VO L . 4 2 , N O. 3

Internal Medicine News
www.inter nalmedicinenews.com T he Leading Inde p endent Ne wspaper for the Inter nist—Since 1968

F E B R UA RY 1 , 2 0 0 9



Breast Cancer Decline Linked to HT Cessation
New WHI data affirm hormonal link.


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

Denver Bureau

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

Genetics in Your Practice
Dr. Matthew R.G. Taylor looks at genome-wide association studies.

Mid-Atlantic Bureau

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 predicted 5 years ago that an antiamyloid disease-modifying therapy was imminent are now reevaluating that optimism—including the geneticist who first suggested the pathologic link between amyloid plaque deposition 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 precursor 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 antagonist, was the disappointment of 2007; tarenflurbil, a gammasecretase 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 getting 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 neither positive nor negative. At this point, the only thing we can See Amyloid page 20

S A N A N T O N I O — Two new statistical analyses of Women’s Health Initiative data persuasively 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-progestin menopausal hormone therapy, and not—as skeptics have argued—to less utilization of mammography. Academic fencing over causality aside, the practical takehome 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 previously recognized, and it swiftly declines after HT is discontinued, Dr. Rowan T. Chlebowski said at the San Antonio Breast Cancer Symposium. “The good news for women here is that the risk rapidly dissipated 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 prevention of cardiovascular disease See Breast Ca page 2

Myelodysplastic Syndrome ‘Severely Underestimated’
Tea Time
Regular consumption of hibiscus tea may help control blood pressure.

San Francisco Bureau

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

S A N F R A N C I S C O — Myelodysplastic syndrome is far more common than previous estimated, 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 million Medicare enrollees. Each year, there are about 76,000 new cases of myelodysplastic syndrome (MDS), according 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 National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program, Dr. Stuart L. Goldberg said at the annual meeting of the American Society of Hematology. The current analysis also showed that during a 3-year follow-up, newly diagnosed MDS patients were more likely than the general Medicare population to have cardiac complications, dyspnea, diabetes, and kidney complications. These See Syndrome page 6




Epilepsy Drug Warnings to Add Suicidal Ideation


The relative risk for suicidality was highest among patients 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 he Food and Drug Administration has directed physicians to inform patients taking anticon- psychiatric patients (8.5 suicidality reports per 1,000 pavulsant medications that the drugs have the po- tients receiving antiepileptic medications, compared with 5.7 per 1,000 for psychiatric patients taking placebo). tential to increase suicidal thoughts and behavior. Among epilepsy patients, 3.4 events per 1,000 were reFamilies and caregivers should also be notified of this risk so that they can be attuned to changes in behavior ported for those receiving antiepileptic medications, in patients receiving antiepileptic medications, accord- compared with 1.0 for those assigned to receive placebo. Four patients randomized to receive antiepileptic ing to the FDA’s alert for health care professionals. Based on an agency review of nearly 200 clinical tri- drugs committed suicide during the trials that were exals of 11 antiepileptic drugs, the directive coincided with amined by the FDA, while no patient assigned to placean FDA announcement that manufacturers of any bo took his or her own life. However, those numbers medication in the class will be required to add warn- were not high enough to justify a warning of suicide on drug labeling, the press release stated. ings about suicidal thoughts or behavior in “The biological reasons for the increase in prescribing information or labeling and to See related the risk for suicidal thoughts and behavior obdevelop medication guides for patients. commentary served in patients being treated with Revised labeling or an explanation “why antiepileptic drugs are unknown,” according they do not believe such labeling changes are on page 9. to the FDA. necessary” must be submitted to the agency A review article about suicidality and within 30 days. Jack Cox, a spokesman for Pfizer Inc., said in a tele- antiepileptic drugs noted that the baseline suicide rate phone interview his firm will comply with the order. among patients with epilepsy is 5 times higher than that “Pfizer will work closely with the FDA to update the la- seen in the general population, and higher still (25-fold) beling of our antiepileptic medications Lyrica [prega- in patients with temporal lobe epilepsy and complex balin] and Neurontin [gabapentin], in a timely manner.” partial seizures (Drug Saf. 2007;30:123-42). Although that article commented on antiepileptic “We have not heard directly from the FDA, but we will work to address any of the agency’s concerns,” said medications’ disparate mechanisms of action and varyTricia Geoghegan, a spokesperson for Ortho-McNeil ing effects on serotonin metabolism (a hypothesized Neurologics, makers of topiramate. Ms. Geoghegan link to suicidality), the FDA report found that the risk noted that the label for Topamax (topiramate) has al- for suicidal thought or behavior was “generally consisways included “content about this topic,” but added that tent” among the 11 drugs studied. As the name implies, antiepileptic drugs were introrevisions will be made should the FDA request them. The agency’s decision drew on data from placebo- duced and approved for the treatment of seizures. controlled clinical trials that enrolled a total of 43,892 However, they are prescribed for conditions, including patients aged 5 and older taking the medications for bipolar disorder, depression, anxiety, neuropathic and chronic pain, and migraine, among others. epilepsy, psychiatric disorders, and other conditions. “Patients being treated with antiepileptic drugs for The FDA meta-analytic review of 199 trials determined that patients receiving antiepileptic drugs were at any indication should be monitored for the emera twofold risk of suicidal behavior or thoughts (0.43%), gence of worsening of depression, suicidal thoughts, compared with patients receiving placebo (0.24%). The or behavior, or any unusual changes in mood or bedifference translates to 1 additional case of suicidality per havior,” said Dr. Russell Katz, director of the division of neurology products in the FDA’s Center for 530 patients treated with antiepileptic drugs.

Los Angeles Bureau

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 stopping medications abruptly. ■ The FDA’s health care alert is available at www.fda.gov/ cder/drug/InfoSheets/HCP/antiepileptics200812.htm.

Drugs to Receive New Suicidality Labeling
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 annual incidence of MDS at about 10,000 cases. But there is reason to believe that this is an underestimate, said Dr. Goldberg, 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 majority of patients with myelodysplasia are elderly, if not very old. And many of these patients may not be referred for evaluation of their cytopenias. Furthermore, if referred, they may not undergo diagnostic bone marrows, or if they undergo a diagnostic bone marrow, it may be done in primary care, and not referred 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 incidence four times what the SEER project has suggested,” Dr. Goldberg said. Compared with the general Medicare population, patients with MDS were significantly 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, comorbidities were more common in patients receiving 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 [resulting 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 Novartis and by Quorum Consulting Inc. in San Francisco. ■

Comorbidities in MDS Patients at 3-Year Follow-Up
MDS patients General Medicare population 74% 42% Dyspnea 51% 28% 43% 33% 1.8% 0.4%
Note: Based on an analysis of data from a random sample of 1.7 million Medicare patients. Source: Dr. Goldberg

Cardiac complications


Kidney complications