In This Edition
Literature at a Glance
A guide to this month’s studies
- Effects of extended VTE prophylaxis in medical patients
- Outcomes with and without preprocedural statins
- Association of subclinical hypothyroidism and CHD
- BP treatment after intracerebral hemorrhage
- Outcomes of ICD therapy in the elderly
- Systems delays and outcomes of STEMI
- D-dimer to predict recurrent VTE
- Stocking height and risk of post-stroke DVT
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.
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.
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.
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.
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