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ACP InternistWeekly



In the News for the Week of 3-13-12




Highlights

Donepezil offers benefits in moderate or severe Alzheimer's; adding memantine doesn't

Donepezil offers cognitive and functional benefits in patients with moderate or severe Alzheimer's disease, while adding memantine does not, a study concluded. More...

Mental health diagnoses in veterans associated with increased risk of opioid use

Military veterans who have received a mental health diagnosis, in particular post-traumatic stress disorder, are more likely to be prescribed opioids, have high-risk opioid use, and experience adverse outcomes, according to a new study. More...


Test yourself

MKSAP Quiz: marked change in overall behavior

This week's quiz asks readers to evaluate a 27-year-old man with a marked change in behavior over a 6-month time frame. More...


Cardiology

Comparison of cardiac risk models has implications for statin use in women

The Reynolds Risk Score was better than the Framingham-based model at determining women's cardiovascular risk, according to a large external validation cohort. More...


Infectious disease

Antibiotic use confers up to tenfold risk of C. diff infection

A patient's risk of developing Clostridium difficile infection is 7 to 10 times higher during antibiotic therapy and in the month after stopping, and an elevated risk still exists three months after stopping antibiotics, a study found. More...


Hearing loss

Guideline issued on sudden hearing loss

The American Academy of Otolaryngology-Head and Neck Foundation recently released a guideline on diagnosis, management and follow-up of sudden hearing loss in adults. More...


FDA update

What makes a misleading ad?

In May 2010, the FDA launched a program designed to help clinicians recognize possible misleading prescription drug promotions and report such promotions to the FDA. More...


Cartoon caption contest

Vote for your favorite entry

ACP InternistWeekly's cartoon caption contest continues. Readers can vote for their favorite caption to determine the winner. More...


Physician editor: Daisy Smith, MD, FACP



Highlights


.
Donepezil offers benefits in moderate or severe Alzheimer's; adding memantine doesn't

Donepezil offers cognitive and functional benefits in patients with moderate or severe Alzheimer's disease, while adding memantine does not, a study concluded.

Researchers wanted to assess three factors:

  • whether donepezil would be associated with better cognition and function at one year compared to not using the drug,
  • whether memantine compared with placebo would be associated with better cognition and function, and
  • whether combining donepezil and memantine would provide any benefits.

Researchers conducted a multicenter, double-blind, placebo-controlled trial among 295 community-dwelling residents and assessed outcomes for 52 weeks. Patients had moderate or severe Alzheimer's disease, were already taking donepezil and scored between 5 and 13 on the Standardized Mini-Mental State Examination (SMMSE).

Participants were randomly assigned to one of four treatments:

  • continuing donepezil and starting placebo,
  • stopping donepezil and starting placebo,
  • stopping donepezil and starting memantine, or
  • continuing donepezil and starting memantine.

Results appeared in the March 8 New England Journal of Medicine.

Patients who continued taking donepezil had higher SMMSE scores (indicating better cognitive function) compared with those who stopped it by an average of 1.9 points (95% CI, 1.3 to 2.5; P<0.001) and lower scores on the Bristol Activities of Daily Living Scale (BADLS) (indicating less functional impairment) by an average of 3 points (95% CI, 1.8 to 4.3; P<0.001).

Patients taking memantine as compared with placebo had higher SMMSE scores by an average of 1.2 points (95% CI, 0.6 to 1.8; P<0.001) and lower BADLS scores by an average of 1.5 points (95% CI, 0.3 to 2.8; P=0.02). Both these values were smaller than the minimum clinically important differences, researchers noted.

There was no significant benefit of adding memantine to donepezil. Scores on the SMMSE were 0.8 point higher with memantine than with placebo (95% CI, −0.1 to 1.6; P=0.07). Scores on the BADLS were 0.5 point lower with memantine than with placebo (95% CI, −2.2 to 1.2; P=0.57).

Donepezil offered larger benefits in patients with moderate disease (SMMSE score, 10 to 13) than in those with severe disease (SMMSE score, 5 to 9). The average difference in scores between the groups assigned to continue donepezil and the groups assigned to discontinue donepezil was 2.6 points (95% CI, 1.5 to 3.7) among patients with moderate disease (P<0.001) and 1.3 points (95% CI, 0.2 to 2.4) among patients with severe disease (P=0.02).

Patients who received memantine instead of placebo had lower Neuropsychiatric Inventory (NPI) scores (indicating fewer behavioral and psychological symptoms) by an average of 4 points (99% CI, 0.6 to 7.4; P=0.002), which did not meet the standard of a clinically important difference. There wasn't a significant difference in scores on the NPI between continuing and stopping donepezil (2.3 points lower with continuation; 95% CI, −1.1 to 5.7; P=0.08). Adding memantine to donepezil resulted in a decrease in the NPI score that was greater by 5.1 points (99% CI, 0.3 to 9.8; P=0.006) than that from placebo.


.
Mental health diagnoses in veterans associated with increased risk of opioid use

Military veterans who have received a mental health diagnosis, in particular post-traumatic stress disorder (PTSD), are more likely to be prescribed opioids, have high-risk opioid use, and experience adverse outcomes, according to a new study.

Researchers performed a retrospective cohort study of veterans of Iraq and Afghanistan who had received one or more diagnoses of non-cancer-related pain within a year of entering the VA health system. The study's main outcome measures were the independent association between mental health disorders and receipt of an opioid prescription, high-risk opioid use, and such adverse outcomes as accidents, overdoses and self-inflicted injuries within a year of a pain-related diagnosis. The study results appeared in the March 7 Journal of the American Medical Association.

Overall, in a cohort of 141,029 veterans who entered the VA health system between Oct. 1, 2005 and Dec. 31, 2010, 15,676 received an opioid prescription within a year of a first pain diagnosis. Such prescriptions were significantly more likely among patients with PTSD (17.8%; adjusted relative risk [RR], 2.58; 95% CI, 2.49 to 2.67) or other mental health diagnoses (11.7%; adjusted RR, 1.74; 95% CI, 1.67 to 1.82) than among patients without mental health disorders (6.5%). Among patients prescribed pain medication, those with PTSD were more likely than those without mental health disorders to receive higher doses of opioids (22.7% vs. 15.9%; adjusted RR, 1.42; 95% CI, 1.31 to 1.54), to receive two or more opioids together (40.7% vs. 7.6%; adjusted RR, 5.46; 95% CI, 4.91 to 6.07), or to refill their opioid prescriptions early (33.8% vs. 20.4%; adjusted RR, 1.64; 95% CI, 1.53 to 1.75). In all veterans, an association was seen between receiving prescription opioids and experiencing adverse clinical outcomes (RR, 2.33; 95% CI, 2.20 to 2.46), but especially among those with PTSD.

The authors acknowledged that their data did not include socioeconomic status and that their results may not be generalizable to all veterans, among other limitations. However, they concluded that mental health diagnoses, particularly a diagnosis of PTSD, were associated with higher risk of receiving opioids, high-risk opioid use, and adverse outcomes in this population of Iraq and Afghanistan veterans. The authors pointed out that many primary care practices may be seeing increasing numbers of returned combat veterans and that physicians should take extra care when prescribing opioids to this population. "These patients may benefit from biopsychosocial models of pain care including evidence-based nonpharmacologic therapies and nonopioid analgesics," the authors wrote. "Integrated treatments that target both mental health disorders and pain simultaneously are effective for both problems and may decrease harms resulting from opioid therapy."

In a separate article published online March 7 by Injury Prevention, researchers examined army personnel data and found that 255 active-duty U.S. soldiers committed suicide in 2007-2008. Male gender, lower enlisted rank, and outpatient treatment for mental health disorders were associated with higher suicide risk, as were mood disorders, anxiety disorders, PTSD, personality or psychotic disorders, substance disorders and adjustment disorder. The authors noted that their findings should be confirmed in studies conducted over a longer time period and with a larger sample, but suggested that suicide prevention efforts should focus on soldiers who are treated for mental disorders or substance abuse.



Test yourself


.
MKSAP Quiz: marked change in overall behavior

A 27-year-old man is evaluated for concerns noted by his wife of a marked change in overall behavior over the past 6 months, including deterioration in his general hygiene and episodes of talking to imaginary people. His employer has also raised concerns about his work performance. The patient has also noted intermittent tingling in the hands and feet. Most recent travel includes 2 years in Oxford, England, between 1995 and 1997. Family history is unremarkable.

On physical examination, vital signs are normal. The patient is fully alert, but oriented only to place and person. His gait is ataxic. He scores 14 of 30 (normal >24/30) on the Mini-Mental State Examination. The remainder of the examination is normal.

Routine laboratory studies are normal. Results of urine drug screen, HIV antibody testing, and the rapid plasma reagin test for syphilis are negative. No abnormalities are noted on CT scan of the head, and electroencephalography shows only nonspecific slowing.

Which of the following is the most appropriate next step in management?

A) Brain biopsy
B) Corneal biopsy
C) Intravenous acyclovir
D) Intravenous dexamethasone
E) Tonsillar biopsy

Click here or scroll to the bottom of the page for the answer and critique.


.

Cardiology


.
Comparison of cardiac risk models has implications for statin use in women

The Reynolds Risk Score was better than the Framingham-based model at determining women's cardiovascular risk, according to a large external validation cohort.

The differences are large enough to have a clinical impact for statin therapy, the researchers noted. They drew a case-cohort sample from the Women's Health Initiative Observational Study (WHI-OS), comprising 1,722 cases of major cardiovascular disease (CVD) (752 myocardial infarctions, 754 ischemic strokes, and 216 other cardiovascular disease deaths) and a random subcohort of 1,994 women without prior CVD.

Researchers estimated risk using the ATP-III score, the Reynolds Risk score and the Framingham CVD model. Results appeared online March 7 in Circulation.

The models found differing percentages of the women to be at intermediate risk of a cardiovascular event (10% or higher risk in the next 10 years): 5.5% according to ATP-III, 10.3% according to Reynolds, and 41.1% according to Framingham. Higher risk (20% or higher in the next 10 years) was predicted for 0.5%, 2.6%, and 10.6% of women by the three models, respectively.

The Reynolds Risk Score appeared relatively well-calibrated for the endpoint of major CVD, the authors noted. The Framingham CVD model, developed for a broader definition of CVD, greatly overestimated risk of major CVD. A similar pattern of overestimation of risk was seen for the ATP III model for coronary heart disease.

To directly compare discrimination of the three models, researchers recalibrated them so that the average predicted risk equaled the overall reweighted population estimate of 4%. After this, the percent of women with estimated risk of 10% or higher was then 6.6% for the ATP-III, 7.7% for Reynolds, and 6.2% for the Framingham CVD model.

The large differences in risk estimates among the models have clinical implications for statin therapy, the authors wrote. In a hypothetical population of 100,000 women, the number who would be classified at 10% or higher risk would be 5,549 with the ATP-III model, 10,304 with the Reynolds score, and 41,074 with the Framingham CVD model.

The authors concluded, "The Reynolds Risk Score significantly improved fit as compared to either the Framingham-based ATP-III CHD risk score or the newer Framingham CVD score. Within the WHI-OS, the greatest impact of the Reynolds Risk Score appeared to be among those women with 5 to 10% 10-year estimated risk according to ATP-III, a group including a large number of women destined to suffer MI or stroke, and in whom trial data indicate efficacy of statin therapy in reducing cardiovascular events."

An editorial noted that using the Reynolds score instead of ATP-III would reclassify a substantial number of women. Of the 5% of women at ATP-III risk of 10% to 20% (intermediate/moderately high risk), 23% would be reclassified in a higher-risk category and 18% in a lesser. Of those originally predicted to have 5% to 10% 10-year (moderate) risk based on ATP-III, 5% would be reclassified as more than 20% and 29% as above 10%. Since 8 to 10 million American women have an ATP-III 10-year risk of 5% to 20%, the Reynolds score could have major impact on CVD prevention in women.

The editorialists added that the three prediction models are overly complex for clinical use, despite online calculators. And trials of statins for primary prevention didn't use Framingham or Reynolds thresholds, making LDL targets in the research and the risk factor scores discordant. Finally, while Reynolds focused on 10-year risk, the clinical issue for many women is lifetime risk.

"Having too much confidence in cardiovascular risk prediction does indeed appear to be a risky proposition," the editorial concluded.



Infectious disease


.
Antibiotic use confers up to tenfold risk of C. diff infection

A patient's risk of developing Clostridium difficile infection (CDI) is 7 to 10 times higher during antibiotic therapy and in the month after stopping, and an elevated risk still exists three months after stopping antibiotics, a study found.

Dutch researchers performed a case-control study in nine hospitals between March 1, 2006 and May 1, 2009. They compared 337 hospitalized patients with diarrhea and a positive toxin test to 337 patients without diarrhea. A control group of 227 patients with diarrhea from a cause other than C. diff was also included. Results were reported in the March Journal of Antimicrobial Chemotherapy.

In the month prior to the reference date, 77% of CDI patients used an antibiotic compared with 48.9% of non-diarrheal patients (P<0.01). Of these, 35% of CDI patients and 25% of non-diarrheal patients were using an antibiotic at the time of diagnosis (P=0.01). On multivariate analysis, there was a more than sixfold increased risk for CDI during antibiotic use and in the first month after stopping antibiotics (odds ratio [OR], 6.67 to 10.37). The risk declined in the period between one and three months after the antibiotic was stopped (OR, 2.7 at three months). The control group comparison yielded similar results. All antibiotic classes were associated with CDI except first-generation cephalosporins and macrolides. The antibiotics with the strongest associated risks were second- and third-generation cephalosporins (OR, 3.3 and 5.3, respectively) and carbapenems (OR, 4.7). Compared with non-diarrheal patients, those with CDI used more antibiotic classes (P<0.01) and more defined daily doses.

One study limitation was the use of various enzyme immunoassays to diagnose CDI. Given their reported sensitivities of between 60% and 85%, some patients could have been missed as having CDI, which in turn might have led to overestimation of the duration of increased risk of non-CDI diarrhea after antibiotic use. Even so, clinicians should be made aware that antibiotic use can greatly increase the risk for CDI, even if the use preceded the symptoms by a month, the researchers wrote.



Hearing loss


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Guideline issued on sudden hearing loss

The American Academy of Otolaryngology-Head and Neck Foundation recently released a guideline on diagnosis, management and follow-up of sudden hearing loss in adults.

To help clinicians manage this condition, especially sudden sensorineural hearing loss, an expert panel reviewed 133 articles and drafted the guideline recommendations, which then underwent extensive peer review. In areas where data were lacking, the panel relied on expert consensus and clinical experience. All guideline statements were graded on strength and on the quality of the supporting evidence.

The panel made a total of 13 guideline statements in the following categories:

  • diagnosis, including exclusion of conductive hearing loss, use of computed tomography, and laboratory testing;
  • shared decision making, including patient education;
  • treatment, including initial corticosteroids, hyperbaric oxygen therapy and salvage therapy; and
  • follow-up, including outcomes assessment and rehabilitation.

The panel also called for further research into the use of steroids as salvage therapy as well as the potential for combination therapy in patients with sudden sensorineural hearing loss, among other areas.

The full guideline was published online March 1 by Otolaryngology-Head and Neck Surgery.



FDA update


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What makes a misleading ad?

In May 2010, the FDA launched a program designed to help clinicians recognize possible misleading prescription drug promotions and report such promotions to the FDA. Since the program's launch, reports have more than tripled over the previous years' average—from approximately 104 to 328 in 2011.

The most common potential problems with promotional pieces are:

  • Overstating the efficacy of a drug. One example would be if promotional materials say, "Drug X delivers results in as little as 3 days" when clinical trials showed results in 12 weeks.
  • Omitting or minimizing the risks of the product. A presentation that includes a drug's benefits but not its risks is one example.
  • Promoting a drug for a wider range of patients than its approval indicates or for a new, unapproved use.
  • Making unsubstantiated comparisons between drugs.

The first drug promotion stopped because of information sent to the FDA's program was a website for Derma-Smoothe/FS® (fluocinolone acetonide) Topical Oil, 0.01% (Derma-Smoothe). Can you spot the problematic messages? Explanation of the answers is given below. The FDA's warning letter to Derma-Smoothe's manufacturer and the manufacturer's response are available online.

Clinicians can report a potentially misleading ad via phone at 877-RX-DDMAC (877-793-3622) or via e-mail. Anonymous reporting is accepted, but providing contact information is encouraged to allow follow-up if more details are needed. More information about the program is available online.

Explanation of answers

  1. The claim "The only product for patients 3 months and older that can be used when their eczema is severe and all over!" suggests use of the drug in a wider range of patients and fails to communicate limitations to the drug's use. Specifically, this claim does not convey that Derma-Smoothe is indicated for moderate to severe atopic dermatitis; does not convey that Derma-Smoothe is only indicated for use up to 4 weeks; and implies that Derma-Smoothe can be used all over the body. The FDA-approved labeling explicitly states that it should not be applied to the diaper area and that the drug should not be used on the face, axillae, or groin unless directed by the physician.
  2. The claim "The only corticosteroid that does not cause adrenal suppression, even when used over 90% of the body!" minimizes the risks of Derma-Smoothe, specifically, the associated risk of HPA axis suppression. According to the approved labeling, the use of topical corticosteroids over large surface areas can increase systemic absorption. The warning further states that children may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios. The image of the baby holding a circular sign with the claim "Safety Concerns" crossed out also minimizes the risk of Derma-Smoothe.
  3. The claim that a full course of treatment is only $45 overstates the efficacy of Derma-Smoothe. This presentation implies that one to two bottles of the drug will eliminate the symptoms of atopic dermatitis, when there is no evidence to support that statement. The image of the baby holding a circular sign with the claim "Disappointing Results" crossed out is also misleading.


Cartoon caption contest


.
Vote for your favorite entry

ACP InternistWeekly's cartoon caption contest continues. Readers can vote for their favorite caption to determine the winner.

acpi-20120313-cartoon.jpg

"Thank you, Mr. Jones. We will now proceed with the wallet biopsy."

"It's part of our effort to update the practice's technology."

"Our office manager is pretty aggressive about collecting co-pays at the time of visit."

Go online to pick the winner, who receives a $50 gift certificate good toward any ACP program, product or service.


.


MKSAP Answer and Critique



The correct answer is E) Tonsillar biopsy. This item is available to MKSAP 15 subscribers as item 60 in the Infectious Diseases section. More information about MKSAP 15 is available online.

Variant Creutzfeldt-Jakob disease (vCJD) was first reported in England in 1995 and is caused by bovine-to-human transmission of bovine spongiform encephalopathy. There are many features that distinguish vCJD from CJD, including presentation at a younger age; disease onset marked by psychiatric symptoms, which can lead to a mistaken diagnosis of depression; a slower disease progression; and the presence of PrPSc (an abnormal form of prion protein) in tonsillar biopsies. A brain biopsy is required to confirm a diagnosis of CJD and will also establish the diagnosis of vCJD, but it is more invasive than a tonsillar biopsy, which will provide the presumptive diagnosis in this patient.

Corneal biopsy is one way to establish the diagnosis of rabies. Rabies encephalitis is much more rapidly progressive than is vCJD and is characterized by hydrophobia, aerophobia, pharyngeal spasms, and hyperactivity followed by coma, respiratory and vascular collapse, and death within 2 weeks after coma onset. This patient's chronic symptoms are not compatible with rabies.

Intravenous acyclovir is appropriate in patients with herpes simplex encephalitis. Clinical features of herpes simplex encephalitis include fever, hemicranial headache, language and behavioral abnormalities, memory impairment, cranial nerve deficits, and seizures as well as MRI findings characterized by edema and hemorrhage in the temporal lobes and hypodense areas and nonhomogeneous contrast enhancement. However, this patient's clinical tempo and findings are not consistent with herpes encephalitis, and acyclovir has no therapeutic role for vCJD. In fact, there is no effective treatment for vCJD, including corticosteroids.

Key Point

  • Variant Creutzfeldt-Jakob disease (vCJD) is characterized by early-onset psychiatric symptoms suggestive of depression, an earlier age of onset than CJD, an absence of periodic sharp waves on electroencephalogram, and presumptive diagnosis by tonsillar biopsy.

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A 19-year-old man is evaluated for a sore throat, daily fever, frontal headache, myalgia, and arthralgia of 5 days' duration. He also has severe discomfort in the lower spine and a rash on his trunk and extremities. He returned from a 7-day trip to the Caribbean 8 days ago. The remainder of the history is noncontributory. Following a physical exam and lab studies, what is the most likely diagnosis?

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