Jane Salodof MacNeil

CHICAGO — After a 30-year drought during which 70 randomized trials failed to improve outcomes in advanced melanoma, the first agent in a new class of drugs has prolonged survival of advanced, pretreated patients in a large international phase III trial.

“This is the first time we have shown a survival benefit in metastatic melanoma,” Dr. Steven O’Day, the lead investigator, announced at the annual meeting of the American Society of Clinical Oncology.

The new agent, ipilimumab, is a monoclonal antibody targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), a gene that limits the ability of T cells to attack cancerous cells.

Median overall survival reached 10.1 months in 137 patients whose only active treatment was ipilimumab and 10 months in 403 patients given ipilimumab with an experimental vaccine. It was 6.4 months in 136 patients who received the vaccine without ipilimumab – a length of time that falls within the 6-9 month life expectancy for patients with metastatic melanoma, according to Dr. O’Day, chief of research and director of the melanoma program at the Angeles Clinic and Research Institute in Los Angeles.

The difference between the study arms treated with ipilimumab and patients who received only the vaccine was highly significant with a hazard ratio of 0.68 (P= .0004).

The one-year survival rate was nearly twice as high in the ipilimumab arms (46% vs. 25%), as was the two-year rate (24% vs. 14%). Some long-term survivors continue to be followed 4.5 years after treatment.

Disease-control rates were also significantly higher in the two ipilimumab arms (28.5% with ipilimumab alone and 20.1% with ipilimumab plus vaccine vs. 11% with the vaccine alone). Best overall response rates likewise were higher (10.9% and 5.7%, respectively, vs. 1.5%).

Addition of the GP 100 peptide vaccine did not appear to improve outcomes, Dr. O’Day noted. The investigators chose it for the control arm because it had drawn responses in a previous trial, and there is no standard of care for these patients. Dacarbazine (DTIC) has long and often been used, but no randomized trial has ever proven it superior to best supportive care.

Disclosures included that research funding was provided by Medarex and Bristol-Myers Squibb, which is developing ipilimumab.

CHICAGO — After a 30-year drought during which 70 randomized trials failed to improve outcomes in advanced melanoma, the first agent in a new class of drugs has prolonged survival of advanced, pretreated patients in a large international phase III trial.

“This is the first time we have shown a survival benefit in metastatic melanoma,” Dr. Steven O’Day, the lead investigator, announced at the annual meeting of the American Society of Clinical Oncology.

The new agent, ipilimumab, is a monoclonal antibody targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), a gene that limits the ability of T cells to attack cancerous cells.

Median overall survival reached 10.1 months in 137 patients whose only active treatment was ipilimumab and 10 months in 403 patients given ipilimumab with an experimental vaccine. It was 6.4 months in 136 patients who received the vaccine without ipilimumab – a length of time that falls within the 6-9 month life expectancy for patients with metastatic melanoma, according to Dr. O’Day, chief of research and director of the melanoma program at the Angeles Clinic and Research Institute in Los Angeles.

The difference between the study arms treated with ipilimumab and patients who received only the vaccine was highly significant with a hazard ratio of 0.68 (P= .0004).

The one-year survival rate was nearly twice as high in the ipilimumab arms (46% vs. 25%), as was the two-year rate (24% vs. 14%). Some long-term survivors continue to be followed 4.5 years after treatment.

Disease-control rates were also significantly higher in the two ipilimumab arms (28.5% with ipilimumab alone and 20.1% with ipilimumab plus vaccine vs. 11% with the vaccine alone). Best overall response rates likewise were higher (10.9% and 5.7%, respectively, vs. 1.5%).

Addition of the GP 100 peptide vaccine did not appear to improve outcomes, Dr. O’Day noted. The investigators chose it for the control arm because it had drawn responses in a previous trial, and there is no standard of care for these patients. Dacarbazine (DTIC) has long and often been used, but no randomized trial has ever proven it superior to best supportive care.

Disclosures included that research funding was provided by Medarex and Bristol-Myers Squibb, which is developing ipilimumab.

CHICAGO — After a 30-year drought during which 70 randomized trials failed to improve outcomes in advanced melanoma, the first agent in a new class of drugs has prolonged survival of advanced, pretreated patients in a large international phase III trial.

“This is the first time we have shown a survival benefit in metastatic melanoma,” Dr. Steven O’Day, the lead investigator, announced at the annual meeting of the American Society of Clinical Oncology.

The new agent, ipilimumab, is a monoclonal antibody targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), a gene that limits the ability of T cells to attack cancerous cells.

Median overall survival reached 10.1 months in 137 patients whose only active treatment was ipilimumab and 10 months in 403 patients given ipilimumab with an experimental vaccine. It was 6.4 months in 136 patients who received the vaccine without ipilimumab – a length of time that falls within the 6-9 month life expectancy for patients with metastatic melanoma, according to Dr. O’Day, chief of research and director of the melanoma program at the Angeles Clinic and Research Institute in Los Angeles.

The difference between the study arms treated with ipilimumab and patients who received only the vaccine was highly significant with a hazard ratio of 0.68 (P= .0004).

The one-year survival rate was nearly twice as high in the ipilimumab arms (46% vs. 25%), as was the two-year rate (24% vs. 14%). Some long-term survivors continue to be followed 4.5 years after treatment.

Disease-control rates were also significantly higher in the two ipilimumab arms (28.5% with ipilimumab alone and 20.1% with ipilimumab plus vaccine vs. 11% with the vaccine alone). Best overall response rates likewise were higher (10.9% and 5.7%, respectively, vs. 1.5%).

Addition of the GP 100 peptide vaccine did not appear to improve outcomes, Dr. O’Day noted. The investigators chose it for the control arm because it had drawn responses in a previous trial, and there is no standard of care for these patients. Dacarbazine (DTIC) has long and often been used, but no randomized trial has ever proven it superior to best supportive care.

Disclosures included that research funding was provided by Medarex and Bristol-Myers Squibb, which is developing ipilimumab.

The Food and Drug Administration has approved sipuleucel-T for treatment of advanced prostate cancer in a much-anticipated ruling that marks the first approval of a vaccine for cancer treatment.

The indication is for use in patients with “asymptomatic or minimally symptomatic prostate cancer that has spread to other parts of the body and is resistant to standard hormone treatment,” according to the FDA announcement.

Sipuleucel-T will be marketed as Provenge by manufacturer Dendreon Corp.

The company announced the vaccine will be available initially at 50 oncology and urology centers that were approved clinical trial sites. Executives said in an investors' call that they expected to serve 2,000 patients within the first 12 months. Initially, the individually tailored vaccine will be manufactured only in the company's New Jersey facility, but Dendreon plans to add facilities in Atlanta and in Orange County, Calif. by mid-2011.

Pricing has been set at $31,000 per infusion, or a total of $93,000 for the therapy. The company has set up a patient-access program to help men who cannot afford co-payments.

The granting of the indication follows a long and tumultuous review process in which protestors icketed after an FDA advisory committee rejected Dendreon's initial application for the vaccine. Early results from a key trial designed to address issues raised by the panel failed to show an improvement in progression-free survival, but researchers were eventually able to demonstrate that men lived longer when treated with sipuleucel-T.

The pivotal Dendreon-sponsored, phase III IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial randomized 512 men with metastatic castration-resistant prostate cancer to sipuleucel-T or placebo. At a median follow-up of 3 years, the vaccine was credited with a 4.1-month gain in overall survival, with men on the vaccine living a median of 25.8 months vs. 21.7 months in the control group.

Adverse events occurred in almost all patients, with chills, fatigue, fever, back pain, nausea, joint ache, and headache being common reactions. Most side effects were mild or moderate, but the FDA noted that about a quarter of patients had serious adverse reactions, including some acute infusion reactions and stroke.

“Cerebrovascular events, including hemorrhagic and ischemic strokes, were observed in 3.5% of patients in the Provenge group, compared with 2.6% of patients in the control group,” it said.

The company announced that it has committed to conducting “a registry of approximately 1,500 patients to further evaluate a small potential safety signal of cerebrovascular events.”

An autologous cellular immunotherapy, sipuleucel-T delivers a patient's own immune cells, extracted via leukapheresis, in a vaccine designed to stimulate an immune response against prostatic acid phosphatase (PAP), an antigen expressed in most prostate cancers. Men received three doses of the vaccine in intravenous injections given at about 2-week intervals.”

“The availability of Provenge provides a new treatment option for men with advanced prostate cancer, who currently have limited effective therapies available,” said Dr. Karen Midthun, acting director of the FDA's Center for Biologics Evaluation and Research, in the FDA announcement.

The International Society for Biological Therapy of Cancer issued a statement hailing the approval as “a significant advance in the development of biological therapy [also called immunotherapy] for cancer treatment.”

Bernard Fox, Ph.D., the society's president, noted that the search for a way to harness the immune system against cancer has lasted more than a century. Dr. Fox had no relevant financial conflicts to disclose.

Emily Hayes of the Pink Sheet contributed to this report. The Pink Sheet and this publication are owned by Elseiver.

The Food and Drug Administration has approved sipuleucel-T for treatment of advanced prostate cancer in a much-anticipated ruling that marks the first approval of a vaccine for cancer treatment.

The indication is for use in patients with “asymptomatic or minimally symptomatic prostate cancer that has spread to other parts of the body and is resistant to standard hormone treatment,” according to the FDA announcement.

Sipuleucel-T will be marketed as Provenge by manufacturer Dendreon Corp.

The company announced the vaccine will be available initially at 50 oncology and urology centers that were approved clinical trial sites. Executives said in an investors' call that they expected to serve 2,000 patients within the first 12 months. Initially, the individually tailored vaccine will be manufactured only in the company's New Jersey facility, but Dendreon plans to add facilities in Atlanta and in Orange County, Calif. by mid-2011.

Pricing has been set at $31,000 per infusion, or a total of $93,000 for the therapy. The company has set up a patient-access program to help men who cannot afford co-payments.

The granting of the indication follows a long and tumultuous review process in which protestors icketed after an FDA advisory committee rejected Dendreon's initial application for the vaccine. Early results from a key trial designed to address issues raised by the panel failed to show an improvement in progression-free survival, but researchers were eventually able to demonstrate that men lived longer when treated with sipuleucel-T.

The pivotal Dendreon-sponsored, phase III IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial randomized 512 men with metastatic castration-resistant prostate cancer to sipuleucel-T or placebo. At a median follow-up of 3 years, the vaccine was credited with a 4.1-month gain in overall survival, with men on the vaccine living a median of 25.8 months vs. 21.7 months in the control group.

Adverse events occurred in almost all patients, with chills, fatigue, fever, back pain, nausea, joint ache, and headache being common reactions. Most side effects were mild or moderate, but the FDA noted that about a quarter of patients had serious adverse reactions, including some acute infusion reactions and stroke.

“Cerebrovascular events, including hemorrhagic and ischemic strokes, were observed in 3.5% of patients in the Provenge group, compared with 2.6% of patients in the control group,” it said.

The company announced that it has committed to conducting “a registry of approximately 1,500 patients to further evaluate a small potential safety signal of cerebrovascular events.”

An autologous cellular immunotherapy, sipuleucel-T delivers a patient's own immune cells, extracted via leukapheresis, in a vaccine designed to stimulate an immune response against prostatic acid phosphatase (PAP), an antigen expressed in most prostate cancers. Men received three doses of the vaccine in intravenous injections given at about 2-week intervals.”

“The availability of Provenge provides a new treatment option for men with advanced prostate cancer, who currently have limited effective therapies available,” said Dr. Karen Midthun, acting director of the FDA's Center for Biologics Evaluation and Research, in the FDA announcement.

The International Society for Biological Therapy of Cancer issued a statement hailing the approval as “a significant advance in the development of biological therapy [also called immunotherapy] for cancer treatment.”

Bernard Fox, Ph.D., the society's president, noted that the search for a way to harness the immune system against cancer has lasted more than a century. Dr. Fox had no relevant financial conflicts to disclose.

Emily Hayes of the Pink Sheet contributed to this report. The Pink Sheet and this publication are owned by Elseiver.

The Food and Drug Administration has approved sipuleucel-T for treatment of advanced prostate cancer in a much-anticipated ruling that marks the first approval of a vaccine for cancer treatment.

The indication is for use in patients with “asymptomatic or minimally symptomatic prostate cancer that has spread to other parts of the body and is resistant to standard hormone treatment,” according to the FDA announcement.

Sipuleucel-T will be marketed as Provenge by manufacturer Dendreon Corp.

The company announced the vaccine will be available initially at 50 oncology and urology centers that were approved clinical trial sites. Executives said in an investors' call that they expected to serve 2,000 patients within the first 12 months. Initially, the individually tailored vaccine will be manufactured only in the company's New Jersey facility, but Dendreon plans to add facilities in Atlanta and in Orange County, Calif. by mid-2011.

Pricing has been set at $31,000 per infusion, or a total of $93,000 for the therapy. The company has set up a patient-access program to help men who cannot afford co-payments.

The granting of the indication follows a long and tumultuous review process in which protestors icketed after an FDA advisory committee rejected Dendreon's initial application for the vaccine. Early results from a key trial designed to address issues raised by the panel failed to show an improvement in progression-free survival, but researchers were eventually able to demonstrate that men lived longer when treated with sipuleucel-T.

The pivotal Dendreon-sponsored, phase III IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial randomized 512 men with metastatic castration-resistant prostate cancer to sipuleucel-T or placebo. At a median follow-up of 3 years, the vaccine was credited with a 4.1-month gain in overall survival, with men on the vaccine living a median of 25.8 months vs. 21.7 months in the control group.

Adverse events occurred in almost all patients, with chills, fatigue, fever, back pain, nausea, joint ache, and headache being common reactions. Most side effects were mild or moderate, but the FDA noted that about a quarter of patients had serious adverse reactions, including some acute infusion reactions and stroke.

“Cerebrovascular events, including hemorrhagic and ischemic strokes, were observed in 3.5% of patients in the Provenge group, compared with 2.6% of patients in the control group,” it said.

The company announced that it has committed to conducting “a registry of approximately 1,500 patients to further evaluate a small potential safety signal of cerebrovascular events.”

An autologous cellular immunotherapy, sipuleucel-T delivers a patient's own immune cells, extracted via leukapheresis, in a vaccine designed to stimulate an immune response against prostatic acid phosphatase (PAP), an antigen expressed in most prostate cancers. Men received three doses of the vaccine in intravenous injections given at about 2-week intervals.”

“The availability of Provenge provides a new treatment option for men with advanced prostate cancer, who currently have limited effective therapies available,” said Dr. Karen Midthun, acting director of the FDA's Center for Biologics Evaluation and Research, in the FDA announcement.

The International Society for Biological Therapy of Cancer issued a statement hailing the approval as “a significant advance in the development of biological therapy [also called immunotherapy] for cancer treatment.”

Bernard Fox, Ph.D., the society's president, noted that the search for a way to harness the immune system against cancer has lasted more than a century. Dr. Fox had no relevant financial conflicts to disclose.

Emily Hayes of the Pink Sheet contributed to this report. The Pink Sheet and this publication are owned by Elseiver.

The Food and Drug Administration has approved sipuleucel-T for treatment of advanced prostate cancer in a much-anticipated ruling that marks the first approval of a vaccine for cancer treatment.

The indication is for use in patients with “asymptomatic or minimally symptomatic prostate cancer that has spread to other parts of the body and is resistant to standard hormone treatment,” according to the FDA announcement. Sipuleucel-T will be marketed as Provenge by manufacturer Dendreon.

The company announced the vaccine will be available initially at 50 oncology and urology centers that were approved clinical trial sites. Executives said in an investors' call that they expected to treat the first patient within a week, and aim to serve 2,000 patients within the first 12 months. Initially, the individually tailored vaccine will be manufactured only in the company's New Jersey facility, but Dendreon plans to add facilities in Atlanta and in Orange County, Calif., by mid-2011.

Pricing has been set at $31,000 per infusion, or a total of $93,000 for the therapy. Executives said they plan to meet with Medicare officials about reimbursement; about three-fourths of the target population is Medicare eligible. The company also has set up a patient-access program to help men who cannot afford copayments.

The granting of the indication follows a long and tumultuous review process in which protestors picketed after an FDA advisory committee rejected Dendreon's initial application for the vaccine. Early results from a key trial designed to address issues raised by the panel failed to show an improvement in progression-free survival, but researchers were eventually able to demonstrate that men lived longer when treated with sipuleucel-T.

The pivotal Dendreon-sponsored, phase III IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial randomized 512 men with metastatic castration-resistant prostate cancer to sipuleucel-T or placebo.

At a median follow-up of 3 years, the vaccine was credited with a 4.1-month gain in overall survival, with men on the vaccine living a median of 25.8 months vs. 21.7 months in the control group.

Adverse events occurred in almost all patients, with chills, fatigue, fever, back pain, nausea, joint ache, and headache being common reactions. Most side effects were mild or moderate, but the FDA noted that about a quarter of patients had serious adverse reactions, including some acute infusion reactions and stroke.

“Cerebrovascular events, including hemorrhagic and ischemic strokes, were observed in 3.5% of patients in the Provenge group, compared with 2.6% of patients in the control group,” the agency said.

The company announced that it has committed to conducting “a registry of approximately 1,500 patients to further evaluate a small potential safety signal of cerebrovascular events.”

An autologous cellular immunotherapy, sipuleucel-T delivers a patient's own immune cells, extracted via leukapheresis, in a vaccine designed to stimulate an immune response against prostatic acid phosphatase (PAP), an antigen expressed in most prostate cancers. Men received three doses of the vaccine in intravenous injections given at about 2-week intervals.

“The availability of Provenge provides a new treatment option for men with advanced prostate cancer, who currently have limited effective therapies available,” said Dr. Karen Midthun, acting director of the FDA's Center for Biologics Evaluation and Research, in the FDA announcement.

Emily Hayes of The Pink Sheet contributed to this report. The Pink Sheet and this publication are owned by Elsevier.

My Take

Price Will Be an Issue for Provenge

After a series of ups and downs, the much-debated prostate cancer vaccine Provenge is now FDA approved. Instead of the end of the discussion, the story is likely only beginning. The price is said to be in the $90,000 range for the treatment course (three monthly injections), and that number will further stimulate talk around “how much is it worth, for how long?” and who should receive the therapy.

With other high-priced therapies, such as bevacizumab (Avastin) or cetuximab (Erbitux), the doses are delivered repeatedly, and the overall cost only increases for those patients who are benefiting clinically. In the case of Provenge, the price is basically one size fits all, and there are no predictive tests as to which patients will likely benefit from the vaccine. Coupling the financial concerns with Dendreon's publicly stated manufacturing shortfall (which will limit access), the launch and utilization of this new therapy will be a story to follow closely in this era of health reform.

HOWARD A. BURRIS III, M.D., is chief medical officer and director of drug development at Sarah Cannon Research Institute in Nashville, Tenn., and editor of

The Food and Drug Administration has approved sipuleucel-T for treatment of advanced prostate cancer in a much-anticipated ruling that marks the first approval of a vaccine for cancer treatment.

The indication is for use in patients with “asymptomatic or minimally symptomatic prostate cancer that has spread to other parts of the body and is resistant to standard hormone treatment,” according to the FDA announcement. Sipuleucel-T will be marketed as Provenge by manufacturer Dendreon.

The company announced the vaccine will be available initially at 50 oncology and urology centers that were approved clinical trial sites. Executives said in an investors' call that they expected to treat the first patient within a week, and aim to serve 2,000 patients within the first 12 months. Initially, the individually tailored vaccine will be manufactured only in the company's New Jersey facility, but Dendreon plans to add facilities in Atlanta and in Orange County, Calif., by mid-2011.

Pricing has been set at $31,000 per infusion, or a total of $93,000 for the therapy. Executives said they plan to meet with Medicare officials about reimbursement; about three-fourths of the target population is Medicare eligible. The company also has set up a patient-access program to help men who cannot afford copayments.

The granting of the indication follows a long and tumultuous review process in which protestors picketed after an FDA advisory committee rejected Dendreon's initial application for the vaccine. Early results from a key trial designed to address issues raised by the panel failed to show an improvement in progression-free survival, but researchers were eventually able to demonstrate that men lived longer when treated with sipuleucel-T.

The pivotal Dendreon-sponsored, phase III IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial randomized 512 men with metastatic castration-resistant prostate cancer to sipuleucel-T or placebo.

At a median follow-up of 3 years, the vaccine was credited with a 4.1-month gain in overall survival, with men on the vaccine living a median of 25.8 months vs. 21.7 months in the control group.

Adverse events occurred in almost all patients, with chills, fatigue, fever, back pain, nausea, joint ache, and headache being common reactions. Most side effects were mild or moderate, but the FDA noted that about a quarter of patients had serious adverse reactions, including some acute infusion reactions and stroke.

“Cerebrovascular events, including hemorrhagic and ischemic strokes, were observed in 3.5% of patients in the Provenge group, compared with 2.6% of patients in the control group,” the agency said.

The company announced that it has committed to conducting “a registry of approximately 1,500 patients to further evaluate a small potential safety signal of cerebrovascular events.”

An autologous cellular immunotherapy, sipuleucel-T delivers a patient's own immune cells, extracted via leukapheresis, in a vaccine designed to stimulate an immune response against prostatic acid phosphatase (PAP), an antigen expressed in most prostate cancers. Men received three doses of the vaccine in intravenous injections given at about 2-week intervals.

“The availability of Provenge provides a new treatment option for men with advanced prostate cancer, who currently have limited effective therapies available,” said Dr. Karen Midthun, acting director of the FDA's Center for Biologics Evaluation and Research, in the FDA announcement.

Emily Hayes of The Pink Sheet contributed to this report. The Pink Sheet and this publication are owned by Elsevier.

My Take

Price Will Be an Issue for Provenge

After a series of ups and downs, the much-debated prostate cancer vaccine Provenge is now FDA approved. Instead of the end of the discussion, the story is likely only beginning. The price is said to be in the $90,000 range for the treatment course (three monthly injections), and that number will further stimulate talk around “how much is it worth, for how long?” and who should receive the therapy.

With other high-priced therapies, such as bevacizumab (Avastin) or cetuximab (Erbitux), the doses are delivered repeatedly, and the overall cost only increases for those patients who are benefiting clinically. In the case of Provenge, the price is basically one size fits all, and there are no predictive tests as to which patients will likely benefit from the vaccine. Coupling the financial concerns with Dendreon's publicly stated manufacturing shortfall (which will limit access), the launch and utilization of this new therapy will be a story to follow closely in this era of health reform.

HOWARD A. BURRIS III, M.D., is chief medical officer and director of drug development at Sarah Cannon Research Institute in Nashville, Tenn., and editor of

The Food and Drug Administration has approved sipuleucel-T for treatment of advanced prostate cancer in a much-anticipated ruling that marks the first approval of a vaccine for cancer treatment.

The indication is for use in patients with “asymptomatic or minimally symptomatic prostate cancer that has spread to other parts of the body and is resistant to standard hormone treatment,” according to the FDA announcement. Sipuleucel-T will be marketed as Provenge by manufacturer Dendreon.

The company announced the vaccine will be available initially at 50 oncology and urology centers that were approved clinical trial sites. Executives said in an investors' call that they expected to treat the first patient within a week, and aim to serve 2,000 patients within the first 12 months. Initially, the individually tailored vaccine will be manufactured only in the company's New Jersey facility, but Dendreon plans to add facilities in Atlanta and in Orange County, Calif., by mid-2011.

Pricing has been set at $31,000 per infusion, or a total of $93,000 for the therapy. Executives said they plan to meet with Medicare officials about reimbursement; about three-fourths of the target population is Medicare eligible. The company also has set up a patient-access program to help men who cannot afford copayments.

The granting of the indication follows a long and tumultuous review process in which protestors picketed after an FDA advisory committee rejected Dendreon's initial application for the vaccine. Early results from a key trial designed to address issues raised by the panel failed to show an improvement in progression-free survival, but researchers were eventually able to demonstrate that men lived longer when treated with sipuleucel-T.

The pivotal Dendreon-sponsored, phase III IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial randomized 512 men with metastatic castration-resistant prostate cancer to sipuleucel-T or placebo.

At a median follow-up of 3 years, the vaccine was credited with a 4.1-month gain in overall survival, with men on the vaccine living a median of 25.8 months vs. 21.7 months in the control group.

Adverse events occurred in almost all patients, with chills, fatigue, fever, back pain, nausea, joint ache, and headache being common reactions. Most side effects were mild or moderate, but the FDA noted that about a quarter of patients had serious adverse reactions, including some acute infusion reactions and stroke.

“Cerebrovascular events, including hemorrhagic and ischemic strokes, were observed in 3.5% of patients in the Provenge group, compared with 2.6% of patients in the control group,” the agency said.

The company announced that it has committed to conducting “a registry of approximately 1,500 patients to further evaluate a small potential safety signal of cerebrovascular events.”

An autologous cellular immunotherapy, sipuleucel-T delivers a patient's own immune cells, extracted via leukapheresis, in a vaccine designed to stimulate an immune response against prostatic acid phosphatase (PAP), an antigen expressed in most prostate cancers. Men received three doses of the vaccine in intravenous injections given at about 2-week intervals.

“The availability of Provenge provides a new treatment option for men with advanced prostate cancer, who currently have limited effective therapies available,” said Dr. Karen Midthun, acting director of the FDA's Center for Biologics Evaluation and Research, in the FDA announcement.

Emily Hayes of The Pink Sheet contributed to this report. The Pink Sheet and this publication are owned by Elsevier.

My Take

Price Will Be an Issue for Provenge

After a series of ups and downs, the much-debated prostate cancer vaccine Provenge is now FDA approved. Instead of the end of the discussion, the story is likely only beginning. The price is said to be in the $90,000 range for the treatment course (three monthly injections), and that number will further stimulate talk around “how much is it worth, for how long?” and who should receive the therapy.

With other high-priced therapies, such as bevacizumab (Avastin) or cetuximab (Erbitux), the doses are delivered repeatedly, and the overall cost only increases for those patients who are benefiting clinically. In the case of Provenge, the price is basically one size fits all, and there are no predictive tests as to which patients will likely benefit from the vaccine. Coupling the financial concerns with Dendreon's publicly stated manufacturing shortfall (which will limit access), the launch and utilization of this new therapy will be a story to follow closely in this era of health reform.

HOWARD A. BURRIS III, M.D., is chief medical officer and director of drug development at Sarah Cannon Research Institute in Nashville, Tenn., and editor of

SCOTTSDALE, ARIZ. — Health care reform may be stalled on Capitol Hill, but states are stepping up to tackle some areas of concern, cancer care advocates said at the annual Community Oncology Conference.

Two key issues gaining traction in state legislatures are parity in payment for oral and intravenous cancer drugs, and a requirement for payers to cover supportive care for patients in clinical trials. In addition, some states are looking for models of what they can do if Congress fails to enact comprehensive reform, experts said at the conference, which was sponsored by the journal Community Oncology. “The momentum toward the states' doing something is increasing,” said Shelagh Foster, government relations director at the American Society of Clinical Oncology.

“We are going to see more of the states taking control of health care reform. … The state reps are a little closer to the people because they are the people. They are concerned; they hear about it more,” agreed John F. Akscin, vice president for government relations at McKesson Specialty Care Solutions of La Vergne, Tenn.

Parity in Payments for Oncolytics

The Community Oncology Alliance lists five states (Hawaii, Indiana, Iowa, Oregon, and Vermont) as requiring payers to cover oral cancer drugs at the same level as intravenous chemotherapy drugs.

Last September, the California legislature passed a parity law (SB 161) that was vetoed by Gov. Arnold Schwarzenegger, noted Mary Kruczynski, director of policy analysis at COA. In his veto message, the governor noted that the bill “limits a plan's ability to control both the appropriateness of the care and the cost by requiring [insurers] to immediately cover every medication as soon as it receives federal approval … placing them at a severe disadvantage when negotiating prices with drug manufacturers.”

In addition, parity measures are under consideration in at least a dozen more states. “Parity bills—they are going to spring up all over the place,” said COA Executive Director Ted A. Okon.

At issue are higher copayments that many insurers require of patients for oral drugs, which tend to be newer and substantially more expensive than intravenous drugs. COA looked at 11 widely used, oral oncology drugs and how they are covered by leading insurers, Ms. Kruczynski said. Three were covered by Medicare Part B; the rest by Medicare Part D. All but one was placed in formulary tiers that require patient copayments as high as 25%-35%. “All had roadblocks, time on the phone to get them approved. All had quantity limits,” she said. “Some had step plans. … To be sure [that the patient] needs that infusible antiemetic, he needs to throw up for 3 days first.”

As part of a project assessing the impact of these policies on cancer care, COA analyzed a database containing information on 5 million prescriptions issued to 500,000 patients from January 2007 to June 2009. It found that 21% of claims for oral oncolytics were rejected and 9% were “reversed,” she said. A reversed claim is one that is approved by the payer and filled by the pharmacy, but not picked up by the patient. The study followed patients for several months after the reversals, she said. Many patients did pick up medicines for heart disease, diabetes, and anxiety. “So we knew they were still alive,” she said. “They were making a conscious decision, or their hand was forced, not to take lifesaving medication.”

When made public, the full parity study will include best practices gleaned from interviews with physicians, nurses, patients, pharmacists, pharmacy benefit managers, medical directors, and staff of copayment assistance foundations that help patients who cannot afford cancer drugs, Ms. Kruczynski added.

Oral cancer drugs are a growing issue, according to Dr. Justin P. Favaro of Oncology Specialists of Charlotte (N.C.), who chaired the study. He counted 34 oral drugs—some off label—that were being used in cancer treatment, and estimated that 25% of new drugs in the pipeline are oral agents. As virtually all are still under patent, prices are high and “all over the map,” Dr. Favaro said, citing the multiple myeloma drug lenalidomide (Revlimid) as a widely used example. The average cost is $74,000 per year, he said; after looking at two different Medicare part D programs, he estimated the average cost to patients to be $8,300 per year. In addition, Revlimid takes a lot of time to prescribe, he said, with a utilization management program for providers, mandatory counseling for patients, extensive paperwork to be filled out, and distribution restricted to specialty pharmacies.

Although easier to administer than in-office infusions, oral drugs pose many challenges, he said. More of the financial burden is being shifted to patients, as payers try to figure out how to cover the higher prices of these drugs. Responsibility for compliance also shifts to patients, as they are expected to take their medications at home and call their oncologists if they are experiencing side effects. And practices must have staff to take those phone calls and manage those side effects.

One of the strategies is having an in-office pharmacy, which helps community oncologists to make sure that their patients are receiving the prescribed oral drugs, and to find assistance if a patient can't afford them. A challenge, however, is that some state laws bar pharmacies in medical practices.

Access to Clinical Trials

Another issue being addressed first by the states is making sure payers cover routine patient care for patients in clinical trials. Typically, trials pay for the cost of a patient's medications, but they do not pick up other expenses that are routine to cancer care. Without such laws or regulations, some payers refuse to cover supportive care, even though they save substantially on medication costs for patients in trials. “I think misconceptions about clinical trials are prevalent both with payers and with federal policy makers,” Ms. Foster said.

Federal Action Expected

Although the speakers agreed that health reform was stalled in Washington, the consensus was that something would pass. “The issues being discussed before [Republican Sen. Scott Brown's] election in Massachusetts are not going away. … The prospects for health reform in some small fashion are good; in large fashion, they are going to be very, very difficult,” Ms. Foster said. Moreover, reforms will come about through regulatory changes regardless of Congressional action, according to Mr. Okon.

Disclosures: The journal Community Oncology and this news organization are owned by Elsevier.

With oral cancer drugs, both the high financial burden and the responsibility for compliance shift to patients.

Source DR. FAVARO

SCOTTSDALE, ARIZ. — Health care reform may be stalled on Capitol Hill, but states are stepping up to tackle some areas of concern, cancer care advocates said at the annual Community Oncology Conference.

Two key issues gaining traction in state legislatures are parity in payment for oral and intravenous cancer drugs, and a requirement for payers to cover supportive care for patients in clinical trials. In addition, some states are looking for models of what they can do if Congress fails to enact comprehensive reform, experts said at the conference, which was sponsored by the journal Community Oncology. “The momentum toward the states' doing something is increasing,” said Shelagh Foster, government relations director at the American Society of Clinical Oncology.

“We are going to see more of the states taking control of health care reform. … The state reps are a little closer to the people because they are the people. They are concerned; they hear about it more,” agreed John F. Akscin, vice president for government relations at McKesson Specialty Care Solutions of La Vergne, Tenn.

Parity in Payments for Oncolytics

The Community Oncology Alliance lists five states (Hawaii, Indiana, Iowa, Oregon, and Vermont) as requiring payers to cover oral cancer drugs at the same level as intravenous chemotherapy drugs.

Last September, the California legislature passed a parity law (SB 161) that was vetoed by Gov. Arnold Schwarzenegger, noted Mary Kruczynski, director of policy analysis at COA. In his veto message, the governor noted that the bill “limits a plan's ability to control both the appropriateness of the care and the cost by requiring [insurers] to immediately cover every medication as soon as it receives federal approval … placing them at a severe disadvantage when negotiating prices with drug manufacturers.”

In addition, parity measures are under consideration in at least a dozen more states. “Parity bills—they are going to spring up all over the place,” said COA Executive Director Ted A. Okon.

At issue are higher copayments that many insurers require of patients for oral drugs, which tend to be newer and substantially more expensive than intravenous drugs. COA looked at 11 widely used, oral oncology drugs and how they are covered by leading insurers, Ms. Kruczynski said. Three were covered by Medicare Part B; the rest by Medicare Part D. All but one was placed in formulary tiers that require patient copayments as high as 25%-35%. “All had roadblocks, time on the phone to get them approved. All had quantity limits,” she said. “Some had step plans. … To be sure [that the patient] needs that infusible antiemetic, he needs to throw up for 3 days first.”

As part of a project assessing the impact of these policies on cancer care, COA analyzed a database containing information on 5 million prescriptions issued to 500,000 patients from January 2007 to June 2009. It found that 21% of claims for oral oncolytics were rejected and 9% were “reversed,” she said. A reversed claim is one that is approved by the payer and filled by the pharmacy, but not picked up by the patient. The study followed patients for several months after the reversals, she said. Many patients did pick up medicines for heart disease, diabetes, and anxiety. “So we knew they were still alive,” she said. “They were making a conscious decision, or their hand was forced, not to take lifesaving medication.”

When made public, the full parity study will include best practices gleaned from interviews with physicians, nurses, patients, pharmacists, pharmacy benefit managers, medical directors, and staff of copayment assistance foundations that help patients who cannot afford cancer drugs, Ms. Kruczynski added.

Oral cancer drugs are a growing issue, according to Dr. Justin P. Favaro of Oncology Specialists of Charlotte (N.C.), who chaired the study. He counted 34 oral drugs—some off label—that were being used in cancer treatment, and estimated that 25% of new drugs in the pipeline are oral agents. As virtually all are still under patent, prices are high and “all over the map,” Dr. Favaro said, citing the multiple myeloma drug lenalidomide (Revlimid) as a widely used example. The average cost is $74,000 per year, he said; after looking at two different Medicare part D programs, he estimated the average cost to patients to be $8,300 per year. In addition, Revlimid takes a lot of time to prescribe, he said, with a utilization management program for providers, mandatory counseling for patients, extensive paperwork to be filled out, and distribution restricted to specialty pharmacies.

Although easier to administer than in-office infusions, oral drugs pose many challenges, he said. More of the financial burden is being shifted to patients, as payers try to figure out how to cover the higher prices of these drugs. Responsibility for compliance also shifts to patients, as they are expected to take their medications at home and call their oncologists if they are experiencing side effects. And practices must have staff to take those phone calls and manage those side effects.

One of the strategies is having an in-office pharmacy, which helps community oncologists to make sure that their patients are receiving the prescribed oral drugs, and to find assistance if a patient can't afford them. A challenge, however, is that some state laws bar pharmacies in medical practices.

Access to Clinical Trials

Another issue being addressed first by the states is making sure payers cover routine patient care for patients in clinical trials. Typically, trials pay for the cost of a patient's medications, but they do not pick up other expenses that are routine to cancer care. Without such laws or regulations, some payers refuse to cover supportive care, even though they save substantially on medication costs for patients in trials. “I think misconceptions about clinical trials are prevalent both with payers and with federal policy makers,” Ms. Foster said.

Federal Action Expected

Although the speakers agreed that health reform was stalled in Washington, the consensus was that something would pass. “The issues being discussed before [Republican Sen. Scott Brown's] election in Massachusetts are not going away. … The prospects for health reform in some small fashion are good; in large fashion, they are going to be very, very difficult,” Ms. Foster said. Moreover, reforms will come about through regulatory changes regardless of Congressional action, according to Mr. Okon.

Disclosures: The journal Community Oncology and this news organization are owned by Elsevier.

With oral cancer drugs, both the high financial burden and the responsibility for compliance shift to patients.

Source DR. FAVARO

SCOTTSDALE, ARIZ. — Health care reform may be stalled on Capitol Hill, but states are stepping up to tackle some areas of concern, cancer care advocates said at the annual Community Oncology Conference.

Two key issues gaining traction in state legislatures are parity in payment for oral and intravenous cancer drugs, and a requirement for payers to cover supportive care for patients in clinical trials. In addition, some states are looking for models of what they can do if Congress fails to enact comprehensive reform, experts said at the conference, which was sponsored by the journal Community Oncology. “The momentum toward the states' doing something is increasing,” said Shelagh Foster, government relations director at the American Society of Clinical Oncology.

“We are going to see more of the states taking control of health care reform. … The state reps are a little closer to the people because they are the people. They are concerned; they hear about it more,” agreed John F. Akscin, vice president for government relations at McKesson Specialty Care Solutions of La Vergne, Tenn.

Parity in Payments for Oncolytics

The Community Oncology Alliance lists five states (Hawaii, Indiana, Iowa, Oregon, and Vermont) as requiring payers to cover oral cancer drugs at the same level as intravenous chemotherapy drugs.

Last September, the California legislature passed a parity law (SB 161) that was vetoed by Gov. Arnold Schwarzenegger, noted Mary Kruczynski, director of policy analysis at COA. In his veto message, the governor noted that the bill “limits a plan's ability to control both the appropriateness of the care and the cost by requiring [insurers] to immediately cover every medication as soon as it receives federal approval … placing them at a severe disadvantage when negotiating prices with drug manufacturers.”

In addition, parity measures are under consideration in at least a dozen more states. “Parity bills—they are going to spring up all over the place,” said COA Executive Director Ted A. Okon.

At issue are higher copayments that many insurers require of patients for oral drugs, which tend to be newer and substantially more expensive than intravenous drugs. COA looked at 11 widely used, oral oncology drugs and how they are covered by leading insurers, Ms. Kruczynski said. Three were covered by Medicare Part B; the rest by Medicare Part D. All but one was placed in formulary tiers that require patient copayments as high as 25%-35%. “All had roadblocks, time on the phone to get them approved. All had quantity limits,” she said. “Some had step plans. … To be sure [that the patient] needs that infusible antiemetic, he needs to throw up for 3 days first.”

As part of a project assessing the impact of these policies on cancer care, COA analyzed a database containing information on 5 million prescriptions issued to 500,000 patients from January 2007 to June 2009. It found that 21% of claims for oral oncolytics were rejected and 9% were “reversed,” she said. A reversed claim is one that is approved by the payer and filled by the pharmacy, but not picked up by the patient. The study followed patients for several months after the reversals, she said. Many patients did pick up medicines for heart disease, diabetes, and anxiety. “So we knew they were still alive,” she said. “They were making a conscious decision, or their hand was forced, not to take lifesaving medication.”

When made public, the full parity study will include best practices gleaned from interviews with physicians, nurses, patients, pharmacists, pharmacy benefit managers, medical directors, and staff of copayment assistance foundations that help patients who cannot afford cancer drugs, Ms. Kruczynski added.

Oral cancer drugs are a growing issue, according to Dr. Justin P. Favaro of Oncology Specialists of Charlotte (N.C.), who chaired the study. He counted 34 oral drugs—some off label—that were being used in cancer treatment, and estimated that 25% of new drugs in the pipeline are oral agents. As virtually all are still under patent, prices are high and “all over the map,” Dr. Favaro said, citing the multiple myeloma drug lenalidomide (Revlimid) as a widely used example. The average cost is $74,000 per year, he said; after looking at two different Medicare part D programs, he estimated the average cost to patients to be $8,300 per year. In addition, Revlimid takes a lot of time to prescribe, he said, with a utilization management program for providers, mandatory counseling for patients, extensive paperwork to be filled out, and distribution restricted to specialty pharmacies.

Although easier to administer than in-office infusions, oral drugs pose many challenges, he said. More of the financial burden is being shifted to patients, as payers try to figure out how to cover the higher prices of these drugs. Responsibility for compliance also shifts to patients, as they are expected to take their medications at home and call their oncologists if they are experiencing side effects. And practices must have staff to take those phone calls and manage those side effects.

One of the strategies is having an in-office pharmacy, which helps community oncologists to make sure that their patients are receiving the prescribed oral drugs, and to find assistance if a patient can't afford them. A challenge, however, is that some state laws bar pharmacies in medical practices.

Access to Clinical Trials

Another issue being addressed first by the states is making sure payers cover routine patient care for patients in clinical trials. Typically, trials pay for the cost of a patient's medications, but they do not pick up other expenses that are routine to cancer care. Without such laws or regulations, some payers refuse to cover supportive care, even though they save substantially on medication costs for patients in trials. “I think misconceptions about clinical trials are prevalent both with payers and with federal policy makers,” Ms. Foster said.

Federal Action Expected

Although the speakers agreed that health reform was stalled in Washington, the consensus was that something would pass. “The issues being discussed before [Republican Sen. Scott Brown's] election in Massachusetts are not going away. … The prospects for health reform in some small fashion are good; in large fashion, they are going to be very, very difficult,” Ms. Foster said. Moreover, reforms will come about through regulatory changes regardless of Congressional action, according to Mr. Okon.

Disclosures: The journal Community Oncology and this news organization are owned by Elsevier.

With oral cancer drugs, both the high financial burden and the responsibility for compliance shift to patients.

Source DR. FAVARO

Major Findings: Neither aspirin nor a combination of aspirin and low-molecular-weight heparin improved live birth rates in a study of 364 women with unexplained recurrent miscarriages.

Data Source: The randomized placebo-controlled ALIFE study.

Disclosures: The ALIFE trial received funding from ZonMW, the Dutch Organization for Health Research and Development (945-27-003); an unrestricted grant from GlaxoSmithKline BV;and study medications (calcium carbasalate and placebo) from Vemedia BV. None of the funding sources were involved in the study protocol preparation, trial management, or data analysis, according to the abstract. Dr. Kaandorp had no financial disclosures. Dr. Middeldorp and another coinvestigator disclosed consultancy, honoraria, and research funding from GSK.

NEW ORLEANS — Neither aspirin nor a combination of aspirin and low-molecular-weight heparin improved live birth rates in a randomized, placebo-controlled trial conducted in 364 women with unexplained recurrent miscarriages.

An intent-to-treat analysis of the ALIFE (Anticoagulants for Living Fetuses) study showed live birth rates in women seeking to carry a pregnancy to term were not affected by prophylaxis. The rates were 54.5% in 123 women given low-dose aspirin and nadroparin (a low-molecular-weight heparin [LMWH]sold in Europe), 50.8% in 120 women given low-dose aspirin alone, and 57% in 121 women given placebo.

When the investigators looked only at women who became pregnant during the trial, the live birth rates were hardly better and not significantly different: 69.1% in 97 women treated with the aspirin-LMWH combination, 61.1% in 99 women given aspirin alone, and 67% in 103 women given placebo.

“We couldn't find the beneficial effects in our study of three treatment arms—[there was] no difference at all,” Dr. Stef P. Kaandorp said during a press briefing at the annual meeting of the American Society of Hematology.

Despite a dearth of evidence in support of anticoagulant prophylaxis, a large albeit unknown number of physicians give these agents to desperate women in the United States and Europe, according to Dr. Kaandorp and his co-investigators at eight centers in The Netherlands.

The desire to help these women carry a child to term is so strong that colleagues in the United States, France, and Israel had argued that giving a placebo would be unethical in this population, senior author Dr. Saskia Middeldorp said in an interview. Obstetricians warned they would not participate if the investigators ignored their advice and went ahead with the trial.

In addition, many pregnant women buy aspirin over-the-counter to prevent miscarriage based on advice from other women in on-line chat rooms, according to Dr. Middeldorp, an internist specializing in vascular medicine at Leiden University Medical Center.

It is not clear whether the trial's findings will put an end to these practices. Dr. Bradford Schwartz, who moderated the press briefing, said the decision in the United States is up to the individual physician.

“I would say this is high-quality data that is likely to influence the way people make their therapeutics decisions. It certainly should influence those decisions,” said Dr. Schwartz, a professor of medicine and biochemistry and dean of the University of Illinois College of Medicine at Urbana-Champaign.

Dr. Kaandorp, a research fellow in the department of obstetrics and gynecology at the Academic Medical Center in Amsterdam, sympathized with physicians who want to help these women, but he was emphatic that anticoagulant prophylaxis is not justified in women with unexplained recurrent miscarriages. “To give medication that is potentially harmful is not the way to do it,” he said.

None of the participants in the study had excess bleeding events, but the study was too small to detect these, Dr. Kaandorp added in response to a question. About 40% of the women who had been injected with LMWH had skin reactions. Half of this group also had bruising, compared with 19% in the aspirin-only group and 12% of women on placebo (P less than .001).

The rationale for using aspirin and heparin to prevent miscarriage is based on the possibility that hypercoagulability might contribute to miscarriage. Evidence supports the use of these agents for this purpose in women with antiphospholipid syndrome (Obstet. Gynecol. 2002;99:135-44), and suggests that recurrent miscarriage might be related to thrombosis risk (Hum. Reprod. 2005;20:1729-32).

A literature review by four of the current authors found, however, “a paucity in studies on the efficacy and safety of aspirin and heparin in women with a history of at least two miscarriages without apparent causes other than inherited thrombophilia” (Cochrane Database Syst. Rev. 2009 Jan. 21;CD004734).

The ALIFE trial excluded women with antiphospholipid syndrome as well as those with a history of thrombosis, uterus anomaly, abnormal karyotype, or indication for anticoagulants. To be eligible, women aged 18-42 years had to have two or more unexplained miscarriages and be either trying to conceive or less than 6 weeks pregnant.

Women in the two aspirin arms took calcium carbasalate (Ascal) equivalent to acetylsalicylic acid 80 mg daily from the day of randomization until 36 weeks of gestational age. Nadroparin 2,850 IU was injected after a pregnancy was confirmed by ultrasound from 6 weeks of gestational age until the end of pregnancy.

The average age was about 33 years, and the median number of unexplained miscarriages was three. Among the women who were randomized, 103 completed treatment in each of the aspirin-plus-nadroparin and placebo arms; 104 took all treatments in the aspirin-only group.

The author could find no significant differences in subgroup analyses of women with inherited thrombophilia, preceding live birth, age less than 36 years, or three or more previous miscarriages. The investigators did see a trend toward improved live birth rate in 47 women with inherited thrombophilia, however (relative risk ratio 1.56, P = .18).

The study was underpowered to draw a conclusion on whether women with inherited thrombophilia might benefit from anticoagulant prophylaxis, Dr. Kaandorp said, promising to explore this question. “At this moment I think we should not treat those women, but should do another trial in that population,” he said.

'We couldn't find the beneficial effects in our study of three treatment arms—[there was] no difference at all.'

Source DR. KAANDORP

My Take

Study Confirms Common Sense

In women in whom no specific cause is found for miscarriage, no specific treatment should be used. Thus a treatment that is specific for pregnant women with inherited thrombophilia or antiphospholipid syndrome should not be given to pregnant women without such diagnoses. If you use aspirin in midpregnancy, you increase the risk of pregnancy loss and placental abruption. So if there is no proven benefit to this treatment, this seems like a bad deal. On the other hand, if a woman comes into an ob.gyn.'s office having had two miscarriages and says, “Do something,” some physicians may say, “Give them what they want.”

But this study has shown that aspirin does not prevent recurrent idiopathic miscarriages and does cause bruising. Low-molecular-weight heparin is probably even worse in terms of potential risks and complications.

If you do not find the problem you are looking for—that is, inherited thrombophilia or antiphospholipid syndrome—treatment is dangerous and not helpful.

Are these data new? Prior studies of aspirin use in pregnancy have demonstrated an increased risk of placental abruption in aspirin-treated women. The current study confirmed what logic told you was the right thing to do: Don't use them.

In practice I occasionally see physicians prescribe a treatment for a pregnant patient, saying, “What harm can it do?” It was that kind of thinking that led to the DES debacle some 40 years ago. When dealing with pregnancy, you can't say, “What harm can it do?” because the results can be disastrous. It is good that these researchers performed this study because it confirmed what most rational physicians know: We should use only treatments definitely shown to work, especially during pregnancy.

GERSON WEISS, M.D., is the chairman of the department of obstetrics and gynecology at New Jersey Medical School, Newark. He said he had no relevant disclosures.

Major Findings: Neither aspirin nor a combination of aspirin and low-molecular-weight heparin improved live birth rates in a study of 364 women with unexplained recurrent miscarriages.

Data Source: The randomized placebo-controlled ALIFE study.

Disclosures: The ALIFE trial received funding from ZonMW, the Dutch Organization for Health Research and Development (945-27-003); an unrestricted grant from GlaxoSmithKline BV;and study medications (calcium carbasalate and placebo) from Vemedia BV. None of the funding sources were involved in the study protocol preparation, trial management, or data analysis, according to the abstract. Dr. Kaandorp had no financial disclosures. Dr. Middeldorp and another coinvestigator disclosed consultancy, honoraria, and research funding from GSK.

NEW ORLEANS — Neither aspirin nor a combination of aspirin and low-molecular-weight heparin improved live birth rates in a randomized, placebo-controlled trial conducted in 364 women with unexplained recurrent miscarriages.

An intent-to-treat analysis of the ALIFE (Anticoagulants for Living Fetuses) study showed live birth rates in women seeking to carry a pregnancy to term were not affected by prophylaxis. The rates were 54.5% in 123 women given low-dose aspirin and nadroparin (a low-molecular-weight heparin [LMWH]sold in Europe), 50.8% in 120 women given low-dose aspirin alone, and 57% in 121 women given placebo.

When the investigators looked only at women who became pregnant during the trial, the live birth rates were hardly better and not significantly different: 69.1% in 97 women treated with the aspirin-LMWH combination, 61.1% in 99 women given aspirin alone, and 67% in 103 women given placebo.

“We couldn't find the beneficial effects in our study of three treatment arms—[there was] no difference at all,” Dr. Stef P. Kaandorp said during a press briefing at the annual meeting of the American Society of Hematology.

Despite a dearth of evidence in support of anticoagulant prophylaxis, a large albeit unknown number of physicians give these agents to desperate women in the United States and Europe, according to Dr. Kaandorp and his co-investigators at eight centers in The Netherlands.

The desire to help these women carry a child to term is so strong that colleagues in the United States, France, and Israel had argued that giving a placebo would be unethical in this population, senior author Dr. Saskia Middeldorp said in an interview. Obstetricians warned they would not participate if the investigators ignored their advice and went ahead with the trial.

In addition, many pregnant women buy aspirin over-the-counter to prevent miscarriage based on advice from other women in on-line chat rooms, according to Dr. Middeldorp, an internist specializing in vascular medicine at Leiden University Medical Center.

It is not clear whether the trial's findings will put an end to these practices. Dr. Bradford Schwartz, who moderated the press briefing, said the decision in the United States is up to the individual physician.

“I would say this is high-quality data that is likely to influence the way people make their therapeutics decisions. It certainly should influence those decisions,” said Dr. Schwartz, a professor of medicine and biochemistry and dean of the University of Illinois College of Medicine at Urbana-Champaign.

Dr. Kaandorp, a research fellow in the department of obstetrics and gynecology at the Academic Medical Center in Amsterdam, sympathized with physicians who want to help these women, but he was emphatic that anticoagulant prophylaxis is not justified in women with unexplained recurrent miscarriages. “To give medication that is potentially harmful is not the way to do it,” he said.

None of the participants in the study had excess bleeding events, but the study was too small to detect these, Dr. Kaandorp added in response to a question. About 40% of the women who had been injected with LMWH had skin reactions. Half of this group also had bruising, compared with 19% in the aspirin-only group and 12% of women on placebo (P less than .001).

The rationale for using aspirin and heparin to prevent miscarriage is based on the possibility that hypercoagulability might contribute to miscarriage. Evidence supports the use of these agents for this purpose in women with antiphospholipid syndrome (Obstet. Gynecol. 2002;99:135-44), and suggests that recurrent miscarriage might be related to thrombosis risk (Hum. Reprod. 2005;20:1729-32).

A literature review by four of the current authors found, however, “a paucity in studies on the efficacy and safety of aspirin and heparin in women with a history of at least two miscarriages without apparent causes other than inherited thrombophilia” (Cochrane Database Syst. Rev. 2009 Jan. 21;CD004734).

The ALIFE trial excluded women with antiphospholipid syndrome as well as those with a history of thrombosis, uterus anomaly, abnormal karyotype, or indication for anticoagulants. To be eligible, women aged 18-42 years had to have two or more unexplained miscarriages and be either trying to conceive or less than 6 weeks pregnant.

Women in the two aspirin arms took calcium carbasalate (Ascal) equivalent to acetylsalicylic acid 80 mg daily from the day of randomization until 36 weeks of gestational age. Nadroparin 2,850 IU was injected after a pregnancy was confirmed by ultrasound from 6 weeks of gestational age until the end of pregnancy.

The average age was about 33 years, and the median number of unexplained miscarriages was three. Among the women who were randomized, 103 completed treatment in each of the aspirin-plus-nadroparin and placebo arms; 104 took all treatments in the aspirin-only group.

The author could find no significant differences in subgroup analyses of women with inherited thrombophilia, preceding live birth, age less than 36 years, or three or more previous miscarriages. The investigators did see a trend toward improved live birth rate in 47 women with inherited thrombophilia, however (relative risk ratio 1.56, P = .18).

The study was underpowered to draw a conclusion on whether women with inherited thrombophilia might benefit from anticoagulant prophylaxis, Dr. Kaandorp said, promising to explore this question. “At this moment I think we should not treat those women, but should do another trial in that population,” he said.

'We couldn't find the beneficial effects in our study of three treatment arms—[there was] no difference at all.'

Source DR. KAANDORP

My Take

Study Confirms Common Sense

In women in whom no specific cause is found for miscarriage, no specific treatment should be used. Thus a treatment that is specific for pregnant women with inherited thrombophilia or antiphospholipid syndrome should not be given to pregnant women without such diagnoses. If you use aspirin in midpregnancy, you increase the risk of pregnancy loss and placental abruption. So if there is no proven benefit to this treatment, this seems like a bad deal. On the other hand, if a woman comes into an ob.gyn.'s office having had two miscarriages and says, “Do something,” some physicians may say, “Give them what they want.”

But this study has shown that aspirin does not prevent recurrent idiopathic miscarriages and does cause bruising. Low-molecular-weight heparin is probably even worse in terms of potential risks and complications.

If you do not find the problem you are looking for—that is, inherited thrombophilia or antiphospholipid syndrome—treatment is dangerous and not helpful.

Are these data new? Prior studies of aspirin use in pregnancy have demonstrated an increased risk of placental abruption in aspirin-treated women. The current study confirmed what logic told you was the right thing to do: Don't use them.

In practice I occasionally see physicians prescribe a treatment for a pregnant patient, saying, “What harm can it do?” It was that kind of thinking that led to the DES debacle some 40 years ago. When dealing with pregnancy, you can't say, “What harm can it do?” because the results can be disastrous. It is good that these researchers performed this study because it confirmed what most rational physicians know: We should use only treatments definitely shown to work, especially during pregnancy.

GERSON WEISS, M.D., is the chairman of the department of obstetrics and gynecology at New Jersey Medical School, Newark. He said he had no relevant disclosures.

Major Findings: Neither aspirin nor a combination of aspirin and low-molecular-weight heparin improved live birth rates in a study of 364 women with unexplained recurrent miscarriages.

Data Source: The randomized placebo-controlled ALIFE study.

Disclosures: The ALIFE trial received funding from ZonMW, the Dutch Organization for Health Research and Development (945-27-003); an unrestricted grant from GlaxoSmithKline BV;and study medications (calcium carbasalate and placebo) from Vemedia BV. None of the funding sources were involved in the study protocol preparation, trial management, or data analysis, according to the abstract. Dr. Kaandorp had no financial disclosures. Dr. Middeldorp and another coinvestigator disclosed consultancy, honoraria, and research funding from GSK.

NEW ORLEANS — Neither aspirin nor a combination of aspirin and low-molecular-weight heparin improved live birth rates in a randomized, placebo-controlled trial conducted in 364 women with unexplained recurrent miscarriages.

An intent-to-treat analysis of the ALIFE (Anticoagulants for Living Fetuses) study showed live birth rates in women seeking to carry a pregnancy to term were not affected by prophylaxis. The rates were 54.5% in 123 women given low-dose aspirin and nadroparin (a low-molecular-weight heparin [LMWH]sold in Europe), 50.8% in 120 women given low-dose aspirin alone, and 57% in 121 women given placebo.

When the investigators looked only at women who became pregnant during the trial, the live birth rates were hardly better and not significantly different: 69.1% in 97 women treated with the aspirin-LMWH combination, 61.1% in 99 women given aspirin alone, and 67% in 103 women given placebo.

“We couldn't find the beneficial effects in our study of three treatment arms—[there was] no difference at all,” Dr. Stef P. Kaandorp said during a press briefing at the annual meeting of the American Society of Hematology.

Despite a dearth of evidence in support of anticoagulant prophylaxis, a large albeit unknown number of physicians give these agents to desperate women in the United States and Europe, according to Dr. Kaandorp and his co-investigators at eight centers in The Netherlands.

The desire to help these women carry a child to term is so strong that colleagues in the United States, France, and Israel had argued that giving a placebo would be unethical in this population, senior author Dr. Saskia Middeldorp said in an interview. Obstetricians warned they would not participate if the investigators ignored their advice and went ahead with the trial.

In addition, many pregnant women buy aspirin over-the-counter to prevent miscarriage based on advice from other women in on-line chat rooms, according to Dr. Middeldorp, an internist specializing in vascular medicine at Leiden University Medical Center.

It is not clear whether the trial's findings will put an end to these practices. Dr. Bradford Schwartz, who moderated the press briefing, said the decision in the United States is up to the individual physician.

“I would say this is high-quality data that is likely to influence the way people make their therapeutics decisions. It certainly should influence those decisions,” said Dr. Schwartz, a professor of medicine and biochemistry and dean of the University of Illinois College of Medicine at Urbana-Champaign.

Dr. Kaandorp, a research fellow in the department of obstetrics and gynecology at the Academic Medical Center in Amsterdam, sympathized with physicians who want to help these women, but he was emphatic that anticoagulant prophylaxis is not justified in women with unexplained recurrent miscarriages. “To give medication that is potentially harmful is not the way to do it,” he said.

None of the participants in the study had excess bleeding events, but the study was too small to detect these, Dr. Kaandorp added in response to a question. About 40% of the women who had been injected with LMWH had skin reactions. Half of this group also had bruising, compared with 19% in the aspirin-only group and 12% of women on placebo (P less than .001).

The rationale for using aspirin and heparin to prevent miscarriage is based on the possibility that hypercoagulability might contribute to miscarriage. Evidence supports the use of these agents for this purpose in women with antiphospholipid syndrome (Obstet. Gynecol. 2002;99:135-44), and suggests that recurrent miscarriage might be related to thrombosis risk (Hum. Reprod. 2005;20:1729-32).

A literature review by four of the current authors found, however, “a paucity in studies on the efficacy and safety of aspirin and heparin in women with a history of at least two miscarriages without apparent causes other than inherited thrombophilia” (Cochrane Database Syst. Rev. 2009 Jan. 21;CD004734).

The ALIFE trial excluded women with antiphospholipid syndrome as well as those with a history of thrombosis, uterus anomaly, abnormal karyotype, or indication for anticoagulants. To be eligible, women aged 18-42 years had to have two or more unexplained miscarriages and be either trying to conceive or less than 6 weeks pregnant.

Women in the two aspirin arms took calcium carbasalate (Ascal) equivalent to acetylsalicylic acid 80 mg daily from the day of randomization until 36 weeks of gestational age. Nadroparin 2,850 IU was injected after a pregnancy was confirmed by ultrasound from 6 weeks of gestational age until the end of pregnancy.

The average age was about 33 years, and the median number of unexplained miscarriages was three. Among the women who were randomized, 103 completed treatment in each of the aspirin-plus-nadroparin and placebo arms; 104 took all treatments in the aspirin-only group.

The author could find no significant differences in subgroup analyses of women with inherited thrombophilia, preceding live birth, age less than 36 years, or three or more previous miscarriages. The investigators did see a trend toward improved live birth rate in 47 women with inherited thrombophilia, however (relative risk ratio 1.56, P = .18).

The study was underpowered to draw a conclusion on whether women with inherited thrombophilia might benefit from anticoagulant prophylaxis, Dr. Kaandorp said, promising to explore this question. “At this moment I think we should not treat those women, but should do another trial in that population,” he said.

'We couldn't find the beneficial effects in our study of three treatment arms—[there was] no difference at all.'

Source DR. KAANDORP

My Take

Study Confirms Common Sense

In women in whom no specific cause is found for miscarriage, no specific treatment should be used. Thus a treatment that is specific for pregnant women with inherited thrombophilia or antiphospholipid syndrome should not be given to pregnant women without such diagnoses. If you use aspirin in midpregnancy, you increase the risk of pregnancy loss and placental abruption. So if there is no proven benefit to this treatment, this seems like a bad deal. On the other hand, if a woman comes into an ob.gyn.'s office having had two miscarriages and says, “Do something,” some physicians may say, “Give them what they want.”

But this study has shown that aspirin does not prevent recurrent idiopathic miscarriages and does cause bruising. Low-molecular-weight heparin is probably even worse in terms of potential risks and complications.

If you do not find the problem you are looking for—that is, inherited thrombophilia or antiphospholipid syndrome—treatment is dangerous and not helpful.

Are these data new? Prior studies of aspirin use in pregnancy have demonstrated an increased risk of placental abruption in aspirin-treated women. The current study confirmed what logic told you was the right thing to do: Don't use them.

In practice I occasionally see physicians prescribe a treatment for a pregnant patient, saying, “What harm can it do?” It was that kind of thinking that led to the DES debacle some 40 years ago. When dealing with pregnancy, you can't say, “What harm can it do?” because the results can be disastrous. It is good that these researchers performed this study because it confirmed what most rational physicians know: We should use only treatments definitely shown to work, especially during pregnancy.

GERSON WEISS, M.D., is the chairman of the department of obstetrics and gynecology at New Jersey Medical School, Newark. He said he had no relevant disclosures.

The presence of lupus anticoagulant, an antiphospholipid antibody, increased the risk of stroke by 40-fold and of heart attack by 5-fold in a Dutch study that compared young women who had survived these conditions with a healthy control group.

Smoking and use of oral contraceptives drove the risk of these arterial thrombosis events yet higher in the survivors who tested positive for lupus anticoagulant, according to a report posted online in the Lancet Neurology.

“Our data suggest that lupus anticoagulant is a major risk factor for arterial thrombotic disease…. Screening for lupus anticoagulant in young women with ischemic stroke seems to be warranted,” wrote Rolf T. Urbanus, Ph.D., of University Medical Centre Utrecht (the Netherlands) and associates (Lancet Neurol. 2009 [doi:10.1016/S1474-4422(09)70239-X]).

Most important is the elucidation that young women with antiphospholipid antibodies should be informed “about the serious risks of cigarette smoking and use of oral contraceptives,” according to an accompanying editorial by Dr. Kathryn F. Kirchoff-Torres and Dr. Steven R. Levine, both of the Stroke Center at Mount Sinai School of Medicine, New York (Lancet Neurol. 2009 [DOI:10.1016/S1474-4422(09)70263-7]).

Lupus anticoagulant is one of several antibodies implicated in antiphospholipid syndrome, an autoimmune disease that is an acquired risk factor for arterial thrombosis. The syndrome is known to be more prevalent in young women. Diagnosis is based on thrombotic events and repeated positive tests for antiphospholipid antibodies, such as those against the phospholipid cardiolipin or the plasma protein beta₂-glycoprotein I, as well as the lupus anticoagulant.

For this analysis, the investigators drew participants from the multicenter RATIO (Risk of Arterial Thrombosis In relation to Oral contraceptives) study, which enrolled women aged 49 years and younger who had been hospitalized with their first ischemic stroke or MI between January 1990 and October 1995. Dr. Urbanus and colleagues also included 50 women who presented with ischemic stroke between 1996 and 2001 at the Utrecht center.

All told, the population comprised 175 women with ischemic stroke, 203 women with MI, and 628 healthy controls who were identified by random-digit dialing of telephone numbers and invited to participate. The average age was 42 years for the MI group and 39 years for the stroke patients and healthy controls.

More than a quarter of the MI and stroke groups but only 6% of the controls had hypertension. Use of oral contraceptives was higher in the stroke group (53%) than in the MI (39%) and control (33%) groups. The MI patients were most likely to be current smokers (82%), followed by those in the stroke (60%) and control (42%) groups.

Analysis of blood samples found lupus anticoagulant in 6 (3%) MI patients and 30 (17%) stroke patients, but only 4 (0.6%) healthy controls. Comparing the women with lupus anticoagulant to those who did not have the antibody produced odds ratios of 5.3 (95% confidence interval, 1.4-20.8) for MI and 43.1 (12.2-152.0) for ischemic stroke, Dr. Urbanus and his associates reported.

In women who used oral contraceptives and carried the lupus anticoagulant risk factor, the odds ratios became 21.6 (1.9-242.0) for MI and 201.0 (22.1-1,828.0) for stroke. Similarly, smoking increased the odds of MI to 337 (6.0-189.0) and of stroke to 87.0 (14.5-523.0), the investigators said.

The authors did not find increased risks with anticardiolipin or antiprothrombin antibodies. Presence of beta₂-glycoprotein I antibodies doubled the risk of stroke (OR 2.3) but did not add to the risk of MI. In women with lupus anticoagulant, the presence of a second antiphospholipid antibody did not increase risk.

The investigators noted that the study had limitations, and the editorial emphasizes that “a few methodological issues … deserve attention.” The odds ratios are much higher than previously reported by other researchers who found increased risk with antiphospholipid antibodies (Stroke 2002;33:2396-400 and Stroke 2004;35:736-41). This may have been a reflection of the low prevalence of lupus anticoagulant in the healthy controls compared with historic data.

Other issues include the timing of the testing for antiphospholipid antibodies, which occurred as long as 10 years after the thrombotic events. “Some aPL [antiphospholipid antibody]-positive patients in the study by Urbanus and colleagues might not, therefore, have been aPL-positive at the time of the thrombotic event, and vice versa, making any claims of causality speculative,” wrote Dr. Kirchoff-Torres, a senior vascular neurology fellow and postdoctoral researcher, and Dr. Levine, professor of neurology and director of the cerebrovascular research training program at Mount Sinai.

Dr. Kirchoff-Torres also cited the wide confidence intervals and noted during an interview that the original study on oral contraceptive risk was not designed to look at antiphospholipid antibodies. In addition, there is no information on young women with fatal MIs or fatal ischemic strokes. It also is not reported how many women with stroke or MI had only the lupus anticoagulant as a risk factor and nothing else.

The data do not justify screening all women being prescribed oral contraceptives at this time, she said, calling such a wide generalization of results premature. Testing might be appropriate, however, in women who have lupus, a personal or family history of autoimmune or thrombotic disease, or abnormalities in normal blood work, she said, suggesting low platelet or elevated activated partial thromboplastin time (aPTT) could be cause for concern.

The study “definitely raises awareness of the importance of taking a careful history and cautioning any women on oral contraceptives not to smoke,” Dr. Kirchoff-Torres said.

The Netherlands Heart Foundation and Leducq Foundation supported the study, and the U.S. National Institutes of Health grants supported the editorial. The authors said that they had no conflicts of interest.

The presence of lupus anticoagulant, an antiphospholipid antibody, increased the risk of stroke by 40-fold and of heart attack by 5-fold in a Dutch study that compared young women who had survived these conditions with a healthy control group.

Smoking and use of oral contraceptives drove the risk of these arterial thrombosis events yet higher in the survivors who tested positive for lupus anticoagulant, according to a report posted online in the Lancet Neurology.

“Our data suggest that lupus anticoagulant is a major risk factor for arterial thrombotic disease…. Screening for lupus anticoagulant in young women with ischemic stroke seems to be warranted,” wrote Rolf T. Urbanus, Ph.D., of University Medical Centre Utrecht (the Netherlands) and associates (Lancet Neurol. 2009 [doi:10.1016/S1474-4422(09)70239-X]).

Most important is the elucidation that young women with antiphospholipid antibodies should be informed “about the serious risks of cigarette smoking and use of oral contraceptives,” according to an accompanying editorial by Dr. Kathryn F. Kirchoff-Torres and Dr. Steven R. Levine, both of the Stroke Center at Mount Sinai School of Medicine, New York (Lancet Neurol. 2009 [DOI:10.1016/S1474-4422(09)70263-7]).

Lupus anticoagulant is one of several antibodies implicated in antiphospholipid syndrome, an autoimmune disease that is an acquired risk factor for arterial thrombosis. The syndrome is known to be more prevalent in young women. Diagnosis is based on thrombotic events and repeated positive tests for antiphospholipid antibodies, such as those against the phospholipid cardiolipin or the plasma protein beta₂-glycoprotein I, as well as the lupus anticoagulant.

For this analysis, the investigators drew participants from the multicenter RATIO (Risk of Arterial Thrombosis In relation to Oral contraceptives) study, which enrolled women aged 49 years and younger who had been hospitalized with their first ischemic stroke or MI between January 1990 and October 1995. Dr. Urbanus and colleagues also included 50 women who presented with ischemic stroke between 1996 and 2001 at the Utrecht center.

All told, the population comprised 175 women with ischemic stroke, 203 women with MI, and 628 healthy controls who were identified by random-digit dialing of telephone numbers and invited to participate. The average age was 42 years for the MI group and 39 years for the stroke patients and healthy controls.

More than a quarter of the MI and stroke groups but only 6% of the controls had hypertension. Use of oral contraceptives was higher in the stroke group (53%) than in the MI (39%) and control (33%) groups. The MI patients were most likely to be current smokers (82%), followed by those in the stroke (60%) and control (42%) groups.

Analysis of blood samples found lupus anticoagulant in 6 (3%) MI patients and 30 (17%) stroke patients, but only 4 (0.6%) healthy controls. Comparing the women with lupus anticoagulant to those who did not have the antibody produced odds ratios of 5.3 (95% confidence interval, 1.4-20.8) for MI and 43.1 (12.2-152.0) for ischemic stroke, Dr. Urbanus and his associates reported.

In women who used oral contraceptives and carried the lupus anticoagulant risk factor, the odds ratios became 21.6 (1.9-242.0) for MI and 201.0 (22.1-1,828.0) for stroke. Similarly, smoking increased the odds of MI to 337 (6.0-189.0) and of stroke to 87.0 (14.5-523.0), the investigators said.

The authors did not find increased risks with anticardiolipin or antiprothrombin antibodies. Presence of beta₂-glycoprotein I antibodies doubled the risk of stroke (OR 2.3) but did not add to the risk of MI. In women with lupus anticoagulant, the presence of a second antiphospholipid antibody did not increase risk.

The investigators noted that the study had limitations, and the editorial emphasizes that “a few methodological issues … deserve attention.” The odds ratios are much higher than previously reported by other researchers who found increased risk with antiphospholipid antibodies (Stroke 2002;33:2396-400 and Stroke 2004;35:736-41). This may have been a reflection of the low prevalence of lupus anticoagulant in the healthy controls compared with historic data.

Other issues include the timing of the testing for antiphospholipid antibodies, which occurred as long as 10 years after the thrombotic events. “Some aPL [antiphospholipid antibody]-positive patients in the study by Urbanus and colleagues might not, therefore, have been aPL-positive at the time of the thrombotic event, and vice versa, making any claims of causality speculative,” wrote Dr. Kirchoff-Torres, a senior vascular neurology fellow and postdoctoral researcher, and Dr. Levine, professor of neurology and director of the cerebrovascular research training program at Mount Sinai.

Dr. Kirchoff-Torres also cited the wide confidence intervals and noted during an interview that the original study on oral contraceptive risk was not designed to look at antiphospholipid antibodies. In addition, there is no information on young women with fatal MIs or fatal ischemic strokes. It also is not reported how many women with stroke or MI had only the lupus anticoagulant as a risk factor and nothing else.

The data do not justify screening all women being prescribed oral contraceptives at this time, she said, calling such a wide generalization of results premature. Testing might be appropriate, however, in women who have lupus, a personal or family history of autoimmune or thrombotic disease, or abnormalities in normal blood work, she said, suggesting low platelet or elevated activated partial thromboplastin time (aPTT) could be cause for concern.

The study “definitely raises awareness of the importance of taking a careful history and cautioning any women on oral contraceptives not to smoke,” Dr. Kirchoff-Torres said.

The Netherlands Heart Foundation and Leducq Foundation supported the study, and the U.S. National Institutes of Health grants supported the editorial. The authors said that they had no conflicts of interest.

The presence of lupus anticoagulant, an antiphospholipid antibody, increased the risk of stroke by 40-fold and of heart attack by 5-fold in a Dutch study that compared young women who had survived these conditions with a healthy control group.

Smoking and use of oral contraceptives drove the risk of these arterial thrombosis events yet higher in the survivors who tested positive for lupus anticoagulant, according to a report posted online in the Lancet Neurology.

“Our data suggest that lupus anticoagulant is a major risk factor for arterial thrombotic disease…. Screening for lupus anticoagulant in young women with ischemic stroke seems to be warranted,” wrote Rolf T. Urbanus, Ph.D., of University Medical Centre Utrecht (the Netherlands) and associates (Lancet Neurol. 2009 [doi:10.1016/S1474-4422(09)70239-X]).

Most important is the elucidation that young women with antiphospholipid antibodies should be informed “about the serious risks of cigarette smoking and use of oral contraceptives,” according to an accompanying editorial by Dr. Kathryn F. Kirchoff-Torres and Dr. Steven R. Levine, both of the Stroke Center at Mount Sinai School of Medicine, New York (Lancet Neurol. 2009 [DOI:10.1016/S1474-4422(09)70263-7]).

Lupus anticoagulant is one of several antibodies implicated in antiphospholipid syndrome, an autoimmune disease that is an acquired risk factor for arterial thrombosis. The syndrome is known to be more prevalent in young women. Diagnosis is based on thrombotic events and repeated positive tests for antiphospholipid antibodies, such as those against the phospholipid cardiolipin or the plasma protein beta₂-glycoprotein I, as well as the lupus anticoagulant.

For this analysis, the investigators drew participants from the multicenter RATIO (Risk of Arterial Thrombosis In relation to Oral contraceptives) study, which enrolled women aged 49 years and younger who had been hospitalized with their first ischemic stroke or MI between January 1990 and October 1995. Dr. Urbanus and colleagues also included 50 women who presented with ischemic stroke between 1996 and 2001 at the Utrecht center.

All told, the population comprised 175 women with ischemic stroke, 203 women with MI, and 628 healthy controls who were identified by random-digit dialing of telephone numbers and invited to participate. The average age was 42 years for the MI group and 39 years for the stroke patients and healthy controls.

More than a quarter of the MI and stroke groups but only 6% of the controls had hypertension. Use of oral contraceptives was higher in the stroke group (53%) than in the MI (39%) and control (33%) groups. The MI patients were most likely to be current smokers (82%), followed by those in the stroke (60%) and control (42%) groups.

Analysis of blood samples found lupus anticoagulant in 6 (3%) MI patients and 30 (17%) stroke patients, but only 4 (0.6%) healthy controls. Comparing the women with lupus anticoagulant to those who did not have the antibody produced odds ratios of 5.3 (95% confidence interval, 1.4-20.8) for MI and 43.1 (12.2-152.0) for ischemic stroke, Dr. Urbanus and his associates reported.

In women who used oral contraceptives and carried the lupus anticoagulant risk factor, the odds ratios became 21.6 (1.9-242.0) for MI and 201.0 (22.1-1,828.0) for stroke. Similarly, smoking increased the odds of MI to 337 (6.0-189.0) and of stroke to 87.0 (14.5-523.0), the investigators said.

The authors did not find increased risks with anticardiolipin or antiprothrombin antibodies. Presence of beta₂-glycoprotein I antibodies doubled the risk of stroke (OR 2.3) but did not add to the risk of MI. In women with lupus anticoagulant, the presence of a second antiphospholipid antibody did not increase risk.

The investigators noted that the study had limitations, and the editorial emphasizes that “a few methodological issues … deserve attention.” The odds ratios are much higher than previously reported by other researchers who found increased risk with antiphospholipid antibodies (Stroke 2002;33:2396-400 and Stroke 2004;35:736-41). This may have been a reflection of the low prevalence of lupus anticoagulant in the healthy controls compared with historic data.

Other issues include the timing of the testing for antiphospholipid antibodies, which occurred as long as 10 years after the thrombotic events. “Some aPL [antiphospholipid antibody]-positive patients in the study by Urbanus and colleagues might not, therefore, have been aPL-positive at the time of the thrombotic event, and vice versa, making any claims of causality speculative,” wrote Dr. Kirchoff-Torres, a senior vascular neurology fellow and postdoctoral researcher, and Dr. Levine, professor of neurology and director of the cerebrovascular research training program at Mount Sinai.

Dr. Kirchoff-Torres also cited the wide confidence intervals and noted during an interview that the original study on oral contraceptive risk was not designed to look at antiphospholipid antibodies. In addition, there is no information on young women with fatal MIs or fatal ischemic strokes. It also is not reported how many women with stroke or MI had only the lupus anticoagulant as a risk factor and nothing else.

The data do not justify screening all women being prescribed oral contraceptives at this time, she said, calling such a wide generalization of results premature. Testing might be appropriate, however, in women who have lupus, a personal or family history of autoimmune or thrombotic disease, or abnormalities in normal blood work, she said, suggesting low platelet or elevated activated partial thromboplastin time (aPTT) could be cause for concern.

The study “definitely raises awareness of the importance of taking a careful history and cautioning any women on oral contraceptives not to smoke,” Dr. Kirchoff-Torres said.

The Netherlands Heart Foundation and Leducq Foundation supported the study, and the U.S. National Institutes of Health grants supported the editorial. The authors said that they had no conflicts of interest.

SANTA FE, N.M. – A privately funded initiative is gearing up to do proof-of-concept prevention trials sooner rather than later in motivated volunteers who carry susceptibility genes for early Alzheimer's disease, but have not yet presented with cognitive impairment.

If any treatments can be shown to prevent precursor brain imaging and biomarker changes, the investigators plan to launch large clinical trials in people who have put their names into an Arizona Alzheimer's Consortium registry of potential participants.

Dr. Pierre N. Tariot announced the initiative at an annual psychiatric symposium sponsored by the University of Arizona. An advisory group of leading investigators will meet in Phoenix in October to set priorities in preparation for requesting a grant from the National Institutes of Health, he told attendees.

“The Holy Grail is either to delay the onset of the illness or prevent it altogether,” said Dr. Tariot, director of the Memory Disorders Center at Banner Alzheimer's Institute in Phoenix. “If we can delay the onset by 5 years we could cut the numbers in half. That is a huge impact. We think that is an achievable goal.”

The general schema, as outlined by Dr. Tariot, is to genotype asymptomatic people who are in their early 40s and come from families with a history of early Alzheimer's disease. Those who screen positive for genes that predict they will develop dementia within the next decade could be invited to participate in one of a series of small placebo-controlled studies.

Within 2 years, the investigators expect to see whether an intervention can alter the course of changes leading to the disease. Rather than waiting years more to see whether the disease is prevented in these subjects, the project would start a clinical trial of a promising therapy in a larger population drawn from the registry at this point.

“The development work has already been done showing what happens to your brain with various types of imaging and biomarkers before you get the illness. … If I have an anti-amyloid therapy I am going to test it in 100 people–50 on drug and 50 on placebo. That is enough to answer the question of whether the trajectory is altered or not,” Dr. Tariot said.

Estrogen, antioxidants, omega-3 fatty acids, exercise, memantine, and other “emerging experimental therapies” also are among the potential interventions under consideration for proof-of-concept studies. Therapies that failed in Alzheimer's intervention trials would not be ruled out, but they must be proven safe, Dr. Tariot said. Hormonal therapies, in particular, might be effective in preventing the disease, even if they cannot stop its progression.

“We think that right now there are roughly a dozen Alzheimer's prevention interventions that might work,” he said.

Except for the publicly funded registry, the investigators are relying on private philanthropy to jump-start the initiative. Dr. Tariot was optimistic that the NIH will be receptive as the project matures, but noted that, despite unanimous enthusiasm for the concept, industry and government have been cautious thus far.

“It is so out of the box, we are not getting any funding,” he said. “So we are actually using philanthropic dollars to launch this initiative. We think once we get going, the field will be changed forever.”

Building an infrastructure for clinical trials is a priority for Dr. Tariot and his colleagues. Along with the research registry, this entails writing protocols for an administrative structure and a scientific and ethical review process, including data and safety monitoring boards that could be in place when the larger trials are funded and ready to start.

The Arizona Alzheimer's Consortium hosts the registry at its Web site, www.azalz.org

Based on their responses to a detailed questionnaire and their location in the state, volunteers are referred to research studies at one or more of the consortium's eight member institutions: Arizona State University, Banner Alzheimer's Institute, Barrow Neurological Institute, Mayo Clinic Arizona, Sun Health Research Institute, Translational Genomics Research Institute, Tucson VA, and the University of Arizona.

Efforts are underway to expand the registry, and thereby the pool of potential volunteers, to other Western states.“There are so many therapies in development that the biggest threat to finding a way to put Alzheimer's disease behind us is not discovery any more. It is clinical trials,” Dr. Tariot said.

He disclosed relationships, including consulting fees and research support, with about 24 companies engaged in Alzheimer's research, but emphasized that he has no investments to disclose and does not serve on any speakers bureaus. Banner Alzheimer's Institute is part of the nonprofit Banner Health System, and has the Banner Alzheimer's Foundation as a philanthropic resource.

SANTA FE, N.M. – A privately funded initiative is gearing up to do proof-of-concept prevention trials sooner rather than later in motivated volunteers who carry susceptibility genes for early Alzheimer's disease, but have not yet presented with cognitive impairment.

If any treatments can be shown to prevent precursor brain imaging and biomarker changes, the investigators plan to launch large clinical trials in people who have put their names into an Arizona Alzheimer's Consortium registry of potential participants.

Dr. Pierre N. Tariot announced the initiative at an annual psychiatric symposium sponsored by the University of Arizona. An advisory group of leading investigators will meet in Phoenix in October to set priorities in preparation for requesting a grant from the National Institutes of Health, he told attendees.

“The Holy Grail is either to delay the onset of the illness or prevent it altogether,” said Dr. Tariot, director of the Memory Disorders Center at Banner Alzheimer's Institute in Phoenix. “If we can delay the onset by 5 years we could cut the numbers in half. That is a huge impact. We think that is an achievable goal.”

The general schema, as outlined by Dr. Tariot, is to genotype asymptomatic people who are in their early 40s and come from families with a history of early Alzheimer's disease. Those who screen positive for genes that predict they will develop dementia within the next decade could be invited to participate in one of a series of small placebo-controlled studies.

Within 2 years, the investigators expect to see whether an intervention can alter the course of changes leading to the disease. Rather than waiting years more to see whether the disease is prevented in these subjects, the project would start a clinical trial of a promising therapy in a larger population drawn from the registry at this point.

“The development work has already been done showing what happens to your brain with various types of imaging and biomarkers before you get the illness. … If I have an anti-amyloid therapy I am going to test it in 100 people–50 on drug and 50 on placebo. That is enough to answer the question of whether the trajectory is altered or not,” Dr. Tariot said.

Estrogen, antioxidants, omega-3 fatty acids, exercise, memantine, and other “emerging experimental therapies” also are among the potential interventions under consideration for proof-of-concept studies. Therapies that failed in Alzheimer's intervention trials would not be ruled out, but they must be proven safe, Dr. Tariot said. Hormonal therapies, in particular, might be effective in preventing the disease, even if they cannot stop its progression.

“We think that right now there are roughly a dozen Alzheimer's prevention interventions that might work,” he said.

Except for the publicly funded registry, the investigators are relying on private philanthropy to jump-start the initiative. Dr. Tariot was optimistic that the NIH will be receptive as the project matures, but noted that, despite unanimous enthusiasm for the concept, industry and government have been cautious thus far.

“It is so out of the box, we are not getting any funding,” he said. “So we are actually using philanthropic dollars to launch this initiative. We think once we get going, the field will be changed forever.”

Building an infrastructure for clinical trials is a priority for Dr. Tariot and his colleagues. Along with the research registry, this entails writing protocols for an administrative structure and a scientific and ethical review process, including data and safety monitoring boards that could be in place when the larger trials are funded and ready to start.

The Arizona Alzheimer's Consortium hosts the registry at its Web site, www.azalz.org

Based on their responses to a detailed questionnaire and their location in the state, volunteers are referred to research studies at one or more of the consortium's eight member institutions: Arizona State University, Banner Alzheimer's Institute, Barrow Neurological Institute, Mayo Clinic Arizona, Sun Health Research Institute, Translational Genomics Research Institute, Tucson VA, and the University of Arizona.

Efforts are underway to expand the registry, and thereby the pool of potential volunteers, to other Western states.“There are so many therapies in development that the biggest threat to finding a way to put Alzheimer's disease behind us is not discovery any more. It is clinical trials,” Dr. Tariot said.

He disclosed relationships, including consulting fees and research support, with about 24 companies engaged in Alzheimer's research, but emphasized that he has no investments to disclose and does not serve on any speakers bureaus. Banner Alzheimer's Institute is part of the nonprofit Banner Health System, and has the Banner Alzheimer's Foundation as a philanthropic resource.

SANTA FE, N.M. – A privately funded initiative is gearing up to do proof-of-concept prevention trials sooner rather than later in motivated volunteers who carry susceptibility genes for early Alzheimer's disease, but have not yet presented with cognitive impairment.

If any treatments can be shown to prevent precursor brain imaging and biomarker changes, the investigators plan to launch large clinical trials in people who have put their names into an Arizona Alzheimer's Consortium registry of potential participants.

Dr. Pierre N. Tariot announced the initiative at an annual psychiatric symposium sponsored by the University of Arizona. An advisory group of leading investigators will meet in Phoenix in October to set priorities in preparation for requesting a grant from the National Institutes of Health, he told attendees.

“The Holy Grail is either to delay the onset of the illness or prevent it altogether,” said Dr. Tariot, director of the Memory Disorders Center at Banner Alzheimer's Institute in Phoenix. “If we can delay the onset by 5 years we could cut the numbers in half. That is a huge impact. We think that is an achievable goal.”

The general schema, as outlined by Dr. Tariot, is to genotype asymptomatic people who are in their early 40s and come from families with a history of early Alzheimer's disease. Those who screen positive for genes that predict they will develop dementia within the next decade could be invited to participate in one of a series of small placebo-controlled studies.

Within 2 years, the investigators expect to see whether an intervention can alter the course of changes leading to the disease. Rather than waiting years more to see whether the disease is prevented in these subjects, the project would start a clinical trial of a promising therapy in a larger population drawn from the registry at this point.

“The development work has already been done showing what happens to your brain with various types of imaging and biomarkers before you get the illness. … If I have an anti-amyloid therapy I am going to test it in 100 people–50 on drug and 50 on placebo. That is enough to answer the question of whether the trajectory is altered or not,” Dr. Tariot said.

Estrogen, antioxidants, omega-3 fatty acids, exercise, memantine, and other “emerging experimental therapies” also are among the potential interventions under consideration for proof-of-concept studies. Therapies that failed in Alzheimer's intervention trials would not be ruled out, but they must be proven safe, Dr. Tariot said. Hormonal therapies, in particular, might be effective in preventing the disease, even if they cannot stop its progression.

“We think that right now there are roughly a dozen Alzheimer's prevention interventions that might work,” he said.

Except for the publicly funded registry, the investigators are relying on private philanthropy to jump-start the initiative. Dr. Tariot was optimistic that the NIH will be receptive as the project matures, but noted that, despite unanimous enthusiasm for the concept, industry and government have been cautious thus far.

“It is so out of the box, we are not getting any funding,” he said. “So we are actually using philanthropic dollars to launch this initiative. We think once we get going, the field will be changed forever.”

Building an infrastructure for clinical trials is a priority for Dr. Tariot and his colleagues. Along with the research registry, this entails writing protocols for an administrative structure and a scientific and ethical review process, including data and safety monitoring boards that could be in place when the larger trials are funded and ready to start.

The Arizona Alzheimer's Consortium hosts the registry at its Web site, www.azalz.org

Based on their responses to a detailed questionnaire and their location in the state, volunteers are referred to research studies at one or more of the consortium's eight member institutions: Arizona State University, Banner Alzheimer's Institute, Barrow Neurological Institute, Mayo Clinic Arizona, Sun Health Research Institute, Translational Genomics Research Institute, Tucson VA, and the University of Arizona.

Efforts are underway to expand the registry, and thereby the pool of potential volunteers, to other Western states.“There are so many therapies in development that the biggest threat to finding a way to put Alzheimer's disease behind us is not discovery any more. It is clinical trials,” Dr. Tariot said.

He disclosed relationships, including consulting fees and research support, with about 24 companies engaged in Alzheimer's research, but emphasized that he has no investments to disclose and does not serve on any speakers bureaus. Banner Alzheimer's Institute is part of the nonprofit Banner Health System, and has the Banner Alzheimer's Foundation as a philanthropic resource.

Fasting plasma glucose variability could be a marker for risk of nocturnal hypoglycemia, according to an analysis of data from more than 7,500 patients treated with insulin detemir for type 1 or type 2 diabetes.

Changes in the coefficient of variance for fasting plasma glucose (CV FPG) correlated with changes in nocturnal hypoglycemia, Dr. Leo Niskanen of Kuopio (Finland) University Hospital, and his coinvestigators reported in the journal Diabetes Research and Clinical Practice (doi:10.1016/j.diabres.2009.08.005).

When patients had less FPG variability after 3 months on insulin detemir (Levemir), the incidence of nocturnal hypoglycemia also was reduced. This was true of both types of diabetes, and was independent of improvement in metabolic control.

“Our results suggest CV FPG can be a useful marker for risk of nocturnal hypoglycemia in the clinical setting, and that glucose instability can be gauged quite simply with home FPG monitoring,” the authors wrote in their conclusion.

They also speculated that reduced variability “may have contributed to the simultaneous improvement of metabolic control and reduction of nocturnal hypoglycemia observed with detemir therapy” in the study.

The analysis was based on the PREDICTIVE study (Predictable Results and Experience in Diabetes Through Intensification and Control to Target: an International Variability Evaluation), a multinational observational investigation sponsored by Novo Nordisk, maker of detemir, that had more than 19,000 patients (Int. J. Clin. Pract. 2007;61:523-8; Diabetes Obes. Metab. 2007;9:428-34).

In the analysis of the relationship between FPG variability and nocturnal hypoglycemia, there were 1,433 type 1 diabetes patients with nocturnal hypoglycemia at baseline and 2,170 without. Among patients with type 2 diabetes, 553 had nocturnal hypoglycemia at baseline, while 3,365 did not.

The incidence of nocturnal hypoglycemia at baseline and 3 months later was based on patient reports. At both time points, patients were asked whether they had had nocturnal hypoglycemic events during the previous 4 weeks.

After 3 months on detemir, the percentage of patients with nocturnal hypoglycemia decreased significantly—from 39.8% to 14.7% of patients with type 1 diabetes and from 14.1% to 3.0% of patients with type 2. The average number of nocturnal hypoglycemia events over 4 weeks also fell from 3.1 to 2.1 for type 1 patients and from 2.7 to 1.9 for type 2.

The investigators found these declines to be correlated with changes in FPG variability. At 3 months, the patients with nocturnal hypoglycemia had significantly higher CV FPG than those who did not report nocturnal hypoglycemia—32.8% vs. 23.0% in the type 1 group and 20.7% vs. 12.7% in the type 2 group.

“These absolute values were similar to baseline, although the [nocturnal hypoglycemia positive] subgroups had decreased in patient number,” they wrote.

The analysis also identified demographic differences between patients who reported nocturnal hypoglycemia at baseline and those who did not. In the type 1 population, patients reporting nocturnal hypoglycemia were significantly more likely to be female (60.4% vs. 50.2%), were older (44.1 years vs. 42.2 years), had a longer duration of diabetes (18.9 years vs. 16.3 years), and had lower FPG (9.1 mmol/L vs. 9.4 mmol/L) than those not reporting nocturnal hypoglycemia.

In the type 2 population, patients reporting nocturnal hypoglycemia were not significantly different in terms of gender or age, but had a significantly longer duration of diabetes (13.7 years vs. 12.7 years), weighed less (86.2 kg vs. 91.7 kg), had a lower HbA_1c (7.9% vs. 8.2%), and had a lower FPG (8.9 mmol/L vs. 9.7 mmol/L).

Dr. Niskanen disclosed receiving speaker fees and research funds from Novo Nordisk. Two of his coauthors are employees of the company, and one owns shares in Novo Nordisk.

Fasting plasma glucose variability could be a marker for risk of nocturnal hypoglycemia, according to an analysis of data from more than 7,500 patients treated with insulin detemir for type 1 or type 2 diabetes.

Changes in the coefficient of variance for fasting plasma glucose (CV FPG) correlated with changes in nocturnal hypoglycemia, Dr. Leo Niskanen of Kuopio (Finland) University Hospital, and his coinvestigators reported in the journal Diabetes Research and Clinical Practice (doi:10.1016/j.diabres.2009.08.005).

When patients had less FPG variability after 3 months on insulin detemir (Levemir), the incidence of nocturnal hypoglycemia also was reduced. This was true of both types of diabetes, and was independent of improvement in metabolic control.

“Our results suggest CV FPG can be a useful marker for risk of nocturnal hypoglycemia in the clinical setting, and that glucose instability can be gauged quite simply with home FPG monitoring,” the authors wrote in their conclusion.

They also speculated that reduced variability “may have contributed to the simultaneous improvement of metabolic control and reduction of nocturnal hypoglycemia observed with detemir therapy” in the study.

The analysis was based on the PREDICTIVE study (Predictable Results and Experience in Diabetes Through Intensification and Control to Target: an International Variability Evaluation), a multinational observational investigation sponsored by Novo Nordisk, maker of detemir, that had more than 19,000 patients (Int. J. Clin. Pract. 2007;61:523-8; Diabetes Obes. Metab. 2007;9:428-34).

In the analysis of the relationship between FPG variability and nocturnal hypoglycemia, there were 1,433 type 1 diabetes patients with nocturnal hypoglycemia at baseline and 2,170 without. Among patients with type 2 diabetes, 553 had nocturnal hypoglycemia at baseline, while 3,365 did not.

The incidence of nocturnal hypoglycemia at baseline and 3 months later was based on patient reports. At both time points, patients were asked whether they had had nocturnal hypoglycemic events during the previous 4 weeks.

After 3 months on detemir, the percentage of patients with nocturnal hypoglycemia decreased significantly—from 39.8% to 14.7% of patients with type 1 diabetes and from 14.1% to 3.0% of patients with type 2. The average number of nocturnal hypoglycemia events over 4 weeks also fell from 3.1 to 2.1 for type 1 patients and from 2.7 to 1.9 for type 2.

The investigators found these declines to be correlated with changes in FPG variability. At 3 months, the patients with nocturnal hypoglycemia had significantly higher CV FPG than those who did not report nocturnal hypoglycemia—32.8% vs. 23.0% in the type 1 group and 20.7% vs. 12.7% in the type 2 group.

“These absolute values were similar to baseline, although the [nocturnal hypoglycemia positive] subgroups had decreased in patient number,” they wrote.

The analysis also identified demographic differences between patients who reported nocturnal hypoglycemia at baseline and those who did not. In the type 1 population, patients reporting nocturnal hypoglycemia were significantly more likely to be female (60.4% vs. 50.2%), were older (44.1 years vs. 42.2 years), had a longer duration of diabetes (18.9 years vs. 16.3 years), and had lower FPG (9.1 mmol/L vs. 9.4 mmol/L) than those not reporting nocturnal hypoglycemia.

In the type 2 population, patients reporting nocturnal hypoglycemia were not significantly different in terms of gender or age, but had a significantly longer duration of diabetes (13.7 years vs. 12.7 years), weighed less (86.2 kg vs. 91.7 kg), had a lower HbA_1c (7.9% vs. 8.2%), and had a lower FPG (8.9 mmol/L vs. 9.7 mmol/L).

Dr. Niskanen disclosed receiving speaker fees and research funds from Novo Nordisk. Two of his coauthors are employees of the company, and one owns shares in Novo Nordisk.

Fasting plasma glucose variability could be a marker for risk of nocturnal hypoglycemia, according to an analysis of data from more than 7,500 patients treated with insulin detemir for type 1 or type 2 diabetes.

Changes in the coefficient of variance for fasting plasma glucose (CV FPG) correlated with changes in nocturnal hypoglycemia, Dr. Leo Niskanen of Kuopio (Finland) University Hospital, and his coinvestigators reported in the journal Diabetes Research and Clinical Practice (doi:10.1016/j.diabres.2009.08.005).

When patients had less FPG variability after 3 months on insulin detemir (Levemir), the incidence of nocturnal hypoglycemia also was reduced. This was true of both types of diabetes, and was independent of improvement in metabolic control.

“Our results suggest CV FPG can be a useful marker for risk of nocturnal hypoglycemia in the clinical setting, and that glucose instability can be gauged quite simply with home FPG monitoring,” the authors wrote in their conclusion.

They also speculated that reduced variability “may have contributed to the simultaneous improvement of metabolic control and reduction of nocturnal hypoglycemia observed with detemir therapy” in the study.

The analysis was based on the PREDICTIVE study (Predictable Results and Experience in Diabetes Through Intensification and Control to Target: an International Variability Evaluation), a multinational observational investigation sponsored by Novo Nordisk, maker of detemir, that had more than 19,000 patients (Int. J. Clin. Pract. 2007;61:523-8; Diabetes Obes. Metab. 2007;9:428-34).

In the analysis of the relationship between FPG variability and nocturnal hypoglycemia, there were 1,433 type 1 diabetes patients with nocturnal hypoglycemia at baseline and 2,170 without. Among patients with type 2 diabetes, 553 had nocturnal hypoglycemia at baseline, while 3,365 did not.

The incidence of nocturnal hypoglycemia at baseline and 3 months later was based on patient reports. At both time points, patients were asked whether they had had nocturnal hypoglycemic events during the previous 4 weeks.

After 3 months on detemir, the percentage of patients with nocturnal hypoglycemia decreased significantly—from 39.8% to 14.7% of patients with type 1 diabetes and from 14.1% to 3.0% of patients with type 2. The average number of nocturnal hypoglycemia events over 4 weeks also fell from 3.1 to 2.1 for type 1 patients and from 2.7 to 1.9 for type 2.

The investigators found these declines to be correlated with changes in FPG variability. At 3 months, the patients with nocturnal hypoglycemia had significantly higher CV FPG than those who did not report nocturnal hypoglycemia—32.8% vs. 23.0% in the type 1 group and 20.7% vs. 12.7% in the type 2 group.

“These absolute values were similar to baseline, although the [nocturnal hypoglycemia positive] subgroups had decreased in patient number,” they wrote.

The analysis also identified demographic differences between patients who reported nocturnal hypoglycemia at baseline and those who did not. In the type 1 population, patients reporting nocturnal hypoglycemia were significantly more likely to be female (60.4% vs. 50.2%), were older (44.1 years vs. 42.2 years), had a longer duration of diabetes (18.9 years vs. 16.3 years), and had lower FPG (9.1 mmol/L vs. 9.4 mmol/L) than those not reporting nocturnal hypoglycemia.

In the type 2 population, patients reporting nocturnal hypoglycemia were not significantly different in terms of gender or age, but had a significantly longer duration of diabetes (13.7 years vs. 12.7 years), weighed less (86.2 kg vs. 91.7 kg), had a lower HbA_1c (7.9% vs. 8.2%), and had a lower FPG (8.9 mmol/L vs. 9.7 mmol/L).

Dr. Niskanen disclosed receiving speaker fees and research funds from Novo Nordisk. Two of his coauthors are employees of the company, and one owns shares in Novo Nordisk.

Hormone therapy in postmenopausal women increases the risk of death from lung cancer, according to a newly published post hoc analysis of the large and influential placebo-controlled Women's Health Initiative trial.

Lung cancer incidence was not higher in women who were treated with estrogen plus progesterone, but they were significantly more likely to die of the disease, the investigators reported. The mortality effect was most pronounced in smokers and former smokers. No difference was seen in mortality from small cell lung cancer.

“Our findings should be considered before the initiation or continuation of combined hormone therapy in postmenopausal women, especially those with a high risk of lung cancer, such as current smokers or long-term past smokers,” concluded the investigators, led by Dr. Rowan T. Chlebowski of Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, Calif. (Lancet 2009 Sept. 19 [doi:10.1016/S0140-6736(09)61526-9

In an accompanying comment, Dr. Apar Kishor Ganti of the University of Nebraska Medical Center in Omaha said that hormone therapy (HT) should probably be avoided in women at high risk for lung cancer—and maybe should not be used at all (Lancet 2009 Sept. 19 [doi:10.1016/S0140-6736(09)61571-3

“These results, along with the findings showing no protection against coronary heart disease, seriously question whether [hormone therapy] has any role in medicine today. It is difficult to presume that the benefits of routine use of such therapy for menopausal symptoms outweigh the increased risks of mortality, especially in the absence of improvement in the quality of life,” wrote Dr. Ganti.

The Women's Health Initiative trial randomized 16,608 mostly healthy postmenopausal women (8,506 to combined hormone therapy and 8,102 to placebo) at 40 centers in the United States from 1993 to 1998.

The trial was halted after an average follow-up of 5.6 years when investigators determined that higher risks of cardiovascular disease, coronary heart disease, stroke, venous thromboembolism, and breast cancer outweighed the benefits from lower risks for fractures and colorectal cancers among women in the combined HT arm.

Lung cancer was not a predefined study outcome, but the investigators became suspicious when deaths from other cancers were not sufficient to explain excess mortality in women treated with HT.

The subsequent intent-to-treat analysis, performed at an average follow-up of 7.9 years, found that more lung cancer occurred in the combined HT arm (109 cases) than in women treated with placebo (85 cases), with non–small cell lung cancer (NSCLC) occurring in 96 and 72 women, respectively, in the two groups.

These differences were not statistically significant, but the curves began to separate after 5 years, with more lung cancer (particularly NSCLC) occurring after that time in women who were given combined HT than in those who had been on placebo.

Among the women who were diagnosed with lung cancer, 78 deaths occurred during follow-up in the combined HT arm vs. 49 in the placebo group, a difference that was statistically significant, with an incidence per year of 0.12% and 0.08%, respectively (hazard ratio, 1.50), the investigators reported.

NSCLC was the cause in 62 of these deaths in the HT arm and in 31 in the placebo group, with an incidence per year of 0.09% vs. 0.05%, respectively (HR, 1.87).

The investigators also reported that an exploratory analysis showed shorter median survival after lung cancer diagnosis in the combined HT population (9.4 months vs. 16.1 months in their control group counterparts), and significantly higher mortality (70% vs. 54%) at 4 years after diagnosis (HR, 1.59).

The Women's Health Initiative was supported by the National Heart, Blood, and Lung Institute of the National Institutes of Health.

Dr. Chlebowski disclosed advisory and consulting relationships with various drug companies. Dr. Ganti declared no conflicts of interest. Dr. Chlebowski presented results from this study at the annual meeting of the American Society of Clinical Oncology earlier this year.

To see a video interview, go to www.youtube.com/user/ClinicalEndoNews

Lung cancer incidence was not higher in HT-treated women, but they were significantly more likely to die of it.

Source DR. CHLEBOWSKI

Hormone therapy in postmenopausal women increases the risk of death from lung cancer, according to a newly published post hoc analysis of the large and influential placebo-controlled Women's Health Initiative trial.

Lung cancer incidence was not higher in women who were treated with estrogen plus progesterone, but they were significantly more likely to die of the disease, the investigators reported. The mortality effect was most pronounced in smokers and former smokers. No difference was seen in mortality from small cell lung cancer.

“Our findings should be considered before the initiation or continuation of combined hormone therapy in postmenopausal women, especially those with a high risk of lung cancer, such as current smokers or long-term past smokers,” concluded the investigators, led by Dr. Rowan T. Chlebowski of Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, Calif. (Lancet 2009 Sept. 19 [doi:10.1016/S0140-6736(09)61526-9

In an accompanying comment, Dr. Apar Kishor Ganti of the University of Nebraska Medical Center in Omaha said that hormone therapy (HT) should probably be avoided in women at high risk for lung cancer—and maybe should not be used at all (Lancet 2009 Sept. 19 [doi:10.1016/S0140-6736(09)61571-3

“These results, along with the findings showing no protection against coronary heart disease, seriously question whether [hormone therapy] has any role in medicine today. It is difficult to presume that the benefits of routine use of such therapy for menopausal symptoms outweigh the increased risks of mortality, especially in the absence of improvement in the quality of life,” wrote Dr. Ganti.

The Women's Health Initiative trial randomized 16,608 mostly healthy postmenopausal women (8,506 to combined hormone therapy and 8,102 to placebo) at 40 centers in the United States from 1993 to 1998.

The trial was halted after an average follow-up of 5.6 years when investigators determined that higher risks of cardiovascular disease, coronary heart disease, stroke, venous thromboembolism, and breast cancer outweighed the benefits from lower risks for fractures and colorectal cancers among women in the combined HT arm.

Lung cancer was not a predefined study outcome, but the investigators became suspicious when deaths from other cancers were not sufficient to explain excess mortality in women treated with HT.

The subsequent intent-to-treat analysis, performed at an average follow-up of 7.9 years, found that more lung cancer occurred in the combined HT arm (109 cases) than in women treated with placebo (85 cases), with non–small cell lung cancer (NSCLC) occurring in 96 and 72 women, respectively, in the two groups.

These differences were not statistically significant, but the curves began to separate after 5 years, with more lung cancer (particularly NSCLC) occurring after that time in women who were given combined HT than in those who had been on placebo.

Among the women who were diagnosed with lung cancer, 78 deaths occurred during follow-up in the combined HT arm vs. 49 in the placebo group, a difference that was statistically significant, with an incidence per year of 0.12% and 0.08%, respectively (hazard ratio, 1.50), the investigators reported.

NSCLC was the cause in 62 of these deaths in the HT arm and in 31 in the placebo group, with an incidence per year of 0.09% vs. 0.05%, respectively (HR, 1.87).

The investigators also reported that an exploratory analysis showed shorter median survival after lung cancer diagnosis in the combined HT population (9.4 months vs. 16.1 months in their control group counterparts), and significantly higher mortality (70% vs. 54%) at 4 years after diagnosis (HR, 1.59).

The Women's Health Initiative was supported by the National Heart, Blood, and Lung Institute of the National Institutes of Health.

Dr. Chlebowski disclosed advisory and consulting relationships with various drug companies. Dr. Ganti declared no conflicts of interest. Dr. Chlebowski presented results from this study at the annual meeting of the American Society of Clinical Oncology earlier this year.

To see a video interview, go to www.youtube.com/user/ClinicalEndoNews

Lung cancer incidence was not higher in HT-treated women, but they were significantly more likely to die of it.

Source DR. CHLEBOWSKI

Hormone therapy in postmenopausal women increases the risk of death from lung cancer, according to a newly published post hoc analysis of the large and influential placebo-controlled Women's Health Initiative trial.

Lung cancer incidence was not higher in women who were treated with estrogen plus progesterone, but they were significantly more likely to die of the disease, the investigators reported. The mortality effect was most pronounced in smokers and former smokers. No difference was seen in mortality from small cell lung cancer.

“Our findings should be considered before the initiation or continuation of combined hormone therapy in postmenopausal women, especially those with a high risk of lung cancer, such as current smokers or long-term past smokers,” concluded the investigators, led by Dr. Rowan T. Chlebowski of Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, Calif. (Lancet 2009 Sept. 19 [doi:10.1016/S0140-6736(09)61526-9

In an accompanying comment, Dr. Apar Kishor Ganti of the University of Nebraska Medical Center in Omaha said that hormone therapy (HT) should probably be avoided in women at high risk for lung cancer—and maybe should not be used at all (Lancet 2009 Sept. 19 [doi:10.1016/S0140-6736(09)61571-3

“These results, along with the findings showing no protection against coronary heart disease, seriously question whether [hormone therapy] has any role in medicine today. It is difficult to presume that the benefits of routine use of such therapy for menopausal symptoms outweigh the increased risks of mortality, especially in the absence of improvement in the quality of life,” wrote Dr. Ganti.

The Women's Health Initiative trial randomized 16,608 mostly healthy postmenopausal women (8,506 to combined hormone therapy and 8,102 to placebo) at 40 centers in the United States from 1993 to 1998.

The trial was halted after an average follow-up of 5.6 years when investigators determined that higher risks of cardiovascular disease, coronary heart disease, stroke, venous thromboembolism, and breast cancer outweighed the benefits from lower risks for fractures and colorectal cancers among women in the combined HT arm.

Lung cancer was not a predefined study outcome, but the investigators became suspicious when deaths from other cancers were not sufficient to explain excess mortality in women treated with HT.

The subsequent intent-to-treat analysis, performed at an average follow-up of 7.9 years, found that more lung cancer occurred in the combined HT arm (109 cases) than in women treated with placebo (85 cases), with non–small cell lung cancer (NSCLC) occurring in 96 and 72 women, respectively, in the two groups.

These differences were not statistically significant, but the curves began to separate after 5 years, with more lung cancer (particularly NSCLC) occurring after that time in women who were given combined HT than in those who had been on placebo.

Among the women who were diagnosed with lung cancer, 78 deaths occurred during follow-up in the combined HT arm vs. 49 in the placebo group, a difference that was statistically significant, with an incidence per year of 0.12% and 0.08%, respectively (hazard ratio, 1.50), the investigators reported.

NSCLC was the cause in 62 of these deaths in the HT arm and in 31 in the placebo group, with an incidence per year of 0.09% vs. 0.05%, respectively (HR, 1.87).

The investigators also reported that an exploratory analysis showed shorter median survival after lung cancer diagnosis in the combined HT population (9.4 months vs. 16.1 months in their control group counterparts), and significantly higher mortality (70% vs. 54%) at 4 years after diagnosis (HR, 1.59).

The Women's Health Initiative was supported by the National Heart, Blood, and Lung Institute of the National Institutes of Health.

Dr. Chlebowski disclosed advisory and consulting relationships with various drug companies. Dr. Ganti declared no conflicts of interest. Dr. Chlebowski presented results from this study at the annual meeting of the American Society of Clinical Oncology earlier this year.

To see a video interview, go to www.youtube.com/user/ClinicalEndoNews

Lung cancer incidence was not higher in HT-treated women, but they were significantly more likely to die of it.

Source DR. CHLEBOWSKI

SANTA FE, N.M. — Twenty years of brain imaging studies in children are leading National Institute of Mental Health investigators to explore whether they can distinguish youngsters who will outgrow attention-deficit/hyperactivity disorder from those for whom it will be a persistent problem.

This new work is built on evidence that normal brain development occurs with a 3-year delay in children with ADHD. In pilot data, the researchers have found a hint that the brains of youngsters who have “good” clinical outcomes compensate for this delay, whereas those of youngsters with “poor” outcomes take a different developmental trajectory.

“Approximately half of them grow up, and follow what their grandmothers said all along: 'He will grow out of it,'” Dr. Judith L. Rapoport, chief of the Child Psychiatry Branch at the NIMH, told attendees at an annual psychiatric symposium sponsored by the University of Arizona.

Her group has accumulated more than 6,000 anatomic MRIs of children whose brains were scanned every 2 years starting at age 4 in a longitudinal study, she said. The subjects were not selected for any particular psychiatric condition, but 300 were subsequently diagnosed with ADHD. In addition, the investigators received 3,000 referrals of children with suspected childhood-onset schizophrenia, among whom it found and scanned 107 children with the rare disorder.

By mapping the normal course of cortical development, the study revealed a process of cortical thinning from ages 5 to 20 that can be seen in Dr. Rapoport's words as “a back-to-front wave of cortical maturation” (PNAS 2004;101:8174-9; Nat. Neurosci. 1999;2:861-3). Comparison of high-intelligence children with those of high and average intelligence subsequently showed the children with high IQs had a developmental trajectory in which key measures were reached 2-3 years later than in the other children.

“We were simply astonished to find out the real difference was between the superior intelligence group and the rest, and it was in the frontal lobes,” Dr. Rapoport recalled, adding that this is “one example that later at least in some brain regions is not associated with deficit and may be associated with the opposite.”

Subsequent work showed later cortical development in the brains of children with ADHD (PNAS 2007;104:19649-54), and that the trajectory of baseline thinning also differed in ADHD between children with better outcomes and those with poor outcomes. Among the findings were that brain asymmetry is not as pronounced in ADHD as in normal children and that the right parietal cortex—a little region that “looks like a freckle”—develops differently in ADHD.

One study showed that cortical thickness “normalizes” in the right parietal cortex of 48 children with ADHD who have “good” outcomes. The difference at a key point in the developmental trajectory was statistically significant when these children were compared with 51 children with poor outcomes and to 161 healthy children without ADHD. The finding “suggests compensatory plastic response for good-outcome subjects,” Dr. Rapoport said of the ongoing study.

Further work suggests that some children with ADHD reach a developmental milestone by their adolescent years, but others do not. She cautioned that her group has not published what it considers “just pilot data” in this regard, but has started to follow 80 hyperactive 5-year-olds in the hope of developing a predictive test based on brain development trajectories that will distinguish the children who are going to outgrow ADHD from “those who are going to continue to have problems.”

The study should produce results in about 5 years, Dr. Rapoport said, forecasting that such a test might help clinicians “single out people for whom resources are really needed, and let us relax more for people for whom, no matter what you do, it is going to turn out fine.”

Treating ADHD with stimulants remains controversial, and there is not good evidence supporting benefit from long-term use, she noted. Her group has found no difference in brain development trajectories when children on stimulants are compared with children not treated with stimulants, she said. That said, she suggested, “Kids' memories of grade school are happier [when given stimulants], because they weren't at odds with everyone all the time.”

For now, Dr. Rapoport strongly discourages parents from spending money on brain imaging tests to diagnose ADHD. While useful for research, the tests currently available are unlikely to have sufficient sensitivity or specificity “that you would want anyone to pay for,” she said.

Predicting Schizophrenia in the Womb

Prenatal screening based on variations in the numbers of certain key genes might be able to identify the carriers of childhood-onset schizo-phrenia and other psychiatric disorders, according to Dr. Rapoport.

About 9% of children with childhood-onset schizophrenia have been found to have genetic abnormalities, Dr. Rapoport explained. When children with multiple copies or deletions of key genes are counted, the proportion with possible genetic markers rises to 36%.

Moreover, many of the genes also are implicated in autism. Both conditions are associated with ahead-of-normal brain development, she said, and the timing of certain milestones might determine which of these or other disorders develops. Of note, three children referred to the team as possibly having childhood-onset schizophrenia subsequently developed bipolar disorder instead.

“I think the world is going to be stood on its head diagnostically when these things get sorted out,” Dr. Rapoport said, estimating that as many as 50% of children with early neurodevelopmental abnormalities could have copy number variants.

SANTA FE, N.M. — Twenty years of brain imaging studies in children are leading National Institute of Mental Health investigators to explore whether they can distinguish youngsters who will outgrow attention-deficit/hyperactivity disorder from those for whom it will be a persistent problem.

This new work is built on evidence that normal brain development occurs with a 3-year delay in children with ADHD. In pilot data, the researchers have found a hint that the brains of youngsters who have “good” clinical outcomes compensate for this delay, whereas those of youngsters with “poor” outcomes take a different developmental trajectory.

“Approximately half of them grow up, and follow what their grandmothers said all along: 'He will grow out of it,'” Dr. Judith L. Rapoport, chief of the Child Psychiatry Branch at the NIMH, told attendees at an annual psychiatric symposium sponsored by the University of Arizona.

Her group has accumulated more than 6,000 anatomic MRIs of children whose brains were scanned every 2 years starting at age 4 in a longitudinal study, she said. The subjects were not selected for any particular psychiatric condition, but 300 were subsequently diagnosed with ADHD. In addition, the investigators received 3,000 referrals of children with suspected childhood-onset schizophrenia, among whom it found and scanned 107 children with the rare disorder.

By mapping the normal course of cortical development, the study revealed a process of cortical thinning from ages 5 to 20 that can be seen in Dr. Rapoport's words as “a back-to-front wave of cortical maturation” (PNAS 2004;101:8174-9; Nat. Neurosci. 1999;2:861-3). Comparison of high-intelligence children with those of high and average intelligence subsequently showed the children with high IQs had a developmental trajectory in which key measures were reached 2-3 years later than in the other children.

“We were simply astonished to find out the real difference was between the superior intelligence group and the rest, and it was in the frontal lobes,” Dr. Rapoport recalled, adding that this is “one example that later at least in some brain regions is not associated with deficit and may be associated with the opposite.”

Subsequent work showed later cortical development in the brains of children with ADHD (PNAS 2007;104:19649-54), and that the trajectory of baseline thinning also differed in ADHD between children with better outcomes and those with poor outcomes. Among the findings were that brain asymmetry is not as pronounced in ADHD as in normal children and that the right parietal cortex—a little region that “looks like a freckle”—develops differently in ADHD.

One study showed that cortical thickness “normalizes” in the right parietal cortex of 48 children with ADHD who have “good” outcomes. The difference at a key point in the developmental trajectory was statistically significant when these children were compared with 51 children with poor outcomes and to 161 healthy children without ADHD. The finding “suggests compensatory plastic response for good-outcome subjects,” Dr. Rapoport said of the ongoing study.

Further work suggests that some children with ADHD reach a developmental milestone by their adolescent years, but others do not. She cautioned that her group has not published what it considers “just pilot data” in this regard, but has started to follow 80 hyperactive 5-year-olds in the hope of developing a predictive test based on brain development trajectories that will distinguish the children who are going to outgrow ADHD from “those who are going to continue to have problems.”

The study should produce results in about 5 years, Dr. Rapoport said, forecasting that such a test might help clinicians “single out people for whom resources are really needed, and let us relax more for people for whom, no matter what you do, it is going to turn out fine.”

Treating ADHD with stimulants remains controversial, and there is not good evidence supporting benefit from long-term use, she noted. Her group has found no difference in brain development trajectories when children on stimulants are compared with children not treated with stimulants, she said. That said, she suggested, “Kids' memories of grade school are happier [when given stimulants], because they weren't at odds with everyone all the time.”

For now, Dr. Rapoport strongly discourages parents from spending money on brain imaging tests to diagnose ADHD. While useful for research, the tests currently available are unlikely to have sufficient sensitivity or specificity “that you would want anyone to pay for,” she said.

Predicting Schizophrenia in the Womb

Prenatal screening based on variations in the numbers of certain key genes might be able to identify the carriers of childhood-onset schizo-phrenia and other psychiatric disorders, according to Dr. Rapoport.

About 9% of children with childhood-onset schizophrenia have been found to have genetic abnormalities, Dr. Rapoport explained. When children with multiple copies or deletions of key genes are counted, the proportion with possible genetic markers rises to 36%.

Moreover, many of the genes also are implicated in autism. Both conditions are associated with ahead-of-normal brain development, she said, and the timing of certain milestones might determine which of these or other disorders develops. Of note, three children referred to the team as possibly having childhood-onset schizophrenia subsequently developed bipolar disorder instead.

“I think the world is going to be stood on its head diagnostically when these things get sorted out,” Dr. Rapoport said, estimating that as many as 50% of children with early neurodevelopmental abnormalities could have copy number variants.

SANTA FE, N.M. — Twenty years of brain imaging studies in children are leading National Institute of Mental Health investigators to explore whether they can distinguish youngsters who will outgrow attention-deficit/hyperactivity disorder from those for whom it will be a persistent problem.

This new work is built on evidence that normal brain development occurs with a 3-year delay in children with ADHD. In pilot data, the researchers have found a hint that the brains of youngsters who have “good” clinical outcomes compensate for this delay, whereas those of youngsters with “poor” outcomes take a different developmental trajectory.

“Approximately half of them grow up, and follow what their grandmothers said all along: 'He will grow out of it,'” Dr. Judith L. Rapoport, chief of the Child Psychiatry Branch at the NIMH, told attendees at an annual psychiatric symposium sponsored by the University of Arizona.

Her group has accumulated more than 6,000 anatomic MRIs of children whose brains were scanned every 2 years starting at age 4 in a longitudinal study, she said. The subjects were not selected for any particular psychiatric condition, but 300 were subsequently diagnosed with ADHD. In addition, the investigators received 3,000 referrals of children with suspected childhood-onset schizophrenia, among whom it found and scanned 107 children with the rare disorder.

By mapping the normal course of cortical development, the study revealed a process of cortical thinning from ages 5 to 20 that can be seen in Dr. Rapoport's words as “a back-to-front wave of cortical maturation” (PNAS 2004;101:8174-9; Nat. Neurosci. 1999;2:861-3). Comparison of high-intelligence children with those of high and average intelligence subsequently showed the children with high IQs had a developmental trajectory in which key measures were reached 2-3 years later than in the other children.

“We were simply astonished to find out the real difference was between the superior intelligence group and the rest, and it was in the frontal lobes,” Dr. Rapoport recalled, adding that this is “one example that later at least in some brain regions is not associated with deficit and may be associated with the opposite.”

Subsequent work showed later cortical development in the brains of children with ADHD (PNAS 2007;104:19649-54), and that the trajectory of baseline thinning also differed in ADHD between children with better outcomes and those with poor outcomes. Among the findings were that brain asymmetry is not as pronounced in ADHD as in normal children and that the right parietal cortex—a little region that “looks like a freckle”—develops differently in ADHD.

One study showed that cortical thickness “normalizes” in the right parietal cortex of 48 children with ADHD who have “good” outcomes. The difference at a key point in the developmental trajectory was statistically significant when these children were compared with 51 children with poor outcomes and to 161 healthy children without ADHD. The finding “suggests compensatory plastic response for good-outcome subjects,” Dr. Rapoport said of the ongoing study.

Further work suggests that some children with ADHD reach a developmental milestone by their adolescent years, but others do not. She cautioned that her group has not published what it considers “just pilot data” in this regard, but has started to follow 80 hyperactive 5-year-olds in the hope of developing a predictive test based on brain development trajectories that will distinguish the children who are going to outgrow ADHD from “those who are going to continue to have problems.”

The study should produce results in about 5 years, Dr. Rapoport said, forecasting that such a test might help clinicians “single out people for whom resources are really needed, and let us relax more for people for whom, no matter what you do, it is going to turn out fine.”

Treating ADHD with stimulants remains controversial, and there is not good evidence supporting benefit from long-term use, she noted. Her group has found no difference in brain development trajectories when children on stimulants are compared with children not treated with stimulants, she said. That said, she suggested, “Kids' memories of grade school are happier [when given stimulants], because they weren't at odds with everyone all the time.”

For now, Dr. Rapoport strongly discourages parents from spending money on brain imaging tests to diagnose ADHD. While useful for research, the tests currently available are unlikely to have sufficient sensitivity or specificity “that you would want anyone to pay for,” she said.

Predicting Schizophrenia in the Womb

Prenatal screening based on variations in the numbers of certain key genes might be able to identify the carriers of childhood-onset schizo-phrenia and other psychiatric disorders, according to Dr. Rapoport.

About 9% of children with childhood-onset schizophrenia have been found to have genetic abnormalities, Dr. Rapoport explained. When children with multiple copies or deletions of key genes are counted, the proportion with possible genetic markers rises to 36%.

Moreover, many of the genes also are implicated in autism. Both conditions are associated with ahead-of-normal brain development, she said, and the timing of certain milestones might determine which of these or other disorders develops. Of note, three children referred to the team as possibly having childhood-onset schizophrenia subsequently developed bipolar disorder instead.

“I think the world is going to be stood on its head diagnostically when these things get sorted out,” Dr. Rapoport said, estimating that as many as 50% of children with early neurodevelopmental abnormalities could have copy number variants.