Mary Ann Moon

The fetuses of women who took SSRIs during pregnancy showed reduced growth of the head but not the body in a study published online March 5 in Archives of General Psychiatry.

In contrast, the fetuses of women who had depressive symptoms but did not take SSRIs during pregnancy showed growth restriction of the entire body, including the head. "Our results indicate a rather specific effect of SSRI use during pregnancy, which differs from [the effect of] depressive symptoms on the fetus," said Hanan El Marroun, Ph.D., of the department of child and adolescent psychiatry, Sophia Children’s Hospital, Rotterdam, the Netherlands, and associates.

Terry Rudd/Elsevier Global Medical News

Fetal head growth is "one of the best prenatal markers of brain volume," and reduced head growth has been linked to poor cognitive performance, behavioral problems, and psychiatric disorders later in life. "Nonetheless, we must be careful not to infer an association of SSRI use in pregnancy with future developmental problems. ... [M]ore long-term drug safety studies are needed before evidence-based recommendations can be derived," the investigators noted.

"Our findings further raise the question whether maternal SSRI treatment during pregnancy is better or worse for the fetus than untreated maternal depression, "they added.

Dr. El Marroun and colleagues studied the relationship between depression and fetal growth using data from the Generation R Study, a population-based prospective cohort study of the offspring of nearly 10,000 women who gave birth in Rotterdam between 2002 and 2006. The children were studied from early fetal life (by means of detailed ultrasonography) through birth and infancy.

For their analysis, Dr. El Marroun and associates assessed 7,696 mother-infant pairs. Most of the mothers (7,027, or 91.3%), who had few depressive symptoms and did not use SSRIs, formed the control group. Another 570 mothers (7.4%) had clinically relevant depressive symptoms but did not use SSRIs, while the remaining 99 mothers (1.3%) used SSRIs during pregnancy.

Mean depression scores on the depression scale of the Brief Symptom Inventory were 0.10 in the control group, 1.45 in the women with depressive symptoms but no SSRIs, and 0.74 for the women taking SSRIs.

Fetuses of women who were depressed but not taking SSRIs showed a slower rate of weight gain, approximately 4.4 g/wk less than the control group. Fetuses of women in the SSRI group showed no such reduction in overall growth.

Fetuses of women who were depressed but not taking SSRIs also showed a reduced head circumference, which was in line with their generally slower weight gain. However, fetuses of mothers using SSRIs showed a much more pronounced reduction in head circumference that was not in line with their normal weight gain.

This link between maternal SSRI use and reduced fetal head circumference remained robust through a series of analyses that adjusted for potentially confounding factors such as maternal ethnicity, smoking status, use of benzodiazepines, and severity of depressive symptoms. However, the effect of maternal SSRI use on head growth was characterized as "rather small," with reductions of only 4 mm or less, the investigators said (Arch. Gen. Psychiatry 2012 March 5 [doi:10.1001/archgenpsychiatry.2011.2333]).

In addition, children born to women using SSRIs were twice as likely to be born preterm as were controls. The absolute rates of preterm birth were 5.1% in the control group, 6.3% in the mothers with depressive symptoms who weren’t taking SSRIs, and 10.1% in the mothers taking SSRIs.

The reason why SSRIs might restrict fetal head growth is not known.

It is possible that treated women had more severe depression than untreated women, or that they had experienced previous bouts of depression. Either scenario could affect maternal physiology, and thus fetal development, the researchers said.

It also is possible that manipulating serotonin levels with SSRIs could directly affect fetal brain growth, as serotonin is known to play an important role in prenatal brain development.

A third possibility is that "epiphenomena of SSRI use" such as smoking, drinking, low socioeconomic status, family stress, malnutrition, or genetic susceptibility could affect fetal head growth. However, when epiphenomena compromise fetal growth, they typically impair head growth last of all, which is known as the brain-sparing effect, Dr. El Marroun and colleagues said.

The study results reinforce that "clinicians must carefully weigh the known risks of untreated depression during pregnancy and the possible adverse effects of SSRIs," they said.

This study was supported by the Sophia Children’s Hospital Foundation and the Netherlands Organization for Health Research and Development (NOHRD). The Generation R Study was supported by Erasmus Medical Centre Rotterdam, Erasmus University Rotterdam, the Netherlands Organization for Scientific Research, and NOHRD. The authors reported no relevant financial disclosures.

The fetuses of women who took SSRIs during pregnancy showed reduced growth of the head but not the body in a study published online March 5 in Archives of General Psychiatry.

In contrast, the fetuses of women who had depressive symptoms but did not take SSRIs during pregnancy showed growth restriction of the entire body, including the head. "Our results indicate a rather specific effect of SSRI use during pregnancy, which differs from [the effect of] depressive symptoms on the fetus," said Hanan El Marroun, Ph.D., of the department of child and adolescent psychiatry, Sophia Children’s Hospital, Rotterdam, the Netherlands, and associates.

Terry Rudd/Elsevier Global Medical News

Fetal head growth is "one of the best prenatal markers of brain volume," and reduced head growth has been linked to poor cognitive performance, behavioral problems, and psychiatric disorders later in life. "Nonetheless, we must be careful not to infer an association of SSRI use in pregnancy with future developmental problems. ... [M]ore long-term drug safety studies are needed before evidence-based recommendations can be derived," the investigators noted.

"Our findings further raise the question whether maternal SSRI treatment during pregnancy is better or worse for the fetus than untreated maternal depression, "they added.

Dr. El Marroun and colleagues studied the relationship between depression and fetal growth using data from the Generation R Study, a population-based prospective cohort study of the offspring of nearly 10,000 women who gave birth in Rotterdam between 2002 and 2006. The children were studied from early fetal life (by means of detailed ultrasonography) through birth and infancy.

For their analysis, Dr. El Marroun and associates assessed 7,696 mother-infant pairs. Most of the mothers (7,027, or 91.3%), who had few depressive symptoms and did not use SSRIs, formed the control group. Another 570 mothers (7.4%) had clinically relevant depressive symptoms but did not use SSRIs, while the remaining 99 mothers (1.3%) used SSRIs during pregnancy.

Mean depression scores on the depression scale of the Brief Symptom Inventory were 0.10 in the control group, 1.45 in the women with depressive symptoms but no SSRIs, and 0.74 for the women taking SSRIs.

Fetuses of women who were depressed but not taking SSRIs showed a slower rate of weight gain, approximately 4.4 g/wk less than the control group. Fetuses of women in the SSRI group showed no such reduction in overall growth.

Fetuses of women who were depressed but not taking SSRIs also showed a reduced head circumference, which was in line with their generally slower weight gain. However, fetuses of mothers using SSRIs showed a much more pronounced reduction in head circumference that was not in line with their normal weight gain.

This link between maternal SSRI use and reduced fetal head circumference remained robust through a series of analyses that adjusted for potentially confounding factors such as maternal ethnicity, smoking status, use of benzodiazepines, and severity of depressive symptoms. However, the effect of maternal SSRI use on head growth was characterized as "rather small," with reductions of only 4 mm or less, the investigators said (Arch. Gen. Psychiatry 2012 March 5 [doi:10.1001/archgenpsychiatry.2011.2333]).

In addition, children born to women using SSRIs were twice as likely to be born preterm as were controls. The absolute rates of preterm birth were 5.1% in the control group, 6.3% in the mothers with depressive symptoms who weren’t taking SSRIs, and 10.1% in the mothers taking SSRIs.

The reason why SSRIs might restrict fetal head growth is not known.

It is possible that treated women had more severe depression than untreated women, or that they had experienced previous bouts of depression. Either scenario could affect maternal physiology, and thus fetal development, the researchers said.

It also is possible that manipulating serotonin levels with SSRIs could directly affect fetal brain growth, as serotonin is known to play an important role in prenatal brain development.

A third possibility is that "epiphenomena of SSRI use" such as smoking, drinking, low socioeconomic status, family stress, malnutrition, or genetic susceptibility could affect fetal head growth. However, when epiphenomena compromise fetal growth, they typically impair head growth last of all, which is known as the brain-sparing effect, Dr. El Marroun and colleagues said.

The study results reinforce that "clinicians must carefully weigh the known risks of untreated depression during pregnancy and the possible adverse effects of SSRIs," they said.

This study was supported by the Sophia Children’s Hospital Foundation and the Netherlands Organization for Health Research and Development (NOHRD). The Generation R Study was supported by Erasmus Medical Centre Rotterdam, Erasmus University Rotterdam, the Netherlands Organization for Scientific Research, and NOHRD. The authors reported no relevant financial disclosures.

The fetuses of women who took SSRIs during pregnancy showed reduced growth of the head but not the body in a study published online March 5 in Archives of General Psychiatry.

In contrast, the fetuses of women who had depressive symptoms but did not take SSRIs during pregnancy showed growth restriction of the entire body, including the head. "Our results indicate a rather specific effect of SSRI use during pregnancy, which differs from [the effect of] depressive symptoms on the fetus," said Hanan El Marroun, Ph.D., of the department of child and adolescent psychiatry, Sophia Children’s Hospital, Rotterdam, the Netherlands, and associates.

Terry Rudd/Elsevier Global Medical News

Fetal head growth is "one of the best prenatal markers of brain volume," and reduced head growth has been linked to poor cognitive performance, behavioral problems, and psychiatric disorders later in life. "Nonetheless, we must be careful not to infer an association of SSRI use in pregnancy with future developmental problems. ... [M]ore long-term drug safety studies are needed before evidence-based recommendations can be derived," the investigators noted.

"Our findings further raise the question whether maternal SSRI treatment during pregnancy is better or worse for the fetus than untreated maternal depression, "they added.

Dr. El Marroun and colleagues studied the relationship between depression and fetal growth using data from the Generation R Study, a population-based prospective cohort study of the offspring of nearly 10,000 women who gave birth in Rotterdam between 2002 and 2006. The children were studied from early fetal life (by means of detailed ultrasonography) through birth and infancy.

For their analysis, Dr. El Marroun and associates assessed 7,696 mother-infant pairs. Most of the mothers (7,027, or 91.3%), who had few depressive symptoms and did not use SSRIs, formed the control group. Another 570 mothers (7.4%) had clinically relevant depressive symptoms but did not use SSRIs, while the remaining 99 mothers (1.3%) used SSRIs during pregnancy.

Mean depression scores on the depression scale of the Brief Symptom Inventory were 0.10 in the control group, 1.45 in the women with depressive symptoms but no SSRIs, and 0.74 for the women taking SSRIs.

Fetuses of women who were depressed but not taking SSRIs showed a slower rate of weight gain, approximately 4.4 g/wk less than the control group. Fetuses of women in the SSRI group showed no such reduction in overall growth.

Fetuses of women who were depressed but not taking SSRIs also showed a reduced head circumference, which was in line with their generally slower weight gain. However, fetuses of mothers using SSRIs showed a much more pronounced reduction in head circumference that was not in line with their normal weight gain.

This link between maternal SSRI use and reduced fetal head circumference remained robust through a series of analyses that adjusted for potentially confounding factors such as maternal ethnicity, smoking status, use of benzodiazepines, and severity of depressive symptoms. However, the effect of maternal SSRI use on head growth was characterized as "rather small," with reductions of only 4 mm or less, the investigators said (Arch. Gen. Psychiatry 2012 March 5 [doi:10.1001/archgenpsychiatry.2011.2333]).

In addition, children born to women using SSRIs were twice as likely to be born preterm as were controls. The absolute rates of preterm birth were 5.1% in the control group, 6.3% in the mothers with depressive symptoms who weren’t taking SSRIs, and 10.1% in the mothers taking SSRIs.

The reason why SSRIs might restrict fetal head growth is not known.

It is possible that treated women had more severe depression than untreated women, or that they had experienced previous bouts of depression. Either scenario could affect maternal physiology, and thus fetal development, the researchers said.

It also is possible that manipulating serotonin levels with SSRIs could directly affect fetal brain growth, as serotonin is known to play an important role in prenatal brain development.

A third possibility is that "epiphenomena of SSRI use" such as smoking, drinking, low socioeconomic status, family stress, malnutrition, or genetic susceptibility could affect fetal head growth. However, when epiphenomena compromise fetal growth, they typically impair head growth last of all, which is known as the brain-sparing effect, Dr. El Marroun and colleagues said.

The study results reinforce that "clinicians must carefully weigh the known risks of untreated depression during pregnancy and the possible adverse effects of SSRIs," they said.

This study was supported by the Sophia Children’s Hospital Foundation and the Netherlands Organization for Health Research and Development (NOHRD). The Generation R Study was supported by Erasmus Medical Centre Rotterdam, Erasmus University Rotterdam, the Netherlands Organization for Scientific Research, and NOHRD. The authors reported no relevant financial disclosures.

Major Finding: None of the eight commercial disease-management companies participating in the pilot program improved quality of care, reduced hospital admissions, decreased emergency department visits, or cut health care costs.

Data Source: A randomized study of eight commercial programs for disease management involving 242,417 Medicare patients with chronic heart failure or diabetes.

Disclosures: This study was funded, designed, conducted, and presented for publication by RTI International. No financial conflicts of interest were reported.

Eight commercial disease-management companies using nurse-based telephone care programs failed to improve quality of care, reduce hospital admissions, decrease emergency department visits, or cut health care costs in a pilot project of fee-for-service Medicare patients.

The Medicare Modernization Act of 2003 mandated that the Centers for Medicare and Medicaid Services test a commercial model for chronic disease management in its fee-for-service beneficiaries.

The agency launched the Medicare Health Support Pilot Program to test this model in 2005, contracting with companies to cover approximately 30,000 chronically ill patients each in eight geographic locations, for a total of about 240,000 patients.

These companies used nurse-based call centers to assess the needs of patients with diabetes and/or heart failure. Each program used “coaches” to improve patients' understanding of their disease(s), their ability to manage self-care, and their ability to communicate with providers.

Companies were required to meet preset targets for clinical quality and patient satisfaction, and to hold health care costs under a preset limit. An independent group, RTI International, won a competitive bid to evaluate the programs.

However, before the evaluation could be completed, five of the eight companies incurred such “substantial financial liability” that they terminated their programs, according to Nancy McCall, Sc.D., and Jerry Cromwell, Ph.D., of RTI International in Washington.

The 242,417 patients who constituted the study subjects were randomly assigned to receive the disease-management services being tested (163,107 subjects) or usual care (79,310 subjects).

All the patients were “quite sick,” requiring at least one hospitalization every year, having substantial comorbidities along with chronic heart failure or diabetes, and incurring an average of $15,000 in Medicare expenditures annually.

All companies were assessed, in comparison with usual care, on 40 evidence-based process-of-care measures. Only seven of these measures represented improvements over usual care, and the absolute percentage-point differences between the groups were found to be negligible.

The disease-management programs “had little success” in curbing hospital admissions and emergency department visits, both for any medical condition in general and for conditions amenable to ambulatory care in particular, the investigators said (N. Engl. J. Med. 2011;365:1704-12).

And average monthly health care costs increased substantially for all patients in the disease-management groups.

Dr. McCall and Dr. Cromwell suggested several possible explanations for the results.

One is that medical care of elderly, chronically ill patients typically covered by Medicare and Medicaid is inherently difficult and expensive, unlike the care of the average patient covered by a commercial disease-management program.

“The health coaches were surprised by the number of health and psychosocial problems that were prevalent among Medicare fee-for-service beneficiaries,” they noted.

In addition, “the unpredictable nature and immediacy of chronic disease flare-ups call for real-time information on health status.” The commercial disease-management programs, with their relative inflexibility, often failed to provide services before patients sought costly acute and/or inpatient care elsewhere.

These findings show “it is unlikely that simply managing the care of elderly patients through telephone contact or an occasional visit will achieve the level of savings Congress had hoped for when it mandated the Medicare Health Support Pilot Program,” Dr. McCall and Dr. Cromwell said.

The results also “suggest that for such programs to be effective, they need to include intensive, costly, personal clinical attention,” they added.

Major Finding: None of the eight commercial disease-management companies participating in the pilot program improved quality of care, reduced hospital admissions, decreased emergency department visits, or cut health care costs.

Data Source: A randomized study of eight commercial programs for disease management involving 242,417 Medicare patients with chronic heart failure or diabetes.

Disclosures: This study was funded, designed, conducted, and presented for publication by RTI International. No financial conflicts of interest were reported.

Eight commercial disease-management companies using nurse-based telephone care programs failed to improve quality of care, reduce hospital admissions, decrease emergency department visits, or cut health care costs in a pilot project of fee-for-service Medicare patients.

The Medicare Modernization Act of 2003 mandated that the Centers for Medicare and Medicaid Services test a commercial model for chronic disease management in its fee-for-service beneficiaries.

The agency launched the Medicare Health Support Pilot Program to test this model in 2005, contracting with companies to cover approximately 30,000 chronically ill patients each in eight geographic locations, for a total of about 240,000 patients.

These companies used nurse-based call centers to assess the needs of patients with diabetes and/or heart failure. Each program used “coaches” to improve patients' understanding of their disease(s), their ability to manage self-care, and their ability to communicate with providers.

Companies were required to meet preset targets for clinical quality and patient satisfaction, and to hold health care costs under a preset limit. An independent group, RTI International, won a competitive bid to evaluate the programs.

However, before the evaluation could be completed, five of the eight companies incurred such “substantial financial liability” that they terminated their programs, according to Nancy McCall, Sc.D., and Jerry Cromwell, Ph.D., of RTI International in Washington.

The 242,417 patients who constituted the study subjects were randomly assigned to receive the disease-management services being tested (163,107 subjects) or usual care (79,310 subjects).

All the patients were “quite sick,” requiring at least one hospitalization every year, having substantial comorbidities along with chronic heart failure or diabetes, and incurring an average of $15,000 in Medicare expenditures annually.

All companies were assessed, in comparison with usual care, on 40 evidence-based process-of-care measures. Only seven of these measures represented improvements over usual care, and the absolute percentage-point differences between the groups were found to be negligible.

The disease-management programs “had little success” in curbing hospital admissions and emergency department visits, both for any medical condition in general and for conditions amenable to ambulatory care in particular, the investigators said (N. Engl. J. Med. 2011;365:1704-12).

And average monthly health care costs increased substantially for all patients in the disease-management groups.

Dr. McCall and Dr. Cromwell suggested several possible explanations for the results.

One is that medical care of elderly, chronically ill patients typically covered by Medicare and Medicaid is inherently difficult and expensive, unlike the care of the average patient covered by a commercial disease-management program.

“The health coaches were surprised by the number of health and psychosocial problems that were prevalent among Medicare fee-for-service beneficiaries,” they noted.

In addition, “the unpredictable nature and immediacy of chronic disease flare-ups call for real-time information on health status.” The commercial disease-management programs, with their relative inflexibility, often failed to provide services before patients sought costly acute and/or inpatient care elsewhere.

These findings show “it is unlikely that simply managing the care of elderly patients through telephone contact or an occasional visit will achieve the level of savings Congress had hoped for when it mandated the Medicare Health Support Pilot Program,” Dr. McCall and Dr. Cromwell said.

The results also “suggest that for such programs to be effective, they need to include intensive, costly, personal clinical attention,” they added.

Major Finding: None of the eight commercial disease-management companies participating in the pilot program improved quality of care, reduced hospital admissions, decreased emergency department visits, or cut health care costs.

Data Source: A randomized study of eight commercial programs for disease management involving 242,417 Medicare patients with chronic heart failure or diabetes.

Disclosures: This study was funded, designed, conducted, and presented for publication by RTI International. No financial conflicts of interest were reported.

Eight commercial disease-management companies using nurse-based telephone care programs failed to improve quality of care, reduce hospital admissions, decrease emergency department visits, or cut health care costs in a pilot project of fee-for-service Medicare patients.

The Medicare Modernization Act of 2003 mandated that the Centers for Medicare and Medicaid Services test a commercial model for chronic disease management in its fee-for-service beneficiaries.

The agency launched the Medicare Health Support Pilot Program to test this model in 2005, contracting with companies to cover approximately 30,000 chronically ill patients each in eight geographic locations, for a total of about 240,000 patients.

These companies used nurse-based call centers to assess the needs of patients with diabetes and/or heart failure. Each program used “coaches” to improve patients' understanding of their disease(s), their ability to manage self-care, and their ability to communicate with providers.

Companies were required to meet preset targets for clinical quality and patient satisfaction, and to hold health care costs under a preset limit. An independent group, RTI International, won a competitive bid to evaluate the programs.

However, before the evaluation could be completed, five of the eight companies incurred such “substantial financial liability” that they terminated their programs, according to Nancy McCall, Sc.D., and Jerry Cromwell, Ph.D., of RTI International in Washington.

The 242,417 patients who constituted the study subjects were randomly assigned to receive the disease-management services being tested (163,107 subjects) or usual care (79,310 subjects).

All the patients were “quite sick,” requiring at least one hospitalization every year, having substantial comorbidities along with chronic heart failure or diabetes, and incurring an average of $15,000 in Medicare expenditures annually.

All companies were assessed, in comparison with usual care, on 40 evidence-based process-of-care measures. Only seven of these measures represented improvements over usual care, and the absolute percentage-point differences between the groups were found to be negligible.

The disease-management programs “had little success” in curbing hospital admissions and emergency department visits, both for any medical condition in general and for conditions amenable to ambulatory care in particular, the investigators said (N. Engl. J. Med. 2011;365:1704-12).

And average monthly health care costs increased substantially for all patients in the disease-management groups.

Dr. McCall and Dr. Cromwell suggested several possible explanations for the results.

One is that medical care of elderly, chronically ill patients typically covered by Medicare and Medicaid is inherently difficult and expensive, unlike the care of the average patient covered by a commercial disease-management program.

“The health coaches were surprised by the number of health and psychosocial problems that were prevalent among Medicare fee-for-service beneficiaries,” they noted.

In addition, “the unpredictable nature and immediacy of chronic disease flare-ups call for real-time information on health status.” The commercial disease-management programs, with their relative inflexibility, often failed to provide services before patients sought costly acute and/or inpatient care elsewhere.

These findings show “it is unlikely that simply managing the care of elderly patients through telephone contact or an occasional visit will achieve the level of savings Congress had hoped for when it mandated the Medicare Health Support Pilot Program,” Dr. McCall and Dr. Cromwell said.

The results also “suggest that for such programs to be effective, they need to include intensive, costly, personal clinical attention,” they added.

The nicotine replacement patch was no more effective than a placebo patch was in promoting sustained abstinence from smoking in a study of 1,050 pregnant women published in the March 1 issue of the New England Journal of Medicine.

In addition, "there was no evidence that nicotine replacement therapy had either a beneficial or harmful effect on birth outcomes." However, adherence rates in this study were so low that the researchers’ ability to assess safety was severely limited, said Dr. Tim Coleman of the U.K. Centre for Tobacco Control Studies and the National Institute for Health Research School for Primary Care Research, Nottingham, and his associates.

"[Our] findings suggest that guidelines for smoking cessation in pregnancy should be revised to encourage the use of only those interventions that have a secure evidence base – specifically, behavioral support," they noted.

Use of the nicotine replacement patch is recommended in several such sets of guidelines, owing to the general consensus that it is probably less harmful than smoking is during pregnancy. But there is no good evidence to support such recommendations because individual clinical trials have been too small to definitively establish whether the patch is either effective or safe, and since a meta-analysis of these studies yielded inconclusive results, Dr. Coleman and his colleagues said.

They performed a multicenter, double-blind, randomized clinical trial involving women at 12-24 weeks’ gestation who were heavy smokers and who agreed, at a regular prenatal clinic visit, to set a quit date. On that day, the study subjects were randomly assigned to receive a 1-month supply of transdermal nicotine-replacement patches (521 women) or placebo patches (529 women).

In addition, midwives who were trained in smoking-cessation techniques provided behavioral support at enrollment, on the quit date, 3 days later, and at the 1-month visit. At that visit, study subjects who had quit smoking were given another 1-month supply of patches.

The women "were offered additional support from local National Health Service smoking-cessation services and were encouraged to ask for support from the midwives or smoking-cessation staff."

The midwives later ascertained the study subjects’ smoking status when they were admitted to the hospital for delivery. They also noted how much behavioral support the women had used and their use of study patches, as well as any nonstudy nicotine replacement therapy.

The primary outcome was self-reported abstinence from smoking between the quit date and delivery, which was validated by analysis of exhaled carbon monoxide and salivary cotinine levels. This rate was 9.4% with active patches and 7.6% with placebo patches, a nonsignificant difference, the investigators said (N. Engl. J. Med. 2012;366:808-18).

After the first month of patch use, the rate of smoking abstinence had been significantly higher with active treatment (21.3%) than with placebo (11.7%), but this difference had not persisted beyond that point, largely because of poor compliance. Only 7.2% of the women in the nicotine-replacement group and only 2.8% of those in the placebo group reported using their patches for more than 1 month.

Most of the women had no further contact with their smoking-cessation counselors after the 1-month visit, and very few sought nonstudy smoking-cessation therapy.

Mean birth weights, rates of preterm birth, rates of low birth weight, and rates of congenital abnormalities were similar between the two study groups. There were significantly more cesarean deliveries in the nicotine-replacement group (20.7%) than in the placebo group (15.3%) – an unexpected finding that "seems likely to be a chance occurrence."

"A much larger sample would be required to comprehensively assess the effect of this therapy on infrequent adverse birth outcomes," Dr. Coleman and his associates noted.

"It is possible that for nicotine-replacement therapy to consistently ameliorate nicotine withdrawal symptoms and be effective throughout pregnancy, a higher dose is required. However, this trial did not include assessment of nicotine metabolism and did not assess withdrawal symptoms," they added.

This study was supported by the U.K. National Institute for Health Research’s Health Technology Assessment Programme. Dr. Sue Cooper reported ties to Action on Smoking and Health Scotland. No financial conflicts of interest were reported by the other researchers.

The nicotine replacement patch was no more effective than a placebo patch was in promoting sustained abstinence from smoking in a study of 1,050 pregnant women published in the March 1 issue of the New England Journal of Medicine.

In addition, "there was no evidence that nicotine replacement therapy had either a beneficial or harmful effect on birth outcomes." However, adherence rates in this study were so low that the researchers’ ability to assess safety was severely limited, said Dr. Tim Coleman of the U.K. Centre for Tobacco Control Studies and the National Institute for Health Research School for Primary Care Research, Nottingham, and his associates.

"[Our] findings suggest that guidelines for smoking cessation in pregnancy should be revised to encourage the use of only those interventions that have a secure evidence base – specifically, behavioral support," they noted.

Use of the nicotine replacement patch is recommended in several such sets of guidelines, owing to the general consensus that it is probably less harmful than smoking is during pregnancy. But there is no good evidence to support such recommendations because individual clinical trials have been too small to definitively establish whether the patch is either effective or safe, and since a meta-analysis of these studies yielded inconclusive results, Dr. Coleman and his colleagues said.

They performed a multicenter, double-blind, randomized clinical trial involving women at 12-24 weeks’ gestation who were heavy smokers and who agreed, at a regular prenatal clinic visit, to set a quit date. On that day, the study subjects were randomly assigned to receive a 1-month supply of transdermal nicotine-replacement patches (521 women) or placebo patches (529 women).

In addition, midwives who were trained in smoking-cessation techniques provided behavioral support at enrollment, on the quit date, 3 days later, and at the 1-month visit. At that visit, study subjects who had quit smoking were given another 1-month supply of patches.

The women "were offered additional support from local National Health Service smoking-cessation services and were encouraged to ask for support from the midwives or smoking-cessation staff."

The midwives later ascertained the study subjects’ smoking status when they were admitted to the hospital for delivery. They also noted how much behavioral support the women had used and their use of study patches, as well as any nonstudy nicotine replacement therapy.

The primary outcome was self-reported abstinence from smoking between the quit date and delivery, which was validated by analysis of exhaled carbon monoxide and salivary cotinine levels. This rate was 9.4% with active patches and 7.6% with placebo patches, a nonsignificant difference, the investigators said (N. Engl. J. Med. 2012;366:808-18).

After the first month of patch use, the rate of smoking abstinence had been significantly higher with active treatment (21.3%) than with placebo (11.7%), but this difference had not persisted beyond that point, largely because of poor compliance. Only 7.2% of the women in the nicotine-replacement group and only 2.8% of those in the placebo group reported using their patches for more than 1 month.

Most of the women had no further contact with their smoking-cessation counselors after the 1-month visit, and very few sought nonstudy smoking-cessation therapy.

Mean birth weights, rates of preterm birth, rates of low birth weight, and rates of congenital abnormalities were similar between the two study groups. There were significantly more cesarean deliveries in the nicotine-replacement group (20.7%) than in the placebo group (15.3%) – an unexpected finding that "seems likely to be a chance occurrence."

"A much larger sample would be required to comprehensively assess the effect of this therapy on infrequent adverse birth outcomes," Dr. Coleman and his associates noted.

"It is possible that for nicotine-replacement therapy to consistently ameliorate nicotine withdrawal symptoms and be effective throughout pregnancy, a higher dose is required. However, this trial did not include assessment of nicotine metabolism and did not assess withdrawal symptoms," they added.

This study was supported by the U.K. National Institute for Health Research’s Health Technology Assessment Programme. Dr. Sue Cooper reported ties to Action on Smoking and Health Scotland. No financial conflicts of interest were reported by the other researchers.

The nicotine replacement patch was no more effective than a placebo patch was in promoting sustained abstinence from smoking in a study of 1,050 pregnant women published in the March 1 issue of the New England Journal of Medicine.

In addition, "there was no evidence that nicotine replacement therapy had either a beneficial or harmful effect on birth outcomes." However, adherence rates in this study were so low that the researchers’ ability to assess safety was severely limited, said Dr. Tim Coleman of the U.K. Centre for Tobacco Control Studies and the National Institute for Health Research School for Primary Care Research, Nottingham, and his associates.

"[Our] findings suggest that guidelines for smoking cessation in pregnancy should be revised to encourage the use of only those interventions that have a secure evidence base – specifically, behavioral support," they noted.

Use of the nicotine replacement patch is recommended in several such sets of guidelines, owing to the general consensus that it is probably less harmful than smoking is during pregnancy. But there is no good evidence to support such recommendations because individual clinical trials have been too small to definitively establish whether the patch is either effective or safe, and since a meta-analysis of these studies yielded inconclusive results, Dr. Coleman and his colleagues said.

They performed a multicenter, double-blind, randomized clinical trial involving women at 12-24 weeks’ gestation who were heavy smokers and who agreed, at a regular prenatal clinic visit, to set a quit date. On that day, the study subjects were randomly assigned to receive a 1-month supply of transdermal nicotine-replacement patches (521 women) or placebo patches (529 women).

In addition, midwives who were trained in smoking-cessation techniques provided behavioral support at enrollment, on the quit date, 3 days later, and at the 1-month visit. At that visit, study subjects who had quit smoking were given another 1-month supply of patches.

The women "were offered additional support from local National Health Service smoking-cessation services and were encouraged to ask for support from the midwives or smoking-cessation staff."

The midwives later ascertained the study subjects’ smoking status when they were admitted to the hospital for delivery. They also noted how much behavioral support the women had used and their use of study patches, as well as any nonstudy nicotine replacement therapy.

The primary outcome was self-reported abstinence from smoking between the quit date and delivery, which was validated by analysis of exhaled carbon monoxide and salivary cotinine levels. This rate was 9.4% with active patches and 7.6% with placebo patches, a nonsignificant difference, the investigators said (N. Engl. J. Med. 2012;366:808-18).

After the first month of patch use, the rate of smoking abstinence had been significantly higher with active treatment (21.3%) than with placebo (11.7%), but this difference had not persisted beyond that point, largely because of poor compliance. Only 7.2% of the women in the nicotine-replacement group and only 2.8% of those in the placebo group reported using their patches for more than 1 month.

Most of the women had no further contact with their smoking-cessation counselors after the 1-month visit, and very few sought nonstudy smoking-cessation therapy.

Mean birth weights, rates of preterm birth, rates of low birth weight, and rates of congenital abnormalities were similar between the two study groups. There were significantly more cesarean deliveries in the nicotine-replacement group (20.7%) than in the placebo group (15.3%) – an unexpected finding that "seems likely to be a chance occurrence."

"A much larger sample would be required to comprehensively assess the effect of this therapy on infrequent adverse birth outcomes," Dr. Coleman and his associates noted.

"It is possible that for nicotine-replacement therapy to consistently ameliorate nicotine withdrawal symptoms and be effective throughout pregnancy, a higher dose is required. However, this trial did not include assessment of nicotine metabolism and did not assess withdrawal symptoms," they added.

This study was supported by the U.K. National Institute for Health Research’s Health Technology Assessment Programme. Dr. Sue Cooper reported ties to Action on Smoking and Health Scotland. No financial conflicts of interest were reported by the other researchers.

A 4-week course of amantadine sped the rate of functional recovery in an international, randomized, double-blind, placebo-controlled trial of patients who had disorders of consciousness following traumatic brain injury.

Both patients given amantadine and those given placebo improved, but the rate of recovery was more rapid with the active drug. It affected "functionally meaningful behaviors such as consistent responses to commands, intelligible speech, reliable yes-or-no communication, and functional-object use," Joseph T. Giacino, Ph.D., of the JFK Johnson Rehabilitation Institute, Edison, N.J., and his associates reported in the March 1 issue of the New England Journal of Medicine.

The rate of recovery attenuated when treatment stopped, and scores on the Disability Rating Scale (DRS) were virtually indistinguishable between the treatment group and the control group 6 weeks later, indicating that the response was drug dependent.

"Practical and ethical constraints required the use of a brief treatment interval and a short-term assessment of the outcome [in this study], because we anticipated that caregivers would withdraw patients who were not making gains in order to try other treatments. Thus, our findings do not address the effects of prolonged treatment on long-term outcomes," the investigators noted.

"Whether treatment with amantadine, as compared with placebo, improves the long-term outcome or simply accelerates recovery en route to an equivalent level of function remains unknown."

The researchers conducted the trial after a pilot study indicated that amantadine improved functional outcomes after traumatic brain injury. They enrolled 184 patients aged 16-65 years who had sustained a nonpenetrating TBI 4-16 weeks previously and who were receiving usual inpatient rehabilitation at 11 medical centers in three countries.

Patients were diagnosed as being in a vegetative state, in which there was wakefulness without behavioral evidence of conscious awareness, or in a minimally conscious state, in which there was at least one clearly discernible behavioral sign of consciousness. All had scores above 11 on the DRS, which ranges from 0 (best) to 29 (worst); none were able to follow commands consistently or to engage in functional communication as assessed using the Coma Recovery Scale-Revised (CRS-R).

A total of 87 patients were randomly assigned to receive amantadine and 97 to receive a visually identical placebo for 4 weeks. They began at a dose of 100 mg twice daily, with escalations to 150 mg twice daily at week 3 and to 200 mg twice daily at week 4 if the DRS score had not improved by at least 2 points from baseline. Then the drug or placebo was tapered, and patients were assessed for another 6 weeks, according to Dr. Giacino and his associates. Dr. Giacino is also director of rehabilitation neuropsychology at the Spaulding Rehabilitation Hospital and is an associate professor in the department of physical medicine and rehabilitation at Harvard Medical School, both in Boston.

The primary outcome measure was the rate of improvement in the DRS score during treatment. DRS scores were assessed weekly by an interdisciplinary treatment team that was blinded to treatment assignment. Study personnel assessed clinically relevant behavioral benchmarks using the CRS-R.

Both study groups had significantly improved DRS scores at the end of the 4 weeks of treatment, but the amantadine group showed significantly faster improvement (–0.24 points/week more). In addition, at the final follow-up assessment, more patients in the amantadine group showed favorable outcomes on the DRS, fewer remained in a vegetative state, and more showed recovery of key behavioral benchmarks, Dr. Giacino and his colleagues said (N. Engl. J. Med. 2012;366:819-26). These benefits were consistent across all subgroups of patients. They were seen both in subjects in a minimally conscious state and in those in a vegetative state. And they were noted regardless of how long after the TBI injury the patients began treatment.

However, the treatment effect declined when drug therapy stopped, until there were no significant differences at the final follow-up assessment between patients who received the active drug and those who received placebo.

In particular, the proportion of patients who were able to engage in each of six clinically relevant behaviors was higher with amantadine during the month of therapy, but the difference between the two study groups was negligible at the final follow-up. These six behaviors were consistent command-following, object recognition, functional use of objects, intelligible verbalization, reliable yes-or-no communication, and sustained attention.

Amantadine "did not increase the risk of adverse medical, neurologic, or behavioral events, including those of greatest concern in this population (e.g., seizure)," the researchers noted.

The drug’s mechanism of action in these patients is uncertain. Amantadine is thought to promote dopaminergic activity "by facilitating presynaptic release and blocking reuptake postsynaptically." It may also enhance neurotransmission "in the dopamine-dependent nigrostriatal, mesolimbic, and frontostriatal circuits that are responsible for mediating arousal, drive, and attentional functions," they added.

"We conclude that amantadine is effective in accelerating the pace of recovery during acute rehabilitation in patients with prolonged post-traumatic disturbances in consciousness. Exposure to amantadine is associated with more rapid emergence of cognitively mediated behaviors that serve as the foundation for functional independence," Dr. Giacino and his associates wrote.

The study was supported by the U.S. National Institute on Disability and Rehabilitation Research. Dr. Giacino reported no relevant financial conflicts of interest, but a coauthor reported ties to Allergan, Merz, Ipsen, and Medtronic. Several other coauthors disclosed providing expert testimony on patients with TBI and disorders of consciousness.

A 4-week course of amantadine sped the rate of functional recovery in an international, randomized, double-blind, placebo-controlled trial of patients who had disorders of consciousness following traumatic brain injury.

Both patients given amantadine and those given placebo improved, but the rate of recovery was more rapid with the active drug. It affected "functionally meaningful behaviors such as consistent responses to commands, intelligible speech, reliable yes-or-no communication, and functional-object use," Joseph T. Giacino, Ph.D., of the JFK Johnson Rehabilitation Institute, Edison, N.J., and his associates reported in the March 1 issue of the New England Journal of Medicine.

The rate of recovery attenuated when treatment stopped, and scores on the Disability Rating Scale (DRS) were virtually indistinguishable between the treatment group and the control group 6 weeks later, indicating that the response was drug dependent.

"Practical and ethical constraints required the use of a brief treatment interval and a short-term assessment of the outcome [in this study], because we anticipated that caregivers would withdraw patients who were not making gains in order to try other treatments. Thus, our findings do not address the effects of prolonged treatment on long-term outcomes," the investigators noted.

"Whether treatment with amantadine, as compared with placebo, improves the long-term outcome or simply accelerates recovery en route to an equivalent level of function remains unknown."

The researchers conducted the trial after a pilot study indicated that amantadine improved functional outcomes after traumatic brain injury. They enrolled 184 patients aged 16-65 years who had sustained a nonpenetrating TBI 4-16 weeks previously and who were receiving usual inpatient rehabilitation at 11 medical centers in three countries.

Patients were diagnosed as being in a vegetative state, in which there was wakefulness without behavioral evidence of conscious awareness, or in a minimally conscious state, in which there was at least one clearly discernible behavioral sign of consciousness. All had scores above 11 on the DRS, which ranges from 0 (best) to 29 (worst); none were able to follow commands consistently or to engage in functional communication as assessed using the Coma Recovery Scale-Revised (CRS-R).

A total of 87 patients were randomly assigned to receive amantadine and 97 to receive a visually identical placebo for 4 weeks. They began at a dose of 100 mg twice daily, with escalations to 150 mg twice daily at week 3 and to 200 mg twice daily at week 4 if the DRS score had not improved by at least 2 points from baseline. Then the drug or placebo was tapered, and patients were assessed for another 6 weeks, according to Dr. Giacino and his associates. Dr. Giacino is also director of rehabilitation neuropsychology at the Spaulding Rehabilitation Hospital and is an associate professor in the department of physical medicine and rehabilitation at Harvard Medical School, both in Boston.

The primary outcome measure was the rate of improvement in the DRS score during treatment. DRS scores were assessed weekly by an interdisciplinary treatment team that was blinded to treatment assignment. Study personnel assessed clinically relevant behavioral benchmarks using the CRS-R.

Both study groups had significantly improved DRS scores at the end of the 4 weeks of treatment, but the amantadine group showed significantly faster improvement (–0.24 points/week more). In addition, at the final follow-up assessment, more patients in the amantadine group showed favorable outcomes on the DRS, fewer remained in a vegetative state, and more showed recovery of key behavioral benchmarks, Dr. Giacino and his colleagues said (N. Engl. J. Med. 2012;366:819-26). These benefits were consistent across all subgroups of patients. They were seen both in subjects in a minimally conscious state and in those in a vegetative state. And they were noted regardless of how long after the TBI injury the patients began treatment.

However, the treatment effect declined when drug therapy stopped, until there were no significant differences at the final follow-up assessment between patients who received the active drug and those who received placebo.

In particular, the proportion of patients who were able to engage in each of six clinically relevant behaviors was higher with amantadine during the month of therapy, but the difference between the two study groups was negligible at the final follow-up. These six behaviors were consistent command-following, object recognition, functional use of objects, intelligible verbalization, reliable yes-or-no communication, and sustained attention.

Amantadine "did not increase the risk of adverse medical, neurologic, or behavioral events, including those of greatest concern in this population (e.g., seizure)," the researchers noted.

The drug’s mechanism of action in these patients is uncertain. Amantadine is thought to promote dopaminergic activity "by facilitating presynaptic release and blocking reuptake postsynaptically." It may also enhance neurotransmission "in the dopamine-dependent nigrostriatal, mesolimbic, and frontostriatal circuits that are responsible for mediating arousal, drive, and attentional functions," they added.

"We conclude that amantadine is effective in accelerating the pace of recovery during acute rehabilitation in patients with prolonged post-traumatic disturbances in consciousness. Exposure to amantadine is associated with more rapid emergence of cognitively mediated behaviors that serve as the foundation for functional independence," Dr. Giacino and his associates wrote.

The study was supported by the U.S. National Institute on Disability and Rehabilitation Research. Dr. Giacino reported no relevant financial conflicts of interest, but a coauthor reported ties to Allergan, Merz, Ipsen, and Medtronic. Several other coauthors disclosed providing expert testimony on patients with TBI and disorders of consciousness.

A 4-week course of amantadine sped the rate of functional recovery in an international, randomized, double-blind, placebo-controlled trial of patients who had disorders of consciousness following traumatic brain injury.

Both patients given amantadine and those given placebo improved, but the rate of recovery was more rapid with the active drug. It affected "functionally meaningful behaviors such as consistent responses to commands, intelligible speech, reliable yes-or-no communication, and functional-object use," Joseph T. Giacino, Ph.D., of the JFK Johnson Rehabilitation Institute, Edison, N.J., and his associates reported in the March 1 issue of the New England Journal of Medicine.

The rate of recovery attenuated when treatment stopped, and scores on the Disability Rating Scale (DRS) were virtually indistinguishable between the treatment group and the control group 6 weeks later, indicating that the response was drug dependent.

"Practical and ethical constraints required the use of a brief treatment interval and a short-term assessment of the outcome [in this study], because we anticipated that caregivers would withdraw patients who were not making gains in order to try other treatments. Thus, our findings do not address the effects of prolonged treatment on long-term outcomes," the investigators noted.

"Whether treatment with amantadine, as compared with placebo, improves the long-term outcome or simply accelerates recovery en route to an equivalent level of function remains unknown."

The researchers conducted the trial after a pilot study indicated that amantadine improved functional outcomes after traumatic brain injury. They enrolled 184 patients aged 16-65 years who had sustained a nonpenetrating TBI 4-16 weeks previously and who were receiving usual inpatient rehabilitation at 11 medical centers in three countries.

Patients were diagnosed as being in a vegetative state, in which there was wakefulness without behavioral evidence of conscious awareness, or in a minimally conscious state, in which there was at least one clearly discernible behavioral sign of consciousness. All had scores above 11 on the DRS, which ranges from 0 (best) to 29 (worst); none were able to follow commands consistently or to engage in functional communication as assessed using the Coma Recovery Scale-Revised (CRS-R).

A total of 87 patients were randomly assigned to receive amantadine and 97 to receive a visually identical placebo for 4 weeks. They began at a dose of 100 mg twice daily, with escalations to 150 mg twice daily at week 3 and to 200 mg twice daily at week 4 if the DRS score had not improved by at least 2 points from baseline. Then the drug or placebo was tapered, and patients were assessed for another 6 weeks, according to Dr. Giacino and his associates. Dr. Giacino is also director of rehabilitation neuropsychology at the Spaulding Rehabilitation Hospital and is an associate professor in the department of physical medicine and rehabilitation at Harvard Medical School, both in Boston.

The primary outcome measure was the rate of improvement in the DRS score during treatment. DRS scores were assessed weekly by an interdisciplinary treatment team that was blinded to treatment assignment. Study personnel assessed clinically relevant behavioral benchmarks using the CRS-R.

Both study groups had significantly improved DRS scores at the end of the 4 weeks of treatment, but the amantadine group showed significantly faster improvement (–0.24 points/week more). In addition, at the final follow-up assessment, more patients in the amantadine group showed favorable outcomes on the DRS, fewer remained in a vegetative state, and more showed recovery of key behavioral benchmarks, Dr. Giacino and his colleagues said (N. Engl. J. Med. 2012;366:819-26). These benefits were consistent across all subgroups of patients. They were seen both in subjects in a minimally conscious state and in those in a vegetative state. And they were noted regardless of how long after the TBI injury the patients began treatment.

However, the treatment effect declined when drug therapy stopped, until there were no significant differences at the final follow-up assessment between patients who received the active drug and those who received placebo.

In particular, the proportion of patients who were able to engage in each of six clinically relevant behaviors was higher with amantadine during the month of therapy, but the difference between the two study groups was negligible at the final follow-up. These six behaviors were consistent command-following, object recognition, functional use of objects, intelligible verbalization, reliable yes-or-no communication, and sustained attention.

Amantadine "did not increase the risk of adverse medical, neurologic, or behavioral events, including those of greatest concern in this population (e.g., seizure)," the researchers noted.

The drug’s mechanism of action in these patients is uncertain. Amantadine is thought to promote dopaminergic activity "by facilitating presynaptic release and blocking reuptake postsynaptically." It may also enhance neurotransmission "in the dopamine-dependent nigrostriatal, mesolimbic, and frontostriatal circuits that are responsible for mediating arousal, drive, and attentional functions," they added.

"We conclude that amantadine is effective in accelerating the pace of recovery during acute rehabilitation in patients with prolonged post-traumatic disturbances in consciousness. Exposure to amantadine is associated with more rapid emergence of cognitively mediated behaviors that serve as the foundation for functional independence," Dr. Giacino and his associates wrote.

The study was supported by the U.S. National Institute on Disability and Rehabilitation Research. Dr. Giacino reported no relevant financial conflicts of interest, but a coauthor reported ties to Allergan, Merz, Ipsen, and Medtronic. Several other coauthors disclosed providing expert testimony on patients with TBI and disorders of consciousness.

Percutaneous coronary implantation with a stent does not reduce mortality, nonfatal myocardial infarction, unplanned revascularization, or angina any better than does medical therapy alone in patients with stable coronary artery disease, according to a meta-analysis in the Feb. 27 issue of Archives of Internal Medicine.

The study findings "support current recommendations for instituting optimal medical therapy in patients with stable CAD [coronary artery disease] rather than proceeding directly to stent implantation," said Dr. Kathleen Stergiopoulos and Dr. David L. Brown of the division of cardiovascular medicine at Stony Brook (N.Y.) University.

In addition to these recommendations, several recent studies have clearly shown that initial percutaneous coronary implantation (PCI) is no better than medical therapy for nonacute CAD. Yet the findings have not been adopted into clinical practice. "Only 44% of patients are treated with optimal medical therapy prior to PCI, and approximately 50% of patients with an occluded infarct-related artery after an MI undergo PCI of that artery," Dr. Stergiopoulos and Dr. Brown noted.

One reason may be that a few recent meta-analyses reported that PCI did have advantages over medical therapy. But these meta-analyses included studies from the 1980s and early 1990s, before stent implantation was widespread and before many advancements in medical therapy had occurred.

"We therefore performed a systematic review and meta-analysis" that compared initial stent implantation plus medical therapy with a strategy of initial medical therapy alone to determine the effect of contemporary interventional and medical strategies on stable CAD. The meta-analysis included only prospective, randomized, clinical trials with a minimum follow-up of 1 year, in which stent implantation comprised at least half of the PCI procedures, and in which medical therapy included aspirin, beta-blockers, ACE inhibitors, and statins.

Eight studies fulfilled these inclusion criteria, involving 7,229 patients treated in 1997-2005. A total of 3,617 patients were randomly assigned to stent placement and 3,612 to medical therapy alone. The mean follow-up was 4.3 years.

There were 649 deaths during follow-up: 322 in the stent group, for a mortality of 8.9%, and 327 in the medical therapy group, for a mortality of 9.1%. These rates are not significantly different, the investigators reported (Arch. Intern. Med. 2012;172:312-9).

Nonfatal MI occurred in 323 patients who received stents (8.9%) and 291 who received medical therapy (8.1%), also a nonsignificant difference.

Unplanned revascularization was required in 774 subjects in the stent group (21.4%) and 1,049 of those in the medical therapy group (30.7%), another nonsignificant difference.

Information on angina status was available only for 4,122 study subjects. The rates of persistent angina were 29% with stent placement and 33% with medical therapy – again, a nonsignificant difference.

The findings of this meta-analysis "fail to support theories suggesting that PCI reduces mortality by improving myocardial blood flow or stabilizing vulnerable plaque in patients with angina, or by improving left ventricular remodeling or electrophysiologic stability in patients with an occluded artery following MI," the investigators said.

Their results also suggest that "up to 76% of patients with stable CAD can avoid PCI altogether if treated with optimal medical therapy, resulting in a lifetime savings of approximately $9,450 per patient in health care costs," they added.

The investigators reported no relevant financial disclosures.

Percutaneous coronary implantation with a stent does not reduce mortality, nonfatal myocardial infarction, unplanned revascularization, or angina any better than does medical therapy alone in patients with stable coronary artery disease, according to a meta-analysis in the Feb. 27 issue of Archives of Internal Medicine.

The study findings "support current recommendations for instituting optimal medical therapy in patients with stable CAD [coronary artery disease] rather than proceeding directly to stent implantation," said Dr. Kathleen Stergiopoulos and Dr. David L. Brown of the division of cardiovascular medicine at Stony Brook (N.Y.) University.

In addition to these recommendations, several recent studies have clearly shown that initial percutaneous coronary implantation (PCI) is no better than medical therapy for nonacute CAD. Yet the findings have not been adopted into clinical practice. "Only 44% of patients are treated with optimal medical therapy prior to PCI, and approximately 50% of patients with an occluded infarct-related artery after an MI undergo PCI of that artery," Dr. Stergiopoulos and Dr. Brown noted.

One reason may be that a few recent meta-analyses reported that PCI did have advantages over medical therapy. But these meta-analyses included studies from the 1980s and early 1990s, before stent implantation was widespread and before many advancements in medical therapy had occurred.

"We therefore performed a systematic review and meta-analysis" that compared initial stent implantation plus medical therapy with a strategy of initial medical therapy alone to determine the effect of contemporary interventional and medical strategies on stable CAD. The meta-analysis included only prospective, randomized, clinical trials with a minimum follow-up of 1 year, in which stent implantation comprised at least half of the PCI procedures, and in which medical therapy included aspirin, beta-blockers, ACE inhibitors, and statins.

Eight studies fulfilled these inclusion criteria, involving 7,229 patients treated in 1997-2005. A total of 3,617 patients were randomly assigned to stent placement and 3,612 to medical therapy alone. The mean follow-up was 4.3 years.

There were 649 deaths during follow-up: 322 in the stent group, for a mortality of 8.9%, and 327 in the medical therapy group, for a mortality of 9.1%. These rates are not significantly different, the investigators reported (Arch. Intern. Med. 2012;172:312-9).

Nonfatal MI occurred in 323 patients who received stents (8.9%) and 291 who received medical therapy (8.1%), also a nonsignificant difference.

Unplanned revascularization was required in 774 subjects in the stent group (21.4%) and 1,049 of those in the medical therapy group (30.7%), another nonsignificant difference.

Information on angina status was available only for 4,122 study subjects. The rates of persistent angina were 29% with stent placement and 33% with medical therapy – again, a nonsignificant difference.

The findings of this meta-analysis "fail to support theories suggesting that PCI reduces mortality by improving myocardial blood flow or stabilizing vulnerable plaque in patients with angina, or by improving left ventricular remodeling or electrophysiologic stability in patients with an occluded artery following MI," the investigators said.

Their results also suggest that "up to 76% of patients with stable CAD can avoid PCI altogether if treated with optimal medical therapy, resulting in a lifetime savings of approximately $9,450 per patient in health care costs," they added.

The investigators reported no relevant financial disclosures.

Percutaneous coronary implantation with a stent does not reduce mortality, nonfatal myocardial infarction, unplanned revascularization, or angina any better than does medical therapy alone in patients with stable coronary artery disease, according to a meta-analysis in the Feb. 27 issue of Archives of Internal Medicine.

The study findings "support current recommendations for instituting optimal medical therapy in patients with stable CAD [coronary artery disease] rather than proceeding directly to stent implantation," said Dr. Kathleen Stergiopoulos and Dr. David L. Brown of the division of cardiovascular medicine at Stony Brook (N.Y.) University.

In addition to these recommendations, several recent studies have clearly shown that initial percutaneous coronary implantation (PCI) is no better than medical therapy for nonacute CAD. Yet the findings have not been adopted into clinical practice. "Only 44% of patients are treated with optimal medical therapy prior to PCI, and approximately 50% of patients with an occluded infarct-related artery after an MI undergo PCI of that artery," Dr. Stergiopoulos and Dr. Brown noted.

One reason may be that a few recent meta-analyses reported that PCI did have advantages over medical therapy. But these meta-analyses included studies from the 1980s and early 1990s, before stent implantation was widespread and before many advancements in medical therapy had occurred.

"We therefore performed a systematic review and meta-analysis" that compared initial stent implantation plus medical therapy with a strategy of initial medical therapy alone to determine the effect of contemporary interventional and medical strategies on stable CAD. The meta-analysis included only prospective, randomized, clinical trials with a minimum follow-up of 1 year, in which stent implantation comprised at least half of the PCI procedures, and in which medical therapy included aspirin, beta-blockers, ACE inhibitors, and statins.

Eight studies fulfilled these inclusion criteria, involving 7,229 patients treated in 1997-2005. A total of 3,617 patients were randomly assigned to stent placement and 3,612 to medical therapy alone. The mean follow-up was 4.3 years.

There were 649 deaths during follow-up: 322 in the stent group, for a mortality of 8.9%, and 327 in the medical therapy group, for a mortality of 9.1%. These rates are not significantly different, the investigators reported (Arch. Intern. Med. 2012;172:312-9).

Nonfatal MI occurred in 323 patients who received stents (8.9%) and 291 who received medical therapy (8.1%), also a nonsignificant difference.

Unplanned revascularization was required in 774 subjects in the stent group (21.4%) and 1,049 of those in the medical therapy group (30.7%), another nonsignificant difference.

Information on angina status was available only for 4,122 study subjects. The rates of persistent angina were 29% with stent placement and 33% with medical therapy – again, a nonsignificant difference.

The findings of this meta-analysis "fail to support theories suggesting that PCI reduces mortality by improving myocardial blood flow or stabilizing vulnerable plaque in patients with angina, or by improving left ventricular remodeling or electrophysiologic stability in patients with an occluded artery following MI," the investigators said.

Their results also suggest that "up to 76% of patients with stable CAD can avoid PCI altogether if treated with optimal medical therapy, resulting in a lifetime savings of approximately $9,450 per patient in health care costs," they added.

The investigators reported no relevant financial disclosures.

A phase-II clinical trial with the longest follow-up to date confirmed that vemurafenib induces a clinical response in more than half of patients with advanced melanoma expressing BRAF^V600 mutations, according to a report in the Feb. 23 issue of the New England Journal of Medicine.

Median overall survival was 16 months in these patients, who had highly unfavorable characteristics at baseline. With follow-up as long as 20 months, this study "provides critical information on long-term survival" that was not available from previous studies of vemurafenib (Zelboraf) in metastatic melanoma, said Dr. Jeffrey A. Sosman of the Vanderbilt-Ingram Cancer Center, Nashville, Tenn., and his associates.

The Food and Drug Administration approved vemurafenib on Aug. 17, 2011 for patients with unresectable or metastatic melanoma with the BRAF^V600E mutation as detected by an FDA-approved test. The FDA acted after a pivotal phase-III trial showed vemurafenib improved overall survival compared with dacarbazine. When the phase-III data were analyzed, median follow-up was just 6.2 months in the experimental arm, and median overall survival had not been reached for patients treated with vemurafenib.

The FDA also considered the currently reported phase-II trial, which included 132 patients with stage-IV melanoma that had progressed despite at least one systemic treatment. Tumor tissue from 56% of patients screened for the trial had a BRAF^V600 mutation, which was required for study entry. Vemurafenib is a potent kinase inhibitor that was developed to target this mutation within cancer cells specifically.

Patients in the study were given oral vemurafenib (960 mg twice daily) and followed every 6 weeks for disease progression at 10 medical centers in the United States and 3 in Australia. Median follow-up for efficacy was 13 months (range, 0.6-20 months). Treatment response was assessed by both the investigative team and by a blinded independent review committee.

The committee found that 8 patients (6%) showed a complete response and 62 (47%) showed a partial response to vemurafenib, for an overall response rate of 53%. A total of 38 patients (29%) showed stable disease. Only 18 (14%) showed progressive disease; 6 patients could not be assessed.

Dr. Sosman and his colleagues found a 5% complete response rate and a 52% partial response rate, for an overall response rate of 57%, which generally accorded with the independent review committee’s findings.

Molecular sequencing showed 122 patients in the trial had BRAF^V600E mutations and 10 patients had BRAF^V600K mutations. Four of the 10 patients with the BRAF^V600K mutation had a partial response and 3 had stable disease.

These response rates are higher than those associated with any previous treatments for advanced melanoma, the researchers noted. The lowest response occurred in patients with an LDL level more than 1.5 times the upper limit of normal.

The median duration of response was 6.7 months, and one-fourth of the subjects remained progression free for more than a year. Median overall survival was 16 months. At the time of the data cut-off (July 1, 2011), 62 patients (47% of the study population) were alive.

"Most objective responses were evident at the time of the first set of scans (week 6), but in some patients, responses did not appear until the patient had been receiving the drug for more than 6 months," the researchers said (N. Engl. J. Med. 2012;366:707-14).

The longer follow-up in this study thus permitted the investigators to observe these late responses.

Overall survival was 77% at 6 months and 58% at 12 months, and it was estimated to be 43% at 18 months, they noted.

Until now, median overall of metastatic melanoma has been 6-10 months, Dr. Sosman and his colleagues noted. In previously untreated patients who responded to ipilimumab (Yervoy) – an immunotherapy also approved last year – it reached 11 months.

Most patients had at least one adverse event related to vemurafenib, but most were not severe. Adverse effects chiefly were arthralgia, rash, photosensitivity, fatigue, and alopecia. Although many patients required dose interruptions (64%) or reductions (45%), "patients were able to receive most of their intended daily dose," the investigators wrote.

Four patients discontinued the study drug altogether, including one who developed a retinal-vein occlusion. Another patient died from rapidly progressive melanoma and renal failure that may have been related to the study drug.

Vemurafenib is known to have the paradoxical effect of promoting cutaneous squamous cell carcinomas or keratoacanthomas, so the study subjects were closely monitored for these. Thirty-four patients (26%) developed such neoplasms, usually at the start of therapy. All were managed with resection and vemurafenib was not discontinued. Another eight patients were found to have basal cell carcinomas.

"As with most targeted therapies that block a driver oncogene," vemurafenib will likely encounter resistance with long-term use, Dr. Sosman and his colleagues said. The mechanisms of resistance to vemurafenib are currently being investigated, so that strategies to prevent or overcome it can be devised.

This study was funded by Hoffman-LaRoche. Dr. Sosman and his associates reported ties to various companies, including Abraxis, Altor, Amgen, BMS, Celldex, Genentech, Genesis Biopharma, GlaxoSmithKline, Hoffman-La Roche, Merck, Novartis, Pfizer, Plexxikon, Prometheus, Roche, and Serametrix.

A phase-II clinical trial with the longest follow-up to date confirmed that vemurafenib induces a clinical response in more than half of patients with advanced melanoma expressing BRAF^V600 mutations, according to a report in the Feb. 23 issue of the New England Journal of Medicine.

Median overall survival was 16 months in these patients, who had highly unfavorable characteristics at baseline. With follow-up as long as 20 months, this study "provides critical information on long-term survival" that was not available from previous studies of vemurafenib (Zelboraf) in metastatic melanoma, said Dr. Jeffrey A. Sosman of the Vanderbilt-Ingram Cancer Center, Nashville, Tenn., and his associates.

The Food and Drug Administration approved vemurafenib on Aug. 17, 2011 for patients with unresectable or metastatic melanoma with the BRAF^V600E mutation as detected by an FDA-approved test. The FDA acted after a pivotal phase-III trial showed vemurafenib improved overall survival compared with dacarbazine. When the phase-III data were analyzed, median follow-up was just 6.2 months in the experimental arm, and median overall survival had not been reached for patients treated with vemurafenib.

The FDA also considered the currently reported phase-II trial, which included 132 patients with stage-IV melanoma that had progressed despite at least one systemic treatment. Tumor tissue from 56% of patients screened for the trial had a BRAF^V600 mutation, which was required for study entry. Vemurafenib is a potent kinase inhibitor that was developed to target this mutation within cancer cells specifically.

Patients in the study were given oral vemurafenib (960 mg twice daily) and followed every 6 weeks for disease progression at 10 medical centers in the United States and 3 in Australia. Median follow-up for efficacy was 13 months (range, 0.6-20 months). Treatment response was assessed by both the investigative team and by a blinded independent review committee.

The committee found that 8 patients (6%) showed a complete response and 62 (47%) showed a partial response to vemurafenib, for an overall response rate of 53%. A total of 38 patients (29%) showed stable disease. Only 18 (14%) showed progressive disease; 6 patients could not be assessed.

Dr. Sosman and his colleagues found a 5% complete response rate and a 52% partial response rate, for an overall response rate of 57%, which generally accorded with the independent review committee’s findings.

Molecular sequencing showed 122 patients in the trial had BRAF^V600E mutations and 10 patients had BRAF^V600K mutations. Four of the 10 patients with the BRAF^V600K mutation had a partial response and 3 had stable disease.

These response rates are higher than those associated with any previous treatments for advanced melanoma, the researchers noted. The lowest response occurred in patients with an LDL level more than 1.5 times the upper limit of normal.

The median duration of response was 6.7 months, and one-fourth of the subjects remained progression free for more than a year. Median overall survival was 16 months. At the time of the data cut-off (July 1, 2011), 62 patients (47% of the study population) were alive.

"Most objective responses were evident at the time of the first set of scans (week 6), but in some patients, responses did not appear until the patient had been receiving the drug for more than 6 months," the researchers said (N. Engl. J. Med. 2012;366:707-14).

The longer follow-up in this study thus permitted the investigators to observe these late responses.

Overall survival was 77% at 6 months and 58% at 12 months, and it was estimated to be 43% at 18 months, they noted.

Until now, median overall of metastatic melanoma has been 6-10 months, Dr. Sosman and his colleagues noted. In previously untreated patients who responded to ipilimumab (Yervoy) – an immunotherapy also approved last year – it reached 11 months.

Most patients had at least one adverse event related to vemurafenib, but most were not severe. Adverse effects chiefly were arthralgia, rash, photosensitivity, fatigue, and alopecia. Although many patients required dose interruptions (64%) or reductions (45%), "patients were able to receive most of their intended daily dose," the investigators wrote.

Four patients discontinued the study drug altogether, including one who developed a retinal-vein occlusion. Another patient died from rapidly progressive melanoma and renal failure that may have been related to the study drug.

Vemurafenib is known to have the paradoxical effect of promoting cutaneous squamous cell carcinomas or keratoacanthomas, so the study subjects were closely monitored for these. Thirty-four patients (26%) developed such neoplasms, usually at the start of therapy. All were managed with resection and vemurafenib was not discontinued. Another eight patients were found to have basal cell carcinomas.

"As with most targeted therapies that block a driver oncogene," vemurafenib will likely encounter resistance with long-term use, Dr. Sosman and his colleagues said. The mechanisms of resistance to vemurafenib are currently being investigated, so that strategies to prevent or overcome it can be devised.

This study was funded by Hoffman-LaRoche. Dr. Sosman and his associates reported ties to various companies, including Abraxis, Altor, Amgen, BMS, Celldex, Genentech, Genesis Biopharma, GlaxoSmithKline, Hoffman-La Roche, Merck, Novartis, Pfizer, Plexxikon, Prometheus, Roche, and Serametrix.

A phase-II clinical trial with the longest follow-up to date confirmed that vemurafenib induces a clinical response in more than half of patients with advanced melanoma expressing BRAF^V600 mutations, according to a report in the Feb. 23 issue of the New England Journal of Medicine.

Median overall survival was 16 months in these patients, who had highly unfavorable characteristics at baseline. With follow-up as long as 20 months, this study "provides critical information on long-term survival" that was not available from previous studies of vemurafenib (Zelboraf) in metastatic melanoma, said Dr. Jeffrey A. Sosman of the Vanderbilt-Ingram Cancer Center, Nashville, Tenn., and his associates.

The Food and Drug Administration approved vemurafenib on Aug. 17, 2011 for patients with unresectable or metastatic melanoma with the BRAF^V600E mutation as detected by an FDA-approved test. The FDA acted after a pivotal phase-III trial showed vemurafenib improved overall survival compared with dacarbazine. When the phase-III data were analyzed, median follow-up was just 6.2 months in the experimental arm, and median overall survival had not been reached for patients treated with vemurafenib.

The FDA also considered the currently reported phase-II trial, which included 132 patients with stage-IV melanoma that had progressed despite at least one systemic treatment. Tumor tissue from 56% of patients screened for the trial had a BRAF^V600 mutation, which was required for study entry. Vemurafenib is a potent kinase inhibitor that was developed to target this mutation within cancer cells specifically.

Patients in the study were given oral vemurafenib (960 mg twice daily) and followed every 6 weeks for disease progression at 10 medical centers in the United States and 3 in Australia. Median follow-up for efficacy was 13 months (range, 0.6-20 months). Treatment response was assessed by both the investigative team and by a blinded independent review committee.

The committee found that 8 patients (6%) showed a complete response and 62 (47%) showed a partial response to vemurafenib, for an overall response rate of 53%. A total of 38 patients (29%) showed stable disease. Only 18 (14%) showed progressive disease; 6 patients could not be assessed.

Dr. Sosman and his colleagues found a 5% complete response rate and a 52% partial response rate, for an overall response rate of 57%, which generally accorded with the independent review committee’s findings.

Molecular sequencing showed 122 patients in the trial had BRAF^V600E mutations and 10 patients had BRAF^V600K mutations. Four of the 10 patients with the BRAF^V600K mutation had a partial response and 3 had stable disease.

These response rates are higher than those associated with any previous treatments for advanced melanoma, the researchers noted. The lowest response occurred in patients with an LDL level more than 1.5 times the upper limit of normal.

The median duration of response was 6.7 months, and one-fourth of the subjects remained progression free for more than a year. Median overall survival was 16 months. At the time of the data cut-off (July 1, 2011), 62 patients (47% of the study population) were alive.

"Most objective responses were evident at the time of the first set of scans (week 6), but in some patients, responses did not appear until the patient had been receiving the drug for more than 6 months," the researchers said (N. Engl. J. Med. 2012;366:707-14).

The longer follow-up in this study thus permitted the investigators to observe these late responses.

Overall survival was 77% at 6 months and 58% at 12 months, and it was estimated to be 43% at 18 months, they noted.

Until now, median overall of metastatic melanoma has been 6-10 months, Dr. Sosman and his colleagues noted. In previously untreated patients who responded to ipilimumab (Yervoy) – an immunotherapy also approved last year – it reached 11 months.

Most patients had at least one adverse event related to vemurafenib, but most were not severe. Adverse effects chiefly were arthralgia, rash, photosensitivity, fatigue, and alopecia. Although many patients required dose interruptions (64%) or reductions (45%), "patients were able to receive most of their intended daily dose," the investigators wrote.

Four patients discontinued the study drug altogether, including one who developed a retinal-vein occlusion. Another patient died from rapidly progressive melanoma and renal failure that may have been related to the study drug.

Vemurafenib is known to have the paradoxical effect of promoting cutaneous squamous cell carcinomas or keratoacanthomas, so the study subjects were closely monitored for these. Thirty-four patients (26%) developed such neoplasms, usually at the start of therapy. All were managed with resection and vemurafenib was not discontinued. Another eight patients were found to have basal cell carcinomas.

"As with most targeted therapies that block a driver oncogene," vemurafenib will likely encounter resistance with long-term use, Dr. Sosman and his colleagues said. The mechanisms of resistance to vemurafenib are currently being investigated, so that strategies to prevent or overcome it can be devised.

This study was funded by Hoffman-LaRoche. Dr. Sosman and his associates reported ties to various companies, including Abraxis, Altor, Amgen, BMS, Celldex, Genentech, Genesis Biopharma, GlaxoSmithKline, Hoffman-La Roche, Merck, Novartis, Pfizer, Plexxikon, Prometheus, Roche, and Serametrix.

A one-time screening with a fecal immunochemical test was as effective as a one-time colonoscopy for detecting colorectal cancer in an intention-to-screen analysis, but colonoscopy found more cancers among patients actually screened, investigators reported in the Feb. 23 issue of the New England Journal of Medicine.

In addition, the fecal immunochemical test (FIT) performed poorly in identifying patients with adenomas, some of which are precancerous, suggesting that reliance on this fecal test would miss opportunities to prevent cancers.

There was no difference in the stage of tumors identified by the two methods in an interim analysis of a 10-year clinical trial that will not be completed until 2021, said Dr. Enrique Quintero of the department of gastroenterology, Hospital Universitario de Canarias, Tenerife, Spain, and his associates.

In the randomized, controlled trial, the researchers had hypothesized that FIT screening every 2 years would prove to be noninferior to one-time colonoscopy "with respect to a reduction in mortality related to colorectal cancer among average-risk subjects" after 10 years. They reported these interim results after the first "round" of screening was completed in 53,302 subjects.

The study subjects were men and women aged 50-69 years who resided in eight regions of Spain and were invited to undergo screening by either FIT (26,599 subjects) or colonoscopy (26,703) at 15 tertiary care hospitals. Only 5,649 of the subjects randomly assigned to colonoscopy agreed to that screen, and only 4,953 actually underwent colonoscopy; another 1,628 opted for FIT instead. This yielded a participation rate of only 24.6% for colonoscopy.

A total of 9,353 subjects assigned to FIT agreed to that screen, and 8,983 of them actually underwent FIT; another 106 opted for colonoscopy instead. This yielded a participation rate of 34.2% for FIT.

Thus, participation rates were very low in both groups, but subjects in the FIT group were more likely to participate than those in the colonoscopy group. This may offset any apparent advantage with colonoscopy, the investigators said.

Colorectal cancer was detected in a similar number of subjects in both groups in this first round of screening. In the intention-to-screen analysis, colorectal cancer was detected in 30 subjects (0.1%) in the colonoscopy group and 33 subjects (0.1%) in the FIT group, Dr. Quintero and his colleagues said (N. Engl. J. Med. 2012;366:697-706).

In an analysis of screening that was actually performed, colorectal cancer was detected in 27 subjects (0.5%) in the colonoscopy group and 36 subjects (0.3%) in the FIT group.

Tumor stage was similar for the two groups. However, colonoscopy was superior to FIT in rate of detection of adenomas, including both advanced adenomas (odds ratio, 4.32) and nonadvanced adenomas (OR, 25.98).

Major complications developed in 24 subjects (0.5%) in the colonoscopy group, including 12 subjects who experienced bleeding and 1 who had a bowel perforation. No major complications developed in the FIT group, except among some subjects with positive findings who then underwent colonoscopy; eight of them experienced bleeding from the colonoscopy.

The primary outcome measure of the trial – the reduction in colorectal cancer mortality after 10 years – cannot be assessed yet. "The most relevant result of this interim analysis is that one-time screening with FIT was very similar to one-time colonoscopy" in detecting colorectal cancer, with no significant difference in tumor stage between the two screening methods.

"Additional cases of colorectal cancer might be detected during ongoing biennial FIT screening, and this could lead to an increased rate of cancer detection and a decreased rate of death in this group," Dr. Quintero and his associates said.

"On the other hand, more tumors might have been prevented in the colonoscopy group owing to the larger number of adenomas detected and removed, in comparison with the FIT group," they noted.

This study was supported by the Asociacion Espanola contra el Cancer, Instituto de Salud Carlos III, FEDER funds, Agencia de Gestio d’Ajuts Universitaris i de Recerca, Obra Social de Kuxta, Diputacion Foral de Gipuzkoa, Departmento de Sanidad del Gobierno Vasco, EITB-Maratoia, Accion Transversal contra el Cancer del CIBERehd, Direcion Xeral de Innovacion e Xestion da Saude Publica, Conselleria de Sanidade, and Xunta de Galicia. Eiken Chemical of Japan, together with Palex Medical and Biogen Diagnostics, donated supplies and automated analyzers used for FIT.

A one-time screening with a fecal immunochemical test was as effective as a one-time colonoscopy for detecting colorectal cancer in an intention-to-screen analysis, but colonoscopy found more cancers among patients actually screened, investigators reported in the Feb. 23 issue of the New England Journal of Medicine.

In addition, the fecal immunochemical test (FIT) performed poorly in identifying patients with adenomas, some of which are precancerous, suggesting that reliance on this fecal test would miss opportunities to prevent cancers.

There was no difference in the stage of tumors identified by the two methods in an interim analysis of a 10-year clinical trial that will not be completed until 2021, said Dr. Enrique Quintero of the department of gastroenterology, Hospital Universitario de Canarias, Tenerife, Spain, and his associates.

In the randomized, controlled trial, the researchers had hypothesized that FIT screening every 2 years would prove to be noninferior to one-time colonoscopy "with respect to a reduction in mortality related to colorectal cancer among average-risk subjects" after 10 years. They reported these interim results after the first "round" of screening was completed in 53,302 subjects.

The study subjects were men and women aged 50-69 years who resided in eight regions of Spain and were invited to undergo screening by either FIT (26,599 subjects) or colonoscopy (26,703) at 15 tertiary care hospitals. Only 5,649 of the subjects randomly assigned to colonoscopy agreed to that screen, and only 4,953 actually underwent colonoscopy; another 1,628 opted for FIT instead. This yielded a participation rate of only 24.6% for colonoscopy.

A total of 9,353 subjects assigned to FIT agreed to that screen, and 8,983 of them actually underwent FIT; another 106 opted for colonoscopy instead. This yielded a participation rate of 34.2% for FIT.

Thus, participation rates were very low in both groups, but subjects in the FIT group were more likely to participate than those in the colonoscopy group. This may offset any apparent advantage with colonoscopy, the investigators said.

Colorectal cancer was detected in a similar number of subjects in both groups in this first round of screening. In the intention-to-screen analysis, colorectal cancer was detected in 30 subjects (0.1%) in the colonoscopy group and 33 subjects (0.1%) in the FIT group, Dr. Quintero and his colleagues said (N. Engl. J. Med. 2012;366:697-706).

In an analysis of screening that was actually performed, colorectal cancer was detected in 27 subjects (0.5%) in the colonoscopy group and 36 subjects (0.3%) in the FIT group.

Tumor stage was similar for the two groups. However, colonoscopy was superior to FIT in rate of detection of adenomas, including both advanced adenomas (odds ratio, 4.32) and nonadvanced adenomas (OR, 25.98).

Major complications developed in 24 subjects (0.5%) in the colonoscopy group, including 12 subjects who experienced bleeding and 1 who had a bowel perforation. No major complications developed in the FIT group, except among some subjects with positive findings who then underwent colonoscopy; eight of them experienced bleeding from the colonoscopy.

The primary outcome measure of the trial – the reduction in colorectal cancer mortality after 10 years – cannot be assessed yet. "The most relevant result of this interim analysis is that one-time screening with FIT was very similar to one-time colonoscopy" in detecting colorectal cancer, with no significant difference in tumor stage between the two screening methods.

"Additional cases of colorectal cancer might be detected during ongoing biennial FIT screening, and this could lead to an increased rate of cancer detection and a decreased rate of death in this group," Dr. Quintero and his associates said.

"On the other hand, more tumors might have been prevented in the colonoscopy group owing to the larger number of adenomas detected and removed, in comparison with the FIT group," they noted.

This study was supported by the Asociacion Espanola contra el Cancer, Instituto de Salud Carlos III, FEDER funds, Agencia de Gestio d’Ajuts Universitaris i de Recerca, Obra Social de Kuxta, Diputacion Foral de Gipuzkoa, Departmento de Sanidad del Gobierno Vasco, EITB-Maratoia, Accion Transversal contra el Cancer del CIBERehd, Direcion Xeral de Innovacion e Xestion da Saude Publica, Conselleria de Sanidade, and Xunta de Galicia. Eiken Chemical of Japan, together with Palex Medical and Biogen Diagnostics, donated supplies and automated analyzers used for FIT.

A one-time screening with a fecal immunochemical test was as effective as a one-time colonoscopy for detecting colorectal cancer in an intention-to-screen analysis, but colonoscopy found more cancers among patients actually screened, investigators reported in the Feb. 23 issue of the New England Journal of Medicine.

In addition, the fecal immunochemical test (FIT) performed poorly in identifying patients with adenomas, some of which are precancerous, suggesting that reliance on this fecal test would miss opportunities to prevent cancers.

There was no difference in the stage of tumors identified by the two methods in an interim analysis of a 10-year clinical trial that will not be completed until 2021, said Dr. Enrique Quintero of the department of gastroenterology, Hospital Universitario de Canarias, Tenerife, Spain, and his associates.

In the randomized, controlled trial, the researchers had hypothesized that FIT screening every 2 years would prove to be noninferior to one-time colonoscopy "with respect to a reduction in mortality related to colorectal cancer among average-risk subjects" after 10 years. They reported these interim results after the first "round" of screening was completed in 53,302 subjects.

The study subjects were men and women aged 50-69 years who resided in eight regions of Spain and were invited to undergo screening by either FIT (26,599 subjects) or colonoscopy (26,703) at 15 tertiary care hospitals. Only 5,649 of the subjects randomly assigned to colonoscopy agreed to that screen, and only 4,953 actually underwent colonoscopy; another 1,628 opted for FIT instead. This yielded a participation rate of only 24.6% for colonoscopy.

A total of 9,353 subjects assigned to FIT agreed to that screen, and 8,983 of them actually underwent FIT; another 106 opted for colonoscopy instead. This yielded a participation rate of 34.2% for FIT.

Thus, participation rates were very low in both groups, but subjects in the FIT group were more likely to participate than those in the colonoscopy group. This may offset any apparent advantage with colonoscopy, the investigators said.

Colorectal cancer was detected in a similar number of subjects in both groups in this first round of screening. In the intention-to-screen analysis, colorectal cancer was detected in 30 subjects (0.1%) in the colonoscopy group and 33 subjects (0.1%) in the FIT group, Dr. Quintero and his colleagues said (N. Engl. J. Med. 2012;366:697-706).

In an analysis of screening that was actually performed, colorectal cancer was detected in 27 subjects (0.5%) in the colonoscopy group and 36 subjects (0.3%) in the FIT group.

Tumor stage was similar for the two groups. However, colonoscopy was superior to FIT in rate of detection of adenomas, including both advanced adenomas (odds ratio, 4.32) and nonadvanced adenomas (OR, 25.98).

Major complications developed in 24 subjects (0.5%) in the colonoscopy group, including 12 subjects who experienced bleeding and 1 who had a bowel perforation. No major complications developed in the FIT group, except among some subjects with positive findings who then underwent colonoscopy; eight of them experienced bleeding from the colonoscopy.

The primary outcome measure of the trial – the reduction in colorectal cancer mortality after 10 years – cannot be assessed yet. "The most relevant result of this interim analysis is that one-time screening with FIT was very similar to one-time colonoscopy" in detecting colorectal cancer, with no significant difference in tumor stage between the two screening methods.

"Additional cases of colorectal cancer might be detected during ongoing biennial FIT screening, and this could lead to an increased rate of cancer detection and a decreased rate of death in this group," Dr. Quintero and his associates said.

"On the other hand, more tumors might have been prevented in the colonoscopy group owing to the larger number of adenomas detected and removed, in comparison with the FIT group," they noted.

This study was supported by the Asociacion Espanola contra el Cancer, Instituto de Salud Carlos III, FEDER funds, Agencia de Gestio d’Ajuts Universitaris i de Recerca, Obra Social de Kuxta, Diputacion Foral de Gipuzkoa, Departmento de Sanidad del Gobierno Vasco, EITB-Maratoia, Accion Transversal contra el Cancer del CIBERehd, Direcion Xeral de Innovacion e Xestion da Saude Publica, Conselleria de Sanidade, and Xunta de Galicia. Eiken Chemical of Japan, together with Palex Medical and Biogen Diagnostics, donated supplies and automated analyzers used for FIT.

Colonoscopic polypectomy reduced the risk of death from colorectal cancer by more than half in a study that followed patients for as long as 23 years, investigators reported in the Feb. 23 issue of the New England Journal of Medicine.

The findings demonstrate that adenomas identified and removed at colonoscopy are clinically important because they have the potential to progress to cancer and cause death, said Ann G. Zauber, Ph.D., of the department of epidemiology and biostatistics at Memorial Sloan-Kettering Cancer Center, New York, and her associates.

The investigators performed long-term follow-up of subjects who had participated in the National Polyp Study, a randomized clinical trial of patients prospectively referred to seven clinical centers for colonoscopy during 1980-1990. The researchers analyzed mortality data from 2,602 of these subjects who had been found to have adenomatous polyps at that initial colonoscopy so they could determine whether removing the lesions had actually saved lives.

The study subjects had been referred for colonoscopy because of positive findings on a barium enema examination (27%), sigmoidoscopy (15%), fecal occult blood testing (11%), or other tests (10%), or because they had symptoms (32%) or a family history of colorectal cancer (5%). The median follow-up was approximately 16 years, with a maximum follow-up of 23 years.

A search of the National Death Index, a registry of all deaths in the United States, was used to identify the 1,246 study subjects (48%) who had died during follow-up, including 12 who died from colorectal cancer.

The authors then determined the expected number of deaths from colorectal cancer in the general population among people of comparable age, sex, and race, and found that 25.4 such deaths would be expected. This figure was determined by using data from the Surveillance, Epidemiology and End Results (SEER) program, and sensitivity analyses confirmed these findings.

This indicated that colonoscopy with polyp removal reduced mortality from colorectal cancer by 53%, compared with the expected rate of this cancer in the general population. "The cumulative mortality rate in the adenoma cohort at 20 years was 0.8%, as compared with an estimated 1.5% in the general population, on the basis of SEER data," Dr. Zauber and her colleagues wrote (N. Engl. J. Med. 2012;366:687-96).

The investigators also compared colorectal cancer mortality in the study cohort against that in a group of 773 National Polyp Study participants who had been found to have nonadenomatous polyps on their initial colonoscopy. During the first 10 years after that colonoscopy, mortality in the adenoma cohort (0.19%) was not significantly different from mortality in this internal control group (0.15%).

Thus, the risk of death from colorectal cancer was comparable between patients whose adenomas were removed at initial colonoscopy and those who only had nonadenomatous polyps, which were also removed, they said.

Finally, Dr. Zauber and her associates used a microsimulation model to estimate what the mortality would have been if the adenomas had not been removed "and the natural history of the adenoma-carcinoma sequence had proceeded without intervention." This model "showed an even larger reduction in mortality [after] polypectomy than the comparison with the SEER incidence-based mortality rates," they noted.

At present, there are three prospective, long-term, randomized controlled trials taking place in northern Europe, Spain, and the United States in which mortality end points after screening colonoscopy will be measured directly. Those data, however, will not be available for at least another decade. In the meantime, the findings of this study indicate that identifying and removing adenomas via colonoscopy significantly cuts the rate of death from colorectal cancer, the authors concluded.

This study was supported by the National Cancer Institute, the Society of Memorial Sloan-Kettering Cancer Center, the Tavel-Reznik Fund, and the Cantor Colon Cancer Fund. The investigators reported no financial conflicts of interest.

Colonoscopic polypectomy reduced the risk of death from colorectal cancer by more than half in a study that followed patients for as long as 23 years, investigators reported in the Feb. 23 issue of the New England Journal of Medicine.

The findings demonstrate that adenomas identified and removed at colonoscopy are clinically important because they have the potential to progress to cancer and cause death, said Ann G. Zauber, Ph.D., of the department of epidemiology and biostatistics at Memorial Sloan-Kettering Cancer Center, New York, and her associates.

The investigators performed long-term follow-up of subjects who had participated in the National Polyp Study, a randomized clinical trial of patients prospectively referred to seven clinical centers for colonoscopy during 1980-1990. The researchers analyzed mortality data from 2,602 of these subjects who had been found to have adenomatous polyps at that initial colonoscopy so they could determine whether removing the lesions had actually saved lives.

The study subjects had been referred for colonoscopy because of positive findings on a barium enema examination (27%), sigmoidoscopy (15%), fecal occult blood testing (11%), or other tests (10%), or because they had symptoms (32%) or a family history of colorectal cancer (5%). The median follow-up was approximately 16 years, with a maximum follow-up of 23 years.

A search of the National Death Index, a registry of all deaths in the United States, was used to identify the 1,246 study subjects (48%) who had died during follow-up, including 12 who died from colorectal cancer.

The authors then determined the expected number of deaths from colorectal cancer in the general population among people of comparable age, sex, and race, and found that 25.4 such deaths would be expected. This figure was determined by using data from the Surveillance, Epidemiology and End Results (SEER) program, and sensitivity analyses confirmed these findings.

This indicated that colonoscopy with polyp removal reduced mortality from colorectal cancer by 53%, compared with the expected rate of this cancer in the general population. "The cumulative mortality rate in the adenoma cohort at 20 years was 0.8%, as compared with an estimated 1.5% in the general population, on the basis of SEER data," Dr. Zauber and her colleagues wrote (N. Engl. J. Med. 2012;366:687-96).

The investigators also compared colorectal cancer mortality in the study cohort against that in a group of 773 National Polyp Study participants who had been found to have nonadenomatous polyps on their initial colonoscopy. During the first 10 years after that colonoscopy, mortality in the adenoma cohort (0.19%) was not significantly different from mortality in this internal control group (0.15%).

Thus, the risk of death from colorectal cancer was comparable between patients whose adenomas were removed at initial colonoscopy and those who only had nonadenomatous polyps, which were also removed, they said.

Finally, Dr. Zauber and her associates used a microsimulation model to estimate what the mortality would have been if the adenomas had not been removed "and the natural history of the adenoma-carcinoma sequence had proceeded without intervention." This model "showed an even larger reduction in mortality [after] polypectomy than the comparison with the SEER incidence-based mortality rates," they noted.

At present, there are three prospective, long-term, randomized controlled trials taking place in northern Europe, Spain, and the United States in which mortality end points after screening colonoscopy will be measured directly. Those data, however, will not be available for at least another decade. In the meantime, the findings of this study indicate that identifying and removing adenomas via colonoscopy significantly cuts the rate of death from colorectal cancer, the authors concluded.

This study was supported by the National Cancer Institute, the Society of Memorial Sloan-Kettering Cancer Center, the Tavel-Reznik Fund, and the Cantor Colon Cancer Fund. The investigators reported no financial conflicts of interest.

Colonoscopic polypectomy reduced the risk of death from colorectal cancer by more than half in a study that followed patients for as long as 23 years, investigators reported in the Feb. 23 issue of the New England Journal of Medicine.

The findings demonstrate that adenomas identified and removed at colonoscopy are clinically important because they have the potential to progress to cancer and cause death, said Ann G. Zauber, Ph.D., of the department of epidemiology and biostatistics at Memorial Sloan-Kettering Cancer Center, New York, and her associates.

The investigators performed long-term follow-up of subjects who had participated in the National Polyp Study, a randomized clinical trial of patients prospectively referred to seven clinical centers for colonoscopy during 1980-1990. The researchers analyzed mortality data from 2,602 of these subjects who had been found to have adenomatous polyps at that initial colonoscopy so they could determine whether removing the lesions had actually saved lives.

The study subjects had been referred for colonoscopy because of positive findings on a barium enema examination (27%), sigmoidoscopy (15%), fecal occult blood testing (11%), or other tests (10%), or because they had symptoms (32%) or a family history of colorectal cancer (5%). The median follow-up was approximately 16 years, with a maximum follow-up of 23 years.

A search of the National Death Index, a registry of all deaths in the United States, was used to identify the 1,246 study subjects (48%) who had died during follow-up, including 12 who died from colorectal cancer.

The authors then determined the expected number of deaths from colorectal cancer in the general population among people of comparable age, sex, and race, and found that 25.4 such deaths would be expected. This figure was determined by using data from the Surveillance, Epidemiology and End Results (SEER) program, and sensitivity analyses confirmed these findings.

This indicated that colonoscopy with polyp removal reduced mortality from colorectal cancer by 53%, compared with the expected rate of this cancer in the general population. "The cumulative mortality rate in the adenoma cohort at 20 years was 0.8%, as compared with an estimated 1.5% in the general population, on the basis of SEER data," Dr. Zauber and her colleagues wrote (N. Engl. J. Med. 2012;366:687-96).

The investigators also compared colorectal cancer mortality in the study cohort against that in a group of 773 National Polyp Study participants who had been found to have nonadenomatous polyps on their initial colonoscopy. During the first 10 years after that colonoscopy, mortality in the adenoma cohort (0.19%) was not significantly different from mortality in this internal control group (0.15%).

Thus, the risk of death from colorectal cancer was comparable between patients whose adenomas were removed at initial colonoscopy and those who only had nonadenomatous polyps, which were also removed, they said.

Finally, Dr. Zauber and her associates used a microsimulation model to estimate what the mortality would have been if the adenomas had not been removed "and the natural history of the adenoma-carcinoma sequence had proceeded without intervention." This model "showed an even larger reduction in mortality [after] polypectomy than the comparison with the SEER incidence-based mortality rates," they noted.

At present, there are three prospective, long-term, randomized controlled trials taking place in northern Europe, Spain, and the United States in which mortality end points after screening colonoscopy will be measured directly. Those data, however, will not be available for at least another decade. In the meantime, the findings of this study indicate that identifying and removing adenomas via colonoscopy significantly cuts the rate of death from colorectal cancer, the authors concluded.

This study was supported by the National Cancer Institute, the Society of Memorial Sloan-Kettering Cancer Center, the Tavel-Reznik Fund, and the Cantor Colon Cancer Fund. The investigators reported no financial conflicts of interest.

Among patients with myocardial infarction, women are more likely than men to present without chest pain or discomfort, and are more likely to die from the event, according to a report in the Feb. 22/29 issue of JAMA.

However, these sex-based differences are most pronounced at younger ages; they become attenuated and nearly disappear with increasing age, said Dr. John G. Canto of the Watson Clinic and Lakeland (Fla.) Regional Medical Center and his associates.

The investigators studied sex-related and age-related differences in MI patients using the "large and clinically rich" database of the National Registry of Myocardial Infarction. The industry-sponsored NRMI contains hospital data on over 2 million patients with confirmed MI treated at 1,977 hospitals across the country between 1994 and 2006.

Dr. Canto and his colleagues analyzed NRMI data on 1,143,513 of these MI patients, of whom 42% were women. For this study, chest pain/discomfort was defined as "any symptom of chest discomfort, sensation, or pressure, or tightness; or arm, neck, or jaw pain ... preceding a diagnosis of acute MI."

Overall, 35.4% of the study subjects presented without chest pain. The proportion was significantly higher among women (42.0%) than men (30.7%), the researchers said (JAMA 2012;307:813-22).

However, this difference decreased in a linear fashion with increasing patient age. For MI patients younger than 45 years, the odds ratio was 1.30; at 45-54 years, it was 1.26; at 55-64 years, it was 1.24; at 65-74 years, it was 1.13; and at 75 years and older, it was 1.03, or practically negligible.

Mortality followed a similar trend within those age groups, but went further in the opposite direction, to a reversal in the oldest patients. The adjusted odds ratio of mortality in women presenting with no chest pain, compared with men presenting with no chest pain, was 1.18 for those younger than age 45, 1.13 for those age 45-54, 1.02 for patients age 55-64, 0.91 at age 65-74, and 0.81 in the patients age 75 and older.

Comorbidity and clinical characteristics clearly accounted for most of the excess mortality in patients who did not have chest pain. These patients were more likely than those with chest pain to have diabetes, to have delayed seeking medical attention at the onset of MI, to present with Killip class III or IV heart failure, and to have non–ST-elevation MI.

Differences in treatment accounted for only a modest amount of the excess mortality in patients who did not have chest pain. These patients were less likely to receive any reperfusion therapies, such as fibrinolysis or percutaneous coronary intervention, and were less likely to receive aspirin, antiplatelet agents, heparin, or beta-blockers during hospitalization. But that was considered a relatively small contributor to their excess mortality.

The reasons for these sex- and age-based differences in symptoms remain unknown. "It is plausible, or even likely, that the pathophysiology or pathobiology of higher mortality observed in younger women also accounts for the apparent differences in MI symptom presentation in this premenopausal or middle-aged group," Dr. Canto and his associates said.

They proposed that younger women with MI may have particularly aggressive cardiovascular disease. Younger women who die from MI are often smokers, don’t have coronary narrowing, and have plaque erosions as opposed to plaque ruptures, whereas older women who die from MI usually have high cholesterol, plaque ruptures rather than erosions, and severe coronary narrowing.

However, it would be premature to change public health messages that currently advise people with the classic signs and symptoms of MI to seek immediate care. "Our results ... are provocative and should be confirmed by others" before existing public health messages, which target men and women equally and irrespective of age, are changed, they noted.

The NRMI was supported by Genentech. Dr. Canto’s associates, but not Dr. Canto, reported ties to numerous industry sources.

Among patients with myocardial infarction, women are more likely than men to present without chest pain or discomfort, and are more likely to die from the event, according to a report in the Feb. 22/29 issue of JAMA.

However, these sex-based differences are most pronounced at younger ages; they become attenuated and nearly disappear with increasing age, said Dr. John G. Canto of the Watson Clinic and Lakeland (Fla.) Regional Medical Center and his associates.

The investigators studied sex-related and age-related differences in MI patients using the "large and clinically rich" database of the National Registry of Myocardial Infarction. The industry-sponsored NRMI contains hospital data on over 2 million patients with confirmed MI treated at 1,977 hospitals across the country between 1994 and 2006.

Dr. Canto and his colleagues analyzed NRMI data on 1,143,513 of these MI patients, of whom 42% were women. For this study, chest pain/discomfort was defined as "any symptom of chest discomfort, sensation, or pressure, or tightness; or arm, neck, or jaw pain ... preceding a diagnosis of acute MI."

Overall, 35.4% of the study subjects presented without chest pain. The proportion was significantly higher among women (42.0%) than men (30.7%), the researchers said (JAMA 2012;307:813-22).

However, this difference decreased in a linear fashion with increasing patient age. For MI patients younger than 45 years, the odds ratio was 1.30; at 45-54 years, it was 1.26; at 55-64 years, it was 1.24; at 65-74 years, it was 1.13; and at 75 years and older, it was 1.03, or practically negligible.

Mortality followed a similar trend within those age groups, but went further in the opposite direction, to a reversal in the oldest patients. The adjusted odds ratio of mortality in women presenting with no chest pain, compared with men presenting with no chest pain, was 1.18 for those younger than age 45, 1.13 for those age 45-54, 1.02 for patients age 55-64, 0.91 at age 65-74, and 0.81 in the patients age 75 and older.

Comorbidity and clinical characteristics clearly accounted for most of the excess mortality in patients who did not have chest pain. These patients were more likely than those with chest pain to have diabetes, to have delayed seeking medical attention at the onset of MI, to present with Killip class III or IV heart failure, and to have non–ST-elevation MI.

Differences in treatment accounted for only a modest amount of the excess mortality in patients who did not have chest pain. These patients were less likely to receive any reperfusion therapies, such as fibrinolysis or percutaneous coronary intervention, and were less likely to receive aspirin, antiplatelet agents, heparin, or beta-blockers during hospitalization. But that was considered a relatively small contributor to their excess mortality.

The reasons for these sex- and age-based differences in symptoms remain unknown. "It is plausible, or even likely, that the pathophysiology or pathobiology of higher mortality observed in younger women also accounts for the apparent differences in MI symptom presentation in this premenopausal or middle-aged group," Dr. Canto and his associates said.

They proposed that younger women with MI may have particularly aggressive cardiovascular disease. Younger women who die from MI are often smokers, don’t have coronary narrowing, and have plaque erosions as opposed to plaque ruptures, whereas older women who die from MI usually have high cholesterol, plaque ruptures rather than erosions, and severe coronary narrowing.

However, it would be premature to change public health messages that currently advise people with the classic signs and symptoms of MI to seek immediate care. "Our results ... are provocative and should be confirmed by others" before existing public health messages, which target men and women equally and irrespective of age, are changed, they noted.

The NRMI was supported by Genentech. Dr. Canto’s associates, but not Dr. Canto, reported ties to numerous industry sources.

Among patients with myocardial infarction, women are more likely than men to present without chest pain or discomfort, and are more likely to die from the event, according to a report in the Feb. 22/29 issue of JAMA.

However, these sex-based differences are most pronounced at younger ages; they become attenuated and nearly disappear with increasing age, said Dr. John G. Canto of the Watson Clinic and Lakeland (Fla.) Regional Medical Center and his associates.

The investigators studied sex-related and age-related differences in MI patients using the "large and clinically rich" database of the National Registry of Myocardial Infarction. The industry-sponsored NRMI contains hospital data on over 2 million patients with confirmed MI treated at 1,977 hospitals across the country between 1994 and 2006.

Dr. Canto and his colleagues analyzed NRMI data on 1,143,513 of these MI patients, of whom 42% were women. For this study, chest pain/discomfort was defined as "any symptom of chest discomfort, sensation, or pressure, or tightness; or arm, neck, or jaw pain ... preceding a diagnosis of acute MI."

Overall, 35.4% of the study subjects presented without chest pain. The proportion was significantly higher among women (42.0%) than men (30.7%), the researchers said (JAMA 2012;307:813-22).

However, this difference decreased in a linear fashion with increasing patient age. For MI patients younger than 45 years, the odds ratio was 1.30; at 45-54 years, it was 1.26; at 55-64 years, it was 1.24; at 65-74 years, it was 1.13; and at 75 years and older, it was 1.03, or practically negligible.

Mortality followed a similar trend within those age groups, but went further in the opposite direction, to a reversal in the oldest patients. The adjusted odds ratio of mortality in women presenting with no chest pain, compared with men presenting with no chest pain, was 1.18 for those younger than age 45, 1.13 for those age 45-54, 1.02 for patients age 55-64, 0.91 at age 65-74, and 0.81 in the patients age 75 and older.

Comorbidity and clinical characteristics clearly accounted for most of the excess mortality in patients who did not have chest pain. These patients were more likely than those with chest pain to have diabetes, to have delayed seeking medical attention at the onset of MI, to present with Killip class III or IV heart failure, and to have non–ST-elevation MI.

Differences in treatment accounted for only a modest amount of the excess mortality in patients who did not have chest pain. These patients were less likely to receive any reperfusion therapies, such as fibrinolysis or percutaneous coronary intervention, and were less likely to receive aspirin, antiplatelet agents, heparin, or beta-blockers during hospitalization. But that was considered a relatively small contributor to their excess mortality.

The reasons for these sex- and age-based differences in symptoms remain unknown. "It is plausible, or even likely, that the pathophysiology or pathobiology of higher mortality observed in younger women also accounts for the apparent differences in MI symptom presentation in this premenopausal or middle-aged group," Dr. Canto and his associates said.

They proposed that younger women with MI may have particularly aggressive cardiovascular disease. Younger women who die from MI are often smokers, don’t have coronary narrowing, and have plaque erosions as opposed to plaque ruptures, whereas older women who die from MI usually have high cholesterol, plaque ruptures rather than erosions, and severe coronary narrowing.

However, it would be premature to change public health messages that currently advise people with the classic signs and symptoms of MI to seek immediate care. "Our results ... are provocative and should be confirmed by others" before existing public health messages, which target men and women equally and irrespective of age, are changed, they noted.

The NRMI was supported by Genentech. Dr. Canto’s associates, but not Dr. Canto, reported ties to numerous industry sources.

The pneumococcal conjugate vaccine, PCV13, may be better in adults than the pneumococcal polysaccharide vaccine, PPSV23, at reducing disease burden because of its potential effectiveness against nonbacteremic pneumococcal pneumonia, according to a report in the Feb. 22/29 issue of JAMA.

PPSV23 covers 23 serotypes while PCV13 covers only 13. However, PPSV23 doesn’t appear to consistently prevent nonbacteremic pneumococcal pneumonia, while PCV13 is more likely to do so, based on preliminary experience.

Photo (c)Micah Young/iStockphoto.com

Because nonbacteremic pneumococcal pneumonia is much more common than invasive pneumococcal disease and is responsible for much more morbidity and mortality, PCV13, despite its narrower serotype coverage, should prevent more pneumococcal disease, reported Dr. Kenneth J. Smith of the section of decision sciences and clinical systems management, University of Pittsburgh, and his associates.

The question of which pneumococcal vaccine to use in adults came to the fore when the Food and Drug Administration recently approved the use of PCV13 in patients aged 50 years and older. Dr. Smith and his colleagues used decision statistical modeling techniques to estimate the cost effectiveness of six different possible pneumococcal vaccine strategies in identical hypothetical cohorts of adults aged 50 and older who were tracked as they aged.

The six strategies were no vaccination, the present U.S. Advisory Committee on Immunization Practices recommendation to vaccinate all adults with PPSV23 at age 65, substituting PCV13 for PPSV23 and vaccinating according to the ACIP recommendations, vaccinating with PCV13 at age 50 and with PPSV23 at age 65, vaccinating with PCV13 at ages 50 and 65 years, and vaccinating with PCV13 at ages 50 and 65, then with PPSV23 at age 75.

The models took into consideration the potential effects of herd immunity, different levels of patient risk of contracting pneumococcal disease, different levels of vaccine effectiveness based on patient age and comorbidity, and three different outcomes after pneumococcal infection: death, disability, or recovery.

"Our analysis favors vaccinating adults with PCV13 instead of PPSV23," chiefly because experts expect that PCV13 will be more effective against nonbacteremic pneumococcal pneumonia than PPSV23 appears to be, the researchers said.

Moreover, the data "suggest that PCV13 administered either as a substitute for PPSV23 [according to] current recommendations or [given] routinely at ages 50 and 65 years might reduce pneumococcal disease burden in an economically reasonable fashion," Dr. Smith and his colleagues wrote (JAMA 2012;307:804-12).

According to their models, substituting PCV13 for PPSV23 would cost $28,900 per quality-adjusted life-year, while staying with PPSV23 would cost $34,000 per quality-adjusted life-year. Even giving PCV13 at age 50 and again at age 65, which would cost $45,100 per quality-adjusted life-year, would still be cost effective, they noted.

However, the study results would not hold true if PCV13’s effectiveness against nonbacteremic pneumococcal pneumonia proves to have been overestimated. If it turns out that PCV13 is not very effective against nonbacteremic pneumococcal pneumonia, then the current PPSV23 recommendations would be superior, the investigators said.

Similarly, the results of this study would not hold true if it turns out that childhood vaccination with PCV13, which has only recently begun, substantially changes herd immunity, reducing disease rates in adults.

This study was supported by the National Institute of Allergy and Infectious Diseases. No relevant financial disclosures were reported among the study’s authors.

The pneumococcal conjugate vaccine, PCV13, may be better in adults than the pneumococcal polysaccharide vaccine, PPSV23, at reducing disease burden because of its potential effectiveness against nonbacteremic pneumococcal pneumonia, according to a report in the Feb. 22/29 issue of JAMA.

PPSV23 covers 23 serotypes while PCV13 covers only 13. However, PPSV23 doesn’t appear to consistently prevent nonbacteremic pneumococcal pneumonia, while PCV13 is more likely to do so, based on preliminary experience.

Photo (c)Micah Young/iStockphoto.com

Because nonbacteremic pneumococcal pneumonia is much more common than invasive pneumococcal disease and is responsible for much more morbidity and mortality, PCV13, despite its narrower serotype coverage, should prevent more pneumococcal disease, reported Dr. Kenneth J. Smith of the section of decision sciences and clinical systems management, University of Pittsburgh, and his associates.

The question of which pneumococcal vaccine to use in adults came to the fore when the Food and Drug Administration recently approved the use of PCV13 in patients aged 50 years and older. Dr. Smith and his colleagues used decision statistical modeling techniques to estimate the cost effectiveness of six different possible pneumococcal vaccine strategies in identical hypothetical cohorts of adults aged 50 and older who were tracked as they aged.

The six strategies were no vaccination, the present U.S. Advisory Committee on Immunization Practices recommendation to vaccinate all adults with PPSV23 at age 65, substituting PCV13 for PPSV23 and vaccinating according to the ACIP recommendations, vaccinating with PCV13 at age 50 and with PPSV23 at age 65, vaccinating with PCV13 at ages 50 and 65 years, and vaccinating with PCV13 at ages 50 and 65, then with PPSV23 at age 75.

The models took into consideration the potential effects of herd immunity, different levels of patient risk of contracting pneumococcal disease, different levels of vaccine effectiveness based on patient age and comorbidity, and three different outcomes after pneumococcal infection: death, disability, or recovery.

"Our analysis favors vaccinating adults with PCV13 instead of PPSV23," chiefly because experts expect that PCV13 will be more effective against nonbacteremic pneumococcal pneumonia than PPSV23 appears to be, the researchers said.

Moreover, the data "suggest that PCV13 administered either as a substitute for PPSV23 [according to] current recommendations or [given] routinely at ages 50 and 65 years might reduce pneumococcal disease burden in an economically reasonable fashion," Dr. Smith and his colleagues wrote (JAMA 2012;307:804-12).

According to their models, substituting PCV13 for PPSV23 would cost $28,900 per quality-adjusted life-year, while staying with PPSV23 would cost $34,000 per quality-adjusted life-year. Even giving PCV13 at age 50 and again at age 65, which would cost $45,100 per quality-adjusted life-year, would still be cost effective, they noted.

However, the study results would not hold true if PCV13’s effectiveness against nonbacteremic pneumococcal pneumonia proves to have been overestimated. If it turns out that PCV13 is not very effective against nonbacteremic pneumococcal pneumonia, then the current PPSV23 recommendations would be superior, the investigators said.

Similarly, the results of this study would not hold true if it turns out that childhood vaccination with PCV13, which has only recently begun, substantially changes herd immunity, reducing disease rates in adults.

This study was supported by the National Institute of Allergy and Infectious Diseases. No relevant financial disclosures were reported among the study’s authors.

The pneumococcal conjugate vaccine, PCV13, may be better in adults than the pneumococcal polysaccharide vaccine, PPSV23, at reducing disease burden because of its potential effectiveness against nonbacteremic pneumococcal pneumonia, according to a report in the Feb. 22/29 issue of JAMA.

PPSV23 covers 23 serotypes while PCV13 covers only 13. However, PPSV23 doesn’t appear to consistently prevent nonbacteremic pneumococcal pneumonia, while PCV13 is more likely to do so, based on preliminary experience.

Photo (c)Micah Young/iStockphoto.com

Because nonbacteremic pneumococcal pneumonia is much more common than invasive pneumococcal disease and is responsible for much more morbidity and mortality, PCV13, despite its narrower serotype coverage, should prevent more pneumococcal disease, reported Dr. Kenneth J. Smith of the section of decision sciences and clinical systems management, University of Pittsburgh, and his associates.

The question of which pneumococcal vaccine to use in adults came to the fore when the Food and Drug Administration recently approved the use of PCV13 in patients aged 50 years and older. Dr. Smith and his colleagues used decision statistical modeling techniques to estimate the cost effectiveness of six different possible pneumococcal vaccine strategies in identical hypothetical cohorts of adults aged 50 and older who were tracked as they aged.

The six strategies were no vaccination, the present U.S. Advisory Committee on Immunization Practices recommendation to vaccinate all adults with PPSV23 at age 65, substituting PCV13 for PPSV23 and vaccinating according to the ACIP recommendations, vaccinating with PCV13 at age 50 and with PPSV23 at age 65, vaccinating with PCV13 at ages 50 and 65 years, and vaccinating with PCV13 at ages 50 and 65, then with PPSV23 at age 75.

The models took into consideration the potential effects of herd immunity, different levels of patient risk of contracting pneumococcal disease, different levels of vaccine effectiveness based on patient age and comorbidity, and three different outcomes after pneumococcal infection: death, disability, or recovery.

"Our analysis favors vaccinating adults with PCV13 instead of PPSV23," chiefly because experts expect that PCV13 will be more effective against nonbacteremic pneumococcal pneumonia than PPSV23 appears to be, the researchers said.

Moreover, the data "suggest that PCV13 administered either as a substitute for PPSV23 [according to] current recommendations or [given] routinely at ages 50 and 65 years might reduce pneumococcal disease burden in an economically reasonable fashion," Dr. Smith and his colleagues wrote (JAMA 2012;307:804-12).

According to their models, substituting PCV13 for PPSV23 would cost $28,900 per quality-adjusted life-year, while staying with PPSV23 would cost $34,000 per quality-adjusted life-year. Even giving PCV13 at age 50 and again at age 65, which would cost $45,100 per quality-adjusted life-year, would still be cost effective, they noted.

However, the study results would not hold true if PCV13’s effectiveness against nonbacteremic pneumococcal pneumonia proves to have been overestimated. If it turns out that PCV13 is not very effective against nonbacteremic pneumococcal pneumonia, then the current PPSV23 recommendations would be superior, the investigators said.

Similarly, the results of this study would not hold true if it turns out that childhood vaccination with PCV13, which has only recently begun, substantially changes herd immunity, reducing disease rates in adults.

This study was supported by the National Institute of Allergy and Infectious Diseases. No relevant financial disclosures were reported among the study’s authors.