Patient Care

ITL: Physician Reviews of HM-Relevant Research


In This Edition

Literature At A Glance

A guide to this month’s studies

  1. Guidelines on steroids and antivirals to treat Bell’s palsy
  2. Probiotics to reduce Clostridium difficile-associated diarrhea
  3. Rates of hemorrhage from warfarin therapy higher in clinical practice
  4. Less experienced doctors incur higher treatment costs
  5. Pay-for-performance incentive reduces mortality in England
  6. No benefit in ultrafiltration to treat acute heart failure
  7. Hospitalized patients often receive too much acetaminophen
  8. Longer anticoagulation therapy beneficial after bioprosthetic aortic valve replacement
  9. Antimicrobial-coated catheters and risk of urinary tract infection
  10. Patient outcomes improve after in-hospital cardiac arrest

Updated Guidelines on Steroids and Antivirals in Bell’s Palsy

Clinical question: Does the use of steroids and/or antivirals improve recovery in patients with newly diagnosed Bell’s palsy?

Background: The American Academy of Neurology’s last recommendation in 2001 stated that steroids were probably effective and antivirals possibly effective. The current review and recommendations looked at additional studies published since 2000.

Study design: Systematic review of MEDLINE and Cochrane Database of Systematic Reviews data published since June 2000.

Setting: Prospective controlled studies from Germany, Sweden, Scotland, Italy, South Korea, Japan, and Bangladesh.

Synopsis: The authors identified nine studies that fulfilled inclusion criteria. Two of these studies examined treatment with steroids alone and were judged to have the lowest risk for bias. Both studies enrolled patients within three days of symptom onset, continued treatment for 10 days, and demonstrated a significant increase in the probability of complete recovery in patients randomized to steroids (NNT 6-8). Two high-quality studies were identified that looked at the addition of antivirals to steroids. Neither study showed a statistically significant benefit.

Of note, the studies did not quantify the risk of harm from steroid use in patients with comorbidities, such as diabetes. Thus, the authors concluded that in some patients, it would be reasonable to consider limiting steroid use.

Bottom line: For patients with new-onset Bell’s palsy, steroids increase the probability of recovery of facial nerve function. Patients offered antivirals should be counseled that a benefit from antivirals has not been established, and, if there is a benefit, it is modest at best.

Citation: Gronseth GS, Paduga R. Evidence-based guideline update: steroids and antivirals for Bell palsy: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2012;79(22):2209-2213.

Probiotic Prophylaxis Reduces Clostridium Difficile-Associated Diarrhea

Clinical question: Are probiotics a safe and efficacious therapy for the prevention of Clostridium difficile-associated diarrhea (CDAD)?

Background: CDAD is the most common cause of hospital-acquired infectious diarrhea in high-income countries. There has been a dramatic rise in the incidence and severity of CDAD since 2002. Previous studies suggested that probiotics might reduce the incidence of CDAD with few adverse events.

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

Setting: Randomized controlled trials from the U.S., Canada, Chile, China, United Kingdom, Turkey, Poland, and Sweden.

Synopsis: Investigators identified 20 trials including 3,818 participants using a systematic search of randomized controlled trials of a specified probiotic of any strain in adults or pediatric subjects treated with antibiotics. Probiotics reduced the incidence of CDAD by 66% (risk ratio 0.34, 95% CI 0.24 to 0.49). Subgroup analyses showed similar results in both adults and children, with lower and high doses, and with different probiotic species.

Of probiotic-treated patients, 9.3% experienced an adverse event compared with 12.6% of control patients (relative risk 0.82, 95% CI 0.65 to 1.05). There was no report of any serious adverse events attributable to probiotics.

One limitation is the considerable variability in the reported risk of CDAD in the control group (0% to 40%). The absolute benefit from probiotics will depend on the risk in patients who do not receive prophylaxis.

Bottom line: Moderate-quality evidence suggests that probiotic prophylaxis results in a large reduction in C. diff-associated diarrhea without an increase in clinically important adverse events.

Citation: Johnston BC, Ma SSY, Goldenberg JZ, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. Ann Intern Med. 2012;157(12):878-888.

Rates of Hemorrhage from Warfarin Therapy Higher in Clinical Practice

Clinical question: What is the incidence of hemorrhage in a large population-based cohort of patients with atrial fibrillation who have started warfarin therapy?

Background: There is strong evidence that supports the use of warfarin to reduce the risk of stroke and systemic embolism in patients with atrial fibrillation. There are currently no large studies offering real-world, population-based estimates of hemorrhage rates among patients taking warfarin.

Study design: Retrospective cohort study.

Setting: Ontario.

Synopsis: This population-based, cohort study included 125,195 residents of Ontario age ≥66 years with atrial fibrillation who started taking warfarin sometime from 1997 to 2008. Hemorrhage was defined as bleeding requiring an emergency department visit or hospital admission. The overall risk of hemorrhage was 3.8% per person-year, but it was 11.8% in the first 30 days of therapy. For subjects age >75 years, the overall risk was 4.6% compared with 2.9% for those between 66 and 75 years.

Most hospital admissions involved gastrointestinal hemorrhages (63%). Almost 1 in 5 people (18%) with hospital admissions for hemorrhages died in the hospital or within seven days of discharge.

Bottom line: Rates of hemorrhage for older patients on warfarin therapy are significantly higher in clinical practice than the rates reported in clinical trials. The difference is likely due to the strict inclusion criteria, younger average age, and close monitoring of patients in clinical trials.

Citation: Gomes T, Mamdani MM, Holbrook AM, Paterson JM, Hellings C, Juurlink DN. Rates of hemorrhage during warfarin therapy for atrial fibrillation. CMAJ. 2013; Jan 21 [Epub ahead of print].

Less Experienced Doctors Incur Higher Treatment Costs

Clinical question: Which physician characteristics are associated with higher cost profiles?

Background: While both public and private insurers increasingly use physician cost profiles to identify physicians whose practice patterns account for more healthcare spending than other physicians, the individual physician characteristics associated with cost-profile performance are unknown.

Study design: Retrospective cohort study.

Setting: Four commercial health plans in Massachusetts.

Synopsis: Data collected from the insurance claims records of 1.13 million patients aged 18-65 years who were enrolled in one of four commercial health plans in Massachusetts in 2004 and 2005 were matched with the public records of 12,116 doctors who were stratified into five groups according to years of experience (<10, 10-19, 20-29, 30-39, and ≥40 years).

A strong association was found between physician experience and cost profiles, with the most experienced doctors—40 or more years of experience—providing the least costly care. Costs increased with each successively less experienced group (by 2.5%, 6.5%, 10%, and 13.2% more, respectively, to treat the same condition). No association was found between cost profiles and other physician characteristics, such as having had malpractice claims or disciplinary actions, board certification status, and practice size.

Differences appear to be driven by high-cost outlier patients. While median costs were similar between physicians with different levels of experience, the costs of treating patients at the 95 percentile of cost were much higher among physicians with less experience.

Bottom line: Doctors in this study with the least experience incurred 13.2% greater costs than their most senior counterparts.

Citation: Mehrotra A, Reid RO, Adams JL, Friedberg MW, McGlynn EA, Hussey PS. Physicians with the least experience have higher cost profiles than do physicians with the most experience. Health Aff (Millwood). 2012;31(11):2453-2463.

Pay-For-Performance Incentive Reduces Mortality in England

Clinical question: Do pay-for-performance programs improve quality of care?

Background: Pay-for-performance programs are being widely adopted both internationally and in the U.S. There is, however, limited evidence that these programs improve patient outcomes, and most prior studies have shown modest or inconsistent improvements in quality of care.

Study design: Prospective cohort study.

Setting: National Health Service (NHS) hospitals in northwest England.

Synopsis: The Advanced Quality program, the first hospital-based pay-for-performance program in England, was introduced in October 2004 in all 24 NHS hospitals in northwest England that provide emergency care. The program used a “tournament” system in which only the top-performing hospitals received bonus payments. There was no penalty for poor performers.

The primary end-point was 30-day in-hospital mortality among patients admitted for pneumonia, heart failure, or acute myocardial infarction. Over the three-year period studied (18 months before and 18 months after introduction of the program), the risk-adjusted mortality for these three conditions decreased significantly with an absolute reduction of 1.3% (95% CI 0.4 to 2.1%; P=0.006). The largest change, for pneumonia, was significant (1.9%, 95% CI 0.9 to 3.0, P<0.001), with nonsignificant reductions for acute myocardial infarction (0.6%, 95% CI -0.4 to 1.7; P=0.23) and heart failure (0.6%, 95% CI -0.6 to 1.8; P=0.30).

Bottom line: The introduction of a pay-for-performance program for all National Health Service hospitals in one region of England was associated with a significant reduction in mortality.

Citation: Sutton M, Nikolova S, Boaden R, Lester H, McDonald R, Roland M. Reduced mortality with hospital pay for performance in England. N Engl J Med. 2012;367(19):1821-1828.

Ultrafiltration Shows No Benefit in Acute Heart Failure

Clinical question: Is ultrafiltration superior to pharmacotherapy in the treatment of patients with acute heart failure and cardiorenal syndrome?

Background: Venovenous ultrafiltration is an alternative to diuretic therapy in patients with acute decompensated heart failure and worsened renal function that could allow greater control of the rate of fluid removal and improve outcomes. Little is known about the efficacy and safety of ultrafiltration compared to standard pharmacological therapy.

Study design: Multicenter randomized controlled trial.

Setting: Fourteen clinical centers in the U.S. and Canada.

Synopsis: One hundred eighty-eight patients admitted to a hospital with acute decompensated heart failure and worsened renal function were randomized to stepped pharmacological therapy or ultrafiltration. Ultrafiltration was inferior to pharmacological therapy with respect to the pre-specified primary composite endpoint, the change in serum creatinine level, and body weight at 96 hours after enrollment (P=0.003). This difference was primarily due to an increase in the serum creatinine level in the ultrafiltration group (0.23 vs. -0.04 mg/dl; P=0.003). There was no significant difference in weight loss at 96 hours (loss of 5.5 kg vs. 5.7kg; P=0.58).

A higher percentage of patients in the ultrafiltration group had a serious adverse event over the 60-day follow-up period (72% vs. 57%, P=0.03). There was no significant difference in the composite rate of death or rehospitalization for heart failure in the ultrafiltration group compared to the pharmacologic-therapy group (38% vs. 35%; P=0.96).

Bottom line: Pharmacological therapy is superior to ultrafiltration in patients with acute decompensated heart failure and worsened renal function.

Citation: Bart BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med. 2012;367:2296-2304.

Hospitalized Patients Often Receive Too Much Acetaminophen

Clinical question: What are the prevalence and factors associated with supratherapeutic dosing of acetaminophen in hospitalized patients?

Background: Acetaminophen is a commonly used medication that at high doses can be associated with significant adverse events, including liver failure. Considerable efforts have been made in the outpatient setting to limit the risks associated with acetaminophen. Little research has examined acetaminophen exposure in the inpatient setting.

Study design: Retrospective cohort study.

Setting: Two academic tertiary-care hospitals in the U.S.

Synopsis: The authors reviewed the electronic medication administration record of all adult patients admitted to two academic hospitals from June 1, 2010, to Aug. 31, 2010. A total of 14,411 patients (60.7%) were prescribed acetaminophen, of whom 955 (6.6%) were prescribed more than the 4g per day (the maximum recommended daily dose) at least once. In addition, 22.3% of patients >65 and 17.6% of patients with chronic liver disease exceeded the recommended limit of 3g per day. Half the supratherapeutic episodes involved doses exceeding 5g a day, often for several days. In adjusted analyses, scheduled administration (rather than as needed), a diagnosis of osteoarthritis, and higher-strength tablets were all associated with a higher risk of exposure to supratherapeutic doses.

Bottom line: A significant proportion of hospitalized patients are exposed to supratherapeutic dosing of acetaminophen.

Citation: Zhou L, Maviglia SM, Mahoney LM, et al. Supra-therapeutic dosing of acetaminophen among hospitalized patients. Arch Intern Med. 2012;172(22):1721-1728.

Longer Anticoagulation Therapy after Bioprosthetic Aortic Valve Replacement Might Be Beneficial

Clinical question: How long should anticoagulation therapy with warfarin be continued after surgical bioprosthetic aortic valve replacement?

Background: Current guidelines recommend a three-month course of anticoagulation therapy after bioprosthetic aortic valve surgery. However, the appropriate duration of post-operative anticoagulation therapy has not been well established

Study design: Retrospective cohort study.

Setting: Denmark.

Synopsis: Using data from the Danish National Registries, 4,075 subjects without atrial fibrillation who underwent bioprosthetic aortic valve implantation from 1997 to 2009 were identified. The association between different durations of warfarin therapy after aortic valve implantation and the combined end point of stroke, thromboembolic events, cardiovascular death, or bleeding episodes was examined.

The risk of adverse outcomes was substantially higher for patients not treated with warfarin compared to treated patents. The estimated adverse event rate was 7 per 100 person-years for untreated patients versus 2.7 per 100 for warfarin-treated patients (adjusted incidence rate ratio [IRR] 2.46, 95% CI 1.09 to 6.48). Patients not treated with warfarin were at higher risk of cardiovascular death within 30 to 89 days after surgery, with an event rate of 31.7 per 100 person-years versus 3.8 per 100 person-years (adjusted IRR 7.61, 95% CI 4.37 to 13.26). The difference in cardiovascular mortality continued to be significant from 90 to 179 days after surgery, with an event rate of 6.5 per 100 person-years versus 2.1 per 100 person-years (IRR 3.51, 95% CI 1.54 to 8.03).

Bottom line: Discontinuation of warfarin therapy within six months of bioprosthetic aortic valve replacement is associated with increased cardiovascular death.

Citation: Mérie C, Køber L, Skov Olsen P, et al. Association of warfarin therapy duration after bioprosthetic aortic valve replacement with risk of mortality, thromboembolic complications, and bleeding. JAMA. 2012;308(20):2118-2125.

Limited Evidence for Antimicrobial-Coated Catheters

Clinical question: Does the use of antimicrobial-coated catheters reduce the risk of catheter-associated urinary tract infection (UTI) compared to standard polytetrafluoroethylene (PTFE) catheters?

Background: UTIs associated with indwelling catheters are a major preventable cause of harm for hospitalized patients. Prior studies have shown that catheters made with antimicrobial coatings can reduce rates of bacteriuria, but their usefulness against symptomatic catheter-associated UTIs remains uncertain.

Study design: Multicenter randomized controlled trial.

Setting: Twenty-four hospitals in the United Kingdom.

Synopsis: A total of 7,102 patients >16 undergoing urethral catheterization for an anticipated duration of <14 days were randomly allocated in a 1:1:1 ratio to receive a silver-alloy-coated catheter, a nitrofural-impregnated silicone catheter, or a standard PTFE-coated catheter. The primary outcome was defined as presence of patient-reported symptoms of UTI and prescription of antibiotic for UTI. Incidence of symptomatic catheter-associated UTI up to six weeks after randomization did not differ significantly between groups and occurred in 12.6% of the PTFE control, 12.5% of the silver alloy group, and 10.6% of the nitrofural group. In secondary outcomes, the nitrofural catheter was associated with a slightly reduced incidence of culture-confirmed symptomatic UTI (absolute risk reduction of 1.4%) and lower rate of bacteriuria, but it also had greater patient-reported discomfort during use and removal.

Bottom line: Antimicrobial-coated catheters do not show a clinically significant benefit over standard PTFE catheters in preventing catheter-associated UTI.

Citation: Pickard R, Lam T, Maclennan G, et al. Antimicrobial catheters for reduction of symptomatic urinary tract infection in adults requiring short-term catheterisation in hospital: a multicentre randomized controlled trial. Lancet. 2012;380:1927-1935.

Outcomes Improve after In-Hospital Cardiac Arrest

Clinical question: Have outcomes after in-hospital cardiac arrest improved with recent advances in resuscitation care?

Background: Over the past decade, quality-improvement (QI) efforts in hospital resuscitation care have included use of mock cardiac arrests, defibrillation by nonmedical personnel, and participation in QI registries. It is unclear what effect these efforts have had on overall survival and neurologic recovery.

Study design: Retrospective cohort study.

Setting: Five hundred fifty-three hospitals in the U.S.

Synopsis: A total of 113,514 patients age >18 with a cardiac arrest occurring from Jan. 1, 2000, to Nov. 19, 2009, were identified. Analyses were separated by initial rhythm (PEA/asystole or ventricular fibrillation/tachycardia). Overall survival to discharge increased significantly to 22.3% in 2009 from 13.7% in 2000, with similar increases within each rhythm group. Rates of acute resuscitation survival (return of spontaneous circulation for at least 20 contiguous minutes after initial arrest) and post-resuscitation survival (survival to discharge among patients surviving acute resuscitation) also improved during the study period. Rates of clinically significant neurologic disability, as defined by cerebral performance scores >1, decreased over time for the overall cohort and the subset with ventricular fibrillation/tachycardia. The study was limited by including only hospitals motivated to participate in a QI registry.

Bottom line: From 2000 to 2009, survival after in-hospital cardiac arrest improved, and rates of clinically significant neurologic disability among survivors decreased.

Citation: Girotra S, Nallamothu B, Spertus J, et al. Trends in survival after in-hospital cardiac arrest. N Engl J Med. 2012;367:1912-1920.

Clinical Shorts


The FDA is continuing to investigate reports of morbidity and mortality associated with high-energy drinks, including 5-Hour Energy, Monster Energy, Rockstar Energy, and Red Bull.

Citation: U.S. Food and Drug Administration. Energy “drinks” and supplements: investigations of adverse event reports. U.S. Food and Drug Administration website. Available at: Accessed Dec. 28, 2012.


In this single-center study of 463 consecutive individuals suspected of having CAP, those on PPIs had 2.2 times the odds of being infected with Streptococcus pneumoniae.

Citation: De Jager CPC, Wever PC, Gemen EFA, et al. Proton pump inhibitor therapy predisposes to community-acquired Streptococcus pneumoniae pneumonia. Aliment Pharmacol Ther. 2012;36(10):941-949.


The FDA has approved Flucelvax, the first seasonal flu vaccine made in mammalian cell cultures rather than fertilized chicken eggs. The vaccine was approved by the European Union in 2007.

Citation: Chapelle R. FDA approves first seasonal influenza vaccine manufactured using cell culture technology. U.S. Food and Drug Administration website. Available at: Accessed Dec. 28, 2012.


The FDA has expanded the approved use of rivaroxaban (Xarelto) to include the treatment of DVT and PE. It had previously been approved for the prevention of VTE after hip/knee surgery and stroke in nonvalvular atrial fibrillation.

Citation: Yao S. FDA expands use of Xarelto to treat, reduce recurrence of blood clots. U.S. Food and Drug Administration website. Available at: Accessed Dec. 28, 2012.

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