CHICAGO—Use of the herb Ginkgo biloba, claimed to have beneficial effects on memory and cognition, was not effective in reducing the rate of dementia or Alzheimer's disease among more than 1,500 elderly study participants after several years of use, according to a study in the November 19 issue of JAMA.
Dementia, especially Alzheimer's disease (AD), is a prevalent chronic disease currently affecting more than 5 million people in the United States and is a leading cause of age-related disability and long-term care placement, according to background information in the article. Ginkgo biloba is prescribed in some areas of the world for preservation of memory; however, there are no medications approved for prevention of dementia, and to date, no clinical trial of adequate design and size has evaluated the safety and effectiveness of Ginkgo biloba in the primary prevention of dementia.
Steven T. DeKosky, M.D., of the University of Pittsburgh, Pa., at the time of the study, and the Ginkgo Evaluation of Memory (GEM) Study Investigators, assessed the effectiveness of Ginkgo biloba in dementia prevention. The study was a randomized, placebo-controlled clinical trial conducted at five academic medical centers in the United States between 2000 and 2008 with a median (midpoint) follow-up of 6.1 years. The trial included 3,069 community volunteers age 75 years or older with normal cognition (n = 2,587) or mild cognitive impairment (MCI; n = 482) at study entry, who were assessed every 6 months for dementia. Participants were randomized to receive either a twice-daily dose of 120-mg extract of Ginkgo biloba (n = 1,545) or placebo (n = 1,524).
The researchers found that during the intervention period, 523 participants were diagnosed with dementia, 246 (16.1 percent) in the placebo group and 277 (17.9 percent) in the Ginkgo biloba group. Of the total dementia cases, 92 percent were classified as possible or probable AD, or AD with evidence of vascular disease of the brain. The rate of total dementia did not differ between participants assigned to Ginkgo biloba vs. placebo (3.3 dementia cases/100 persons, per year exposed, among persons randomized to Ginkgo biloba vs. 2.9/100 persons, per year exposed, among persons randomized to placebo). The rate of Alzheimer-type dementia also did not differ between the two treatment groups (3.0/100 persons, per year exposed vs. 2.6/100 persons, per year exposed). Ginkgo biloba also had no effect on the rate of progression to dementia in participants with MCI.
The adverse event profiles for Ginkgo biloba and placebo were similar and there were no statistically significant differences in the rate of serious adverse events.
"Based on the results of this trial, Ginkgo biloba cannot be recommended for the purpose of preventing dementia," the authors write.
"These results confirm that randomized trials remain critical to the spectrum of translational research necessary to develop new therapies and to determine whether the purported in-vitro, epidemiologic, and surrogate measures of therapeutic benefit are true not only for traditional pharmaceutical therapies but also for complementary therapies. Of almost equal importance from these results is the provision of a strong rationale for including older individuals in randomized trials testing promising interventions for preventing or delaying dementia onset."
(JAMA. 2008;300:2253-2262. Editor's Note: Dr. DeKosky is now with the University of Virginia School of Medicine, Charlottesville. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.
EDITORIAL: GINKGO BILOBA EXTRACT AND PREVENTING ALZHEIMER DISEASE
In an accompanying editorial, Lon S. Schneider, M.D., of the University of Southern California, Los Angeles, comments on the findings of DeKosky and colleagues.
"Despite 2 decades of research with standardized extracts of Ginkgo biloba, considerable uncertainty about its pharmacology and clinical effects remains. Preclinical scientific reports exude promise but generally have not identified the relevant active molecules of this biochemically complex extract, and the preclinical promise has not translated to clinical research benefits. The clinical research, in turn, has not adequately defined potential cognitive indications, potentially effective dosing ranges, pharmacodynamic markers, or convincing evidence for efficacy for any one cognitive condition. The GEM study adds to the substantial body of evidence that Ginkgo biloba extract as it is generally used does not prevent dementia in individuals with or without cognitive impairment and is not effective for Alzheimer disease."
(JAMA. 2008;300:2306-2308. Editor's Note: Please see the article for additional information, including financial disclosures, funding and support, etc.
WIDELY-USED CANCER DRUG ASSOCIATED WITH SIGNIFICANTLY INCREASED RISK OF BLOOD CLOTS
CHICAGO—An analysis of randomized controlled trials indicates that use of the cancer drug bevacizumab is associated with an increased risk of venous thromboembolism (blood clots in the deep veins of the legs or in the lungs), according to an article in the November 19 issue of JAMA.
Angiogenesis, a process involving the proliferation of new blood vessels, plays a crucial role in the growth and metastasis of cancer. Bevacizumab, a new, widely-used angiogenesis inhibitor, has shown benefits in the treatment of many types of malignancy including colorectal cancer, non-small cell lung cancer (NSCLC), renal cell cancer and breast cancer. Concerns have arisen regarding the use of bevacizumab and the risk of venous thromboembolism, one of the leading causes of illness and death in patients with cancer.
To determine the risk of venous thromboembolism associated with bevacizumab use, Shobha Rani Nalluri, M.D., of Stony Brook University, Stony Brook, N.Y., and colleagues conducted a meta-analysis of 15 randomized controlled trials (RCTs), which included a total of 7,956 patients with a variety of advanced solid tumors.
The researchers found that among patients receiving bevacizumab, the incidence of all-grade venous thromboembolism was 11.9 percent, and for high-grade venous thromboembolism, it was 6.3 percent. The risk of developing venous thromboembolism was 33 percent greater with bevacizumab than with controls. The risk was significantly increased for both all-grade and high-grade venous thromboembolism. Both high (5 mg/kg per week) and low (2.5 mg/kg per week) doses of bevacizumab were associated with a 31 percent increased risk of venous thromboembolism.
The incidence of all-grade venous thromboembolism with bevacizumab varied among different tumors. The highest incidence was observed among patients with colorectal cancer (19.1 percent); for patients with NSCLC, the incidence was 14.9 percent, while for patients with breast cancer, the incidence of all-grade venous thromboembolism was 7.3 percent. The lowest incidence was seen in patients with renal cancer at 3.0 percent.
"The association of venous thromboembolism with new agents presents a challenge for recognition because many RCTs may not be powered to reveal a significant relationship. Our meta-analysis of 15 RCTs has overcome this limitation of individual trials and demonstrated that bevacizumab may be associated with a significantly increased risk of venous thromboembolism in patients with a variety of metastatic solid tumors. The increased risk is observed not only for all-grade venous thromboembolism, but also for clinically significant high-grade venous thromboembolism. This finding will help physicians and patients to recognize the risk of venous thromboembolism with the administration of bevacizumab," the authors write.
(JAMA. 2008;300:2277-2285. Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.
STUDY DOCUMENTS WHAT MAY BE FIRST CASES OF CERTAIN TICK-BORNE DISEASE IN CHINA
CHICAGO—It appears that for the first time human granulocytic anaplasmosis (HGA), an emerging tick-borne infectious disease found in the U.S. and Europe, has been identified in China and apparently was transmitted from person to person, according to a study in the November 19 issue of JAMA.
HGA was recognized in the United States in 1990 and in Europe in 1997, with the annual number of infections reported in the U.S. steadily increasing. Data suggests that infection rates in endemic areas are as high as 15 percent to 36 percent, implying that the diagnosis is often missed or that infection is mild or asymptomatic, according to background information in the article. "Because epidemiological, clinical, and microbiological information about HGA is limited, the disease is likely underrecognized and underreported worldwide," the authors write.
Lijuan Zhang, M.D., Ph.D., of the National Institute of Communicable Disease Control and Prevention, China CDC, Beijing, and colleagues conducted a study to determine the origin and transmission of the apparent first cases of HGA acquired in China, as well as the first finding of human-to-human transmission. A cluster of cases among health care workers and family members following exposure to a patient with disease symptoms consistent with HGA prompted the investigation. Subsequent questioning of the patient's family revealed that she was bitten by a tick 12 days before onset of fever.
After exposure to the index patient (initial person with symptoms), whose fatal illness was characterized by fever and hemorrhage at a primary care hospital and regional tertiary care hospital's isolation ward, secondary cases (health care workers and family members) with fever who were suspected of being exposed were tested for antibodies against the bacteria Anaplasma phagocytophilum. Potential sources of exposure were investigated.
In a regional hospital of Anhui Province, China, between November 9 and 17, 2006, a cluster of nine patients with fever and other symptoms were diagnosed with HGA. No patients had tick bites. All nine patients had contact with the index patient within 12 hours of her death from suspected fatal HGA while she experienced extensive hemorrhage and underwent endotracheal intubation (the placement of a flexible plastic tube into the trachea for the purpose of ventilating the lungs). The patients indicated they were unlikely to have used gloves or wash after contact with the index patient.
Among the 28 individuals who reported close contact (20 inches or less) with the index patient during the final 12 hours of her life, nine were infected. The index patient was exposed to 20 contacts for more than 2 hours, and nine were infected. All nine infected patients reported contact with blood and seven had contact with respiratory secretions. Those persons with skin exposure to blood or respiratory secretions, or those with pre-existing skin lesions or injuries followed by exposure to blood were significantly more likely to be infected.
"The most remarkable aspect of these cases was that transmission was very unlikely to be tick-borne, but was closely associated with blood or respiratory secretion exposure from an index patient who died of a [sudden and severe] illness with hemorrhage," the authors write.
"Although it is likely that routine blood and body fluid precautions will protect against such future events, strict adherence to protective protocols is mandatory even if communicability is deemed unlikely. The lessons of this study remain relevant to the daily hospital and health care unit operations to prevent any additional [hospital] outbreaks of HGA. Moreover, as China advances into its future, it must also now become prepared to deal with the increasing threat that tick-borne rickettsial pathogens [parasitic bacteria that live in anthropods (as ticks and mites) and can cause disease if transmitted to human beings] have been already brought to the United States and Europe."
(JAMA. 2008;300:2263-2270. Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.
EDITORIAL: NOSOCOMIAL TRANSMISSION OF HUMAN GRANULOCYTIC ANAPLASMOSIS?
Peter J. Krause, M.D., of the Yale School of Medicine, New Haven, Conn., and Gary P. Wormser, M.D., of New York Medical College, Valhalla, N.Y., write that these findings provide a reminder regarding safety precautions against disease transmission.
"What is the significance of the investigation by Zhang et al? It may represent the first report of human-to-human transmission of A phagocytophilum and the first report of human HGA infection in China. This report certainly serves to reinforce the importance of adopting standard blood and body fluid precautions for all patients and especially for those with HGA; these precautions are the accepted standard of care in the United States. The report also should stimulate further investigation of the existence of A phagocytophilum in the region of China where this outbreak originated. In addition, it is essential to emphasize that fulfilling the case definition of HGA used for epidemiological surveillance in the United States does not provide diagnostic certainty, unless the diagnosis was established by the microbiological gold standard of culturing the microorganism. Therefore, the findings of the study by Zhang et al, while interesting and provocative, should be regarded as preliminary."
(JAMA. 2008;300:2308-2309. Available pre-embargo to the media at www.jamamedia.org)
Editor's Note: Please see the article for additional information, including financial disclosures, funding and support, etc.
FOR WOMEN WHO BECOME PREGNANT AFTER BARIATRIC SURGERY, RISK FOR SOME MATERNAL AND NEWBORN COMPLICATIONS MAY BE LOWER
CHICAGO—A review of previously published studies suggests that rates of adverse outcomes for mothers or pregnant women and newborn babies, such as gestational diabetes and low birth weight, may be lower after bariatric surgery compared with pregnant women who are obese, according to an article in the November 19 issue of JAMA.
"Obesity has reached epidemic levels in the United States and is a leading cause of health-related disorders. Rates of surgical weight loss procedures have grown steeply and women account for many of these patients. Large numbers of women in their childbearing years may undergo bariatric surgery, which may change fertility following weight loss, alter nutritional requirements during pregnancy, or impact contraception to prevent pregnancy," the authors write.
Melinda A. Maggard, M.D., M.S.H.S., of the Rand Corporation, Santa Monica, Calif., and colleagues conducted a review of articles on bariatric surgery among women of reproductive age to estimate the incidence of bariatric surgery among these women and to assess associations of bariatric surgery with pregnancy outcomes. The researchers identified 75 articles for inclusion in the review.
An analysis of the data indicated that the incidence of bariatric surgery in the U.S. increased by 800 percent between 1998 and 2005 (from 12,480 to 113,500 cases). Women accounted for 83 percent of procedures in the 18- to 45-year age group, and between 2003 and 2005, more than 50,000 women in this age group underwent inpatient bariatric surgery procedures annually (49 percent of all bariatric surgery cases). A review of several of the studies showed lower maternal complication rates after bariatric surgery than in obese women without bariatric surgery, or rates approaching those of nonobese controls. Gestational diabetes (0 percent vs. 22.1 percent) and preeclampsia (0 percent vs. 3.1 percent) were lower in the bariatric surgery group than in the obese comparison group. Maternal weight gain was reduced in the surgical group.
Newborn outcomes were similar or better after surgery compared with obese women without laparoscopic adjustable gastric band surgery (7.7 percent vs. 7.1 percent for premature delivery; 7.7 percent vs. 10.6 percent for low birth weight; 7.7 percent vs. 14.6 percent for macrosomia [overly large body]). No differences in these newborn outcomes were found after gastric bypass compared with nonobese controls.
"Research is needed to better delineate the extent to which surgery and subsequent weight loss improve fertility and pregnancy outcomes. Optimizing success for contraception and producing healthy neonates following surgery will require a multidisciplinary effort by surgeons, primary care physicians, reproductive fertility specialists, obstetricians, and patients," the authors conclude.
(JAMA. 2008;300:2286-2296. Also available: A more detailed review of this topic will be available after publication of the JAMA article at the Agency for Healthcare Research and Quality website: http://www.ahrq.gov/downloads/pub/evidence/pdf/bariatricrep/barirep.pdf
Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.
STUDY FINDS ASSOCIATION BETWEEN MALE BIRTH DEFECT AND CERTAIN GENETIC MUTATIONS
CHICAGO—A small percentage of males born with cryptorchidism (failure of one or both testicles to descend into the scrotum), the most frequent congenital birth defect in male children, are more likely to have genetic mutations, including for a syndrome that is a common genetic cause of infertility, according to a study in the November 19 issue of JAMA.
Cryptorchidism occurs in 2-4 percent of full-term male births. "Although cryptorchidism is often considered a mild malformation, it can seriously affect men's health, representing the best characterized risk factor for infertility and testicular cancer in adulthood," the authors write. The cause of cryptorchidism remains mostly unknown.
Alberto Ferlin, Ph.D., of the University of Padova, Italy, and colleagues conducted a study to examine the frequency of genetic alterations in cryptorchidism. The study included 600 male infants with cryptorchidism, who were followed up for 2 to 3 years (through January 2008), and 300 male children who did not have cryptorchidism as controls.
The researchers found that the overall frequency of genetic alterations in boys with cryptorchidism was low (17/600 [2.8 percent]) and was statistically significantly higher than controls, both among children with persistent (since before birth) cryptorchidism (16/303 [5.3 percent] vs. 1/300 [0.3 percent] in controls) and among those with bilateral (both testes) cryptorchidism (10/120 [8.3 percent]). Children with persistent cryptorchidism had 17 times the odds of having a genetic alteration; the odds were 27 times higher for boys with bilateral persistent cryptorchidism.
The most common genetic findings in those with cryptorchidism were eight cases of Klinefelter syndrome (a chromosome condition that is the most common genetic cause of male infertility) and five cases of mutations in the INSL3 receptor gene (a regulator of testicular descent). When considering birth weight and gestational age, genetic alterations were found exclusively in those with normal weight and gestational age.
"We found that chromosomal aberrations represent the most frequent genetic alteration in participants with isolated cryptorchidism, particularly in those with persistent cryptorchidism (1.6 percent in the unilateral forms and 4.2 percent in the bilateral forms), and that chromosomal alterations were exclusively represented by Klinefelter syndrome," the authors write.
"In this study, we found genetic alterations in a small percentage of boys with cryptorchidism. We found a significant association between bilateral and persistent cryptorchidism and genetic alterations, including mutations in the INSL3 receptor gene and Klinefelter syndrome. Genetic alterations were not found in participants with low birth weight or low gestational age …"
(JAMA. 2008;300:2271-2276. Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.