ATLANTA — For patients with permanent atrial fibrillation, lenient control of heart rate does not result in worse outcomes than stricter control, a multicenter, randomized trial showed.

Through three years, the rate of adverse outcomes was similar in the two groups (12.9% with lenient control and 14.9% with strict control), establishing noninferiority for the lenient approach, according to Isabelle Van Gelder, MD, of University Medical Center Groningen in the Netherlands, and colleagues.

The lenient group achieved its heart rate targets with significantly fewer total healthcare visits (75 versus 684, P<0.001), Van Gelder reported at the American College of Cardiology meeting here. The results were published simultaneously online in the New England Journal of Medicine.

“Lenient rate control is more convenient, since fewer outpatient visits, fewer examinations, lower doses of rate-control drugs, and less of the combination of drugs are needed,” Van Gelder said in her presentation.

“Therefore, lenient rate control may be adopted as the first-choice rate-control strategy in patients with permanent atrial fibrillation, and this applies to both high- and low-risk patients.”

Ralph Brindis, MD, MPH, a cardiologist at Kaiser Permanente in Oakland, Calif., and president-elect of the ACC, said at a press briefing at which the results were discussed that “the concept that you actually as a clinician can feel comfortable having a patient at a higher resting heart rate is huge.”

He added, however, that choice of treatment needs to be patient-focused, “because if the patient is not doing well with a high resting heart rate, or with exercise heart rate goes way up, then that’s a patient we might clearly want to be more aggressive with.”

Van Gelder said the results call into question existing guidelines. Recommendations from the ACC, American Heart Association, and European Society of Cardiology advise strict heart rate control — a heart rate less than 80 beats per minute at rest and less than 110 bpm during moderate exercise — to improve outcomes. That advice is not based on clinical evidence.

Van Gelder said she thinks the guidelines should be changed to reflect the new findings.

But Brindis disagreed, pointing to the relatively small number of patients included in the study.

“I don’t think I would change our guidelines at this time,” he said, adding, however, that “I find [the study] a little freeing.”

To see whether more lenient control — a heart rate less than 110 bpm at all times — would work as well as strict control at preventing cardiovascular morbidity and mortality, Van Gelder and colleagues undertook the RACE II trial at 33 centers in the Netherlands.

All 614 patients had permanent atrial fibrillation for up to 12 months (median three months), were 80 or younger (mean age 68), and had a mean resting heart rate greater than 80 bpm at baseline.

The two groups of patients were well-matched at baseline, except for a higher prevalence of coronary artery disease and statin use, and higher diastolic pressure, in the lenient group.

During a dose-adjustment phase, patients in both groups were given one or more negative dromotropic drugs until the heart rate target or targets were achieved. At the end of this phase, the mean resting heart rate was 93 bpm in the lenient group and 76 bpm in the strict group (P<0.001).

Nearly all of the patients in the lenient group (97.7%) reached their target, compared with just 67% of the strict group (P<0.001).

The primary endpoint was a composite of cardiovascular death, heart failure hospitalization, stroke, systemic embolism, major bleeding, arrhythmic events, life-threatening adverse effects from the rate-control drugs, and implantation of a pacemaker or cardioverter-defibrillator.

Through follow-up lasting two to three years, 12.9% of the patients in the lenient group and 14.9% in the strict group reached that endpoint (absolute difference -2%, 90% CI -7.6% to 3.5%). Because the upper bound of the confidence interval was less than 10%, noninferiority of the lenient approach was established.

Rates of most of the components of the primary endpoint were also similar in the two groups. The lone exception was stroke, which occurred less frequently in the lenient group (1.6% versus 3.9%; HR 0.35, 95% CI 0.13 to 0.92).

Ralph Sacco, MD, a neurologist at the University of Miami in Florida, said there was no clear explanation for the difference in stroke risk, although it could have something to do with the increased number of visits in the strict group.

“Obviously, when there’s closer follow-up and closer observation, it may be that investigators more easily recorded vascular symptoms including stroke,” said Sacco, incoming president of the AHA.

Van Gelder noted that the numbers of strokes were low, precluding firm conclusions.

Symptoms of atrial fibrillation, hospitalizations, and adverse events occurred at similar rates in the two groups.

In an editorial that accompanied the NEJM article, Paul Dorian, MD, of St. Michael’s Hospital in Toronto, noted a number of limitations in the study: It is possible that rapid ventricular rates may take many years to result in cardiac deterioration, illness, or death, and thus, the benefits of strict rate control might take decades to become apparent. The subgroup that may have a particular benefit from strict rate control — patients with atrial fibrillation who have very rapid ventricular responses — may have been underrepresented. The data on symptoms and quality of life were somewhat limited. As in all randomized trials, selection bias might have limited enrollment to patients who were relatively well.

Nevertheless, he wrote, “a heart-rate target of less than 110 beats per minute at rest, although it may make physicians feel uncomfortable, is probably as useful as the current guideline-recommended target heart rates at rest and during exercise, at least in the medium term.”

Sacco noted that if clinicians don’t have to worry about rate control, they can concentrate on controlling other risk factors and oral anticoagulation.

“If we now know that a lenient rate control is as good as strict rate control, if not slightly better for stroke risk, I think that’s one less thing we have to be focused on.”

The study was supported by the Netherlands Heart Foundation and unrestricted educational grants from AstraZeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, Medtronic, Roche, and Sanofi Aventis France (paid to the Interuniversity Cardiology Institute of the Netherlands).

Van Gelder reported receiving consulting fees from sanofi-aventis, Boehringer Ingelheim, and Cardiome, grant support from Medtronic, Biotronik, and St. Jude Medical, and lecture fees from sanofi-aventis, Boehringer Ingelheim, and Medtronic. Her co-authors reported relationships with Boehringer Ingelheim, sanofi-aventis, AstraZeneca, St. Jude Medical, Boston Scientific, Medapharma, Merck, Medtronic, Biosense Webster, Amgen, Pfizer, Biosite-Inverness, and Menarini.

Dorian reported receiving consulting fees from Sanofi, Boehringer Ingelheim, Cardiome, and St. Jude Medical, and grants, honoraria, and payment for the development of educational programs from Sanofi and Boehringer Ingelheim.

Oral cancer’s spread to the mandible could not hide from a type of MRI that may facilitate more accurate staging and surgical planning, data from laboratory studies suggest.

Sweep imaging with Fourier transform (SWIFT) provided fine-detail views of cortical and medullary bone specimens, and the images exhibited good correlation with histopathologic findings.

The in-vitro studies did not specifically examine SWIFT’s ability to identify early cortical bone invasion by oral cancer. However, the high-quality images obtained from the investigation provide reason for optimism, the researchers reported in the September issue of Archives of Otolaryngology Head and Neck Surgery.

“Our study is very promising in that it offers a SWIFT-based MRI technique for accurate assessment of minute changes of cortical and medullary bone in three dimensions without any ionizing radiation,” Ayse Tuba Karagulle Kendi, MD, of the University of Minnesota in Minneapolis, and co-authors wrote.

“It has the potential to precisely determine the extent of mandibular bone invasion associated with oral carcinoma. This study is a crucial step toward the goal of developing a robust and noninvasive approach for preoperative imaging of mandibular invasion,” they added.

Carcinoma of the oral cavity often spreads to the mandible, but in many instances does not cross the periosteal layer, obviating the need for mandibulectomy. Limitations of current imaging techniques often preclude determination of bone invasion prior to surgery, the authors noted.

MRI and CT have been used most often to evaluate mandibular invasion of oral cancer, but conventional protocols in both modalities have drawbacks that often lead to unsatisfactory images.

The development of SWIFT has created new opportunities for more accurate preoperative assessment of the mandible in patients with carcinoma of the oral cavity, the authors continued. Employing time-shared excitation and signal acquisition, SWIFT allows detection of signals with a broad range of relaxation times, facilitating finely delineated evaluation of cortical and medullary bone.

The principal advantage of SWIFT involves to its protocol of near-simultaneous excitation and acquisition.

“SWIFT obtains signal from cortical bone that has a fast-decaying signal, produces less distortion from magnetic susceptibility, and is less sensitive to motion artifacts,” Kendi and colleagues wrote.

To assess the feasibility of SWIFT to detect bone invasion by oral cancer, the authors examined two mandibular specimens obtained from segmental resections. Imaging was performed by means of a 9.4-T, 31-cm horizontal MRI scanner, using a home-built, single-loop, 25-mm coil.

The SWIFT sequence involved excitation bandwidth and acquisition spectral width of 125 kHz, repetition time of 2.5 milliseconds, and 128,000 projections. Acquisition time averaged about eight minutes.

“SWIFT images of the specimens revealed detailed bone and soft-tissue anatomy, including soft-tissue tumor, cortical bone, and medullary bone,” the authors wrote in describing the images they obtained. “SWIFT demonstrated fine anatomic details, including nutrient vessels and fine trabecular bone structure.”

“SWIFT produced evidence of cortical bone invasion as cortical interruption of the hypointense signal of cortical bone. Medullary bone invasion was also demonstrated in both specimens as extension of soft-tissue tumor into the medullary cavity and replacement of medullary fat with tumor,” they said.

SWIFT imaging provided finely detailed images of the demarcation between tumor-free medullary bone and tumor invasion, they added.

“The correlations between the histologic and MR images of these two specimens clearly show malignant invasion that has not been previously demonstrated with MR techniques,” Kendi and colleagues wrote in their discussion of the findings. “The data described in this report suggest that [SWIFT] MRI has a great deal of potential in accurately determining bone invasion preoperatively.”

Co-authors Djaudat S. Idiyatullin and Michael Garwood disclosed relationships with Steady State Imaging.

Idiyatullin, Garwood, and co-author Curtis A. Corum disclosed royalty interests in products related to the research described in the article.

ORLANDO — A subset analysis of data from the JUPITER trial indicates that apparently healthy women treated with rosuvastatin (Crestor) reduced their relative risk of major cardiovascular events by 46%, slightly higher than the 42% reduction seen in men.

Analysis of outcomes from the 6,801 women enrolled in the 17,802-patient trial suggests that the benefit of statin therapy in patients whose only risk factors are age and an elevated level of C-reactive protein is not gender-specific, as had been suggested by some skeptics when full JUPITER results were reported a year ago.

The benefit in women was mainly driven by a 76% reduction in the need for arterial revascularization compared with placebo (P<0.001), Samia Mora, MD, MPH, of the Brigham and Women’s Hospital in Boston, reported at the American Heart Association meeting here.

In terms of safety, rosuvastatin was not associated with a significant increase in myopathy or cancer in men or women, but, compared with placebo, there was a higher incidence of physician-reported diabetes in women on rosuvastatin (1.59% versus 1.05%, respectively, P=0.008) but not in men (1.48% versus 1.32%, respectively, P=0.29).

Over the course of the past year a number of additional analyses of the data have been reported at cardiology meetings, and the publication list of JUPITER findings has grown almost monthly.

In each case those additional analyses have targeted areas — such as gender — that were flagged as possibly problematic when the results were initially reported, and in each case the observed benefit has been similar and significant, for example a 46% risk reduction versus placebo for women (P=0.002) and 42% versus placebo for men (P=0.001).

Here at AHA, another post-hoc analysis drilled down to patients who achieved LDL levels of less than 50 mg/dL and found that they had no increased risk of adverse events but did achieve a reduction in cardiovascular events similar to that seen in patients with levels above 50 mg/dL.

A third analysis found that the subset of patients with impaired fasting glucose at baseline also achieved similar benefits from rosuvastatin versus placebo.

“The JUPITER trial is phenomenal in that it provides information on a very important topic; the use of statins for primary prevention of cardiovascular disease in men and in women at risk based on elevated C-reactive protein,” said Mary Cushman, MD, of the University of Vermont in Burlington.

“The findings of relative risk reduction with statin treatment in women is important and was observed in all subgroups shown. The number needed to treat in women was higher in order to prevent one cardiovascular event over five years; however, this number was still very reasonable,” Cushman, who was not involved in the trial, added.

Based on this analysis, treating 36 women with 20 mg of rosuvastatin for less than two years would prevent one heart attack, cardiovascular death, stroke, or revascularization, which was slightly higher than the NNT of 25 reported for the total JUPITER population, “but still a very reasonable number,” said Cushman.

In the landmark trial, 17,802 men and women, mean age 66 and no history of atherosclerosis, who had an elevated biomarker for inflammation — highly sensitive C-reactive protein — were randomized to aggressive lipid therapy with 20 mg rosuvastatin or to placebo.

Participants who took rosuvastatin for 1.9 years reduced median LDL cholesterol to 55 mg/dL, down from a median of 108 mg/dL. The corresponding reduction in the rate of MI, stroke, arterial revascularization, or cardiovascular death was 44% (P<0.00001).

The JUPITER trial was funded by AstraZeneca.

Mora has disclosed research grants from Merck and AstraZeneca, and grants for educational activities from Pfizer.

Cushman disclosed research funding from Amgen.

SAN FRANCISCO — Pretreating patients for two days with high dose atorvastatin (Lipitor) before elective stenting does not reduce the incidence of periprocedural myocardial infarction, researchers reported here.

The incidence of MI based on troponin I release was 17% in patients who received statins versus 16% in those who did not, while the rates based on creatine kinase-MB (CK-MB) were 10% and 12%, respectively, said Josef Veselka, MD, of University Hospital Motol in Prague, Czech Republic.

Veselka reported results of the STATINS PRE-PCI trial at the Transcatheter Cardiovascular Therapeutics meeting.

The trial randomized 100 patients with stable angina to atorvastatin 80 mg for two days prior to stenting and 100 patients to stenting without pretreatment.

Results from the randomized patients were also compared with a registry of 193 patients who were on maintenance statin therapy before stenting.

Troponin I and CK-MB were measured 16 to 24 hours after stenting.

The two arms of the randomized study were well matched, except for gender — 54% of the atorvastatin patients were men, while men accounted for 79% of the control group (P<0.001).

The study was powered to demonstrate a reduction in the primary endpoint from 18% in the control group to 5% in the atorvastatin group, Veselka said.

The findings appear to contradict a series of published studies — most recently NAPLES II, which found that an 80 mg atorvastatin loading dose reduced the incidence of perioperative MI by 6.3% (P=0.014).

Those reports also included the published results of a pilot, nonrandomized study by Veselka et al that found a significant reduction in events for patients who were taking simvastatin (Zocor) 20 mg prior to stenting versus patients who were not on statin therapy (12% versus 20%, P=0.04).

Veselka acknowledged the dissonance with previous studies but said that the majority of those studies, including NAPLES II, “came from the same country [Italy],” which could limit the generalizability of the findings.

Moreover, he said he doubted the magnitude of the benefit reported in the previous studies “which is why we believed there was a need for this trial.”

Gregory J. Dehmer, MD, of the Scott and White Clinic in Temple, Texas, who moderated the session where Veselka presented PRE-PCI, pointed out that the benefit of an “atorvastatin bomb” as the high dose is sometimes known, is not new and is likely to have some credibility.

In 1999 the AVERT trial found that patients with stable coronary artery disease who were randomized to 80 mg atorvastatin had a lower event rate than patients randomized to balloon angioplasty (N Engl J Med 1999; 341: 70-76), Dehmer said.

And while “stents are better than balloons,” Dehmer cautioned the audience of interventional cardiologists that it might be wise not to challenge the statin contribution to improved outcomes.

No funding source for the trial was disclosed.

Veselka said that he did not “have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.”

Dehmer said he had no disclosures.

WASHINGTON, March 19 — Buildings with low-pollution certifications are still susceptible to spikes in fine particulates, researchers said here.

Although buildings that meet Leadership in Energy and Environmental Design (LEED) standards did have relatively low average levels of airborne particulates, the averages sometimes masked brief, massive surges, reported Patricia Fritz, M.Eng., of the New York Department of Health.

The findings, presented here at the American Academy of Allergy, Asthma, and Immunology annual meeting, suggest that LEED certification is an imperfect approach to guaranteeing indoor air quality.

The nongovernmental certification program originated in the international architecture and design community as a way to encourage “green” building technologies.

In addition to recommending materials and design methods to limit the impact on the outside environment, LEED standards also address indoor environmental quality and the health of building occupants.

Indoor air pollution is not currently regulated in the U.S. except under workplace standards, which are generally regarded as weak.

The LEED program has, therefore, developed its own standards for indoor air pollution. For fine particulates — particles of 10 microns or less (PM10) — the limit is a four-hour average of 50 mcg/m3. The current EPA standard for outdoor particulate pollution is a 24-hour average of 150 mcg/m3.

Fritz and other researchers sampled the air in 142 new buildings seeking LEED certification. Sampling was done following construction but before they were occupied, the method recommended under the certification program.

The four-hour averages were all well within the LEED limit, mainly in a range of 10 to 20 mcg/m3.

But when the investigators ran a vacuum cleaner for a few minutes to simulate the effects of human activity, the PM10 readings spiked to as much as 60 mcg/m3.

Even larger surges were seen when indoor sampling coincided with nearby outdoor construction activity.

Indoor PM10 readings shot beyond 200 mcg/m3 for a period of about 15 minutes, then dropped back to less than 30 mcg/m3 at the end of the workday.

When the researchers tested for particulates in occupied schools, apartments, and offices, they also found that PM10 levels increased to well beyond the LEED limit when people were inside doing normal activities.

“Quiescent sampling may not represent PM10 exposure levels once spaces are occupied,” they concluded.

On the other hand, Fritz and colleagues found that buildings receiving LEED certification had significantly lower levels of PM10s than those that failed, suggesting the program has value in reducing indoor pollution.

A limitation of the study was that it did not address levels of PM2.5 (particles smaller than 2.5 microns). The LEED standards do not set limits for these ultrafine particles, although they are considered more dangerous to health than larger particulates.

Mark Windt, M.D., an allergist and pulmonologist in North Hampton, N.H., who was not involved in the study, said the 200-mcg/m3 spikes in PM10 were “absolutely” a potential health threat.

But such levels are mainly a concern if people are exposed to them repeatedly, he said.

Dr. Windt said it was imperative that the government develop binding standards for indoor exposures to particulates and other pollutants.

No external funding for the study was reported.

The study authors and Dr. Windt reported no potential conflicts of interest.

Primary source: Journal of Allergy and Clinical Immunology

Source reference:
Horner E, et al “Greenbuildings: LEED certification requirements for indoor airborne particles can reduce indoor PM10 exposure” J Allergy Clin Immunol 2009; 123: S173.

TUCSON, Ariz., Oct. 1 — The urbanization of Africa in the early part of the 20th century may be partly responsible for the spread of HIV, researchers here said.

The suggestion was derived from an analysis of a tissue sample taken in 1960 in what was then Leopoldville, the colonial capital of the Belgian Congo, according to Michael Worobey, D. Phil., of the University of Arizona, and colleagues.

HIV RNA taken from the sample, which had been fixed in paraffin, provided the second oldest viral sequence, next to one from a blood sample — also from Leopoldville — taken in 1959, Dr. Worobey and colleagues wrote in the Oct. 2 issue of Nature.

The key finding is that the two samples — both of HIV-1 Group M — are sufficiently different that their earliest common ancestor must have existed about 50 years previously, the researchers said.

At that time, Leopoldville — and most population centers in central Africa — was small, providing only a small pool in which HIV could spread. But as the cities grew, HIV diversified, the researchers suggested.

“For the first time we have been able to compare two relatively ancient HIV strains,” Dr. Worobey said.

“That helped us to calibrate how quickly the virus evolved and make some really robust inferences about when it crossed into humans, how quickly the epidemic grew from that time, and what factors allowed the virus to enter and become a successful human pathogen,” he said.

Using polymerase chain reaction methods, Dr. Worobey and colleagues scanned 27 Bouin’s-fixed paraffin-embedded blocks of tissue sampled in Leopoldville (now Kinshasa) from 1958 through 1960.

One of the samples contained RNA from HIV-1 Group M, the pathogen responsible for more than 95% of HIV infections worldwide. There are two other HIV-1 groups, as well as HIV-2, but they are less important in the pandemic.

The HIV sample — dubbed DRC60 — was independently sequenced by two different labs and then compared with the other “ancient” sample, known as ZR59.

The researchers found that DRC60 belongs to Group M subtype A — one of 11 subtypes — while ZR59 belongs to subtype D.

Analysis showed that the sequences differed by about 12%, greater than 99.2% of within-subtype comparisons, the researchers said. For instance, the uncorrected pairwise distance between DCR60 and ZR59 in their overlapping env region was 11.7%.

“Because each subtype represents several decades of independent evolution in the human population,” the researchers said, “the extensive divergence between DRC60 and ZR59 indicates that the HIV-1 M group founder virus began to diversify in the human population (and that HIV-1 probably entered Kinshasa) decades before 1960.”

A statistical analysis suggested that Group M had relatively slow growth in the first half of the twentieth century — a time when colonial centers such as Leopoldville had been established and were beginning to grow, the researchers said.

The notion that HIV was spreading among humans for several decades before AIDS was first recognized “should not be surprising,” said Paul Sharp, Ph.D., of the University of Edinburgh, and Beatrice Hahn, M.D., of the University of Alabama at Birmingham.

If the epidemic grew exponentially, the curve would suggest that there were only a few thousand HIV-infected individuals by 1960, all in central Africa, they said in an accompanying News & Views article.

And because AIDS has a variety of symptoms and often a long period without any symptoms at all, “it is easy to imagine how the nascent epidemic went unrecognized,” they said.

Nevertheless, the work by Dr. Worobey and colleagues allows “a remarkably detailed picture of the time and place of origin of HIV-1 group M viruses and their early diversification, and thus of the prehistory of the AIDS pandemic.”

Drs. Sharp and Hahn, with colleagues, reported in 2006 that the closest animal match to HIV-1 Group M — a simian immunodeficiency virus (SIV) — was found in chimpanzees in Cameroon, about 440 miles (700 km) from Kinshasa.

The simplest explanation of how SIV jumped to humans would be through exposure to the blood of infected chimps, they argued. But then why did the pandemic start in Leopoldville and why not until the 20th century?

“The answer may be that, for an AIDS epidemic to get kick-started, HIV needs to be seeded in a large population center,” they said. “But cities of significant size did not exist in central Africa before 1900.”

Indeed, Dr. Worobey and colleagues said, before 1910 there was not a single population center of more than 10,000 people anywhere in Central Africa.

“I think the picture that has emerged here — where changes the human population experienced may have opened the door to the spread of HIV — is a good reminder that we can make changes now that could help reverse the epidemic,” Dr. Worobey said.

The researchers said that archived tissue samples in African hospitals form “a vast source of clinical material” that could “yield important insights into the pathogenesis, virulence, and evolution of pandemic AIDS viruses.”

The study was supported by the National Institute of Allergy and Infectious Diseases and the David and Lucile Packard Foundation. The researchers did not report any conflicts.

Primary source: Nature

Source reference:
Worobey M, et al “Direct evidence of extensive diversity of HIV-1 in Kinshasa by 1960″ Nature 2008; 455: 661-665.

Additional source: Nature

Source reference:
Sharp PM, Hahn BH “Prehistory of HIV-1″ Nature 2008; 455: 605-606.

A combined exercise and educational program produced a significant reduction in knee injuries among young female soccer players, researchers found.
Injuries that did occur were less severe among players who took part in the program, Liisa Byberg, PhD, of Uppsala University in Sweden, and colleagues reported in the Jan. 11 Archives of Internal Medicine.
The program, which was aimed at improving body control and reducing strain on the knee joint among players 13 to 19, did not require additional equipment and could be worked into a typical soccer practice.
Only three of the 48 teams who participated reported less than 75% compliance with the intervention.

“The high compliance rate in this study suggests that the program is easy to implement and incorporate into regular soccer practice,” the researchers wrote.

In an accompanying editorial, Mitchell Katz, MD, of the San Francisco Department of Public Health, and Rita Redberg, MD, of the University of California San Francisco, said preventing injuries in team sports should be a health priority.

“Undoubtedly, part of the success of the intervention derives from its development by a physician in collaboration with an orthopedic surgeon, a physiotherapist, and soccer coaches, specifically for female soccer players,” they wrote.

This approach “is likely to be successful not only in preventing other soccer-related injuries but also in preventing injuries in other competitive sports such as football, basketball, and tennis.”

Knee injuries among young female soccer players are expected to increase because of the growing popularity of women’s soccer worldwide, Byberg and colleagues noted. Females also appear to have higher injury rates than males.

To help address this problem, Byberg and her colleagues developed HarmoKnee, a soccer-specific warmup and exercise routine designed to improve motor skills, body control, strength, and muscle activation. The intervention also included education about injury risk for the athletes, parents, and coaches.

In one Swedish county — Uppland — 48 soccer teams agreed to perform the intervention. The exercise portion was performed twice a week during the preseason and once a week during the season.

In another county — Dalarna — 49 teams continued to train as usual for the entire season.

By the end of the season, there had been three knee injuries in the intervention group and 13 in the control group.

There were five injuries to the anterior cruciate ligament, all in the control group, which “is important because these injuries often require long rehabilitation and frequently lead to permanently reduced function and early retirement from soccer,” the researchers noted in the journal.

After adjustment for several factors related to injury risk, the exercise program was associated with significant reductions in total knee injuries (rate ratio 0.17, 95% CI 0.04 to 0.64) and noncontact injuries (rate ratio 0.06, 95% CI 0.01 to 0.46).

The injuries that did occur were less severe in the intervention group. All three were considered major, but each player returned to action within six months.

In the control group, however, 11 of the 13 injuries were considered severe, and only four of the players were able to play within six months.

Compliance with the intervention extended beyond the study — a year later, 44% of the teams were still performing at least part of the exercise program and 19% were performing it in its entirety.

The researchers noted that the study was limited by the lack of individual-level data, the low number of injuries, and the possibly biased measurement of compliance.

This study was supported by Folksam, the Uppsala County Council, the Swedish Athletic Institute of Education in Uppland, the Uppland Football Association, the Dalarna Football Association, and the Department of Research and Development, Uppsala Primary Care, Uppsala County Council.

Neither the study authors nor the editorialists made any financial disclosures.

INDIANAPOLIS, Nov. 8 – Ritalin (methylphenidate), long an approach to attention deficit hyperactivity disorder (ADHD) in children, may be effective for treating hyperactivity in autism and related pervasive developmental disorders, according to investigators here.

Nearly 50% of children with pervasive developmental disorders and hyperactivity responded to the drug, but the magnitude of the response was less than that seen with children with ADHD, reported investigator David J. Posey, M.D., of the Indiana University School of Medicine here, and colleagues in the November issue of Archives of General Psychiatry.

Seventy-two children, ages five to 14 years, participated in the randomized, placebo-controlled, crossover trial. The trial included a one-week phase to test whether the participants could tolerate three different dose levels of the medication. This was followed by a four-week crossover phase during which the children were given one of three doses of Ritalin or placebo in random order to assess effectiveness.

Children showing a positive response were treated for an additional eight weeks to ensure that gains were stable. Response to treatment was assessed by parents and teachers using standardized ratings of behavior.

Thirty-five children (49%) responded to the drug, which is less than response rates of 70% to 80% reported for children with ADHD. Responders were defined as those who showed at least a 25% decrease in hyperactivity symptoms. Some children showed as much as a 54% decrease in symptoms. The effect sizes ranged from 0.20 to 0.54, suggesting a small to medium magnitude of response.

The drug did not improve symptoms of irritability, lethargy, social withdrawal, stereotypy, or inappropriate speech. Increased social withdrawal was associated with higher doses of the medication, which is consistent with adverse events reported in other studies.

Overall, 18% of the children withdrew from the study because of adverse events, most commonly irritability. Other adverse events at the highest dose included appetite decrease (24%), difficulty falling asleep (16%), and stomach or abdominal discomfort (12%).

“At present, methylphenidate is a reasonable choice to target hyperactivity in the context of pervasive developmental disorders, given modest group effects and a response rate that approaches 50%,” the study authors concluded.

“However, caregivers should be cautioned about the strong possibility of adverse effects. In addition, practitioners should be prepared to suspend treatment if considerable adverse effects are reported,” they added.

The authors also raised the possibility that “the use of psychostimulants added to another psychotropic medication may be associated with a greater rate of response than when used alone. For example, persons with autism already receiving an antipsychotic medication might be protected to some extent from adverse effects associated with psychostimulants (e.g., irritability, insomnia, loss of appetite).”

Ritalin is also sold under the brand names Concerta, Metadate, and Methylin. The study was not supported by any of the drug-makers.

Primary source: Archives of General Psychiatry

Source reference:
Posey DJ et al. Randomized, controlled, crossover trial of methylphenidate in pervasive developmental disorders with hyperactivity. Archives of General Psychiatry. 2005; 62:1266-1274.

EDINBURGH, Scotland, July 9 — Noninvasive ventilation was more effective than standard oxygen therapy for patients with acute cardiogenic pulmonary edema, a study found.

However, the treatment failed to improve seven-day or 30-day mortality, Alasdair Gray, M.D., of the University of Edinburgh, and colleagues in the Three Interventions in Cardiogenic Pulmonary Edema trial reported in the July 10 issue of the New England Journal of Medicine.

Their multicenter, open, prospective, randomized controlled trial included 1,069 patients (mean age 77.7, 56.9% female). Patients were recruited from 26 emergency departments in district and regional hospitals in Britain from July 2003 to April 2007.

Of these, 367 patients were assigned to standard oxygen therapy, 346 to continuous positive airway pressure (CPAP) and 356 or noninvasive intermittent positive-pressure ventilation.

Reviewing earlier studies, the researchers wrote that noninvasive ventilation, either by CPAP or noninvasive intermittent positive-pressure ventilation, appears to relieve respiratory distress and can avert tracheal intubation. But some systematic reviews have suggested that CPAP may also reduce mortality.

On the other hand, they said, one meta-analysis suggested an increase in the rate of acute myocardial infarction among patients treated with noninvasive intermittent positive-pressure ventilation.

All previous randomized controlled trials have been small and most were conducted at single centers, with considerable variation in study populations, ventilation type and therapies, the researchers wrote.

So the investigators undertook the new trial to determine whether noninvasive ventilation reduces mortality and whether there are important differences in outcomes associated with the method of treatment.

In fact, there was no significant difference in seven-day mortality between patients receiving standard oxygen therapy (9.8%) and those undergoing noninvasive ventilation (9.5%, P=0.87).

There was also no significant difference in the combined endpoint of death or intubation within seven days between the two groups given noninvasive ventilation (11.7% for CPAP and 11.1% for noninvasive intermittent positive-pressure ventilation, P=0.81).

Compared with standard oxygen therapy, noninvasive ventilation was associated with greater mean improvements at one hour after the beginning of treatment as follows:

Patient-reported dyspnea (treatment difference 0.7 on a visual-analogue scale ranging from 1 to 10, 95% CI 0.2 to 1.3, P=0.008)
Heart rate (treatment difference four beats per minute, 95% CI 1 to 6, P=0.004)
Acidosis (treatment difference pH 0.03, 95% CI 0.02 to 0.04, P

GAITHERSBURG, Md. — An FDA advisory panel has unanimously recommended approval of the investigational Pipeline Embolization Device to wall off large intracranial aneurysms in patients who are unlikely to respond to currently available treatments.

The Neurological Devices Panel voted 9-0 that the benefits of the device — made by Menlo Park, Calif.-based Chestnut Medical Technologies — outweigh its risks. The company is seeking an indication for the Pipeline Embolization Device for the endovascular treatment of large or giant wide-necked intracranial aneurysms in the cavernous and paraclinoid regions of the internal carotid artery.

In the company’s trial, the device was 74% effective at achieving complete aneurysm occlusion.

If the FDA follows the advice of its advisory panel and approves the Pipeline device, it would offer patients with very large, hard-to-treat aneurysms a way to rid themselves of symptoms such as severe headaches and vision disturbances, and greatly lessen the risk of aneurysm rupture.

About half of all people who experience an intracranial aneurysm rupture will die. Among those who live, one-third will be permanently disabled, according to information from Chestnut Medical Technologies.

The FDA does not have to follow the advice of its advisory panels, but it often does, particularly in cases where panels are unanimously supportive of the medical device.

Approval would be a very big deal, Peter Nelson, MD, chief of interventional radiology at New York University, told MedPage Today following Friday’s meeting.

“This is a transforming event in cerebrovascular surgery,” said Nelson, who has implanted the device in about 75 patients in the U.S.

Large aneurysms, which measure between 10 mm and 25 mm, and giant aneurysms, which are greater than 25 mm in size, are rare, with about 2,000 reported cases each year. There is a greater risk of rupture with giant aneurysms, and they are much more difficult to treat.

Smaller, uniformly shaped aneurysms with small necks attaching them to the artery can be treated by surgically clipping the base of the aneurysm, or by pushing platinum coils into the aneurysms to initiate a clotting reaction. But clipping the base of an large aneurysm is very difficult and extremely risky, and often coils won’t fit into an oddly-shaped aneurysm, explained Nelson.

The flexible Pipeline, which resembles a mesh tube, is inserted into the artery from which the aneurysm has developed. It works by cutting off the blood supply to the aneurysm, which, over time, eliminates the aneurysm altogether.

The panel based its endorsement on company’s multicenter, single-arm study that enrolled 104 patients with a total of 106 large or giant aneurysms who underwent a procedure with the Pipeline device. The device was effective in complete aneurysm occlusion without major parent vessel stenosis in 78 of 106 (74%) of the cases.

The committee voted 9-0 that the device is effective.

The study’s primary safety endpoint of ipsilateral stroke and neurologic death was met. In total, 5.6% of cases met the predefined safety endpoint of serious safety events after surgery, including stroke, hemorrhage, and “possible neurologic death.”

The panel also voted 9-0 that the Pipeline device is safe.

The panel heard stories from eight patients who received the device as part of the trial. All of them were stricken with debilitating headaches, sought medical treatment, and eventually learned through MRI that they had massive aneurysms.

All of the patients said the Pipeline device saved their lives, and urged FDA approval.