and 12-month time points and were greater in those with higher CPAP usage and higher baseline sleepiness scores. Secondary endpoints, including quality of life, mobility, cognitive function, and cardiovascular events, were similar between groups. A major limitation of the trial was the lack of a sham CPAP control arm. (See "Sleep apnea and other causes of impaired sleep in older adults", section on 'Treatment'.)
OTHER PULMONARY MEDICINE
Approval of the direct factor Xa inhibitor edoxaban (January 2015)
The US Food and Drug Administration has approved the oral direct factor Xa inhibitor edoxaban (Savaysa; Lixiana in Japan) for the prevention of stroke in nonvalvular atrial fibrillation and the treatment of venous thromboembolism, based upon earlier randomized trials demonstrating non-inferiority to warfarin [22-24]. Dosing is once daily at a fixed dose without monitoring. There are Boxed Warnings regarding avoidance of edoxaban in patients with atrial fibrillation who have a creatinine clearance >95 mL/minute, spinal/epidural hematoma in patients undergoing neuraxial procedures, and ischemic events following premature discontinuation. (See "Atrial fibrillation: Anticoagulant therapy to prevent embolization" and "Lower extremity deep venous thrombosis: Long-term anticoagulation (10 days to three months)" and "Anticoagulation in acute pulmonary embolism" and "Anticoagulation with direct thrombin inhibitors and direct factor Xa inhibitors", section on 'Edoxaban'.)
Rituximab as maintenance therapy in ANCA-associated vasculitis (November 2014)
Azathioprine and methotrexate are conventionally considered the preferred drugs for maintenance therapy in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). The Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN) trial compared rituximab with azathioprine as maintenance therapy in 115 patients who had achieved remission after induction therapy with cyclophosphamide and glucocorticoids . Major relapse rates at 28 months were lower for rituximab (5 versus 29 percent). Rates of adverse events were also similar. However, the dosing of azathioprine in this trial was not consistent with the practice of many experts, and this may have contributed to the excess relapse rate. In addition, most patients had GPA, a positive PR3-ANCA, and were newly diagnosed rather than relapsed patients. It is not clear whether or not these data apply to other groups of patients with ANCA-associated vasculitis or to patients induced with rituximab rather than cyclophosphamide. Thus, either rituximab or azathioprine (or methotrexate although it was not evaluated in this trial) can be used as maintenance therapy in patients with GPA or MPA while awaiting further data to confirm these findings. (See "Maintenance immunosuppressive therapy in granulomatosis with polyangiitis and microscopic polyangiitis", section on 'Rituximab'.)
Lower risk of fatal bleeding with target specific oral anticoagulants versus warfarin (November 2014)
All anticoagulants carry a risk of bleeding, and the lack of an antidote for direct factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) and the direct thrombin inhibitor dabigatran increases concerns about this risk. Reassuringly, a meta-analysis of 12 randomized trials in patients with atrial fibrillation or venous thromboembolism that compared bleeding risk with these agents versus vitamin K antagonists found lower rates of fatal bleeding, major bleeding, and intracranial bleeding with the direct factor Xa and direct thrombin inhibitors . Individual patient factors continue to play a role in anticoagulant choice and the development of reversal agents for the factor Xa and thrombin inhibitors is underway. (See "Management of bleeding in patients receiving target-specific oral anticoagulants", section on 'Risk of bleeding'.)
Investigational agent for reversal of multiple anticoagulants (November 2014)
Reversal agents for the target specific oral anticoagulants are lacking. In a study of 80 healthy volunteers given a therapeutic dose of the direct factor Xa inhibitor edoxaban, a reversal agent under development (PER977) normalized the whole blood clotting time within 10 minutes; in contrast, normalization of the clotting time took 12 to 15 hours in individuals given edoxaban followed by placebo . In addition to binding direct factor Xa inhibitors, PER977 also binds the direct thrombin inhibitor dabigatran, as well as unfractionated and low molecular weight heparins. (See "Management of bleeding in patients receiving target-specific oral anticoagulants", section on 'Antidotes under development'.)
Infection prevention measures for cystic fibrosis (October 2014)
Evidence is accumulating that a variety of respiratory pathogens can be transmitted among individuals with cystic fibrosis (CF) within the health care system. In particular, highly transmissible strains of Pseudomonas aeruginosa have been reported. Compared with sporadic strains of P. aeruginosa, infection with highly transmissible strains is associated with increased need for health care and antibiotics. To minimize risk of transmission, the CF Foundation has published updated guidelines for infection prevention and control to be applied to all individuals with CF, regardless of respiratory tract culture results . The guidelines include the following measures:
●Clinicians should use contact precautions (gown and surgical masks) at all times when caring for patients with CF.
●Patients with CF should wear surgical masks in the health care setting.
●Patients with CF should not congregate within or outside of the health care setting, should remain at least six feet away from other patients with CF, and be cared for in single-patient rooms when they require admission.
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- Namazy J, Cabana MD, Scheuerle AE, et al. The Xolair Pregnancy Registry (EXPECT): The safety of omalizumab use during pregnancy. J Allergy Clin Immunol 2015; 135:407.
- Gauvreau GM, Boulet LP, Leigh R, et al. A Nonsteroidal Glucocorticoid Receptor Agonist Inhibits Allergen-induced Late Asthmatic Responses. Am J Respir Crit Care Med 2015; 191:161.
- Świerczyńska-Krępa M, Sanak M, Bochenek G, et al. Aspirin desensitization in patients with aspirin-induced and aspirin-tolerant asthma: a double-blind study. J Allergy Clin Immunol 2014; 134:883.
- Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 2014; 371:1198.
- Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 2014; 371:1189.
- Nwokoro C, Pandya H, Turner S. Intermittent montelukast in children aged 10 months to 5 years with wheeze (WAIT trial): a multicentre, randomised, placebo-controlled trial. Lancet Respir Med 2014.
- Koegelenberg CF, Noor F, Bateman ED, et al. Efficacy of varenicline combined with nicotine replacement therapy vs varenicline alone for smoking cessation: a randomized clinical trial. JAMA 2014; 312:155.
- Deslee G, Klooster K, Hetzel M, et al. Lung volume reduction coil treatment for patients with severe emphysema: a European multicentre trial. Thorax 2014; 69:980.
- Cohen L, Athaide V, Wickham ME, et al. The effect of ketamine on intracranial and cerebral perfusion pressure and health outcomes: a systematic review. Ann Emerg Med 2015; 65:43.
- Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2015.
- Karvellas CJ, Cavazos J, Battenhouse H, et al. Effects of antimicrobial prophylaxis and blood stream infections in patients with acute liver failure: a retrospective cohort study. Clin Gastroenterol Hepatol 2014; 12:1942.
- Oostdijk EA, Kesecioglu J, Schultz MJ, et al. Effects of decontamination of the oropharynx and intestinal tract on antibiotic resistance in ICUs: a randomized clinical trial. JAMA 2014; 312:1429.
- Holst LB, Haase N, Wetterslev J, et al. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med 2014; 371:1381.
- Harvey SE, Parrott F, Harrison DA, et al. Trial of the route of early nutritional support in critically ill adults. N Engl J Med 2014; 371:1673.
- van Zanten AR, Sztark F, Kaisers UX, et al. High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition and nosocomial infections in the ICU: a randomized clinical trial. JAMA 2014; 312:514.
- Langleben D, Orfanos SE, Giovinazzo M, et al. Acute vasodilator responsiveness and microvascular recruitment in idiopathic pulmonary arterial hypertension. Ann Intern Med 2015; 162:154.
- Kearon C, Spencer FA, O'Keeffe D, et al. d-Dimer Testing to Select Patients With a First Unprovoked Venous Thromboembolism Who Can Stop Anticoagulant Therapy: A Cohort Study. Ann Intern Med 2015; 162:27.
- Büller HR, Bethune C, Bhanot S, et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med 2015; 372:232.
- Travers RJ, Shenoi RA, Kalathottukaren MT, et al. Nontoxic polyphosphate inhibitors reduce thrombosis while sparing hemostasis. Blood 2014; 124:3183.
- McMillan A, Bratton DJ, Faria R, et al. Continuous positive airway pressure in older people with obstructive sleep apnoea syndrome (PREDICT): a 12-month, multicentre, randomised trial. Lancet Respir Med 2014; 2:804.
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- Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369:2093.
- Hokusai-VTE Investigators, Büller HR, Décousus H, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369:1406.
- Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med 2014; 371:1771.
- Chai-Adisaksopha C, Crowther M, Isayama T, Lim W. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood 2014; 124:2450.
- Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014; 371:2141.
- Saiman L, Siegel JD, LiPuma JJ, et al. Infection prevention and control guideline for cystic fibrosis: 2013 update. Infect Control Hosp Epidemiol 2014; 35 Suppl 1:S1.