Latest Research

October 6, 2006

A summary of the "must-read" articles from the journals in that pile on your desk.

Myocardial Infarctions Drop After Colorado Smoking Ban

Pueblo's 2003 smoking ban may have prevented heart attacks by cutting secondhand smoke exposure

One and a half years after the city of Pueblo in Colorado initiated a smoking ban, hospitalizations for acute myocardial infarction had dropped by almost 25 percent, suggesting that reducing secondhand smoke exposure may prevent heart attacks, according to a report published online Sept. 25 in Circulation: Journal of the American Heart Association.

Carl Bartecchi, M.D., from the University of Colorado Health Sciences Center in Pueblo, and colleagues compared hospitalizations for acute myocardial infarction (AMI) 1.5 years before and 1.5 years after the city (population 103,648) implemented a smoke-free ordinance. Rates of AMI were also compared with those from outside the city limits and from a nearby El Paso County that does not have a smoking ban.

The investigators found that AMI hospitalizations were down in Pueblo city limit residents after the smoking ban (relative risk, 0.73) while a non-significant change was observed during the same time outside the city limits and among El Paso County residents.

While the study does prove the causal relationship between secondhand smoke and AMI, the authors note a similar decline was observed in a smaller study in Helena, Mont. "Taken together, we suggest that these data indicate a smoking ordinance may be a vehicle for reducing the burden of ischemic heart disease," the authors conclude.

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Early Statin Therapy for Cardiac Events Reduces Deaths

Benefits are evident between four and 12 months of treatment

In patients with acute coronary syndrome, early intensive use of statins can reduce death and cardiovascular events after four months of use, according to a study in the Sept. 25 issue of the Archives of Internal Medicine.

Eddie Hulten, M.D., M.P.H., of the Walter Reed Army Medical Center in Washington, D.C., and colleagues conducted a meta-analysis of 13 randomized, controlled trials involving 17,963 adults who were given statin therapy within 14 days of hospitalization for acute coronary syndrome.

The benefits in terms of reduced cardiovascular events, particularly cardiovascular death, unstable angina and revascularization, began to accrue between four and 12 months, and remained for up to two years. Over the course of two years' follow-up, there was an almost 20 percent reduction in adverse coronary events.

"There is no significant evidence that reduction in low-density lipoprotein cholesterol level explains these beneficial effects," the authors write. "The dosing regimen with the most evidence for beneficial effects to date is 80-mg atorvastatin, begun within 14 days of hospitalization for acute coronary syndrome. Our analysis was limited in its ability to explore the sources of heterogeneity in these data. We recommend that a pooled analysis using patient-level data be performed as soon as possible," they conclude.

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Menthol Cigarettes Harder to Quit, More Blacks Smoke Them

Non-menthol and menthol types equally harmful

Menthol cigarettes are harder to quit than their non-menthol counterparts, but both types carry the same risk of atherosclerosis and decline in pulmonary function, according to a study in the Sept. 25 issue of the Archives of Internal Medicine.

Mark J. Pletcher, M.D., M.P.H., of the University of California San Francisco, and colleagues conducted a study of 1,535 smokers, 972 of whom smoked menthol and 563 of whom smoked non-menthol cigarettes. Among the cohort, 89 percent of African Americans smoked menthol, compared with just 29 percent of European Americans.

In terms of pack-year of exposure, smokers of both types of cigarettes had similar odds of developing tobacco-related coronary calcification and had similar 10-year pulmonary function decline. Among menthol smokers, there was a significantly higher risk of relapse from attempts to stop smoking.

"The preference for mentholated cigarettes among U.S. smokers is highly associated with ethnicity and seems to be relatively stable across time," the authors write. "It is possible…that switching from menthol cigarettes to non-menthol cigarettes might facilitate subsequent smoking cessation, especially in African Americans, and thereby reduce tobacco-related health disparities," they conclude, adding that their research lends support to the policy goal of regulating tobacco additives and replacing tobacco with "clean" sources of nicotine.

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Cancer Risk Higher Among Japanese with Diabetes

Men especially at risk for cancer of liver, pancreas and kidneys

Japanese adults with diabetes mellitus, particularly men, are at increased risk of cancer, notably of the liver, pancreas and kidneys, according to the results of a study published in the Sept. 25 issue of the Archives of Internal Medicine.

Manami Inoue, M.D., Ph.D., of the National Cancer Center in Tokyo, Japan, and colleagues conducted a study among 97,771 adults in the general population, comprising 46,548 men and 51,223 women aged 40 to 69. They were enrolled in the Japan Public Health Center-Based Prospective Study from 1990 to 1994 and were followed up until the end of 2003 for cancer incidence.

During the course of the study there were 6,462 cases of newly diagnosed cancer, and among men with diabetes mellitus there was a 27 percent higher incidence of total cancers, with an especially high hazard ratio for liver, pancreas and kidney cancer. There was also a moderate increase among those with diabetes mellitus in incidence of colon cancer and stomach cancer, although the latter was of borderline significance.

Among women, the impact of diabetes mellitus on cancer risk was less pronounced, and was only of statistical significance for stomach and liver cancers.

"The remarkable increase in the diagnosis of diabetes mellitus in Japan in recent years may affect future trends in the incidence and type of cancer," the authors conclude.

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Many Docs Prescribing New Drugs Fail in Communication

While many physicians spell out new medication's goal, only a third explain possible ill-effects

Only about one-third of physicians prescribing new medications warn patients about possible adverse effects or advise how long to take it, researchers report in the Sept. 25 issue of the Archives of Internal Medicine.

Derjung M. Tarn, M.D., Ph.D., of the University of California Los Angeles, and colleagues used surveys and transcripts of audiotaped office visits to measure the quality of physician communication during 185 office visits involving 45 California health care providers who prescribed 243 new medications.

The researchers found that physicians carried out a mean of 3.1 of five expected communication tasks when prescribing new medication, including 3.7 for psychiatric, 3.5 for pulmonary and 3.4 for cardiovascular medication.

Physicians often explained a new medication's goal (87 percent), and said its name (74 percent), but less often outlined adverse effects (35 percent), how long to take it (34 percent), how many tablets to take (55 percent), how often or when (58 percent).

"When initiating new medications, physicians often fail to communicate critical elements of medication use," the authors write. "This might contribute to misunderstandings about medication directions of necessity and, in turn, lead to patient failure to take medications as directed."

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Trachoma Treatment Could Interrupt Course of Infection

Antibiotic treatment may interrupt time necessary for acquired immunity

The rise in trachoma reinfection suggests treatment could be interrupting the length of infection course necessary for developing immunity, thereby increasing disease prevalence, according to a paper in the Sept. 27 issue of the Journal of the American Medical Association.

Berna Atik, M.D., of the Children's Hospital Oakland Research Institute in Oakland, Calif., and colleagues performed a longitudinal study of 3,186 children in three Vietnamese communes — one participating in the surgery, antibiotics, facial cleanliness and environmental improvement (SAFE) strategy; another in the surgery and antibiotics (SA) strategy; and a third participating in surgery only. Chlamydial testing and disease grading were performed every six months for three years, while children in the first two communes with active trachoma and their household members were given azithromycin at baseline and a year later.

Reinfection rose significantly between 12 and 36 months for children in the SAFE and SA strategies, compared with those in the surgery-only commune after 24 months. The SAFE and SA groups had significantly higher reinfection risks at 36 months compared to the children in the surgery-only commune.

"It has been proposed that treatment for trachoma control must be continued indefinitely until underlying conditions are improved to prevent reintroduction of infection. Based on our findings, treatment appears to result in increased rates of reinfection that may adversely affect the prevalence of disease over time," the authors conclude.

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HIV RNA Levels Minimally Predictive for CD4 Decline

Other factors influence CD4 cell loss in untreated people

In untreated disease, plasma HIV RNA levels have only a minimally predictive value for CD4 cell decline rate, according to a report in the Sept. 27 issue of the Journal of the American Medical Association.

Benigno Rodriguez, M.D., of the Center for AIDS Research, Case Western Reserve University in Cleveland, and colleagues analyzed two HIV-infected cohorts. In one group, 1,289 patients were chronically infected and were antiretroviral treatment-naive; the other group had 1,512 such patients. Both groups were untreated for the six-month observation period.

Despite a trend toward higher CD4 cell loss with higher presenting HIV RNA levels, just a small proportion of CD4 cell loss variability was actually linked to plasma HIV RNA levels. Multiple measurements and restricting the analysis to patients with high HIV RNA levels improved the correlation minimally.

"The results of our study challenge the concept that CD4 cell depletion inchronic HIV infection is mostly attributable to the direct effects of HIV replication. Future efforts to delineate the relative contribution of other mechanisms will be crucial to the understanding of HIV immunopathogenesis and to the ability to attenuate it," the authors conclude.

AbstractFull Text (subscription or payment may be required)Editorial

New Models Better Predictors of Lynch Syndrome Mutations

Methodology accurately predicts at-risk individuals with more sensitivity and specificity

The PREMM model (Prediction of Mutations in MLH1 and MSH2) can accurately predict genetic-testing outcomes for those at risk for Lynch syndrome, while the MMRpro can be an accurate model for screening and genetic counseling for those at high risk for the syndrome who have no tumor samples, according to two papers in the Sept. 27 issue of the Journal of the American Medical Association.

Judith Balmana, M.D., of the Dana-Farber Cancer Institute in Boston, and colleagues found the PREMM1,2 model to be strongly predictive of mutations in 1,914 unrelated probands. The model analyzed two or more separate diagnoses of colorectal or endometrial cancer and family history — first-degree relatives with colorectal or endometrial cancer. Some authors in this study received honoraria from, or were employed by, Myriad Genetics Laboratories, Inc.

In the second study, Sining Chen, Ph.D., of the Johns Hopkins Bloomberg School of Public Health in Baltimore, and colleagues found the MMRpro model to be more sensitive and specific than current clinical guidelines in identifying at-risk individuals for Lynch syndrome who could benefit from MMR germline testing. The model estimated genetic parameters and specified a mutation-prediction and cancer-risk prediction.

"These prediction rules should form very useful tools for clinicians and their patients, as well as for epidemiologists who wish to assess both the magnitude of the hereditary non-polyposis colorectal cancer problem and the potential usefulness of preventive efforts," write James Ford, M.D., and Alice Whittemore, Ph.D., in an accompanying editorial.

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Type I Diabetics Often Relapse After Islet Transplant

Researchers find that most patients with good initial response need insulin again after two years

In patients with unstable type 1 diabetes, islet transplantation can restore endogenous insulin production and glycemic stability, but insulin independence is usually not sustainable, according to a report in the Sept. 28 issue of the New England Journal of Medicine.

A.M. James Shapiro, M.D., of the University of Alberta in Edmonton, Canada, and colleagues studied 36 transplant patients.

Sixteen (44 percent) of the subjects met the primary end point — insulin independence with adequate glycemic control one year after the final transplantation. Ten (28 percent) had partial function and 10 (28 percent) had complete graft loss. Although 21 subjects (58 percent) attained insulin independence with good glycemic control during the trial, 16 of them (76 percent) required insulin again after two years.

"Islet transplantation is at a crossroads," state the authors of an accompanying editorial. "It is clear that poor long-term results, high costs, and the relatively high incidence of major and minor serious adverse events make it difficult to argue for expansion of islet transplantation to the general population. Nonetheless, the dramatic discoveries and successful dissemination of information in a relatively short period encourage us to believe these advances will continue apace."

Immunosuppressive agents used in the study were provided by Astellas, Wyeth and Roche, which also provided grants and other compensation to some authors.

AbstractFull Text (subscription or payment may be required)Editorial

Transfusions Can Transmit Human Herpesvirus 8

High rate of seroconversion observed in Uganda, but study's relevance may be different in the United States

The Kaposi's sarcoma-associated virus, human herpesvirus 8 (HHV-8), is transmissible by blood transfusion, according to the results of a study published in the Sept. 28 issue of the New England Journal of Medicine.

Wolfgang Hladik, M.D., of the Global Acquired Immunodeficiency Syndrome Program in Entebbe, Uganda, and colleagues studied 1,811 Ugandan patients who received blood transfusions between December 2000 and October 2001.

Of the 991 patients who were HHV-8-seronegative before transfusion, 43 percent received HHV-8-seropositive blood and 57 percent received seronegative blood. The researchers found that HHV-8 seroconversion occurred in 41 patients. They also found that blood units stored for four days or less were more often associated with seroconversion than those stored for more than four days (excess risk, 4.2 percent).

"The relevance of our findings with respect to the U.S. blood supply may be different from that in Uganda, since the seroprevalence of HHV-8 among blood donors in the United States is low (3.5 percent)," the authors conclude. "Most blood products in the United States are leukocyte reduced, but the efficacy of this technique for reducing the risk of HHV-8 infection has not been evaluated. The risk of transfusion-associated Kaposi's sarcoma would be highest among HIV-infected and other immunocompromised recipients. Selective screening of blood products for immunocompromised populations may be warranted if this approach is found to be effective."

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Sentinel-Node Biopsy Can Improve Melanoma Survival

Staging procedure improves survival in patients with an intermediate-thickness primary melanoma

In patients with newly diagnosed melanoma, sentinel-node biopsy provides important prognostic information and identifies patients with nodal metastases whose survival can be prolonged by immediate lymphadenectomy, according to a study in the Sept. 28 issue of the New England Journal of Medicine.

Donald L. Morton, M.D., of the John Wayne Cancer Institute at Saint John's Health Center in Santa Monica, Calif., and colleagues randomly assigned 1,347 patients to either wide excision and sentinel-node biopsy with immediate lymphadenectomy if nodal micrometastases were detected on biopsy, or postoperative observation of regional lymph nodes with lymphadenectomy if nodal relapse occurred.

Among 1,269 patients with an intermediate-thickness primary melanoma, the researchers found a higher five-year disease-free survival rate in the biopsy group compared to the observation group (78.3 percent versus 73.1 percent). Among patients with nodal metastases, the researchers also found a higher five-year survival in those who underwent immediate lymphadenectomy than among those in whom lymphadenectomy was delayed (72.3 percent versus 52.4 percent).

"The results of the study by Morton et al. convincingly show that sentinel-node biopsy is a standard-of-care staging procedure and is justified in patients with melanoma with tumor thicknesses of 1.2 to 3.5 mm who have a sufficient risk of nodal metastases," state the authors of an accompanying editorial.

AbstractFull Text (subscription or payment may be required)Editorial

Pepcid May Help Treat Chronic Heart Failure

Famotidine improves both cardiac symptoms and ventricular remodeling

Famotidine (Pepcid), the over-the-counter medication for the treatment of heartburn and acid reflux, reduces both cardiac symptoms and ventricular remodeling associated with chronic heart failure, according to a study published online Sept. 25 in the Journal of the American College of Cardiology.

To test the hypothesis that a blockade of histamine H2 receptors could be of benefit in treating chronic heart failure patients, Masafumi Kitakaze, M.D., Ph.D., of the National Cardiovascular Center in Suita, Japan, and colleagues conducted a prospective study of 50 chronic heart failure patients randomized to receive 30 mg/day of famotidine or teprenone for six months.

Those in the famotidine group had decreased New York Heart Association functional class and plasma B-type natriuretic peptide levels. This reflected decreased left ventricular end-diastolic and end-systolic lengths (LVDd and LVDs, respectively) with unaltered fractional shortening.

The authors are cautiously optimistic about their findings. "Now we need to conduct a large-scale trial to confirm the present findings," said Kitakaze in a statement. "The large-scale trial based on the results [of] our present research may not help current heart failure patients because it takes time, but we hope it helps our children and grandchildren and others in the future."

AbstractFull Text (subscription or payment may be required)Editorial

Nonallergic Asthma Linked to Obesity in Adults

Highest prevalence seen in women

Higher body mass index is associated with a higher risk of asthma, and the relationship is strongest in nonallergic women with asthma, according to a study in the September issue of Chest.

Yue Chen, Ph.D., of the University of Ottawa, Ontario, Canada, and colleagues analyzed self-reported data from a national survey of 86,144 Canadians aged 20 to 64 years who had physician-diagnosed asthma. Respondents answered questions about weight, allergies, and smoking. The incidence of asthma was determined by body mass index, age, and allergy history separately for men and women.

The risk of obesity associated with asthma was stronger in women (adjusted odds ratio, 1.85) than men (adjusted odds ratio, 1.21). For each unit increase in body mass index, nonallergic women had a 7.1 percent increase, allergic women had a 4 percent increase, nonallergic men had a 3.4 percent increase and allergic men had a 2.4 percent increase in asthma risk. Women without allergies had a greater risk of obesity-related asthma than allergic women (adjusted odds ratio of 2.53 and 1.57 respectively), as did men (1.30 and 1.18 respectively).

"Our study demonstrated that obesity associated with asthma was modified by sex and history of allergy. A stronger association was found in women than in men, and in those with no allergy history than in those with allergy history," the authors concluded.

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Sleep Apnea Risk May Be More Common Than Thought

National Sleep Foundation survey suggests 31 percent of men and 21 percent of women at risk

The risk for obstructive sleep apnea in American adults could be as high as 26 percent, a much higher incidence than has been previously estimated, according to a study in the September issue of Chest.

David M. Hiestand, M.D., of the University of Kentucky College of Medicine in Lexington, and colleagues analyzed data from the 2005 National Sleep Foundation's (NSF) sample poll of 1,506 U.S. adults. The data set included responses to questions about snoring, apnea, and daytime sleepiness. Body mass index was also calculated.

Twenty-six percent of respondents met criteria for a high risk of obstructive sleep apnea. These findings are striking because the well-known 1993 Wisconsin Sleep Cohort Study suggested only 4 percent of men and 2 percent of women met the criteria for obstructive sleep apnea. In the NSF study, obesity was correlated with a high risk (57 percent) for sleep apnea along with self-reported sleep problems and chronic disease.

"The 2005 NSF poll indicates that one in four Americans is at high risk for obstructive sleep apnea, with increasing risk up to the age of 65 years. Considering the serious adverse health and quality-of-life consequences of sleep-disordered breathing, efforts to expedite diagnosis and treatment are urgently needed," the authors concluded.

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Inhaled Corticosteroids Reduce COPD Short-Term Mortality

Mortality rates lower for corticosteroid use compared with bronchodilators

Recent exposure to inhaled corticosteroids reduces mortality in patients with chronic obstructive pulmonary disease (COPD), according to a report in the September issue of Chest.

Nicholas R. Anthonisen, M.D., Ph.D., and colleagues from the University of Manitoba in Winnipeg, Canada, compared mortality rates 90 to 365 days after patients with COPD were discharged from a hospital after being treated with or without inhaled corticosteroids.

Patients older than 65 years treated with corticosteroids showed a 25 percent reduction in mortality compared with untreated patients, and an even larger reduction was found in patients between 35 and 64 years, the researchers found. Reduced mortality was largely due to a reduction in cardiovascular-related deaths. Patients receiving bronchodilators alone suffered higher mortality rates than those receiving no bronchodilators or bronchodilators in combination with corticosteroids. The protective effect from corticosteroids was dependent on recent exposure (within 30 days).

"The findings from this study are intriguing for clinicians and point to the need for further research to define the role and mechanisms of the effect of inhaled corticosteroids on both cardiovascular and respiratory mortality," W. Michael Alberts, M.D., F.C.C.P., President of the American College of Chest Physicians, said in a prepared statement.

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Non-Cancerous Lesions Linked to Higher Lung Cancer Risk

Smokers, older subjects and men have more non-malignant conditions

Certain non-cancerous conditions apparent on chest X-rays are linked to an increased risk for lung cancer and mortality, according to a study published in the September issue of Chest.

Paul F. Pinsky, Ph.D., of the National Institutes of Health in Bethesda, Md., and colleagues reported the mortality and cancer rates of more than 70,000 subjects enrolled in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Researchers analyzed non-cancerous lesions and lesions suspicious for lung cancer.

Non-suspicious lesions were seen in 35 percent of X-rays and suspicious lesions were seen in 8 percent. At 10.7 percent, granulomas were the most prevalent non-malignant lesions and carried no extra risk for lung cancer or mortality. Chronic obstructive pulmonary disease, heart abnormalities and pulmonary fibrosis were, however, associated with an increased risk for lung cancer and mortality. Smokers, older subjects and men had more non-malignant conditions.

"Several abnormalities commonly identified on chest X-rays convey excess risk for lung cancer incidence and for premature death from respiratory or cardiovascular diseases," the authors write. "Surveillance and treatment of these abnormalities may therefore be clinically important."

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Angioplasty is Cost-Effective Alternative to Bypass

Better techniques mean cost benefits of angioplasty sustained over long-term

In men at high risk of death from heart bypass surgery, percutaneous coronary intervention is just as effective and has significant cost benefits that are sustained even after five years, according to a study published online Sept. 11 in Circulation: Journal of the American Heart Association.

Kevin T. Stroupe, Ph.D., of Northwestern University in Chicago, and colleagues conducted a cost analysis of 454 patients at 16 Department of Veterans Affairs medical centers, of whom 218 underwent percutaneous coronary intervention and 227 had coronary artery bypass grafting surgery.

At the three-year mark, there was a $20,468 cost differential between percutaneous procedures ($63,896) and bypass surgery ($84,364). Survival rates were essentially the same — 0.82 for percutaneous procedures versus 0.79 for bypass patients. After five years, percutaneous interventions became more cost-effective. While the cost differential was slightly narrower (a difference of $18,732; $81,790 for percutaneous, $100,522 for bypass), five-year survival for percutaneous patients was 0.75 compared with 0.70 for CABG patients.

Over time "angioplasty techniques have improved and patients are getting stents, which help prevent the arteries from closing up again," said Stroupe in a statement. While drug-eluting stents add to the initial cost, this "is likely to be less than the gap between angioplasty and bypass surgery that was found after five years," he added.

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Two Markers a Sign of Risk in Acute Coronary Syndrome

High levels of two chemicals should flag patients for more aggressive treatment

High levels of two biomarkers — troponin-T and N-terminal pro-B-type natriuretic peptide (NT-proBNP) — can help in the process of risk stratification for patients with non-ST-segment elevation acute coronary syndromes (ACS), according to a study published in the Sept. 19 issue of the Journal of the American College of Cardiology.

Stefan K. James, M.D., Ph.D., of the Academic Hospital, Uppsala, Sweden, and colleagues analyzed data on 2,340 patients with non-ST-segment elevation ACS who underwent coronary revascularization. Among 30-day survivors of the procedure, one-year mortality was calculated and stratified by levels of biomarkers as well as by status of revascularization.

There was an association between elevated levels of troponin-T or NT-proBNP biomarkers and high mortality. However, when one or both of the biomarkers were elevated, there was a lower rate of mortality following revascularization, suggesting a greater benefit for such patients. Those without elevated levels of the two markers had relatively low one-year mortality and no reduction in risk after revascularization. Such patients actually had a significant increase in one-year mortality after revascularization.

"In centers where early revascularization can be performed with low procedural mortality, patients with elevated levels of both markers are at high risk of death that appears to be reduced by coronary revascularization," the authors concluded. "Measurement of troponin-T and NT-pro-BNP levels should be included in risk stratification and early management strategy decisions for patients with ACS."

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I.V. Iron Sucrose Helps Heart Failure-Related Anemia

It boosts exercise capacity and reduces symptoms in chronic heart failure patients

In patients with chronic heart failure (CHF), intravenous iron sucrose alone is a safe and effective treatment for anemia, even without costly concomitant erythropoietin, according to a study in the Sept. 19 issue of the Journal of the American College of Cardiology.

Aidan P. Bolger, B.Sc., M.R.C.P., of The Heart Hospital in London, U.K., and colleagues conducted a small study of 16 patients with stable CHF and anemia. Over a 12-day course of outpatient treatment, they each received a maximum of 1 gram of iron sucrose by bolus intravenous injections and were followed up for a mean of 92 days.

Hemoglobin (Hb) levels rose during the course of the study, from an average 11.2 to 12.6 g/dL. The patients recorded positive improvements in their Minnesota Living with Heart Failure score, which fell from an average 33 to 19. The distance they were able to walk in six minutes rose from an average 242 m to 286 m, and changes in these two scores correlated with changes in Hb. None of the subjects experienced adverse events due to the treatment.

"Intravenous iron sucrose, when used without concomitant erythropoietin, is a simple and safe therapy that increases Hb, reduces symptoms and improves exercise capacity in anemic patients with CHF," the authors write. "Further assessment of its efficacy should be made in a multi-center, randomized, placebo-controlled trial."

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Pressure Therapy Boosts Excercise Time in Heart Failure

Editorial suggests results of study may be due to placebo effect

Enhanced external counterpulsation (EECP) improves exercise tolerance in patients with chronic heart failure, according to results of the PEECH (Prospective Evaluation of Enhanced External Counterpulsation in Congestive Heart Failure) trial published in the Sept. 19 Journal of the American College of Cardiology.

Arthur M. Feldman, M.D., of Jefferson Medical College in Philadelphia, and colleagues randomized 187 patients with heart failure to standard pharmacologic therapy with or without 35 one-hour sessions of EECP. EECP involves sequential upward inflation of pneumatic cuffs around the lower extremities at the onset of diastole and rapid release before the onset of systole.

At six months, 35 percent of subjects receiving EECP increased exercise time by 60 seconds or more compared with 25 percent of the control subjects. EECP also improved New York Heart Association functional class and quality of life measurements compared with controls.

In an accompanying editorial, Stephen S. Gottlieb, M.D., from the University of Maryland in Baltimore, and a colleague suggest the modest "training effect" seen in the PEECH study is largely due to a placebo effect, especially because no change in oxygen consumption was observed in the EECP group. The added time the EECP group spent receiving treatment might have influenced patient outcome.

The study was supported by Vasomedical, Inc., and some of the authors have received compensation or are employees of the company which designs EECP systems.

AbstractFull Text (subscription or payment may be required)Editorial

Exercise Test Assesses Risk in Congenital Heart Disease

Blunted heart rate increase during exercise signals increased risk

Exercise testing can identify a subpopulation of patients with adult congenital heart disease (ACHD) that are at increased risk for death, according to a report in the Sept. 19 Journal of the American College of Cardiology.

Michael A. Gatzoulis, M.D., Ph.D., of Royal Brompton Hospital in London, U.K., and colleagues asked whether chronotropic incompetence — a blunted increase in heart rate during exercise — can predict mortality in ACHD patients as it does for patients with acquired heart disease.

Lower values for heart rate reserve, peak heart rate, heart rate recovery after exercise and peak oxygen consumption were predictive of higher mortality in 727 ACHD patients tested. In addition, heart rate reserve in combination with peak oxygen consumption identified a subpopulation with a 3.8-fold increase in mortality.

The development of risk stratification methods for ACHD such as exercise testing will help direct resources to those at the greatest risk, the authors suggest. "Exercise testing should be considered as part of the routine assessment of adults with congenital heart disease," they conclude.

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Acupuncture Has Small Benefit for Low Back Pain

Treatment is cost effective in the longer term

A short course of acupuncture has a small benefit for the treatment of low back pain and is cost effective in the longer term, according to two studies published online Sept. 15 in BMJ.

In the first study, Hugh MacPherson, Ph.D., from the University of York in the U.K., and colleagues randomized 241 patients aged 18 to 65 years with non-specific low back pain to either 10 acupuncture treatments (160 patients) or usual care (81 patients). The research team found that acupuncture caused a small improvement in pain scores, which was strongest after 24 months.

In the second study, members of the same group performed a cost-benefit analysis of acupuncture on the same set of patients. They found that the cost of acupuncture was higher, at a cost of about $864, versus $648 for usual care during the two-year study. However, the cost per quality-adjusted life year gained was about $7,969, which they note is below the nearly $38,000 threshold used in the United Kingdom to determine whether a health technology is affordable.

"Referral to a qualified traditional acupuncturist for a short course of treatment seems safe and acceptable to patients with low back pain," the researchers conclude of the first study. Of the second study, the team concludes that "acupuncture care for low back pain seems to be cost effective in the longer term."

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Sleep-Related Breathing Disorder Associated with Depression

Risk of depression roughly twice as high as those without sleep apnea

Patients who have even minimal sleep-related breathing disorder have at least a 1.6-fold increase in the risk of depression, according to a study in the Sept. 18 issue of the Archives of Internal Medicine.

Paul E. Peppard, Ph.D., and colleagues of the University of Wisconsin-Madison assessed 1,408 adults for sleep-related breathing using polysomnography (the apnea-hypopnea index) and depression using the Zung depression scale. Participants were evaluated every four years and collectively completed 3,202 sleep studies.

Compared with patients without sleep-related breathing problems, the risk of depression increased as the frequency of apnea episodes increased. The odds of depression increased 1.6-fold in those with minimal sleep-related breathing disorder (apnea-hypopnea index between 0 and 5) to 2.6-fold in those with moderate or worse sleep-related breathing (apnea-hypopnea index of 15 or more).

"Our longitudinal findings of a dose-response association between sleep-related breathing disorder and depression provide evidence consistent with a causal link between these conditions and should heighten clinical suspicion of depression in patients with sleep-related breathing disorder," Peppard and colleagues conclude.

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Sleep Problems Linked to Poor Diabetes Control in Blacks

Glycemic control poor in black patients with too little sleep, low sleep quality

Too little sleep and low sleep quality are associated with poor glycemic control in black patients with type 2 diabetes, according to a study in the Sept. 18 issue of the Archives of Internal Medicine.

Kristen L. Knutson, Ph.D., of the University of Chicago in Illinois, and colleagues examined the association between glycemic control (through hemoglobin A1c levels) and sleep duration and quality (through the Pittsburgh Sleep Quality Index) in 161 black patients with type 2 diabetes. They also determined the perceived sleep debt, which was the difference between the preferred and actual amount of weekday sleep.

The researchers found that the mean sleep duration was 6.0 hours, with 71 percent of patients having poor quality sleep. Hemoglobin A1c levels were associated with perceived sleep debt in those with no diabetic complications, while hemoglobin A1c levels were associated with sleep quality in those with at least one complication.

"The present study identifies sleep as a potential factor influencing glucose control in a specific population of patients with type 2 diabetes," Knutson and colleagues conclude. "Additional research is needed to determine whether optimizing sleep duration and quality may improve glucose control in patients with type 2 diabetes."

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More Than 1.6 Million Use Therapy for Insomnia

Insomnia linked to obesity, depression, congestive heart failure

More than 1.6 million U.S. adults use alternative medicine to treat their insomnia or sleep troubles, with a strong association between insomnia and chronic health conditions such as depression, according to a study in the Sept. 18 issue of the Archives of Internal Medicine.

Nancy J. Pearson, Ph.D., and colleagues from the National Institutes of Health in Bethesda, Md., examined the prevalence of insomnia in adults and the use of complementary and alternative medicine therapies using data from the 2002 National Health Interview Survey.

The researchers found that 17.4 percent of respondents had insomnia or trouble sleeping over a one-year period, with 4.5 percent of these reporting use of an alternative therapy as treatment. There was a strong association between insomnia or trouble sleeping and chronic health conditions including anxiety or depression (odds ratio 5.64), congestive heart failure (OR, 2.24), hypertension (OR, 1.32) and obesity (OR, 1.15), but not diabetes.

"According to the National Health Interview Survey analysis, over 1.6 million civilian, non-institutionalized adult U.S. citizens use complementary and alternative medicine to treat insomnia or trouble sleeping," Pearson and colleagues write. "Our data justify further research on the efficacy of these complementary and alternative medicine therapies."

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Allergic Rhinitis Interferes with Sleep

Patients with severe allergic rhinitis have more sleep problems than those with milder forms

Allergic rhinitis hinders the quality of sleep, and patients with more severe forms of rhinitis have more sleep disturbances than those with milder forms, researchers report in the Sept. 18 issue of the Archives of Internal Medicine.

Damien Leger, M.D., of Assistance Publique Hopitaux de Paris in France, and colleagues studied sleep patterns and allergic rhinitis in 591 patients being treated by 260 allergy and ear, nose and throat specialists across France. The patients had the condition for at least a year.

The researchers found that allergic rhinitis interferes with all aspects of sleep. Patients with severe allergic rhinitis had more sleep problems than patients with mild allergic rhinitis. Sleep was equally affected, whether allergic rhinitis was intermittent or persistent.

"These data underline the close relationship between allergic rhinitis and sleep and highlight the need for clinicians, particularly general practitioners, to be attentive in this respect," the authors conclude.

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Fetal Survival in Preeclampsia Improves Over Decades

Aggressive obstetric management of preeclampsia may lead to fewer fetal deaths

Since the late 1960s, fetal survival following a preeclamptic pregnancy has dramatically increased because of improved medical management, according to a Norwegian study published in the Sept. 20 issue of the Journal of the American Medical Association.

Olga Basso, Ph.D., of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., and colleagues analyzed 1967-2003 data on 770,613 Norwegian pregnancies without preeclampsia and 33,835 pregnancies complicated by preeclampsia.

Among preeclamptic pregnancies, the researchers found that inductions before 37 weeks of gestation increased from 8 percent in 1967-1978 to nearly 20 percent in 1991-2003. Between the two time periods, neonatal deaths in all infants born before 34 weeks of gestation declined from more than 25 percent to 5 percent. The researchers also found that the adjusted odds ratio for stillbirth decreased from 4.2 in 1967-1978 to 1.3 in 1991-2003 for preeclamptic compared with non-preeclamptic pregnancies and that the odds ratio for neonatal death after preeclamptic pregnancy remained relatively stable (1.7 in 1967-1978 versus 2.0 in 1991-2003).

"This stability in neonatal risk is remarkable, considering the increasing number of very preterm deliveries in recent years resulting from aggressive obstetric management of preeclampsia," the authors conclude. "Modern medical management of preeclampsia appears to have been effective in preventing fetal death without causing an increase in infant or maternal death."

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Fatty Fish May Lower Women's Risk of Kidney Cancer

Swedish study finds that a fatty fish-rich diet is associated with an up to 74 percent lower risk

Women who consume a diet rich in fatty fish such as salmon, herring, sardines and mackerel may have a significantly lower risk of renal cell carcinoma than women who consume little or no fish, according to a study published in the Sept. 20 issue of the Journal of the American Medical Association.

Alicja Wolk, D.M.Sc., of the Karolinska Institute in Stockholm, Sweden, and colleagues studied 61,433 Swedish women aged 40 to 76 years who were cancer-free at baseline (March 1987 to December 1990).

After a mean 15.3 years of follow-up, there were a total of 150 cases of renal cell carcinoma. After adjusting for potential confounders, the researchers found an inverse association between fatty fish consumption and renal cell carcinoma, but found no such association with lean fish consumption. For women who ate fatty fish at least once a week, the multivariate rate ratio was 0.56 compared to women who reported no fish consumption. For women who consistently reported fatty fish consumption, the multivariate rate ratio was 0.26 compared to women who reported no fish consumption.

"Our results support the hypothesis that frequent consumption of fatty fish may lower the risk of renal cell carcinoma possibly due to increased intake of fish oil rich in eicosapentaenoic acid and docosahexaneoic acid as well as vitamin D," the authors write. "Our results, however, require confirmation because this is the first epidemiological study addressing this issue."

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Lipoprotein(a) May Predict Cardiovascular Events

Women with the highest levels found to have 1.47 times the risk as those with lowest levels

Women with levels of lipoprotein(a) in the 90th percentile or higher, especially those who also have elevated low-density lipoprotein cholesterol (LDL-C), are at increased risk of myocardial infarction and strokes, according to a study published in the Sept. 20 issue of the Journal of the American Medical Association.

Jacqueline Suk Danik, M.D., M.P.H., of Brigham and Women's Hospital in Boston, and colleagues followed 27,791 initially healthy women for up to 10 years.

The researchers identified 899 incident cardiovascular events. After adjusting for potential confounders, they found that women in the highest quintile of lipoprotein(a) (at least 44 mg/dL) were 1.47 times more likely to develop cardiovascular events than women in the lowest quintile (3.4 mg/dL or less). But they determined that this finding was almost exclusively driven by extremely elevated lipoprotein(a) levels among subjects with LDL-C levels above the median.

"While of pathophysiological interest, we do not believe our data support generalized screening of lipoprotein(a) in the population as a whole because only extremely high levels were associated with cardiovascular risk," the authors write. "Determination of lipoprotein(a) levels should thus be reserved for high-risk subsets of the population such as individuals with premature myocardial infarction who have otherwise normal risk profiles or are at particularly high risk because of circumstances such as familial hypercholesteremia."

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New Reviews Shed Light on Vioxx Cardiovascular Risks

Same risks not seen with other cox-2 inhibitors, including Celebrex

Two new meta-analyses confirm that the cyclooxygenase-2 inhibitor rofecoxib (Vioxx) is indeed associated with an increased risk of cardiovascular problems, renal events, and arrhythmia, but similar risks were not seen with other cox-2 inhibitors, including celecoxib (Celebrex). The findings were released early online Sept. 12 in Journal of the American Medical Association.

In the first study, David Henry, M.B. Ch.B., and Patricia McGettigan, M.D., from the University of Newcastle in New South Wales, Australia, performed a review and meta-analysis of 23 studies examining cardiovascular risks and use of non-steroidal anti-inflammatory drugs or cox-2 inhibitors. They found an elevated risk with the use of rofecoxib (relative risk 1.33 or 2.19, depending on dose) and diclofenac (RR 1.4), but no increased risk with celecoxib, naproxen, piroxicam, and ibuprofen.

In the second study, Eric L. Ding, B.A., and colleagues from Harvard University in Boston, performed a meta-analysis of 114 studies examining the risk of renal events and arrhythmia after treatment with selective cox-2 inhibitors. They found that only rofecoxib was associated with an increased risk of arrhythmia (RR 2.90) and composite renal events (RR 1.53), while celecoxib was associated with a decreased risk of renal dysfunction (RR 0.61) and hypertension (RR 0.83).

The findings suggest that Vioxx increases the risk of acute myocardial infarction at either low or high doses, and that Celebrex does so at high doses (above 200 mg/d), with the risk at low doses unclear. "For most patients with arthritis or other conditions who require chronic pain relief, naproxen appears to be the safest NSAID choice from a cardiovascular perspective," according to an editorial by David J. Graham, M.D. M.P.H., of the U.S. Food and Drug Administration in Silver Spring, Md. "For patients at high risk of NSAID-related gastrointestinal tract complications, naproxen plus a proton pump inhibitor is less costly and as effective, and probably safer, than low-dose celecoxib."

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Program Does Encourage Pediatric Drug Studies

FDA 'pediatric exclusivity' program grants extension of drug marketing rights

The U.S. Food and Drug Administration's "pediatric exclusivity" program, whereby companies are granted a six-month extension of marketing rights for performing drug studies on children, has been successful, although only about half of studies are eventually published, according to a study in the Sept. 13 issue of Journal of the American Medical Association.

Daniel K. Benjamin, M.D. Ph.D. M.P.H., from the Duke Clinical Research Institute in Durham, N.C., and colleagues identified clinical trials conducted between 1998 and 2004 for pediatric exclusivity.

The researchers identified 253 trials that were submitted to the FDA. Half of the studies examined efficacy, 33 percent were single- or multiple-dose pharmacokinetic studies, and 17 percent were safety studies. Half of the studies resulted in positive labeling changes, the researchers found. However, only 45 percent of the studies were eventually published, with studies examining efficacy or resulting in positive labeling changes more likely to be published.

"The pediatric exclusivity program has been successful in encouraging drug studies in children," Benjamin and colleagues concluded. "However, the dissemination of these results in the peer-reviewed literature is limited."

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Waiting to Treat Otitis Media Cuts Down on Antibiotic Use

Substantial reduction in antibiotics as patients try painkillers first

It is possible to substantially reduce antibiotic use among pediatric patients with acute otitis media by adopting a wait-and-see prescription (WASP) approach, according to a study published in the Sept. 13 issue of the Journal of the American Medical Association.

David M. Spiro M.D., M.P.H., formerly of Yale University School of Medicine, New Haven, Conn., and colleagues randomized 283 patients aged six months to 12 years with acute otitis media into two groups: One received a standard prescription of antibiotics (145 patients), and the other received a WASP for antibiotics (138 patients). Ibuprofen and otic analgesic drops were prescribed to both groups.

Among the WASP group, 62 percent did not fill the prescription for antibiotics, compared with 13 percent in the standard prescription group. However, the two groups experienced similar outcomes in terms of fever, otalgia and unscheduled visits for medical treatment.

"The WASP approach may interrupt the cycle of antibiotic prescription, the expectation of parents to immediately treat acute otitis media with an antibiotic, and subsequent medical visits for this illness," the authors concluded.

In an accompanying editorial Paul Little, M.B.B.S., M.D., F.R.C.G.P., of the University of Southampton, Southampton, U.K., writes that delayed prescribing should be acceptable as long as parents are "given clear information about the timing of antibiotic use and specific guidelines for signs and symptoms that should trigger reassessment."

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Syncope Boosts Cardiac Arrest Risk in Long-QT Syndrome

Among adolescents with the hereditary condition, risk is reduced by treatment with β-blockers

In adolescents with hereditary long-QT syndrome (LQTS), the timing and frequency of syncope, gender and QTc interval are all risk factors that can play a role in sudden cardiac death, according to a study published in the Sept. 13 issue of the Journal of the American Medical Association.

Jenny B. Hobbs, M.D., of the University of Rochester Medical Center, Rochester, N.Y., and colleagues conducted a study of 2,772 patients from the International Long QT Syndrome Registry. Of these, 81 patients had aborted cardiac arrest, and 45 experienced sudden cardiac death. Of the 81 patients who experienced aborted cardiac arrest, nine subsequently had sudden cardiac death.

Those who had a syncope once or twice within the past two years were 12-18 times more likely to experience a life-threatening event than those with no syncope over the same time frame. In the former group, use of β-blockers reduced the risk by 64 percent. For those aged 13 to 20 years old there were no significant sex differences in terms of risk, but males aged 10 to 12 had a four times higher risk than females of cardiac arrest.

"This clinically oriented risk-stratification approach might serve as a useful guide for prophylactic treatment decisions to reduce the risk of sudden death in patients with LQTS during the high-risk teenage years," the authors wrote.

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Green Tea Linked to Reduced Cardiovascular Mortality

Consumption has no impact on cancer risk

Consumption of green tea is associated with reduced risk of death from all causes and from cardiovascular disease in Japanese adults but does not confer any benefits in terms of reduced risk of death from cancer, according to a study published in the Sept. 13 issue of the Journal of the American Medical Association.

Shinichi Kuriyama, M.D., Ph.D., of the Tohoku University of Public Policy, Sendai, Japan, and colleagues followed a cohort of 40,530 Japanese adults for up to 11 years for all-cause mortality and for up to seven years for specific cause mortality. The cohort comprised adults aged 40 to 79 years with no history of stroke, coronary heart disease or cancer at baseline.

During the course of the study, 4,209 subjects died, including 892 due to cardiovascular disease and 1,134 due to cancer. There was an inverse association between consumption of green tea and all-cause mortality, as well as mortality from cardiovascular causes, and the association was more pronounced in women. The strongest inverse association was for stroke mortality.

The authors noted that the higher incidence of smoking among men may explain why they appeared to gain less benefit from drinking green tea as it was impossible to eliminate the effects of residual confounding. "Clinical trials are ultimately necessary to confirm the protective effect of green tea on mortality," they wrote.

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Bone Marrow Transplants to Heart Have Mixed Results

Three studies show either zero or modest improvement in heart function months after transplantation

Attempts to regenerate damaged cardiac muscle by transplanting bone marrow cells directly into the heart have shown mixed results, according to three reports in the Sept. 21 New England Journal of Medicine.

Ketil Lunde, M.D., from Oslo, Norway, and members of the Autologous Stem-Cell Transplantation in Acute Myocardial Infarction (ASTAMI) study found that intracoronary injection of autologous bone marrow cells had no effect on left ventricular ejection fraction (LVEF) in randomized patients with acute ST-segment elevation MI, also treated with percutaneous coronary intervention.

In a similar but larger study, Andreas Zeiher, M.D., of Johann Wolfgang Goethe University in Frankfurt, Germany, and members of the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial found a modest but significant improvement in LVEF (5.5 percent versus 3.0 percent) four months after bone marrow transplantation, and a reduction in adverse events at one year compared with control. The effect was most apparent in patients with the worst baseline LVEF.

In another study by Zeiher and colleagues called the Transplantation of Progenitor Cells and Recovery of LV Function in Patients with Chronic Ischemic Heart Disease (TOPCARE-CHD) trial, the investigators found that bone marrow cells are better than circulating blood progenitor cells for transplantation, with bone marrow cells again causing a moderate yet significant improvement in LVEF at three months.

These studies "represent a milestone in this rapidly developing field while serving as a cogent reminder that many important clinical and fundamental questions have yet to be addressed," according to Anthony Rosenzweig, M.D., in an accompanying editorial.

Private support was provided in both studies authored by Zeiher who, along with another author, is a cofounder of t2cure, a for-profit company focused on regenerative therapies for cardiovascular disease.

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Eculizumab Treats Paroxysmal Nocturnal Hemoglobinuria

Drug stabilizes hemoglobin in nearly half of treated study patients

A humanized monoclonal antibody against terminal complement protein C5, called eculizumab, is effective for treating patients with paroxysmal nocturnal hemoglobinuria (PNH), according to a report in the Sept. 21 issue of the New England Journal of Medicine.

Peter Hillmen, M.B., Ch.B., Ph.D., of Leeds General Infirmary in Leeds, U.K., and colleagues conducted a multi-center, double-blind, randomized, placebo-controlled trial to test the safety and efficacy of eculizumab. Eighty-seven patients were randomized to either placebo or drug at 600 mg weekly for four weeks and then 900 mg every other week up to 26 weeks.

Hemoglobin levels were stabilized in 49 percent of patients receiving eculizumab compared to none in the placebo group. Drug treatment eliminated the requirement for transfusions and reduced intravascular hemolysis by 85.8 percent compared with the placebo group. In addition, the eculizumab group reported greater quality of life improvements than the placebo group.

"The data provide support for the central role of intravascular hemolysis in the pathogenesis of the disease and indicate that eculizumab is an effective treatment in patients with PNH," the authors conclude.

The study was funded by Alexion Pharmaceuticals, the manufacturer of eculizumab. In addition, some of the authors are employees of or have received consulting fees from the company.

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ACE Inhibitor Does Not Prevent Diabetes in At-Risk Patients

Ramipril does not prevent progression to type 2 diabetes, but promotes normoglycemia

Despite hopes to the contrary, patients with impaired glucose tolerance or impaired fasting glucose cannot reduce their chances of developing type 2 diabetes by taking the ACE inhibitor ramipril, according to a study released early online Sept. 15 in the New England Journal of Medicine.

Jackie Bosch, M.Sc, and other members of the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) Trial randomized 5,269 patients with impaired fasting glucose or impaired glucose tolerance to take up to 15 mg of ramipril per day or placebo for three years. None of the patients had cardiovascular disease. Patients were also randomized to rosiglitazone or placebo, but the results will be reported separately.

Overall, there was no difference between the two groups in the primary endpoint, which was the development of diabetes or death (18.1 percent of the ramipril group; 19.5 percent of the placebo group). Patients taking ramipril were 1.16 times more likely to achieve normoglycemia, but the difference was relatively modest (42.5 percent of ramipril group; 38.2 percent of placebo group).

"Given the primary findings of the DREAM trial, ramipril cannot be recommended for the prevention of type 2 diabetes," according to an editorial by Julie Ingelfinger, M.D., and Caren Solomon, M.D., M.P.H. The drug may provide a small side benefit of improving glycemia in patients taking it for another indication, but diet and exercise are still the best options for reducing the diabetes rate in at-risk patients, they concluded.

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Coated Stents May Be Better Than Bare Stents for Acute MI

Drug-coated stents likely to reduce the need for repeat revascularization

Patients with acute myocardial infarction with ST-segment elevation who receive drug-eluting stents have fewer adverse events compared to those receiving uncoated stents, according to two reports in the Sept. 14 issue of the New England Journal of Medicine.

Gerrit Laarman, M.D., Ph.D., from Amsterdam, the Netherlands, and colleagues found that patients with ST-segment elevation acute MI who were randomly assigned to receive a paclitaxel-eluting stent had fewer serious adverse events, including cardiac-related death, reinfarction and revascularization, than those who received uncoated stents (8.8 percent vs. 12.8 percent), although the difference was not statistically significant. The study included 619 patients.

In the second study of 712 patients with acute myocardial infarction with ST-segment elevation undergoing percutaneous coronary intervention (PCI), Christian Spaulding, M.D., Paris, France, and colleagues found that sirolimus-coated stents reduced target-vessel revascularization and neointimal proliferation at eight months compared to uncoated stents (7.3 percent vs. 14.3 percent). There were no differences in cardiac-related death or restenosis.

"The data from these two trials indicate that drug-eluting stents can be used safely in the setting of primary PCI and are likely to reduce the need for repeated revascularization," according to Frans Van de Werf, M.D., Ph.D., Leuven, Belgium, in an editorial. However, he added that more data is needed before drug-eluting stents can be recommended for all patients receiving primary PCI.

Some of the authors in each study are either employees of, or have received compensation from, Johnson & Johnson and Boston Scientific, both manufactures of drug-coated stents used in these studies.

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Chemotherapy Cuts Local Recurrence in Rectal Cancer

Survival rates similar, but chemotherapy may improve quality of life

Adding fluorouracil-based chemotherapy to the treatment regimen of patients with resectable rectal cancer significantly improves local control of the disease, no matter if it is administered before or after surgery, according to a report in the Sept. 14 issue of the New England Journal of Medicine.

Jean-François Bosset, M.D., of the University of Franche-Comté, Besançon, France, and colleagues randomly assigned patients with resectable stage T3 or T4 rectal cancer to one of four regimens: preoperative radiotherapy, preoperative chemoradiotherapy, preoperative radiotherapy and postoperative chemotherapy, or preoperative chemoradiotherapy and postoperative chemotherapy.

The authors found that five-year survival was similar for patients receiving either pre- or post-operative chemotherapy, or no chemotherapy, but that local recurrence was reduced in those receiving chemotherapy at any time. Recurrence occurred in 8.7 percent, 9.6 percent and 7.6 percent in the groups treated with chemotherapy preoperatively, postoperatively, or both, respectively, compared to 17.1 percent in the untreated group. Patient adherence to chemotherapy was lower when it was given after surgery (42.9 vs. 82 percent).

"Chemotherapy, regardless of whether it is administered before or after surgery, confers a significant benefit with respect to local control," the authors wrote. "Quality of life will become an increasingly relevant end point in new trials."

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Fingolimod Reduces Multiple Sclerosis Activity, Lesions

Treatment associated with some adverse side effects, long-term studies are needed

The oral immunomodulating agent fingolimod reduces lesions and disease activity associated with relapsing multiple sclerosis, according to a report in the Sept. 14 issue of the New England Journal of Medicine.

Ludwig Kappos, M.D., of University Hospital in Basel, Switzerland, and colleagues randomly assigned 281 patients with relapsing multiple sclerosis to receive 1.25 or 5 mg fingolimod, or placebo, once daily and followed them for six months to measure disease activity and the number of gadolinium-enhanced lesions detected by magnetic resonance imaging.

Patients treated with fingolimod had fewer lesions (1-3 lesions vs. 5 lesions) and a lower relapse rate (0.35-0.36 vs. 0.77) compared to the placebo group, the authors found. In an extended double-blind study, both measures remained low in fingolimod-treated patients and those initially receiving placebo showed improvement after switching to the drug.

Not entirely unexpected, treatment was associated with some adverse side effects including lower heart rate, higher arterial pressure, and airway obstruction, according to Steffen Massberg, M.D., Ph.D., and Ulrich von Andrian, M.D., Ph.D., from Harvard Medical School in Boston. "The results of the current proof-of-concept study by Kappos et al. are certainly promising and should provide a strong incentive for long-term follow-up trials on a large scale," they wrote in an editorial.

The study was supported by Novartis Pharma, Basel, Switzerland, and some of the authors are employees of the company.

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Avandia Helps Prevent Diabetes in High-Risk Adults

It reduces the risk of diabetes by two-thirds but also may slightly increase the risk of heart failure

In adults with impaired fasting glucose, impaired glucose tolerance, or both, the addition of rosiglitazone to lifestyle changes may significantly reduce the risk of developing type 2 diabetes, according to a study published online Sept. 15 by The Lancet.

DREAM (Diabetes reduction assessment with ramipril and rosiglitazone medication) trial investigators in Hamilton, Ontario, randomly assigned 5,269 adults aged 30 and older to receive either rosiglitazone or placebo and followed them for a median of three years. They assessed subjects at two and six months and every six months thereafter, and stressed the importance of healthy diet and lifestyle at each visit.

The researchers found that 50.5 percent of the rosiglitazone subjects became normoglycemic compared to 30.3 percent of the control subjects. They also found that cardiovascular event rates were similar in both groups, but identified 14 (0.5 percent) rosiglitazone subjects who developed heart failure compared to two (0.1 percent) control subjects.

"Balancing both the benefits and risks suggests that for every 1,000 people treated with rosiglitazone for three years, about 144 cases of diabetes will be prevented, with an excess of four to five cases of congestive heart failure," the authors conclude.

The DREAM trial is funded by the Canadian Institutes of Health Research as well as by Sanofi-Aventis, GlaxoSmithKline, and King Pharmaceuticals.

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Four Biomarkers Identify Tuberculosis Infection

Markers have a diagnostic accuracy of about 80 percent

A set of four biomarkers can diagnose tuberculosis infection with an accuracy of about 80 percent, according to the results of a study published in the Sept. 16 issue of The Lancet.

Sanjeev Krishna, F.Med.Sci., from St. George's Hospital Medical School in London, U.K., and colleagues examined proteomic profiles in the serum of 102 patients with tuberculosis and 91 controls using SELDI-ToF mass spectrometry. An additional 77 tuberculosis patients and 79 controls were used to validate the markers. Control patients had a range of inflammatory conditions whose clinical features can mimic tuberculosis. Subjects were from the United Kingdom, Uganda, Angola and The Gambia.

The researchers identified four biomarkers (serum amyloid A protein, transthyretin, neopterin, and C reactive protein) that in various combinations gave a diagnostic accuracy of up to 84 percent. These biomarkers gave a diagnostic accuracy up to 78 percent when tested on the independent set of patients.

"Further evidence of the absolute specificity of these tuberculosis markers, and generation of mass-spectral serum patterns from patients in the early stages of disease, could eventually have a huge effect on the clinical outcomes of tuberculosis infection worldwide by reducing the time between infection, diagnosis, and onset of therapy," Stuart J. Cordwell, Ph.D., from the University of Sydney in Australia, and colleagues write in an accompanying editorial.

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Mortality Higher in Some With Bilateral Oophorectomy

Greater mortality risk mostly found in women under 45 who do not take estrogen

Women who have a prophylactic bilateral oophorectomy before age 45 and do not take estrogen replacement therapy have a 1.7 times higher risk of dying from any cause than women the same age who have intact ovaries, researchers report online in the Sept. 14 issue of The Lancet Oncology.

Walter A. Rocca, M.D., of the Mayo Clinic, in Rochester, Minn., and colleagues compared survival in 1,293 premenopausal women living in Olmsted County, Minn., between 1950 and 1987, who underwent unilateral oophorectomy for reasons unrelated to cancer, 1,097 women who had bilateral oophorectomy, and 2,390 controls.

The researchers found survival in the women who had unilateral oophorectomy similar to that of controls. And overall, a bilateral oophorectomy was not associated with a higher mortality risk. But the women who underwent prophylactic bilateral oophorectomy before age 45 had a higher mortality risk (hazard ratio 1.67) than controls, a risk found primarily in women who were not given estrogen until age 45.

"Although prophylactic bilateral oophorectomy done before age 45 years is associated with increased mortality, it is uncertain whether it is causal or merely a marker of underlying risk," the authors wrote.

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Shortened Treatment Benefits Medulloblastoma Patients

Risk-adapted radiotherapy plus chemotherapy improves survival in high-risk patients

The five-year survival in patients with high-risk medulloblastoma can be improved by using risk-adjusted radiotherapy plus a shortened course of chemotherapy, according to a study published online Sept. 7 in The Lancet Oncology.

After tumor resection, Amar Gajjar, M.D., from St. Jude Children's Research Hospital in Memphis, Tenn., and colleagues treated 119 children with medulloblastoma with risk-adapted levels of craniospinal radiation. Patients were classified as average-risk if they had 1.5 square cm or less of residual tumor and no metastatic disease or as high-risk if they had more than 1.5 square cm of residual tumor and metastatic disease. Six weeks after radiotherapy, patients received dose-intensive cyclophosphamide-based chemotherapy for four months rather than the usual one year.

The researchers found that the five-year overall survival was 85 percent in the average-risk group and 70 percent in the high-risk group, with a five-year event-free survival of 83 percent and 70 percent, respectively. The histological subtype was available for nearly all patients and correlated with the five-year event-free survival, ranging from 57 percent for large-cell anaplastic tumors to 84 percent for classic histology.

"Risk-adapted radiotherapy followed by a shortened schedule of dose-intensive chemotherapy can be used to improve the outcome of patients with high-risk medulloblastoma," Gajjar and colleagues conclude.

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Aggressive Treatment Benefits Metabolic Syndrome

High-dose statin therapy reduces risk of major cardiovascular events

High doses of atorvastatin can reduce the risk of cardiovascular events in those with coronary heart disease and metabolic syndrome, according to a study published online Sept. 5 in The Lancet.

Prakash C. Deedwania, M.D., from the University of California San Francisco, and colleagues studied 10,001 coronary heart disease patients aged 35 to 75, of whom 5,584 also had metabolic syndrome. Patients were randomly assigned to receive 10 mg/day or 80 mg/day atorvastatin.

After three months, levels of low-density lipoprotein fell in those with metabolic syndrome, with a bigger decrease in those receiving 80 mg/day atorvastatin. After a median follow-up of 4.9 years, those with metabolic syndrome had significantly fewer major cardiovascular events if they were taking the higher dose (9.5 percent versus 13 percent, hazard ratio 0.71). However, all patients with metabolic syndrome were at higher risk of having a major cardiovascular event than those without metabolic syndrome (hazard ratio 1.44), which was significantly reduced by treatment with 80 mg/day atorvastatin.

The results "support the concept of the higher the risk, the greater the need to treat and to treat aggressively," Andre J. Scheen, M.D., of CHU Sart Tilman in Liege, Belgium, writes in an accompanying editorial.

The study was funded by Pfizer, and the company's employees helped in data collection and analysis.

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Dapoxetine Helps Men with Premature Ejaculation

Phase III trials show that it doubles the average time to ejaculation compared to placebo

Dapoxetine, a selective serotonin reuptake inhibitor developed specifically for moderate-to-severe premature ejaculation, is a safe and effective treatment for men affected by the condition, according to a study published in the Sept. 9 issue of The Lancet.

Jon L. Pryor, M.D., of the University of Minnesota in Minneapolis, and colleagues conducted two phase III trials in which 874 men took 30 milligrams of dapoxetine and 870 men took 60 mg of dapoxetine one to three hours before sexual activity, and 870 men took a placebo.

At baseline, the subjects' average time to ejaculation after vaginal penetration was under one minute. After 12 weeks, the researchers found that average time to ejaculation increased to 3.32 minutes for the 60-mg group, 2.78 minutes for the 30-mg group and 1.75 minutes for the placebo group. In the 30-mg and 60-mg groups, side effects included nausea (8.7 and 20.1 percent, respectively), diarrhea (3.9 and 6.8 percent, respectively), headache (5.9 and 6.8 percent, respectively) and dizziness (3 and 6.2 percent, respectively).

"In view of the distress and interpersonal difficulties generally associated with this condition, availability of an effective treatment, especially for those with the most severe premature ejaculation, might encourage men with premature ejaculation to seek a physician diagnosis, and could provide a substantial benefit for men and their partners," the authors conclude.

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Avian Flu Vaccine Safe and Effective in Clinical Trial

Low doses of vaccine induce antibodies in up to 78 percent of subjects

A phase I trial of an H5N1 influenza vaccine shows that low doses of vaccine are safe and can induce antibody responses in up to 78 percent of subjects, according to a study published online Sept. 7 in The Lancet.

Jiangtao Lin, M.D., of the Chinese-Japanese Friendship Hospital in Beijing, China, and colleagues conducted a phase I clinical trial of an inactivated whole-virion influenza A (H5N1) vaccine on volunteers aged 18 to 60 years old. Twenty-four volunteers each were randomized to receive two doses of a placebo or vaccines containing 1.25, 2.5, 5 or 10 micrograms of haemagglutinin plus an aluminum hydroxide adjuvant on days 0 and 28.

The researchers found that all doses of vaccine induced antibody responses after the first dose, with 78 percent seropositivity observed after two doses of 10 μg vaccine. The vaccine was well-tolerated at all doses, with no serious adverse events. Most reactions were mild and transient, with pain, swelling and fever being the most commonly reported side effects. The authors note that the 10 μg vaccine "met all European regulatory requirements for annual licensing of seasonal influenza vaccine."

"These findings identify a potential dose-sparing approach that could be crucial for a global supply of pandemic vaccine," Iain Stephenson, M.D., of the Leicester Royal Infirmary in the U.K., writes in an accompanying editorial.

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Pharmacy Bar-Code System Cuts Dispensing Errors

Scanning all doses slashes target dispensing errors up to 96 percent, but selective scanning ups risks

Scanning all medication doses dispensed by hospital pharmacies using a bar-code system significantly reduces dispensing errors and potentially harmful patient drug reactions, researchers report in the Sept. 19 issue of the Annals of Internal Medicine.

Eric G. Poon, M.D., of Brigham and Women's Hospital in Boston, and colleagues compared dispensation of 115,164 medication doses before the installation of a hospital pharmacy bar-code system with 253,984 doses dispensed afterwards. Two implementation methods involved scanning each dose; a third involved scanning only one dose if several doses of the same drug were dispensed.

The researchers found that the bar-code system cut target potential adverse drug event rates 74 percent and all potential adverse drug events 63 percent. Scanning all doses slashed target dispensing errors 93 to 96 percent, reducing possible adverse drug events 86 to 97 percent.

Not scanning each dose cut target dispensing errors only 60 percent and increased target potential drug reactions 2.4-fold.

"The overall rates of dispensing errors and potential adverse drug events substantially decreased after implementing bar-code technology," the authors write. "However, the technology should be configured to scan every dose during the dispensing process."

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Self-Reported Sexual Identity Doesn't Help Assess HIV Risk

'Heterosexual' men who have sex with men less likely to get tested or use condoms

A patient's self-reported sexual identity is an unreliable measure of the risk of HIV and sexually transmitted disease risk, according to a study published in the Sept. 19 issue of the Annals of Internal Medicine.

Preeti Pathela, Dr.P.H., of the New York City Department of Health and Mental Hygiene, and colleagues conducted a population-based telephone survey of 4,193 men in New York City, and gathered information on the number and gender of sex partners in the past year, condom use during the most recent sexual encounter, HIV testing history and sexual identity.

Among the respondents who reported a sexual identity, 12 percent reported having sex with other men. Among this group, those who identified themselves as heterosexual were more likely to report only one sexual partner in the past year compared with gay men, but they were less likely to have had an HIV test during the previous year and to have used a condom during their most recent sexual encounter.

"Medical providers cannot rely on patients' self-reported identities to appropriately assess risk for HIV infection and sexually transmitted diseases; they must inquire about behavior. Public health prevention messages should target risky sexual activities rather than a person's sexual identity," the authors conclude.

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Multislice CT Noninvasive Way to Detect Coronary Stenoses

Exposure to radiation similar to that from cardiac catheterization

Multislice computed tomography (CT) is a sensitive, noninvasive diagnostic tool for suspected coronary artery disease, according to a study in the Sept. 19 issue of the Annals of Internal Medicine comparing the technique to magnetic resonance imaging and conventional coronary angiography.

Marc Dewey, M.D., of Humboldt-Universitat zu Berlin in Berlin, Germany, and colleagues conducted a study involving 129 patients who underwent testing for suspected coronary artery disease, of which 108 had both multislice CT and magnetic resonance imaging (MRI) within a median of one day prior to conventional coronary angiography.

The sensitivity of multislice CT was 92 percent, compared with 74 percent for MRI, and it also had 82 percent sensitivity for detecting clinically significant stenoses, compared with 54 percent for MRI. While MRI does not expose patients to radiation, multislice CT does, but the dose exposure in 73 patients was similar to that received during diagnostic cardiac catheterization.

"The best use of multislice CT (which most would prefer over MRI because of its higher sensitivity, despite its higher risks) would be in a patient whose post-test probability after a negative study would be so low that invasive coronary angiography would be unnecessary," according to an editorial by Philip Greenland, M.D. While this would rule out most angiography candidates, "I believe that it can be useful in an important, albeit small, subset of patients with chest pain," he writes.

Some study authors have received grants and compensation from Toshiba Medical Systems, sponsor of multislice CT coronary angiography.

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One in Four AIDS Patient Deaths Is from Non-HIV Causes

Cardiovascular disease, non-AIDS-defining cancer and substance abuse chief factors

About one-quarter of deaths among patients with AIDS are due to non-HIV-related causes, according to a study in the Sept. 19 issue of the Annals of Internal Medicine.

Judith E. Sackoff, Ph.D., of the New York City Department of Health and Mental Hygiene, and colleagues conducted a study of 68,669 subjects aged 13 or older living with AIDS between 1999 and 2004. For those who died, they gathered data on the underlying cause of death as stated on the death certificate.

Whereas 19.8 percent of deaths in 1999 were due to non-HIV-related causes, 26.3 percent were not HIV-related in 2004, an increase of 32.8 percent. Substance abuse, cardiovascular disease or a non-AIDS-defining type of cancer accounted for 76 percent of the non-HIV-related deaths. Injection drug users were significantly more likely than men who have sex with men to die of HIV-related and non-HIV-related causes.

The authors note that many of the non-HIV-related deaths were preventable. "Reducing deaths from these causes requires a shift in the health care model for persons with AIDS from a primary focus on managing HIV infection to providing care that addresses all aspects of physical and mental health," they conclude.

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Prepared jointly by the editors of Medical Economics and HealthDay's Physicians Briefing (www.physiciansbriefing.com).