JAMA

doi: 10.1001/jama.2010.497pmid: N/A

B-Vitamin Therapy and Diabetic Nephropathy Patients with diabetic nephropathy often have high plasma homocysteine levels. In a randomized placebo-controlled trial, House and colleagues assessed whether high doses of B-vitamin therapy—an intervention known to lower homocysteine levels—could slow the progression of diabetic nephropathy. During a mean (SD) 31.9 (14.4) months of follow-up, the authors found that compared with placebo, high doses of B vitamin were associated with lower levels of homocysteine but a more rapid decline in renal function and higher rates of myocardial infarction and stroke. Coronary Artery Calcium Score and Risk Prediction The coronary artery calcium score has been shown to be associated with the risk of future coronary heart disease (CHD) events. In an analysis of data from the Multi-Ethnic Study of Atherosclerosis—a population-based cohort without known cardiovascular disease at baseline—Polonsky and colleagues Article found that adding the coronary artery calcium score to a prediction model based on traditional risk factors improved the classification of incident CHD risk and placed more individuals in the most extreme risk categories. In an editorial, Ioannidis and Tzoulaki Article define characteristics of clinically useful predictors of disease risk and discuss whether the coronary artery calcium score is ready for routine use. Hematopoietic Stem Cell Transplantation To assess current global use of hematopoietic stem cell transplantation, Gratwohl and colleagues from the Worldwide Network for Blood and Marrow Transplantation analyzed data from a retrospective survey representing patients who received transplants in 2006 at 1327 centers in 71 participating countries. The authors found significant differences in transplant rates between countries and continental regions by indication and donor type. They also report macroeconomic factors including gross national income, governmental health care expenditures, and transplant team density that were associated with transplant rates. Cancer Imaging Among Medicare Beneficiaries Dinan and colleagues analyzed nationally representative Medicare claims for beneficiaries diagnosed with breast, colorectal, lung, or prostate cancer; leukemia; or non-Hodgkin lymphoma in 1999 through 2006 to assess changes in the use and cost of diagnostic imaging. The authors report that conventional radiograph rates decreased or remained the same during the period of study, whereas the use of other imaging techniques increased significantly and outpaced total cancer costs to Medicare. CLINICIAN'S CORNER The Older Driver With Cognitive Impairment Care of the Aging Patient Mr W is a 92-year-old retired college professor who lives with his wife in a community with little public transportation. He reports some memory loss and has greater difficulty determining driving routes. Recent neuropsychological testing is consistent with mild cognitive impairment. Carr and Ott Article summarize the literature on dementia and driving and discuss evidence-based assessment of fitness-to-drive and physicians' legal and ethical obligations. A commentary by Eby and Molnar Article discusses the role of physicians in evaluating patients' fitness to drive. A Piece of My Mind “What was his bedside manner like? Was he curious about interesting cases? How did he feel about the power of medicine to change people's lives? I had no answers for these questions.” From “Nana's Words.” Medical News & Perspectives Widespread off-label prescribing of antipsychotic drugs continues despite serious concerns about the drugs' metabolic and cardiac risks. Commentary Patient-centered medical homes: why now? Author in the Room Teleconference Join Roger Chou, MD, Wednesday, May 19, from 2 to 3 PM eastern time to discuss predicting whether low back pain may become persistent and disabling. To register, go to http://www.ihi.org/AuthorintheRoom. Readers Respond How would you counsel a 42-year-old man with hypercholesterolemia who is considering whether to drink alcohol to improve his cardiovascular health? Go to www.jama.com to read the case, and submit your response, which may be selected for online publication. Submission deadline is May 23. Audio Commentary Dr DeAngelis summarizes and comments on this week's issue. Go to http://jama.ama-assn.org/misc/audiocommentary.dtl. JAMA Patient Page For your patients: Information about older drivers and cognitive impairment.

doi: 10.1001/jama.303.16.1571pmid: N/A

The Key and Critical Objectives of JAMA Key Objective To promote the science and art of medicine and the betterment of the public health Critical Objectives To maintain the highest standards of editorial integrity independent of any special interests To publish original, important, well-documented, peer-reviewed articles on a diverse range of medical topics To provide physicians with continuing education in basic and clinical science to support informed clinical decisions To enable physicians to remain informed in multiple areas of medicine, including developments in fields other than their own To improve health and health care internationally by elevating the quality of medical care, disease prevention, and research To foster responsible and balanced debate on issues that affect medicine and health care To anticipate important issues and trends in medicine and health care To inform readers about nonclinical aspects of medicine and public health, including the political, philosophic, ethical, legal, environmental, economic, historical, and cultural To recognize that, in addition to these specific objectives, THE JOURNAL has a social responsibility to improve the total human condition and to promote the integrity of science To achieve the highest level of ethical medical journalism and to produce a publication that is timely, credible, and enjoyable to read Editorial staff EDITOR IN CHIEF Catherine D. DeAngelis, MD, MPH Executive Deputy Editor: Phil B. Fontanarosa, MD, MBA Deputy Editors: Richard M. Glass, MD, Drummond Rennie, MD, Margaret A. Winker, MD Managing Deputy Editor: Annette Flanagin Senior Contributing Editor: M. Therese Southgate, MD Senior Editors: Robert M. Golub, MD, Ronna Henry, MD Associate Senior Editor: Roxanne K. Young Contributing Editors: Derek C. Angus, MD, MPH, Helene M. Cole, MD, Thomas B. Cole, MD, MPH, David S. Cooper, MD, J. Michael Gaziano, MD, MPH, Edward H. Livingston, MD, David H. Mark, MD, MPH, Mary McGrae McDermott, MD, Robert A. McNutt, MD, Boris Pasche, MD, PhD, Eric D. Peterson, MD, MPH, Jeanette M. Smith, MD, Janet M. Torpy, MD, John L. Zeller, MD, PhD, Gianna Zuccotti, MD, MPH, Jody W. Zylke, MD Statistical Editor: Naomi Vaisrub, PhD Associate Editor: Charlene Breedlove Fishbein Fellow: Huan J. Chang, MD, MPH Contributing Writers: Christine K. Cassel, MD, Frank F. Davidoff, MD, Allan S. Detsky, MD, PhD, Lawrence O. Gostin, JD, LLD, Jeffrey P. 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Hoven, MD (chair-elect); Christopher K. Kay; Edward L. Langston, MD; Jeremy A. Lazarus, MD; Justin B. Mahida; Mary Anne McCaffree, MD; Nancy H. Nielsen, MD, PhD; Rebecca J. Patchin, MD (chair); J. James Rohack, MD; Steven J. Stack, MD; Robert M. Wah, MD; Cecil B. Wilson, MD

Torpy, Janet M.

doi: 10.1001/jama.2010.380pmid: 20424237

The painters of the Hudson River School loved nature. The American landscape, in its variety and majesty, became their subject. These artists, including George Inness, Thomas Cole, Frederic Church, and Louis Rémy Mignot (1831-1870), showcased Nature's beauty, sometimes in pure representation, sometimes replete with allegory. Thomas Cole taught Frederic Church; in turn, Church mentored Mignot, who accompanied the elder painter on his 1857 trip to Ecuador. Mignot, inhabiting the fringes of the Hudson River group, did not quite adhere to the typical background of the other painters, who were mostly reared in the northeast United States. A first-generation American of French ancestry and a Roman Catholic, Mignot was born in Charleston, South Carolina. His education, opposed by his merchant father—a confectioner—took place in the Netherlands, at The Hague, after his father's death. Despite these fundamental differences, Mignot's work echoed the focus, the intensity, and the grand scale of the paintings by his Hudson River School colleagues. Niagara Falls, its sublimity incomparable elsewhere in North America, had been described by French explorer Louis Hennepin in 1683. The Franciscan Récollet priest—now best remembered by the eponymous county whose seat is Minneapolis, Minnesota—was the first European to write about the Falls; he wove tales of horror at its “dreadful roaring and bellowing,” calling the “frightful abyss” a “prodigious cadence of water.” The tourist trade began at Niagara before 1800, and has continued to the present day, yet simply visiting the Falls was not enough to satisfy the intrepid inventors who strove to tame the surging water. Diverting a portion of Niagara's stream has generated hydroelectric power since 1881; now Niagara Falls' energy serves the populations of New York and Toronto, from the single largest water-generated source of power in the world. The relentless grinding of water, over time as powerful as shifting land masses, means that Niagara Falls, the conduit for the contents of the Great Lakes as they flow northward into Lake Ontario, spell their own eventual evanescence. Erosion and water's motive power have caused gradual retreat of the Falls and one day, the Falls will no longer exist in their present form. Because of Mignot's Niagara (cover ), the mid-19th-century majesty of Niagara Falls, unlike their reality, will never fade away. Louis Rémy Mignot, Niagara, circa 1866, American. Oil on canvas. 123.8 × 232.4 cm. Courtesy of the Brooklyn Museum (http://www.brooklynmuseum.org/) Brooklyn, New York; gift of Arthur S. Fairchild, 1992.118. Studying Niagara invites the inevitable comparison to other renowned paintings of the Falls from fellow Hudson River School artists Inness (in 1884 [JAMA cover, June 14, 1985], 1885, 1889, and 1893) and Church (in 1857 and 1867). Early critics of Mignot's work posited that his Niagara was merely a copy of that of Church. Yet observing the paintings simultaneously, stark differences arise—Mignot's version is clearly not just a replica. For depiction of pure motion, Mignot's Niagara triumphs: one can almost feel the spray, hear the thunderous roar, and breathe the droplet-laden mist emanating from the cataract. Brilliant use of brushwork and color lend credibility to the canvas, while emerald water rushes to the brink and surrenders to the inexorable force of gravity. Roiling whirlpools await below, a death trap to those that would approach the base of the Falls, yet their danger is not seen in Mignot's painting. The gorge's Canadian side is barely visible in Mignot's depiction of the Falls, and the shoreline remains nondescript. Mignot encompasses the Falls in a close-up from the American edge. In their paintings, Church and Inness both show a broader perspective of the Falls, including the Falls' base; Inness (1884) and Church (1867) also painted from the American side, and Church's 1857 depiction displays the Canadian viewpoint. Mignot leaves no doubt that the Falls themselves, not the setting nor their history, reign supreme. Mignot painted Niagara after he moved to London in 1862; he had visited Niagara Falls in June, immediately preceding his transatlantic voyage. He exiled himself to England because of anti-Southern sentiment in New York and never returned to the United States. However, his Niagara, initially exhibited to critical success in London, traveled to Chicago for the 1893 World's Columbian Exposition, 23 years after the artist's death. In 1868, Mignot visited France and Switzerland; he exhibited at the Paris Salon, one time, in 1870. Unfortunately, this was the summer of the Franco-Prussian War, and in Paris at the time of the Siege, Mignot contracted what appears to have been smallpox. Ill at the time of his return to England, he died in Brighton and is buried at the Brighton Cemetery. Despite critical and financial successes while he was alive, he left his family impoverished, and the widow Mignot arranged several posthumous exhibits and sales to raise funds. His death at 39 years of age truncated Mignot's already established, yet so full-of-promise, career: critic Henry Tuckerman, 3 years before Mignot died, described him as a “master of color.” Tuckerman's words of praise have, as their perfect example, Mignot's grand painting of the awesome force that is Niagara.

Rockey, Paul

doi: 10.1001/jama.2010.306pmid: N/A

She asked me to read it, like a curbside consult. She wanted my advice. I did it right—a pint of strong ale, a dark bar, hard rock music pulsing. I stayed on task—doctor to doctor—scribbled notes, made my own suggestions. I read it like a patient's chart. But neither beer nor legalese could blunt the blow of “predecease.”

Ahmad, Tariq

doi: 10.1001/jama.2010.480pmid: 20424238

At random instances, when I am working in the hospital, I greatly miss Nana, my grandfather. I wish I could sit down with him and discuss an interesting patient, or an article I just read, preferably over a cup of tea. You see, my grandfather was a renowned surgeon in Pakistan. He played an important role in creating the country's medical institutions and trained a generation of physicians. He performed surgery on thousands of people, including myself, and the residual well-healed scars remain a vanishing signature of his skillful workmanship. But my love for Nana runs far deeper than the stitch marks on my forehead where he fixed the gash of an ugly hockey-stick wound. I was transferred to his care when I was barely 3 years old because my parents' priorities lay elsewhere. He stepped into the shoes of a guardian quite effortlessly. This was despite being in his mid-70s, running a hospital, and spending long days in the operating theater. I would be dropped off at school in the morning, fetched in the afternoon, and delivered to his office at the hospital. Of course, he would never be in his office. It did not matter in the least to me because he always had a refrigerator full of soda, a cupboard full of candy, and a plethora of medical books with distorted and forbidden pictures. There were stacks of x-rays, an examination table with complicated instruments, and a highly entertaining desk calculator with computer games. When these playthings would lose their appeal, an entire hospital was available for my exploration needs. As I grew older and inched toward adolescence, Nana approached frailty. His walk slowed, he took more naps, and eventually he cut down on his doctoring. Soon the family coerced him into selling his beloved hospital, and that decision was his knock-out blow. He rapidly deteriorated into a shadow of his former self. Dementia was the official diagnosis, but I am sure that depression played a significant role. He would sit in our garden for hours and stare into space. His eyes lost their trademark twinkle. One day, he stopped talking and soon afterward descended into a coma. Nana spent his last few weeks in a makeshift ICU bed in our house. He never opened his eyes or spoke again. One day, his blood pressure fell and he stopped breathing. There was a flurry of activity as his children, all physicians, tried unsuccessfully to resuscitate him. But he had died, and when I touched his hand it was cold and hard. The years passed and I joined the ranks of driven premedical undergraduates studying organic chemistry and cramming for the MCAT. On especially difficult days, it would occur to me that Nana might have appreciated my efforts. And that would give me strength. But these memories of a grandfather long gone were unformed—they melted together the warm comfort of a parent with a child's perception of a physician. I knew nothing about the nature of his passion for medicine. I knew nothing of how he approached his patients. What was his bedside manner like? Was he curious about interesting cases? How did he feel about the power of medicine to change people's lives? I had no answers for these questions; in fact, back then, I was not yet mature enough even to ask them. And then, on one of her visits to me in Boston, my aunt brought along a book she had found during spring cleaning. Its pages were yellowed and moth-eaten with a layer of powder. A strong wind could have evaporated it. It was, she said, a collection of some of Nana's writings that one of his students had assembled. I placed it in my desk drawer and dared not expose the emotional weight it promised. I did not touch the book for many months. My justification was that the long hours as a medicine intern simply did not afford me the luxury. The truth was, in fact, that I was unprepared to deal with the emotional weight of uncovering my Nana's writings. It was as if someone had offered me the chance to sit down and talk with him, this time, not as a restless child, but as a fellow physician. And I was petrified. One evening, my curiosity got the better of me, and I finally started reading. I remained glued to his words all night, following every contour of the typed letters, pausing to absorb the meaning behind every sentence, and imagining him typing his thoughts. Chills ran down my spine as I read his descriptions of observations that I too had noticed along the way to becoming a physician. We were two physicians separated by continents and half a century, but connected by the words in a decomposing book. My grandfather had written treatises on guarding against contamination in the hospital, on how best to diagnose appendicitis, on details of operating-theater design. He reported on fascinating patients he had treated and new surgical procedures he had attempted. His words were infused with a logical bluntness that demanded attention, and he constructed his arguments with the calm assurance of a gifted teacher. I was transported to his classroom where he would have held his lectures and poured forth his knowledge, unselfishly sharing all that he knew with his students. I read his candid description of being a young British army surgeon in Iraq in the 1920s and treating infantry men who feigned abdominal pain so that he would suspect appendicitis, operate on them, and allow them to return home on medical leave. His descriptions were surprisingly concise, but there was a lot said between the lines, and a lot more left unsaid. Here was a South Asian surgeon stationed in Iraq, caring for frightened men whose military had thrust them into harsh surroundings due to an imperial misstep. It was a time when racism was far deeper and institutionalized, and he was countries away from his family; and yet, from his words, he appears to have practiced his art with quiet dedication. As I turned to the last chapter, a sense of déjà-vu set in. The chapter began with before-and-after pictures of young women. The women in the before pictures had had their noses cut off, one would guess based on the ragged edges that surrounded the wound, in a brutal fashion. The after pictures showed their surgically reconstructed noses. I remembered these pictures from when I would enter his office after school—they lined the back wall and were the first thing a visitor would see. As a child, I barely noticed them, because they appeared to fit perfectly into the strange aura of the place. As I read on, I learned that these were women from villages around Karachi whose husbands, in fits of rage, had punished them by cutting off their noses. These women escaped to the city, where Nana housed them, reconstructed their noses, and helped them find work. He wanted to restore to them a portion of the dignity that had been brutally stolen away. I have discovered that Nana is a lot closer to me than I realized. He was teaching me, by example, when I was unaware of being taught. He showed me, by the twinkle in his eye when he would practice medicine, that it is not a mere profession, but a calling that can enwrap one's existence with endless joy. That to be a good physician requires the utmost dedication in the face of difficult times; as well as the curiosity of a scientist and the heart of a poet. He showed me that medicine can transform people's lives.

Kuehn, Bridget M.

doi: 10.1001/jama.2010.453pmid: 20424239

Despite their association with serious cardiac and metabolic risks, atypical antipsychotics are widely used off-label with few data to support their efficacy, according to recent studies probing use of this class of drugs in the United States. Furthermore, physicians often do not follow through on precautions to reduce these risks. The studies provide new insights on physician prescribing behavior and the effect of warnings aimed at minimizing risks. The findings have raised new concerns about the public health impact and costs of widespread off-label antipsychotic use. Sales of antipsychotic drugs have increased steadily since 2004, and now top sales for other popular drug classes such as lipid regulators and proton pump inhibitors. Antipsychotic drugs became the top-selling drug class in the United States in 2008, edging out lipid regulators and proton pump inhibitors, according to IMS Health, a company that gathers and analyzes data on pharmaceuticals. Sales of antipsychotic drugs in 2008 reached $14.6 billion, up from $9.6 billion in 2004. Antidepressants now rank fifth, with sales of $9.6 billion in 2008. This commercial success suggests that atypical antipsychotics were being used widely beyond indications approved by the US Food and Drug Administration (FDA), which until lately were limited to conditions such as schizophrenia and bipolar mania. The studies confirm this trend. Researchers speculate that some of the enthusiasm for atypical antipsychotics may have been driven by a perception that these drugs were more effective and had fewer adverse effects than their predecessors. However, a growing body of evidence indicates these drugs are no more effective and are associated with serious risks of their own. Since the period examined in many of the studies, the FDA has expanded some of the indications for these drugs. This, in turn, is likely to drive further increases in antipsychotic prescribing. For example, aripiprazole was approved for use as an adjunctive therapy for major depression in late 2007, as was quetiapine in December 2009. Safety warnings The new findings suggest that warnings about the potential risks associated with use of atypical antipsychotics may have had limited or unintended effects. In 2003, the FDA announced it would require makers of atypical antipsychotics to include warnings about the risks of hyperglycemia and diabetes, including death, in patients taking these drugs. Additionally, the revised labels noted that physicians should monitor glucose levels in patients with diabetes or with risk factors for the disease. The American Psychiatric Association and the American Diabetes Association also published a consensus statement outlining the risks and recommending glucose monitoring (http://care.diabetesjournals.org/content/27/2/596.full). Yet a study that examined Medicaid records for 109 451 individuals who began taking atypical antipsychotics between 2002 and 2005 and 203 527 controls in California, Missouri, and Oregon found low levels of baseline glucose monitoring in patients taking the drugs and little boost in such monitoring after the warning (Morrato EH et al. Arch Gen Psychiatry. 2010;67[1]:17-24). The findings were consistent with studies that examined patients covered by private insurers, the authors noted. However, the authors did find evidence that the physicians were shifting away from atypical antipsychotics associated with the highest metabolic risks, and toward those that appeared to have lower risks. Surveys suggest that while psychiatrists are aware of the warning and understand the importance of metabolic screening, other factors may be interfering, said Elaine H. Morrato, DrPH, MPH, of the Colorado School of Public Health, in Aurora. For example, patients may have limited access to testing, or may be receiving care from multiple sources. Furthermore, patients with disorders treated with antipsychotics may have psychosocial problems that make them less likely to follow through with recommended monitoring. Morrato emphasized the importance of physicians conducting baseline and routine follow-up screening when using these drugs. She also encouraged physicians to make sure that their patients understand why it is important to follow through with the screening. In 2005, the FDA warned physicians that use of atypical antipsychotics to treat behavior problems in elderly patients increased the risk of death. While there is some evidence that rates of prescribing have decreased in this population, use for this indication remains common. One analysis looked at records from 2003 to 2008 in IMS Health's National Disease and Therapeutic Index, a nationally representative audit of office-based physicians' use of medications to treat patients. It found that before the warning was issued, physician prescribing of this class of medications was increasing 34% annually overall and rising 16% annually in patients with dementia (Dorsey ER et al. Arch Intern Med. 2010;170[1]:96-103). After the advisory, overall use of atypical antipsychotics decreased 2%; use in elderly patients with dementia decreased 19%, although a substantial amount continued. One limitation of the study is that it captured only information about use in nursing home patients in the care of office-based physicians. G. Caleb Alexander, MD, one of the studies’ authors and an assistant professor of medicine at the University of Chicago, said that the study was not designed to assess whether the use of these drugs was appropriate. But he noted that the management of agitation in patients with dementia presents dilemmas for physicians and family members who may perceive a short-term benefit of using these drugs despite the risks. “There are a limited number of pharmacologic options to treat the agitation that many patients with dementia have,” he said. “This is partly why there is such an emphasis on trying to improve nonpharmacologic interventions, such as trying to optimize the environment the patient is in, maximize the patient's orientation and limit confusion, and otherwise comfort the patient and provide a setting where drug therapy can be avoided or minimized.” Alexander said that the results suggest a substantial change in the trajectory of second-generation antipsychotic prescribing, including unintended effects on prescribing for patients with indications other than dementia. He said more research is needed on the impact of such warnings and how they might be improved. A second study, published simultaneously, looked specifically at nursing home residents and found continued high rates of prescribing in 2006, including variations in prescribing by facility (Chen Y et al. Arch Intern Med. 2010;170[1]:89-95). The study, which analyzed a nationwide sample of more than 16 000 nursing home residents, found that 4818 (29%) received at least one antipsychotic in 2006; of these, 1545 (32%) had no clinical indication cited. Additionally, patients were 1.37 times more likely to receive an antipsychotic if they lived in a facility with a high rate of prescribing than if they lived in a facility in which such prescribing was low. Becky A. Briesacher, PhD, one of the studies’ authors and an associate professor of medicine at the University of Massachusetts Medical School in Worcester, said the fact that studies including more recent data find greater declines in prescribing may mean there was a delayed reaction to the FDA warning. However, the finding that characteristics of facilities, not just patients, contribute to prescribing requires further probing. Briesacher explained that it is not clear what role might have been played by factors such as a lack of qualified staff or greater institutional acceptance of antipsychotic use. More education, Briesacher said, could promote more informed use of these drugs. “One thing we need to do is make sure the risks are well understood by physicians, nursing staff, and families,” she said. She also noted that in nursing homes with high rates of prescribing, patients were often given the drugs in their first week of residence, while facilities with lower rates waited longer. She explained that the first week in a new place may be a vulnerable time for patients, who may be disoriented or frightened. “Waiting until patients are more settled may help,” she said. Wide off-label use Other findings suggest that wide off-label prescribing continues and that in some cases physicians may not be aware that these applications are off-label. An analysis of prescribing data from the Department of Veterans Affairs found that 60.2% of the 279 778 individuals who received at least one prescription for an antipsychotic medication in fiscal year 2007 had no record of a diagnosis for an FDA-approved indication (Leslie DL et al. Psychiatr Serv. 2010;60[9]:1175-1181). Rates of off-label antipsychotic use were highest among patients diagnosed with other psychoses (40.7%), major depression (20.5%), Alzheimer disease or other dementia-like illness (20%), and posttraumatic stress disorder (19.4%). Douglas L. Leslie, PhD, professor of public health sciences and psychiatry at the Penn State College of Medicine in Hershey, Pa, said that physicians may be choosing to prescribe these drugs off-label—despite the limited evidence supporting their use—because they have heard anecdotal stories of benefit. Leslie and colleagues also noted the tremendous costs of such off-label use. The dose typically used in schizophrenia patients costs $10 per day. Adjusting for the lower doses typically used for off-label applications, the researchers estimate that $4 billion to $5 billion of the $13.1 billion spent in the United States on antipsychotic drugs in 2007 may have been for off-label uses with little or no documented benefit. “It's hard to justify, especially when we have good evidence-based treatments for mental disorders. The money would be better spent using those strategies,” Leslie said. One recent survey suggests that some physicians may not realize they are prescribing drugs off-label. The random mail survey of 599 primary care physicians and 600 psychiatrists (with an adjusted response rate of 47%) between November 2007 and August 2008 asked physicians about 14 drug-indication pairs (Chen DT et al. Pharmacoepidemiol Drug Saf. 2009;18[11]:1094-1100). It found that on average the physicians correctly identified the FDA approval status of half the drugs, though accuracy increased to 60% when the scientists looked only at drugs the physician reported prescribing frequently. Additionally, 42% of the physicians reported prescribing quetiapine for dementia with agitation, and 19% mistakenly believed the drug was approved for this indication. Alexander, who was a member of the research team, suggested a number of possible reasons for this disconnect. To begin with, the evidence base for drugs is enormous and difficult for physicians to master. Moreover, with psychiatric drugs, which are frequently used off-label for evidence-based and non–evidence-based reasons, Alexander said, there may be greater room for clinical innovation, greater difficulty establishing the boundaries of evidence, and more shared mechanisms of disease. “I think [antipsychotic drugs] have been widely overused,” Alexander said. “Efforts are needed to educate physicians more regarding the evidence base, and prescribers need to have more scrutiny and restraint in using psychotropic therapies.”

Mitka, Mike

doi: 10.1001/jama.2010.454pmid: 20424240

Stenting may soon join the treatment arsenal available to patients needing correction of severe carotid artery stenosis to minimize stroke risk. Whether it should be available remains a question. A new study suggests that carotid artery stenting is basically as safe and effective as endarterectomy, but another study argues in favor of the surgery over the intervention. At the February meeting of the American Stroke Association in San Antonio, Tex, researchers presented data gathered from the United States and Canada showing that carotid artery stenting was basically as safe and effective in preventing stroke, myocardial infarction, or death as carotid endarterectomy, the gold standard for treating severe carotid artery stenosis. The findings come from the Carotid Revascularization Endarterectomy vs Stenting Trial (CREST), sponsored by the National Institute of Neurological Disorders and Stroke (NINDS). Additional funding was provided by Abbott Laboratories, maker of the stent used in the study. But just a day before the CREST presentation, results were published from the International Carotid Stenting Study (ICSS), which compared endarterectomy and carotid artery stenting and found the surgical procedure superior (International Carotid Stenting Study Investigators. Lancet. 2010;375[9719]:985-997). ICSS was funded by the Medical Research Council, the Stroke Association, Sanofi-Synthélabo, and the European Union. The CREST researchers randomized 2502 individuals (35% female and 9% minorities) with asymptomatic and symptomatic (a nondisabling stroke or transient ischemic attack within the previous 6 months) carotid artery stenosis to undergo either an endarterectomy or carotid artery stenting. The procedures were performed at 117 centers over a 9-year period. The primary end point was overall incidence of stroke, myocardial infarction, or death at 30 days postprocedure or ipsilateral stroke at follow-up (a mean average of 2.5 years postprocedure). Within 30 days, 2.3% of the CREST surgical patients and 4.1% of patients undergoing stenting had a stroke, while 2.3% of surgical patients and 1.1% of stenting patients had a myocardial infarction. Age was also a factor, with patients aged 69 years or younger faring slightly better with stents and those older than 69 years doing slightly better with endarterectomy; average patient age was 69 years. Men and women had similar outcomes. No data were presented comparing the outcomes in asymptomatic with symptomatic patients. The findings from CREST may have economic and insurance coverage implications. Currently the US Centers for Medicare & Medicaid Services (CMS) pays for carotid artery stenting only in patients who are at high risk for endarterectomy (such as those with congestive heart failure, unstable angina, or a recent myocardial infarction, and those who have a symptomatic narrowing of the carotid artery of at least 70%). Recent efforts by pro-stent groups to have the CMS expand its coverage have been rejected, with the agency saying more rigorous research was needed. Whether the CREST findings are enough to persuade the CMS to change its mind remains to be seen. As for ICSS, between 2001 and 2008, researchers randomized 1713 patients with symptomatic carotid artery stenosis to either procedure performed at 50 academic centers in Europe, Australia, New Zealand, and Canada; about 30% of enrollees were women, and the average age was about 70 years. The primary end point for ICSS, which is ongoing, is the 3-year rate of fatal or disabling stroke in any site. What the ICSS results included was a 120-day interim safety analysis, with stroke, procedural myocardial infarction, or death as the primary end point. At 120 days, the absolute risk of such an event was 8.5% for the group undergoing stenting and 5.2% for those having an endarterectomy. Risks of any stroke and all-cause death were also higher in the stenting group than in the endarterectomy group. There were 3 procedural myocardial infarctions, all fatal, recorded in the stenting group compared with 4 nonfatal procedural myocardial infarctions in the endarterectomy group. Researchers affiliated with ICSS also published a substudy of that trial looking at the rate of ischemic brain injury detectable on magnetic resonance imaging. The researchers performed imaging 1 to 3 days before treatment, 1 to 3 days after treatment, and 27 to 33 days later among 124 individuals in the stenting group and 107 in the endarterectomy group. They concluded that about 3 times as many patients in the stenting group as in the endarterectomy group had new ischemic lesions (based on diffusion-weighted imaging) and that embolic protection devices designed to capture debris when inserting a stent were not effective (Bonati LH et al. Lancet Neurol. 2010;9[4]:353-362). Praise and criticism The pros and cons of both studies were quickly raised following their release. Criticism of CREST focused on its enrollment of asymptomatic in addition to symptomatic patients, and concern over whether a further breakout of the numbers would reveal an unacceptably high proportion of adverse events occurring in the asymptomatic patients (who arguably are at much lower risk than symptomatic patients for such events from carotid artery stenosis). As for ICSS, critics suggested that the interventionists placing the stents may not have had the experience or expertise of those treating patients in CREST; also, in ICSS, a choice of stents was available, while in CREST, the same type of device was implanted in all patients. Still, Ralph L. Sacco, MD, chair of the department of neurology at the University of Miami's Miller School of Medicine and president-elect of the American Heart Association, said, caveats aside, it appears that stenting may play a role in treating carotid artery stenosis. “CREST does show that endarterectomy and carotid stenting have similar efficacy, and that similar efficacy does seem to translate to the asymptomatic group,” Sacco said. “CREST shows that endarterectomy and stenting have long-term durability once you get through the 30-day postprocedural period. Our guidelines committee will have to digest the findings from CREST.” Walter J. Koroshetz, MD, NINDS deputy director, said the CREST findings suggest that stenting may become an attractive option for treating carotid artery stenosis in certain asymptomatic patients. “The vast majority of patients have asymptomatic disease and their risk of stroke is low—perhaps an annual risk of 3%,” Koroshetz said. “But with endarterectomy, there is a 3% procedural risk, so there it is important to use a less risky procedure.” The next important step, added Koroshetz, is to better determine which patients with asymptomatic carotid artery stenosis are truly in danger of experiencing a stroke. “What we really do not know is, with the many millions of people with asymptomatic carotid stenosis, how do we choose those at the highest risk of stroke?” he said. “We have had some promising predictive models, but none have made it to prime time. That is where the science will eventually go.” It is also important to know how well stenting and endarterectomy will perform over the long term, said Koroshetz. To that end, NINDS has agreed to fund, at least through 2015, further research using the CREST participants to track restenosis rates for those receiving a stent and determine the durability of both procedures. Koroshetz was also among those who suggested that the level of expertise of the surgeons implanting the devices in ICSS may not have been as good as those doing so in CREST, accounting in part for the poorer stenting results. Martin M. Brown, MD, an ICSS researcher, said the interventionists they used had adequate training and that the procedures reflected real-world settings. “What you want to know is what happens in your good local hospital; we thought it was important to have average centers involved rather than the top-flight centers,” Brown said. “Because you have to remember, once stenting is approved, every surgeon in the country will do stenting.” Treating asymptomatic patients Moving to treat the asymptomatic population gives pause to Lee H. Schwamm, MD, professor of neurology at Harvard Medical School in Boston. While the adverse event risk rates appear acceptably low, Schwamm warned that the numbers may not be revealing all the facts. “We have to look for unmeasured confounders; preventive stroke care has improved dramatically over the time these trials commenced,” Schwamm said. “The problem comes with the asymptomatic patients: how would they have done without treatment in either arm? If we do not know that, then how can we decide whether or not the complication rates are acceptable?” Schwamm is also concerned about how the medical profession views outcomes compared with the way patients see them. Specifically, he noted the higher stroke rate in CREST for those undergoing stenting compared with those undergoing endarterectomy. The study's conclusion is that both procedures are basically equal in safety and efficacy due to surgery's higher rate of myocardial infarctions. Furthermore, the CREST presentation did not specify the severity of strokes and myocardial infarctions. “For most patients, a minor myocardial infarction does not affect them for very long, but many minor strokes still leave many patients with strong and lingering effects,” Schwamm said. Schwamm said the CREST results—which were presented at the stroke meeting and had not yet appeared in a peer-reviewed journal—need to be published to allow others to view the data and parse out meaningful outcomes. “For example, a 4.1% stroke risk up front for stenting is probably reasonable, but here is the real kicker: what if most of these strokes occurred in the asymptomatic patients? These are patients who otherwise may never have experienced a stroke,” Schwamm said. “That is a critical piece of information, and we should not be jumping on the bandwagon of stenting and endarterectomy being equivalent until we have had the opportunity to see the full, peer-reviewed data.”

Mitka, Mike

doi: 10.1001/jama.2010.455pmid: 20424241

The US Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP) is recommending reducing the vaccine schedule for postexposure prophylaxis to prevent human rabies in individuals who have not previously received rabies vaccine. The proposed schedule reduces the number of vaccine doses given from 5 doses to 4 doses. The schedule for individuals who had previously been vaccinated against rabies remains the same. Proposed Rabies Postexposure Prophylaxis Schedule For those who have not been previously vaccinated: Immediate, thorough cleaning of all wounds with soap and water and irrigation with a virucidal agent (if available) Administration of human rabies immunoglobulin Administration of human diploid cell vaccine or purified chick embryo vaccine on days 0, 3, 7, and 14 For those who have been previously vaccinated: Immediate, thorough cleaning of all wounds with soap and water and irrigation with a virucidal agent (if available) Human rabies immunoglobulin should not be administered Administration of human diploid cell vaccine or purified chick embryo vaccine on days 0 and 3 More detailed information is available at: http://www.cdc.gov/mmwr/pdf/rr/rr5902.pdf ACIP is making the recommendation because evidence fails to show additional benefit from a fifth dose and eliminating it would produce an estimated annual US cost savings of about $16.6 million. In the United States, about 23 000 individuals each year are exposed to potentially rabid animals and receive rabies postexposure prophylaxis. As a result of such preventive measures, human rabies is now rare in the United States, averaging only 1 or 2 cases annually since 1960. Rabies is a zoonotic disease caused by RNA viruses in the family Rhabdoviridae, genus Lyssavirus, and is transmitted in the saliva of rabid mammals, most often via a bite. After these viruses enter the central nervous system, they cause acute, progressive encephalomyelitis. The incubation period usually ranges from 1 to 3 months after exposure, but can vary from days to years. While ACIP is recommending cutting back on the number of doses, prompt treatment (proper wound care, the administration of rabies immunoglobulin, and vaccine) remains essential. Once clinical signs of rabies appear, the disease is nearly always fatal. Postexposure prophylaxis for rabies in individuals not previously vaccinated includes immediate thorough cleansing of all wounds with soap, water and, if available, a virucidal agent. Human rabies immunoglobulin should also be administered, if anatomically feasible, around and into the wounds, with any remaining volume being administered at an intramuscular site distant from vaccine administration. The vaccine, either human diploid cell or purified chick embryo cell, should be administered in single 1.0-mL doses (administered in adult deltoid muscles or the anterolateral aspect of a child's thigh) on days 0, 3, 7, and 14. For persons who have previously received rabies vaccine, wound cleansing remains the same as for those not vaccinated but human rabies immunoglobulin should not be administered. Either vaccine should be given in single 1-m/L doses on days 0 and 3. These regimens—for rabies vaccine-naive and previously exposed—apply to individuals in all age groups, including children. This article was corrected online for error in data on 4/29/2010, prior to publication of the correction in print.

Kuehn, Bridget M.

doi: 10.1001/jama.2010.456pmid: N/A

To provide a local supply of physicians who can administer quality long-term care to patients living with HIV/AIDS in Africa, the US National Institutes of Health (NIH) and the President's Emergency Plan for AIDS Relief (PEPFAR) have launched a program to strengthen the medical education system on the continent. The Medical Education Partnership Initiative will bring together expertise and resources from the Office of the US Global AIDS Coordinator, the Health Resources and Services Administration, the US Centers for Disease Control and Prevention, numerous NIH offices, and the Department of Defense. It aims to facilitate PEPFAR's goal of boosting the number of new health care workers in Africa by 140 000. The program is accepting proposals aimed at building a robust medical workforce in Africa that can provide a sustained response to the HIV/AIDS epidemic and preparing local scientists to conduct multidisciplinary research and to more rapidly translate results into interventions in their communities (http://grants.nih.gov/grants/guide/rfa-files/RFA-TW-10-008.html).

Kuehn, Bridget M.

doi: 10.1001/jama.2010.458pmid: N/A

Individuals who have impulsive or antisocial traits have an exaggerated response to anticipated reward, according to a study funded by the National Institute on Drug Abuse. Scientists from Vanderbilt University in Nashville used positron emission tomography (PET) to assess the relationship between traits associated with psychopathy and dopamine release following amphetamine administration in 30 normal volunteers (Buckholtz JW et al. Nat Neurosci. 10.1038/nn.2510 [published online March 14, 2010]). They found a strong correlation between higher scores related to impulsive or antisocial characteristics on the psychopathic personality inventory and dopamine release. Additionally, functional magnetic resonance imaging of 24 individuals (18 of whom also underwent PET testing) indicated that those with such traits had a greater neurological response to the anticipation of a monetary reward. Individuals with substance abuse problems also have demonstrated a similar pattern of excessive reward response, according to the authors. They conclude that a hypersensitive reward system may underlie both substance abuse and psychopathy.