May 29, 2011

New Diagnostic Criteria for Alzheimer's Published

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Dr. Reisa Sperling
Dr. Reisa Sperling
From Medscape Education Clinical Briefs
April 28, 2011 — New diagnostic criteria for Alzheimer's disease (AD), including mild cognitive impairment (MCI) due to AD and a new "for research purposes only" category of preclinical AD, are now published.

Draft criteria were first presented last summer at the International Conference on Alzheimer's Disease and were subject to feedback from the research and practice community. They are now published in 3 final documents, along with an introductory summary, online April 19 in Alzheimer's & Dementia: The Journal of the Alzheimer's Association.

The 3 working groups were convened by the National Institute on Aging (NIA) and the Alzheimer's Association to update criteria established by the National Institute of Neurological Disorders and Stroke/Alzheimer's Disease and Related Disorders Association — now the Alzheimer's Association — in 1984.

The guidelines published today were "extensively revised" from those presented last summer, Creighton H. Phelps, director of the Alzheimer's Disease Centers Program at NIA, told reporters during a press teleconference.

"The revised guidelines that we're presenting address particularly the difference between information that can be used in clinical practice and that which is intended for use only in research settings," Dr. Phelps said. "They also present a distinction between the underlying disease process and clinically observable disease states."

"Special attention" is paid in the new document to how biomarkers may be used to add levels of confidence to clinical findings in MCI and AD, primarily in the research setting, he added.

In fact, the take on biomarkers appears to be one of the biggest changes from last summer's presentation. The working groups had developed these documents in isolation from each other and had come to somewhat divergent positions on the use of biomarkers, such as advanced imaging and cerebrospinal fluid (CSF) markers of disease. The working group on MCI had urged their inclusion at least in the research setting, for example, whereas the AD working group had not addressed the use of biomarkers at all.

Clifford R. Jack Jr., from the Department of Radiology at Mayo Clinic in Rochester, Minnesota, lead author of the overview document, said that a small working committee was formed specifically to harmonize the documents.

They worked to make not only the terminology for biomarkers more consistent, Dr. Jack said, "but also the concepts and what they actually measure — in other words, what pathology individual biomarkers that are discussed map onto and also the business of how they should be used.

"So there was that effort, and we think we were successful by and large in harmonizing those aspects of biomarkers as they are treated in the 3 documents," he added.

"Another thing that we tried to do in revision of these documents after last summer was to make it a little clearer what was there for clinical use now vs what is a research agenda for the future," Dr. Phelps told Medscape Medical News. "I think that's come out in discussion fairly well today, but that was a little murky last summer."

Dementia Due to AD

Guy McKhann, MD, from Johns Hopkins University School of Medicine in Baltimore, Maryland, who chaired the Alzheimer's Disease Dementia Workgroup, was instrumental to the definition of the 1984 diagnostic criteria and headed the working group on dementia due to AD.

During the briefing, Dr. McKhann pointed out that the diagnosis of AD is still a clinical one in this document. "Primarily, we're asking the physician, with the help of an informant — members of the family, even the patient — to make a judgment as to whether or not dementia has occurred or is occurring."

Biomarkers can assist in the diagnosis of AD but are not essential; rather they are used in research studies to augment certainty about a given diagnosis, he said. "But for the practicing physician — and I would caution that people who see these folks first are not necessarily neurologists or psychiatrists; they are people who are geriatricians, general practitioners, internists — the people who see these people first, are first making this distinction on clinical grounds."

They aimed to make the diagnostic criteria sufficiently flexible to serve both general healthcare providers without access to imaging, CSF measures, or neuropsychological testing, as well as specialized investigators in clinical trial settings, the study authors note.

The working group retained the framework of probable AD dementia from the 1984 criteria, but "on the basis of the past 27 years of experience," made several changes to the clinical criteria for the diagnosis. They also retained the term "possible AD dementia," they write, "but redefined it in a manner more focused than before."

Biomarker evidence was incorporated after all into diagnostic formulations for probable and possible AD at least for research settings, they note. "The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia," they write. "Much work lies ahead for validating the biomarker diagnosis of AD dementia."

Also incorporated are the concepts of a continuum of disease and the distinction between AD and other types of dementia or mixed dementias, Dr. McKhann noted.

MCI Due to AD

The MCI working group was chaired by Marilyn Albert, MD, also from Johns Hopkins University School of Medicine, who presented their findings here. The term MCI has been in use in the field since about 2000, largely based on the work of Ron Peterson, MD, from the Mayo Clinic, Rochester, Minnesota, she said.

"What this term has come to mean is people who have mild progressive symptoms, changes in mental abilities — usually memory but not always memory — and that these become progressive over time," Dr. Albert said. "What has been learned in the field in the last 10 or so years is a very large number of these individuals — although certainly not all of them — ultimately will progress to have Alzheimer's dementia."

As in the AD document, for the purposes of clinical practice, the diagnostic criteria for MCI are not much changed and are meant to be used by physicians in any setting.

"There are some very minor differences that have to do with who can provide the source of information about whether or not there have been changes [in cognition] and whether or not these changes have some minor impact on functional ability, but overall, the clinical criteria that we're describing are extremely similar to what's been used for the last 10 years in the field," Dr. Albert noted.

The big change has been the discussion of biomarkers to increase diagnostic certainty, she noted, "but the use of biomarkers is recommended currently now only in research settings because there's an enormous amount we still have to learn about them."

That is a somewhat more circumspect view than she took last summer, when she suggested that although "we recognize that there's much more that needs to be learned about all of these biomarkers to be able to move them out into community settings, but we believe the time is right, and we urge everyone to move ahead."

In the new document, the MCI working group actually developed 2 sets of criteria: 1 outlining "core clinical criteria" for use by providers without access to advanced imaging or CSF analysis and 1 describing research criteria that incorporate biomarkers for use in research and clinical trials settings, even though, they note, "considerable work is needed to validate the criteria that use biomarkers and to standardize biomarker analysis for the use in community settings.

"The final set of criteria for mild cognitive impairment due to AD has 4 levels of certainty, depending on the presence and nature of the biomarker findings," they write. These are as follows:
  1. Concern regarding a change in cognition: This concern can now be identified by the patient, an informant, or a skilled clinician, they note. In previous criteria, the patient had to express concern and then be corroborated by an informant.
  2. Impairment in one or more cognitive domains: Performance should be lower than would be expected for the patients' age and education, they note, and if repeat assessments are available, should show decline over time. Although impairments may begin in any cognitive domain, including executive function, language, attention. or visuospatial skills, impairment in episodic memory occurs most often in those who progress to AD.
  3. Preservation of independence in functional abilities: Those with MCI may take more time, be less efficient, and make more errors in daily tasks, such as paying bills and preparing a meal, but they generally maintain independence of function with minimal assistance.
  4. Not demented: Changes should be sufficiently mild that there is no evidence of social or occupational impairment.
Preclinical AD Working Group

Finally, the third group, chaired by Reisa Sperling, MD, from Harvard Medical School in Boston, Massachusetts, outlined a preclinical stage of AD.

There's converging evidence that the pathophysiologic process of AD begins years, probably more than a decade, before the time that we make a diagnosis of dementia, Dr. Sperling said. "This long preclinical phase of AD provides a critical opportunity for potential intervention with disease-modifying therapy."

The document and the writers of the document were both clear, though, that there is no utility of this classification for the purposes of day to day practice. "I want to emphasize since the preclinical might be the most controversial that we are really proposing our guidelines for research purposes only, and at this time they really do not have any use in clinical practice," Dr. Sperling said.

"The main conceptual point that our group felt we wanted to work towards was to define AD on the basis of underlying brain changes rather than just requiring clinical symptoms."

For many chronic conditions, including cancer, heart disease, diabetes, and osteoporosis, there are factors associated with risk for the disease, such as high cholesterol or blood glucose levels, the presence of which help to define a higher-risk population but that do not mean that the individual at risk will develop the disease with 100% certainty. However, at a population level, screening and treating those with evidence of early disease can significantly reduce mortality, Dr. Sperling noted.

"So we propose a staging framework to try to better define individuals at the greatest risk for going on towards clinical impairment," she said.

The stages include the following:
  • Stage 1 — asymptomatic cerebral amyloidosis;
  • Stage 2 — amyloidosis plus evidence of "downstream" neurodegeneration; and
  • Stage 3 — amyloidosis, neuronal injury, plus subtle cognitive/behavioral decline.
"The main change in our criteria from what we published last July is the idea that we acknowledge that these individuals may or may not progress to the clinical stage of the disease but that we've tried to make a research framework that will allow us to best test these hypotheses," Dr. Sperling noted.

"We've now included some subtle behavioral symptoms, such as apathy, which may precede the clinical symptoms of MCI by a few years, and tried to come up with a very specific way of staging individuals who are at most risk for Alzheimer's disease dementia in the future," she added.

Expanded Recognition

William Thies, PhD, chief medical and scientific officer at the Alzheimer's Association in Chicago, Illinois, pointed out that the new criteria will result in little change in current clinical practice.

"However, the expanded recognition of the course of Alzheimer's disease will have more immediate importance in the research area," he said. "In the future, the new criteria will drive research into earlier diagnosis, better treatment, and a better understanding of the public health impact of Alzheimer's disease."

The criteria will be validated during the next few years, he added. Further research will require identification of further markers of early pathology and allow development of drugs "that will prevent that early pathology from causing the catastrophic symptoms of full-blown disease."

Dr. Jack serves as a consultant for Eli Lilly, Eisai, and Elan, is an investigator in clinical trials sponsored by Baxter and Pfizer Inc, and owns stock in Johnson and Johnson; Dr. Albert serves as a consultant to Genentech and Eli Lilly and receives grants to her institution from GE Healthcare; Dr. McKhann serves on a Data Safety Monitoring Board for Merck; and Dr. Sperling has served as a site investigator and/or consultant to several companies developing imaging biomarkers and pharmacological treatments for early AD, including Avid, Bayer, Bristol-Myers-Squibb, Elan, Eisai, Janssen, Pfizer, and Wyeth. Disclosures for coauthors appear in the publications.

Alzheimers Dement. Published online April 19, 2011. Full text

Related Link
The full text of the guidelines are available on the Alzheimer’s Association Web site.

May 15, 2011

Even Short-Term NSAID Use Risky in Cardiac Patients

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Dr. Anne-Marie Schjerning Olsen
MEDSCAPE NEWS (May 9, 2011) - In patients with prior myocardial infarction (MI), most nonsteroidal anti-inflammatory drugs (NSAIDs), even when taken for as little as 1 week, are associated with an increased risk for death and recurrent MI, new observational data indicate.

Use of NSAIDs was associated with a 45% increased risk for death or recurrent MI in the first 7 days of treatment and a 55% increased risk if treatment continued to 3 months. The findings were published online May 9 in Circulation.

"We found that short-term treatment with most NSAIDs was associated with increased and instantaneous cardiovascular risk," first author Anne-Marie Schjerning Olsen, MB, from Copenhagen University in Hellerup, Denmark, told Medscape Medical News.

"Our results indicate that there is no apparent safe therapeutic window for NSAIDs in patients with prior MI and challenge the current recommendations of low-dose and short-term use of NSAIDs as being safe," she said.

Results 'Completely Consistent' With 2007 AHA Advisory

In a 2007 scientific statement, the American Heart Association (AHA) advised clinicians about the risks of NSAID use among patients with known cardiovascular disease or those at risk for ischemic heart disease and provided a stepped-care approach for use of these agents in this patient population.

Asked to comment on the new study, Elliott Antman, MD, from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, and lead author of the 2007 advisory, said, "Essentially, what this paper shows is that there is a gradient of risk among NSAIDs; some are associated with more risk than others; none appear to be completely safe, and the researchers could not identify a period that appeared to be safe, no matter how short."

"This is completely consistent with the advice that we put forward in 2007, which is to use the safest drug, in the lowest dose required to control musculoskeletal symptoms, for the shortest period of time," Dr. Antman told Medscape Medical News.

"We do have to be practical here," Dr. Antman said, "because despite very best efforts with physical therapy and nonpharmacologic treatments, there are individuals who have severe, debilitating arthritis, lupus, or rheumatoid arthritis and we do have to have a treatment plan for those patients." The AHA's stepped-care approach provides such a plan, Dr. Antman noted.

First Time-to-Event Analysis

Using the Danish National Patient Registry, Dr. Olsen and colleagues identified 83,675 patients who were admitted to a hospital with a first MI between 1997 and 2006 and were discharged alive. Their average age was 68 years, and 63% were men.

At least 1 prescription claim for NSAID treatment after discharge was identified for 35,405 patients (42.3%), most commonly ibuprofen (23%) and diclofenac (13.4%). The most commonly prescribed selective cyclooxygenase (COX)-2 inhibitors were rofecoxib (4.7%) and celecoxib (4.8%).

During the observation period, 35,257 deaths or recurrent MIs (42.1%) were registered in the database. According to the investigators, the risk for death or recurrent MI was elevated at the beginning of NSAID treatment (hazard ratio [HR], 1.45; 95% confidence interval [CI], 1.29 - 1.62) and the risk persisted throughout treatment (HR after 90 days, 1.55; 95% CI, 1.46 - 1.64).

All NSAIDs, except naproxen, were associated with an increased risk for death or recurrent MI, with diclofenac having the highest risk (HR in the first week of treatment, 3.26; 95% CI, 2.57 - 3.86).
"Particularly worrying," Dr. Olsen told Medscape Medical News, "was the fact that the widely used nonselective NSAID diclofenac was associated with early and higher cardiovascular risk than the selective COX-2 inhibitor rofecoxib, which was withdrawn from the market in 2004 due to its unfavorable cardiovascular risk profile."

"The accumulating evidence suggests that we must limit NSAID use to the absolute minimum in patients with established cardiovascular disease," she added.

"If NSAID therapy is necessary for patients with known cardiovascular disease, the doctors should choose a more selective COX-1 inhibitor in minimum dose (eg, naproxen ≤ 500 mg daily or ibuprofen ≤ 1200 mg daily) for the shortest period of time," she added.

Dr. Antman said this paper provides a "good reminder" for clinicians and patients about the risks of NSAIDs in this patient population.

"Many of the drugs that we are talking about," he noted, "can be obtained over-the-counter, and it is the presumption of many patients that if it is a drug that they can get over-the-counter it must be 'safer.' Very often they don't report those medications to their physician when they go for an office visit."

The authors and Dr. Antman have reported no relevant financial relationships.


Circulation. Published online May 9, 2011. Abstract

May 14, 2011

A Doctors's 5 Worst Financial Mistakes

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You're probably not a crack accountant or a financial whiz. There's no shame in admitting that. How to handle money isn't something that's taught in medical school, but in many respects what you do with your money is as important as the skills it takes to make it.

May 09, 2011

Keratoderma

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From medscape

History

This 31-year-old African-American female presented with a 20-year history of severe hyperkeratosis of the bilateral plantar areas. The keratoderma began in her preteen years and by the age of 17 had covered almost the entire soles. She has gradually developed deep fissures that have added more pain to an already uncomfortable condition. Because of the pain, she developed an abnormal gait.

May 08, 2011

Aspirin in Primary Prevention: New Meta-Analysis

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From Heartwire
April 29, 2011 (Birmingham, Alabama) -- A new meta-analysis of studies of aspirin in primary prevention in a total of 90 000 subjects has suggested a 14% reduction in total cardiovascular events (driven by a 19% reduction in nonfatal myocardial infarction [MI]) and a nonsignificant reduction in overall mortality and stroke.

But clinical-trials guru Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA) is not overly impressed with these new data and continues to be skeptical about the role of aspirin in primary prevention.

Kaul commented to heartwire : "The key finding of this meta-analysis is that aspirin use is associated with a statistically significant reduction in nonfatal MI. However, the clinical significance of this finding is not clear, as annualized risk difference or the number-needed-to-treat data are not presented. It is also not clear whether the data analysis included silent MIs identified on ECG examination. It is important to emphasize that, with the exception of one trial (the Thrombosis Prevention Trial), the primary end point was not met in any one of the studies included. For guiding clinical practice, an estimate of benefit/risk is necessary, which these data don't provide. In addition to significant statistical heterogeneity, there is also clinical heterogeneity (in aspirin dose, treatment duration, concomitant medications, etc) that might impact interpretation of the data. Lack of patient-level data precludes adjustment for variability in critical prognostic covariates and does not permit the more robust time-to-event analysis."

The latest meta-analysis, published online April 8, 2011 in the American Journal of Cardiology, adds three new studies--the Aspirin for Asymptomatic Atherosclerosis (AAA) trial, the Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial, and the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) trial--to the previous meta-analysis published by the Antithrombotic Trialists' Collaboration (ATTC) in 2009.

Lead author Dr Alfred Bartolucci (University of Alabama at Birmingham) told heartwire : "Our results are in line with the ATTC meta-analysis, but we have added more patients, so the results become stronger."

Meta-Analysis: Predefined End Points

End pointOdds ratio (95% CI)p
Total CHD0.85 (0.69–1.06)0.154
Nonfatal MI0.81 (0.67–0.99)0.042
Total CV events0.86 (0.80–0.93)0.001
Stroke0.92 (0.83–1.02)0.116
CV mortality0.96 (0.80–1.14)0.619
All-cause mortality0.94 (0.88–1.01)0.115
But What About the Bleeding Risk?

Bartolucci was reluctant to be drawn into the controversy that has been simmering recently over claims that recommendations for the use of aspirin in primary prevention are too enthusiastic. This has been based on concerns about the bleeding risk associated with taking daily aspirin. In particular, the ATTC investigators found that the same people who would derive the greatest benefit (those at higher risk of heart disease) are also at higher bleeding risk with aspirin. This led them to conclude that "there is not good evidence of substantial benefit that outweighs risk enough to justify a public policy recommending routine use in primary prevention."

The current meta-analysis did not show a significant increase in gastrointestinal (GI) bleeding with aspirin, but Bartolucci said he would not recommend that people take aspirin for primary prevention if they were at risk of GI bleeding.
The GI bleeding rate with aspirin varied in the nine studies included from 0.3% to 4.5%. Bartolucci attributed this variation to different patient populations.

He noted that many of these studies included people who were not at especially high risk of heart disease. "Many of these studies just included normal middle-aged individuals. Some had risk factors, some did not."

Bartolucci was not eager to make recommendations based on his data. "We're just reporting the data. People have to interpret it for themselves," he told heartwire. "Our bottom-line results apply to the average person. But not everyone fits into the average."

When pushed, he said he thought there was a major role for aspirin in primary prevention but that people needed to consult with their doctor to make sure they could tolerate it. He added: "The benefit of aspirin in primary prevention is still there. And we are now getting more knowledge of how different groups of individuals, such as diabetics, are at risk of CHD."
But Kaul disagreed. "In my opinion, the proper use of a meta-analysis is not only to harness power from inadequately powered individual trials to derive a pooled estimate of treatment effect but also to identify consistency of treatment effects across important subgroups. I also do not consider a meta-analytic p value of <0.05 to provide strong evidence," he told heartwire .

Kaul added: "Positive secondary end points have typically (and generously) been used to support aspirin recommendations by professional societies. However, the FDA continues (rightly so) not to endorse aspirin for primary prevention, even without considering the contemporary negative trials."

This study was supported by an unrestricted research grant from Bayer HealthCare AG.