EYE UPDATE

From Journal Watch (July 15, 2014)

 

Insulin or Sulfonylureas to Supplement Metformin in Patients with Diabetes

 

Comment: Recent studies of patients with type 2 diabetes have suggested that monotherapy with sulfonylureas is associated with worse cardiovascular outcomes than monotherapy with metformin.

In contrast, in the current study, researchers examined add-on therapy with sulfonylurea or insulin in patients who were already receiving metformin. The authors expected patients who were receiving insulin to fare better because their glycemic control would be better, but the results showed the opposite. Clinical recommendations based on these results would be premature, because this study might not account for all confounding factors.

 

Zoster Raises Risk for Stroke

Excess risk for cerebrovascular accident in zoster patients persists for 6 months then disappears.

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Case reports have suggested that herpes zoster acutely raises risk of cerebrovascular accident (CVA).

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Among adults with new diagnoses of zoster, overall risk for both ischemic and hemorrhagic stroke rose significantly in the first month after diagnosis, slowly diminished during the following 6 months, and vanished by 1 year. The effect was mitigated by antiviral treatment.

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Both herpes zoster ophthalmicus and zoster in other trigeminal nerve branches raised stroke risk almost three times higher than zoster in other dermatomes. This risk peaked in the second and third month after diagnosis; it was somewhat attenuated by treatment but still remained significantly elevated over baseline.

 

Comment: These data provide additional evidence of the benefits of antiviral treatment during episodes of zoster and imply that the benefits of vaccination might exceed its much advertised effects on preventing postherpetic neuralgia.

 

Head-to-Head Comparison of IV and Oral Methylprednisolone for MS Relapses

In equivalent doses, both oral and intravenous formulations were associated with improvement in multiple sclerosis patients.

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Patients with multiple sclerosis (MS) relapses that affect function and quality of life are offered intravenous methylprednisone (1000mg daily for 3 to 5 days) to hasten recovery. For cost and convenience reasons, some physicians prescribe oral steroids in an equivalent dose.

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In this double-blind, placebo-controlled, randomized trial, researchers recruited 49 patients with moderate MS relapses. Three-day courses of methylprednisolone were given either intravenously (1000mg daily) or orally (1250mg daily). Among 44 patients who finished the study, improvement on a standardized disability scale was not significantly different in the treatment groups at 1, 4, and 12 weeks.

 

Comment: This small study provides class 1 evidence that oral and intravenous formulations of glucosteroids, when used in equivalent doses, are equally efficacious in improving disability for those with moderately severe MS relapses.

From Journal Watch (July 1, 2014)

 

High Rate of Antibiotic Prescribing for Acute Bronchitis – Still

Clinicians continue to ignore evidence-based recommendations against antibiotic therapy.

 

During the past 15 years, national education programs have focused on eliminating inappropriate use of antibiotics generally and expensive, broad-spectrum antibiotic specifically.

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Between 1996 and 2010, the overall rate of antibiotic prescribing was 71%, with little variation by patients’ age, sex, race, or insurance status, or by region or population density (rural or urban). Prescribing of extended macrolides increased from 25% to 40% during the 15-year study. Other antibiotic – most commonly, broad-spectrum antibiotic – were prescribed at 35% of visits.

 

Comment: The authors bemoan the apparent lack of effect of 15 years of practice guideline dissemination, evidence-based exhortations, and educational efforts, although the antibiotic prescribing rate for acute bronchitis might have been higher by now without these measures. Physician education, of whatever sort, apparently is not the key factor.

 

New Oral Anticoagulants in Older Adults

For patients 75 or older, the balance of efficacy and bleeding risk appears similar to that of younger patients.

Clinicians might be concerned about the relative safety of the newer oral anticoagulants (dabigatran [Pradaxa], rivaroxaban [Xarelto], and apixaban [Eliquis]) in older patients.

For older patients, rates of major bleeding or “clinically relevant bleeding” were virtually identical in the new anticoagulant and conventional treatment groups; this finding held true for studies in which new agents were compared with warfarin.

 

Comment: This analysis provides reassurance that the balance of efficacy and safety of dabigatran, rivaroxaban, and apixaban extends to older patients.   

 

From Journal Watch (June 15, 2014)

 

Again, No Benefit of ω-3 Fatty Acid Supplementation for Preventing Cardiovascular Disease

Addition of anti-inflammatory lutein and zeaxanthin did not help.

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Consumption of fatty fish rich in long-chain ω-3 polyunsaturated fatty acids is associated with lower risk for cardiovascular disease and death, but no CV benefits have been demonstrated for supplementation with ω-3 fatty acids.

 

Comment: As with most dietary supplements, epidemiological associations that suggest lower risk have not been borne out in clinical trials of supplementation. Eating Atlantic salmon and trout is still a better bet.

 

Simple Tests of Physical Capability Predict Mortality in Middle Age

These tests included grip strength, chair rise speed, and standing balance time.

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Greater physical capability is associated with later mortality in elders, but whether the same is true in middle-aged adults is unknown.

 

Comment: Based on the findings, prescriptions for physical conditioning is reasonable in patients with low physical capability.

From Journal Watch (June 1, 2014)

 

Vitamin and Mineral Supplements for Primary Prevention of Cardiovascular Disease and Cancer

A sizable proportion of U.S. adults take vitamin and mineral supplements for presumed health benefits.

 

Key Points

• Substantial and consistent evidence shows that vitamin E supplementation has no effect on CV disease, cancer, or mortality: Not recommended.

• New evidence increases certainty that vitamin E does not prevent CV disease or cancer.

 

Comment: Evidence is insufficient to suggest substantial benefits or harms from supplements in healthy adults who consume a reasonably balanced diet. At this time, no simple alternative to consuming a balanced diet exists. These recommendations are unlikely to impact the many billions of dollars spent annually on vitamin and mineral supplements.

 

Screening Flexible Sigmoidoscopy and Colonoscopy Are Associated with Less Colorectal Cancer and Lower Mortality

Of course, a big challenge is encouraging people to be screened.

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In four randomized controlled trials, researchers assessed screening flexible sigmoidoscopy versus no endoscopy in 438,000 participants.  

 

Comment: This meta-analysis shows convincingly that screening flexible sigmoidoscopy lowers distal colorectal cancer incidence and mortality and strongly suggests that screening colonoscopy is protective against developing and dying from proximal and distal colon cancers. Of course, adherence to screening with these tests might be challenging: In the four randomized trials of flexible sigmoidoscopy, participation in the intervention ranged from 58% to 87%.

Understanding Primary Nonadherence to Prescribed Medications

Primary nonadherence to medications is defined as never filling a prescription; secondary nonadherence is defined as filling a prescription but not taking the medication as prescribed. In this study from Quebec, Canada, researchers evaluated the incidence and characteristics of primary nonadherence.

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Overall, 31% of new prescriptions were not filled within 9 months. Older patients were more adherent than younger patients. Cost played a significant role – compared with patients who were charged the maximum copayment, patients who received free medications were 63% more likely to fill prescriptions.

 

Comment: This Canadian study is notable for its focus on primary nonadherence. Close to one-third of prescriptions were never filled. The findings are concerning and likely apply to other countries, too. As noted by the authors, indentifying potential interventions is important; providing more follow-up care and lowering drug costs also could have a substantial positive effect. However, we should acknowledge that some prescribed medications are unnecessary or even harmful; patients might have good reasons not to fill those prescriptions.

From Journal Watch (May 15, 2014)

 

Careful Meta-Analyses Cast Doubts on Flu Drugs

The Cochrane Collaboration again concludes that both oseltamivir and zanamivir are overrated.

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Cochran reviewers have been skeptical about the efficacy of the neuraminidase inhibitors zanamivir (Relenza) and oseltamivir (Tamiflu) for treating patients with influenza. However, because much of the proprietary data on these drugs have been unavailable for public review, their conclusions have been tentative. Now two new Cochrane reviews incorporate thousands of pages of previously unavailable data from the drugs’ manufacturers.

 

Comment: These two long, meticulously documented analyses deliver a consistent message. The neuraminidase inhibitors oseltamivir and zanamivir are modestly effective in preventing symptomatic influenza and minimally effective in treating it. Data regarding the much-hyped oseltamivir are particularly damning. In the words of the researchers, “these findings provide reason to question the stockpiling of oseltamivir, its inclusion on the WHO list of essential drugs, and its use in clinical practice as an anti-influenza drug.”

 

Direct-to-Patient Education Limits Benzodiazepine Use in Older Adults

The same approach used by pharmaceutical companies to promote medication use also can be used to limit inappropriate use.

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Although medical professional organizations have recommended against benzodiazepine use in older adults because of an association with excess risk for cognitive decline, falls, and hip fractures. Physicians continue to write and refill prescriptions at a high rate. To test the effectiveness of direct-to-patient education on discontinuation of benzodiazepine, investigators in Canada randomized 30 pharmacies to provide a patient-education intervention or usual care to older adult patients for whom they refilled benzodiazepine prescriptions. The intervention group received booklets containing detailed assessments of their benzodiazepine use, information on benzodiazepines’ risk, testimonials about successful quitting, alternative approaches to treating insomnia and anxiety, tapering recommendations, and instructions to discuss discontinuation with their physicians or pharmacists.

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About 85% of participants completed follow-up. At 6 months, 27% of intervention participants versus 5% of controls had discontinued benzodiazepine.

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In follow-up interviews, one third of the intervention participants who did not attempt to taper use cited “discouragement” by their physician or pharmacist as the reason.

 

Comment: This important proof-of-concept study shows that going directly to patients can be effective in reducing use of potentially dangerous medications. The direct-to-consumer approach employed by pharmaceutical companies to promote medications might be equally effective in limiting inappropriate use. Why physicians would actually “discourage” tapering of benzodiazepines – as reported by some patients in this study – is unclear.

 

New All-Oral Hepatitis C Regimens Are on the Horizon

Cure rates with two new combinations approach 100% in some patient populations.

 

Comment: These studies demonstrate that nearly all patients with chronic hepatitis C can be cured with all-oral regimens. Sofosbuvir already is FDA approved; it manufacturer is currently seeking FDA approval for the sofosbuvir/ledipasvir fixed-dose combination used in the first set of trials. None of the drugs (except for ribavirin) used in the second set of trails have been FDA approved as of May 15, 2014.

An editorialist believes that these regimens will be manageable by primary care physicians. However, the elephant in the room is cost. Various critics have chastised Gilead, the company that makes sofosbuvir, for pricing the drug at US$1000 per pill.

 

To Stop Overtreatment, a Lab Withholds Results

Without easy access to urine culture results, treatment rates plunged for patients with asymptomatic bacteria.

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Evidence clearly indicates that patients with asymptomatic bacteria should not be treated (other than those who are pregnant or are about to undergo invasive genitourinary tract procedures). And yet, studies show that many patients with the condition continue to receive antibiotics.

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In hopes of modifying irrational prescribing behavior, researchers changed the way in which the microbiology lab in a single Toronto hospital reported results of urine cultures. All urine cultures were processed as usual, but, during two nonconsecutive months, culture results obtained from noncatheterized patients were not posted to medical records. Instead, clinicians saw a reminder that bacteriuria in asymptomatic noncatheterized patients usually does not indicate infection; clinicians were invited to call the microbiology lab if they still wanted details on specific cultures.

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Compared with months during which all cultures were reported out as usual, during the study months treatment rates for asymptomatic bacteriuria among noncatheterized patients fell.

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No noncatheterized patient with urinary tract infection went untreated (most received empirical antibiotics before culture results were available), and no clinical harms befell any patient who went untreated.

 

Comment: The temptation to act on information can be overwhelming. This study confirms that removing the information often removes the temptation. It is an effective technique, if a little dishonest (editorialists call it “asymmetric paternalism”). I suspect we will all be seeing more of this kind of behavioral modification tool in the future.

 

Early introduction of Complementary Foods Lowers Risk for Allergy at Age 6

As the prevalence of food allergies increases in Western countries, the practice of delaying introduction of allergenic foods to infants in hopes of preventing food allergies and other allergic disease has been called into question. Guidelines now recommend earlier introduction of all foods.

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Children introduced to fewer than four common foods during the first year had more than three times the risk for asthma and more than four times the risk for food allergy than did children introduced to all six foods. Fish, eggs, and dairy consumption were associated with >50% less risk for asthma.

 

Comment: This study provides further evidence that early introduction of complementary foods prevents allergic disease. We still should recommend exclusive breast milk during the first 4 months of life, but then encourage food diversity during the remainder of the first year.

 

From Journal Watch (May 1, 2014)

 

New Recommendations for Lab-Based Sexually Transmitted Disease Diagnosis

Nucleic acid amplification tests are preferred for diagnosing gonorrhea and chlamydia in both genital and extragenital infections.

• Nucleic acid amplification tests (NAATs) are now the preferred means of diagnosing chlamydia and gonorrhea because of the sensitivity of the tests and east of specimen collection.

 

• Present generation NAATs are sensitive and specific enough that routine reconfirmation is unnecessary for both positive and negative results.

 

• Routine testing for cure with NAATs immediately after treatment should be avoided, because NAATs cannot discriminate between viable and nonviable bacteria and might remain positive for weeks after treatment.

 

Improved Physician Well-Being with Training in Mindfulness and Reflection

Distress and burnout are highly prevalent in medical students, residents, and physicians. More than 40% of randomized participants reported emotional exhaustion or burnout at baseline.

 

Comment: An editorialist noted the generally discouraging levels of stress, depression, exhaustion, and depersonalization that characterized this group of Mayo Clinic physicians and almost certainly all physicians as well.

From Journal Watch (April 15, 2014)

 

Delayed or No Antibiotic Prescriptions for Patients with Acute Respiratory Tract Infections

Antibiotic use decreased markedly without affecting symptom severity or duration.

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Many patients expect to receive antibiotics for acute respiratory tract infections, and many clinicians prescribe them. In this trial, investigators in the U.K. assessed the effects of no or delayed antibiotic use in 900 primary care patients with acute respiratory tract infections.

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Significantly more patients who were prescribed antibiotics immediately used them (97%) and believed they were effective (93%), yet experienced similar symptom severity and duration as did patients who received delayed or no antibiotics.

 

Comment: In this study, strategies of delayed or no antibiotic prescriptions in patients with acute respiratory tract infections resulted in at least 60% fewer patients using antibiotic, with no effects on symptom severity and duration, compared with immediate antibiotic prescription. Obviously, widespread implementation of such strategies would help prevent overuse of antibiotics and emergence of antibiotic resistance.

 

Penicillin Allergy Is Associated with Longer Hospital Stays and More Antibiotic Use

Penicillin allergy is reported by roughly 10% of the U.S. population, but, in a recent study in which participants who reported penicillin allergy were skin tested and given oral challenges, fewer than 10% were truly allergic. This overreporting leads clinicians to prescribe other antibiotics, which can be more expensive, less efficacious, and more likely to cause adverse effects.

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During the 3-year study, the extra hospital days associated with penicillin allergy cost the health care system an estimated US$ 60 million.

 

Neuroimaging for Headache: Usually Unnecessary But Ordered Often

Neuroimaging rates roughly doubled from 2000 to 2010.

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The American College of Radiology recommends against routine neuroimaging in patients with uncomplicated headache. A new study suggests that the rate of neuroimaging is inappropriately high and continues to increase.

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Neuroimaging rates for all patients with headaches increased from 8% in 2000 to 15% in 2010.

 

Comment: Epidemiological data like these cannot identify the “right” rate for neuroimaging for headache. Other studies show that imaging identifies serious intracranial abnormalities in 1% to 3% of patients, whether those patients have headaches or not. The authors note that annual cost of this imaging is roughly US$ 1 billion. However, there is likely additional cost – and sometimes, patient anxiety – attributable to identification and further evaluation of the incidental findings. As we all know, patient anxiety and legal exposure often influence neuroimaging use even in the absence of neurological deficits or other complicating factors.   

 

Estimating the Potential Effect of the New Cholesterol Guidelines

The 2013 ACC-AHA guidelines recommend statin therapy for most people who are 60 to 75.

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Anyone who has plugged numbers into the new risk calculator from the American College of Cardiology and American Heart Association (ACC-AHA) will recognize that more people – especially older adults without clinical evidence of cardiovascular (CV) disease – would be classified as “eligible” for statin therapy according to the new cholesterol guidelines.

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The proportion of 60-to-75-year-olds recommended for statin therapy would rise from 48% to 77%. This difference reflects the fact that the new guidelines recommend treating people whose 10-year CV risk exceeds 7.5%, even when their LDL cholesterol levels are as low as 70mg/dL.

 

From Journal Watch (April 1, 2014)

 

New Treatment Helps Prevent Autistic Behavior in Rodents

Administering a diuretic before delivery triggered a normal pathway and eliminated autistic behavior in offspring.

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In neonatal animals, γ-aminobutyric acid (GABA) switches from being an excitatory neurotransmitter to being an inhibitory neurotransmitter. The surge of maternal oxytocin at birth affects chloride channels in fetal neurons, causing chloride concentrations to drop – and the “GABA switch” to be activated. In contrast, in two rodent models of autism, chloride concentrations remain high and GABA remains an excitatory neurotransmitter after birth.

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Using rats from these autism models, A French team administered an FDA-approved diuretic, bumetanide, to rodent mothers 1 day before delivery. The treatment triggered the change in chloride concentrations, activated the GABA switch, and eliminated autistic behavior in offspring.

 

Comment: A perinatal treatment with an FDA-approved diuretic, bumetanide, eliminated autistic behavior in two rodent models of autism. If these rodent models offer lessons about human autism spectrum disorders, the results are obviously of great interest. Intriguingly, treating autistic children with bumetanide improves symptoms (Transl Psychiatry 2012; 2:e202), so the rodent studies indeed might be applicable to humans. However, better biomarkers to identify pregnancies in which children might be at risk for developing autism are required before randomized treatment trials to prevent autism are likely.

 

Is Chronic Urticaria Caused by Food Additives?

Almost never – and testing for additives is rarely indicated.

 

Chronic idiopathic urticaria affects 1% of the population and is defined as hives with no discernible cause that persists for 6 weeks or longer.

 

Comment: Food Additives rarely cause chronic idiopathic urticaria; the authors estimate the prevalence is <1%. In general, laboratory testing rarely helps identify a cause for chronic urticaria. Food or food additive testing, rarely, if ever, is indicated.