Medical Year in Review: Excerpts From Journal Watch (www.jwatch.org)
Journal Watch (General Medicine) is published by the same publisher as The New England Journal of Medicine. This newsletter-like booklet is published every two weeks and gives a "Cliffs Notes-like" summary (with expert commentary) on contemporary issues in general medicine. We have selected topics we feel may be of interest to many of you. This reading will truly expand your scope of clinical knowledge.
General Medicine Updates
From Journal Watch (August 1, 2015)
Reversing Dabigatran(Pradaxa)-Induced Anticoagulation
Idarucizumab immediately reversed dabigatran-induced increases in clotting variables without causing serious adverse events.
Researchers have developed a monoclonal antibody fragment, idarucizumab, which tightly binds to dabigatran and nullifies its anticoagulant activity.
Infusion of idarucizumab resulted in immediate and complete reversal of the dabigatran-induced increases in clotting tests. No serious or severe adverse events were observed.
Comment: The introduction of antidotes to the new oral anticoagulants is an important step, and it raises the question of whether every patient starting on one of these drugs should receive a vial containing the specific antidote to be used if bleeding occurs.
Major Step Toward a Vaccine for Chlamydia trachomatis
Nanoparticle technology might be the key to developing certain vaccines.
Worldwide, more than 100 million people (including >1 million people in the U.S.) become infected with Chlamydia trachomatis annually. infection with C. trachomatis is the most common known cause for infertility and ectopic pregnancy and the most common infectious cause if blindness. Attempts to create vaccines against C. trachomatis have generated little immune response where it is needed most – at mucosal surfaces.
Previous research shows that monoclonal nanoparticles are taken up rapidly by mucosal epithelial cells.
Comment: Success of vaccine in mice, even “humanized” mice, is no guarantee of success in humans. Nevertheless, the superiority of this vaccine to past vaccines is encouraging. Indeed, the same novel approach probably will be tried with vaccines against other organisms, such as HIV, against which mucosal protection is critical.
U.S. Breast Cancer Screening Data Lead to Questions About the Value of Mammography
Higher uptake of mammography is associated with more cancer diagnoses but not with lower cancer-specific mortality.
Comment: Although several explanations for these epidemiological findings are possible, the most compelling is that widespread mammography leads to overdiagnosis of clinically unimportant cancers that have no effect on mortality. According to editorialists, these findings should encourage clinicians who are counseling patients about mammography to be more explicit about overdiagnosis risk.
Managing Dyslipidemia in Adults
Eliminate LDL cholesterol and non-HDL cholesterol levels as specific treatment targets. Evidence supports use of moderate, fixed-dose statin therapy to lower risk for early all-cause death and adverse cardiovascular events.
Routine use of additional testing to refine risk prediction is not recommended.
Coronary artery calcium (CAC) scores improve net reclassification by 5% to 16%, but this effect is considered to be small.
Fasting lipid measurement and routine monitoring are not required. Nonfasting total and HDL cholesterol levels differ little from fasting measurements. Routine monitoring of lipids, creatinine kinase, or liver function during follow-up is not recommended.
The new guideline suggests initiation of moderate-dose statin therapy for most patients.
From Journal Watch (July 15, 2015)
Gastrointestinal Bleeding Associated with Dabigatran(Pradaxa) or Rivaroxaban (Xarelto) Is Similar to That Associated with Warfarin
Investigators found no statistically significant differences in risks for GI bleeding between either dabigatran or rivaroxaban use and warfarin use.
Notably, risk for GI bleeding increased at a faster rate with increasing age among novel anticoagulant users than among warfarin users, especially among the oldest patients (age, >75).
Comment: These two “real-world” retrospective studies suggest that, in general, risk for GI bleeding associated with dabigatran or rivaroxaban is similar to that associated with warfarin. In most U.S. studies, researchers have evaluated 150-mg dabigatran. Yet, evidence suggests that the 110-mg dose (not available in the U.S.) is not only effective, but also is associated with lower GI bleeding risk for patients with atrial fibrillation. Similar evidence exists for rivaroxaban dosing.
Should Macrolides Be Used for Patients with Community-Acquired Pneumonia?
Streptococcus pneumoniae is implicated in 20% to 60% of community-acquired pneumonia (CAP) cases that require hospitalization. Macrolide antibiotics are recommended alone or in combination for patients with CAP. However, the prevalence of macrolide resistance in S. pneumoniae is currently 35%.
Comment: An editorialist notes the clinical relevance of macrolide resistance remains unclear. This might be because, in addition to antibacterial activity, macrolides have immunomodulatory effects that can improve clinical outcomes. Therefore, these agents appear to still have a role in treating patients (particularly hospitalized patients) with CAP when they are used in combination with other antibiotics.
From Journal Watch (July 1, 2015)
TMP-SMX – Not Good for Severe Staph Infections
Trimethoprim-sulfamethoxazole possibly was less effective than vancomycin for treating severe MRSA infections, particularly bacteremias.
Vancomycin is the antibiotic used most commonly to treat severe methicillin-resistant Staphylococcus aureus (MRSA) infections. MRSA usually is sensitive to trimethoprim-sulfamethoxazole (TMP/SMX), which is effective in treating MRSA skin infections.
Comment: Although TMP/SMX has proven useful in dermal MRSA infections, it should not be used in place of vancomycin for severe staph infections.
Remarkable Seasonality in Human Immune System
Some diseases have a higher incidence in certain seasons. For example, the incidence of cardiovascular disease deaths, rheumatoid arthritis, type 1 diabetes, and neuropsychiatric conditions is greater in the winter. These diseases also are characterized by inflammation.
About 23% of the human genome exhibits significant seasonal variation: Some genes are upregulated in summer and others produce transcripts more abundantly in winter.
Comment: This interesting study might explain why the incidence of certain diseases is more common in the winter.
What Are the Drivers of Higher Healthcare Costs?
Lack of guideline awareness and a desire to provide reassurance play major roles.
In this study, researchers surveyed hospitalists about their practice patterns in two common clinical scenarios: preoperative evaluation and syncope.
More than 1000 U.S. hospitalists were randomly administered two clinical vignettes, each of which included four different presentation versions. Overuse (defined by practice choices that were not supported by guidelines) was noted in 53% to 65% of preoperative evaluation vignettes and in 82% to 85% of syncope vignettes. In overuse cases, physicians were more likely to have made their decision based on reassuring others or themselves than based on incorrect knowledge of the evidence (preoperative evaluation, 63% vs. 37%; syncope, 69% vs. 31%.
Comment: A common reason for overuse in this study was participants’ failure to incorporate guidelines into their decisions. Even without knowing the occupation of a patient’s family member or what tests were requested, physicians still evaluated patients appropriately in only 48% and 17% of the preoperative and syncope vignettes, respectively. Addressing clinicians’ desires to reassure patients and maximize patient satisfaction (along with addressing continued fear of litigation) will be challenging, but these are important factors in lowering healthcare expenditures.
From Journal Watch (June 1, 2015)
Glucosamine and Chondroitin for Knee Arthritis: Another Randomized Trial
The effectiveness of glucosamine and chondroitin for knee osteoarthritis remains controversial; numerous trials have been conducted with varying results. In the largest randomized placebo-controlled trial, which involved 1583 patients, neither of these agents – nor their combination – improved outcomes compared with placebo.
The Numbers Behind Antibiotic Overuse
More than 8 in 10 Americans received antibiotic prescriptions in 2011.
A total of 252.5 million course of outpatient antibiotics were prescribed in 2011, for an overall rate of 842 prescriptions per 1000 persons. Amoxicillin was the most commonly prescribed antibiotic among children and teenagers, and azithromycin was the antibiotic most commonly prescribed among adults. Women were almost twice as likely as men to receive antibiotic; for both children and adults. Per-physician prescribing rates were highest for dermatologists, family practitioners, and pediatricians.
Comment: That 8 of every 10 Americans take an antibiotic every year is staggering. This country’s love affair with antibiotic – particularly for viral respiratory ailments among adults – has become an addiction. If the poultry industry can promise to eliminate unnecessary antibiotic use, as Tyson Foods did last month, surely physicians can do so as well. Granted, some patients cannot be reasoned with, but for the coughing adult seeking an azithromycin “Z-Pak,” I have found the following to be surprisingly effective: “I have some wonderful news for you. This time you don’t need one!”
Revised Head Lice Review
Head lice are not a health hazard and do not signify poor hygiene. However, social stigma and mandated school absence are problematic.
Lice are transmitted by direct head to head contact: Lice crawl – they cannot jump or fly. Lice survive for <1 day off the scalp.
No healthy child should be excluded from school because of head lice or nits. No-nit policies for return to school should be abandoned.
Comment: Because children actively infected with head lice have likely been infected for several weeks, barring them for school is not likely to reduce classroom transmission and will only increase absenteeism.
From Journal Watch (May 15, 2015)
Update on the Association Between Statins and Diabetes
Emerging evidence suggests that statins cause diabetes in a small percentage of treated patients. During 6 years of follow-up, men who took statins were significantly more likely to develop diabetes than those who did not take statins (11.2% vs. 5.8%). Most statin users (84%) took simvastin or atorvastatin, both drugs were associated, in a dose-response fashion, with incident diabetes.
Statin therapy was associated with both insulin resistance and reduced insulin secretion.
Digoxin Use in Atrial Fibrillation: A Last Resort
Debate continues about the effectiveness and safety of digoxin. Many recent studies have raised concerns about its use in patients with atrial fibrillation.
Comment: This observational study raises further concerns about the safety of digoxin for patients with atrial fibrillation. Certainly, use of digoxin in one third of patients with atrial fibrillation, as occurred in this study, is too high.
Is Low Blood Pressure Harmful in Patients with Dementia or Cognitive Impairment?
In an observational study, low daytime BP was associated with faster cognitive decline.
Comment: Despite the medical complexity of these patients and the limitations of a cohort study, these results suggest that overly aggressive treatment of hypertension in older adults with dementia or cognitive impairment is harmful; clearly, clinical trials are indicated.
M & T Commentary: It is beyond our clinical expertise, but this makes sense to us. It is known that nocturnal systemic hypotension can contribute to worsening of normal tension glaucoma; thus, it seems reasonable to us that a good healthy blood supply to the head holds virtue in both cerebral and optic nerve health.
Acetaminophen Might Not Be As Safe As You Think
In the two studies in which overall mortality was assessed, mortality was elevated among acetaminophen uses. Dose-response effects also were noted in studies that showed associations between acetaminophen use and adverse cardiovascular events; adverse upper gastrointestinal events; and adverse kidney events.
Comment: This review suggests that acetaminophen might not be as safe as we have generally assumed. However, the results should be interpreted with caution because of the likelihood of “confounding by indication” in these observational studies (i.e., acetaminophen is a first-line analgesic for patients with chronic or serious illness who can’t take other analgesics, and therefore it might be associated with – but not cause – higher risk for death.) This limitation remains probable although, in each of the included studies, researchers did attempt to control for confounding factors. Nonetheless, clinicians and patients should be aware of potential adverse effects of regular long-term use of acetaminophen.
From Journal Watch (March 1, 2015)
New Meta-Analysis Clarifies Oseltamivir’s Benefits and Risks
A patient-level meta-analysis confirms this drug’s modest antiviral activity and substantial side effects.
Oseltamivir (Tamiflu) “modestly reduces” duration of symptoms but causes nausea and vomiting and, possibly, adverse psychiatric effects.
In all trials, patients with fever and at least two influenza symptoms of shorter than 36 hours’ duration were treated with oseltamivir (75mg) or placebo twice daily for 5 days. Median time to alleviation of all symptoms was significantly shorter in those who received oseltamivir than in those who received placebo (98 vs. 123 hours). Patients taking oseltamivir experienced significantly more nausea and vomiting (5 more patients with vomiting per 100 treated patients) but no excess psychiatric symptoms.
Comment: This analysis confirms oseltamivir’s antiviral activity, its modest effect on duration of influenza symptoms, and its substantial side effects. Ideally, treatment with oseltamivir should be limited to patients with confirmed influenza, with careful evaluation of potential benefits and harms.
New Direct Oral Anticoagulants for Cancer-Associated VTE: How Effective?
These drugs appear to be comparable to warfarin in patients with cancer-associated venous thromboembolism.
Researchers have conducted a meta-analysis to determine the efficacy of the new direct oral anticoagulants (DOACs): dabigatran [Pradaxa], rivaroxaban [Xarelto], apixaban [Eliquis], and edoxaban [Savaysa] in such patients.
Major bleeding and clinically relevant bleeding also were slightly, but nonsignificantly, less common with DOACs than with vitamin K antagonists.
Comment: The new direct oral anticoagulants might be considered as alternatives to low-molecular-weight heparins or vitamin K antagonists for treating VTE in cancer patients.
Weight Management Interventions Are Uncommon in Overweight and Obese Patients
A patient who is told she or he is obese by a physician is more likely to attempt to lose weight. However, physicians often fail to diagnose and prescribe weight loss interventions in obese patients.
Lifestyle advice was the most common intervention for overweight and obese patients, and anti-obesity drug prescriptions was the most common for morbidly obese patients.
Comment: In this study, most overweight or obese patients didn’t receive documented weight management interventions, and, among those who did, follow-up was uncommon. These results, which are consistent with those of another recent study suggest that overweight and obesity are “hidden in plain sight” to clinicians. Efforts should be made to increase diagnosis and management plan rates.
From Journal Watch (February 15, 2015)
Is Coenzyme Q10 Effective in Statin Myopathy?
Placebo-controlled trials have failed to find a beneficial effect.
Comment: Coenzyme Q10 supplementation is not beneficial in patients with myalgia attributed to statin therapy.
Postoperative Complications After Carotid Endarterectomy
The 30-day rate of stroke or death was 3% in a large U.S. cohort.
Perioperative complications – especially stroke or death – are key considerations when patients consider carotid endarterectomy.
Comment: Ideally, patients undergoing carotid endarterectomy would have access to surgeon-specific and institution-specific rates of postoperative stroke and death. Because this information often is unavailable, studies like this one are necessary to inform clinical decision-making. Interestingly, most endarterectomies in this database were done for asymptomatic carotid stenosis; with contemporary medical management, whether surgery confers any long-term benefit in these patients is unclear.
Working Long Hours is Associated with Risky Alcohol Use
The likelihood of risky alcohol consumption was 12% higher among those who worked >55 hours weekly.
Comment: Working long hours is associated with greater likelihood of high alcohol use and new-onset risk alcohol use.The authors speculate that long working hours and work-related factors, such as high demands and lack of control, contribute to stress at work; affected workers might use alcohol to alleviate this stress.
From Journal Watch (February 1, 2015)
A Potent New Antibiotic (and a New Antibiotic Discovery Method)
Teixobactin, with activity against Gram-positive organisms, might be the first in a long line of new antibiotic discoveries.
The number of new antibiotics has been diminishing, and the number of antibiotic-resistant bacteria has been growing. Teixobactin is a potent antibiotic against Staphylococcus aureus, Mycobacterium tuberculosis, and Streptococcus pneumoniae, but not against most Gram-negative bacteria. None of many mutant strains of S. aureus or M. tuberculosis were resistant to teixobactin, and serial passage of S. aureus in the presence of teixabactin during 27 days did not produce resistant organisms. No toxicity against mammalian cells was noted. Teixobactin perfectly protected mice against intraperitoneal injection of S. aureus.
Comment: The new antibiotic, teixobactin, still must be tested in humans, but appears to be very promising. Perhaps more importantly, a novel technique for identifying new antibiotics has been developed.
Should Patients with Mild Hypertension Be Treated?
A modest reduction in blood pressure might prevent stroke or death.
Clinical trials have shown convincingly that treating patients who have stage 2 hypertension (systolic blood pressure [BP] >160mmHg or diastolic BP > 100mmHg) prevents adverse cardiac events and deaths; whether this is true for patients with mild hypertension is less clear.
During medial follow-up of 45 years, average BP reduction in treated versus control patients was 3.6/2.4mmHg. Odds ratios indicated significant reductions in stroke (0.72), cardiovascular-related deaths (0.75), and overall deaths (0.78). Differences in adverse cardiovascular events, adverse coronary events, and heart failure did not reach statistical significance.
Comment: This meta-analysis indicates that treating patients with stage 1 hypertension lowers risk for stroke and death.
Treatment with Fish Oils Might Be Effective in Patients with Early Rheumatoid Arthritis
The addition of fish oils to traditional disease-modifying antirheumatic drug therapy lowered risk for treatment failure.
In this double-blind trial from Australia, 140 patients with early RA (median duration, 4 months) were randomized 2:1 to receive high-dose fish oil (5.5g EPA + DHA daily) or fish oil at a low dose (control; 400mg EPA + DHA daily). All patients received triple therapy with the disease-modifying antirheumatic drugs (DMARDs) methotrexate, hydroxychloroquine, and sulfasalazine.
At 1 year, fewer patients in the high-dose fish oil group required additional treatment with leflunomide (an indicator of failure of triple DMARD therapy) than did controls (10/5% vs. 32%). In addition, time to first remission was significantly shorter in the high-dose fish oil group (adjusted hazard ratio, 2.09).
Comment: That fish oil might act as an anti-inflammatory is biochemically plausible, and many studies suggest that they do so in patients with RA. Previous studies suggested that fish oils augmented traditional RA therapy; these findings support that hypothesis and show that we can increase the effectiveness of current therapies with minimal risk and cost.
Recommendations on Medical Television Talk Shows: Where’s the Evidence?
Medical evidence is lacking for many recommendations made on The Dr. Oz Show and The Doctors.
The most common recommendations made during The Dr. Oz Show was dietary advice; during The Doctors, the most common recommendation was to consult a healthcare provider.
Of 160 randomly selected recommendations (80 from each show), only 54% were supported by case studies or higher-level published evidence. In fact, evidence contradicted or was not found for 54% and 38% of recommendations made on The Dr. Oz Show and The Doctors respectively.
Comment: Until medical talk show producers and hosts improve the quality of recommendations made on their shows, consumers and clinicians should be skeptical about these recommendations.
From Journal Watch (January 1, 2015)
Are New Oral Anticoagulants Safer Than Vitamin K Antagonists?
The new direct oral anticoagulants (DOACs: dabigatran [Pradaxa], rivaroxaban [Xarelto], apixaban [Eliquis], and edoxaban [Savaysa] have been compared with vitamin K antagonists (VKAs: warfarin and similar agents) for acute venous thromboembolism (VTE) in six recent phase III clinical trials encompassing more than 27,000 patients. A meta-analysis of those trials yielded the following results:
Recurrent VTD occurred at similar rates in patients treated with DOACs and VKAs (2.0% and 2.2%)
DOACs were associated with a 39% relative reduction in major bleeding. No significant differences in recurrent VTGEs were observed with DOACs versus VKAs in patients with deep vein thrombosis or pulmonary embolism.
Comment: The new direct oral anticoagulants are as effective as VKAs in patients with venous thromboembolism and are associated with less major bleeding. Their drawbacks include the lack of a specific antidote, contraindication in those with creatinine clearance <30mL/minute/1.73m2, and substantial cost.
From Journal Watch (December 15, 2014)
Growing Use of Cardiac Stress Testing in the U.S.
Concern has been growing that cardiac stress testing – especially with imaging – often is performed unnecessarily.
The researchers estimated that 14% of stress tests without imaging and 30% of tests with imaging would be “rarely appropriate.”
Comment: These results should not surprise primary care clinicians or cardiologists. Stress tests with imaging are ordered excessively. Some of this testing undoubtedly is driven by economic incentives (e.g., cardiologists whose practices own nuclear imaging equipment).
Home-Based Primary Care: A Promising Approach
In frail elders, HBPC lowered hospital admissions and overall costs.
Home-based primary care (HBPC) refers to interdisciplinary provision of extensive medical and social services in the home.
Comment: In these studies, comprehensive home care by truly interdisciplinary teams lowered hospital admissions and overall costs; in both studies, cost savings were concentrated in the frailest and sickest of patients. Although clinical outcomes were not tracked in these studies, I’d bet that quality of care was maintained or enhanced in these programs.
For Patients with Newly Diagnosed Type 2 Diabetes, Metformin Is the Best First Choice
Initial metformin yielded a lower likelihood of needing a second agent compared with other drug classes.
Metformin is recommended by several organizations and guidelines as first-line therapy in patients with newly-diagnosed type 2 diabetes, but clinicians often start with other classes of hypoglycemics.
Patients who initiated therapy with drug classes other than metformin were about 60% more likely to require a second agent, either another oral drug or insulin.
Comment: The finding that metformin was the initial choice in fewer than 60% of patients suggests that we need to develop approaches to change physician behavior.
TMP/SMX Is Associated with Sudden Death in Patients Who Take Renin-Angiotensin Inhibitors
A possible mechanism is trimethoprim-induced hyperkalemia in older patients taking ACE inhibitors or ARBs.
Renin-angiotensin inhibitors – angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) – are associated with hyperkalemia in about 10% of patients. Trimethoprim/sulfamethoxazole (TMP/SMX) also is associated with hyperkalemia, via trimethoprim-induced reduction in potassium excretion in the distal renal tubule.
Compared with amoxicillin (used as the reference exposure because it is not associated with hyperkalemia), TMP/SMX was associated with significantly greater risk for sudden death within 7 days (adjusted odds ratio, 1.4) and within 14 days (AOR, 1.5) of exposure.
Comment: The authors estimate that the excess risk corresponds to approximately 3 sudden deaths with TMP/SMX versus 1 sudden death with amoxicillin per 1000 prescriptions. This finding is not trivial, given the large number of patients receiving ACE inhibitors and ARBs and how often TMP/SMX is prescribed.
From Journal Watch (December 1, 2014)
Anticholinergic Drugs Might Lead to Hospitalization for Delirium
Older patients who used two or more of these drugs were several-fold more likely to be hospitalized for cognitive impairment.
Many drugs that are prescribed widely to older people have anticholinergic properties. 30 drugs were considered to have strong anticholinergic potential, including drugs used for bladder and bowel overactivity, antipsychotics, tricyclic antidepressants, paroxetine, antihistamines, and several anti-Parkinson drugs.
Comment: Anyone who does hospital medicine surely has seen patients admitted for anticholinergic drug-induced delirium. In many cases, the potential adverse effects do not justify the marginal expected benefit.
Fluoroquinolone Antibiotic and Polyneuropathy
Primarily on the basis of case reports submitted to the FDA, the agency recently required a change in the labeling of fluoroquinolone antibiotics to include a warning about risk for polyneuropathy associated with these drugs.
Comment: Because of their widespread use and the observed twofold higher risk for polyneuropathy after treatment with oral fluoroquinolones, this class of antibiotic might be an important (and often unrecognized) cause of polyneuropathy.
Treating the Cephalosporin-Allergic Patient Who Has Gonorrhea
Antibiotic resistance has become so pervasive among strains of Neisseria gonorrheae that, as of 2007, cephalosporins were the only CDC-recommended agents for treating U.S. patients with gonorrhea.
Researchers evaluated two combination regimens for treating uncomplicated urogenital or pharyngeal gonorrhea in almost 600 patients. Patients were randomized to receive 2g of oral azithromycin plus either 240mg of gentamicin intramuscularly or 320mg of oral gemifloxacin. Azithromycin is not recommended for use alone against N. gonorrheae because of rapid emergence of resistance; gentamicin is used successfully for gonorrhea treatment in some parts of the world.
A microbiologic cure was achieved by all patients who received azithromycin plus gemifloxacin. Both regimens carried a sizeable risk for gastrointestinal side effects – nausea in 28% to 37% of patients and diarrhea in 18% to 23%.
Comment: Although both of these tested combinations are effective, the frequency of side effects (which reflect the known toxicity of such high doses of azithromycin) mean they cannot serve as more than stop-gap measures until better alternatives are available.
How Well We Smell Predicts How Long We’ll Live
In an older cohort, anosmia was associated with tripled 5-year mortality.
Olfactory dysfunction can be an early manifestation of neurodegenerative disease in humans.
Anosmic and hyposmic people were approximately 3.4 times and 1.5 times, respectively, more likely to die during the study than normosmic individuals – a “dose-response” relation.
Comment: This study identified olfactory function as a powerful predictor of 5-year mortality, even after researchers accounted for many other factors that affect mortality. Olfactory dysfunction is a marker of cellular-regeneration capacity or that – as the only cranial nerve directly exposed to the environment – it reflects cumulative toxic environmental exposures.
From Journal Watch (November 15, 2014)
Stem Cells Can Be Turned Into Functional Human Pancreatic β Cells
A new culture method can produce billions of functional differentiated cells.
The discoveries of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have sparked hope that new class can be created to replace cells destroyed by disease.
A team fromtheHarvard Stem Cell Institute reports that it has discovered a combination of factors that, when placed in the culture media around human stem cells, transforms them into functioning pancreatic β cells in a few weeks. These β cells promptly started to produce insulin in response to repeated glucose challenges both in vitro and when they were placed in diabetic mice.
The cells restored normoglycemia in a controlled fashion (without causing hypoglycemia). Experience with human islet transplantation indicates that the number of β cells produced by this method is sufficient to treat diabetes in humans successfully.
Comment: We can effectively replace β cells that have been destroyed by type 1 diabetes by transplanting adult islet cells, but such cadaveric donor cells are available in extremely limited numbers. Until this report, experiments with stem cells had not produced mature, functional β cells in sufficient numbers to cure patients with type 1 diabetes. These findings are being hailed as a landmark in stem cell biology, because they suggest that cell-availability limitations have been overcome for treating type 1 diabetes.
M & T Commentary: This is truly extremely exciting news! Our chief pathologist informs us that the adult induced pluripotent stem cells far outperform embryonic stem cell transplantation.
Do Artificial Sweeteners Cause Glucose Intolerance?
In mice, artificial sweeteners lead to alterations in the microbiome and changes in glucose absorption.
Noncaloric artificial sweeteners, such as saccharine, sucralose, and aspartame, were introduced to control body weight and lower risk for diseases linked to obesity. Yet the epidemic of type 2 diabetes and obesity has coincided with introduction of noncaloric sweeteners. Most of us assume that the epidemic of obesity and type 2 diabetes led to more use of noncaloric sweeteners. However, researchers in Israel report that the opposite might be true. Use of noncaloric sweeteners might have contributed to the epidemic.
Mice that are given noncaloric sweeteners develop glucose intolerance quickly, compared with mice that are given sucrose or glucose. Introduction of dietary noncaloric sweeteners promptly alters the mouse microbiome to favor biochemical pathways that enhance absorption of calorie-rich glucose and short-chain fatty acids. Giving antibiotic to the glucose-intolerant mice eliminated glucose intolerance, and transplanting feces from sweetener-fed animals into germ-free animals produced glucose intolerance in these control animals, whereas feces transplanted from glucose-fed mice into controls didn’t produce glucose intolerance.
Seven healthy human volunteers who did not regularly consume noncaloric sweeteners were placed on a diet that contained noncaloric sweeteners. Within 1 week, four participants developed glucose intolerance. Stool from these people, when transplanted to mice, also produced glucose intolerance. Stool from the three humans who did not develop glucose intolerance did not produce glucose intolerance in mice.
Comment: This report argues that, although artificial sweeteners lack calories, they can change the gut microbiome in a way that leads to absorption of more calories and that compromises glucose tolerance. That surprising claim surely will be tested.
Deeper Compressions During CPR Lead to Improved Survival
Of 9266 patients with out-of-hospital cardiac arrest, 31% had return of spontaneous circulation, and 7% survived to hospital discharge. Survival increased with compression depth until it peaked at a depth of 4.6cm. Survival was highest when compression depth was between 4.0 and 5.5cm.
Comment: For effective CPR, we should aim for a compression depth of 4.0 to 5.5cm. Notably, 36% of cases in this study still had an average depth of 3.8cm (the minimum depth recommended in the 2005 AHA guidelines), so we still need to push a little harder.
Direct-Acting Oral Anticoagulants Lower 2-Year Mortality in Atrial Fibrillation Patients
Compared with warfarin, the new agents mitigated all-cause bleeding-related mortality.
The new direct-acting oral anticoagulants (DOACs, dabigatran [Pradaxa], rivaroxaban [Xarelto], apixaban [Eliquis], and edoxaban [Savaysa]) were noninferior to vitamin K antagonists in clinical trials of stroke prevention in patients with atrial fibrillation.
Compared with warfarin, DOAC therapy was associated with significantly lower 2-year all-cause mortality (relative risk, 0.89). In addition, bleeding-related mortality was strikingly less common (RR, 0.54), which was mainly due to fewer instances of intracranial bleeding (RR, 0.42).
Comment: Individual trials of each DOAC versus vitamin K antagonists have not shown significantly fewer ischemic strokes, but most studies have reported lower incidence of intracranial hemorrhage. Major bleeding in patients treated with vitamin K antagonists usually occurs within the first 6 months of therapy. Whether the difference in bleeding between DOACs and warfarin persists longer term is uncertain, because the median duration of patient follow-up in the reported trials was only 2 to 3 years.
Monoclonal Antibody Treatment and Vaccine Produce Encouraging Results Against Ebola Virus
Treatment and preventing Ebola infections is possible.
Two research groups report encouraging results in treating and preventing Ebola infections in nonhuman primates.
An international team tested a combination of several monoclonal antibodies that has shown efficacy against Ebola virus in primates (rhesus macaques). The antibodies were administered to 18 monkeys, with the first dose given 3 to 5 days after the animals were inoculated with the virus. Three control animals were inoculated with the virus but not treated. Almost all of the animals experienced symptoms and signs of Ebola infection and had laboratory markers of disease at the time of first antibody treatment. All of the treated animals survived, whereas all of the control died.
A second international team reported progress with a vaccine. Past research shows that human-derived adenovirus-type vectors containing Ebola virus antigens generate a potentially protective immune response – except in the considerable fraction of people who have been exposed to human adenovirus in the past and who consequently have antibodies against human adenovirus vectors. Therefore, the researchers developed a chimpanzee-derived adenovirus vector. In macaques, the vaccine rapidly induced both acute and durable protection against an Ebola virus challenge given 5 weeks after immunization. In unvaccinated animals, the virus challenge was lethal.
Comment: The success in nonhuman primates of these two therapies – passive antibody treatment of established disease and durable prophylaxis against subsequent disease – offers hope that we can find better ways of curtailing outbreaks of disease caused by Ebola virus.
Antibiotic Prescribing Increases as the Clinic Day Drags On
During the day, the prescription rate increased from 26% to 35% for conditions for which antibiotics are not indicated.
One possible cause of inappropriate antibiotic prescribing is “decision fatigue,” a decline in the quality of decision-making caused by repeated decision-making demands.
Comment: This concept is interesting and important, given the increasing concerns about inappropriate antibiotic use as a primary cause of rising antibiotic resistance.
M & T Commentary: All doctors need to be aware that antibiotics of all stripes are overused, and we should do our best to prescribe appropriately.
From Journal Watch (November 1, 2014)
Genetic Studies Suggest That Diabetes Risk is Inherent in the Action of Statins
Inhibition of HMG-CoA reductase seems to be lightly linked to excess risk for diabetes.
Statin drugs significantly raise risk for new-onset type 2 diabetes mellitus.
Comment: These data strongly suggest that the diabetogenic effect of statins is inherent in inhibition of HMG-CoA and that this effect is mediated by body weight or other modifiable factors. However, for patients whose baseline cardiovascular risk is sufficiently high, risk reductions that are achieved with statins will greatly outweigh risks associated with excess incidence of type 2 diabetes.
Medication Adherence Is Higher with Generic Statins Than with Brand-Name Statins
Many factors affect medication adherence, including out-of-pocket costs.
Analysis involved about 90,000 patients, 93% of whom had initiated generic states. Mean copayments were US$10 for generic statins and $48 for the brand-name versions. Adherence was higher among generic statin uses (77% vs. 71%).
Comment: The finding that medication adherence was higher among generic statin users than among those who took brand-name statins was not surprising. However, the finding that generic statin initiation also was associated with better clinical outcomes is new and highlights the importance of considering cost when prescribing medications.
M & T Commentary: This finding has obvious correlations to the care of our patients with glaucoma.
Zoster Vaccine Is Effective When Given Before Immunosuppression in Older Adults
Vaccination prior to immunosuppression lowered the incidence of subsequent herpes zoster by 42%.
Age and immunosuppression are major risk factors for herpes zoster (HZ). Although zoster vaccine is safe for immunocompetent older individuals, it is contraindicated in those with immunosuppression because it contains live attenuated virus. However, most immunosuppression in adults is acquired, and whether zoster vaccination administered at an earlier time confers protection from HZ once immunosuppression has occurred is unknown.
Of the participants, 16,776 had not been vaccinated, and 4710 had received the zoster vaccine before the start of chemotherapy. HZ incidence rates were significantly lower in vaccinated patients than in unvaccinated patients (13 vs. 22 per 1000 person-years). Six patients in the unvaccinated group – but none in the vaccinated group – were hospitalized for HZ.
Comment: These findings suggest that zoster vaccine confers protection against HZ among older adults who subsequently receive chemotherapy. As editorialists note, the findings underscore the importance of administering zoster vaccine to all immunocompetent older individuals.
M & T Commentary: Optometrists should encourage their over-50 year-old patients to speak to their primary care providers regarding Zostavax.
From Journal Watch (October 15, 2014)
Inappropriate Medication Use Is Common in Patients with Advanced Dementia
Cholinesterase inhibitors, memantine, or lipid-lowering agents often are prescribed.
Fifty-four percent were taking at least one medication of questionable benefit – most commonly, cholinesterase inhibitors, memantine, lipid-lowering agents, or antiplatelet agents. Among patients receiving such medications, about one-third of medication expense was attributed to medications of questionable value.
Comment: Although several antidementia drugs are FDA-approved for use in patients with severe Alzheimer dementia, their clinical benefit is marginal at best, and they can cause various adverse effects. Lipid-lowering drugs have no meaningful role in treating patients with end-stage dementia. To improve this situation, clinicians must pay attention to the evolving status of their patients and review medication lists regularly to eliminate unnecessary medications, save money, and prevent side effects.
NSAIDs Are a Major Cause of Anaphylaxis-Related ED Visits
Epinephrine is first-line treatment for drug-induced anaphylaxis, but it is underused.
Almost 50% of reactions were caused by nonsteroidal anti-inflammatory drugs (NSAIDs). All NSAIDs reactions were nonallergic, and most featured urticaria or angioedema and bronchospasm or dyspnea. Only 34% of patients with moderate-to-severe anaphylaxis received epinephrine in the emergency department.
Comment: Physicians should be aware that medications can cause both allergic and nonallergic anaphylaxis reactions. Although the most severe reactions involving cardiogenic shock are IgE mediated, non-IgE-mediated causes such as NSAIDs and radiocontrast still are life-threatening and actually might be more common. Epinephrine is used. Regardless of cause or mechanism, it is always first-line treatment for anaphylaxis.
From Journal Watch (October 1, 2014)
Telephone Triage in Primary Care Prevents Unnecessary Office Visits
Health outcomes were the same with or without a triage system.
Many primary care practices are seeking to improve quality of care and patient satisfaction without adding to workload or costs. In some practices, nurses or physicians triage urgent patient calls through initial telephone consultations rather than have receptionists schedule same-day office visits, but the effects of this strategy have not been measured in large-scale trials.
Investigators in the U.K. randomized 42 primary care practices to telephone triage by physicians or by nurses (with computerized algorithm support) or to usual care. In triage practices, patients who called with urgent concerns received prompt return phone calls from nurses or physicians, who either addressed problems definitively by phone or planned further management by phone or in the office.
During 28 days after initial patient contact, physician triage and nurse triage were associated with 33% and 48% more primary care contacts per patient (in-person plus phone) but 39% and 20% fewer face-to-face physician visits per patient than were generated by usual care. Mean duration of triage calls was 4 minutes for physicians and 6.5 minutes for nurses. Patients who received nurse triage reported lower overall satisfaction than usual-care and physician triage recipients. All three strategies yielded equivalent health outcomes and similar costs.
Comment: These results suggest that triage systems can redistribute work and prevent unnecessary office visits without compromising patient care or adding to costs. In many U.S. practices, however, delivering care by phone is impractical, because it is not reimbursed.
From Journal Watch (September 15, 2014)
Is Hydroxychloroquine Effective for Patients with Symptomatic Sjögren Syndrome?
The drug was no better than placebo in relieving dryness, fatigue, and pain.
Troubling symptoms of Sjögren syndrome include oral and ocular dryness, joint and soft-tissue pain, and fatigue. Treatments include hydroxychloroquine, methotrexate, and biologic therapies (e.g.., rituximab [Rituxan]), but none of these agents alter symptoms significantly in controlled trials. In this study, investigators in France randomized 120 patients with Sjögren syndrome to receive hydroxychloroquine or placebo for 24 weeks; all patients then received hydroxychloroquine between weeks 24 and 48.
At 24 weeks, the proportion of patients who reported >30% reductions from baseline in at least two of three symptoms (i.e., dryness, fatigue, and pain) was no different in the two groups. In patients who received placebo for 24 weeks followed by hydroxychloroquine through week 48, dryness, fatigue, and pain scores at 48 weeks did not differ significantly from those at 24 weeks.
Comment: Among study participants, the proportion of those with anti-SSA antibodies or high immunoglobulin levels was relatively low, few had synovitis, and virtually none had serious systemic manifestations. For patients like those in the study, one might defer use of hydroxychloroquine, but whether the drug is effective in patients with synovitis, small-vessel vasculitis, and other serious manifestations remains an open question.
M & T Commentary: Since it appears that hydroxychloroquine is modestly effective in this study (similar to Restasis), it is imperative the rheumatologists be especially attentive to appropriate, conservative dosing, and individualization of therapeutic intervention. It would be a shame to create Plaquenil maculotoxicity with minimal systemic benefit. In fact, it would be a shame to create such maculopathy in any circumstance!
From Journal Watch (September 1, 2014)
Acetaminophen Isn’t Effective for Acute Low-Back Pain
Most patients’ pain had resolved by 12 weeks, whether they received acetaminophen or placebo.
Researchers randomized 1654 Australian patients with recent-onset low-back pain who were seen at primary care centers to receive as long as 4 weeks of treatment with one of three blinded treatment regimens. Median time to recovery (i.e., start of a 7-day period with pain rated as 0-1 on a 10-point scale) was not significantly shorter in any group. At 12 weeks, about 85% of patients in each group had recovered.
Comment: Acetaminophen has little or no effect on recovery from acute back pain, and guidelines recommending its use should be reassessed. Advice, reassurance, and patience might be the most effective interventions for what is usually a self-limited condition.
Fecal Transplantation for CDI Is Safe and Effective in Immunocompromised Patients
The overall cure rate was 89%, with one death occurring from aspiration.
Given that immunocompromised patients are at excess risk for infection, is performing fecal microbiota transplantation for Clostridium difficile infection (CDI) safe in this population?
Comment: These results indicate that fecal transplantation is safe and effective for treating recurrent or refractory CDI in immunocompromised patients.
Snapshot of Statin Hepatoxicity
In a U.S. registry of drug-induced liver injury, 22 of 1188 cases involved statins.
Nineteen of the 22 patients were symptomatic at the time of presentation. Fifteen patients were jaundiced. Seventeen patients presented within the first year of treatment.
Comment: Although asymptomatic and transient mild elevations in serum transaminases occasionally occur early in the course of statin therapy, clinically evident statin hepatoxicity is quite rare. This report provides a nice overview and suggests that outcomes usually are favorable.
Wait as Long as Possible for Noncardiac Surgery After Stroke
Risk for postoperative adverse cardiovascular events was especially high during the first 9 months after stroke.
Comment: We probably should wait at least 9 months before scheduling stroke patients for elective noncardiac surgery.
M & T Commentary: We doubt this would be relevant to cataract surgery.
From Journal Watch (August 1, 2014)
Sublingual Dust Mite Tablets Are Effective for Allergic Rhinitis
After 1 year of treatment, benefits persist for at least 1 additional year.
In 2014, three sublingual allergen immunotherapy tablets have been approved by the FDA: Grastek contains Timothy extract; Oralair contains cross-reacting sweet vernal, orchard, perennial rye, Timothy, and Kentucky blue grass extracts; and Ragwitek contains ragweed extract. These tablets are started 3 to 4 months before, and continued throughout their pollen seasons; they can be administered at home with very low risk for anaphylaxis.
In an industry-funded, European study, 509 patients were randomized to receive sublingual house dust mite or placebo tablets daily for 1 year. After 4 months of therapy, the active-treatment group had a mean adjusted score that was about 20% lower than the placebo group’s mean score. The dust mite tablets’ effects were maintained in the following year with no additional treatment. No patient experienced anaphylaxis.
Comment: The role of sublingual immunotherapy for allergic rhinitis and asthma is evolving. We don’t know whether using more than one sublingual extract will reduce effectiveness, so currently, only monotherapy should be prescribed. For patients whose allergies are not controlled with nasal steroids and who have year-round symptoms predominantly due to dust mites, I think sublingual tablets will be an attractive home-administered option. However, we will have to wait until we have an FDA-approved tablet, and the price tag might make it harder to swallow (currently approved sublingual allergy products cost about US $6 to $8 daily.
A “Bionic Pancreas” for Type 1 Diabetics
Researchers in Boston describe the use of a wearable, automated “bionic pancreas” in 20 adults and 32 adolescents with type 1 diabetes. The apparatus consisted of a subcutaneous sensor that monitored glucose continuously and a subcutaneous infusion pump that administered both insulin and glucagon. Automatically adaptive algorithms coordinated glucose levels and hormone infusion rates via wireless communication.
Blood glucose levels <60mg/dL were significantly less common during treatment with the bionic pancreas than during control treatment in adults; among adolescents, frequency of hypoglycemia was similar in the two groups.
Comment: A bionic pancreas described in this report brings us one step closer to an ideal artificial pancreas. However, this technology still has several limitations (e.g., intermittent problems with wireless connectivity) and it is not yet FDA-approved for use in the U.S. Although this study was supported by nonindustry funding sources, several device companies are involved in developing artificial pancreas systems.
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.
Case reports have suggested that herpes zoster acutely raises risk of cerebrovascular accident (CVA).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
About 85% of participants completed follow-up. At 6 months, 27% of intervention participants versus 5% of controls had discontinued benzodiazepine.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.