Medicolegal Issues

The latest research you need to know


Literature at a Glance

A guide to this month’s studies.

Simple Clinical Score Predicts Intracerebral Hemorrhage after Thrombolysis

Clinical question: Is there a simple scoring tool that will predict the risk of intracerebral hemorrhage (ICH) following IV tissue-plasminogen activator (t-PA) in ischemic strokes?

Background: The use of t-PA in acute ischemic stroke (AIS) is about 2% to 4%, due in part to fear of conversion of an ischemic event to an ICH. Several studies using t-PA after AIS have identified risk factors for ICH; however, none has looked at the cumulative risk and prognosis for an individual candidate based on these factors.

Study design: Retrospective, observational cohort study.

Setting: The National Institute of Neurological Disorders and Stroke Trials 1 and 2, and consecutive patients treated at Beth Israel Deaconess Medical Center, Boston.

Synopsis: After an extensive literature review, a five-point scale to determine the risk of hemorrhage after t-PA (HAT) was developed using the top four predictive factors based on odds ratios. These included the National Institutes of Health Stroke Scale (NIHSS), presence and extent of hypodensity on initial CT scan, history of diabetes, and high baseline serum glucose. The predictive value of this scale was tested against two independent cohorts of patients with AIS treated with IV t-PA. The HAT scale was able to reasonably predict both the risk of ICH following t-PA and the functional outcome at 90 days. Higher scores on the scale tended to do worse, especially scores of three or more. Its retrospective nature and small number of patients experiencing ICH limit this study.

Bottom line: The HAT score is a quick bedside tool that can help in the counseling of patients and families in conjunction with the risks and benefits of t-PA after ischemic stroke.

Citation: Lou M, Safdar A, Mehdiratta M, et al. The HAT Score: a simple grading scale for predicting hemorrhage after thrombolysis. Neurology. 2008;71:1417-1423.

Nonfasting Triglycerides Predict Stroke Risk

Clinical question: Is there a correlation between nonfasting triglyceride levels and ischemic stroke?

Background: Most individuals are in a nonfasting state, with the exception of several hours prior to breakfast. Fasting cholesterol levels exclude most remnant lipoproteins, which might play a role in early atherosclerotic disease. Increased levels of triglycerides in a nonfasting state indicate the presence of these remnants.

Study design: Prospective, population-based cohort study.

Setting: The Copenhagen City Heart Study.

Synopsis: The study included 13,956 individuals between the ages of 20 and 93 with a follow-up period of up to 31 years. Cholesterol levels were checked during four evaluation periods: 1976-1978, 1981-1983, 1991-1994, and 2001-2003. Eighty-two percent of the participants had eaten a meal within three hours of the blood draw; the other 18% had eaten more than three hours prior to the draw. The study showed an association between increasing nonfasting triglyceride levels and a step-wise increase in the risk of ischemic stroke. The highest risk came in individuals with nonfasting triglyceride levels > 443mg/dl, which was associated with a three- to fourfold greater risk of ischemic stroke. The study was limited in that it evaluated a homogenous group of individuals, which may not reflect other racial or ethnic populations.

Bottom line: Increasing levels of nonfasting triglycerides are associated with an increased risk of ischemic stroke.

Citation: Freiberg J, Tybjaerg-Hansen A, Jensen JS, Nordestgaard BG. Nonfasting triglycerides and risk of ischemic stroke in the general population. JAMA. 2008;300(18):2142-2152.

Short Takes


Dissemination of hepatocellular carcinoma outside the liver following a biopsy remains a concern. Systematic review and meta-analysis showed tumor tract seeding to have an incidence of 2.7% overall, or 0.9% per year, although it did not show an effect on long-term survival.

Citation: Silva MA, Hegab B, Hyde C, Guo B, Buckles JAC, Mirza DF. Needle track seeding following biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-analysis. Gut. 2008;57:1592-1596.


Approximately half of surveyed internists prescribed treatment intended as a placebo, including vitamins and over-the-counter analgesics, and more than half felt the practice was ethically acceptable.

Citation: Tilburt JC, Emanuel EJ, Kaptchuk TJ, Curlin FA, Miller FG. Prescribing “placebo treatments”: results of national survey of U.S. internists and rheumatologists. BMJ. 2008;337:a1938.


Rates of major cardiovascular events in patients with mild to moderate aortic stenosis were not improved by lipid-lowering therapy in this randomized double trial.

Citation: Rossebø AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359:1343-1356.


A nested-case control trial evaluated the risks of COPD medications in veterans who were recently diagnosed with COPD. The authors found an increased risk of cardiovascular deaths in those using ipratropium and an increased risk in pulmonary deaths with the use of theophylline.

Citation: Lee TA, Pickard AS, Au DH, Bartle B, Weiss KB. Risk for death with medications for recently diagnosed chronic obstructive pulmonary disease. Ann Intern Med. 2008;149:380-390.


Prospective, observational cohort study showed that shorter length of hospitalization for community-acquired pneumonia was not associated with an increase in short-term, post-discharge mortality or hospital readmission.

Citation: Capelastegui A, Espana PP, Quintana JM, et al. Declining length of hospital stay for pneumonia and postdischarge outcomes. Am J Med. 2008;121(10):845-852.


This population-based surveillance study showed the risk of sudden cardiac death (SCD) following MI was not associated with recurrent ischemia. However, heart failure independently increased the risk of SCD, indicating the need for close follow-up in these patients.

Citation: Adabag AS, Therneau TM, Gersh BJ, Weston SA, Roger VL. Sudden death after myocardial infarction. JAMA. 2008;300(17):2022-2027.


Meta-analysis of randomized-controlled trials suggests increased risk of cardiovascular death, MI, or stroke among patients with COPD who take ipratropium bromide or tiotropium bromide for more than 30 days.

Citation: Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA. 2008;300(12):1439-1451.


A systematic review of six cohort studies, aimed at eliminating selection bias, showed conflicting mortality benefits in patients with prosthetic and native valve infective endocarditis treated surgically.

Citation: Tleyjeh IM, Kashour T, Zimmerman V, Steckelberg JM, Wilson WR, Baddour LM. The role of valve surgery in infective endocarditis management: a systematic review of observational studies that included propensity score analysis. Am Heart J. 2008;156:901-909.

Proton-Pump Inhibitor (PPI) Use Increases the Risk of Community-Acquired Pneumonia (CAP)

Clinical question: Is there an association between PPI use and CAP?

Background: CAP is associated with significant morbidity, annually accounting for billions of healthcare dollars. Proton-pump inhibitors (PPI) are a mainstay treatment for gastric acid suppression. Previous studies have suggested using PPIs may increase the risk of developing CAP.

Study design: Nested case control study.

Setting: Outpatient general practices, United Kingdom.

Synopsis: The association between PPI use and CAP was evaluated in a cohort of more than 7 million patients using the UK’s general-practice research database. Eligible participants were divided into two groups: case patients and control patients. Initial results indicated an increased risk of CAP with PPI use. After adjusting for confounding variables, the use of a PPI was strongly associated with CAP development when used within 30 days prior of the diagnosis, and most notably within 48 hours of diagnosis. It also was noted that the risk of developing CAP with longer-term PPI use was much lower. This inverse temporal relationship was noted in two previous studies. The limitations of this study were related to presumed adherence and compliance with PPI therapy. There also was no radiographic data to support the diagnosis of pneumonia in these cases, both of which could bias the results.

Bottom line: There appears to be an increased risk of CAP with PPI use. This risk is most notable within 48 hours. However, long-term, chronic PPI use was not associated with an increased risk of CAP.

Citation: Sarkar M, Hennessy S, Yang YX. Proton-pump inhibitor use and the risk for community-acquired pneumonia. Ann Intern Med. 2008;149:391-398.

Clopidogrel Prior to Percutaneous Intervention (PCI) Might Improve Outcomes in Patients with Acute ST-Elevation Myocardial Infarction (STEMI)

Clinical question: Does pretreatment with clopidogrel prior to PCI in acute STEMI improve outcomes?

Background: Extant guidelines for early utilization of clopidogrel in STEMI patients are based on results of studies of patients with non-ST-elevation acute coronary syndromes or treatment with thrombolytics.

Study design: Systematic review.

Setting: MEDLINE and Cochrane Controlled Trials Register of randomized controlled trials.

Synopsis: The authors selected 38 treatment groups, including 8,429 patients with STEMI who underwent primary PCI. They found a statistically significant difference in initial patency, and further found clopidogrel pretreatment was an independent predictor of early reperfusion and improved clinical outcome. This study suggests a benefit to pretreatment with clopidogrel but likely is not sufficient to establish such pretreatment as the standard of care. The limitations of this study were a retrospective review/meta-analysis, as the ability to limit the influence of confounding variables is reduced.

Bottom line: Pretreatment with clopidogrel in patients with acute STEMI undergoing primary PCI appears beneficial based on the results of this review of available evidence.

Citation: Vlaar PJ, Svilaas T, Damman K, et al. Impact of pretreatment with clopidogrel on initial patency and outcomes in patients treated with primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: a systematic review. Circulation. 2008;118:1828-1836.

High-Dose Clopidogrel after PCI Is Beneficial

Clinical question: Does high-dose clopidogrel improve patient outcome following PCI?

Background: Studies have shown antiplatelet resistance after PCI is associated with an increased risk of cardiovascular events, including in-stent thrombosis and death. Other studies have shown the benefit of high-dose clopidogrel by the inhibition of platelet aggregation. Limited information is available regarding the applicability to patients after PCI.

Study design: Retrospective study of 2,954 consecutive patients divided into two groups, low-dose and high-dose clopidogrel use.

Setting: Single hospital in France.

Synopsis: The low-dose study group undergoing PCI was pretreated with 300 mg clopidogrel, followed by ASA 75 mg and clopidogrel 75 mg daily for two months. The second group undergoing PCI was pretreated with 600 mg clopidogrel followed by ASA 75 mg and clopidogrel 150 mg for 15 days, then maintained on ASA 75 mg and clopidogrel 75 mg. Patients received follow-up at two months and were evaluated for in-stent thrombosis, myocardial infarction (MI), death, and hemorrhagic complications. The two groups were matched one-to-one using propensity scoring and the nearest-pair-matching method blinded to patient outcome.

The high-dose clopidogrel group showed a decreased incidence of MI, in-stent thrombosis, and death. This benefit confirms the importance of achieving early and adequate antiplatelet therapy. However, the study authors noted a higher percentage of major bleeding and minor bleeding, although the increase was not statistically significant (2.8% vs. 3.5%, P=0.379, and 7.4% vs. 8.2%, P=0.699, respectively).

Bottom line: High-dose clopidogrel before and within the first 15 days after PCI decreases the risk of MI, in-stent thrombosis, and death, with no statistical increase in bleeding complications. Long-range studies beyond the two-month interval might be beneficial.

Citation: Lemesle G, Delhaye C, Sudre A, et al. Impact of high loading and maintenance dose of clopidogrel within the first 15 days after percutaneous coronary intervention on patient outcome. Am Heart J. 2008;10:1-8.

B-Type Natriuretic Peptide (BNP) Identifies Patients Developing Sepsis-Induced Myocardial Depression

Clinical question: Can plasma BNP be used as a marker to identify patients at risk for sepsis-induced depression of myocardial function?

Background: Previous studies have established BNP levels are increased in patients with septic shock but have not examined the relationship between plasma BNP concentration and left ventricular (LV) systolic dysfunction.

Study design: Prospective cohort.

Setting: Academic medical center.

Synopsis: The authors divided 93 prospectively selected ICU patients with severe sepsis into two groups: one with normal left ventricular (LV) function and a group with LV systolic dysfunction. Comparison of the plasma BNP concentrations between these two groups demonstrated a significant positive correlation between the BNP level and the degree of LV systolic dysfunction, suggesting BNP is a reasonable marker for identification of septic patients with sepsis-induced myocardial depression.

Further, the study’s results suggest BNP measurements early in the course of septic shock might be useful prognostic indicators. However, it is unclear to what extent the knowledge gained from such measurements would alter care management, or how BNP compares to echocardiography in terms of diagnostic and prognostic utility. Thus, these results might not be adequate to justify the routine measurement of BNP in patients with severe sepsis.

Bottom line: Elevated BNP in septic patients is associated with the presence or risk of sepsis-induced myocardial depression, and might be a negative prognostic indicator.

Citation: Post F, Weilemann LS, Messow CM, Sinning C, Munzel T. B-type natriuretic peptide as a marker for sepsis-induced myocardial depression in intensive care patients. Crit Care Med. 2008;36:3030–3037.

High Risk of Death with Thrombolytic Use in Low-Risk Pulmonary Embolism (PE)

Clinical question: Is there an advantage to thrombolytic therapy in the treatment of acute PE versus treatment with unfractionated or low-molecular-weight (LMW) heparin?

Background: Given the high mortality linked to PE, consistent indications for thrombolytic therapy in acute PE are needed. An assessment of the prevalence of thrombolytic therapy and mortality, as compared with standard anticoagulation, has been described inconsistently.

Study design: Retrospective cohort study.

Setting: 186 acute-care hospitals in Pennsylvania.

Synopsis: Using a database of ICD-9 codes, 15,116 patients were reviewed. Logistic regression was used to evaluate the association between thrombolytic therapy and 30-day mortality. Poisson regression was used to evaluate the association between thrombolytic therapy and in-hospital mortality. For those receiving thrombolysis and considered unlikely candidates for the therapy based on documentation at presentation (low predicted probability), the in-hospital mortality and overall 30-day mortality rate were higher when compared with those who did not receive thrombolysis. An exception to this was a group of patients with high predicted probability of receiving thrombolysis. In this group, thrombolysis was not associated with increased risk. Limitations to the study include lack of assessment of right ventricular function, changes in condition after presentation, lack of long-term outcomes, and lack of exact cause of death.

Bottom line: Thrombolytic therapy is associated with higher mortality in patients with hemodynamically uncomplicated PE, and therefore not indicated. Thrombolytic therapy in a subgroup of patients with hemodynamic instability or right ventricular dysfunction improves the clinical course and outcome.

Citation: Ibrahim SA, Stone RA, Obrosky S, Geng M, Fine MJ, Aujesky D. Thrombolytic therapy and mortality in patients with acute pulmonary embolism. Arch Intern Med. 2008;168(20):2183-2190.

Hospitalists Improve Patient Flow in the ED

Clinical question: Can active-bed management by hospitalists reduce ED throughput times and diversionary status?

Background: ED overcrowding leads to ambulance diversion, which has been associated with increased mortality. A primary cause of ED crowding is inpatient boarding, which can reduce patient satisfaction and quality of care. Previous studies targeting the ED have had little impact on throughput and ambulance diversion.

Study design: Pre-post case study in a single institution.

Setting: Academic teaching hospital in Baltimore.

Synopsis: ED throughput times and ambulance diversion hours were measured for all adult patients registered in the department from November 2005 to February 2006 (control period) and November 2006 to February 2007 (intervention period). Active-bed management was defined as appointing a hospitalist to assess bed availability in real time and assigning department of medicine admissions to the appropriate clinical setting, as well as the creation of a bed director. Although the ED census was 8.8% higher during the intervention period, throughput time for admitted patients decreased by 98 minutes per patient, to 458 from 360. The time spent under diversionary status for overcrowding or lack of ICU beds decreased by 6% and 27%, respectively. Limitations of this study include the pre-post design and the implementation at a single institution. Additionally, active-bed management is expensive, and in this case required the hiring of three full-time-equivalent faculty. However, this study successfully demonstrates that a quality improvement partnership between hospitalists and the ED can substantially reduce overcrowding.

Bottom line: Active-bed management by hospitalists improves ED throughput by decreasing the length of time admitted patients spend in the ED and reducing ambulance diversion hours.

Citation: Howell E, Bessman E, Kravet S, Kolodner K, Marshall R, Wright S. Active bed management by hospitalists and emergency department throughput. Ann Int Med. 2008;149(11):804-810.

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