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In the Literature

From: The Hospitalist, April 2008

The latest research you need to know

by Rowena Delos Santos MD, Prasanth Gogenini, MD, Anita Hart, MD, Hae-won Kim, MD, Francis Mcbee-Orzulak, MD, Satyen Nichani, MD, William Repaskey, MD, Jeffrey Rohde, MD, Bing Xue, MD, and Robert Chang, MD

Literature at a Glance

A guide to this month’s abstracts


Methadone and Levomethadyl Cause Prolonged QTc Compared with Bupernorphine

A randomized double-blind trial of 165 opioid-addicted participants demonstrates that buprenorphine is associated with significantly less QTc prolongation (0%) compared with treatment with methadone (23%) or levomethadyl (28%).

Citation: Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MC. QT-interval effects of methadone, levomethadyl and buprenorphine in a randomized trail. Arch Intern Med. 2007;167:2469-2475..

Elevated BMI in Childhood Increases Risk of Coronary Heart Disease in Adulthood

A cohort study of 276,835 children with 5,063,622 person-years of follow-up showed a linear increase in risk of coronary heart disease as body-mass index increased in boys and girls ages 7 to 13.

Citation: Baker JL, Olsen LW, Sorensen TIA. Childhood body-mass index and the risk of coronary heart disease in adulthood. N Engl J Med. 2007;357:2329-2337.

Pre-emptive Ablation Reduces Incidence of ICD Firing

A randomized control trial of patients with myocardial infarction (MI) within one month and spontaneous ventricular tachycardia/fibrillation to either ablation and defibrillator placement or defibrillator alone. Ablation provided no mortality benefit but reduced ICD firing/pacing (37% vs. 12%).

Citation: Reddy VY, Reynolds MR, Neuzil P, et. al. Prophylactic catheter ablation for the prevention of defibrillator therapy. N Engl J Med. 2007;357:2567-2565.

Dexmedetomidine Causes Fewer Side Effects than Lorazepam in Ventilated Patients

Double-blind, randomized controlled trial demonstrated that dexmedetomidine (an alpha 2 agonist) sedated, mechanically ventilated intensive-care unit patients had more days without delirium or coma than patients treated with lorazepam.

Citation: Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs. lorazepam on acute brain dysfunction in mechanically ventilated patients. JAMA 2007;298(22):2644-2653

Rosiglitazone Increases Risk of CONGESTIVE HEART FAILURE, MI, Mortality

Population-based case-control cohort study of elderly patients (65 or older) with type 2 diabetes found that rosiglitazone was associated with an increased risk of congestive heart failure (RR, 1.60), MI (RR, 1.40) and all-cause mortality (RR, 1.29) compared with other oral diabetic agents. Pioglitazone was not associated with adverse outcomes, potentially because of the relatively small number of patients receiving it.

Citation: Lipscombe LL, Gomes T, Levesque LE, Hux JE, Juurlink DN, Alter DA. Thiazolidinediones and cardiovascular outcomes in older patients with diabetes. JAMA. 2007;298:2634-2643.

CRT Not Beneficial in Heart Failure Patients with Narrow QRS

Randomized trial of cardiac resynchronization therapy (CRT) of heart failure patients with dyssynchrony showed no benefit with QRS less than 120 milliseconds, but did improve six-minute walk and New York Heart Association classification if QRS was more than 120 and less than 130 milliseconds. Patients with QRS more than 130 milliseconds were not studied.

Citation: Beshai JF, Grimm RA, Nagueh SF, et al. Cardiac-resynchronization therapy in heart failure with narrow QRS complexes. N Engl J Med. 2007;357:2461-2471.

Early Nephrology Referral Reduces Mortality in Patients with Chronic Kidney Disease

Meta-analysis of more than 12,000 patients with chronic kidney disease showed that early referral to nephrologists shortened hospital stay by 12 days from the initiation of dialysis (CI 8.0-16.1, p=0.0007) and decreased mortality (RR 1.99, CI 1.66-2.39).

Citation: Chan MR, Dall AT, Fletcher KE, Lu N, Trivedi H. Outcomes in patients with chronic kidney disease referred late to nephrologists: a meta-analysis. Am J Med. 2007; 120:1063-1070.

Do Steroids Affect the Outcome in Patients with Meningitis?

Background: Pyogenic (bacterial) meningitis has high morbidity and mortality. Studies suggest some benefit of steroids in children but provide limited evidence for adult use.

Study design: Intention-to-treat, randomized control trial.

Setting: Single hospital in Vietnam.

Synopsis: Of 435 patients older than 14 with suspected meningitis all received lumbar puncture with randomization to IV dexamethasone or placebo for four days. Results showed 69% of patients had definite meningitis, 28.3% were probable, and 2.8% had an alternative diagnosis based on culture results.

The primary outcome was death after one month, which did not differ among groups (risk ratio [RR] 0.79, confidence interval [CI] 0.45-1.39).

Predefined subgroup analysis of patients with definitive meningitis showed a significant reduction in mortality at one month (RR 0.43, CI 0.2-0.94) and death/disability at six months (odds ratio [OR] 0.56, CI 0.32-0.98).

In patients with probable meningitis, those who received steroids demonstrated a trend toward harm (OR 2.65, CI 0.73-9.63).

Probable versus definite meningitis was determined retrospectively based on cultures. The most common isolate was Streptococcus suis.

Bottom line: This study provides some evidence for using steroids in adults with confirmed bacterial meningitis. Clinical application is limited by bacterial epidemiology and the difficulty of prospectively separating patients who would benefit from those who might be harmed.

Citation: Nguyen TH, Tran TH, Thwaites G, et. al. Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis. N Engl J Med. 2007;357:2431-2439.

Which Probiotic Preparations Best Reduce the Duration of Acute Diarrhea in Children?

Background: Probiotics have been suggested as an adjunctive therapy to reduce the severity and duration of acute diarrhea in children. However, there are no clear data to suggest if specific probiotic agents are superior to others.

Study design: Prospective single-blind, randomized, controlled trial.

Setting: Outpatient primary care in Naples, Italy.

Synopsis: This study compared five commercially available probiotic preparations (mix of Lactobacillus delbrueckii var bulgaricus/Streptococcus thermophilus/L. acidophilus/ Bifido-bacterium bifidum; L. rhamnosus strain GG; Saccharomyces boulardii; Bacillus clausii; or Enterococcus faecium SF68) and a control group in the treatment of outpatient acute diarrhea in 571 children age 3 months to 36 months.

The primary outcomes were the duration of diarrhea and the number and consistency of stools. The groups receiving Lactobacillus GG and the mixture had a shorter total duration of diarrhea (78.5 and 70 hours, respectively), decreased total number of stools, and improved stool consistency when compared with the control (115.5 hours). The other therapies showed no improvement over the control group. These data report on products commercially available in Italy, which may differ greatly from products available locally.

Bottom line: Probiotic preparations for the treatment of acute diarrhea in children should be chosen based on effectiveness data.

Citation: Canani RB, Cirillo P, Terrin G, et al. Probiotics for treatment of acute diarrhoea in children: randomised clinical trial of five different preparations. BMJ 2007;335:340-345.

Is CTPA a Reliable Alternative to V/Q Scan for Diagnosing PE?

Background: Computed tomography pulmonary angiogram (CTPA) has replaced ventilation/perfusion (V/Q) scanning at many hospitals as the test of choice for ruling out pulmonary embolism (PE). But limited clinical data compare CTPA with V/Q scanning in those suspected of having venous thromboembolism (VTE).

Study design: Randomized, investigator blinded, controlled trial.

Setting: The emergency departments (ED), inpatient wards, and outpatient clinics of five academic centers.

Synopsis: In the study, 1,411 patients were enrolled from five medical centers. Of 694 patients randomized to CTPA, 133 (19.2%) were diagnosed with VTE in the initial evaluation period, while 101 of 712 patients (14.2%) receiving a V/Q scan were diagnosed with VTE.

Patients not initially diagnosed with VTE were monitored. At three-month follow-up, 0.4% of the CTPA group and 1.0% of the V/Q group had a diagnosed VTE.

The overall rate of VTE found in the initial diagnostic period was significantly greater in patients randomized to CTPA (19.2% vs. 14.2%; difference, 5.0%; 95% CI; 1.1% to 8.9% p=.01). This suggests CTPA has a higher false positive rate or detects clinically insignificant thrombi.

Bottom line: CTPA was not inferior to V/Q scanning for excluding clinically meaningful PE, but CTPA diagnosed about 30% more patients with VTE than did V/Q scanning.

Citation: Anderson DR, Kahn SR, Rodger MA, et al. Computed tomographic pulmonary angiography vs. ventilation-perfusion lung scanning in patients with suspected pulmonary embolism: a randomized controlled trial. JAMA. 2007;298(23):2743-2753.

Does the Hospitalist Model Improve Length of Stay, Quality, and Cost of Care?

Background: The hospitalist model, with increased physician availability and expertise but greater discontinuity of care, is becoming more prevalent in U.S. medicine. What little is known about how this model will affect patient care is derived from a number of small studies.

Study design: Retrospective cohort study.

Setting: 45 small to midsize, predominantly nonteaching hospitals throughout the U.S.

Synopsis: Using the Premier Healthcare Informatics database, this study examined information on 76,926 patients admitted for seven common diagnoses to one of three services: hospitalist, general internist, or family physician. Analysis showed that patients on a hospitalist service had a 0.4-day shorter length of stay (p<0.001) compared with those on a general internist or family physician service.

The cost to patients cared for by a hospitalist was lower than the cost of family physicians ($125 less, p=0.33) and internists ($268 less, p=0.02). There was no difference found in death rate or 14-day readmission rate among the three services.

Given the retrospective design of this study, no causal relationship can be deduced. This study is further limited by its lack of specific data on the physicians categorized into one of the three groups solely by administrative data. The authors had concerns that the biases inherent to the retrospective nature of their work accounted for the significant difference found between hospitalists and internists.

Bottom line: The hospitalist model is associated with modest improvements in length of stay as compared with traditional inpatient approaches.

Citation: Lindenauer PK, Rothberg MB, Pekow PS, et. al. Outcomes of care by hospitalists, general internists, and family physicians. N Engl J Med. 2007;357:2589-2600.

What Is the Stroke Risk Soon after TIA, and What Factors Drive the Variability of Previous Findings?

Background: Many studies have attempted to estimate the risk of stroke in the early period after a transient ischemic attack (TIA). These studies vary widely in their calculation of the estimated risk. Further, the clinical and methodological factors underlying this variability are unclear.

Study design: Systematic review and meta-analysis.

Setting: Community and hospital.

Synopsis: Searching the Coch­rane review database, MEDLINE, EMBASE, CINAHL, and BIOSIS, 11 studies from 1973 to 2006 were included for meta-analysis, selected from 694 potential candidate studies identified on initial screening. The studies ranged in size from 62 to 2,285 patients.

The pooled estimate of risk for stroke following TIA was found to be 3.5%, 8%, and 9.2% at two, 30, and 90 days following TIA, respectively. However, there was significant heterogeneity for all periods considered (p<0.001).

Outcome ascertainment was identified as a major source of methodological heterogeneity. When risk of stroke at follow-up was determined by passive ascertainment (e.g., administrative documentation) the early risk of stroke was 3.1% two days after TIA, 6.4% at 30 days, and 8.7% at 90 days. But active ascertainment (e.g., direct, personal contact with study participants) determined stroke risk to be 9.9%, 13.4%, and 17.4% at two, 30, and 90 days after TIA, respectively.

Bottom line: Based on analysis of completed studies that included directly observed follow-up of study participants, the early risk of stroke after TIA is approximately 15% to 20% at 90 days following the sentinel event.

Citation: Wu CM, McLaughlin K, Lorenzetti DL, Hill MD, Manns BJ, Ghali WA. Early risk of stroke after transient ischemic attack. Arch Intern Med. 2007;167:2417-2422.

What Is the 1-year Ischemia and Mortality Rate for Three Anti-thrombotic Therapies for Early Invasive Management of ACS?

Background: Early interventional or surgical revascularization has improved morbidity and mortality in patients with acute coronary syndrome (ACS). The optimal anti-thrombotic regimen to reduce late ischemic and death rates has not been determined.

Study design: Prospective, open-label randomized control trial.

Setting: 450 academic and community-based institutions in 17 countries.

Synopsis: A total of 13,819 patients were enrolled between August 2003 and December 2005. They were assigned to heparin plus glycoprotein (GP) IIb/IIIa inhibitors (n=4,603), bivalirudin (Angiomax) plus IIb/IIIa inhibitors (n=4,604), or bivalirudin monotherapy (n=4,612).

For patients receiving GP IIb/IIIa inhibitors, a 2x2 factorial design assigned half the heparin and bivalirudin groups to routine upstream GP inhibitor administration (4,605 patients). The other half received selective GP IIb/IIIa inhibitors administration if PCI was indicated (4,602 patients).

At one year, there was no statistically significant difference in ischemia or mortality rate among the three therapy groups. No difference in ischemia rate was detected between the two GP IIb/IIIa inhibitor utilization strategies.

Since the hypotheses and the power for the one-year analysis in this trial were not prospectively determined, the results are considered to be exploratory and hypothesis generating.

Bottom line: At one year, there is no statistically significant difference in ischemia or mortality rate for the three antithrombotic regiments and the two glycoprotein utilization strategies.

Citation: Stone GW, Ware JH, Bertrand ME, et. al. Antithrombotic strategies in patients with acute coronary syndromes undergoing early invasive management. One-year results from the ACUITY trial. JAMA 2007;298:2497-2505.

What Is the PE Risk after Discontinuing Anticoagulation in Patients with Symptomatic VTE?

Background: The natural history of patients with symptomatic VTE who have completed anticoagulation is not well understood.

Study design: Inception cohort using pooled data from a prospective cohort study and one arm of an open-label randomized trial.

Setting: Academic medical centers in Canada, Sweden, and Italy.

Synopsis: Using pooled data from two previous studies, 2,052 patients with a first diagnosis of symptomatic VTE (lower-extremity deep-vein thrombosis [DVT], PE, or both) were evaluated for fatal PE after a standard course of therapy (mean of six months) with a vitamin K antagonist.

Patients were followed for up to 120 months. The investigators found an annual event risk of 0.19-0.49 per 100 person-years for fatal PE. Patients with prolonged immobility, active cancer, and thrombophilia were excluded, as were those with recurrent acute DVT.

Secondary analysis revealed an incidence of any fatal, definite or probable PE within the first year of discontinuing therapy of 0.35%-0.81%.

After the first year, the annual event risk ranged from 0.15-0.40 events per 100 person-years. Patients with advanced age, idiopathic VTE as well as those presenting with PE had higher rates of fatal PE.

Bottom line: There is a real though small (less than 1%) risk of fatal PE in the first year following discontinuation of anticoagulation for the first VTE episode. The optimal course of treatment for patients with idiopathic VTE is yet to be determined.

Citation: Douketis JD, Gu CS, Schulman S, et al. The risk for fatal pulmonary embolism after discontinuing anticoagulant therapy for venous thromboembolism. Ann Intern Med. 2007;147(11):766-774.

Do the Beers Criteria Predict ED Visits Associated with Adverse Drug Events?

Background: Adverse drug events are common in the elderly. The Beers criteria are a consensus-based list of 41 medications that are considered inappropriate for use in older adults and often lead to poor outcomes.

Study design: Retrospective medical record review and data analysis.

Setting: Three nationally representative, U.S. public health surveillance systems: the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance System (NEISS-CADES), 2004-2005; the National Ambulatory Medical Care Survey (NAMCS), 2004; and National Hospital Ambulatory Medical Care Survey (NHAMCS), 2004.

Synopsis: Using data collected from ED visits at 58 hospitals in the NEISS-CADES system, this study estimated that 177,504 visits for adverse drug events occur annually in the United States. Only 8.8% of such visits were attributable to the 41 medications included in the Beers criteria. Three drug classes (anticoagulant and antiplatelet agents, antidiabetic agents, and narrow therapeutic index agents) accounted for nearly half of all such ED visits. Warfarin (17.3%), insulin (13%), and digoxin (3.2%) were the most commonly implicated medications, collectively accounting for 33% of visits (CI, 27.8% to 38.7%).

This study suggests that because of the common use and high risk of adverse events associated with these three drugs, interventions targeting their use may prevent ED visits for adverse drug events in the elderly, compared with interventions aimed at reducing the use of medications identified in the Beers criteria.

This study only included adverse drug events identified in the ED and relied on the diagnosis and documentation of such events by the ED physician.

Bottom line: Beers criteria medications, although considered inappropriate for use in the elderly, were associated with significantly fewer ED visits for adverse events compared with warfarin, digoxin, and insulin.

Citation: Budnitz DS, Shehab N, Kegler SR, et. al. Medication use leading to emergency department visits for adverse drug events in older adults. Ann Intern Med. 2007;147:755-765. TH

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