Latest Research

April 6, 2007

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

ACC: Reconstituted HDL Infusions May Help Atherosclerosis

HDL treatment does not affect coronary atheroma volume, but improves plaque characterizations

Infusions of reconstituted high-density lipoprotein (HDL) cholesterol may have some benefit for atherosclerosis, according to study findings published online March 26 in the Journal of the American Medical Association to coincide with American College of Cardiology's annual meeting in New Orleans.

Jean-Claude Tardif, M.D., of the Montreal Heart Institute in Quebec, Canada, and colleagues randomized 60 patients to receive four weekly infusions of placebo, 111 to receive 40 milligrams per kilogram of reconstituted HDL (known as CSL-111), and 12 to receive 80 mg/kg of CSL-111. CSL-111 consists of apolipoprotein A-I from human plasma combined with soybean phosphatidylcholine that resembles HDL. The researchers performed intravascular ultrasound and quantitative coronary angiography on the patients to assess coronary atheroma at baseline and two to three weeks after the last infusion.

The highest dosage was discontinued early because of abnormal results on liver function tests. The differences in coronary atheroma volume after treatment did not differ significantly between the groups. Plaque characterizations on intravascular ultrasound and coronary score on quantitative coronary angiography did show benefits from treatment with CSL-111 compared with placebo.

While it's too early to determine the clinical significance of these findings, "elevation of HDL remains a valid target in vascular disease," the authors conclude.

AbstractFull Text

ACC: Crestor Does Not Reverse Subclinical Atherosclerosis

Researchers find that rosuvastatin reduces rate of arterial thickening but doesn't induce regression

Rosuvastatin slows the rate of arterial thickening and halts but does not reverse atherosclerosis in middle-aged adults with Framingham risk scores of less than 10 percent and evidence of subclinical atherosclerosis, according to a report published online March 25 in the Journal of the American Medical Association to coincide with the American College of Cardiology's annual conference in New Orleans.

During the two-year Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin (METEOR) study, John R. Crouse III, M.D., of the Wake Forest University School of Medicine in Winston-Salem, N.C., and colleagues randomly assigned 984 patients to receive either rosuvastatin or placebo.

Compared to the placebo group, the researchers found that the rosuvastatin group had significantly slower progression of maximum carotid intima-media thickness at 12 sites and no significant progression of atherosclerosis. They also found that the rosuvastatin group had significant reductions of total and low-density lipoprotein cholesterol and triglycerides (34, 49 and 16 percent, respectively) and an 8 percent increase in high-density lipoprotein cholesterol.

"Should low-risk individuals undergo routine arterial imaging followed by statin therapy when evidence of asymptomatic disease is discovered?" asks the author of an accompanying editorial. "On the basis of current evidence, including the METEOR trial, the answer is clearly no."

The study was funded by AstraZeneca.

AbstractFull TextEditorial

ACC: Tolvaptan Does Not Cut Acute Heart Failure Mortality

Studies show no reduced risk of rehospitalization or death, but significant symptom improvement

In patients with acute heart failure, tolvaptan does not reduce the risk of rehospitalization or death, but may improve some symptoms, according to two studies published online March 25 in the Journal of the American Medical Association to coincide with the American College of Cardiology's annual conference in New Orleans.

Both studies are based on the 10-month Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trials, in which 4,133 patients with acute decompensated heart failure were randomly assigned to receive either tolvaptan or placebo.

Marvin A. Konstam, M.D., of Tufts-New England Medical Center in Boston, and colleagues found no significant group differences in the combined outcome of cardiovascular death or hospitalization for heart failure (42 percent in the tolvaptan group versus 40.2 percent in the placebo group). But they found that the tolvaptan group had significantly greater improvements in body weight, dyspnea and edema.

Mihai Gheorghiade, M.D., of Northwestern University in Chicago, and colleagues observed similar improvements in the tolvaptan group and no group differences in the frequency of serious adverse events.

"These findings would suggest some short-term benefit of tolvaptan on certain acute symptoms of acute decompensated heart failure without evidence of harm, and represent an important contribution for understanding the management of patients with acute decompensated heart failure," states the author of an accompanying editorial.

The study was funded by Otsuka, Inc.

Abstract - KonstamFull TextAbstract - GheorghiadeFull TextEditorial

ACC: Investigational Drug Cuts Lipids But May Be Unsafe

LY518674 may be effective, but may also increase serum creatinine and some lipoproteins

LY518674, an investigational peroxisome proliferator-activated receptor (PPAR) alpha agonist, improves lipid levels but may not be safe, according to the results of a study published online March 25 in the Journal of the American Medical Association to coincide with the American College of Cardiology's annual conference in New Orleans.

Steven E. Nissen, M.D., of the Cleveland Clinic Foundation in Ohio, and colleagues conducted two trials, the first of which randomized 309 patients with atherogenic dyslipidemia to receive LY518674, fenofibrate or placebo. In the second study, they randomized 304 patients with hypercholesterolemia to receive atorvastatin or placebo for four weeks, followed by LY518674 or placebo for 12 more weeks.

In both studies, the researchers found that LY518674 significantly reduced triglyceride levels and increased high-density lipoprotein cholesterol levels. But the studies raised safety concerns as both LY518674 and fenofibrate increased serum creatinine levels in some patients, although there were no cases of rhabdomyolysis or acute renal failure. In addition, LY518674 increased LDL-C and Apo A-II.

"The results of this pair of trials demonstrate the challenges in developing new PPAR agonists as therapeutic agents. These drugs modulate activity of a large number of genes, some of which produce unknown effects," the authors write. "Accordingly, the beneficial effects of PPAR activation appear to be associated with a variety of untoward effects, which may include oncogenesis, renal dysfunction, rhabdomyolysis, and cardiovascular toxicity."

The study was funded by Eli Lilly and Co.

AbstractFull Text

Data Murky on Drug Company Payments to Physicians

Publicly available data paints limited picture of how much is paid and to whom

Despite laws in two states mandating public access to data on payments by pharmaceutical companies to physicians, the available data provide only a limited picture of such transactions, according to a study in the March 21 issue of the Journal of the American Medical Association.

Joseph S. Ross, M.D., of the Mount Sinai School of Medicine in New York City, and colleagues analyzed publicly available data from Vermont and Minnesota from 2002 to 2004, to ascertain disclosures of payments to physicians of $100 or more.

The investigators found that in Vermont, 61 percent of payments were not disclosed because they were designated as trade secrets by pharmaceutical companies. In three out of four cases, there was insufficient information to identify the recipient. Of the 12,227 publicly disclosed payments totaling $2.18 million, there were 2,416 payments of $100 or more.

In Minnesota, only one-quarter of pharmaceutical companies filed in each of the three years, disclosing 6,946 payments totaling $30.96 million, of which 6,233 were for $100 or more. Only the data from Minnesota provided physician-specific analysis.

"The impact of disclosure laws on increasing transparency of physician-industry relations is compromised by incomplete disclosure as well as insufficient access to information," the authors conclude. "Making these payments publicly available will require more stringent laws with clear mechanisms for enforcement."

AbstractFull Text (subscription or payment may be required)Editorial

Decades After Childhood Leukemia, Cancer Risk Rises

Cumulative incidence increases steadily for 30 years after treatment

In patients treated for acute lymphoblastic leukemia in childhood, the cumulative incidence rate of secondary cancers increases steadily for 30 years after treatment, according to study findings published in the March 21 issue of the Journal of the American Medical Association.

Nobuko Hijiya, M.D., of St. Jude Children's Research Hospital in Memphis, Tenn., and colleagues conducted a study of 2,169 patients with acute lymphoblastic leukemia who were followed up for between 2.4 and 41.3 years (median 18.7 years).

Overall, 123 patients developed secondary cancers, including 46 myeloid malignancies, three lymphomas, 14 basal cell carcinomas, 16 other carcinomas, six sarcomas, 16 meningiomas and 22 other brain tumors. At 15 years, the cumulative incidence of secondary cancers was 4.17 percent, rising to 10.85 percent at 30 years. Excluding meningiomas and basal cell carcinomas, previous childhood acute lymphoblastic leukemia patients had a 13.5-fold higher risk of incidence of cancer than the general population, at 3.99 percent at 15 years and 6.27 percent at 30 years.

"Although the majority of the late-occurring secondary neoplasms are low-grade tumors, the increase in incidence of more aggressive malignant neoplasms is significantly higher than expected in the general population," the authors write. "These results suggest that lifelong follow-up of acute lymphoblastic leukemia survivors is needed to ascertain the full impact of treatment and other leukemia-related factors on secondary neoplasm development," they conclude.

AbstractFull Text (subscription or payment may be required)

Clinical Trials Exclude Patients for Questionable Reasons

Patients commonly excluded for medical conditions, age, medications, gender

Clinical trials frequently exclude patients because they have common co-morbid conditions or are taking popular prescription medications, or due to gender or age, according to a report in the March 21 issue of the Journal of the American Medical Association. In particular, drug intervention and multicenter trials tend to have poorly justified exclusions that may limit their applicability of the results to the general population.

Robert A. Fowler, M.D., from Sunnybrook Hospital in Toronto, Ontario, Canada, and colleagues analyzed the nature and extent of exclusion criteria in 283 randomized controlled clinical trials that had been published. They judged the criteria as strongly, potentially, or poorly justified.

The researchers found that exclusion criteria often included common medical conditions (81.3 percent of trials), age (72.1 percent), commonly prescribed medications (54.1 percent), and female sex (39.2 percent). Twelve percent of studies did not report exclusion criteria. Only 47.2 percent of all exclusion criteria were graded as strongly justified for a specific trial.

Drug intervention trials and multicenter trials had a higher number of exclusion criteria (risk ratio 1.35 and 1.26, respectively), according to the study. Industry-sponsored trials and drug intervention trials were more likely to exclude individuals for reasons including concomitant medication use and medical co-morbidities, which were graded as poorly justified.

Such exclusions "may impair the generalizability of randomized controlled trial results," Fowler and colleagues conclude. "These findings highlight a need for careful consideration and transparent reporting and justification of exclusion criteria in clinical trials."

AbstractFull Text (subscription or payment may be required)

Delay in Clamping Umbilical Cord Beneficial to Infant

Hematologic, iron status improved in first six months of life

A delay in clamping the umbilical cord of a full-term infant by at least two minutes improves their hematologic and iron status and lowers their risk of anemia at 2 to 6 months of age, according to a meta-analysis in the March 21 issue of the Journal of the American Medical Association.

Eileen K. Hutton, Ph.D., from McMaster University in Hamilton, Ontario, and Eman S. Hassan, from the University of British Columbia in Vancouver, Canada, identified and performed a meta-analysis of 15 controlled clinical trials comparing the benefits of early or late umbilical cord clamping in 1,912 infants born at 37 weeks' gestation or more. Clamping was performed immediately after birth in most of the 911 early clamping cases, while clamping was delayed for at least two minutes in the 1,001 late clamping cases.

The researchers found that late clamping was beneficial after two to six months, with improved hematologic status (hematocrit), iron status (ferritin concentration), and stored iron, as well as a lower risk of anemia (relative risk 0.53). However, late clamping was also associated with an increased risk of asymptomatic polycythemia (relative risk 3.82).

The study "provides evidence that favors delaying clamping for at least two minutes after birth of a full-term infant," William Oh, M.D., from Brown Medical School and Women & Infants Hospital in Providence, R.I., writes in an accompanying editorial.

AbstractFull Text (subscription or payment may be required)Editorial

U.S. Black-White Life Expectancy Gap Narrowing

Further convergence relies on concerted efforts in public health

The gap between black and white life expectancy in the United States is narrowing, but concerted efforts in specific areas of public health are required to further narrow the divide, according to a study in the March 21 issue of the Journal of the American Medical Association.

Sam Harper, Ph.D., of McGill University in Montreal, Quebec, Canada, and colleagues analyzed data from the U.S. National Vital Statistics and found that for men, the black-white life expectancy gap widened by two years from 1983 to 1993. The three main causes were HIV, homicide and heart disease. From 1993 to 2003, however, the gap narrowed by 25 percent from 8.44 years to 6.33 years, largely due to improvements in mortality for blacks aged 15 to 49.

From 1983 to 1993, the gap in black-white female life expectancy increased by 0.5 years as improvements in stroke were counterbalanced by increased mortality due to HIV and slower heart disease declines. However, from 1993 to 2003, the gap narrowed by a year (from 5.59 years to 4.54 years), half of which was due to improved heart disease mortality rates, homicide and unintentional injuries.

"Further narrowing of the gap will require concerted efforts in public health and health care to address the major causes of the remaining gap from cardiovascular diseases, homicide, HIV and infant mortality," the authors conclude.

AbstractFull Text

International Study Shows High Impact of Arterial Disease

About 15 to 21 percent of those with atherosclerotic disease die or have a cardiovascular event each year

About one in seven outpatients with established atherosclerotic disease dies or is hospitalized each year due to a stroke, myocardial infarction or other cardiovascular event, according to the results of an international study published in the March 21 issue of the Journal of the American Medical Association.

Ph. Gabriel Steg, M.D., from Hopital Bichat-Claude Bernard in Paris, France, and colleagues examined the one-year cardiovascular event rates for 64,977 patients in 44 countries in 2003-2004. The patients had established atherosclerotic arterial disease or at least three risk factors for atherothrombosis.

The overall rate for cardiovascular death, myocardial infarction or stroke was 4.69 percent in those with established disease and 2.15 percent in patients with multiple risk factors only. About 15.2 percent of patients with coronary heart disease had a myocardial infarction, stroke or cardiovascular-related death, as did 14.53 percent of those with cardiovascular disease, and 21.14 percent of those with peripheral arterial disease. The rates increased with increasing number of symptomatic arterial disease locations, and ranged from 5.31 to 26.27 percent.

The study "demonstrates that the cardiovascular disease epidemic remains a critical and urgent international public health problem," Mary M. McDermott, M.D., from Northwestern University Feinberg School of Medicine in Chicago, writes in an accompanying editorial.

The patient registry was sponsored by Sanofi-Aventis, Bristol-Myers Squibb and the Waksman Foundation (Tokyo).

AbstractFull TextEditorial

ACC: Medical Therapy Alone OK for Stable Coronary Disease

Preventive percutaneous coronary intervention does not reduce mortality or morbidity risk

Patients with stable coronary artery disease can be safely treated with medical therapy alone without percutaneous coronary intervention, according to a report published online March 26 in the New England Journal of Medicine to coincide with the American College of Cardiology's meeting in New Orleans. Performing an angioplasty does not appear to reduce mortality or morbidity in such patients.

William E. Boden, M.D., of Buffalo General Hospital in Buffalo, N.Y., and colleagues conducted a trial with 2,287 patients from 50 U.S. and Canadian centers. The patients had evidence of myocardial ischemia and significant coronary artery disease and were randomized to undergo percutaneous coronary intervention and optimal medical therapy (1,149 patients), or the medical therapy alone (1,138 patients). They were followed-up for a median of 4.6 years.

In the percutaneous coronary intervention group, there were 211 primary events, compared with 202 events in the medical therapy group. In terms of deaths, myocardial infarctions and strokes, there were no significant differences between the two groups.

"Our findings reinforce existing clinical practice guidelines, which state that percutaneous coronary intervention can be safely deferred in patients with stable coronary artery disease, even in those with extensive, multivessel involvement and inducible ischemia, provided that intensive, multifaceted medical therapy is instituted and maintained," the authors conclude.

AbstractFull TextEditorial

ACC: Torcetrapib Does Not Add Benefit Over Statin Alone

Drug alters cholesterol levels but does not slow disease

Although torcetrapib reduces levels of low-density lipoprotein cholesterol and raises levels of high-density lipoprotein cholesterol, it does not slow the progression of coronary atherosclerosis more than atorvastatin alone, according to two reports published early online March 26 in the New England Journal of Medicine. The studies were presented at the American College of Cardiology's annual meeting in New Orleans.

Steven E. Nissen, M.D., of the Cleveland Clinic Foundation in Ohio, and colleagues studied 1,188 coronary disease patients who underwent intravascular ultrasonography and were all treated with atorvastatin to bring levels of low-density lipoprotein cholesterol down to less than 100 mg per deciliter. The patients were then randomized to receive either atorvastatin monotherapy or atorvastatin plus 60 mg of torcetrapib a day. After 24 months, 910 patients underwent ultrasound scanning again to ascertain progression of the disease.

Although the dual therapy favorably altered cholesterol levels, there was no impact on disease progression and the treatment was associated with a 4.6 mm Hg increase in mean systolic blood pressure.

In the second study, John J.P. Kastelein, M.D., Ph.D., of the University of Amsterdam, and colleagues found similar results in a trial of 850 patients with familial hypercholesterolemia.

"The lack of efficacy may be related to the mechanism of action of this drug or to molecule-specific adverse effects," Nissen and colleagues conclude. "Our findings demonstrate the great difficulty in developing therapies to interrupt the atherosclerotic disease process. Twenty years after the introduction of statins, we are still waiting for the next breakthrough."

The studies were supported by Pfizer.

Abstract - NissenFull TextAbstract - KasteleinFull TextEditorial

Enterovirus 71 Infection May Cause Neurological Defects

Virus should possibly be added to list of emerging infections

Children infected with enterovirus 71 who show central nervous system involvement and cardiopulmonary failure may experience neurological sequelae, delayed neurodevelopment and reduced cognitive functioning, according to a report in the March 22 issue of the New England Journal of Medicine.

Luan-Yin Chang, M.D., Ph.D., from the National Taiwan University in Taipei, and colleagues conducted a follow-up of 142 children after enterovirus 71 infection with central nervous system involvement to determine the long-term neurologic and psychiatric effects of the infection.

The researchers found that up to 56 percent of patients with poliomyelitis-like syndrome or encephalomyelitis had sequelae involving limb weakness and atrophy. The rate increased to 64 percent for those with added cardiopulmonary failure, with many of these patients requiring a feeding tube and ventilator support. Delayed neurodevelopment increased from 5 percent to 75 percent for those with central nervous system involvement, without or with cardiopulmonary failure, respectively. Cognitive measures also were lower for those with added cardiopulmonary failure.

"It would be prudent to add enterovirus 71 to the list of emerging infections that threaten us, develop a plan to respond to an outbreak, and take the first steps toward developing a vaccine," John F. Modlin, M.D., from the Dartmouth Medical School in Lebanon, N.H., writes in an accompanying editorial.

AbstractFull Text (subscription or payment may be required)Editorial

Cardiac Risk Greater with Some Firefighter Duties Than Others

Risk of heart disease-related death 12 to 136 times higher with fire suppression compared to other duties

Certain duties are more dangerous than others for firefighters when considering the risk of death from coronary heart disease, according to a report in the March 22 issue of the New England Journal of Medicine. Heart disease causes 45 percent of deaths among firefighters on active duty.

Stefanos Kales, M.D., of Harvard Medical School in Cambridge, Mass., and colleagues examined the duty-specific risks of death from coronary heart disease among U.S. firefighters between 1994 to 2004, excluding those from the Sept. 11, 2001 terrorist attacks.

Using data from the Federal Emergency Management Agency, the investigators found that 32.1 percent of coronary heart disease-related active duty deaths were associated with fire suppression. Others occurred in firefighters responding or returning from an alarm (13.4 and 17.4 percent, respectively), and while performing non-emergency duties (15.4 percent).

"Although at least moderate exercise may mitigate the trigger effects of extreme exertion, minimizing the overall risk involves the usual menu of primary and secondary prevention measures," according to Linda Rosenstock, M.D., and Jorn Olsen, M.D., Ph.D., of the University of California Los Angeles, in an accompanying editorial. "These measures include promoting healthy behaviors (such as a heart-healthy diet, no tobacco or excessive alcohol, and regular exercise) and modifying conditions (such as hypertension, diabetes and obesity) that pose additional risks."

AbstractFull TextEditorial

Port-Wine Stains Redarken After Laser Treatment

Ten-year follow-up shows that, despite continued treatments, stains often redarken

Redarkening of port-wine stain capillary malformations can occur many years after standard pulsed-dye-laser treatment, researchers report in the March 22 issue of the New England Journal of Medicine.

Menno Huikeshoven, M.D., Ph.D., from the University of Amsterdam in the Netherlands, and colleagues performed a 10-year follow-up of a previously conducted prospective study to investigate the long-term effect of pulsed-dye-laser treatment of port-wine stains. Overall, 51 of the original 89 patients were included in the study.

Although the patients had received a median of seven additional treatments since the original five average treatments in the initial study, objective color measurements determined that the stains were significantly darker than after the initial treatments. The stains were lighter than before treatment, however. While 59 percent of patients reported that the stain color was unchanged since the last treatment, 6 percent said it was lighter and 35 percent said it was darker.

"Although pulsed-dye-laser therapy remains the gold standard for the treatment of port-wine stains and has a persistent beneficial effect, the current study objectively shows that redarkening occurs at long-term follow-up," the authors write. "Therefore, we recommend that before commencing pulsed-dye-laser therapy, all patients should be informed of the possibility of redarkening of the stain after treatment."

AbstractFull Text (subscription or payment may be required)

Vitiligo-Associated Autoimmune Disease Gene Identified

Linkage study implicates innate immune system in autoimmune/autoinflammatory disease

A mediator of the innate immune system may play a key role in the development of vitiligo and several epidemiologically related autoimmune and autoinflammatory diseases, according to a report in the March 22 issue of the New England Journal of Medicine.

Richard Spritz, M.D., of the University of Colorado at Denver and Health Sciences Center in Aurora, Colo., and colleagues collected DNA from 656 individuals from 114 families in the United States and United Kingdom. Each family had at least two members with vitiligo and at least one with an additional, associated autoimmune or autoinflammatory disease. The team genotyped single-nucleotide polymorphisms (SNPs) on the short arm of chromosome 17 to identify genes linked to vitiligo-associated multiple autoimmune disease.

The team identified a region with a maximal multipoint lod score of 4.59 and centered at 4.3 cM, that likely contained a gene associated with the disease. SNP genotyping and DNA sequencing identified one candidate gene, NALP1 (NACHT leucine-rich-repeat protein 1, a gene implicated in the innate immune response). Variants of the gene were associated with vitiligo alone, autoimmune and autoinflammatory disease, or both. At least two independent variants, one within the gene itself and a second in the promoter, contributed to disease risk.

The authors note, however, that "the SNPs that we have implicated may not be the causal variants; identification of such variants will require the demonstration of specific effects on NALP1 transcription, mRNA, or protein function."

AbstractFull Text (subscription or payment may be required)Editorial

Transplants Show Promise for Herniated Cervical Disc

Fresh-frozen composite disc allografts show good results in preliminary study

A preliminary study of five patients suggests that intervertebral disc transplantation can be used to treat degenerative spinal disease, according to a report in the March 24 issue of The Lancet.

Keith D.K. Luk, F.R.C.S., of the University of Hong Kong, and colleagues performed the transplants with fresh-frozen composite disc allografts after disc excision in five patients who had cervical disc herniation. The patients, who had an average age of 47, were followed-up for a minimum of five years.

Three months after surgery, all patients showed good union of the graft endplates, and by the end of follow-up all reported improvements in neurological symptoms compared with those prior to surgery. There were signs of mild disc degeneration but motion and stability of the spinal unit was preserved and there was no immunoreaction or olisthesis.

"On the basis of experience gained from the initial five patients?a second series of patients has undergone allograft transplantation with modified techniques. We are also pursuing further experiments in non-degenerated grafts serving as a scaffold for cell and growth factor treatment," the authors conclude.

Such disc transplantation "could open a new dimension in the treatment of degenerative disc disease," according to the authors of an accompanying editorial.

AbstractFull Text (subscription or payment may be required)Editorial

Study Suggests Lamotrigine Is Drug of Choice for Epilepsy

It is a cost-effective alternative to the standard drug treatment, carbamazepine

Lamotrigine is a better, cost-effective alternative to the standard drug treatment for partial-onset epilepsy, carbamazepine, according to the results of a randomized trial of five different medications published in the March 24 issue of The Lancet.

Anthony G. Marson, M.D., of the University of Liverpool in the U.K., and colleagues conducted an unblinded, randomized, controlled trial of carbamazepine, gabapentin, lamotrigine, oxcarbazepine and topiramate in 1,721 patients recruited from hospital-based outpatient clinics in the United Kingdom. The study outcomes were time to treatment failure and 12-month remission.

Lamotrigine was a significantly better drug in terms of time to treatment failure compared to carbamazepine, gabapentin and topiramate. In terms of time to 12-month remission, carbamazepine performed better than gabapentin, while the results suggested it had an insignificant advantage over lamotrigine, topiramate and oxcarbazepine. When the data was analyzed to ascertain the proportion of patients who went into remission for 12 months, there was no advantage to using carbamazepine versus lamotrigine.

"Two further antiepileptic drugs have been licensed in the United Kingdom since this study was designed (levetiracetam and zonisamide), both of which are said to be effective in generalized epilepsies," the authors write. "The same question that applied to lamotrigine and topiramate now apply to these drugs, for which we need similarly robust comparative trials against valproate in similar populations of patients."

AbstractFull Text (subscription or payment may be required)Editorial

Bisphosphonates Stave Off Bone Loss in Prostate Cancer

Once-weekly alendronate increases bone mineral density, reduces bone turnover

Once-weekly oral bisphosphonate therapy can stave off bone loss among men with prostate cancer who are undergoing androgen deprivation therapy, according to a report in the March 20 issue of the Annals of Internal Medicine.

Susan L. Greenspan, M.D., of the University of Pittsburgh, and colleagues randomized 112 men with prostate cancer to receive either 70 mg of alendronate once weekly or placebo. All study participants received calcium and vitamin D.

When the study began, 39 percent of men had osteoporosis and 52 percent had low bone mass. At one year, bone mineral density increased by 3.7 percent in the spine and 1.6 percent in the femoral neck among men who took alendronate. Men in the placebo group experienced losses at these sites. There was a net bone mineral density difference of 5 percent at the spine and 2 percent at the femoral neck among the two groups. Rates of bone turnover also decreased among men taking alendronate. The study did not assess differences in fractures.

"It is important for physicians to evaluate these patients' skeletal integrity and provide timely and appropriate preventive and therapeutic measures," the study authors conclude.

Greenspan has received funding and honoraria from Merck & Co., although the company did not fund the study.

AbstractFull Text

Rheumatoid Arthritis Therapies Have Similar 2-Year Results

Frequent monitoring and adjustment of therapy are key to effective treatment

An analysis of four treatment strategies suggests that all can limit the progression of rheumatoid arthritis if patients are monitored frequently and their therapy adjusted, although combination therapy is initially more successful at controlling the disease. The findings are published in the March 20 issue of the Annals of Internal Medicine.

Yvonne Goekoop-Ruiterman, M.D., of Leiden University Medical Center in Leiden, the Netherlands, and colleagues compared four treatment approaches in 508 patients with early rheumatoid arthritis: sequential monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with tapered high-dose prednisone (group 3), and initial combination therapy with infliximab (group 4). Therapies were adjusted every three months during the two-year study depending on functional ability and radiographic joint damage.

Two-thirds of patients in groups 1 and 2 required treatment adjustment, compared to 42 percent in group 3 and 28 percent in group 4. At two years, 33, 31, 36 and 53 percent of patients in groups 1 through 4, respectively, were maintained on just one drug. Physical function improved in all groups over two years, by a mean 0.6 points (as measured by health assessment questionnaire), and at the end of two years, 42 percent of all patients were in remission (compared to 31 percent after one year).

"Initial combination therapies seem to provide earlier clinical improvement and less progression of joint damage, but all treatment strategies eventually showed similar clinical improvements. In addition, combination therapy can be withdrawn successfully and less treatment adjustments are needed than with initial monotherapies," the authors write. "With intensive and objective monitoring of disease activity and adjustments of therapy, low disease activity is a realistic goal that can be achieved with all treatment strategies."

AbstractFull TextEditorial

Too Many Barriers Deprive Dying Patients of Hospice Care

Helping physicians strategize about discussing a patient's prognosis could help

Only one-third of terminally ill patients in the United States seek hospice care, but removing barriers to talking about such care could allow more patients to use the support earlier in their illness, researchers report in the March 20 issue of the Annals of Internal Medicine.

David J. Casarett, M.D., of the Philadelphia Veterans Affairs Medical Center, and colleagues analyzed ways of discussing hospice admission with patients with limited or uncertain life expectancy, and different attitudes towards seeking treatment or cures. They note that the median hospice stay lasts three weeks, and 10 percent of patients enter hospice care on the last day of their lives.

Barriers to discussing hospice care included a Medicare eligibility requirement that patients have six months to live and give up seeking cures, and patients' and families' aversion to the idea that patients have such limited life expectancy, the researchers found.

"Physicians can overcome many of these challenges by considering indicators of a limited prognosis, framing the hospice discussion in terms of the patient's goals and needs for care, and recommending hospice when they think it is the best option," the authors write.

AbstractFull Text

Depression Similar in Primary Care, Specialty Setting

Study suggests aggressive management strategies needed in both settings

The symptoms and severity of depression, including suicide risk, are similar in patients being treated in primary care and specialty settings, according to the results of a study published in the March/April issue of the Annals of Family Medicine.

Bradley N. Gaynes, M.D., from the University of North Carolina in Chapel Hill, and colleagues measured baseline depression in 2,541 patients with major depressive disorder who were being treated at 41 clinics, including 23 specialty care sites.

Patients at both settings had similar levels of depression as measured by the 30-item Inventory of Depressive Symptomatology -- Clinician Rated and the Psychiatric Diagnostic Screening Questionnaire. Patients in each setting showed similar levels of suicide risk and anxiety disorders including social phobia.

"In this large, broadly inclusive U.S. sample, the risk factors for chronic and recurrent depressive illness were frequently present, highlighting a clear risk for treatment resistance and the need for aggressive management strategies in both settings," the authors write.

The authors report numerous affiliations with pharmaceutical companies.

AbstractFull Text

Lawsuit Does Not Change Physican Approach to Patients

Patients just as likely to play role in screening decision, even after lawsuit on shared decision making

Physicians in a Virginia practice continued to share decision-making with patients even after a member of the practice was successfully sued by a prostate cancer patient who had declined prostate-specific antigen testing. The findings are published in the March/April issue of the Annals of Family Medicine.

Alex Krist, M.D., and colleagues from Virginia Commonwealth University in Fairfax, Va., analyzed data from an ongoing randomized, controlled trial of patient-physician prostate screening discussions. During the study, a physician was successfully sued at the practice after allowing a patient to make his own decision about screening.

Using patient and physician questionnaire responses, the investigators found that patients were just as likely to report having a say in their decision before, during and after the lawsuit (91, 87 and 90 percent, respectively). However, after the lawsuit, physicians were more than three times as likely to say they made the final decision about screening (3.3 percent before, 11.1 percent after). Prostate-specific antigen testing increased by 6 percent, though national rates stayed the same during that time.

"At least in this limited setting of patient-physician discussions of prostate-specific antigen screening, our data on the shared decision-making process do not support the premise of defensive medicine -- that the threat or experience of adverse litigation will alter clinician behavior," the authors write.

Krist is a partial owner of a family practice residency where the study was conducted.

AbstractFull Text

Myocardial Infarct Mortality Similar in Urban, Rural Setting

After adjustment for confounding factors, researchers find mortality not different between two settings

After controlling for confounders, myocardial infarction mortality is similar for patients treated at urban and rural hospitals, according to the results of an Iowa study published in the March/April issue of the Annals of Family Medicine.

Paul A. James, M.D., and colleagues from the University of Iowa in Iowa City used data from 12,191 Iowa residents hospitalized for acute myocardial infarction at 116 hospitals across the state to compare in-hospital mortality in urban and rural regions.

Initially, the researchers found that the risk-adjusted mortality for urban and rural hospitals was 6.4 percent and 14 percent, respectively. However, mortality rates were similar after using an instrumental variable technique to adjust for the confounding factors such as patient age and severity of disease.

"Current methods to monitor quality may be flawed if they do not adequately control for selection bias caused by unmeasured confounders," the authors write. "By showing an important influence of such confounders, we believe that this study strongly challenges the contention that care for myocardial infarction is inferior in rural hospitals."

AbstractFull Text

Regular Health Exams Increase Cancer Screening

Those undergoing regular exams more likely to get mammography, prostate-specific antigen test, colorectal screening

Regular, preventive health examinations increase the likelihood that eligible patients will undergo screening for breast, prostate and colorectal cancer, according to study findings published in the March 26 issue of the Archives of Internal Medicine.

Joshua J. Fenton, M.D., of the University of California-Davis, and colleagues conducted a retrospective cohort study of 64,288 subjects, aged 52 to 78 years, enrolled in a Washington state health plan and eligible for colorectal, breast or prostate cancer screening. The authors sought to determine the extent to which preventive or periodic health care examinations contributed to cancer screening.

The investigators found that 52.4 percent of patients received a preventive health care examination during a period between 2002-2003. Receiving a preventive health care examination increased the likelihood of having colorectal cancer testing by 40.4 percent, screening mammography by 14.2 percent and prostate-specific antigen testing by 39.4 percent.

"The preventive health examination may serve as a clinically important forum for the promotion of evidence-based colorectal cancer and breast cancer screening and of prostate cancer screening, which is not universally recommended," the authors conclude.

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Web Reminder Increases Mammography Screening

Web-based system helps schedulers remind patients of exam dates

Use of the Web-based Preventive Care Reminder System, or PRECARES, which office staff use to remind patients to schedule a mammogram, helps increase screening rates, according to a report in the March 26 issue of the Archives of Internal Medicine.

Rajeev Chaudhry, of the Mayo Clinic in Rochester, Minn., and colleagues conducted a randomized, controlled trial of the Web-based PRECARES system to determine if automatic reminders can encourage the use of screening.

Overall, 3,326 women were assigned to the intervention group and received two monthly letters starting three months before screening was due, with an additional phone call for non-responsive patients. An additional 3,339 women were assigned to the control group.

The investigators found that the screening rate for the intervention group was 64.3 percent, compared to 55.3 percent for the control group. In a subgroup analysis of employees, e-mails were found to be better at increasing screening rates than letters or the control group (72.2, 68.1 and 57.5 percent, respectively).

"Many preventive screening services can be delivered without involvement of physicians or physician visits, and office staff can manage the preventive service needs of patients, which should also decrease the costs incurred by practices, patients and insurers," the authors write.

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Long-Term Aspirin May Cut All-Cause Mortality in Women

Findings pronounced in older women, those with cardiovascular risk

Long-term aspirin use may lower the risk of all-cause mortality for women, especially older women and those who have cardiovascular risk factors, according to a report in the March 26 issue of the Archives of Internal Medicine.

Andrew Chan, M.D., from Massachusetts General Hospital and Harvard Medical School in Boston, and colleagues conducted a prospective study of 79,439 women with no history of cardiovascular disease or cancer enrolled in the Nurses' Health Study to determine the influence of long-term aspirin use on total mortality in women.

The authors documented 9,477 deaths during the 24-year study period. Compared with no aspirin use, current use of aspirin cut all-cause mortality by 25 percent and cardiovascular disease mortality by 38 percent. The effect was more apparent in older women and in those with cardiovascular risk factors. Any effect on cancer rates, however, was not seen until after 10 years of aspirin use.

"These new findings by Chan et al. cannot overcome the accumulated evidence that aspirin is not particularly effective for the primary prevention of death from cardiovascular disease in women," warns John A. Baron, M.D., of Dartmouth Medical School in Lebanon, N.H., in an accompanying editorial. He argues that the Women's Health Study, which included 40,000 women, found no difference in mortality from aspirin use over 11 years.

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Nitric Oxide May Harm Patients with Acute Lung Injury

While it improves oxygenation in short-term, nitric oxide seems to inflict renal damage without reducing mortality rates

Nitric oxide offers adults and children with acute lung injury or acute respiratory distress syndrome some modest, temporary benefits in terms of oxygenation, but it does not reduce death rates and may cause kidney damage, researchers report in a study published online March 23 in BMJ.

Neill K.J. Adhikari, M.D., of the University of Toronto in Canada, and colleagues analyzed 12 placebo-controlled studies of nitric oxide in 1,237 patients with acute respiratory distress syndrome or acute lung injury.

Nitric oxide had no major impact on ventilator-free days, ventilation duration or hospital deaths. On the first day, patients treated with nitric oxide experienced a 14 percent drop in the oxygenation index and a 13 percent increase in the ratio of partial pressure of oxygen to fraction of inspired oxygen. Although oxygenation benefits lasted until day four, the risk of renal damage was 1.5 times greater than in those treated with placebo.

"Nitric oxide is associated with limited improvement in oxygenation in patients with acute lung injury or acute respiratory distress syndrome but confers no mortality benefit and may cause harm," the authors write. "We do not recommend its routine use in these severely ill patients."

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Minimally Invasive CABG May Be Better Than Stent

Three studies suggest stents are less efficacious and cost-effective than minimally invasive bypass surgery for some patients

When it comes to revascularizing the heart, some patients may be better off with minimally invasive coronary artery bypass than stenting, according to three reports published in the March 24 issue of BMJ. The findings call into question the proliferation of stent procedures, which now outnumber surgical interventions by four-to-one.

Thanos Athanasiou, M.D., Ph.D., of Imperial College London, and colleagues performed a meta-analysis of 12 studies encompassing 1,952 patients that compared stenting and minimally invasive left internal thoracic artery bypass in patients with isolated lesions of the left anterior descending artery.

There was no difference in the rate of myocardial infarction, stroke or mortality. However, recurrence of angina (odds ratio, 2.62), the risk of repeat revascularization (OR, 4.63) and major adverse coronary and cerebral events (OR, 2.86) were higher in patients who had stents. An additional study by Athanasiou found that bypass surgery was more cost-effective than stents for such patients. And a third study by Harry Hemingway, M.D., of the University College London Medical School, found that stenting was not cost-effective compared to bypass grafting or medical management alone, depending on the type of lesions.

"A multidisciplinary approach should be a minimum mandatory 'standard of care' to ensure that patients are offered the most clinically appropriate treatment," according to an editorial by David Taggart, M.D., Ph.D., of the University of Oxford, U.K.

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Cardiac Risk High in Women with Trans Fat Intake

Highest consumers of trans fat have triple the cardiac risk of women with lower intake

Women with the highest trans fat consumption have three times the risk of developing coronary heart disease as women with the lowest intake, researchers report in the March 26 issue of Circulation: Journal of the American Heart Association.

Frank B. Hu, M.D., Ph.D., of the Harvard School of Public Health in Boston, and colleagues analyzed data from 32,826 participants in the Nurses' Health Study. During six years of follow-up there were 166 incident cases of coronary heart disease, and these were matched with 327 controls.

There was an association between dietary intake of trans fats and total trans fatty acid content in erythrocytes, as well as increased plasma low-density lipoprotein cholesterol and decreased plasma high-density lipoprotein cholesterol. The association was sustained even when factors such as age, smoking status and other cardiovascular risk factors were taken into account. Women in the highest quartile of intake were 3.3 times as likely to have heart disease as those in the lowest quartile.

"Trans fat intake has been substantially reduced in European countries, whereas intake in the United States is relatively stable," the authors conclude. "Elimination of partially hydrogenated oils and other sources of trans fat from diet is likely to make an important contribution to the goal of reducing the burden of cardiovascular disease."

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AHA Recommends Statins for Child Hypercholesterolemia

AHA statement calls for more intense monitoring of children with high cholesterol

Statins should be the first choice of medication for high-risk children who meet the criteria to start cholesterol-lowering therapy, according to new recommendations from the American Heart Association (AHA) published online March 21 in Circulation: Journal of the American Heart Association.

Brian W. McCrindle, M.D., of the University of Toronto in Ontario, Canada, and colleagues examined data published since the dissemination of the 1992 National Cholesterol Education Program (NCEP) guidelines on cholesterol treatment in children.

While lifestyle changes are still the best way to treat high cholesterol in children, the new recommendations suggest starting statins in children whose low-density lipoprotein levels are greater than or equal to 190 milligrams per deciliter of blood. By contrast, the current NCEP guidelines advocate the use of bile acid-binding resins. The threshold for drug therapy should be lowered among children with high-risk lipid abnormalities who have additional risk factors or high-risk conditions, according to the new recommendation.

Children who are overweight or obese in addition to having a family history of heart disease should have their fasting lipid profile evaluated. Moreover, children who are overweight or obese should also be screened for the presence of risk factors associated with the metabolic syndrome.

"This new statement addresses a greater need for recognizing young patients with multiple risk factors and how those factors could influence the decision to treat with medications or not," McCrindle said in a statement.

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Bronchodilators Not Needed Before Bronchoscopy

In COPD patients, premedication neither improves safety nor prevents decreased lung function

It may be unnecessary to administer short-acting beta-agonists prior to bronchoscopy in patients with chronic obstructive pulmonary disease (COPD), according to study findings published in the March issue of Chest.

Daiana Stolz, M.D., of the University Hospital Basel in Basel, Switzerland, and colleagues randomly assigned 120 patients to receive either salbutamol, placebo or no inhaled medication prior to bronchoscopy.

After bronchoscopy, the researchers found that forced expiratory volume in one second (FEV1) decreased by a median of 4.7 percent in the salbutamol group, 4.8 percent in the placebo group, and 10 percent in the group that received no inhaled medication.

"The inhalation of salbutamol neither improved safety nor prevented decrease in FEV1," the authors write. "Thus, routine inhalation of a short-acting beta-agonist cannot be recommended as a premedication for bronchoscopy in COPD patients."

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Inhaled Corticosteroids Help COPD in Short-Term Only

Short-term treatment results in improved lung function, but long-term treatment is ineffective

Patients with chronic obstructive pulmonary disease (COPD) may benefit from six months of treatment with inhaled corticosteroids. Longer-term treatment, however, is no better than placebo at improving lung function, according to study findings published in the March issue of Chest.

Joan B. Soriano, M.D., of the International Center for Advanced Respiratory Medicine, Bunyola, Mallorca in Illes Balears, Spain, and colleagues pooled the results of seven studies including 3,911 patients with moderate to severe chronic obstructive pulmonary disease. Patients were randomly assigned to receive either inhaled corticosteroids or placebo for more than 12 months.

The researchers found that the first six months of inhaled corticosteroid use resulted in a significant mean increase of 2.42 in forced expiratory volume in one second (FEV1) compared to placebo. Short-term therapy was most likely to improve lung function in ex-smokers, especially female ex-smokers, according to the study. But the researchers also found that longer-term inhaled corticosteroid use (six to 36 months) was no more effective than placebo at halting a decline in lung function.

"Previous meta-analyses on this topic, because they relied largely on published data, could not differentiate the short-term effects from the long-term effects of inhaled corticosteroid therapy," the authors write. "Moreover, they could not determine the potential modifying effects of gender and smoking status on FEV1 changes related to corticosteroid therapy."

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ACC: Tilarginine Does Not Cut Cardiogenic Shock Death Risk

After six months, 58 percent of patients on tilarginine die, versus 59 percent on placebo

The once-promising drug, tilarginine acetate, does not decrease mortality risk for patients up to six months after acute myocardial infarction and cardiogenic shock, researchers report in the March 26 online edition of the Journal of the American Medical Association. The findings were released early to coincide with the American College of Cardiology meeting in New Orleans.

Judith S. Hochman, M.D., of the New York University School of Medicine in New York City, and colleagues compared the effects of tilarginine with placebo in 658 unstable myocardial infarction patients with cardiogenic shock treated at 130 medical centers from January 2005 to August 2006.

The study was halted at 398 patients after reaching a pre-determined futility benchmark. At six-month follow-up, death rates were similar between patients on tilarginine and placebo, as were the duration of shock and its resolution.

After one month, 48 percent of tilarginine patients had heart failure, versus 51 percent on placebo. After six months, 58 percent of tilarginine patients died, versus 59 percent on placebo.

"Tilarginine, 1-mg/kg bolus and five-hour infusion, did not reduce mortality rates in patients with refractory cardiogenic shock complicating myocardial infarction, despite an open-infarct artery," the authors write. "Early mortality rates in this patient group are high."

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Adjunct Antidepressants Ineffective for Bipolar Disorder

No improvement in mood stabilizer effectiveness, no effect on risk of treatment-emergent affective switch

Adjunct antidepressant therapy does not improve the effectiveness of mood stabilizers in treating bipolar disorder, nor does it affect the risk of treatment-emergent affective switch, according to the results of a study released online March 28 in the New England Journal of Medicine.

Gary S. Sachs, M.D., from Massachusetts General Hospital in Boston, and colleagues treated 366 subjects with bipolar depression with a mood stabilizer plus a placebo, or with a mood stabilizer plus antidepressant therapy for 26 weeks.

The researchers found that similar percentages of subjects in the placebo group (27.3 percent) and the antidepressant group (23.5 percent) had a durable recovery, which was defined as eight consecutive weeks of euthymia. The two groups were also similar in terms of rates of treatment-emergent affective switch, the report indicates.

"The use of adjunctive, standard antidepressant medication, as compared with the use of mood stabilizers, was not associated with increased efficacy or with increased risk of treatment-emergent affective switch," Sachs and colleagues conclude.

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Mutant Telomerase Present in Some Pulmonary Fibrosis

Study finds that 8 percent of probands have heterozygous mutations, leading to short telomeres

Some families with idiopathic pulmonary fibrosis have mutations in telomerase components and short telomeres, researchers report in the March 29 issue of the New England Journal of Medicine.

Mary Y. Armanios, M.D., from the Johns Hopkins University School of Medicine in Baltimore, Md., and colleagues screened 73 probands with idiopathic pulmonary fibrosis for mutations in human telomerase reverse transcriptase and human telomerase RNA.

The researchers found that six probands (8 percent) had heterozygous mutations in either telomerase component, resulting in short telomeres. Short telomeres were also found in asymptomatic individuals with mutant telomerase. Dyskeratosis congenita, a hereditary disorder also caused by mutations in the same two telomerase components, was not observed in five of the six affected families.

"Mutations in the genes encoding telomerase components can appear as familial idiopathic pulmonary fibrosis," the authors conclude. "Our findings support the idea that pathways leading to telomere shortening are involved in the pathogenesis of this disease."

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MRI Recommended for Breast Cancer Screening

Study finds MRI has high sensitivity, specificity for contralateral breast cancer

Magnetic resonance imaging (MRI) of the contralateral breast in women with breast cancer can detect occult cancers that are missed by mammography, according to study findings published online March 28 in the New England Journal of Medicine. The results were released at the same time as new guidelines from the American Cancer Society (ACS), which recommend annual MRIs in addition to mammograms for high-risk women.

The ACS suggests that MRIs be conducted along with mammograms beginning at age 30 in women with BRCA1 or BRCA2 gene mutations, a 20 to 25 percent lifetime risk of breast cancer, chest irradiation between the ages of 10 and 30 or other high-risk conditions, such as Li-Fraumeni syndrome.

In the study, Constance D. Lehman, M.D., Ph.D., from the University of Washington Medical Center in Seattle, and colleagues performed MRI on the contralateral breast of 969 women with a recent diagnosis of unilateral breast cancer. The women showed no signs of cancer in the contralateral breast by clinical or mammographic examination.

The researchers found cancer in the contralateral breast of 3.1 percent of the women, with a sensitivity of 91 percent, a specificity of 88 percent and a negative predictive value of 99 percent.

"This study gives us a clearer indication that if an MRI of the opposite breast is negative, women diagnosed with cancer in only one breast can more confidently opt against having a double (or bilateral) mastectomy," said John E. Niederhuber, M.D., director of the National Cancer Institute, in a statement.

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