Literature Review

Clinical question: Does the pharmacologic renin-angiotensin-aldosterone (RAAS) system blockade increase the risk for contrast-induced acute kidney injury (CI-AKI) after cardiac catheterization?

Background: Prior prospective studies have demonstrated conflicting results regarding the deleterious versus protective effects of RAAS blockade prior to cardiac catheterization.

Study design: Retrospective, propensity-score-matched cohort study.

Setting: Single-center teaching hospital in South Korea.

Synopsis: Researchers identified patients who had cardiac catheterization and applied propensity-score matching to generate cohorts of periprocedural angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) users versus non-users. CI-AKI occurred more frequently in patients treated with ACEIs/ARBs compared to those who were not (11.4% vs. 6.3%, respectively; P<0.001).

This study was limited by its observational design. Although the propensity-score matching improves the internal validity, it is possible that unaccounted confounders were present. This trial might stimulate interest in re-examining this issue in larger prospective trials, but it should not alter current practice.

Bottom line: RAAS blockade during cardiac catheterization is associated with increased risk for CI-AKI, but further randomized trials are needed to confirm this conclusion.

Citation: Rim MY, Ro H, Kang WC, et al. The effect of renin-angiotensin-aldosterone system blockade on contrast-induced acute kidney injury: a propensity-matched study. Am J Kidney Dis. 2012;60:576-582.

Clinical question: Does the pharmacologic renin-angiotensin-aldosterone (RAAS) system blockade increase the risk for contrast-induced acute kidney injury (CI-AKI) after cardiac catheterization?

Background: Prior prospective studies have demonstrated conflicting results regarding the deleterious versus protective effects of RAAS blockade prior to cardiac catheterization.

Study design: Retrospective, propensity-score-matched cohort study.

Setting: Single-center teaching hospital in South Korea.

Synopsis: Researchers identified patients who had cardiac catheterization and applied propensity-score matching to generate cohorts of periprocedural angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) users versus non-users. CI-AKI occurred more frequently in patients treated with ACEIs/ARBs compared to those who were not (11.4% vs. 6.3%, respectively; P<0.001).

This study was limited by its observational design. Although the propensity-score matching improves the internal validity, it is possible that unaccounted confounders were present. This trial might stimulate interest in re-examining this issue in larger prospective trials, but it should not alter current practice.

Bottom line: RAAS blockade during cardiac catheterization is associated with increased risk for CI-AKI, but further randomized trials are needed to confirm this conclusion.

Citation: Rim MY, Ro H, Kang WC, et al. The effect of renin-angiotensin-aldosterone system blockade on contrast-induced acute kidney injury: a propensity-matched study. Am J Kidney Dis. 2012;60:576-582.

Clinical question: Does the pharmacologic renin-angiotensin-aldosterone (RAAS) system blockade increase the risk for contrast-induced acute kidney injury (CI-AKI) after cardiac catheterization?

Background: Prior prospective studies have demonstrated conflicting results regarding the deleterious versus protective effects of RAAS blockade prior to cardiac catheterization.

Study design: Retrospective, propensity-score-matched cohort study.

Setting: Single-center teaching hospital in South Korea.

Synopsis: Researchers identified patients who had cardiac catheterization and applied propensity-score matching to generate cohorts of periprocedural angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) users versus non-users. CI-AKI occurred more frequently in patients treated with ACEIs/ARBs compared to those who were not (11.4% vs. 6.3%, respectively; P<0.001).

This study was limited by its observational design. Although the propensity-score matching improves the internal validity, it is possible that unaccounted confounders were present. This trial might stimulate interest in re-examining this issue in larger prospective trials, but it should not alter current practice.

Bottom line: RAAS blockade during cardiac catheterization is associated with increased risk for CI-AKI, but further randomized trials are needed to confirm this conclusion.

Citation: Rim MY, Ro H, Kang WC, et al. The effect of renin-angiotensin-aldosterone system blockade on contrast-induced acute kidney injury: a propensity-matched study. Am J Kidney Dis. 2012;60:576-582.

Clinical question: Did the 2008 Center for Medicare & Medicaid Services (CMS) policy denying additional payment for hospital-acquired conditions result in decreased rates of nosocomial infections?

Background: In an effort to curtail preventable complications, CMS implemented a policy of nonpayment for certain healthcare-acquired conditions beginning in October 2008. The effect of this policy on rates of nosocomial infections, including central venous catheter-associated bloodstream infections and catheter-associated urinary tract infections, is unknown.

Study design: Quasi-experimental.

Setting: Data collected from 398 hospitals participating in the National Healthcare Safety Network of the Centers for Disease Control and Prevention.

Synopsis: Investigators analyzed rates of nosocomial infections in participating hospitals before and after implementation of the 2008 nonpayment policy. The rates of decline in central venous catheter infections were not significantly different in the pre-implementation and post-implementation periods (4.8% per quarter and 4.7% per quarter, respectively; incidence-rate ratio 1.0; P=0.97). Similar results were found with regard to catheter-associated UTIs before and after policy initiation (3.9% per quarter and 0.9% per quarter, incidence-rate ratio 1.03; P=0.08). Results did not vary between states with and without mandatory reporting of nosocomial infections.

While this study’s broad scope limits the ability to draw firm conclusions, it does highlight the need for careful evaluation and quantification of the outcomes resulting from CMS’ expansion of policies for financial incentives and disincentives.

Bottom line: National rates of decline in nosocomial infections were unchanged before and after implementation of CMS’ nonpayment policy in 2008.

Citation: Lee GM, Kleinman K, Soumerai SB, et al. Effect of nonpayment for preventable infections in U.S. hospitals. N Engl J Med. 2012;367:1428-1437

Clinical question: Did the 2008 Center for Medicare & Medicaid Services (CMS) policy denying additional payment for hospital-acquired conditions result in decreased rates of nosocomial infections?

Background: In an effort to curtail preventable complications, CMS implemented a policy of nonpayment for certain healthcare-acquired conditions beginning in October 2008. The effect of this policy on rates of nosocomial infections, including central venous catheter-associated bloodstream infections and catheter-associated urinary tract infections, is unknown.

Study design: Quasi-experimental.

Setting: Data collected from 398 hospitals participating in the National Healthcare Safety Network of the Centers for Disease Control and Prevention.

Synopsis: Investigators analyzed rates of nosocomial infections in participating hospitals before and after implementation of the 2008 nonpayment policy. The rates of decline in central venous catheter infections were not significantly different in the pre-implementation and post-implementation periods (4.8% per quarter and 4.7% per quarter, respectively; incidence-rate ratio 1.0; P=0.97). Similar results were found with regard to catheter-associated UTIs before and after policy initiation (3.9% per quarter and 0.9% per quarter, incidence-rate ratio 1.03; P=0.08). Results did not vary between states with and without mandatory reporting of nosocomial infections.

While this study’s broad scope limits the ability to draw firm conclusions, it does highlight the need for careful evaluation and quantification of the outcomes resulting from CMS’ expansion of policies for financial incentives and disincentives.

Bottom line: National rates of decline in nosocomial infections were unchanged before and after implementation of CMS’ nonpayment policy in 2008.

Citation: Lee GM, Kleinman K, Soumerai SB, et al. Effect of nonpayment for preventable infections in U.S. hospitals. N Engl J Med. 2012;367:1428-1437

Clinical question: Did the 2008 Center for Medicare & Medicaid Services (CMS) policy denying additional payment for hospital-acquired conditions result in decreased rates of nosocomial infections?

Background: In an effort to curtail preventable complications, CMS implemented a policy of nonpayment for certain healthcare-acquired conditions beginning in October 2008. The effect of this policy on rates of nosocomial infections, including central venous catheter-associated bloodstream infections and catheter-associated urinary tract infections, is unknown.

Study design: Quasi-experimental.

Setting: Data collected from 398 hospitals participating in the National Healthcare Safety Network of the Centers for Disease Control and Prevention.

Synopsis: Investigators analyzed rates of nosocomial infections in participating hospitals before and after implementation of the 2008 nonpayment policy. The rates of decline in central venous catheter infections were not significantly different in the pre-implementation and post-implementation periods (4.8% per quarter and 4.7% per quarter, respectively; incidence-rate ratio 1.0; P=0.97). Similar results were found with regard to catheter-associated UTIs before and after policy initiation (3.9% per quarter and 0.9% per quarter, incidence-rate ratio 1.03; P=0.08). Results did not vary between states with and without mandatory reporting of nosocomial infections.

While this study’s broad scope limits the ability to draw firm conclusions, it does highlight the need for careful evaluation and quantification of the outcomes resulting from CMS’ expansion of policies for financial incentives and disincentives.

Bottom line: National rates of decline in nosocomial infections were unchanged before and after implementation of CMS’ nonpayment policy in 2008.

Citation: Lee GM, Kleinman K, Soumerai SB, et al. Effect of nonpayment for preventable infections in U.S. hospitals. N Engl J Med. 2012;367:1428-1437

Clinical question: How does radiofrequency ablation compare to antiarrhythmic therapy as first-line treatment for paroxysmal atrial fibrillation (AF)?

Background: Current American College of Cardiology/American Heart Association (ACC/AHA) guidelines support radiofrequency ablation in high-volume centers for select patients with symptomatic, paroxysmal AF who have failed antiarrhythmic therapy (Class I recommendation). Little data exist regarding catheter ablation as a first-line intervention.

Study design: Randomized prospective cohort study.

Setting: Multicenter Danish trial.

Synopsis: Investigators randomized patients with symptomatic paroxysmal AF who were deemed to be good candidates for rhythm control to antiarrhythmic therapy versus radiofrequency catheter ablation. Patients had seven-day Holter monitoring at three, six, 12, 18, and 24 months. There was no significant difference in the cumulative burden of AF between the antiarrhythmic and ablation groups (19% and 13%, respectively; P=0.10). Secondary outcomes including quality of life and cumulative burden of symptomatic AF did not vary significantly between the groups. Crossover was high, with 35% of patients randomized to antiarrhythmic therapy eventually undergoing catheter ablation during the trial. There was no statistically significant difference in adverse events between the two groups.

This trial lends credence to the current ACC/AHA guidelines recommending radiofrequency ablation as second-line therapy for patients with AF after failing antiarrhythmics.

Bottom line: Radiofrequency ablation and antiarrhythmic therapy have similar efficacy as first-line therapy in paroxysmal AF.

Citation: Nielsen JC, Johannessen A, Raatikainen P, et al. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. N Engl J Med. 2012;367:1587-1595.

Clinical question: How does radiofrequency ablation compare to antiarrhythmic therapy as first-line treatment for paroxysmal atrial fibrillation (AF)?

Background: Current American College of Cardiology/American Heart Association (ACC/AHA) guidelines support radiofrequency ablation in high-volume centers for select patients with symptomatic, paroxysmal AF who have failed antiarrhythmic therapy (Class I recommendation). Little data exist regarding catheter ablation as a first-line intervention.

Study design: Randomized prospective cohort study.

Setting: Multicenter Danish trial.

Synopsis: Investigators randomized patients with symptomatic paroxysmal AF who were deemed to be good candidates for rhythm control to antiarrhythmic therapy versus radiofrequency catheter ablation. Patients had seven-day Holter monitoring at three, six, 12, 18, and 24 months. There was no significant difference in the cumulative burden of AF between the antiarrhythmic and ablation groups (19% and 13%, respectively; P=0.10). Secondary outcomes including quality of life and cumulative burden of symptomatic AF did not vary significantly between the groups. Crossover was high, with 35% of patients randomized to antiarrhythmic therapy eventually undergoing catheter ablation during the trial. There was no statistically significant difference in adverse events between the two groups.

This trial lends credence to the current ACC/AHA guidelines recommending radiofrequency ablation as second-line therapy for patients with AF after failing antiarrhythmics.

Bottom line: Radiofrequency ablation and antiarrhythmic therapy have similar efficacy as first-line therapy in paroxysmal AF.

Citation: Nielsen JC, Johannessen A, Raatikainen P, et al. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. N Engl J Med. 2012;367:1587-1595.

Clinical question: How does radiofrequency ablation compare to antiarrhythmic therapy as first-line treatment for paroxysmal atrial fibrillation (AF)?

Background: Current American College of Cardiology/American Heart Association (ACC/AHA) guidelines support radiofrequency ablation in high-volume centers for select patients with symptomatic, paroxysmal AF who have failed antiarrhythmic therapy (Class I recommendation). Little data exist regarding catheter ablation as a first-line intervention.

Study design: Randomized prospective cohort study.

Setting: Multicenter Danish trial.

Synopsis: Investigators randomized patients with symptomatic paroxysmal AF who were deemed to be good candidates for rhythm control to antiarrhythmic therapy versus radiofrequency catheter ablation. Patients had seven-day Holter monitoring at three, six, 12, 18, and 24 months. There was no significant difference in the cumulative burden of AF between the antiarrhythmic and ablation groups (19% and 13%, respectively; P=0.10). Secondary outcomes including quality of life and cumulative burden of symptomatic AF did not vary significantly between the groups. Crossover was high, with 35% of patients randomized to antiarrhythmic therapy eventually undergoing catheter ablation during the trial. There was no statistically significant difference in adverse events between the two groups.

This trial lends credence to the current ACC/AHA guidelines recommending radiofrequency ablation as second-line therapy for patients with AF after failing antiarrhythmics.

Bottom line: Radiofrequency ablation and antiarrhythmic therapy have similar efficacy as first-line therapy in paroxysmal AF.

Citation: Nielsen JC, Johannessen A, Raatikainen P, et al. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. N Engl J Med. 2012;367:1587-1595.

In This Edition

Literature At A Glance

A guide to this month’s studies

1. Interventions that improve discharge handovers reviewed
2. Duration of in-hospital cardiac resuscitation and survival rates
3. Early sepsis intervention strategies to decrease mortality risk
4. Hypoglycemia linked to increased mortality in critically ill
5. Increased bleeding risk for cardiac patients
6. Hospital-run vs. anesthesiologist-run preoperative clinics
7. Postoperative delirium and cognitive impairment in cardiac patients
8. Benefits of resuming anticoagulants after GI bleeding
9. Preoperative hyponatremia and risk of perioperative mortality

Systematic Review Highlights Several Interventions That Improve Discharge Handovers

Clinical question: Do interventions to improve patient handovers at discharge have positive effects on patient care?

Background: The transition from hospital to primary care is often suboptimal and has been associated with unfavorable outcomes, including hospital readmission, increased healthcare utilization, and adverse drug events post-discharge. This review sought to characterize different types of interventions aimed at improving discharge handovers and to evaluate their effects.

Study design: Systematic review of randomized controlled trials.

Setting: Studies published from January 1990 to March 2011.

Synopsis: Review of published databases identified 36 randomized controlled studies on interventions to improve discharge handovers. Studies were blindly evaluated by two reviewers on quality, interventions, and outcomes. There was significant heterogeneity in interventions and outcomes; thus, statistical analysis was not possible. Most studies evaluated multicomponent interventions and had more than one outcome measure.

Of the 36 studies reviewed, 25 reported statistically significant improvements in outcomes, including reduced hospital utilization and improved continuity of care. Effective interventions included medication reconciliation; structured discharge information (facilitated by electronic resources); multidisciplinary discharge planning; shared involvement in arranging care between inpatient and outpatient physicians; and Web-based access to discharge information by the outpatient provider.

The complexity of the interventions and the heterogeneity of reported results did not allow for firm conclusions to be drawn regarding which specific interventions had the strongest effects.

Bottom line: Interventions that target the quality and safety of handovers between hospital and outpatient providers at discharge can significantly reduce hospital utilization and improve continuity of care.

Citation: Hesselink G, Schoonhoven L, Barach P, et al. Improving patient handovers from hospital to primary care: a systematic review. Ann Intern Med. 2012;157:417-428.

Longer Duration of In-Hospital Cardiac Resuscitation Associated with Increased Survival

Clinical question: Are prolonged cardiac resuscitation efforts associated with improved outcomes?

Background: There is little evidence or guidelines on how long to maintain resuscitative efforts during in-hospital cardiac arrest, leading to variation in practice. This study characterized patterns of resuscitation duration and relationship to the return of spontaneous circulation and survival to discharge.

Study design: Retrospective observational study.

Setting: Four hundred thirty-five U.S. hospitals reporting data to the American Heart Association’s Get With The Guidelines: Resuscitation registry.

Synopsis: Using duration of resuscitation in nonsurvivors as a surrogate for the tendency of a facility to perform prolonged efforts, hospitals were divided into quartiles. Overall, of 64,339 patients in the registry, 31,198 (48.5%) had return of circulation and 9,912 (15.4%) survived to discharge. Resuscitative efforts in nonsurvivors ranged from a median of 16 to 25 minutes between the lowest and highest quartiles.

There was a stepwise increase in the likelihood for patients to have return of spontaneous circulation and to survive to discharge between each quartile. Specifically, comparing shortest to longest, there was a significant adjusted odds ratio of 1.12 for both the return of circulation (P<0.0001) and survival to discharge (P=0.021). The survival benefit was most apparent for those with pulseless electrical activity or asystole as initial rhythms, as compared to ventricular tachycardia or fibrillation.

Limitations included the study’s observational design, which meant causality could not be determined. Additionally, the study did not account for the quality of resuscitative efforts (e.g. depth of chest compressions, adherence with guidelines), which might have influenced outcomes. Importantly, the study looked at survival to discharge, but it did not evaluate long-term survival or functional status post-discharge, which might better reflect the success of resuscitation.

Bottom line: Prolonged resuscitative efforts were observed to be associated with increased likelihood of return of spontaneous circulation and survival to discharge; this data might provide clinical guidance in determining when to stop resuscitation efforts.

Citation: Goldberger ZD, Chan PS, Berg RA, et al. Duration of resuscitation efforts and survival after in-hospital cardiac arrest: an observational study. Lancet. 2012;380:1473-1481.

Early Sepsis Intervention Strategies Decrease Mortality, Length of Stay, and Cost

Clinical question: For patients with sepsis or septic shock, what is the impact of a real-time comprehensive continuous quality-improvement (QI) initiative on in-hospital mortality, morbidity, and healthcare resource utilization in community and tertiary-care hospitals in the U.S.?

Background: Multiple single-center trials have demonstrated that early sepsis intervention strategies (early goal-directed therapy, resuscitation bundles) improve in-hospital mortality. Little is known about the effectiveness of incorporating these strategies into a real-time continuous QI initiative and implementing interventions across multiple sites simultaneously.

Study design: Pre-post at some sites and concurrent implementation design at other sites.

Setting: Five community and six-tertiary care U.S. hospitals.

Synopsis: The GENeralized Early Sepsis Intervention Strategies (GENESIS) project was a CQI initiative that combined several QI concepts with validated early sepsis interventions known as resuscitation bundles (RB). Continuous QI was implemented on patients with severe sepsis or septic shock in both before and after designs (eight hospitals), and in concurrent designs (three hospitals). The control group was comprised of historical controls treated before GENESIS and patients with incomplete implementation of RB, totaling 1,554 patients. The treatment group included patients treated after GENESIS and those with complete RB compliance, totaling 4,801 patients.

Compared with the control group, patients in the treatment group had a 33% decreased risk of in-hospital mortality (RR 0.67, 95% CI 0.63-0.72), an absolute decrease in hospital length of stay (LOS) by 5.1 days (20.7 days vs. 15.6 days, P<0.001) and a $47,923 reduction in total hospital charges (P<0.001). Limitations included the study design (not a prospective randomized trial), and the possibility of other concurrent unmeasured quality initiatives taking place at the study sites, which might have contributed to improved outcomes.

Bottom line: Early sepsis intervention strategies in the form of a comprehensive continuous QI initiative can decrease mortality, hospital LOS, and cost in both tertiary-care and community hospitals.

Citation: Cannon CM, Holthaus CV, Zubrow MT, et al. The GENESIS project (GENeralized Early Sepsis Intervention Strategies): a multicenter quality improvement collaborative. J Intensive Care Med. 2012; Aug 17. doi:10.1177/0885066612453025.

Hypoglycemia Associated with Increased Mortality in the Critically Ill

Clinical question: Is hypoglycemia associated with mortality in critically ill patients?

Background: Initial studies suggested that intensive glucose control reduces mortality in surgical ICU patients and reduces morbidity in medical ICU patients, but further studies have not supported these findings. Recent literature shows conflicting results on the effects of intense glucose control in critically ill patients.

Study design: Post-hoc analysis of the NICE-SUGAR study database.

Setting: ICUs in 42 hospitals in Australia, New Zealand, and Canada.

Synopsis: The NICE-SUGAR study was a multicenter trial that randomized 6,104 ICU patients to intensive (glucose 80 to 108 mg/dL) or conventional glucose control (≤180 mg/dL). Patients were followed for 90 days or until death, with death being the primary end point. Severe hypoglycemia (<40 mg/dL) was recorded in 6.8% of patients in the intensive glucose control group versus 0.5% in the conventional group. The study showed that intensive glucose control was associated with increased mortality among adult ICU patients.

Using the NICE-SUGAR database, the authors conducted a Cox regression analysis to examine the associations between hypoglycemia and death. A total of 2,714 patients had moderate hypoglycemia (glucose 41 to 70 mg/dL), and 223 patients had severe hypoglycemia. The hazard ratio for mortality was 1.41 (95% CI 1.21-1.62, P<0.001) for patients with moderate hypoglycemia and 2.10 (95% CI 1.59-2.77, P<0.001) for severe hypoglycemia, compared to patients without hypoglycemia.

These findings show a strong association between mortality and hypoglycemia but do not prove causality. Hospitalists caring for ICU patients must be aware that hypoglycemia is associated with mortality and focus on avoiding hypoglycemia. The American Diabetes Association currently recommends a target blood glucose level of 140 to 180 mg/dL for most critically ill patients.

Bottom line: Hypoglycemia (glucose <70 mg/dL) is associated with increased risk of mortality in ICU patients.

Citation: Finfer S, Chittock DR, Su SY, et al. Hypoglycemia and risk of death in critically ill patients. New Engl J Med. 2012;367(12):1108-1118.

Increased Bleeding Risk for Cardiac Patients on Multiple Antithrombotic Drugs

Clinical question: Is there an increased risk of bleeding in atrial fibrillation patients treated with multiple antithrombotic agents following acute myocardial infarction (MI) or percutaneous coronary intervention (PCI)?

Background: Current treatment for atrial fibrillation patients with MI or PCI includes vitamin K antagonist (VKA) therapy to prevent stroke and antiplatelet agents to prevent further coronary events. There are inconsistent findings on the safety and efficacy of combined therapy with VKA, aspirin, and clopidogrel, specifically with regard to bleeding risk.

Study design: Retrospective cohort study.

Setting: Nationwide registry in Denmark.

Synopsis: Using the National Patient Registry in Denmark, 11,480 patients with atrial fibrillation who were admitted for MI or PCI were identified. Patients were grouped by medication regimen, including monotherapy (aspirin, clopidogrel, or VKA), dual therapy (dual antiplatelet or VKA+antiplatelet), or triple therapy (VKA+aspirin+clopidogrel). The primary outcome was nonfatal or fatal bleeding within one year.

Patients receiving triple therapy had the highest rate of bleeding, with a crude incidence of 14.2 events per 100 person-years. Patients treated with VKA+aspirin+clopidogel were significantly more likely than those on VKA+antiplatelet (HR 1.47, 95% CI 1.04-2.08) or dual antiplatelet (HR 2.20, 95% CI 1.58-3.08) treatment to have a bleeding event within 90 days, and similar trends were seen at 90 to 360 days. There was no significant difference in thromboembolic events among patients on VKA+aspirin+clopidogrel versus VKA+antiplatelet therapy.

Only bleeding events that required hospitalization were recorded, which might underestimate the bleeding risks of these regimens. Additionally, INR levels were not determined, which could impact both bleeding and thromboembolic outcomes.

However, this study does suggest that there are significant bleeding risks among patients treated with triple therapy. Hospitalists should weigh the risks of thromboembolic events with bleeding risks in patients with atrial fibrillation and MI/PCI, and only prescribe VKA+aspirin+clopidogrel with these risks in mind.

Bottom line: Immediate and continued bleeding risk is increased in patients with atrial fibrillation admitted with PCI or MI who are placed on triple antithrombotic therapy with VKA+aspirin+clopidogrel.

Citation: Lamberts M, Olesen JB, Ruwald MH, et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention. Circulation. 2012;126:1185-1193.

Hospitalist-Run Preoperative Clinic Improves Outcomes in Complex Surgical Patients

Clinical question: Do hospitalist-run preoperative clinics improve outcomes for medically complex patients undergoing noncardiac surgery compared to traditional anesthesiologist-run preoperative clinics?

Background: Studies of perioperative medical consultation have shown inconsistent effects on quality of care, but preoperative medical consultation has only been evaluated in the immediate preoperative period (one day prior to surgery or less). Little is known about the impact of involving hospitalists earlier in the preoperative period.

Study design: Retrospective, pre-post study.

Setting: Veterans Affairs Greater Los Angeles Healthcare System (VAGLAHS).

Synopsis: In July 2004, the VAGLAHS Preoperative Clinic transitioned from being anesthesiologist-run to hospitalist-run. Mid-level providers were trained on preoperative medical assessment, and patients were only evaluated by anesthesia staff on the day of surgery, after they had been deemed medically acceptable for surgery. All patients seen in the clinic from July 2003 to July 2005 were included in the study. Period A included patients evaluated when anesthesia staff supervised the clinic. Period B included patients evaluated during the first year of the hospitalist-run system.

There were 1,101 patients with inpatient surgeries in Period A, and 1,126 patients in Period B. Mean length of stay (LOS) decreased to 5.28 days during the hospitalist-run model from 9.87 days during the anesthesiologist-run model. LOS reductions were most notable in patients with ASA scores of 3 or higher; LOS reductions were not seen in an internal control of surgical patients who were not evaluated in the preoperative clinic. Inpatient mortality was also reduced in Period B compared with Period A, to 4 cases (0.36%) from 14 cases (1.27%) (P=0.0158). Specific processes that led to improved outcomes for patients in Period B could not be identified. The VA study setting might limit the generalizability of the results.

Bottom line: A hospitalist-run preoperative clinic was associated with decreased LOS and inpatient mortality compared with a traditional anesthesiologist-run clinic.

Citation: Vazirani S, Lankarani-Fard A, Lian LJ, Stelzner M, Asch SM. Preoperative processes and outcomes after implementation of a hospitalist-run preoperative clinic. J Hosp Med. 2012 Sep 7. doi:10.1002/jhm.1968.

Delirium after Cardiac Surgery Associated with Prolonged Cognitive Impairment

Clinical question: Is postoperative delirium associated with decreased cognitive function in the first year after cardiac surgery?

Background: In general populations, delirium has been associated with long-term decline in cognitive ability. Delirium and cognitive dysfunction are both common following cardiac surgery, but the effects of postoperative delirium on the trajectory of cognitive function over time is unclear.

Study design: Prospective cohort study.

Setting: Two academic medical centers and a Veterans Administration hospital.

Synopsis: Two hundred twenty-five patients aged 60 or older who were scheduled to undergo coronary artery bypass grafting or valve replacement surgery were included. Patients underwent preoperative assessment cognitive function with the use of the Mini-Mental State Examination (MMSE). Starting on postoperative Day 2, patients underwent daily assessment for delirium. After discharge, cognitive function was reassessed at months one, six, and 12.

Postoperative delirium occurred in 103 patients (46%). Patients with delirium were older, had higher comorbidity scores, and had lower MMSE scores at baseline. Among the overall study population, adjusted MMSE scores dropped 4.6 points from baseline to postoperative Day 2, then were observed to increase by approximately one point per day during postoperative days 3 to 5 with minimal change thereafter. Patients with delirium had greater decrease in cognitive function in the immediate postoperative period compared to patients without delirium (7.7 points vs. 2.1, P<0.001).

Patients without delirium returned to their baseline cognitive ability by one month postoperatively, while patients who had delirium were still making gains up to six months post-operatively, never returning to baseline level of function by one year. Unmeasured confounders and uncertain sensitivity of the MMSE to detect mild cognitive impairment might limit these findings.

Bottom line: Cognitive function decreases in the immediate postoperative period following cardiac surgery. Compared to patients without delirium, patients with delirium experience more dramatic and prolonged cognitive impairment postoperatively, without returning to their preoperative level of cognitive function at one year.

Citation: Saczynski JS, Marcantonio ER, Quach L, et al. Cognitive trajectories after postoperative delirium. New Engl J Med. 2012;367:30-39.

Benefits of Resuming Anticoagulation after GI Bleed Outweigh Risks for Most Patients

Clinical question: In warfarin-treated patients who have experienced gastrointestinal (GI) bleeding, what are the patterns of restarting warfarin therapy and the incidence of thrombosis, recurrent GI bleed, and death in the 90 days following index bleed?

Background: In warfarin-treated patients who experience GI bleeding, warfarin is often temporarily held or permanently discontinued, placing patients at increased risk for developing thromboembolism. Little is known about the risks, benefits, and timing of restarting warfarin in this patient population.

Study design: Retrospective cohort study.

Setting: Kaiser Permanente Colorado.

Synopsis: Using clinical and administrative databases, 442 patients who presented with GI bleeding while receiving warfarin therapy were identified. Patients were grouped by whether they resumed warfarin (n=260, including 41 patients in whom anticoagulation was never interrupted), or did not resume warfarin therapy (n=182) in the 90 days following index GI bleed. Patients with prosthetic heart valves or GI bleeding localized to the rectum/anus were more commonly restarted on warfarin, whereas older patients and those in whom the source of bleeding was not identified were less likely to be restarted on warfarin therapy.

Restarting warfarin therapy after index GI bleed was associated with lower risk of thrombosis (HR 0.05, 95% CI 0.01-0.58) and death from any cause (HR 0.31, 95% CI 0.15-0.62), and it was not associated with a significant increase in risk for recurrent GI bleed (HR 1.32, 95% CI 0.50-3.57).

The authors concluded that for many patients who experience a warfarin-associated GI bleed, the benefits of restarting warfarin therapy outweigh the risks. No conclusions were made regarding the optimal timing of resuming therapy. Limitations included the use of administrative data and inability to determine the potential influence of aspirin use on outcomes.

Bottom line: Resuming warfarin in the 90 days following a warfarin-associated GI bleed is associated with decreased risk of thrombosis and death without increased risk for recurrent GI bleed.

Citation: Witt DM, Delate T, Garcia DA, et al. Risk of thromboembolism, recurrent hemorrhage, and death after warfarin therapy interruption for gastrointestinal tract bleeding. Arch Intern Med. 2012 Sep 12. doi:10.1001/archinternmed.2012.4261.

Preoperative Hyponatremia Associated with Increased Risk for Perioperative Complications and Mortality

Clinical question: Is preoperative hyponatremia an indicator of perioperative morbidity and mortality?

Background: Hyponatremia is a common diagnosis in the hospital setting and is associated with adverse outcomes, even in mild cases. However, it is unclear if this association exists in surgical patients when detected preoperatively.

Study design: Retrospective cohort study.

Setting: Academic and community hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP).

Synopsis: A total of 75,423 adult patients with hyponatremia (sodium <135 mEq/L) who were undergoing major surgery were compared to 888,840 patients with normal preoperative sodium levels over a six-year period. The primary outcome was 30-day mortality. Secondary outcomes included postoperative major coronary events, stroke, wound infection, pneumonia, and length of stay (LOS).

Compared to patients with normal sodium levels, those with preoperative hyponatremia had higher rates of perioperative mortality (5.2% vs. 1.3%; adjusted odds ratio 1.44, 95% CI 1.38-1.50), with increased risk that correlated with increasing severity of hyponatremia. Association with postoperative mortality was particularly strong among hyponatremic patients with ASA scores of 1 or 2 and those undergoing nonemergency surgery.

Patients with preoperative hyponatremia were also found to have increased risk for all postoperative complications evaluated, with the exception of stroke. Limitations included the potential for unmeasured confounders and not being able to account for the role of medications used perioperatively. Research is needed to determine whether correcting preoperative hyponatremia lessens the risk of mortality and other postoperative complications.

Bottom line: Among patients undergoing major surgery, preoperative hyponatremia is a predictor of postoperative 30-day mortality and morbidity.

Citation: Leung AA, McAlister FA, Rogers SO, et al. Preoperative hyponatremia and perioperative complications. Arch Intern Med. 2012;172:1-8.

In This Edition

Literature At A Glance

A guide to this month’s studies

1. Interventions that improve discharge handovers reviewed
2. Duration of in-hospital cardiac resuscitation and survival rates
3. Early sepsis intervention strategies to decrease mortality risk
4. Hypoglycemia linked to increased mortality in critically ill
5. Increased bleeding risk for cardiac patients
6. Hospital-run vs. anesthesiologist-run preoperative clinics
7. Postoperative delirium and cognitive impairment in cardiac patients
8. Benefits of resuming anticoagulants after GI bleeding
9. Preoperative hyponatremia and risk of perioperative mortality

Systematic Review Highlights Several Interventions That Improve Discharge Handovers

Clinical question: Do interventions to improve patient handovers at discharge have positive effects on patient care?

Background: The transition from hospital to primary care is often suboptimal and has been associated with unfavorable outcomes, including hospital readmission, increased healthcare utilization, and adverse drug events post-discharge. This review sought to characterize different types of interventions aimed at improving discharge handovers and to evaluate their effects.

Study design: Systematic review of randomized controlled trials.

Setting: Studies published from January 1990 to March 2011.

Synopsis: Review of published databases identified 36 randomized controlled studies on interventions to improve discharge handovers. Studies were blindly evaluated by two reviewers on quality, interventions, and outcomes. There was significant heterogeneity in interventions and outcomes; thus, statistical analysis was not possible. Most studies evaluated multicomponent interventions and had more than one outcome measure.

Of the 36 studies reviewed, 25 reported statistically significant improvements in outcomes, including reduced hospital utilization and improved continuity of care. Effective interventions included medication reconciliation; structured discharge information (facilitated by electronic resources); multidisciplinary discharge planning; shared involvement in arranging care between inpatient and outpatient physicians; and Web-based access to discharge information by the outpatient provider.

The complexity of the interventions and the heterogeneity of reported results did not allow for firm conclusions to be drawn regarding which specific interventions had the strongest effects.

Bottom line: Interventions that target the quality and safety of handovers between hospital and outpatient providers at discharge can significantly reduce hospital utilization and improve continuity of care.

Citation: Hesselink G, Schoonhoven L, Barach P, et al. Improving patient handovers from hospital to primary care: a systematic review. Ann Intern Med. 2012;157:417-428.

Longer Duration of In-Hospital Cardiac Resuscitation Associated with Increased Survival

Clinical question: Are prolonged cardiac resuscitation efforts associated with improved outcomes?

Background: There is little evidence or guidelines on how long to maintain resuscitative efforts during in-hospital cardiac arrest, leading to variation in practice. This study characterized patterns of resuscitation duration and relationship to the return of spontaneous circulation and survival to discharge.

Study design: Retrospective observational study.

Setting: Four hundred thirty-five U.S. hospitals reporting data to the American Heart Association’s Get With The Guidelines: Resuscitation registry.

Synopsis: Using duration of resuscitation in nonsurvivors as a surrogate for the tendency of a facility to perform prolonged efforts, hospitals were divided into quartiles. Overall, of 64,339 patients in the registry, 31,198 (48.5%) had return of circulation and 9,912 (15.4%) survived to discharge. Resuscitative efforts in nonsurvivors ranged from a median of 16 to 25 minutes between the lowest and highest quartiles.

There was a stepwise increase in the likelihood for patients to have return of spontaneous circulation and to survive to discharge between each quartile. Specifically, comparing shortest to longest, there was a significant adjusted odds ratio of 1.12 for both the return of circulation (P<0.0001) and survival to discharge (P=0.021). The survival benefit was most apparent for those with pulseless electrical activity or asystole as initial rhythms, as compared to ventricular tachycardia or fibrillation.

Limitations included the study’s observational design, which meant causality could not be determined. Additionally, the study did not account for the quality of resuscitative efforts (e.g. depth of chest compressions, adherence with guidelines), which might have influenced outcomes. Importantly, the study looked at survival to discharge, but it did not evaluate long-term survival or functional status post-discharge, which might better reflect the success of resuscitation.

Bottom line: Prolonged resuscitative efforts were observed to be associated with increased likelihood of return of spontaneous circulation and survival to discharge; this data might provide clinical guidance in determining when to stop resuscitation efforts.

Citation: Goldberger ZD, Chan PS, Berg RA, et al. Duration of resuscitation efforts and survival after in-hospital cardiac arrest: an observational study. Lancet. 2012;380:1473-1481.

Early Sepsis Intervention Strategies Decrease Mortality, Length of Stay, and Cost

Clinical question: For patients with sepsis or septic shock, what is the impact of a real-time comprehensive continuous quality-improvement (QI) initiative on in-hospital mortality, morbidity, and healthcare resource utilization in community and tertiary-care hospitals in the U.S.?

Background: Multiple single-center trials have demonstrated that early sepsis intervention strategies (early goal-directed therapy, resuscitation bundles) improve in-hospital mortality. Little is known about the effectiveness of incorporating these strategies into a real-time continuous QI initiative and implementing interventions across multiple sites simultaneously.

Study design: Pre-post at some sites and concurrent implementation design at other sites.

Setting: Five community and six-tertiary care U.S. hospitals.

Synopsis: The GENeralized Early Sepsis Intervention Strategies (GENESIS) project was a CQI initiative that combined several QI concepts with validated early sepsis interventions known as resuscitation bundles (RB). Continuous QI was implemented on patients with severe sepsis or septic shock in both before and after designs (eight hospitals), and in concurrent designs (three hospitals). The control group was comprised of historical controls treated before GENESIS and patients with incomplete implementation of RB, totaling 1,554 patients. The treatment group included patients treated after GENESIS and those with complete RB compliance, totaling 4,801 patients.

Compared with the control group, patients in the treatment group had a 33% decreased risk of in-hospital mortality (RR 0.67, 95% CI 0.63-0.72), an absolute decrease in hospital length of stay (LOS) by 5.1 days (20.7 days vs. 15.6 days, P<0.001) and a $47,923 reduction in total hospital charges (P<0.001). Limitations included the study design (not a prospective randomized trial), and the possibility of other concurrent unmeasured quality initiatives taking place at the study sites, which might have contributed to improved outcomes.

Bottom line: Early sepsis intervention strategies in the form of a comprehensive continuous QI initiative can decrease mortality, hospital LOS, and cost in both tertiary-care and community hospitals.

Citation: Cannon CM, Holthaus CV, Zubrow MT, et al. The GENESIS project (GENeralized Early Sepsis Intervention Strategies): a multicenter quality improvement collaborative. J Intensive Care Med. 2012; Aug 17. doi:10.1177/0885066612453025.

Hypoglycemia Associated with Increased Mortality in the Critically Ill

Clinical question: Is hypoglycemia associated with mortality in critically ill patients?

Background: Initial studies suggested that intensive glucose control reduces mortality in surgical ICU patients and reduces morbidity in medical ICU patients, but further studies have not supported these findings. Recent literature shows conflicting results on the effects of intense glucose control in critically ill patients.

Study design: Post-hoc analysis of the NICE-SUGAR study database.

Setting: ICUs in 42 hospitals in Australia, New Zealand, and Canada.

Synopsis: The NICE-SUGAR study was a multicenter trial that randomized 6,104 ICU patients to intensive (glucose 80 to 108 mg/dL) or conventional glucose control (≤180 mg/dL). Patients were followed for 90 days or until death, with death being the primary end point. Severe hypoglycemia (<40 mg/dL) was recorded in 6.8% of patients in the intensive glucose control group versus 0.5% in the conventional group. The study showed that intensive glucose control was associated with increased mortality among adult ICU patients.

Using the NICE-SUGAR database, the authors conducted a Cox regression analysis to examine the associations between hypoglycemia and death. A total of 2,714 patients had moderate hypoglycemia (glucose 41 to 70 mg/dL), and 223 patients had severe hypoglycemia. The hazard ratio for mortality was 1.41 (95% CI 1.21-1.62, P<0.001) for patients with moderate hypoglycemia and 2.10 (95% CI 1.59-2.77, P<0.001) for severe hypoglycemia, compared to patients without hypoglycemia.

These findings show a strong association between mortality and hypoglycemia but do not prove causality. Hospitalists caring for ICU patients must be aware that hypoglycemia is associated with mortality and focus on avoiding hypoglycemia. The American Diabetes Association currently recommends a target blood glucose level of 140 to 180 mg/dL for most critically ill patients.

Bottom line: Hypoglycemia (glucose <70 mg/dL) is associated with increased risk of mortality in ICU patients.

Citation: Finfer S, Chittock DR, Su SY, et al. Hypoglycemia and risk of death in critically ill patients. New Engl J Med. 2012;367(12):1108-1118.

Increased Bleeding Risk for Cardiac Patients on Multiple Antithrombotic Drugs

Clinical question: Is there an increased risk of bleeding in atrial fibrillation patients treated with multiple antithrombotic agents following acute myocardial infarction (MI) or percutaneous coronary intervention (PCI)?

Background: Current treatment for atrial fibrillation patients with MI or PCI includes vitamin K antagonist (VKA) therapy to prevent stroke and antiplatelet agents to prevent further coronary events. There are inconsistent findings on the safety and efficacy of combined therapy with VKA, aspirin, and clopidogrel, specifically with regard to bleeding risk.

Study design: Retrospective cohort study.

Setting: Nationwide registry in Denmark.

Synopsis: Using the National Patient Registry in Denmark, 11,480 patients with atrial fibrillation who were admitted for MI or PCI were identified. Patients were grouped by medication regimen, including monotherapy (aspirin, clopidogrel, or VKA), dual therapy (dual antiplatelet or VKA+antiplatelet), or triple therapy (VKA+aspirin+clopidogrel). The primary outcome was nonfatal or fatal bleeding within one year.

Patients receiving triple therapy had the highest rate of bleeding, with a crude incidence of 14.2 events per 100 person-years. Patients treated with VKA+aspirin+clopidogel were significantly more likely than those on VKA+antiplatelet (HR 1.47, 95% CI 1.04-2.08) or dual antiplatelet (HR 2.20, 95% CI 1.58-3.08) treatment to have a bleeding event within 90 days, and similar trends were seen at 90 to 360 days. There was no significant difference in thromboembolic events among patients on VKA+aspirin+clopidogrel versus VKA+antiplatelet therapy.

Only bleeding events that required hospitalization were recorded, which might underestimate the bleeding risks of these regimens. Additionally, INR levels were not determined, which could impact both bleeding and thromboembolic outcomes.

However, this study does suggest that there are significant bleeding risks among patients treated with triple therapy. Hospitalists should weigh the risks of thromboembolic events with bleeding risks in patients with atrial fibrillation and MI/PCI, and only prescribe VKA+aspirin+clopidogrel with these risks in mind.

Bottom line: Immediate and continued bleeding risk is increased in patients with atrial fibrillation admitted with PCI or MI who are placed on triple antithrombotic therapy with VKA+aspirin+clopidogrel.

Citation: Lamberts M, Olesen JB, Ruwald MH, et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention. Circulation. 2012;126:1185-1193.

Hospitalist-Run Preoperative Clinic Improves Outcomes in Complex Surgical Patients

Clinical question: Do hospitalist-run preoperative clinics improve outcomes for medically complex patients undergoing noncardiac surgery compared to traditional anesthesiologist-run preoperative clinics?

Background: Studies of perioperative medical consultation have shown inconsistent effects on quality of care, but preoperative medical consultation has only been evaluated in the immediate preoperative period (one day prior to surgery or less). Little is known about the impact of involving hospitalists earlier in the preoperative period.

Study design: Retrospective, pre-post study.

Setting: Veterans Affairs Greater Los Angeles Healthcare System (VAGLAHS).

Synopsis: In July 2004, the VAGLAHS Preoperative Clinic transitioned from being anesthesiologist-run to hospitalist-run. Mid-level providers were trained on preoperative medical assessment, and patients were only evaluated by anesthesia staff on the day of surgery, after they had been deemed medically acceptable for surgery. All patients seen in the clinic from July 2003 to July 2005 were included in the study. Period A included patients evaluated when anesthesia staff supervised the clinic. Period B included patients evaluated during the first year of the hospitalist-run system.

There were 1,101 patients with inpatient surgeries in Period A, and 1,126 patients in Period B. Mean length of stay (LOS) decreased to 5.28 days during the hospitalist-run model from 9.87 days during the anesthesiologist-run model. LOS reductions were most notable in patients with ASA scores of 3 or higher; LOS reductions were not seen in an internal control of surgical patients who were not evaluated in the preoperative clinic. Inpatient mortality was also reduced in Period B compared with Period A, to 4 cases (0.36%) from 14 cases (1.27%) (P=0.0158). Specific processes that led to improved outcomes for patients in Period B could not be identified. The VA study setting might limit the generalizability of the results.

Bottom line: A hospitalist-run preoperative clinic was associated with decreased LOS and inpatient mortality compared with a traditional anesthesiologist-run clinic.

Citation: Vazirani S, Lankarani-Fard A, Lian LJ, Stelzner M, Asch SM. Preoperative processes and outcomes after implementation of a hospitalist-run preoperative clinic. J Hosp Med. 2012 Sep 7. doi:10.1002/jhm.1968.

Delirium after Cardiac Surgery Associated with Prolonged Cognitive Impairment

Clinical question: Is postoperative delirium associated with decreased cognitive function in the first year after cardiac surgery?

Background: In general populations, delirium has been associated with long-term decline in cognitive ability. Delirium and cognitive dysfunction are both common following cardiac surgery, but the effects of postoperative delirium on the trajectory of cognitive function over time is unclear.

Study design: Prospective cohort study.

Setting: Two academic medical centers and a Veterans Administration hospital.

Synopsis: Two hundred twenty-five patients aged 60 or older who were scheduled to undergo coronary artery bypass grafting or valve replacement surgery were included. Patients underwent preoperative assessment cognitive function with the use of the Mini-Mental State Examination (MMSE). Starting on postoperative Day 2, patients underwent daily assessment for delirium. After discharge, cognitive function was reassessed at months one, six, and 12.

Postoperative delirium occurred in 103 patients (46%). Patients with delirium were older, had higher comorbidity scores, and had lower MMSE scores at baseline. Among the overall study population, adjusted MMSE scores dropped 4.6 points from baseline to postoperative Day 2, then were observed to increase by approximately one point per day during postoperative days 3 to 5 with minimal change thereafter. Patients with delirium had greater decrease in cognitive function in the immediate postoperative period compared to patients without delirium (7.7 points vs. 2.1, P<0.001).

Patients without delirium returned to their baseline cognitive ability by one month postoperatively, while patients who had delirium were still making gains up to six months post-operatively, never returning to baseline level of function by one year. Unmeasured confounders and uncertain sensitivity of the MMSE to detect mild cognitive impairment might limit these findings.

Bottom line: Cognitive function decreases in the immediate postoperative period following cardiac surgery. Compared to patients without delirium, patients with delirium experience more dramatic and prolonged cognitive impairment postoperatively, without returning to their preoperative level of cognitive function at one year.

Citation: Saczynski JS, Marcantonio ER, Quach L, et al. Cognitive trajectories after postoperative delirium. New Engl J Med. 2012;367:30-39.

Benefits of Resuming Anticoagulation after GI Bleed Outweigh Risks for Most Patients

Clinical question: In warfarin-treated patients who have experienced gastrointestinal (GI) bleeding, what are the patterns of restarting warfarin therapy and the incidence of thrombosis, recurrent GI bleed, and death in the 90 days following index bleed?

Background: In warfarin-treated patients who experience GI bleeding, warfarin is often temporarily held or permanently discontinued, placing patients at increased risk for developing thromboembolism. Little is known about the risks, benefits, and timing of restarting warfarin in this patient population.

Study design: Retrospective cohort study.

Setting: Kaiser Permanente Colorado.

Synopsis: Using clinical and administrative databases, 442 patients who presented with GI bleeding while receiving warfarin therapy were identified. Patients were grouped by whether they resumed warfarin (n=260, including 41 patients in whom anticoagulation was never interrupted), or did not resume warfarin therapy (n=182) in the 90 days following index GI bleed. Patients with prosthetic heart valves or GI bleeding localized to the rectum/anus were more commonly restarted on warfarin, whereas older patients and those in whom the source of bleeding was not identified were less likely to be restarted on warfarin therapy.

Restarting warfarin therapy after index GI bleed was associated with lower risk of thrombosis (HR 0.05, 95% CI 0.01-0.58) and death from any cause (HR 0.31, 95% CI 0.15-0.62), and it was not associated with a significant increase in risk for recurrent GI bleed (HR 1.32, 95% CI 0.50-3.57).

The authors concluded that for many patients who experience a warfarin-associated GI bleed, the benefits of restarting warfarin therapy outweigh the risks. No conclusions were made regarding the optimal timing of resuming therapy. Limitations included the use of administrative data and inability to determine the potential influence of aspirin use on outcomes.

Bottom line: Resuming warfarin in the 90 days following a warfarin-associated GI bleed is associated with decreased risk of thrombosis and death without increased risk for recurrent GI bleed.

Citation: Witt DM, Delate T, Garcia DA, et al. Risk of thromboembolism, recurrent hemorrhage, and death after warfarin therapy interruption for gastrointestinal tract bleeding. Arch Intern Med. 2012 Sep 12. doi:10.1001/archinternmed.2012.4261.

Preoperative Hyponatremia Associated with Increased Risk for Perioperative Complications and Mortality

Clinical question: Is preoperative hyponatremia an indicator of perioperative morbidity and mortality?

Background: Hyponatremia is a common diagnosis in the hospital setting and is associated with adverse outcomes, even in mild cases. However, it is unclear if this association exists in surgical patients when detected preoperatively.

Study design: Retrospective cohort study.

Setting: Academic and community hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP).

Synopsis: A total of 75,423 adult patients with hyponatremia (sodium <135 mEq/L) who were undergoing major surgery were compared to 888,840 patients with normal preoperative sodium levels over a six-year period. The primary outcome was 30-day mortality. Secondary outcomes included postoperative major coronary events, stroke, wound infection, pneumonia, and length of stay (LOS).

Compared to patients with normal sodium levels, those with preoperative hyponatremia had higher rates of perioperative mortality (5.2% vs. 1.3%; adjusted odds ratio 1.44, 95% CI 1.38-1.50), with increased risk that correlated with increasing severity of hyponatremia. Association with postoperative mortality was particularly strong among hyponatremic patients with ASA scores of 1 or 2 and those undergoing nonemergency surgery.

Patients with preoperative hyponatremia were also found to have increased risk for all postoperative complications evaluated, with the exception of stroke. Limitations included the potential for unmeasured confounders and not being able to account for the role of medications used perioperatively. Research is needed to determine whether correcting preoperative hyponatremia lessens the risk of mortality and other postoperative complications.

Bottom line: Among patients undergoing major surgery, preoperative hyponatremia is a predictor of postoperative 30-day mortality and morbidity.

Citation: Leung AA, McAlister FA, Rogers SO, et al. Preoperative hyponatremia and perioperative complications. Arch Intern Med. 2012;172:1-8.

In This Edition

Literature At A Glance

A guide to this month’s studies

1. Interventions that improve discharge handovers reviewed
2. Duration of in-hospital cardiac resuscitation and survival rates
3. Early sepsis intervention strategies to decrease mortality risk
4. Hypoglycemia linked to increased mortality in critically ill
5. Increased bleeding risk for cardiac patients
6. Hospital-run vs. anesthesiologist-run preoperative clinics
7. Postoperative delirium and cognitive impairment in cardiac patients
8. Benefits of resuming anticoagulants after GI bleeding
9. Preoperative hyponatremia and risk of perioperative mortality

Systematic Review Highlights Several Interventions That Improve Discharge Handovers

Clinical question: Do interventions to improve patient handovers at discharge have positive effects on patient care?

Background: The transition from hospital to primary care is often suboptimal and has been associated with unfavorable outcomes, including hospital readmission, increased healthcare utilization, and adverse drug events post-discharge. This review sought to characterize different types of interventions aimed at improving discharge handovers and to evaluate their effects.

Study design: Systematic review of randomized controlled trials.

Setting: Studies published from January 1990 to March 2011.

Synopsis: Review of published databases identified 36 randomized controlled studies on interventions to improve discharge handovers. Studies were blindly evaluated by two reviewers on quality, interventions, and outcomes. There was significant heterogeneity in interventions and outcomes; thus, statistical analysis was not possible. Most studies evaluated multicomponent interventions and had more than one outcome measure.

Of the 36 studies reviewed, 25 reported statistically significant improvements in outcomes, including reduced hospital utilization and improved continuity of care. Effective interventions included medication reconciliation; structured discharge information (facilitated by electronic resources); multidisciplinary discharge planning; shared involvement in arranging care between inpatient and outpatient physicians; and Web-based access to discharge information by the outpatient provider.

The complexity of the interventions and the heterogeneity of reported results did not allow for firm conclusions to be drawn regarding which specific interventions had the strongest effects.

Bottom line: Interventions that target the quality and safety of handovers between hospital and outpatient providers at discharge can significantly reduce hospital utilization and improve continuity of care.

Citation: Hesselink G, Schoonhoven L, Barach P, et al. Improving patient handovers from hospital to primary care: a systematic review. Ann Intern Med. 2012;157:417-428.

Longer Duration of In-Hospital Cardiac Resuscitation Associated with Increased Survival

Clinical question: Are prolonged cardiac resuscitation efforts associated with improved outcomes?

Background: There is little evidence or guidelines on how long to maintain resuscitative efforts during in-hospital cardiac arrest, leading to variation in practice. This study characterized patterns of resuscitation duration and relationship to the return of spontaneous circulation and survival to discharge.

Study design: Retrospective observational study.

Setting: Four hundred thirty-five U.S. hospitals reporting data to the American Heart Association’s Get With The Guidelines: Resuscitation registry.

Synopsis: Using duration of resuscitation in nonsurvivors as a surrogate for the tendency of a facility to perform prolonged efforts, hospitals were divided into quartiles. Overall, of 64,339 patients in the registry, 31,198 (48.5%) had return of circulation and 9,912 (15.4%) survived to discharge. Resuscitative efforts in nonsurvivors ranged from a median of 16 to 25 minutes between the lowest and highest quartiles.

There was a stepwise increase in the likelihood for patients to have return of spontaneous circulation and to survive to discharge between each quartile. Specifically, comparing shortest to longest, there was a significant adjusted odds ratio of 1.12 for both the return of circulation (P<0.0001) and survival to discharge (P=0.021). The survival benefit was most apparent for those with pulseless electrical activity or asystole as initial rhythms, as compared to ventricular tachycardia or fibrillation.

Limitations included the study’s observational design, which meant causality could not be determined. Additionally, the study did not account for the quality of resuscitative efforts (e.g. depth of chest compressions, adherence with guidelines), which might have influenced outcomes. Importantly, the study looked at survival to discharge, but it did not evaluate long-term survival or functional status post-discharge, which might better reflect the success of resuscitation.

Bottom line: Prolonged resuscitative efforts were observed to be associated with increased likelihood of return of spontaneous circulation and survival to discharge; this data might provide clinical guidance in determining when to stop resuscitation efforts.

Citation: Goldberger ZD, Chan PS, Berg RA, et al. Duration of resuscitation efforts and survival after in-hospital cardiac arrest: an observational study. Lancet. 2012;380:1473-1481.

Early Sepsis Intervention Strategies Decrease Mortality, Length of Stay, and Cost

Clinical question: For patients with sepsis or septic shock, what is the impact of a real-time comprehensive continuous quality-improvement (QI) initiative on in-hospital mortality, morbidity, and healthcare resource utilization in community and tertiary-care hospitals in the U.S.?

Background: Multiple single-center trials have demonstrated that early sepsis intervention strategies (early goal-directed therapy, resuscitation bundles) improve in-hospital mortality. Little is known about the effectiveness of incorporating these strategies into a real-time continuous QI initiative and implementing interventions across multiple sites simultaneously.

Study design: Pre-post at some sites and concurrent implementation design at other sites.

Setting: Five community and six-tertiary care U.S. hospitals.

Synopsis: The GENeralized Early Sepsis Intervention Strategies (GENESIS) project was a CQI initiative that combined several QI concepts with validated early sepsis interventions known as resuscitation bundles (RB). Continuous QI was implemented on patients with severe sepsis or septic shock in both before and after designs (eight hospitals), and in concurrent designs (three hospitals). The control group was comprised of historical controls treated before GENESIS and patients with incomplete implementation of RB, totaling 1,554 patients. The treatment group included patients treated after GENESIS and those with complete RB compliance, totaling 4,801 patients.

Compared with the control group, patients in the treatment group had a 33% decreased risk of in-hospital mortality (RR 0.67, 95% CI 0.63-0.72), an absolute decrease in hospital length of stay (LOS) by 5.1 days (20.7 days vs. 15.6 days, P<0.001) and a $47,923 reduction in total hospital charges (P<0.001). Limitations included the study design (not a prospective randomized trial), and the possibility of other concurrent unmeasured quality initiatives taking place at the study sites, which might have contributed to improved outcomes.

Bottom line: Early sepsis intervention strategies in the form of a comprehensive continuous QI initiative can decrease mortality, hospital LOS, and cost in both tertiary-care and community hospitals.

Citation: Cannon CM, Holthaus CV, Zubrow MT, et al. The GENESIS project (GENeralized Early Sepsis Intervention Strategies): a multicenter quality improvement collaborative. J Intensive Care Med. 2012; Aug 17. doi:10.1177/0885066612453025.

Hypoglycemia Associated with Increased Mortality in the Critically Ill

Clinical question: Is hypoglycemia associated with mortality in critically ill patients?

Background: Initial studies suggested that intensive glucose control reduces mortality in surgical ICU patients and reduces morbidity in medical ICU patients, but further studies have not supported these findings. Recent literature shows conflicting results on the effects of intense glucose control in critically ill patients.

Study design: Post-hoc analysis of the NICE-SUGAR study database.

Setting: ICUs in 42 hospitals in Australia, New Zealand, and Canada.

Synopsis: The NICE-SUGAR study was a multicenter trial that randomized 6,104 ICU patients to intensive (glucose 80 to 108 mg/dL) or conventional glucose control (≤180 mg/dL). Patients were followed for 90 days or until death, with death being the primary end point. Severe hypoglycemia (<40 mg/dL) was recorded in 6.8% of patients in the intensive glucose control group versus 0.5% in the conventional group. The study showed that intensive glucose control was associated with increased mortality among adult ICU patients.

Using the NICE-SUGAR database, the authors conducted a Cox regression analysis to examine the associations between hypoglycemia and death. A total of 2,714 patients had moderate hypoglycemia (glucose 41 to 70 mg/dL), and 223 patients had severe hypoglycemia. The hazard ratio for mortality was 1.41 (95% CI 1.21-1.62, P<0.001) for patients with moderate hypoglycemia and 2.10 (95% CI 1.59-2.77, P<0.001) for severe hypoglycemia, compared to patients without hypoglycemia.

These findings show a strong association between mortality and hypoglycemia but do not prove causality. Hospitalists caring for ICU patients must be aware that hypoglycemia is associated with mortality and focus on avoiding hypoglycemia. The American Diabetes Association currently recommends a target blood glucose level of 140 to 180 mg/dL for most critically ill patients.

Bottom line: Hypoglycemia (glucose <70 mg/dL) is associated with increased risk of mortality in ICU patients.

Citation: Finfer S, Chittock DR, Su SY, et al. Hypoglycemia and risk of death in critically ill patients. New Engl J Med. 2012;367(12):1108-1118.

Increased Bleeding Risk for Cardiac Patients on Multiple Antithrombotic Drugs

Clinical question: Is there an increased risk of bleeding in atrial fibrillation patients treated with multiple antithrombotic agents following acute myocardial infarction (MI) or percutaneous coronary intervention (PCI)?

Background: Current treatment for atrial fibrillation patients with MI or PCI includes vitamin K antagonist (VKA) therapy to prevent stroke and antiplatelet agents to prevent further coronary events. There are inconsistent findings on the safety and efficacy of combined therapy with VKA, aspirin, and clopidogrel, specifically with regard to bleeding risk.

Study design: Retrospective cohort study.

Setting: Nationwide registry in Denmark.

Synopsis: Using the National Patient Registry in Denmark, 11,480 patients with atrial fibrillation who were admitted for MI or PCI were identified. Patients were grouped by medication regimen, including monotherapy (aspirin, clopidogrel, or VKA), dual therapy (dual antiplatelet or VKA+antiplatelet), or triple therapy (VKA+aspirin+clopidogrel). The primary outcome was nonfatal or fatal bleeding within one year.

Patients receiving triple therapy had the highest rate of bleeding, with a crude incidence of 14.2 events per 100 person-years. Patients treated with VKA+aspirin+clopidogel were significantly more likely than those on VKA+antiplatelet (HR 1.47, 95% CI 1.04-2.08) or dual antiplatelet (HR 2.20, 95% CI 1.58-3.08) treatment to have a bleeding event within 90 days, and similar trends were seen at 90 to 360 days. There was no significant difference in thromboembolic events among patients on VKA+aspirin+clopidogrel versus VKA+antiplatelet therapy.

Only bleeding events that required hospitalization were recorded, which might underestimate the bleeding risks of these regimens. Additionally, INR levels were not determined, which could impact both bleeding and thromboembolic outcomes.

However, this study does suggest that there are significant bleeding risks among patients treated with triple therapy. Hospitalists should weigh the risks of thromboembolic events with bleeding risks in patients with atrial fibrillation and MI/PCI, and only prescribe VKA+aspirin+clopidogrel with these risks in mind.

Bottom line: Immediate and continued bleeding risk is increased in patients with atrial fibrillation admitted with PCI or MI who are placed on triple antithrombotic therapy with VKA+aspirin+clopidogrel.

Citation: Lamberts M, Olesen JB, Ruwald MH, et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention. Circulation. 2012;126:1185-1193.

Hospitalist-Run Preoperative Clinic Improves Outcomes in Complex Surgical Patients

Clinical question: Do hospitalist-run preoperative clinics improve outcomes for medically complex patients undergoing noncardiac surgery compared to traditional anesthesiologist-run preoperative clinics?

Background: Studies of perioperative medical consultation have shown inconsistent effects on quality of care, but preoperative medical consultation has only been evaluated in the immediate preoperative period (one day prior to surgery or less). Little is known about the impact of involving hospitalists earlier in the preoperative period.

Study design: Retrospective, pre-post study.

Setting: Veterans Affairs Greater Los Angeles Healthcare System (VAGLAHS).

Synopsis: In July 2004, the VAGLAHS Preoperative Clinic transitioned from being anesthesiologist-run to hospitalist-run. Mid-level providers were trained on preoperative medical assessment, and patients were only evaluated by anesthesia staff on the day of surgery, after they had been deemed medically acceptable for surgery. All patients seen in the clinic from July 2003 to July 2005 were included in the study. Period A included patients evaluated when anesthesia staff supervised the clinic. Period B included patients evaluated during the first year of the hospitalist-run system.

There were 1,101 patients with inpatient surgeries in Period A, and 1,126 patients in Period B. Mean length of stay (LOS) decreased to 5.28 days during the hospitalist-run model from 9.87 days during the anesthesiologist-run model. LOS reductions were most notable in patients with ASA scores of 3 or higher; LOS reductions were not seen in an internal control of surgical patients who were not evaluated in the preoperative clinic. Inpatient mortality was also reduced in Period B compared with Period A, to 4 cases (0.36%) from 14 cases (1.27%) (P=0.0158). Specific processes that led to improved outcomes for patients in Period B could not be identified. The VA study setting might limit the generalizability of the results.

Bottom line: A hospitalist-run preoperative clinic was associated with decreased LOS and inpatient mortality compared with a traditional anesthesiologist-run clinic.

Citation: Vazirani S, Lankarani-Fard A, Lian LJ, Stelzner M, Asch SM. Preoperative processes and outcomes after implementation of a hospitalist-run preoperative clinic. J Hosp Med. 2012 Sep 7. doi:10.1002/jhm.1968.

Delirium after Cardiac Surgery Associated with Prolonged Cognitive Impairment

Clinical question: Is postoperative delirium associated with decreased cognitive function in the first year after cardiac surgery?

Background: In general populations, delirium has been associated with long-term decline in cognitive ability. Delirium and cognitive dysfunction are both common following cardiac surgery, but the effects of postoperative delirium on the trajectory of cognitive function over time is unclear.

Study design: Prospective cohort study.

Setting: Two academic medical centers and a Veterans Administration hospital.

Synopsis: Two hundred twenty-five patients aged 60 or older who were scheduled to undergo coronary artery bypass grafting or valve replacement surgery were included. Patients underwent preoperative assessment cognitive function with the use of the Mini-Mental State Examination (MMSE). Starting on postoperative Day 2, patients underwent daily assessment for delirium. After discharge, cognitive function was reassessed at months one, six, and 12.

Postoperative delirium occurred in 103 patients (46%). Patients with delirium were older, had higher comorbidity scores, and had lower MMSE scores at baseline. Among the overall study population, adjusted MMSE scores dropped 4.6 points from baseline to postoperative Day 2, then were observed to increase by approximately one point per day during postoperative days 3 to 5 with minimal change thereafter. Patients with delirium had greater decrease in cognitive function in the immediate postoperative period compared to patients without delirium (7.7 points vs. 2.1, P<0.001).

Patients without delirium returned to their baseline cognitive ability by one month postoperatively, while patients who had delirium were still making gains up to six months post-operatively, never returning to baseline level of function by one year. Unmeasured confounders and uncertain sensitivity of the MMSE to detect mild cognitive impairment might limit these findings.

Bottom line: Cognitive function decreases in the immediate postoperative period following cardiac surgery. Compared to patients without delirium, patients with delirium experience more dramatic and prolonged cognitive impairment postoperatively, without returning to their preoperative level of cognitive function at one year.

Citation: Saczynski JS, Marcantonio ER, Quach L, et al. Cognitive trajectories after postoperative delirium. New Engl J Med. 2012;367:30-39.

Benefits of Resuming Anticoagulation after GI Bleed Outweigh Risks for Most Patients

Clinical question: In warfarin-treated patients who have experienced gastrointestinal (GI) bleeding, what are the patterns of restarting warfarin therapy and the incidence of thrombosis, recurrent GI bleed, and death in the 90 days following index bleed?

Background: In warfarin-treated patients who experience GI bleeding, warfarin is often temporarily held or permanently discontinued, placing patients at increased risk for developing thromboembolism. Little is known about the risks, benefits, and timing of restarting warfarin in this patient population.

Study design: Retrospective cohort study.

Setting: Kaiser Permanente Colorado.

Synopsis: Using clinical and administrative databases, 442 patients who presented with GI bleeding while receiving warfarin therapy were identified. Patients were grouped by whether they resumed warfarin (n=260, including 41 patients in whom anticoagulation was never interrupted), or did not resume warfarin therapy (n=182) in the 90 days following index GI bleed. Patients with prosthetic heart valves or GI bleeding localized to the rectum/anus were more commonly restarted on warfarin, whereas older patients and those in whom the source of bleeding was not identified were less likely to be restarted on warfarin therapy.

Restarting warfarin therapy after index GI bleed was associated with lower risk of thrombosis (HR 0.05, 95% CI 0.01-0.58) and death from any cause (HR 0.31, 95% CI 0.15-0.62), and it was not associated with a significant increase in risk for recurrent GI bleed (HR 1.32, 95% CI 0.50-3.57).

The authors concluded that for many patients who experience a warfarin-associated GI bleed, the benefits of restarting warfarin therapy outweigh the risks. No conclusions were made regarding the optimal timing of resuming therapy. Limitations included the use of administrative data and inability to determine the potential influence of aspirin use on outcomes.

Bottom line: Resuming warfarin in the 90 days following a warfarin-associated GI bleed is associated with decreased risk of thrombosis and death without increased risk for recurrent GI bleed.

Citation: Witt DM, Delate T, Garcia DA, et al. Risk of thromboembolism, recurrent hemorrhage, and death after warfarin therapy interruption for gastrointestinal tract bleeding. Arch Intern Med. 2012 Sep 12. doi:10.1001/archinternmed.2012.4261.

Preoperative Hyponatremia Associated with Increased Risk for Perioperative Complications and Mortality

Clinical question: Is preoperative hyponatremia an indicator of perioperative morbidity and mortality?

Background: Hyponatremia is a common diagnosis in the hospital setting and is associated with adverse outcomes, even in mild cases. However, it is unclear if this association exists in surgical patients when detected preoperatively.

Study design: Retrospective cohort study.

Setting: Academic and community hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP).

Synopsis: A total of 75,423 adult patients with hyponatremia (sodium <135 mEq/L) who were undergoing major surgery were compared to 888,840 patients with normal preoperative sodium levels over a six-year period. The primary outcome was 30-day mortality. Secondary outcomes included postoperative major coronary events, stroke, wound infection, pneumonia, and length of stay (LOS).

Compared to patients with normal sodium levels, those with preoperative hyponatremia had higher rates of perioperative mortality (5.2% vs. 1.3%; adjusted odds ratio 1.44, 95% CI 1.38-1.50), with increased risk that correlated with increasing severity of hyponatremia. Association with postoperative mortality was particularly strong among hyponatremic patients with ASA scores of 1 or 2 and those undergoing nonemergency surgery.

Patients with preoperative hyponatremia were also found to have increased risk for all postoperative complications evaluated, with the exception of stroke. Limitations included the potential for unmeasured confounders and not being able to account for the role of medications used perioperatively. Research is needed to determine whether correcting preoperative hyponatremia lessens the risk of mortality and other postoperative complications.

Bottom line: Among patients undergoing major surgery, preoperative hyponatremia is a predictor of postoperative 30-day mortality and morbidity.

Citation: Leung AA, McAlister FA, Rogers SO, et al. Preoperative hyponatremia and perioperative complications. Arch Intern Med. 2012;172:1-8.

In This Edition

Literature At A Glance

A guide to this month’s studies

1. Burnout among physicians and the general workforce
2. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke
3. Performance of the HEMORR2AGES, ATRIA, and HAS-BLED bleeding risk prediction scores in patients with atrial fibrillation undergoing anticoagulation
4. Probiotics for secondary prevention of hepatic encephalopathy
5. Capsule endoscopy for acute obscure GI bleeding
6. Perceptions of readmitted patients transitioning from hospital to home
7. Thirty-day readmissions after acute myocardial infarction
8. One-hour rule-out or rule-in for AMI patients in chest pain
9. Aspirin increases bleed risk without reducing risk of stroke in CKD and NVAF patients

Burnout among Physicians and the General Workforce

Clinical question: What is the degree and distribution of burnout within the physician workforce, and how does that compare to the general U.S. workforce?

Background: Professional burnout, work satisfaction, and work-life balance are critical elements to understand in the physician workforce. It is well documented that physicians are at high risk for burnout; however, few extensive studies have looked at rates and the identification of high-risk subpopulations.

Study design: Cross-sectional survey.

Setting: U.S. workforce.

Synopsis: This study included 7,288 physicians (26.7% response rate) and 5,930 controls from the general U.S. population. Validated survey instruments were employed to assess the degree and presence of burnout, depression, and satisfaction with work-life balance.

In aggregate, using a validated, two-item burnout measure, 35.2% of physicians were characterized as having burnout, compared with 27.6% of the general population (P<0.001). Within the physician community, the specialties with the highest risk of burnout included emergency medicine, general internal medicine, family medicine, and neurology.

Important limitations of this study include that the physician and general population surveys were performed at different times (six months apart), that the groups were not ideally matched (age and sex, for example), and the overall response rate of the physician survey was low.

This study sheds light on an important topic for hospitalists. Future studies should continue to probe the problem of burnout and look for creative solutions to mitigate risks that might threaten professional longevity.

Bottom line: Burnout is prevalent among physicians, especially when compared to the general workforce. Physician specialties in front-line patient care are at highest risk.

Citation: Shanafelt TD, Boone S, Tan L, et al. Burnout and satisfaction with work-life balance among US physicians relative to the general US population. Arch Intern Med. 2012;20 [Epub ahead of print].

Effects of Clopidogrel Added to Aspirin in Patients with Recent Lacunar Stroke

Clinical question: Does the addition of clopidogrel to aspirin reduce the risk of any type of recurrent stroke, or affect the risk of bleeding or death, in patients who recently suffered a lacunar stroke?

Background: There are no prior randomized, multicenter trials on secondary prevention of lacunar stroke; aspirin is the standard antiplatelet therapy in this setting.

Study design: Double-blind, randomized, multicenter trial.

Setting: Eighty-two clinical centers in North America, Latin America, and Spain.

Synopsis: Researchers enrolled 3,020 patients from 2003 to 2011; criteria included age >30 years old and symptomatic lacunar stroke (proven by MRI) in the preceding 180 days.

Results showed no significant difference between recurrent strokes (any type) in the aspirin-only group (2.7% per year) versus the aspirin-plus-clopidogrel group (2.5% per year). Major hemorrhage risk was much higher in the aspirin-plus-clopidogrel group (2.1% per year) versus aspirin-only group (1.1% per year). All-cause mortality also was much higher in the aspirin-plus-clopidogrel group (N=113) versus the aspirin-only group (N=77).

Bottom line: The addition of clopidogrel to aspirin for secondary prevention does not significantly reduce the risk of recurrent stroke, but it does significantly increase the risk of bleeding and death.

Citation: Benavente OR, Hart RG, McClure LA, et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012;367:817-825.

Bleeding Risk Prediction Scores in Patients with Atrial Fibrillation Undergoing Anticoagulation

Clinical question: What are the relative predictive values of the HEMORR2AGES, ATRIA, and HAS-BLED risk-prediction schemes?

Background: The tools predict bleeding risk in patients anticoagulated for atrial fibrillation (afib), but it is unknown which is the best to predict clinically relevant bleeding.

Study design: Post-hoc analysis.

Setting: Data previously collected for the AMADEUS trial (2,293 patients taking warfarin; 251 had at least one clinically relevant bleeding event) were used to test each of the three bleeding risk-prediction schemes on the same data set.

Synopsis: Using three analysis methods (net reclassification improvement, receiver-operating characteristic [ROC], and decision-curve analysis), the researchers compared the three schemes’ performance. HAS-BLED performed best in all three of the analysis methods.

The HAS-BLED score calculation requires the following patient information: history of hypertension, renal disease, liver disease, stroke, prior major bleeding event, and labile INR; age >65; and use of antiplatelet agents, aspirin, and alcohol.

Bottom line: HAS-BLED was the best of the three schemes, although all three had only modest ability to predict clinically relevant bleeding.

Citation: Apostolakis S, Lane DA, Guo Y, et al. Performance of the HEMORRAGES, ATRIA and HAS-BLED bleeding risk-prediction scores in patients with atrial fibrillation undergoing anticoagulation. J Am Coll Cardiol. 2012;60(9):861-867

Probiotics for Secondary Prevention of Hepatic Encephalopathy

Clinical question: Are probiotics as effective as lactulose for secondary prevention of hepatic encephalopathy (HE)?

Background: Probiotics alter the gut flora, resulting in decreased ammonia production and absorption. Probiotics have been shown to reduce the incidence of low-grade HE. However, studies on probiotics usage for secondary prevention of HE are lacking.

Study design: Prospective, randomized, controlled, nonblinded, single-center study.

Setting: Tertiary-care center, New Delhi.

Synopsis: Three hundred sixty patients who had recovered from HE from October 2008 to December 2009 were screened; 235 met the inclusion criteria. They were randomized to receive either lactulose (Gp-L), probiotics (Gp-P), or no therapy (Gp-N). The Gp-L group received 30 to 60 ml of lactulose in two to three divided doses; the Gp-P group received three capsules per day containing lactobacillus, bifidobacterium, and Streptococcus salivarius strains.

The primary endpoints were the development of overt HE (assessed by the West Haven Criteria) or a follow-up of 12 months. Lactulose therapy was significantly more effective in secondary prophylaxis than no therapy (26.2% vs. 56.9%, P=0.001), as was probiotics therapy compared with no therapy (34.4% vs. 56.9%, P=0.02), but no significant difference was found between lactulose and probiotics therapy (26.2% vs. 34.4%, P=0.349).

The major limitation of the study was its open-label design. The study also used a high concentration of probiotics, and the results could be strain-specific and hence require validation with other probiotics combinations. The Gp-N group continued the previous therapy (excluding lactulose), with an unknown number on rifaximin.

Bottom line: Lactulose and probiotics are equally effective in secondary prophylaxis of hepatic encephalopathy.

Citation: Agrawal A, Sharma BC, Sharma P, Sarin SK. Secondary prophylaxis of hepatic encephalopathy in cirrhosis: an open-label, randomized controlled trial of lactulose, probiotics and no therapy. Am J Gastroenterol. 2012;107:1043-1050.

Capsule Endoscopy for Acute Obscure GI Bleeding

Clinical question: What testing modality is most appropriate for acute obscure GI bleeding: capsule endoscopy (CE) or angiography?

Background: Acute obscure GI bleeding (OGIB): remains a diagnostic challenge, accounting for 7% to 8% of patients presenting with GI bleeding. CE enables direct visualization of small bowel mucosa but lacks the ability for therapeutic intervention. Angiography is frequently chosen for massive bleeding; however, it is invasive and does not enable visualization of the bowel.

Study design: Prospective, randomized, controlled, blinded, single-center study.

Setting: Prince of Wales Hospital, Hong Kong.

Synopsis: Ninety-one patients with active OGIB from June 2005 to November 2007 were assessed for eligibility; 60 met the criteria and were randomized to either CE or angiography. Overt OGIB was defined as patients who had nondiagnostic upper endoscopy and colonoscopy.

The primary outcome was diagnostic yield of CE or mesenteric angiography in identifying the bleeding source. Secondary outcomes were long-term rebleeding rates, readmissions for bleeding or anemia, blood transfusions, and death.

CE was positive in 16 patients (53.3%) and angiography was positive in six patients (20%). The diagnostic yield of CE was significantly higher than angiography (difference=33.3%, 95% CI 8.9-52.8%, P=0.016). The mean follow-up period was 48.5 months. The cumulative risk of rebleeding was higher in the angiography group, but this was not statistically significant. There was no significant difference in rates of subsequent hospitalization, death, or transfusions between the two groups.

The study based the sample-size estimation on the diagnostic yield rather than clinical outcomes and, hence, was underpowered to detect any significant differences in clinical outcomes.

Bottom line: CE has a higher diagnostic yield than angiography in patients with active overt OGIB.

Citation: Leung WK, Ho S, Suen B, et al. Capsule endoscopy of angiography in patients with acute overt gastrointestinal bleeding: a prospective randomized study with long term follow up. Am J Gastroenterol. 2012;107:1370-1376.

Perceptions of Readmitted Patients Transitioning from Hospital to Home

Clinical question: What are patient-reported reasons for readmission to the hospital after discharge?

Background: Reducing readmissions is a critical component to improving the value of healthcare. While readmission reduction is a goal of all hospitals, there is much to be gleaned from evaluating patients’ view of the problem. This study used a survey to assess the patient’s viewpoint.

Study design: Cross-sectional survey.

Setting: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center, Philadelphia.

Synopsis: A survey of 36 questions was posed to 1,084 patients who were readmitted within 30 days of discharge from November 2010 to July 2011 (32% of eligible patients). The data were subdivided based on socioeconomic status and medical versus surgical patients.

Some issues patients raised regarding discharge planning included difficulty with paying for medications, challenges with travel to pharmacies, and concern over medication side effects.

Patients with low socioeconomic status had more difficulty taking medications and following instructions, had more depression, and had less social support.

Bottom line: Readmission rates are affected by a patient’s social situation. A team approach to discharge planning might mitigate some of these factors.

Citation: Kangovi S, Grande D, Meehan P, Mitra N, Shannon R, Long JA. Perceptions of readmitted patients on the transition from hospital to home. J Hosp Med. 2012 [Epub ahead of print].

30-Day Readmissions after Acute Myocardial Infarction

Clinical question: What are potential predictors of 30-day readmissions after acute myocardial infarction (MI)?

Background: Much attention has been given to evaluate the causes of readmissions of heart failure, acute MI, and pneumonia. This study looked at 30-day readmissions after an acute myocardial infarction (AMI).

Study design: Retrospective cohort study.

Setting: Olmstead County Hospital, Rochester, Minn.

Synopsis: A chart review of AMI based on ICD-9 codes from 1987 to 2010 identified 3,010 patients. Patients were verified using symptoms, cardiac enzymes, and EKG changes at the time of event. Interventions evaluated included fibrinolytic therapy, CABG, or primary PCI.

Survival increased to 96% from 89% during the period from 1987 to 2010. Researchers also noted more comorbid conditions, such as diabetes mellitus, COPD, and hypertension, noted over time. Of the patients evaluated, 643 readmissions occurred for 561 patients (18.6%). Of these, the most frequent causes were ischemic heart disease, respiratory symptoms, and heart failure. Comorbid conditions, such as diabetes, COPD, anemia, higher killip class on initial admission, duration of prior hospitalization, and procedural complications, independently increased the risk of readmission.

Bottom line: In addition to factors unrelated to an AMI, a patient’s comorbid conditions, post-procedure complications, and duration of hospitalization influence the risk of readmission.

Citation: Dunlay SM, Weston SA, Killian JM, et al. Thirty-day rehospitalizations after acute myocardial infarction: a cohort study. Ann Intern Med. 2012;157(1):11-18.

One-Hour Rule-Out or Rule-In for AMI in Chest Pain

Clinical question: How can we use the newly developed high-sensitivity cardiac troponin (hs-cTnT) to shorten the time to rule in and rule out AMI?

Background: The hs-cTnT assays available appear to improve the early diagnosis of AMI when compared to the regular cardiac troponins, but no clear guidelines are available as how to best use them in clinical practice.

Study design: Prospective, multicenter study.

Setting: Switzerland hospitals.

Synopsis: The study enrolled 872 unselected patients presenting to the ED with acute chest pain. Hs-cTnT level was measured in a blinded fashion at presentation and after one hour. Two independent cardiologists using all available medical records adjudicated the final AMI diagnosis. Optimal thresholds for rule-out were selected to allow for 100% sensitivity and negative predictive value. Rule-out criteria were defined as baseline hs-cTnT level <12 ng/L and an absolute change within the first hour of <3 ng/L. Rule-in criteria was defined as baseline hs-cTnT >52 ng/L or an absolute increase within the first hour of >5 ng/L.

AMI was the final diagnosis in 17% of patients; AMI was ruled out in 60%; and the remaining 23% were placed in observation.

Primary prognostic endpoint was 30-day mortality rate, which was 0.2% in the rule-out group, validating the suitability of these patients for early discharge.

Study limitations were that it was an observational study not used for clinical decision-making, no dialysis patients were included, and only one specific hs-cTnT assay was tested.

Bottom line: Using hs-cTnT levels at presentation and absolute changes within the first hour, a safe rule-out or rule-in of AMI can be performed in 77% of patients presenting with chest pain.

Citation: Reichlin T, Schindler C, Drexler B, et al. One-hour rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin T. Arch Intern Med. 2012;172(16):1-8.

Aspirin Increases Bleed Risk without Reducing Risk of Stroke in CKD and NVAF Patients

Clinical question: Is there a difference between aspirin and warfarin in preventing thromboembolic complications and risk of bleeding in patients with chronic kidney disease (CKD) and nonvalvular afib (NVAF)?

Background: Data are lacking on risks and benefits of aspirin and warfarin in CKD, as this group of patients largely has been excluded from anticoagulation therapy trials for NVAF. This study examined the risks and benefits of aspirin and warfarin in patients with CKD with NVAF.

Study design: Retrospective, observational cohort study.

Setting: Danish National Registries.

Synopsis: Of 132,372 patients with NVAF, 2.7% had CKD and 0.7% had end-stage renal disease (ESRD). Compared to patients with no CKD, there was increased risk of stroke or systemic thromboembolism in patients with ESRD (HR, 1.83; 95% CI, 1.57-2.14) and with non-end-stage CKD (HR 1.49; 95% CI 1.38-1.59).

In patients with CKD, warfarin significantly reduced stroke risk (HR, 0.76; 95% CI, 0.64-0.91) and significantly increased bleeding risk (HR, 1.33; 95% CI, 1.16-1.53); aspirin significantly increased bleeding risk (HR, 1.17; 95% CI, 1.02-1.34) with no reduction in stroke risk.

Bottom line: CKD was associated with an increased risk of stroke among NVAF patients. While both aspirin and warfarin were associated with increased risk of bleeding, there was a reduction in the risk of stroke with warfarin, but not with aspirin.

Citation: Olesen JB, Lip GY, Kamper AL, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med. 2012;367(7):625-635.

In This Edition

Literature At A Glance

A guide to this month’s studies

1. Burnout among physicians and the general workforce
2. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke
3. Performance of the HEMORR2AGES, ATRIA, and HAS-BLED bleeding risk prediction scores in patients with atrial fibrillation undergoing anticoagulation
4. Probiotics for secondary prevention of hepatic encephalopathy
5. Capsule endoscopy for acute obscure GI bleeding
6. Perceptions of readmitted patients transitioning from hospital to home
7. Thirty-day readmissions after acute myocardial infarction
8. One-hour rule-out or rule-in for AMI patients in chest pain
9. Aspirin increases bleed risk without reducing risk of stroke in CKD and NVAF patients

Burnout among Physicians and the General Workforce

Clinical question: What is the degree and distribution of burnout within the physician workforce, and how does that compare to the general U.S. workforce?

Background: Professional burnout, work satisfaction, and work-life balance are critical elements to understand in the physician workforce. It is well documented that physicians are at high risk for burnout; however, few extensive studies have looked at rates and the identification of high-risk subpopulations.

Study design: Cross-sectional survey.

Setting: U.S. workforce.

Synopsis: This study included 7,288 physicians (26.7% response rate) and 5,930 controls from the general U.S. population. Validated survey instruments were employed to assess the degree and presence of burnout, depression, and satisfaction with work-life balance.

In aggregate, using a validated, two-item burnout measure, 35.2% of physicians were characterized as having burnout, compared with 27.6% of the general population (P<0.001). Within the physician community, the specialties with the highest risk of burnout included emergency medicine, general internal medicine, family medicine, and neurology.

Important limitations of this study include that the physician and general population surveys were performed at different times (six months apart), that the groups were not ideally matched (age and sex, for example), and the overall response rate of the physician survey was low.

This study sheds light on an important topic for hospitalists. Future studies should continue to probe the problem of burnout and look for creative solutions to mitigate risks that might threaten professional longevity.

Bottom line: Burnout is prevalent among physicians, especially when compared to the general workforce. Physician specialties in front-line patient care are at highest risk.

Citation: Shanafelt TD, Boone S, Tan L, et al. Burnout and satisfaction with work-life balance among US physicians relative to the general US population. Arch Intern Med. 2012;20 [Epub ahead of print].

Effects of Clopidogrel Added to Aspirin in Patients with Recent Lacunar Stroke

Clinical question: Does the addition of clopidogrel to aspirin reduce the risk of any type of recurrent stroke, or affect the risk of bleeding or death, in patients who recently suffered a lacunar stroke?

Background: There are no prior randomized, multicenter trials on secondary prevention of lacunar stroke; aspirin is the standard antiplatelet therapy in this setting.

Study design: Double-blind, randomized, multicenter trial.

Setting: Eighty-two clinical centers in North America, Latin America, and Spain.

Synopsis: Researchers enrolled 3,020 patients from 2003 to 2011; criteria included age >30 years old and symptomatic lacunar stroke (proven by MRI) in the preceding 180 days.

Results showed no significant difference between recurrent strokes (any type) in the aspirin-only group (2.7% per year) versus the aspirin-plus-clopidogrel group (2.5% per year). Major hemorrhage risk was much higher in the aspirin-plus-clopidogrel group (2.1% per year) versus aspirin-only group (1.1% per year). All-cause mortality also was much higher in the aspirin-plus-clopidogrel group (N=113) versus the aspirin-only group (N=77).

Bottom line: The addition of clopidogrel to aspirin for secondary prevention does not significantly reduce the risk of recurrent stroke, but it does significantly increase the risk of bleeding and death.

Citation: Benavente OR, Hart RG, McClure LA, et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012;367:817-825.

Bleeding Risk Prediction Scores in Patients with Atrial Fibrillation Undergoing Anticoagulation

Clinical question: What are the relative predictive values of the HEMORR2AGES, ATRIA, and HAS-BLED risk-prediction schemes?

Background: The tools predict bleeding risk in patients anticoagulated for atrial fibrillation (afib), but it is unknown which is the best to predict clinically relevant bleeding.

Study design: Post-hoc analysis.

Setting: Data previously collected for the AMADEUS trial (2,293 patients taking warfarin; 251 had at least one clinically relevant bleeding event) were used to test each of the three bleeding risk-prediction schemes on the same data set.

Synopsis: Using three analysis methods (net reclassification improvement, receiver-operating characteristic [ROC], and decision-curve analysis), the researchers compared the three schemes’ performance. HAS-BLED performed best in all three of the analysis methods.

The HAS-BLED score calculation requires the following patient information: history of hypertension, renal disease, liver disease, stroke, prior major bleeding event, and labile INR; age >65; and use of antiplatelet agents, aspirin, and alcohol.

Bottom line: HAS-BLED was the best of the three schemes, although all three had only modest ability to predict clinically relevant bleeding.

Citation: Apostolakis S, Lane DA, Guo Y, et al. Performance of the HEMORRAGES, ATRIA and HAS-BLED bleeding risk-prediction scores in patients with atrial fibrillation undergoing anticoagulation. J Am Coll Cardiol. 2012;60(9):861-867

Probiotics for Secondary Prevention of Hepatic Encephalopathy

Clinical question: Are probiotics as effective as lactulose for secondary prevention of hepatic encephalopathy (HE)?

Background: Probiotics alter the gut flora, resulting in decreased ammonia production and absorption. Probiotics have been shown to reduce the incidence of low-grade HE. However, studies on probiotics usage for secondary prevention of HE are lacking.

Study design: Prospective, randomized, controlled, nonblinded, single-center study.

Setting: Tertiary-care center, New Delhi.

Synopsis: Three hundred sixty patients who had recovered from HE from October 2008 to December 2009 were screened; 235 met the inclusion criteria. They were randomized to receive either lactulose (Gp-L), probiotics (Gp-P), or no therapy (Gp-N). The Gp-L group received 30 to 60 ml of lactulose in two to three divided doses; the Gp-P group received three capsules per day containing lactobacillus, bifidobacterium, and Streptococcus salivarius strains.

The primary endpoints were the development of overt HE (assessed by the West Haven Criteria) or a follow-up of 12 months. Lactulose therapy was significantly more effective in secondary prophylaxis than no therapy (26.2% vs. 56.9%, P=0.001), as was probiotics therapy compared with no therapy (34.4% vs. 56.9%, P=0.02), but no significant difference was found between lactulose and probiotics therapy (26.2% vs. 34.4%, P=0.349).

The major limitation of the study was its open-label design. The study also used a high concentration of probiotics, and the results could be strain-specific and hence require validation with other probiotics combinations. The Gp-N group continued the previous therapy (excluding lactulose), with an unknown number on rifaximin.

Bottom line: Lactulose and probiotics are equally effective in secondary prophylaxis of hepatic encephalopathy.

Citation: Agrawal A, Sharma BC, Sharma P, Sarin SK. Secondary prophylaxis of hepatic encephalopathy in cirrhosis: an open-label, randomized controlled trial of lactulose, probiotics and no therapy. Am J Gastroenterol. 2012;107:1043-1050.

Capsule Endoscopy for Acute Obscure GI Bleeding

Clinical question: What testing modality is most appropriate for acute obscure GI bleeding: capsule endoscopy (CE) or angiography?

Background: Acute obscure GI bleeding (OGIB): remains a diagnostic challenge, accounting for 7% to 8% of patients presenting with GI bleeding. CE enables direct visualization of small bowel mucosa but lacks the ability for therapeutic intervention. Angiography is frequently chosen for massive bleeding; however, it is invasive and does not enable visualization of the bowel.

Study design: Prospective, randomized, controlled, blinded, single-center study.

Setting: Prince of Wales Hospital, Hong Kong.

Synopsis: Ninety-one patients with active OGIB from June 2005 to November 2007 were assessed for eligibility; 60 met the criteria and were randomized to either CE or angiography. Overt OGIB was defined as patients who had nondiagnostic upper endoscopy and colonoscopy.

The primary outcome was diagnostic yield of CE or mesenteric angiography in identifying the bleeding source. Secondary outcomes were long-term rebleeding rates, readmissions for bleeding or anemia, blood transfusions, and death.

CE was positive in 16 patients (53.3%) and angiography was positive in six patients (20%). The diagnostic yield of CE was significantly higher than angiography (difference=33.3%, 95% CI 8.9-52.8%, P=0.016). The mean follow-up period was 48.5 months. The cumulative risk of rebleeding was higher in the angiography group, but this was not statistically significant. There was no significant difference in rates of subsequent hospitalization, death, or transfusions between the two groups.

The study based the sample-size estimation on the diagnostic yield rather than clinical outcomes and, hence, was underpowered to detect any significant differences in clinical outcomes.

Bottom line: CE has a higher diagnostic yield than angiography in patients with active overt OGIB.

Citation: Leung WK, Ho S, Suen B, et al. Capsule endoscopy of angiography in patients with acute overt gastrointestinal bleeding: a prospective randomized study with long term follow up. Am J Gastroenterol. 2012;107:1370-1376.

Perceptions of Readmitted Patients Transitioning from Hospital to Home

Clinical question: What are patient-reported reasons for readmission to the hospital after discharge?

Background: Reducing readmissions is a critical component to improving the value of healthcare. While readmission reduction is a goal of all hospitals, there is much to be gleaned from evaluating patients’ view of the problem. This study used a survey to assess the patient’s viewpoint.

Study design: Cross-sectional survey.

Setting: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center, Philadelphia.

Synopsis: A survey of 36 questions was posed to 1,084 patients who were readmitted within 30 days of discharge from November 2010 to July 2011 (32% of eligible patients). The data were subdivided based on socioeconomic status and medical versus surgical patients.

Some issues patients raised regarding discharge planning included difficulty with paying for medications, challenges with travel to pharmacies, and concern over medication side effects.

Patients with low socioeconomic status had more difficulty taking medications and following instructions, had more depression, and had less social support.

Bottom line: Readmission rates are affected by a patient’s social situation. A team approach to discharge planning might mitigate some of these factors.

Citation: Kangovi S, Grande D, Meehan P, Mitra N, Shannon R, Long JA. Perceptions of readmitted patients on the transition from hospital to home. J Hosp Med. 2012 [Epub ahead of print].

30-Day Readmissions after Acute Myocardial Infarction

Clinical question: What are potential predictors of 30-day readmissions after acute myocardial infarction (MI)?

Background: Much attention has been given to evaluate the causes of readmissions of heart failure, acute MI, and pneumonia. This study looked at 30-day readmissions after an acute myocardial infarction (AMI).

Study design: Retrospective cohort study.

Setting: Olmstead County Hospital, Rochester, Minn.

Synopsis: A chart review of AMI based on ICD-9 codes from 1987 to 2010 identified 3,010 patients. Patients were verified using symptoms, cardiac enzymes, and EKG changes at the time of event. Interventions evaluated included fibrinolytic therapy, CABG, or primary PCI.

Survival increased to 96% from 89% during the period from 1987 to 2010. Researchers also noted more comorbid conditions, such as diabetes mellitus, COPD, and hypertension, noted over time. Of the patients evaluated, 643 readmissions occurred for 561 patients (18.6%). Of these, the most frequent causes were ischemic heart disease, respiratory symptoms, and heart failure. Comorbid conditions, such as diabetes, COPD, anemia, higher killip class on initial admission, duration of prior hospitalization, and procedural complications, independently increased the risk of readmission.

Bottom line: In addition to factors unrelated to an AMI, a patient’s comorbid conditions, post-procedure complications, and duration of hospitalization influence the risk of readmission.

Citation: Dunlay SM, Weston SA, Killian JM, et al. Thirty-day rehospitalizations after acute myocardial infarction: a cohort study. Ann Intern Med. 2012;157(1):11-18.

One-Hour Rule-Out or Rule-In for AMI in Chest Pain

Clinical question: How can we use the newly developed high-sensitivity cardiac troponin (hs-cTnT) to shorten the time to rule in and rule out AMI?

Background: The hs-cTnT assays available appear to improve the early diagnosis of AMI when compared to the regular cardiac troponins, but no clear guidelines are available as how to best use them in clinical practice.

Study design: Prospective, multicenter study.

Setting: Switzerland hospitals.

Synopsis: The study enrolled 872 unselected patients presenting to the ED with acute chest pain. Hs-cTnT level was measured in a blinded fashion at presentation and after one hour. Two independent cardiologists using all available medical records adjudicated the final AMI diagnosis. Optimal thresholds for rule-out were selected to allow for 100% sensitivity and negative predictive value. Rule-out criteria were defined as baseline hs-cTnT level <12 ng/L and an absolute change within the first hour of <3 ng/L. Rule-in criteria was defined as baseline hs-cTnT >52 ng/L or an absolute increase within the first hour of >5 ng/L.

AMI was the final diagnosis in 17% of patients; AMI was ruled out in 60%; and the remaining 23% were placed in observation.

Primary prognostic endpoint was 30-day mortality rate, which was 0.2% in the rule-out group, validating the suitability of these patients for early discharge.

Study limitations were that it was an observational study not used for clinical decision-making, no dialysis patients were included, and only one specific hs-cTnT assay was tested.

Bottom line: Using hs-cTnT levels at presentation and absolute changes within the first hour, a safe rule-out or rule-in of AMI can be performed in 77% of patients presenting with chest pain.

Citation: Reichlin T, Schindler C, Drexler B, et al. One-hour rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin T. Arch Intern Med. 2012;172(16):1-8.

Aspirin Increases Bleed Risk without Reducing Risk of Stroke in CKD and NVAF Patients

Clinical question: Is there a difference between aspirin and warfarin in preventing thromboembolic complications and risk of bleeding in patients with chronic kidney disease (CKD) and nonvalvular afib (NVAF)?

Background: Data are lacking on risks and benefits of aspirin and warfarin in CKD, as this group of patients largely has been excluded from anticoagulation therapy trials for NVAF. This study examined the risks and benefits of aspirin and warfarin in patients with CKD with NVAF.

Study design: Retrospective, observational cohort study.

Setting: Danish National Registries.

Synopsis: Of 132,372 patients with NVAF, 2.7% had CKD and 0.7% had end-stage renal disease (ESRD). Compared to patients with no CKD, there was increased risk of stroke or systemic thromboembolism in patients with ESRD (HR, 1.83; 95% CI, 1.57-2.14) and with non-end-stage CKD (HR 1.49; 95% CI 1.38-1.59).

In patients with CKD, warfarin significantly reduced stroke risk (HR, 0.76; 95% CI, 0.64-0.91) and significantly increased bleeding risk (HR, 1.33; 95% CI, 1.16-1.53); aspirin significantly increased bleeding risk (HR, 1.17; 95% CI, 1.02-1.34) with no reduction in stroke risk.

Bottom line: CKD was associated with an increased risk of stroke among NVAF patients. While both aspirin and warfarin were associated with increased risk of bleeding, there was a reduction in the risk of stroke with warfarin, but not with aspirin.

Citation: Olesen JB, Lip GY, Kamper AL, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med. 2012;367(7):625-635.

In This Edition

Literature At A Glance

A guide to this month’s studies

1. Burnout among physicians and the general workforce
2. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke
3. Performance of the HEMORR2AGES, ATRIA, and HAS-BLED bleeding risk prediction scores in patients with atrial fibrillation undergoing anticoagulation
4. Probiotics for secondary prevention of hepatic encephalopathy
5. Capsule endoscopy for acute obscure GI bleeding
6. Perceptions of readmitted patients transitioning from hospital to home
7. Thirty-day readmissions after acute myocardial infarction
8. One-hour rule-out or rule-in for AMI patients in chest pain
9. Aspirin increases bleed risk without reducing risk of stroke in CKD and NVAF patients

Burnout among Physicians and the General Workforce

Clinical question: What is the degree and distribution of burnout within the physician workforce, and how does that compare to the general U.S. workforce?

Background: Professional burnout, work satisfaction, and work-life balance are critical elements to understand in the physician workforce. It is well documented that physicians are at high risk for burnout; however, few extensive studies have looked at rates and the identification of high-risk subpopulations.

Study design: Cross-sectional survey.

Setting: U.S. workforce.

Synopsis: This study included 7,288 physicians (26.7% response rate) and 5,930 controls from the general U.S. population. Validated survey instruments were employed to assess the degree and presence of burnout, depression, and satisfaction with work-life balance.

In aggregate, using a validated, two-item burnout measure, 35.2% of physicians were characterized as having burnout, compared with 27.6% of the general population (P<0.001). Within the physician community, the specialties with the highest risk of burnout included emergency medicine, general internal medicine, family medicine, and neurology.

Important limitations of this study include that the physician and general population surveys were performed at different times (six months apart), that the groups were not ideally matched (age and sex, for example), and the overall response rate of the physician survey was low.

This study sheds light on an important topic for hospitalists. Future studies should continue to probe the problem of burnout and look for creative solutions to mitigate risks that might threaten professional longevity.

Bottom line: Burnout is prevalent among physicians, especially when compared to the general workforce. Physician specialties in front-line patient care are at highest risk.

Citation: Shanafelt TD, Boone S, Tan L, et al. Burnout and satisfaction with work-life balance among US physicians relative to the general US population. Arch Intern Med. 2012;20 [Epub ahead of print].

Effects of Clopidogrel Added to Aspirin in Patients with Recent Lacunar Stroke

Clinical question: Does the addition of clopidogrel to aspirin reduce the risk of any type of recurrent stroke, or affect the risk of bleeding or death, in patients who recently suffered a lacunar stroke?

Background: There are no prior randomized, multicenter trials on secondary prevention of lacunar stroke; aspirin is the standard antiplatelet therapy in this setting.

Study design: Double-blind, randomized, multicenter trial.

Setting: Eighty-two clinical centers in North America, Latin America, and Spain.

Synopsis: Researchers enrolled 3,020 patients from 2003 to 2011; criteria included age >30 years old and symptomatic lacunar stroke (proven by MRI) in the preceding 180 days.

Results showed no significant difference between recurrent strokes (any type) in the aspirin-only group (2.7% per year) versus the aspirin-plus-clopidogrel group (2.5% per year). Major hemorrhage risk was much higher in the aspirin-plus-clopidogrel group (2.1% per year) versus aspirin-only group (1.1% per year). All-cause mortality also was much higher in the aspirin-plus-clopidogrel group (N=113) versus the aspirin-only group (N=77).

Bottom line: The addition of clopidogrel to aspirin for secondary prevention does not significantly reduce the risk of recurrent stroke, but it does significantly increase the risk of bleeding and death.

Citation: Benavente OR, Hart RG, McClure LA, et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012;367:817-825.

Bleeding Risk Prediction Scores in Patients with Atrial Fibrillation Undergoing Anticoagulation

Clinical question: What are the relative predictive values of the HEMORR2AGES, ATRIA, and HAS-BLED risk-prediction schemes?

Background: The tools predict bleeding risk in patients anticoagulated for atrial fibrillation (afib), but it is unknown which is the best to predict clinically relevant bleeding.

Study design: Post-hoc analysis.

Setting: Data previously collected for the AMADEUS trial (2,293 patients taking warfarin; 251 had at least one clinically relevant bleeding event) were used to test each of the three bleeding risk-prediction schemes on the same data set.

Synopsis: Using three analysis methods (net reclassification improvement, receiver-operating characteristic [ROC], and decision-curve analysis), the researchers compared the three schemes’ performance. HAS-BLED performed best in all three of the analysis methods.

The HAS-BLED score calculation requires the following patient information: history of hypertension, renal disease, liver disease, stroke, prior major bleeding event, and labile INR; age >65; and use of antiplatelet agents, aspirin, and alcohol.

Bottom line: HAS-BLED was the best of the three schemes, although all three had only modest ability to predict clinically relevant bleeding.

Citation: Apostolakis S, Lane DA, Guo Y, et al. Performance of the HEMORRAGES, ATRIA and HAS-BLED bleeding risk-prediction scores in patients with atrial fibrillation undergoing anticoagulation. J Am Coll Cardiol. 2012;60(9):861-867

Probiotics for Secondary Prevention of Hepatic Encephalopathy

Clinical question: Are probiotics as effective as lactulose for secondary prevention of hepatic encephalopathy (HE)?

Background: Probiotics alter the gut flora, resulting in decreased ammonia production and absorption. Probiotics have been shown to reduce the incidence of low-grade HE. However, studies on probiotics usage for secondary prevention of HE are lacking.

Study design: Prospective, randomized, controlled, nonblinded, single-center study.

Setting: Tertiary-care center, New Delhi.

Synopsis: Three hundred sixty patients who had recovered from HE from October 2008 to December 2009 were screened; 235 met the inclusion criteria. They were randomized to receive either lactulose (Gp-L), probiotics (Gp-P), or no therapy (Gp-N). The Gp-L group received 30 to 60 ml of lactulose in two to three divided doses; the Gp-P group received three capsules per day containing lactobacillus, bifidobacterium, and Streptococcus salivarius strains.

The primary endpoints were the development of overt HE (assessed by the West Haven Criteria) or a follow-up of 12 months. Lactulose therapy was significantly more effective in secondary prophylaxis than no therapy (26.2% vs. 56.9%, P=0.001), as was probiotics therapy compared with no therapy (34.4% vs. 56.9%, P=0.02), but no significant difference was found between lactulose and probiotics therapy (26.2% vs. 34.4%, P=0.349).

The major limitation of the study was its open-label design. The study also used a high concentration of probiotics, and the results could be strain-specific and hence require validation with other probiotics combinations. The Gp-N group continued the previous therapy (excluding lactulose), with an unknown number on rifaximin.

Bottom line: Lactulose and probiotics are equally effective in secondary prophylaxis of hepatic encephalopathy.

Citation: Agrawal A, Sharma BC, Sharma P, Sarin SK. Secondary prophylaxis of hepatic encephalopathy in cirrhosis: an open-label, randomized controlled trial of lactulose, probiotics and no therapy. Am J Gastroenterol. 2012;107:1043-1050.

Capsule Endoscopy for Acute Obscure GI Bleeding

Clinical question: What testing modality is most appropriate for acute obscure GI bleeding: capsule endoscopy (CE) or angiography?

Background: Acute obscure GI bleeding (OGIB): remains a diagnostic challenge, accounting for 7% to 8% of patients presenting with GI bleeding. CE enables direct visualization of small bowel mucosa but lacks the ability for therapeutic intervention. Angiography is frequently chosen for massive bleeding; however, it is invasive and does not enable visualization of the bowel.

Study design: Prospective, randomized, controlled, blinded, single-center study.

Setting: Prince of Wales Hospital, Hong Kong.

Synopsis: Ninety-one patients with active OGIB from June 2005 to November 2007 were assessed for eligibility; 60 met the criteria and were randomized to either CE or angiography. Overt OGIB was defined as patients who had nondiagnostic upper endoscopy and colonoscopy.

The primary outcome was diagnostic yield of CE or mesenteric angiography in identifying the bleeding source. Secondary outcomes were long-term rebleeding rates, readmissions for bleeding or anemia, blood transfusions, and death.

CE was positive in 16 patients (53.3%) and angiography was positive in six patients (20%). The diagnostic yield of CE was significantly higher than angiography (difference=33.3%, 95% CI 8.9-52.8%, P=0.016). The mean follow-up period was 48.5 months. The cumulative risk of rebleeding was higher in the angiography group, but this was not statistically significant. There was no significant difference in rates of subsequent hospitalization, death, or transfusions between the two groups.

The study based the sample-size estimation on the diagnostic yield rather than clinical outcomes and, hence, was underpowered to detect any significant differences in clinical outcomes.

Bottom line: CE has a higher diagnostic yield than angiography in patients with active overt OGIB.

Citation: Leung WK, Ho S, Suen B, et al. Capsule endoscopy of angiography in patients with acute overt gastrointestinal bleeding: a prospective randomized study with long term follow up. Am J Gastroenterol. 2012;107:1370-1376.

Perceptions of Readmitted Patients Transitioning from Hospital to Home

Clinical question: What are patient-reported reasons for readmission to the hospital after discharge?

Background: Reducing readmissions is a critical component to improving the value of healthcare. While readmission reduction is a goal of all hospitals, there is much to be gleaned from evaluating patients’ view of the problem. This study used a survey to assess the patient’s viewpoint.

Study design: Cross-sectional survey.

Setting: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center, Philadelphia.

Synopsis: A survey of 36 questions was posed to 1,084 patients who were readmitted within 30 days of discharge from November 2010 to July 2011 (32% of eligible patients). The data were subdivided based on socioeconomic status and medical versus surgical patients.

Some issues patients raised regarding discharge planning included difficulty with paying for medications, challenges with travel to pharmacies, and concern over medication side effects.

Patients with low socioeconomic status had more difficulty taking medications and following instructions, had more depression, and had less social support.

Bottom line: Readmission rates are affected by a patient’s social situation. A team approach to discharge planning might mitigate some of these factors.

Citation: Kangovi S, Grande D, Meehan P, Mitra N, Shannon R, Long JA. Perceptions of readmitted patients on the transition from hospital to home. J Hosp Med. 2012 [Epub ahead of print].

30-Day Readmissions after Acute Myocardial Infarction

Clinical question: What are potential predictors of 30-day readmissions after acute myocardial infarction (MI)?

Background: Much attention has been given to evaluate the causes of readmissions of heart failure, acute MI, and pneumonia. This study looked at 30-day readmissions after an acute myocardial infarction (AMI).

Study design: Retrospective cohort study.

Setting: Olmstead County Hospital, Rochester, Minn.

Synopsis: A chart review of AMI based on ICD-9 codes from 1987 to 2010 identified 3,010 patients. Patients were verified using symptoms, cardiac enzymes, and EKG changes at the time of event. Interventions evaluated included fibrinolytic therapy, CABG, or primary PCI.

Survival increased to 96% from 89% during the period from 1987 to 2010. Researchers also noted more comorbid conditions, such as diabetes mellitus, COPD, and hypertension, noted over time. Of the patients evaluated, 643 readmissions occurred for 561 patients (18.6%). Of these, the most frequent causes were ischemic heart disease, respiratory symptoms, and heart failure. Comorbid conditions, such as diabetes, COPD, anemia, higher killip class on initial admission, duration of prior hospitalization, and procedural complications, independently increased the risk of readmission.

Bottom line: In addition to factors unrelated to an AMI, a patient’s comorbid conditions, post-procedure complications, and duration of hospitalization influence the risk of readmission.

Citation: Dunlay SM, Weston SA, Killian JM, et al. Thirty-day rehospitalizations after acute myocardial infarction: a cohort study. Ann Intern Med. 2012;157(1):11-18.

One-Hour Rule-Out or Rule-In for AMI in Chest Pain

Clinical question: How can we use the newly developed high-sensitivity cardiac troponin (hs-cTnT) to shorten the time to rule in and rule out AMI?

Background: The hs-cTnT assays available appear to improve the early diagnosis of AMI when compared to the regular cardiac troponins, but no clear guidelines are available as how to best use them in clinical practice.

Study design: Prospective, multicenter study.

Setting: Switzerland hospitals.

Synopsis: The study enrolled 872 unselected patients presenting to the ED with acute chest pain. Hs-cTnT level was measured in a blinded fashion at presentation and after one hour. Two independent cardiologists using all available medical records adjudicated the final AMI diagnosis. Optimal thresholds for rule-out were selected to allow for 100% sensitivity and negative predictive value. Rule-out criteria were defined as baseline hs-cTnT level <12 ng/L and an absolute change within the first hour of <3 ng/L. Rule-in criteria was defined as baseline hs-cTnT >52 ng/L or an absolute increase within the first hour of >5 ng/L.

AMI was the final diagnosis in 17% of patients; AMI was ruled out in 60%; and the remaining 23% were placed in observation.

Primary prognostic endpoint was 30-day mortality rate, which was 0.2% in the rule-out group, validating the suitability of these patients for early discharge.

Study limitations were that it was an observational study not used for clinical decision-making, no dialysis patients were included, and only one specific hs-cTnT assay was tested.

Bottom line: Using hs-cTnT levels at presentation and absolute changes within the first hour, a safe rule-out or rule-in of AMI can be performed in 77% of patients presenting with chest pain.

Citation: Reichlin T, Schindler C, Drexler B, et al. One-hour rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin T. Arch Intern Med. 2012;172(16):1-8.

Aspirin Increases Bleed Risk without Reducing Risk of Stroke in CKD and NVAF Patients

Clinical question: Is there a difference between aspirin and warfarin in preventing thromboembolic complications and risk of bleeding in patients with chronic kidney disease (CKD) and nonvalvular afib (NVAF)?

Background: Data are lacking on risks and benefits of aspirin and warfarin in CKD, as this group of patients largely has been excluded from anticoagulation therapy trials for NVAF. This study examined the risks and benefits of aspirin and warfarin in patients with CKD with NVAF.

Study design: Retrospective, observational cohort study.

Setting: Danish National Registries.

Synopsis: Of 132,372 patients with NVAF, 2.7% had CKD and 0.7% had end-stage renal disease (ESRD). Compared to patients with no CKD, there was increased risk of stroke or systemic thromboembolism in patients with ESRD (HR, 1.83; 95% CI, 1.57-2.14) and with non-end-stage CKD (HR 1.49; 95% CI 1.38-1.59).

In patients with CKD, warfarin significantly reduced stroke risk (HR, 0.76; 95% CI, 0.64-0.91) and significantly increased bleeding risk (HR, 1.33; 95% CI, 1.16-1.53); aspirin significantly increased bleeding risk (HR, 1.17; 95% CI, 1.02-1.34) with no reduction in stroke risk.

Bottom line: CKD was associated with an increased risk of stroke among NVAF patients. While both aspirin and warfarin were associated with increased risk of bleeding, there was a reduction in the risk of stroke with warfarin, but not with aspirin.

Citation: Olesen JB, Lip GY, Kamper AL, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med. 2012;367(7):625-635.

Clinical question: Does the addition of clopidogrel to aspirin reduce the risk of any type of recurrent stroke, or affect the risk of bleeding or death, in patients who recently suffered a lacunar stroke?

Background: There are no prior randomized, multicenter trials on secondary prevention of lacunar stroke; aspirin is the standard antiplatelet therapy in this setting.

Study design: Double-blind, randomized, multicenter trial.

Setting: Eighty-two clinical centers in North America, Latin America, and Spain.

Synopsis: Researchers enrolled 3,020 patients from 2003 to 2011; criteria included age >30 years old and symptomatic lacunar stroke (proven by MRI) in the preceding 180 days.

Results showed no significant difference between recurrent strokes (any type) in the aspirin-only group (2.7% per year) versus the aspirin-plus-clopidogrel group (2.5% per year). Major hemorrhage risk was much higher in the aspirin-plus-clopidogrel group (2.1% per year) versus aspirin-only group (1.1% per year). All-cause mortality also was much higher in the aspirin-plus-clopidogrel group (N=113) versus the aspirin-only group (N=77).

Bottom line: The addition of clopidogrel to aspirin for secondary prevention does not significantly reduce the risk of recurrent stroke, but it does significantly increase the risk of bleeding and death.

Citation: Benavente OR, Hart RG, McClure LA, et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012;367:817-825.

For more physician reviews of recent HM-relevant literature, visit our website.

Clinical question: Does the addition of clopidogrel to aspirin reduce the risk of any type of recurrent stroke, or affect the risk of bleeding or death, in patients who recently suffered a lacunar stroke?

Background: There are no prior randomized, multicenter trials on secondary prevention of lacunar stroke; aspirin is the standard antiplatelet therapy in this setting.

Study design: Double-blind, randomized, multicenter trial.

Setting: Eighty-two clinical centers in North America, Latin America, and Spain.

Synopsis: Researchers enrolled 3,020 patients from 2003 to 2011; criteria included age >30 years old and symptomatic lacunar stroke (proven by MRI) in the preceding 180 days.

Results showed no significant difference between recurrent strokes (any type) in the aspirin-only group (2.7% per year) versus the aspirin-plus-clopidogrel group (2.5% per year). Major hemorrhage risk was much higher in the aspirin-plus-clopidogrel group (2.1% per year) versus aspirin-only group (1.1% per year). All-cause mortality also was much higher in the aspirin-plus-clopidogrel group (N=113) versus the aspirin-only group (N=77).

Bottom line: The addition of clopidogrel to aspirin for secondary prevention does not significantly reduce the risk of recurrent stroke, but it does significantly increase the risk of bleeding and death.

Citation: Benavente OR, Hart RG, McClure LA, et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012;367:817-825.

For more physician reviews of recent HM-relevant literature, visit our website.

Clinical question: Does the addition of clopidogrel to aspirin reduce the risk of any type of recurrent stroke, or affect the risk of bleeding or death, in patients who recently suffered a lacunar stroke?

Background: There are no prior randomized, multicenter trials on secondary prevention of lacunar stroke; aspirin is the standard antiplatelet therapy in this setting.

Study design: Double-blind, randomized, multicenter trial.

Setting: Eighty-two clinical centers in North America, Latin America, and Spain.

Synopsis: Researchers enrolled 3,020 patients from 2003 to 2011; criteria included age >30 years old and symptomatic lacunar stroke (proven by MRI) in the preceding 180 days.

Results showed no significant difference between recurrent strokes (any type) in the aspirin-only group (2.7% per year) versus the aspirin-plus-clopidogrel group (2.5% per year). Major hemorrhage risk was much higher in the aspirin-plus-clopidogrel group (2.1% per year) versus aspirin-only group (1.1% per year). All-cause mortality also was much higher in the aspirin-plus-clopidogrel group (N=113) versus the aspirin-only group (N=77).

Bottom line: The addition of clopidogrel to aspirin for secondary prevention does not significantly reduce the risk of recurrent stroke, but it does significantly increase the risk of bleeding and death.

Citation: Benavente OR, Hart RG, McClure LA, et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012;367:817-825.

For more physician reviews of recent HM-relevant literature, visit our website.

In This Edition

Literature At A Glance

A guide to this month’s studies

1. Initial trophic feedings effective for patients with acute lung injury
2. IM vs. IV benzodiazepines in status epilepticus
3. CDI risk following antibiotic cessation
4. Acid suppression associated with increased complications in CDI patients
5. Perioperative statins and cardiac events in surgical patients
6. Enoxaparin vs. unfractionated heparin during PCI
7. Optimal serum potassium levels for AMI patients
8. PPIs superior to H2-blockers for lowering UGI bleeding following ACS and STEMI

Initial Lower-Volume Enteral Feeding Better Tolerated, but Has No Mortality Benefit

Clinical question: In mechanically ventilated patients with acute lung injury, do initial lower-volume enteral feedings (trophic feedings) improve clinical outcomes when compared with full enteral feedings?

Background: Malnutrition in critically ill patients is associated with poor outcomes, but conflicting data exist regarding the best timing, amount, and formulation of enteral nutrition to initiate. Initiation of lower-volume enteral feeding with periodic assessment of gastric residual volume is common practice, but the effects of this practice are unknown.

Study design: Multicenter randomized controlled open-label study.

Setting: Forty-four hospitals in the National Heart, Lung, and Blood Institute (NHLBI) Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network.

Synopsis: One thousand patients with acute lung injury receiving mechanical ventilation for longer than 72 hours were randomized using a Web-based system to receive either trophic or full enteric feedings for the first six days of mechanical ventilation. After the sixth day, a full enteric feeding protocol was used in all patients. All analyses were by intention-to-treat.

There was no significant difference between the trophic and full enteral feeding groups with regard to the primary outcome of ventilator-free days through Day 28 (14.9% vs. 15.0%, P=0.89). There were also no significant differences between groups in secondary outcomes, which included 60-day mortality, ICU-free days, organ-failure-free days, or the incidence of new infections. However, gastrointestinal intolerances occurred less often in the trophic feeding group, and these patients received fewer anti-diarrheal and prokinetic agents. The full feeding group gained 2.1 liters of fluid by Day 7, but this fluid gain did not cause significant differences in measures of circulatory or pulmonary physiology.

Limitations include open-label study design and inclusion of only critically ill adult medical patients with acute lung injury.

Bottom line: Initial lower-volume tube feedings in mechanically ventilated patients with acute lung injury did not improve clinical outcomes compared with full enteral feedings, but they were associated with fewer instances of gastrointestinal intolerance.

Citation: National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA. 2012;307:795-803.

Intramuscular Benzodiazepines as Good as IV Benzodiazepines in Status Epilepticus

Clinical question: Is intramuscular (IM) midazolam noninferior to intravenous lorazepam in patients in status epilepticus?

Background: Studies have shown that IV benzodiazepines, particularly lorazepam, are effective for patients in status epilepticus. Studies have not evaluated IM benzodiazepines. However, many emergency medical service (EMS) agencies use IM midazolam because IM administration is easier than IV administration, and midazolam has a longer nonrefrigerated shelf life than lorazepam does.

Study design: Randomized, double-blinded clinical trial.

Setting: Thirty-three EMS agencies across the United States.

Synopsis: Based on the 893 adults and children in status epilepticus included in this double-blind study, the researchers found IM midazolam to be noninferior to, and in fact superior to, IV lorazepam for treating seizures prior to arrival at EDs. Specifically, they found 10% more (95% CI 4.0% to 16.1%; P<0.001 for noninferiority and P<0.001 for superiority) seizure-free patients arriving at EDs when IM midazolam was administered. Seizures ceased in patients given IM midazolam in less time on average than it took for paramedics to administer IV lorazepam.

Hospitalists might be less inclined than EMS personnel to use IM midazolam because their patients have established IV access and refrigerated drugs are readily available. However, since IM midazolam was superior to IV lorazepam in this prehospital study, a similar trial in hospitalized patients is warranted. In subsequent trials, it would be useful to administer both midazolam and lorazepam via IM and IV routes, and IM injections by an autoinjector could be compared with the conventional manner.

Bottom line: In the prehospital setting, IM midazolam is at least as good as IV lorazepam in treating status epilepticus in children and adults.

Citation: Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012;366:591-600.

Clostridium Difficile Infection Risk Remains High at Least Three Months after Antibiotics Are Stopped

Clinical question: How long are patients at higher risk for Clostridium difficile infection (CDI) after completing antibiotics?

Background: Studies have shown that patients given antibiotics are at higher risk for CDI than those who are not, particularly if they take multiple antibiotics at high doses for a prolonged period of time. However, it is not known how long a patient remains at high risk for CDI after completing antibiotic therapy.

Study design: Case-control study.

Setting: Nine hospitals in Netherlands.

Synopsis: The study compared 337 hospitalized patients who had CDI with 337 nondiarrheal controls and 227 non-CDI diarrheal controls. The study showed a seven- to tenfold increased risk for CDI during antibiotic treatment and in the 30 days following cessation of antibiotics. A 2.7-fold increased risk of CDI was seen in the one- to three-month period after antibiotic treatment was stopped.

Because researchers only obtained information about antibiotic use in the three months preceding the onset of diarrhea, it is unknown if CDI risk remains elevated longer than three months after antibiotics are stopped. Also of note, the enzyme immunoassays used in this study to diagnose C. diff had sensitivities of between 60% and 85%.

As hospitalists, this information can be used to advise patients about their continued risk for CDI after cessation of antibiotics. Further studies are needed to determine the risk after three months.

Bottom line: Patients are at highest risk for CDI up to one month after stopping antibiotics but continue to be at higher risk for at least two additional months.

Citation: Hensgens MPN, Goorhuis A, Dekkers OM, Kuijper EJ. Time interval of increased risk for Clostridium difficile infection after exposure to antibiotics. J Antimicrob Chemother. 2012;67:742-748.

Acid Suppression and Poor Outcomes in C. Diff Patients

Clinical question: What are potential modifiable risk factors associated with increased complications and mortality in patients hospitalized with C. diff infection (CDI)?

Background: CDI is a growing cause of morbidity and mortality in hospitalized patients. Evidence is growing for the association of acid suppression, among other modifiable risk factors, with complications and mortality in patients with CDI.

Study design: Retrospective case review.

Setting: Naval medical center.

Synopsis: A laboratory, medical record, and pharmacy database query found 485 patients with CDI. Complications of CDI were defined as ICU admission, surgery, and megacolon. Factors significantly associated with CDI complications and mortality were admission for CDI, corticosteroid use >5 mg per day, age ≥80 years, and prescription acid suppression (including H2-blockers and proton-pump inhibitors).

The latter two risk factors were associated with mortality alone. In multivariable regression, the odds of mortality among patients on acid suppression was more than four times the odds of those not on acid suppression (OR 4.74, 95% CI, 1.57 to 14.36).

Although this is a retrospective cohort study and cannot prove a causal relationship, the data add to a growing body of evidence supporting the risk of CDI complications and mortality for those on acid suppression.

Bottom line: In hospitalized patients with CDI, acid suppression is associated with increased complications and mortality and should be discontinued in this population when possible.

Citation: Morrison RH, Hall NS, Said M, et al. Risk factors associated with complications and mortality in patients with Clostridium difficile infection. Clin Infect Dis. 2011;53:1173-1178.

Perioperative Statins Reduce Cardiac Events for Surgical Patients

Clinical question: Does perioperative statin use improve cardiac outcomes (death, myocardial infarction, atrial fibrillation, and ICU and hospital lengths of stay) in statin-naive patients undergoing cardiac or non-cardiac surgery?

Background: Statins have been hypothesized to reduce perioperative cardiac complications because they reduce vascular and systemic inflammation caused by surgery, and several meta-analyses have demonstrated their efficacy. To date, no meta-analyses have specifically evaluated the benefits of perioperative statins in non-cardiac surgery from randomized controlled trials.

Study design: Systematic review of the literature and meta-analysis.

Setting: Fifteen randomized controlled trials of hospitalized surgical patients.

Synopsis: A systematic review examined the effects of statins on a variety of perioperative cardiac outcomes (death, myocardial infarction, atrial fibrillation, and ICU and hospital lengths of stay); 11 of the 15 patients were undergoing cardiac surgery.

Perioperative statins decreased the risk of atrial fibrillation in patients undergoing cardiac surgery (RR 0.56; 95% CI 0.45-0.69; number needed to treat [NNT], 6). In both cardiac and non-cardiac surgical patients, statins reduced the risk of myocardial infarction (RR 0.53; 95% CI 0.38 to 0.74; NNT 23). Statin treatment also reduced the mean length of hospital stay (in days, mean difference -0.32; 95% CI, -0.53 to -0.11) but did not reduce the length of ICU stay (mean difference -0.08; 95% CI, -0.25 to 0.10). Risk of death was not reduced with statin treatment (RR 0.62; 95% CI, 0.34 to 1.14).

Bottom line: Perioperative statins reduce the risk of postoperative atrial fibrillation in cardiac surgical patients, the risk of postoperative MI in cardiac and non-cardiac surgical patients, and the mean length of hospital stay.

Citation: Chopra V, Wesorick DH, Sussman JB, et al. Effect of perioperative statins on death, myocardial infarction, atrial fibrillation, and length of stay: a systematic review and meta-analysis. Arch Surg. 2012;147:181-188.

Enoxaparin Safe and Effective during Percutaneous Coronary Intervention

Clinical question: Is enoxaparin safe and efficacious compared with unfractionated heparin during percutaneous coronary intervention (PCI)?

Background: Despite problems with the use of unfractionated heparin during PCI, current guidelines give it a Class 1 recommendation for PCI in ST-elevation myocardial infarction (MI). There is growing evidence that enoxaparin can provide predictable, effective anticoagulation during PCI. Although several trials have examined this issue, none have been sufficiently powered to evaluate mortality.

Study design: Systematic review and meta-analysis.

Setting: Twenty-three trials or registries of patients undergoing PCI.

Synopsis: A systematic review found 23 trials representing 30,966 patients that examined the effects of enoxaparin versus unfractionated heparin on risk of mortality, MI, complications of MI, and major bleeding. Of these, 10,243 (33.1%) patients underwent primary PCI for ST elevation MI, 8,750 (28.2%) underwent PCI after fibrinolysis, and 11,973 (38.7%) patients had either scheduled PCI or PCI for non-ST elevation acute coronary syndrome.

Of all the patients, 13,943 (45%) received enoxaparin and 17,023 (55%) received unfractionated heparin. Enoxaparin was associated with significant reductions in all-cause mortality (RR 0.66; 95% CI, 0.57 to 0.76), composite of death or MI (RR 0.68; 95% CI, 0.57 to 0.81), and complications of MI (RR 0.75; 95% CI, 0.6 to 0.85). For patients who received primary PCI for ST elevation MI, enoxaparin reduced the risk of complications of MI by 44% (RR 0.56; 95% CI, 0.42 to 0.76). Enoxaparin also reduced the risk of major bleeding (RR 0.80, 95% CI, 0.68 to 0.95) with even more striking results for the 14 studies that compared intravenous enoxaparin to unfractionated heparin (RR 0.66; 95% CI, 0.52 to 0.83).

Bottom line: Enoxaparin is safe and efficacious when used during PCI. Patients who receive enoxaparin during PCI have reduced risk for death, MI, complications of MI, and major bleeding when compared with patients who receive unfractionated heparin.

Citation: Silvain J, Beygui F, Barthelmy O, et al. Efficacy and safety of enoxaparin versus unfractionated heparin during percutaneous coronary intervention: systematic review and meta-analysis. BMJ. 2012;344:e553.

Serum Potassium Levels and Mortality in Acute Myocardial Infarction

Clinical question: What is the relationship between serum potassium levels and mortality in acute myocardial infarction (AMI) patients?

Background: Several smaller studies in the pre-beta-blocker and pre-reperfusion era recommended maintaining serum potassium levels between 4.0 mEq/L and 5.0 mEq/L in AMI patients. However, current studies examining the relationship between potassium levels and mortality in AMI patients are lacking.

Study design: Retrospective cohort study.

Setting: Multicenter study involving 67 hospitals in the U.S.

Synopsis: Using the Cerner Health Facts database, which included 38,689 patients with biomarker-confirmed AMI, this study showed there was a U-shaped relationship between mean post-admission serum potassium level and in-hospital mortality.

Compared with the reference group of 3.5 mEq/L to less than 4.0 mEq/L (mortality rate 4.8%; 95% CI, 4.4% to 5.2%), mortality was comparable for those with mean post-admission potassium of 4.0 mEq/L to less than 4.5 mEq/L (5.0%; 95% CI, 4.7% to 5.3%). Mortality was twice as great for potassium of 4.5 mEq/L to less than 5.0 mEq/L (10.0%; 95% CI, 9.1% to 10.9%), and even greater for higher potassium strata. Similarly, mortality rates were higher for potassium levels of less than 3.5 mEq/L. Rates of ventricular fibrillation or cardiac arrest were higher among patients with potassium levels of less than 3.0 mEq/L or more than 5.0 mEq/L.

Bottom line: For inpatients with AMI, serum potassium levels of 3.5 mEq/L to 4.5 mEq/L should be maintained for the best outcomes. Repletion of serum potassium to levels greater than 4.5 mEq/L is associated with increased mortality and should be avoided.

Citation: Goyal A, Spertus JA, Gosch K, et al. Serum potassium levels and mortality in acute myocardial infarction. JAMA. 2012;307:157-164.

Proton-Pump Inhibitors Better than H2-Blockers in ACS and STEMI

Clinical question: Are proton-pump inhibitors (PPIs) better than H2-blockers at preventing UGI bleeding in patients after acute coronary syndrome (ACS) or ST-elevation myocardial infarction (STEMI)?

Background: It is not definitively known if PPIs are the same or better than H2-blockers in preventing UGI bleeding in patients on high-risk medications (aspirin, clopidogrel, and anticoagulants) after ACS or STEMI.

Study design: Randomized double-blinded controlled trial.

Setting: Single hospital.

Synopsis: Patients with ACS or STEMI were treated with aspirin, clopidogrel, and enoxaparin or thrombolytics. They were then randomized to either esomeprazole 20 mg or famotidine 40 mg, both administered nightly. They were followed throughout their hospital stay and were then followed between four and 52 weeks after discharge (mean duration: 19 weeks for esomeprazole, 18 weeks for famotidine). The primary end point was time to a composite outcome, consisting of UGI bleeding, obstruction, or perforation. Overall, 313 patients were randomized (164 to esomeprazole and 149 to famotidine).

The treatment groups were equivalent in baseline characteristics, and compliance in both groups was excellent (>98%). The primary endpoint occurred in three patients in the esomeprazole group and in 12 patients in the famotidine group (hazard ratio 0.21; 95% CI, 0.06 to 0.75; P=0.008).

Bottom line: PPIs are superior to H2-blockers in reducing UGI bleeding in patients on high-risk medications (aspirin, clopidogrel, and enoxaparin or thrombolytics) after ACS and STEMI. This confirms the recommendations of the 2010 ACCF/ACG/AHA Expert Consensus that PPIs should be used in those on dual antiplatelet therapy on anticoagulants.

Citation: Ng FH, Tunggal P, Chu WM, et al. Esomeprazole compared with famotidine in the prevention of upper gastrointestinal bleeding in patients with acute coronary syndrome or myocardial infarction. Am J Gastroenterol. 2012;107:389-396.

In This Edition

Literature At A Glance

A guide to this month’s studies

1. Initial trophic feedings effective for patients with acute lung injury
2. IM vs. IV benzodiazepines in status epilepticus
3. CDI risk following antibiotic cessation
4. Acid suppression associated with increased complications in CDI patients
5. Perioperative statins and cardiac events in surgical patients
6. Enoxaparin vs. unfractionated heparin during PCI
7. Optimal serum potassium levels for AMI patients
8. PPIs superior to H2-blockers for lowering UGI bleeding following ACS and STEMI

Initial Lower-Volume Enteral Feeding Better Tolerated, but Has No Mortality Benefit

Clinical question: In mechanically ventilated patients with acute lung injury, do initial lower-volume enteral feedings (trophic feedings) improve clinical outcomes when compared with full enteral feedings?

Background: Malnutrition in critically ill patients is associated with poor outcomes, but conflicting data exist regarding the best timing, amount, and formulation of enteral nutrition to initiate. Initiation of lower-volume enteral feeding with periodic assessment of gastric residual volume is common practice, but the effects of this practice are unknown.

Study design: Multicenter randomized controlled open-label study.

Setting: Forty-four hospitals in the National Heart, Lung, and Blood Institute (NHLBI) Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network.

Synopsis: One thousand patients with acute lung injury receiving mechanical ventilation for longer than 72 hours were randomized using a Web-based system to receive either trophic or full enteric feedings for the first six days of mechanical ventilation. After the sixth day, a full enteric feeding protocol was used in all patients. All analyses were by intention-to-treat.

There was no significant difference between the trophic and full enteral feeding groups with regard to the primary outcome of ventilator-free days through Day 28 (14.9% vs. 15.0%, P=0.89). There were also no significant differences between groups in secondary outcomes, which included 60-day mortality, ICU-free days, organ-failure-free days, or the incidence of new infections. However, gastrointestinal intolerances occurred less often in the trophic feeding group, and these patients received fewer anti-diarrheal and prokinetic agents. The full feeding group gained 2.1 liters of fluid by Day 7, but this fluid gain did not cause significant differences in measures of circulatory or pulmonary physiology.

Limitations include open-label study design and inclusion of only critically ill adult medical patients with acute lung injury.

Bottom line: Initial lower-volume tube feedings in mechanically ventilated patients with acute lung injury did not improve clinical outcomes compared with full enteral feedings, but they were associated with fewer instances of gastrointestinal intolerance.

Citation: National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA. 2012;307:795-803.

Intramuscular Benzodiazepines as Good as IV Benzodiazepines in Status Epilepticus

Clinical question: Is intramuscular (IM) midazolam noninferior to intravenous lorazepam in patients in status epilepticus?

Background: Studies have shown that IV benzodiazepines, particularly lorazepam, are effective for patients in status epilepticus. Studies have not evaluated IM benzodiazepines. However, many emergency medical service (EMS) agencies use IM midazolam because IM administration is easier than IV administration, and midazolam has a longer nonrefrigerated shelf life than lorazepam does.

Study design: Randomized, double-blinded clinical trial.

Setting: Thirty-three EMS agencies across the United States.

Synopsis: Based on the 893 adults and children in status epilepticus included in this double-blind study, the researchers found IM midazolam to be noninferior to, and in fact superior to, IV lorazepam for treating seizures prior to arrival at EDs. Specifically, they found 10% more (95% CI 4.0% to 16.1%; P<0.001 for noninferiority and P<0.001 for superiority) seizure-free patients arriving at EDs when IM midazolam was administered. Seizures ceased in patients given IM midazolam in less time on average than it took for paramedics to administer IV lorazepam.

Hospitalists might be less inclined than EMS personnel to use IM midazolam because their patients have established IV access and refrigerated drugs are readily available. However, since IM midazolam was superior to IV lorazepam in this prehospital study, a similar trial in hospitalized patients is warranted. In subsequent trials, it would be useful to administer both midazolam and lorazepam via IM and IV routes, and IM injections by an autoinjector could be compared with the conventional manner.

Bottom line: In the prehospital setting, IM midazolam is at least as good as IV lorazepam in treating status epilepticus in children and adults.

Citation: Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012;366:591-600.

Clostridium Difficile Infection Risk Remains High at Least Three Months after Antibiotics Are Stopped

Clinical question: How long are patients at higher risk for Clostridium difficile infection (CDI) after completing antibiotics?

Background: Studies have shown that patients given antibiotics are at higher risk for CDI than those who are not, particularly if they take multiple antibiotics at high doses for a prolonged period of time. However, it is not known how long a patient remains at high risk for CDI after completing antibiotic therapy.

Study design: Case-control study.

Setting: Nine hospitals in Netherlands.

Synopsis: The study compared 337 hospitalized patients who had CDI with 337 nondiarrheal controls and 227 non-CDI diarrheal controls. The study showed a seven- to tenfold increased risk for CDI during antibiotic treatment and in the 30 days following cessation of antibiotics. A 2.7-fold increased risk of CDI was seen in the one- to three-month period after antibiotic treatment was stopped.

Because researchers only obtained information about antibiotic use in the three months preceding the onset of diarrhea, it is unknown if CDI risk remains elevated longer than three months after antibiotics are stopped. Also of note, the enzyme immunoassays used in this study to diagnose C. diff had sensitivities of between 60% and 85%.

As hospitalists, this information can be used to advise patients about their continued risk for CDI after cessation of antibiotics. Further studies are needed to determine the risk after three months.

Bottom line: Patients are at highest risk for CDI up to one month after stopping antibiotics but continue to be at higher risk for at least two additional months.

Citation: Hensgens MPN, Goorhuis A, Dekkers OM, Kuijper EJ. Time interval of increased risk for Clostridium difficile infection after exposure to antibiotics. J Antimicrob Chemother. 2012;67:742-748.

Acid Suppression and Poor Outcomes in C. Diff Patients

Clinical question: What are potential modifiable risk factors associated with increased complications and mortality in patients hospitalized with C. diff infection (CDI)?

Background: CDI is a growing cause of morbidity and mortality in hospitalized patients. Evidence is growing for the association of acid suppression, among other modifiable risk factors, with complications and mortality in patients with CDI.

Study design: Retrospective case review.

Setting: Naval medical center.

Synopsis: A laboratory, medical record, and pharmacy database query found 485 patients with CDI. Complications of CDI were defined as ICU admission, surgery, and megacolon. Factors significantly associated with CDI complications and mortality were admission for CDI, corticosteroid use >5 mg per day, age ≥80 years, and prescription acid suppression (including H2-blockers and proton-pump inhibitors).

The latter two risk factors were associated with mortality alone. In multivariable regression, the odds of mortality among patients on acid suppression was more than four times the odds of those not on acid suppression (OR 4.74, 95% CI, 1.57 to 14.36).

Although this is a retrospective cohort study and cannot prove a causal relationship, the data add to a growing body of evidence supporting the risk of CDI complications and mortality for those on acid suppression.

Bottom line: In hospitalized patients with CDI, acid suppression is associated with increased complications and mortality and should be discontinued in this population when possible.

Citation: Morrison RH, Hall NS, Said M, et al. Risk factors associated with complications and mortality in patients with Clostridium difficile infection. Clin Infect Dis. 2011;53:1173-1178.

Perioperative Statins Reduce Cardiac Events for Surgical Patients

Clinical question: Does perioperative statin use improve cardiac outcomes (death, myocardial infarction, atrial fibrillation, and ICU and hospital lengths of stay) in statin-naive patients undergoing cardiac or non-cardiac surgery?

Background: Statins have been hypothesized to reduce perioperative cardiac complications because they reduce vascular and systemic inflammation caused by surgery, and several meta-analyses have demonstrated their efficacy. To date, no meta-analyses have specifically evaluated the benefits of perioperative statins in non-cardiac surgery from randomized controlled trials.

Study design: Systematic review of the literature and meta-analysis.

Setting: Fifteen randomized controlled trials of hospitalized surgical patients.

Synopsis: A systematic review examined the effects of statins on a variety of perioperative cardiac outcomes (death, myocardial infarction, atrial fibrillation, and ICU and hospital lengths of stay); 11 of the 15 patients were undergoing cardiac surgery.

Perioperative statins decreased the risk of atrial fibrillation in patients undergoing cardiac surgery (RR 0.56; 95% CI 0.45-0.69; number needed to treat [NNT], 6). In both cardiac and non-cardiac surgical patients, statins reduced the risk of myocardial infarction (RR 0.53; 95% CI 0.38 to 0.74; NNT 23). Statin treatment also reduced the mean length of hospital stay (in days, mean difference -0.32; 95% CI, -0.53 to -0.11) but did not reduce the length of ICU stay (mean difference -0.08; 95% CI, -0.25 to 0.10). Risk of death was not reduced with statin treatment (RR 0.62; 95% CI, 0.34 to 1.14).

Bottom line: Perioperative statins reduce the risk of postoperative atrial fibrillation in cardiac surgical patients, the risk of postoperative MI in cardiac and non-cardiac surgical patients, and the mean length of hospital stay.

Citation: Chopra V, Wesorick DH, Sussman JB, et al. Effect of perioperative statins on death, myocardial infarction, atrial fibrillation, and length of stay: a systematic review and meta-analysis. Arch Surg. 2012;147:181-188.

Enoxaparin Safe and Effective during Percutaneous Coronary Intervention

Clinical question: Is enoxaparin safe and efficacious compared with unfractionated heparin during percutaneous coronary intervention (PCI)?

Background: Despite problems with the use of unfractionated heparin during PCI, current guidelines give it a Class 1 recommendation for PCI in ST-elevation myocardial infarction (MI). There is growing evidence that enoxaparin can provide predictable, effective anticoagulation during PCI. Although several trials have examined this issue, none have been sufficiently powered to evaluate mortality.

Study design: Systematic review and meta-analysis.

Setting: Twenty-three trials or registries of patients undergoing PCI.

Synopsis: A systematic review found 23 trials representing 30,966 patients that examined the effects of enoxaparin versus unfractionated heparin on risk of mortality, MI, complications of MI, and major bleeding. Of these, 10,243 (33.1%) patients underwent primary PCI for ST elevation MI, 8,750 (28.2%) underwent PCI after fibrinolysis, and 11,973 (38.7%) patients had either scheduled PCI or PCI for non-ST elevation acute coronary syndrome.

Of all the patients, 13,943 (45%) received enoxaparin and 17,023 (55%) received unfractionated heparin. Enoxaparin was associated with significant reductions in all-cause mortality (RR 0.66; 95% CI, 0.57 to 0.76), composite of death or MI (RR 0.68; 95% CI, 0.57 to 0.81), and complications of MI (RR 0.75; 95% CI, 0.6 to 0.85). For patients who received primary PCI for ST elevation MI, enoxaparin reduced the risk of complications of MI by 44% (RR 0.56; 95% CI, 0.42 to 0.76). Enoxaparin also reduced the risk of major bleeding (RR 0.80, 95% CI, 0.68 to 0.95) with even more striking results for the 14 studies that compared intravenous enoxaparin to unfractionated heparin (RR 0.66; 95% CI, 0.52 to 0.83).

Bottom line: Enoxaparin is safe and efficacious when used during PCI. Patients who receive enoxaparin during PCI have reduced risk for death, MI, complications of MI, and major bleeding when compared with patients who receive unfractionated heparin.

Citation: Silvain J, Beygui F, Barthelmy O, et al. Efficacy and safety of enoxaparin versus unfractionated heparin during percutaneous coronary intervention: systematic review and meta-analysis. BMJ. 2012;344:e553.

Serum Potassium Levels and Mortality in Acute Myocardial Infarction

Clinical question: What is the relationship between serum potassium levels and mortality in acute myocardial infarction (AMI) patients?

Background: Several smaller studies in the pre-beta-blocker and pre-reperfusion era recommended maintaining serum potassium levels between 4.0 mEq/L and 5.0 mEq/L in AMI patients. However, current studies examining the relationship between potassium levels and mortality in AMI patients are lacking.

Study design: Retrospective cohort study.

Setting: Multicenter study involving 67 hospitals in the U.S.

Synopsis: Using the Cerner Health Facts database, which included 38,689 patients with biomarker-confirmed AMI, this study showed there was a U-shaped relationship between mean post-admission serum potassium level and in-hospital mortality.

Compared with the reference group of 3.5 mEq/L to less than 4.0 mEq/L (mortality rate 4.8%; 95% CI, 4.4% to 5.2%), mortality was comparable for those with mean post-admission potassium of 4.0 mEq/L to less than 4.5 mEq/L (5.0%; 95% CI, 4.7% to 5.3%). Mortality was twice as great for potassium of 4.5 mEq/L to less than 5.0 mEq/L (10.0%; 95% CI, 9.1% to 10.9%), and even greater for higher potassium strata. Similarly, mortality rates were higher for potassium levels of less than 3.5 mEq/L. Rates of ventricular fibrillation or cardiac arrest were higher among patients with potassium levels of less than 3.0 mEq/L or more than 5.0 mEq/L.

Bottom line: For inpatients with AMI, serum potassium levels of 3.5 mEq/L to 4.5 mEq/L should be maintained for the best outcomes. Repletion of serum potassium to levels greater than 4.5 mEq/L is associated with increased mortality and should be avoided.

Citation: Goyal A, Spertus JA, Gosch K, et al. Serum potassium levels and mortality in acute myocardial infarction. JAMA. 2012;307:157-164.

Proton-Pump Inhibitors Better than H2-Blockers in ACS and STEMI

Clinical question: Are proton-pump inhibitors (PPIs) better than H2-blockers at preventing UGI bleeding in patients after acute coronary syndrome (ACS) or ST-elevation myocardial infarction (STEMI)?

Background: It is not definitively known if PPIs are the same or better than H2-blockers in preventing UGI bleeding in patients on high-risk medications (aspirin, clopidogrel, and anticoagulants) after ACS or STEMI.

Study design: Randomized double-blinded controlled trial.

Setting: Single hospital.

Synopsis: Patients with ACS or STEMI were treated with aspirin, clopidogrel, and enoxaparin or thrombolytics. They were then randomized to either esomeprazole 20 mg or famotidine 40 mg, both administered nightly. They were followed throughout their hospital stay and were then followed between four and 52 weeks after discharge (mean duration: 19 weeks for esomeprazole, 18 weeks for famotidine). The primary end point was time to a composite outcome, consisting of UGI bleeding, obstruction, or perforation. Overall, 313 patients were randomized (164 to esomeprazole and 149 to famotidine).

The treatment groups were equivalent in baseline characteristics, and compliance in both groups was excellent (>98%). The primary endpoint occurred in three patients in the esomeprazole group and in 12 patients in the famotidine group (hazard ratio 0.21; 95% CI, 0.06 to 0.75; P=0.008).

Bottom line: PPIs are superior to H2-blockers in reducing UGI bleeding in patients on high-risk medications (aspirin, clopidogrel, and enoxaparin or thrombolytics) after ACS and STEMI. This confirms the recommendations of the 2010 ACCF/ACG/AHA Expert Consensus that PPIs should be used in those on dual antiplatelet therapy on anticoagulants.

Citation: Ng FH, Tunggal P, Chu WM, et al. Esomeprazole compared with famotidine in the prevention of upper gastrointestinal bleeding in patients with acute coronary syndrome or myocardial infarction. Am J Gastroenterol. 2012;107:389-396.

In This Edition

Literature At A Glance

A guide to this month’s studies

1. Initial trophic feedings effective for patients with acute lung injury
2. IM vs. IV benzodiazepines in status epilepticus
3. CDI risk following antibiotic cessation
4. Acid suppression associated with increased complications in CDI patients
5. Perioperative statins and cardiac events in surgical patients
6. Enoxaparin vs. unfractionated heparin during PCI
7. Optimal serum potassium levels for AMI patients
8. PPIs superior to H2-blockers for lowering UGI bleeding following ACS and STEMI

Initial Lower-Volume Enteral Feeding Better Tolerated, but Has No Mortality Benefit

Clinical question: In mechanically ventilated patients with acute lung injury, do initial lower-volume enteral feedings (trophic feedings) improve clinical outcomes when compared with full enteral feedings?

Background: Malnutrition in critically ill patients is associated with poor outcomes, but conflicting data exist regarding the best timing, amount, and formulation of enteral nutrition to initiate. Initiation of lower-volume enteral feeding with periodic assessment of gastric residual volume is common practice, but the effects of this practice are unknown.

Study design: Multicenter randomized controlled open-label study.

Setting: Forty-four hospitals in the National Heart, Lung, and Blood Institute (NHLBI) Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network.

Synopsis: One thousand patients with acute lung injury receiving mechanical ventilation for longer than 72 hours were randomized using a Web-based system to receive either trophic or full enteric feedings for the first six days of mechanical ventilation. After the sixth day, a full enteric feeding protocol was used in all patients. All analyses were by intention-to-treat.

There was no significant difference between the trophic and full enteral feeding groups with regard to the primary outcome of ventilator-free days through Day 28 (14.9% vs. 15.0%, P=0.89). There were also no significant differences between groups in secondary outcomes, which included 60-day mortality, ICU-free days, organ-failure-free days, or the incidence of new infections. However, gastrointestinal intolerances occurred less often in the trophic feeding group, and these patients received fewer anti-diarrheal and prokinetic agents. The full feeding group gained 2.1 liters of fluid by Day 7, but this fluid gain did not cause significant differences in measures of circulatory or pulmonary physiology.

Limitations include open-label study design and inclusion of only critically ill adult medical patients with acute lung injury.

Bottom line: Initial lower-volume tube feedings in mechanically ventilated patients with acute lung injury did not improve clinical outcomes compared with full enteral feedings, but they were associated with fewer instances of gastrointestinal intolerance.

Citation: National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA. 2012;307:795-803.

Intramuscular Benzodiazepines as Good as IV Benzodiazepines in Status Epilepticus

Clinical question: Is intramuscular (IM) midazolam noninferior to intravenous lorazepam in patients in status epilepticus?

Background: Studies have shown that IV benzodiazepines, particularly lorazepam, are effective for patients in status epilepticus. Studies have not evaluated IM benzodiazepines. However, many emergency medical service (EMS) agencies use IM midazolam because IM administration is easier than IV administration, and midazolam has a longer nonrefrigerated shelf life than lorazepam does.

Study design: Randomized, double-blinded clinical trial.

Setting: Thirty-three EMS agencies across the United States.

Synopsis: Based on the 893 adults and children in status epilepticus included in this double-blind study, the researchers found IM midazolam to be noninferior to, and in fact superior to, IV lorazepam for treating seizures prior to arrival at EDs. Specifically, they found 10% more (95% CI 4.0% to 16.1%; P<0.001 for noninferiority and P<0.001 for superiority) seizure-free patients arriving at EDs when IM midazolam was administered. Seizures ceased in patients given IM midazolam in less time on average than it took for paramedics to administer IV lorazepam.

Hospitalists might be less inclined than EMS personnel to use IM midazolam because their patients have established IV access and refrigerated drugs are readily available. However, since IM midazolam was superior to IV lorazepam in this prehospital study, a similar trial in hospitalized patients is warranted. In subsequent trials, it would be useful to administer both midazolam and lorazepam via IM and IV routes, and IM injections by an autoinjector could be compared with the conventional manner.

Bottom line: In the prehospital setting, IM midazolam is at least as good as IV lorazepam in treating status epilepticus in children and adults.

Citation: Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012;366:591-600.

Clostridium Difficile Infection Risk Remains High at Least Three Months after Antibiotics Are Stopped

Clinical question: How long are patients at higher risk for Clostridium difficile infection (CDI) after completing antibiotics?

Background: Studies have shown that patients given antibiotics are at higher risk for CDI than those who are not, particularly if they take multiple antibiotics at high doses for a prolonged period of time. However, it is not known how long a patient remains at high risk for CDI after completing antibiotic therapy.

Study design: Case-control study.

Setting: Nine hospitals in Netherlands.

Synopsis: The study compared 337 hospitalized patients who had CDI with 337 nondiarrheal controls and 227 non-CDI diarrheal controls. The study showed a seven- to tenfold increased risk for CDI during antibiotic treatment and in the 30 days following cessation of antibiotics. A 2.7-fold increased risk of CDI was seen in the one- to three-month period after antibiotic treatment was stopped.

Because researchers only obtained information about antibiotic use in the three months preceding the onset of diarrhea, it is unknown if CDI risk remains elevated longer than three months after antibiotics are stopped. Also of note, the enzyme immunoassays used in this study to diagnose C. diff had sensitivities of between 60% and 85%.

As hospitalists, this information can be used to advise patients about their continued risk for CDI after cessation of antibiotics. Further studies are needed to determine the risk after three months.

Bottom line: Patients are at highest risk for CDI up to one month after stopping antibiotics but continue to be at higher risk for at least two additional months.

Citation: Hensgens MPN, Goorhuis A, Dekkers OM, Kuijper EJ. Time interval of increased risk for Clostridium difficile infection after exposure to antibiotics. J Antimicrob Chemother. 2012;67:742-748.

Acid Suppression and Poor Outcomes in C. Diff Patients

Clinical question: What are potential modifiable risk factors associated with increased complications and mortality in patients hospitalized with C. diff infection (CDI)?

Background: CDI is a growing cause of morbidity and mortality in hospitalized patients. Evidence is growing for the association of acid suppression, among other modifiable risk factors, with complications and mortality in patients with CDI.

Study design: Retrospective case review.

Setting: Naval medical center.

Synopsis: A laboratory, medical record, and pharmacy database query found 485 patients with CDI. Complications of CDI were defined as ICU admission, surgery, and megacolon. Factors significantly associated with CDI complications and mortality were admission for CDI, corticosteroid use >5 mg per day, age ≥80 years, and prescription acid suppression (including H2-blockers and proton-pump inhibitors).

The latter two risk factors were associated with mortality alone. In multivariable regression, the odds of mortality among patients on acid suppression was more than four times the odds of those not on acid suppression (OR 4.74, 95% CI, 1.57 to 14.36).

Although this is a retrospective cohort study and cannot prove a causal relationship, the data add to a growing body of evidence supporting the risk of CDI complications and mortality for those on acid suppression.

Bottom line: In hospitalized patients with CDI, acid suppression is associated with increased complications and mortality and should be discontinued in this population when possible.

Citation: Morrison RH, Hall NS, Said M, et al. Risk factors associated with complications and mortality in patients with Clostridium difficile infection. Clin Infect Dis. 2011;53:1173-1178.

Perioperative Statins Reduce Cardiac Events for Surgical Patients

Clinical question: Does perioperative statin use improve cardiac outcomes (death, myocardial infarction, atrial fibrillation, and ICU and hospital lengths of stay) in statin-naive patients undergoing cardiac or non-cardiac surgery?

Background: Statins have been hypothesized to reduce perioperative cardiac complications because they reduce vascular and systemic inflammation caused by surgery, and several meta-analyses have demonstrated their efficacy. To date, no meta-analyses have specifically evaluated the benefits of perioperative statins in non-cardiac surgery from randomized controlled trials.

Study design: Systematic review of the literature and meta-analysis.

Setting: Fifteen randomized controlled trials of hospitalized surgical patients.

Synopsis: A systematic review examined the effects of statins on a variety of perioperative cardiac outcomes (death, myocardial infarction, atrial fibrillation, and ICU and hospital lengths of stay); 11 of the 15 patients were undergoing cardiac surgery.

Perioperative statins decreased the risk of atrial fibrillation in patients undergoing cardiac surgery (RR 0.56; 95% CI 0.45-0.69; number needed to treat [NNT], 6). In both cardiac and non-cardiac surgical patients, statins reduced the risk of myocardial infarction (RR 0.53; 95% CI 0.38 to 0.74; NNT 23). Statin treatment also reduced the mean length of hospital stay (in days, mean difference -0.32; 95% CI, -0.53 to -0.11) but did not reduce the length of ICU stay (mean difference -0.08; 95% CI, -0.25 to 0.10). Risk of death was not reduced with statin treatment (RR 0.62; 95% CI, 0.34 to 1.14).

Bottom line: Perioperative statins reduce the risk of postoperative atrial fibrillation in cardiac surgical patients, the risk of postoperative MI in cardiac and non-cardiac surgical patients, and the mean length of hospital stay.

Citation: Chopra V, Wesorick DH, Sussman JB, et al. Effect of perioperative statins on death, myocardial infarction, atrial fibrillation, and length of stay: a systematic review and meta-analysis. Arch Surg. 2012;147:181-188.

Enoxaparin Safe and Effective during Percutaneous Coronary Intervention

Clinical question: Is enoxaparin safe and efficacious compared with unfractionated heparin during percutaneous coronary intervention (PCI)?

Background: Despite problems with the use of unfractionated heparin during PCI, current guidelines give it a Class 1 recommendation for PCI in ST-elevation myocardial infarction (MI). There is growing evidence that enoxaparin can provide predictable, effective anticoagulation during PCI. Although several trials have examined this issue, none have been sufficiently powered to evaluate mortality.

Study design: Systematic review and meta-analysis.

Setting: Twenty-three trials or registries of patients undergoing PCI.

Synopsis: A systematic review found 23 trials representing 30,966 patients that examined the effects of enoxaparin versus unfractionated heparin on risk of mortality, MI, complications of MI, and major bleeding. Of these, 10,243 (33.1%) patients underwent primary PCI for ST elevation MI, 8,750 (28.2%) underwent PCI after fibrinolysis, and 11,973 (38.7%) patients had either scheduled PCI or PCI for non-ST elevation acute coronary syndrome.

Of all the patients, 13,943 (45%) received enoxaparin and 17,023 (55%) received unfractionated heparin. Enoxaparin was associated with significant reductions in all-cause mortality (RR 0.66; 95% CI, 0.57 to 0.76), composite of death or MI (RR 0.68; 95% CI, 0.57 to 0.81), and complications of MI (RR 0.75; 95% CI, 0.6 to 0.85). For patients who received primary PCI for ST elevation MI, enoxaparin reduced the risk of complications of MI by 44% (RR 0.56; 95% CI, 0.42 to 0.76). Enoxaparin also reduced the risk of major bleeding (RR 0.80, 95% CI, 0.68 to 0.95) with even more striking results for the 14 studies that compared intravenous enoxaparin to unfractionated heparin (RR 0.66; 95% CI, 0.52 to 0.83).

Bottom line: Enoxaparin is safe and efficacious when used during PCI. Patients who receive enoxaparin during PCI have reduced risk for death, MI, complications of MI, and major bleeding when compared with patients who receive unfractionated heparin.

Citation: Silvain J, Beygui F, Barthelmy O, et al. Efficacy and safety of enoxaparin versus unfractionated heparin during percutaneous coronary intervention: systematic review and meta-analysis. BMJ. 2012;344:e553.

Serum Potassium Levels and Mortality in Acute Myocardial Infarction

Clinical question: What is the relationship between serum potassium levels and mortality in acute myocardial infarction (AMI) patients?

Background: Several smaller studies in the pre-beta-blocker and pre-reperfusion era recommended maintaining serum potassium levels between 4.0 mEq/L and 5.0 mEq/L in AMI patients. However, current studies examining the relationship between potassium levels and mortality in AMI patients are lacking.

Study design: Retrospective cohort study.

Setting: Multicenter study involving 67 hospitals in the U.S.

Synopsis: Using the Cerner Health Facts database, which included 38,689 patients with biomarker-confirmed AMI, this study showed there was a U-shaped relationship between mean post-admission serum potassium level and in-hospital mortality.

Compared with the reference group of 3.5 mEq/L to less than 4.0 mEq/L (mortality rate 4.8%; 95% CI, 4.4% to 5.2%), mortality was comparable for those with mean post-admission potassium of 4.0 mEq/L to less than 4.5 mEq/L (5.0%; 95% CI, 4.7% to 5.3%). Mortality was twice as great for potassium of 4.5 mEq/L to less than 5.0 mEq/L (10.0%; 95% CI, 9.1% to 10.9%), and even greater for higher potassium strata. Similarly, mortality rates were higher for potassium levels of less than 3.5 mEq/L. Rates of ventricular fibrillation or cardiac arrest were higher among patients with potassium levels of less than 3.0 mEq/L or more than 5.0 mEq/L.

Bottom line: For inpatients with AMI, serum potassium levels of 3.5 mEq/L to 4.5 mEq/L should be maintained for the best outcomes. Repletion of serum potassium to levels greater than 4.5 mEq/L is associated with increased mortality and should be avoided.

Citation: Goyal A, Spertus JA, Gosch K, et al. Serum potassium levels and mortality in acute myocardial infarction. JAMA. 2012;307:157-164.

Proton-Pump Inhibitors Better than H2-Blockers in ACS and STEMI

Clinical question: Are proton-pump inhibitors (PPIs) better than H2-blockers at preventing UGI bleeding in patients after acute coronary syndrome (ACS) or ST-elevation myocardial infarction (STEMI)?

Background: It is not definitively known if PPIs are the same or better than H2-blockers in preventing UGI bleeding in patients on high-risk medications (aspirin, clopidogrel, and anticoagulants) after ACS or STEMI.

Study design: Randomized double-blinded controlled trial.

Setting: Single hospital.

Synopsis: Patients with ACS or STEMI were treated with aspirin, clopidogrel, and enoxaparin or thrombolytics. They were then randomized to either esomeprazole 20 mg or famotidine 40 mg, both administered nightly. They were followed throughout their hospital stay and were then followed between four and 52 weeks after discharge (mean duration: 19 weeks for esomeprazole, 18 weeks for famotidine). The primary end point was time to a composite outcome, consisting of UGI bleeding, obstruction, or perforation. Overall, 313 patients were randomized (164 to esomeprazole and 149 to famotidine).

The treatment groups were equivalent in baseline characteristics, and compliance in both groups was excellent (>98%). The primary endpoint occurred in three patients in the esomeprazole group and in 12 patients in the famotidine group (hazard ratio 0.21; 95% CI, 0.06 to 0.75; P=0.008).

Bottom line: PPIs are superior to H2-blockers in reducing UGI bleeding in patients on high-risk medications (aspirin, clopidogrel, and enoxaparin or thrombolytics) after ACS and STEMI. This confirms the recommendations of the 2010 ACCF/ACG/AHA Expert Consensus that PPIs should be used in those on dual antiplatelet therapy on anticoagulants.

Citation: Ng FH, Tunggal P, Chu WM, et al. Esomeprazole compared with famotidine in the prevention of upper gastrointestinal bleeding in patients with acute coronary syndrome or myocardial infarction. Am J Gastroenterol. 2012;107:389-396.

In This Edition

Literature At A Glance

A guide to this month’s studies

1. Procalcitonin to guide antimicrobial use in ICU patients
2. Platelet reactivity and event rates after PCI
3. Conservative treatment of necrotizing pancreatitis
4. Use of MRI to diagnose Takotsubo cardiomyopathy
5. Rates of inadvertent medication discontinuation after hospitalization
6. Role of history and physical exam in diagnosing medical illness
7. Red-cell distribution width and rates of mortality

Procalcitonin-Guided Therapy Decreases Antimicrobial Duration in ICU Patients

Clinical question: Can utilization of serum procalcitonin (PCT) levels safely reduce antimicrobial exposure in ICU patients?

Background: Serum PCT levels are elevated in bacterial infections and sepsis and have been used in some settings to guide antimicrobial therapy. Randomized controlled trials have demonstrated reduction of antibiotic use with PCT measurement. This systematic review assessed the safety and effectiveness of PCT measurements in reducing antimicrobial exposure in ICU patients.

Study design: Systematic review.

Setting: Adult medical and surgical ICUs.

Synopsis: A search of MEDLINE and EMBASE yielded 1,018 publications related to PCT, critically ill patients, and antimicrobial therapy. Six randomized controlled trials involving 1,476 patients were reviewed. The duration of antimicrobial use was significantly decreased in all five studies that evaluated treatment duration. The remaining study only assessed the impact of PCT on initiation of antimicrobial therapy and did not demonstrate decreased antimicrobial exposure. Compared with the control group, patients randomized to PCT-guided therapy had relative reductions in duration of first antibiotic course by 21%, down to 38%, and decreases in days of antimicrobial therapy per 1,000 ICU patient days by 20%, down to 23%. PCT intervention also was associated with a 23% to 37% increase in days alive without antimicrobial therapy during the first 28 days. The length of ICU stay was significantly decreased in two studies but was not significantly different in the other studies. There were no significant differences in rates of mortality, infection relapse, or days free of mechanical ventilation.

Bottom line: PCT guidance reduced antimicrobial exposure of ICU patients without increasing rates of mortality or infection relapse.

Citation: Agarwal R, Schwartz DN. Procalcitonin to guide duration of antimicrobial therapy in intensive care units: a systematic review. Clin Infect Dis. 2011;53:379-387.

High Residual Platelet Reactivity Increases Risk of Cardiovascular Events among Patients with Acute Coronary Syndromes Undergoing PCI

Clinical question: Is high residual platelet reactivity (HRPR) in patients receiving clopidogrel associated with increased risk of ischemic events after percutaneous coronary intervention (PCI)?

Background: Studies have demonstrated an increased risk of cardiovascular events associated with HRPR in patients receiving clopidogrel while undergoing PCI. However, these studies have used a variety of platelet function tests, and thresholds for positive tests have not been established. In addition, these studies have enrolled heterogeneous populations with short-term follow-up and few have included patients with acute coronary syndromes (ACSs).

Study design: Prospective cohort study.

Setting: Cardiology service of a referral center in Italy.

Synopsis: This study included 1,789 consecutive patients with ACS undergoing PCI. Patients were given 325 mg aspirin and a 600-mg loading dose of clopidogrel on admission, followed by a daily maintenance dose of aspirin 325 mg and clopidogrel 75 mg for at least six months. Platelet reactivity was measured using adenosine diphosphate (ADP) testing, and those with HRPR (≥70% platelet aggregation) were given increased dosing of clopidogrel or switched to ticlopidine using ADP test guidance. At two-year follow-up, patients with HRPR experienced an increased composite endpoint of cardiac death, myocardial infarction, urgent coronary revascularization, and stroke with a combined event rate of 14.6% in patients with HRPR and 8.7% in patients with low residual platelet reactivity (95% CI, 1.6%-11.1%; P=0.003). Stent thrombosis was also higher in HRPR patients (absolute risk increase 3.2%; 95% CI, 0.4%-6.7%; P=0.01).

This study is nonrandomized, and residual unmeasured confounding cannot be excluded. In addition, use of non-antiplatelet drugs and adherence to recommended drugs might have influenced outcomes.

Bottom line: HRPR is associated with increased risk of ischemic events in patients with ACS receiving antiplatelet agents after PCI.

Citation: Parodi G, Marcucci R, Valenti R, et al. High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI. JAMA. 2011;306:1215-1223.

Conservative Treatment of Necrotizing Pancreatitis Is Associated with Improved Outcomes

Clinical question: What are the outcomes of conservative and interventional management of necrotizing pancreatitis?

Background: Open necrosectomy was historically the treatment of choice for necrotizing pancreatitis, but, currently, pancreatic necrosis is only managed invasively when complicated by infection. Other changes in management over time have included a shift in the timing of intervention and the use of minimally invasive techniques. Existing studies do not reflect these changes in practice patterns and have been limited by small sample sizes or the exclusion of important subgroups of patients.

Study design: Prospective cohort study.

Setting: Twenty-one Dutch hospitals.

Synopsis: This study included 639 patients with acute necrotizing pancreatitis confirmed by imaging. Overall mortality was 15%. Conservative treatment was performed in 62% of the patients with a mortality of 7%; however, patients with organ failure (pulmonary, circulatory, and/or renal) who received conservative therapy had a mortality rate of 37%. Intervention (percutaneous drainage, video-assisted retroperitoneal debridement, endoscopic transluminal necrosectomy, laparotomy) in patients with suspected or confirmed infected pancreatic necrosis was performed on 38% of the patients with associated mortality of 27%. Interventions performed within the first 14 days of hospitalization resulted in a 56% mortality rate, whereas interventions performed after Day 29 resulted in a 15% mortality rate (P<0.001). Patients with organ failure experienced significantly greater mortality compared with patients with no organ failure (35% vs. 2%; P<0.001). Primary percutaneous drainage was associated with fewer complications than was primary necrosectomy (42% vs. 64%; P=0.003).

This study was nonrandomized, and final decisions regarding management were left to the treating physician. Notably, while there was no significant difference in APACHE II scores between the conservative and intervention groups, intervention patients had more severe pancreatic disease and scored higher on other measures of disease severity.

Bottom line: Patients with necrotizing pancreatitis can frequently be managed conservatively, though the presence of organ failure and parenchymal necrosis confer poorer prognosis. When intervention is indicated, postponing intervention and utilizing minimally invasive techniques decrease morbidity and mortality.

Citation: Van Santvoort HC, Bakker OJ, Bollen TL, et al. A conservative and minimally invasive approach to necrotizing pancreatitis improves outcome. Gastroenterology. 2011;141:1254-1263.

Cardiac MRI Complements Clinical Findings in Diagnosis of Stress Cardiomyopathy

Clinical question: What are the clinical features and cardiovascular MRI findings in patients with stress (Takotsubo) cardiomyopathy?

Background: Stress cardiomyopathy (SC) is characterized by acute and profound reversible left ventricular dysfunction that is thought to result from increased sympathetic activity related to emotional and/or physical stress. Prior studies evaluating the clinical features of SC were limited by small sample sizes and single-center enrollment, and cardiac MRI use in SC has not been well studied.

Study design: Prospective cohort study.

Setting: Seven North American and European tertiary-care centers.

Synopsis: This study enrolled 256 patients who met diagnostic criteria for SC according to Mayo criteria. Postmenopausal women were most commonly affected; only 11% of participants were men and 8% were women younger than 50 years old. An identifiable stressor was found in 71% of the patients. Clinical presentation was notable for symptoms of acute coronary syndrome (ACS) in 88% of patients, abnormal electrocardiogram in 87%, and elevated troponin T in 90%. Coronary angiography was normal in three-fourths of patients, and no patients had features of acute plaque rupture. Typical apical ballooning was seen on left ventriculography in 82% of patients.

Cardiac MRI findings included severe left ventricular dysfunction in a noncoronary distribution, myocardial edema in areas of regional wall abnormalities, absence of high signal areas in late gadolinium enhancement (e.g., absence of necrosis/fibrosis), and increased early gadolinium uptake (i.e. early inflammation). Repeat cardiac MRI four weeks after initial diagnosis showed near or complete resolution of imaging findings.

Bottom line: Stress cardiomyopathy typically presents like ACS, usually affects postmenopausal women, is often preceded by a stressful event, and is characterized by cardiac MRI findings of regional wall motion abnormalities, reversible myocardial injury, and the absence of fibrosis. Cardiac MRI may be valuable in diagnosing SC in patients who present without the classic clinical features.

Citation: Eitel I, von Knobelsdorff-Brenkenhoff F, Bernhardt P, et al. Clinical characteristics and cardiovascular magnetic resonance findings in stress (Takotsubo) cardiomyopathy. JAMA. 2011;306:277-286.

Increased Risk of Potentially Inadvertent Medication Discontinuation Following Acute-Care Hospitalization

Clinical question: Are medications for chronic diseases inadvertently discontinued after acute-care hospitalization, and is this risk increased in patients who had an ICU stay?

Background: Transitions of care are associated with medical errors. Two such transitions are a shift from the ICU to floor setting and from the inpatient to outpatient setting. Medications for chronic diseases might be held during hospitalization for a variety of reasons, and medication errors may occur if these drugs are not restarted when the acute problem resolves or the patient is discharged from the hospital.

Study design: Population-based cohort study.

Setting: Ontario, Canada.

Synopsis: Using four separate databases, administrative records were reviewed for 396,380 patients aged >65 years who were continuous users of at least one of five evidence-based medication groups for common chronic diseases. Medications included statins, antiplatelet/anticoagulant agents, levothyroxine, respiratory inhalers, and gastric acid suppressants. The primary outcome was potentially unintentional medication discontinuation (measured by failure to renew the prescription at 90 days) for hospitalized versus nonhospitalized patients. All medication groups had statistically significant adjusted odds ratios ranging from 1.18 (95% CI, 1.14-1.23) for discontinuation of levothyroxine to 1.86 (95% CI, 1.77-1.97) for discontinuation of antiplatelet/anticoagulant medications. Treatment in an ICU further increased this risk compared with nonhospitalized patients, and increased the risk for medication discontinuation in four of the five medication groups when compared with patients hospitalized without ICU treatment.

Important study limitations include the lack of appropriate clinical details to classify medication discontinuation as unintentional and the inability of administrative data to prove causality. This study highlights the importance of medication reconciliation and calls attention to inadvertent medication discontinuation during care transitions (see “Reconciliation Act,”).

Bottom line: Patients discharged from the hospital, particularly after ICU treatment, have a higher risk of discontinuation of long-term medications for chronic medical problems when compared with nonhospitalized patients.

Citation: Bell CM, Brener SS, Gunraj N, et al. Association of ICU or hospital admission with unintentional discontinuation of medications for chronic diseases. JAMA. 2011;306:840-847.

Clinical Exam Remains Valuable in the Diagnosis of Patients Admitted to a Medicine Service

Clinical question: Is a clinical exam useful in the diagnosis of newly admitted patients to a general medicine service?

Background: The clinical exam, which comprises the history and physical examination, has long been described as essential to the diagnosis of illness. However, the literature supporting this claim is limited to the ambulatory setting. There has not been evaluation of the clinical exam as a diagnostic tool in the hospital setting, where more advanced testing is readily available.

Study design: Retrospective chart review.

Setting: Urban academic medical center.

Synopsis: The study included 442 adult patients consecutively admitted from the emergency department to the general medicine service who were separately assessed by one senior resident (SR) and one experienced hospital physician (HP) not involved with the case. The SR and HP each made an initial diagnosis and documented the most helpful component(s) in arriving at that diagnosis. Outcomes included comparison of the SR and HP’s admission diagnosis with the discharge diagnosis, and the diagnostic value of the various components of the clinical exam and initial studies.

Compared with the discharge diagnosis, the SR’s initial diagnosis was correct in 80.1% of cases, while the HP was correct in 84.4%. The patient’s history was the most important element in the initial assessment, independently influencing approximately 20% of the correct diagnoses for both physicians. Approximately 60% of correct diagnoses were established using the history and/or physical, and more than 90% were made using a combination of history, physical exam, and/or basic tests (admission labs, electrocardiogram, chest X-ray).

The generalizability of these results is limited by the retrospective, single-center study design, involvement of only one resident physician, and the lack of information regarding number of experienced clinicians and types of diagnoses.

Bottom line: Among patients admitted to a general medicine service, the most powerful tool in obtaining an accurate diagnosis was the combination of a patient’s history and a physical exam.

Citation: Paley L, Zornitzki T, Cohen J, et al. Utility of clinical examination in the diagnosis of emergency department patients admitted to the department of medicine of an academic hospital. Arch Intern Med. 2011;171:1394-1396.

RDW Predicts All-Cause Mortality and Bloodstream Infection in ICU Patients

Clinical question: Among patients admitted to the ICU, is red blood cell distribution width (RDW) a reliable indicator of mortality?

Background: The RDW is an inexpensive test that is commonly included in routine laboratory studies. It has been associated with multiple disease processes and found to be a strong predictor of mortality in the general adult population. However, there has been limited study of the association between RDW and outcomes in critically ill patients.

Study design: Observational cohort study.

Setting: Urban tertiary-care academic medical center.

Synopsis: Data from 51,413 adult patients who received critical care between 1997 and 2007 were obtained from a computerized registry and evaluated for the primary outcome of 30-day mortality after critical-care initiation. Secondary outcomes included 90-day, 365-day, and in-hospital mortality, as well as bloodstream infection. Logistic regression examined both primary and secondary outcomes in association with pre-established RDW quintiles. After multivariable adjustment, RDW was found to be associated with mortality at 30, 90, and 365 days, in addition to in-hospital mortality. The highest RDW quintile (RDW >15.8%) had an adjusted OR of 2.61 (95% CI, 2.37-2.86; P<0.001) for the primary outcome, with similar risk for secondary outcomes of mortality. A subgroup of 18,525 patients with blood culture data was analyzed and an adjusted OR of 1.44 was found in the highest RDW quintile for the secondary outcome of bloodstream infection.

Bottom line: Red blood cell distribution width is a strong independent predictor of all-cause mortality and bloodstream infection in patients receiving intensive care.

Citation: Bazick HS, Chang D, Mahadevappa K, Gibbons FK, Christopher KB. Red cell distribution width and all-cause mortality in critically ill patients. Crit Care Med. 2011;39:1913-1921.

In This Edition

Literature At A Glance

A guide to this month’s studies

1. Procalcitonin to guide antimicrobial use in ICU patients
2. Platelet reactivity and event rates after PCI
3. Conservative treatment of necrotizing pancreatitis
4. Use of MRI to diagnose Takotsubo cardiomyopathy
5. Rates of inadvertent medication discontinuation after hospitalization
6. Role of history and physical exam in diagnosing medical illness
7. Red-cell distribution width and rates of mortality

Procalcitonin-Guided Therapy Decreases Antimicrobial Duration in ICU Patients

Clinical question: Can utilization of serum procalcitonin (PCT) levels safely reduce antimicrobial exposure in ICU patients?

Background: Serum PCT levels are elevated in bacterial infections and sepsis and have been used in some settings to guide antimicrobial therapy. Randomized controlled trials have demonstrated reduction of antibiotic use with PCT measurement. This systematic review assessed the safety and effectiveness of PCT measurements in reducing antimicrobial exposure in ICU patients.

Study design: Systematic review.

Setting: Adult medical and surgical ICUs.

Synopsis: A search of MEDLINE and EMBASE yielded 1,018 publications related to PCT, critically ill patients, and antimicrobial therapy. Six randomized controlled trials involving 1,476 patients were reviewed. The duration of antimicrobial use was significantly decreased in all five studies that evaluated treatment duration. The remaining study only assessed the impact of PCT on initiation of antimicrobial therapy and did not demonstrate decreased antimicrobial exposure. Compared with the control group, patients randomized to PCT-guided therapy had relative reductions in duration of first antibiotic course by 21%, down to 38%, and decreases in days of antimicrobial therapy per 1,000 ICU patient days by 20%, down to 23%. PCT intervention also was associated with a 23% to 37% increase in days alive without antimicrobial therapy during the first 28 days. The length of ICU stay was significantly decreased in two studies but was not significantly different in the other studies. There were no significant differences in rates of mortality, infection relapse, or days free of mechanical ventilation.

Bottom line: PCT guidance reduced antimicrobial exposure of ICU patients without increasing rates of mortality or infection relapse.

Citation: Agarwal R, Schwartz DN. Procalcitonin to guide duration of antimicrobial therapy in intensive care units: a systematic review. Clin Infect Dis. 2011;53:379-387.

High Residual Platelet Reactivity Increases Risk of Cardiovascular Events among Patients with Acute Coronary Syndromes Undergoing PCI

Clinical question: Is high residual platelet reactivity (HRPR) in patients receiving clopidogrel associated with increased risk of ischemic events after percutaneous coronary intervention (PCI)?

Background: Studies have demonstrated an increased risk of cardiovascular events associated with HRPR in patients receiving clopidogrel while undergoing PCI. However, these studies have used a variety of platelet function tests, and thresholds for positive tests have not been established. In addition, these studies have enrolled heterogeneous populations with short-term follow-up and few have included patients with acute coronary syndromes (ACSs).

Study design: Prospective cohort study.

Setting: Cardiology service of a referral center in Italy.

Synopsis: This study included 1,789 consecutive patients with ACS undergoing PCI. Patients were given 325 mg aspirin and a 600-mg loading dose of clopidogrel on admission, followed by a daily maintenance dose of aspirin 325 mg and clopidogrel 75 mg for at least six months. Platelet reactivity was measured using adenosine diphosphate (ADP) testing, and those with HRPR (≥70% platelet aggregation) were given increased dosing of clopidogrel or switched to ticlopidine using ADP test guidance. At two-year follow-up, patients with HRPR experienced an increased composite endpoint of cardiac death, myocardial infarction, urgent coronary revascularization, and stroke with a combined event rate of 14.6% in patients with HRPR and 8.7% in patients with low residual platelet reactivity (95% CI, 1.6%-11.1%; P=0.003). Stent thrombosis was also higher in HRPR patients (absolute risk increase 3.2%; 95% CI, 0.4%-6.7%; P=0.01).

This study is nonrandomized, and residual unmeasured confounding cannot be excluded. In addition, use of non-antiplatelet drugs and adherence to recommended drugs might have influenced outcomes.

Bottom line: HRPR is associated with increased risk of ischemic events in patients with ACS receiving antiplatelet agents after PCI.

Citation: Parodi G, Marcucci R, Valenti R, et al. High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI. JAMA. 2011;306:1215-1223.

Conservative Treatment of Necrotizing Pancreatitis Is Associated with Improved Outcomes

Clinical question: What are the outcomes of conservative and interventional management of necrotizing pancreatitis?

Background: Open necrosectomy was historically the treatment of choice for necrotizing pancreatitis, but, currently, pancreatic necrosis is only managed invasively when complicated by infection. Other changes in management over time have included a shift in the timing of intervention and the use of minimally invasive techniques. Existing studies do not reflect these changes in practice patterns and have been limited by small sample sizes or the exclusion of important subgroups of patients.

Study design: Prospective cohort study.

Setting: Twenty-one Dutch hospitals.

Synopsis: This study included 639 patients with acute necrotizing pancreatitis confirmed by imaging. Overall mortality was 15%. Conservative treatment was performed in 62% of the patients with a mortality of 7%; however, patients with organ failure (pulmonary, circulatory, and/or renal) who received conservative therapy had a mortality rate of 37%. Intervention (percutaneous drainage, video-assisted retroperitoneal debridement, endoscopic transluminal necrosectomy, laparotomy) in patients with suspected or confirmed infected pancreatic necrosis was performed on 38% of the patients with associated mortality of 27%. Interventions performed within the first 14 days of hospitalization resulted in a 56% mortality rate, whereas interventions performed after Day 29 resulted in a 15% mortality rate (P<0.001). Patients with organ failure experienced significantly greater mortality compared with patients with no organ failure (35% vs. 2%; P<0.001). Primary percutaneous drainage was associated with fewer complications than was primary necrosectomy (42% vs. 64%; P=0.003).

This study was nonrandomized, and final decisions regarding management were left to the treating physician. Notably, while there was no significant difference in APACHE II scores between the conservative and intervention groups, intervention patients had more severe pancreatic disease and scored higher on other measures of disease severity.

Bottom line: Patients with necrotizing pancreatitis can frequently be managed conservatively, though the presence of organ failure and parenchymal necrosis confer poorer prognosis. When intervention is indicated, postponing intervention and utilizing minimally invasive techniques decrease morbidity and mortality.

Citation: Van Santvoort HC, Bakker OJ, Bollen TL, et al. A conservative and minimally invasive approach to necrotizing pancreatitis improves outcome. Gastroenterology. 2011;141:1254-1263.

Cardiac MRI Complements Clinical Findings in Diagnosis of Stress Cardiomyopathy

Clinical question: What are the clinical features and cardiovascular MRI findings in patients with stress (Takotsubo) cardiomyopathy?

Background: Stress cardiomyopathy (SC) is characterized by acute and profound reversible left ventricular dysfunction that is thought to result from increased sympathetic activity related to emotional and/or physical stress. Prior studies evaluating the clinical features of SC were limited by small sample sizes and single-center enrollment, and cardiac MRI use in SC has not been well studied.

Study design: Prospective cohort study.

Setting: Seven North American and European tertiary-care centers.

Synopsis: This study enrolled 256 patients who met diagnostic criteria for SC according to Mayo criteria. Postmenopausal women were most commonly affected; only 11% of participants were men and 8% were women younger than 50 years old. An identifiable stressor was found in 71% of the patients. Clinical presentation was notable for symptoms of acute coronary syndrome (ACS) in 88% of patients, abnormal electrocardiogram in 87%, and elevated troponin T in 90%. Coronary angiography was normal in three-fourths of patients, and no patients had features of acute plaque rupture. Typical apical ballooning was seen on left ventriculography in 82% of patients.

Cardiac MRI findings included severe left ventricular dysfunction in a noncoronary distribution, myocardial edema in areas of regional wall abnormalities, absence of high signal areas in late gadolinium enhancement (e.g., absence of necrosis/fibrosis), and increased early gadolinium uptake (i.e. early inflammation). Repeat cardiac MRI four weeks after initial diagnosis showed near or complete resolution of imaging findings.

Bottom line: Stress cardiomyopathy typically presents like ACS, usually affects postmenopausal women, is often preceded by a stressful event, and is characterized by cardiac MRI findings of regional wall motion abnormalities, reversible myocardial injury, and the absence of fibrosis. Cardiac MRI may be valuable in diagnosing SC in patients who present without the classic clinical features.

Citation: Eitel I, von Knobelsdorff-Brenkenhoff F, Bernhardt P, et al. Clinical characteristics and cardiovascular magnetic resonance findings in stress (Takotsubo) cardiomyopathy. JAMA. 2011;306:277-286.

Increased Risk of Potentially Inadvertent Medication Discontinuation Following Acute-Care Hospitalization

Clinical question: Are medications for chronic diseases inadvertently discontinued after acute-care hospitalization, and is this risk increased in patients who had an ICU stay?

Background: Transitions of care are associated with medical errors. Two such transitions are a shift from the ICU to floor setting and from the inpatient to outpatient setting. Medications for chronic diseases might be held during hospitalization for a variety of reasons, and medication errors may occur if these drugs are not restarted when the acute problem resolves or the patient is discharged from the hospital.

Study design: Population-based cohort study.

Setting: Ontario, Canada.

Synopsis: Using four separate databases, administrative records were reviewed for 396,380 patients aged >65 years who were continuous users of at least one of five evidence-based medication groups for common chronic diseases. Medications included statins, antiplatelet/anticoagulant agents, levothyroxine, respiratory inhalers, and gastric acid suppressants. The primary outcome was potentially unintentional medication discontinuation (measured by failure to renew the prescription at 90 days) for hospitalized versus nonhospitalized patients. All medication groups had statistically significant adjusted odds ratios ranging from 1.18 (95% CI, 1.14-1.23) for discontinuation of levothyroxine to 1.86 (95% CI, 1.77-1.97) for discontinuation of antiplatelet/anticoagulant medications. Treatment in an ICU further increased this risk compared with nonhospitalized patients, and increased the risk for medication discontinuation in four of the five medication groups when compared with patients hospitalized without ICU treatment.

Important study limitations include the lack of appropriate clinical details to classify medication discontinuation as unintentional and the inability of administrative data to prove causality. This study highlights the importance of medication reconciliation and calls attention to inadvertent medication discontinuation during care transitions (see “Reconciliation Act,”).

Bottom line: Patients discharged from the hospital, particularly after ICU treatment, have a higher risk of discontinuation of long-term medications for chronic medical problems when compared with nonhospitalized patients.

Citation: Bell CM, Brener SS, Gunraj N, et al. Association of ICU or hospital admission with unintentional discontinuation of medications for chronic diseases. JAMA. 2011;306:840-847.

Clinical Exam Remains Valuable in the Diagnosis of Patients Admitted to a Medicine Service

Clinical question: Is a clinical exam useful in the diagnosis of newly admitted patients to a general medicine service?

Background: The clinical exam, which comprises the history and physical examination, has long been described as essential to the diagnosis of illness. However, the literature supporting this claim is limited to the ambulatory setting. There has not been evaluation of the clinical exam as a diagnostic tool in the hospital setting, where more advanced testing is readily available.

Study design: Retrospective chart review.

Setting: Urban academic medical center.

Synopsis: The study included 442 adult patients consecutively admitted from the emergency department to the general medicine service who were separately assessed by one senior resident (SR) and one experienced hospital physician (HP) not involved with the case. The SR and HP each made an initial diagnosis and documented the most helpful component(s) in arriving at that diagnosis. Outcomes included comparison of the SR and HP’s admission diagnosis with the discharge diagnosis, and the diagnostic value of the various components of the clinical exam and initial studies.

Compared with the discharge diagnosis, the SR’s initial diagnosis was correct in 80.1% of cases, while the HP was correct in 84.4%. The patient’s history was the most important element in the initial assessment, independently influencing approximately 20% of the correct diagnoses for both physicians. Approximately 60% of correct diagnoses were established using the history and/or physical, and more than 90% were made using a combination of history, physical exam, and/or basic tests (admission labs, electrocardiogram, chest X-ray).

The generalizability of these results is limited by the retrospective, single-center study design, involvement of only one resident physician, and the lack of information regarding number of experienced clinicians and types of diagnoses.

Bottom line: Among patients admitted to a general medicine service, the most powerful tool in obtaining an accurate diagnosis was the combination of a patient’s history and a physical exam.

Citation: Paley L, Zornitzki T, Cohen J, et al. Utility of clinical examination in the diagnosis of emergency department patients admitted to the department of medicine of an academic hospital. Arch Intern Med. 2011;171:1394-1396.

RDW Predicts All-Cause Mortality and Bloodstream Infection in ICU Patients

Clinical question: Among patients admitted to the ICU, is red blood cell distribution width (RDW) a reliable indicator of mortality?

Background: The RDW is an inexpensive test that is commonly included in routine laboratory studies. It has been associated with multiple disease processes and found to be a strong predictor of mortality in the general adult population. However, there has been limited study of the association between RDW and outcomes in critically ill patients.

Study design: Observational cohort study.

Setting: Urban tertiary-care academic medical center.

Synopsis: Data from 51,413 adult patients who received critical care between 1997 and 2007 were obtained from a computerized registry and evaluated for the primary outcome of 30-day mortality after critical-care initiation. Secondary outcomes included 90-day, 365-day, and in-hospital mortality, as well as bloodstream infection. Logistic regression examined both primary and secondary outcomes in association with pre-established RDW quintiles. After multivariable adjustment, RDW was found to be associated with mortality at 30, 90, and 365 days, in addition to in-hospital mortality. The highest RDW quintile (RDW >15.8%) had an adjusted OR of 2.61 (95% CI, 2.37-2.86; P<0.001) for the primary outcome, with similar risk for secondary outcomes of mortality. A subgroup of 18,525 patients with blood culture data was analyzed and an adjusted OR of 1.44 was found in the highest RDW quintile for the secondary outcome of bloodstream infection.

Bottom line: Red blood cell distribution width is a strong independent predictor of all-cause mortality and bloodstream infection in patients receiving intensive care.

Citation: Bazick HS, Chang D, Mahadevappa K, Gibbons FK, Christopher KB. Red cell distribution width and all-cause mortality in critically ill patients. Crit Care Med. 2011;39:1913-1921.

In This Edition

Literature At A Glance

A guide to this month’s studies

1. Procalcitonin to guide antimicrobial use in ICU patients
2. Platelet reactivity and event rates after PCI
3. Conservative treatment of necrotizing pancreatitis
4. Use of MRI to diagnose Takotsubo cardiomyopathy
5. Rates of inadvertent medication discontinuation after hospitalization
6. Role of history and physical exam in diagnosing medical illness
7. Red-cell distribution width and rates of mortality

Procalcitonin-Guided Therapy Decreases Antimicrobial Duration in ICU Patients

Clinical question: Can utilization of serum procalcitonin (PCT) levels safely reduce antimicrobial exposure in ICU patients?

Background: Serum PCT levels are elevated in bacterial infections and sepsis and have been used in some settings to guide antimicrobial therapy. Randomized controlled trials have demonstrated reduction of antibiotic use with PCT measurement. This systematic review assessed the safety and effectiveness of PCT measurements in reducing antimicrobial exposure in ICU patients.

Study design: Systematic review.

Setting: Adult medical and surgical ICUs.

Synopsis: A search of MEDLINE and EMBASE yielded 1,018 publications related to PCT, critically ill patients, and antimicrobial therapy. Six randomized controlled trials involving 1,476 patients were reviewed. The duration of antimicrobial use was significantly decreased in all five studies that evaluated treatment duration. The remaining study only assessed the impact of PCT on initiation of antimicrobial therapy and did not demonstrate decreased antimicrobial exposure. Compared with the control group, patients randomized to PCT-guided therapy had relative reductions in duration of first antibiotic course by 21%, down to 38%, and decreases in days of antimicrobial therapy per 1,000 ICU patient days by 20%, down to 23%. PCT intervention also was associated with a 23% to 37% increase in days alive without antimicrobial therapy during the first 28 days. The length of ICU stay was significantly decreased in two studies but was not significantly different in the other studies. There were no significant differences in rates of mortality, infection relapse, or days free of mechanical ventilation.

Bottom line: PCT guidance reduced antimicrobial exposure of ICU patients without increasing rates of mortality or infection relapse.

Citation: Agarwal R, Schwartz DN. Procalcitonin to guide duration of antimicrobial therapy in intensive care units: a systematic review. Clin Infect Dis. 2011;53:379-387.

High Residual Platelet Reactivity Increases Risk of Cardiovascular Events among Patients with Acute Coronary Syndromes Undergoing PCI

Clinical question: Is high residual platelet reactivity (HRPR) in patients receiving clopidogrel associated with increased risk of ischemic events after percutaneous coronary intervention (PCI)?

Background: Studies have demonstrated an increased risk of cardiovascular events associated with HRPR in patients receiving clopidogrel while undergoing PCI. However, these studies have used a variety of platelet function tests, and thresholds for positive tests have not been established. In addition, these studies have enrolled heterogeneous populations with short-term follow-up and few have included patients with acute coronary syndromes (ACSs).

Study design: Prospective cohort study.

Setting: Cardiology service of a referral center in Italy.

Synopsis: This study included 1,789 consecutive patients with ACS undergoing PCI. Patients were given 325 mg aspirin and a 600-mg loading dose of clopidogrel on admission, followed by a daily maintenance dose of aspirin 325 mg and clopidogrel 75 mg for at least six months. Platelet reactivity was measured using adenosine diphosphate (ADP) testing, and those with HRPR (≥70% platelet aggregation) were given increased dosing of clopidogrel or switched to ticlopidine using ADP test guidance. At two-year follow-up, patients with HRPR experienced an increased composite endpoint of cardiac death, myocardial infarction, urgent coronary revascularization, and stroke with a combined event rate of 14.6% in patients with HRPR and 8.7% in patients with low residual platelet reactivity (95% CI, 1.6%-11.1%; P=0.003). Stent thrombosis was also higher in HRPR patients (absolute risk increase 3.2%; 95% CI, 0.4%-6.7%; P=0.01).

This study is nonrandomized, and residual unmeasured confounding cannot be excluded. In addition, use of non-antiplatelet drugs and adherence to recommended drugs might have influenced outcomes.

Bottom line: HRPR is associated with increased risk of ischemic events in patients with ACS receiving antiplatelet agents after PCI.

Citation: Parodi G, Marcucci R, Valenti R, et al. High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI. JAMA. 2011;306:1215-1223.

Conservative Treatment of Necrotizing Pancreatitis Is Associated with Improved Outcomes

Clinical question: What are the outcomes of conservative and interventional management of necrotizing pancreatitis?

Background: Open necrosectomy was historically the treatment of choice for necrotizing pancreatitis, but, currently, pancreatic necrosis is only managed invasively when complicated by infection. Other changes in management over time have included a shift in the timing of intervention and the use of minimally invasive techniques. Existing studies do not reflect these changes in practice patterns and have been limited by small sample sizes or the exclusion of important subgroups of patients.

Study design: Prospective cohort study.

Setting: Twenty-one Dutch hospitals.

Synopsis: This study included 639 patients with acute necrotizing pancreatitis confirmed by imaging. Overall mortality was 15%. Conservative treatment was performed in 62% of the patients with a mortality of 7%; however, patients with organ failure (pulmonary, circulatory, and/or renal) who received conservative therapy had a mortality rate of 37%. Intervention (percutaneous drainage, video-assisted retroperitoneal debridement, endoscopic transluminal necrosectomy, laparotomy) in patients with suspected or confirmed infected pancreatic necrosis was performed on 38% of the patients with associated mortality of 27%. Interventions performed within the first 14 days of hospitalization resulted in a 56% mortality rate, whereas interventions performed after Day 29 resulted in a 15% mortality rate (P<0.001). Patients with organ failure experienced significantly greater mortality compared with patients with no organ failure (35% vs. 2%; P<0.001). Primary percutaneous drainage was associated with fewer complications than was primary necrosectomy (42% vs. 64%; P=0.003).

This study was nonrandomized, and final decisions regarding management were left to the treating physician. Notably, while there was no significant difference in APACHE II scores between the conservative and intervention groups, intervention patients had more severe pancreatic disease and scored higher on other measures of disease severity.

Bottom line: Patients with necrotizing pancreatitis can frequently be managed conservatively, though the presence of organ failure and parenchymal necrosis confer poorer prognosis. When intervention is indicated, postponing intervention and utilizing minimally invasive techniques decrease morbidity and mortality.

Citation: Van Santvoort HC, Bakker OJ, Bollen TL, et al. A conservative and minimally invasive approach to necrotizing pancreatitis improves outcome. Gastroenterology. 2011;141:1254-1263.

Cardiac MRI Complements Clinical Findings in Diagnosis of Stress Cardiomyopathy

Clinical question: What are the clinical features and cardiovascular MRI findings in patients with stress (Takotsubo) cardiomyopathy?

Background: Stress cardiomyopathy (SC) is characterized by acute and profound reversible left ventricular dysfunction that is thought to result from increased sympathetic activity related to emotional and/or physical stress. Prior studies evaluating the clinical features of SC were limited by small sample sizes and single-center enrollment, and cardiac MRI use in SC has not been well studied.

Study design: Prospective cohort study.

Setting: Seven North American and European tertiary-care centers.

Synopsis: This study enrolled 256 patients who met diagnostic criteria for SC according to Mayo criteria. Postmenopausal women were most commonly affected; only 11% of participants were men and 8% were women younger than 50 years old. An identifiable stressor was found in 71% of the patients. Clinical presentation was notable for symptoms of acute coronary syndrome (ACS) in 88% of patients, abnormal electrocardiogram in 87%, and elevated troponin T in 90%. Coronary angiography was normal in three-fourths of patients, and no patients had features of acute plaque rupture. Typical apical ballooning was seen on left ventriculography in 82% of patients.

Cardiac MRI findings included severe left ventricular dysfunction in a noncoronary distribution, myocardial edema in areas of regional wall abnormalities, absence of high signal areas in late gadolinium enhancement (e.g., absence of necrosis/fibrosis), and increased early gadolinium uptake (i.e. early inflammation). Repeat cardiac MRI four weeks after initial diagnosis showed near or complete resolution of imaging findings.

Bottom line: Stress cardiomyopathy typically presents like ACS, usually affects postmenopausal women, is often preceded by a stressful event, and is characterized by cardiac MRI findings of regional wall motion abnormalities, reversible myocardial injury, and the absence of fibrosis. Cardiac MRI may be valuable in diagnosing SC in patients who present without the classic clinical features.

Citation: Eitel I, von Knobelsdorff-Brenkenhoff F, Bernhardt P, et al. Clinical characteristics and cardiovascular magnetic resonance findings in stress (Takotsubo) cardiomyopathy. JAMA. 2011;306:277-286.

Increased Risk of Potentially Inadvertent Medication Discontinuation Following Acute-Care Hospitalization

Clinical question: Are medications for chronic diseases inadvertently discontinued after acute-care hospitalization, and is this risk increased in patients who had an ICU stay?

Background: Transitions of care are associated with medical errors. Two such transitions are a shift from the ICU to floor setting and from the inpatient to outpatient setting. Medications for chronic diseases might be held during hospitalization for a variety of reasons, and medication errors may occur if these drugs are not restarted when the acute problem resolves or the patient is discharged from the hospital.

Study design: Population-based cohort study.

Setting: Ontario, Canada.

Synopsis: Using four separate databases, administrative records were reviewed for 396,380 patients aged >65 years who were continuous users of at least one of five evidence-based medication groups for common chronic diseases. Medications included statins, antiplatelet/anticoagulant agents, levothyroxine, respiratory inhalers, and gastric acid suppressants. The primary outcome was potentially unintentional medication discontinuation (measured by failure to renew the prescription at 90 days) for hospitalized versus nonhospitalized patients. All medication groups had statistically significant adjusted odds ratios ranging from 1.18 (95% CI, 1.14-1.23) for discontinuation of levothyroxine to 1.86 (95% CI, 1.77-1.97) for discontinuation of antiplatelet/anticoagulant medications. Treatment in an ICU further increased this risk compared with nonhospitalized patients, and increased the risk for medication discontinuation in four of the five medication groups when compared with patients hospitalized without ICU treatment.

Important study limitations include the lack of appropriate clinical details to classify medication discontinuation as unintentional and the inability of administrative data to prove causality. This study highlights the importance of medication reconciliation and calls attention to inadvertent medication discontinuation during care transitions (see “Reconciliation Act,”).

Bottom line: Patients discharged from the hospital, particularly after ICU treatment, have a higher risk of discontinuation of long-term medications for chronic medical problems when compared with nonhospitalized patients.

Citation: Bell CM, Brener SS, Gunraj N, et al. Association of ICU or hospital admission with unintentional discontinuation of medications for chronic diseases. JAMA. 2011;306:840-847.

Clinical Exam Remains Valuable in the Diagnosis of Patients Admitted to a Medicine Service

Clinical question: Is a clinical exam useful in the diagnosis of newly admitted patients to a general medicine service?

Background: The clinical exam, which comprises the history and physical examination, has long been described as essential to the diagnosis of illness. However, the literature supporting this claim is limited to the ambulatory setting. There has not been evaluation of the clinical exam as a diagnostic tool in the hospital setting, where more advanced testing is readily available.

Study design: Retrospective chart review.

Setting: Urban academic medical center.

Synopsis: The study included 442 adult patients consecutively admitted from the emergency department to the general medicine service who were separately assessed by one senior resident (SR) and one experienced hospital physician (HP) not involved with the case. The SR and HP each made an initial diagnosis and documented the most helpful component(s) in arriving at that diagnosis. Outcomes included comparison of the SR and HP’s admission diagnosis with the discharge diagnosis, and the diagnostic value of the various components of the clinical exam and initial studies.

Compared with the discharge diagnosis, the SR’s initial diagnosis was correct in 80.1% of cases, while the HP was correct in 84.4%. The patient’s history was the most important element in the initial assessment, independently influencing approximately 20% of the correct diagnoses for both physicians. Approximately 60% of correct diagnoses were established using the history and/or physical, and more than 90% were made using a combination of history, physical exam, and/or basic tests (admission labs, electrocardiogram, chest X-ray).

The generalizability of these results is limited by the retrospective, single-center study design, involvement of only one resident physician, and the lack of information regarding number of experienced clinicians and types of diagnoses.

Bottom line: Among patients admitted to a general medicine service, the most powerful tool in obtaining an accurate diagnosis was the combination of a patient’s history and a physical exam.

Citation: Paley L, Zornitzki T, Cohen J, et al. Utility of clinical examination in the diagnosis of emergency department patients admitted to the department of medicine of an academic hospital. Arch Intern Med. 2011;171:1394-1396.

RDW Predicts All-Cause Mortality and Bloodstream Infection in ICU Patients

Clinical question: Among patients admitted to the ICU, is red blood cell distribution width (RDW) a reliable indicator of mortality?

Background: The RDW is an inexpensive test that is commonly included in routine laboratory studies. It has been associated with multiple disease processes and found to be a strong predictor of mortality in the general adult population. However, there has been limited study of the association between RDW and outcomes in critically ill patients.

Study design: Observational cohort study.

Setting: Urban tertiary-care academic medical center.

Synopsis: Data from 51,413 adult patients who received critical care between 1997 and 2007 were obtained from a computerized registry and evaluated for the primary outcome of 30-day mortality after critical-care initiation. Secondary outcomes included 90-day, 365-day, and in-hospital mortality, as well as bloodstream infection. Logistic regression examined both primary and secondary outcomes in association with pre-established RDW quintiles. After multivariable adjustment, RDW was found to be associated with mortality at 30, 90, and 365 days, in addition to in-hospital mortality. The highest RDW quintile (RDW >15.8%) had an adjusted OR of 2.61 (95% CI, 2.37-2.86; P<0.001) for the primary outcome, with similar risk for secondary outcomes of mortality. A subgroup of 18,525 patients with blood culture data was analyzed and an adjusted OR of 1.44 was found in the highest RDW quintile for the secondary outcome of bloodstream infection.

Bottom line: Red blood cell distribution width is a strong independent predictor of all-cause mortality and bloodstream infection in patients receiving intensive care.

Citation: Bazick HS, Chang D, Mahadevappa K, Gibbons FK, Christopher KB. Red cell distribution width and all-cause mortality in critically ill patients. Crit Care Med. 2011;39:1913-1921.

In This Edition

Literature At A Glance

A guide to this month’s studies

1. Atelectasis and fever
2. Heparin dosing frequency for VTE prophylaxis
3. Perioperative cardiac risk calculator
4. Diagnosing subarachnoid hemorrhage without an LP
5. Model to predict risk of bleeding on warfarin
6. Risk of death with tiotropium use in COPD
7. BNP to predict perioperative mortality
8. Beta-blockers and COPD

No Association Found between Atelectasis and Early Postopera-tive Fever

Clinical question: Is atelectasis really a major cause of early (up to 48 hours) postoperative fever (EPF)?

Background: Both fever and atelectasis are common findings in the postoperative period. EPF is believed to be noninfectious, and many textbooks consider atelectasis to be the most common cause. However, this association is controversial with no clear evidence.

Study design: Systematic review of prospective studies evaluating atelectasis and postoperative fever using PubMed and Scopus databases.

Setting: Postoperative patients (predominantly cardiac, maxillofacial, and abdominal surgeries). Lung surgery patients were excluded.

Synopsis: Eight prospective studies (four interventional and four observational) with 998 patients were included for review. All studies diagnosed atelectasis based on chest imaging but only three studies used the conventional definition of ≥38°C for fever. Seven studies individually reported no association between atelectasis and EPF.

Only five studies had eligible data for pooling and analysis. EPF was found to be a very weak indicator (diagnostic OR 1.4; 95% CI 0.92-2.12) of atelectasis. EPF also fared poorly for ruling out (sensitivity 13% to 47%) or ruling in (specificity 41% to 87%) the diagnosis of atelectasis with similarly poor positive and negative predictive values.

The results of this study, however, should be interpreted with caution. It was not a formal meta-analysis, due to the heterogeneity of the studies included with regard to the definition of fever, time points of imaging, and the variation of end points.

Bottom line: Since there is no clinical evidence to prove an association between atelectasis and fever, it is presumed that atelectasis may not be a cause of EPF.

Citation: Mavros MN, Velmahos GC, Falagas ME. Atelectasis as a cause of postoperative fever: where is the clinical evidence? Chest. 2011;140:418-424.

Unfractionated Heparin Can be Given Either BID or TID for Throm-boprophylaxis

Clinical question: Which is the best dosing frequency of unfractionated heparin (UFH) in preventing venous thromboembolism?

Background: Low-dose UFH is commonly used in hospitals for pharmacologic prophylaxis against venous thromboembolism. However, the risks and benefits of BID vs. TID dosing are not clear.

Study design: Mixed-treatment comparison (MTC) meta-analysis of RCTs.

Setting: RCTs on thromboprophylaxis regimens, selected from two previous systematic reviews and an updated literature search.

Synopsis: Included in the analysis were 27,667 patients from 16 RCTs comparing three prophylactic regimens (UFH BID, UFH TID, or low-molecular-weight heparin) with each other or with controls. Stroke and some myocardial infarction patients were excluded. The outcomes measured were DVT, pulmonary embolism (PE), major bleeding, and death. As compared with controls, all three regimens significantly reduced DVT (ranging from 58% to 72%), showed a nonsignificant trend toward reduction in PE (by 46% to 67%), and had no difference in risk of major bleeding or death.

UFH BID vs. TID were compared indirectly by using data from their trials against control patients or low-molecular-weight heparin. There was no significant difference between UFH TID and BID in reducing DVT (RR 1.56, CI 0.64-4.33), PE (RR 1.67, CI 0.49-208.9), mortality (RR 1.17, CI 0.72-1.95), or causing major bleeding (RR 0.89, CI 0.08-7.05). Additionally, both UFH dosing frequencies were similar to low-molecular-weight heparin in all four measured outcomes. This evidence is of moderate quality due to the lack of a direct comparison between UFH BID vs. TID.

Bottom line: Both BID and TID dosing of UFH are acceptable thromboprophylaxis regimens in hospitalized medical patients with no difference in effect on DVT, PE, major bleeding, or death.

Citation: Phung OJ, Kahn SR, Cook DJ, et al. Dosing frequency of unfractionated heparin thromboprophylaxis: a meta-analysis. Chest. 2011;140: 374-381.

New Cardiac-Risk Calculator Improves Prediction of Intra-/Postoperative Myocardial Infarction and Cardiac Arrest

Clinical question: Can a more accurate risk calculator than the Revised Cardiac Risk Index (RCRI) be developed and validated to predict postoperative cardiac events?

Background: The majority of perioperative deaths are secondary to cardiac-related events. The RCRI is the most commonly used preoperative risk stratification tool, but it has limitations and low discriminatory ability.

Study design: Multicenter prospective National Surgical Quality Improvement Program database study.

Setting: More than 250 academic and community U.S. hospitals.

Synopsis: Data were obtained from patients over a two-year period (2007 and 2008). From the 2007 data set (n=211,410), perioperative myocardial infarction or cardiac arrest (MICA) was seen in 1,371 patients (0.65%). After multivariate analysis on the 2007 data set, five risk predictors were obtained (increasing age, American anesthesiology class, dependent functional status, abnormal serum creatinine of >1.5 mg/dL, and type of surgery). This was validated utilizing the 2008 data set (n=257,385), where MICA was seen in 1,401 patients (0.54%).

The risk-predictive model showed excellent discrimination (distinguishing between events and nonevents) after application of C statistics to the dataset. The discriminatory ability was better when compared with the RCRI model. Limitations included nonavailability of information on preoperative stress test, arrhythmia, and aortic valve disease.

Bottom line: The new risk calculator model would help predict MICA more accurately, which in turn would help in preoperative optimization and patient counseling.

Citation: Gupta PK, Gupta H, Sundaram A, et al. Development and validation of a risk calculator for prediction of cardiac risk after surgery. Circ. 2011;124:381-387.

Third-Generation CT Scans are Very Sensitive in Detecting Subarachnoid Hemorrhage

Clinical question: Are modern third-generation CT scans good enough to exclude subarachnoid hemorrhage (SAH) without a lumbar puncture (LP)?

Background: SAH is a neurosurgical emergency identified in about 1% of patients with headache in the emergency department. As the standard of care, all patients with suspected SAH have to undergo LP if a CT scan of the brain is normal. However, LP causes pain and delays discharge from the emergency department.

Study design: Prospective multicenter cohort study.

Setting: Eleven tertiary-care Canadian emergency departments.

Synopsis: From November 2000 to December 2009, data on all alert patients (n=3,132) who presented with acute headache and underwent emergent head CT were collected. Of these, 240 had SAH (7.7%). The sensitivity of CT overall for detecting SAH was 92.9% and the specificity was 100%. For the 953 patients scanned within six hours of headache onset, all 121 patients with SAH were identified by CT, yielding a sensitivity of 100% and specificity of 100%.

The study was limited largely by the lack of a consensus definition on the diagnosis of SAH and by some patient enrollment issues in the emergency department. Overall, these findings should give clinicians more confidence in forgoing an LP in patients with a negative head CT if done within six hours of the onset of their headache.

Bottom line: Modern third-generation CT scans are extremely sensitive for SAH if performed within six hours of the headache onset and interpreted by a qualified radiologist, thus possibly excluding the need for an LP.

Citation: Perry JJ, Stiell IG, Sivilotti ML, et al. Sensitivity of computed tomography performed within six hours of onset of headache for diagnosis of subarachnoid haemorrhage: prospective cohort study. Br Med J. 2011;343:d4277.

Improved Model Stratifies Risk of Warfarin-Associated Bleeding in Patients with Atrial Fibrillation

Clinical question: Can a simple scoring model accurately assess the risk of warfarin-associated bleeding in a cohort of patients with atrial fibrillation?

Background: It is well known that anticoagulants, such as warfarin, dramatically reduce the risk of thromboembolic events in patients with atrial fibrillation. Despite this, clinicians often find themselves weighing the risks and benefits of anticoagulation in this cohort of patients, and improved models to assess those risks are needed.

Study design: Retrospective cohort study.

Setting: Kaiser Permanente of Northern California.

Synopsis: From a cohort of 13,559 adult patients with atrial fibrillation, the investigators used chart review to determine hemorrhagic events in this population and developed a model using Cox regression to assess hemorrhagic risk in certain patient populations. Final input variables for the model included anemia, severe renal disease, age ≥75, prior hemorrhage, and hypertension. When collapsed into three risk tiers (low, intermediate, and high), the scoring model nicely differentiated low (<1% annual) from high (5.8% annual) bleeding risk.

This study is limited by the lack of information on concomitant use of NSAIDs or aspirin in these patients and the lack of external validation of the model. Despite those limitations, it may serve as a valuable tool for clinicians. As the number of alternatives to warfarin rise and as those agents become more familiar, it will become increasingly important to accurately assess hemorrhage risk with various anticoagulants.

Bottom line: The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) risk scoring system is a reliable and easy way for clinicians to estimate the degree of bleeding risk in patients anticoagulated with warfarin for atrial fibrillation.

Citation: Fang MC, Go AS, Chang Y, et al. A new risk scheme to predict warfarin-associated hemorrhage: the ATRIA (anticoagulation and risk factors in atrial fibrillation) study. J Am Coll Cardiol. 2011;58:395-401.

Tiotropium Mist Inhaler Associated with Increased Mortality

Clinical question: Does the mist-inhaler formulation of tiotropium increase mortality in patients with chronic obstructive pulmonary disease (COPD) when compared with placebo?

Background: Tiotropium is used in patients with COPD to reduce both symptoms of dyspnea and exacerbations of COPD. Tiotropium comes in two formulations: a powder (approved in the U.S.) and the mist inhaler (not approved in the U.S. but approved in 55 other countries). There are concerns based on recent studies that tiotropium may increase cardiovascular events and death.

Study design: Meta-analysis of five randomized controlled trials (RCTs) comparing tiotropium mist inhaler with a placebo.

Setting: Multinational studies.

Synopsis: This study of 6,522 patients with COPD showed a 52% increased risk of all-cause mortality with the use of the tiotropium mist inhaler when compared with placebo. It is important to note that there are data showing higher plasma concentrations with the approved mist-inhaler doses when compared with the powder formulation doses. Further, a possible dose effect was seen in this study (though not statistically significant), with higher tiotropium doses associated with a high-risk ratio for the mortality endpoint.

Limitations of this study include the fact that the dosage of the tiotropium varied, as did the length of follow-up for patients. Given that death was a relatively rare event (<1%), estimates are imprecise. Even given these limitations, this study sheds light on the debate over the safety of tiotropium, specifically the mist-inhaler formulation. Caution should be used when prescribing the mist-inhaler formulation of tiotropium, and an understanding of the potential cardiovascular risks should be communicated to patients prior to initiating therapy.

Bottom line: This study shows that the mist-inhaler formulation of tiotropium is associated with an increased risk of cardiovascular mortality.

Citation: Singh S, Loke YK, Enright PL, Furnberg CD. Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials. Br Med J. 2011;342: d3215.

B-Type Natriuretic Peptide (BNP) Is an Independent Predictor of Cardiovascular Events in Patients Undergoing Vascular Surgery

Clinical question: Can preoperative natriuretic peptide levels be used to independently predict perioperative cardiovascular events in patients undergoing vascular surgery?

Background: Currently we use the type of surgery, exercise tolerance, and clinical risk factors to predict perioperative cardiovascular risk. Clinical risk factors, based on the Revised Cardiac Risk Index, or RCRI, include history of ischemic heart disease, heart failure, cerebrovascular events, diabetes mellitus, and renal insufficiency. Recent studies have shown that the pre-operative natriuretic peptides can independently predict perioperative cardiovascular events.

Study design: Individual patient meta-analysis.

Setting: Data sets obtained from six multinational studies.

Synopsis: This meta-analysis included datasets from five studies that used BNP (632 patients) and one study that used NT-proBNP (218 patients) to assess the postoperative cardiovascular events in patients undergoing vascular surgery. Patients with elevated BNP level are at a higher risk of cardiac death (OR 4.3, 95% CI: 1.7-11.3) and all-cause mortality (OR 3.1, 95% CI: 1.4-6.7) within 30 days of vascular surgery. When the RCRI-based groups were reclassified using natriuretic peptide level, the improvement in discrimination was statistically significant. Limitations of this study include: 1) Individual patient data was not obtained for all studies that met the search criteria; and 2) Different types of BNP assays were used in different studies included.

Bottom line: Preoperative BNP level is an independent predictor of cardiovascular events at 30 days after vascular surgery. The addition of preoperative BNP level improves the predictive performance of the RCRI score.

Citation: Rodseth RN, Lurati Buse GA, Bolliger D, et al. The predictive ability of pre-operative B-type natriuretic peptide in vascular patients for major adverse cardiac events: an individual patient data meta-analysis. J Am Coll Cardiol. 2011;58:522-529.

Beta-Blockers May be Beneficial in Patients with Chronic Obstructive Pulmonary Disease

Clinical question: Is it beneficial to use beta-blockers in patients with chronic obstructive pulmonary disease (COPD) if there is an indication?

Background: Patients with COPD may have concomitant cardiovascular disease, which may warrant use of beta-blockers. Many physicians are concerned about using beta-blockers in COPD patients due to the risk of bronchospasm. Evidence suggests that cardio-selective beta-blockers do not cause deterioration of pulmonary status in COPD patients. There is also growing evidence that beta-blockers may be beneficial in patients with COPD.

Study design: Retrospective cohort study.

Setting: Data obtained from a disease-specific (COPD) database in Scotland.

Synopsis: This study included 5,977 patients who were older than 50 and excluded patients with history of malignancy. Beta-blockers were associated with a 22% reduction in all-cause mortality. There was no significant difference between cardio-selective and nonselective beta-blockers. The benefits of beta-blockers in COPD patients were independent of history of cardiovascular disease. There was no significant decline in pulmonary function (FEV1) over time. Beta-blocker usage also reduced the number of hospital admissions for COPD exacerbation. These benefits were shown in patients using different type of inhalers.

Bottom line: In patients older than 50, beta-blockers may not only reduce COPD exacerbations and hospital admissions, but also reduce all-cause mortality without adversely affecting pulmonary function.

Citation: Short PM, Lipworth SI, Elder DH, Schembri S, Lipworth BJ. Effect of beta blockers in treatment of chronic obstructive pulmonary disease: a retrospective cohort study. Br Med J. 2011;342:d2549.

In This Edition

Literature At A Glance

A guide to this month’s studies

1. Atelectasis and fever
2. Heparin dosing frequency for VTE prophylaxis
3. Perioperative cardiac risk calculator
4. Diagnosing subarachnoid hemorrhage without an LP
5. Model to predict risk of bleeding on warfarin
6. Risk of death with tiotropium use in COPD
7. BNP to predict perioperative mortality
8. Beta-blockers and COPD

No Association Found between Atelectasis and Early Postopera-tive Fever

Clinical question: Is atelectasis really a major cause of early (up to 48 hours) postoperative fever (EPF)?

Background: Both fever and atelectasis are common findings in the postoperative period. EPF is believed to be noninfectious, and many textbooks consider atelectasis to be the most common cause. However, this association is controversial with no clear evidence.

Study design: Systematic review of prospective studies evaluating atelectasis and postoperative fever using PubMed and Scopus databases.

Setting: Postoperative patients (predominantly cardiac, maxillofacial, and abdominal surgeries). Lung surgery patients were excluded.

Synopsis: Eight prospective studies (four interventional and four observational) with 998 patients were included for review. All studies diagnosed atelectasis based on chest imaging but only three studies used the conventional definition of ≥38°C for fever. Seven studies individually reported no association between atelectasis and EPF.

Only five studies had eligible data for pooling and analysis. EPF was found to be a very weak indicator (diagnostic OR 1.4; 95% CI 0.92-2.12) of atelectasis. EPF also fared poorly for ruling out (sensitivity 13% to 47%) or ruling in (specificity 41% to 87%) the diagnosis of atelectasis with similarly poor positive and negative predictive values.

The results of this study, however, should be interpreted with caution. It was not a formal meta-analysis, due to the heterogeneity of the studies included with regard to the definition of fever, time points of imaging, and the variation of end points.

Bottom line: Since there is no clinical evidence to prove an association between atelectasis and fever, it is presumed that atelectasis may not be a cause of EPF.

Citation: Mavros MN, Velmahos GC, Falagas ME. Atelectasis as a cause of postoperative fever: where is the clinical evidence? Chest. 2011;140:418-424.

Unfractionated Heparin Can be Given Either BID or TID for Throm-boprophylaxis

Clinical question: Which is the best dosing frequency of unfractionated heparin (UFH) in preventing venous thromboembolism?

Background: Low-dose UFH is commonly used in hospitals for pharmacologic prophylaxis against venous thromboembolism. However, the risks and benefits of BID vs. TID dosing are not clear.

Study design: Mixed-treatment comparison (MTC) meta-analysis of RCTs.

Setting: RCTs on thromboprophylaxis regimens, selected from two previous systematic reviews and an updated literature search.

Synopsis: Included in the analysis were 27,667 patients from 16 RCTs comparing three prophylactic regimens (UFH BID, UFH TID, or low-molecular-weight heparin) with each other or with controls. Stroke and some myocardial infarction patients were excluded. The outcomes measured were DVT, pulmonary embolism (PE), major bleeding, and death. As compared with controls, all three regimens significantly reduced DVT (ranging from 58% to 72%), showed a nonsignificant trend toward reduction in PE (by 46% to 67%), and had no difference in risk of major bleeding or death.

UFH BID vs. TID were compared indirectly by using data from their trials against control patients or low-molecular-weight heparin. There was no significant difference between UFH TID and BID in reducing DVT (RR 1.56, CI 0.64-4.33), PE (RR 1.67, CI 0.49-208.9), mortality (RR 1.17, CI 0.72-1.95), or causing major bleeding (RR 0.89, CI 0.08-7.05). Additionally, both UFH dosing frequencies were similar to low-molecular-weight heparin in all four measured outcomes. This evidence is of moderate quality due to the lack of a direct comparison between UFH BID vs. TID.

Bottom line: Both BID and TID dosing of UFH are acceptable thromboprophylaxis regimens in hospitalized medical patients with no difference in effect on DVT, PE, major bleeding, or death.

Citation: Phung OJ, Kahn SR, Cook DJ, et al. Dosing frequency of unfractionated heparin thromboprophylaxis: a meta-analysis. Chest. 2011;140: 374-381.

New Cardiac-Risk Calculator Improves Prediction of Intra-/Postoperative Myocardial Infarction and Cardiac Arrest

Clinical question: Can a more accurate risk calculator than the Revised Cardiac Risk Index (RCRI) be developed and validated to predict postoperative cardiac events?

Background: The majority of perioperative deaths are secondary to cardiac-related events. The RCRI is the most commonly used preoperative risk stratification tool, but it has limitations and low discriminatory ability.

Study design: Multicenter prospective National Surgical Quality Improvement Program database study.

Setting: More than 250 academic and community U.S. hospitals.

Synopsis: Data were obtained from patients over a two-year period (2007 and 2008). From the 2007 data set (n=211,410), perioperative myocardial infarction or cardiac arrest (MICA) was seen in 1,371 patients (0.65%). After multivariate analysis on the 2007 data set, five risk predictors were obtained (increasing age, American anesthesiology class, dependent functional status, abnormal serum creatinine of >1.5 mg/dL, and type of surgery). This was validated utilizing the 2008 data set (n=257,385), where MICA was seen in 1,401 patients (0.54%).

The risk-predictive model showed excellent discrimination (distinguishing between events and nonevents) after application of C statistics to the dataset. The discriminatory ability was better when compared with the RCRI model. Limitations included nonavailability of information on preoperative stress test, arrhythmia, and aortic valve disease.

Bottom line: The new risk calculator model would help predict MICA more accurately, which in turn would help in preoperative optimization and patient counseling.

Citation: Gupta PK, Gupta H, Sundaram A, et al. Development and validation of a risk calculator for prediction of cardiac risk after surgery. Circ. 2011;124:381-387.

Third-Generation CT Scans are Very Sensitive in Detecting Subarachnoid Hemorrhage

Clinical question: Are modern third-generation CT scans good enough to exclude subarachnoid hemorrhage (SAH) without a lumbar puncture (LP)?

Background: SAH is a neurosurgical emergency identified in about 1% of patients with headache in the emergency department. As the standard of care, all patients with suspected SAH have to undergo LP if a CT scan of the brain is normal. However, LP causes pain and delays discharge from the emergency department.

Study design: Prospective multicenter cohort study.

Setting: Eleven tertiary-care Canadian emergency departments.

Synopsis: From November 2000 to December 2009, data on all alert patients (n=3,132) who presented with acute headache and underwent emergent head CT were collected. Of these, 240 had SAH (7.7%). The sensitivity of CT overall for detecting SAH was 92.9% and the specificity was 100%. For the 953 patients scanned within six hours of headache onset, all 121 patients with SAH were identified by CT, yielding a sensitivity of 100% and specificity of 100%.

The study was limited largely by the lack of a consensus definition on the diagnosis of SAH and by some patient enrollment issues in the emergency department. Overall, these findings should give clinicians more confidence in forgoing an LP in patients with a negative head CT if done within six hours of the onset of their headache.

Bottom line: Modern third-generation CT scans are extremely sensitive for SAH if performed within six hours of the headache onset and interpreted by a qualified radiologist, thus possibly excluding the need for an LP.

Citation: Perry JJ, Stiell IG, Sivilotti ML, et al. Sensitivity of computed tomography performed within six hours of onset of headache for diagnosis of subarachnoid haemorrhage: prospective cohort study. Br Med J. 2011;343:d4277.

Improved Model Stratifies Risk of Warfarin-Associated Bleeding in Patients with Atrial Fibrillation

Clinical question: Can a simple scoring model accurately assess the risk of warfarin-associated bleeding in a cohort of patients with atrial fibrillation?

Background: It is well known that anticoagulants, such as warfarin, dramatically reduce the risk of thromboembolic events in patients with atrial fibrillation. Despite this, clinicians often find themselves weighing the risks and benefits of anticoagulation in this cohort of patients, and improved models to assess those risks are needed.

Study design: Retrospective cohort study.

Setting: Kaiser Permanente of Northern California.

Synopsis: From a cohort of 13,559 adult patients with atrial fibrillation, the investigators used chart review to determine hemorrhagic events in this population and developed a model using Cox regression to assess hemorrhagic risk in certain patient populations. Final input variables for the model included anemia, severe renal disease, age ≥75, prior hemorrhage, and hypertension. When collapsed into three risk tiers (low, intermediate, and high), the scoring model nicely differentiated low (<1% annual) from high (5.8% annual) bleeding risk.

This study is limited by the lack of information on concomitant use of NSAIDs or aspirin in these patients and the lack of external validation of the model. Despite those limitations, it may serve as a valuable tool for clinicians. As the number of alternatives to warfarin rise and as those agents become more familiar, it will become increasingly important to accurately assess hemorrhage risk with various anticoagulants.

Bottom line: The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) risk scoring system is a reliable and easy way for clinicians to estimate the degree of bleeding risk in patients anticoagulated with warfarin for atrial fibrillation.

Citation: Fang MC, Go AS, Chang Y, et al. A new risk scheme to predict warfarin-associated hemorrhage: the ATRIA (anticoagulation and risk factors in atrial fibrillation) study. J Am Coll Cardiol. 2011;58:395-401.

Tiotropium Mist Inhaler Associated with Increased Mortality

Clinical question: Does the mist-inhaler formulation of tiotropium increase mortality in patients with chronic obstructive pulmonary disease (COPD) when compared with placebo?

Background: Tiotropium is used in patients with COPD to reduce both symptoms of dyspnea and exacerbations of COPD. Tiotropium comes in two formulations: a powder (approved in the U.S.) and the mist inhaler (not approved in the U.S. but approved in 55 other countries). There are concerns based on recent studies that tiotropium may increase cardiovascular events and death.

Study design: Meta-analysis of five randomized controlled trials (RCTs) comparing tiotropium mist inhaler with a placebo.

Setting: Multinational studies.

Synopsis: This study of 6,522 patients with COPD showed a 52% increased risk of all-cause mortality with the use of the tiotropium mist inhaler when compared with placebo. It is important to note that there are data showing higher plasma concentrations with the approved mist-inhaler doses when compared with the powder formulation doses. Further, a possible dose effect was seen in this study (though not statistically significant), with higher tiotropium doses associated with a high-risk ratio for the mortality endpoint.

Limitations of this study include the fact that the dosage of the tiotropium varied, as did the length of follow-up for patients. Given that death was a relatively rare event (<1%), estimates are imprecise. Even given these limitations, this study sheds light on the debate over the safety of tiotropium, specifically the mist-inhaler formulation. Caution should be used when prescribing the mist-inhaler formulation of tiotropium, and an understanding of the potential cardiovascular risks should be communicated to patients prior to initiating therapy.

Bottom line: This study shows that the mist-inhaler formulation of tiotropium is associated with an increased risk of cardiovascular mortality.

Citation: Singh S, Loke YK, Enright PL, Furnberg CD. Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials. Br Med J. 2011;342: d3215.

B-Type Natriuretic Peptide (BNP) Is an Independent Predictor of Cardiovascular Events in Patients Undergoing Vascular Surgery

Clinical question: Can preoperative natriuretic peptide levels be used to independently predict perioperative cardiovascular events in patients undergoing vascular surgery?

Background: Currently we use the type of surgery, exercise tolerance, and clinical risk factors to predict perioperative cardiovascular risk. Clinical risk factors, based on the Revised Cardiac Risk Index, or RCRI, include history of ischemic heart disease, heart failure, cerebrovascular events, diabetes mellitus, and renal insufficiency. Recent studies have shown that the pre-operative natriuretic peptides can independently predict perioperative cardiovascular events.

Study design: Individual patient meta-analysis.

Setting: Data sets obtained from six multinational studies.

Synopsis: This meta-analysis included datasets from five studies that used BNP (632 patients) and one study that used NT-proBNP (218 patients) to assess the postoperative cardiovascular events in patients undergoing vascular surgery. Patients with elevated BNP level are at a higher risk of cardiac death (OR 4.3, 95% CI: 1.7-11.3) and all-cause mortality (OR 3.1, 95% CI: 1.4-6.7) within 30 days of vascular surgery. When the RCRI-based groups were reclassified using natriuretic peptide level, the improvement in discrimination was statistically significant. Limitations of this study include: 1) Individual patient data was not obtained for all studies that met the search criteria; and 2) Different types of BNP assays were used in different studies included.

Bottom line: Preoperative BNP level is an independent predictor of cardiovascular events at 30 days after vascular surgery. The addition of preoperative BNP level improves the predictive performance of the RCRI score.

Citation: Rodseth RN, Lurati Buse GA, Bolliger D, et al. The predictive ability of pre-operative B-type natriuretic peptide in vascular patients for major adverse cardiac events: an individual patient data meta-analysis. J Am Coll Cardiol. 2011;58:522-529.

Beta-Blockers May be Beneficial in Patients with Chronic Obstructive Pulmonary Disease

Clinical question: Is it beneficial to use beta-blockers in patients with chronic obstructive pulmonary disease (COPD) if there is an indication?

Background: Patients with COPD may have concomitant cardiovascular disease, which may warrant use of beta-blockers. Many physicians are concerned about using beta-blockers in COPD patients due to the risk of bronchospasm. Evidence suggests that cardio-selective beta-blockers do not cause deterioration of pulmonary status in COPD patients. There is also growing evidence that beta-blockers may be beneficial in patients with COPD.

Study design: Retrospective cohort study.

Setting: Data obtained from a disease-specific (COPD) database in Scotland.

Synopsis: This study included 5,977 patients who were older than 50 and excluded patients with history of malignancy. Beta-blockers were associated with a 22% reduction in all-cause mortality. There was no significant difference between cardio-selective and nonselective beta-blockers. The benefits of beta-blockers in COPD patients were independent of history of cardiovascular disease. There was no significant decline in pulmonary function (FEV1) over time. Beta-blocker usage also reduced the number of hospital admissions for COPD exacerbation. These benefits were shown in patients using different type of inhalers.

Bottom line: In patients older than 50, beta-blockers may not only reduce COPD exacerbations and hospital admissions, but also reduce all-cause mortality without adversely affecting pulmonary function.

Citation: Short PM, Lipworth SI, Elder DH, Schembri S, Lipworth BJ. Effect of beta blockers in treatment of chronic obstructive pulmonary disease: a retrospective cohort study. Br Med J. 2011;342:d2549.

In This Edition

Literature At A Glance

A guide to this month’s studies

1. Atelectasis and fever
2. Heparin dosing frequency for VTE prophylaxis
3. Perioperative cardiac risk calculator
4. Diagnosing subarachnoid hemorrhage without an LP
5. Model to predict risk of bleeding on warfarin
6. Risk of death with tiotropium use in COPD
7. BNP to predict perioperative mortality
8. Beta-blockers and COPD

No Association Found between Atelectasis and Early Postopera-tive Fever

Clinical question: Is atelectasis really a major cause of early (up to 48 hours) postoperative fever (EPF)?

Background: Both fever and atelectasis are common findings in the postoperative period. EPF is believed to be noninfectious, and many textbooks consider atelectasis to be the most common cause. However, this association is controversial with no clear evidence.

Study design: Systematic review of prospective studies evaluating atelectasis and postoperative fever using PubMed and Scopus databases.

Setting: Postoperative patients (predominantly cardiac, maxillofacial, and abdominal surgeries). Lung surgery patients were excluded.

Synopsis: Eight prospective studies (four interventional and four observational) with 998 patients were included for review. All studies diagnosed atelectasis based on chest imaging but only three studies used the conventional definition of ≥38°C for fever. Seven studies individually reported no association between atelectasis and EPF.

Only five studies had eligible data for pooling and analysis. EPF was found to be a very weak indicator (diagnostic OR 1.4; 95% CI 0.92-2.12) of atelectasis. EPF also fared poorly for ruling out (sensitivity 13% to 47%) or ruling in (specificity 41% to 87%) the diagnosis of atelectasis with similarly poor positive and negative predictive values.

The results of this study, however, should be interpreted with caution. It was not a formal meta-analysis, due to the heterogeneity of the studies included with regard to the definition of fever, time points of imaging, and the variation of end points.

Bottom line: Since there is no clinical evidence to prove an association between atelectasis and fever, it is presumed that atelectasis may not be a cause of EPF.

Citation: Mavros MN, Velmahos GC, Falagas ME. Atelectasis as a cause of postoperative fever: where is the clinical evidence? Chest. 2011;140:418-424.

Unfractionated Heparin Can be Given Either BID or TID for Throm-boprophylaxis

Clinical question: Which is the best dosing frequency of unfractionated heparin (UFH) in preventing venous thromboembolism?

Background: Low-dose UFH is commonly used in hospitals for pharmacologic prophylaxis against venous thromboembolism. However, the risks and benefits of BID vs. TID dosing are not clear.

Study design: Mixed-treatment comparison (MTC) meta-analysis of RCTs.

Setting: RCTs on thromboprophylaxis regimens, selected from two previous systematic reviews and an updated literature search.

Synopsis: Included in the analysis were 27,667 patients from 16 RCTs comparing three prophylactic regimens (UFH BID, UFH TID, or low-molecular-weight heparin) with each other or with controls. Stroke and some myocardial infarction patients were excluded. The outcomes measured were DVT, pulmonary embolism (PE), major bleeding, and death. As compared with controls, all three regimens significantly reduced DVT (ranging from 58% to 72%), showed a nonsignificant trend toward reduction in PE (by 46% to 67%), and had no difference in risk of major bleeding or death.

UFH BID vs. TID were compared indirectly by using data from their trials against control patients or low-molecular-weight heparin. There was no significant difference between UFH TID and BID in reducing DVT (RR 1.56, CI 0.64-4.33), PE (RR 1.67, CI 0.49-208.9), mortality (RR 1.17, CI 0.72-1.95), or causing major bleeding (RR 0.89, CI 0.08-7.05). Additionally, both UFH dosing frequencies were similar to low-molecular-weight heparin in all four measured outcomes. This evidence is of moderate quality due to the lack of a direct comparison between UFH BID vs. TID.

Bottom line: Both BID and TID dosing of UFH are acceptable thromboprophylaxis regimens in hospitalized medical patients with no difference in effect on DVT, PE, major bleeding, or death.

Citation: Phung OJ, Kahn SR, Cook DJ, et al. Dosing frequency of unfractionated heparin thromboprophylaxis: a meta-analysis. Chest. 2011;140: 374-381.

New Cardiac-Risk Calculator Improves Prediction of Intra-/Postoperative Myocardial Infarction and Cardiac Arrest

Clinical question: Can a more accurate risk calculator than the Revised Cardiac Risk Index (RCRI) be developed and validated to predict postoperative cardiac events?

Background: The majority of perioperative deaths are secondary to cardiac-related events. The RCRI is the most commonly used preoperative risk stratification tool, but it has limitations and low discriminatory ability.

Study design: Multicenter prospective National Surgical Quality Improvement Program database study.

Setting: More than 250 academic and community U.S. hospitals.

Synopsis: Data were obtained from patients over a two-year period (2007 and 2008). From the 2007 data set (n=211,410), perioperative myocardial infarction or cardiac arrest (MICA) was seen in 1,371 patients (0.65%). After multivariate analysis on the 2007 data set, five risk predictors were obtained (increasing age, American anesthesiology class, dependent functional status, abnormal serum creatinine of >1.5 mg/dL, and type of surgery). This was validated utilizing the 2008 data set (n=257,385), where MICA was seen in 1,401 patients (0.54%).

The risk-predictive model showed excellent discrimination (distinguishing between events and nonevents) after application of C statistics to the dataset. The discriminatory ability was better when compared with the RCRI model. Limitations included nonavailability of information on preoperative stress test, arrhythmia, and aortic valve disease.

Bottom line: The new risk calculator model would help predict MICA more accurately, which in turn would help in preoperative optimization and patient counseling.

Citation: Gupta PK, Gupta H, Sundaram A, et al. Development and validation of a risk calculator for prediction of cardiac risk after surgery. Circ. 2011;124:381-387.

Third-Generation CT Scans are Very Sensitive in Detecting Subarachnoid Hemorrhage

Clinical question: Are modern third-generation CT scans good enough to exclude subarachnoid hemorrhage (SAH) without a lumbar puncture (LP)?

Background: SAH is a neurosurgical emergency identified in about 1% of patients with headache in the emergency department. As the standard of care, all patients with suspected SAH have to undergo LP if a CT scan of the brain is normal. However, LP causes pain and delays discharge from the emergency department.

Study design: Prospective multicenter cohort study.

Setting: Eleven tertiary-care Canadian emergency departments.

Synopsis: From November 2000 to December 2009, data on all alert patients (n=3,132) who presented with acute headache and underwent emergent head CT were collected. Of these, 240 had SAH (7.7%). The sensitivity of CT overall for detecting SAH was 92.9% and the specificity was 100%. For the 953 patients scanned within six hours of headache onset, all 121 patients with SAH were identified by CT, yielding a sensitivity of 100% and specificity of 100%.

The study was limited largely by the lack of a consensus definition on the diagnosis of SAH and by some patient enrollment issues in the emergency department. Overall, these findings should give clinicians more confidence in forgoing an LP in patients with a negative head CT if done within six hours of the onset of their headache.

Bottom line: Modern third-generation CT scans are extremely sensitive for SAH if performed within six hours of the headache onset and interpreted by a qualified radiologist, thus possibly excluding the need for an LP.

Citation: Perry JJ, Stiell IG, Sivilotti ML, et al. Sensitivity of computed tomography performed within six hours of onset of headache for diagnosis of subarachnoid haemorrhage: prospective cohort study. Br Med J. 2011;343:d4277.

Improved Model Stratifies Risk of Warfarin-Associated Bleeding in Patients with Atrial Fibrillation

Clinical question: Can a simple scoring model accurately assess the risk of warfarin-associated bleeding in a cohort of patients with atrial fibrillation?

Background: It is well known that anticoagulants, such as warfarin, dramatically reduce the risk of thromboembolic events in patients with atrial fibrillation. Despite this, clinicians often find themselves weighing the risks and benefits of anticoagulation in this cohort of patients, and improved models to assess those risks are needed.

Study design: Retrospective cohort study.

Setting: Kaiser Permanente of Northern California.

Synopsis: From a cohort of 13,559 adult patients with atrial fibrillation, the investigators used chart review to determine hemorrhagic events in this population and developed a model using Cox regression to assess hemorrhagic risk in certain patient populations. Final input variables for the model included anemia, severe renal disease, age ≥75, prior hemorrhage, and hypertension. When collapsed into three risk tiers (low, intermediate, and high), the scoring model nicely differentiated low (<1% annual) from high (5.8% annual) bleeding risk.

This study is limited by the lack of information on concomitant use of NSAIDs or aspirin in these patients and the lack of external validation of the model. Despite those limitations, it may serve as a valuable tool for clinicians. As the number of alternatives to warfarin rise and as those agents become more familiar, it will become increasingly important to accurately assess hemorrhage risk with various anticoagulants.

Bottom line: The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) risk scoring system is a reliable and easy way for clinicians to estimate the degree of bleeding risk in patients anticoagulated with warfarin for atrial fibrillation.

Citation: Fang MC, Go AS, Chang Y, et al. A new risk scheme to predict warfarin-associated hemorrhage: the ATRIA (anticoagulation and risk factors in atrial fibrillation) study. J Am Coll Cardiol. 2011;58:395-401.

Tiotropium Mist Inhaler Associated with Increased Mortality

Clinical question: Does the mist-inhaler formulation of tiotropium increase mortality in patients with chronic obstructive pulmonary disease (COPD) when compared with placebo?

Background: Tiotropium is used in patients with COPD to reduce both symptoms of dyspnea and exacerbations of COPD. Tiotropium comes in two formulations: a powder (approved in the U.S.) and the mist inhaler (not approved in the U.S. but approved in 55 other countries). There are concerns based on recent studies that tiotropium may increase cardiovascular events and death.

Study design: Meta-analysis of five randomized controlled trials (RCTs) comparing tiotropium mist inhaler with a placebo.

Setting: Multinational studies.

Synopsis: This study of 6,522 patients with COPD showed a 52% increased risk of all-cause mortality with the use of the tiotropium mist inhaler when compared with placebo. It is important to note that there are data showing higher plasma concentrations with the approved mist-inhaler doses when compared with the powder formulation doses. Further, a possible dose effect was seen in this study (though not statistically significant), with higher tiotropium doses associated with a high-risk ratio for the mortality endpoint.

Limitations of this study include the fact that the dosage of the tiotropium varied, as did the length of follow-up for patients. Given that death was a relatively rare event (<1%), estimates are imprecise. Even given these limitations, this study sheds light on the debate over the safety of tiotropium, specifically the mist-inhaler formulation. Caution should be used when prescribing the mist-inhaler formulation of tiotropium, and an understanding of the potential cardiovascular risks should be communicated to patients prior to initiating therapy.

Bottom line: This study shows that the mist-inhaler formulation of tiotropium is associated with an increased risk of cardiovascular mortality.

Citation: Singh S, Loke YK, Enright PL, Furnberg CD. Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials. Br Med J. 2011;342: d3215.

B-Type Natriuretic Peptide (BNP) Is an Independent Predictor of Cardiovascular Events in Patients Undergoing Vascular Surgery

Clinical question: Can preoperative natriuretic peptide levels be used to independently predict perioperative cardiovascular events in patients undergoing vascular surgery?

Background: Currently we use the type of surgery, exercise tolerance, and clinical risk factors to predict perioperative cardiovascular risk. Clinical risk factors, based on the Revised Cardiac Risk Index, or RCRI, include history of ischemic heart disease, heart failure, cerebrovascular events, diabetes mellitus, and renal insufficiency. Recent studies have shown that the pre-operative natriuretic peptides can independently predict perioperative cardiovascular events.

Study design: Individual patient meta-analysis.

Setting: Data sets obtained from six multinational studies.

Synopsis: This meta-analysis included datasets from five studies that used BNP (632 patients) and one study that used NT-proBNP (218 patients) to assess the postoperative cardiovascular events in patients undergoing vascular surgery. Patients with elevated BNP level are at a higher risk of cardiac death (OR 4.3, 95% CI: 1.7-11.3) and all-cause mortality (OR 3.1, 95% CI: 1.4-6.7) within 30 days of vascular surgery. When the RCRI-based groups were reclassified using natriuretic peptide level, the improvement in discrimination was statistically significant. Limitations of this study include: 1) Individual patient data was not obtained for all studies that met the search criteria; and 2) Different types of BNP assays were used in different studies included.

Bottom line: Preoperative BNP level is an independent predictor of cardiovascular events at 30 days after vascular surgery. The addition of preoperative BNP level improves the predictive performance of the RCRI score.

Citation: Rodseth RN, Lurati Buse GA, Bolliger D, et al. The predictive ability of pre-operative B-type natriuretic peptide in vascular patients for major adverse cardiac events: an individual patient data meta-analysis. J Am Coll Cardiol. 2011;58:522-529.

Beta-Blockers May be Beneficial in Patients with Chronic Obstructive Pulmonary Disease

Clinical question: Is it beneficial to use beta-blockers in patients with chronic obstructive pulmonary disease (COPD) if there is an indication?

Background: Patients with COPD may have concomitant cardiovascular disease, which may warrant use of beta-blockers. Many physicians are concerned about using beta-blockers in COPD patients due to the risk of bronchospasm. Evidence suggests that cardio-selective beta-blockers do not cause deterioration of pulmonary status in COPD patients. There is also growing evidence that beta-blockers may be beneficial in patients with COPD.

Study design: Retrospective cohort study.

Setting: Data obtained from a disease-specific (COPD) database in Scotland.

Synopsis: This study included 5,977 patients who were older than 50 and excluded patients with history of malignancy. Beta-blockers were associated with a 22% reduction in all-cause mortality. There was no significant difference between cardio-selective and nonselective beta-blockers. The benefits of beta-blockers in COPD patients were independent of history of cardiovascular disease. There was no significant decline in pulmonary function (FEV1) over time. Beta-blocker usage also reduced the number of hospital admissions for COPD exacerbation. These benefits were shown in patients using different type of inhalers.

Bottom line: In patients older than 50, beta-blockers may not only reduce COPD exacerbations and hospital admissions, but also reduce all-cause mortality without adversely affecting pulmonary function.

Citation: Short PM, Lipworth SI, Elder DH, Schembri S, Lipworth BJ. Effect of beta blockers in treatment of chronic obstructive pulmonary disease: a retrospective cohort study. Br Med J. 2011;342:d2549.

Clinical question: What is the effect of fluid resuscitation on mortality in children with shock in resource-limited settings?

Background: Rapid fluid resuscitation is typically recommended for children who present with shock. In resource-limited settings, particularly in Africa, this practice is not commonplace. The exact role of early fluid resuscitation, in addition to the optimal type of fluid (saline or albumin), is unknown.

Study design: Multicenter, randomized, controlled trial.

Setting: Six clinical centers in Africa.

Synopsis: This study was stopped after data for 3,141 of a projected 3,600 enrolled children demonstrated increased mortality in the bolus groups vs. control. Children aged 60 days to 12 years who presented with a severe febrile illness and impaired perfusion without severe hypotension were randomized openly to three groups: saline bolus, albumin bolus, or no bolus (control). Baseline characteristics of the groups were similar. After 48 hours, mortality in the albumin, saline, and control groups was 10.6%, 10.5%, and 7.3% respectively. The relative risk for any bolus vs. control was 1.45 (95% CI, 1.13-1.86; P=.003).

The results of this study are strengthened by the large number of children enrolled and the solid study design. However, it is difficult to immediately generalize the findings due to the unique nature of the study population and environment, which included a high proportion of patients with malaria and notable constraints on resources. Nonetheless, questions are raised regarding the routine practice of rapid and early fluid resuscitation in patients with shock and without clear hypovolemia.

Bottom line: Fluid resuscitation is not beneficial in resource-limited settings for children in shock who are not hypotensive.

Citation: Matiland K, Kiguli S, Opoka RO, et. al. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011;364:2483-2495.

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

Clinical question: What is the effect of fluid resuscitation on mortality in children with shock in resource-limited settings?

Background: Rapid fluid resuscitation is typically recommended for children who present with shock. In resource-limited settings, particularly in Africa, this practice is not commonplace. The exact role of early fluid resuscitation, in addition to the optimal type of fluid (saline or albumin), is unknown.

Study design: Multicenter, randomized, controlled trial.

Setting: Six clinical centers in Africa.

Synopsis: This study was stopped after data for 3,141 of a projected 3,600 enrolled children demonstrated increased mortality in the bolus groups vs. control. Children aged 60 days to 12 years who presented with a severe febrile illness and impaired perfusion without severe hypotension were randomized openly to three groups: saline bolus, albumin bolus, or no bolus (control). Baseline characteristics of the groups were similar. After 48 hours, mortality in the albumin, saline, and control groups was 10.6%, 10.5%, and 7.3% respectively. The relative risk for any bolus vs. control was 1.45 (95% CI, 1.13-1.86; P=.003).

The results of this study are strengthened by the large number of children enrolled and the solid study design. However, it is difficult to immediately generalize the findings due to the unique nature of the study population and environment, which included a high proportion of patients with malaria and notable constraints on resources. Nonetheless, questions are raised regarding the routine practice of rapid and early fluid resuscitation in patients with shock and without clear hypovolemia.

Bottom line: Fluid resuscitation is not beneficial in resource-limited settings for children in shock who are not hypotensive.

Citation: Matiland K, Kiguli S, Opoka RO, et. al. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011;364:2483-2495.

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

Clinical question: What is the effect of fluid resuscitation on mortality in children with shock in resource-limited settings?

Background: Rapid fluid resuscitation is typically recommended for children who present with shock. In resource-limited settings, particularly in Africa, this practice is not commonplace. The exact role of early fluid resuscitation, in addition to the optimal type of fluid (saline or albumin), is unknown.

Study design: Multicenter, randomized, controlled trial.

Setting: Six clinical centers in Africa.

Synopsis: This study was stopped after data for 3,141 of a projected 3,600 enrolled children demonstrated increased mortality in the bolus groups vs. control. Children aged 60 days to 12 years who presented with a severe febrile illness and impaired perfusion without severe hypotension were randomized openly to three groups: saline bolus, albumin bolus, or no bolus (control). Baseline characteristics of the groups were similar. After 48 hours, mortality in the albumin, saline, and control groups was 10.6%, 10.5%, and 7.3% respectively. The relative risk for any bolus vs. control was 1.45 (95% CI, 1.13-1.86; P=.003).

The results of this study are strengthened by the large number of children enrolled and the solid study design. However, it is difficult to immediately generalize the findings due to the unique nature of the study population and environment, which included a high proportion of patients with malaria and notable constraints on resources. Nonetheless, questions are raised regarding the routine practice of rapid and early fluid resuscitation in patients with shock and without clear hypovolemia.

Bottom line: Fluid resuscitation is not beneficial in resource-limited settings for children in shock who are not hypotensive.

Citation: Matiland K, Kiguli S, Opoka RO, et. al. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011;364:2483-2495.

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