Mary Ann Moon

Patients who received off-label recombinant activated factor VII for bleeding episodes had higher rates of arterial thromboembolic events than did those who received placebo, according to a pooled analysis of data from 35 clinical trials published Nov. 4 in the New England Journal of Medicine.

In particular, the rate of coronary arterial thromboembolic events was nearly three times higher in patients randomly assigned to receive rFVIIa off-label than in those assigned to placebo. The rate of adverse events also increased with advancing patient age and with higher doses of the drug, said Dr. Marcel Levi of the University of Amsterdam and his associates.

rFVIIa, marketed as NovoSeven by Novo Nordisk, is approved for the prevention or treatment of bleeding in patients with hemophilia or factor VII deficiency, but an increasing number of small studies have shown its usefulness for severe bleeding in other clinical conditions, including severe trauma, transplant surgery, intracerebral hemorrhage, and overreaction to anticoagulation therapy.

"Most of the safety data on off-label indications are retrospective and involve subjects [who already have] a relatively high risk of adverse events, including thrombosis, making interpretation of these findings difficult," Dr. Levi and his colleagues noted.

To better assess the drug’s thromboembolic profile, they pooled the data from 26 randomized, placebo-controlled trials involving 4,119 patients with a variety of clinical conditions and 9 randomized, placebo-controlled trials involving 349 healthy volunteers. A total of 29 of these 35 trials were sponsored by Novo Nordisk.

Most of these patients had spontaneous CNS bleeding (31%), advanced liver disease (28%), or trauma (19%). The mean age was approximately 51 years; some of the studies included children, including one that included infants.

Overall, the rate of thromboembolic events was 10.2% in subjects who received rFVIIa – significantly higher than the 8.7% rate in subjects who received placebo (N. Engl. J. Med. 2010;363:1791-1800).

Further analysis showed that almost all of this difference was caused by an excess of arterial thromboembolic events in those who received active treatment (5.5%), compared with those who received placebo (3.2%). There was no significant difference between the two groups in venous thromboembolic events.

Approximately 54% of the arterial thromboembolic events were coronary in nature. In this large subgroup of subjects, the rate of such events was almost three times higher in patients who received active drug, compared with those who received placebo.

The rate of arterial thromboembolic events increased with advancing patient age. In those older than 65 years the rate was 9% with the active drug, compared with 3.8% with placebo. In those older than 75 years the rate was 10.8% with the active drug and 4.1% with placebo. There also was a significant dose-dependent effect.

"This article should serve as a template for pharmaceutical companies to report all studies involving the use of a given drug, on-label and off-label, so that physicians can fully appreciate the benefit and risks when making therapeutic decisions," Dr. Louis M. Aledort wrote in an accompanying editorial (N. Engl. J. Med. 2010;363:1853-4).

"The authors appropriately warn readers that these data warrant scrutiny when rFVIIa is used on an off-label basis. The thrombolic sequelae reported here are not inconsequential," noted Dr. Aledort, professor of medicine, hematology, and medical oncology at Mount Sinai School of Medicine, New York.

The thrombotic risks associated with labeled indications for rFVIIa are low. In this study, the risks in healthy volunteers also were low. But for all other study subjects, the risks are substantially higher, even after adjusting for age and different types of bleeding, he wrote.

This pooled analysis was funded by Novo Nordisk, maker of NovoSeven. Dr. Levi’s associates in this study have ties to Norvo Nordisk or are employees and have equity interest in the company. Dr. Aledort reported ties to Baxter, CSL Behring, Grifols, Octapharma, Inspiration, GlaxoSmithKline, and Amgen.

Patients who received off-label recombinant activated factor VII for bleeding episodes had higher rates of arterial thromboembolic events than did those who received placebo, according to a pooled analysis of data from 35 clinical trials published Nov. 4 in the New England Journal of Medicine.

In particular, the rate of coronary arterial thromboembolic events was nearly three times higher in patients randomly assigned to receive rFVIIa off-label than in those assigned to placebo. The rate of adverse events also increased with advancing patient age and with higher doses of the drug, said Dr. Marcel Levi of the University of Amsterdam and his associates.

rFVIIa, marketed as NovoSeven by Novo Nordisk, is approved for the prevention or treatment of bleeding in patients with hemophilia or factor VII deficiency, but an increasing number of small studies have shown its usefulness for severe bleeding in other clinical conditions, including severe trauma, transplant surgery, intracerebral hemorrhage, and overreaction to anticoagulation therapy.

"Most of the safety data on off-label indications are retrospective and involve subjects [who already have] a relatively high risk of adverse events, including thrombosis, making interpretation of these findings difficult," Dr. Levi and his colleagues noted.

To better assess the drug’s thromboembolic profile, they pooled the data from 26 randomized, placebo-controlled trials involving 4,119 patients with a variety of clinical conditions and 9 randomized, placebo-controlled trials involving 349 healthy volunteers. A total of 29 of these 35 trials were sponsored by Novo Nordisk.

Most of these patients had spontaneous CNS bleeding (31%), advanced liver disease (28%), or trauma (19%). The mean age was approximately 51 years; some of the studies included children, including one that included infants.

Overall, the rate of thromboembolic events was 10.2% in subjects who received rFVIIa – significantly higher than the 8.7% rate in subjects who received placebo (N. Engl. J. Med. 2010;363:1791-1800).

Further analysis showed that almost all of this difference was caused by an excess of arterial thromboembolic events in those who received active treatment (5.5%), compared with those who received placebo (3.2%). There was no significant difference between the two groups in venous thromboembolic events.

Approximately 54% of the arterial thromboembolic events were coronary in nature. In this large subgroup of subjects, the rate of such events was almost three times higher in patients who received active drug, compared with those who received placebo.

The rate of arterial thromboembolic events increased with advancing patient age. In those older than 65 years the rate was 9% with the active drug, compared with 3.8% with placebo. In those older than 75 years the rate was 10.8% with the active drug and 4.1% with placebo. There also was a significant dose-dependent effect.

"This article should serve as a template for pharmaceutical companies to report all studies involving the use of a given drug, on-label and off-label, so that physicians can fully appreciate the benefit and risks when making therapeutic decisions," Dr. Louis M. Aledort wrote in an accompanying editorial (N. Engl. J. Med. 2010;363:1853-4).

"The authors appropriately warn readers that these data warrant scrutiny when rFVIIa is used on an off-label basis. The thrombolic sequelae reported here are not inconsequential," noted Dr. Aledort, professor of medicine, hematology, and medical oncology at Mount Sinai School of Medicine, New York.

The thrombotic risks associated with labeled indications for rFVIIa are low. In this study, the risks in healthy volunteers also were low. But for all other study subjects, the risks are substantially higher, even after adjusting for age and different types of bleeding, he wrote.

This pooled analysis was funded by Novo Nordisk, maker of NovoSeven. Dr. Levi’s associates in this study have ties to Norvo Nordisk or are employees and have equity interest in the company. Dr. Aledort reported ties to Baxter, CSL Behring, Grifols, Octapharma, Inspiration, GlaxoSmithKline, and Amgen.

Patients who received off-label recombinant activated factor VII for bleeding episodes had higher rates of arterial thromboembolic events than did those who received placebo, according to a pooled analysis of data from 35 clinical trials published Nov. 4 in the New England Journal of Medicine.

In particular, the rate of coronary arterial thromboembolic events was nearly three times higher in patients randomly assigned to receive rFVIIa off-label than in those assigned to placebo. The rate of adverse events also increased with advancing patient age and with higher doses of the drug, said Dr. Marcel Levi of the University of Amsterdam and his associates.

rFVIIa, marketed as NovoSeven by Novo Nordisk, is approved for the prevention or treatment of bleeding in patients with hemophilia or factor VII deficiency, but an increasing number of small studies have shown its usefulness for severe bleeding in other clinical conditions, including severe trauma, transplant surgery, intracerebral hemorrhage, and overreaction to anticoagulation therapy.

"Most of the safety data on off-label indications are retrospective and involve subjects [who already have] a relatively high risk of adverse events, including thrombosis, making interpretation of these findings difficult," Dr. Levi and his colleagues noted.

To better assess the drug’s thromboembolic profile, they pooled the data from 26 randomized, placebo-controlled trials involving 4,119 patients with a variety of clinical conditions and 9 randomized, placebo-controlled trials involving 349 healthy volunteers. A total of 29 of these 35 trials were sponsored by Novo Nordisk.

Most of these patients had spontaneous CNS bleeding (31%), advanced liver disease (28%), or trauma (19%). The mean age was approximately 51 years; some of the studies included children, including one that included infants.

Overall, the rate of thromboembolic events was 10.2% in subjects who received rFVIIa – significantly higher than the 8.7% rate in subjects who received placebo (N. Engl. J. Med. 2010;363:1791-1800).

Further analysis showed that almost all of this difference was caused by an excess of arterial thromboembolic events in those who received active treatment (5.5%), compared with those who received placebo (3.2%). There was no significant difference between the two groups in venous thromboembolic events.

Approximately 54% of the arterial thromboembolic events were coronary in nature. In this large subgroup of subjects, the rate of such events was almost three times higher in patients who received active drug, compared with those who received placebo.

The rate of arterial thromboembolic events increased with advancing patient age. In those older than 65 years the rate was 9% with the active drug, compared with 3.8% with placebo. In those older than 75 years the rate was 10.8% with the active drug and 4.1% with placebo. There also was a significant dose-dependent effect.

"This article should serve as a template for pharmaceutical companies to report all studies involving the use of a given drug, on-label and off-label, so that physicians can fully appreciate the benefit and risks when making therapeutic decisions," Dr. Louis M. Aledort wrote in an accompanying editorial (N. Engl. J. Med. 2010;363:1853-4).

"The authors appropriately warn readers that these data warrant scrutiny when rFVIIa is used on an off-label basis. The thrombolic sequelae reported here are not inconsequential," noted Dr. Aledort, professor of medicine, hematology, and medical oncology at Mount Sinai School of Medicine, New York.

The thrombotic risks associated with labeled indications for rFVIIa are low. In this study, the risks in healthy volunteers also were low. But for all other study subjects, the risks are substantially higher, even after adjusting for age and different types of bleeding, he wrote.

This pooled analysis was funded by Novo Nordisk, maker of NovoSeven. Dr. Levi’s associates in this study have ties to Norvo Nordisk or are employees and have equity interest in the company. Dr. Aledort reported ties to Baxter, CSL Behring, Grifols, Octapharma, Inspiration, GlaxoSmithKline, and Amgen.

For men with prostate cancer, use of GnRH agonists rose dramatically in the 1990s, when Medicare reimbursement for the drugs was highly profitable for physicians, and dropped just as dramatically after 2004, when reimbursement was cut drastically, according to a report in the Nov. 4 New England Journal of Medicine.

The recent reductions in use were most profound among patients for whom the drugs were probably not beneficial and therefore inappropriate. In contrast, among the types of patients for whom the drugs’ benefit has been established, use did not change with reimbursement level, said Dr. Vahakn B. Shahinian of the University of Michigan, Ann Arbor, and his associates.

"Our findings suggest that reductions in reimbursement may influence the delivery of care in a potentially beneficial way, with even the modest changes in 2004 [in reimbursement policy] associated with a substantial decrease in the use of inappropriate therapy," they noted.

The investigators used data from the Surveillance, Epidemiology, and End Results (SEER) Medicare database on older cancer patients to test their hypothesis that, given the 50% cut over 2 years in reimbursement to physicians administering the GnRH agonists, the use of the androgen-deprivation therapy "would decline markedly for indications for which there was limited evidence of efficacy" but would continue to be used for evidence-based indications.

The researchers categorized the use of androgen-deprivation therapy in 54,925 prostate cancer patients seen from 1994 through 2005 as inappropriate, appropriate, or discretionary – the last category being for therapy of uncertain benefit because of insufficient evidence or because reasonable alternatives were available.

"Reimbursement for GnRH agonists per monthly dose fell from $356 in 2003 to $311 in 2004 and to $176 in 2005," Dr. Shahinian and his colleagues noted.

The rate of inappropriate use of the drugs increased steadily from 30% in 1994 to a peak of 45% in 2002, then dropped precipitously, according to the analysis. "In the inappropriate-use group, there was a dramatic drop in rates ... from 39% in the fourth quarter of 2003 to 30% in the first quarter of 2004, with a continued decline to 22% by the end of 2005," the researchers said (New Engl. J. Med. 2010;363:1822-32).

In the discretionary-use group, the rate of use also was highest in 2003, "gradually declined in 2004, and dropped more markedly in 2005," they added. Rates of use did not decline in the appropriate-use group.

"These findings are consistent with previous research on the influence of financial incentives on the delivery of health care," the investigators said. "Financial incentives are most likely to have an effect on physicians’ behavior in cases in which medical uncertainty exists, as opposed to cases in which care is clearly lifesaving."

It is possible that increasing recognition of the adverse effects of androgen-deprivation therapy may have contributed to some of the reductions in use of the drugs. One major study published in 2005 demonstrated a link between the treatment and fracture risk. Since the changes in reimbursement policy roughly coincided with this publication, "it is difficult to separate out the contributions of these influences," the researchers noted.

The corollary to their findings is that reimbursement policies should be carefully crafted to avoid inadvertently providing incentives for care for which no clear benefit has been established, they added.

This study was funded by the American Cancer Society. Dr. Shahinian reported working as a consultant to Amgen.

For men with prostate cancer, use of GnRH agonists rose dramatically in the 1990s, when Medicare reimbursement for the drugs was highly profitable for physicians, and dropped just as dramatically after 2004, when reimbursement was cut drastically, according to a report in the Nov. 4 New England Journal of Medicine.

The recent reductions in use were most profound among patients for whom the drugs were probably not beneficial and therefore inappropriate. In contrast, among the types of patients for whom the drugs’ benefit has been established, use did not change with reimbursement level, said Dr. Vahakn B. Shahinian of the University of Michigan, Ann Arbor, and his associates.

"Our findings suggest that reductions in reimbursement may influence the delivery of care in a potentially beneficial way, with even the modest changes in 2004 [in reimbursement policy] associated with a substantial decrease in the use of inappropriate therapy," they noted.

The investigators used data from the Surveillance, Epidemiology, and End Results (SEER) Medicare database on older cancer patients to test their hypothesis that, given the 50% cut over 2 years in reimbursement to physicians administering the GnRH agonists, the use of the androgen-deprivation therapy "would decline markedly for indications for which there was limited evidence of efficacy" but would continue to be used for evidence-based indications.

The researchers categorized the use of androgen-deprivation therapy in 54,925 prostate cancer patients seen from 1994 through 2005 as inappropriate, appropriate, or discretionary – the last category being for therapy of uncertain benefit because of insufficient evidence or because reasonable alternatives were available.

"Reimbursement for GnRH agonists per monthly dose fell from $356 in 2003 to $311 in 2004 and to $176 in 2005," Dr. Shahinian and his colleagues noted.

The rate of inappropriate use of the drugs increased steadily from 30% in 1994 to a peak of 45% in 2002, then dropped precipitously, according to the analysis. "In the inappropriate-use group, there was a dramatic drop in rates ... from 39% in the fourth quarter of 2003 to 30% in the first quarter of 2004, with a continued decline to 22% by the end of 2005," the researchers said (New Engl. J. Med. 2010;363:1822-32).

In the discretionary-use group, the rate of use also was highest in 2003, "gradually declined in 2004, and dropped more markedly in 2005," they added. Rates of use did not decline in the appropriate-use group.

"These findings are consistent with previous research on the influence of financial incentives on the delivery of health care," the investigators said. "Financial incentives are most likely to have an effect on physicians’ behavior in cases in which medical uncertainty exists, as opposed to cases in which care is clearly lifesaving."

It is possible that increasing recognition of the adverse effects of androgen-deprivation therapy may have contributed to some of the reductions in use of the drugs. One major study published in 2005 demonstrated a link between the treatment and fracture risk. Since the changes in reimbursement policy roughly coincided with this publication, "it is difficult to separate out the contributions of these influences," the researchers noted.

The corollary to their findings is that reimbursement policies should be carefully crafted to avoid inadvertently providing incentives for care for which no clear benefit has been established, they added.

This study was funded by the American Cancer Society. Dr. Shahinian reported working as a consultant to Amgen.

For men with prostate cancer, use of GnRH agonists rose dramatically in the 1990s, when Medicare reimbursement for the drugs was highly profitable for physicians, and dropped just as dramatically after 2004, when reimbursement was cut drastically, according to a report in the Nov. 4 New England Journal of Medicine.

The recent reductions in use were most profound among patients for whom the drugs were probably not beneficial and therefore inappropriate. In contrast, among the types of patients for whom the drugs’ benefit has been established, use did not change with reimbursement level, said Dr. Vahakn B. Shahinian of the University of Michigan, Ann Arbor, and his associates.

"Our findings suggest that reductions in reimbursement may influence the delivery of care in a potentially beneficial way, with even the modest changes in 2004 [in reimbursement policy] associated with a substantial decrease in the use of inappropriate therapy," they noted.

The investigators used data from the Surveillance, Epidemiology, and End Results (SEER) Medicare database on older cancer patients to test their hypothesis that, given the 50% cut over 2 years in reimbursement to physicians administering the GnRH agonists, the use of the androgen-deprivation therapy "would decline markedly for indications for which there was limited evidence of efficacy" but would continue to be used for evidence-based indications.

The researchers categorized the use of androgen-deprivation therapy in 54,925 prostate cancer patients seen from 1994 through 2005 as inappropriate, appropriate, or discretionary – the last category being for therapy of uncertain benefit because of insufficient evidence or because reasonable alternatives were available.

"Reimbursement for GnRH agonists per monthly dose fell from $356 in 2003 to $311 in 2004 and to $176 in 2005," Dr. Shahinian and his colleagues noted.

The rate of inappropriate use of the drugs increased steadily from 30% in 1994 to a peak of 45% in 2002, then dropped precipitously, according to the analysis. "In the inappropriate-use group, there was a dramatic drop in rates ... from 39% in the fourth quarter of 2003 to 30% in the first quarter of 2004, with a continued decline to 22% by the end of 2005," the researchers said (New Engl. J. Med. 2010;363:1822-32).

In the discretionary-use group, the rate of use also was highest in 2003, "gradually declined in 2004, and dropped more markedly in 2005," they added. Rates of use did not decline in the appropriate-use group.

"These findings are consistent with previous research on the influence of financial incentives on the delivery of health care," the investigators said. "Financial incentives are most likely to have an effect on physicians’ behavior in cases in which medical uncertainty exists, as opposed to cases in which care is clearly lifesaving."

It is possible that increasing recognition of the adverse effects of androgen-deprivation therapy may have contributed to some of the reductions in use of the drugs. One major study published in 2005 demonstrated a link between the treatment and fracture risk. Since the changes in reimbursement policy roughly coincided with this publication, "it is difficult to separate out the contributions of these influences," the researchers noted.

The corollary to their findings is that reimbursement policies should be carefully crafted to avoid inadvertently providing incentives for care for which no clear benefit has been established, they added.

This study was funded by the American Cancer Society. Dr. Shahinian reported working as a consultant to Amgen.

Patients who received off-label recombinant activated factor VII for bleeding episodes had higher rates of arterial thromboembolic events than did those who received placebo, according to a pooled analysis of data from 35 clinical trials published Nov. 4 in the New England Journal of Medicine.

In particular, the rate of coronary arterial thromboembolic events was nearly three times higher in patients randomly assigned to receive rFVIIa off-label than in those assigned to placebo. The rate of adverse events also increased with advancing patient age and with higher doses of the drug, said Dr. Marcel Levi of the University of Amsterdam and his associates.

rFVIIa, marketed as NovoSeven by Novo Nordisk, is approved for the prevention or treatment of bleeding in patients with hemophilia or factor VII deficiency, but an increasing number of small studies have shown its usefulness for severe bleeding in other clinical conditions, including severe trauma, transplant surgery, intracerebral hemorrhage, and overreaction to anticoagulation therapy.

"Most of the safety data on off-label indications are retrospective and involve subjects [who already have] a relatively high risk of adverse events, including thrombosis, making interpretation of these findings difficult," Dr. Levi and his colleagues noted.

To better assess the drug’s thromboembolic profile, they pooled the data from 26 randomized, placebo-controlled trials involving 4,119 patients with a variety of clinical conditions and 9 randomized, placebo-controlled trials involving 349 healthy volunteers. A total of 29 of these 35 trials were sponsored by Novo Nordisk.

Most of these patients had spontaneous CNS bleeding (31%), advanced liver disease (28%), or trauma (19%). The mean age was approximately 51 years; some of the studies included children, including one that included infants.

Overall, the rate of thromboembolic events was 10.2% in subjects who received rFVIIa – significantly higher than the 8.7% rate in subjects who received placebo (N. Engl. J. Med. 2010;363:1791-1800).

Further analysis showed that almost all of this difference was caused by an excess of arterial thromboembolic events in those who received active treatment (5.5%), compared with those who received placebo (3.2%). There was no significant difference between the two groups in venous thromboembolic events.

Approximately 54% of the arterial thromboembolic events were coronary in nature. In this large subgroup of subjects, the rate of such events was almost three times higher in patients who received active drug, compared with those who received placebo.

The rate of arterial thromboembolic events increased with advancing patient age. In those older than 65 years the rate was 9% with the active drug, compared with 3.8% with placebo. In those older than 75 years the rate was 10.8% with the active drug and 4.1% with placebo. There also was a significant dose-dependent effect.

"This article should serve as a template for pharmaceutical companies to report all studies involving the use of a given drug, on-label and off-label, so that physicians can fully appreciate the benefit and risks when making therapeutic decisions," Dr. Louis M. Aledort wrote in an accompanying editorial (N. Engl. J. Med. 2010;363:1853-4).

"The authors appropriately warn readers that these data warrant scrutiny when rFVIIa is used on an off-label basis. The thrombolic sequelae reported here are not inconsequential," noted Dr. Aledort, professor of medicine, hematology, and medical oncology at Mount Sinai School of Medicine, New York.

The thrombotic risks associated with labeled indications for rFVIIa are low. In this study, the risks in healthy volunteers also were low. But for all other study subjects, the risks are substantially higher, even after adjusting for age and different types of bleeding, he wrote.

This pooled analysis was funded by Novo Nordisk, maker of NovoSeven. Dr. Levi’s associates in this study have ties to Norvo Nordisk or are employees and have equity interest in the company. Dr. Aledort reported ties to Baxter, CSL Behring, Grifols, Octapharma, Inspiration, GlaxoSmithKline, and Amgen.

Patients who received off-label recombinant activated factor VII for bleeding episodes had higher rates of arterial thromboembolic events than did those who received placebo, according to a pooled analysis of data from 35 clinical trials published Nov. 4 in the New England Journal of Medicine.

In particular, the rate of coronary arterial thromboembolic events was nearly three times higher in patients randomly assigned to receive rFVIIa off-label than in those assigned to placebo. The rate of adverse events also increased with advancing patient age and with higher doses of the drug, said Dr. Marcel Levi of the University of Amsterdam and his associates.

rFVIIa, marketed as NovoSeven by Novo Nordisk, is approved for the prevention or treatment of bleeding in patients with hemophilia or factor VII deficiency, but an increasing number of small studies have shown its usefulness for severe bleeding in other clinical conditions, including severe trauma, transplant surgery, intracerebral hemorrhage, and overreaction to anticoagulation therapy.

"Most of the safety data on off-label indications are retrospective and involve subjects [who already have] a relatively high risk of adverse events, including thrombosis, making interpretation of these findings difficult," Dr. Levi and his colleagues noted.

To better assess the drug’s thromboembolic profile, they pooled the data from 26 randomized, placebo-controlled trials involving 4,119 patients with a variety of clinical conditions and 9 randomized, placebo-controlled trials involving 349 healthy volunteers. A total of 29 of these 35 trials were sponsored by Novo Nordisk.

Most of these patients had spontaneous CNS bleeding (31%), advanced liver disease (28%), or trauma (19%). The mean age was approximately 51 years; some of the studies included children, including one that included infants.

Overall, the rate of thromboembolic events was 10.2% in subjects who received rFVIIa – significantly higher than the 8.7% rate in subjects who received placebo (N. Engl. J. Med. 2010;363:1791-1800).

Further analysis showed that almost all of this difference was caused by an excess of arterial thromboembolic events in those who received active treatment (5.5%), compared with those who received placebo (3.2%). There was no significant difference between the two groups in venous thromboembolic events.

Approximately 54% of the arterial thromboembolic events were coronary in nature. In this large subgroup of subjects, the rate of such events was almost three times higher in patients who received active drug, compared with those who received placebo.

The rate of arterial thromboembolic events increased with advancing patient age. In those older than 65 years the rate was 9% with the active drug, compared with 3.8% with placebo. In those older than 75 years the rate was 10.8% with the active drug and 4.1% with placebo. There also was a significant dose-dependent effect.

"This article should serve as a template for pharmaceutical companies to report all studies involving the use of a given drug, on-label and off-label, so that physicians can fully appreciate the benefit and risks when making therapeutic decisions," Dr. Louis M. Aledort wrote in an accompanying editorial (N. Engl. J. Med. 2010;363:1853-4).

"The authors appropriately warn readers that these data warrant scrutiny when rFVIIa is used on an off-label basis. The thrombolic sequelae reported here are not inconsequential," noted Dr. Aledort, professor of medicine, hematology, and medical oncology at Mount Sinai School of Medicine, New York.

The thrombotic risks associated with labeled indications for rFVIIa are low. In this study, the risks in healthy volunteers also were low. But for all other study subjects, the risks are substantially higher, even after adjusting for age and different types of bleeding, he wrote.

This pooled analysis was funded by Novo Nordisk, maker of NovoSeven. Dr. Levi’s associates in this study have ties to Norvo Nordisk or are employees and have equity interest in the company. Dr. Aledort reported ties to Baxter, CSL Behring, Grifols, Octapharma, Inspiration, GlaxoSmithKline, and Amgen.

Patients who received off-label recombinant activated factor VII for bleeding episodes had higher rates of arterial thromboembolic events than did those who received placebo, according to a pooled analysis of data from 35 clinical trials published Nov. 4 in the New England Journal of Medicine.

In particular, the rate of coronary arterial thromboembolic events was nearly three times higher in patients randomly assigned to receive rFVIIa off-label than in those assigned to placebo. The rate of adverse events also increased with advancing patient age and with higher doses of the drug, said Dr. Marcel Levi of the University of Amsterdam and his associates.

rFVIIa, marketed as NovoSeven by Novo Nordisk, is approved for the prevention or treatment of bleeding in patients with hemophilia or factor VII deficiency, but an increasing number of small studies have shown its usefulness for severe bleeding in other clinical conditions, including severe trauma, transplant surgery, intracerebral hemorrhage, and overreaction to anticoagulation therapy.

"Most of the safety data on off-label indications are retrospective and involve subjects [who already have] a relatively high risk of adverse events, including thrombosis, making interpretation of these findings difficult," Dr. Levi and his colleagues noted.

To better assess the drug’s thromboembolic profile, they pooled the data from 26 randomized, placebo-controlled trials involving 4,119 patients with a variety of clinical conditions and 9 randomized, placebo-controlled trials involving 349 healthy volunteers. A total of 29 of these 35 trials were sponsored by Novo Nordisk.

Most of these patients had spontaneous CNS bleeding (31%), advanced liver disease (28%), or trauma (19%). The mean age was approximately 51 years; some of the studies included children, including one that included infants.

Overall, the rate of thromboembolic events was 10.2% in subjects who received rFVIIa – significantly higher than the 8.7% rate in subjects who received placebo (N. Engl. J. Med. 2010;363:1791-1800).

Further analysis showed that almost all of this difference was caused by an excess of arterial thromboembolic events in those who received active treatment (5.5%), compared with those who received placebo (3.2%). There was no significant difference between the two groups in venous thromboembolic events.

Approximately 54% of the arterial thromboembolic events were coronary in nature. In this large subgroup of subjects, the rate of such events was almost three times higher in patients who received active drug, compared with those who received placebo.

The rate of arterial thromboembolic events increased with advancing patient age. In those older than 65 years the rate was 9% with the active drug, compared with 3.8% with placebo. In those older than 75 years the rate was 10.8% with the active drug and 4.1% with placebo. There also was a significant dose-dependent effect.

"This article should serve as a template for pharmaceutical companies to report all studies involving the use of a given drug, on-label and off-label, so that physicians can fully appreciate the benefit and risks when making therapeutic decisions," Dr. Louis M. Aledort wrote in an accompanying editorial (N. Engl. J. Med. 2010;363:1853-4).

"The authors appropriately warn readers that these data warrant scrutiny when rFVIIa is used on an off-label basis. The thrombolic sequelae reported here are not inconsequential," noted Dr. Aledort, professor of medicine, hematology, and medical oncology at Mount Sinai School of Medicine, New York.

The thrombotic risks associated with labeled indications for rFVIIa are low. In this study, the risks in healthy volunteers also were low. But for all other study subjects, the risks are substantially higher, even after adjusting for age and different types of bleeding, he wrote.

This pooled analysis was funded by Novo Nordisk, maker of NovoSeven. Dr. Levi’s associates in this study have ties to Norvo Nordisk or are employees and have equity interest in the company. Dr. Aledort reported ties to Baxter, CSL Behring, Grifols, Octapharma, Inspiration, GlaxoSmithKline, and Amgen.

Illnesses and injuries requiring hospitalization of elderly people usually increase the patient’s level of disability, regardless of what that level was prior to the event, according to a report in the Nov. 3 issue of JAMA.

Similarly, an illness or injury requiring that an elderly patient restrict his or her activity for at least half a day also tends to increase the level of disability. "These results provide strong evidence that intervening events have an important role in precipitating and, subsequently, perpetuating the disabling process," said Dr. Thomas M. Gill of Yale University, New Haven, Conn., and his associates.

"The dynamic nature of disability has only recently been elucidated," they noted. "We have previously shown that illnesses and injuries leading to either hospitalization or restricted activity are strongly associated with the initial onset of disability. The current study extends this earlier work by demonstrating that exposure to these intervening illnesses and injuries also is associated with the subsequent course of disability."

To characterize the nature of disability in the population, Dr. Gill and his colleagues examined data from an ongoing longitudinal study of 754 community-living people who were aged 70 and older and were not disabled at enrollment in 1998-1999. Researchers had followed the study subjects by monthly telephone interviews and in-home assessments of physical and cognitive status every 18 months until 2008 or when a participant died (median, 9 years).

A total of 117 subjects (16%) survived and remained nondisabled through the follow-up. The remaining 637 subjects became disabled to some degree at some time during the study.

"Intervening events" prompting hospitalization were classified into nine categories: cardiac, infection, fall-related injury, stroke, arthritis, cancer, gastrointestinal bleeding, other medical causes, and other surgical causes. Fall-related injury was by far the intervening event most strongly associated with worsening disability.

Hospitalization for an illness or injury was particularly strongly associated with the onset of new disability or the worsening of existing disability. This is probably due in part to the potent disabling effects of serious illness and of hospitalization itself, the investigators said.

Of the 637 subjects who became disabled at some time, 91% had at least one hospital admission and 94% had at least one spell of restricted activity. In contrast, people who did not incur an injury or illness requiring hospitalization or restricted activity were at extremely low risk of becoming disabled.

"Our results support the hypothesis that illnesses and injuries leading to hospitalization act not only to precipitate and worsen disability but also to hasten death and to impede recovery from disability, thereby prolonging the disabling process," Dr. Gill and his associates said (JAMA 2010;304:1919-28).

Periods of restricted activity were not as strongly associated with disability as was hospitalization. However, restricted activity is still an important trigger of worsening disability because it is much more common than hospitalization, said the researchers.

All the associations found in this study were accentuated by the presence of physical frailty, as measured by diminished walking speed.

"Given the central role of intervening illnesses and injuries on the disabling process, more aggressive efforts are warranted to prevent their occurrence; to manage them more effectively and reduce subsequent complications, especially in the hospital setting; and, after an event, to enhance restorative interventions in the subacute, home care, and outpatient settings," the investigators said.

The study was funded by the National Institute on Aging. The investigators reported no financial conflict of interest.

Illnesses and injuries requiring hospitalization of elderly people usually increase the patient’s level of disability, regardless of what that level was prior to the event, according to a report in the Nov. 3 issue of JAMA.

Similarly, an illness or injury requiring that an elderly patient restrict his or her activity for at least half a day also tends to increase the level of disability. "These results provide strong evidence that intervening events have an important role in precipitating and, subsequently, perpetuating the disabling process," said Dr. Thomas M. Gill of Yale University, New Haven, Conn., and his associates.

"The dynamic nature of disability has only recently been elucidated," they noted. "We have previously shown that illnesses and injuries leading to either hospitalization or restricted activity are strongly associated with the initial onset of disability. The current study extends this earlier work by demonstrating that exposure to these intervening illnesses and injuries also is associated with the subsequent course of disability."

To characterize the nature of disability in the population, Dr. Gill and his colleagues examined data from an ongoing longitudinal study of 754 community-living people who were aged 70 and older and were not disabled at enrollment in 1998-1999. Researchers had followed the study subjects by monthly telephone interviews and in-home assessments of physical and cognitive status every 18 months until 2008 or when a participant died (median, 9 years).

A total of 117 subjects (16%) survived and remained nondisabled through the follow-up. The remaining 637 subjects became disabled to some degree at some time during the study.

"Intervening events" prompting hospitalization were classified into nine categories: cardiac, infection, fall-related injury, stroke, arthritis, cancer, gastrointestinal bleeding, other medical causes, and other surgical causes. Fall-related injury was by far the intervening event most strongly associated with worsening disability.

Hospitalization for an illness or injury was particularly strongly associated with the onset of new disability or the worsening of existing disability. This is probably due in part to the potent disabling effects of serious illness and of hospitalization itself, the investigators said.

Of the 637 subjects who became disabled at some time, 91% had at least one hospital admission and 94% had at least one spell of restricted activity. In contrast, people who did not incur an injury or illness requiring hospitalization or restricted activity were at extremely low risk of becoming disabled.

"Our results support the hypothesis that illnesses and injuries leading to hospitalization act not only to precipitate and worsen disability but also to hasten death and to impede recovery from disability, thereby prolonging the disabling process," Dr. Gill and his associates said (JAMA 2010;304:1919-28).

Periods of restricted activity were not as strongly associated with disability as was hospitalization. However, restricted activity is still an important trigger of worsening disability because it is much more common than hospitalization, said the researchers.

All the associations found in this study were accentuated by the presence of physical frailty, as measured by diminished walking speed.

"Given the central role of intervening illnesses and injuries on the disabling process, more aggressive efforts are warranted to prevent their occurrence; to manage them more effectively and reduce subsequent complications, especially in the hospital setting; and, after an event, to enhance restorative interventions in the subacute, home care, and outpatient settings," the investigators said.

The study was funded by the National Institute on Aging. The investigators reported no financial conflict of interest.

Illnesses and injuries requiring hospitalization of elderly people usually increase the patient’s level of disability, regardless of what that level was prior to the event, according to a report in the Nov. 3 issue of JAMA.

Similarly, an illness or injury requiring that an elderly patient restrict his or her activity for at least half a day also tends to increase the level of disability. "These results provide strong evidence that intervening events have an important role in precipitating and, subsequently, perpetuating the disabling process," said Dr. Thomas M. Gill of Yale University, New Haven, Conn., and his associates.

"The dynamic nature of disability has only recently been elucidated," they noted. "We have previously shown that illnesses and injuries leading to either hospitalization or restricted activity are strongly associated with the initial onset of disability. The current study extends this earlier work by demonstrating that exposure to these intervening illnesses and injuries also is associated with the subsequent course of disability."

To characterize the nature of disability in the population, Dr. Gill and his colleagues examined data from an ongoing longitudinal study of 754 community-living people who were aged 70 and older and were not disabled at enrollment in 1998-1999. Researchers had followed the study subjects by monthly telephone interviews and in-home assessments of physical and cognitive status every 18 months until 2008 or when a participant died (median, 9 years).

A total of 117 subjects (16%) survived and remained nondisabled through the follow-up. The remaining 637 subjects became disabled to some degree at some time during the study.

"Intervening events" prompting hospitalization were classified into nine categories: cardiac, infection, fall-related injury, stroke, arthritis, cancer, gastrointestinal bleeding, other medical causes, and other surgical causes. Fall-related injury was by far the intervening event most strongly associated with worsening disability.

Hospitalization for an illness or injury was particularly strongly associated with the onset of new disability or the worsening of existing disability. This is probably due in part to the potent disabling effects of serious illness and of hospitalization itself, the investigators said.

Of the 637 subjects who became disabled at some time, 91% had at least one hospital admission and 94% had at least one spell of restricted activity. In contrast, people who did not incur an injury or illness requiring hospitalization or restricted activity were at extremely low risk of becoming disabled.

"Our results support the hypothesis that illnesses and injuries leading to hospitalization act not only to precipitate and worsen disability but also to hasten death and to impede recovery from disability, thereby prolonging the disabling process," Dr. Gill and his associates said (JAMA 2010;304:1919-28).

Periods of restricted activity were not as strongly associated with disability as was hospitalization. However, restricted activity is still an important trigger of worsening disability because it is much more common than hospitalization, said the researchers.

All the associations found in this study were accentuated by the presence of physical frailty, as measured by diminished walking speed.

"Given the central role of intervening illnesses and injuries on the disabling process, more aggressive efforts are warranted to prevent their occurrence; to manage them more effectively and reduce subsequent complications, especially in the hospital setting; and, after an event, to enhance restorative interventions in the subacute, home care, and outpatient settings," the investigators said.

The study was funded by the National Institute on Aging. The investigators reported no financial conflict of interest.

Adolescents living in rural areas of the United States are more likely to abuse prescription drugs than are those living in urban areas, according to a report published online Nov. 1 in the Archives of Pediatrics and Adolescent Medicine.

Even after study data were adjusted to account for differences between rural and urban adolescents in sociodemographics, health factors, and the abuse of other drugs, researchers found that residency in a rural area was independently associated with a significantly higher prevalence of prescription drug abuse. This pattern was not seen for abuse of any other substances, such as marijuana, cocaine, hallucinogens, inhalants, or alcohol, said Jennifer R. Havens, Ph.D., of the center on drug and alcohol research at the University of Kentucky, Lexington, and her associates.

Nationally, the rate of nonmedical use of prescription drugs ballooned by 212% between 1992 and 2003 among adolescents, to a rate nearly three times higher than that among people older than 18 years.

Many studies have assessed substance abuse among urban adolescents, but few have examined abuse among their rural counterparts. Moreover, the conclusions of the urban studies may not be generalizable to rural areas "owing to a unique set of contextual influences" that affect rural life, the investigators noted.

In particular, "the decimation of rural economies, precipitated by declines in the agricultural, manufacturing, and mining industries, and evidenced by high rates of unemployment," has contributed to profound economic and social decline in rural areas. Physical isolation, lack of insurance coverage, unavailability of local detoxification and psychiatric services, mistrust of the medical establishment, and the perceived stigma associated with seeking health care (especially mental health care) are all obstacles that disproportionately affect rural patients, they said.

To assess drug use among rural youths, Dr. Havens and her colleagues used data from the federal government’s National Survey on Drug Use and Health, an annual survey of a nationally representative sample of adolescents and adults that measures the prevalence and correlates of substance abuse. For this analysis, they included self-reported responses from 17,842 boys and girls aged 12-17 years.

Compared with respondents from urban and suburban areas, those from rural areas had significantly less income, were significantly more likely to have dropped out of school, and were significantly less likely to report excellent overall health. The prevalence of major depressive episodes was the same across the three geographic areas.

Adolescents residing in rural areas were 26% more likely than those in urban areas to report recent nonmedical use of prescription drugs, particularly pain relievers and tranquilizers. In all, 13% of rural adolescents reported any lifetime abuse of prescription drugs, compared with only 10% of urban adolescents, the researchers said (Arch. Pediatr. Adolesc. Med. 2010 Nov. 1 [doi:10.1001/archpediatrics.2010.217]).

Among the rural adolescents, nonmedical use of prescription drugs strongly correlated with dropping out of school and with having only one parent. Rural adolescents were 32% less likely to use illicit prescription drugs if they lived in a two-parent household than if they lived with only one parent.

It would seem, then, that interventions aimed at improving school retention and involving family members in adolescents’ lives might help prevent or reduce nonmedical prescription drug use in this population, Dr. Havens and her associates said.

Rural youths with a history of one or more major depressive episodes were more likely to abuse prescription drugs than were other youths, suggesting that they have poorer access to medical and/or psychiatric care than do adolescents residing in urban or suburban areas. This points to another potential source of intervention, "namely school-based counseling for mental health and substance abuse," the researchers added.

A particularly interesting finding was that the odds that a rural adolescent would abuse prescription drugs increased as that individual’s self-assessed health status declined. Other studies have shown that the prevalence of chronic pain is higher in rural areas, and that rural patients are less likely to have their health care needs met and more likely to forgo needed health care. This suggests that rural adolescents may have higher rates of self-medicating for pain, and that improving their health care could reduce the rate of self-medication, Dr. Havens and her colleagues said.

Future research should examine factors associated with use of pain relievers and tranquilizers among rural adolescents as "a next logical step," they added.

No financial conflicts of interest were reported.

Adolescents living in rural areas of the United States are more likely to abuse prescription drugs than are those living in urban areas, according to a report published online Nov. 1 in the Archives of Pediatrics and Adolescent Medicine.

Even after study data were adjusted to account for differences between rural and urban adolescents in sociodemographics, health factors, and the abuse of other drugs, researchers found that residency in a rural area was independently associated with a significantly higher prevalence of prescription drug abuse. This pattern was not seen for abuse of any other substances, such as marijuana, cocaine, hallucinogens, inhalants, or alcohol, said Jennifer R. Havens, Ph.D., of the center on drug and alcohol research at the University of Kentucky, Lexington, and her associates.

Nationally, the rate of nonmedical use of prescription drugs ballooned by 212% between 1992 and 2003 among adolescents, to a rate nearly three times higher than that among people older than 18 years.

Many studies have assessed substance abuse among urban adolescents, but few have examined abuse among their rural counterparts. Moreover, the conclusions of the urban studies may not be generalizable to rural areas "owing to a unique set of contextual influences" that affect rural life, the investigators noted.

In particular, "the decimation of rural economies, precipitated by declines in the agricultural, manufacturing, and mining industries, and evidenced by high rates of unemployment," has contributed to profound economic and social decline in rural areas. Physical isolation, lack of insurance coverage, unavailability of local detoxification and psychiatric services, mistrust of the medical establishment, and the perceived stigma associated with seeking health care (especially mental health care) are all obstacles that disproportionately affect rural patients, they said.

To assess drug use among rural youths, Dr. Havens and her colleagues used data from the federal government’s National Survey on Drug Use and Health, an annual survey of a nationally representative sample of adolescents and adults that measures the prevalence and correlates of substance abuse. For this analysis, they included self-reported responses from 17,842 boys and girls aged 12-17 years.

Compared with respondents from urban and suburban areas, those from rural areas had significantly less income, were significantly more likely to have dropped out of school, and were significantly less likely to report excellent overall health. The prevalence of major depressive episodes was the same across the three geographic areas.

Adolescents residing in rural areas were 26% more likely than those in urban areas to report recent nonmedical use of prescription drugs, particularly pain relievers and tranquilizers. In all, 13% of rural adolescents reported any lifetime abuse of prescription drugs, compared with only 10% of urban adolescents, the researchers said (Arch. Pediatr. Adolesc. Med. 2010 Nov. 1 [doi:10.1001/archpediatrics.2010.217]).

Among the rural adolescents, nonmedical use of prescription drugs strongly correlated with dropping out of school and with having only one parent. Rural adolescents were 32% less likely to use illicit prescription drugs if they lived in a two-parent household than if they lived with only one parent.

It would seem, then, that interventions aimed at improving school retention and involving family members in adolescents’ lives might help prevent or reduce nonmedical prescription drug use in this population, Dr. Havens and her associates said.

Rural youths with a history of one or more major depressive episodes were more likely to abuse prescription drugs than were other youths, suggesting that they have poorer access to medical and/or psychiatric care than do adolescents residing in urban or suburban areas. This points to another potential source of intervention, "namely school-based counseling for mental health and substance abuse," the researchers added.

A particularly interesting finding was that the odds that a rural adolescent would abuse prescription drugs increased as that individual’s self-assessed health status declined. Other studies have shown that the prevalence of chronic pain is higher in rural areas, and that rural patients are less likely to have their health care needs met and more likely to forgo needed health care. This suggests that rural adolescents may have higher rates of self-medicating for pain, and that improving their health care could reduce the rate of self-medication, Dr. Havens and her colleagues said.

Future research should examine factors associated with use of pain relievers and tranquilizers among rural adolescents as "a next logical step," they added.

No financial conflicts of interest were reported.

Adolescents living in rural areas of the United States are more likely to abuse prescription drugs than are those living in urban areas, according to a report published online Nov. 1 in the Archives of Pediatrics and Adolescent Medicine.

Even after study data were adjusted to account for differences between rural and urban adolescents in sociodemographics, health factors, and the abuse of other drugs, researchers found that residency in a rural area was independently associated with a significantly higher prevalence of prescription drug abuse. This pattern was not seen for abuse of any other substances, such as marijuana, cocaine, hallucinogens, inhalants, or alcohol, said Jennifer R. Havens, Ph.D., of the center on drug and alcohol research at the University of Kentucky, Lexington, and her associates.

Nationally, the rate of nonmedical use of prescription drugs ballooned by 212% between 1992 and 2003 among adolescents, to a rate nearly three times higher than that among people older than 18 years.

Many studies have assessed substance abuse among urban adolescents, but few have examined abuse among their rural counterparts. Moreover, the conclusions of the urban studies may not be generalizable to rural areas "owing to a unique set of contextual influences" that affect rural life, the investigators noted.

In particular, "the decimation of rural economies, precipitated by declines in the agricultural, manufacturing, and mining industries, and evidenced by high rates of unemployment," has contributed to profound economic and social decline in rural areas. Physical isolation, lack of insurance coverage, unavailability of local detoxification and psychiatric services, mistrust of the medical establishment, and the perceived stigma associated with seeking health care (especially mental health care) are all obstacles that disproportionately affect rural patients, they said.

To assess drug use among rural youths, Dr. Havens and her colleagues used data from the federal government’s National Survey on Drug Use and Health, an annual survey of a nationally representative sample of adolescents and adults that measures the prevalence and correlates of substance abuse. For this analysis, they included self-reported responses from 17,842 boys and girls aged 12-17 years.

Compared with respondents from urban and suburban areas, those from rural areas had significantly less income, were significantly more likely to have dropped out of school, and were significantly less likely to report excellent overall health. The prevalence of major depressive episodes was the same across the three geographic areas.

Adolescents residing in rural areas were 26% more likely than those in urban areas to report recent nonmedical use of prescription drugs, particularly pain relievers and tranquilizers. In all, 13% of rural adolescents reported any lifetime abuse of prescription drugs, compared with only 10% of urban adolescents, the researchers said (Arch. Pediatr. Adolesc. Med. 2010 Nov. 1 [doi:10.1001/archpediatrics.2010.217]).

Among the rural adolescents, nonmedical use of prescription drugs strongly correlated with dropping out of school and with having only one parent. Rural adolescents were 32% less likely to use illicit prescription drugs if they lived in a two-parent household than if they lived with only one parent.

It would seem, then, that interventions aimed at improving school retention and involving family members in adolescents’ lives might help prevent or reduce nonmedical prescription drug use in this population, Dr. Havens and her associates said.

Rural youths with a history of one or more major depressive episodes were more likely to abuse prescription drugs than were other youths, suggesting that they have poorer access to medical and/or psychiatric care than do adolescents residing in urban or suburban areas. This points to another potential source of intervention, "namely school-based counseling for mental health and substance abuse," the researchers added.

A particularly interesting finding was that the odds that a rural adolescent would abuse prescription drugs increased as that individual’s self-assessed health status declined. Other studies have shown that the prevalence of chronic pain is higher in rural areas, and that rural patients are less likely to have their health care needs met and more likely to forgo needed health care. This suggests that rural adolescents may have higher rates of self-medicating for pain, and that improving their health care could reduce the rate of self-medication, Dr. Havens and her colleagues said.

Future research should examine factors associated with use of pain relievers and tranquilizers among rural adolescents as "a next logical step," they added.

No financial conflicts of interest were reported.

Gait speed independently predicts both major morbidity and mortality in elderly patients who are about to undergo cardiac surgery, according to a prospective, blinded study reported in the Nov. 9 issue of the Journal of the American College of Cardiology.

"This simple, rapid, and inexpensive test effectively stratifies patients beyond traditional estimates of risk, which tend to be inaccurate in the elderly," said Dr. Jonathan Afilalo of McGill University, Montreal, and his associates.

Half the cardiac surgeries done in North America involve elderly patients (aged at least 70 years), but scoring systems for estimating operative risk perform poorly in this age group, "overestimating mortality by as much as 250%," they noted.

Dr. Afilalo and his colleagues performed what they described as the first study to test the value of gait speed as a predictor of poor outcomes in elderly cardiac surgery patients. The prospective, blinded study involved 131 patients (mean age, 76 years) who were scheduled to undergo elective coronary artery bypass and/or valve replacement or repair via standard sternotomy at four university-affiliated medical centers across Canada and the United States.

Before surgery, the study subjects were timed as they walked a distance of 5 meters in a well-lit hallway; subjects were permitted to use an aid such as a cane or walker if needed. A time of 6 seconds or longer was classified as a slow gait speed, whereas any time under 6 seconds was classified as a normal gait speed.

The primary composite end point was in-hospital mortality or any of five major complications (stroke, renal failure, prolonged ventilation, deep sternal wound infection, and need for reoperation).

In all, 60 patients (46%) were judged to have slow gait speed before surgery. Interestingly, gait speed did not correlate with the Society of Thoracic Surgeons’ risk score, "suggesting that these were representing distinct domains," the investigators said.

After surgery, 30 patients (23%) experienced the primary composite end point.

Slow gait speed was a strong and independent predictor, associated with a 3.17-fold increase in risk of the primary end point. Moreover, adding gait speed to existing risk prediction models improved their performance in predicting which patients would experience an adverse event and which patients would need "to be discharged to a health care facility for ongoing medical care or rehabilitation."

Women with slow gait speed appeared to be at particularly high risk for adverse outcomes.

The study findings have three clinical implications.

"First, by refining risk predictions in this challenging group, clinicians can have a more comprehensive assessment of their patient and provide a more accurate estimate of risk to the patient," Dr. Afilalo and his associates said (J. Am. Coll. Cardiol. 2010;56:1668-76).

Second, clinicians can better assess which elderly patients might have better success with less-invasive techniques such as transcatheter valve implantation.

And third, patients who were found to have slow gait speed might benefit from extra interventions in the perioperative period, such as more intensive monitoring, early mobilization, low-intensity exercise training, or planned discharge to a specialized rehabilitation facility, they said.

The investigators reported no financial conflicts of interest.

Gait speed independently predicts both major morbidity and mortality in elderly patients who are about to undergo cardiac surgery, according to a prospective, blinded study reported in the Nov. 9 issue of the Journal of the American College of Cardiology.

"This simple, rapid, and inexpensive test effectively stratifies patients beyond traditional estimates of risk, which tend to be inaccurate in the elderly," said Dr. Jonathan Afilalo of McGill University, Montreal, and his associates.

Half the cardiac surgeries done in North America involve elderly patients (aged at least 70 years), but scoring systems for estimating operative risk perform poorly in this age group, "overestimating mortality by as much as 250%," they noted.

Dr. Afilalo and his colleagues performed what they described as the first study to test the value of gait speed as a predictor of poor outcomes in elderly cardiac surgery patients. The prospective, blinded study involved 131 patients (mean age, 76 years) who were scheduled to undergo elective coronary artery bypass and/or valve replacement or repair via standard sternotomy at four university-affiliated medical centers across Canada and the United States.

Before surgery, the study subjects were timed as they walked a distance of 5 meters in a well-lit hallway; subjects were permitted to use an aid such as a cane or walker if needed. A time of 6 seconds or longer was classified as a slow gait speed, whereas any time under 6 seconds was classified as a normal gait speed.

The primary composite end point was in-hospital mortality or any of five major complications (stroke, renal failure, prolonged ventilation, deep sternal wound infection, and need for reoperation).

In all, 60 patients (46%) were judged to have slow gait speed before surgery. Interestingly, gait speed did not correlate with the Society of Thoracic Surgeons’ risk score, "suggesting that these were representing distinct domains," the investigators said.

After surgery, 30 patients (23%) experienced the primary composite end point.

Slow gait speed was a strong and independent predictor, associated with a 3.17-fold increase in risk of the primary end point. Moreover, adding gait speed to existing risk prediction models improved their performance in predicting which patients would experience an adverse event and which patients would need "to be discharged to a health care facility for ongoing medical care or rehabilitation."

Women with slow gait speed appeared to be at particularly high risk for adverse outcomes.

The study findings have three clinical implications.

"First, by refining risk predictions in this challenging group, clinicians can have a more comprehensive assessment of their patient and provide a more accurate estimate of risk to the patient," Dr. Afilalo and his associates said (J. Am. Coll. Cardiol. 2010;56:1668-76).

Second, clinicians can better assess which elderly patients might have better success with less-invasive techniques such as transcatheter valve implantation.

And third, patients who were found to have slow gait speed might benefit from extra interventions in the perioperative period, such as more intensive monitoring, early mobilization, low-intensity exercise training, or planned discharge to a specialized rehabilitation facility, they said.

The investigators reported no financial conflicts of interest.

Gait speed independently predicts both major morbidity and mortality in elderly patients who are about to undergo cardiac surgery, according to a prospective, blinded study reported in the Nov. 9 issue of the Journal of the American College of Cardiology.

"This simple, rapid, and inexpensive test effectively stratifies patients beyond traditional estimates of risk, which tend to be inaccurate in the elderly," said Dr. Jonathan Afilalo of McGill University, Montreal, and his associates.

Half the cardiac surgeries done in North America involve elderly patients (aged at least 70 years), but scoring systems for estimating operative risk perform poorly in this age group, "overestimating mortality by as much as 250%," they noted.

Dr. Afilalo and his colleagues performed what they described as the first study to test the value of gait speed as a predictor of poor outcomes in elderly cardiac surgery patients. The prospective, blinded study involved 131 patients (mean age, 76 years) who were scheduled to undergo elective coronary artery bypass and/or valve replacement or repair via standard sternotomy at four university-affiliated medical centers across Canada and the United States.

Before surgery, the study subjects were timed as they walked a distance of 5 meters in a well-lit hallway; subjects were permitted to use an aid such as a cane or walker if needed. A time of 6 seconds or longer was classified as a slow gait speed, whereas any time under 6 seconds was classified as a normal gait speed.

The primary composite end point was in-hospital mortality or any of five major complications (stroke, renal failure, prolonged ventilation, deep sternal wound infection, and need for reoperation).

In all, 60 patients (46%) were judged to have slow gait speed before surgery. Interestingly, gait speed did not correlate with the Society of Thoracic Surgeons’ risk score, "suggesting that these were representing distinct domains," the investigators said.

After surgery, 30 patients (23%) experienced the primary composite end point.

Slow gait speed was a strong and independent predictor, associated with a 3.17-fold increase in risk of the primary end point. Moreover, adding gait speed to existing risk prediction models improved their performance in predicting which patients would experience an adverse event and which patients would need "to be discharged to a health care facility for ongoing medical care or rehabilitation."

Women with slow gait speed appeared to be at particularly high risk for adverse outcomes.

The study findings have three clinical implications.

"First, by refining risk predictions in this challenging group, clinicians can have a more comprehensive assessment of their patient and provide a more accurate estimate of risk to the patient," Dr. Afilalo and his associates said (J. Am. Coll. Cardiol. 2010;56:1668-76).

Second, clinicians can better assess which elderly patients might have better success with less-invasive techniques such as transcatheter valve implantation.

And third, patients who were found to have slow gait speed might benefit from extra interventions in the perioperative period, such as more intensive monitoring, early mobilization, low-intensity exercise training, or planned discharge to a specialized rehabilitation facility, they said.

The investigators reported no financial conflicts of interest.

Adolescents living in rural areas of the United States are more likely to abuse prescription drugs than are those living in urban areas, according to a report published online Nov. 1 in the Archives of Pediatrics and Adolescent Medicine.

Even after study data were adjusted to account for differences between rural and urban adolescents in sociodemographics, health factors, and the abuse of other drugs, researchers found that residency in a rural area was independently associated with a significantly higher prevalence of prescription drug abuse. This pattern was not seen for abuse of any other substances, such as marijuana, cocaine, hallucinogens, inhalants, or alcohol, said Jennifer R. Havens, Ph.D., of the center on drug and alcohol research at the University of Kentucky, Lexington, and her associates.

Nationally, the rate of nonmedical use of prescription drugs ballooned by 212% between 1992 and 2003 among adolescents, to a rate nearly three times higher than that among people older than 18 years.

Many studies have assessed substance abuse among urban adolescents, but few have examined abuse among their rural counterparts. Moreover, the conclusions of the urban studies may not be generalizable to rural areas "owing to a unique set of contextual influences" that affect rural life, the investigators noted.

In particular, "the decimation of rural economies, precipitated by declines in the agricultural, manufacturing, and mining industries, and evidenced by high rates of unemployment," has contributed to profound economic and social decline in rural areas. Physical isolation, lack of insurance coverage, unavailability of local detoxification and psychiatric services, mistrust of the medical establishment, and the perceived stigma associated with seeking health care (especially mental health care) are all obstacles that disproportionately affect rural patients, they said.

To assess drug use among rural youths, Dr. Havens and her colleagues used data from the federal government’s National Survey on Drug Use and Health, an annual survey of a nationally representative sample of adolescents and adults that measures the prevalence and correlates of substance abuse. For this analysis, they included self-reported responses from 17,842 boys and girls aged 12-17 years.

Compared with respondents from urban and suburban areas, those from rural areas had significantly less income, were significantly more likely to have dropped out of school, and were significantly less likely to report excellent overall health. The prevalence of major depressive episodes was the same across the three geographic areas.

Adolescents residing in rural areas were 26% more likely than those in urban areas to report recent nonmedical use of prescription drugs, particularly pain relievers and tranquilizers. In all, 13% of rural adolescents reported any lifetime abuse of prescription drugs, compared with only 10% of urban adolescents, the researchers said (Arch. Pediatr. Adolesc. Med. 2010 Nov. 1 [doi:10.1001/archpediatrics.2010.217]).

Among the rural adolescents, nonmedical use of prescription drugs strongly correlated with dropping out of school and with having only one parent. Rural adolescents were 32% less likely to use illicit prescription drugs if they lived in a two-parent household than if they lived with only one parent.

It would seem, then, that interventions aimed at improving school retention and involving family members in adolescents’ lives might help prevent or reduce nonmedical prescription drug use in this population, Dr. Havens and her associates said.

Rural youths with a history of one or more major depressive episodes were more likely to abuse prescription drugs than were other youths, suggesting that they have poorer access to medical and/or psychiatric care than do adolescents residing in urban or suburban areas. This points to another potential source of intervention, "namely school-based counseling for mental health and substance abuse," the researchers added.

A particularly interesting finding was that the odds that a rural adolescent would abuse prescription drugs increased as that individual’s self-assessed health status declined. Other studies have shown that the prevalence of chronic pain is higher in rural areas, and that rural patients are less likely to have their health care needs met and more likely to forgo needed health care. This suggests that rural adolescents may have higher rates of self-medicating for pain, and that improving their health care could reduce the rate of self-medication, Dr. Havens and her colleagues said.

Future research should examine factors associated with use of pain relievers and tranquilizers among rural adolescents as "a next logical step," they added.

No financial conflicts of interest were reported.

Adolescents living in rural areas of the United States are more likely to abuse prescription drugs than are those living in urban areas, according to a report published online Nov. 1 in the Archives of Pediatrics and Adolescent Medicine.

Even after study data were adjusted to account for differences between rural and urban adolescents in sociodemographics, health factors, and the abuse of other drugs, researchers found that residency in a rural area was independently associated with a significantly higher prevalence of prescription drug abuse. This pattern was not seen for abuse of any other substances, such as marijuana, cocaine, hallucinogens, inhalants, or alcohol, said Jennifer R. Havens, Ph.D., of the center on drug and alcohol research at the University of Kentucky, Lexington, and her associates.

Nationally, the rate of nonmedical use of prescription drugs ballooned by 212% between 1992 and 2003 among adolescents, to a rate nearly three times higher than that among people older than 18 years.

Many studies have assessed substance abuse among urban adolescents, but few have examined abuse among their rural counterparts. Moreover, the conclusions of the urban studies may not be generalizable to rural areas "owing to a unique set of contextual influences" that affect rural life, the investigators noted.

In particular, "the decimation of rural economies, precipitated by declines in the agricultural, manufacturing, and mining industries, and evidenced by high rates of unemployment," has contributed to profound economic and social decline in rural areas. Physical isolation, lack of insurance coverage, unavailability of local detoxification and psychiatric services, mistrust of the medical establishment, and the perceived stigma associated with seeking health care (especially mental health care) are all obstacles that disproportionately affect rural patients, they said.

To assess drug use among rural youths, Dr. Havens and her colleagues used data from the federal government’s National Survey on Drug Use and Health, an annual survey of a nationally representative sample of adolescents and adults that measures the prevalence and correlates of substance abuse. For this analysis, they included self-reported responses from 17,842 boys and girls aged 12-17 years.

Compared with respondents from urban and suburban areas, those from rural areas had significantly less income, were significantly more likely to have dropped out of school, and were significantly less likely to report excellent overall health. The prevalence of major depressive episodes was the same across the three geographic areas.

Adolescents residing in rural areas were 26% more likely than those in urban areas to report recent nonmedical use of prescription drugs, particularly pain relievers and tranquilizers. In all, 13% of rural adolescents reported any lifetime abuse of prescription drugs, compared with only 10% of urban adolescents, the researchers said (Arch. Pediatr. Adolesc. Med. 2010 Nov. 1 [doi:10.1001/archpediatrics.2010.217]).

Among the rural adolescents, nonmedical use of prescription drugs strongly correlated with dropping out of school and with having only one parent. Rural adolescents were 32% less likely to use illicit prescription drugs if they lived in a two-parent household than if they lived with only one parent.

It would seem, then, that interventions aimed at improving school retention and involving family members in adolescents’ lives might help prevent or reduce nonmedical prescription drug use in this population, Dr. Havens and her associates said.

Rural youths with a history of one or more major depressive episodes were more likely to abuse prescription drugs than were other youths, suggesting that they have poorer access to medical and/or psychiatric care than do adolescents residing in urban or suburban areas. This points to another potential source of intervention, "namely school-based counseling for mental health and substance abuse," the researchers added.

A particularly interesting finding was that the odds that a rural adolescent would abuse prescription drugs increased as that individual’s self-assessed health status declined. Other studies have shown that the prevalence of chronic pain is higher in rural areas, and that rural patients are less likely to have their health care needs met and more likely to forgo needed health care. This suggests that rural adolescents may have higher rates of self-medicating for pain, and that improving their health care could reduce the rate of self-medication, Dr. Havens and her colleagues said.

Future research should examine factors associated with use of pain relievers and tranquilizers among rural adolescents as "a next logical step," they added.

No financial conflicts of interest were reported.

Adolescents living in rural areas of the United States are more likely to abuse prescription drugs than are those living in urban areas, according to a report published online Nov. 1 in the Archives of Pediatrics and Adolescent Medicine.

Even after study data were adjusted to account for differences between rural and urban adolescents in sociodemographics, health factors, and the abuse of other drugs, researchers found that residency in a rural area was independently associated with a significantly higher prevalence of prescription drug abuse. This pattern was not seen for abuse of any other substances, such as marijuana, cocaine, hallucinogens, inhalants, or alcohol, said Jennifer R. Havens, Ph.D., of the center on drug and alcohol research at the University of Kentucky, Lexington, and her associates.

Nationally, the rate of nonmedical use of prescription drugs ballooned by 212% between 1992 and 2003 among adolescents, to a rate nearly three times higher than that among people older than 18 years.

Many studies have assessed substance abuse among urban adolescents, but few have examined abuse among their rural counterparts. Moreover, the conclusions of the urban studies may not be generalizable to rural areas "owing to a unique set of contextual influences" that affect rural life, the investigators noted.

In particular, "the decimation of rural economies, precipitated by declines in the agricultural, manufacturing, and mining industries, and evidenced by high rates of unemployment," has contributed to profound economic and social decline in rural areas. Physical isolation, lack of insurance coverage, unavailability of local detoxification and psychiatric services, mistrust of the medical establishment, and the perceived stigma associated with seeking health care (especially mental health care) are all obstacles that disproportionately affect rural patients, they said.

To assess drug use among rural youths, Dr. Havens and her colleagues used data from the federal government’s National Survey on Drug Use and Health, an annual survey of a nationally representative sample of adolescents and adults that measures the prevalence and correlates of substance abuse. For this analysis, they included self-reported responses from 17,842 boys and girls aged 12-17 years.

Compared with respondents from urban and suburban areas, those from rural areas had significantly less income, were significantly more likely to have dropped out of school, and were significantly less likely to report excellent overall health. The prevalence of major depressive episodes was the same across the three geographic areas.

Adolescents residing in rural areas were 26% more likely than those in urban areas to report recent nonmedical use of prescription drugs, particularly pain relievers and tranquilizers. In all, 13% of rural adolescents reported any lifetime abuse of prescription drugs, compared with only 10% of urban adolescents, the researchers said (Arch. Pediatr. Adolesc. Med. 2010 Nov. 1 [doi:10.1001/archpediatrics.2010.217]).

Among the rural adolescents, nonmedical use of prescription drugs strongly correlated with dropping out of school and with having only one parent. Rural adolescents were 32% less likely to use illicit prescription drugs if they lived in a two-parent household than if they lived with only one parent.

It would seem, then, that interventions aimed at improving school retention and involving family members in adolescents’ lives might help prevent or reduce nonmedical prescription drug use in this population, Dr. Havens and her associates said.

Rural youths with a history of one or more major depressive episodes were more likely to abuse prescription drugs than were other youths, suggesting that they have poorer access to medical and/or psychiatric care than do adolescents residing in urban or suburban areas. This points to another potential source of intervention, "namely school-based counseling for mental health and substance abuse," the researchers added.

A particularly interesting finding was that the odds that a rural adolescent would abuse prescription drugs increased as that individual’s self-assessed health status declined. Other studies have shown that the prevalence of chronic pain is higher in rural areas, and that rural patients are less likely to have their health care needs met and more likely to forgo needed health care. This suggests that rural adolescents may have higher rates of self-medicating for pain, and that improving their health care could reduce the rate of self-medication, Dr. Havens and her colleagues said.

Future research should examine factors associated with use of pain relievers and tranquilizers among rural adolescents as "a next logical step," they added.

No financial conflicts of interest were reported.

As many as 97% of all adolescents who are diagnosed as having major depressive disorder recover within 4 years, but nearly half of them have a recurrence during that time, according to a report published online Nov. 1 in the Archives of General Psychiatry.

As expected, those who respond well to short-term treatment are more likely to recover. Surprisingly, however, full responders to short-term treatment are no less likely to develop a recurrence than are partial or nonresponders, said John Curry, Ph.D., of the child and family study center at Duke University, Durham, N.C., and his associates.

The investigators sought to characterize both recovery from and recurrences of major depression among adolescents. They performed an extended, 5-year follow-up of 196 subjects who had participated in TADS (Treatment for Adolescents With Depression Study), an 18-week trial that compared responses to fluoxetine, cognitive-behavioral therapy, a combination of the two, and placebo.

The researchers described this as "the largest treatment follow-up sample of depressed adolescents to date."

Approximately 97% of the study subjects recovered from their index episode of major depression. A total of 30% recovered at 6 months, 66% at 12 months, 85% at 18 months, 88% at 24 months, 92% at 30 months, 95% at 36 months, and 97% at 42 months.

As Dr. Curry and his colleagues had hypothesized, recovery at 2 years was significantly more likely to occur among adolescents who had fully responded to short-term treatment (96% recovery rate) than among those who had shown only a partial response or no response in the short term (79% recovery rate). Also as expected, recovery at 2 years was associated with less-severe depression, absence of sleep, or appetite disturbance, as well as better functioning during the depressive episode.

Of the 189 patients who recovered, 101 (53%) remained well throughout 5 years of follow-up, whereas 88 (47%) had a recurrence. Most of these patients had only a single recurrence, but 12 patients had two recurrences and 2 patients had three recurrences during that time. The cumulative recurrence rates were approximately 2% at 1 year post diagnosis, 12% at 2 years, 30% at 3 years, and 38% at 4 years, the investigators said (Arch. Gen. Psychiatry 2010 Nov. 1 [doi:10.1001/archgenpsychiatry.2010.150]).

The mean interval between recovery and onset of a first recurrence was 22 months.

Contrary to expectations, the recurrence rate among full responders (54%) was not lower than that among nonresponders or partial responders (46%). Also unexpected was the finding that patients who received the optimal therapy from the start – fluoxetine plus CBT – had a recurrence rate (49%) that was not significantly different from that of patients who had first been treated with less-than-optimal therapy or even placebo (46%).

Female sex proved to be the most robust predictor of recurrence. "To our knowledge, this is the first study documenting higher recurrence rates among treated adolescent females," the investigators noted.

In the literature, there is no sex difference in recurrence among adults; a community-based study did show such a difference but only in patients aged 19-23 years. "This age range overlaps ours, suggesting that female vulnerability to recurrence may be age-related." Hormonal factors, low perceived mastery, or a ruminative response style characteristic of females in this age group might be responsible, Dr. Curry and his associates said.

Another possible contributor to this sex difference may be related to anxiety. Concomitant anxiety disorder is a predictor of recurrence, and such disorders were more common among females (28%) than among males (15%) in this study.

The investigators also looked at the emergence of bipolar disorder among this population and found this to be a relatively rare occurrence. In all, 9 females and 3 males (6% of the study subjects overall) were diagnosed as having bipolar disorder during follow-up, and 9 of these 12 had not responded to short-term treatment. Bipolar disorder tended to emerge at the end of follow-up, when subjects were a mean age of 18 years old.

The investigators said the most significant limitation of their study was that slightly fewer than half of the TADS participants took part. "This likely reflects the difficulty of maintaining a sample of adolescents during a period when many are moving away from home," they wrote.

This study was funded by the National Institute of Mental Health. Dr. Curry disclosed ties to the REACH Institute, an organization dedicated to quickly disseminating the latest scientific findings on the mental health of children to professionals and families. His associates disclosed ties to numerous pharmaceutical companies.

As many as 97% of all adolescents who are diagnosed as having major depressive disorder recover within 4 years, but nearly half of them have a recurrence during that time, according to a report published online Nov. 1 in the Archives of General Psychiatry.

As expected, those who respond well to short-term treatment are more likely to recover. Surprisingly, however, full responders to short-term treatment are no less likely to develop a recurrence than are partial or nonresponders, said John Curry, Ph.D., of the child and family study center at Duke University, Durham, N.C., and his associates.

The investigators sought to characterize both recovery from and recurrences of major depression among adolescents. They performed an extended, 5-year follow-up of 196 subjects who had participated in TADS (Treatment for Adolescents With Depression Study), an 18-week trial that compared responses to fluoxetine, cognitive-behavioral therapy, a combination of the two, and placebo.

The researchers described this as "the largest treatment follow-up sample of depressed adolescents to date."

Approximately 97% of the study subjects recovered from their index episode of major depression. A total of 30% recovered at 6 months, 66% at 12 months, 85% at 18 months, 88% at 24 months, 92% at 30 months, 95% at 36 months, and 97% at 42 months.

As Dr. Curry and his colleagues had hypothesized, recovery at 2 years was significantly more likely to occur among adolescents who had fully responded to short-term treatment (96% recovery rate) than among those who had shown only a partial response or no response in the short term (79% recovery rate). Also as expected, recovery at 2 years was associated with less-severe depression, absence of sleep, or appetite disturbance, as well as better functioning during the depressive episode.

Of the 189 patients who recovered, 101 (53%) remained well throughout 5 years of follow-up, whereas 88 (47%) had a recurrence. Most of these patients had only a single recurrence, but 12 patients had two recurrences and 2 patients had three recurrences during that time. The cumulative recurrence rates were approximately 2% at 1 year post diagnosis, 12% at 2 years, 30% at 3 years, and 38% at 4 years, the investigators said (Arch. Gen. Psychiatry 2010 Nov. 1 [doi:10.1001/archgenpsychiatry.2010.150]).

The mean interval between recovery and onset of a first recurrence was 22 months.

Contrary to expectations, the recurrence rate among full responders (54%) was not lower than that among nonresponders or partial responders (46%). Also unexpected was the finding that patients who received the optimal therapy from the start – fluoxetine plus CBT – had a recurrence rate (49%) that was not significantly different from that of patients who had first been treated with less-than-optimal therapy or even placebo (46%).

Female sex proved to be the most robust predictor of recurrence. "To our knowledge, this is the first study documenting higher recurrence rates among treated adolescent females," the investigators noted.

In the literature, there is no sex difference in recurrence among adults; a community-based study did show such a difference but only in patients aged 19-23 years. "This age range overlaps ours, suggesting that female vulnerability to recurrence may be age-related." Hormonal factors, low perceived mastery, or a ruminative response style characteristic of females in this age group might be responsible, Dr. Curry and his associates said.

Another possible contributor to this sex difference may be related to anxiety. Concomitant anxiety disorder is a predictor of recurrence, and such disorders were more common among females (28%) than among males (15%) in this study.

The investigators also looked at the emergence of bipolar disorder among this population and found this to be a relatively rare occurrence. In all, 9 females and 3 males (6% of the study subjects overall) were diagnosed as having bipolar disorder during follow-up, and 9 of these 12 had not responded to short-term treatment. Bipolar disorder tended to emerge at the end of follow-up, when subjects were a mean age of 18 years old.

The investigators said the most significant limitation of their study was that slightly fewer than half of the TADS participants took part. "This likely reflects the difficulty of maintaining a sample of adolescents during a period when many are moving away from home," they wrote.

This study was funded by the National Institute of Mental Health. Dr. Curry disclosed ties to the REACH Institute, an organization dedicated to quickly disseminating the latest scientific findings on the mental health of children to professionals and families. His associates disclosed ties to numerous pharmaceutical companies.

As many as 97% of all adolescents who are diagnosed as having major depressive disorder recover within 4 years, but nearly half of them have a recurrence during that time, according to a report published online Nov. 1 in the Archives of General Psychiatry.

As expected, those who respond well to short-term treatment are more likely to recover. Surprisingly, however, full responders to short-term treatment are no less likely to develop a recurrence than are partial or nonresponders, said John Curry, Ph.D., of the child and family study center at Duke University, Durham, N.C., and his associates.

The investigators sought to characterize both recovery from and recurrences of major depression among adolescents. They performed an extended, 5-year follow-up of 196 subjects who had participated in TADS (Treatment for Adolescents With Depression Study), an 18-week trial that compared responses to fluoxetine, cognitive-behavioral therapy, a combination of the two, and placebo.

The researchers described this as "the largest treatment follow-up sample of depressed adolescents to date."

Approximately 97% of the study subjects recovered from their index episode of major depression. A total of 30% recovered at 6 months, 66% at 12 months, 85% at 18 months, 88% at 24 months, 92% at 30 months, 95% at 36 months, and 97% at 42 months.

As Dr. Curry and his colleagues had hypothesized, recovery at 2 years was significantly more likely to occur among adolescents who had fully responded to short-term treatment (96% recovery rate) than among those who had shown only a partial response or no response in the short term (79% recovery rate). Also as expected, recovery at 2 years was associated with less-severe depression, absence of sleep, or appetite disturbance, as well as better functioning during the depressive episode.

Of the 189 patients who recovered, 101 (53%) remained well throughout 5 years of follow-up, whereas 88 (47%) had a recurrence. Most of these patients had only a single recurrence, but 12 patients had two recurrences and 2 patients had three recurrences during that time. The cumulative recurrence rates were approximately 2% at 1 year post diagnosis, 12% at 2 years, 30% at 3 years, and 38% at 4 years, the investigators said (Arch. Gen. Psychiatry 2010 Nov. 1 [doi:10.1001/archgenpsychiatry.2010.150]).

The mean interval between recovery and onset of a first recurrence was 22 months.

Contrary to expectations, the recurrence rate among full responders (54%) was not lower than that among nonresponders or partial responders (46%). Also unexpected was the finding that patients who received the optimal therapy from the start – fluoxetine plus CBT – had a recurrence rate (49%) that was not significantly different from that of patients who had first been treated with less-than-optimal therapy or even placebo (46%).

Female sex proved to be the most robust predictor of recurrence. "To our knowledge, this is the first study documenting higher recurrence rates among treated adolescent females," the investigators noted.

In the literature, there is no sex difference in recurrence among adults; a community-based study did show such a difference but only in patients aged 19-23 years. "This age range overlaps ours, suggesting that female vulnerability to recurrence may be age-related." Hormonal factors, low perceived mastery, or a ruminative response style characteristic of females in this age group might be responsible, Dr. Curry and his associates said.

Another possible contributor to this sex difference may be related to anxiety. Concomitant anxiety disorder is a predictor of recurrence, and such disorders were more common among females (28%) than among males (15%) in this study.

The investigators also looked at the emergence of bipolar disorder among this population and found this to be a relatively rare occurrence. In all, 9 females and 3 males (6% of the study subjects overall) were diagnosed as having bipolar disorder during follow-up, and 9 of these 12 had not responded to short-term treatment. Bipolar disorder tended to emerge at the end of follow-up, when subjects were a mean age of 18 years old.

The investigators said the most significant limitation of their study was that slightly fewer than half of the TADS participants took part. "This likely reflects the difficulty of maintaining a sample of adolescents during a period when many are moving away from home," they wrote.

This study was funded by the National Institute of Mental Health. Dr. Curry disclosed ties to the REACH Institute, an organization dedicated to quickly disseminating the latest scientific findings on the mental health of children to professionals and families. His associates disclosed ties to numerous pharmaceutical companies.

Gait speed independently predicts both major morbidity and mortality in elderly patients who are about to undergo cardiac surgery, according to a prospective, blinded study reported in the Nov. 9 issue of the Journal of the American College of Cardiology.

"This simple, rapid, and inexpensive test effectively stratifies patients beyond traditional estimates of risk, which tend to be inaccurate in the elderly," said Dr. Jonathan Afilalo of McGill University, Montreal, and his associates.

Half the cardiac surgeries done in North America involve elderly patients (aged at least 70 years), but scoring systems for estimating operative risk perform poorly in this age group, "overestimating mortality by as much as 250%," they noted.

Dr. Afilalo and his colleagues performed what they described as the first study to test the value of gait speed as a predictor of poor outcomes in elderly cardiac surgery patients. The prospective, blinded study involved 131 patients (mean age, 76 years) who were scheduled to undergo elective coronary artery bypass and/or valve replacement or repair via standard sternotomy at four university-affiliated medical centers across Canada and the United States.

Before surgery, the study subjects were timed as they walked a distance of 5 meters in a well-lit hallway; subjects were permitted to use an aid such as a cane or walker if needed. A time of 6 seconds or longer was classified as a slow gait speed, whereas any time under 6 seconds was classified as a normal gait speed.

The primary composite end point was in-hospital mortality or any of five major complications (stroke, renal failure, prolonged ventilation, deep sternal wound infection, and need for reoperation).

In all, 60 patients (46%) were judged to have slow gait speed before surgery. Interestingly, gait speed did not correlate with the Society of Thoracic Surgeons’ risk score, "suggesting that these were representing distinct domains," the investigators said.

After surgery, 30 patients (23%) experienced the primary composite end point.

Slow gait speed was a strong and independent predictor, associated with a 3.17-fold increase in risk of the primary end point. Moreover, adding gait speed to existing risk prediction models improved their performance in predicting which patients would experience an adverse event and which patients would need "to be discharged to a health care facility for ongoing medical care or rehabilitation."

Women with slow gait speed appeared to be at particularly high risk for adverse outcomes.

The study findings have three clinical implications.

"First, by refining risk predictions in this challenging group, clinicians can have a more comprehensive assessment of their patient and provide a more accurate estimate of risk to the patient," Dr. Afilalo and his associates said (J. Am. Coll. Cardiol. 2010;56:1668-76).

Second, clinicians can better assess which elderly patients might have better success with less-invasive techniques such as transcatheter valve implantation.

And third, patients who were found to have slow gait speed might benefit from extra interventions in the perioperative period, such as more intensive monitoring, early mobilization, low-intensity exercise training, or planned discharge to a specialized rehabilitation facility, they said.

The investigators reported no financial conflicts of interest.

Gait speed independently predicts both major morbidity and mortality in elderly patients who are about to undergo cardiac surgery, according to a prospective, blinded study reported in the Nov. 9 issue of the Journal of the American College of Cardiology.

"This simple, rapid, and inexpensive test effectively stratifies patients beyond traditional estimates of risk, which tend to be inaccurate in the elderly," said Dr. Jonathan Afilalo of McGill University, Montreal, and his associates.

Half the cardiac surgeries done in North America involve elderly patients (aged at least 70 years), but scoring systems for estimating operative risk perform poorly in this age group, "overestimating mortality by as much as 250%," they noted.

Dr. Afilalo and his colleagues performed what they described as the first study to test the value of gait speed as a predictor of poor outcomes in elderly cardiac surgery patients. The prospective, blinded study involved 131 patients (mean age, 76 years) who were scheduled to undergo elective coronary artery bypass and/or valve replacement or repair via standard sternotomy at four university-affiliated medical centers across Canada and the United States.

Before surgery, the study subjects were timed as they walked a distance of 5 meters in a well-lit hallway; subjects were permitted to use an aid such as a cane or walker if needed. A time of 6 seconds or longer was classified as a slow gait speed, whereas any time under 6 seconds was classified as a normal gait speed.

The primary composite end point was in-hospital mortality or any of five major complications (stroke, renal failure, prolonged ventilation, deep sternal wound infection, and need for reoperation).

In all, 60 patients (46%) were judged to have slow gait speed before surgery. Interestingly, gait speed did not correlate with the Society of Thoracic Surgeons’ risk score, "suggesting that these were representing distinct domains," the investigators said.

After surgery, 30 patients (23%) experienced the primary composite end point.

Slow gait speed was a strong and independent predictor, associated with a 3.17-fold increase in risk of the primary end point. Moreover, adding gait speed to existing risk prediction models improved their performance in predicting which patients would experience an adverse event and which patients would need "to be discharged to a health care facility for ongoing medical care or rehabilitation."

Women with slow gait speed appeared to be at particularly high risk for adverse outcomes.

The study findings have three clinical implications.

"First, by refining risk predictions in this challenging group, clinicians can have a more comprehensive assessment of their patient and provide a more accurate estimate of risk to the patient," Dr. Afilalo and his associates said (J. Am. Coll. Cardiol. 2010;56:1668-76).

Second, clinicians can better assess which elderly patients might have better success with less-invasive techniques such as transcatheter valve implantation.

And third, patients who were found to have slow gait speed might benefit from extra interventions in the perioperative period, such as more intensive monitoring, early mobilization, low-intensity exercise training, or planned discharge to a specialized rehabilitation facility, they said.

The investigators reported no financial conflicts of interest.

Gait speed independently predicts both major morbidity and mortality in elderly patients who are about to undergo cardiac surgery, according to a prospective, blinded study reported in the Nov. 9 issue of the Journal of the American College of Cardiology.

"This simple, rapid, and inexpensive test effectively stratifies patients beyond traditional estimates of risk, which tend to be inaccurate in the elderly," said Dr. Jonathan Afilalo of McGill University, Montreal, and his associates.

Half the cardiac surgeries done in North America involve elderly patients (aged at least 70 years), but scoring systems for estimating operative risk perform poorly in this age group, "overestimating mortality by as much as 250%," they noted.

Dr. Afilalo and his colleagues performed what they described as the first study to test the value of gait speed as a predictor of poor outcomes in elderly cardiac surgery patients. The prospective, blinded study involved 131 patients (mean age, 76 years) who were scheduled to undergo elective coronary artery bypass and/or valve replacement or repair via standard sternotomy at four university-affiliated medical centers across Canada and the United States.

Before surgery, the study subjects were timed as they walked a distance of 5 meters in a well-lit hallway; subjects were permitted to use an aid such as a cane or walker if needed. A time of 6 seconds or longer was classified as a slow gait speed, whereas any time under 6 seconds was classified as a normal gait speed.

The primary composite end point was in-hospital mortality or any of five major complications (stroke, renal failure, prolonged ventilation, deep sternal wound infection, and need for reoperation).

In all, 60 patients (46%) were judged to have slow gait speed before surgery. Interestingly, gait speed did not correlate with the Society of Thoracic Surgeons’ risk score, "suggesting that these were representing distinct domains," the investigators said.

After surgery, 30 patients (23%) experienced the primary composite end point.

Slow gait speed was a strong and independent predictor, associated with a 3.17-fold increase in risk of the primary end point. Moreover, adding gait speed to existing risk prediction models improved their performance in predicting which patients would experience an adverse event and which patients would need "to be discharged to a health care facility for ongoing medical care or rehabilitation."

Women with slow gait speed appeared to be at particularly high risk for adverse outcomes.

The study findings have three clinical implications.

"First, by refining risk predictions in this challenging group, clinicians can have a more comprehensive assessment of their patient and provide a more accurate estimate of risk to the patient," Dr. Afilalo and his associates said (J. Am. Coll. Cardiol. 2010;56:1668-76).

Second, clinicians can better assess which elderly patients might have better success with less-invasive techniques such as transcatheter valve implantation.

And third, patients who were found to have slow gait speed might benefit from extra interventions in the perioperative period, such as more intensive monitoring, early mobilization, low-intensity exercise training, or planned discharge to a specialized rehabilitation facility, they said.

The investigators reported no financial conflicts of interest.

Estrogen-plus-progestin hormone therapy raises the incidence of invasive breast cancer, the percentage of such cancers that have spread to the lymph nodes at excision, cancer-related mortality, and all-cause mortality, according to updated results of a multicenter, randomized trial.

These conclusions from an 11-year follow-up of 15,408 subjects in the Women's Health Initiative randomized clinical trial are the direct opposite of those reported by most observational studies of the issue, which linked combined hormone therapy with breast cancers that have more favorable characteristics and with longer patient survival.

The new findings likely foretell another substantial decline in the use of postmenopausal hormone therapy and a subsequent decrease in breast cancer incidence, much as the initial reports from the WHI study did, said Dr. Rowan T. Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, Calif., and his colleagues.

They undertook the WHI update in part because “the influence of estrogen-plus-progestin on breast cancer mortality has not been addressed in a randomized trial setting.”

The WHI involved 16,608 postmenopausal women randomized to either conjugated equine estrogens plus medroxyprogesterone or placebo beginning in 1993. The study was halted early, in 2002, when an interim analysis found evidence of harm with the treatment. Subjects were advised to discontinue the hormone therapy, and the study was extended to 2005-2009, most of the original study subjects consenting to participate in a median follow-up of 11 years.

In women on active hormone therapy, the rate of invasive breast cancer during the extended follow-up was 0.42% per year, compared with 0.34% for placebo.

Breast cancers in the hormone therapy group had a 24% rate of positive lymph nodes, vs. 16% for placebo. There were 2.6 and 1.3 deaths per 10,000 women per year due to breast cancer, respectively; and all-cause mortality was 5.3 and 3.4 deaths per 10,000 women per year, respectively (JAMA 2010;304:1684-92).

The Women's Health Initiative was funded by the National Heart, Lung, and Blood Institute. Dr. Chlebowski reported ties to AstraZeneca, Novartis, Pfizer, and Amgen. His associates reported ties to Procter & Gamble, Wyeth Laboratories (maker of Prempro used in the WHI), Upsher-Smith Laboratories, Meditrina Pharmaceuticals Merck, Boehringer Ingelheim, and Organon, and have served as legal consultants regarding hormone therapy.

View on the News

Risks of Cancer Underestimated

“It is probable that the increase in breast cancer deaths due to hormone therapy has been underestimated in the current study, and that with longer follow-up, the deleterious effect will appear larger,” said Dr. Peter B. Bach.

The mortality curves of the two study groups appear to be continuing to separate at the end of the current follow-up period. And the difference between the two study groups in cumulative breast cancer incidence also appears to be continuing to widen. Both trends indicate that the number of deaths associated with hormone therapy will continue to rise as time passes.

DR. PETER B. BACH is with the Health Outcomes Research Group at Memorial Sloan-Kettering Cancer Center, New York. He reported no financial disclosures. These comments are taken from his editorial accompanying the WHI report (JAMA 2010;304:1719-20).

Estrogen-plus-progestin hormone therapy raises the incidence of invasive breast cancer, the percentage of such cancers that have spread to the lymph nodes at excision, cancer-related mortality, and all-cause mortality, according to updated results of a multicenter, randomized trial.

These conclusions from an 11-year follow-up of 15,408 subjects in the Women's Health Initiative randomized clinical trial are the direct opposite of those reported by most observational studies of the issue, which linked combined hormone therapy with breast cancers that have more favorable characteristics and with longer patient survival.

The new findings likely foretell another substantial decline in the use of postmenopausal hormone therapy and a subsequent decrease in breast cancer incidence, much as the initial reports from the WHI study did, said Dr. Rowan T. Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, Calif., and his colleagues.

They undertook the WHI update in part because “the influence of estrogen-plus-progestin on breast cancer mortality has not been addressed in a randomized trial setting.”

The WHI involved 16,608 postmenopausal women randomized to either conjugated equine estrogens plus medroxyprogesterone or placebo beginning in 1993. The study was halted early, in 2002, when an interim analysis found evidence of harm with the treatment. Subjects were advised to discontinue the hormone therapy, and the study was extended to 2005-2009, most of the original study subjects consenting to participate in a median follow-up of 11 years.

In women on active hormone therapy, the rate of invasive breast cancer during the extended follow-up was 0.42% per year, compared with 0.34% for placebo.

Breast cancers in the hormone therapy group had a 24% rate of positive lymph nodes, vs. 16% for placebo. There were 2.6 and 1.3 deaths per 10,000 women per year due to breast cancer, respectively; and all-cause mortality was 5.3 and 3.4 deaths per 10,000 women per year, respectively (JAMA 2010;304:1684-92).

The Women's Health Initiative was funded by the National Heart, Lung, and Blood Institute. Dr. Chlebowski reported ties to AstraZeneca, Novartis, Pfizer, and Amgen. His associates reported ties to Procter & Gamble, Wyeth Laboratories (maker of Prempro used in the WHI), Upsher-Smith Laboratories, Meditrina Pharmaceuticals Merck, Boehringer Ingelheim, and Organon, and have served as legal consultants regarding hormone therapy.

View on the News

Risks of Cancer Underestimated

“It is probable that the increase in breast cancer deaths due to hormone therapy has been underestimated in the current study, and that with longer follow-up, the deleterious effect will appear larger,” said Dr. Peter B. Bach.

The mortality curves of the two study groups appear to be continuing to separate at the end of the current follow-up period. And the difference between the two study groups in cumulative breast cancer incidence also appears to be continuing to widen. Both trends indicate that the number of deaths associated with hormone therapy will continue to rise as time passes.

DR. PETER B. BACH is with the Health Outcomes Research Group at Memorial Sloan-Kettering Cancer Center, New York. He reported no financial disclosures. These comments are taken from his editorial accompanying the WHI report (JAMA 2010;304:1719-20).

Estrogen-plus-progestin hormone therapy raises the incidence of invasive breast cancer, the percentage of such cancers that have spread to the lymph nodes at excision, cancer-related mortality, and all-cause mortality, according to updated results of a multicenter, randomized trial.

These conclusions from an 11-year follow-up of 15,408 subjects in the Women's Health Initiative randomized clinical trial are the direct opposite of those reported by most observational studies of the issue, which linked combined hormone therapy with breast cancers that have more favorable characteristics and with longer patient survival.

The new findings likely foretell another substantial decline in the use of postmenopausal hormone therapy and a subsequent decrease in breast cancer incidence, much as the initial reports from the WHI study did, said Dr. Rowan T. Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, Calif., and his colleagues.

They undertook the WHI update in part because “the influence of estrogen-plus-progestin on breast cancer mortality has not been addressed in a randomized trial setting.”

The WHI involved 16,608 postmenopausal women randomized to either conjugated equine estrogens plus medroxyprogesterone or placebo beginning in 1993. The study was halted early, in 2002, when an interim analysis found evidence of harm with the treatment. Subjects were advised to discontinue the hormone therapy, and the study was extended to 2005-2009, most of the original study subjects consenting to participate in a median follow-up of 11 years.

In women on active hormone therapy, the rate of invasive breast cancer during the extended follow-up was 0.42% per year, compared with 0.34% for placebo.

Breast cancers in the hormone therapy group had a 24% rate of positive lymph nodes, vs. 16% for placebo. There were 2.6 and 1.3 deaths per 10,000 women per year due to breast cancer, respectively; and all-cause mortality was 5.3 and 3.4 deaths per 10,000 women per year, respectively (JAMA 2010;304:1684-92).

The Women's Health Initiative was funded by the National Heart, Lung, and Blood Institute. Dr. Chlebowski reported ties to AstraZeneca, Novartis, Pfizer, and Amgen. His associates reported ties to Procter & Gamble, Wyeth Laboratories (maker of Prempro used in the WHI), Upsher-Smith Laboratories, Meditrina Pharmaceuticals Merck, Boehringer Ingelheim, and Organon, and have served as legal consultants regarding hormone therapy.

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Risks of Cancer Underestimated

“It is probable that the increase in breast cancer deaths due to hormone therapy has been underestimated in the current study, and that with longer follow-up, the deleterious effect will appear larger,” said Dr. Peter B. Bach.

The mortality curves of the two study groups appear to be continuing to separate at the end of the current follow-up period. And the difference between the two study groups in cumulative breast cancer incidence also appears to be continuing to widen. Both trends indicate that the number of deaths associated with hormone therapy will continue to rise as time passes.

DR. PETER B. BACH is with the Health Outcomes Research Group at Memorial Sloan-Kettering Cancer Center, New York. He reported no financial disclosures. These comments are taken from his editorial accompanying the WHI report (JAMA 2010;304:1719-20).