Patient Care

In the Literature: HM-Related Research You Need to Know


Literature at a Glance

A guide to this month’s studies

Oral Rivaroxaban Could Play a Role in VTE Treatment

Clinical question: Is oral rivaroxaban an acceptable treatment option for acute symptomatic deep-vein thrombosis (DVT) and venous thromboembolism (VTE)?

Background: Treatment of acute DVT requires frequent laboratory monitoring, which may be obviated by the use of fixed-dose oral rivaroxaban.

Study designs: Parallel randomized, open-label, event-driven, noninferiority study (the acute DVT study) and randomized, double-blind, placebo-controlled, event-driven superiority trial (continued treatment study).

Setting: Multicenter study.

Synopsis: The acute DVT study randomly assigned 3,449 patients with acute DVT to oral rivaroxaban 15 mg twice daily for three weeks followed by 20 mg daily for three, six, or 12 months or enoxaparin 1 mg/kg subcutaneously twice daily and daily warfarin until a therapeutic INR was achieved, at which time the enoxaparin was discontinued. Rivaroxaban was not inferior in terms of preventing recurrent VTE (2.1% vs. 3.0%; P<0.001). Major or clinically relevant nonmajor bleeding occurred equally in both groups (8.1%).

The continued treatment study randomly assigned 1,196 patients with six to 12 months of prior VTE treatment to rivaroxaban 20 mg daily versus placebo for six or 12 months. Rivaroxaban was superior in preventing recurrent VTE (1.3% vs. 7.1%; P<0.001). A statistically nonsignificant increase in major bleeding was reported with rivaroxaban (0.7% vs. 0.0%). The open-label design and pharmaceutical support create potential for bias.

Bottom line: Oral rivaroxaban might offer a simplified, effective, and safe alternative to enoxaparin and warfarin for short- and long-term VTE treatment.

Citation: The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363 (26):2499-2510.

Clinical Shorts


A population-based prospective cohort study of patients with severe pneumonia found 27% one-year mortality with higher one-year and 30-day mortality among completely dependent patients compared with independent or limited-mobility patients.

Citation: Sligl WI, Eurich DT, Marrie TJ, Majumdar SR. Only severely limited, premorbid functional status is associated with short- and long-term mortality in patients with pneumonia who are critically ill: a prospective observational study. Chest. 2011;139(1):88-94.


Blinded, randomized trial of 2,871 ICU patients showed that probiotics significantly decreased the risk of ventilator-associated pneumonia (19% incidence vs. 40% with routine care); number needed to treat was five.

Citation: Morrow LE, Kollef MH, Casale TB. Probiotic prophylaxis of ventilator-associated pneumonia: a blinded, randomized, controlled trial. Am J Respir Crit Care Med. 2010;182(8):1058-1064.

Dabigatran Might Be a Cost-Effective Alternative to Warfarin in Atrial Fibrillation

Clinical question: Is dabigatran cost-effective compared to warfarin for prevention of stroke in atrial fibrillation?

Background: Dabigatran, a direct thrombin inhibitor, is FDA-approved for the prevention of stroke and systemic embolism in atrial fibrillation. In the 2009 RE-LY trial, dabigatran 150 mg twice daily was associated with fewer embolic strokes than warfarin with similar episodes of major hemorrhage. Dabigatran costs more than warfarin; its cost-effectiveness is unknown.

Study design: Markov decision model.

Setting: Data from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY), a multinational randomized trial, and other anticoagulation studies.

Synopsis: This model simulated costs and outcomes for a theoretical cohort of patients >65 with atrial fibrillation and CHADS2 score ≥1 taking either lifelong warfarin or dabigatran. The model included assumptions about costs and quality-of-life effects of INR monitoring, stroke, hemorrhage, and myocardial infarction. Because U.S. pricing for dabigatran was pending, the authors assumed $13 per day.

Both life expectancy in quality-adjusted life years (QALYs) and lifetime costs were higher for dabigatran than for warfarin (10.84 vs. 10.28 QALYs and $168,398 vs. $143,193, respectively). The incremental cost per QALY for dabigatran was $45,372. Limitations include dependence on data from a single-manufacturer-sponsored trial with limited follow-up.

Retail costs for dabigatran are now known to be about $8 per day. When the model is adjusted to that price, an additional QALY would cost $12,000, well below the commonly accepted threshold of $50,000.

Bottom line: Dabigatran is likely a cost-effective alternative to warfarin in nonvalvular atrial fibrillation.

Citation: Freeman JV, Zhu RP, Owens DK, et al. Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation. Ann Intern Med. 2011;154(1):1-11.

Effects of New ACGME Mandates on Patients and Residents Unclear

Clinical question: How will new intern duty-hour standards impact patient care, residents’ health, and education?

Background: The Accreditation Council for Graduate Medical Education (ACGME) has mandated new duty-hour standards that limit interns’ shifts to 16 hours and night float to six consecutive nights. They also strongly recommend a nighttime nap.

Study design: Systematic review of English-language, original research studies addressing shift length, night float, or protected sleep time, published from 1989 to 2010.

Synopsis: Sixty-four out of 5,345 articles met eligibility criteria, including four randomized controlled trials and five multi-institutional studies. Although 73% of studies examining shift length supported reducing hours, optimal shift duration was not determined. All studies addressing night float examined five to seven consecutive nights of work; data were too heterogeneous for generalization. Data on protected sleep time were too limited to determine effect on residents and patients.

The majority of studies were conducted at single institutions and study designs carried high risk for interpretation bias. Additionally, publication bias might have influenced the results of this review of English-language-only studies.

Bottom line: The available studies that attempt to elucidate the effects of major changes in residency training have significant limitations, and the potential impact of the new standards on patients and residents remains uncertain.

Citation: Reed DA, Fletcher KE, Arora VM. Systematic review: association of shift length, protected sleep time, and night float with patient care, residents’ health, and education. Ann Intern Med. 2010;153:829-842.

Clinical Shorts


Retrospective cohort study using a national registry showed that 22.5% of ICDs did not meet guidelines for implantation, and recipients of non-evidence-based devices had increased rates of in-hospital death and procedural complications.

Citation: Al-Khatib SM, Hellkamp A, Curtis J, et al. Non-evidence-based ICD implantations in the United States. JAMA. 2011;305(1):43-49.


In a randomized, open-label, multicenter study of 316 patients after cardiac surgery, post-operative atrial fibrillation rates were similar with amiodarone prophylaxis (24.8%) and metoprolol (23.9%); equivalence was not proven.

Citation: Halonen J, Loponen P, Järvinen O, et al. Metoprolol versus amiodarone in prevention of atrial fibrillation after cardiac surgery: a randomized trial. Ann Intern Med. 2010;153:703-709.

Admission to Stroke Centers for Acute Ischemic Stroke Might Improve Mortality

Clinical question: Does admission to a certified stroke center improve survival in patients with acute ischemic stroke?

Background: Since 2003, the Joint Commission has designated fewer than 700 acute-care hospitals as certified stroke centers. However, no large studies have examined whether patients with acute stroke admitted to stroke centers have lower mortality than those admitted to noncertified acute-care hospitals.

Study design: Observational cohort study.

Setting: All acute-care hospitals in New York state.

Synopsis: Data from the New York Statewide Planning and Research Cooperative System identified 30,947 adult patients who were hospitalized with acute stroke over a two-year period. Mean age of patients was 73. Thirty-day all-cause mortality was compared between stroke centers and all other acute-care hospitals. Secondary outcomes were one-day, seven-day, and one-year all-cause mortality. To adjust for unmeasured confounders, the analyses accounted for distance to the nearest stroke center relative to the distance to the nearest acute-care hospital.

Almost half the patients in this study were admitted to stroke centers, where they had an adjusted absolute risk reduction in 30-day mortality of 2.5%. Seven-day mortality was reduced 1.3% and one-year mortality was reduced 3.0%. These findings were statistically significant.

There were no differences in one-day mortality, 30-day readmission rates, or rates of discharge to skilled nursing facilities between hospital designation.

The study was not designed to identify which elements of a certified stroke center contribute to the mortality benefit and did not account for stroke severity. Results may not be generalizable beyond New York state.

Bottom line: Admission to an acute-stroke center is associated with a modest reduction in mortality.

Citation: Xian Y, Holloway RG, Chan PS, et al. Association between stroke center hospitalization for acute ischemic stroke and mortality. JAMA. 2011;305(4):373-380.

Mortality from MRSA Pneumonia Increases with Higher Vancomycin Minimum Inhibitory Concentration

Clinical question: Does vancomycin minimum inhibitory concentration (MIC) affect mortality due to healthcare-associated pneumonia (HCAP), ventilator-associated pneumonia (VAP), and hospital-acquired pneumonia (HAP) from methicillin-resistant Staphylococcus aureus (MRSA)?

Background: S. aureus is considered vancomycin-susceptible if the MIC is ≤2 mg/mL. Mortality from MRSA bacteremia increases as vancomycin MIC rises. The effect of higher vancomycin MICs on outcomes in MRSA pneumonia is not known.

Study design: Prospective cohort study.

Setting: Four academic centers in Kentucky, Ohio, Michigan, and Florida.

Synopsis: One hundred fifty-eight patients with HCAP, VAP, or HAP based on American Thoracic Society/Infectious Disease Society of American (ATS/IDSA) definitions and ≥1 MRSA-positive blood or respiratory culture were identified from the prospectively collected Improving Medicine through Pathway Assessment of Critical Therapy in Hospital-Acquired Pneumonia (IMPACT-HAP) database. All were treated with a regimen including vancomycin based on 2005 ATS/IDSA guidelines.

Vancomycin MIC was ≤1 mg/mL in 27% of MRSA isolates; 1.5 mg/mL in 55%; and ≥2mg/mL in 18%. Overall, all-cause 28-day mortality was 32%. After correcting for confounding factors, such as age and comorbid illnesses, all-cause 28-day mortality was higher in patients with higher vancomycin MICs (adjusted odds ratio of death 2.97 per 1 mg/mL increase in vancomycin MIC). Heteroresistance to vancomycin was present in 21% of MRSA isolates but was not associated with an increase in mortality.

Bottom line: Death due to MRSA HCAP, VAP, and HAP increases as the vancomycin MIC increases, even with MICs within the susceptible range.

Citation: Haque NZ, Zuniga LC, Peyrani P, et al. Relationship of vancomycin minimum inhibitory concentration to mortality in patients with methicillin-resistant Staphylococcus aureus hospital-acquired, ventilator-associated, or health-care-associated pneumonia. Chest. 2010;138(6): 1356-1362.

Clinical Short


In a randomized, double-blinded, double-dummy study of 3,866 patients undergoing elective hip surgery, prophylaxis with apixaban was associated with lower rates of VTE (ARR 2.5 percentage points) than enoxaparin without increased bleeding.

Citation: Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM for the ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010;363:2487-2498.

More Frequent In-Center Hemodialysis Improves Outcomes

Clinical question: Does more frequent hemodialysis reduce mortality, improve cardiovascular outcomes, and improve quality of life in patients undergoing maintenance hemodialysis?

Background: Despite technological improvements over the last 40 years, hemodialysis is still associated with significant morbidity, mortality, and decreased quality of life. The optimal frequency of hemodialysis remains uncertain.

Study design: Randomized clinical trial with blinded analysis.

Setting: Eleven university-based and 54 community-based hemodialysis facilities in North America.

Synopsis: Researchers randomized 245 patients with end-stage renal disease to receive hemodialysis either three times per week or six times per week. Composite of death or one-year increase in left ventricular mass as assessed by cardiac MR was one primary outcome; composite outcome of death or one-year decrease in self-reported physical health was a co-primary outcome.

Frequent hemodialysis was associated with benefits in both composite primary outcomes (hazard ratio [HR] 0.61 for death/increase in left ventricular mass; HR 0.70 for death/decreased physical health). Notably, patients with frequent dialysis were more likely to undergo interventions related to vascular access than with conventional dialysis (HR 1.71). Blood pressure control (P<0.001) and hyperphosphotemia (P=0.002) also were improved with frequent dialysis.

Depression, cognitive performance, albumin, and anemia did not improve. Direct impact on mortality and hospital admission could not be assessed. Results might not be generalizable.

Bottom line: More frequent hemodialysis was associated with a significant reduction in left ventricular mass, improvement in self-reported physical health, and a reduction in mortality using combined composite outcomes. Further cost-benefit and quality-of-life analyses are needed to determine optimal dosing of hemodialysis.

Citation: FHN Trial Group. In-center hemodialysis six times per week versus three times per week. N Engl J Med. 2010;363:2287-2300.

BNP Testing in the Emergency Department Might Decrease Hospital Length Of Stay

Clinical question: Does BNP testing of patients presenting to the ED with acute dyspnea reduce admissions, shorten length of stay (LOS), or improve short-term survival?

Background: B-type natriuretic peptide (BNP) and the N-terminal peptide of its precursor, pro-BNP, are widely used to evaluate patients with acute dyspnea to distinguish cardiac from noncardiac causes. However, clinical outcomes related to this commonly used test are not clearly understood.

Study design: Systematic review and meta-analysis of randomized trials.

Setting: Five randomized controlled trials in EDs in five hospitals (Switzerland, Canada, the Netherlands, United States, and Australia) involving 2,513 patients.

Synopsis: Studies compared BNP testing with routine testing and clinical assessment and described >1 of three clinical outcomes: hospital admission rate, LOS, and mortality. Nonrandomized and retrospective studies and subgroup analyses of larger studies were excluded.

Testing with BNP decreased LOS by a mean of 1.22 days and critical-care-unit stay was modestly reduced (-0.56 days). This change was attributed to improved acute management and more rapid discharge with knowledge of BNP values. There was a nonsignificant trend toward decreased hospital admission from the ED in the BNP group (odds ratio 0.82). The effect of BNP testing on mortality was inconclusive.

Bottom line: BNP testing in the ED is associated with decreased hospital LOS, as well as a trend toward decreased admission rates from the ED. There is no conclusive effect on mortality.

Citation: Lam LL, Cameron PA, Schneider HG, Abramson MJ, Müller C, Krum H. Meta-analysis: effect of B-type natriuretic peptide testing on clinical outcome in patients with acute dyspnea in the emergency setting. Ann Intern Med. 2010;153:728-735.

Clinical Short


Pre-post study of weekly structured family meetings versus usual communication showed no reduction in length of stay, tracheostomy, percutaneous gastrostomy, or aggressiveness of care in long-stay ICU patients.

Citation: Daly BJ, Douglas SL, O’Toole E, et al. Effectiveness trial of an intensive communication structure for families of long-stay ICU patients. Chest. 2010;138(6):1340-1348.

Vaccination Reduces Incidence of Herpes Zoster in Community-Dwelling Adults Age 60 and Older

Clinical question: What is the impact of herpes zoster vaccination on the incidence of disease in older community-dwelling adults with and without chronic medical conditions?

Background: Live-attenuated vaccination was recently approved in older adults to reduce the incidence of herpes zoster and postherpetic neuralgia. Vaccination practices and efficacy in a clinical setting among patients with varying comorbidities are unknown.

Study design: Retrospective cohort.

Setting: Single health plan in California.

Synopsis: Data were collected from 2007 to 2009 on 75,761 health-plan members who received the vaccine. The data were compared with unvaccinated, age-matched controls. Vaccine recipients were more likely to be white and female, with more outpatient visits and fewer chronic diseases.

A 55% percent reduction in the incidence of herpes zoster was found among recipients. Benefit was seen across all age groups and comorbidities. Incidence of herpes zoster increased as age increased, but the relative rate reduction with vaccination remained nearly constant, including among those older than 80. Patients with chronic diseases also had an increased baseline incidence of herpes zoster but a similar relative reduction with vaccination. The study was not designed to look at post-herpetic neuralgia or to assess severity or duration of symptoms in herpes zoster cases.

Bottom line: Vaccination for herpes zoster is indicated for all adults age 60 and older, including the oldest and most medically complicated, in whom vaccination is not contraindicated.

Citation: Tseng HF, Smith N, Harpaz R, Bialek SR, Sy LS, Jacobsen SJ. Herpes zoster vaccine in older adults and the risk of subsequent herpes zoster disease. JAMA. 2011; 305(2):160-166.

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Have a story idea or a clinical question you’d like answered? We’d like to hear about it. Send your questions and story ideas to Editor Jason Carris, [email protected], or to Physician Editor Jeff Glasheen, MD, SFHM, [email protected].

For-Profit Hospital Status Might Increase Risk of 30-Day Readmission to Different Hospitals

Clinical question: Are patients admitted to a for-profit hospital more likely to be readmitted to a different hospital if rehospitalized within 30 days?

Background: Thirty-day readmission occurs in 20% of hospitalized Medicare patients, with at least a quarter of rehospitalized patients admitted to a different hospital. Recent healthcare legislation proposes penalties to reduce readmission rates. This could provide unintended incentives for hospitals to divert patients at high risk for readmission to other hospitals.

Study design: Observational cohort study.

Setting: Hospitalized Medicare patients.

Synopsis: Analysis of a 5% sample of Medicare patients readmitted within 30 days of discharge over a 22-month period identified 74,564 patients who were rehospitalized in a facility different from their initial admission. For-profit status of the initial and subsequent hospital was identified. Twenty-eight percent of patients initially admitted to a for-profit hospital were readmitted to a different hospital within 30 days. By comparison, only 21% of patients initially admitted to a nonprofit hospital were readmitted to a different hospital (P<.001).

The most significant risk factors for readmission to a different hospital were admission to a lower-volume hospital (221% increased risk), disability (21% increased risk), admission to an academic hospital (18% increased risk), and admission to a for-profit hospital (17% increased risk). Thirty-day mortality did not differ between patients readmitted to the same or different hospital, regardless of for-profit status. Admission to a different hospital was associated with increased cost.

This study was not designed to look at why patients were rehospitalized at different hospitals, and findings cannot be generalized beyond Medicare patients.

Bottom line: Discharge from a for-profit hospital is one of several risk factors for 30-day readmission to a different hospital.

Citation: Kind AJ, Bartels C, Mell MW, Mullahy J, Smith M. For-profit hospital status and rehospitalizations at different hospitals: an analysis of Medicare data. Ann Intern Med. 2010;153(11):718-727. TH

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