Patient Care

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


In This Edition

Literature at a Glance

A guide to this month’s studies

Extending Anticoagulant Prophylaxis after Medical Hospitalization Decreases VTE, Increases Major Bleeding

Clinical question: For patients with acute medical illness, does extending low-molecular-weight heparin (LMWH) administration for up to 28 days after discharge reduce the incidence of venous thromboembolism (VTE)?

Background: DVT and pulmonary embolism (PE) are common hospital-acquired complications. LMWH has been shown to reduce VTE for medical and surgical patients, and extended-duration LMWH reduces VTE in high-risk surgical patients. Whether extending anticoagulant prophylaxis after discharge for acutely ill medical patients with reduced mobility improves outcomes is unknown.

Study design: Randomized, placebo-controlled trial.

Setting: Three hundred seventy hospitals in 20 countries.

Synopsis: Eligible patients were >40 years old, hospitalized with acute medical illness, and had reduced mobility for ≥3 days. Patients received enoxaparin 40 mg SC daily prophylaxis while hospitalized and were then randomized to an additional 28±4 days of enoxaparin or placebo. Patients received a screening ultrasound to assess for asymptomatic DVT. The primary outcome was a composite of asymptomatic proximal DVT, symptomatic DVT or PE, or fatal PE during the period of extended prophylaxis.

An interim analysis indicated that extended prophylaxis was ineffective; at that time, the protocol was amended to target patients with severe immobility or with moderate immobility plus an additional risk factor (e.g. cancer, prior VTE, or age >75).

The study found that extended prophylaxis decreased the composite VTE outcome (2.5% vs 4.0%, P<0.05) and symptomatic VTE (0.2% vs 1.0%, P<0.05). The incidence of major bleeding was increased in the extended prophylaxis group (0.8% vs 0.3%, P<0.05). There was no difference in mortality.

The unplanned, midstudy protocol amendment to target higher-risk patients is a concern, though the final analyses included patients pre- and post-amendment.

Bottom line: Extending LMWH beyond hospitalization for patients admitted with acute medical illness and decreased mobility decreases VTE, but increases major bleeding.

Citation: Hull RD, Schellong SM, Tapson VF, et al. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010;153(1);8-18.

Clinical Short


Restrospective cohort study of 1,166 patients treated for CDI with metronidizole or vancomycin found that the 527 patients treated with PPIs within 14 days of diagnosis had a 42% increased risk of CDI recurrence.

Citation: Linsky A, Gupta K, Lawler EV, Fonda JR, Hermos JA. Proton pump inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med. 2010;170(9):772-778.

Preprocedural Statin Therapy Reduces Postprocedural Myocardial Infarction

Clinical question: Does statin therapy reduce periprocedural cardiovascular events?

Background: Myocardial infarction (MI) and death are inherent risks of invasive procedures. Reduction of these risks in certain patient populations has been shown with the use of a beta blockade. Statins have shown promise during acute coronary syndrome. Questions remain about the role of statin therapy before invasive procedures in reducing adverse cardiovascular events.

Study design: Meta-analysis of randomized controlled trials.

Setting: Twenty-one studies involving 4,805 patients, published from inception of MEDLINE, Cochrane, and Clinicaltrials to February 2010.

Synopsis: The use of statins one to seven days preprocedure significantly reduced post-procedural MI in percutaneous coronary interventions (PCI) (P<0.0001). Statins given approximately four weeks in advance of noncardiac surgical procedures also significantly reduced postprocedural MI (P=0.004). An absolute risk reduction of 5.8% for postprocedural MI was found after PCI and 4.1% in noncardiac surgical procedures.

Statins did not show a significant reduction in postprocedural MI (P=0.40) or all-cause mortality (P=0.15) in coronary artery bypass graft surgery (CABG). However, statins did reduce post-CABG atrial fibrillation (P<0.0001).

The 21 studies used a variety of drugs and doses. However, the PCI studies favored atorvastatin 40 mg; more than half the CABG studies used atorvastatin 20 mg; and 91% of the noncardiac surgical studies used fluvastatin 80 mg. Dedicated trials are needed to demonstrate optimal statin agent, dose, and timing of therapy.

Bottom line: Preprocedural statin therapy reduces postprocedural MI after both PCI and noncardiac procedures but not after CABG.

Citation: Winchester DE, Wen X, Xie L, Bavry AA. Evidence of pre-procedural statin therapy: a meta-analysis of randomized trials. J Am Coll Cardiol. 2010;56(19); 1099-1109.

Subclinical Hypothyroidism Increases the Risk of Coronary Heart Disease and Mortality

Clinical question: What are the risks of coronary heart disease (CHD) and mortality among adults with subclinical hypothyroidism?

Background: Subclinical hypo-thyroidism is defined as an elevated serum thyroid stimulating hormone (TSH) level with a normal T4 concentration. Controversy exists regarding the treatment of subclinical hypothyroidism. Because of the association with hyperlipidemia and atherosclerosis, treatment of subclinical hypothyroidism is thought to be beneficial. Previous data from large prospective cohort studies regarding this association are conflicting.

Study design: Study-level meta-analysis of prospective cohort studies.

Setting: Eleven prospective cohorts in the U.S., Europe, Australia, Brazil, and Japan from 1972 to 2007.

Synopsis: Among 55,287 adults, 3,450 (6.2%) had subclinical hypothyroidism and 51,837 were euthyroid. Using Cox proportional hazard models, the association of subclinical hypothyroidism with CHD and mortality were determined for each cohort.

The risk of CHD events and CHD mortality increased with higher TSH concentrations.

In age- and sex-adjusted analyses, the hazard ratio (HR) for CHD events were as follows: HR=1.0 (TSH=4.5-6.9 mIU/L); HR=1.17 (TSH=7-9.9 mIU/L), and HR=1.89 (TSH=10-19.9 mIU/L). Similarly, HRs for CHD mortality showed an increasing trend: 1.09, 1.42, and 1.58, respectively.

Although the association is clearly established here, randomized controlled trials are needed to address whether thyroxine replacement can prevent CHD and the TSH threshold that will provide the most clinical benefit.

Bottom line: Subclinical hypo-thyroidism is associated with an increased risk for CHD events and mortality, primarily in patients with TSH concentrations of 10 mIU/L or higher.

Citation: Rodondi N, den Elzen WP, Bauer DC, et al. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. 2010;304(12): 1365-1374.

Clinical Shorts


Retrospective cohort study of 240 patients with retrievable IVC filters found a documented plan to attempt retrieval in only 30%, and that 21% of patients without a plan had no contraindication to retrieval.

Citation: Mission JF, Kerlan RK Jr., Tan JH, Fang MC. Rates and predictors of plans for inferior vena cava filter retrieval in hospitalized patients. J Gen Intern Med. 2010;25(4):321-325.


Randomized trial of 250 patients with chronic back pain due to lumbar osteoarthritis found that oral glucosamine 1,500 mg did not improve pain scores at six months or one year compared with placebo.

Citation: Wilkens P, Scheel IB, Grundnes O, Hellum C, Storheim K. Effect of glucosamine on pain-related disability in patients with chronic low back pain and degenerative lumbar osteoarthritis: a randomized controlled trial. JAMA. 2010;304(1):45-52.

Reduction in Hematoma Growth after Acute Intracerebral Hemorrhage Associated with Lower Blood Pressure

Clinical question: Does intensive systolic blood pressure (SBP) <140 mmHg within one hour reduce hematoma growth after acute intracerebral bleeding?

Background: Early elevation of blood pressure after an acute intracerebral bleed is strongly associated with hematoma growth and worse outcomes. The pilot phase of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT) showed that early intensive blood pressure lowering reduced hematoma growth within six hours after onset of intracerebral hemorrhage.

Study design: Randomized controlled trial in which patients received an early intensive blood-pressure-lowering treatment (goal SBP<140 mmHg within one hour) or the AHA recommended best practice guidelines (goal SBP <180 mmHg), which were published in 1999.

Setting: Network of hospitals in China, South Korea, and Australia.

Synopsis: From 2005 to 2007, the study examined 404 patients with computed-tomography (CT) evidence of intracerebral hemorrhage, elevated SBP (150 mmHg-220 mmHg), and ability to commence BP lowering treatment within six hours of onset. Hematoma volumes were measured in the intensive treatment and guideline groups based on CT scans done at baseline and after 24 hours.

No significant association was found between the baseline SBP and the absolute or proportional growth of the hematoma. However, in the intensively treated patients who achieved target SBP within the first 24 hours, a significant association was found with the absolute and proportional hematoma growth.

Maximum reduction of hematoma growth occurred in the group with a median SBP of 135 mmHg.

This single-observational study did not include patients with severe intracranial bleeding who died or required surgical evacuation within the first 24 hours.

Hematoma size reduction did not improve survival or outcomes.

Bottom line: Intensive SBP lowering from 140 mmHg to 130 mmHg within one hour reduces hematoma growth after an intracranial hemorrhage.

Citation: Arima H, Anderson CS, Wang JG, et al. Lower treatment blood pressure is associated with the greatest reduction in hematoma growth after acute intracerebral hemorrhage. Hypertension. 2010;56(5):852-858.

Implantable Cardioverter-Defibrillator (ICD) Therapy for Primary Prevention of Sudden Cardiac Death Might Not Provide Survival Benefit to Elderly

Clinical question: Does ICD therapy for primary prevention of sudden cardiac death in individuals with severe left ventricular dysfunction improve survival in elderly patients?

Background: Several clinical trials of select individuals with severe left ventricular dysfunction (EF <40%) have demonstrated that ICD therapy is associated with a reduction in overall mortality. Given the costs and risks associated with ICD placement, it is important to assess how this therapy affects survival in younger versus older individuals.

Study design: Meta-analysis of five randomized controlled trials.

Setting: Five trials (MADIT-II, DEFINITE, DINAMIT, SCDHeFT, and IRIS).

Synopsis: All included studies compared ICD therapy to standard medical care in the primary prevention of sudden cardiac death in individuals with severe left ventricular dysfunction. Elderly patients comprised 44% of the 5,783 patients included in the study; elderly patients were defined as >65 in three studies, and >60 in two studies. Pooled analysis of the three trials examining ICD use for primary prevention found a nonsignificant reduction in all-cause mortality compared with medical therapy in elderly patients (HR 0.81 [95% CI 0.62 to 1.05], P=0.11). The two remaining studies involving post-MI patients showed no statistically significant reduction in mortality in elderly patients.

In contrast, pooled data from younger patients in the five trials showed that prophylactic ICD therapy reduced all-cause mortality.

None of the selected trials demonstrated evidence of selection, performance, detection, or attrition bias. Only a small number of studies were included, and four potentially relevant trials were not included because mortality data by age group were not available.

Trials including cardiac resynchronization therapy (CRT) were excluded from this meta-analysis, and elderly patients meeting criteria for CRT comprise an important group that must be considered separately.

Bottom line: There is no definitive reduction in mortality with prophylactic ICD therapy in elderly patients with severe left ventricular dysfunction.

Citation: Santangeli P, Di Biase L, Dello Russo A, et al. Meta-analysis: age and effectiveness of prophylactic implantable cardioverter-defibrillators. Ann Intern Med. 2010;153(9):592-599.

System Delay Is Mortality Marker in STEMI Patients Treated with Primary PCI

Clinical question: What is the relationship between system delays to reperfusion therapy and mortality in patients with ST-segment-elevation myocardial infarction (STEMI)?

Background: In patients with STEMI, an early reperfusion strategy is often sought, and several studies have focused on the association between door-to-balloon delay and outcomes. Focusing more broadly on the time from first contact with the healthcare system to the initiation of reperfusion therapy (system delay) might be a more relevant approach.

Study design: Historical follow-up study.

Setting: Three high-volume PCI centers in Denmark.

Synopsis: Using population-based medical registries of 6,209 Danish patients treated for STEMI with percutaneous coronary intervention (PCI), the authors examined the association between delays in reperfusion therapy and mortality. System delay encompassed the entire time from first contact with the healthcare system to the initiation of reperfusion therapy.

Overall, shorter system delay was associated with significantly decreased mortality, as were the individual components of system delay (prehospital delay and door-to-balloon delay). The shortest delays (0-60 minutes) corresponded to a mortality rate of 15%, and the longest delays (181-360 minutes) corresponded to a mortality rate of 31%. Patients were followed for a median of 3.4 years.

This study is unique, as it is the first to look at the association between system delay and outcomes in patients with STEMI transported by EMS and treated with primary PCI. The study highlights the harmful impact of longer system delays on mortality. Limitations of this study include possible underestimation of system delay and challenges surrounding the right marker for reperfusion.

Bottom line: System delay might serve as a broad, comprehensive marker for predicting mortality in patients with STEMI treated with primary PCI.

Citation: Terkelsen CJ, Sorensen JT, Maeng M, et al. System delay and mortality among patients with STEMI treated with primary percutaneous coronary intervention. JAMA. 2010;304(7): 763-771.

Clinical Shorts


Prospective data from 323 nursing home residents with advanced dementia and suspected pneumonia found that patients treated with antimicrobial agents versus no treatment had improved survival but did not have improved comfort scores.

Citation: Givens JL, Jones RN, Shaffer ML, Kiely DK, Mitchell SL. Survival and comfort after treatment of pneumonia in advanced dementia. Arch Intern Med. 2010;170(13):1102-1107.


Double-blind randomized controlled trial of 12,064 patients with history of myocardial infarction given 2 mg folic acid and 1 mg vitamin B12 daily vs. placebo found reductions in homocysteine levels, but no significant reduction in coronary events, death, or cancer incidence.

Citation: Armitage JM, Bowman L, Clarke RJ, et al. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA. 2010;303(24):2486-2494.

D-Dimer Is Effective in Determining the Risk of VTE Recurrence after First Unprovoked Event

Clinical question: Does the timing, patient age, or cut point level affect the predictive value of a D-dimer in predicting VTE recurrence after a first unprovoked event?

Background: Anticoagulation duration after a first unprovoked VTE is at least three months, but it can be indefinite in patients with stable anticoagulation and low bleeding risk. Measuring a D-dimer level after discontinuation of anticoagulation is helpful in determining which patients might benefit from prolonged anticoagulation. However, several unanswered questions remain regarding D-dimer testing.

Study design: Patient-level meta-analysis.

Setting: Pooled patient-level data from seven prospective studies.

Synopsis: Patient-level data were obtained for all patients enrolled using post-treatment D-dimer measurement to predict recurrent VTE in patients with a first unprovoked VTE who had completed at least three months of anticoagulation therapy. The mean length of follow-up was 30 months. Patients with a positive D-dimer had recurrent VTE at a rate of 8.8 per 100 patient-years while those with a negative D-dimer had a rate of 3.7 per 100 patient-years.

Univariate analysis revealed an HR of 2.59 for patients with a positive versus a negative test result. The analysis also showed that the timing of the test, the age of the patient, and the actual cut points used for the various D-dimer tests did not affect the analysis significantly.

These studies’ strength is their large sample sizes and the use of prospective studies. The weaknesses include a mostly white patient population and incomplete data on all patients.

Bottom line: D-dimer testing is useful in predicting VTE recurrence after treatment for a first unprovoked event regardless of patient age, post-treatment timing, or the assay cut point used.

Citation: Douketis J, Tosetto A, Marcucci M, et al. Patient-level meta-analysis: effect of measurement timing, threshold, and patient age on ability of D-dimer testing to assess recurrence risk after unprovoked venous thromboembolism. Ann Intern Med. 2010;153(8): 523-531.

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Thigh-High Stockings Are Better than Knee-High Stockings for Post-Stroke DVT Prophylaxis

Clinical question: Are thigh-high compression stockings better then knee-high stockings in immobilized acute-stroke patients?

Background: DVT is common in hospitalized stroke patients with immobility. Graduated compression stockings are often used for DVT prophylaxis, but the CLOTS-1 trial recently found that thigh-high stockings were ineffective after acute stroke. It is unclear if the more commonly used knee-high stockings are more effective than thigh-high stockings.

Study design: Parallel-group trial (the CLOTS-2 trial).

Setting: One hundred twelve hospitals in nine countries.

Synopsis: More than 3,100 patients with acute stroke and immobilization were recruited from January 2002 to May 2009. Patients were randomized to receive thigh-high or knee-high stockings. Patients also received usual care, including anticoagulants and a screening ultrasound for asymptomatic proximal DVT at seven to 10 days. Approximately 640 patients in each group also underwent ultrasound at 25-30 days.

Overall, 6.3% of patients in the thigh-high group had DVT, compared with 8.8% in the knee-high group (P=0.007). There were no significant differences in the secondary outcomes of pulmonary embolism or death. The thigh-high stockings had a higher number of adverse skin events. Enrollment was stopped early when the CLOTS-1 trial showed no difference in DVT rates between thigh-high stockings and no stockings.

Bottom line: Knee-high graduated compression stockings lead to worse outcomes than thigh-high stockings for DVT prophylaxis in immobilized acute-stroke patients.

Citation: CLOTS (Clots in Legs Or sTockings after Stroke) Trial Collaboration. Thigh-length versus below-knee stockings for deep venous thrombosis prophylaxis after stroke: a randomized trial. Ann Intern Med. 2010;153(9):553-562. TH

Pediatric HM Literature

Co-Infection with Pertussis in Infants Hospitalized for Bronchiolitis

Reviewed by Pediatric Editor Mark Shen, MD, medical director of hospital medicine at Dell Children’s Medical Center, Austin, Texas.

Clinical question: How often are infants admitted with bronchiolitis co-infected with Bordatella pertussis?

Background: Infants admitted for bronchiolitis have previously been reported to have co-infection with B. pertussis. Given the nonspecific symptoms associated with early B. pertussis infection, as well as the epidemiology of ongoing outbreaks, it might be useful to better define the risk of co-infection in the seasonal surge of acute bronchiolitis.

Study design: Retrospective cohort study.

Setting: One university hospital in Finland.

Synopsis: A prior study had generated nasopharyngeal aspirate samples for viral antigen detection from 205 healthy, full-term infants younger than 6 months hospitalized for bronchiolitis from 2001 to 2004. Of these samples, 142 (69%) were of quality sufficient for B. pertussis PCR testing in 2009.

Twelve (8.5%) of the 142 infants admitted with bronchiolitis were found to have B. pertussis. Eleven of the 12 infants were co-infected with at least one other virus (RSV in eight of them). Infants who tested positive for pertussis were more often found to have coughing spells (41.7% vs. 14.6% in those who tested negative).

The reported rate of co-infection in this study is higher than other recent reports from the U.S., likely due to the fact that samples were collected during a time period when the incidence of pertussis was relatively high in Finland.

Nevertheless, given the magnitude of a recent pertussis outbreak in California, it might be useful to consider co-infection in young infants admitted for bronchiolitis in areas with a relatively higher incidence of pertussis.

Although the retrospective nature of this study and the lack of a reported definition of coughing spells make further conclusions difficult to draw, cough might deserve further scrutiny during bronchiolitis season.

Bottom line: Consider co-infection with pertussis in young infants admitted with bronchiolitis.

Citation: Nuolivirta K, Koponen P, He Q, et al. Bordatella pertussis infection is common in nonvaccinated infants admitted for bronchiolitis. Pediatr Infect Dis J. 2010;29(11):1013-1015.

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