NEW ORLEANS — Treatment of chronic obstructive pulmonary disease (COPD) with either of the two leading inhaled corticosteroid formulations appears to give patients similar results in controlling their conditions, researchers reported here at the 2010 American Thoracic Society annual meeting.

In a comparison of outcomes in 3385 patients taking budesonide/formoterol fumarate dehydrate (Symbicort) with outcomes in 3385 patients taking fluticasone/propionate/salmeterol (Advair), there were no statistical differences in medical services utilization for either treatment, Christopher M. Blanchette, PhD, director of the clinical outcomes research division at the Lovelace Respiratory Research Institute, in Kannapolis, N.C., and colleagues wrote in a poster presentation.

For example, 140 of the budesonide cohort required hospitalization for COPD (4.1%) compared with 117 of the fluticasone patients (3.5%), but that was not statistically different (P=0.144).

In addition, 60 of the budesonide patients (1.8%) required pneumonia-related hospitalization compared with 65 of the fluticasone patients (1.9%), also not significant (P=0.652).

“Budesonide/formoterol fumarate dehydrate combination and fluticasone propionate/salmeterol combination demonstrated comparable real-world effectiveness as measured by number of exacerbation and pneumonia events during the evaluation period,” the researchers wrote.

Blanchette and colleagues mined data from the PHARMetrics Patient-Centric Database, which includes information from 70 health plans and more than 9 million patients. They concentrated on reports of patients from 2003 to 2009 who were diagnosed with COPD and who were prescribed either of the corticosteroid combination products. They identified 3390 patients on budesonide/formoterol fumarate dehydrate and 90,700 patients on the fluticasone/propionate/salmeterol combination.

The research team then matched and compared outcomes for each cohort.

“There were no differences in overall adherence rates and treatment costs between the budesonide-containing formula and the fluticasone-containing formula,” the authors reported in the poster. “However, patients taking budesonide had lower rescue medication use, suggesting a potentially higher level of symptom control.”

They found that 1175 patients using the budesonide formulation required the use of short-acting beta-agonists (34.7%) as a rescue medication compared with 1336 patients who were using the fluticasone formulation (39.5%), which was a significant difference (P<0.001).

Similar usage was noted for nebulized short-acting beta-agonists. The researchers observed that 265 patients on budesonide (7.8%) and 331 patients on fluticasone (9.8%) required use of ipratropium compounds as rescue medication, also a significant difference (P=0.005).

The study was funded by AstraZeneca. Blanchette did not have disclosures. A co-author of the paper is an employee of AstraZeneca.

BOSTON, Nov. 14 — In the widely publicized death of an arthritis gene therapy trial participant last summer, the treatment was not responsible, asserted the study’s academic leader here.

The FDA put the phase I-II trial of tgAAC94 for treatment of active inflammatory arthritis on clinical hold, allowing no further treatment or enrollment of new patients, until it ascertained the cause of the patient’s illness and subsequent death.

But Philip Mease, M.D., of Seattle Rheumatology Associates and the University of Washington, said at the American College of Rheumatology meeting here that there was no evidence from autopsy studies and genomic analyses that the virally delivered tumor necrosis factor alpha (TNFa) antagonist gene had anything to do with the death.

A massive histoplasmosis infection and retroperitoneal hemorrhage killed the 36-year-old woman, Dr. Mease said.

Levels of the adeno-associated virus vector (AAV) were undetectable, or nearly so, in tissues outside the woman’s knee where it had been injected, he said.

In the trial, 127 patients with rheumatoid or psoriatic arthritis or ankylosing spondylitis were randomized to receive an initial blinded dose of placebo or several doses tgAAC94. They were scheduled for a second open-label dose of the study drug 12-30 weeks later.

Dr. Mease said the woman had a low-grade fever and fatigue for several days before she came in for her second dose. She was receiving the highest dose used in the trial, 10 trillion tgAAC94 particles per milliliter.

Within a few days after the second injection, her condition worsened. She was hospitalized and finally died 23 days after initially becoming ill.

“After exhaustive investigation of this particular case, this was considered not to be related to the study agent by the [study's] data monitoring committee,” Dr. Mease said.

The committee is an independent review body not including the study investigators.

Genetic analyses of tissue samples from the woman showed 500,000 copies/microgram of tgAAC94 in the injected knee, but fewer than 30 copies/microgram in other tissues including the other knee, liver, spleen, tonsil, and bowel. Wild-type AAV copies were found at low or undetectable levels in the various tissues, Dr. Mease said.

He said the investigation found no evidence that the agent had been contaminated with Histoplasma or other organisms.

The patient was also receiving adalimumab (Humira) and her measurements of systemic TNF antagonist levels were no higher than would be expected with that treatment, Dr. Mease said.

Her systemic levels of anti-TNF activity were consistent with her concurrent treatment with adalimumab.

Another scientist who has looked into the case as part of the FDA investigation generally agreed with Dr. Mease’s findings, although he cautioned, “It’s not a closed case.”

Eric Matteson, M.D., of the Mayo Clinic in Rochester, Minn., called it unlikely that the gene therapy was responsible for the woman’s death.

Nevertheless, some issues remain unresolved and may remain that way for a long time, he said. “It’s still an open question,” said Dr. Matteson. The possibility that tgAAC94 contributed to the infection cannot be conclusively ruled out.

“How much of the anti-TNF (activity) was from the systemically given drug and how much was from virally expressed drug,” he said, is the unanswered question. “We need to understand how to measure these two products,” he added. Current assays, however, cannot distinguish between them.

He noted that patients with rheumatoid arthritis are at increased risk for infection because of their disease. When they receive anti-TNF therapy, “their drugs further increase their risk. How much their risk is further increased [by gene therapy] is still under investigation,” said Dr. Matteson.

“When we look at the risks, they seem globally acceptable. But it has to be discussed with [each] patient,” he said.

The trial was sponsored by Targeted Genetics Corp., which hopes to develop the tgAAC94 gene therapy product for inflammatory arthritis.

Targeted Genetics said that since the trial began in October 2005, 127 patients have received an initial dose of active drug or placebo, and 74 of the 127 have been assigned to a second dose of active drug.

In March 2006, said the company, it received approval from the FDA to amend its protocol for the tgAAC94 clinical trial to include a higher dose group and increase the number of patients.

In all, the company said, the 127 adults have been randomized into three dose levels to receive a single intra-articular injection of either tgAAC94 or placebo into the knee, ankle, wrist, metacarpophalangeal joint, or elbow, followed by an open-label injection of tgAAC94 after 12 to 30 weeks, depending on when arthritis symptoms in the target joint meet criteria for reinjection.

The case echoed the 1999 death of 18-year-old Jesse Gelsinger, who was participating in a gene therapy trial at the University of Pennsylvania for ornithine transcarboxylase deficiency. His death was believed to have been triggered by a severe immune response to the adenovirus carrier.

The vector that the tgAAC94 agent uses is thought to be safer. It delivers a gene that expresses an immunoglobulin protein that targets the TNF receptor. Its mechanism is similar to existing anti-TNF drugs such as infliximab (Remicade) and adalimumab.

By injecting the product directly into the joint, the hope has been to avoid the risks associated with systemic anti-TNF therapy, chiefly increased vulnerability to infection.

Another severe adverse event in the trial, a case of septic arthritis in the injected joint, was considered related to the treatment, Dr. Mease said. In other patients, he said, the treatment was well tolerated.

Dr. Matteson agreed, saying, “The experience with the other patients was good.”

Dr. Matteson said the FDA panel would meet soon to decide whether to lift or maintain the clinical hold on the tgAAC94 trial. He said the meeting had not been scheduled but would probably occur in December.

“The new data are very encouraging and we are hopeful we can resume this clinical trial soon,” said H. Stewart Parker, president and chief executive officer of Targeted Genetics, in a press release. “Based on the clinical data generated and evaluated to date, we are now working with our advisory board to design the next phase of our clinical program.”

Dr. Mease said that the limited efficacy data showed “trends toward improvement in target joint swelling and tenderness at all doses.” In addition to restarting the dosing, if allowed by the FDA, he said the group plans to collect MRI imaging data and correlate it with clinical assessments.

Primary source: American College of Rheumatology

Source reference:
Abstract 2084 presented Nov. 10

SAN DIEGO, May 20 — This exclusive live broadcast focuses on investigations into the creation of liver cells from embryonic stem cells, a link between recurrent UTIs and primary biliary cirrhosis, and the most efficacious treatments for hepatitis C.

WASHINGTON — Rosiglitazone (Avandia) should be pulled from the market because of the “serious” cardiovascular risk the diabetes drug poses, which exceeds that of competitor pioglitazone (Actos), FDA staff reviewers again recommended.

Rosiglitazone is no more effective at improving glycemic control in type 2 diabetes than pioglitazone and provides no known unique health benefits, and while both drugs increase the risk of congestive heart failure, rosiglitazone’s effect is “substantially greater,” FDA reviewers wrote in a massive briefing document released Friday.

“Our review of the literature finds no evidence of a unique or meaningful health benefit from rosiglitazone that is not also provided by pioglitazone and there is substantial evidence that rosiglitazone increases cardiovascular risk compared with pioglitazone,” wrote David Graham, MD, and Kate Gelperin, MD, both epidemiologists with the FDA.

Graham and Gelperin had reached the same conclusion in a report requested by the Senate Finance Committee in February.

Whether a joint panel of outside medical experts will agree with their assessment remains to be seen. The panel will meet July 13 and 14 to make their recommendations about rosiglitazone, among them whether the drug should be pulled from the market.

The FDA does not have to follow the advice of its advisory committees, but it usually does.

Advice Redux

Next week’s meeting will be the second time an advisory panel was tasked with guiding the FDA on what to do about rosiglitazone.

In 2007, a panel voted 20 to 3 that the drug increased cardiovascular risk, but then 22 to 1 that the benefits outweighed the risks.

In their current review, the FDA staff blasted the logic in the 2007 decision and said the panel failed to prove what, exactly, the benefits of rosiglitazone were. Since then, the benefits of the drug are still just as unclear, they said.

“In the three years since that advisory committee meeting, the Office of New Drugs has not answered the question of what are the unique health benefits of rosiglitazone that have justified its continued marketing,” the reviewers wrote.

They criticized the FDA mindset that “rosiglitazone is safe and remains so until ‘definitive proof’ forces reconsideration.”

“In our opinion, this approach is inconsistent with public health policy that places patient safety first,” Graham and Gelperin wrote.

On the RECORD

Since much of the rosiglitazone debate has been fueled by a seemingly endless array of dueling meta-analyses and observational data — famously initiated by a 2007 meta-analysis by Steven E. Nissen, MD, of the Cleveland Clinic — many observers have expressed hope that the FDA would gain access to new, unpublished data rather than simply rehashing what is already in the public space.

And indeed, the briefing documents released today included an analysis of the controversial RECORD trial, which GlaxoSmithKline has leaned on as one of its main defenses on the cardiovascular safety of rosiglitazone.

That open-label trial, which was requested by and designed in conjunction with European regulators, showed no elevation in the combined endpoint that includes death, myocardial infarction, and stroke compared with active control (hazard ratio 0.93, 95% confidence interval 0.74 to 1.15, P=0.5).

The trial also met its primary outcome of noninferiority in the composite of cardiovascular death and cardiovascular hospitalizations with a hazard ratio of 0.99 for rosiglitazone versus control (95% CI 0.85 to 1.15).

When the company sent the FDA its completed results of RECORD, it also submitted a proposed change to the labeling to remove mention of risk of myocardial ischemia.

But staff reviewers led by Thomas Marciniak, MD, of the cardiovascular and renal products department, scathingly criticized the trial on design, conduct, and results.

“Our review of RECORD leads us to conclude that its design and execution were biased in a manner that consistently favored not finding a cardiovascular effect if it was present,” they wrote in the document. “In our view, it provides no credible evidence of rosiglitazone’s cardiovascular safety.”

For example, most errors in handling case report forms on cardiovascular events appeared to be in favor of rosiglitazone.

In the FDA’s review of a random sample of these reports, all four cases of report mishandling, all eight cases of failure to refer events for adjudication, and nine of 14 missed events were in patients given rosiglitazone.

“While these numbers may seem small compared with the size of the trial, note that about 15 more MIs in the rosiglitazone arms are needed to change the GlaxoSmithKline MI results to a relative risk of 1.4 and a P-value of 0.042,” the reviewers wrote.

Furthermore, they noted, the bias of the study design was toward the null, the primary endpoint was inappropriate (major adverse cardiovascular events would have been better), and there were substantial errors in both endpoint determinations and the censoring date for patients without endpoints.

Also, the final results of the trial were reported in an intent-to-treat manner, ignoring the extensive crossovers that arose as patients and physicians — who knew which drug they were on because of the open-label design — grew concerned over the media firestorm after the initial Nissen meta-analysis.

The FDA reviewers believe that intent-to-treat was not a valid approach and instead they censored the data once good follow-up fell below 90% with 80% of patients still on treatment as randomized. That point occurred at 3.4 years rather than the five to seven years used by GlaxoSmithKline.

In the FDA reviewers’ analysis, the hazard ratios with rosiglitazone versus placebo were: 1.42 for MI (95% lower confidence limit 0.93, 95% upper confidence limit 2.16) 0.96 for strokes (95% LCL 0.60, 95% UCL 1.54) 0.95 for cardiovascular death (95% LCL 0.57, 95% UCL 1.60) 1.13 for major adverse cardiovascular events (95% LCL 0.85, 95% UCL 1.50)

These data, added to additional evidence from the trial, suggest that the elevated MI risk is real, the reviewers concluded.

“One does not have to be a mathematician or to perform the calculations to estimate that incorporating our RECORD results into a meta-analysis similar to Nissen’s will produce a risk for MIs that is highly statistically significant,” they wrote in the briefing documents.

FDA Staff Blast Postmarketing Study

Following the 2007 FDA advisory committee meeting, FDA required GlaxoSmithKline to conduct a head-to-head outcomes trial comparing rosiglitazone to pioglitazone. That trial — called TIDE — was hampered by sluggish enrollment of patients — possibly because of safety concerns.

Graham and Gelperin called TIDE “unethical and exploitative,” arguing that GlaxoSmithKline never proved rosiglitazone is equivalent to pioglitazone.

“That is, there must be equal evidence favoring both therapies. But that is not the case here because no one has argued that rosiglitazone is safer than or preferable to pioglitazone,” FDA reviewers wrote. “In our view, the TIDE trial is unethical because it subjects human beings to unnecessary risks without any possibility of a meaningful, unique health benefit from rosiglitazone.”

They also said the informed consent document for TIDE was misleading.

“Given the weight of evidence regarding cardiovascular risks with rosiglitazone, we believe that TIDE is an unethical study and that it was unethical before it was started,” Graham and Gelperin wrote.

At next week’s meeting, the Endocrinologic and Metabolic Drugs and the Drug Safety and Risk Management Advisory Committees will also consider the TIDE study, and may vote to halt it, or modify it in some way.

In the company’s briefing documents, GlaxoSmithKline said it remains committed to finishing the TIDE trial.

The FDA hopes to avoid some of the sticky ethical questions washed up by the TIDE trial. It asked the Institute of Medicine (IOM) to come up with a framework for obtaining informed consent when comparing two drugs, one of which is believed to carry an increased risk.

On Friday, the IOM published a number of recommendations for the FDA when planning a postmarketing, randomized safety trial, including that the agency order such trials only when a responsible policy decision cannot be made without the new evidence, and that the informed consent process continues throughout the trial to include relevant findings that might influence a “participant’s willingness to accept the risks associated with the trial.

Panelists at next week’s meeting will likely place great weight on an analysis based on data from the Centers for Medicare and Medicaid Services which was published online two weeks ago.

That observational retrospective cohort study of 227,571 Medicare patients 65 and older from July 2006 to June 2009 found that rosiglitazone was associated with a significantly elevated risk of all other endpoints including stroke, heart failure, death, and a composite with MI of all four endpoints.

Company Defends the Drug, Europe Investigates

A spokeswoman for GlaxoSmithKline said the company stands behind the safety and efficacy of rosiglitazone.

“Avandia has a positive benefit-risk profile. When you look at the science and the totality of the data -– especially the most rigorous scientific studies -– Avandia has been shown to be a safe and effective diabetes medicine when used appropriately according to its labeling,” said Mary Anne Rhyne, director of U.S. Media relations for GlaxoSmithKline. “Avandia is an important medicine for the treatment of type 2 diabetes, who often need two or three medicines to help maintain their blood sugar levels.”

Following the lead of the U.S. agency, Europe’s version of the FDA will also launch a review into rosiglitazone.

The European Medicines Agency announced Friday that its Committee for Medicinal Products for Humans will review the safety of rosiglitazone when it meets July 19 to July 22.

The committee may decide to suspend marketing for rosiglitazone or remove it from the market.

Primary source: FDA Briefing Document

Source reference:
“Advisory Committee Meeting for NDA 21071 Avandia (rosiglitazone maleate tablet)” July 13 and 14, 2010.

WASHINGTON — Healthcare reform in Massachusetts — a.k.a. Romneycare — has resulted in a higher percentage of residents with medical insurance and better self-reported health, but climbing costs are still an issue, a statewide survey showed.

More than 94% of the state’s nonelderly residents reported having insurance, up from 87% before the law was enacted, Sharon Long, PhD, of the University of Minnesota in Minneapolis, and two graduate students, reported online in Health Affairs.

And 65% of respondents said they had “very good” or “excellent” health, up from 60% in 2006.

Other reports, including one by the CDC, have found even higher coverage rates in Massachusetts.

But, the percentage of Massachusetts residents who reported having trouble paying their medical bills in 2006 was about the same in 2010 — nearly 20%.

In 2006, Massachusetts enacted a healthcare reform law that requires every resident to have insurance and offers subsidies to help pay for private health insurance, a health insurance exchange, and insurance market reforms. The law has become a blueprint for the national healthcare reform passed in 2010.

Long’s findings are based on 2010 data collected from a random telephone survey of 3,000 nonelderly adults that asked questions about insurance status, characteristics of coverage, access to and use of medical care, and affordability. Long and her team compared the 2010 results to those from a similar poll in 2006.

Besides the improved scores on health status, Massachusetts residents also reported improved access to medical care and said they were more likely to have a usual place to go when they were sick (up about 5 percentage points) and were more likely to have received preventive care (up 6 percentage points).

Emergency room visits decreased from 2006 to 2010, while ED use in the nation as a whole increased during that time frame, the researchers said.

There were also reduction in inpatient hospital stays.

But, despite the gains in access reported, nearly 25% of nonelderly residents in Massachusetts said they did not get needed care in 2010 (especially for prescription drugs and dental care). That’s a trend seen elsewhere in the country, however, as people put off medical care because of the recession.

But the cost of healthcare continues to rise — as it does in the rest of the nation — at least in part because Massachusetts’s reform efforts did not include cost-containment measures.

According to a national survey of employers, in 2006, the average employee contribution for single coverage was $1,011; and in 2010, that increased to $1,200.

Although one in five Massachusetts residents reported having trouble paying their medical bills, a smaller percentage said they had high levels of out-of-pocket spending (6.1% in 2010 compared with 9.8% in 2006).

“Healthcare costs in Massachusetts, as in the rest of the country, continue to grow faster than wages and inflation,” wrote the study authors.

Despite high costs, the study authors said the state has made impressive gains in improving healthcare coverage, access, and (at least the self-reported) health of residents. In addition, very few people in the state lack insurance, and there are no signs that employers in the state have dropped coverage or scaled back scope of coverage in order to save money.

The study authors conclude that as the nation works to implement reform, the Massachusetts experience provides an “optimistic prognosis of potential gains.”

But, acknowledging the contentious debate before passage of the federal Affordable Care Act and the legal challenges to it, the study authors concluded, “it is likely that the path to near universal coverage nationally will be slower and bumpier than it was for Massachusetts in 2006.”

The study was funded by the Blue Cross Blue Shield of Massachusetts Foundation. Earlier years of the study were also funded by the Commonwealth Fund and the Robert Wood Johnson Foundation. The survey was conducted by Social Science Research Solutions.

BOSTON, Jan. 31 — Insofar as pain-free knees are concerned, recreational exercise is orthopedically irrelevant to middle-age and older persons, researchers here reported.

Among those without knee osteoarthritis in the first place, recreational exercise neither caused it to develop nor protected against it, they found in a study of nearly 1,300 participants.

Even though overweight patients in the study had an increased risk of developing knee osteoarthritis, physical activity — walking, jogging, or other self-reported activity — did not contribute to this risk, David Felson, M.D., of Boston University, and colleagues. reported in the February issue of Arthritis Care and Research.

Furthermore, despite previous studies that suggested that exercise might prevent loss of joint space, there was no evidence that physical activity benefits cartilage, they said.

Although regular exercise is recommended for middle-age and older persons, its effect on the development of osteoarthritis in older persons, especially those who are overweight, has been unclear, Dr. Felson said.

In a study to evaluate the long-term effect of recreational exercise on knee osteoarthritis, 1,279 participants (mean age at 1993-1994 baseline, 53.2 years) from the Framingham Offspring cohort were asked about recreational activities including walking or jogging for exercise and working up a sweat. They were also asked to compare their activity levels with others.

Participants (age range 26-81 years) were then asked about knee pain, and weight-bearing anteroposterior and lateral knee radiographs were obtained.

Knees with osteoarthritis even in one knee at baseline were excluded, while the investigators focused on three knee-specific outcomes: new radiographic osteoarthritis, symptomatic disease, and tibiofemoral joint-space loss.

Approximately nine years later (2002-2005), the subjects were reexamined. Radiographs were read for osteoarthritis features in both tibiofemoral and patellofemoral compartments and were scored for tibiofemoral joint-space narrowing, using the Kellgren and Lawrence scale.

Of 2,259 knees eligible for incident radiographic osteoarthritis, 215 (9.5%) developed new disease, with most (181 knees) developing disease in the tibiofemoral compartment.

However, after adjusting for age, sex, body mass index (BMI), knee-injury history, and correlation between knees, the researchers found that neither recreational walking (more miles per week), jogging, running, intensity of workouts (frequent working up a sweat), nor high activity levels relative to peers were associated with a decrease or increase in the risk of knee osteoarthritis.

Generally the risk of osteoarthritis was close to null (adjusted OR 1.10) for those who walked the most (six or more miles a week), with confidence bounds narrow enough to suggest that neither a substantial increase nor a decrease in risk was being missed, the researchers said.

When the researchers compared working up a sweat or physical activity with others the same age, the findings were similar: physical activity appeared to have little effect on the risk of knee osteoarthritis.

Comparing radiographs taken at baseline and at the end of the study, the investigators reported that joint space width was also unaffected by activity or weight and that there was no evidence that physical activity benefits cartilage.

Persons with a BMI above the median (27.7 kg/m2 for men and 25.7 kg/ m2 for women; mean BMI >30 kg m2/ for both) had no increase in the risk of osteoarthritis according to different types of activity.

For example, the OR of walking at least six miles a week and subsequent knee arthritis in overweight subjects was 0.95 (95% CI 0.55-1.620). Similar results for these subjects were found for working up a sweat three or more times a week (OR 1.04, CI 0.55-1.96).

Even though overweight persons in this cohort had an increased risk of developing osteoarthritis, physical activity did not contribute to this increase, the researchers said.

The study had many strengths, including the large number of subjects and the review of specific activities. However, limitations included the lack of MRI imaging at the baseline evaluation, and the shortage of joggers and runners to evaluate the effect of running on osteoarthritis. The results for symptomatic osteoarthritis did not suggest any effect of running, but confidence bounds were wide, the researchers said.

In conclusion, Dr. Felson wrote, walking for exercise and other recreational activities in older persons without knee osteoarthritis do not affect these individuals’ risk of developing the knee disorder, even if they are overweight.

Although dynamic loading may have a trophic effect on cartilage, the investigators found no measurable protective effect of recommended weight-bearing exercise on osteoarthritis. Physical activity can be done safely without concern that a person will develop knee osteoarthritis as a consequence, the researchers concluded.

In the same journal issue, a Dutch review paper of predictive factors for knee osteoarthritis supported Dr. Felson’s findings.

In an overview of 37 studies up to December 2003, researchers from the Netherlands, led by J.N. Belo, M.D., of Erasmus Medical Center in Rotterdam, found no strong evidence that regular exercise, as well as sex, knee pain, quadriceps strength, and knee injury, were associated with the progression of knee osteoarthritis.

On the other hand, Dr. Belo said, the presence of generalized osteoarthritis and the level of hyaluronic acid in the joints were predictive of disease progression.

Conflicting evidence for associations was found for several factors including body mass index and age. Limited evidence for an association with progression of knee osteoarthritis was found for several factors, including the alignment (varus/valgus) of the joint.

Limited evidence for no association with progression of osteoarthritis was also found for several factors, including meniscectomy, several markers of bone or cartilage turnover, and the clinical diagnosis of localized osteoarthritis.

Generalized osteoarthritis and level of hyaluronic acid seem to be associated with the radiologic progression of knee osteoarthritis. Knee pain, radiologic severity at baseline, sex, quadriceps strength, knee injury, and regular sport activities seem not to be related. For other factors, the evidence was limited or conflicting, Dr. Belo concluded.

Future study of clinical progression of knee osteoarthritis is of major importance because of its implications for patient information and appropriate medical treatment. In the case of strong evidence for either the presence or the absence of an association, future scientific consensus is needed on how to summarize the evidence provided by studies with a small sample size.

“In summary, this review provides the currently available evidence, but also identifies the lack of data with respect to prognostic factors of progression of knee osteoarthritis,” Dr. Belo’s team wrote.

In an accompanying editorial, Marian Minor, Ph.D., of the University of Missouri in Columbia, wrote that Dr. Felson and his colleagues have produced a useful and valid study that supports recommending regular moderate physical activity without undue fear that such activities may increase the risk of knee osteoarthritis.

A most intriguing question arising from this study concerns the other variables that might be making important contributions to the manifestation and progression of knee osteoarthritis, Dr. Minor said. “Our inability to find the answer to this question within this as well as in most other studies is not due to poor design or implementation, but results from missing data” she said.

Future research, Dr. Minor suggested, should characterize subjects in terms of variables relevant to knee osteoarthritis. These variables will likely include individual characteristics, such as age of onset, occupational and medical history, rate and site of progression, remission and repair, responses to various pharmacologic agents, physical interventions, as well as social and environmental factors.

“In addition to improving the usefulness of knee osteoarthritis research, our ultimate aim must be to produce evidence that assists clinical decision-making and individualized recommendations regarding safety and effectiveness of interventions, including physical activity,” Dr. Minor concluded.

No financial disclosures were reported for any of the investigators.

Primary source: Arthritis Care and Research

Source reference:

Felson, DT, et al “Effect of Recreational Physical Activities on the Development of Knee Osteoarthritis in Older Adults of Different Weights: The Framingham Study” Arthritis Care and Research 2007; doi:10.1002/art.22464.

Additional source: Arthritis Care and Research

Source reference:

Belo JN, et al “Prognostic Factors of Progression of Osteoarthritis of the Knee: A Systematic Review of Observational Studies” Arthritis Care and Research 2007; doi: 10.1002/art. 22475.

Additional source: Arthritis Care and Research

Source reference:

Minor MA, “Physical Activity and Knee Osteoarthritis: Answers and Questions” Arthritis Care and Research 2007; doi: 10.1002/art.22485.

MINNEAPOLIS, Oct. 5 — Patients seem more skeptical than their doctors do on the safety of menstrual suppression with continuous-use oral contraceptives, but the women like the idea, survey results suggested

Asked whether they were interested in suppressing their menstrual periods, about two-thirds of women said they were “extremely” or “somewhat” interested, but also said they were not sure that the practice was safe, reported Kurt Barnhart M.D., M.S.C.E., of the University of Pennsylvania.

Yet 97% of physicians surveyed said that the use of continuous oral contraceptives for menstrual suppression is “medically safe and acceptable,” said Dr. Barnhart, at a meeting of the Association of Reproductive Health Professionals’ here.

“The gap between physician and patient understanding concerning the necessity of monthly periods is obvious,” said Dr. Barnhart. “It is our hope that based on these findings physicians will begin to more readily initiate a dialog with their female patients about continuous therapy, helping to eliminate the misconception that periods are a medical necessity and to emphasize the safety and viability of menstrual suppression.”

Dr. Barnhart presented results of two nationwide surveys of practitioner and patient attitudes about menstrual suppression.

Dr. Barnhart and colleagues conducted an online survey of women from the ages of 18 to 49 (of those older than 35 only non-smokers were included). The women had to have intact uteruses and regular menstrual periods.

They also surveyed healthcare professionals, including obstetrician/gynecologists, primary care physicians, and nurse practitioners.

The practitioners had to have full-time office-based practices of at least 30 hours per week for at least two years, with a minimum of 75 female patients per week. The physicians also had to have prescribed or plan to prescribe oral contraceptives to patients 60 and under.

The online patient questionnaire included 59 questions related to demographics, oral contraceptive use and awareness, and attitudes and beliefs regarding menstruation.

Practitioners were asked 141 questions about demographics, practice information, patterns of prescribing of oral contraceptives, experiences with oral contraceptives and attitudes and beliefs about menstruation.

The participants included 500 women in the patient study, and 299 (44.8% female) professionals in the practitioner survey.

The authors found that 32% of women were extremely interested and 31% were somewhat interested in not having their periods. But the practitioners reported that only 16.8% of patients actually asked about the possibility.

Only 12% of patients, however, said that they had talked to their doctors in the past year about eliminating or reducing the number of periods they had annually, and 71% of these women said they brought the topic up first.

Asked whether having a period was medically necessary, 20.2% of women said no, whereas 45.4% agreed with the statement “my period is necessary because it cleanses my body.”

Among those practitioners whose patients were on continuous oral contraceptives, 97% agreed that “skipping your menstrual cycle is medically acceptable,” but reported that only 38% of their patients feel that it is medically acceptable.

In contrast, four out of five physicians reported discussing continuous use oral contraceptive use with their patients, and 77% reported that they raised the topic.

“We’ve found that physicians and their patients discuss this topic differently, with doctors using the medical term menstrual suppression, while their patients simply talk about not having a period,” he said. “Breaking down this language barrier by speaking in simpler, more patient-friendly terms could have a significant positive impact on understanding.”

Dr. Barnhart did not discuss whether questions about patient or physician perceptions of the safety of oral contraceptives were included in the survey.

The survey was funded by Wyeth, maker of a continuous-use contraceptive. Dr. Barnhart has served as a consultant to the company, and his co-authors Cindy Karcewski and Amy Marren, M.D., are employees of the company.

Primary source: Association of Reproductive Health Professionals

Source reference:
Barnhart K et al. “Knowledge and Understanding of Menses Inhibition or Reduction Among Women and Physicians.” Presented Sept. 27

People with Parkinson’s disease appear to be at increased risk for melanoma and prostate cancer, and this greater risk may extend to their close and distant relatives, a new study suggests.

University of Utah School of Medicine researchers discovered the possible connection after analyzing data from the Utah Population Database (UPDB), which contains birth, death and family relationship data for more than 2.2 million people. Some of the records extend back over 15 generations.

The database is also linked with the Utah Cancer Registry and Utah death certificates dating back to 1904.

For this study, the researchers looked at nearly 3,000 people with at least three generations of genealogical data who had died of Parkinson’s disease. The risk of prostate cancer and melanoma was much higher than expected in this group of people, and an increased risk was also seen in their first-, second-, and third-degree relatives.

“In our study, we not only identified an increased risk for prostate cancer and melanoma among individuals with Parkinson’s disease and their relatives, but also established a reciprocal risk for Parkinson’s disease among individuals with these two cancers and their relatives,” co-author Dr. Stefan-M Pulst, professor and chair of the department of neurology, explained in a university news release. “Collectively, these data strongly support a genetic association between Parkinson’s disease and both prostate cancer and melanoma.”

The data might also highlight new avenues of research, the authors added.

“Our findings point to the existence of underlying pathophysiologic changes that are common to Parkinson’s disease, prostate cancer, and melanoma,” co-author Lisa Cannon-Albright, professor of internal medicine and division chief of epidemiology, pointed out in the news release. “Exploring the precise genetic links among these diseases could improve our understanding of Parkinson’s disease and influence strategies for prostate and skin cancer screening.”

The study is slated to be presented this week at the annual meeting of the American Academy of Neurology in Honolulu. Experts note that research presented at medical meetings has not undergone the rigorous peer review of studies published in reputable journals, and should be considered preliminary.

More information

The U.S. National Institute of Neurological Disorders and Stroke has more about Parkinson’s disease.

Delivery-related deaths of term infants decreased nearly 40% over two decades in Scotland, most likely because fewer babies died from lack of oxygen during childbirth, a new study found.

The risk of delivery-related perinatal death decreased from 8.8 to 5.5 deaths per 10,000 births between 1988 and 2007 (unadjusted change -38%; 95% CI -51% to -21%), according to results of a study in the Aug. 12 Journal of the American Medical Association.

The decrease was mostly attributable to a significant drop in deaths ascribed to intrapartum anoxia, which decreased 48% over the two decades from 5.7 to 3.0 per 10,000 births (95% CI -62% to -29%), the study found.

No significant change was seen in the risk of death from other causes.

“The pattern of the decline suggests that this was primarily due to a reduced number of severely anoxic infants, rather than improved neonatal resuscitation. The change was paralleled by increased rates of cesarean delivery, but there is no direct evidence supporting a causal association between the two trends,” Gordon C. S. Smith, MD, PhD, of the University of Cambridge, and colleagues wrote.

Smith and colleagues analyzed data from more than 1 million Scottish births over two decades from Scottish Morbidity Record 02, a registry of births, and the Scottish Stillbirth and Infant Death Survey, a registry of perinatal deaths.

Participants included all term births of single infants in the cephalic presentation but excluded perinatal deaths due to congenital anomaly or predelivery stillbirth.

During the study period, 719 infants suffered delivery-related perinatal deaths. Of those, 219 were intrauterine fetal deaths following the onset of labor but before birth (intrapartum stillbirths), and 500 occurred during the first four weeks of the live-born infants’ lives (neonatal deaths).

Of these perinatal deaths, 432 (60.1 percent) were attributed to a lack of oxygen occurring during delivery and 287 (39.9 percent) were attributed to other causes.

When the researchers analyzed the deaths attributed to intrapartum anoxia in relation to the phase of delivery, they found that the drop in deaths was similar in: Intrapartum stillbirths (2.6 to 1.1 per 10,000 births; unadjusted change -60%; 95% CI -75% to -34%) Neonatal deaths (3.1 to 1.9 per 10,000 births; unadjusted change -38%; 95% CI -59% to -7%)

These findings held after adjustment for maternal, fetal, and obstetric factors.

The authors noted that because their study was confined to infants in a cephalic presentation, the decrease in infant mortality cannot be explained by increased rates of planned cesarean delivery for breech presentation.

They said that left two potential explanations for the reduced rates of perinatal death: severe anoxia during labor or improved resuscitation of anoxic infants who were live born.

“Our interpretation of our analysis is that the observed changes are most likely to reflect reduced rates of fetuses experiencing severe anoxia during labor,” the authors wrote.

They cautioned, however, that determining what led to the drop in deaths from anoxia is complex and was not addressed by their study.

“The association was not materially affected by statistical adjustment for maternal age, height, parity, socioeconomic deprivation status, gestational age, birth weight percentile, fetal sex, onset of labor, and hospital throughput,” they wrote.

“However, we lacked information on other maternal characteristics that could plausibly have changed during the study period and could affect the risk of complications, such as maternal body mass index.”

The study was funded by the Medical Research Council and Royal College of Obstetricians and Gynaecologists.

The researchers reported no financial conflicts of interest.

Primary source: Journal of the American Medical Association

Source reference:

Smith G, et al “Rates of and factors associated with delivery-related perinatal death among term infants in Scotland” JAMA 2009; 6: 661-68.

ROCKVILLE, Md., Dec. 2 – The FDA warned today that NeutroSpec, a contrast agent used to aid the diagnosis of appendicitis, has been linked two deaths from cardiopulmonary failure.

The FDA warning noted that cardiopulmonary reactions occur within 30 minutes of injection with the agent, which is a murine IgM monoclonal antibody to be labeled with Technetium.

In addition to the two deaths, there have been reports of serious cardiopulmonary events including “cardiac arrest, hypoxia, dyspnea, and hyptension requiring resuscitation with fluids, vassopressors and oxygen,” the FDA said.

The FDA advised close monitoring of all NeutroSpec patients for at least an hour after injection. In addition, clinicians using this agent are advised to have resuscitation equipment and appropriately trained resuscitation personnel available.

Patients with underlying cardiopulmonary conditions may be at higher risk, so use of NeutroSpec in these patients requires careful consideration of “known and potential risks and benefits.”

NeutroSpec [Technetium (99m Tc) fanolesomab] is used for scintigraphic imaging of patients with equivocal signs and symptoms of appendicitis. The agent is approved for use in patients age five and older.

Technetium binds with high affinity to polymophonuclear leucocytes which migrate to the site of an infected appendix. Technetium emits gamma rays, which are detected with a gamma camera, thereby pinpointing the infection.

NeutroSpec is marketed by Mallinckrodt, Palatin Technologies.