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Internal Medicine News

S UICIDALITY W ARNING , PAGE 6 Internal Medicine News www.inter V O L .


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The Leading Independent Newspaper for the Internist—Since 1968

F EBRUARY 1, 2009

Newspaper for the Internist—Since 1968 F EBRUARY 1, 2009 Dr. Rachelle Doody says the phase II

Dr. Rachelle Doody says the phase II trial of bapineuzumab ‘at least had some signal’ that the agent is safe and effective.

Amyloid Theory Sputters for AD


Mid-Atlantic Bureau

T he amyloid hypothesis isn’t dead, but it seems to be limping a bit in the

race for an Alzheimer’s cure. Some researchers who pre- dicted 5 years ago that an anti- amyloid disease-modifying ther- apy was imminent are now reevaluating that optimism—in- cluding the geneticist who first suggested the pathologic link between amyloid plaque depo- sition and Alzheimer’s disease. “Everything is taking a lot longer than I thought it would; there’s no question about that,” John Hardy, Ph.D., said in an interview. In 1991, Dr. Hardy, a professor of neuroscience at University College London, postulated that -amyloid deposition was the root of a pathologic cascade that resulted in Alzheimer’s disease. The concurrent discovery that a mutation in the amyloid pre- cursor protein (APP) gene

caused early-onset Alzheimer’s, coupled with the association of plaque deposition and early Alzheimer’s in Down syndrome patients, added weight to the theory (Trends Pharmicol. Sci. 1991;12:383-8). A new research boom was born. But the first phase III trials of antiamyloid agents have brought no good news. Tramiprosate, a -amyloid an- tagonist, was the disappointment of 2007; tarenflurbil, a gamma- secretase modulator, this year’s downer. And positive findings in bapineuzumab’s phase II trial were slim. A post hoc analysis showed that some patients with mild to moderate Alzheimer’s, with no genetic risk factors, had cognitive improvement after get- ting the vaccine. Apparently, the finding was enough for Elan Pharmaceuticals Inc. and Wyeth Pharmaceuticals, but maybe not for Dr. Hardy. “The data right now are nei- ther positive nor negative. At this point, the only thing we can See Amyloid page 20



  I N S I D E Self-Harm Some abused teens may deliberately embed foreign objects


Some abused teens may deliberately embed foreign objects into soft tissues.



Genetics in Your Practice

Dr. Matthew R.G. Taylor looks at genome-wide association studies.



Taylor looks at genome-wide association studies. PAGE 28 Tea Time Regular consumption of hibiscus tea may

Tea Time

Regular consumption of hibiscus tea may help control blood pressure.





Medicare panel suggests boosting physician fees by 1.1% in 2010.



boosting physician fees by 1.1% in 2010. PAGE 33 Breast Cancer Decline Linked to HT Cessation

Breast Cancer Decline Linked to HT Cessation

New WHI data affirm hormonal link.


Denver Bureau

S A N A NTONIO — Two new

statistical analyses of Women’s Health Initiative data persua- sively indicate that the recent abrupt decline in breast cancer incidence in the United States is attributable to a dramatic drop

in the use of estrogen-plus-prog-

estin menopausal hormone therapy, and not—as skeptics have argued—to less utilization of mammography. Academic fencing over causal- ity aside, the practical take- home message from the latest Women’s Health Initiative (WHI) data analyses is that the

breast cancer risk imparted by hormone therapy rises sooner

and more steeply than previ-

ously recognized, and it swiftly declines after HT is discontin- ued, Dr. Rowan T. Chlebowski said at the San Antonio Breast Cancer Symposium. “The good news for women here is that the risk rapidly dis-

sipated in just a year or year and a half,” said Dr. Chlebowski, a medical oncologist at the Los Angeles Biomedical Research Institute in Torrance, Calif. The WHI was a very large National Institutes of Health– sponsored study on the preven- tion of cardiovascular disease See Breast Ca page 2

Myelodysplastic Syndrome ‘Severely Underestimated’


San Francisco Bureau

— dysplastic syndrome is far more common than previous estimat- ed, and patients with this blood disorder tend to be older and

sicker than the general Medicare population, based on an analysis of claims by more than 1.7 mil- lion Medicare enrollees. Each year, there are about 76,000 new cases of myelo- dysplastic syndrome (MDS), ac- cording to the study of the Medicare Standard Analytic File,

a random sampling of 5% of




Medicare patients. This is about eightfold greater than previous

estimates based on the Nation-

al Cancer Institute’s Surveil- lance, Epidemiology, and End Results (SEER) Program, Dr. Stuart L. Goldberg said at the annual meeting of the Ameri- can Society of Hematology. The current analysis also showed that during a 3-year fol- low-up, newly diagnosed MDS patients were more likely than the general Medicare popula- tion to have cardiac complica- tions, dyspnea, diabetes, and kidney complications. These See Syndrome page 6




Epilepsy Drug Warnings to Add Suicidal Ideation


Los Angeles Bureau

The relative risk for suicidality was highest among pa- tients receiving drugs for epilepsy (3.5), compared with psychiatric (1.5) and other indications (1.9). However, the absolute rate of events was highest in psychiatric patients (8.5 suicidality reports per 1,000 pa- tients receiving antiepileptic medications, compared with 5.7 per 1,000 for psychiatric patients taking placebo). Among epilepsy patients, 3.4 events per 1,000 were re- ported for those receiving antiepileptic medications, compared with 1.0 for those assigned to receive placebo. Four patients randomized to receive antiepileptic drugs committed suicide during the trials that were ex- amined by the FDA, while no patient assigned to place- bo took his or her own life. However, those numbers were not high enough to justify a warning of suicide

on drug labeling, the press release stated.

T he Food and Drug Administration has directed physicians to inform patients taking anticon- vulsant medications that the drugs have the po-

tential to increase suicidal thoughts and behavior. Families and caregivers should also be notified of this risk so that they can be attuned to changes in behavior in patients receiving antiepileptic medications, accord-

ing to the FDA’s alert for health care professionals. Based on an agency review of nearly 200 clinical tri-

als of 11 antiepileptic drugs, the directive coincided with an FDA announcement that manufacturers of any medication in the class will be required to add warn- ings about suicidal thoughts or behavior in

prescribing information or labeling and to develop medication guides for patients. Revised labeling or an explanation “why they do not believe such labeling changes are

necessary” must be submitted to the agency within 30 days. Jack Cox, a spokesman for Pfizer Inc., said in a tele- phone interview his firm will comply with the order. “Pfizer will work closely with the FDA to update the la- beling of our antiepileptic medications Lyrica [prega- balin] and Neurontin [gabapentin], in a timely manner.” “We have not heard directly from the FDA, but we will work to address any of the agency’s concerns,” said Tricia Geoghegan, a spokesperson for Ortho-McNeil Neurologics, makers of topiramate. Ms. Geoghegan noted that the label for Topamax (topiramate) has al- ways included “content about this topic,” but added that revisions will be made should the FDA request them. The agency’s decision drew on data from placebo- controlled clinical trials that enrolled a total of 43,892 patients aged 5 and older taking the medications for epilepsy, psychiatric disorders, and other conditions. The FDA meta-analytic review of 199 trials deter- mined that patients receiving antiepileptic drugs were at a twofold risk of suicidal behavior or thoughts (0.43%), compared with patients receiving placebo (0.24%). The difference translates to 1 additional case of suicidality per 530 patients treated with antiepileptic drugs.

See related commentary on page 9.

“The biological reasons for the increase in the risk for suicidal thoughts and behavior ob- served in patients being treated with antiepileptic drugs are unknown,” according

to the FDA. A review article about suicidality and antiepileptic drugs noted that the baseline suicide rate among patients with epilepsy is 5 times higher than that seen in the general population, and higher still (25-fold) in patients with temporal lobe epilepsy and complex partial seizures (Drug Saf. 2007;30:123-42). Although that article commented on antiepileptic medications’ disparate mechanisms of action and vary- ing effects on serotonin metabolism (a hypothesized link to suicidality), the FDA report found that the risk for suicidal thought or behavior was “generally consis- tent” among the 11 drugs studied. As the name implies, antiepileptic drugs were intro- duced and approved for the treatment of seizures. However, they are prescribed for conditions, including bipolar disorder, depression, anxiety, neuropathic and chronic pain, and migraine, among others. “Patients being treated with antiepileptic drugs for any indication should be monitored for the emer- gence of worsening of depression, suicidal thoughts, or behavior, or any unusual changes in mood or be- havior,” said Dr. Russell Katz, director of the division of neurology products in the FDA’s Center for

Drug Evaluation and Research, in a statement. “Symptoms such as anxiety, agitation, aggression, hostility, mania, and insomnia may be precursors to emerging suicidality,” the alert stated. Although physicians were encouraged to discuss the risks and benefits of continuing treatment, they were

also urged to warn patients and families against stop-

ping medications abruptly.

The FDA’s health care alert is available at


Drugs to Receive New Suicidality Labeling

T he Food and Drug Administration called for new labeling for these drugs, some of which

also are available in generic form:

Carbamazepine (marketed as Cabatrol, Equetro, Tegretol, Tegretol XR) Clonazepam (marketed as Klonopin) Clorazepate (marketed as Tranxene)

Divalproex sodium (marketed as Depakote, Depakote ER, Depakene) Ethosuximide (marketed as Zarontin) Ethotoin (marketed as Peganone) Felbamate (marketed as Felbatol) Gabapentin (marketed as Neurontin) Lamotrigine (marketed as Lamictal) Lacosamide (marketed as Vimpat) Levetiracetam (marketed as Keppra) Mephenytoin (marketed as Mesantoin) Methosuximide (marketed as Celontin) Oxcarbazepine (marketed as Trileptal) Phenytoin (marketed as Dilantin Suspension) Pregabalin (marketed as Lyrica) Primidone (marketed as Mysoline) Tiagabine (marketed as Gabitril) Topiramate (marketed as Topamax) Trimethadione (marketed as Tridione) Zonisamide (marketed as Zonegran)

High Incidence

Syndrome from page 1

comorbidities (see box) contribute to high mortality: Over a 3-year period, 39% of MDS patients died. This rate is even higher among patients whose MDS was caused by chemotherapy—63% over 3 years. Previous SEER estimates put the an- nual incidence of MDS at about 10,000 cases. But there is reason to believe that this is an underestimate, said Dr. Gold- berg, a hematologist/oncologist in group practice in Hackensack, N.J. “Until recently myelodysplasia was not considered to be a form of cancer, and therefore [was] not tracked by our registries,” Dr. Goldberg said. “The ma- jority of patients with myelodysplasia are elderly, if not very old. And many of these patients may not be referred for evaluation of their cytopenias. Further- more, if referred, they may not undergo diagnostic bone marrows, or if they un- dergo a diagnostic bone marrow, it may be done in primary care, and not re- ferred to the tumor registry. Thus, we think that the myelodysplastic syn-

dromes may be severely underestimated.” The study focused on the Medicare Standard Analytic File for 2003. Of more than 1.7 million Medicare patients in the sample, 5,594 had the diagnostic code for MDS, of which 3,078 were new cases. That translated to an age-adjusted incidence of 181 per 100,000 patients, or about 76,600 patients in the entire Medicare system. Of those patients, only 53% actually underwent diagnostic bone marrow studies. “Therefore, even if we exclude the clinical cases, we still have an inci- dence four times what the SEER project has suggested,” Dr. Goldberg said. Compared with the general Medicare population, patients with MDS were sig- nificantly older, with 72% of them aged 70 years or above compared with 57% of the general population. And they were more likely to be male (49% vs. 42%) and white (90% vs. 86%). Among patients with MDS, comor- bidities were more common in patients re- ceiving blood transfusions. Of patients receiving transfusions, 80% had cardiac complications, vs. 69% of the others. This was also true of new cases of diabetes (48% vs. 32%) and dyspnea (62% vs. 41%).

“These data give support to the use of chelation therapy to remove the iron [re- sulting from transfusions] so we don’t see the secondary comorbid problems,” Dr. Goldberg said. The average newly diagnosed case of MDS resulted in $28,023 in Medicare

payments in 2003, compared with $6,739 in the general Medicare population. Dr. Goldberg acknowledged serving on the speakers bureau of Novartis. The research was supported by Novar- tis and by Quorum Consulting Inc. in

San Francisco.

Comorbidities in MDS Patients at 3-Year Follow-Up

MDS patients General Medicare population 74% Cardiac complications 42% 51% Dyspnea 28% 43% Diabetes 33%
MDS patients
General Medicare population
Cardiac complications
Kidney complications

Note: Based on an analysis of data from a random sample of 1.7 million Medicare patients. Source: Dr. Goldberg