From Medscape Medical News
Robert Lowes
July 27, 2010 — Once a person loses excess weight, the next great battle is keeping those pounds from coming back a year or 2 later.
Calling a personal coach every month about the latest scale reading or hamburger binge is one solution. Another — one more within reach of the average patient — is consistently logging in to an interactive Internet version of a personal coach, according to a study from the Kaiser Permanente Center for Health Research.
The key word is "consistently." Participants in a study funded by the National Institutes of Health who visited a weight-management Web site almost every month maintained more of their weight loss than patients who checked in sporadically. However, those assigned to a personal coach regained the least amount of weight overall compared with participants who used the Web sites and those whose weight maintenance was self-directed.
The study, published online today in the Journal of Medical Internet Research, was part of a 30-month, 4-center, randomized clinical trial that examined 3 ways to keep lost weight from returning. Enrollees were obese or overweight, as defined by body mass index, and were taking medication for hypertension or hyperlipidemia.
For 6 months preceding the trial, patients reduced caloric intake and exercised in an effort to slim down. Those who lost 4 kg or more — the average reduction was 8.6 kg, or 19 pounds — were randomly assigned to 3 groups for weight maintenance. One group was self-directed, another contacted a health counselor once a month, and a third group relied on an interactive Web site.
On the Web site, participants could record their weight, caloric intake, and minutes of exercise and compare that information with the goals they had set for themselves. A bulletin board allowed them to read other patients' success stories and share their own, as well as get advice from experts on exercise and behavior change. Those who did not log on to the site as often received email reminders, and when they failed to enter data, they were automatically prompted to do so.
At the end of 30 months, participants assigned to a personal coach regained the least amount of weight — 4 kg — of the 3 groups. The rebound was 5.2 kg for patients in the Web site group and 5.5 kg for those in the self-directed group.
Consistent Use of Web Site Almost as Good as Personal Coach
Although the results for the Internet approach as a whole fell short of those achieved with a personal coach, the Web site worked better for people who used it more consistently. Consistent users — defined as patients who recorded their weight at the Web site at least once a month for 26 months of a 28-month portion of the trial — regained 4.5 kg, or only a half a kilogram more than the figure posted by patients with personal coaches. The next most faithful subcategory of Web site users recorded their weight for 14 to 25 months and regained 6.3 kg, whereas minimal users checked in for 13 months or less and put back on 7.4 kg.
The consistent users, who represented 61% of all the patients assigned to the Internet group, came into the trial with the lowest weight and body mass index of the 3 user categories and lost the most weight during the initial 6 months. Compared with minimal users, consistent users were more likely to be older, men, more educated, and not black.
Success with the Web site requires persistence, but not an onerous amount of time, noted study lead author Kristine Funk, MS, RD, a research associate for the Kaiser Permanente Center for Health Research. Individual sessions on average lasted only 3 to 5 minutes.
"It wasn't so much the amount of time, but the regularity that counted," Ms. Funk told Medscape Medical News.
A weight-management Web site appears to be a good alternative to a living, breathing personal coach, who may not be affordable or practical for many patients, she noted. Patients should look for a site where they can enter data on weight, caloric consumption, and exercise, and receive reminders when they do not supply this information.
"You want a Web site that asks you to be accountable," said Ms. Funk.
The site, she added, should allow users to connect online to experts and other patients "who are going through similar struggles." Another must is accurate health information in educational articles.
Ms. Funk said she was not in a position to recommend weight-management sites, but that "they're out there." The one employed in the study no longer exists.
The study was funded by the National Institutes of Health. The authors have disclosed no relevant financial relationships.
J Med Internet Res. Published online July 27, 2010.
Thursday, July 29, 2010
Friday, July 23, 2010
Cleaning Products Linked to Breast Cancer?
From WebMD Health News
Kathleen Doheny
July 22, 2010 -- Frequent use of household cleaning products may boost breast cancer risk, according to a new study that drew criticism from medical experts and the cleaning industry.
Air fresheners and products to control mold and mildew were particularly linked, says researcher Julia Brody, PhD, executive director of the Silent Spring Institute in Newton, Mass., who led the study.
It is published in the journal Environmental Health.
The study is believed to be the first published report linking household cleaning products and breast cancer risk. "Many laboratory studies led us to be concerned about particular compounds in cleaning products and air fresheners," Brody tells WebMD.
While Brody sees a link, others are not convinced. ''What this study really shows is, when a study relies on people's memory of their exposure, and people are concerned about that exposure, you don't get reliable answers," says Michael Thun, MD, vice president emeritus of epidemiology for the American Cancer Society.
Cleaning Products and Breast Cancer: Study Details
Brody and her co-researchers conducted telephone interviews with 787 women who had been diagnosed with breast cancer and 721 women who did not have breast cancer. "We asked women about past use of cleaning products -- in the past year, their typical use," Brody says.
''For pesticide use, we asked about use in houses they lived in in the past," she says.
''We found links [to breast cancer] for combined cleaning products used -- many different products taken together -- and air fresheners and mold and mildew control products."
The strongest link, she says, is looking at all cleaning products combined. "For combined cleaning product use, the risk is about twice as high [for breast cancer] for women who said they used the most compared to women who said they used the least."
Insect repellent use seemed to be linked, Brody says, but there was very little association found between other pesticides and breast cancer risk.
Specifying exactly how much exposure to the products may raise risk is difficult, she says. For combined products use, women were divided into four groups; those in the fourth group, who used the most, had about twice the risk as those in the group that used the least.
For solid air fresheners, for instance, those who used it seven or more times a year had twice the risk of breast cancer as those who never used it.
Brody also found that women who had breast cancer and thought that chemicals and pollutants contribute much to cancer risk were more likely to report high use of cleaning products. But Brody isn't sure what's driving what -- whether women who get breast cancer then begin to wonder if cleaning products played a role, or other factors.
Second Opinion
When studies look at data from the past -- what scientists call retrospective studies -- and ask people to rely on their memories, "the results aren't going to be interpretable," says Thun, who reviewed the study findings for WebMD.
''I'd say that the study really isn't informative about their actual risk," he says. "It's much more informative about why this particular line of study is not reliable. It's not informative. And it is not going to answer the questions."
As to the risk of cleaning products, Thun says, "The jury's out. We know there is a lot of concern about cleaning products from environmental groups."
Ideally, the way to study the potential link, he says, is to define the exposure to cleaning products in advance, then follow the women. He concedes this is difficult and time consuming and ''probably not going to happen."
Still, the "self-report" technique is unreliable, he says, especially in those already diagnosed. "If I have breast cancer, I am going to be looking for a reason," he says.
''There's concern because of recall bias," agrees Susan Brown, director of health education at Susan G. Komen for the Cure in Dallas. Understanding the effects of cleaning products will take more study, including research that follows a group of women over time, she tells WebMD.
''It is our experience that once people are diagnosed with breast cancer, they are so interested in trying to figure out what caused it, they look at things in a different way,'' Brown says."They look at every exposure, every behavior as suspect, perhaps part of the reason they got breast cancer. It's perfectly natural, but that doesn't necessarily lead to good science."
What should women concerned about cleaning products do until more research is in? Thun says environmental groups offer suggestions on using simpler cleaning products, such as soap and water and baking soda.
Thun also suggests focusing on known ways to reduce breast cancer risk, including maintaining a healthy weight, engaging in physical activity, minimizing alcohol intake, and avoiding hormone replacement therapy.
Industry Response
In a statement, the American Cleaning Institute challenged the findings. The research, according to the statement, "far overreaches in its conclusions based on self-reported uses of cleaning products by persons diagnosed with breast cancer."
It continues that ''the research is rife with innuendo and speculation about the safety of cleaning products and their ingredients."
Also taking issue with the look-back approach, the statement notes that women were asked to recall products they used in the past.
Brody defends her study. "This is a first look and there are cautions about interpreting it," she says.
In ongoing research, her team is testing air and dust in women's homes and finding compounds from consumer products that could be harmful, she says. "We are focusing on understanding exposures from consumer products," she says, to identify which are potentially harmful.
SOURCES:
Kathleen Doheny
July 22, 2010 -- Frequent use of household cleaning products may boost breast cancer risk, according to a new study that drew criticism from medical experts and the cleaning industry.
Air fresheners and products to control mold and mildew were particularly linked, says researcher Julia Brody, PhD, executive director of the Silent Spring Institute in Newton, Mass., who led the study.
It is published in the journal Environmental Health.
The study is believed to be the first published report linking household cleaning products and breast cancer risk. "Many laboratory studies led us to be concerned about particular compounds in cleaning products and air fresheners," Brody tells WebMD.
While Brody sees a link, others are not convinced. ''What this study really shows is, when a study relies on people's memory of their exposure, and people are concerned about that exposure, you don't get reliable answers," says Michael Thun, MD, vice president emeritus of epidemiology for the American Cancer Society.
Cleaning Products and Breast Cancer: Study Details
Brody and her co-researchers conducted telephone interviews with 787 women who had been diagnosed with breast cancer and 721 women who did not have breast cancer. "We asked women about past use of cleaning products -- in the past year, their typical use," Brody says.
''For pesticide use, we asked about use in houses they lived in in the past," she says.
''We found links [to breast cancer] for combined cleaning products used -- many different products taken together -- and air fresheners and mold and mildew control products."
The strongest link, she says, is looking at all cleaning products combined. "For combined cleaning product use, the risk is about twice as high [for breast cancer] for women who said they used the most compared to women who said they used the least."
Insect repellent use seemed to be linked, Brody says, but there was very little association found between other pesticides and breast cancer risk.
Specifying exactly how much exposure to the products may raise risk is difficult, she says. For combined products use, women were divided into four groups; those in the fourth group, who used the most, had about twice the risk as those in the group that used the least.
For solid air fresheners, for instance, those who used it seven or more times a year had twice the risk of breast cancer as those who never used it.
Brody also found that women who had breast cancer and thought that chemicals and pollutants contribute much to cancer risk were more likely to report high use of cleaning products. But Brody isn't sure what's driving what -- whether women who get breast cancer then begin to wonder if cleaning products played a role, or other factors.
Second Opinion
When studies look at data from the past -- what scientists call retrospective studies -- and ask people to rely on their memories, "the results aren't going to be interpretable," says Thun, who reviewed the study findings for WebMD.
''I'd say that the study really isn't informative about their actual risk," he says. "It's much more informative about why this particular line of study is not reliable. It's not informative. And it is not going to answer the questions."
As to the risk of cleaning products, Thun says, "The jury's out. We know there is a lot of concern about cleaning products from environmental groups."
Ideally, the way to study the potential link, he says, is to define the exposure to cleaning products in advance, then follow the women. He concedes this is difficult and time consuming and ''probably not going to happen."
Still, the "self-report" technique is unreliable, he says, especially in those already diagnosed. "If I have breast cancer, I am going to be looking for a reason," he says.
''There's concern because of recall bias," agrees Susan Brown, director of health education at Susan G. Komen for the Cure in Dallas. Understanding the effects of cleaning products will take more study, including research that follows a group of women over time, she tells WebMD.
''It is our experience that once people are diagnosed with breast cancer, they are so interested in trying to figure out what caused it, they look at things in a different way,'' Brown says."They look at every exposure, every behavior as suspect, perhaps part of the reason they got breast cancer. It's perfectly natural, but that doesn't necessarily lead to good science."
What should women concerned about cleaning products do until more research is in? Thun says environmental groups offer suggestions on using simpler cleaning products, such as soap and water and baking soda.
Thun also suggests focusing on known ways to reduce breast cancer risk, including maintaining a healthy weight, engaging in physical activity, minimizing alcohol intake, and avoiding hormone replacement therapy.
Industry Response
In a statement, the American Cleaning Institute challenged the findings. The research, according to the statement, "far overreaches in its conclusions based on self-reported uses of cleaning products by persons diagnosed with breast cancer."
It continues that ''the research is rife with innuendo and speculation about the safety of cleaning products and their ingredients."
Also taking issue with the look-back approach, the statement notes that women were asked to recall products they used in the past.
Brody defends her study. "This is a first look and there are cautions about interpreting it," she says.
In ongoing research, her team is testing air and dust in women's homes and finding compounds from consumer products that could be harmful, she says. "We are focusing on understanding exposures from consumer products," she says, to identify which are potentially harmful.
SOURCES:
Thursday, July 22, 2010
Supplements Improve Outcomes for HIV-Positive Patients
From Medscape Medical News
Norra MacReady
July 20, 2010 (Vienna, Austria) — Nutritional supplementation improves immune function and survival in HIV-infected people, according to findings presented here at AIDS 2010: XVIII International AIDS Conference.
In 3 studies conducted in the United States and Botswana, supplementation with vitamin and mineral antioxidants was associated with longer survival, less immune failure, and better mitochondrial function in CD4+ cells, Marianna K. Baum, PhD, said in a poster session. Dr. Baum, who is professor of dietetics and nutrition at Florida International University in Miami, participated in all 3 investigations.
The first 2 studies were small preliminary trials involving HIV-infected patients in Miami, about half of whom were homeless, Dr. Baum told Medscape Medical News.
They all had normal plasma albumin levels, but 50% to 65% had low levels of zinc or B vitamins, and about one third were deficient in vitamin A. About 20% of these patients also had wasting. "They may not have had frank malnutrition, but their nutritional status wasn't great," Dr. Baum said. Many of these patients obtained their meals from soup kitchens, and if they did not feel up to standing in long lines or sitting in the hot Florida sun, they might go several days without food, she noted.
In the first study, the investigators examined the effect of zinc supplementation on the prevention of immune failure in 40 HIV-positive adults on antiretroviral therapy (ART). The participants, all of whom had an undetectable viral load, were randomly assigned to receive zinc or placebo and were followed for 18 months. Immune failure was defined as a CD4 cell count below 200 cells/mm3.
Over the 18 months, 4 patients in the placebo group (21%) experienced immune failure, compared with none in the zinc group (0%; P = .043). Dr. Baum and her coauthors conclude that zinc supplementation is safe and might prevent immunologic failure in HIV-positive patients on stable ART.
HIV infection and long-term ART use increase cellular oxidative stress and might damage mitochondria, which can have implications for immune function, Dr. Baum said.
In the second study, conducted on a different but similar population, she and her colleagues randomized 13 patients to supplementation with multiple antioxidants, including vitamins C, E, and B complex, selenium, N-acetyl cysteine, and alpha-lipoic acid, as well as zinc, and compared outcomes with those in 12 patients given a placebo for 8 weeks.
Over that time period, patients receiving the antioxidants had increased CD4% (β = 8.61; P = .06), CD4/CD8 ratio (β = .277; P = .09), and activity of complex IV, an enzyme involved in oxidative phosphorylation within the mitochondria (P = .016), suggesting decreased mitochondrial damage.
These findings were encouraging even if the CD4 results did not quite attain statistical significance, Dr. Baum told Medscape Medical News. "It was pretty amazing that within 2 months we could have this effect on such a small number of patients. We showed that micronutrients can be immunostimulatory even in people with good viral control."
The outcomes were even more promising in Botswana, where 875 HIV-positive adults participated in a prospective randomized clinical trial comparing supplementation with vitamins C, E, and B complex plus selenium with multivitamins alone, selenium alone, and placebo.
These patients had CD4 cell counts above 350 cells/mm3 and were not receiving ART at the time of enrollment. Over the subsequent 24 months, the patients were followed for events of combined outcomes of disease progression, which the investigators defined as a CD4 count below 250 cells/mm3, the development of an AIDS-defining condition, or death.
Time to any event indicating disease progression was longer among people receiving any type of nutritional supplementation than among those not receiving nutritional supplements (hazard ratio, 0.65; P = .0157).
People in Botswana are relatively well nourished, yet "this simple micronutrient supplementation was safe, improved CD4 count, and prolonged the time to AIDS-defining conditions," Dr. Baum said. "We recommend that, at least in Africa, people in the early stages of HIV infection have their nutritional status monitored and receive supplements when appropriate. This should probably occur in the United States too."
The authors have disclosed no relevant financial relationships.
AIDS 2010: XVIII International AIDS Conference: Abstracts MOPE0100, MOPE0101, and MOPE0102. Presented July 19, 2010.
Norra MacReady
July 20, 2010 (Vienna, Austria) — Nutritional supplementation improves immune function and survival in HIV-infected people, according to findings presented here at AIDS 2010: XVIII International AIDS Conference.
In 3 studies conducted in the United States and Botswana, supplementation with vitamin and mineral antioxidants was associated with longer survival, less immune failure, and better mitochondrial function in CD4+ cells, Marianna K. Baum, PhD, said in a poster session. Dr. Baum, who is professor of dietetics and nutrition at Florida International University in Miami, participated in all 3 investigations.
The first 2 studies were small preliminary trials involving HIV-infected patients in Miami, about half of whom were homeless, Dr. Baum told Medscape Medical News.
They all had normal plasma albumin levels, but 50% to 65% had low levels of zinc or B vitamins, and about one third were deficient in vitamin A. About 20% of these patients also had wasting. "They may not have had frank malnutrition, but their nutritional status wasn't great," Dr. Baum said. Many of these patients obtained their meals from soup kitchens, and if they did not feel up to standing in long lines or sitting in the hot Florida sun, they might go several days without food, she noted.
In the first study, the investigators examined the effect of zinc supplementation on the prevention of immune failure in 40 HIV-positive adults on antiretroviral therapy (ART). The participants, all of whom had an undetectable viral load, were randomly assigned to receive zinc or placebo and were followed for 18 months. Immune failure was defined as a CD4 cell count below 200 cells/mm3.
Over the 18 months, 4 patients in the placebo group (21%) experienced immune failure, compared with none in the zinc group (0%; P = .043). Dr. Baum and her coauthors conclude that zinc supplementation is safe and might prevent immunologic failure in HIV-positive patients on stable ART.
HIV infection and long-term ART use increase cellular oxidative stress and might damage mitochondria, which can have implications for immune function, Dr. Baum said.
In the second study, conducted on a different but similar population, she and her colleagues randomized 13 patients to supplementation with multiple antioxidants, including vitamins C, E, and B complex, selenium, N-acetyl cysteine, and alpha-lipoic acid, as well as zinc, and compared outcomes with those in 12 patients given a placebo for 8 weeks.
Over that time period, patients receiving the antioxidants had increased CD4% (β = 8.61; P = .06), CD4/CD8 ratio (β = .277; P = .09), and activity of complex IV, an enzyme involved in oxidative phosphorylation within the mitochondria (P = .016), suggesting decreased mitochondrial damage.
These findings were encouraging even if the CD4 results did not quite attain statistical significance, Dr. Baum told Medscape Medical News. "It was pretty amazing that within 2 months we could have this effect on such a small number of patients. We showed that micronutrients can be immunostimulatory even in people with good viral control."
The outcomes were even more promising in Botswana, where 875 HIV-positive adults participated in a prospective randomized clinical trial comparing supplementation with vitamins C, E, and B complex plus selenium with multivitamins alone, selenium alone, and placebo.
These patients had CD4 cell counts above 350 cells/mm3 and were not receiving ART at the time of enrollment. Over the subsequent 24 months, the patients were followed for events of combined outcomes of disease progression, which the investigators defined as a CD4 count below 250 cells/mm3, the development of an AIDS-defining condition, or death.
Time to any event indicating disease progression was longer among people receiving any type of nutritional supplementation than among those not receiving nutritional supplements (hazard ratio, 0.65; P = .0157).
People in Botswana are relatively well nourished, yet "this simple micronutrient supplementation was safe, improved CD4 count, and prolonged the time to AIDS-defining conditions," Dr. Baum said. "We recommend that, at least in Africa, people in the early stages of HIV infection have their nutritional status monitored and receive supplements when appropriate. This should probably occur in the United States too."
The authors have disclosed no relevant financial relationships.
AIDS 2010: XVIII International AIDS Conference: Abstracts MOPE0100, MOPE0101, and MOPE0102. Presented July 19, 2010.
Painters Have a Brush With Bladder Cancer Risk
From Medscape Medical News
Neil Osterweil
July 22, 2010 — Painters and others exposed to paint on the job are at significantly greater risk of developing bladder cancer than other workers, even when potential confounders, such as smoking and other occupational exposures, are taken into account, say authors of a meta-analysis of 41 studies.
Neela Guha, PhD, MPH, and colleagues from the International Agency for Research on Cancer in Lyon, France, report their findings in the August issue of Occupational and Environmental Medicine.
The overall summary relative risk (RR) for bladder cancer in painters was 1.25 (95% confidence interval [CI], 1.16 - 1.34); the risks did not diminish after adjustment for smoking status (RR, 1.28; 95% CI, 1.15 - 1.43) or other occupational exposures (RR, 1.27; 95% CI. 0.99 - 1.63).
The risks were significantly higher for women (RR, 1.55; 95% CI, 1.08 - 2.23) than for men (RR, 1.24; 95% CI, 1.15 - 1.34); this difference was statistically significant, even though the data on women painters came from only 4 studies, the investigators note.
In addition, the RR for veteran painters — those with more than 10 years of exposure — was 1.81 (95% CI, 1.20 - 2.75), compared with those who had less than 10 years of exposure (RR, 1.41; 95% CI, 1.00 - 2.01).
Population at Risk
The population at risk might include people who apply paint to surfaces for a living and to allied trades, such as plasterers, wallpaper hangers, and wood refinishers (French polishers), the researchers note. The findings are largely on based data from 30 case–control studies, but include 2 cohort studies and 8 record-linkage studies spanning 50 years.
"Because several million people are employed as painters worldwide, even a modest increase in the relative risk is remarkable. It is important for cancer control and prevention to design studies with more specific exposure assessment that quantifies individual agents or classes of agents to identify the underlying carcinogenic agents encountered in painting," the investigators note.
They point out that the association between bladder cancer and painting remained even when smoking was taken into consideration. Cigarette smoking is responsible for about two thirds of bladder cancer cases in men and about one third of cases in women the industrialized world, they note, adding that the excess risk is likely attributed to aromatic amines in smoke, some of which are found in paint.
Real Risk Is Low
These results are interesting but not surprising, and the strength of the association is fairly mild, said J. Stephen Jones, MD, professor of surgery and chair of the Department of Regional Urology at the Cleveland Clinic in Ohio, in an interview with Medscape Medical News.
Dr. Jones noted that the RR of about 1.25 and the CIs ranging from 1.16 to 1.34 are similar to previous reports in the literature. However, the real risks are actually still fairly low, he said.
"Let's say that people have a 1 in 100 chance of getting bladder cancer in their lifetime. That's a very small increase for any given person that they actually might get bladder cancer. So although the numbers start sounding kind of concerning, when you really think about [how much] Mr. Smith going to work in the morning [increases] the risk that he, in his lifetime, is going to get bladder cancer, he's still not going to get bladder cancer the overwhelming majority of times. That why most painters don't get bladder cancer," he said.
Arnold Chin, MD, PhD, a urologist at the Ronald Reagan UCLA Medical Center in Los Angeles, California, and researcher at UCLA's Jonsson Comprehensive Cancer Center, told Medscape Medical News that a different recently published meta-analysis looking at risks for bladder and lung cancer in painters found no increased risk for either cancer, compared with nonpainters (Crit Rev Toxicol. 2010;40:101-125).
The authors of that meta-analysis write: "Residual confounding by smoking and socioeconomic status, lack of exposure group effect, and publication bias limit the ability of the meta-analyses to explain associations observed between occupational painting and lung and bladder cancers. Given the long latencies for lung and bladder cancers, these weak associations, if real, may not be elucidated through studies of occupational painting today."
Neither Dr. Jones nor Dr. Chin were involved in either study, and were approached for independent comment by Medscape Medical News.
The authors, Dr. Jones, and Dr. Chin have disclosed no relevant financial relationships.
Occup Environ Med. 2010;67:568-573. Abstract
Neil Osterweil
July 22, 2010 — Painters and others exposed to paint on the job are at significantly greater risk of developing bladder cancer than other workers, even when potential confounders, such as smoking and other occupational exposures, are taken into account, say authors of a meta-analysis of 41 studies.
Neela Guha, PhD, MPH, and colleagues from the International Agency for Research on Cancer in Lyon, France, report their findings in the August issue of Occupational and Environmental Medicine.
The overall summary relative risk (RR) for bladder cancer in painters was 1.25 (95% confidence interval [CI], 1.16 - 1.34); the risks did not diminish after adjustment for smoking status (RR, 1.28; 95% CI, 1.15 - 1.43) or other occupational exposures (RR, 1.27; 95% CI. 0.99 - 1.63).
The risks were significantly higher for women (RR, 1.55; 95% CI, 1.08 - 2.23) than for men (RR, 1.24; 95% CI, 1.15 - 1.34); this difference was statistically significant, even though the data on women painters came from only 4 studies, the investigators note.
In addition, the RR for veteran painters — those with more than 10 years of exposure — was 1.81 (95% CI, 1.20 - 2.75), compared with those who had less than 10 years of exposure (RR, 1.41; 95% CI, 1.00 - 2.01).
Population at Risk
The population at risk might include people who apply paint to surfaces for a living and to allied trades, such as plasterers, wallpaper hangers, and wood refinishers (French polishers), the researchers note. The findings are largely on based data from 30 case–control studies, but include 2 cohort studies and 8 record-linkage studies spanning 50 years.
"Because several million people are employed as painters worldwide, even a modest increase in the relative risk is remarkable. It is important for cancer control and prevention to design studies with more specific exposure assessment that quantifies individual agents or classes of agents to identify the underlying carcinogenic agents encountered in painting," the investigators note.
They point out that the association between bladder cancer and painting remained even when smoking was taken into consideration. Cigarette smoking is responsible for about two thirds of bladder cancer cases in men and about one third of cases in women the industrialized world, they note, adding that the excess risk is likely attributed to aromatic amines in smoke, some of which are found in paint.
Real Risk Is Low
These results are interesting but not surprising, and the strength of the association is fairly mild, said J. Stephen Jones, MD, professor of surgery and chair of the Department of Regional Urology at the Cleveland Clinic in Ohio, in an interview with Medscape Medical News.
Dr. Jones noted that the RR of about 1.25 and the CIs ranging from 1.16 to 1.34 are similar to previous reports in the literature. However, the real risks are actually still fairly low, he said.
"Let's say that people have a 1 in 100 chance of getting bladder cancer in their lifetime. That's a very small increase for any given person that they actually might get bladder cancer. So although the numbers start sounding kind of concerning, when you really think about [how much] Mr. Smith going to work in the morning [increases] the risk that he, in his lifetime, is going to get bladder cancer, he's still not going to get bladder cancer the overwhelming majority of times. That why most painters don't get bladder cancer," he said.
Arnold Chin, MD, PhD, a urologist at the Ronald Reagan UCLA Medical Center in Los Angeles, California, and researcher at UCLA's Jonsson Comprehensive Cancer Center, told Medscape Medical News that a different recently published meta-analysis looking at risks for bladder and lung cancer in painters found no increased risk for either cancer, compared with nonpainters (Crit Rev Toxicol. 2010;40:101-125).
The authors of that meta-analysis write: "Residual confounding by smoking and socioeconomic status, lack of exposure group effect, and publication bias limit the ability of the meta-analyses to explain associations observed between occupational painting and lung and bladder cancers. Given the long latencies for lung and bladder cancers, these weak associations, if real, may not be elucidated through studies of occupational painting today."
Neither Dr. Jones nor Dr. Chin were involved in either study, and were approached for independent comment by Medscape Medical News.
The authors, Dr. Jones, and Dr. Chin have disclosed no relevant financial relationships.
Occup Environ Med. 2010;67:568-573. Abstract
News Report Links Avandia Panelists to Drug Makers
From Heartwire
Michael O'Riordan
July 21, 2010 (Rockville, Maryland) — A US Food and Drug Administration (FDA) advisory panel member who voted to keep rosiglitazone (Avandia) on the market without any labeling changes received financial compensation from GlaxoSmithKline, the maker of the controversial diabetes drug, according to a report in the Wall Street Journal.
Dr David Capuzzi (Lankenau Institute for Medical Research, Philadelphia, PA) earned $14 750 as a member of the company's speaker's bureau, but received the money related to talks about Lovaza, an omega-3 polyunsaturated fatty acid approved by the FDA to lower triglycerides, and not for rosiglitazone.
"I have not given any talks [to doctors' groups] promoting Avandia," he told the Journal.
In a statement released Tuesday, panel member Dr Abraham Thomas (Henry Ford Hospital, Detroit, MI) said that he was also paid twice to speak, in this case for Takeda Pharmaceuticals, the makers of rival pioglitazone (Actos). Again reported in the Journal, Thomas said he was paid between $2000 and $3000 in 2007 and 2008 as part of Takeda's diabetes speakers' bureau, and disclosed this information to the FDA. Last Wednesday, Thomas called for rosiglitazone to be removed from the market.
Capuzzi received $3750 from the company between April 2009 and March 2010, as reported on the GSK website, and received an additional $8000 in speaking fees prior to that period. He earned another $3000 in second quarter of 2010. A GSK spokesperson told heartwire that Capuzzi was paid to serve on a rosiglitazone advisory board prior to 2008.
In an emailed statement provided to heart wire , FDA spokesperson Karen Riley said the agency is currently investigating the issue. "At this point, the FDA plans to conclude its investigations by the end of this week," wrote Riley. "Until then, we cannot provide any detail on future actions."
As reported by heartwire , Capuzzi was one of three doctors to vote for the drug to stay on the market without any labeling changes. As part of the complex recommendations, 12 of 33 voting panelists from both the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee felt the safety risks were too great to allow rosiglitazone to stay on the market. Of the remaining 20 votes--one member abstained--panelists said the drug could stay on the market with severe restrictions, while some believed the drug could remain with increased warnings.
The FDA told the Journal they are trying to determine if there was disclosure regarding Capuzzi, and if there was, why it wasn't conveyed to the committee.
References
Michael O'Riordan
July 21, 2010 (Rockville, Maryland) — A US Food and Drug Administration (FDA) advisory panel member who voted to keep rosiglitazone (Avandia) on the market without any labeling changes received financial compensation from GlaxoSmithKline, the maker of the controversial diabetes drug, according to a report in the Wall Street Journal.
Dr David Capuzzi (Lankenau Institute for Medical Research, Philadelphia, PA) earned $14 750 as a member of the company's speaker's bureau, but received the money related to talks about Lovaza, an omega-3 polyunsaturated fatty acid approved by the FDA to lower triglycerides, and not for rosiglitazone.
"I have not given any talks [to doctors' groups] promoting Avandia," he told the Journal.
In a statement released Tuesday, panel member Dr Abraham Thomas (Henry Ford Hospital, Detroit, MI) said that he was also paid twice to speak, in this case for Takeda Pharmaceuticals, the makers of rival pioglitazone (Actos). Again reported in the Journal, Thomas said he was paid between $2000 and $3000 in 2007 and 2008 as part of Takeda's diabetes speakers' bureau, and disclosed this information to the FDA. Last Wednesday, Thomas called for rosiglitazone to be removed from the market.
Capuzzi received $3750 from the company between April 2009 and March 2010, as reported on the GSK website, and received an additional $8000 in speaking fees prior to that period. He earned another $3000 in second quarter of 2010. A GSK spokesperson told heartwire that Capuzzi was paid to serve on a rosiglitazone advisory board prior to 2008.
In an emailed statement provided to heart wire , FDA spokesperson Karen Riley said the agency is currently investigating the issue. "At this point, the FDA plans to conclude its investigations by the end of this week," wrote Riley. "Until then, we cannot provide any detail on future actions."
As reported by heartwire , Capuzzi was one of three doctors to vote for the drug to stay on the market without any labeling changes. As part of the complex recommendations, 12 of 33 voting panelists from both the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee felt the safety risks were too great to allow rosiglitazone to stay on the market. Of the remaining 20 votes--one member abstained--panelists said the drug could stay on the market with severe restrictions, while some believed the drug could remain with increased warnings.
The FDA told the Journal they are trying to determine if there was disclosure regarding Capuzzi, and if there was, why it wasn't conveyed to the committee.
References
Drinking Alcohol Temporarily Heightens Stroke Risk
From Medscape Medical News
Allison Gandey
July 22, 2010 — Drinking even small amounts of alcohol increases the risk for ischemic stroke, a controversial new study suggests. Results from the Stroke Onset Study show double the risk for stroke an hour after consuming as little as a single serving of wine, beer, or hard liquor.
Previous research has suggested that regular heavy drinking increases the risk for ischemic stroke, but other studies have linked light to moderate alcohol intake to a decreased risk.
Alcohol recommendations
"The evidence on heavy drinking is consistent," senior investigator Murray Mittleman, MD, from Harvard Medical School in Boston, Massachusetts, said in a news release. "Both in the long and short term it raises stroke risk, but we're finding it's more complicated with light to moderate drinking," he said.
The preliminary findings are published online July 15 in Stroke.
In this multicenter study, investigators interviewed 390 stroke patients about 3 days after hospitalization. The researchers used a case-crossover approach to compare alcohol consumption in the hour before stroke symptoms with the frequency of use during the past year.
They found that 64% of patients drank alcohol the year before their stroke. Some of these patients (27%) drank within 24 hours of their symptoms, and some patients (3.6%) had had a drink within 1 hour of stroke.
The researchers, led by Elizabeth Mostofsky, MPH, also at Harvard, report that the relative risk for stroke in the hour after drinking was 2.3 (95% confidence interval, 1.4 - 4.0; P = .002). They report that the relative risks were similar for different types of alcoholic beverages.
Small Study, Preliminary Findings
Asked by Medscape Medical News to comment, Markku Kaste, MD, from the Department of Neurology at Helsinki University Central Hospital in Finland, recommended that clinicians continue following American Heart Association guidelines, which suggest that alcohol may be consumed in moderation.
Why did this new study find even a single glass could increase the risk for stroke? Dr. Kaste said it could be a chance finding from such a small study, or the participants may have had other unrecognized risk factors. Dr. Kaste says he thinks it is unlikely that 1 drink could trigger stroke.
During an interview, William Weiner, MD, from the University of Maryland Medical Center in Baltimore, said he is concerned about the high number of preliminary association studies he is seeing lately.
"It seems like every time I turn around, I'm reading another association study in the field of neurology," Dr. Weiner said. "We're being told we need more of this or less of something else. Patients tend to get excited about these findings, but we need to be very cautious, because most will not turn out."
Dr. Weiner said he agrees such studies should be conducted and published, but he says the caveats must be emphasized. "It's important we let people know how early these investigations are."
The researchers acknowledge that many questions remain. Although this study suggested that even small amounts of alcohol may be problematic, Dr. Mittleman said this temporary increased risk may eventually be outweighed by the longer-term health benefits of moderate alcohol consumption. "The impact of alcohol on your risk of ischemic stroke appears to depend on how much and how often you drink," he said.
This study was supported by the American Heart Association in Dallas, Texas. The researchers have disclosed no relevant financial relationships.
Stroke. Published online July 15, 2010.
Allison Gandey
July 22, 2010 — Drinking even small amounts of alcohol increases the risk for ischemic stroke, a controversial new study suggests. Results from the Stroke Onset Study show double the risk for stroke an hour after consuming as little as a single serving of wine, beer, or hard liquor.
Previous research has suggested that regular heavy drinking increases the risk for ischemic stroke, but other studies have linked light to moderate alcohol intake to a decreased risk.
Alcohol recommendations
"The evidence on heavy drinking is consistent," senior investigator Murray Mittleman, MD, from Harvard Medical School in Boston, Massachusetts, said in a news release. "Both in the long and short term it raises stroke risk, but we're finding it's more complicated with light to moderate drinking," he said.
The preliminary findings are published online July 15 in Stroke.
In this multicenter study, investigators interviewed 390 stroke patients about 3 days after hospitalization. The researchers used a case-crossover approach to compare alcohol consumption in the hour before stroke symptoms with the frequency of use during the past year.
They found that 64% of patients drank alcohol the year before their stroke. Some of these patients (27%) drank within 24 hours of their symptoms, and some patients (3.6%) had had a drink within 1 hour of stroke.
The researchers, led by Elizabeth Mostofsky, MPH, also at Harvard, report that the relative risk for stroke in the hour after drinking was 2.3 (95% confidence interval, 1.4 - 4.0; P = .002). They report that the relative risks were similar for different types of alcoholic beverages.
Small Study, Preliminary Findings
Asked by Medscape Medical News to comment, Markku Kaste, MD, from the Department of Neurology at Helsinki University Central Hospital in Finland, recommended that clinicians continue following American Heart Association guidelines, which suggest that alcohol may be consumed in moderation.
Why did this new study find even a single glass could increase the risk for stroke? Dr. Kaste said it could be a chance finding from such a small study, or the participants may have had other unrecognized risk factors. Dr. Kaste says he thinks it is unlikely that 1 drink could trigger stroke.
During an interview, William Weiner, MD, from the University of Maryland Medical Center in Baltimore, said he is concerned about the high number of preliminary association studies he is seeing lately.
"It seems like every time I turn around, I'm reading another association study in the field of neurology," Dr. Weiner said. "We're being told we need more of this or less of something else. Patients tend to get excited about these findings, but we need to be very cautious, because most will not turn out."
Dr. Weiner said he agrees such studies should be conducted and published, but he says the caveats must be emphasized. "It's important we let people know how early these investigations are."
The researchers acknowledge that many questions remain. Although this study suggested that even small amounts of alcohol may be problematic, Dr. Mittleman said this temporary increased risk may eventually be outweighed by the longer-term health benefits of moderate alcohol consumption. "The impact of alcohol on your risk of ischemic stroke appears to depend on how much and how often you drink," he said.
This study was supported by the American Heart Association in Dallas, Texas. The researchers have disclosed no relevant financial relationships.
Stroke. Published online July 15, 2010.
Wednesday, July 21, 2010
FDA to Look Into Possible Cancer Risk With ARBs
From Heartwire > Alerts, Approvals and Safety Changes > Alerts
Lisa Nainggolan
July 16, 2010 (Bethesda, Maryland) — The US FDA has become the latest regulatory agency to say it will investigate a possible link between angiotensin-receptor blockers (ARBs) and cancer, in a safety alert for human medical products issued yesterday [1].
The move follows a meta-analysis reported in Lancet Oncology last month, which found a modest, but significant, increased risk of primarily lung cancer associated with the use of these antihypertensive agents.
The week after this paper was published, the European Medicines Agency (EMA) announced it would review the possible risk of cancer in patients taking ARBs, based on this. But many hypertension doctors are unhappy about the meta-analysis, citing many flaws, as reported by heartwire ; they also fear it will stop patients from taking their much-needed medication.
In its safety alert, the FDA says it has "not concluded that ARBs increase the risk of cancer. The agency is reviewing information related to this safety concern and will update the public when additional information is available. FDA believes the benefits of ARBs continue to outweigh their potential risks."
References
Lisa Nainggolan
July 16, 2010 (Bethesda, Maryland) — The US FDA has become the latest regulatory agency to say it will investigate a possible link between angiotensin-receptor blockers (ARBs) and cancer, in a safety alert for human medical products issued yesterday [1].
The move follows a meta-analysis reported in Lancet Oncology last month, which found a modest, but significant, increased risk of primarily lung cancer associated with the use of these antihypertensive agents.
The week after this paper was published, the European Medicines Agency (EMA) announced it would review the possible risk of cancer in patients taking ARBs, based on this. But many hypertension doctors are unhappy about the meta-analysis, citing many flaws, as reported by heartwire ; they also fear it will stop patients from taking their much-needed medication.
In its safety alert, the FDA says it has "not concluded that ARBs increase the risk of cancer. The agency is reviewing information related to this safety concern and will update the public when additional information is available. FDA believes the benefits of ARBs continue to outweigh their potential risks."
References
Tuesday, July 20, 2010
Triglyceride and Waist Measurements Predict Heart-Disease Risk
From Heartwire
Triglyceride and Waist Measurements Predict Heart-Disease Risk
Sue Hughes
July 19, 2010 (Quebec, Quebec City) — Using two simple and inexpensive measurements--triglycerides and waist circumference--can identify patients with intra-abdominal obesity who have an increased risk of coronary artery disease and can add value in detecting risk of heart disease when used with traditional risk models such as Framingham, a new study suggests.
The study, published online July 19, 2010 in the Canadian Medical Association Journal, was conducted by a team led by Dr Benoit Arsenault (l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, QC).
A Step Beyond Metabolic Syndrome?
Coauthor Dr Jean Pierre Després (l'Institut Universitaire de Cardiologie et de Pneumologie de Québec) told heartwire that he believes the combination of a large waist measurement plus high triglyceride level, termed the "hypertriglyceridemic-waist phenotype," is the next step beyond metabolic syndrome.
"We are not proposing that this is a new definition of metabolic syndrome. But we are suggesting that this is a new phenomenon beyond the metabolic syndrome that can identify individuals at increased risk of heart disease who may fall through the net if we just use traditional risk factors," he said.
This is a new phenomenon beyond the metabolic syndrome that can identify individuals at increased risk of heart disease who may fall through the net if we just use traditional risk factors.
Metabolic syndrome, a condition that is the subject of much argument over its relevance, is defined as having three of the following risk factors: increased waist circumference, elevated triglycerides, reduced HDL cholesterol, elevated blood pressure, or elevated fasting glucose.
The latter three risk factors are normally measured as part of traditional risk evaluations for heart disease, so Després is saying that the focus should therefore be on waist and triglycerides, which have now been shown to add value over and above traditional risk factors.
"These two simple measurements are the cheapest way of finding those people who are at risk from this lousy lifestyle we now lead--those with visceral obesity and related metabolic disorders. Because it is measuring the two components of the metabolic syndrome not captured by Framingham or other traditional risk scores, it is picking up the risk of metabolic syndrome not found by those traditional scores," he added.
In the paper, the authors explain that although obesity is a health hazard, not every obese person has the expected metabolic abnormalities associated with excess body fat, and these tend to occur more often in those people with an excess of intra-abdominal or visceral adipose tissue. They have previously proposed that waist circumference can be used as an easy measurement of intra-abdominal adiposity, with elevated triglyceride levels further identifying "dysfunctional" adipose tissue. They suggest that hypertriglyceridemia combined with an increased waistline could be a marker of lipid overflow resulting from a relative defect of adipose tissue to clear and store the excess triglycerides from overeating and lack of physical activity.
EPIC-Norfolk Study
In the current study, they report on the performance of this phenotype as a screening tool for coronary heart disease among participants in the EPIC-Norfolk study, a population-based study involving 25 668 men and women aged 45 to 79 years in Norfolk, UK, who completed a baseline questionnaire and attended a clinic visit.
These two simple measurements are the cheapest way of finding those people who are at risk from this lousy lifestyle we now lead.
The hypertriglyceridemic-waist phenotype was defined as a waist circumference of 90 cm or more and a triglyceride level of 2.0 mmol/L or more in men and a waist circumference of 85 cm or more and a triglyceride level of 1.5 mmol/L or more in women.
Coronary artery disease developed in 2109 participants during the study follow-up. Compared with participants who had a waist circumference and triglyceride level below the threshold, those with the hypertriglyceridemic-waist phenotype had higher blood pressure, higher levels of apolipoprotein B and C-reactive protein, lower levels of HDL cholesterol and apolipoprotein A-I, and smaller LDL particles.
Both men and women with the hypertriglyceridemic-waist phenotype had an increased risk of developing heart disease than those who did not have the phenotype, and this increase remained significant after researchers accounted for traditional risk factors.
Hazard Ratio for Heart Disease With Hypertriglyceridemic-Waist Phenotype
Group Unadjusted HR (95% CI) Adjusted* HR (95% CI)
Men 2.40 (2.02–2.87) 1.28 (1.07–1.54)
Women 3.84 (3.20–4.62) 1.67 (1.35–2.06)
*Adjusted for age, total cholesterol level, HDL, systolic blood pressure, smoking status, and presence of diabetes
Després believes the measurement of triglycerides and waist is particularly important to pick up patients who have normal traditional risk scores. "If they have hypertension or diabetes or raised cholesterol, they will be picked up with traditional methods, but we found in our study that patients with normal values on traditional risk scores had double or triple the risk of developing heart disease if they had hypertriglyceridemic waist. It is these people who are slipping through the net at the moment but can be easily identified with these two simple tests," he added.
Triglyceride and Waist Measurements Predict Heart-Disease Risk
Sue Hughes
July 19, 2010 (Quebec, Quebec City) — Using two simple and inexpensive measurements--triglycerides and waist circumference--can identify patients with intra-abdominal obesity who have an increased risk of coronary artery disease and can add value in detecting risk of heart disease when used with traditional risk models such as Framingham, a new study suggests.
The study, published online July 19, 2010 in the Canadian Medical Association Journal, was conducted by a team led by Dr Benoit Arsenault (l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, QC).
A Step Beyond Metabolic Syndrome?
Coauthor Dr Jean Pierre Després (l'Institut Universitaire de Cardiologie et de Pneumologie de Québec) told heartwire that he believes the combination of a large waist measurement plus high triglyceride level, termed the "hypertriglyceridemic-waist phenotype," is the next step beyond metabolic syndrome.
"We are not proposing that this is a new definition of metabolic syndrome. But we are suggesting that this is a new phenomenon beyond the metabolic syndrome that can identify individuals at increased risk of heart disease who may fall through the net if we just use traditional risk factors," he said.
This is a new phenomenon beyond the metabolic syndrome that can identify individuals at increased risk of heart disease who may fall through the net if we just use traditional risk factors.
Metabolic syndrome, a condition that is the subject of much argument over its relevance, is defined as having three of the following risk factors: increased waist circumference, elevated triglycerides, reduced HDL cholesterol, elevated blood pressure, or elevated fasting glucose.
The latter three risk factors are normally measured as part of traditional risk evaluations for heart disease, so Després is saying that the focus should therefore be on waist and triglycerides, which have now been shown to add value over and above traditional risk factors.
"These two simple measurements are the cheapest way of finding those people who are at risk from this lousy lifestyle we now lead--those with visceral obesity and related metabolic disorders. Because it is measuring the two components of the metabolic syndrome not captured by Framingham or other traditional risk scores, it is picking up the risk of metabolic syndrome not found by those traditional scores," he added.
In the paper, the authors explain that although obesity is a health hazard, not every obese person has the expected metabolic abnormalities associated with excess body fat, and these tend to occur more often in those people with an excess of intra-abdominal or visceral adipose tissue. They have previously proposed that waist circumference can be used as an easy measurement of intra-abdominal adiposity, with elevated triglyceride levels further identifying "dysfunctional" adipose tissue. They suggest that hypertriglyceridemia combined with an increased waistline could be a marker of lipid overflow resulting from a relative defect of adipose tissue to clear and store the excess triglycerides from overeating and lack of physical activity.
EPIC-Norfolk Study
In the current study, they report on the performance of this phenotype as a screening tool for coronary heart disease among participants in the EPIC-Norfolk study, a population-based study involving 25 668 men and women aged 45 to 79 years in Norfolk, UK, who completed a baseline questionnaire and attended a clinic visit.
These two simple measurements are the cheapest way of finding those people who are at risk from this lousy lifestyle we now lead.
The hypertriglyceridemic-waist phenotype was defined as a waist circumference of 90 cm or more and a triglyceride level of 2.0 mmol/L or more in men and a waist circumference of 85 cm or more and a triglyceride level of 1.5 mmol/L or more in women.
Coronary artery disease developed in 2109 participants during the study follow-up. Compared with participants who had a waist circumference and triglyceride level below the threshold, those with the hypertriglyceridemic-waist phenotype had higher blood pressure, higher levels of apolipoprotein B and C-reactive protein, lower levels of HDL cholesterol and apolipoprotein A-I, and smaller LDL particles.
Both men and women with the hypertriglyceridemic-waist phenotype had an increased risk of developing heart disease than those who did not have the phenotype, and this increase remained significant after researchers accounted for traditional risk factors.
Hazard Ratio for Heart Disease With Hypertriglyceridemic-Waist Phenotype
Group Unadjusted HR (95% CI) Adjusted* HR (95% CI)
Men 2.40 (2.02–2.87) 1.28 (1.07–1.54)
Women 3.84 (3.20–4.62) 1.67 (1.35–2.06)
*Adjusted for age, total cholesterol level, HDL, systolic blood pressure, smoking status, and presence of diabetes
Després believes the measurement of triglycerides and waist is particularly important to pick up patients who have normal traditional risk scores. "If they have hypertension or diabetes or raised cholesterol, they will be picked up with traditional methods, but we found in our study that patients with normal values on traditional risk scores had double or triple the risk of developing heart disease if they had hypertriglyceridemic waist. It is these people who are slipping through the net at the moment but can be easily identified with these two simple tests," he added.
Simple Tool May Identify Patients at Increased Risk for Adverse Drug Reaction
From Medscape Medical News
Simple Tool May Identify Patients at Increased Risk for Adverse Drug Reaction
Laurie Barclay, MD
July 19, 2010 — A simple tool may identify older patients at increased risk for an adverse drug reaction (ADR), according to the results of a study reported in the July 12 issue of Archives of Internal Medicine.
"Older patients are particularly vulnerable to drug-related illnesses because they are usually on multiple drug regimens, which expose them to the risk of drug interactions, and because age is associated with changes in pharmacokinetics and pharmacodynamics," write Graziano Onder, MD, PhD, from Catholic University of the Sacred Heart in Rome, Italy, and colleagues. "The aim of the present study was to develop and validate a method of identifying elderly patients who are at increased risk for an ...ADR."
To develop the GerontoNet ADR Risk Score, the investigators used data from 5936 patients in the Gruppo Italiano di Farmacoepidemiologia nell'Anziano (Italian Group of Pharmacoepidemiology in the Elderly). Mean age was 78.0 ± 7.2 years. The score was calculated with use of variables associated with ADRs, which were identified by a stepwise logistic regression analysis. In a validation study, the ADR risk score was validated in a sample of older adults admitted to 4 European university hospitals (n = 483; mean age, 80.3 ± 7.6 years).
ADRs occurred in 383 (6.5%) of the 5936 patients in the Gruppo Italiano di Farmacoepidemiologia nell'Anziano sample (derivation cohort). The strongest predictors of ADRs were used to compute the ADR risk score.
These were the number of drugs and history of ADR, followed by heart failure, liver disease, presence of 4 or more comorbid conditions, and kidney failure.
In the derivation cohort, the area under the receiver operator characteristic (ROC) curve, which measures risk score performance at predicting ADRs, was 0.71 (95% confidence interval [CI], 0.68 - 0.73). Of 483 patients in the validation study, 56 (11.6%) had an ADR. In this sample, the area under the ROC curve was 0.70 (95% CI, 0.63 - 0.78).
"This study proposes a practical and simple method of identifying patients who are at an increased risk of an ADR," the study authors write. "This approach may be useful in clinical practice as a tool to identify patients at risk and in research to target a population that can benefit from interventions aimed to reduce drug-related illness."
Limitations of this study include lack of generalizability to younger persons who are living in the community or to those in different countries, and small sample size in the validation study.
In an accompanying invited commentary, Edward L. Schneider, MD, and Vito M. Campese, MD, from University of Southern California, Los Angeles, suggest some practical strategies for reducing ADRs. These include increased use of geriatric expertise, computerized physician entry of prescription orders, and increased communication between physicians and pharmacists.
"We applaud Onder and colleagues for devising a score to assist physicians in preventing ADRs in the older population and encourage other clinician scientists to become engaged in combating this serious menace to the health and well-being of today's and tomorrow's seniors," Drs. Schneider and Campese write.
This study was funded by a grant from the GerontoNet Group, a network of academic departments of geriatric medicine in the European Union, supported by Servier. The study authors have disclosed no relevant financial relationships.
Arch Intern Med. 2010;170:1142-1148, 1148-1149.
Simple Tool May Identify Patients at Increased Risk for Adverse Drug Reaction
Laurie Barclay, MD
July 19, 2010 — A simple tool may identify older patients at increased risk for an adverse drug reaction (ADR), according to the results of a study reported in the July 12 issue of Archives of Internal Medicine.
"Older patients are particularly vulnerable to drug-related illnesses because they are usually on multiple drug regimens, which expose them to the risk of drug interactions, and because age is associated with changes in pharmacokinetics and pharmacodynamics," write Graziano Onder, MD, PhD, from Catholic University of the Sacred Heart in Rome, Italy, and colleagues. "The aim of the present study was to develop and validate a method of identifying elderly patients who are at increased risk for an ...ADR."
To develop the GerontoNet ADR Risk Score, the investigators used data from 5936 patients in the Gruppo Italiano di Farmacoepidemiologia nell'Anziano (Italian Group of Pharmacoepidemiology in the Elderly). Mean age was 78.0 ± 7.2 years. The score was calculated with use of variables associated with ADRs, which were identified by a stepwise logistic regression analysis. In a validation study, the ADR risk score was validated in a sample of older adults admitted to 4 European university hospitals (n = 483; mean age, 80.3 ± 7.6 years).
ADRs occurred in 383 (6.5%) of the 5936 patients in the Gruppo Italiano di Farmacoepidemiologia nell'Anziano sample (derivation cohort). The strongest predictors of ADRs were used to compute the ADR risk score.
These were the number of drugs and history of ADR, followed by heart failure, liver disease, presence of 4 or more comorbid conditions, and kidney failure.
In the derivation cohort, the area under the receiver operator characteristic (ROC) curve, which measures risk score performance at predicting ADRs, was 0.71 (95% confidence interval [CI], 0.68 - 0.73). Of 483 patients in the validation study, 56 (11.6%) had an ADR. In this sample, the area under the ROC curve was 0.70 (95% CI, 0.63 - 0.78).
"This study proposes a practical and simple method of identifying patients who are at an increased risk of an ADR," the study authors write. "This approach may be useful in clinical practice as a tool to identify patients at risk and in research to target a population that can benefit from interventions aimed to reduce drug-related illness."
Limitations of this study include lack of generalizability to younger persons who are living in the community or to those in different countries, and small sample size in the validation study.
In an accompanying invited commentary, Edward L. Schneider, MD, and Vito M. Campese, MD, from University of Southern California, Los Angeles, suggest some practical strategies for reducing ADRs. These include increased use of geriatric expertise, computerized physician entry of prescription orders, and increased communication between physicians and pharmacists.
"We applaud Onder and colleagues for devising a score to assist physicians in preventing ADRs in the older population and encourage other clinician scientists to become engaged in combating this serious menace to the health and well-being of today's and tomorrow's seniors," Drs. Schneider and Campese write.
This study was funded by a grant from the GerontoNet Group, a network of academic departments of geriatric medicine in the European Union, supported by Servier. The study authors have disclosed no relevant financial relationships.
Arch Intern Med. 2010;170:1142-1148, 1148-1149.
Friday, July 16, 2010
Heart-Healthy Lifestyle Change Usually Requires Combinations of Cognitive Approaches
From Heartwire
Reed Miller
July 14, 2010 (Dallas, Texas) — A program of counseling with extended follow-up in conjunction with self-monitoring and goal-setting is the best approach to affecting sustainable lifestyle changes to reduce cardiovascular risk, according to a new scientific statement from the American Heart Association [1].
The new statement, published online July 12, 2010 in Circulation, was created by the AHA's Prevention Committee of the Council on Cardiovascular Nursing. It is based on analyses of 74 studies of US adults between January 1997 and May 2007, measuring effects of behavioral change on blood pressure, cholesterol levels, physical activity and fitness, and diet, including intake of fat, calories, salt, fiber, and fruits and vegetables.
Council chair Dr Nancy Artinian (Wayne State University, Detroit, MI) told heartwire the key finding of the council's review is that risk-factor mitigation plans that integrate more than one cognitive lifestyle change approach are more likely to be successful than those focused on just one. An example of a cognitive behavior change strategies includes patients setting specific and attainable goals such as a particular weight-loss target. Another is self-monitoring--patients are also more likely to succeed if they monitor their progress by, for example, weighing themselves regularly or keeping a log of what they eat.
Providers can help patients meet their goals by staying in contact and routinely providing feedback. For example, the doctor can encourage patients to stick with their plan by showing them how their weight loss has reduced their blood pressure and pointing out how their symptoms of hypertension have disappeared as a result, Artinian explained.
On the other hand, nonindividualized efforts to influence patient behavior do not usually work, Artinian said. "We've learned that just using brochures or paper information that is not personalized to the individual is probably not going to work . . . unless they can personalize it to their own life, and they're probably going to need some help doing that."
The research summarized in the statement confirms that minorities and individuals of low socioeconomic background are often at more risk for heart disease. Fortunately, "we've also learned there are interventions that do work for all [people], but those interventions or lifestyle change adaptations may need to be culturally adapted for use with a minority group."
The statement doesn't include any specific public-policy recommendations, but "we know we're going to need some healthcare policy changes, within the healthcare system," Artinian said. "We need to make it easier for healthcare providers to focus on prevention and help people work through lifestyle changes, because at the moment, healthcare providers face a lot of barriers. We all live in toxic environments. It's very difficult to stay healthy these days."
As examples of positive public-policy changes, in its release about the new scientific statement, AHA cites provisions in the latest federal healthcare reform legislation that will provide more reimbursement to support prevention services like lifestyle counseling [2]. The organization also commends proposals to improve product packaging and restaurant menus to help individuals make better choices.
"I'm looking forward to the future when we will have a healthcare system that gives more weight to the importance of prevention and changing lifestyle behaviors to help people stay healthy and reduce cardiovascular risk," Artinian said.
Artinian said the impetus to write the statement was the realization "that healthcare providers were very good about telling patients that they need to make lifestyle changes, and there was a great deal of evidence that high-risk factors are going to increase morbidity and mortality, but what we didn't know a lot about, and what healthcare providers needed assistance with, is helping patients translate that behavior into their everyday life. It's very difficult for people to change behavior and maintain it over a lifetime.
"When we started out doing this, we didn't know a thing about anything, and everybody said the studies are so diverse that we're never going to be able to home in and make sense of everything," she recalled. "So the fact that we did weed through all of the studies and work together and come up with recommendations was maybe a little bit surprising. . . . But now we have a consensus."
References
Reed Miller
July 14, 2010 (Dallas, Texas) — A program of counseling with extended follow-up in conjunction with self-monitoring and goal-setting is the best approach to affecting sustainable lifestyle changes to reduce cardiovascular risk, according to a new scientific statement from the American Heart Association [1].
The new statement, published online July 12, 2010 in Circulation, was created by the AHA's Prevention Committee of the Council on Cardiovascular Nursing. It is based on analyses of 74 studies of US adults between January 1997 and May 2007, measuring effects of behavioral change on blood pressure, cholesterol levels, physical activity and fitness, and diet, including intake of fat, calories, salt, fiber, and fruits and vegetables.
Council chair Dr Nancy Artinian (Wayne State University, Detroit, MI) told heartwire the key finding of the council's review is that risk-factor mitigation plans that integrate more than one cognitive lifestyle change approach are more likely to be successful than those focused on just one. An example of a cognitive behavior change strategies includes patients setting specific and attainable goals such as a particular weight-loss target. Another is self-monitoring--patients are also more likely to succeed if they monitor their progress by, for example, weighing themselves regularly or keeping a log of what they eat.
Providers can help patients meet their goals by staying in contact and routinely providing feedback. For example, the doctor can encourage patients to stick with their plan by showing them how their weight loss has reduced their blood pressure and pointing out how their symptoms of hypertension have disappeared as a result, Artinian explained.
On the other hand, nonindividualized efforts to influence patient behavior do not usually work, Artinian said. "We've learned that just using brochures or paper information that is not personalized to the individual is probably not going to work . . . unless they can personalize it to their own life, and they're probably going to need some help doing that."
The research summarized in the statement confirms that minorities and individuals of low socioeconomic background are often at more risk for heart disease. Fortunately, "we've also learned there are interventions that do work for all [people], but those interventions or lifestyle change adaptations may need to be culturally adapted for use with a minority group."
The statement doesn't include any specific public-policy recommendations, but "we know we're going to need some healthcare policy changes, within the healthcare system," Artinian said. "We need to make it easier for healthcare providers to focus on prevention and help people work through lifestyle changes, because at the moment, healthcare providers face a lot of barriers. We all live in toxic environments. It's very difficult to stay healthy these days."
As examples of positive public-policy changes, in its release about the new scientific statement, AHA cites provisions in the latest federal healthcare reform legislation that will provide more reimbursement to support prevention services like lifestyle counseling [2]. The organization also commends proposals to improve product packaging and restaurant menus to help individuals make better choices.
"I'm looking forward to the future when we will have a healthcare system that gives more weight to the importance of prevention and changing lifestyle behaviors to help people stay healthy and reduce cardiovascular risk," Artinian said.
Artinian said the impetus to write the statement was the realization "that healthcare providers were very good about telling patients that they need to make lifestyle changes, and there was a great deal of evidence that high-risk factors are going to increase morbidity and mortality, but what we didn't know a lot about, and what healthcare providers needed assistance with, is helping patients translate that behavior into their everyday life. It's very difficult for people to change behavior and maintain it over a lifetime.
"When we started out doing this, we didn't know a thing about anything, and everybody said the studies are so diverse that we're never going to be able to home in and make sense of everything," she recalled. "So the fact that we did weed through all of the studies and work together and come up with recommendations was maybe a little bit surprising. . . . But now we have a consensus."
References
Lifestyle Factors Do Not Influence Genetic Risk for Breast Cancer
From Medscape Medical News
Zosia Chustecka
June 2, 2010 — A large analysis of data from the British Million Women Study has found no interaction between environmental risk factors for breast cancer and common low-penetrance susceptibility single-nucleotide polymorphisms (SNPs) that have been associated with breast cancer risk. The new study is published online June 2 in The Lancet.
This study looked at 12 SNPs that have been associated with breast cancer in published genome-wide association studies that have reported a small increase in the risk for breast cancer (relative risk of around 1.2 per allele). The study did not did not investigate BRCA1 and BRCA2 genes, which confer a much higher risk for breast cancer but are found in a relatively smaller number of women.
"We looked at whether lifestyle factors for breast cancer, such as hormone-replacement therapy (HRT), alcohol consumption, and reproductive history, influence the genetic risk. The answer is, they do not," said lead author Ruth Travis, DPhil, from the Cancer Epidemiology Unit at Oxford University, United Kingdom, in a statement.
"This study provides another piece in the jigsaw, helping us to understand how genes and lifestyle affect breast cancer risk," added coauthor Jane Green, MD, from the same unit. "Genes account for only a small proportion of breast cancers and, for most women, the main risk factors remain the lifestyle factors, such as childbearing, use of HRT, obesity, and alcohol consumption. The good news is that some of these are modifiable, so by changing their behavior women can alter their risk of breast cancer."
Testing Gene–Environment Interactions
The researchers used data collected in the Million Women Study, which involved 1.3 million middle-aged women (mean age, 56 years) who had been invited for a routine mammogram from 1996 to 2001. They identified 7610 women who developed breast cancer, and compared them with 10,196 control subjects without the disease.
The team then tested for interactions between 12 polymorphisms that had previously been associated with breast cancer and 10 environmental risk factors for breast cancer (age at menarche, parity, age at first delivery, breast-feeding, menopausal status, age at menopause, use of HRT, body mass index, height, and alcohol consumption). The researchers note that the effects of most of these 10 environmental factors on breast cancer incidence have already been shown to be highly significant for the entire Million Women Study cohort.
There was no convincing evidence for any gene–environment interactions, the team reports.
"Most of the environmental factors are more strongly associated with breast cancer risk than are the genotypic factors we studied" note the researchers. "Current use of HRT is the strongest environmental risk factor in this cohort . . . and the associated relative risks are much greater than for any of the SNPs studied here," they add.
"The function of most of the SNPs is unclear, and future investigations might show them to be only markers of true causal variants," they add.
The authors note that, since they designed their study, another 5 SNPs associated with breast cancer have been identified, although the associated relative risk for breast cancer is not large.
"Of course, there are always more SNPs to study, but to date, none of these seem to contribute to breast cancer in a big way," says Steven Narod, MD, from the Women's College Research Institute in Toronto, Ontario, in an accompanying editorial.
The SNP approach might have been "oversold," he suggests. "Others have come to the conclusion that SNPs, alone or in combination, are not that helpful in predicting cancer risk."
Recently, several experts have expressed concern over the advertising of genetic-susceptibility tests based on SNPs that are sold directly to the general public, as previously reported by Medscape Oncology.
Coming back to the issue of preventive oncology, Dr. Narod says that the crucial question that remains is why having a baby at age 25 should influence the risk for breast cancer at age 65.
"Unfortunately the genes studied here do not provide any new clues," he concludes.
The authors and editorialist have disclosed no relevant financial relationships.
Lancet. Published online June 2, 2010.
Zosia Chustecka
June 2, 2010 — A large analysis of data from the British Million Women Study has found no interaction between environmental risk factors for breast cancer and common low-penetrance susceptibility single-nucleotide polymorphisms (SNPs) that have been associated with breast cancer risk. The new study is published online June 2 in The Lancet.
This study looked at 12 SNPs that have been associated with breast cancer in published genome-wide association studies that have reported a small increase in the risk for breast cancer (relative risk of around 1.2 per allele). The study did not did not investigate BRCA1 and BRCA2 genes, which confer a much higher risk for breast cancer but are found in a relatively smaller number of women.
"We looked at whether lifestyle factors for breast cancer, such as hormone-replacement therapy (HRT), alcohol consumption, and reproductive history, influence the genetic risk. The answer is, they do not," said lead author Ruth Travis, DPhil, from the Cancer Epidemiology Unit at Oxford University, United Kingdom, in a statement.
"This study provides another piece in the jigsaw, helping us to understand how genes and lifestyle affect breast cancer risk," added coauthor Jane Green, MD, from the same unit. "Genes account for only a small proportion of breast cancers and, for most women, the main risk factors remain the lifestyle factors, such as childbearing, use of HRT, obesity, and alcohol consumption. The good news is that some of these are modifiable, so by changing their behavior women can alter their risk of breast cancer."
Testing Gene–Environment Interactions
The researchers used data collected in the Million Women Study, which involved 1.3 million middle-aged women (mean age, 56 years) who had been invited for a routine mammogram from 1996 to 2001. They identified 7610 women who developed breast cancer, and compared them with 10,196 control subjects without the disease.
The team then tested for interactions between 12 polymorphisms that had previously been associated with breast cancer and 10 environmental risk factors for breast cancer (age at menarche, parity, age at first delivery, breast-feeding, menopausal status, age at menopause, use of HRT, body mass index, height, and alcohol consumption). The researchers note that the effects of most of these 10 environmental factors on breast cancer incidence have already been shown to be highly significant for the entire Million Women Study cohort.
There was no convincing evidence for any gene–environment interactions, the team reports.
"Most of the environmental factors are more strongly associated with breast cancer risk than are the genotypic factors we studied" note the researchers. "Current use of HRT is the strongest environmental risk factor in this cohort . . . and the associated relative risks are much greater than for any of the SNPs studied here," they add.
"The function of most of the SNPs is unclear, and future investigations might show them to be only markers of true causal variants," they add.
The authors note that, since they designed their study, another 5 SNPs associated with breast cancer have been identified, although the associated relative risk for breast cancer is not large.
"Of course, there are always more SNPs to study, but to date, none of these seem to contribute to breast cancer in a big way," says Steven Narod, MD, from the Women's College Research Institute in Toronto, Ontario, in an accompanying editorial.
The SNP approach might have been "oversold," he suggests. "Others have come to the conclusion that SNPs, alone or in combination, are not that helpful in predicting cancer risk."
Recently, several experts have expressed concern over the advertising of genetic-susceptibility tests based on SNPs that are sold directly to the general public, as previously reported by Medscape Oncology.
Coming back to the issue of preventive oncology, Dr. Narod says that the crucial question that remains is why having a baby at age 25 should influence the risk for breast cancer at age 65.
"Unfortunately the genes studied here do not provide any new clues," he concludes.
The authors and editorialist have disclosed no relevant financial relationships.
Lancet. Published online June 2, 2010.
Tuesday, July 13, 2010
Weight Loss Linked to Improvements in Hot Flushes in Overweight, Obese Women
From Medscape Medical News
Laurie Barclay, MD
July 12, 2010 — Weight loss is linked to improvements in hot flushes in overweight and obese women, according to the results of a randomized controlled trial reported in the July 12 issue of Archives of Internal Medicine.
"Higher body mass index is associated with worse hot flushes during menopause but the effect of weight loss on flushing is unclear," write Alison J. Huang, MD, from the University of California, San Francisco, and colleagues from the Program to Reduce Incontinence by Diet and Exercise investigators. "Hot flushes are among the most common concerns of women during menopause and persist for five or more years past menopause in as many as one-third of women."
Women who were overweight or obese and had urinary incontinence (n = 338) were randomly assigned to an intensive behavioral weight loss program (intervention) or to a structured health education program (control) for 6 months.
The intensive intervention, which included weekly 1-hour group sessions with experts in nutrition, exercise, and behavior change, was intended to result in an average loss of 7% to 9% of baseline weight by 6 months. By brisk walking or similarly intense activities, participants were encouraged to increase physical activity to at least 200 minutes per week. A reduced-calorie diet (1200 - 1500 calories) was also recommended, and women were offered sample meal plans with appropriate food choices and meal-replacement products.
Hot flushes were evaluated with use of self-administered questionnaires, and weight, body mass index, abdominal circumference, physical activity, caloric intake, blood pressure, and physical and mental function were evaluated at baseline and at 6 months. Effects of the intervention on bothersome hot flushes and potential mediating factors were determined with use of repeated-measures proportional odds models.
At baseline, hot flushes were slightly bothersome in nearly half of women (n = 154). Compared with control, the intervention improved bothersome flushes in more than twice as many women (odds ratio [OR] for improvement by 1 Likert category, 2.25; 95% confidence interval [CI], 1.20 - 4.21). After adjustment for multiple potential mediators, the effect of the intervention on flushing was modestly decreased (OR, 1.92; 95% CI, 0.95 - 3.89).
Weight loss was associated with improvement in hot flushes (OR, 1.32; 95% CI, 1.08 - 1.61; per 5-kg decrease), as were body mass index (OR, 1.17; 95% CI, 1.05 - 1.30; per 1-point decrease) and abdominal circumference (OR, 1.32; 95% CI, 1.07 - 1.64; per 5-cm decrease). However, changes in physical activity, calorie intake, blood pressure, and physical and mental functioning had no effect on hot flushes.
"Among women who were overweight or obese and had bothersome hot flushes, an intensive behavioural weight loss intervention resulted in improvement in flushing relative to control," the study authors write.
Limitations of this study include inability to determine the effects of specific nutrient components or the timing of meals, limited generalizability to women without incontinence, assessment of hot flushes by a single self-report, and a greater proportion of women lost to follow-up in the control group vs the intervention group.
"From a clinical perspective, our findings suggest that women who are overweight or obese and have bothersome hot flushes may be counseled that behavioral weight loss efforts may decrease the burden of their symptoms," the study authors conclude. "Further research is needed to assess for other biophysiologic factors associated with weight loss that may influence these symptoms in women who are overweight or obese. It should also evaluate whether women's perceptions of self-management success while attempting to change their lifestyle or lose weight may modify their experience of these symptoms."
The National Institute of Diabetes and Digestive and Kidney Disease, the Office of Research on Women's Health, and the National Center for Research Resources, a component of the Clinical and Translational Science Award for Medical Research at the National Institutes of Health supported this study.
Laurie Barclay, MD
July 12, 2010 — Weight loss is linked to improvements in hot flushes in overweight and obese women, according to the results of a randomized controlled trial reported in the July 12 issue of Archives of Internal Medicine.
"Higher body mass index is associated with worse hot flushes during menopause but the effect of weight loss on flushing is unclear," write Alison J. Huang, MD, from the University of California, San Francisco, and colleagues from the Program to Reduce Incontinence by Diet and Exercise investigators. "Hot flushes are among the most common concerns of women during menopause and persist for five or more years past menopause in as many as one-third of women."
Women who were overweight or obese and had urinary incontinence (n = 338) were randomly assigned to an intensive behavioral weight loss program (intervention) or to a structured health education program (control) for 6 months.
The intensive intervention, which included weekly 1-hour group sessions with experts in nutrition, exercise, and behavior change, was intended to result in an average loss of 7% to 9% of baseline weight by 6 months. By brisk walking or similarly intense activities, participants were encouraged to increase physical activity to at least 200 minutes per week. A reduced-calorie diet (1200 - 1500 calories) was also recommended, and women were offered sample meal plans with appropriate food choices and meal-replacement products.
Hot flushes were evaluated with use of self-administered questionnaires, and weight, body mass index, abdominal circumference, physical activity, caloric intake, blood pressure, and physical and mental function were evaluated at baseline and at 6 months. Effects of the intervention on bothersome hot flushes and potential mediating factors were determined with use of repeated-measures proportional odds models.
At baseline, hot flushes were slightly bothersome in nearly half of women (n = 154). Compared with control, the intervention improved bothersome flushes in more than twice as many women (odds ratio [OR] for improvement by 1 Likert category, 2.25; 95% confidence interval [CI], 1.20 - 4.21). After adjustment for multiple potential mediators, the effect of the intervention on flushing was modestly decreased (OR, 1.92; 95% CI, 0.95 - 3.89).
Weight loss was associated with improvement in hot flushes (OR, 1.32; 95% CI, 1.08 - 1.61; per 5-kg decrease), as were body mass index (OR, 1.17; 95% CI, 1.05 - 1.30; per 1-point decrease) and abdominal circumference (OR, 1.32; 95% CI, 1.07 - 1.64; per 5-cm decrease). However, changes in physical activity, calorie intake, blood pressure, and physical and mental functioning had no effect on hot flushes.
"Among women who were overweight or obese and had bothersome hot flushes, an intensive behavioural weight loss intervention resulted in improvement in flushing relative to control," the study authors write.
Limitations of this study include inability to determine the effects of specific nutrient components or the timing of meals, limited generalizability to women without incontinence, assessment of hot flushes by a single self-report, and a greater proportion of women lost to follow-up in the control group vs the intervention group.
"From a clinical perspective, our findings suggest that women who are overweight or obese and have bothersome hot flushes may be counseled that behavioral weight loss efforts may decrease the burden of their symptoms," the study authors conclude. "Further research is needed to assess for other biophysiologic factors associated with weight loss that may influence these symptoms in women who are overweight or obese. It should also evaluate whether women's perceptions of self-management success while attempting to change their lifestyle or lose weight may modify their experience of these symptoms."
The National Institute of Diabetes and Digestive and Kidney Disease, the Office of Research on Women's Health, and the National Center for Research Resources, a component of the Clinical and Translational Science Award for Medical Research at the National Institutes of Health supported this study.
Monday, July 12, 2010
Cardiorespiratory Aerobic Exercise May Be Helpful in Rheumatoid Arthritis
From MedscapeCME Clinical Briefs
News Author: Laurie Barclay, MD
CME Author: Laurie Barclay, MD
Arthritis Care Res. 2010;62:984-992.
Clinical Context
June 30, 2010 — Cardiorespiratory aerobic exercise may be safe and modestly beneficial in patients with rheumatoid arthritis (RA), according to the results of a meta-analysis of randomized controlled trials (RCTs) reported in the July issue of Arthritis Care & Research.
"Several lines of evidence have emphasized an improvement in aerobic capacity and muscle strength after physical exercise programs in ...RA patients," write Athan Baillet, MS, from University of Grenoble Medical School in Grenoble, France, and colleagues. "Our objective was to evaluate the efficacy of aerobic exercises in RA on quality of life, function, and clinical and radiological outcomes by a systematic literature review and a meta-analysis."
The reviewers searched MEDLINE, EMBASE, and Cochrane databases up to July 2009, as well as abstracts presented in the past 5 years at rheumatology scientific meetings, for RCTs of aerobic exercises vs nonaerobic interventions in patients with RA. Study endpoints included postintervention quality of life, Health Assessment Questionnaire (HAQ) evaluation of function, pain measured with a visual analog scale (VAS), joint count, Disease Activity Score in 28 joints (DAS28), and radiologic damage.
Efficacy of aerobic exercises vs nonaerobic interventions was determined with use of standardized mean differences (SMDs). The investigators assessed the heterogeneity of included trials and pooled SMDs for meta-analysis using the inverse of variance model.
There were 14 RCTs, enrolling a total of 1040 patients, meeting selection criteria. Benefits associated with the exercise intervention included improved postintervention quality of life (SMD, 0.39; P < .0001), better HAQ score (SMD, 0.24; P = .0009), lower pain VAS (SMD, 0.31; P = .02), and less radiologic damage. Both groups had similar global compliance, DAS28, adverse events, and joint count, suggesting safety of the exercise intervention.
"Cardiorespiratory aerobic conditioning in stable RA appears to be safe and improves some of the most important outcome measures," the review authors write. "However, the degree of the effect of aerobic exercise on the abovementioned parameters is small."
Limitations of this review include potential bias related to data extraction by a single reviewer, lack of blinding of outcome evaluators in some studies, and lack of analysis of the effect of baseline activity. In addition, this review could not determine optimal exercise intensity, duration, frequency, and type, and the findings could not be generalized to older patients with RA.
"Besides the positive effect of the intervention on patients' psychological well-being, aerobic exercise should be considered as a safe therapy, the efficacy of which has been underestimated," the review authors conclude. "The clinically meaningful and economic impact of such treatment must be investigated in further trials in order to clearly define the place of aerobic exercises in RA management."
An unrestricted educational grant from Abbott France supported this review.
Arthritis Care Res. 2010;62:984-992.
Although pharmacotherapy is the mainstay of RA treatment, physical therapy is important in maintaining joint mobility and muscle strength. In patients with RA, evidence to date suggests that physical exercise programs may improve aerobic capacity as well as muscle strength.
Previously, patients with RA were not encouraged to participate in weight-bearing exercise, which was thought to increase disease activity and joint damage. However, an RCT showed that an exercise program was more beneficial than conventional joint therapy in disability and quality of life.
News Author: Laurie Barclay, MD
CME Author: Laurie Barclay, MD
Arthritis Care Res. 2010;62:984-992.
Clinical Context
June 30, 2010 — Cardiorespiratory aerobic exercise may be safe and modestly beneficial in patients with rheumatoid arthritis (RA), according to the results of a meta-analysis of randomized controlled trials (RCTs) reported in the July issue of Arthritis Care & Research.
"Several lines of evidence have emphasized an improvement in aerobic capacity and muscle strength after physical exercise programs in ...RA patients," write Athan Baillet, MS, from University of Grenoble Medical School in Grenoble, France, and colleagues. "Our objective was to evaluate the efficacy of aerobic exercises in RA on quality of life, function, and clinical and radiological outcomes by a systematic literature review and a meta-analysis."
The reviewers searched MEDLINE, EMBASE, and Cochrane databases up to July 2009, as well as abstracts presented in the past 5 years at rheumatology scientific meetings, for RCTs of aerobic exercises vs nonaerobic interventions in patients with RA. Study endpoints included postintervention quality of life, Health Assessment Questionnaire (HAQ) evaluation of function, pain measured with a visual analog scale (VAS), joint count, Disease Activity Score in 28 joints (DAS28), and radiologic damage.
Efficacy of aerobic exercises vs nonaerobic interventions was determined with use of standardized mean differences (SMDs). The investigators assessed the heterogeneity of included trials and pooled SMDs for meta-analysis using the inverse of variance model.
There were 14 RCTs, enrolling a total of 1040 patients, meeting selection criteria. Benefits associated with the exercise intervention included improved postintervention quality of life (SMD, 0.39; P < .0001), better HAQ score (SMD, 0.24; P = .0009), lower pain VAS (SMD, 0.31; P = .02), and less radiologic damage. Both groups had similar global compliance, DAS28, adverse events, and joint count, suggesting safety of the exercise intervention.
"Cardiorespiratory aerobic conditioning in stable RA appears to be safe and improves some of the most important outcome measures," the review authors write. "However, the degree of the effect of aerobic exercise on the abovementioned parameters is small."
Limitations of this review include potential bias related to data extraction by a single reviewer, lack of blinding of outcome evaluators in some studies, and lack of analysis of the effect of baseline activity. In addition, this review could not determine optimal exercise intensity, duration, frequency, and type, and the findings could not be generalized to older patients with RA.
"Besides the positive effect of the intervention on patients' psychological well-being, aerobic exercise should be considered as a safe therapy, the efficacy of which has been underestimated," the review authors conclude. "The clinically meaningful and economic impact of such treatment must be investigated in further trials in order to clearly define the place of aerobic exercises in RA management."
An unrestricted educational grant from Abbott France supported this review.
Arthritis Care Res. 2010;62:984-992.
Although pharmacotherapy is the mainstay of RA treatment, physical therapy is important in maintaining joint mobility and muscle strength. In patients with RA, evidence to date suggests that physical exercise programs may improve aerobic capacity as well as muscle strength.
Previously, patients with RA were not encouraged to participate in weight-bearing exercise, which was thought to increase disease activity and joint damage. However, an RCT showed that an exercise program was more beneficial than conventional joint therapy in disability and quality of life.
Sunday, July 11, 2010
Hormonal therapy & menopause
Hormone Therapy in Postmenopausal Women: 2010 NAMS Position Statement: Benefits and Risks of HT
Benefits and Risks of HT
Confusion can arise among healthcare providers, the lay public, and the media when general concepts of risk are discussed. Understanding HT risks in particular is critical to clinical decision making around menopause and beyond. Because these issues are crucial to a discussion of the role of HT in an individual woman, a special addendum to the 2008 paper was added in this paper to address risk concepts (see Addendum A at http://www.menopause.org/PSHT08.pdf).
Use of HT should be consistent with treatment goals, benefits, and risks for the individual woman. The benefit-risk ratio for an individual woman continually changes with her age and her menopause-related symptoms (eg, vasomotor symptoms, sleep disturbance, vaginal atrophy, dyspareunia, or diminished libido), any of which may have an adverse impact on quality of life (QOL). Risk factors are related to: a woman's baseline disease risks, her age, age at menopause, cause of menopause, time since menopause, and prior use of any hormone including type, route of administration, dose, and medical conditions that emerged during treatment.
Potential benefits and risks are described below for the relevant clinical outcomes.
Vasomotor Symptoms
ET, with or without a progestogen, is the most effective treatment for menopause-related vasomotor symptoms (ie, hot flashes and night sweats) and their potential consequences (eg, diminished sleep quality, irritability, and reduced QOL). Treatment of moderate to severe vasomotor symptoms remains the primary indication for HT. Every systemic ET and EPT product has regulatory agency approval for this indication.
Maximizing the benefit and minimizing the risks of HT are addressed later in this paper. For example, using lower dose preparations has been associated with similar benefits in clinical trials and in some observational studies with lower risks.
Vaginal Symptoms
ET is the most effective treatment for moderate to severe symptoms of vulvar and vaginal atrophy (eg, vaginal dryness, dyspareunia, and atrophic vaginitis). Many systemic ET and EPT products and all local vaginal ET products have regulatory agency approval for treating these vaginal symptoms. Lower doses than previously used, and less frequent administration, often yield satisfactory results. Some systemic ultralow dose regimens may be inadequate for relief of vaginal symptoms. When HT is used for systemic vasomotor symptoms, enquiry about the adequacy of therapy for urogenital atrophy is important. When HT is considered solely for urogenital atrophy, local vaginal ET is generally recommended.
Sexual Function
Relief of moderate to severe vaginal atrophy with systemic or local HT can be effective in relieving dyspareunia, a common cause of intercourse avoidance. Local estrogen may improve coital satisfaction by improving lubrication and increasing blood flow and sensation in vaginal tissues. One oral systemic ET product is approved in the United States for the treatment of pain with intercourse. HT is not recommended as the sole treatment of other problems of sexual function, including diminished libido.
Urinary Health
Local ET may benefit some women with urge incontinence who have vaginal atrophy. Whether ET by any route is effective in treating overactive bladder is unclear. There is controversy as to whether local ET can improve certain cases of pure stress incontinence. On the other hand, systemic HT may worsen or provoke stress incontinence, perhaps related to changes in uterine volume or periurethral collagen.
Local ET may help reduce the risk of recurrent urinary tract infection (UTI) by a direct proliferative effect on the urethra and bladder epithelia, helping to restore the acidic environment and normal lactobacillus-predominant flora of the vagina, and thus discouraging colonization of the vagina by pathogens associated with UTI. Clinically, only ET administered by the vaginal route has been shown in an RCT to be effective in reducing the risk of recurrent UTI. However, no ET/EPT product has regulatory agency approval for any urinary health indication.
Change in Body Weight/Mass
Body mass index (BMI) increases with age in midlife, with the peak BMI occurring between ages 50 and 59. At this time of life, other factors may also contribute to weight gain, including a decrease in energy expenditure and an increase in energy intake coupled with a decrease in metabolic rate. In women, the hormonal changes associated with the menopause transition can affect body composition and add to the tendency to gain weight. No statistically significant difference in mean weight gain or BMI has been demonstrated between women who use HT and those who do not.
Quality of Life
Although no HT product has regulatory agency approval for enhancing QOL, an improvement in health-related quality of life (HQOL) can result with HT use because of decreased menopause symptoms and perhaps other mechanisms, including improved sleep and a possible elevation of mood that leads to a feeling of well-being. Whether HT improves HQOL in asymptomatic women is unknown, nor are data available to determine the effect of HT on global QOL (the sense of well-being with or without symptoms or physical impairments).
Osteoporosis
Bone strength depends on both bone quality and bone mineral density (BMD). Changes in BMD alone may not always reflect fracture risk. There is RCT evidence that HT reduces postmenopausal osteoporotic fractures, including hip fractures, even in women without osteoporosis, although no HT product has regulatory agency approval for treatment of osteoporosis. Many systemic HT products, however, have regulatory agency approval for prevention of postmenopausal osteoporosis through long-term treatment; a current list of these products can be found on the NAMS Web site (http://www.menopause.org/edumaterials/otcharts.pdf).
Extended use of HT is an option for women who have established reduction in bone mass, regardless of menopause symptoms; for prevention of further bone loss and/or reduction of osteoporotic fracture when alternate therapies are not appropriate or cause side effects; or when the benefits of extended use are expected to exceed the risks. The optimal time to initiate HT and the optimal duration of therapy have not been established, but HT would largely be used in the early years after menopause. The benefits of HT on bone mass dissipate quickly after discontinuation of treatment.
Cardiovascular Effects
Three primary cardiovascular effects are discussed: coronary heart disease (CHD), stroke, and venous thromboembolism (VTE).
Coronary Heart Disease Most observational and preclinical studies support the potential benefits of systemic HT in reducing the risk of CHD. Most RCTs do not. However, it is now understood that the characteristics of women participating in observational studies are markedly different from those of women enrolled in RCTs, and that some of these demographic or biologic differences, or both, influence baseline cardiovascular risks and may modify the effects of HT on cardiovascular risk.
Timing of Initiation. Data indicate that the disparity in findings between observational studies and RCTs is related in part to the timing of initiation of HT in relation to age and proximity to menopause. Most women studied in observational studies of CHD risk were younger than age 55 at the time HT was initiated and within 2 to 3 years of menopause. On the other hand, women enrolled to date in RCTs with clinical cardiovascular endpoints were an average of 63 to 64 years old and more than 10 years beyond menopause. When analyzed by age and time since menopause at initiation of HT, the ET arm of the WHI is in general agreement with observational studies indicating that ET may reduce CHD risk (coronary revascularization and composite outcomes) when initiated in younger and more recently postmenopausal women. In a secondary analysis of WHI data, there was a statistically significant reduction in the composite endpoint of myocardial infarction, coronary artery revascularization, and coronary death in women who were randomized to ET during ages 50 to 59. Combined data from both the ET and EPT trials of the WHI show a statistical trend of an HT effect relative to placebo on CHD by time since menopause, indicating that women who initiate HT more than 10 years beyond menopause are at increased risk for CHD, and those women who initiate HT within 10 years of menopause tend to have a lower risk of CHD. However, statistical modeling of the combined WHI data, including further data from WHI observational studies, did not find that CHD risks varied by the timing of HT initiation.
Duration of Therapy. Observational studies suggest that longer duration of HT use is associated with reduced risk of CHD and related mortality. The WHI RCTs and the WHI observational study suggest a pattern of lower risk of CHD among women who used HT for 5 or more years, but this is not conclusive, and should be considered in light of other factors altered by duration of therapy, such as breast cancer.
In contrast, in the short term, HT is associated with an increase in CHD risk among women who are more distant from menopause at the time of HT initiation.
Coronary Artery Calcium. Observational studies show that long-term HT is associated with less accumulation of coronary artery calcium, which is strongly correlated with atheromatous plaque burden and future risk of clinical CHD events. In an ancillary substudy of younger women (<60 y) in the WHI ET trial, after an average of 7 years of treatment, women who had been randomized to ET had lower levels of coronary artery calcium than those randomized to placebo. These findings suggest that ET initiated by recently postmenopausal women may slow the development of calcified atherosclerotic plaque.
Stroke Results of observational studies of the risk of stroke with HT have been inconsistent. Several studies (including the Nurses' Health Study [NHS], the largest prospective study of HT and stroke) indicated an increased risk of ischemic stroke consistent with the findings from the WHI, whereas other studies showed no effect on stroke risk. The WHI EPT and ET trials demonstrated an increased risk of ischemic stroke and no effect on risk of hemorrhagic stroke. In these trials, there were 8 additional strokes per 10,000 women per year of EPT and 11 additional strokes per 10,000 women per year of ET when the entire cohort was analyzed. In recent analyses that combined results from the WHI EPT and ET trials, HT in younger women (ages 50–59) at study entry had no significant effect on risk of stroke (relative risk [RR], 1.13; 95% confidence interval [CI], 0.73–1.76). In the Framingham Heart Study, natural menopause at age 42 or younger was associated with elevated risk of ischemic stroke.
In women randomized in the WHI within 5 years of menopause, there were 3 additional strokes per 10,000 women per year of EPT, which is not statistically significant. The excess risk of stroke in this age group observed in the WHI studies would fall into the "rare" risk category. Stroke risk was not significantly increased in the Heart and Estrogen/progestin Replacement Study (HERS) and Women's Estrogen for Stroke Trial (WEST) secondary prevention trials. The Women's International Study of long Duration Oestrogen after Menopause (WISDOM) RCT found no excess of stroke in EPT users compared with women on placebo in 1 year.
Findings of increased stroke risk are largely driven by effects of HT on ischemic stroke, as neither ET nor EPT seems to affect the risk of hemorrhagic stroke. However, with few women in younger age groups in the WHI trials, the CIs have been wide, which means that there was not significant statistical power to reach a conclusion. In the NHS, among women ages 50 to 59, the RR of stroke for current EPT users tended to be elevated (RR, 1.34; 95% CI, 0.84–2.13) and was significantly increased for current users of ET (RR, 1.58; 95% CI, 1.06–2.37). Lower doses of estrogen (eg, 0.3 mg CE) were not associated with an increased risk in the NHS, although this was based on the relatively few women who were taking lower doses.
No studies indicate that postmenopausal HT is effective for reducing the risk of a recurrent stroke among women with established cardiovascular disease (CVD) or for prevention of a first stroke, and it may increase the rate of first strokes particularly in women initiating HT over age 60. HT cannot be recommended for the primary or secondary prevention of stroke. Although stroke was not increased in the group ages 50 to 59 in the combined analysis of the WHI, it was almost doubled in the ET group less than 10 years since menopause. This apparent contradiction in the data is hard to explain, but may be due to relatively few events and the difficulty in accurately timing onset of menopause in the ET group.
Venous Thromboembolism Data from both observational studies and RCTs demonstrate an increased risk of VTE with oral HT. In the WHI trials, there were 18 additional VTEs per 10,000 women per year of EPT and 7 additional VTEs per 10,000 women per year of ET when the entire cohort was analyzed. VTE risk in RCTs emerges soon after HT initiation (ie, during the first 1–2 y), and the magnitude of the excess risk seems to decrease somewhat over time. In the WHI trials, the absolute excess VTE risk associated with either EPT or ET was lower in women who started HT before age 60 than in older women who initiated HT after age 60. There were 7 additional VTEs per 10,000 women per year of EPT and 4 additional VTEs per 10,000 women per year of ET in women ages 50 to 59 who were randomized to HT. These risks fall into the rare risk category. The baseline risk of VTE also increases relative to BMI. For obese women (BMI >30), the baseline risk was almost threefold greater. At any BMI, the risk of VTE doubled with HT, and returned to baseline soon after HT discontinuation.
Growing evidence suggests that women with a prior history of VTE or women who possess factor V Leiden are at increased risk for VTE with HT use. There are limited observational data suggesting lower risks of VTE with transdermal than with oral ET, but there are no comparative RCT data on this subject. Lower doses of oral ET may also confer less VTE risk than higher doses, but no comparative RCT data are available to confirm this assumption.
Cardiovascular Effects Conclusion HT is currently not recommended as a sole or primary indication for coronary protection in women of any age. Initiation of HT by women ages 50 to 59 years or by those within 10 years of menopause to treat typical menopause symptoms (eg, vasomotor, vaginal) does not seem to increase the risk of CHD events. There is emerging evidence that initiation of ET in early postmenopause may reduce CHD risk.
Diabetes Mellitus
Aging is associated with an increased risk of non-insulin-dependent diabetes mellitus (DM), also known as adult-onset DM or type 2 DM (T2DM). Although no HT product has regulatory agency approval to prevent DM, large RCTs demonstrate that HT reduces the new onset of T2DM. Women who received active treatment in the WHI EPT arm had an annualized incidence of DM requiring treatment of 0.61% versus 0.76% in placebo-treated women. This translates into a statistically significant 21% reduction (hazard ratio [HR], 0.79; 95% CI, 0.67–0.93) in incident-treated DM, or 15 fewer cases per 10,000 women per year of therapy. A similar statistically significant risk reduction was also noted in the HERS trial (HR, 0.65; 95% CI, 0.48–0.89). In the WHI ET trial, there was a 12% reduction (HR, 0.88; 95% CI, 0.77–1.01) in incident DM, or 14 fewer cases per 10,000 women per year of ET. It is presently unclear whether the mechanism for this benefit is through less centripetal weight gain, reduced insulin resistance in women receiving combined EPT, or some other factor. Meta-analysis data suggest that HT is associated with an improvement in insulin resistance in postmenopausal women. There is inadequate evidence to recommend HT as the sole or primary indication for the prevention of DM in peri- or postmenopausal women.
Optimal glucose control is a prime goal of therapy in postmenopausal women who have T2DM. Some data suggest that postmenopausal women with T2DM who use oral ET may require lower doses of medications for glycemic control.
In women with T2DM, measures to reduce CHD risk are probably of greatest concern. If HT is prescribed, the specific agent, dose, regimen, and route of administration may be important. Transdermal ET administration may offer advantages over the oral route. Serum triglyceride levels and thrombotic factors, which are often increased in patients who have DM, are not increased further with transdermal HT. Moreover, adverse alterations in blood pressure in both nonhypertensive and hypertensive women (although viewed as being rare, if not idiosyncratic, reactions) have been reported only with oral therapy.
Endometrial Cancer
Unopposed systemic ET in postmenopausal women with an intact uterus is associated with increased endometrial cancer risk related to the ET dose and duration of use. Standard-dose therapy (0.625 mg/d CE or the equivalent), when used for more than 3 years, is associated with up to a fivefold increased risk of endometrial cancer; if used for 10 years, the risk increases up to tenfold. This increased risk persists for several years after ET discontinuation. To negate this increased risk, adequate concomitant progestogen is recommended for women with an intact uterus when using systemic ET (see Progestogen indication). HT is not recommended in women with a history of endometrial cancer.
Breast Cancer
Estrogen-progestogen Therapy Diagnosis of breast cancer increases with EPT use beyond 3 to 5 years. In the WHI, this increased risk, in absolute terms, was 8 total breast cancers per 10,000 women using EPT for 5 or more years. Studies have not clarified whether the risk differs between continuous and sequential use of progestogen, with observational studies suggesting risk may be greater with continuous use of progestogen. It is also not clear whether there is a class effect from the progestogen or whether the specific agent used influences breast cancer risk. Early data from a large observational trial suggest that EPT with micronized progesterone may not be associated with an increased risk of breast cancer if used for up to 5 years, but these findings should not be overemphasized and require confirmation.
EPT and, to a lesser extent, ET, increase breast cell proliferation, breast pain, and mammographic density, and EPT may impede the diagnostic interpretation of mammograms. Evolving but not conclusive evidence suggests that the increased risk of breast cancer with EPT may be a result of promotion of preexisting cancers that are too small to be diagnosed by imaging studies or clinical examination. Modest trends suggest that the risk of breast cancer dissipates somewhat over the 3 years after cessation of EPT.
In the WHI, the increase in breast cancer risk was limited to those who had used EPT before enrollment because there was no increased risk of breast cancer in women who were EPT-naive (ie, had not previously used HT). A total of 82% of the women in this study (average age at study entry, 63 y) were hormone-naive. As most women initiate EPT shortly after menopause, a reanalysis of the data examined the effect of a "gap time" (duration of time between onset of menopause and start of EPT) on breast cancer risk. Those starting EPT shortly after menopause experienced an increased risk of breast cancer over the next 5 years, whereas those with a gap time of greater than 5 years did not. The French E3N (a prospective cohort study on French women that examined the potential relationship between pre- and postmenopausal breast cancer occurrence) also reported a greater risk of breast cancer in those women with a short as opposed to a long gap time.
Estrogen Therapy Women in the ET arm of the WHI demonstrated no increase in risk of breast cancer after an average of 7.1 years of use, with 6 fewer cases of invasive breast cancer per 10,000 women per year of ET use, which is not statistically significant. The decrease in risk was observed in all three age groups studied (ie, starting ET at 50–59, 60–69, and 70–79 y). However, the risk was statistically significantly reduced in three subgroups upon post hoc analysis: fewer breast cancers with localized disease were diagnosed in the ET group than in the placebo group (HR, 0.69; 95% CI, 0.51–0.95); a similar reduction was found for ductal carcinomas (HR, 0.71; 95% CI, 0.52–0.99); and a larger, significant reduction was observed in a 6-month follow-up when the women were no longer using ET (HR, 0.67; 95% CI, 0.47–0.97). When ET was extended beyond 10 to 15 years in observational studies, breast cancer risk seemed to increase.
After Breast Cancer Controversy surrounds the issue of safety of EPT in survivors of breast cancer. Observational studies suggest that EPT is safe and perhaps even protective against recurrence of breast cancer. However, these data have been questioned because of the potential bias from selection of women at low risk of recurrence using ET. Two concurrent RCTs reported conflicting results, with one reporting no harm and the other a statistically significant 2.4-fold increase in new breast cancer events. These data would indicate that ET use in breast cancer survivors has not been proven to be safe and may be associated with an increased risk of recurrence.
Ovarian Cancer
Cancer of the ovaries causes more deaths than any other cancer of the reproductive system, primarily because it is usually detected in an advanced stage. In the United States, the 1- and 5-year survival rates are 79% and 53%, respectively. If ovarian cancer is detected and treated early, 95% of women survive at least 5 years; however, only 25% of cases are detected at the earliest, localized stage. Ovarian cancer accounts for 4% of all malignancies among US women and is the fifth leading cause of cancer deaths among US and Canadian women.
Published data on the role of HT and risk of ovarian cancer are conflicting. Most epidemiologic studies have shown no association or a modest increase. There is a relatively large volume of observational trial data that points to an association between HT use and increased ovarian cancer risk.
In the WHI (the only RCT to date to study ovarian cancer), postmenopausal women taking daily continuous-combined EPT for an average follow-up of 5.6 years did not exhibit a statistically significant increase in ovarian cancer. There were 20 cases of invasive ovarian cancer among EPT recipients (n = 8,506) and 12 cases among those taking placebo (n = 8,102). This translates to 42 cases per 100,000 for HT users and 27 cases per 100,000 per year for the placebo group.
Case control and cohort epidemiological studies have reported ovarian cancer risks with both ET and EPT. A large population-based study of peri- and postmenopausal Danish women, followed for an average of 8 years, found that current HT users had incidence ratios of 1.38 (95% CI, 1.26–1.51) for all ovarian tumors and 1.44 (95% CI, 1.30–1.58) for epithelial ovarian cancer. A total of 2 to 4 years after HT cessation, risk declined to 0.98 (95% CI, 0.75–1.28). The risk attributable to HT was 0.6 women per 1,000 per 5 years.
One meta-analysis reported an increase in annual ovarian cancer risk for EPT of 1.11-fold (95% CI, 1.02–1.21) and 1.28-fold (95% CI, 1.18–1.40) for ET. A second meta-analysis reported an RR of 1.24 (95% CI, 1.15–1.34) for any HT. Current HT users for less than 5 years had no significant increase in risk (RR, 1.04; 95% CI 0.91–1.20) compared with women who had used HT for more than 5 years (RR, 1.47; 95% CI, 1.12–1.92), with higher risks for ET than for EPT.
The association between ovarian cancer and HT beyond 5 years, if any, would fall into the rare or very rare category. Women at increased risk of ovarian cancer (eg, those with a family history) should be counseled about this rare association.
Lung Cancer
The leading cause of cancer mortality in North American women and men is lung cancer; 87% of the deaths occur in smokers, and lung cancer annually results in twice as many deaths in women as does breast cancer.
In a post-hoc analysis of the EPT arm of the WHI that combined data from 0 to 4 years of follow-up, the incidence of non-small cell lung cancer (which accounts for about 80% of lung cancer) was not significantly increased (HR, 1.23; 95% CI, 0.92–1.63; P = 0.16), but the number of deaths and the number of poorly differentiated and metastatic tumors increased in the treatment group (HR 1.87; 95% CI, 1.22–2.88; P = 0.004). The cases were essentially limited to past and current smokers and to women older than age 60. As the WHI was not designed to assess lung cancer and chest imaging was not part of the study protocol, the findings are preliminary and require validation in further studies.
The overall data, including the WHI analysis, suggest that initiating EPT in older women with a history of smoking may promote the growth of existing lung cancers. However, evidence from the WHI and some case-control and cohort studies of HT in a younger population (
Several, but not all, studies of midlife women suggest that depressive symptoms are no more common after the menopause transition than before, and most midlife women do not experience more depressive symptoms than younger women do. However, the menopause transition itself, as well as early postmenopause, may be times of heightened vulnerability for a subgroup of women. For women without a history of prior depression, several community-based longitudinal studies have observed an increased risk of onset of major or minor depression during perimenopause or early postmenopause compared with premenopause.
For postmenopausal women without clinical depression, evidence is mixed concerning the effects of HT on mood. Several small, short-term trials among middle-aged women suggested that HT improves mood, whereas other trial results showed no change.
Progestogens in EPT may worsen mood in some women, possibly in those with a history of premenstrual syndrome, premenstrual depressive disorder, or clinical depression.
Only a few RCTs have examined the effects of HT in middle-aged or older women who have depression. Two small RCTs support the antidepressant efficacy of short-term ET in depressed perimenopausal women, whereas one RCT failed to demonstrate the antidepressant efficacy of ET in depressed women who were 5 to 10 years postmenopause. It is controversial whether ET might in some circumstances augment antidepressant effects of selective serotonin reuptake inhibitors.
In conclusion, although HT might have a positive effect on mood and behavior, HT is not an antidepressant and should not be considered as such. Evidence is insufficient to support its use for the treatment of depression.
Cognitive Aging and Dementia
The term "cognition" describes the group of mental processes by which knowledge is acquired or used. With advancing age, performance tends to decline on many, but not all, cognitive tests. Dementia is the progressive decline in cognitive function due to damage or disease in the brain beyond what might be expected from normal cognitive aging. Alzheimer's disease (AD) is the most common cause of dementia.
Findings from well-characterized cohorts suggest that natural menopause has little effect on memory performance or other areas of cognitive function.
For postmenopausal women over age 65, findings from several large, well-designed clinical trials indicate that HT does not improve memory or other cognitive abilities. One trial within WHI-the Women's Health Initiative Memory Study (WHIMS)-of women ages 65 to 79 reported an increase in dementia incidence with HT use. The estimate of dementia cases attributed to HT was 12 per 10,000 persons per year of ET use and 23 per 10,000 persons per year of EPT use.
By way of contrast, a number of observational studies have reported associations between HT and reduced risk of developing AD. HT exposure in observational studies is more likely to involve use by younger women closer to the age of menopause than by women eligible for the WHIMS trial. Speculatively, this difference implies an early window during which HT use might reduce AD risk. However, recall bias and the healthy-user bias may account for protective associations in the observational studies. No clinical trial data address long-term cognitive consequences of HT exposure during the menopause transition and early postmenopause. For women with AD, limited clinical results suggest that ET has no substantial effect on dementia symptoms or progression.
Based on these considerations, HT cannot be recommended at any age for the sole or primary indication of preventing cognitive aging or dementia. HT seems to increase the incidence of dementia when initiated in women age 65 and older. Similarly, HT should not be used to enhance cognitive function in younger postmenopausal women with intact ovaries, although very small clinical trials support the use of ET initiated immediately after menopause induced by bilateral oophorectomy. Available data do not adequately address whether HT used soon after menopause increases or decreases later dementia risk. Limited data do not support the use of HT as treatment of AD.
Premature Menopause and Premature Ovarian Insufficiency
Women experiencing premature menopause (≤40 y) or premature ovarian insufficiency are medically a distinctly different group than women who reach menopause at the median age of 51.3 years. Premature menopause and premature ovarian insufficiency are associated with a lower risk of breast cancer and earlier onset of osteoporosis, CHD, Parkinson's disease; premature bilateral oophorectomy is possibly associated with cognitive decline as well. There are inadequate data regarding HT in these populations. Most observational reports suggest an increased risk of CHD with early natural or surgical menopause in the absence of HT and a protective effect of HT when HT is administered. The existing data regarding HT in women experiencing menopause at the median age should not be extrapolated to women experiencing premature menopause and initiating HT at that time. The risks attributable to HT use by these young women receiving HT may be smaller and the benefits potentially greater than those in older women who commence HT at or beyond the median age of menopause, although no comparative data exist.
Total Mortality
The WHI trials are consistent with observational studies indicating that HT may reduce total mortality when initiated soon after menopause. The WHI suggests that both ET and EPT nonsignificantly reduce total mortality by 30% when initiated in women younger than age 60, and when data from the ET and EPT arms were combined, that reduction with HT use was statistically significant. In contrast, HT was not associated with mortality reduction among women who initiated HT at age 60 or older.
Benefits and Risks of HT
Confusion can arise among healthcare providers, the lay public, and the media when general concepts of risk are discussed. Understanding HT risks in particular is critical to clinical decision making around menopause and beyond. Because these issues are crucial to a discussion of the role of HT in an individual woman, a special addendum to the 2008 paper was added in this paper to address risk concepts (see Addendum A at http://www.menopause.org/PSHT08.pdf).
Use of HT should be consistent with treatment goals, benefits, and risks for the individual woman. The benefit-risk ratio for an individual woman continually changes with her age and her menopause-related symptoms (eg, vasomotor symptoms, sleep disturbance, vaginal atrophy, dyspareunia, or diminished libido), any of which may have an adverse impact on quality of life (QOL). Risk factors are related to: a woman's baseline disease risks, her age, age at menopause, cause of menopause, time since menopause, and prior use of any hormone including type, route of administration, dose, and medical conditions that emerged during treatment.
Potential benefits and risks are described below for the relevant clinical outcomes.
Vasomotor Symptoms
ET, with or without a progestogen, is the most effective treatment for menopause-related vasomotor symptoms (ie, hot flashes and night sweats) and their potential consequences (eg, diminished sleep quality, irritability, and reduced QOL). Treatment of moderate to severe vasomotor symptoms remains the primary indication for HT. Every systemic ET and EPT product has regulatory agency approval for this indication.
Maximizing the benefit and minimizing the risks of HT are addressed later in this paper. For example, using lower dose preparations has been associated with similar benefits in clinical trials and in some observational studies with lower risks.
Vaginal Symptoms
ET is the most effective treatment for moderate to severe symptoms of vulvar and vaginal atrophy (eg, vaginal dryness, dyspareunia, and atrophic vaginitis). Many systemic ET and EPT products and all local vaginal ET products have regulatory agency approval for treating these vaginal symptoms. Lower doses than previously used, and less frequent administration, often yield satisfactory results. Some systemic ultralow dose regimens may be inadequate for relief of vaginal symptoms. When HT is used for systemic vasomotor symptoms, enquiry about the adequacy of therapy for urogenital atrophy is important. When HT is considered solely for urogenital atrophy, local vaginal ET is generally recommended.
Sexual Function
Relief of moderate to severe vaginal atrophy with systemic or local HT can be effective in relieving dyspareunia, a common cause of intercourse avoidance. Local estrogen may improve coital satisfaction by improving lubrication and increasing blood flow and sensation in vaginal tissues. One oral systemic ET product is approved in the United States for the treatment of pain with intercourse. HT is not recommended as the sole treatment of other problems of sexual function, including diminished libido.
Urinary Health
Local ET may benefit some women with urge incontinence who have vaginal atrophy. Whether ET by any route is effective in treating overactive bladder is unclear. There is controversy as to whether local ET can improve certain cases of pure stress incontinence. On the other hand, systemic HT may worsen or provoke stress incontinence, perhaps related to changes in uterine volume or periurethral collagen.
Local ET may help reduce the risk of recurrent urinary tract infection (UTI) by a direct proliferative effect on the urethra and bladder epithelia, helping to restore the acidic environment and normal lactobacillus-predominant flora of the vagina, and thus discouraging colonization of the vagina by pathogens associated with UTI. Clinically, only ET administered by the vaginal route has been shown in an RCT to be effective in reducing the risk of recurrent UTI. However, no ET/EPT product has regulatory agency approval for any urinary health indication.
Change in Body Weight/Mass
Body mass index (BMI) increases with age in midlife, with the peak BMI occurring between ages 50 and 59. At this time of life, other factors may also contribute to weight gain, including a decrease in energy expenditure and an increase in energy intake coupled with a decrease in metabolic rate. In women, the hormonal changes associated with the menopause transition can affect body composition and add to the tendency to gain weight. No statistically significant difference in mean weight gain or BMI has been demonstrated between women who use HT and those who do not.
Quality of Life
Although no HT product has regulatory agency approval for enhancing QOL, an improvement in health-related quality of life (HQOL) can result with HT use because of decreased menopause symptoms and perhaps other mechanisms, including improved sleep and a possible elevation of mood that leads to a feeling of well-being. Whether HT improves HQOL in asymptomatic women is unknown, nor are data available to determine the effect of HT on global QOL (the sense of well-being with or without symptoms or physical impairments).
Osteoporosis
Bone strength depends on both bone quality and bone mineral density (BMD). Changes in BMD alone may not always reflect fracture risk. There is RCT evidence that HT reduces postmenopausal osteoporotic fractures, including hip fractures, even in women without osteoporosis, although no HT product has regulatory agency approval for treatment of osteoporosis. Many systemic HT products, however, have regulatory agency approval for prevention of postmenopausal osteoporosis through long-term treatment; a current list of these products can be found on the NAMS Web site (http://www.menopause.org/edumaterials/otcharts.pdf).
Extended use of HT is an option for women who have established reduction in bone mass, regardless of menopause symptoms; for prevention of further bone loss and/or reduction of osteoporotic fracture when alternate therapies are not appropriate or cause side effects; or when the benefits of extended use are expected to exceed the risks. The optimal time to initiate HT and the optimal duration of therapy have not been established, but HT would largely be used in the early years after menopause. The benefits of HT on bone mass dissipate quickly after discontinuation of treatment.
Cardiovascular Effects
Three primary cardiovascular effects are discussed: coronary heart disease (CHD), stroke, and venous thromboembolism (VTE).
Coronary Heart Disease Most observational and preclinical studies support the potential benefits of systemic HT in reducing the risk of CHD. Most RCTs do not. However, it is now understood that the characteristics of women participating in observational studies are markedly different from those of women enrolled in RCTs, and that some of these demographic or biologic differences, or both, influence baseline cardiovascular risks and may modify the effects of HT on cardiovascular risk.
Timing of Initiation. Data indicate that the disparity in findings between observational studies and RCTs is related in part to the timing of initiation of HT in relation to age and proximity to menopause. Most women studied in observational studies of CHD risk were younger than age 55 at the time HT was initiated and within 2 to 3 years of menopause. On the other hand, women enrolled to date in RCTs with clinical cardiovascular endpoints were an average of 63 to 64 years old and more than 10 years beyond menopause. When analyzed by age and time since menopause at initiation of HT, the ET arm of the WHI is in general agreement with observational studies indicating that ET may reduce CHD risk (coronary revascularization and composite outcomes) when initiated in younger and more recently postmenopausal women. In a secondary analysis of WHI data, there was a statistically significant reduction in the composite endpoint of myocardial infarction, coronary artery revascularization, and coronary death in women who were randomized to ET during ages 50 to 59. Combined data from both the ET and EPT trials of the WHI show a statistical trend of an HT effect relative to placebo on CHD by time since menopause, indicating that women who initiate HT more than 10 years beyond menopause are at increased risk for CHD, and those women who initiate HT within 10 years of menopause tend to have a lower risk of CHD. However, statistical modeling of the combined WHI data, including further data from WHI observational studies, did not find that CHD risks varied by the timing of HT initiation.
Duration of Therapy. Observational studies suggest that longer duration of HT use is associated with reduced risk of CHD and related mortality. The WHI RCTs and the WHI observational study suggest a pattern of lower risk of CHD among women who used HT for 5 or more years, but this is not conclusive, and should be considered in light of other factors altered by duration of therapy, such as breast cancer.
In contrast, in the short term, HT is associated with an increase in CHD risk among women who are more distant from menopause at the time of HT initiation.
Coronary Artery Calcium. Observational studies show that long-term HT is associated with less accumulation of coronary artery calcium, which is strongly correlated with atheromatous plaque burden and future risk of clinical CHD events. In an ancillary substudy of younger women (<60 y) in the WHI ET trial, after an average of 7 years of treatment, women who had been randomized to ET had lower levels of coronary artery calcium than those randomized to placebo. These findings suggest that ET initiated by recently postmenopausal women may slow the development of calcified atherosclerotic plaque.
Stroke Results of observational studies of the risk of stroke with HT have been inconsistent. Several studies (including the Nurses' Health Study [NHS], the largest prospective study of HT and stroke) indicated an increased risk of ischemic stroke consistent with the findings from the WHI, whereas other studies showed no effect on stroke risk. The WHI EPT and ET trials demonstrated an increased risk of ischemic stroke and no effect on risk of hemorrhagic stroke. In these trials, there were 8 additional strokes per 10,000 women per year of EPT and 11 additional strokes per 10,000 women per year of ET when the entire cohort was analyzed. In recent analyses that combined results from the WHI EPT and ET trials, HT in younger women (ages 50–59) at study entry had no significant effect on risk of stroke (relative risk [RR], 1.13; 95% confidence interval [CI], 0.73–1.76). In the Framingham Heart Study, natural menopause at age 42 or younger was associated with elevated risk of ischemic stroke.
In women randomized in the WHI within 5 years of menopause, there were 3 additional strokes per 10,000 women per year of EPT, which is not statistically significant. The excess risk of stroke in this age group observed in the WHI studies would fall into the "rare" risk category. Stroke risk was not significantly increased in the Heart and Estrogen/progestin Replacement Study (HERS) and Women's Estrogen for Stroke Trial (WEST) secondary prevention trials. The Women's International Study of long Duration Oestrogen after Menopause (WISDOM) RCT found no excess of stroke in EPT users compared with women on placebo in 1 year.
Findings of increased stroke risk are largely driven by effects of HT on ischemic stroke, as neither ET nor EPT seems to affect the risk of hemorrhagic stroke. However, with few women in younger age groups in the WHI trials, the CIs have been wide, which means that there was not significant statistical power to reach a conclusion. In the NHS, among women ages 50 to 59, the RR of stroke for current EPT users tended to be elevated (RR, 1.34; 95% CI, 0.84–2.13) and was significantly increased for current users of ET (RR, 1.58; 95% CI, 1.06–2.37). Lower doses of estrogen (eg, 0.3 mg CE) were not associated with an increased risk in the NHS, although this was based on the relatively few women who were taking lower doses.
No studies indicate that postmenopausal HT is effective for reducing the risk of a recurrent stroke among women with established cardiovascular disease (CVD) or for prevention of a first stroke, and it may increase the rate of first strokes particularly in women initiating HT over age 60. HT cannot be recommended for the primary or secondary prevention of stroke. Although stroke was not increased in the group ages 50 to 59 in the combined analysis of the WHI, it was almost doubled in the ET group less than 10 years since menopause. This apparent contradiction in the data is hard to explain, but may be due to relatively few events and the difficulty in accurately timing onset of menopause in the ET group.
Venous Thromboembolism Data from both observational studies and RCTs demonstrate an increased risk of VTE with oral HT. In the WHI trials, there were 18 additional VTEs per 10,000 women per year of EPT and 7 additional VTEs per 10,000 women per year of ET when the entire cohort was analyzed. VTE risk in RCTs emerges soon after HT initiation (ie, during the first 1–2 y), and the magnitude of the excess risk seems to decrease somewhat over time. In the WHI trials, the absolute excess VTE risk associated with either EPT or ET was lower in women who started HT before age 60 than in older women who initiated HT after age 60. There were 7 additional VTEs per 10,000 women per year of EPT and 4 additional VTEs per 10,000 women per year of ET in women ages 50 to 59 who were randomized to HT. These risks fall into the rare risk category. The baseline risk of VTE also increases relative to BMI. For obese women (BMI >30), the baseline risk was almost threefold greater. At any BMI, the risk of VTE doubled with HT, and returned to baseline soon after HT discontinuation.
Growing evidence suggests that women with a prior history of VTE or women who possess factor V Leiden are at increased risk for VTE with HT use. There are limited observational data suggesting lower risks of VTE with transdermal than with oral ET, but there are no comparative RCT data on this subject. Lower doses of oral ET may also confer less VTE risk than higher doses, but no comparative RCT data are available to confirm this assumption.
Cardiovascular Effects Conclusion HT is currently not recommended as a sole or primary indication for coronary protection in women of any age. Initiation of HT by women ages 50 to 59 years or by those within 10 years of menopause to treat typical menopause symptoms (eg, vasomotor, vaginal) does not seem to increase the risk of CHD events. There is emerging evidence that initiation of ET in early postmenopause may reduce CHD risk.
Diabetes Mellitus
Aging is associated with an increased risk of non-insulin-dependent diabetes mellitus (DM), also known as adult-onset DM or type 2 DM (T2DM). Although no HT product has regulatory agency approval to prevent DM, large RCTs demonstrate that HT reduces the new onset of T2DM. Women who received active treatment in the WHI EPT arm had an annualized incidence of DM requiring treatment of 0.61% versus 0.76% in placebo-treated women. This translates into a statistically significant 21% reduction (hazard ratio [HR], 0.79; 95% CI, 0.67–0.93) in incident-treated DM, or 15 fewer cases per 10,000 women per year of therapy. A similar statistically significant risk reduction was also noted in the HERS trial (HR, 0.65; 95% CI, 0.48–0.89). In the WHI ET trial, there was a 12% reduction (HR, 0.88; 95% CI, 0.77–1.01) in incident DM, or 14 fewer cases per 10,000 women per year of ET. It is presently unclear whether the mechanism for this benefit is through less centripetal weight gain, reduced insulin resistance in women receiving combined EPT, or some other factor. Meta-analysis data suggest that HT is associated with an improvement in insulin resistance in postmenopausal women. There is inadequate evidence to recommend HT as the sole or primary indication for the prevention of DM in peri- or postmenopausal women.
Optimal glucose control is a prime goal of therapy in postmenopausal women who have T2DM. Some data suggest that postmenopausal women with T2DM who use oral ET may require lower doses of medications for glycemic control.
In women with T2DM, measures to reduce CHD risk are probably of greatest concern. If HT is prescribed, the specific agent, dose, regimen, and route of administration may be important. Transdermal ET administration may offer advantages over the oral route. Serum triglyceride levels and thrombotic factors, which are often increased in patients who have DM, are not increased further with transdermal HT. Moreover, adverse alterations in blood pressure in both nonhypertensive and hypertensive women (although viewed as being rare, if not idiosyncratic, reactions) have been reported only with oral therapy.
Endometrial Cancer
Unopposed systemic ET in postmenopausal women with an intact uterus is associated with increased endometrial cancer risk related to the ET dose and duration of use. Standard-dose therapy (0.625 mg/d CE or the equivalent), when used for more than 3 years, is associated with up to a fivefold increased risk of endometrial cancer; if used for 10 years, the risk increases up to tenfold. This increased risk persists for several years after ET discontinuation. To negate this increased risk, adequate concomitant progestogen is recommended for women with an intact uterus when using systemic ET (see Progestogen indication). HT is not recommended in women with a history of endometrial cancer.
Breast Cancer
Estrogen-progestogen Therapy Diagnosis of breast cancer increases with EPT use beyond 3 to 5 years. In the WHI, this increased risk, in absolute terms, was 8 total breast cancers per 10,000 women using EPT for 5 or more years. Studies have not clarified whether the risk differs between continuous and sequential use of progestogen, with observational studies suggesting risk may be greater with continuous use of progestogen. It is also not clear whether there is a class effect from the progestogen or whether the specific agent used influences breast cancer risk. Early data from a large observational trial suggest that EPT with micronized progesterone may not be associated with an increased risk of breast cancer if used for up to 5 years, but these findings should not be overemphasized and require confirmation.
EPT and, to a lesser extent, ET, increase breast cell proliferation, breast pain, and mammographic density, and EPT may impede the diagnostic interpretation of mammograms. Evolving but not conclusive evidence suggests that the increased risk of breast cancer with EPT may be a result of promotion of preexisting cancers that are too small to be diagnosed by imaging studies or clinical examination. Modest trends suggest that the risk of breast cancer dissipates somewhat over the 3 years after cessation of EPT.
In the WHI, the increase in breast cancer risk was limited to those who had used EPT before enrollment because there was no increased risk of breast cancer in women who were EPT-naive (ie, had not previously used HT). A total of 82% of the women in this study (average age at study entry, 63 y) were hormone-naive. As most women initiate EPT shortly after menopause, a reanalysis of the data examined the effect of a "gap time" (duration of time between onset of menopause and start of EPT) on breast cancer risk. Those starting EPT shortly after menopause experienced an increased risk of breast cancer over the next 5 years, whereas those with a gap time of greater than 5 years did not. The French E3N (a prospective cohort study on French women that examined the potential relationship between pre- and postmenopausal breast cancer occurrence) also reported a greater risk of breast cancer in those women with a short as opposed to a long gap time.
Estrogen Therapy Women in the ET arm of the WHI demonstrated no increase in risk of breast cancer after an average of 7.1 years of use, with 6 fewer cases of invasive breast cancer per 10,000 women per year of ET use, which is not statistically significant. The decrease in risk was observed in all three age groups studied (ie, starting ET at 50–59, 60–69, and 70–79 y). However, the risk was statistically significantly reduced in three subgroups upon post hoc analysis: fewer breast cancers with localized disease were diagnosed in the ET group than in the placebo group (HR, 0.69; 95% CI, 0.51–0.95); a similar reduction was found for ductal carcinomas (HR, 0.71; 95% CI, 0.52–0.99); and a larger, significant reduction was observed in a 6-month follow-up when the women were no longer using ET (HR, 0.67; 95% CI, 0.47–0.97). When ET was extended beyond 10 to 15 years in observational studies, breast cancer risk seemed to increase.
After Breast Cancer Controversy surrounds the issue of safety of EPT in survivors of breast cancer. Observational studies suggest that EPT is safe and perhaps even protective against recurrence of breast cancer. However, these data have been questioned because of the potential bias from selection of women at low risk of recurrence using ET. Two concurrent RCTs reported conflicting results, with one reporting no harm and the other a statistically significant 2.4-fold increase in new breast cancer events. These data would indicate that ET use in breast cancer survivors has not been proven to be safe and may be associated with an increased risk of recurrence.
Ovarian Cancer
Cancer of the ovaries causes more deaths than any other cancer of the reproductive system, primarily because it is usually detected in an advanced stage. In the United States, the 1- and 5-year survival rates are 79% and 53%, respectively. If ovarian cancer is detected and treated early, 95% of women survive at least 5 years; however, only 25% of cases are detected at the earliest, localized stage. Ovarian cancer accounts for 4% of all malignancies among US women and is the fifth leading cause of cancer deaths among US and Canadian women.
Published data on the role of HT and risk of ovarian cancer are conflicting. Most epidemiologic studies have shown no association or a modest increase. There is a relatively large volume of observational trial data that points to an association between HT use and increased ovarian cancer risk.
In the WHI (the only RCT to date to study ovarian cancer), postmenopausal women taking daily continuous-combined EPT for an average follow-up of 5.6 years did not exhibit a statistically significant increase in ovarian cancer. There were 20 cases of invasive ovarian cancer among EPT recipients (n = 8,506) and 12 cases among those taking placebo (n = 8,102). This translates to 42 cases per 100,000 for HT users and 27 cases per 100,000 per year for the placebo group.
Case control and cohort epidemiological studies have reported ovarian cancer risks with both ET and EPT. A large population-based study of peri- and postmenopausal Danish women, followed for an average of 8 years, found that current HT users had incidence ratios of 1.38 (95% CI, 1.26–1.51) for all ovarian tumors and 1.44 (95% CI, 1.30–1.58) for epithelial ovarian cancer. A total of 2 to 4 years after HT cessation, risk declined to 0.98 (95% CI, 0.75–1.28). The risk attributable to HT was 0.6 women per 1,000 per 5 years.
One meta-analysis reported an increase in annual ovarian cancer risk for EPT of 1.11-fold (95% CI, 1.02–1.21) and 1.28-fold (95% CI, 1.18–1.40) for ET. A second meta-analysis reported an RR of 1.24 (95% CI, 1.15–1.34) for any HT. Current HT users for less than 5 years had no significant increase in risk (RR, 1.04; 95% CI 0.91–1.20) compared with women who had used HT for more than 5 years (RR, 1.47; 95% CI, 1.12–1.92), with higher risks for ET than for EPT.
The association between ovarian cancer and HT beyond 5 years, if any, would fall into the rare or very rare category. Women at increased risk of ovarian cancer (eg, those with a family history) should be counseled about this rare association.
Lung Cancer
The leading cause of cancer mortality in North American women and men is lung cancer; 87% of the deaths occur in smokers, and lung cancer annually results in twice as many deaths in women as does breast cancer.
In a post-hoc analysis of the EPT arm of the WHI that combined data from 0 to 4 years of follow-up, the incidence of non-small cell lung cancer (which accounts for about 80% of lung cancer) was not significantly increased (HR, 1.23; 95% CI, 0.92–1.63; P = 0.16), but the number of deaths and the number of poorly differentiated and metastatic tumors increased in the treatment group (HR 1.87; 95% CI, 1.22–2.88; P = 0.004). The cases were essentially limited to past and current smokers and to women older than age 60. As the WHI was not designed to assess lung cancer and chest imaging was not part of the study protocol, the findings are preliminary and require validation in further studies.
The overall data, including the WHI analysis, suggest that initiating EPT in older women with a history of smoking may promote the growth of existing lung cancers. However, evidence from the WHI and some case-control and cohort studies of HT in a younger population (
Several, but not all, studies of midlife women suggest that depressive symptoms are no more common after the menopause transition than before, and most midlife women do not experience more depressive symptoms than younger women do. However, the menopause transition itself, as well as early postmenopause, may be times of heightened vulnerability for a subgroup of women. For women without a history of prior depression, several community-based longitudinal studies have observed an increased risk of onset of major or minor depression during perimenopause or early postmenopause compared with premenopause.
For postmenopausal women without clinical depression, evidence is mixed concerning the effects of HT on mood. Several small, short-term trials among middle-aged women suggested that HT improves mood, whereas other trial results showed no change.
Progestogens in EPT may worsen mood in some women, possibly in those with a history of premenstrual syndrome, premenstrual depressive disorder, or clinical depression.
Only a few RCTs have examined the effects of HT in middle-aged or older women who have depression. Two small RCTs support the antidepressant efficacy of short-term ET in depressed perimenopausal women, whereas one RCT failed to demonstrate the antidepressant efficacy of ET in depressed women who were 5 to 10 years postmenopause. It is controversial whether ET might in some circumstances augment antidepressant effects of selective serotonin reuptake inhibitors.
In conclusion, although HT might have a positive effect on mood and behavior, HT is not an antidepressant and should not be considered as such. Evidence is insufficient to support its use for the treatment of depression.
Cognitive Aging and Dementia
The term "cognition" describes the group of mental processes by which knowledge is acquired or used. With advancing age, performance tends to decline on many, but not all, cognitive tests. Dementia is the progressive decline in cognitive function due to damage or disease in the brain beyond what might be expected from normal cognitive aging. Alzheimer's disease (AD) is the most common cause of dementia.
Findings from well-characterized cohorts suggest that natural menopause has little effect on memory performance or other areas of cognitive function.
For postmenopausal women over age 65, findings from several large, well-designed clinical trials indicate that HT does not improve memory or other cognitive abilities. One trial within WHI-the Women's Health Initiative Memory Study (WHIMS)-of women ages 65 to 79 reported an increase in dementia incidence with HT use. The estimate of dementia cases attributed to HT was 12 per 10,000 persons per year of ET use and 23 per 10,000 persons per year of EPT use.
By way of contrast, a number of observational studies have reported associations between HT and reduced risk of developing AD. HT exposure in observational studies is more likely to involve use by younger women closer to the age of menopause than by women eligible for the WHIMS trial. Speculatively, this difference implies an early window during which HT use might reduce AD risk. However, recall bias and the healthy-user bias may account for protective associations in the observational studies. No clinical trial data address long-term cognitive consequences of HT exposure during the menopause transition and early postmenopause. For women with AD, limited clinical results suggest that ET has no substantial effect on dementia symptoms or progression.
Based on these considerations, HT cannot be recommended at any age for the sole or primary indication of preventing cognitive aging or dementia. HT seems to increase the incidence of dementia when initiated in women age 65 and older. Similarly, HT should not be used to enhance cognitive function in younger postmenopausal women with intact ovaries, although very small clinical trials support the use of ET initiated immediately after menopause induced by bilateral oophorectomy. Available data do not adequately address whether HT used soon after menopause increases or decreases later dementia risk. Limited data do not support the use of HT as treatment of AD.
Premature Menopause and Premature Ovarian Insufficiency
Women experiencing premature menopause (≤40 y) or premature ovarian insufficiency are medically a distinctly different group than women who reach menopause at the median age of 51.3 years. Premature menopause and premature ovarian insufficiency are associated with a lower risk of breast cancer and earlier onset of osteoporosis, CHD, Parkinson's disease; premature bilateral oophorectomy is possibly associated with cognitive decline as well. There are inadequate data regarding HT in these populations. Most observational reports suggest an increased risk of CHD with early natural or surgical menopause in the absence of HT and a protective effect of HT when HT is administered. The existing data regarding HT in women experiencing menopause at the median age should not be extrapolated to women experiencing premature menopause and initiating HT at that time. The risks attributable to HT use by these young women receiving HT may be smaller and the benefits potentially greater than those in older women who commence HT at or beyond the median age of menopause, although no comparative data exist.
Total Mortality
The WHI trials are consistent with observational studies indicating that HT may reduce total mortality when initiated soon after menopause. The WHI suggests that both ET and EPT nonsignificantly reduce total mortality by 30% when initiated in women younger than age 60, and when data from the ET and EPT arms were combined, that reduction with HT use was statistically significant. In contrast, HT was not associated with mortality reduction among women who initiated HT at age 60 or older.
Management of Osteoporosis in Postmenopausal Women
From Menopause
Management of Osteoporosis in Postmenopausal Women: 2010 Position Statement of The North American Menopause Society
Posted: 01/20/2010; Menopause. 2010;17(1):25-54. © 2010 The North American Menopause Society
Objective: To update the evidence-based position statement published by The North American Menopause Society (NAMS) in 2006 regarding the management of osteoporosis in postmenopausal women.
Methods: NAMS followed the general principles established for evidence-based guidelines to create this updated document. A panel of clinicians and researchers expert in the field of metabolic bone diseases and/or women's health was enlisted to review the 2006 NAMS position statement, compile supporting statements, and reach consensus on recommendations. The panel's recommendations were reviewed and approved by the NAMS Board of Trustees.
Results: Osteoporosis, which is especially prevalent among older postmenopausal women, increases the risk of fractures. Hip and spine fractures are associated with particularly high morbidity and mortality in this population. Given the health implications of osteoporotic fractures, the primary goal of osteoporosis therapy is to prevent fractures, which is accomplished by slowing or stopping bone loss, maintaining bone strength, and minimizing or eliminating factors that may contribute to fractures. The evaluation of postmenopausal women for osteoporosis risk requires a medical history, physical examination, and diagnostic tests. Major risk factors for postmenopausal osteoporosis (as defined by bone mineral density) include advanced age, genetics, lifestyle factors (such as low calcium and vitamin D intake, smoking), thinness, and menopause status. The most common risk factors for osteoporotic fracture are advanced age, low bone mineral density, and previous fracture as an adult. Management focuses first on nonpharmacologic measures, such as a balanced diet, adequate calcium and vitamin D intake, adequate exercise, smoking cessation, avoidance of excessive alcohol intake, and fall prevention.
If pharmacologic therapy is indicated, government-approved options are bisphosphonates, selective estrogen-receptor modulators, parathyroid hormone, estrogens, and calcitonin.
Conclusions: Management strategies for postmenopausal women involve identifying those at risk for fracture, followed by instituting measures that focus on reducing modifiable risk factors through dietary and lifestyle changes and, if indicated, pharmacologic therapy.
Introduction
Osteoporosis becomes a serious health threat for aging postmenopausal women by predisposing them to an increased risk of fracture. Osteoporotic fractures are associated with substantial morbidity and mortality in postmenopausal women, especially older women.
In response to the need to define standards of clinical practice in North America as they relate to menopause-associated health conditions, The North American Menopause Society (NAMS) has created this evidence-based position statement. The objective of this position statement is to provide guidance on the prevention, diagnosis, and treatment of osteoporosis in postmenopausal women to physicians, physician assistants, nurse practitioners, nurses, and other healthcare professionals caring for postmenopausal women, especially those in the clinical practice fields of obstetrics and gynecology, internal medicine, family medicine, and geriatrics.
This position statement is an update of the NAMS position statement published in 2006.[1] Since then, the publication of additional scientific evidence has created a need to update the position statement.
For this revision, NAMS conducted a search of the medical literature published since the previous position statement was submitted for publication in February 2006. A search was made for clinical trials, meta-analyses, and clinical practice guidelines published in English and related to osteoporosis in postmenopausal women, using the MEDLINE database. The Medical Subject Headings (MeSH) used for the search were postmenopausal osteoporosis and bone loss with subheadings for epidemiology, etiology, diagnosis, prevention and control, and therapy. The National Guideline Clearinghouse was searched for relevant clinical practice guidelines, and the Cochrane Library was searched for relevant systematic reviews. Priority was given to evidence from randomized controlled clinical trials and meta-analyses of such trials, followed by evidence from controlled observational studies, using criteria described elsewhere.[2–4] Conclusions from other evidence-based guidelines also were reviewed. Because standards of care and available treatment options differ throughout the world, the focus is limited to therapies available in North America.
To help with this revision, NAMS enlisted a five-person Editorial Board composed of endocrinologists, internists, and rheumatologists from both clinical practice and research with expertise in metabolic bone diseases or women's health. The Editorial Board reviewed the previous position statement and incorporated data published since that statement, compiled supporting statements, and made recommendations. Where the evidence was contradictory or inadequate to form a conclusion, a consensus-based opinion was established. (Practice parameter standards related to NAMS position statements have been described in an editorial.[5]) The NAMS Board of Trustees was responsible for the final review and approval of this document. Updates to this revised position statement will be published as developments occur in scientific research that substantially alters the conclusions.
http://www.medscape.com/viewarticle/714984
Management of Osteoporosis in Postmenopausal Women: 2010 Position Statement of The North American Menopause Society
Posted: 01/20/2010; Menopause. 2010;17(1):25-54. © 2010 The North American Menopause Society
Objective: To update the evidence-based position statement published by The North American Menopause Society (NAMS) in 2006 regarding the management of osteoporosis in postmenopausal women.
Methods: NAMS followed the general principles established for evidence-based guidelines to create this updated document. A panel of clinicians and researchers expert in the field of metabolic bone diseases and/or women's health was enlisted to review the 2006 NAMS position statement, compile supporting statements, and reach consensus on recommendations. The panel's recommendations were reviewed and approved by the NAMS Board of Trustees.
Results: Osteoporosis, which is especially prevalent among older postmenopausal women, increases the risk of fractures. Hip and spine fractures are associated with particularly high morbidity and mortality in this population. Given the health implications of osteoporotic fractures, the primary goal of osteoporosis therapy is to prevent fractures, which is accomplished by slowing or stopping bone loss, maintaining bone strength, and minimizing or eliminating factors that may contribute to fractures. The evaluation of postmenopausal women for osteoporosis risk requires a medical history, physical examination, and diagnostic tests. Major risk factors for postmenopausal osteoporosis (as defined by bone mineral density) include advanced age, genetics, lifestyle factors (such as low calcium and vitamin D intake, smoking), thinness, and menopause status. The most common risk factors for osteoporotic fracture are advanced age, low bone mineral density, and previous fracture as an adult. Management focuses first on nonpharmacologic measures, such as a balanced diet, adequate calcium and vitamin D intake, adequate exercise, smoking cessation, avoidance of excessive alcohol intake, and fall prevention.
If pharmacologic therapy is indicated, government-approved options are bisphosphonates, selective estrogen-receptor modulators, parathyroid hormone, estrogens, and calcitonin.
Conclusions: Management strategies for postmenopausal women involve identifying those at risk for fracture, followed by instituting measures that focus on reducing modifiable risk factors through dietary and lifestyle changes and, if indicated, pharmacologic therapy.
Introduction
Osteoporosis becomes a serious health threat for aging postmenopausal women by predisposing them to an increased risk of fracture. Osteoporotic fractures are associated with substantial morbidity and mortality in postmenopausal women, especially older women.
In response to the need to define standards of clinical practice in North America as they relate to menopause-associated health conditions, The North American Menopause Society (NAMS) has created this evidence-based position statement. The objective of this position statement is to provide guidance on the prevention, diagnosis, and treatment of osteoporosis in postmenopausal women to physicians, physician assistants, nurse practitioners, nurses, and other healthcare professionals caring for postmenopausal women, especially those in the clinical practice fields of obstetrics and gynecology, internal medicine, family medicine, and geriatrics.
This position statement is an update of the NAMS position statement published in 2006.[1] Since then, the publication of additional scientific evidence has created a need to update the position statement.
For this revision, NAMS conducted a search of the medical literature published since the previous position statement was submitted for publication in February 2006. A search was made for clinical trials, meta-analyses, and clinical practice guidelines published in English and related to osteoporosis in postmenopausal women, using the MEDLINE database. The Medical Subject Headings (MeSH) used for the search were postmenopausal osteoporosis and bone loss with subheadings for epidemiology, etiology, diagnosis, prevention and control, and therapy. The National Guideline Clearinghouse was searched for relevant clinical practice guidelines, and the Cochrane Library was searched for relevant systematic reviews. Priority was given to evidence from randomized controlled clinical trials and meta-analyses of such trials, followed by evidence from controlled observational studies, using criteria described elsewhere.[2–4] Conclusions from other evidence-based guidelines also were reviewed. Because standards of care and available treatment options differ throughout the world, the focus is limited to therapies available in North America.
To help with this revision, NAMS enlisted a five-person Editorial Board composed of endocrinologists, internists, and rheumatologists from both clinical practice and research with expertise in metabolic bone diseases or women's health. The Editorial Board reviewed the previous position statement and incorporated data published since that statement, compiled supporting statements, and made recommendations. Where the evidence was contradictory or inadequate to form a conclusion, a consensus-based opinion was established. (Practice parameter standards related to NAMS position statements have been described in an editorial.[5]) The NAMS Board of Trustees was responsible for the final review and approval of this document. Updates to this revised position statement will be published as developments occur in scientific research that substantially alters the conclusions.
http://www.medscape.com/viewarticle/714984
Tuesday, July 6, 2010
HOW TO REGISTER AS A VOTERS - Malaysia
WHAT IS MEANT BY THE REGISTRATION OF ELECTORS ?
The Registration of Electors, as provided for under the law, enables qualified Malaysian citizens to register as electors. The registration is carried out throughout the year. In addition it allows the Registered Electors who have changed their address to register at the new place of residence. Electors are also encouraged to check their names in the verified Electoral Rolls.
WHY DO YOU NEED TO REGISTER ?
To secure your right to vote in an election and exercise your right as a citizen.
WHO IS A QUALIFIED ELECTOR?
- A Malaysian citizen
- Has attained 21 years of age:
- Is residing in any Election Constituency in Malaysia; and
- Has not been disqualified.
HOW TO REGISTER ?
- Go personally to the Registration Centre;
- Take along your Identity Card;
- Ensure Form A is correctly filled by the staff before signing the form; and
- Keep one copy of the form as proof of your registration.
WHERE CAN YOU REGISTER ?
Election Commission of Malaysia Headquarters
OR
State Election Offices
OR
All Post Offices with computer facilities in the country;
Commission’s mobile teams;
AND
Other places specified by the Election Commission as Registration Centres.
The Registration of Electors, as provided for under the law, enables qualified Malaysian citizens to register as electors. The registration is carried out throughout the year. In addition it allows the Registered Electors who have changed their address to register at the new place of residence. Electors are also encouraged to check their names in the verified Electoral Rolls.
WHY DO YOU NEED TO REGISTER ?
To secure your right to vote in an election and exercise your right as a citizen.
WHO IS A QUALIFIED ELECTOR?
- A Malaysian citizen
- Has attained 21 years of age:
- Is residing in any Election Constituency in Malaysia; and
- Has not been disqualified.
HOW TO REGISTER ?
- Go personally to the Registration Centre;
- Take along your Identity Card;
- Ensure Form A is correctly filled by the staff before signing the form; and
- Keep one copy of the form as proof of your registration.
WHERE CAN YOU REGISTER ?
Election Commission of Malaysia Headquarters
OR
State Election Offices
OR
All Post Offices with computer facilities in the country;
Commission’s mobile teams;
AND
Other places specified by the Election Commission as Registration Centres.
Monday, July 5, 2010
Increased CV Events Halts Testosterone Trial in Older Men
From Medscape Medical News
Fran Lowry
July 1, 2010 — Testosterone treatment in men aged 65 years and older who have limitations in mobility is associated with an increased risk for cardiovascular events, including myocardial infarction and hypertension, according to a study published online June 30 in the New England Journal of Medicine.
Because of these events, the treatment phase of the trial, which was supported by the National Institute on Aging of the National Institutes of Health, has been stopped.
"In men, an age-related decline in the serum testosterone concentration is associated with reduced muscle mass and lower extremity strength, limitations in physical function, and poor mobility," write Shehzad Basaria, MD, from Boston University School of Medicine, Massachusetts, and colleagues. "Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men. The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied."
The Testosterone in Older Men with Mobility Limitations trial was undertaken to address this question.
In the trial, 209 men were randomly assigned to receive 10 g of a transdermal gel, containing either placebo or 100 mg of testosterone, to be applied to the skin once daily for 6 months. Efficacy outcomes were changes in chest- and leg-press strength and the ability to walk and climb stairs.
The men in the trial were an average of 74 years old and had high rates of chronic diseases such as diabetes and cardiovascular disease.
The treatment phase of the trial was stopped on December 31, 2009, after a review by the study's data and safety monitoring board, which found that 23 of the 106 men who had received testosterone experienced adverse cardiovascular-related events during the study compared with 5 of the 103 men who received placebo. In addition, 7 men in the testosterone group and 1 in the placebo group had atherosclerosis-related events.
The cardiovascular-related events included myocardial infarction, arrhythmias, hypertension, and 1 death from a suspected myocardial infarction.
At the time the trial was stopped, the testosterone group had significantly greater improvements in leg-press and chest-press strength, and in stair climbing while carrying a load.
Limited Generalizability
The study authors write that the generalizability of their data about the safety of testosterone is limited by several factors, including the study's small size and the fact that the study population was older and had higher rates of chronic diseases and mobility limitation than individuals in most other studies.
They note that physicians and patients, especially older men, should consider the study findings on adverse effects along with other information on the risks and benefits of testosterone therapy, and that further research is needed to clarify the safety issues raised by this trial.
The authors also state that chance may have played a role in the outcomes observed, and that the diversity of the adverse cardiac events that were seen in the prematurely terminated trial makes them less easily explained by a single mechanistic explanation.
Finally, the study authors caution against extrapolating their study findings to other doses and formulations of testosterone or to other populations, "particularly young men who have hypogonadism without cardiovascular disease or limitations in mobility."
The study was funded by the National Institute on Aging of the National Institutes of Health. Dr. Basaria reports financial relationships with Novartis, GlaxoSmithKline, Solvay Pharmaceuticals, Merck, and Ligand Pharmaceuticals.
N Engl J Med. Published online June 30, 2010.
Fran Lowry
July 1, 2010 — Testosterone treatment in men aged 65 years and older who have limitations in mobility is associated with an increased risk for cardiovascular events, including myocardial infarction and hypertension, according to a study published online June 30 in the New England Journal of Medicine.
Because of these events, the treatment phase of the trial, which was supported by the National Institute on Aging of the National Institutes of Health, has been stopped.
"In men, an age-related decline in the serum testosterone concentration is associated with reduced muscle mass and lower extremity strength, limitations in physical function, and poor mobility," write Shehzad Basaria, MD, from Boston University School of Medicine, Massachusetts, and colleagues. "Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men. The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied."
The Testosterone in Older Men with Mobility Limitations trial was undertaken to address this question.
In the trial, 209 men were randomly assigned to receive 10 g of a transdermal gel, containing either placebo or 100 mg of testosterone, to be applied to the skin once daily for 6 months. Efficacy outcomes were changes in chest- and leg-press strength and the ability to walk and climb stairs.
The men in the trial were an average of 74 years old and had high rates of chronic diseases such as diabetes and cardiovascular disease.
The treatment phase of the trial was stopped on December 31, 2009, after a review by the study's data and safety monitoring board, which found that 23 of the 106 men who had received testosterone experienced adverse cardiovascular-related events during the study compared with 5 of the 103 men who received placebo. In addition, 7 men in the testosterone group and 1 in the placebo group had atherosclerosis-related events.
The cardiovascular-related events included myocardial infarction, arrhythmias, hypertension, and 1 death from a suspected myocardial infarction.
At the time the trial was stopped, the testosterone group had significantly greater improvements in leg-press and chest-press strength, and in stair climbing while carrying a load.
Limited Generalizability
The study authors write that the generalizability of their data about the safety of testosterone is limited by several factors, including the study's small size and the fact that the study population was older and had higher rates of chronic diseases and mobility limitation than individuals in most other studies.
They note that physicians and patients, especially older men, should consider the study findings on adverse effects along with other information on the risks and benefits of testosterone therapy, and that further research is needed to clarify the safety issues raised by this trial.
The authors also state that chance may have played a role in the outcomes observed, and that the diversity of the adverse cardiac events that were seen in the prematurely terminated trial makes them less easily explained by a single mechanistic explanation.
Finally, the study authors caution against extrapolating their study findings to other doses and formulations of testosterone or to other populations, "particularly young men who have hypogonadism without cardiovascular disease or limitations in mobility."
The study was funded by the National Institute on Aging of the National Institutes of Health. Dr. Basaria reports financial relationships with Novartis, GlaxoSmithKline, Solvay Pharmaceuticals, Merck, and Ligand Pharmaceuticals.
N Engl J Med. Published online June 30, 2010.
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