Mary Ann Moon

To give clinicians “the most up-to-date evidence-based recommendations for the prevention of ischemic stroke among survivors of ischemic stroke or transient ischemic attack,” the American Heart Association and American Stroke Association published updated guidelines online Oct. 21 in the journal Stroke.

The new guidelines, intended to help clinicians select preventive therapies for individual patients, have been endorsed by the American Academy of Neurology as an educational tool for neurologists. The American Association of Neurological Surgeons and the Congress of Neurological Surgeons have affirmed their educational content as well.

“Since the last update [in 2006], we’ve had results from several studies testing different interventions. We need to reevaluate the science every few years to optimize prevention,” Dr. Karen L. Furie, chair of the 18-member writing committee and director of the stroke service at Massachusetts General Hospital, Boston, said in a statement accompanying the updated guidelines.

Approximately one-fourth of the nearly 800,000 strokes that occur each year in the United States are recurrences in patients who have already had a stroke or TIA, Dr. Furie and her colleagues noted (Stroke 2010 Oct. 21 [doi:10.1161/STR.0b013e3181f7d043]).

New recommendations in the guidelines cover control of risk factors, interventions for atherosclerotic disease, antithrombotic therapies for cardioembolism, and use of antiplatelet drugs for noncardioembolic stroke.

Controlling Risk Factors

While the clinical usefulness of screening patients for the metabolic syndrome remains controversial, the guidelines advise that if patients are already diagnosed as having the disorder, they should be counseled to improve their diet, exercise, and lose weight to reduce their stroke risk. The individual components of the metabolic syndrome that raise the risk of stroke – particularly dyslipidemia and hypertension – should be treated. Survivors of TIA or stroke who have diabetes should follow existing treatment guidelines for glycemic control and blood pressure management.

Interventions for Atherosclerotic Disease

The writing committee recommended that patients with stenosis of the carotid artery or vertebral artery should receive optimal medical therapy, including antiplatelet drugs, statins, and risk factor modification. In patients whose TIA or stroke was due to 50%-99% stenosis of a major intracranial artery, they advised prescribing aspirin therapy (50-325 mg daily) over warfarin. Long-term maintenance of blood pressure at less than 140/90 mm Hg and total cholesterol at less than 200 mg/dL “may be reasonable,” they wrote. The usefulness of angioplasty, with or without stent placement, for an intracranial artery stenosis is not yet known in this population and is considered investigational. Extracranial-intracranial bypass surgery is not recommended.

For patients with atherosclerotic ischemic stroke or TIA who do not have coronary heart disease, the committee stated that “it is reasonable to target a reduction of at least 50% in LDL-C or a target LDL-C level of less than 70 mg/dL.”

Antithrombotics for Cardio- and Noncardioembolic Stroke

The guidelines recommend that patients who need anticoagulation therapy but cannot take oral anticoagulants should be given aspirin alone. They warn that the combination of aspirin plus clopidogrel “carries a risk of bleeding similar to that of warfarin and therefore is not recommended for patients with a hemorrhagic contraindication to warfarin.”

Any temporary interruption to anticoagulation therapy in patients who have atrial fibrillation and are otherwise at high risk for stroke calls for the use of bridging therapy with subcutaneous administration of low-molecular-weight heparin, according to the guidelines.

Dr. Furie and the committee members recommended caution in using warfarin in patients who have cardiomyopathy characterized by systolic dysfunction (a left ventricular ejection fraction of 35% or less) because of a lack of proven benefit.

Evidence is also insufficient to establish whether anticoagulation therapy is better than aspirin therapy for secondary stroke prevention in patients who have a patent foramen ovale.

The guidelines also address secondary stroke prevention under a variety of special circumstances, such as cases of arterial dissection, hyperhomocysteinemia, hypercoagulable states, and sickle cell disease. They also detail management specific to women, particularly concerning pregnancy and the use of postmenopausal hormone replacement.

Dr. Furie reported receiving research grants from the National Institute of Neurological Disorders and Stroke as well as the ASA-Bugher Foundation Center for Stroke Prevention Research. Some of her 17 coauthors disclosed receiving research support from, being a speaker for, or consulting to or sitting on an advisory board for, companies that manufacture drugs commonly prescribed for stroke prevention.

The guidelines can be obtained at the American Heart Association and American Stroke Association website.

To give clinicians “the most up-to-date evidence-based recommendations for the prevention of ischemic stroke among survivors of ischemic stroke or transient ischemic attack,” the American Heart Association and American Stroke Association published updated guidelines online Oct. 21 in the journal Stroke.

The new guidelines, intended to help clinicians select preventive therapies for individual patients, have been endorsed by the American Academy of Neurology as an educational tool for neurologists. The American Association of Neurological Surgeons and the Congress of Neurological Surgeons have affirmed their educational content as well.

“Since the last update [in 2006], we’ve had results from several studies testing different interventions. We need to reevaluate the science every few years to optimize prevention,” Dr. Karen L. Furie, chair of the 18-member writing committee and director of the stroke service at Massachusetts General Hospital, Boston, said in a statement accompanying the updated guidelines.

Approximately one-fourth of the nearly 800,000 strokes that occur each year in the United States are recurrences in patients who have already had a stroke or TIA, Dr. Furie and her colleagues noted (Stroke 2010 Oct. 21 [doi:10.1161/STR.0b013e3181f7d043]).

New recommendations in the guidelines cover control of risk factors, interventions for atherosclerotic disease, antithrombotic therapies for cardioembolism, and use of antiplatelet drugs for noncardioembolic stroke.

Controlling Risk Factors

While the clinical usefulness of screening patients for the metabolic syndrome remains controversial, the guidelines advise that if patients are already diagnosed as having the disorder, they should be counseled to improve their diet, exercise, and lose weight to reduce their stroke risk. The individual components of the metabolic syndrome that raise the risk of stroke – particularly dyslipidemia and hypertension – should be treated. Survivors of TIA or stroke who have diabetes should follow existing treatment guidelines for glycemic control and blood pressure management.

Interventions for Atherosclerotic Disease

The writing committee recommended that patients with stenosis of the carotid artery or vertebral artery should receive optimal medical therapy, including antiplatelet drugs, statins, and risk factor modification. In patients whose TIA or stroke was due to 50%-99% stenosis of a major intracranial artery, they advised prescribing aspirin therapy (50-325 mg daily) over warfarin. Long-term maintenance of blood pressure at less than 140/90 mm Hg and total cholesterol at less than 200 mg/dL “may be reasonable,” they wrote. The usefulness of angioplasty, with or without stent placement, for an intracranial artery stenosis is not yet known in this population and is considered investigational. Extracranial-intracranial bypass surgery is not recommended.

For patients with atherosclerotic ischemic stroke or TIA who do not have coronary heart disease, the committee stated that “it is reasonable to target a reduction of at least 50% in LDL-C or a target LDL-C level of less than 70 mg/dL.”

Antithrombotics for Cardio- and Noncardioembolic Stroke

The guidelines recommend that patients who need anticoagulation therapy but cannot take oral anticoagulants should be given aspirin alone. They warn that the combination of aspirin plus clopidogrel “carries a risk of bleeding similar to that of warfarin and therefore is not recommended for patients with a hemorrhagic contraindication to warfarin.”

Any temporary interruption to anticoagulation therapy in patients who have atrial fibrillation and are otherwise at high risk for stroke calls for the use of bridging therapy with subcutaneous administration of low-molecular-weight heparin, according to the guidelines.

Dr. Furie and the committee members recommended caution in using warfarin in patients who have cardiomyopathy characterized by systolic dysfunction (a left ventricular ejection fraction of 35% or less) because of a lack of proven benefit.

Evidence is also insufficient to establish whether anticoagulation therapy is better than aspirin therapy for secondary stroke prevention in patients who have a patent foramen ovale.

The guidelines also address secondary stroke prevention under a variety of special circumstances, such as cases of arterial dissection, hyperhomocysteinemia, hypercoagulable states, and sickle cell disease. They also detail management specific to women, particularly concerning pregnancy and the use of postmenopausal hormone replacement.

Dr. Furie reported receiving research grants from the National Institute of Neurological Disorders and Stroke as well as the ASA-Bugher Foundation Center for Stroke Prevention Research. Some of her 17 coauthors disclosed receiving research support from, being a speaker for, or consulting to or sitting on an advisory board for, companies that manufacture drugs commonly prescribed for stroke prevention.

The guidelines can be obtained at the American Heart Association and American Stroke Association website.

To give clinicians “the most up-to-date evidence-based recommendations for the prevention of ischemic stroke among survivors of ischemic stroke or transient ischemic attack,” the American Heart Association and American Stroke Association published updated guidelines online Oct. 21 in the journal Stroke.

The new guidelines, intended to help clinicians select preventive therapies for individual patients, have been endorsed by the American Academy of Neurology as an educational tool for neurologists. The American Association of Neurological Surgeons and the Congress of Neurological Surgeons have affirmed their educational content as well.

“Since the last update [in 2006], we’ve had results from several studies testing different interventions. We need to reevaluate the science every few years to optimize prevention,” Dr. Karen L. Furie, chair of the 18-member writing committee and director of the stroke service at Massachusetts General Hospital, Boston, said in a statement accompanying the updated guidelines.

Approximately one-fourth of the nearly 800,000 strokes that occur each year in the United States are recurrences in patients who have already had a stroke or TIA, Dr. Furie and her colleagues noted (Stroke 2010 Oct. 21 [doi:10.1161/STR.0b013e3181f7d043]).

New recommendations in the guidelines cover control of risk factors, interventions for atherosclerotic disease, antithrombotic therapies for cardioembolism, and use of antiplatelet drugs for noncardioembolic stroke.

Controlling Risk Factors

While the clinical usefulness of screening patients for the metabolic syndrome remains controversial, the guidelines advise that if patients are already diagnosed as having the disorder, they should be counseled to improve their diet, exercise, and lose weight to reduce their stroke risk. The individual components of the metabolic syndrome that raise the risk of stroke – particularly dyslipidemia and hypertension – should be treated. Survivors of TIA or stroke who have diabetes should follow existing treatment guidelines for glycemic control and blood pressure management.

Interventions for Atherosclerotic Disease

The writing committee recommended that patients with stenosis of the carotid artery or vertebral artery should receive optimal medical therapy, including antiplatelet drugs, statins, and risk factor modification. In patients whose TIA or stroke was due to 50%-99% stenosis of a major intracranial artery, they advised prescribing aspirin therapy (50-325 mg daily) over warfarin. Long-term maintenance of blood pressure at less than 140/90 mm Hg and total cholesterol at less than 200 mg/dL “may be reasonable,” they wrote. The usefulness of angioplasty, with or without stent placement, for an intracranial artery stenosis is not yet known in this population and is considered investigational. Extracranial-intracranial bypass surgery is not recommended.

For patients with atherosclerotic ischemic stroke or TIA who do not have coronary heart disease, the committee stated that “it is reasonable to target a reduction of at least 50% in LDL-C or a target LDL-C level of less than 70 mg/dL.”

Antithrombotics for Cardio- and Noncardioembolic Stroke

The guidelines recommend that patients who need anticoagulation therapy but cannot take oral anticoagulants should be given aspirin alone. They warn that the combination of aspirin plus clopidogrel “carries a risk of bleeding similar to that of warfarin and therefore is not recommended for patients with a hemorrhagic contraindication to warfarin.”

Any temporary interruption to anticoagulation therapy in patients who have atrial fibrillation and are otherwise at high risk for stroke calls for the use of bridging therapy with subcutaneous administration of low-molecular-weight heparin, according to the guidelines.

Dr. Furie and the committee members recommended caution in using warfarin in patients who have cardiomyopathy characterized by systolic dysfunction (a left ventricular ejection fraction of 35% or less) because of a lack of proven benefit.

Evidence is also insufficient to establish whether anticoagulation therapy is better than aspirin therapy for secondary stroke prevention in patients who have a patent foramen ovale.

The guidelines also address secondary stroke prevention under a variety of special circumstances, such as cases of arterial dissection, hyperhomocysteinemia, hypercoagulable states, and sickle cell disease. They also detail management specific to women, particularly concerning pregnancy and the use of postmenopausal hormone replacement.

Dr. Furie reported receiving research grants from the National Institute of Neurological Disorders and Stroke as well as the ASA-Bugher Foundation Center for Stroke Prevention Research. Some of her 17 coauthors disclosed receiving research support from, being a speaker for, or consulting to or sitting on an advisory board for, companies that manufacture drugs commonly prescribed for stroke prevention.

The guidelines can be obtained at the American Heart Association and American Stroke Association website.

To give clinicians “the most up-to-date evidence-based recommendations for the prevention of ischemic stroke among survivors of ischemic stroke or transient ischemic attack,” the American Heart Association and American Stroke Association published updated guidelines online Oct. 21 in the journal Stroke.

The new guidelines, intended to help clinicians select preventive therapies for individual patients, have been endorsed by the American Academy of Neurology as an educational tool for neurologists. The American Association of Neurological Surgeons and the Congress of Neurological Surgeons have affirmed their educational content as well.

“Since the last update [in 2006], we’ve had results from several studies testing different interventions. We need to reevaluate the science every few years to optimize prevention,” Dr. Karen L. Furie, chair of the 18-member writing committee and director of the stroke service at Massachusetts General Hospital, Boston, said in a statement accompanying the updated guidelines.

Approximately one-fourth of the nearly 800,000 strokes that occur each year in the United States are recurrences in patients who have already had a stroke or TIA, Dr. Furie and her colleagues noted (Stroke 2010 Oct. 21 [doi:10.1161/STR.0b013e3181f7d043]).

New recommendations in the guidelines cover control of risk factors, interventions for atherosclerotic disease, antithrombotic therapies for cardioembolism, and use of antiplatelet drugs for noncardioembolic stroke.

Controlling Risk Factors

While the clinical usefulness of screening patients for the metabolic syndrome remains controversial, the guidelines advise that if patients are already diagnosed as having the disorder, they should be counseled to improve their diet, exercise, and lose weight to reduce their stroke risk. The individual components of the metabolic syndrome that raise the risk of stroke – particularly dyslipidemia and hypertension – should be treated. Survivors of TIA or stroke who have diabetes should follow existing treatment guidelines for glycemic control and blood pressure management.

Interventions for Atherosclerotic Disease

The writing committee recommended that patients with stenosis of the carotid artery or vertebral artery should receive optimal medical therapy, including antiplatelet drugs, statins, and risk factor modification. In patients whose TIA or stroke was due to 50%-99% stenosis of a major intracranial artery, they advised prescribing aspirin therapy (50-325 mg daily) over warfarin. Long-term maintenance of blood pressure at less than 140/90 mm Hg and total cholesterol at less than 200 mg/dL “may be reasonable,” they wrote. The usefulness of angioplasty, with or without stent placement, for an intracranial artery stenosis is not yet known in this population and is considered investigational. Extracranial-intracranial bypass surgery is not recommended.

For patients with atherosclerotic ischemic stroke or TIA who do not have coronary heart disease, the committee stated that “it is reasonable to target a reduction of at least 50% in LDL-C or a target LDL-C level of less than 70 mg/dL.”

Antithrombotics for Cardio- and Noncardioembolic Stroke

The guidelines recommend that patients who need anticoagulation therapy but cannot take oral anticoagulants should be given aspirin alone. They warn that the combination of aspirin plus clopidogrel “carries a risk of bleeding similar to that of warfarin and therefore is not recommended for patients with a hemorrhagic contraindication to warfarin.”

Any temporary interruption to anticoagulation therapy in patients who have atrial fibrillation and are otherwise at high risk for stroke calls for the use of bridging therapy with subcutaneous administration of low-molecular-weight heparin, according to the guidelines.

Dr. Furie and the committee members recommended caution in using warfarin in patients who have cardiomyopathy characterized by systolic dysfunction (a left ventricular ejection fraction of 35% or less) because of a lack of proven benefit.

Evidence is also insufficient to establish whether anticoagulation therapy is better than aspirin therapy for secondary stroke prevention in patients who have a patent foramen ovale.

The guidelines also address secondary stroke prevention under a variety of special circumstances, such as cases of arterial dissection, hyperhomocysteinemia, hypercoagulable states, and sickle cell disease. They also detail management specific to women, particularly concerning pregnancy and the use of postmenopausal hormone replacement.

Dr. Furie reported receiving research grants from the National Institute of Neurological Disorders and Stroke as well as the ASA-Bugher Foundation Center for Stroke Prevention Research. Some of her 17 coauthors disclosed receiving research support from, being a speaker for, or consulting to or sitting on an advisory board for, companies that manufacture drugs commonly prescribed for stroke prevention.

The guidelines can be obtained on the American Heart Association and American Stroke Association website.

To give clinicians “the most up-to-date evidence-based recommendations for the prevention of ischemic stroke among survivors of ischemic stroke or transient ischemic attack,” the American Heart Association and American Stroke Association published updated guidelines online Oct. 21 in the journal Stroke.

The new guidelines, intended to help clinicians select preventive therapies for individual patients, have been endorsed by the American Academy of Neurology as an educational tool for neurologists. The American Association of Neurological Surgeons and the Congress of Neurological Surgeons have affirmed their educational content as well.

“Since the last update [in 2006], we’ve had results from several studies testing different interventions. We need to reevaluate the science every few years to optimize prevention,” Dr. Karen L. Furie, chair of the 18-member writing committee and director of the stroke service at Massachusetts General Hospital, Boston, said in a statement accompanying the updated guidelines.

Approximately one-fourth of the nearly 800,000 strokes that occur each year in the United States are recurrences in patients who have already had a stroke or TIA, Dr. Furie and her colleagues noted (Stroke 2010 Oct. 21 [doi:10.1161/STR.0b013e3181f7d043]).

New recommendations in the guidelines cover control of risk factors, interventions for atherosclerotic disease, antithrombotic therapies for cardioembolism, and use of antiplatelet drugs for noncardioembolic stroke.

Controlling Risk Factors

While the clinical usefulness of screening patients for the metabolic syndrome remains controversial, the guidelines advise that if patients are already diagnosed as having the disorder, they should be counseled to improve their diet, exercise, and lose weight to reduce their stroke risk. The individual components of the metabolic syndrome that raise the risk of stroke – particularly dyslipidemia and hypertension – should be treated. Survivors of TIA or stroke who have diabetes should follow existing treatment guidelines for glycemic control and blood pressure management.

Interventions for Atherosclerotic Disease

The writing committee recommended that patients with stenosis of the carotid artery or vertebral artery should receive optimal medical therapy, including antiplatelet drugs, statins, and risk factor modification. In patients whose TIA or stroke was due to 50%-99% stenosis of a major intracranial artery, they advised prescribing aspirin therapy (50-325 mg daily) over warfarin. Long-term maintenance of blood pressure at less than 140/90 mm Hg and total cholesterol at less than 200 mg/dL “may be reasonable,” they wrote. The usefulness of angioplasty, with or without stent placement, for an intracranial artery stenosis is not yet known in this population and is considered investigational. Extracranial-intracranial bypass surgery is not recommended.

For patients with atherosclerotic ischemic stroke or TIA who do not have coronary heart disease, the committee stated that “it is reasonable to target a reduction of at least 50% in LDL-C or a target LDL-C level of less than 70 mg/dL.”

Antithrombotics for Cardio- and Noncardioembolic Stroke

The guidelines recommend that patients who need anticoagulation therapy but cannot take oral anticoagulants should be given aspirin alone. They warn that the combination of aspirin plus clopidogrel “carries a risk of bleeding similar to that of warfarin and therefore is not recommended for patients with a hemorrhagic contraindication to warfarin.”

Any temporary interruption to anticoagulation therapy in patients who have atrial fibrillation and are otherwise at high risk for stroke calls for the use of bridging therapy with subcutaneous administration of low-molecular-weight heparin, according to the guidelines.

Dr. Furie and the committee members recommended caution in using warfarin in patients who have cardiomyopathy characterized by systolic dysfunction (a left ventricular ejection fraction of 35% or less) because of a lack of proven benefit.

Evidence is also insufficient to establish whether anticoagulation therapy is better than aspirin therapy for secondary stroke prevention in patients who have a patent foramen ovale.

The guidelines also address secondary stroke prevention under a variety of special circumstances, such as cases of arterial dissection, hyperhomocysteinemia, hypercoagulable states, and sickle cell disease. They also detail management specific to women, particularly concerning pregnancy and the use of postmenopausal hormone replacement.

Dr. Furie reported receiving research grants from the National Institute of Neurological Disorders and Stroke as well as the ASA-Bugher Foundation Center for Stroke Prevention Research. Some of her 17 coauthors disclosed receiving research support from, being a speaker for, or consulting to or sitting on an advisory board for, companies that manufacture drugs commonly prescribed for stroke prevention.

The guidelines can be obtained on the American Heart Association and American Stroke Association website.

To give clinicians “the most up-to-date evidence-based recommendations for the prevention of ischemic stroke among survivors of ischemic stroke or transient ischemic attack,” the American Heart Association and American Stroke Association published updated guidelines online Oct. 21 in the journal Stroke.

The new guidelines, intended to help clinicians select preventive therapies for individual patients, have been endorsed by the American Academy of Neurology as an educational tool for neurologists. The American Association of Neurological Surgeons and the Congress of Neurological Surgeons have affirmed their educational content as well.

“Since the last update [in 2006], we’ve had results from several studies testing different interventions. We need to reevaluate the science every few years to optimize prevention,” Dr. Karen L. Furie, chair of the 18-member writing committee and director of the stroke service at Massachusetts General Hospital, Boston, said in a statement accompanying the updated guidelines.

Approximately one-fourth of the nearly 800,000 strokes that occur each year in the United States are recurrences in patients who have already had a stroke or TIA, Dr. Furie and her colleagues noted (Stroke 2010 Oct. 21 [doi:10.1161/STR.0b013e3181f7d043]).

New recommendations in the guidelines cover control of risk factors, interventions for atherosclerotic disease, antithrombotic therapies for cardioembolism, and use of antiplatelet drugs for noncardioembolic stroke.

Controlling Risk Factors

While the clinical usefulness of screening patients for the metabolic syndrome remains controversial, the guidelines advise that if patients are already diagnosed as having the disorder, they should be counseled to improve their diet, exercise, and lose weight to reduce their stroke risk. The individual components of the metabolic syndrome that raise the risk of stroke – particularly dyslipidemia and hypertension – should be treated. Survivors of TIA or stroke who have diabetes should follow existing treatment guidelines for glycemic control and blood pressure management.

Interventions for Atherosclerotic Disease

The writing committee recommended that patients with stenosis of the carotid artery or vertebral artery should receive optimal medical therapy, including antiplatelet drugs, statins, and risk factor modification. In patients whose TIA or stroke was due to 50%-99% stenosis of a major intracranial artery, they advised prescribing aspirin therapy (50-325 mg daily) over warfarin. Long-term maintenance of blood pressure at less than 140/90 mm Hg and total cholesterol at less than 200 mg/dL “may be reasonable,” they wrote. The usefulness of angioplasty, with or without stent placement, for an intracranial artery stenosis is not yet known in this population and is considered investigational. Extracranial-intracranial bypass surgery is not recommended.

For patients with atherosclerotic ischemic stroke or TIA who do not have coronary heart disease, the committee stated that “it is reasonable to target a reduction of at least 50% in LDL-C or a target LDL-C level of less than 70 mg/dL.”

Antithrombotics for Cardio- and Noncardioembolic Stroke

The guidelines recommend that patients who need anticoagulation therapy but cannot take oral anticoagulants should be given aspirin alone. They warn that the combination of aspirin plus clopidogrel “carries a risk of bleeding similar to that of warfarin and therefore is not recommended for patients with a hemorrhagic contraindication to warfarin.”

Any temporary interruption to anticoagulation therapy in patients who have atrial fibrillation and are otherwise at high risk for stroke calls for the use of bridging therapy with subcutaneous administration of low-molecular-weight heparin, according to the guidelines.

Dr. Furie and the committee members recommended caution in using warfarin in patients who have cardiomyopathy characterized by systolic dysfunction (a left ventricular ejection fraction of 35% or less) because of a lack of proven benefit.

Evidence is also insufficient to establish whether anticoagulation therapy is better than aspirin therapy for secondary stroke prevention in patients who have a patent foramen ovale.

The guidelines also address secondary stroke prevention under a variety of special circumstances, such as cases of arterial dissection, hyperhomocysteinemia, hypercoagulable states, and sickle cell disease. They also detail management specific to women, particularly concerning pregnancy and the use of postmenopausal hormone replacement.

Dr. Furie reported receiving research grants from the National Institute of Neurological Disorders and Stroke as well as the ASA-Bugher Foundation Center for Stroke Prevention Research. Some of her 17 coauthors disclosed receiving research support from, being a speaker for, or consulting to or sitting on an advisory board for, companies that manufacture drugs commonly prescribed for stroke prevention.

The guidelines can be obtained on the American Heart Association and American Stroke Association website.

The use of DHA-rich fish oil supplements during pregnancy did not reduce the rate of postpartum depression in mothers or improve neurodevelopment in their children, according to a report in the Oct. 20 issue of JAMA.

“Current recommendations suggest that pregnant women increase their dietary DHA [docosahexaenoic acid] to improve their health outcomes as well as those of their children,” and the industry “successfully markets prenatal supplements with DHA to optimize brain function of mother and infant,” noted Maria Makrides, Ph.D., of Women’s and Children’s Hospital at Flinders Medical Centre in Adelaide, Australia, and her associates.

However, intervention trials with open-label designs, small sample sizes, high attrition rates, or poor statistical power have produced inconclusive results. Dr. Makrides and her colleagues performed the DOMINO (DHA to Optimize Mother Infant Outcome) trial to assess the efficacy and safety of DHA supplements.

In the double-blind trial, 2,320 women with singleton pregnancies who were attending five Australian perinatal centers were randomly assigned to take three fish oil capsules (1,197 women) or placebo capsules containing vegetable oil (1,202 women) daily. The fish oil capsules contained 800 mg/day of DHA and 100 mg/day of eicosapentaenoic acid. The study subjects were enrolled before they reached 21 weeks’ gestation and took the supplements until delivery (JAMA 2010;304:1675-83).

The primary maternal outcome was a high level of depressive symptoms during the first 6 months post partum, as assessed by a score of more than 12 on the self-administered Edinburgh Postnatal Depression Scale. The incidence of that outcome was not significantly different between women who took fish oil capsules (9.7%) and the control subjects (11.2%).

In addition, the percentage of women who received a medical diagnosis of depression during the study did not differ significantly between the two groups, the investigators noted.

The primary childhood outcome was neurodevelopment at age 18 months, as assessed by scores on the Cognitive and Language Composite Scales of the BSID-III (Bayley Scales of Infant and Toddler Development, third edition). Neither the mean cognitive scores nor the mean language scores differed significantly between children of mothers who took fish oil supplements and children of the control mothers. Similarly, scores on measures of motor development, social-emotional behavior, and adaptive behavior were not significantly different.

The women who took fish oil supplements had a lower rate of very preterm birth (1.1%), compared with the control group (2.3%). However, that was offset by their higher rate of postterm births requiring obstetric intervention (17.6% vs 13.7%).

Adverse effects, including rates of hemorrhage and antenatal hospitalization, did not differ between the two study groups. The only adverse event that occurred more often in the DHA group than in the controls was eructation.

Despite the lack of evidence supporting the use of fish oil capsules in pregnancy, current recommendations steer women to do just that, the investigators said. In fact, 64% of the women who were initially screened but ineligible to take part in the trial were excluded because they were already taking prenatal supplements containing DHA, the researchers said.

But the results of the DOMINO trial “do not support routine DHA supplementation for pregnant women to reduce depressive symptoms or to improve cognitive or language outcomes in early childhood,” Dr. Makrides and her associates said.

The Australian National Health and Medical Research Council funded the DOMINO study. Dr. Makrides reported serving on scientific advisory boards for Nestle, Fonterrra, and Nutricia.

The use of DHA-rich fish oil supplements during pregnancy did not reduce the rate of postpartum depression in mothers or improve neurodevelopment in their children, according to a report in the Oct. 20 issue of JAMA.

“Current recommendations suggest that pregnant women increase their dietary DHA [docosahexaenoic acid] to improve their health outcomes as well as those of their children,” and the industry “successfully markets prenatal supplements with DHA to optimize brain function of mother and infant,” noted Maria Makrides, Ph.D., of Women’s and Children’s Hospital at Flinders Medical Centre in Adelaide, Australia, and her associates.

However, intervention trials with open-label designs, small sample sizes, high attrition rates, or poor statistical power have produced inconclusive results. Dr. Makrides and her colleagues performed the DOMINO (DHA to Optimize Mother Infant Outcome) trial to assess the efficacy and safety of DHA supplements.

In the double-blind trial, 2,320 women with singleton pregnancies who were attending five Australian perinatal centers were randomly assigned to take three fish oil capsules (1,197 women) or placebo capsules containing vegetable oil (1,202 women) daily. The fish oil capsules contained 800 mg/day of DHA and 100 mg/day of eicosapentaenoic acid. The study subjects were enrolled before they reached 21 weeks’ gestation and took the supplements until delivery (JAMA 2010;304:1675-83).

The primary maternal outcome was a high level of depressive symptoms during the first 6 months post partum, as assessed by a score of more than 12 on the self-administered Edinburgh Postnatal Depression Scale. The incidence of that outcome was not significantly different between women who took fish oil capsules (9.7%) and the control subjects (11.2%).

In addition, the percentage of women who received a medical diagnosis of depression during the study did not differ significantly between the two groups, the investigators noted.

The primary childhood outcome was neurodevelopment at age 18 months, as assessed by scores on the Cognitive and Language Composite Scales of the BSID-III (Bayley Scales of Infant and Toddler Development, third edition). Neither the mean cognitive scores nor the mean language scores differed significantly between children of mothers who took fish oil supplements and children of the control mothers. Similarly, scores on measures of motor development, social-emotional behavior, and adaptive behavior were not significantly different.

The women who took fish oil supplements had a lower rate of very preterm birth (1.1%), compared with the control group (2.3%). However, that was offset by their higher rate of postterm births requiring obstetric intervention (17.6% vs 13.7%).

Adverse effects, including rates of hemorrhage and antenatal hospitalization, did not differ between the two study groups. The only adverse event that occurred more often in the DHA group than in the controls was eructation.

Despite the lack of evidence supporting the use of fish oil capsules in pregnancy, current recommendations steer women to do just that, the investigators said. In fact, 64% of the women who were initially screened but ineligible to take part in the trial were excluded because they were already taking prenatal supplements containing DHA, the researchers said.

But the results of the DOMINO trial “do not support routine DHA supplementation for pregnant women to reduce depressive symptoms or to improve cognitive or language outcomes in early childhood,” Dr. Makrides and her associates said.

The Australian National Health and Medical Research Council funded the DOMINO study. Dr. Makrides reported serving on scientific advisory boards for Nestle, Fonterrra, and Nutricia.

The use of DHA-rich fish oil supplements during pregnancy did not reduce the rate of postpartum depression in mothers or improve neurodevelopment in their children, according to a report in the Oct. 20 issue of JAMA.

“Current recommendations suggest that pregnant women increase their dietary DHA [docosahexaenoic acid] to improve their health outcomes as well as those of their children,” and the industry “successfully markets prenatal supplements with DHA to optimize brain function of mother and infant,” noted Maria Makrides, Ph.D., of Women’s and Children’s Hospital at Flinders Medical Centre in Adelaide, Australia, and her associates.

However, intervention trials with open-label designs, small sample sizes, high attrition rates, or poor statistical power have produced inconclusive results. Dr. Makrides and her colleagues performed the DOMINO (DHA to Optimize Mother Infant Outcome) trial to assess the efficacy and safety of DHA supplements.

In the double-blind trial, 2,320 women with singleton pregnancies who were attending five Australian perinatal centers were randomly assigned to take three fish oil capsules (1,197 women) or placebo capsules containing vegetable oil (1,202 women) daily. The fish oil capsules contained 800 mg/day of DHA and 100 mg/day of eicosapentaenoic acid. The study subjects were enrolled before they reached 21 weeks’ gestation and took the supplements until delivery (JAMA 2010;304:1675-83).

The primary maternal outcome was a high level of depressive symptoms during the first 6 months post partum, as assessed by a score of more than 12 on the self-administered Edinburgh Postnatal Depression Scale. The incidence of that outcome was not significantly different between women who took fish oil capsules (9.7%) and the control subjects (11.2%).

In addition, the percentage of women who received a medical diagnosis of depression during the study did not differ significantly between the two groups, the investigators noted.

The primary childhood outcome was neurodevelopment at age 18 months, as assessed by scores on the Cognitive and Language Composite Scales of the BSID-III (Bayley Scales of Infant and Toddler Development, third edition). Neither the mean cognitive scores nor the mean language scores differed significantly between children of mothers who took fish oil supplements and children of the control mothers. Similarly, scores on measures of motor development, social-emotional behavior, and adaptive behavior were not significantly different.

The women who took fish oil supplements had a lower rate of very preterm birth (1.1%), compared with the control group (2.3%). However, that was offset by their higher rate of postterm births requiring obstetric intervention (17.6% vs 13.7%).

Adverse effects, including rates of hemorrhage and antenatal hospitalization, did not differ between the two study groups. The only adverse event that occurred more often in the DHA group than in the controls was eructation.

Despite the lack of evidence supporting the use of fish oil capsules in pregnancy, current recommendations steer women to do just that, the investigators said. In fact, 64% of the women who were initially screened but ineligible to take part in the trial were excluded because they were already taking prenatal supplements containing DHA, the researchers said.

But the results of the DOMINO trial “do not support routine DHA supplementation for pregnant women to reduce depressive symptoms or to improve cognitive or language outcomes in early childhood,” Dr. Makrides and her associates said.

The Australian National Health and Medical Research Council funded the DOMINO study. Dr. Makrides reported serving on scientific advisory boards for Nestle, Fonterrra, and Nutricia.

Estrogen-plus-progestin hormone therapy raises the incidence of invasive breast cancer, the percentage of such cancers that have spread to the lymph nodes at excision, cancer-related mortality, and all-cause mortality, according to a report in the Oct. 20 issue of JAMA.

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

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

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

The WHI involved 16,608 postmenopausal women randomly assigned to receive either conjugated equine estrogens plus medroxyprogesterone or placebo beginning in 1993. The study was halted early, in 2002, when an interim analysis found evidence of harm with the treatment. Subjects were advised to discontinue the hormone therapy, and the study was extended to 2005-2009, with all but 17% of the original study subjects consenting to participate in a median follow-up of 11 years.

Among study subjects who took active hormone therapy, there were 385 cases of invasive breast cancer during the extended follow-up, a rate of 0.42% per year. Among those who took placebo, there were significantly fewer cases: 293, a rate of 0.34% per year.

In addition, a significantly larger proportion of breast cancers in the hormone therapy group had positive lymph nodes (81, or 24%), compared with the placebo group (43, or 16%).

And significantly more women who took active treatment died of breast cancer, compared with those who took placebo. The 25 deaths in the active-treatment group represent 2.6 per 10,000 women per year. In contrast, the 12 breast cancer deaths in the placebo group represent 1.3 deaths per 10,000 women per year, Dr. Chlebowski and his colleagues said (JAMA 2010;304:1684-92).

All-cause mortality showed a similar effect: there were 51 deaths (5.3 per 10,000 women per year) with hormone therapy, compared with 31 deaths (3.4 per 10,000 women per year) with placebo.

Unlike observational studies, this study showed no evidence that hormone therapy was associated with estrogen-receptor-positive tumors, which carry a more favorable prognosis. Subgroup analyses also showed no differences in breast cancer risks between the two study groups related to patient age, body mass index, or a shorter duration of hormone treatment.

The discrepancies between the findings of this study and those reported in previous observational studies “likely are related to potential confounding in the observational analyses,” the investigators said.

Reproductive hormones, especially progestin, stimulate angiogenesis. The study results suggest that the potent stimulation by hormone therapy may facilitate growth and metastasis of already established cancers. Unless this risk can be mitigated, “the use of combined hormone therapy – other than short-term therapy in women with climacteric symptoms not ameliorated by other therapies – seems unwarranted,” they added.

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

Estrogen-plus-progestin hormone therapy raises the incidence of invasive breast cancer, the percentage of such cancers that have spread to the lymph nodes at excision, cancer-related mortality, and all-cause mortality, according to a report in the Oct. 20 issue of JAMA.

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

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

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

The WHI involved 16,608 postmenopausal women randomly assigned to receive either conjugated equine estrogens plus medroxyprogesterone or placebo beginning in 1993. The study was halted early, in 2002, when an interim analysis found evidence of harm with the treatment. Subjects were advised to discontinue the hormone therapy, and the study was extended to 2005-2009, with all but 17% of the original study subjects consenting to participate in a median follow-up of 11 years.

Among study subjects who took active hormone therapy, there were 385 cases of invasive breast cancer during the extended follow-up, a rate of 0.42% per year. Among those who took placebo, there were significantly fewer cases: 293, a rate of 0.34% per year.

In addition, a significantly larger proportion of breast cancers in the hormone therapy group had positive lymph nodes (81, or 24%), compared with the placebo group (43, or 16%).

And significantly more women who took active treatment died of breast cancer, compared with those who took placebo. The 25 deaths in the active-treatment group represent 2.6 per 10,000 women per year. In contrast, the 12 breast cancer deaths in the placebo group represent 1.3 deaths per 10,000 women per year, Dr. Chlebowski and his colleagues said (JAMA 2010;304:1684-92).

All-cause mortality showed a similar effect: there were 51 deaths (5.3 per 10,000 women per year) with hormone therapy, compared with 31 deaths (3.4 per 10,000 women per year) with placebo.

Unlike observational studies, this study showed no evidence that hormone therapy was associated with estrogen-receptor-positive tumors, which carry a more favorable prognosis. Subgroup analyses also showed no differences in breast cancer risks between the two study groups related to patient age, body mass index, or a shorter duration of hormone treatment.

The discrepancies between the findings of this study and those reported in previous observational studies “likely are related to potential confounding in the observational analyses,” the investigators said.

Reproductive hormones, especially progestin, stimulate angiogenesis. The study results suggest that the potent stimulation by hormone therapy may facilitate growth and metastasis of already established cancers. Unless this risk can be mitigated, “the use of combined hormone therapy – other than short-term therapy in women with climacteric symptoms not ameliorated by other therapies – seems unwarranted,” they added.

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

Estrogen-plus-progestin hormone therapy raises the incidence of invasive breast cancer, the percentage of such cancers that have spread to the lymph nodes at excision, cancer-related mortality, and all-cause mortality, according to a report in the Oct. 20 issue of JAMA.

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

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

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

The WHI involved 16,608 postmenopausal women randomly assigned to receive either conjugated equine estrogens plus medroxyprogesterone or placebo beginning in 1993. The study was halted early, in 2002, when an interim analysis found evidence of harm with the treatment. Subjects were advised to discontinue the hormone therapy, and the study was extended to 2005-2009, with all but 17% of the original study subjects consenting to participate in a median follow-up of 11 years.

Among study subjects who took active hormone therapy, there were 385 cases of invasive breast cancer during the extended follow-up, a rate of 0.42% per year. Among those who took placebo, there were significantly fewer cases: 293, a rate of 0.34% per year.

In addition, a significantly larger proportion of breast cancers in the hormone therapy group had positive lymph nodes (81, or 24%), compared with the placebo group (43, or 16%).

And significantly more women who took active treatment died of breast cancer, compared with those who took placebo. The 25 deaths in the active-treatment group represent 2.6 per 10,000 women per year. In contrast, the 12 breast cancer deaths in the placebo group represent 1.3 deaths per 10,000 women per year, Dr. Chlebowski and his colleagues said (JAMA 2010;304:1684-92).

All-cause mortality showed a similar effect: there were 51 deaths (5.3 per 10,000 women per year) with hormone therapy, compared with 31 deaths (3.4 per 10,000 women per year) with placebo.

Unlike observational studies, this study showed no evidence that hormone therapy was associated with estrogen-receptor-positive tumors, which carry a more favorable prognosis. Subgroup analyses also showed no differences in breast cancer risks between the two study groups related to patient age, body mass index, or a shorter duration of hormone treatment.

The discrepancies between the findings of this study and those reported in previous observational studies “likely are related to potential confounding in the observational analyses,” the investigators said.

Reproductive hormones, especially progestin, stimulate angiogenesis. The study results suggest that the potent stimulation by hormone therapy may facilitate growth and metastasis of already established cancers. Unless this risk can be mitigated, “the use of combined hormone therapy – other than short-term therapy in women with climacteric symptoms not ameliorated by other therapies – seems unwarranted,” they added.

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

Major Finding: Risk of death was cut by 23%, median survival was prolonged by 4 months, and estimated 3-year survival was improved by 9% with sipuleucel-T, compared with placebo, in men who had metastatic castration-resistant prostate cancer.

Data Source: A multicenter double-blind randomized clinical trial involving 512 patients.

Disclosures: Dendreon Corp., the maker of sipuleucel-T, sponsored the study, which was designed, conducted, and analyzed by Dendreon employees in collaboration with clinical investigators. Coauthors also reported ties to AstraZeneca, Centocor Ortho Biotech, Celegen, Millenium, Sanofi-Aventis, Novartis, Natrogen Therapeutics, Merck, Pfizer, Johnson & Johnson, Amgen, Ferring, and Endo Pharmaceutical.

The immunotherapy sipuleucel-T significantly prolonged survival in a study of 512 men with metastatic castration-resistant prostate cancer, confirming the results of two smaller previous trials of this therapeutic “cancer vaccine,” according to a report.

The experimental treatment increased median survival by 4.1 months and raised the estimated probability of 3-year survival from 23% to 32%, compared with placebo, significant improvements in this population of men with advanced disease, said Dr. Philip W. Kantoff of the Dana-Farber Cancer Institute and Harvard Medical School, Boston, and his coauthors.

As with the previous studies, this trial also showed that sipuleucel-T (Provenge, Dendreon Corp.) did not hinder tumor progression'a paradoxical finding that has yet to be explained, they noted.

Data from the study were pivotal to the Food and Drug Administration's decision earlier this year to approve the immunotherapy for the treatment of asymptomatic or minimally symptomatic castration-resistant prostate cancer.

Dr. Kantoff and his colleagues assessed sipuleucel-T in patients with asymptomatic or minimally symptomatic disease who had an expected survival of at least 6 months. Serum PSA levels were 5 ng/mL or more, and serum testosterone levels were less than 50 ng/dL. All had previous androgen-deprivation therapy.

The subjects were enrolled at 75 medical centers in the United States and Canada, and stratified by Gleason score, number of bone metastases, and bisphosphonate use. They were randomized to receive three 1-hour infusions of active drug (341 patients) or placebo (171 patients) every 2 weeks, completing the course of therapy within 1 month. More than 92% of the subjects received all three infusions. Median follow-up was 34 months.

Mortality was about 62% with active therapy and 71% with placebo, a relative reduction in the risk of death of 22%. Median survival was about 26 months with sipuleucel-T, significantly longer than the 22 months with placebo. Estimated probability of survival at 36 months was about 32% with sipuleucel-T, significantly higher than the 23% with placebo.

These benefits were seen across all subgroups of patients, regardless of their status with respect to adverse factors such as high PSA, lactate dehydrogenase, or alkaline phosphatase levels; a greater number of bone metastases; high Gleason score; poor performance status; and the presence of pain.

However, the median time to disease progression, as measured by CT and bone scanning, was not significantly different between the two study groups, at 14.6 weeks for sipuleucel-T and 14.4 weeks for placebo. The reason for this discrepancy is not yet known, but it might be because of “the delayed onset of antitumor responses after active immunotherapy, relative to objective disease progression, which occurred early in this group of patients,” Dr. Kantoff and his associates said (N. Engl. J. Med. 2010;363:411-22).

Sipuleucel-T was generally well tolerated, with only three patients not receiving the entire course of treatment because of infusion-related events. “Adverse events that were more frequently reported for sipuleucel-T than for placebo were generally consistent with the release of cytokines,” such as chills, fever, fatigue, nausea, headache, flu-like illness, and myalgia. Most of these developed within 1 day of an infusion and resolved within 1-2 days. One case of bacteremia associated with the catheter infusion was reported.

There was no increase in the rate of cerebrovascular events, as has been reported previously with sipuleucel-T, the investigators noted.

View on the News

Why no Evidence of Antitumor Effect?

The current study findings raise questions as to why survival improved even though there was no evidence of an antitumor effect.

“It is hard to understand how the natural history of a cancer can be affected without some apparent measurable change in the tumor, either evidence of tumor shrinkage or at least disease stabilization reflected in a delay in tumor progression,” said Dr. Dan L. Longo.

“This lack of tumor effect raises concern that the results could have been influenced by an unmeasured prognostic variable that was accidentally imbalanced in study-group assignment,” he added.

In the future, researchers may need to account for other factors that have recently been discovered to affect prognosis–such as statin use, duration of the first off-treatment interval, and circulating tumor cells, Dr. Longo said.

He also noted that the high cost of sipuleucel-T therapy may curtail its use.

“The manufacturer has set the cost of a 1-month course of sipuleucel-T at $93,000, or $23,000 per month of survival advantage,” he noted.

DAN L. LONGO, M.D., a deputy editor of the New England Journal of Medicine, is an internist and oncologist at the National Institutes of Health's Biomedical Research Center, Baltimore. These comments are taken from his editorial accompanying Dr. Kantoff's article (N. Engl. J. Med. 2010;363:479-81).

Major Finding: Risk of death was cut by 23%, median survival was prolonged by 4 months, and estimated 3-year survival was improved by 9% with sipuleucel-T, compared with placebo, in men who had metastatic castration-resistant prostate cancer.

Data Source: A multicenter double-blind randomized clinical trial involving 512 patients.

Disclosures: Dendreon Corp., the maker of sipuleucel-T, sponsored the study, which was designed, conducted, and analyzed by Dendreon employees in collaboration with clinical investigators. Coauthors also reported ties to AstraZeneca, Centocor Ortho Biotech, Celegen, Millenium, Sanofi-Aventis, Novartis, Natrogen Therapeutics, Merck, Pfizer, Johnson & Johnson, Amgen, Ferring, and Endo Pharmaceutical.

The immunotherapy sipuleucel-T significantly prolonged survival in a study of 512 men with metastatic castration-resistant prostate cancer, confirming the results of two smaller previous trials of this therapeutic “cancer vaccine,” according to a report.

The experimental treatment increased median survival by 4.1 months and raised the estimated probability of 3-year survival from 23% to 32%, compared with placebo, significant improvements in this population of men with advanced disease, said Dr. Philip W. Kantoff of the Dana-Farber Cancer Institute and Harvard Medical School, Boston, and his coauthors.

As with the previous studies, this trial also showed that sipuleucel-T (Provenge, Dendreon Corp.) did not hinder tumor progression'a paradoxical finding that has yet to be explained, they noted.

Data from the study were pivotal to the Food and Drug Administration's decision earlier this year to approve the immunotherapy for the treatment of asymptomatic or minimally symptomatic castration-resistant prostate cancer.

Dr. Kantoff and his colleagues assessed sipuleucel-T in patients with asymptomatic or minimally symptomatic disease who had an expected survival of at least 6 months. Serum PSA levels were 5 ng/mL or more, and serum testosterone levels were less than 50 ng/dL. All had previous androgen-deprivation therapy.

The subjects were enrolled at 75 medical centers in the United States and Canada, and stratified by Gleason score, number of bone metastases, and bisphosphonate use. They were randomized to receive three 1-hour infusions of active drug (341 patients) or placebo (171 patients) every 2 weeks, completing the course of therapy within 1 month. More than 92% of the subjects received all three infusions. Median follow-up was 34 months.

Mortality was about 62% with active therapy and 71% with placebo, a relative reduction in the risk of death of 22%. Median survival was about 26 months with sipuleucel-T, significantly longer than the 22 months with placebo. Estimated probability of survival at 36 months was about 32% with sipuleucel-T, significantly higher than the 23% with placebo.

These benefits were seen across all subgroups of patients, regardless of their status with respect to adverse factors such as high PSA, lactate dehydrogenase, or alkaline phosphatase levels; a greater number of bone metastases; high Gleason score; poor performance status; and the presence of pain.

However, the median time to disease progression, as measured by CT and bone scanning, was not significantly different between the two study groups, at 14.6 weeks for sipuleucel-T and 14.4 weeks for placebo. The reason for this discrepancy is not yet known, but it might be because of “the delayed onset of antitumor responses after active immunotherapy, relative to objective disease progression, which occurred early in this group of patients,” Dr. Kantoff and his associates said (N. Engl. J. Med. 2010;363:411-22).

Sipuleucel-T was generally well tolerated, with only three patients not receiving the entire course of treatment because of infusion-related events. “Adverse events that were more frequently reported for sipuleucel-T than for placebo were generally consistent with the release of cytokines,” such as chills, fever, fatigue, nausea, headache, flu-like illness, and myalgia. Most of these developed within 1 day of an infusion and resolved within 1-2 days. One case of bacteremia associated with the catheter infusion was reported.

There was no increase in the rate of cerebrovascular events, as has been reported previously with sipuleucel-T, the investigators noted.

View on the News

Why no Evidence of Antitumor Effect?

The current study findings raise questions as to why survival improved even though there was no evidence of an antitumor effect.

“It is hard to understand how the natural history of a cancer can be affected without some apparent measurable change in the tumor, either evidence of tumor shrinkage or at least disease stabilization reflected in a delay in tumor progression,” said Dr. Dan L. Longo.

“This lack of tumor effect raises concern that the results could have been influenced by an unmeasured prognostic variable that was accidentally imbalanced in study-group assignment,” he added.

In the future, researchers may need to account for other factors that have recently been discovered to affect prognosis–such as statin use, duration of the first off-treatment interval, and circulating tumor cells, Dr. Longo said.

He also noted that the high cost of sipuleucel-T therapy may curtail its use.

“The manufacturer has set the cost of a 1-month course of sipuleucel-T at $93,000, or $23,000 per month of survival advantage,” he noted.

DAN L. LONGO, M.D., a deputy editor of the New England Journal of Medicine, is an internist and oncologist at the National Institutes of Health's Biomedical Research Center, Baltimore. These comments are taken from his editorial accompanying Dr. Kantoff's article (N. Engl. J. Med. 2010;363:479-81).

Major Finding: Risk of death was cut by 23%, median survival was prolonged by 4 months, and estimated 3-year survival was improved by 9% with sipuleucel-T, compared with placebo, in men who had metastatic castration-resistant prostate cancer.

Data Source: A multicenter double-blind randomized clinical trial involving 512 patients.

Disclosures: Dendreon Corp., the maker of sipuleucel-T, sponsored the study, which was designed, conducted, and analyzed by Dendreon employees in collaboration with clinical investigators. Coauthors also reported ties to AstraZeneca, Centocor Ortho Biotech, Celegen, Millenium, Sanofi-Aventis, Novartis, Natrogen Therapeutics, Merck, Pfizer, Johnson & Johnson, Amgen, Ferring, and Endo Pharmaceutical.

The immunotherapy sipuleucel-T significantly prolonged survival in a study of 512 men with metastatic castration-resistant prostate cancer, confirming the results of two smaller previous trials of this therapeutic “cancer vaccine,” according to a report.

The experimental treatment increased median survival by 4.1 months and raised the estimated probability of 3-year survival from 23% to 32%, compared with placebo, significant improvements in this population of men with advanced disease, said Dr. Philip W. Kantoff of the Dana-Farber Cancer Institute and Harvard Medical School, Boston, and his coauthors.

As with the previous studies, this trial also showed that sipuleucel-T (Provenge, Dendreon Corp.) did not hinder tumor progression'a paradoxical finding that has yet to be explained, they noted.

Data from the study were pivotal to the Food and Drug Administration's decision earlier this year to approve the immunotherapy for the treatment of asymptomatic or minimally symptomatic castration-resistant prostate cancer.

Dr. Kantoff and his colleagues assessed sipuleucel-T in patients with asymptomatic or minimally symptomatic disease who had an expected survival of at least 6 months. Serum PSA levels were 5 ng/mL or more, and serum testosterone levels were less than 50 ng/dL. All had previous androgen-deprivation therapy.

The subjects were enrolled at 75 medical centers in the United States and Canada, and stratified by Gleason score, number of bone metastases, and bisphosphonate use. They were randomized to receive three 1-hour infusions of active drug (341 patients) or placebo (171 patients) every 2 weeks, completing the course of therapy within 1 month. More than 92% of the subjects received all three infusions. Median follow-up was 34 months.

Mortality was about 62% with active therapy and 71% with placebo, a relative reduction in the risk of death of 22%. Median survival was about 26 months with sipuleucel-T, significantly longer than the 22 months with placebo. Estimated probability of survival at 36 months was about 32% with sipuleucel-T, significantly higher than the 23% with placebo.

These benefits were seen across all subgroups of patients, regardless of their status with respect to adverse factors such as high PSA, lactate dehydrogenase, or alkaline phosphatase levels; a greater number of bone metastases; high Gleason score; poor performance status; and the presence of pain.

However, the median time to disease progression, as measured by CT and bone scanning, was not significantly different between the two study groups, at 14.6 weeks for sipuleucel-T and 14.4 weeks for placebo. The reason for this discrepancy is not yet known, but it might be because of “the delayed onset of antitumor responses after active immunotherapy, relative to objective disease progression, which occurred early in this group of patients,” Dr. Kantoff and his associates said (N. Engl. J. Med. 2010;363:411-22).

Sipuleucel-T was generally well tolerated, with only three patients not receiving the entire course of treatment because of infusion-related events. “Adverse events that were more frequently reported for sipuleucel-T than for placebo were generally consistent with the release of cytokines,” such as chills, fever, fatigue, nausea, headache, flu-like illness, and myalgia. Most of these developed within 1 day of an infusion and resolved within 1-2 days. One case of bacteremia associated with the catheter infusion was reported.

There was no increase in the rate of cerebrovascular events, as has been reported previously with sipuleucel-T, the investigators noted.

View on the News

Why no Evidence of Antitumor Effect?

The current study findings raise questions as to why survival improved even though there was no evidence of an antitumor effect.

“It is hard to understand how the natural history of a cancer can be affected without some apparent measurable change in the tumor, either evidence of tumor shrinkage or at least disease stabilization reflected in a delay in tumor progression,” said Dr. Dan L. Longo.

“This lack of tumor effect raises concern that the results could have been influenced by an unmeasured prognostic variable that was accidentally imbalanced in study-group assignment,” he added.

In the future, researchers may need to account for other factors that have recently been discovered to affect prognosis–such as statin use, duration of the first off-treatment interval, and circulating tumor cells, Dr. Longo said.

He also noted that the high cost of sipuleucel-T therapy may curtail its use.

“The manufacturer has set the cost of a 1-month course of sipuleucel-T at $93,000, or $23,000 per month of survival advantage,” he noted.

DAN L. LONGO, M.D., a deputy editor of the New England Journal of Medicine, is an internist and oncologist at the National Institutes of Health's Biomedical Research Center, Baltimore. These comments are taken from his editorial accompanying Dr. Kantoff's article (N. Engl. J. Med. 2010;363:479-81).

An intensive lifestyle intervention produced significant improvements in weight, cardiovascular fitness, blood pressure, hemoglobin A_1c, triglycerides, and HDL-cholesterol, which were largely maintained throughout 4 years of follow-up.

The study, involving 5,145 overweight or obese patients with type 2 diabetes, compared the intensive intervention against usual patient care, which included standard diabetes education.

“Effects of the magnitude that we observed for fitness, HDL-C and HbA_1c levels, and blood pressure have been associated with decreased cardiovascular events and mortality in previous medication trials and observational studies. said Rena R. Wing, Ph.D., of the department of psychiatry at Miriam Hospital/Brown University, Providence, R.I., and her associates in the LookAHEAD (Action for Health in Diabetes) trial. “The critical question is whether the differences between groups in risk factors will translate into differences in the development of CVD [cardiovascular disease]. These results will not be available for several additional years.”

The researchers previously reported on the 1-year benefits of the intensive lifestyle intervention, compared with usual care. They now report that patients who received the intervention maintained the positive changes they made for 3 more years, albeit with some regression to baseline levels of all measures.

The trial enrolled subjects aged 45-76 years at 16 U.S. medical centers. About 60% of the subjects were women, and 37% were from racial or ethnic minorities. The average body mass index was 36 kg/m

In all, 2,570 subjects were randomly assigned to intensive intervention and 2,575 to usual care with diabetes education.

The intervention included dietary modification with a calorie goal of 1,200-1,800 kcal a day, less than 30% of calories from fat, and at least 15% of calories from protein. A portion-controlled diet was provided. The exercise goal was at least 175 minutes of physical activity a week at an intensity level comparable with that of brisk walking. Behavioral strategies included self-monitoring, goal setting, and problem solving.

Subjects in the intervention group met individually and in groups every week for the first 6 months and three times a month for the next 6 months. During years 2 through 4, they were seen individually at least once a month, contacted by phone or e-mail once a month, and attended three group sessions and assorted group classes throughout the year.

These sessions were led by registered dieticians, behavioral counselors, or exercise specialists trained in lifestyle counseling. At each session, subjects were weighed, their self-monitoring records were reviewed, and a new lesson was presented. Complete physical assessments were performed annually, and subjects were given a $100 honorarium to encourage participation.

“Averaged across the 4 years, participants in the [intervention] group experienced greater improvements in weight, fitness, glycemic control, blood pressure, and levels of HDL-C and triglycerides than those in the [usual care] group,” the researchers said, noting that “the mean maximal weight loss (8.6%) in the [intervention] group occurred at 1 year, but participants … maintained a mean weight loss of 4.7% at year 4, compared with 1.1% in the [usual-care] group” (Arch. Intern. Med. 2010;170:1566-75).

At 1-year follow-up, cardiovascular fitness rose by 20% in the intervention group and 5% in the usual-care group. It regressed over time, but at year 4 the fitness level of the intervention group was still 5% over baseline, whereas that of the usual-care group was 1% below baseline.

The intervention group maintained greater improvements than did the usual-care group in systolic blood pressure, HbA_1c levels, and HDL-C levels, but initial improvements in diastolic blood pressure and triglycerides disappeared by year 4. There were no differences between the groups in improvement in LDL-C levels.

“This study shows that lifestyle interventions can produce long-term weight loss and improvement in fitness and sustained beneficial effects on CVD risk factors,” the investigators said.

“Although the differences between the two groups were greatest initially and decreased over time for several measures, the differences between the groups averaged across the 4 years were substantial and indicate that the [intervention] group spent a considerable time at lower CVD risk,” they added.“Longer follow-up will [help] determine whether the differences between groups in CVD risk factors can be maintained and whether the [intensive intervention] has positive effects on cardiovascular morbidity and mortality.”

The LookAHEAD study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; Office of Research on Women's Health; Centers for Disease Control and Prevention; U.S. Department of Veterans Affairs; Indian Health Service; and research centers at Johns Hopkins Medical Institutions, Massachusetts General Hospital, Massachusetts Institute of Technology, Colorado Health Sciences Center, University of Tennessee at Memphis, and the University of Pittsburgh. FedEx Corp., Health Management Resources, LifeScan Inc., OPTIFAST, Hoffmann-La Roche, Abbott Nutrition, and Slim-Fast have committed to make major contributions to the ongoing trial. Dr. Wing's associates reported financial ties to BodyMedia Inc., University of Pittsburgh Medical Center Health Plan, Proctor & Gamble, and Free & Clear.

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Solid Evidence of Sustained Benefit

For patients with type 2 diabetes, these exciting findings provide solid evidence of the sustained benefit of simple interventions on numerous important cardiovascular risk factors. The results are particularly encouraging because, unlike drug therapy for the disorder, lifestyle interventions carry little risk of inducing hypoglycemia, said Dr. Prakash C. Deedwania.

However, it is unlikely that the frequent and regular instruction, visits with registered dietitians and exercise specialists, special diets given free of charge, and monetary incentives used in this intervention can be translated on a broad scale to clinical practice. And the recidivism that occurred over time toward baseline levels raises questions about the long-term sustainability of such an intensive intervention in everyday clinical practice.

Overall, however, the LookAHEAD findings show that “simple, established approaches based on conventional wisdom work well, and there is no need to rush to newer or novel approaches unless convincing evidence supports such a move,” he said.

DR. DEEDWANIA is chief of cardiology at Veterans Affairs Central California Health Care System, Fresno. He reported no relevant financial disclosures. These comments are taken from his editorial accompanying the LookAHEAD report (Arch. Intern. Med. 2010;170:1575-7).

Vitals

An intensive lifestyle intervention produced significant improvements in weight, cardiovascular fitness, blood pressure, hemoglobin A_1c, triglycerides, and HDL-cholesterol, which were largely maintained throughout 4 years of follow-up.

The study, involving 5,145 overweight or obese patients with type 2 diabetes, compared the intensive intervention against usual patient care, which included standard diabetes education.

“Effects of the magnitude that we observed for fitness, HDL-C and HbA_1c levels, and blood pressure have been associated with decreased cardiovascular events and mortality in previous medication trials and observational studies. said Rena R. Wing, Ph.D., of the department of psychiatry at Miriam Hospital/Brown University, Providence, R.I., and her associates in the LookAHEAD (Action for Health in Diabetes) trial. “The critical question is whether the differences between groups in risk factors will translate into differences in the development of CVD [cardiovascular disease]. These results will not be available for several additional years.”

The researchers previously reported on the 1-year benefits of the intensive lifestyle intervention, compared with usual care. They now report that patients who received the intervention maintained the positive changes they made for 3 more years, albeit with some regression to baseline levels of all measures.

The trial enrolled subjects aged 45-76 years at 16 U.S. medical centers. About 60% of the subjects were women, and 37% were from racial or ethnic minorities. The average body mass index was 36 kg/m

In all, 2,570 subjects were randomly assigned to intensive intervention and 2,575 to usual care with diabetes education.

The intervention included dietary modification with a calorie goal of 1,200-1,800 kcal a day, less than 30% of calories from fat, and at least 15% of calories from protein. A portion-controlled diet was provided. The exercise goal was at least 175 minutes of physical activity a week at an intensity level comparable with that of brisk walking. Behavioral strategies included self-monitoring, goal setting, and problem solving.

Subjects in the intervention group met individually and in groups every week for the first 6 months and three times a month for the next 6 months. During years 2 through 4, they were seen individually at least once a month, contacted by phone or e-mail once a month, and attended three group sessions and assorted group classes throughout the year.

These sessions were led by registered dieticians, behavioral counselors, or exercise specialists trained in lifestyle counseling. At each session, subjects were weighed, their self-monitoring records were reviewed, and a new lesson was presented. Complete physical assessments were performed annually, and subjects were given a $100 honorarium to encourage participation.

“Averaged across the 4 years, participants in the [intervention] group experienced greater improvements in weight, fitness, glycemic control, blood pressure, and levels of HDL-C and triglycerides than those in the [usual care] group,” the researchers said, noting that “the mean maximal weight loss (8.6%) in the [intervention] group occurred at 1 year, but participants … maintained a mean weight loss of 4.7% at year 4, compared with 1.1% in the [usual-care] group” (Arch. Intern. Med. 2010;170:1566-75).

At 1-year follow-up, cardiovascular fitness rose by 20% in the intervention group and 5% in the usual-care group. It regressed over time, but at year 4 the fitness level of the intervention group was still 5% over baseline, whereas that of the usual-care group was 1% below baseline.

The intervention group maintained greater improvements than did the usual-care group in systolic blood pressure, HbA_1c levels, and HDL-C levels, but initial improvements in diastolic blood pressure and triglycerides disappeared by year 4. There were no differences between the groups in improvement in LDL-C levels.

“This study shows that lifestyle interventions can produce long-term weight loss and improvement in fitness and sustained beneficial effects on CVD risk factors,” the investigators said.

“Although the differences between the two groups were greatest initially and decreased over time for several measures, the differences between the groups averaged across the 4 years were substantial and indicate that the [intervention] group spent a considerable time at lower CVD risk,” they added.“Longer follow-up will [help] determine whether the differences between groups in CVD risk factors can be maintained and whether the [intensive intervention] has positive effects on cardiovascular morbidity and mortality.”

The LookAHEAD study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; Office of Research on Women's Health; Centers for Disease Control and Prevention; U.S. Department of Veterans Affairs; Indian Health Service; and research centers at Johns Hopkins Medical Institutions, Massachusetts General Hospital, Massachusetts Institute of Technology, Colorado Health Sciences Center, University of Tennessee at Memphis, and the University of Pittsburgh. FedEx Corp., Health Management Resources, LifeScan Inc., OPTIFAST, Hoffmann-La Roche, Abbott Nutrition, and Slim-Fast have committed to make major contributions to the ongoing trial. Dr. Wing's associates reported financial ties to BodyMedia Inc., University of Pittsburgh Medical Center Health Plan, Proctor & Gamble, and Free & Clear.

View on the News

Solid Evidence of Sustained Benefit

For patients with type 2 diabetes, these exciting findings provide solid evidence of the sustained benefit of simple interventions on numerous important cardiovascular risk factors. The results are particularly encouraging because, unlike drug therapy for the disorder, lifestyle interventions carry little risk of inducing hypoglycemia, said Dr. Prakash C. Deedwania.

However, it is unlikely that the frequent and regular instruction, visits with registered dietitians and exercise specialists, special diets given free of charge, and monetary incentives used in this intervention can be translated on a broad scale to clinical practice. And the recidivism that occurred over time toward baseline levels raises questions about the long-term sustainability of such an intensive intervention in everyday clinical practice.

Overall, however, the LookAHEAD findings show that “simple, established approaches based on conventional wisdom work well, and there is no need to rush to newer or novel approaches unless convincing evidence supports such a move,” he said.

DR. DEEDWANIA is chief of cardiology at Veterans Affairs Central California Health Care System, Fresno. He reported no relevant financial disclosures. These comments are taken from his editorial accompanying the LookAHEAD report (Arch. Intern. Med. 2010;170:1575-7).

Vitals

An intensive lifestyle intervention produced significant improvements in weight, cardiovascular fitness, blood pressure, hemoglobin A_1c, triglycerides, and HDL-cholesterol, which were largely maintained throughout 4 years of follow-up.

The study, involving 5,145 overweight or obese patients with type 2 diabetes, compared the intensive intervention against usual patient care, which included standard diabetes education.

“Effects of the magnitude that we observed for fitness, HDL-C and HbA_1c levels, and blood pressure have been associated with decreased cardiovascular events and mortality in previous medication trials and observational studies. said Rena R. Wing, Ph.D., of the department of psychiatry at Miriam Hospital/Brown University, Providence, R.I., and her associates in the LookAHEAD (Action for Health in Diabetes) trial. “The critical question is whether the differences between groups in risk factors will translate into differences in the development of CVD [cardiovascular disease]. These results will not be available for several additional years.”

The researchers previously reported on the 1-year benefits of the intensive lifestyle intervention, compared with usual care. They now report that patients who received the intervention maintained the positive changes they made for 3 more years, albeit with some regression to baseline levels of all measures.

The trial enrolled subjects aged 45-76 years at 16 U.S. medical centers. About 60% of the subjects were women, and 37% were from racial or ethnic minorities. The average body mass index was 36 kg/m

In all, 2,570 subjects were randomly assigned to intensive intervention and 2,575 to usual care with diabetes education.

The intervention included dietary modification with a calorie goal of 1,200-1,800 kcal a day, less than 30% of calories from fat, and at least 15% of calories from protein. A portion-controlled diet was provided. The exercise goal was at least 175 minutes of physical activity a week at an intensity level comparable with that of brisk walking. Behavioral strategies included self-monitoring, goal setting, and problem solving.

Subjects in the intervention group met individually and in groups every week for the first 6 months and three times a month for the next 6 months. During years 2 through 4, they were seen individually at least once a month, contacted by phone or e-mail once a month, and attended three group sessions and assorted group classes throughout the year.

These sessions were led by registered dieticians, behavioral counselors, or exercise specialists trained in lifestyle counseling. At each session, subjects were weighed, their self-monitoring records were reviewed, and a new lesson was presented. Complete physical assessments were performed annually, and subjects were given a $100 honorarium to encourage participation.

“Averaged across the 4 years, participants in the [intervention] group experienced greater improvements in weight, fitness, glycemic control, blood pressure, and levels of HDL-C and triglycerides than those in the [usual care] group,” the researchers said, noting that “the mean maximal weight loss (8.6%) in the [intervention] group occurred at 1 year, but participants … maintained a mean weight loss of 4.7% at year 4, compared with 1.1% in the [usual-care] group” (Arch. Intern. Med. 2010;170:1566-75).

At 1-year follow-up, cardiovascular fitness rose by 20% in the intervention group and 5% in the usual-care group. It regressed over time, but at year 4 the fitness level of the intervention group was still 5% over baseline, whereas that of the usual-care group was 1% below baseline.

The intervention group maintained greater improvements than did the usual-care group in systolic blood pressure, HbA_1c levels, and HDL-C levels, but initial improvements in diastolic blood pressure and triglycerides disappeared by year 4. There were no differences between the groups in improvement in LDL-C levels.

“This study shows that lifestyle interventions can produce long-term weight loss and improvement in fitness and sustained beneficial effects on CVD risk factors,” the investigators said.

“Although the differences between the two groups were greatest initially and decreased over time for several measures, the differences between the groups averaged across the 4 years were substantial and indicate that the [intervention] group spent a considerable time at lower CVD risk,” they added.“Longer follow-up will [help] determine whether the differences between groups in CVD risk factors can be maintained and whether the [intensive intervention] has positive effects on cardiovascular morbidity and mortality.”

The LookAHEAD study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; Office of Research on Women's Health; Centers for Disease Control and Prevention; U.S. Department of Veterans Affairs; Indian Health Service; and research centers at Johns Hopkins Medical Institutions, Massachusetts General Hospital, Massachusetts Institute of Technology, Colorado Health Sciences Center, University of Tennessee at Memphis, and the University of Pittsburgh. FedEx Corp., Health Management Resources, LifeScan Inc., OPTIFAST, Hoffmann-La Roche, Abbott Nutrition, and Slim-Fast have committed to make major contributions to the ongoing trial. Dr. Wing's associates reported financial ties to BodyMedia Inc., University of Pittsburgh Medical Center Health Plan, Proctor & Gamble, and Free & Clear.

View on the News

Solid Evidence of Sustained Benefit

For patients with type 2 diabetes, these exciting findings provide solid evidence of the sustained benefit of simple interventions on numerous important cardiovascular risk factors. The results are particularly encouraging because, unlike drug therapy for the disorder, lifestyle interventions carry little risk of inducing hypoglycemia, said Dr. Prakash C. Deedwania.

However, it is unlikely that the frequent and regular instruction, visits with registered dietitians and exercise specialists, special diets given free of charge, and monetary incentives used in this intervention can be translated on a broad scale to clinical practice. And the recidivism that occurred over time toward baseline levels raises questions about the long-term sustainability of such an intensive intervention in everyday clinical practice.

Overall, however, the LookAHEAD findings show that “simple, established approaches based on conventional wisdom work well, and there is no need to rush to newer or novel approaches unless convincing evidence supports such a move,” he said.

DR. DEEDWANIA is chief of cardiology at Veterans Affairs Central California Health Care System, Fresno. He reported no relevant financial disclosures. These comments are taken from his editorial accompanying the LookAHEAD report (Arch. Intern. Med. 2010;170:1575-7).

Vitals

The use of oral bisphosphonates was not associated with esophageal or gastric cancer in a large cohort study in the United Kingdom, according to a large U.K. database analysis.

Oral bisphosphonates cause serious esophagitis in some users. Reflux esophagitis is a known risk factor for esophageal cancer, but it is not known whether bisphosphonates-associated esophagitis also predisposes patients to develop gastric cancer, said Chris R. Cardwell, Ph.D., of Queen's University Belfast (Ireland) and his associates.

“The U.S. Food and Drug Administration recently reported 23 cases of esophageal cancer (between 1995 and 2008) in patients using the bisphosphonate alendronate and a further 31 cases in patients using bisphosphonates in Europe and Japan, possibly indicating risk of malignancy,” they noted.

Dr. Cardwell and his colleagues searched for a possible link between the drugs and esophageal or gastric cancer using the General Practice Research Database (GPRD), “the world's largest computerized database of anonymized longitudinal patient records,” which includes 500 general practices and covers about 6% of the population in the United Kingdom.

They reviewed the records of 41,826 patients aged 40 years and older who used bisphosphonates and the same number of control patients matched for age, sex, and medical practice. During a mean follow-up of 4.5 years, 287 of these patients developed esophageal or gastric cancer.

There were no significant differences between cases and controls in risk for esophageal cancer, gastric cancer, or both cancers combined. This result did not change when the data were adjusted to account for possible confounders of gastric cancer risk, such as smoking, alcohol use, and use of drugs including NSAIDs, proton pump inhibitors, and H₂ receptor antagonists.

Moreover, the risk of these cancers was no higher in patients who took larger daily doses of bisphosphonates or in those who had a longer duration of bisphosphonate use, the investigators said (JAMA 2010;304:657-63).

In addition, the risk of gastric cancer was not significantly different between men and women exposed to bisphosphonates, and it did not differ across several different bisphosphonate medications.

There also was no association between cancer risk and bisphosphonate use in the subgroup of patients who had a history of gastroesophageal reflux disease.

“In conclusion … we found no evidence for a substantially increased risk of esophageal (or gastric) cancer in persons using oral bisphosphonates.

“These drugs should not be withheld, on the basis of possible esophageal cancer risk, from patients with a genuine clinical indication for their use,” they said.

Access to the GPRD database was funded by the Medical Research Council. No financial conflicts of interest were reported.

The use of oral bisphosphonates was not associated with esophageal or gastric cancer in a large cohort study in the United Kingdom, according to a large U.K. database analysis.

Oral bisphosphonates cause serious esophagitis in some users. Reflux esophagitis is a known risk factor for esophageal cancer, but it is not known whether bisphosphonates-associated esophagitis also predisposes patients to develop gastric cancer, said Chris R. Cardwell, Ph.D., of Queen's University Belfast (Ireland) and his associates.

“The U.S. Food and Drug Administration recently reported 23 cases of esophageal cancer (between 1995 and 2008) in patients using the bisphosphonate alendronate and a further 31 cases in patients using bisphosphonates in Europe and Japan, possibly indicating risk of malignancy,” they noted.

Dr. Cardwell and his colleagues searched for a possible link between the drugs and esophageal or gastric cancer using the General Practice Research Database (GPRD), “the world's largest computerized database of anonymized longitudinal patient records,” which includes 500 general practices and covers about 6% of the population in the United Kingdom.

They reviewed the records of 41,826 patients aged 40 years and older who used bisphosphonates and the same number of control patients matched for age, sex, and medical practice. During a mean follow-up of 4.5 years, 287 of these patients developed esophageal or gastric cancer.

There were no significant differences between cases and controls in risk for esophageal cancer, gastric cancer, or both cancers combined. This result did not change when the data were adjusted to account for possible confounders of gastric cancer risk, such as smoking, alcohol use, and use of drugs including NSAIDs, proton pump inhibitors, and H₂ receptor antagonists.

Moreover, the risk of these cancers was no higher in patients who took larger daily doses of bisphosphonates or in those who had a longer duration of bisphosphonate use, the investigators said (JAMA 2010;304:657-63).

In addition, the risk of gastric cancer was not significantly different between men and women exposed to bisphosphonates, and it did not differ across several different bisphosphonate medications.

There also was no association between cancer risk and bisphosphonate use in the subgroup of patients who had a history of gastroesophageal reflux disease.

“In conclusion … we found no evidence for a substantially increased risk of esophageal (or gastric) cancer in persons using oral bisphosphonates.

“These drugs should not be withheld, on the basis of possible esophageal cancer risk, from patients with a genuine clinical indication for their use,” they said.

Access to the GPRD database was funded by the Medical Research Council. No financial conflicts of interest were reported.

The use of oral bisphosphonates was not associated with esophageal or gastric cancer in a large cohort study in the United Kingdom, according to a large U.K. database analysis.

Oral bisphosphonates cause serious esophagitis in some users. Reflux esophagitis is a known risk factor for esophageal cancer, but it is not known whether bisphosphonates-associated esophagitis also predisposes patients to develop gastric cancer, said Chris R. Cardwell, Ph.D., of Queen's University Belfast (Ireland) and his associates.

“The U.S. Food and Drug Administration recently reported 23 cases of esophageal cancer (between 1995 and 2008) in patients using the bisphosphonate alendronate and a further 31 cases in patients using bisphosphonates in Europe and Japan, possibly indicating risk of malignancy,” they noted.

Dr. Cardwell and his colleagues searched for a possible link between the drugs and esophageal or gastric cancer using the General Practice Research Database (GPRD), “the world's largest computerized database of anonymized longitudinal patient records,” which includes 500 general practices and covers about 6% of the population in the United Kingdom.

They reviewed the records of 41,826 patients aged 40 years and older who used bisphosphonates and the same number of control patients matched for age, sex, and medical practice. During a mean follow-up of 4.5 years, 287 of these patients developed esophageal or gastric cancer.

There were no significant differences between cases and controls in risk for esophageal cancer, gastric cancer, or both cancers combined. This result did not change when the data were adjusted to account for possible confounders of gastric cancer risk, such as smoking, alcohol use, and use of drugs including NSAIDs, proton pump inhibitors, and H₂ receptor antagonists.

Moreover, the risk of these cancers was no higher in patients who took larger daily doses of bisphosphonates or in those who had a longer duration of bisphosphonate use, the investigators said (JAMA 2010;304:657-63).

In addition, the risk of gastric cancer was not significantly different between men and women exposed to bisphosphonates, and it did not differ across several different bisphosphonate medications.

There also was no association between cancer risk and bisphosphonate use in the subgroup of patients who had a history of gastroesophageal reflux disease.

“In conclusion … we found no evidence for a substantially increased risk of esophageal (or gastric) cancer in persons using oral bisphosphonates.

“These drugs should not be withheld, on the basis of possible esophageal cancer risk, from patients with a genuine clinical indication for their use,” they said.

Access to the GPRD database was funded by the Medical Research Council. No financial conflicts of interest were reported.

A “meaningful proportion” of patients aged 65 years and older who have advanced cancer and a limited life expectancy undergo unnecessary screening for other cancers, needlessly exposing them to physical risk and psychological distress, according to a report in the Oct. 13 issue of JAMA.

Dr. Camelia S. Sima of the department of epidemiology and biostatistics at Memorial Sloan-Kettering Cancer Center, New York, and her associates said the terminally ill patients “have essentially no chance of benefiting from these procedures,” which they said were the result of a “culture of screening on ‘autopilot.’?”

They noted, however, that current guidelines “do not directly address the appropriateness of screening for individuals with terminal illnesses.”

"The most plausible interpretation of our data is that efforts to foster adherence to screening have led to deeply ingrained habits."

The screening rates were one-third to one-half the rates in a matched control population of healthy adults who were followed over the same time period. Dr. Sima and her colleagues noted that rates of unnecessary cancer screening are likely to be even higher in the general population of patients with advanced cancer, which would include younger patients and those who are commercially insured (JAMA 2010;304:1584-91).

The investigators analyzed 1998-2005 data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry, which is linked with Medicare claims. They identified 87,736 Medicare patients (median age, 77 years) who survived at least 2 months after a diagnosis of advanced lung, colorectal, breast, gastroesophageal, or pancreatic cancer, and were followed until death or 2008.

Although such cancers have a median survival of less than 2 years, 15% of the men had PSA testing. About 9% of the women underwent screening mammography and 6% underwent Pap testing. Two percent of men and women underwent lower GI endoscopy screening for colorectal cancer.

The data did not indicate whether this screening was ordered by oncologists or primary care physicians, nor whether it was driven by patient demand. But “whatever the impetus, screening utilization by patients with advanced cancer adds to the mounting concern about overdiagnosis,” the researchers said.

“The most plausible interpretation of our data is that efforts to foster adherence to screening have led to deeply ingrained habits. Patients and their health care practitioners accustomed to obtaining screening tests at regular intervals continue to do so even when the benefits have been rendered futile in the face of competing risk from advanced cancer,” Dr. Sima and her associates said.

As an example of this “autopilot” screening, they noted that 20% of the study population continued to undergo regular testing of cholesterol levels even though their life expectancy was drastically limited.

Furthermore, we hypothesize that neither primary care physicians nor oncologists routinely engage in the difficult discussions that require explanation of why continuation of procedures to which patients have become accustomed is no longer necessary.

“There is substantial evidence that even when physicians recognize that life expectancy is limited, they do not consistently communicate prognosis, and patients may use denial as a coping strategy to face impending loss. Our findings represent one manifestation of this communication deficit.”

Any attempt to limit patient care “is routinely met with vocal opposition,” but this overuse of cancer screening “is likely to be relatively uncontroversial,” the investigators said.

“Each medical specialty needs to engage in thoughtful self-scrutiny to identify episodes of unnecessary care. We suggest that the road to a high-performing, high-value health care system will be paved with small stones such as the example we have identified.”

This study was supported in part by a grant from the National Cancer Institute. Dr. Sima and her colleagues did not report any financial disclosures.

A “meaningful proportion” of patients aged 65 years and older who have advanced cancer and a limited life expectancy undergo unnecessary screening for other cancers, needlessly exposing them to physical risk and psychological distress, according to a report in the Oct. 13 issue of JAMA.

Dr. Camelia S. Sima of the department of epidemiology and biostatistics at Memorial Sloan-Kettering Cancer Center, New York, and her associates said the terminally ill patients “have essentially no chance of benefiting from these procedures,” which they said were the result of a “culture of screening on ‘autopilot.’?”

They noted, however, that current guidelines “do not directly address the appropriateness of screening for individuals with terminal illnesses.”

"The most plausible interpretation of our data is that efforts to foster adherence to screening have led to deeply ingrained habits."

The screening rates were one-third to one-half the rates in a matched control population of healthy adults who were followed over the same time period. Dr. Sima and her colleagues noted that rates of unnecessary cancer screening are likely to be even higher in the general population of patients with advanced cancer, which would include younger patients and those who are commercially insured (JAMA 2010;304:1584-91).

The investigators analyzed 1998-2005 data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry, which is linked with Medicare claims. They identified 87,736 Medicare patients (median age, 77 years) who survived at least 2 months after a diagnosis of advanced lung, colorectal, breast, gastroesophageal, or pancreatic cancer, and were followed until death or 2008.

Although such cancers have a median survival of less than 2 years, 15% of the men had PSA testing. About 9% of the women underwent screening mammography and 6% underwent Pap testing. Two percent of men and women underwent lower GI endoscopy screening for colorectal cancer.

The data did not indicate whether this screening was ordered by oncologists or primary care physicians, nor whether it was driven by patient demand. But “whatever the impetus, screening utilization by patients with advanced cancer adds to the mounting concern about overdiagnosis,” the researchers said.

“The most plausible interpretation of our data is that efforts to foster adherence to screening have led to deeply ingrained habits. Patients and their health care practitioners accustomed to obtaining screening tests at regular intervals continue to do so even when the benefits have been rendered futile in the face of competing risk from advanced cancer,” Dr. Sima and her associates said.

As an example of this “autopilot” screening, they noted that 20% of the study population continued to undergo regular testing of cholesterol levels even though their life expectancy was drastically limited.

Furthermore, we hypothesize that neither primary care physicians nor oncologists routinely engage in the difficult discussions that require explanation of why continuation of procedures to which patients have become accustomed is no longer necessary.

“There is substantial evidence that even when physicians recognize that life expectancy is limited, they do not consistently communicate prognosis, and patients may use denial as a coping strategy to face impending loss. Our findings represent one manifestation of this communication deficit.”

Any attempt to limit patient care “is routinely met with vocal opposition,” but this overuse of cancer screening “is likely to be relatively uncontroversial,” the investigators said.

“Each medical specialty needs to engage in thoughtful self-scrutiny to identify episodes of unnecessary care. We suggest that the road to a high-performing, high-value health care system will be paved with small stones such as the example we have identified.”

This study was supported in part by a grant from the National Cancer Institute. Dr. Sima and her colleagues did not report any financial disclosures.

A “meaningful proportion” of patients aged 65 years and older who have advanced cancer and a limited life expectancy undergo unnecessary screening for other cancers, needlessly exposing them to physical risk and psychological distress, according to a report in the Oct. 13 issue of JAMA.

Dr. Camelia S. Sima of the department of epidemiology and biostatistics at Memorial Sloan-Kettering Cancer Center, New York, and her associates said the terminally ill patients “have essentially no chance of benefiting from these procedures,” which they said were the result of a “culture of screening on ‘autopilot.’?”

They noted, however, that current guidelines “do not directly address the appropriateness of screening for individuals with terminal illnesses.”

"The most plausible interpretation of our data is that efforts to foster adherence to screening have led to deeply ingrained habits."

The screening rates were one-third to one-half the rates in a matched control population of healthy adults who were followed over the same time period. Dr. Sima and her colleagues noted that rates of unnecessary cancer screening are likely to be even higher in the general population of patients with advanced cancer, which would include younger patients and those who are commercially insured (JAMA 2010;304:1584-91).

The investigators analyzed 1998-2005 data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry, which is linked with Medicare claims. They identified 87,736 Medicare patients (median age, 77 years) who survived at least 2 months after a diagnosis of advanced lung, colorectal, breast, gastroesophageal, or pancreatic cancer, and were followed until death or 2008.

Although such cancers have a median survival of less than 2 years, 15% of the men had PSA testing. About 9% of the women underwent screening mammography and 6% underwent Pap testing. Two percent of men and women underwent lower GI endoscopy screening for colorectal cancer.

The data did not indicate whether this screening was ordered by oncologists or primary care physicians, nor whether it was driven by patient demand. But “whatever the impetus, screening utilization by patients with advanced cancer adds to the mounting concern about overdiagnosis,” the researchers said.

“The most plausible interpretation of our data is that efforts to foster adherence to screening have led to deeply ingrained habits. Patients and their health care practitioners accustomed to obtaining screening tests at regular intervals continue to do so even when the benefits have been rendered futile in the face of competing risk from advanced cancer,” Dr. Sima and her associates said.

As an example of this “autopilot” screening, they noted that 20% of the study population continued to undergo regular testing of cholesterol levels even though their life expectancy was drastically limited.

Furthermore, we hypothesize that neither primary care physicians nor oncologists routinely engage in the difficult discussions that require explanation of why continuation of procedures to which patients have become accustomed is no longer necessary.

“There is substantial evidence that even when physicians recognize that life expectancy is limited, they do not consistently communicate prognosis, and patients may use denial as a coping strategy to face impending loss. Our findings represent one manifestation of this communication deficit.”

Any attempt to limit patient care “is routinely met with vocal opposition,” but this overuse of cancer screening “is likely to be relatively uncontroversial,” the investigators said.

“Each medical specialty needs to engage in thoughtful self-scrutiny to identify episodes of unnecessary care. We suggest that the road to a high-performing, high-value health care system will be paved with small stones such as the example we have identified.”

This study was supported in part by a grant from the National Cancer Institute. Dr. Sima and her colleagues did not report any financial disclosures.

Buprenorphine implants helped approximately 40% of patients addicted to opioids markedly reduce their drug use for 6 months in a phase III study of this new method of delivery, according to a report in the Oct. 13 issue of JAMA.

In addition, two-thirds of the study subjects who received the implants completed 24 weeks of treatment without experiencing cravings or withdrawal symptoms compelling them to drop out, said Dr. Walter Ling of the UCLA Integrated Substance Abuse Programs, Los Angeles, and his associates.

In comparison, studies of sublingual buprenorphine found a median adherence of only 40 days in clinical settings, and 6-month clinical trials report subject retention rates of 35%-38%, the investigators noted.

The implantable formulation of buprenorphine was developed to address dependent patients’ problems with adherence and “diversion,” or using the drug for some purpose other than treatment, such as selling it. The implants deliver an initial pulse of buprenorphine followed by the release of a constant, low level for 6 months. This avoids the peaks and troughs in plasma levels that occur with other methods of delivery.

Dr. Ling and his colleagues performed their industry-sponsored phase III study at 18 community addiction treatment centers across the United States. In all, 108 subjects were randomly assigned to receive four buprenorphine implants and 55 to receive four placebo implants in the subdermal space in the inner side of the nondominant arm.

The study subjects were allowed to receive supplemental sublingual buprenorphine-plus-naloxone tablets if they experienced significant withdrawal symptoms or cravings. They also were allowed to get one additional implant if necessary. All also received individual drug counseling twice a week for 3 months and weekly thereafter.

The patients’ use of illicit drugs was monitored throughout the study by urinalyses done 3 times per week.

The primary outcome measure was early treatment response, assessed as the percentage of the 48 urine samples obtained during the first 16 weeks of the trial that were negative for illicit opioids. This rate was 40% with the buprenorphine implants, compared with 28% with the placebo implants, the investigators said (JAMA 2010;304:1576-83).

For the full 6-month treatment period, in which 72 urine samples were analyzed for each subject, 37% were negative for illicit opioids in the buprenorphine group, compared with 22% in the placebo group.

Treatment adherence was significantly better with the active treatment at 16 weeks (82% with buprenorphine vs. 51% with placebo) and at the conclusion of the study (66% vs. 31%). Throughout the study, the implant group also had significantly lower scores on measures of opiate withdrawal and opioid craving.

No patients who received buprenorphine implants were classified as treatment failures, while 31% who received placebo implants were.

Adverse reactions at the treatment site were common and expected in both groups, and resolved without incident in all but three patients. One serious adverse event may have been related to treatment: A pulmonary embolism and exacerbation of chronic obstructive pulmonary disease occurred in a patient with a history of pulmonary embolism and COPD, whose respiratory function might have been impaired by the buprenorphine. One patient in the placebo group also had a serious adverse event, cellulitis at the implant site.

“There were no clinically meaningful changes” in vital signs, physical exam findings, electrocardiograms, hematology values, or coagulation values.

In addition, no evidence was found of attempted removal of the implants, so “diversion” appears unlikely with this method of delivery, Dr. Ling and his associates said.

The investigators cited several limitations. For example, all of the patients received psychosocial counseling in addition to the implants. Also, they pointed out that their trial is not “statistically powered to examine efficacy within subgroups of patients.”

This study was funded by Titan Pharmaceuticals, maker of the buprenorphine implants, which was involved in the design and management of the study, data collection and analysis, and preparation and approval of the manuscript. Dr. Ling and his associates reported numerous ties to drug and device manufacturers.

Buprenorphine implants helped approximately 40% of patients addicted to opioids markedly reduce their drug use for 6 months in a phase III study of this new method of delivery, according to a report in the Oct. 13 issue of JAMA.

In addition, two-thirds of the study subjects who received the implants completed 24 weeks of treatment without experiencing cravings or withdrawal symptoms compelling them to drop out, said Dr. Walter Ling of the UCLA Integrated Substance Abuse Programs, Los Angeles, and his associates.

In comparison, studies of sublingual buprenorphine found a median adherence of only 40 days in clinical settings, and 6-month clinical trials report subject retention rates of 35%-38%, the investigators noted.

The implantable formulation of buprenorphine was developed to address dependent patients’ problems with adherence and “diversion,” or using the drug for some purpose other than treatment, such as selling it. The implants deliver an initial pulse of buprenorphine followed by the release of a constant, low level for 6 months. This avoids the peaks and troughs in plasma levels that occur with other methods of delivery.

Dr. Ling and his colleagues performed their industry-sponsored phase III study at 18 community addiction treatment centers across the United States. In all, 108 subjects were randomly assigned to receive four buprenorphine implants and 55 to receive four placebo implants in the subdermal space in the inner side of the nondominant arm.

The study subjects were allowed to receive supplemental sublingual buprenorphine-plus-naloxone tablets if they experienced significant withdrawal symptoms or cravings. They also were allowed to get one additional implant if necessary. All also received individual drug counseling twice a week for 3 months and weekly thereafter.

The patients’ use of illicit drugs was monitored throughout the study by urinalyses done 3 times per week.

The primary outcome measure was early treatment response, assessed as the percentage of the 48 urine samples obtained during the first 16 weeks of the trial that were negative for illicit opioids. This rate was 40% with the buprenorphine implants, compared with 28% with the placebo implants, the investigators said (JAMA 2010;304:1576-83).

For the full 6-month treatment period, in which 72 urine samples were analyzed for each subject, 37% were negative for illicit opioids in the buprenorphine group, compared with 22% in the placebo group.

Treatment adherence was significantly better with the active treatment at 16 weeks (82% with buprenorphine vs. 51% with placebo) and at the conclusion of the study (66% vs. 31%). Throughout the study, the implant group also had significantly lower scores on measures of opiate withdrawal and opioid craving.

No patients who received buprenorphine implants were classified as treatment failures, while 31% who received placebo implants were.

Adverse reactions at the treatment site were common and expected in both groups, and resolved without incident in all but three patients. One serious adverse event may have been related to treatment: A pulmonary embolism and exacerbation of chronic obstructive pulmonary disease occurred in a patient with a history of pulmonary embolism and COPD, whose respiratory function might have been impaired by the buprenorphine. One patient in the placebo group also had a serious adverse event, cellulitis at the implant site.

“There were no clinically meaningful changes” in vital signs, physical exam findings, electrocardiograms, hematology values, or coagulation values.

In addition, no evidence was found of attempted removal of the implants, so “diversion” appears unlikely with this method of delivery, Dr. Ling and his associates said.

The investigators cited several limitations. For example, all of the patients received psychosocial counseling in addition to the implants. Also, they pointed out that their trial is not “statistically powered to examine efficacy within subgroups of patients.”

This study was funded by Titan Pharmaceuticals, maker of the buprenorphine implants, which was involved in the design and management of the study, data collection and analysis, and preparation and approval of the manuscript. Dr. Ling and his associates reported numerous ties to drug and device manufacturers.

Buprenorphine implants helped approximately 40% of patients addicted to opioids markedly reduce their drug use for 6 months in a phase III study of this new method of delivery, according to a report in the Oct. 13 issue of JAMA.

In addition, two-thirds of the study subjects who received the implants completed 24 weeks of treatment without experiencing cravings or withdrawal symptoms compelling them to drop out, said Dr. Walter Ling of the UCLA Integrated Substance Abuse Programs, Los Angeles, and his associates.

In comparison, studies of sublingual buprenorphine found a median adherence of only 40 days in clinical settings, and 6-month clinical trials report subject retention rates of 35%-38%, the investigators noted.

The implantable formulation of buprenorphine was developed to address dependent patients’ problems with adherence and “diversion,” or using the drug for some purpose other than treatment, such as selling it. The implants deliver an initial pulse of buprenorphine followed by the release of a constant, low level for 6 months. This avoids the peaks and troughs in plasma levels that occur with other methods of delivery.

Dr. Ling and his colleagues performed their industry-sponsored phase III study at 18 community addiction treatment centers across the United States. In all, 108 subjects were randomly assigned to receive four buprenorphine implants and 55 to receive four placebo implants in the subdermal space in the inner side of the nondominant arm.

The study subjects were allowed to receive supplemental sublingual buprenorphine-plus-naloxone tablets if they experienced significant withdrawal symptoms or cravings. They also were allowed to get one additional implant if necessary. All also received individual drug counseling twice a week for 3 months and weekly thereafter.

The patients’ use of illicit drugs was monitored throughout the study by urinalyses done 3 times per week.

The primary outcome measure was early treatment response, assessed as the percentage of the 48 urine samples obtained during the first 16 weeks of the trial that were negative for illicit opioids. This rate was 40% with the buprenorphine implants, compared with 28% with the placebo implants, the investigators said (JAMA 2010;304:1576-83).

For the full 6-month treatment period, in which 72 urine samples were analyzed for each subject, 37% were negative for illicit opioids in the buprenorphine group, compared with 22% in the placebo group.

Treatment adherence was significantly better with the active treatment at 16 weeks (82% with buprenorphine vs. 51% with placebo) and at the conclusion of the study (66% vs. 31%). Throughout the study, the implant group also had significantly lower scores on measures of opiate withdrawal and opioid craving.

No patients who received buprenorphine implants were classified as treatment failures, while 31% who received placebo implants were.

Adverse reactions at the treatment site were common and expected in both groups, and resolved without incident in all but three patients. One serious adverse event may have been related to treatment: A pulmonary embolism and exacerbation of chronic obstructive pulmonary disease occurred in a patient with a history of pulmonary embolism and COPD, whose respiratory function might have been impaired by the buprenorphine. One patient in the placebo group also had a serious adverse event, cellulitis at the implant site.

“There were no clinically meaningful changes” in vital signs, physical exam findings, electrocardiograms, hematology values, or coagulation values.

In addition, no evidence was found of attempted removal of the implants, so “diversion” appears unlikely with this method of delivery, Dr. Ling and his associates said.

The investigators cited several limitations. For example, all of the patients received psychosocial counseling in addition to the implants. Also, they pointed out that their trial is not “statistically powered to examine efficacy within subgroups of patients.”

This study was funded by Titan Pharmaceuticals, maker of the buprenorphine implants, which was involved in the design and management of the study, data collection and analysis, and preparation and approval of the manuscript. Dr. Ling and his associates reported numerous ties to drug and device manufacturers.

A “meaningful proportion” of patients aged 65 years and older who have advanced cancer and a limited life expectancy undergo unnecessary screening for other cancers, needlessly exposing them to physical risk and psychological distress, according to a report in the Oct. 13 issue of JAMA.

Dr. Camelia S. Sima of the department of epidemiology and biostatistics at Memorial Sloan-Kettering Cancer Center, New York, and her associates said the terminally ill patients “have essentially no chance of benefiting from these procedures,” which they said were the result of a “culture of screening on ‘autopilot.’?”

They noted, however, that current guidelines “do not directly address the appropriateness of screening for individuals with terminal illnesses.”

The screening rates were one-third to one-half the rates in a matched control population of healthy adults who were followed over the same time period. Dr. Sima and her colleagues noted that rates of unnecessary cancer screening are likely to be even higher in the general population of patients with advanced cancer, which would include younger patients and those who are commercially insured (JAMA 2010;304:1584-91).

The investigators analyzed 1998-2005 data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry, which is linked with Medicare claims. They identified 87,736 Medicare patients (median age, 77 years) who survived at least 2 months after a diagnosis of advanced lung, colorectal, breast, gastroesophageal, or pancreatic cancer, and were followed until death or 2008.

Although such cancers have a median survival of less than 2 years, 15% of the men had PSA testing. About 9% of the women underwent screening mammography and 6% underwent Pap testing. Two percent of men and women underwent lower GI endoscopy screening for colorectal cancer.

The data did not indicate whether this screening was ordered by oncologists or primary care physicians, nor whether it was driven by patient demand. But “whatever the impetus, screening utilization by patients with advanced cancer adds to the mounting concern about overdiagnosis,” the researchers said.

“The most plausible interpretation of our data is that efforts to foster adherence to screening have led to deeply ingrained habits. Patients and their health care practitioners accustomed to obtaining screening tests at regular intervals continue to do so even when the benefits have been rendered futile in the face of competing risk from advanced cancer,” Dr. Sima and her associates said.

As an example of this “autopilot” screening, they noted that 20% of the study population continued to undergo regular testing of cholesterol levels even though their life expectancy was drastically limited.

“Furthermore, we hypothesize that neither primary care physicians nor oncologists routinely engage in the difficult discussions that require explanation of why continuation of procedures to which patients have become accustomed is no longer necessary.

“There is substantial evidence that even when physicians recognize that life expectancy is limited, they do not consistently communicate prognosis, and patients may use denial as a coping strategy to face impending loss. Our findings represent one manifestation of this communication deficit.”

Any attempt to limit patient care “is routinely met with vocal opposition,” but this overuse of cancer screening “is likely to be relatively uncontroversial,” the investigators said.

“Each medical specialty needs to engage in thoughtful self-scrutiny to identify episodes of unnecessary care. We suggest that the road to a high-performing, high-value health care system will be paved with small stones such as the example we have identified.”

This study was supported in part by a grant from the National Cancer Institute. Dr. Sima and her colleagues did not report any financial disclosures.

A “meaningful proportion” of patients aged 65 years and older who have advanced cancer and a limited life expectancy undergo unnecessary screening for other cancers, needlessly exposing them to physical risk and psychological distress, according to a report in the Oct. 13 issue of JAMA.

Dr. Camelia S. Sima of the department of epidemiology and biostatistics at Memorial Sloan-Kettering Cancer Center, New York, and her associates said the terminally ill patients “have essentially no chance of benefiting from these procedures,” which they said were the result of a “culture of screening on ‘autopilot.’?”

They noted, however, that current guidelines “do not directly address the appropriateness of screening for individuals with terminal illnesses.”

The screening rates were one-third to one-half the rates in a matched control population of healthy adults who were followed over the same time period. Dr. Sima and her colleagues noted that rates of unnecessary cancer screening are likely to be even higher in the general population of patients with advanced cancer, which would include younger patients and those who are commercially insured (JAMA 2010;304:1584-91).

The investigators analyzed 1998-2005 data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry, which is linked with Medicare claims. They identified 87,736 Medicare patients (median age, 77 years) who survived at least 2 months after a diagnosis of advanced lung, colorectal, breast, gastroesophageal, or pancreatic cancer, and were followed until death or 2008.

Although such cancers have a median survival of less than 2 years, 15% of the men had PSA testing. About 9% of the women underwent screening mammography and 6% underwent Pap testing. Two percent of men and women underwent lower GI endoscopy screening for colorectal cancer.

The data did not indicate whether this screening was ordered by oncologists or primary care physicians, nor whether it was driven by patient demand. But “whatever the impetus, screening utilization by patients with advanced cancer adds to the mounting concern about overdiagnosis,” the researchers said.

“The most plausible interpretation of our data is that efforts to foster adherence to screening have led to deeply ingrained habits. Patients and their health care practitioners accustomed to obtaining screening tests at regular intervals continue to do so even when the benefits have been rendered futile in the face of competing risk from advanced cancer,” Dr. Sima and her associates said.

As an example of this “autopilot” screening, they noted that 20% of the study population continued to undergo regular testing of cholesterol levels even though their life expectancy was drastically limited.

“Furthermore, we hypothesize that neither primary care physicians nor oncologists routinely engage in the difficult discussions that require explanation of why continuation of procedures to which patients have become accustomed is no longer necessary.

“There is substantial evidence that even when physicians recognize that life expectancy is limited, they do not consistently communicate prognosis, and patients may use denial as a coping strategy to face impending loss. Our findings represent one manifestation of this communication deficit.”

Any attempt to limit patient care “is routinely met with vocal opposition,” but this overuse of cancer screening “is likely to be relatively uncontroversial,” the investigators said.

“Each medical specialty needs to engage in thoughtful self-scrutiny to identify episodes of unnecessary care. We suggest that the road to a high-performing, high-value health care system will be paved with small stones such as the example we have identified.”

This study was supported in part by a grant from the National Cancer Institute. Dr. Sima and her colleagues did not report any financial disclosures.

A “meaningful proportion” of patients aged 65 years and older who have advanced cancer and a limited life expectancy undergo unnecessary screening for other cancers, needlessly exposing them to physical risk and psychological distress, according to a report in the Oct. 13 issue of JAMA.

Dr. Camelia S. Sima of the department of epidemiology and biostatistics at Memorial Sloan-Kettering Cancer Center, New York, and her associates said the terminally ill patients “have essentially no chance of benefiting from these procedures,” which they said were the result of a “culture of screening on ‘autopilot.’?”

They noted, however, that current guidelines “do not directly address the appropriateness of screening for individuals with terminal illnesses.”

The screening rates were one-third to one-half the rates in a matched control population of healthy adults who were followed over the same time period. Dr. Sima and her colleagues noted that rates of unnecessary cancer screening are likely to be even higher in the general population of patients with advanced cancer, which would include younger patients and those who are commercially insured (JAMA 2010;304:1584-91).

The investigators analyzed 1998-2005 data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry, which is linked with Medicare claims. They identified 87,736 Medicare patients (median age, 77 years) who survived at least 2 months after a diagnosis of advanced lung, colorectal, breast, gastroesophageal, or pancreatic cancer, and were followed until death or 2008.

Although such cancers have a median survival of less than 2 years, 15% of the men had PSA testing. About 9% of the women underwent screening mammography and 6% underwent Pap testing. Two percent of men and women underwent lower GI endoscopy screening for colorectal cancer.

The data did not indicate whether this screening was ordered by oncologists or primary care physicians, nor whether it was driven by patient demand. But “whatever the impetus, screening utilization by patients with advanced cancer adds to the mounting concern about overdiagnosis,” the researchers said.

“The most plausible interpretation of our data is that efforts to foster adherence to screening have led to deeply ingrained habits. Patients and their health care practitioners accustomed to obtaining screening tests at regular intervals continue to do so even when the benefits have been rendered futile in the face of competing risk from advanced cancer,” Dr. Sima and her associates said.

As an example of this “autopilot” screening, they noted that 20% of the study population continued to undergo regular testing of cholesterol levels even though their life expectancy was drastically limited.

“Furthermore, we hypothesize that neither primary care physicians nor oncologists routinely engage in the difficult discussions that require explanation of why continuation of procedures to which patients have become accustomed is no longer necessary.

“There is substantial evidence that even when physicians recognize that life expectancy is limited, they do not consistently communicate prognosis, and patients may use denial as a coping strategy to face impending loss. Our findings represent one manifestation of this communication deficit.”

Any attempt to limit patient care “is routinely met with vocal opposition,” but this overuse of cancer screening “is likely to be relatively uncontroversial,” the investigators said.

“Each medical specialty needs to engage in thoughtful self-scrutiny to identify episodes of unnecessary care. We suggest that the road to a high-performing, high-value health care system will be paved with small stones such as the example we have identified.”

This study was supported in part by a grant from the National Cancer Institute. Dr. Sima and her colleagues did not report any financial disclosures.