Lancet Oncol. Published online July 1, 2010.
News Author: Zosia Chustecka
CME Author: Désirée Lie, MD, MSEd
Clinical Context
PSA screening has been shown to reduce prostate cancer mortality rates at a screening period of 9 years, but the follow-up period may have been inadequate, and longer follow-up may demonstrate greater benefits.
This is a population-based, randomized study of a cohort of men who were invited to receive PSA screening every 2 years from inception to determine the effect of screening on prostate cancer diagnosis and mortality.
Study Highlights
* The study began in 1994 and involved a sample of men living in a city in Sweden. These men were identified by computer randomization and were then randomly assigned to either screening or no screening.
* 3 birth cohorts were included: those born in 1930 to 1934, 1935 to 1939, and 1940 to 1944.
* Men with existing prostate cancer and those who migrated or died before screening were excluded.
* Screening consisted of invitations every 2 years for PSA testing.
* The upper age of screening was predetermined as 69 years.
* The control group did not receive an invitation for screening.
* The incidence of prostate cancer was determined by linkage of the cohort with the West Swedish Regional Cancer Registry every third month. In 2009, all 6 regional cancer registries in Sweden were linked, and cancer data were obtained.
* The cause-of-death certificate was used to identify cases, and an independent committee adjudicated causes of death.
* There were 9952 evaluable men in each group.
* Median age was 56 years at baseline, and 20,000 men were randomly assigned.
* 76% of men in the screening group participated in at least 1 screening.
* 33% of men who received screening had an increased PSA level.
* Of those with an increased PSA level, 93% had a prostate biopsy at least once.
* The maximal follow-up period of 14 years was reached by 78% of the men in the screening group.
* Prostate cancer was diagnosed in 11.4% of men in the screening group and 7.2% in the control group.
* Of those with detected prostate cancer in the screening group, 78.7% were diagnosed directly as a result of screening.
* The cumulative incidence of prostate cancer at 14 years was 12.7% in the screening group vs 8.2% in the control group (hazard ratio, 1.64; P < .0001).
* The hazard ratio was 5.2 in the first year, decreasing to 3.7, 2.6, 2.1, then 1.2 by 8 years or more.
* Prostate cancers diagnosed in the screening group were more likely to be early stage, and the number of advanced cancers was lower in the screening group vs the control group.
* The difference in stage distribution was reflected in treatment, with the screening group more likely to be treated with surveillance or curative treatment.
* In men diagnosed with prostate cancer, the median follow-up after diagnosis was 6.7 years in the screening group vs 4.3 years in the control group.
* The RR of dying of prostate cancer was 0.56 (P = .002) in the screening group vs the control group.
* The absolute cumulative risk reduction was 0.5% (from 0.9% - 0.4% in the control group).
* In a secondary analysis, the RR of death from prostate cancer for those who attended screening vs the control group was 0.44 (P = .0002), whereas for those in the screening group who were invited for a screening but chose not to attend, the RR was 1.05
* Attendees who started screening when older than 60 years were at a higher risk of dying of prostate cancer vs men who were younger at study entry.
* The cumulative risk for deaths not related to prostate cancer was similar in the 2 groups.
* The NNS to prevent 1 prostate cancer–related death was 293, and the NNT was 12.
* When restricted to attendees of screening, the respective numbers were 234 and 15.
* The authors concluded that a PSA prostate cancer screening program was acceptable to men (response rate, 76%) and that screening was associated with an increased diagnosis of prostate cancer and a reduced mortality rate from the disease.
* However, they cautioned that benefits take a long time to achieve, are associated with risks for overdiagnosis and overtreatment, and may not be beneficial in older men.
Clinical Implications
* PSA screening every 2 years in men aged 50 to 69 years is associated with a 64% higher rate of diagnosis of prostate cancer vs no screening.
* PSA screening every 2 years in men aged 50 to 69 years is associated with lower mortality rates from prostate cancer.
Tuesday, July 27, 2010
Friday, July 23, 2010
Agitation, Depression, Apathy Predictors of Progression from MCI to Dementia
From Medscape Medical News
Agitation, Depression, Apathy Predictors of Progression from MCI to Dementia
Caroline Cassels
July 23, 2010 (Honolulu, Hawaii) — Agitation, apathy, and depression significantly predict progression from mild cognitive impairment (MCI) to incident dementia, according to the latest findings from the Mayo Clinic Study on Aging.
Presented here at the Alzheimer's Association International Conference on Alzheimer's Disease 2010, the prospective study showed that individuals with MCI and depression had a 63% increased risk of developing dementia compared with their counterparts with MCI alone. Similarly, the investigators found that the risk for dementia doubled for those with MCI and apathy compared with those with MCI without apathy. The risk is much higher (almost 3 times the increased risk) for persons with MCI and agitation.
"Our results suggest that neuropsychiatric symptoms may be very important clinical markers in predicting the progression from MCI to incident dementia. Additionally, this clinical marker is much cheaper than biomarkers," lead investigator Yonas E. Geda, MD, associate professor of neurology and psychiatry at the Mayo Clinic College of Medicine, Rochester, Minnesota, told Medscape Medical News.
Dr. Yonas E. Geda
According to Dr. Geda, previous relatively smaller studies indicate that neuropsychiatric symptoms such as depression and apathy predict progression from MCI to dementia, prompting the investigators to look at this hypothesis in a population-based setting with a larger sample size.
"We wanted to address this hypothesis in a definitive way using a much larger sample," said Dr. Geda. The prospective study included 275 patients with MCI who were followed-up for a median of 2.8 years to the outcome of incident dementia, as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria.
Neuropsychiatric symptoms were assessed using the 12-item Neuropsychiatric Inventory Questionnaire.
Three neuropsychiatric symptoms — agitation, depression, and apathy — were significantly associated with progression to dementia.
According to the study, among 71 MCI patients with depression, 28 (40%) developed incident dementia, whereas of 201 MCI patients without depression, 51 (25%) developed incident dementia.
Of 49 MCI patients with apathy, 21 (43%) developed incident dementia, whereas of 226 MCI patients without apathy, 58 (26%) developed incident dementia.
A time-to-event cohort analysis was conducted. Hazard ratios (HR) and 95% confidence intervals (CI) were used to estimate the risk of progressing from MCI to incident dementia as predicted by depression, apathy, or agitation.
After adjusting for age, sex, and education, the results revealed that the HR for incident dementia in subjects who had MCI with apathy was 2.08 (95% CI, 1.25 - 3.48; P = .005), and for MCI with depression the HR was 1.63 (95% CI, 1.02 - 2.60; P = .043). MCI with agitation had an HR of 2.67 (95% CI, 1.46 - 4.88; P = .001).
Dr. Geda said the investigators, who include copresenter Mayo Clinic medical student Richard G. Cockerill, BSc, were surprised that there was no association between anxiety and progression from MCI to dementia.
"These findings suggest that clinicians should not stop at the diagnosis of MCI, but they should also conduct a neuropsychiatric assessment using standard instruments and look for depression, apathy, and agitation. We need a future interventional study to determine if treatment of neuropsychiatric symptoms could delay the progression from MCI to incident dementia," said Dr. Geda.
A prediction model developed by investigators at Johns Hopkins University, Baltimore, Maryland, indicates that delaying dementia by just 1 year could reduce the prevalence of Alzheimer's disease by nearly 800,000 cases in 2050.
The study was supported by the National Institutes of Health, Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program, and the Harold Amos Medical Faculty Development Program.
Alzheimer's Association International Conference on Alzheimer's Disease 2010: Abstract 01-05-05. Presented July 11, 2010.
Agitation, Depression, Apathy Predictors of Progression from MCI to Dementia
Caroline Cassels
July 23, 2010 (Honolulu, Hawaii) — Agitation, apathy, and depression significantly predict progression from mild cognitive impairment (MCI) to incident dementia, according to the latest findings from the Mayo Clinic Study on Aging.
Presented here at the Alzheimer's Association International Conference on Alzheimer's Disease 2010, the prospective study showed that individuals with MCI and depression had a 63% increased risk of developing dementia compared with their counterparts with MCI alone. Similarly, the investigators found that the risk for dementia doubled for those with MCI and apathy compared with those with MCI without apathy. The risk is much higher (almost 3 times the increased risk) for persons with MCI and agitation.
"Our results suggest that neuropsychiatric symptoms may be very important clinical markers in predicting the progression from MCI to incident dementia. Additionally, this clinical marker is much cheaper than biomarkers," lead investigator Yonas E. Geda, MD, associate professor of neurology and psychiatry at the Mayo Clinic College of Medicine, Rochester, Minnesota, told Medscape Medical News.
Dr. Yonas E. Geda
According to Dr. Geda, previous relatively smaller studies indicate that neuropsychiatric symptoms such as depression and apathy predict progression from MCI to dementia, prompting the investigators to look at this hypothesis in a population-based setting with a larger sample size.
"We wanted to address this hypothesis in a definitive way using a much larger sample," said Dr. Geda. The prospective study included 275 patients with MCI who were followed-up for a median of 2.8 years to the outcome of incident dementia, as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria.
Neuropsychiatric symptoms were assessed using the 12-item Neuropsychiatric Inventory Questionnaire.
Three neuropsychiatric symptoms — agitation, depression, and apathy — were significantly associated with progression to dementia.
According to the study, among 71 MCI patients with depression, 28 (40%) developed incident dementia, whereas of 201 MCI patients without depression, 51 (25%) developed incident dementia.
Of 49 MCI patients with apathy, 21 (43%) developed incident dementia, whereas of 226 MCI patients without apathy, 58 (26%) developed incident dementia.
A time-to-event cohort analysis was conducted. Hazard ratios (HR) and 95% confidence intervals (CI) were used to estimate the risk of progressing from MCI to incident dementia as predicted by depression, apathy, or agitation.
After adjusting for age, sex, and education, the results revealed that the HR for incident dementia in subjects who had MCI with apathy was 2.08 (95% CI, 1.25 - 3.48; P = .005), and for MCI with depression the HR was 1.63 (95% CI, 1.02 - 2.60; P = .043). MCI with agitation had an HR of 2.67 (95% CI, 1.46 - 4.88; P = .001).
Dr. Geda said the investigators, who include copresenter Mayo Clinic medical student Richard G. Cockerill, BSc, were surprised that there was no association between anxiety and progression from MCI to dementia.
"These findings suggest that clinicians should not stop at the diagnosis of MCI, but they should also conduct a neuropsychiatric assessment using standard instruments and look for depression, apathy, and agitation. We need a future interventional study to determine if treatment of neuropsychiatric symptoms could delay the progression from MCI to incident dementia," said Dr. Geda.
A prediction model developed by investigators at Johns Hopkins University, Baltimore, Maryland, indicates that delaying dementia by just 1 year could reduce the prevalence of Alzheimer's disease by nearly 800,000 cases in 2050.
The study was supported by the National Institutes of Health, Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program, and the Harold Amos Medical Faculty Development Program.
Alzheimer's Association International Conference on Alzheimer's Disease 2010: Abstract 01-05-05. Presented July 11, 2010.
Quadrivalent HPV Vaccine Safe and Effective in Men
From Reuters Health Information
By Karla Gale
NEW YORK (Reuters Health) Jul 22 - The quadrivalent human papillomavirus (HPV) vaccine (Gardasil) prevents infection and disease in men, according to data presented today at AIDS 2010 in Vienna.
In fact, the efficacy data were so good that the U.S. Food and Drug Administration stopped the trial early so that men in the placebo group could get the vaccine, presenter Dr. Heiko Jessen from Berlin, Germany, told Reuters Health.
Infection with oncogenic HPV can cause cancers of the penis, anus, and head and neck in men, and AIDS substantially increases the risk of HPV-related invasive cancers. Earlier this year the US Centers for Disease Control and Prevention issued a "permissive recommendation" for HPV vaccination in males ages 9 through 26. (See Reuters Health reports of Jan 4, 2010 and Jul 31, 2009.)
The randomized, double-blind, placebo-controlled trial started out with more than 4000 healthy men aged 16 to 26 years from 18 countries. The per-protocol analysis, reported here, involved 1400 men (including 200 men who have sex with men) in each arm followed for 3 years, Dr. Jessen said.
As noted in their meeting abstract, the researchers detected 3 external genital lesions related to HPV types 6, 11, 16 or 18 in the vaccine arm and 31 in the placebo arm - primarily condylomata acuminate - for an efficacy of 90.4%.
Efficacy against HPV vaccine types was 85.6%, and against HPV DNA detection at any time was 44.7%.
"People who are immune may still have HPV DNA," Dr. Jessen said, but the significance is unknown.
There were no cases of penile, perianal or perineal intraepithelial neoplasia, but one wouldn't expect these in young healthy men during a short follow-up trial, he added. The research team will continue to follow the participants.
"For now it makes sense to give the HPV vaccine to boys and men ages 9 to 26," Dr. Jessen said, but his group intends to examine its efficacy in older men as well, particularly in men who have sex with men, who are at higher risk for HPV-related malignancy.
There were no serious vaccine-related adverse experiences, he added.
The study was funded by Merck, which manufactures the vaccine
By Karla Gale
NEW YORK (Reuters Health) Jul 22 - The quadrivalent human papillomavirus (HPV) vaccine (Gardasil) prevents infection and disease in men, according to data presented today at AIDS 2010 in Vienna.
In fact, the efficacy data were so good that the U.S. Food and Drug Administration stopped the trial early so that men in the placebo group could get the vaccine, presenter Dr. Heiko Jessen from Berlin, Germany, told Reuters Health.
Infection with oncogenic HPV can cause cancers of the penis, anus, and head and neck in men, and AIDS substantially increases the risk of HPV-related invasive cancers. Earlier this year the US Centers for Disease Control and Prevention issued a "permissive recommendation" for HPV vaccination in males ages 9 through 26. (See Reuters Health reports of Jan 4, 2010 and Jul 31, 2009.)
The randomized, double-blind, placebo-controlled trial started out with more than 4000 healthy men aged 16 to 26 years from 18 countries. The per-protocol analysis, reported here, involved 1400 men (including 200 men who have sex with men) in each arm followed for 3 years, Dr. Jessen said.
As noted in their meeting abstract, the researchers detected 3 external genital lesions related to HPV types 6, 11, 16 or 18 in the vaccine arm and 31 in the placebo arm - primarily condylomata acuminate - for an efficacy of 90.4%.
Efficacy against HPV vaccine types was 85.6%, and against HPV DNA detection at any time was 44.7%.
"People who are immune may still have HPV DNA," Dr. Jessen said, but the significance is unknown.
There were no cases of penile, perianal or perineal intraepithelial neoplasia, but one wouldn't expect these in young healthy men during a short follow-up trial, he added. The research team will continue to follow the participants.
"For now it makes sense to give the HPV vaccine to boys and men ages 9 to 26," Dr. Jessen said, but his group intends to examine its efficacy in older men as well, particularly in men who have sex with men, who are at higher risk for HPV-related malignancy.
There were no serious vaccine-related adverse experiences, he added.
The study was funded by Merck, which manufactures the vaccine
Continued Antihypertensive Treatment Safe After Stroke
From Medscape Medical News
Continued Antihypertensive Treatment Safe After Stroke
Emma Hitt, PhD
July 23, 2010 — Continuing antihypertensive medication after a stroke does not appear to reduce 2-week death or dependency, cardiovascular event rate, or mortality at 6 months, according to new research.
Thompson G. Robinson, MD, published the findings of a randomized study — Continue Or Stop post-Stroke Antihypertensives Collaborative Study (COSSACS) — online July 12 in Lancet Neurology.
The study sought to assess the efficacy and safety of continuing or stopping preexisting antihypertensive drugs within 48 hours of when a patient had undergone nondysphagic, ischemic, or hemorrhagic stroke, and within 48 hours of the last dose of antihypertensive drugs.
"A spontaneous decrease in blood pressure usually occurs 4 to 10 days after stroke, but substantial reductions in blood pressure can be associated with cerebral hypoperfusion as a consequence of poststroke cerebral dysautoregulation," Dr. Robinson and colleagues note.
The prospective trial included patients from 49 participating UK National Institute for Health Research Stroke Research Network centers from January 1, 2003, to March 31, 2009.
Patients were randomly assigned to either continue (n = 379) or stop (n = 384) preexisting antihypertensive drugs for 2 weeks after their stroke. Of the patients who continued antihypertensive drugs, 72 of 379 reached the primary endpoint (death or dependency [modified Rankin scale score ≥ 3 points] at 2 weeks) compared with 82 of 384 patients in the stop group, which was not a significant difference between groups (P = .3).
The difference between the 2 groups in systolic blood pressure at 2 weeks was 13 mm Hg (95% confidence interval, 10 - 17 mm Hg), and the difference in diastolic blood pressure was 8 mm Hg (95% confidence interval, 6 - 10 mm Hg; P < .0001).
The incidences of serious adverse events, 6-month mortality, and major cardiovascular events were similar between groups.
"These neutral results might be because COSSACS was underpowered owing to early termination of the trial, and support the continuation of ongoing research trials," the investigators conclude.
According to the researchers, a post hoc analysis found that continuing antihypertensive drugs might be associated with reduced 2-week death and dependency in patients with ischemic stroke confirmed on neuroimaging. "However, this post-hoc subgroup analysis requires further evaluation in patient populations with well-defined stroke subtypes," they write.
A related editorial by Craig S. Anderson, MD, from the University of Sydney and Royal Prince Alfred Hospital, Australia, noted that the study was "underpowered...but still worthwhile," and the "safety data are useful in guiding clinical practice."
Dr. Anderson concluded that the findings add to an "emerging consistent message: oral antihypertensive treatment can be used safely in nearly all patients within the first few days of mildly disabling or non-disabling stroke or transient ischaemic attack because of the modest size (about 6–12 mm Hg systolic) and speed (several hours) of the blood-pressure reduction."
The authors have disclosed no relevant financial relationships.
Lancet Neurol. Published online July 12, 2010.
Continued Antihypertensive Treatment Safe After Stroke
Emma Hitt, PhD
July 23, 2010 — Continuing antihypertensive medication after a stroke does not appear to reduce 2-week death or dependency, cardiovascular event rate, or mortality at 6 months, according to new research.
Thompson G. Robinson, MD, published the findings of a randomized study — Continue Or Stop post-Stroke Antihypertensives Collaborative Study (COSSACS) — online July 12 in Lancet Neurology.
The study sought to assess the efficacy and safety of continuing or stopping preexisting antihypertensive drugs within 48 hours of when a patient had undergone nondysphagic, ischemic, or hemorrhagic stroke, and within 48 hours of the last dose of antihypertensive drugs.
"A spontaneous decrease in blood pressure usually occurs 4 to 10 days after stroke, but substantial reductions in blood pressure can be associated with cerebral hypoperfusion as a consequence of poststroke cerebral dysautoregulation," Dr. Robinson and colleagues note.
The prospective trial included patients from 49 participating UK National Institute for Health Research Stroke Research Network centers from January 1, 2003, to March 31, 2009.
Patients were randomly assigned to either continue (n = 379) or stop (n = 384) preexisting antihypertensive drugs for 2 weeks after their stroke. Of the patients who continued antihypertensive drugs, 72 of 379 reached the primary endpoint (death or dependency [modified Rankin scale score ≥ 3 points] at 2 weeks) compared with 82 of 384 patients in the stop group, which was not a significant difference between groups (P = .3).
The difference between the 2 groups in systolic blood pressure at 2 weeks was 13 mm Hg (95% confidence interval, 10 - 17 mm Hg), and the difference in diastolic blood pressure was 8 mm Hg (95% confidence interval, 6 - 10 mm Hg; P < .0001).
The incidences of serious adverse events, 6-month mortality, and major cardiovascular events were similar between groups.
"These neutral results might be because COSSACS was underpowered owing to early termination of the trial, and support the continuation of ongoing research trials," the investigators conclude.
According to the researchers, a post hoc analysis found that continuing antihypertensive drugs might be associated with reduced 2-week death and dependency in patients with ischemic stroke confirmed on neuroimaging. "However, this post-hoc subgroup analysis requires further evaluation in patient populations with well-defined stroke subtypes," they write.
A related editorial by Craig S. Anderson, MD, from the University of Sydney and Royal Prince Alfred Hospital, Australia, noted that the study was "underpowered...but still worthwhile," and the "safety data are useful in guiding clinical practice."
Dr. Anderson concluded that the findings add to an "emerging consistent message: oral antihypertensive treatment can be used safely in nearly all patients within the first few days of mildly disabling or non-disabling stroke or transient ischaemic attack because of the modest size (about 6–12 mm Hg systolic) and speed (several hours) of the blood-pressure reduction."
The authors have disclosed no relevant financial relationships.
Lancet Neurol. Published online July 12, 2010.
Thursday, July 22, 2010
Most Patients With CVD Can Fly Safely, Says British Society
From Heartwire
Lisa Nainggolan
July 20, 2010 (Exeter, United Kingdom) — Most people with cardiovascular disease who are not critically ill can safely fly on commercial aircraft, the British Cardiovascular Society has concluded in a new report [1]. The document includes "guidance-at-a-glance" and is aimed primarily at general practitioners, lead author Dr David Smith (Royal Devon and Exeter NHS Foundation Trust, Exeter, UK) told heartwire . It will also be "translated" into "even more straightforward" guidance for patients by the British Heart Foundation, he noted.
Smith said this guidance, the first ever from the British Cardiovascular Society, "tries to go through the detail. In general, we've tried to allow people to fly, unless there is a very good reason not to, whereas the way various other people have looked at this is to say, 'Who shall we restrict?' " Of the many existing guidelines on passenger fitness to fly, most include some reference to cardiovascular disorders, but many are contrary in their advice, particularly with reference to the time required between an event or medical procedure and the flight, he said. "In our view, they were not necessarily based on thinking about the underlying processes, and they often do not separate patients out into higher- and lower-risk categories."
A large proportion of the new document is devoted to looking at the underlying effects of the cabin environment and then seeing whether this is likely to produce a deleterious effect on somebody who has existing heart disease, Smith said. "We've tried to support all our recommendations with analysis of the underlying physiology and physics. The overwhelming conclusion is that the cabin environment poses a very little threat. It's not the flying that's the problem. What we try to emphasize is that it's the stability, or instability, of someone's underlying condition that indicates the probability of a spontaneous event occurring while they are in the air."
Minimal Restrictions on Flying for Most With Pacemakers, ICDs
Smith and colleagues explain that the main impact of air travel is the inhalation of air with reduced oxygen content in a pressurized environment, resulting in lower circulating oxygen levels in the blood, known as hypobaric hypoxia. Passengers already at high risk of angina, myocardial infarction, heart failure, or abnormal heart rhythms might be adversely affected by hypoxia, but the blood oxygen levels induced by flying "appear to have little or no adverse circulatory effects," certainly not for short- and medium-haul flights, they state.
The guidance-at-a-glance, which appears in the first two pages of the document, goes into detail about various cardiovascular conditions, and divides each into low, medium, and high risk, with accompanying lay explanations. It then goes on to give advice on flying for each level of that condition. For example, for post-STEMI and NSTEMI, those at low risk are advised that they can fly three days after their event, and those at medium risk can fly after 10 days. However, those at high risk--ejection fraction <40%, signs and symptoms of heart failure, and those awaiting further investigation, revascularization, or device therapy--are advised to "defer travel" until their condition is stable.
After uncomplicated elective PCI, the guidelines state that patients can fly "after two days." Likewise, patients with pacemakers implanted are advised they can fly after two days, unless they have suffered a pneumothorax, in which case they should wait until two weeks after it has fully healed. The same advice applies to those with ICDs, with the added recommendation that they should not fly after the ICD has delivered a shock until the condition is considered stable.
"We hope we've clarified a lot of things that people worry about. Cosmic rays, effects on their pacemakers, for example, have been addressed in some detail," Smith said. "People are concerned about their defibrillators, pacemakers, and stents . . . and we hope this will allay fears and give guidance as to what people should do if they are going to fly and they have underlying heart disease."
Venous Thromboembolism Risk Low
There is also guidance for the avoidance of deep vein thrombosis (DVT) and venous thromboembolism; although a long-haul flight doubles the risk of DVT, it is similar to that incurred during car, bus, or train travel for a similar period, the doctors state. And the absolute risk of DVT for a fit and healthy person is one in 6000 for a flight of more than four hours, they note, pointing out that pilots are at no greater risk than the general population.
Even those at high risk--those who have already had a DVT, recent surgery lasting more than 30 minutes, known thrombophilia, or pregnancy, and those who are obese (BMI>30 kg/m2)--can still fly, provided they consume plenty of fluids, exclude caffeine and alcohol, wear compression stockings, and take a low-molecular-weight heparin, they say. Aspirin is not recommended.
Smith reports no conflict of interest.
References
Lisa Nainggolan
July 20, 2010 (Exeter, United Kingdom) — Most people with cardiovascular disease who are not critically ill can safely fly on commercial aircraft, the British Cardiovascular Society has concluded in a new report [1]. The document includes "guidance-at-a-glance" and is aimed primarily at general practitioners, lead author Dr David Smith (Royal Devon and Exeter NHS Foundation Trust, Exeter, UK) told heartwire . It will also be "translated" into "even more straightforward" guidance for patients by the British Heart Foundation, he noted.
Smith said this guidance, the first ever from the British Cardiovascular Society, "tries to go through the detail. In general, we've tried to allow people to fly, unless there is a very good reason not to, whereas the way various other people have looked at this is to say, 'Who shall we restrict?' " Of the many existing guidelines on passenger fitness to fly, most include some reference to cardiovascular disorders, but many are contrary in their advice, particularly with reference to the time required between an event or medical procedure and the flight, he said. "In our view, they were not necessarily based on thinking about the underlying processes, and they often do not separate patients out into higher- and lower-risk categories."
A large proportion of the new document is devoted to looking at the underlying effects of the cabin environment and then seeing whether this is likely to produce a deleterious effect on somebody who has existing heart disease, Smith said. "We've tried to support all our recommendations with analysis of the underlying physiology and physics. The overwhelming conclusion is that the cabin environment poses a very little threat. It's not the flying that's the problem. What we try to emphasize is that it's the stability, or instability, of someone's underlying condition that indicates the probability of a spontaneous event occurring while they are in the air."
Minimal Restrictions on Flying for Most With Pacemakers, ICDs
Smith and colleagues explain that the main impact of air travel is the inhalation of air with reduced oxygen content in a pressurized environment, resulting in lower circulating oxygen levels in the blood, known as hypobaric hypoxia. Passengers already at high risk of angina, myocardial infarction, heart failure, or abnormal heart rhythms might be adversely affected by hypoxia, but the blood oxygen levels induced by flying "appear to have little or no adverse circulatory effects," certainly not for short- and medium-haul flights, they state.
The guidance-at-a-glance, which appears in the first two pages of the document, goes into detail about various cardiovascular conditions, and divides each into low, medium, and high risk, with accompanying lay explanations. It then goes on to give advice on flying for each level of that condition. For example, for post-STEMI and NSTEMI, those at low risk are advised that they can fly three days after their event, and those at medium risk can fly after 10 days. However, those at high risk--ejection fraction <40%, signs and symptoms of heart failure, and those awaiting further investigation, revascularization, or device therapy--are advised to "defer travel" until their condition is stable.
After uncomplicated elective PCI, the guidelines state that patients can fly "after two days." Likewise, patients with pacemakers implanted are advised they can fly after two days, unless they have suffered a pneumothorax, in which case they should wait until two weeks after it has fully healed. The same advice applies to those with ICDs, with the added recommendation that they should not fly after the ICD has delivered a shock until the condition is considered stable.
"We hope we've clarified a lot of things that people worry about. Cosmic rays, effects on their pacemakers, for example, have been addressed in some detail," Smith said. "People are concerned about their defibrillators, pacemakers, and stents . . . and we hope this will allay fears and give guidance as to what people should do if they are going to fly and they have underlying heart disease."
Venous Thromboembolism Risk Low
There is also guidance for the avoidance of deep vein thrombosis (DVT) and venous thromboembolism; although a long-haul flight doubles the risk of DVT, it is similar to that incurred during car, bus, or train travel for a similar period, the doctors state. And the absolute risk of DVT for a fit and healthy person is one in 6000 for a flight of more than four hours, they note, pointing out that pilots are at no greater risk than the general population.
Even those at high risk--those who have already had a DVT, recent surgery lasting more than 30 minutes, known thrombophilia, or pregnancy, and those who are obese (BMI>30 kg/m2)--can still fly, provided they consume plenty of fluids, exclude caffeine and alcohol, wear compression stockings, and take a low-molecular-weight heparin, they say. Aspirin is not recommended.
Smith reports no conflict of interest.
References
First-Morning Void May Be Best Predictor of Renal Events in Diabetic Nephropathy
From Medscape Medical News
Laurie Barclay, MD
July 22, 2010 — Albumin-to-creatinine ratio (ACR) in a first-morning void may be the best predictor of renal events in patients with type 2 diabetes and kidney disease, according to the results of the Reduction in Endpoints in Non Insulin Dependent Diabetes Mellitus with the Angiotensin-II Antagonist Losartan (RENAAL) trial reported Online First July 15 in the Journal of the American Society of Nephrology.
"From a clinical point of view, these results are very important, because they imply that collection of first morning voids, which is clearly more convenient than collecting a 24-hour urine, can be used for assessment of proteinuria," said lead author Hiddo J. Lambers Heerspink, PharmD, PhD, from University Medical Center Groningen, in Groningen, the Netherlands, in a news release.
With a study sample of 701 participants with type 2 diabetes and nephropathy enrolled in the RENAAL trial, the goal of the study was to compare prediction of renal events by urinary protein excretion (UPE) and urinary albumin excretion (UAE) from a 24-hour urine collection vs urinary albumin concentration (UAC) and ACR from a first-morning void. Time to a doubling of serum creatinine or end-stage renal disease was the main study endpoint.
There were 202 renal events during follow-up. For each 1-SD increase in the log-transformed measures, the hazard ratios (HRs) for the risk for a renal outcome were 3.16 (95% confidence interval [CI], 2.60 - 3.86) for UAE, 3.02 (95% CI, 2.53 - 3.62) for UPE, 3.23 (95% CI, 2.67 - 3.91) for UAC, and 4.36 (95% CI, 3.50 - 5.45) for ACR. Compared with the other measures, the area under the receiver operating characteristic curve was significantly higher for ACR.
"[F]or predicting renal disease progression in patients with type 2 diabetes and nephropathy, collecting first morning void urine samples and measuring the albumin:creatinine ratio appear to be superior when compared with measuring 24-hour urinary albumin excretion," the study authors write. "These results are clinically important because they imply that collection of first morning voids, which is clearly more convenient than collecting a 24-hour urine, can be used for assessment of proteinuria."
Limitations of this study include inability to directly apply the results to individuals without diabetes or nephropathy. In addition, total protein concentrations were not measured in a first-morning void urine sample, precluding comparison between protein-to-creatinine ratios and ACRs derived from a first-morning void.
In an accompanying editorial, Bryan Kestenbaum, MD, and Ian de Boer, MD, from the University of Washington in Seattle, discuss the implications of this study for clinical practice and for clinical research.
"Given data from this study and the considerable patient effort required for a 24-hour urine collection, we agree with the authors that the first morning albumin:creatinine ratio is in general the logical choice for quantifying proteinuria in clinical practice," they write.
"First, urine ACR represents more than simply proteinuria, and associations of urine ACR with disease outcomes should be interpreted in the context of dual contributions of urine albumin excretion and urine creatinine. Second, this study [begs] the questions, 'Why is low urine creatinine excretion associated with adverse kidney and cardiovascular disease outcomes independent of standard measures of body composition?' 'Does a low urine creatinine concentration reflect low muscle mass, low muscle quality, or both?' 'Is a low urine creatinine concentration a modifiable therapeutic target?'"
The RENAAL study was sponsored by Merck & Co, Inc. One of the study authors is an employee of Merck, and 4 other study authors are members of the RENAAL Steering Committee and have received grants from Merck. The editorialists have disclosed no relevant financial relationships.
J Am Soc Nephrol. Published online July 15, 2010.
Laurie Barclay, MD
July 22, 2010 — Albumin-to-creatinine ratio (ACR) in a first-morning void may be the best predictor of renal events in patients with type 2 diabetes and kidney disease, according to the results of the Reduction in Endpoints in Non Insulin Dependent Diabetes Mellitus with the Angiotensin-II Antagonist Losartan (RENAAL) trial reported Online First July 15 in the Journal of the American Society of Nephrology.
"From a clinical point of view, these results are very important, because they imply that collection of first morning voids, which is clearly more convenient than collecting a 24-hour urine, can be used for assessment of proteinuria," said lead author Hiddo J. Lambers Heerspink, PharmD, PhD, from University Medical Center Groningen, in Groningen, the Netherlands, in a news release.
With a study sample of 701 participants with type 2 diabetes and nephropathy enrolled in the RENAAL trial, the goal of the study was to compare prediction of renal events by urinary protein excretion (UPE) and urinary albumin excretion (UAE) from a 24-hour urine collection vs urinary albumin concentration (UAC) and ACR from a first-morning void. Time to a doubling of serum creatinine or end-stage renal disease was the main study endpoint.
There were 202 renal events during follow-up. For each 1-SD increase in the log-transformed measures, the hazard ratios (HRs) for the risk for a renal outcome were 3.16 (95% confidence interval [CI], 2.60 - 3.86) for UAE, 3.02 (95% CI, 2.53 - 3.62) for UPE, 3.23 (95% CI, 2.67 - 3.91) for UAC, and 4.36 (95% CI, 3.50 - 5.45) for ACR. Compared with the other measures, the area under the receiver operating characteristic curve was significantly higher for ACR.
"[F]or predicting renal disease progression in patients with type 2 diabetes and nephropathy, collecting first morning void urine samples and measuring the albumin:creatinine ratio appear to be superior when compared with measuring 24-hour urinary albumin excretion," the study authors write. "These results are clinically important because they imply that collection of first morning voids, which is clearly more convenient than collecting a 24-hour urine, can be used for assessment of proteinuria."
Limitations of this study include inability to directly apply the results to individuals without diabetes or nephropathy. In addition, total protein concentrations were not measured in a first-morning void urine sample, precluding comparison between protein-to-creatinine ratios and ACRs derived from a first-morning void.
In an accompanying editorial, Bryan Kestenbaum, MD, and Ian de Boer, MD, from the University of Washington in Seattle, discuss the implications of this study for clinical practice and for clinical research.
"Given data from this study and the considerable patient effort required for a 24-hour urine collection, we agree with the authors that the first morning albumin:creatinine ratio is in general the logical choice for quantifying proteinuria in clinical practice," they write.
"First, urine ACR represents more than simply proteinuria, and associations of urine ACR with disease outcomes should be interpreted in the context of dual contributions of urine albumin excretion and urine creatinine. Second, this study [begs] the questions, 'Why is low urine creatinine excretion associated with adverse kidney and cardiovascular disease outcomes independent of standard measures of body composition?' 'Does a low urine creatinine concentration reflect low muscle mass, low muscle quality, or both?' 'Is a low urine creatinine concentration a modifiable therapeutic target?'"
The RENAAL study was sponsored by Merck & Co, Inc. One of the study authors is an employee of Merck, and 4 other study authors are members of the RENAAL Steering Committee and have received grants from Merck. The editorialists have disclosed no relevant financial relationships.
J Am Soc Nephrol. Published online July 15, 2010.
FDA Warns Abbott Diabetes Care About Manufacturing Practices of Its Glucose Meters
From Medscape Medical News > Alerts, Approvals and Safety Changes > Medscape Alerts
Robert Lowes
July 21, 2010 — Abbott Diabetes Care has received a warning letter from the US Food and Drug Administration (FDA) about how it manufactures its FreeStyle glucose meters.
The meters include the FreeStyle Navigator Continuous Glucose Monitoring System, currently unavailable in the United States as a result of what the company calls a "supply interruption."
In a July 2 letter, the FDA faulted Abbott Diabetes Care, a unit of Abbott, with violations of quality-control requirements, including how it followed up on the discovery of empty blister packs and scratches on glucose-meter test strips.
The FDA also stated that the company lacked enough qualified personnel to ensure that manufacturing processes met agency standards. The job description for the director of quality systems, for example, required this employee to have a bachelor's degree in a scientific, engineering, or technical discipline. The person in this position instead had a business administration degree, according to the agency.
The warning letter stemmed from an FDA inspection of the company's facilities in Alameda, California, earlier this year.
In a press release, Abbott Diabetes Care said it "has taken and continues to take the actions necessary to address the items outlined in the letter and is communicating those actions directly to the agency."
Warning Letter Comes On Top of Other Agency Actions
The warning letter, posted Tuesday on the agency's Web site, is the latest in a series of FDA actions involving glucose meters from Abbott Diabetes Care. In August 2009, the agency announced that patients with diabetes who receive therapeutic products containing certain sugars other than glucose could experience serious, although rare, injuries if their glucose meters used test strips that incorporated the GDH-PQQ enzyme. Such test strips will react with nonglucose sugars such as maltose to produce a falsely high glucose reading, which might cause patients with diabetes to take too much insulin. The FDA identified Abbott Diabetes Care as one of several glucose meter manufacturers that relied on GDH-PQQ test strips.
Since then, the company has won FDA clearance for new test strips based on another enzyme that is not affected by maltose and other common nonglucose sugars. Abbott spokesperson Gregory Miley told Medscape Medical News that the new test strips would hit the US marketplace later this year.
In May, the FDA also announced a class 2 recall of the FreeStyle Navigator Continuous Glucose Monitoring System because of the possibility of cracks in the device's plastic housing near the battery compartment, which could allow moisture to enter and trigger device failure or inaccurate readings. Mr. Miley said that the company had alerted both its customers and the FDA about this problem in April 2009.
In April 2010, Abbott Diabetes Care disclosed that it was experiencing a "supply interruption" with the FreeStyle Navigator system and therefore was unable to provide patients with replacement receivers and transmitters, or sell the complete system to new customers. Mr. Miley told Medscape Medical News that the company had resumed selling the product in 6 European countries and Israel.
"We're working as quickly as we can on it for the United States," he said.
Mr. Miley declined to say what caused the supply interruption.
The full text of the warning letter to Abbott Diabetes Care about its manufacturing processes for glucose meters is available on the agency's Web site.
To report adverse events related to these devices, contact MedWatch by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to MedWatch, FDA, 5600 Fishers Lane, Rockville, Maryland 20852-9787.
Robert Lowes
July 21, 2010 — Abbott Diabetes Care has received a warning letter from the US Food and Drug Administration (FDA) about how it manufactures its FreeStyle glucose meters.
The meters include the FreeStyle Navigator Continuous Glucose Monitoring System, currently unavailable in the United States as a result of what the company calls a "supply interruption."
In a July 2 letter, the FDA faulted Abbott Diabetes Care, a unit of Abbott, with violations of quality-control requirements, including how it followed up on the discovery of empty blister packs and scratches on glucose-meter test strips.
The FDA also stated that the company lacked enough qualified personnel to ensure that manufacturing processes met agency standards. The job description for the director of quality systems, for example, required this employee to have a bachelor's degree in a scientific, engineering, or technical discipline. The person in this position instead had a business administration degree, according to the agency.
The warning letter stemmed from an FDA inspection of the company's facilities in Alameda, California, earlier this year.
In a press release, Abbott Diabetes Care said it "has taken and continues to take the actions necessary to address the items outlined in the letter and is communicating those actions directly to the agency."
Warning Letter Comes On Top of Other Agency Actions
The warning letter, posted Tuesday on the agency's Web site, is the latest in a series of FDA actions involving glucose meters from Abbott Diabetes Care. In August 2009, the agency announced that patients with diabetes who receive therapeutic products containing certain sugars other than glucose could experience serious, although rare, injuries if their glucose meters used test strips that incorporated the GDH-PQQ enzyme. Such test strips will react with nonglucose sugars such as maltose to produce a falsely high glucose reading, which might cause patients with diabetes to take too much insulin. The FDA identified Abbott Diabetes Care as one of several glucose meter manufacturers that relied on GDH-PQQ test strips.
Since then, the company has won FDA clearance for new test strips based on another enzyme that is not affected by maltose and other common nonglucose sugars. Abbott spokesperson Gregory Miley told Medscape Medical News that the new test strips would hit the US marketplace later this year.
In May, the FDA also announced a class 2 recall of the FreeStyle Navigator Continuous Glucose Monitoring System because of the possibility of cracks in the device's plastic housing near the battery compartment, which could allow moisture to enter and trigger device failure or inaccurate readings. Mr. Miley said that the company had alerted both its customers and the FDA about this problem in April 2009.
In April 2010, Abbott Diabetes Care disclosed that it was experiencing a "supply interruption" with the FreeStyle Navigator system and therefore was unable to provide patients with replacement receivers and transmitters, or sell the complete system to new customers. Mr. Miley told Medscape Medical News that the company had resumed selling the product in 6 European countries and Israel.
"We're working as quickly as we can on it for the United States," he said.
Mr. Miley declined to say what caused the supply interruption.
The full text of the warning letter to Abbott Diabetes Care about its manufacturing processes for glucose meters is available on the agency's Web site.
To report adverse events related to these devices, contact MedWatch by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to MedWatch, FDA, 5600 Fishers Lane, Rockville, Maryland 20852-9787.
Vitamin E–Rich Foods May Reduce Long-Term Risk for Dementia
From Medscape Medical News
Allison Gandey
July 22, 2010 — Vitamin E may play a modest role in altering the course of dementia, say researchers. Compared with participants with the lowest intake, investigators found that those patients with higher vitamin E intake were 25% less likely to develop dementia.
"When beta-amyloid — a hallmark of pathologic Alzheimer disease — accumulates in the brain, an inflammatory response is likely evoked that produces nitric oxide radicals and downstream neurodegenerative effects," report investigators led by Elizabeth Devore, ScD, from the Erasmus Medical Center in Rotterdam, the Netherlands.
"Vitamin E is a powerful fat-soluble antioxidant that may help to inhibit the pathogenesis of dementia."
The results appear in the July issue of the Archives of Neurology and suggest that dietary antioxidants affect the early stages of dementia.
Vitamin E is found in whole-grain foods, eggs, milk, nuts, seeds, avocado, spinach, and unheated vegetable oils. The Rotterdam Study previously found that higher dietary intakes of vitamins E and C were associated with a lower risk for dementia and Alzheimer's disease.
In this new long-term follow-up of the Rotterdam Study, investigators followed participants for 9.6 years. The population-based prospective cohort study included 5395 people free of disease at baseline.
A total of 465 people developed dementia. Of these, 365 were diagnosed with Alzheimer's disease. The investigators found that higher dietary intake of vitamin E, but not vitamin C, beta carotene, or flavonoids, was associated with lower long-term risk for dementia.
These results conflict with previous findings, which suggested a link between vitamin C intake and dementia risk. "The result was modest in our analysis," note the investigators, who reported a hazard ratio of 0.66 (95% confidence interval, 0.44 - 1.00). "Chance is the most likely explanation," they add. "Alternatively, vitamin C intake could be important exclusively at later stages of dementia development, but this is less likely because results of previous studies suggest that dietary antioxidants affect early stages of dementia pathogenesis."
Long-Term Prospective Study
The investigators adjusted for age, education, apolipoprotein E ε4 genotype, total energy, alcohol intake, smoking habits, body mass index, and supplement use. They found that higher vitamin E intake at study baseline was associated with lower long-term risk for dementia (P = .02 for trend).
Asked by Medscape Medical News to comment, Maria Carrillo, PhD, senior director of medical and scientific relations at the Alzheimer's Association, pointed out the National Institutes of Health have been calling for long-term prospective studies such as this one. "These are important studies, and this one was conducted by a fantastic, internationally renowned group."
Dr. Carrillo acknowledged the finding is preliminary — it is still too early for specific recommendations on vitamin E intake, and excessive use can have negative cardiovascular effects, she said.
"Future studies should continue to evaluate dietary intake of antioxidants relative to dementia risk," note the investigators, "including different points at which antioxidant intake might modulate risk."
This study was supported by the Netherlands Organization for Scientific Research, the National Institutes of Health, and a US Fulbright Fellowship to the Netherlands. The researchers have disclosed no relevant financial relationships.
Arch Neurol. 2010;67:819-825. Abstract
Allison Gandey
July 22, 2010 — Vitamin E may play a modest role in altering the course of dementia, say researchers. Compared with participants with the lowest intake, investigators found that those patients with higher vitamin E intake were 25% less likely to develop dementia.
"When beta-amyloid — a hallmark of pathologic Alzheimer disease — accumulates in the brain, an inflammatory response is likely evoked that produces nitric oxide radicals and downstream neurodegenerative effects," report investigators led by Elizabeth Devore, ScD, from the Erasmus Medical Center in Rotterdam, the Netherlands.
"Vitamin E is a powerful fat-soluble antioxidant that may help to inhibit the pathogenesis of dementia."
The results appear in the July issue of the Archives of Neurology and suggest that dietary antioxidants affect the early stages of dementia.
Vitamin E is found in whole-grain foods, eggs, milk, nuts, seeds, avocado, spinach, and unheated vegetable oils. The Rotterdam Study previously found that higher dietary intakes of vitamins E and C were associated with a lower risk for dementia and Alzheimer's disease.
In this new long-term follow-up of the Rotterdam Study, investigators followed participants for 9.6 years. The population-based prospective cohort study included 5395 people free of disease at baseline.
A total of 465 people developed dementia. Of these, 365 were diagnosed with Alzheimer's disease. The investigators found that higher dietary intake of vitamin E, but not vitamin C, beta carotene, or flavonoids, was associated with lower long-term risk for dementia.
These results conflict with previous findings, which suggested a link between vitamin C intake and dementia risk. "The result was modest in our analysis," note the investigators, who reported a hazard ratio of 0.66 (95% confidence interval, 0.44 - 1.00). "Chance is the most likely explanation," they add. "Alternatively, vitamin C intake could be important exclusively at later stages of dementia development, but this is less likely because results of previous studies suggest that dietary antioxidants affect early stages of dementia pathogenesis."
Long-Term Prospective Study
The investigators adjusted for age, education, apolipoprotein E ε4 genotype, total energy, alcohol intake, smoking habits, body mass index, and supplement use. They found that higher vitamin E intake at study baseline was associated with lower long-term risk for dementia (P = .02 for trend).
Asked by Medscape Medical News to comment, Maria Carrillo, PhD, senior director of medical and scientific relations at the Alzheimer's Association, pointed out the National Institutes of Health have been calling for long-term prospective studies such as this one. "These are important studies, and this one was conducted by a fantastic, internationally renowned group."
Dr. Carrillo acknowledged the finding is preliminary — it is still too early for specific recommendations on vitamin E intake, and excessive use can have negative cardiovascular effects, she said.
"Future studies should continue to evaluate dietary intake of antioxidants relative to dementia risk," note the investigators, "including different points at which antioxidant intake might modulate risk."
This study was supported by the Netherlands Organization for Scientific Research, the National Institutes of Health, and a US Fulbright Fellowship to the Netherlands. The researchers have disclosed no relevant financial relationships.
Arch Neurol. 2010;67:819-825. Abstract
Rule Developed to Diagnose Gout Using Clinical Variables
From Medscape Medical News
Emma Hitt, PhD
July 22, 2010 — A diagnostic rule involving 7 clinical variables is useful in helping to determine which patients are at high risk for gout and should undergo further testing with joint fluid aspiration to test for the presence of monosodium urate (MSU) crystals.
Hein J. E. M. Janssens, MD, with the Department of Primary and Community Care, Radboud University Nijmegen Medical Center, in Nijmegen, the Netherlands, and colleagues reported their findings in the July 12, 2010, issue of the Archives of Internal Medicine.
The 7 variables, which the researchers describe as "easily ascertainable in primary care," include male sex, previous patient-reported arthritis attack, onset within 1 day, joint redness, involvement of the first metatarsophalangeal joint (MTP1), hypertension or 1 or more cardiovascular diseases, and serum uric acid level of more than 5.88 mg/dL.
"The presented diagnostic rule helps family physicians to select patients with high vs low probability of gout and to restrict the use of joint fluid aspiration to test for the presence of MSU crystals for patients with remaining uncertainty about the diagnosis," Dr. Janssens and colleagues write.
To validate the diagnostic rule, the investigators recruited 381 patients with monoarthritis. These patients had a mean age of 57.7 years, and 285 (74.8%) were men. MSU crystals were identified in 216 (56.7%) of the patients.
A total of 328 patients (86.1%) had an index test diagnosis of gout. Of these 328 patients, mean age was 58.0 (13.5) years, and 261 (79.6%) were men. MSU crystals was identified in 209 (63.7%) of these patients. On the reference test, the positive and negative predictive values of family physician diagnosis of gout were 0.64 and 0.87, respectively.
When the diagnostic rule was used (score ranging from 0 - 13), a score of 4 or less ruled out gout in almost 100% of patients. According to the researchers, in these patients, a differential diagnosis of rheumatoid arthritis, pseudogout, psoriatic arthritis, and reactive arthritis vs gout should be considered.
Among patients with a score of 8 or higher, gout was confirmed in more than 80%, indicating that gout-specific management options such as "systemic corticosteroid use (instead of nonsteroidal anti-inflammatory drugs), uric acid–lowering therapy if indicated, and evaluation of gout-associated cardiovascular and renal diseases" should be used. A false-positive diagnosis of gout was found in 17% of patients at this score range; by contrast, the family physician false-positive diagnosis rate was 36.3%.
A midrange score (> 4 to < 8) leaves uncertainty about the diagnosis. In these patients, of which approximately 30% had gout, "analysis of synovial fluid from the affected joint for the presence of MSU crystals should be considered if necessary for future management," the researchers suggest.
An online calculator for computing the diagnostic rule is available at the Nijmegen Medical Center Web site.
The study authors have disclosed no relevant financial relationships.
Arch Intern Med. 2010;170:1120-1126. Abstract
Emma Hitt, PhD
July 22, 2010 — A diagnostic rule involving 7 clinical variables is useful in helping to determine which patients are at high risk for gout and should undergo further testing with joint fluid aspiration to test for the presence of monosodium urate (MSU) crystals.
Hein J. E. M. Janssens, MD, with the Department of Primary and Community Care, Radboud University Nijmegen Medical Center, in Nijmegen, the Netherlands, and colleagues reported their findings in the July 12, 2010, issue of the Archives of Internal Medicine.
The 7 variables, which the researchers describe as "easily ascertainable in primary care," include male sex, previous patient-reported arthritis attack, onset within 1 day, joint redness, involvement of the first metatarsophalangeal joint (MTP1), hypertension or 1 or more cardiovascular diseases, and serum uric acid level of more than 5.88 mg/dL.
"The presented diagnostic rule helps family physicians to select patients with high vs low probability of gout and to restrict the use of joint fluid aspiration to test for the presence of MSU crystals for patients with remaining uncertainty about the diagnosis," Dr. Janssens and colleagues write.
To validate the diagnostic rule, the investigators recruited 381 patients with monoarthritis. These patients had a mean age of 57.7 years, and 285 (74.8%) were men. MSU crystals were identified in 216 (56.7%) of the patients.
A total of 328 patients (86.1%) had an index test diagnosis of gout. Of these 328 patients, mean age was 58.0 (13.5) years, and 261 (79.6%) were men. MSU crystals was identified in 209 (63.7%) of these patients. On the reference test, the positive and negative predictive values of family physician diagnosis of gout were 0.64 and 0.87, respectively.
When the diagnostic rule was used (score ranging from 0 - 13), a score of 4 or less ruled out gout in almost 100% of patients. According to the researchers, in these patients, a differential diagnosis of rheumatoid arthritis, pseudogout, psoriatic arthritis, and reactive arthritis vs gout should be considered.
Among patients with a score of 8 or higher, gout was confirmed in more than 80%, indicating that gout-specific management options such as "systemic corticosteroid use (instead of nonsteroidal anti-inflammatory drugs), uric acid–lowering therapy if indicated, and evaluation of gout-associated cardiovascular and renal diseases" should be used. A false-positive diagnosis of gout was found in 17% of patients at this score range; by contrast, the family physician false-positive diagnosis rate was 36.3%.
A midrange score (> 4 to < 8) leaves uncertainty about the diagnosis. In these patients, of which approximately 30% had gout, "analysis of synovial fluid from the affected joint for the presence of MSU crystals should be considered if necessary for future management," the researchers suggest.
An online calculator for computing the diagnostic rule is available at the Nijmegen Medical Center Web site.
The study authors have disclosed no relevant financial relationships.
Arch Intern Med. 2010;170:1120-1126. Abstract
Wednesday, July 21, 2010
Depression and Erectile Dysfunction Are Independent Risk Factors for Heart Disease
From Heartwire
Depression and Erectile Dysfunction Are Independent Risk Factors for Heart Disease
Sue Hughes
July 16, 2010 (Florence, Italy) — The presence of depressive symptoms increased the risk of cardiovascular events in men with erectile dysfunction, a new study has shown [1].
The study, published in the August 2010 issue of the Journal of Sexual Medicine, was conducted by a team led by Dr Elisa Bandini (University of Florence, Italy). Bandini commented to heartwire : "In a large sample of men with erectile dysfunction, after controlling for other risk factors, we found that those with severe depression had increased risk of cardiovascular events. We know that depression and erectile dysfunction are both risk factors for heart disease, but this study shows that these risk factors are independent of each other."
She added: "Our results show that when evaluating patients for sexual dysfunction, doctors should think about general health as well. Erectile dysfunction may be the first disease or depression may be first disease, but we should look beyond these initial conditions to look at secondary consequences such as increased cardiovascular risk. If we treat depression and sexual dysfunction, we may be able to improve cardiovascular outcomes, too."
What is important . . . is the broader concept of the sexual-medicine problem no longer being just about a man's performance in the bedroom, but about his psychological mood and his cardiovascular health.
Editor-in-chief of the Journal of Sexual Medicine, Dr Irwin Goldstein (Alvarado Hospital, San Diego, CA), added: "What is important about this study is the broader concept of the sexual-medicine problem no longer being just about a man's performance in the bedroom, but about his psychological mood and his cardiovascular health. This is a valid reason for a woman to encourage her partner to seek help for his erectile dysfunction."
In the study, 1687 patients with erectile dysfunction were screened for depression using the Middlesex Hospital Questionnaire. Those in the highest quintile of depression score were compared with the rest of the sample. Results showed a positive relationship between depression score and progressive erectile dysfunction, even after adjustment for confounding factors. During a mean follow up of 4.3 years, there were a total of 139 cardiovascular events, 15 of which were fatal. Unadjusted incidence of cardiovascular events was significantly associated with baseline depressive symptoms. And severe depressive symptomatology was independently associated with a higher incidence of cardiovascular events in a Cox regression model controlling for degree of erectile dysfunction, partner’s hypoactive sexual desire, age, chronic diseases score, and another measure of psychopathology.
Association Still There After Controlling for Obesity
Because obesity is an important risk factor for cardiovascular events in subjects with sexual dysfunction, the authors looked at whether the presence of obesity might explain the effect of depression on cardiovascular events in this study. But in an alternative Cox model, they showed that depressive symptoms retained an independent ability to predict cardiovascular events, although their effect was more evident in leaner subjects.
The need for a regular screening for cardiac morbidity in men with erectile dysfunction is even greater in those patients showing depressive symptoms.
While no study has yet evaluated the possible effect of treatment of depression on the incidence of cardiovascular events, Bandini et al say that their study suggests that recognizing depressive symptoms in erectile-dysfunction subjects is mandatory not only for improving their sexual life, but also for preventing heart disease.
They conclude: "Owing to the complex multidimensional relationships existing among erectile dysfunction, cardiovascular disease, and depression, clinicians involved in the management of sexual dysfunction should be aware that the presence of one component of this triad necessitates inquiry regarding the other two components."
They add: "The wellness of the body, of the couple, and of the mind independently affects the cardiovascular fate of men with erectile dysfunction," and "the need for a regular screening for cardiac morbidity in men with erectile dysfunction is even greater in those patients showing depressive symptoms."
Depression and Erectile Dysfunction Are Independent Risk Factors for Heart Disease
Sue Hughes
July 16, 2010 (Florence, Italy) — The presence of depressive symptoms increased the risk of cardiovascular events in men with erectile dysfunction, a new study has shown [1].
The study, published in the August 2010 issue of the Journal of Sexual Medicine, was conducted by a team led by Dr Elisa Bandini (University of Florence, Italy). Bandini commented to heartwire : "In a large sample of men with erectile dysfunction, after controlling for other risk factors, we found that those with severe depression had increased risk of cardiovascular events. We know that depression and erectile dysfunction are both risk factors for heart disease, but this study shows that these risk factors are independent of each other."
She added: "Our results show that when evaluating patients for sexual dysfunction, doctors should think about general health as well. Erectile dysfunction may be the first disease or depression may be first disease, but we should look beyond these initial conditions to look at secondary consequences such as increased cardiovascular risk. If we treat depression and sexual dysfunction, we may be able to improve cardiovascular outcomes, too."
What is important . . . is the broader concept of the sexual-medicine problem no longer being just about a man's performance in the bedroom, but about his psychological mood and his cardiovascular health.
Editor-in-chief of the Journal of Sexual Medicine, Dr Irwin Goldstein (Alvarado Hospital, San Diego, CA), added: "What is important about this study is the broader concept of the sexual-medicine problem no longer being just about a man's performance in the bedroom, but about his psychological mood and his cardiovascular health. This is a valid reason for a woman to encourage her partner to seek help for his erectile dysfunction."
In the study, 1687 patients with erectile dysfunction were screened for depression using the Middlesex Hospital Questionnaire. Those in the highest quintile of depression score were compared with the rest of the sample. Results showed a positive relationship between depression score and progressive erectile dysfunction, even after adjustment for confounding factors. During a mean follow up of 4.3 years, there were a total of 139 cardiovascular events, 15 of which were fatal. Unadjusted incidence of cardiovascular events was significantly associated with baseline depressive symptoms. And severe depressive symptomatology was independently associated with a higher incidence of cardiovascular events in a Cox regression model controlling for degree of erectile dysfunction, partner’s hypoactive sexual desire, age, chronic diseases score, and another measure of psychopathology.
Association Still There After Controlling for Obesity
Because obesity is an important risk factor for cardiovascular events in subjects with sexual dysfunction, the authors looked at whether the presence of obesity might explain the effect of depression on cardiovascular events in this study. But in an alternative Cox model, they showed that depressive symptoms retained an independent ability to predict cardiovascular events, although their effect was more evident in leaner subjects.
The need for a regular screening for cardiac morbidity in men with erectile dysfunction is even greater in those patients showing depressive symptoms.
While no study has yet evaluated the possible effect of treatment of depression on the incidence of cardiovascular events, Bandini et al say that their study suggests that recognizing depressive symptoms in erectile-dysfunction subjects is mandatory not only for improving their sexual life, but also for preventing heart disease.
They conclude: "Owing to the complex multidimensional relationships existing among erectile dysfunction, cardiovascular disease, and depression, clinicians involved in the management of sexual dysfunction should be aware that the presence of one component of this triad necessitates inquiry regarding the other two components."
They add: "The wellness of the body, of the couple, and of the mind independently affects the cardiovascular fate of men with erectile dysfunction," and "the need for a regular screening for cardiac morbidity in men with erectile dysfunction is even greater in those patients showing depressive symptoms."
New Guidelines Recommend Early Suppression of HIV to Stave Off Progression
From Medscape Medical News
New Guidelines Recommend Early Suppression of HIV to Stave Off Progression
Daniel M. Keller, PhD
July 19, 2010 (Vienna, Austria) — New treatment guidelines for adults with HIV infection, presented here at AIDS 2010: XVIII International AIDS Conference, emphasize the importance of starting antiretroviral therapy (ART) early and continuing treatment without interruption, except in the setting of a clinical trial.
Dr. Melanie Thompson
At a news conference highlighting the July 21 issue of JAMA, a theme issue on HIV/AIDS, Melanie Thompson, MD, from the AIDS Research Consortium of Atlanta, Georgia, and chair of the International AIDS Society–USA Antiretroviral Therapy Guidelines Panel, outlined the new guidelines, updated from 2008.
The availability of the drugs and laboratory tools recommended mean that the guidelines apply to the international, developed-world setting. Currently, there are 23 antiretroviral drugs and 6 fixed-dose combinations commonly used in the United States, Dr. Thompson said.
"Increasing evidence that insidious damage occurs during 'asymptomatic' HIV infection underscores the potential benefit of ART, even when the risk of traditional AIDS-defining diseases is relatively low," the guidelines authors note.
On the basis of our understanding of the progressive destruction of the immune system by HIV infection and the finding that immune compromise can be prevented with newer drugs that suppress viral replication, the guidelines panel formulated broader recommendations than in the past for the initiation of treatment. They considered information that was presented or published between August 2008 and May 2010, including that on the timing of therapy, choice of regimens, monitoring of therapy, and the efficacy and safety of newer drugs.
Initiate ART as Early as Possible
ART can be started at any CD4+ cell count. It is recommended for asymptomatic individuals with counts at 500 cells/μL or below, and should be considered for asymptomatic individuals with counts above 500 cells/μL. The 2008 guidelines recommended a threshold CD4+ count of 350 cells/μL.
The new guidelines also recommends initiation of ART for patients with symptomatic disease regardless of the CD4+ cell count. Clinicians should confirm patient readiness for treatment before initiating ART.
Non-AIDS events can be a major contributor to morbidity and mortality in the presence of ongoing viral replication, suggesting that viral suppression with ART might improve the length and quality of patients' lives.
"Uncontrolled HIV replication is associated with immune activation and inflammation, which now we know is also associated with non-AIDS illnesses. These illnesses include cardiovascular disease, hepatic disease, renal disease, and certain kinds of malignancies," Dr. Thompson said.
Therefore, the guidelines recommend treatment for pregnant patients, patients older than 60 years, those infected with hepatitis B or C or with HIV-associated kidney disease, those with active cardiovascular disease or at high risk for it, and those with opportunistic diseases or symptomatic primary HIV infection. In addition, ART should be initiated when there is a high risk for HIV transmission, such as between serodiscordant sex partners.
The guideline authors note that many HIV-infected patients first present with advanced disease, and they recommend universal HIV testing and early provision of treatment to take best advantage of advances in ART, along with efforts at prevention. "Antiretroviral therapy and high CD4 counts are associated with decreased disease," Dr. Thompson said.
Treatment Should Be Individualized
Individual patient conditions should determine therapeutic choices. But in general, the guidelines suggest fixed-dose drug combinations for convenience. The initial recommended nucleoside or nucleotide-analogue reverse-transcriptase inhibitor combination consists of tenofovir and emtricitabine. A third component should be the nonnucleoside reverse-transcriptase inhibitor efavirenz, a ritonavir-boosted protease inhibitor, or the integrase inhibitor raltegravir.
The goal of therapy in both treatment-naive and treatment-experienced patients should be viral RNA suppression below detectable limits using commercially available tests. Frequent monitoring of plasma HIV-1 RNA levels is indicated when therapy begins or is changed because of virologic failure, and should continue until the viral load becomes undetectable and for some time thereafter. Monitoring can be done at 6-month intervals once the viral load is suppressed for a year and the CD4+ cell counts stabilize at 350 cells/μL or above in treatment-compliant patients.
When to Change Therapy and to What
If virologic failure occurs, it should be detected and treated as soon as possible with at least 2, and ideally 3, active drugs to head off the accumulation of resistance mutations. Switching to agents in new classes of drugs should be considered, keeping in mind previous and new HIV resistance profiles, previous drug exposure, drug interactions, and patient drug tolerance. If feasible, a regimen with the fewest drugs and lowest pill burden is desirable.
Conference moderator Catherine DeAngelis, MD, MPH, editor-in-chief of JAMA in Chicago, Illinois, told Medscape Medical News that the guidelines are a model for current best treatment practices in HIV. Dr. DeAngelis was not involved in the development of the guidelines.
"These guidelines are meant for resource-rich areas, not for the resource poor," she said. "Will it be an issue [to follow them] for a clinician functioning in a resource-rich environment? Probably not. Will it be a problem anywhere else? Probably yes, in fact, definitely yes."
This work was funded by the InternationalAIDS Society–USA. Panel members serve in volunteer capacities (i.e., are not compensated). No private sector or government funding was used to support the effort.
JAMA. 2010;304:321-333.
AIDS 2010: XVIII International AIDS Conference. Presented July 19, 2010.
New Guidelines Recommend Early Suppression of HIV to Stave Off Progression
Daniel M. Keller, PhD
July 19, 2010 (Vienna, Austria) — New treatment guidelines for adults with HIV infection, presented here at AIDS 2010: XVIII International AIDS Conference, emphasize the importance of starting antiretroviral therapy (ART) early and continuing treatment without interruption, except in the setting of a clinical trial.
Dr. Melanie Thompson
At a news conference highlighting the July 21 issue of JAMA, a theme issue on HIV/AIDS, Melanie Thompson, MD, from the AIDS Research Consortium of Atlanta, Georgia, and chair of the International AIDS Society–USA Antiretroviral Therapy Guidelines Panel, outlined the new guidelines, updated from 2008.
The availability of the drugs and laboratory tools recommended mean that the guidelines apply to the international, developed-world setting. Currently, there are 23 antiretroviral drugs and 6 fixed-dose combinations commonly used in the United States, Dr. Thompson said.
"Increasing evidence that insidious damage occurs during 'asymptomatic' HIV infection underscores the potential benefit of ART, even when the risk of traditional AIDS-defining diseases is relatively low," the guidelines authors note.
On the basis of our understanding of the progressive destruction of the immune system by HIV infection and the finding that immune compromise can be prevented with newer drugs that suppress viral replication, the guidelines panel formulated broader recommendations than in the past for the initiation of treatment. They considered information that was presented or published between August 2008 and May 2010, including that on the timing of therapy, choice of regimens, monitoring of therapy, and the efficacy and safety of newer drugs.
Initiate ART as Early as Possible
ART can be started at any CD4+ cell count. It is recommended for asymptomatic individuals with counts at 500 cells/μL or below, and should be considered for asymptomatic individuals with counts above 500 cells/μL. The 2008 guidelines recommended a threshold CD4+ count of 350 cells/μL.
The new guidelines also recommends initiation of ART for patients with symptomatic disease regardless of the CD4+ cell count. Clinicians should confirm patient readiness for treatment before initiating ART.
Non-AIDS events can be a major contributor to morbidity and mortality in the presence of ongoing viral replication, suggesting that viral suppression with ART might improve the length and quality of patients' lives.
"Uncontrolled HIV replication is associated with immune activation and inflammation, which now we know is also associated with non-AIDS illnesses. These illnesses include cardiovascular disease, hepatic disease, renal disease, and certain kinds of malignancies," Dr. Thompson said.
Therefore, the guidelines recommend treatment for pregnant patients, patients older than 60 years, those infected with hepatitis B or C or with HIV-associated kidney disease, those with active cardiovascular disease or at high risk for it, and those with opportunistic diseases or symptomatic primary HIV infection. In addition, ART should be initiated when there is a high risk for HIV transmission, such as between serodiscordant sex partners.
The guideline authors note that many HIV-infected patients first present with advanced disease, and they recommend universal HIV testing and early provision of treatment to take best advantage of advances in ART, along with efforts at prevention. "Antiretroviral therapy and high CD4 counts are associated with decreased disease," Dr. Thompson said.
Treatment Should Be Individualized
Individual patient conditions should determine therapeutic choices. But in general, the guidelines suggest fixed-dose drug combinations for convenience. The initial recommended nucleoside or nucleotide-analogue reverse-transcriptase inhibitor combination consists of tenofovir and emtricitabine. A third component should be the nonnucleoside reverse-transcriptase inhibitor efavirenz, a ritonavir-boosted protease inhibitor, or the integrase inhibitor raltegravir.
The goal of therapy in both treatment-naive and treatment-experienced patients should be viral RNA suppression below detectable limits using commercially available tests. Frequent monitoring of plasma HIV-1 RNA levels is indicated when therapy begins or is changed because of virologic failure, and should continue until the viral load becomes undetectable and for some time thereafter. Monitoring can be done at 6-month intervals once the viral load is suppressed for a year and the CD4+ cell counts stabilize at 350 cells/μL or above in treatment-compliant patients.
When to Change Therapy and to What
If virologic failure occurs, it should be detected and treated as soon as possible with at least 2, and ideally 3, active drugs to head off the accumulation of resistance mutations. Switching to agents in new classes of drugs should be considered, keeping in mind previous and new HIV resistance profiles, previous drug exposure, drug interactions, and patient drug tolerance. If feasible, a regimen with the fewest drugs and lowest pill burden is desirable.
Conference moderator Catherine DeAngelis, MD, MPH, editor-in-chief of JAMA in Chicago, Illinois, told Medscape Medical News that the guidelines are a model for current best treatment practices in HIV. Dr. DeAngelis was not involved in the development of the guidelines.
"These guidelines are meant for resource-rich areas, not for the resource poor," she said. "Will it be an issue [to follow them] for a clinician functioning in a resource-rich environment? Probably not. Will it be a problem anywhere else? Probably yes, in fact, definitely yes."
This work was funded by the InternationalAIDS Society–USA. Panel members serve in volunteer capacities (i.e., are not compensated). No private sector or government funding was used to support the effort.
JAMA. 2010;304:321-333.
AIDS 2010: XVIII International AIDS Conference. Presented July 19, 2010.
Tuesday, July 20, 2010
Fibromyalgia: Expert Insights on Improving Treatment Adherence
From MedscapeCME Rheumatology
Lesley M. Arnold, MD
Introduction
Fibromyalgia is a common chronic widespread pain disorder that is often linked to other symptoms, including fatigue, sleep disturbances, cognitive impairment, depression, and anxiety.[1] This condition is also associated with a substantial compromise in quality of life, self-reported loss of function, work disability, and increased work absenteeism, as well as a higher use of healthcare services.[1] Although recent developments in pharmacologic and nonpharmacologic therapies have led to improvements in the care of patients with fibromyalgia, lack of adherence represents an issue that may limit the effectiveness of these treatment approaches. Assessing and improving treatment adherence is therefore a critical aspect in the management of fibromyalgia. The problem of treatment nonadherence in some patients with fibromyalgia is not unique to this condition. Nonadherence is a main concern in the management of many medical disorders. Importantly, there is now evidence about possible reasons for treatment nonadherence in some patients with fibromyalgia, and based on patients' experiences, treatment approaches that may enhance compliance are being developed.
The goals of this article are to review evidence about nonadherence to fibromyalgia treatments and the potential consequences on patient outcomes, and to present approaches to assess and manage this issue in patients with fibromyalgia.
Nonpharmacologic Treatments for Fibromyalgia
Exercise
The use of exercise as a therapy for fibromyalgia has been supported by multiple studies. The Cochrane review evaluating exercise trials in fibromyalgia published up to 2005 concluded that moderate-intensity aerobic training may improve overall well-being and physical function, with little or no difference in pain or tenderness.[2] However, attrition rates were high in most studies (range: 13%-44%), and there were some indications that adherence to both exercise intensity and frequency was poor.[2] For example, 132 patients with fibromyalgia who entered a randomized, controlled trial of a community-based exercise program were randomly assigned to either graded aerobic exercise or relaxation twice weekly for 12 weeks.[3] At the end of the intervention, a significantly higher number of patients in the exercise arm (35% [24/69]) felt much better or very much better, compared with those in the relaxation arm (18% [12/67]). At 12 months follow-up, these benefits were maintained in 38% (26/69) and 22% (15/67) of the participants, respectively (difference not significant). The study, however, was limited by adherence issues, as only 53% of the total group attended more than one third of the classes. The reasons for low adherence included initial increases in pain and stiffness immediately after exercise and the patients' belief that exercise worsened their condition, suggesting that strategies such as education and cognitive behavior therapy may improve adherence to exercise.
Education and Exercise
Recent fibromyalgia trials have explored the possibility that education in combination with exercise may help to improve patient outcomes. The effects of exercise and education were separately evaluated in a 12-week study of a supervised aerobic exercise program, a self-management education program, and the combination of exercise and education in 152 women with fibromyalgia.[7] The program -- based on the American College of Sport Medicine (ACSM) recommendations for maintaining and developing cardiorespiratory fitness in healthy adults -- required patients to meet 3 times a week for an average duration of 20-40 minutes per session, and included walking, pool exercise, or low-impact aerobics, as well as heart rate monitoring and ratings of perceived exertion. Patients were instructed to begin at a comfortable level and strive to increase exercise intensity and duration to meet the ACSM guidelines. The education group, based on principles of self-management, met once a week for 1.5-2 hours per session. The control group was given written instructions for basic stretches and general coping strategies, and patients were contacted once or twice throughout the 12-week period to ensure that they were completing a logbook that documented the course of fibromyalgia and weekly goals (also given to treatment groups) and to answer questions about their condition. At the end of the program, significant differences were seen among the groups only when adherence was taken into consideration. For patients who adhered to the protocol (only about half of the total group), the combination of supervised exercise and group education improved self-efficacy to cope with some symptoms compared with the control group, although this significant difference was lost at the sixth-month follow-up evaluation. The high dropout rate suggested that patients with fibromyalgia may have difficulty adhering to treatments that involve exercise and behavior modification. Alternatively, patients may have dropped out because of preprogram beliefs about exercise and education that were not addressed in the study. The study did not identify comorbid depression or anxiety among the participants, and could not assess the possible role of comorbid mood symptoms on outcomes. These results suggest that encouragement to adopt or enhance a physically active lifestyle instead of promoting exercise may be a more appropriate approach to treatment programs in some patients with fibromyalgia.
In summary, studies to date support the role of exercise with or without education in the treatment of fibromyalgia. Based on the evidence presented, Table 1 summarizes strategies to improve adherence to these potentially effective nonpharmacologic approaches to fibromyalgia management.
Table 1. Strategies to Improve Exercise Adherence in Fibromyalgia
Educate patients about the role of exercise in fibromyalgia treatment
• Given that many patients do not tolerate high-intensity aerobic exercise, low/moderate-intensity graded aerobic exercise may be preferable and may lead to improvements in global well-being and physical function
• A gradual increase in exercise (as tolerated) to reach a goal of 30-60 min of low/moderate-intensity aerobic exercise at least 2-3 times/week for > 10 weeks appears to be associated with maintenance of improvements
Guide patients on exercise initiation and maintenance
• It is recommended that patients initially do less than they think they can accomplish and slowly build endurance. Write a "prescription" for exercise with clear instructions on progression and follow-up based on response
• Encouraging patients to adopt/enhance a physically active wellness lifestyle instead of promoting exercise may be more appropriate for some patients
• Supervised group exercise interventions may be preferable to home-based exercise regimens, especially at the initiation of an exercise program
Address the factors that contribute to low exercise adherence • Discuss any barriers to exercise and develop plans to address these barriers
• Implementing targeted self-management group education programs (ie, Fibromyalgia Self Help Course developed by the Arthritis Foundation) may be helpful in enhancing the effects of exercise
• The addition of cognitive-behavioral therapy may help patients with stress and may help them react less to bodily sensations
• Pharmacologic treatments may help reduce symptoms, improving exercise tolerability
Cognitive-Behavioral Therapy
Although cognitive-behavioral therapy is often recommended to improve adherence to other fibromyalgia treatments, studies indicate that adherence to this therapy is also sometimes problematic. In one study, 145 patients with fibromyalgia were randomly assigned to either standard medical care that included pharmacologic treatment and suggestions for aerobic fitness, or the same standard medical treatment and the addition of 6 group cognitive-behavioral therapy sessions specifically aimed at improving physical function over a 4-week period.[9]
The therapy focused on instruction and practice of 9 skills including the relaxation response, visual imagery techniques, pacing skills, pleasant activity scheduling, communication and assertiveness training, cognitive restructuring principles, stress management, and problem solving. A significantly higher number of patients who completed the cognitive-behavioral therapy protocol (35%) achieved a clinically meaningful and sustained improvement in physical functional status compared with the control group (12%). Despite a low level of adherence to cognitive-behavioral therapy (only 15% of patients consistently reached their stated monthly therapy goals), the study provided some evidence that targeted, brief group cognitive-behavioral therapy in conjunction with standard medical care might improve physical function in some patients with fibromyalgia. In an attempt to improve adherence, this study was designed to offer patients the choice to pursue a personally tailored goal for skill use, or to follow the therapist's recommendations for goal setting. Personalizing the goal, however, did not improve adherence or outcomes. In addition, the pattern of adherence (ie, never meeting goals, sometimes meeting goals, always meeting goals) was not significantly related to improved physical functioning, suggesting that other factors beyond adherence (ie, rapport with the therapist, motivation for change, sense of control over symptoms of fibromyalgia) were more relevant in improving outcomes. Therefore, despite problems with adherence to the treatment plan, patients still reported some benefit from the therapy.
Adherence to a 3-month multimodal program for fibromyalgia that included small group educational sessions, cognitive-behavioral therapy, and exercise demonstrations was adversely affected by patient report of multiple barriers, such as pain, fatigue, stressful events, too much effort, presence of other illness, and lack of time.[10] In addition, pain catastrophizing, a maladaptive coping style that includes rumination about pain and feelings of helplessness, also predicted lower adherence to the treatment program. Based on these findings, patients and their healthcare providers should address problems that may prevent engagement in recommended treatments
There may also be other barriers to cognitive-behavioral therapy that affect adherence, such as availability of cognitive-behavioral therapists and cost of therapy. Less costly self-management programs that provide cognitive-behavioral therapy to a broader group of individuals with fibromyalgia may address some of these barriers. For example, the FibroGuide developed by researchers at the University of Michigan, available online at http://www.fibroguide.com, offers a self-management program that is based in part on cognitive-behavioral principles. Clinicians may also help improve adherence to these Web-based programs by monitoring the patient's progress and reinforcing positive gains.
Pharmacologic Treatments for Fibromyalgia
There are currently 3 medications approved by the US Food and Drug Administration (FDA) for the management of fibromyalgia: the alpha-2-delta ligand, pregabalin, and the serotonin and norepinephrine reuptake inhibitors, duloxetine and milnacipran. Non-FDA-approved medications for which there is evidence supporting their use in fibromyalgia include tricyclic antidepressants, cyclobenzaprine, gabapentin, and others.[1] It is likely that medication options will expand in the future. Although advances in the treatment of fibromyalgia are encouraging, the issue of lack of adherence to pharmacologic therapies persists, and is therefore starting to receive some attention in studies.
In many of the clinical trials evaluating medication treatment for fibromyalgia, the most common cause for premature discontinuation of medication is treatment-emergent adverse events. In the pivotal fibromyalgia trials of milnacipran, 23%-26% of patients discontinued the drug prematurely because of adverse events, mainly nausea, palpitations, headache, constipation, increased heart rate, increased sweating, vomiting, and dizziness.[13] In the duloxetine pivotal fibromyalgia trials, 19.5 % of duloxetine-treated patients discontinued because of adverse events, most commonly nausea, somnolence, fatigue, and insomnia.[14] Finally, in the pregabalin pivotal fibromyalgia trials, 19% of patients on pregabalin also discontinued early because of adverse events, mostly dizziness, somnolence, fatigue, headache, balance disorders, and weight gain.[15] In a pooled analysis of data from 5 clinical trials of duloxetine treatment of fibromyalgia, the common treatment-emergent adverse events occurred early in treatment and had a relatively rapid resolution. For example, nausea, the most common adverse event, had a median time to onset of 1 day and median time to resolution of 6 days.[16] Similarly, in a recent milnacipran trial, 70% of the episodes of nausea in the treatment groups resolved within 3 weeks after onset.[17] In a trial of pregabalin, the median time to onset for dizziness and somnolence in the pregabalin groups was ≤ 1 day.[18] The median duration of dizziness in patients who did not withdraw from the study was 6 days for patients taking 300 mg/day pregabalin and 15 days in those taking 450 mg/day pregabalin. The median duration of somnolence in patients who did not withdraw from the study was 21 days in those taking 300 mg/day pregabalin and 18 days in those taking 450 mg/day pregabalin.
Educating patients about the possible resolution of side effects over time may help patients adhere to ongoing treatment that is otherwise effective. In addition, a "start low, go slow" dosing strategy may minimize the risk for adverse events early in treatment and may improve medication adherence. For example, it has been shown that duloxetine started at 30 mg/day for the first week of therapy may improve tolerability.[14] A slow titration of milnacipran may also help patients continue therapy. A recent milnacipran study used flexible dose titration to 100 mg/day over 4-6 weeks (rather than 2 weeks as currently recommended), which led to fewer patient withdrawals because of adverse events than previous milnacipran studies.[17] Taking medications associated with gastrointestinal side effects (ie, duloxetine and milnacipran) with food can also improve tolerability.[19] Dosing strategies for pregabalin that appear to improve tolerability but are not FDA-approved, include beginning with a low dose of pregabalin (eg, 50-75 mg) at bedtime, increasing as tolerated at bedtime only, and later adding daytime doses as tolerated to reach the recommended total daily dose of pregabalin for fibromyalgia.
Education about adverse effects that may persist and about ways to manage these adverse events is also important in helping patients adhere to ongoing effective medication treatment. Based on clinical experience, clinicians have found that addressing potential weight gain with pregabalin or other medications at the start of therapy and asking patients to keep a food diary during the early phase of treatment can help increase their awareness of their eating patterns and allow them to take steps to minimize the risk for weight gain. Studies of combination therapy for fibromyalgia are limited; however, in some patients who have difficulty tolerating recommended doses of medication, a trial of combinations of lower doses may improve response.[20] Finally, it is important for most patients to attempt to titrate up to the known effective doses of medication to reduce the possibility of discontinuation due to lack of efficacy. For example, patients with higher duloxetine average daily dose (> 30 mg/day) were more likely to adhere to treatment, possibly because they were experiencing some benefit from the treatment.[21]
Patient-physician discordance on communication and satisfaction has also been found to predict overall nonadherence to medication in patients with fibromyalgia.[22] Predictors of high general adherence to health professionals' recommendations for fibromyalgia treatment included low patient psychological distress and low patient-physician discordance on patient well-being.[23] Discrepancies between the patient's and the physician's views on the patient's well-being might contribute to treatment nonadherence if the physician prescribes treatments that are inconsistent with the patient's view of their illness. Psychological distress may adversely affect adherence by interfering with the patient's ability to recall treatment instructions, disrupt the interpersonal relationship with the healthcare provider, and diminish the patient's motivation to make changes. Thus, it is important to identify and address psychological distress in patients with fibromyalgia.[23] In some cases, distress is a manifestation of comorbid psychiatric problems that also need to be assessed and treated.
The patient-physician relationship is important for medication adherence in fibromyalgia.[22] Continuity of care and more frequent visits at the start of treatment will improve patient-physician rapport and adherence to treatment. The development of an alliance with patients that includes discussion of findings from the evaluation, education about fibromyalgia and treatment options, and involvement of the patient in treatment planning will likely enhance adherence.[23] Table 2 summarizes strategies to improve medication adherence in fibromyalgia.
Table 2. Strategies to Improve Medication Adherence in Fibromyalgia
Involve patients in treatment planning
• Review findings from the evaluation
• Review history of treatment trials, including dose, duration, tolerability, and efficacy
• Discuss treatment options, including risks and benefits
Educate patients about fibromyalgia and discuss risks/benefits of pharmacologic treatment options
• Review strategies to reduce risk for adverse events
• Establish a plan for continuity of care (ie, more frequent follow-up visits during the first months of treatment to address safety and tolerability)
Identify and manage any barriers that may interfere with the implementation of and with patients' understanding of treatment plans
• Assess psychological distress or psychiatric comorbidity
• Determine patients' understanding of and satisfaction with the treatment plan
Summary
Adherence to nonpharmacologic and pharmacologic treatments for fibromyalgia may be problematic for some patients, and may interfere with the effectiveness of available therapies. However, there are several strategies that may be helpful in addressing the problem of nonadherence. Adherence to treatment recommendations is most likely enhanced if the healthcare provider develops a therapeutic alliance with the patient, involving him or her in treatment planning.
Lesley M. Arnold, MD
Introduction
Fibromyalgia is a common chronic widespread pain disorder that is often linked to other symptoms, including fatigue, sleep disturbances, cognitive impairment, depression, and anxiety.[1] This condition is also associated with a substantial compromise in quality of life, self-reported loss of function, work disability, and increased work absenteeism, as well as a higher use of healthcare services.[1] Although recent developments in pharmacologic and nonpharmacologic therapies have led to improvements in the care of patients with fibromyalgia, lack of adherence represents an issue that may limit the effectiveness of these treatment approaches. Assessing and improving treatment adherence is therefore a critical aspect in the management of fibromyalgia. The problem of treatment nonadherence in some patients with fibromyalgia is not unique to this condition. Nonadherence is a main concern in the management of many medical disorders. Importantly, there is now evidence about possible reasons for treatment nonadherence in some patients with fibromyalgia, and based on patients' experiences, treatment approaches that may enhance compliance are being developed.
The goals of this article are to review evidence about nonadherence to fibromyalgia treatments and the potential consequences on patient outcomes, and to present approaches to assess and manage this issue in patients with fibromyalgia.
Nonpharmacologic Treatments for Fibromyalgia
Exercise
The use of exercise as a therapy for fibromyalgia has been supported by multiple studies. The Cochrane review evaluating exercise trials in fibromyalgia published up to 2005 concluded that moderate-intensity aerobic training may improve overall well-being and physical function, with little or no difference in pain or tenderness.[2] However, attrition rates were high in most studies (range: 13%-44%), and there were some indications that adherence to both exercise intensity and frequency was poor.[2] For example, 132 patients with fibromyalgia who entered a randomized, controlled trial of a community-based exercise program were randomly assigned to either graded aerobic exercise or relaxation twice weekly for 12 weeks.[3] At the end of the intervention, a significantly higher number of patients in the exercise arm (35% [24/69]) felt much better or very much better, compared with those in the relaxation arm (18% [12/67]). At 12 months follow-up, these benefits were maintained in 38% (26/69) and 22% (15/67) of the participants, respectively (difference not significant). The study, however, was limited by adherence issues, as only 53% of the total group attended more than one third of the classes. The reasons for low adherence included initial increases in pain and stiffness immediately after exercise and the patients' belief that exercise worsened their condition, suggesting that strategies such as education and cognitive behavior therapy may improve adherence to exercise.
Education and Exercise
Recent fibromyalgia trials have explored the possibility that education in combination with exercise may help to improve patient outcomes. The effects of exercise and education were separately evaluated in a 12-week study of a supervised aerobic exercise program, a self-management education program, and the combination of exercise and education in 152 women with fibromyalgia.[7] The program -- based on the American College of Sport Medicine (ACSM) recommendations for maintaining and developing cardiorespiratory fitness in healthy adults -- required patients to meet 3 times a week for an average duration of 20-40 minutes per session, and included walking, pool exercise, or low-impact aerobics, as well as heart rate monitoring and ratings of perceived exertion. Patients were instructed to begin at a comfortable level and strive to increase exercise intensity and duration to meet the ACSM guidelines. The education group, based on principles of self-management, met once a week for 1.5-2 hours per session. The control group was given written instructions for basic stretches and general coping strategies, and patients were contacted once or twice throughout the 12-week period to ensure that they were completing a logbook that documented the course of fibromyalgia and weekly goals (also given to treatment groups) and to answer questions about their condition. At the end of the program, significant differences were seen among the groups only when adherence was taken into consideration. For patients who adhered to the protocol (only about half of the total group), the combination of supervised exercise and group education improved self-efficacy to cope with some symptoms compared with the control group, although this significant difference was lost at the sixth-month follow-up evaluation. The high dropout rate suggested that patients with fibromyalgia may have difficulty adhering to treatments that involve exercise and behavior modification. Alternatively, patients may have dropped out because of preprogram beliefs about exercise and education that were not addressed in the study. The study did not identify comorbid depression or anxiety among the participants, and could not assess the possible role of comorbid mood symptoms on outcomes. These results suggest that encouragement to adopt or enhance a physically active lifestyle instead of promoting exercise may be a more appropriate approach to treatment programs in some patients with fibromyalgia.
In summary, studies to date support the role of exercise with or without education in the treatment of fibromyalgia. Based on the evidence presented, Table 1 summarizes strategies to improve adherence to these potentially effective nonpharmacologic approaches to fibromyalgia management.
Table 1. Strategies to Improve Exercise Adherence in Fibromyalgia
Educate patients about the role of exercise in fibromyalgia treatment
• Given that many patients do not tolerate high-intensity aerobic exercise, low/moderate-intensity graded aerobic exercise may be preferable and may lead to improvements in global well-being and physical function
• A gradual increase in exercise (as tolerated) to reach a goal of 30-60 min of low/moderate-intensity aerobic exercise at least 2-3 times/week for > 10 weeks appears to be associated with maintenance of improvements
Guide patients on exercise initiation and maintenance
• It is recommended that patients initially do less than they think they can accomplish and slowly build endurance. Write a "prescription" for exercise with clear instructions on progression and follow-up based on response
• Encouraging patients to adopt/enhance a physically active wellness lifestyle instead of promoting exercise may be more appropriate for some patients
• Supervised group exercise interventions may be preferable to home-based exercise regimens, especially at the initiation of an exercise program
Address the factors that contribute to low exercise adherence • Discuss any barriers to exercise and develop plans to address these barriers
• Implementing targeted self-management group education programs (ie, Fibromyalgia Self Help Course developed by the Arthritis Foundation) may be helpful in enhancing the effects of exercise
• The addition of cognitive-behavioral therapy may help patients with stress and may help them react less to bodily sensations
• Pharmacologic treatments may help reduce symptoms, improving exercise tolerability
Cognitive-Behavioral Therapy
Although cognitive-behavioral therapy is often recommended to improve adherence to other fibromyalgia treatments, studies indicate that adherence to this therapy is also sometimes problematic. In one study, 145 patients with fibromyalgia were randomly assigned to either standard medical care that included pharmacologic treatment and suggestions for aerobic fitness, or the same standard medical treatment and the addition of 6 group cognitive-behavioral therapy sessions specifically aimed at improving physical function over a 4-week period.[9]
The therapy focused on instruction and practice of 9 skills including the relaxation response, visual imagery techniques, pacing skills, pleasant activity scheduling, communication and assertiveness training, cognitive restructuring principles, stress management, and problem solving. A significantly higher number of patients who completed the cognitive-behavioral therapy protocol (35%) achieved a clinically meaningful and sustained improvement in physical functional status compared with the control group (12%). Despite a low level of adherence to cognitive-behavioral therapy (only 15% of patients consistently reached their stated monthly therapy goals), the study provided some evidence that targeted, brief group cognitive-behavioral therapy in conjunction with standard medical care might improve physical function in some patients with fibromyalgia. In an attempt to improve adherence, this study was designed to offer patients the choice to pursue a personally tailored goal for skill use, or to follow the therapist's recommendations for goal setting. Personalizing the goal, however, did not improve adherence or outcomes. In addition, the pattern of adherence (ie, never meeting goals, sometimes meeting goals, always meeting goals) was not significantly related to improved physical functioning, suggesting that other factors beyond adherence (ie, rapport with the therapist, motivation for change, sense of control over symptoms of fibromyalgia) were more relevant in improving outcomes. Therefore, despite problems with adherence to the treatment plan, patients still reported some benefit from the therapy.
Adherence to a 3-month multimodal program for fibromyalgia that included small group educational sessions, cognitive-behavioral therapy, and exercise demonstrations was adversely affected by patient report of multiple barriers, such as pain, fatigue, stressful events, too much effort, presence of other illness, and lack of time.[10] In addition, pain catastrophizing, a maladaptive coping style that includes rumination about pain and feelings of helplessness, also predicted lower adherence to the treatment program. Based on these findings, patients and their healthcare providers should address problems that may prevent engagement in recommended treatments
There may also be other barriers to cognitive-behavioral therapy that affect adherence, such as availability of cognitive-behavioral therapists and cost of therapy. Less costly self-management programs that provide cognitive-behavioral therapy to a broader group of individuals with fibromyalgia may address some of these barriers. For example, the FibroGuide developed by researchers at the University of Michigan, available online at http://www.fibroguide.com, offers a self-management program that is based in part on cognitive-behavioral principles. Clinicians may also help improve adherence to these Web-based programs by monitoring the patient's progress and reinforcing positive gains.
Pharmacologic Treatments for Fibromyalgia
There are currently 3 medications approved by the US Food and Drug Administration (FDA) for the management of fibromyalgia: the alpha-2-delta ligand, pregabalin, and the serotonin and norepinephrine reuptake inhibitors, duloxetine and milnacipran. Non-FDA-approved medications for which there is evidence supporting their use in fibromyalgia include tricyclic antidepressants, cyclobenzaprine, gabapentin, and others.[1] It is likely that medication options will expand in the future. Although advances in the treatment of fibromyalgia are encouraging, the issue of lack of adherence to pharmacologic therapies persists, and is therefore starting to receive some attention in studies.
In many of the clinical trials evaluating medication treatment for fibromyalgia, the most common cause for premature discontinuation of medication is treatment-emergent adverse events. In the pivotal fibromyalgia trials of milnacipran, 23%-26% of patients discontinued the drug prematurely because of adverse events, mainly nausea, palpitations, headache, constipation, increased heart rate, increased sweating, vomiting, and dizziness.[13] In the duloxetine pivotal fibromyalgia trials, 19.5 % of duloxetine-treated patients discontinued because of adverse events, most commonly nausea, somnolence, fatigue, and insomnia.[14] Finally, in the pregabalin pivotal fibromyalgia trials, 19% of patients on pregabalin also discontinued early because of adverse events, mostly dizziness, somnolence, fatigue, headache, balance disorders, and weight gain.[15] In a pooled analysis of data from 5 clinical trials of duloxetine treatment of fibromyalgia, the common treatment-emergent adverse events occurred early in treatment and had a relatively rapid resolution. For example, nausea, the most common adverse event, had a median time to onset of 1 day and median time to resolution of 6 days.[16] Similarly, in a recent milnacipran trial, 70% of the episodes of nausea in the treatment groups resolved within 3 weeks after onset.[17] In a trial of pregabalin, the median time to onset for dizziness and somnolence in the pregabalin groups was ≤ 1 day.[18] The median duration of dizziness in patients who did not withdraw from the study was 6 days for patients taking 300 mg/day pregabalin and 15 days in those taking 450 mg/day pregabalin. The median duration of somnolence in patients who did not withdraw from the study was 21 days in those taking 300 mg/day pregabalin and 18 days in those taking 450 mg/day pregabalin.
Educating patients about the possible resolution of side effects over time may help patients adhere to ongoing treatment that is otherwise effective. In addition, a "start low, go slow" dosing strategy may minimize the risk for adverse events early in treatment and may improve medication adherence. For example, it has been shown that duloxetine started at 30 mg/day for the first week of therapy may improve tolerability.[14] A slow titration of milnacipran may also help patients continue therapy. A recent milnacipran study used flexible dose titration to 100 mg/day over 4-6 weeks (rather than 2 weeks as currently recommended), which led to fewer patient withdrawals because of adverse events than previous milnacipran studies.[17] Taking medications associated with gastrointestinal side effects (ie, duloxetine and milnacipran) with food can also improve tolerability.[19] Dosing strategies for pregabalin that appear to improve tolerability but are not FDA-approved, include beginning with a low dose of pregabalin (eg, 50-75 mg) at bedtime, increasing as tolerated at bedtime only, and later adding daytime doses as tolerated to reach the recommended total daily dose of pregabalin for fibromyalgia.
Education about adverse effects that may persist and about ways to manage these adverse events is also important in helping patients adhere to ongoing effective medication treatment. Based on clinical experience, clinicians have found that addressing potential weight gain with pregabalin or other medications at the start of therapy and asking patients to keep a food diary during the early phase of treatment can help increase their awareness of their eating patterns and allow them to take steps to minimize the risk for weight gain. Studies of combination therapy for fibromyalgia are limited; however, in some patients who have difficulty tolerating recommended doses of medication, a trial of combinations of lower doses may improve response.[20] Finally, it is important for most patients to attempt to titrate up to the known effective doses of medication to reduce the possibility of discontinuation due to lack of efficacy. For example, patients with higher duloxetine average daily dose (> 30 mg/day) were more likely to adhere to treatment, possibly because they were experiencing some benefit from the treatment.[21]
Patient-physician discordance on communication and satisfaction has also been found to predict overall nonadherence to medication in patients with fibromyalgia.[22] Predictors of high general adherence to health professionals' recommendations for fibromyalgia treatment included low patient psychological distress and low patient-physician discordance on patient well-being.[23] Discrepancies between the patient's and the physician's views on the patient's well-being might contribute to treatment nonadherence if the physician prescribes treatments that are inconsistent with the patient's view of their illness. Psychological distress may adversely affect adherence by interfering with the patient's ability to recall treatment instructions, disrupt the interpersonal relationship with the healthcare provider, and diminish the patient's motivation to make changes. Thus, it is important to identify and address psychological distress in patients with fibromyalgia.[23] In some cases, distress is a manifestation of comorbid psychiatric problems that also need to be assessed and treated.
The patient-physician relationship is important for medication adherence in fibromyalgia.[22] Continuity of care and more frequent visits at the start of treatment will improve patient-physician rapport and adherence to treatment. The development of an alliance with patients that includes discussion of findings from the evaluation, education about fibromyalgia and treatment options, and involvement of the patient in treatment planning will likely enhance adherence.[23] Table 2 summarizes strategies to improve medication adherence in fibromyalgia.
Table 2. Strategies to Improve Medication Adherence in Fibromyalgia
Involve patients in treatment planning
• Review findings from the evaluation
• Review history of treatment trials, including dose, duration, tolerability, and efficacy
• Discuss treatment options, including risks and benefits
Educate patients about fibromyalgia and discuss risks/benefits of pharmacologic treatment options
• Review strategies to reduce risk for adverse events
• Establish a plan for continuity of care (ie, more frequent follow-up visits during the first months of treatment to address safety and tolerability)
Identify and manage any barriers that may interfere with the implementation of and with patients' understanding of treatment plans
• Assess psychological distress or psychiatric comorbidity
• Determine patients' understanding of and satisfaction with the treatment plan
Summary
Adherence to nonpharmacologic and pharmacologic treatments for fibromyalgia may be problematic for some patients, and may interfere with the effectiveness of available therapies. However, there are several strategies that may be helpful in addressing the problem of nonadherence. Adherence to treatment recommendations is most likely enhanced if the healthcare provider develops a therapeutic alliance with the patient, involving him or her in treatment planning.
Antibodies Induced by HIV Vaccines May Give False-Positive HIV Test Results
From Medscape Medical News
Antibodies Induced by HIV Vaccines May Give False-Positive HIV Test Results
Daniel M. Keller, PhD
July 20, 2010 — Trials of vaccines designed to prevent HIV infection might induce antibodies that will cause false-positive results on routine antibody tests for HIV infection. Although the goal of much vaccine development is to induce the production of protective antibodies, they might also cause a state of vaccine-induced seropositivity/reactivity (VISP), which can confound the interpretation of HIV tests in the absence of HIV infection.
Dr. Lindsey Baden
In the July 21 issue of JAMA, which focuses on HIV/AIDS, Lindsey Baden, MD, from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, said that more than 30,000 people have participated in clinical trials of a variety of potential prophylactic vaccines against HIV. These vaccines have used a variety of delivery methods and antigenic compounds and were aimed at inducing different forms of immunity. Dr. Baden discussed the findings at AIDS 2010: XVIII International AIDS Conference in Vienna, Austria.
"The goal of HIV vaccines is to elicit an immune response against HIV. The goal of HIV testing is to see if there is the presence of an immune response to HIV," Dr. Baden explained. "VISP occurs when the antibody or the immune response elicited cross-reacts with the diagnostic test; there can be confusion if one is not aware of this possibility."
VISP might have important ramifications, Dr. Baden said. "Participants may be at risk for misdiagnosis, and if that occurs, then many social harms occur . . . related to insurance, military service, blood [and] tissue donation, immigration, and a variety of other issues that may arise."
Dr. Baden and coworkers studied VISP occurring with various vaccines that were studied by the HIV Vaccine Trials Network. VISP was determined using 3 common US Food and Drug Administration–approved enzyme immunoassay (EIA) test kits. They evaluated VISP in healthy HIV-seronegative adults who participated in any of 25 phase 1 or 2 phase 2a vaccine trials conducted between 2000 and 2010 in the United States and internationally.
VISP was defined as a positive reaction on 1 or more of the EIA tests and a Western blot result that was negative, indeterminate, or atypical-positive — meaning a blot profile consistent with the vaccine product — in conjunction with a negative test for HIV-1 by nucleic acid testing.
Of the 2176 trial participants receiving a test vaccine, 908 (41.7%; 95% confidence interval [CI], 39.6% - 43.8%) had VISP. The occurrence of VISP varied greatly according to the kind of vaccine being tested (e.g., 86.7% for an adenovirus 5 product but only 6.3% for a DNA-alone product). Similarly, results varied substantially according to the test kit used (range, 8.8% to 40.9% VISP).
Dr. Baden concluded that VISP is a common but highly variable outcome in people who participate in vaccine trials. "The occurrence of this is dependent on several factors, including the vaccine or delivery system, the insert used in the vaccine, and the diagnostic test," he said.
These results indicate the need to develop novel rapid-detection methods that do not detect candidate vaccine antigens; several candidate diagnostics are now being investigated that use antigens that are unlikely to be used in vaccines, he noted.
But Dr. Baden said the easiest way to minimize the concern about false-positive test results is for healthcare providers to be aware of the issue as more people participate in vaccine studies. "All they need to do is ask their patients, and if their patients say they are in a vaccine study, then that should be an important consideration in how diagnostic testing is performed," he advised. In addition, testing might best be done by the vaccine trial site, which would be familiar with results related to the specific vaccine.
Because trial participants with VISP might subsequently become infected with HIV, appropriate testing is imperative, Dr. Baden emphasized, including testing for HIV RNA. Trial sites should also test for VISP at the end of the trial and tell participants their VISP status so that they can inform their healthcare providers.
Jason Haukoos, MD, MSc, assistant professor of surgery at the University of Colorado and an emergency physician in the Department of Emergency Medicine at the Denver Health Medical Center, told Medscape Medical News that relatively few patients have been in HIV vaccine trials, so concerns about VISP are small and Dr. Baden's work should go a long way toward solving the problem of false-positive results caused by VISP.
"And there are also a lot of diagnostics coming out now . . . [that will] not only look for antibodies but also antigens," he said. "If you have a combination antibody–antigen assay, then the VISP issue, I think, goes away on some level." He added that, unfortunately, we are still a long way from having an approved vaccine that will be used widely, so the problem of VISP for the near term is minimal.
Melanie Thompson, MD, from the AIDS Research Consortium of Atlanta, Georgia, and chair of the International AIDS Society–USA Antiretroviral Therapy Guidelines Panel, who was not involved in the study, agreed that false-positive HIV test results from VISP are not yet a problem given the small number of trial participants.
"As vaccine studies are expanding, it is going to become a more general issue," she told Medscape Medical News. Patients in vaccine trials will need to be aware of the issue "because they are going to educate the doctors in the community about VISP," she said. "Any HIV testers in the community need to be aware that persons who have been in vaccine trials may have a false-positive HIV test on the antibody testing."
Even in countries with limited healthcare resources, where many of the vaccine trials occur, she said the problem of VISP should be small if the test sites encourage their trial subjects to come back to them for HIV testing, where the proper test methodologies exist, if they have a positive test result elsewhere.
The work was funded by the National Institute of Allergy and Infectious Diseases and by a University of Washington Center for AIDS Research grant.
JAMA. 2010;304:275-283. Abstract
AIDS 2010: XVIII International AIDS Conference. Presented July 18, 2010.
Antibodies Induced by HIV Vaccines May Give False-Positive HIV Test Results
Daniel M. Keller, PhD
July 20, 2010 — Trials of vaccines designed to prevent HIV infection might induce antibodies that will cause false-positive results on routine antibody tests for HIV infection. Although the goal of much vaccine development is to induce the production of protective antibodies, they might also cause a state of vaccine-induced seropositivity/reactivity (VISP), which can confound the interpretation of HIV tests in the absence of HIV infection.
Dr. Lindsey Baden
In the July 21 issue of JAMA, which focuses on HIV/AIDS, Lindsey Baden, MD, from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, said that more than 30,000 people have participated in clinical trials of a variety of potential prophylactic vaccines against HIV. These vaccines have used a variety of delivery methods and antigenic compounds and were aimed at inducing different forms of immunity. Dr. Baden discussed the findings at AIDS 2010: XVIII International AIDS Conference in Vienna, Austria.
"The goal of HIV vaccines is to elicit an immune response against HIV. The goal of HIV testing is to see if there is the presence of an immune response to HIV," Dr. Baden explained. "VISP occurs when the antibody or the immune response elicited cross-reacts with the diagnostic test; there can be confusion if one is not aware of this possibility."
VISP might have important ramifications, Dr. Baden said. "Participants may be at risk for misdiagnosis, and if that occurs, then many social harms occur . . . related to insurance, military service, blood [and] tissue donation, immigration, and a variety of other issues that may arise."
Dr. Baden and coworkers studied VISP occurring with various vaccines that were studied by the HIV Vaccine Trials Network. VISP was determined using 3 common US Food and Drug Administration–approved enzyme immunoassay (EIA) test kits. They evaluated VISP in healthy HIV-seronegative adults who participated in any of 25 phase 1 or 2 phase 2a vaccine trials conducted between 2000 and 2010 in the United States and internationally.
VISP was defined as a positive reaction on 1 or more of the EIA tests and a Western blot result that was negative, indeterminate, or atypical-positive — meaning a blot profile consistent with the vaccine product — in conjunction with a negative test for HIV-1 by nucleic acid testing.
Of the 2176 trial participants receiving a test vaccine, 908 (41.7%; 95% confidence interval [CI], 39.6% - 43.8%) had VISP. The occurrence of VISP varied greatly according to the kind of vaccine being tested (e.g., 86.7% for an adenovirus 5 product but only 6.3% for a DNA-alone product). Similarly, results varied substantially according to the test kit used (range, 8.8% to 40.9% VISP).
Dr. Baden concluded that VISP is a common but highly variable outcome in people who participate in vaccine trials. "The occurrence of this is dependent on several factors, including the vaccine or delivery system, the insert used in the vaccine, and the diagnostic test," he said.
These results indicate the need to develop novel rapid-detection methods that do not detect candidate vaccine antigens; several candidate diagnostics are now being investigated that use antigens that are unlikely to be used in vaccines, he noted.
But Dr. Baden said the easiest way to minimize the concern about false-positive test results is for healthcare providers to be aware of the issue as more people participate in vaccine studies. "All they need to do is ask their patients, and if their patients say they are in a vaccine study, then that should be an important consideration in how diagnostic testing is performed," he advised. In addition, testing might best be done by the vaccine trial site, which would be familiar with results related to the specific vaccine.
Because trial participants with VISP might subsequently become infected with HIV, appropriate testing is imperative, Dr. Baden emphasized, including testing for HIV RNA. Trial sites should also test for VISP at the end of the trial and tell participants their VISP status so that they can inform their healthcare providers.
Jason Haukoos, MD, MSc, assistant professor of surgery at the University of Colorado and an emergency physician in the Department of Emergency Medicine at the Denver Health Medical Center, told Medscape Medical News that relatively few patients have been in HIV vaccine trials, so concerns about VISP are small and Dr. Baden's work should go a long way toward solving the problem of false-positive results caused by VISP.
"And there are also a lot of diagnostics coming out now . . . [that will] not only look for antibodies but also antigens," he said. "If you have a combination antibody–antigen assay, then the VISP issue, I think, goes away on some level." He added that, unfortunately, we are still a long way from having an approved vaccine that will be used widely, so the problem of VISP for the near term is minimal.
Melanie Thompson, MD, from the AIDS Research Consortium of Atlanta, Georgia, and chair of the International AIDS Society–USA Antiretroviral Therapy Guidelines Panel, who was not involved in the study, agreed that false-positive HIV test results from VISP are not yet a problem given the small number of trial participants.
"As vaccine studies are expanding, it is going to become a more general issue," she told Medscape Medical News. Patients in vaccine trials will need to be aware of the issue "because they are going to educate the doctors in the community about VISP," she said. "Any HIV testers in the community need to be aware that persons who have been in vaccine trials may have a false-positive HIV test on the antibody testing."
Even in countries with limited healthcare resources, where many of the vaccine trials occur, she said the problem of VISP should be small if the test sites encourage their trial subjects to come back to them for HIV testing, where the proper test methodologies exist, if they have a positive test result elsewhere.
The work was funded by the National Institute of Allergy and Infectious Diseases and by a University of Washington Center for AIDS Research grant.
JAMA. 2010;304:275-283. Abstract
AIDS 2010: XVIII International AIDS Conference. Presented July 18, 2010.
FDA: Antibiotics in Livestock Affects Human Health
From WebMD Health News
FDA: Antibiotics in Livestock Affects Human Health
Daniel J. DeNoon
June 29, 2010 — Giving animals antibiotics in order to increase food production is a threat to public health and should be stopped, the FDA said today.
The federal agency says it has the power to ban the practice, but it's starting by issuing "draft guidance" in hopes the food industry will make voluntary changes. After a 60-day public comment period, the guidance will become FDA policy.
The guidance is based on two principles:
* Antibiotics should be given to food animals only to protect their health.
* All animal use of antibiotics should be overseen by veterinarians.
"We are seeing the emergence of multidrug-resistant pathogens," FDA Deputy Commissioner Joshua Sharfstein, MD, said at a news conference. "FDA believes overall weight of evidence supports the conclusion that using medically important antimicrobial drugs for production purposes is not appropriate."
Sharfstein said it's a public health issue when antibiotics important for human health are given to animals on a massive scale. Such use encourages the growth of drug-resistant bacteria that can cause hard-to-treat human disease.
Like humans, animals sometimes need antibiotics to fight or prevent specific infections. The FDA says it has no problem with this.
But producers regularly give antibiotics to food animals because it makes them gain weight faster or makes them gain more weight from the food they eat. This is the practice the FDA wants to end.
Sharfstein hopes that by offering the carrot of voluntary guidelines, industry will avoid the stick of new regulations.
"We are not expecting people to change tomorrow. This is the first step in FDA establishing principles from which we could move to other steps, such as oversight," Sharfstein said. "This does not tell people what to do, it establishes principles and tells people how to achieve those principles."
FDA: Antibiotics in Livestock Affects Human Health
Daniel J. DeNoon
June 29, 2010 — Giving animals antibiotics in order to increase food production is a threat to public health and should be stopped, the FDA said today.
The federal agency says it has the power to ban the practice, but it's starting by issuing "draft guidance" in hopes the food industry will make voluntary changes. After a 60-day public comment period, the guidance will become FDA policy.
The guidance is based on two principles:
* Antibiotics should be given to food animals only to protect their health.
* All animal use of antibiotics should be overseen by veterinarians.
"We are seeing the emergence of multidrug-resistant pathogens," FDA Deputy Commissioner Joshua Sharfstein, MD, said at a news conference. "FDA believes overall weight of evidence supports the conclusion that using medically important antimicrobial drugs for production purposes is not appropriate."
Sharfstein said it's a public health issue when antibiotics important for human health are given to animals on a massive scale. Such use encourages the growth of drug-resistant bacteria that can cause hard-to-treat human disease.
Like humans, animals sometimes need antibiotics to fight or prevent specific infections. The FDA says it has no problem with this.
But producers regularly give antibiotics to food animals because it makes them gain weight faster or makes them gain more weight from the food they eat. This is the practice the FDA wants to end.
Sharfstein hopes that by offering the carrot of voluntary guidelines, industry will avoid the stick of new regulations.
"We are not expecting people to change tomorrow. This is the first step in FDA establishing principles from which we could move to other steps, such as oversight," Sharfstein said. "This does not tell people what to do, it establishes principles and tells people how to achieve those principles."
Patients With Diabetes Have Alternatives to Rosiglitazone (Avandia), Experts Say
From Medscape Medical News
Robert Lowes
July 19, 2010 — Clinicians do not lack for alternative therapies if patients with type 2 diabetes ask to be switched from rosiglitazone (Avandia, GlaxoSmithKline) to another glucose-lowering medication, according to the American Diabetes Association (ADA) and 2 other expert groups. The drug is again under increased scrutiny over cardiovascular risks.
"I don't think any physician or patient should worry that they don't have a good option if they're uncomfortable with Avandia," Richard Bergenstal, MD, ADA president of medicine and science, told Medscape Medical News.
Dr. Bergenstal, who also is executive director of the International Diabetes Center at Park Nicollet Health Services in St. Louis Park, Minnesota, said published clinical algorithms can guide physicians in selecting the right drug or combination of drugs. Such algorithms, he said, take into account factors such as efficacy, the risk for hypoglycemia, weight gain, and other adverse effects, as well as cost.
"We used to just ask which medication lowers blood sugar the most," he said. "Now it's a little more complicated."
In their joint statement released July 12, the ADA, the Endocrine Society (ES), and the American Association of Clinical Endocrinologists (AACE) urged patients now receiving rosiglitazone to continue taking it unless they receive instructions from their healthcare provider to the contrary.
"Until further clarification is provided by the [US Food and Drug Administration (FDA)], the decision whether or not to use any medication must remain that of the treating provider in direct discussion with the individual patient," the groups said.
The statement came 2 days before an advisory committee to the FDA voted 20–12 with 1 abstention to recommend that the FDA keep rosiglitazone on the market.
A majority of members also recommended that the agency add a tougher warning about the risk for heart attacks and other cardiovascular events to the label.
This seemingly contradictory conclusion reflects the conflicting drug-safety data that the committee weighed.
Physicians now are waiting to hear from the FDA itself, which has promised to evaluate the advisory committee proceedings and reach a decision as quickly as possible.
Regardless of the FDA's verdict, physicians and patients alike should know that there are multiple classes of drugs, often with more than 1 agent in a class, that can be used to maintain glucose control in patients with type 2 diabetes, according to the statement by the ADA, ES, and AACE:
* sulfonylureas,
* meglitinides,
* biguanides,
* thiazolidinediones,
* alpha-glucosidase inhibitors, and
* dipeptidyl peptidase-4 inhibitors.
The ADA lists these classes on its Web site.
Rosiglitazone is 1 of 2 FDA-approved medications in the thiazolidinedione class for lowering glucose; the other is pioglitazone (Actos, Takeda Pharmaceuticals). In its deliberations last week, the FDA advisory panel voted 21–4 in affirming that pioglitazone is safer than rosiglitazone.
Consensus Statement Goes Against Rosiglitazone Use
In June, the ADA announced on its Web site that it does not have an official position favoring or recommending against FDA-approved medications to lower glucose. Such positions, however, do appear in a consensus statement of the ADA and the European Association for the Study of Diabetes (EASD) that was published in Diabetes Care in January 2009. The ADA notes that this consensus statement "does not reflect the official position of the ADA but rather the expert opinion of the authors."
For most patients with type 2 diabetes, the consensus statement recommended as a "well-validated core therapy" a combination of lifestyle changes — namely, weight loss and increased physical activity — and metformin (Glucophage; Bristol-Myers Squibb), which belongs to the biguanide class. If this first-tier therapy fails to achieve or maintain glycemic goals, clinicians can prescribe either insulin or a sulfonylurea (except for chlorpropamide or glybenclamide) in addition to metformin.
The consensus group unanimously advised against prescribing rosiglitazone, although it noted that the evidence on the drug's cardiovascular risk is "not conclusive." The group found a second-tier use for its chemical cousin pioglitazone, however: Clinicians may consider it when "hypoglycemia is particularly undesirable (e.g., in patients who have hazardous jobs)," according to the consensus statement.
There is no dearth of algorithms for the role of medications in glycemic control. The AACE and the American College of Endocrinology (ACE) published one last fall that lays out a path from monotherapy to triple therapy. The algorithm prioritizes choices of medication based on "safety, risk of hypoglycemia, efficacy, simplicity, anticipated degree of patient adherence, and the cost of medications." The guidelines from AACE and ACE do not contain a blanket statement against prescribing rosiglitazone.
The International Diabetes Center at Park Nicollet Health Services has developed its own algorithm. Similar to the consensus statement of the ADA and EASD, it recommends pioglitazone, but not rosiglitazone, as part of dual or triple drug therapy when clinicians are targeting insulin resistance.
"Why have a sleepless night about whether you should have prescribed rosiglitazone or not?" said Dr. Bergenstal in explaining the rationale behind the algorithm.
Switching to a New Diabetes Drug Could Pose Greater Risks
The joint statement from the ADA, AACE, and ES informs clinicians and patients that they have alternatives to rosiglitazone but does not advise physicians to automatically switch patients from this drug to something else.
That advice echoes that of Daniel Einhorn, MD, the president of the AACE and medical director of the Scripps Whittier Diabetes Institute in La Jolla, California.
If patients tell him that they are worried about continuing with rosiglitazone, Dr. Einhorn said, he will discuss other drug therapies. However, he has not asked patients to stop using rosiglitazone — yet.
"So far, there is no FDA signal to discontinue the drug," he said. "All we can say is that serious safety questions have been raised. If you've done well on Avandia for years, why switch to another drug that may come with more risks for you?"
At the same time, Dr. Einhorn said he is no longer writing new prescriptions for rosiglitazone while the drug is under FDA review, and he doubts that any other physicians are writing them. He acknowledged that the status of the drug is confusing for clinicians, but then, so are the safety data that the FDA advisory committee heard.
"If the data was clear," said Dr. Einhorn, "we wouldn't be having this discussion."
Robert Lowes
July 19, 2010 — Clinicians do not lack for alternative therapies if patients with type 2 diabetes ask to be switched from rosiglitazone (Avandia, GlaxoSmithKline) to another glucose-lowering medication, according to the American Diabetes Association (ADA) and 2 other expert groups. The drug is again under increased scrutiny over cardiovascular risks.
"I don't think any physician or patient should worry that they don't have a good option if they're uncomfortable with Avandia," Richard Bergenstal, MD, ADA president of medicine and science, told Medscape Medical News.
Dr. Bergenstal, who also is executive director of the International Diabetes Center at Park Nicollet Health Services in St. Louis Park, Minnesota, said published clinical algorithms can guide physicians in selecting the right drug or combination of drugs. Such algorithms, he said, take into account factors such as efficacy, the risk for hypoglycemia, weight gain, and other adverse effects, as well as cost.
"We used to just ask which medication lowers blood sugar the most," he said. "Now it's a little more complicated."
In their joint statement released July 12, the ADA, the Endocrine Society (ES), and the American Association of Clinical Endocrinologists (AACE) urged patients now receiving rosiglitazone to continue taking it unless they receive instructions from their healthcare provider to the contrary.
"Until further clarification is provided by the [US Food and Drug Administration (FDA)], the decision whether or not to use any medication must remain that of the treating provider in direct discussion with the individual patient," the groups said.
The statement came 2 days before an advisory committee to the FDA voted 20–12 with 1 abstention to recommend that the FDA keep rosiglitazone on the market.
A majority of members also recommended that the agency add a tougher warning about the risk for heart attacks and other cardiovascular events to the label.
This seemingly contradictory conclusion reflects the conflicting drug-safety data that the committee weighed.
Physicians now are waiting to hear from the FDA itself, which has promised to evaluate the advisory committee proceedings and reach a decision as quickly as possible.
Regardless of the FDA's verdict, physicians and patients alike should know that there are multiple classes of drugs, often with more than 1 agent in a class, that can be used to maintain glucose control in patients with type 2 diabetes, according to the statement by the ADA, ES, and AACE:
* sulfonylureas,
* meglitinides,
* biguanides,
* thiazolidinediones,
* alpha-glucosidase inhibitors, and
* dipeptidyl peptidase-4 inhibitors.
The ADA lists these classes on its Web site.
Rosiglitazone is 1 of 2 FDA-approved medications in the thiazolidinedione class for lowering glucose; the other is pioglitazone (Actos, Takeda Pharmaceuticals). In its deliberations last week, the FDA advisory panel voted 21–4 in affirming that pioglitazone is safer than rosiglitazone.
Consensus Statement Goes Against Rosiglitazone Use
In June, the ADA announced on its Web site that it does not have an official position favoring or recommending against FDA-approved medications to lower glucose. Such positions, however, do appear in a consensus statement of the ADA and the European Association for the Study of Diabetes (EASD) that was published in Diabetes Care in January 2009. The ADA notes that this consensus statement "does not reflect the official position of the ADA but rather the expert opinion of the authors."
For most patients with type 2 diabetes, the consensus statement recommended as a "well-validated core therapy" a combination of lifestyle changes — namely, weight loss and increased physical activity — and metformin (Glucophage; Bristol-Myers Squibb), which belongs to the biguanide class. If this first-tier therapy fails to achieve or maintain glycemic goals, clinicians can prescribe either insulin or a sulfonylurea (except for chlorpropamide or glybenclamide) in addition to metformin.
The consensus group unanimously advised against prescribing rosiglitazone, although it noted that the evidence on the drug's cardiovascular risk is "not conclusive." The group found a second-tier use for its chemical cousin pioglitazone, however: Clinicians may consider it when "hypoglycemia is particularly undesirable (e.g., in patients who have hazardous jobs)," according to the consensus statement.
There is no dearth of algorithms for the role of medications in glycemic control. The AACE and the American College of Endocrinology (ACE) published one last fall that lays out a path from monotherapy to triple therapy. The algorithm prioritizes choices of medication based on "safety, risk of hypoglycemia, efficacy, simplicity, anticipated degree of patient adherence, and the cost of medications." The guidelines from AACE and ACE do not contain a blanket statement against prescribing rosiglitazone.
The International Diabetes Center at Park Nicollet Health Services has developed its own algorithm. Similar to the consensus statement of the ADA and EASD, it recommends pioglitazone, but not rosiglitazone, as part of dual or triple drug therapy when clinicians are targeting insulin resistance.
"Why have a sleepless night about whether you should have prescribed rosiglitazone or not?" said Dr. Bergenstal in explaining the rationale behind the algorithm.
Switching to a New Diabetes Drug Could Pose Greater Risks
The joint statement from the ADA, AACE, and ES informs clinicians and patients that they have alternatives to rosiglitazone but does not advise physicians to automatically switch patients from this drug to something else.
That advice echoes that of Daniel Einhorn, MD, the president of the AACE and medical director of the Scripps Whittier Diabetes Institute in La Jolla, California.
If patients tell him that they are worried about continuing with rosiglitazone, Dr. Einhorn said, he will discuss other drug therapies. However, he has not asked patients to stop using rosiglitazone — yet.
"So far, there is no FDA signal to discontinue the drug," he said. "All we can say is that serious safety questions have been raised. If you've done well on Avandia for years, why switch to another drug that may come with more risks for you?"
At the same time, Dr. Einhorn said he is no longer writing new prescriptions for rosiglitazone while the drug is under FDA review, and he doubts that any other physicians are writing them. He acknowledged that the status of the drug is confusing for clinicians, but then, so are the safety data that the FDA advisory committee heard.
"If the data was clear," said Dr. Einhorn, "we wouldn't be having this discussion."
Healthy Weight, Rather Than Fitness, Most Important for Preventing High Blood Pressure
From Heartwire
Michael O'Riordan
July 19, 2010 (Dallas, Texas) — Individuals who have a healthy body weight are more likely than those who are physically fit to have lower blood pressure, according to the results of a new study [1]. In a comparison of fitness vs fatness, body mass index (BMI) was more important than cardiorespiratory fitness for predicting systolic blood pressure, report researchers.
"Our findings suggest that achieving normal-weight status should be the primary goal for hypertension prevention, and only modest levels of cardiorespiratory fitness are needed to obtain optimal blood pressure among individuals who are normal weight," write Dr Jennifer Chen (University of Texas Southwestern Medical Center, Dallas) and colleagues in the July issue of the American Heart Journal.
The results are from the Cooper Center Longitudinal Study, an analysis of 35 061 patients presenting to a clinic for a comprehensive medical examination between 1990 and present. The purpose of the study was to analyze the relative importance of BMI and cardiorespiratory fitness on systolic blood pressure. Studies have shown that exercise and cardiorespiratory fitness are associated with lower hypertension risk, including reductions in systolic blood pressure of 3 or 4 mm Hg with exercise training.
"A key unanswered question is whether hypertension prevention should be focused on weight control by any acceptable intervention, or whether cardiorespiratory fitness, independent of BMI, is a more important first target for prevention of hypertension," explain the researchers.
In this cohort, consisting mainly of white men (average age, 46 years), normal-weight individuals had a mean systolic blood pressure 12 mm Hg lower than obese individuals (115 vs 127 mm Hg, p<0.001). In contrast, individuals with high levels of fitness, those in the highest quartile, had a 6 mm Hg lower systolic blood pressure than those least fit (119 vs 125 mm Hg, p<0.001).
When assessing BMI and cardiorespiratory fitness concurrently, there was a significant increase in systolic blood pressure by BMI quartile for every level of fitness, including those with low and high levels of fitness. However, level of fitness was associated with blood pressure only in individuals with the lowest and highest BMI, not in women with BMIs of 21 to 27 kg/m2 or men with BMIs of 25 to 30 kg/m2 (BMI quartiles 2 and 3).
The researchers point out that obesity might be such an important determinant of hypertension that the benefits of other lifestyle factors are not obtained until individuals get down to a healthy weight. They also note that the beneficial effects of exercise on blood pressure are modest in obese subjects because of the "competing effects of obesity on vascular and metabolic pathways," including the effects on arterial compliance, sympathetic activity, insulin sensitivity, vascular resistance, and release of endothelium-derived nitric oxide.
References
Michael O'Riordan
July 19, 2010 (Dallas, Texas) — Individuals who have a healthy body weight are more likely than those who are physically fit to have lower blood pressure, according to the results of a new study [1]. In a comparison of fitness vs fatness, body mass index (BMI) was more important than cardiorespiratory fitness for predicting systolic blood pressure, report researchers.
"Our findings suggest that achieving normal-weight status should be the primary goal for hypertension prevention, and only modest levels of cardiorespiratory fitness are needed to obtain optimal blood pressure among individuals who are normal weight," write Dr Jennifer Chen (University of Texas Southwestern Medical Center, Dallas) and colleagues in the July issue of the American Heart Journal.
The results are from the Cooper Center Longitudinal Study, an analysis of 35 061 patients presenting to a clinic for a comprehensive medical examination between 1990 and present. The purpose of the study was to analyze the relative importance of BMI and cardiorespiratory fitness on systolic blood pressure. Studies have shown that exercise and cardiorespiratory fitness are associated with lower hypertension risk, including reductions in systolic blood pressure of 3 or 4 mm Hg with exercise training.
"A key unanswered question is whether hypertension prevention should be focused on weight control by any acceptable intervention, or whether cardiorespiratory fitness, independent of BMI, is a more important first target for prevention of hypertension," explain the researchers.
In this cohort, consisting mainly of white men (average age, 46 years), normal-weight individuals had a mean systolic blood pressure 12 mm Hg lower than obese individuals (115 vs 127 mm Hg, p<0.001). In contrast, individuals with high levels of fitness, those in the highest quartile, had a 6 mm Hg lower systolic blood pressure than those least fit (119 vs 125 mm Hg, p<0.001).
When assessing BMI and cardiorespiratory fitness concurrently, there was a significant increase in systolic blood pressure by BMI quartile for every level of fitness, including those with low and high levels of fitness. However, level of fitness was associated with blood pressure only in individuals with the lowest and highest BMI, not in women with BMIs of 21 to 27 kg/m2 or men with BMIs of 25 to 30 kg/m2 (BMI quartiles 2 and 3).
The researchers point out that obesity might be such an important determinant of hypertension that the benefits of other lifestyle factors are not obtained until individuals get down to a healthy weight. They also note that the beneficial effects of exercise on blood pressure are modest in obese subjects because of the "competing effects of obesity on vascular and metabolic pathways," including the effects on arterial compliance, sympathetic activity, insulin sensitivity, vascular resistance, and release of endothelium-derived nitric oxide.
References
Friday, July 16, 2010
Obesity at Age 20 Linked to Early Death
From WebMD Health News
Obesity at Age 20 Linked to Early Death
Denise Mann
July 15, 2010 — Men who are obese at age 20 are twice as likely to die young, according to new research presented at the International Congress on Obesity in Stockholm, Sweden.
As it stands, more than two-thirds of U.S. adults aged 20 and older are overweight or obese, according to the National Institutes of Health in Bethesda, MD.
"Entering adult life as obese leads to a life-long doubling of the risk of dying prematurely," study researcher Esther Zimmermann, PhD, of the Institute of Preventive Medicine in Copenhagen University Hospital in Denmark, tells WebMD in an email. "The best advice is to avoid beginning adult life as obese [because] if you enter adult life as obese, the majority will remain obese as adults."
Zimmerman and colleagues tracked about 5,500 Swedish men from age 20 to age 80 and found that the 1,930 men who were obese when they were 20 were twice as likely to die at any given age than were their counterparts who were not obese at age 20. Starting at age 55, men who were obese at 20 died an average of eight years earlier than their counterparts who were not obese at age 20.
What's more, their chance of dying early increased by 10% for each body mass index (BMI) unit above 25. BMI takes height and weight into account to measure body fat. If your BMI is greater than 25, you are considered overweight. If it is over 30, you are considered obese.
Study participants completed follow-up surveys at age 35 and 46. More than 70% of men who were obese at age 20 remained so during these follow-up exams. By contrast, just 4% of men who were not obese at age 20 went on to become obese, the study showed. Researchers adjusted for other factors known to affect mortality such as smoking status.
"Entering adult life as obese had a life-long effect on mortality," she says. The next step is to study why those individuals who were obese at age 20 died earlier, she says.
Second Opinion
This game plan makes sense to Randall Urban, MD, professor and chair of internal medicine at the University of Texas Medical Branch in Galveston.
"This is a valuable study, and I think the results raise a lot of questions such as why are people who are obese at age 20 are dying sooner," he says. "We need to break down why they did worse and see how many people develop diabetes or heart disease," he says. Obesity is a major risk factor for diabetes and heart disease.
"This is a fascinating beginning and we really need to dig down further in this group to understand why they are dying earlier," he says.
Such information will help shape more effective prevention strategies. "Obesity is a marker that there will be problems down the road," he says. "In broad strokes, we can say that if obese people change their lifestyle, they will do better, but there may be more to it than this."
George L. Blackburn, MD, PhD, the S. Daniel Abraham Associate Professor of Nutrition and associate director of nutrition at Harvard Medical School in Boston, tells WebMD that this new information may help individuals grasp the consequences of obesity.
"In this day and age, everyone wants to live as long as they can, and we really haven't had the [mortality] card to play before," he says.
"This is another wake-up call," he tells WebMD. "On top of all the problems that the obese have, obesity doubles your risk of death if you are obese at age 20."
Importantly, Blackburn adds, "it is never too late to make healthy changes," he says.
SOURCES:
Obesity at Age 20 Linked to Early Death
Denise Mann
July 15, 2010 — Men who are obese at age 20 are twice as likely to die young, according to new research presented at the International Congress on Obesity in Stockholm, Sweden.
As it stands, more than two-thirds of U.S. adults aged 20 and older are overweight or obese, according to the National Institutes of Health in Bethesda, MD.
"Entering adult life as obese leads to a life-long doubling of the risk of dying prematurely," study researcher Esther Zimmermann, PhD, of the Institute of Preventive Medicine in Copenhagen University Hospital in Denmark, tells WebMD in an email. "The best advice is to avoid beginning adult life as obese [because] if you enter adult life as obese, the majority will remain obese as adults."
Zimmerman and colleagues tracked about 5,500 Swedish men from age 20 to age 80 and found that the 1,930 men who were obese when they were 20 were twice as likely to die at any given age than were their counterparts who were not obese at age 20. Starting at age 55, men who were obese at 20 died an average of eight years earlier than their counterparts who were not obese at age 20.
What's more, their chance of dying early increased by 10% for each body mass index (BMI) unit above 25. BMI takes height and weight into account to measure body fat. If your BMI is greater than 25, you are considered overweight. If it is over 30, you are considered obese.
Study participants completed follow-up surveys at age 35 and 46. More than 70% of men who were obese at age 20 remained so during these follow-up exams. By contrast, just 4% of men who were not obese at age 20 went on to become obese, the study showed. Researchers adjusted for other factors known to affect mortality such as smoking status.
"Entering adult life as obese had a life-long effect on mortality," she says. The next step is to study why those individuals who were obese at age 20 died earlier, she says.
Second Opinion
This game plan makes sense to Randall Urban, MD, professor and chair of internal medicine at the University of Texas Medical Branch in Galveston.
"This is a valuable study, and I think the results raise a lot of questions such as why are people who are obese at age 20 are dying sooner," he says. "We need to break down why they did worse and see how many people develop diabetes or heart disease," he says. Obesity is a major risk factor for diabetes and heart disease.
"This is a fascinating beginning and we really need to dig down further in this group to understand why they are dying earlier," he says.
Such information will help shape more effective prevention strategies. "Obesity is a marker that there will be problems down the road," he says. "In broad strokes, we can say that if obese people change their lifestyle, they will do better, but there may be more to it than this."
George L. Blackburn, MD, PhD, the S. Daniel Abraham Associate Professor of Nutrition and associate director of nutrition at Harvard Medical School in Boston, tells WebMD that this new information may help individuals grasp the consequences of obesity.
"In this day and age, everyone wants to live as long as they can, and we really haven't had the [mortality] card to play before," he says.
"This is another wake-up call," he tells WebMD. "On top of all the problems that the obese have, obesity doubles your risk of death if you are obese at age 20."
Importantly, Blackburn adds, "it is never too late to make healthy changes," he says.
SOURCES:
Tuesday, July 13, 2010
"Enriched Environment" Slows Tumor Growth in Mice
From Medscape Medical News
Zosia Chustecka
July 12, 2010 — Tumors grew more slowly and some even disappeared when mice with cancer were housed in an "enriched environment," where they had more space and more things to do.
"Simply placing the animals in a more complex living environment" produced effects "profound enough to significantly influence the growth of highly malignant cancers," researchers suggest.
The study is reported in the July 9 issue of Cell.
The researchers, led by Matthew During, MD, ScD, from Ohio State University, in Columbus, have previously shown that an enriched environment is good for the brain and can protect mice against cerebral insults such as epilepsy and neurotoxins.
The latest results show that such stimulation is also good for the body. "The same enriched environment also activates pathways that reduce the proliferative state with respect to cancer," Dr. During told Medscape Medical News.
"We believe that our results suggest that people should be challenged socially and physically, perhaps engage in team sports or competitive activities involving larger social groups, in addition to increased physical activity," he said.
"It means we shouldn't simply be avoiding stress but rather making our lives richer, more complex, more challenging, and a little stressful."
Its relevance to human cancer is highly questionable.
However, when asked about the study, Maurie Markman, MD, professor of medicine and chair of gynecologic medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston, who has an oncology videoblog on Medscape Medical News, answered with a "no comment."
"This is a mouse model and like all such artificial models, its relevance to human cancer is highly questionable," Dr. Markman said.
Significant Reduction in Cancer Burden
The enriched environment significantly reduced the cancer burden in 2 different mouse models: syngeneic melanoma and colon cancer.
Tumor mass shrank by 77% and tumor volume by 43%, and after 3 weeks in their new housing, 5% of mice showed no evidence of cancer.
No such changes were seen in a control group of mice in regular housing.
"Our results demonstrate that living in an enriched environment leads to a significant inhibition of cancer growth," the researchers conclude.
The fact that such an effect was seen even though the enriched environment was introduced after the establishment of the peripheral tumor suggests that there is "potential therapeutic relevance," the researchers note.
"This approach may have therapeutic significance in people who already have cancer," Dr. During said.
The team notes that serum from mice housed in the enriched environment was markedly lower in leptin than that from control mice; the environment was also shown to inhibit cancer proliferation in vitro.
In addition, the mice housed in the enriched environment showed:
* a small but significant increase in serum corticosterone, consistent with mild stress and elevation of the hypothalamus–pituitary axis
* activation of the hypothalamus with induction of immediate early genes, including brain-derived neurotrophic factor (BDNF)
* enhanced activity of natural killer cells.
The researchers propose that the biologic mechanism involved centers of activation of the hypothalamic–sympathoneural–adipocyte axis. More specifically, they suggest that environmental stimuli induce the expression of hypothalamic BDNF expression, and that this leads to sympathoneural activation. The elevated sympathetic drive activates adipocytes, which leads to a reduced production of leptin and release of adipokines, which have both direct mitogenic and antimitogenic activity and can also influence peripheral tumor growth indirectly through its effects on angiogenesis.
In addition, the researchers note that "direct transfer of BDNF can mimic the antiproliferative effects" of an enriched environment, and they suggest that either environmental or direct molecular approaches to inducing hypothalamic BNDF expression have therapeutic potential.
Dr. During noted that one approach that his team is now pursuing is the development of a defective viral vector expressing BDNF, which might have therapeutic potential in humans.
The authors have disclosed no relevant financial relationships.
Cell. 2010;142;52-64. Abstract
Zosia Chustecka
July 12, 2010 — Tumors grew more slowly and some even disappeared when mice with cancer were housed in an "enriched environment," where they had more space and more things to do.
"Simply placing the animals in a more complex living environment" produced effects "profound enough to significantly influence the growth of highly malignant cancers," researchers suggest.
The study is reported in the July 9 issue of Cell.
The researchers, led by Matthew During, MD, ScD, from Ohio State University, in Columbus, have previously shown that an enriched environment is good for the brain and can protect mice against cerebral insults such as epilepsy and neurotoxins.
The latest results show that such stimulation is also good for the body. "The same enriched environment also activates pathways that reduce the proliferative state with respect to cancer," Dr. During told Medscape Medical News.
"We believe that our results suggest that people should be challenged socially and physically, perhaps engage in team sports or competitive activities involving larger social groups, in addition to increased physical activity," he said.
"It means we shouldn't simply be avoiding stress but rather making our lives richer, more complex, more challenging, and a little stressful."
Its relevance to human cancer is highly questionable.
However, when asked about the study, Maurie Markman, MD, professor of medicine and chair of gynecologic medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston, who has an oncology videoblog on Medscape Medical News, answered with a "no comment."
"This is a mouse model and like all such artificial models, its relevance to human cancer is highly questionable," Dr. Markman said.
Significant Reduction in Cancer Burden
The enriched environment significantly reduced the cancer burden in 2 different mouse models: syngeneic melanoma and colon cancer.
Tumor mass shrank by 77% and tumor volume by 43%, and after 3 weeks in their new housing, 5% of mice showed no evidence of cancer.
No such changes were seen in a control group of mice in regular housing.
"Our results demonstrate that living in an enriched environment leads to a significant inhibition of cancer growth," the researchers conclude.
The fact that such an effect was seen even though the enriched environment was introduced after the establishment of the peripheral tumor suggests that there is "potential therapeutic relevance," the researchers note.
"This approach may have therapeutic significance in people who already have cancer," Dr. During said.
The team notes that serum from mice housed in the enriched environment was markedly lower in leptin than that from control mice; the environment was also shown to inhibit cancer proliferation in vitro.
In addition, the mice housed in the enriched environment showed:
* a small but significant increase in serum corticosterone, consistent with mild stress and elevation of the hypothalamus–pituitary axis
* activation of the hypothalamus with induction of immediate early genes, including brain-derived neurotrophic factor (BDNF)
* enhanced activity of natural killer cells.
The researchers propose that the biologic mechanism involved centers of activation of the hypothalamic–sympathoneural–adipocyte axis. More specifically, they suggest that environmental stimuli induce the expression of hypothalamic BDNF expression, and that this leads to sympathoneural activation. The elevated sympathetic drive activates adipocytes, which leads to a reduced production of leptin and release of adipokines, which have both direct mitogenic and antimitogenic activity and can also influence peripheral tumor growth indirectly through its effects on angiogenesis.
In addition, the researchers note that "direct transfer of BDNF can mimic the antiproliferative effects" of an enriched environment, and they suggest that either environmental or direct molecular approaches to inducing hypothalamic BNDF expression have therapeutic potential.
Dr. During noted that one approach that his team is now pursuing is the development of a defective viral vector expressing BDNF, which might have therapeutic potential in humans.
The authors have disclosed no relevant financial relationships.
Cell. 2010;142;52-64. Abstract
More Damning Evidence Against GSK and FDA on Rosiglitazone
From Heartwire
Sue Hughes
July 13, 2010 (Washington DC) — Further evidence has come to light suggesting that GlaxoSmithKline knew about an increased cardiac risk with the diabetes drug rosiglitazone (Avandia) as early as 2001 but withheld the data and that certain officials at the FDA conspired with the company to minimize the impact of later safety results. The news comes on the same day that the FDA advisory panel starts its two-day hearing on the cardiovascular safety of the drug.
The findings are from a deposition from a former manager in the FDA's drug-safety unit to lawyers suing GlaxoSmithKline and from several emails to and from company employees discussing the negative results and the need to keep them quiet. These have surfaced as part of the inquiry by Sens Charles Grassley (R-IA), and Max Baucus (D-MT) into Avandia [1].
Dr Rosemary Johann-Liang, the former FDA drug safety manager, left the FDA in 2007 following her recommendation that GlaxoSmithKline add more information about health risks to Avandia's label, a Bloomberg report notes [2].
It adds that the FDA waited 17 months after Johann-Liang's recommendation before implementing a safety warning and excluded her from safety review meetings.
In her deposition, Johann-Liang stated that FDA officials provided the company with details of internal agency discussions about strengthening the warnings.
An email obtained by the New York Times implicates Dr John Jenkins, director of the FDA's office of new drugs, in the matter [3].
The email from a company official states: "It is clear the office of new drugs is trying to find minimal language that will satisfy the office of drug safety." Johann-Liang is reported to have testified that the leaks "should not have happened" and violated FDA policy.
Other emails document internal conversations at GlaxoSmithKline about concealing cardiac results with rosiglitazone.
In one 2001 communication, Dr Martin I Freed, a GlaxoSmithKline executive, answering a question about possible publication of the data, wrote: "Not a chance. These put Avandia in quite a negative light. . . . It is a difficult story to tell and we would hope that these do not see the light of day."
Another email from Freed, talking about concealing the data, says: "This was done for the US business, way under the radar," adding: "Per sr mgmt request, these data should not see the light of day to anyone outside of GlaxoSmithKline."
Another document was reported to estimate lost sales if Avandia's cardiovascular safety risk "intensifies" at "$600 million from 2002 to 2004 alone."
GlaxoSmithKline denies concealing data. A company spokesperson said the comments quoted had been "intentionally taken out of context" and that the company has been entirely forthcoming with the FDA and the Senate committee. "Cherry-picking a handful of documents from more than 14 million pages of documents distorts the record and is misleading," she added.
Glaxosmithkline Says Reports Are "Cherry Picking"
GlaxoSmithKline said the documents released by the Senate Finance Committee have been taken out of context and are therefore incomplete and misleading [4].
It says one of the studies discussed was looking at the effect of pioglitazone (Actos, Takeda Pharmaceuticals) on LDL and triglycerides; it was not a study on rosiglitazone and heart attack and did not contribute any significant new information. Data from the other two studies referenced by the committee were submitted to the FDA in 1999 and are also publicly available on its Clinical Study Register. It adds: "Cherry-picking a handful of documents from more than 14 million pages of documents distorts the record and is misleading" [5].
References
Sue Hughes
July 13, 2010 (Washington DC) — Further evidence has come to light suggesting that GlaxoSmithKline knew about an increased cardiac risk with the diabetes drug rosiglitazone (Avandia) as early as 2001 but withheld the data and that certain officials at the FDA conspired with the company to minimize the impact of later safety results. The news comes on the same day that the FDA advisory panel starts its two-day hearing on the cardiovascular safety of the drug.
The findings are from a deposition from a former manager in the FDA's drug-safety unit to lawyers suing GlaxoSmithKline and from several emails to and from company employees discussing the negative results and the need to keep them quiet. These have surfaced as part of the inquiry by Sens Charles Grassley (R-IA), and Max Baucus (D-MT) into Avandia [1].
Dr Rosemary Johann-Liang, the former FDA drug safety manager, left the FDA in 2007 following her recommendation that GlaxoSmithKline add more information about health risks to Avandia's label, a Bloomberg report notes [2].
It adds that the FDA waited 17 months after Johann-Liang's recommendation before implementing a safety warning and excluded her from safety review meetings.
In her deposition, Johann-Liang stated that FDA officials provided the company with details of internal agency discussions about strengthening the warnings.
An email obtained by the New York Times implicates Dr John Jenkins, director of the FDA's office of new drugs, in the matter [3].
The email from a company official states: "It is clear the office of new drugs is trying to find minimal language that will satisfy the office of drug safety." Johann-Liang is reported to have testified that the leaks "should not have happened" and violated FDA policy.
Other emails document internal conversations at GlaxoSmithKline about concealing cardiac results with rosiglitazone.
In one 2001 communication, Dr Martin I Freed, a GlaxoSmithKline executive, answering a question about possible publication of the data, wrote: "Not a chance. These put Avandia in quite a negative light. . . . It is a difficult story to tell and we would hope that these do not see the light of day."
Another email from Freed, talking about concealing the data, says: "This was done for the US business, way under the radar," adding: "Per sr mgmt request, these data should not see the light of day to anyone outside of GlaxoSmithKline."
Another document was reported to estimate lost sales if Avandia's cardiovascular safety risk "intensifies" at "$600 million from 2002 to 2004 alone."
GlaxoSmithKline denies concealing data. A company spokesperson said the comments quoted had been "intentionally taken out of context" and that the company has been entirely forthcoming with the FDA and the Senate committee. "Cherry-picking a handful of documents from more than 14 million pages of documents distorts the record and is misleading," she added.
Glaxosmithkline Says Reports Are "Cherry Picking"
GlaxoSmithKline said the documents released by the Senate Finance Committee have been taken out of context and are therefore incomplete and misleading [4].
It says one of the studies discussed was looking at the effect of pioglitazone (Actos, Takeda Pharmaceuticals) on LDL and triglycerides; it was not a study on rosiglitazone and heart attack and did not contribute any significant new information. Data from the other two studies referenced by the committee were submitted to the FDA in 1999 and are also publicly available on its Clinical Study Register. It adds: "Cherry-picking a handful of documents from more than 14 million pages of documents distorts the record and is misleading" [5].
References
No Letup for GSK: EMA Set to Review Rosiglitazone
From Heartwire
Lisa Nainggolan
July 12, 2010 (London, United Kingdom) — There is to be no calm before the storm of the two-day FDA advisory committee hearing on the cardiovascular safety of rosiglitazone (Avandia, GlaxoSmithKline)--the latest squall has blown in from the European Medicines Agency (EMA), which has announced that it, too, will look into the safety of the drug, starting at its plenary meeting next week, July 19–22 [1,2].
The EMA says it will review Avandia and two medicines containing rosiglitazone combined with other diabetes drugs: with metformin, marketed as Avandamet, and with glimepiride (Amaryl, Sanofi-Aventis), sold as Avaglim.
EMA spokesperson Monika Benstetter told heartwire that the fate of rosiglitazone in Europe may not be known until later in the summer or early autumn. "Nobody knows yet whether we will be finalizing this process next week; it may well be that it will carry on. It could be that we will have an opinion during the July Committee for Medicinal Products for Human Use [CHMP] meeting, but depending on the data, it may not be concluded."
She indicated, however, that any further evaluation would take weeks, rather than months. This would also allow the EMA to see how the FDA responds to its advisory committees' conclusions to be issued this week, she noted.
The EMA announcement came on Friday, the same day that nearly 1000 pages of documents were posted on the FDA website as briefing material for the safety hearing that starts in the US tomorrow. The bulk of the FDA material overwhelmingly points to an increased risk of adverse cardiovascular events with rosiglitazone over pioglitazone (Actos, Takeda Pharmaceuticals) and other diabetes drugs. But posted alongside these were data from the sponsor, which insists that it indicates that rosiglitazone has a positive risk/benefit profile and is "an important medicine for patients with type 2 diabetes."
EMA Options: Change, Suspend, or Revoke Authorization for Rosiglitazone
This latest EMA review of rosiglitazone was "triggered," said Benstetter, by the publication, two weeks ago, of two new papers: an observational study on rosiglitazone in Archives of Internal Medicine and a meta-analysis in the Journal of the American Medical Association.
In its press release, the EMA notes that at the time of authorization, Avandia, Avandamet, and Avaglim were contraindicated in patients with heart failure or a history of heart failure, and since then, the product information has been updated "to include warnings and contraindications on the use of these medicines in patients with heart problems."
The EMA last reviewed rosiglitazone earlier this year, when the CHMP issued a limited renewal of the marketing authorization for Avandia for a further five years, Benstetter said.
"Once all relevant data on the benefits and the risks of rosiglitazone have been looked at, the [EMA's] CHMP will issue an opinion on whether or not the marketing authorizations for these medicines should be revoked, suspended, or changed," its statement indicates.
References
Lisa Nainggolan
July 12, 2010 (London, United Kingdom) — There is to be no calm before the storm of the two-day FDA advisory committee hearing on the cardiovascular safety of rosiglitazone (Avandia, GlaxoSmithKline)--the latest squall has blown in from the European Medicines Agency (EMA), which has announced that it, too, will look into the safety of the drug, starting at its plenary meeting next week, July 19–22 [1,2].
The EMA says it will review Avandia and two medicines containing rosiglitazone combined with other diabetes drugs: with metformin, marketed as Avandamet, and with glimepiride (Amaryl, Sanofi-Aventis), sold as Avaglim.
EMA spokesperson Monika Benstetter told heartwire that the fate of rosiglitazone in Europe may not be known until later in the summer or early autumn. "Nobody knows yet whether we will be finalizing this process next week; it may well be that it will carry on. It could be that we will have an opinion during the July Committee for Medicinal Products for Human Use [CHMP] meeting, but depending on the data, it may not be concluded."
She indicated, however, that any further evaluation would take weeks, rather than months. This would also allow the EMA to see how the FDA responds to its advisory committees' conclusions to be issued this week, she noted.
The EMA announcement came on Friday, the same day that nearly 1000 pages of documents were posted on the FDA website as briefing material for the safety hearing that starts in the US tomorrow. The bulk of the FDA material overwhelmingly points to an increased risk of adverse cardiovascular events with rosiglitazone over pioglitazone (Actos, Takeda Pharmaceuticals) and other diabetes drugs. But posted alongside these were data from the sponsor, which insists that it indicates that rosiglitazone has a positive risk/benefit profile and is "an important medicine for patients with type 2 diabetes."
EMA Options: Change, Suspend, or Revoke Authorization for Rosiglitazone
This latest EMA review of rosiglitazone was "triggered," said Benstetter, by the publication, two weeks ago, of two new papers: an observational study on rosiglitazone in Archives of Internal Medicine and a meta-analysis in the Journal of the American Medical Association.
In its press release, the EMA notes that at the time of authorization, Avandia, Avandamet, and Avaglim were contraindicated in patients with heart failure or a history of heart failure, and since then, the product information has been updated "to include warnings and contraindications on the use of these medicines in patients with heart problems."
The EMA last reviewed rosiglitazone earlier this year, when the CHMP issued a limited renewal of the marketing authorization for Avandia for a further five years, Benstetter said.
"Once all relevant data on the benefits and the risks of rosiglitazone have been looked at, the [EMA's] CHMP will issue an opinion on whether or not the marketing authorizations for these medicines should be revoked, suspended, or changed," its statement indicates.
References
Salsa, Guacamole Transmit Food-borne Illnesses
From WebMD Health News
Katrina Woznicki
July 13, 2010 — The CDC has identified salsa and guacamole as two significant sources of food-borne illnesses, according to a new report released today.
The rate of food-borne illnesses has more than doubled for salsa and guacamole served at restaurants, researchers say. Nearly one out of every 25 restaurant-related outbreaks that occurred between 1998 and 2008 was traced back to these two popular foods. The findings were presented at the International Conference on Emerging Infectious Diseases in Atlanta.
The CDC, which has been tracking food-borne illness outbreaks since 1973, found that there were no salsa or guacamole-linked outbreaks reported before 1984. The CDC reported that:
* Out of 136 salsa or guacamole outbreaks, 84% occurred in restaurants and delis.
* Salsa and guacamole outbreaks accounted for 1.5% of all food establishment outbreaks between 1984 and 1987; that figured jumped to 3.9% between 1998 and 2008.
* Poor storage, such as temperature, were reported in nearly one third of the salsa and guacamole outbreaks.
* Food workers were the source of contamination in 20% of the restaurant outbreaks.
Salsa, Guacamole: Proper Storage Essential to Prevent Bacteria
Guacamole is made with fresh avocados and salsa is also made with fresh ingredients, including tomatoes, onions, and peppers. If these ingredients and foods are not properly stored and refrigerated, they can spoil quickly and foster bacteria, such as salmonella.
“Salsa and guacamole often contain diced raw produce, including hot peppers, tomatoes, and cilantro, each of which has been implicated in past outbreaks,” says Magdalena Kendall, a researcher at the Oak Ridge Institute for Science and Education in Oak Ridge, Tenn., which is part of the U.S. Department of Energy, which collaborated on the CDC study.
Salsa and guacamole are often prepared in large batches so there is the potential for a small amount of bacteria to reach multiple people at once, Kendall says.
"Awareness that salsa and guacamole can transmit food-borne illness, particularly in restaurants, is key to preventing future outbreaks,” Kendall says. “We want restaurants and anyone preparing fresh salsa and guacamole at home to be aware that these foods containing raw ingredients should be carefully prepared and refrigerated to help prevent illness.”
Food-borne illness can be caused by bacteria, like salmonella, viruses, parasites, or even toxins and metals. More than 200 known diseases are transmitted through food, according to the CDC, causing a range of symptoms from a mild upset stomach to life-threatening organ failure. In the United States, food-borne illnesses cause about 9,000 deaths and as many as 81 million illnesses every year. Food-borne illnesses are often underreported, so these estimates may be lower than actual figures.
During the spring and summer of 2008, a massive outbreak traced back to jalapeno peppers and tomatoes used in salsa sickened more than 1,400 people with salmonella. The outbreak swept across 43 states, the District of Columbia, and Canada. Nearly 300 people were hospitalized.
Katrina Woznicki
July 13, 2010 — The CDC has identified salsa and guacamole as two significant sources of food-borne illnesses, according to a new report released today.
The rate of food-borne illnesses has more than doubled for salsa and guacamole served at restaurants, researchers say. Nearly one out of every 25 restaurant-related outbreaks that occurred between 1998 and 2008 was traced back to these two popular foods. The findings were presented at the International Conference on Emerging Infectious Diseases in Atlanta.
The CDC, which has been tracking food-borne illness outbreaks since 1973, found that there were no salsa or guacamole-linked outbreaks reported before 1984. The CDC reported that:
* Out of 136 salsa or guacamole outbreaks, 84% occurred in restaurants and delis.
* Salsa and guacamole outbreaks accounted for 1.5% of all food establishment outbreaks between 1984 and 1987; that figured jumped to 3.9% between 1998 and 2008.
* Poor storage, such as temperature, were reported in nearly one third of the salsa and guacamole outbreaks.
* Food workers were the source of contamination in 20% of the restaurant outbreaks.
Salsa, Guacamole: Proper Storage Essential to Prevent Bacteria
Guacamole is made with fresh avocados and salsa is also made with fresh ingredients, including tomatoes, onions, and peppers. If these ingredients and foods are not properly stored and refrigerated, they can spoil quickly and foster bacteria, such as salmonella.
“Salsa and guacamole often contain diced raw produce, including hot peppers, tomatoes, and cilantro, each of which has been implicated in past outbreaks,” says Magdalena Kendall, a researcher at the Oak Ridge Institute for Science and Education in Oak Ridge, Tenn., which is part of the U.S. Department of Energy, which collaborated on the CDC study.
Salsa and guacamole are often prepared in large batches so there is the potential for a small amount of bacteria to reach multiple people at once, Kendall says.
"Awareness that salsa and guacamole can transmit food-borne illness, particularly in restaurants, is key to preventing future outbreaks,” Kendall says. “We want restaurants and anyone preparing fresh salsa and guacamole at home to be aware that these foods containing raw ingredients should be carefully prepared and refrigerated to help prevent illness.”
Food-borne illness can be caused by bacteria, like salmonella, viruses, parasites, or even toxins and metals. More than 200 known diseases are transmitted through food, according to the CDC, causing a range of symptoms from a mild upset stomach to life-threatening organ failure. In the United States, food-borne illnesses cause about 9,000 deaths and as many as 81 million illnesses every year. Food-borne illnesses are often underreported, so these estimates may be lower than actual figures.
During the spring and summer of 2008, a massive outbreak traced back to jalapeno peppers and tomatoes used in salsa sickened more than 1,400 people with salmonella. The outbreak swept across 43 states, the District of Columbia, and Canada. Nearly 300 people were hospitalized.
Subscribe to:
Posts (Atom)