Jennie Smith

A study indirectly comparing three oral anticoagulant drugs – dabigatran, rivaroxaban, and apixaban – has revealed potential differences among the agents in their relative efficacy and safety when used for stroke prevention in atrial fibrillation.

However, its authors found more similarities than differences overall, and stopped short of saying that the differences they found should have meaning for clinicians in choosing one over another. Only a head-to-head trial comparing the new agents could do that, they said.

The study, published in the August issue of the Journal of the American College of Cardiology, used data from phase III, randomized, controlled trials that had enrolled more than 50,000 patients (J. Am. Coll. Cardiol. 2012;60:738-46). The authors, led by Dr. Gregory Y.H. Lip of the University of Birmingham (England) compared each of the agents – including two different doses of dabigatran, 150 mg b.i.d. and 110 mg b.i.d. – with warfarin.

Overall, the investigators found that the newer agents offered significant advantages over warfarin, with 21% reduced risk of stroke or systemic embolism; 23% reduced risk of stroke; 53% lower risk of hemorrhagic stroke; and 12% less risk of all-cause mortality. The risk of major bleeding was 13% lower with the new agents, compared with warfarin.

Dr. Lip and his colleagues reported that they found no profound significant differences in efficacy between apixaban and dabigatran at either dose, or between rivaroxaban and dabigatran 110 mg; dabigatran 150 mg was seen as superior to rivaroxaban for some end points, with a 26% lower risk of stroke or systemic embolism and a 56% lower risk of hemorrhagic stroke.

Some significant differences were also seen for safety end points. The risk of major bleeding was 34% lower for apixaban than for rivaroxaban, and 26% lower for apixaban than for dabigatran 150 mg, but not significantly different between apixaban and dabigatran 110 mg. Compared with rivaroxaban, dabigatran 110 mg was associated with 23% less risk of major bleeding and 54% less intracranial bleeding.

Dr. Lip and his colleagues acknowledged that their study, because it was an indirect comparison analysis, had automatic limitations, such as the fact that it could not adjust for patient demography and stroke risk of the different trial populations; nor could it account for differences in warfarin control between the trials, with mean time in therapeutic range better in some trials than others.

Although indirect comparison "is still considered a reasonable statistical tool to qualify a comparison of effects that have not yet been investigated head to head," only head-to-head comparison, they concluded, would "fully answer the question of efficacy/safety differences between the new drugs for stroke prevention in AF."

Dr. Lip disclosed having served as a consultant for Bayer, Astellas, and other companies; and having been a speaker for Bayer, Pfizer, and other companies. Two of Dr. Lip’s coauthors on the study, Dr. Torben Bjerregaard Larsen and Dr. Lars Hvilsted Rasmussen, disclosed having been speakers for BMS/Pfizer and Boehringer Ingelheim.

A study indirectly comparing three oral anticoagulant drugs – dabigatran, rivaroxaban, and apixaban – has revealed potential differences among the agents in their relative efficacy and safety when used for stroke prevention in atrial fibrillation.

However, its authors found more similarities than differences overall, and stopped short of saying that the differences they found should have meaning for clinicians in choosing one over another. Only a head-to-head trial comparing the new agents could do that, they said.

The study, published in the August issue of the Journal of the American College of Cardiology, used data from phase III, randomized, controlled trials that had enrolled more than 50,000 patients (J. Am. Coll. Cardiol. 2012;60:738-46). The authors, led by Dr. Gregory Y.H. Lip of the University of Birmingham (England) compared each of the agents – including two different doses of dabigatran, 150 mg b.i.d. and 110 mg b.i.d. – with warfarin.

Overall, the investigators found that the newer agents offered significant advantages over warfarin, with 21% reduced risk of stroke or systemic embolism; 23% reduced risk of stroke; 53% lower risk of hemorrhagic stroke; and 12% less risk of all-cause mortality. The risk of major bleeding was 13% lower with the new agents, compared with warfarin.

Dr. Lip and his colleagues reported that they found no profound significant differences in efficacy between apixaban and dabigatran at either dose, or between rivaroxaban and dabigatran 110 mg; dabigatran 150 mg was seen as superior to rivaroxaban for some end points, with a 26% lower risk of stroke or systemic embolism and a 56% lower risk of hemorrhagic stroke.

Some significant differences were also seen for safety end points. The risk of major bleeding was 34% lower for apixaban than for rivaroxaban, and 26% lower for apixaban than for dabigatran 150 mg, but not significantly different between apixaban and dabigatran 110 mg. Compared with rivaroxaban, dabigatran 110 mg was associated with 23% less risk of major bleeding and 54% less intracranial bleeding.

Dr. Lip and his colleagues acknowledged that their study, because it was an indirect comparison analysis, had automatic limitations, such as the fact that it could not adjust for patient demography and stroke risk of the different trial populations; nor could it account for differences in warfarin control between the trials, with mean time in therapeutic range better in some trials than others.

Although indirect comparison "is still considered a reasonable statistical tool to qualify a comparison of effects that have not yet been investigated head to head," only head-to-head comparison, they concluded, would "fully answer the question of efficacy/safety differences between the new drugs for stroke prevention in AF."

Dr. Lip disclosed having served as a consultant for Bayer, Astellas, and other companies; and having been a speaker for Bayer, Pfizer, and other companies. Two of Dr. Lip’s coauthors on the study, Dr. Torben Bjerregaard Larsen and Dr. Lars Hvilsted Rasmussen, disclosed having been speakers for BMS/Pfizer and Boehringer Ingelheim.

A study indirectly comparing three oral anticoagulant drugs – dabigatran, rivaroxaban, and apixaban – has revealed potential differences among the agents in their relative efficacy and safety when used for stroke prevention in atrial fibrillation.

However, its authors found more similarities than differences overall, and stopped short of saying that the differences they found should have meaning for clinicians in choosing one over another. Only a head-to-head trial comparing the new agents could do that, they said.

The study, published in the August issue of the Journal of the American College of Cardiology, used data from phase III, randomized, controlled trials that had enrolled more than 50,000 patients (J. Am. Coll. Cardiol. 2012;60:738-46). The authors, led by Dr. Gregory Y.H. Lip of the University of Birmingham (England) compared each of the agents – including two different doses of dabigatran, 150 mg b.i.d. and 110 mg b.i.d. – with warfarin.

Overall, the investigators found that the newer agents offered significant advantages over warfarin, with 21% reduced risk of stroke or systemic embolism; 23% reduced risk of stroke; 53% lower risk of hemorrhagic stroke; and 12% less risk of all-cause mortality. The risk of major bleeding was 13% lower with the new agents, compared with warfarin.

Dr. Lip and his colleagues reported that they found no profound significant differences in efficacy between apixaban and dabigatran at either dose, or between rivaroxaban and dabigatran 110 mg; dabigatran 150 mg was seen as superior to rivaroxaban for some end points, with a 26% lower risk of stroke or systemic embolism and a 56% lower risk of hemorrhagic stroke.

Some significant differences were also seen for safety end points. The risk of major bleeding was 34% lower for apixaban than for rivaroxaban, and 26% lower for apixaban than for dabigatran 150 mg, but not significantly different between apixaban and dabigatran 110 mg. Compared with rivaroxaban, dabigatran 110 mg was associated with 23% less risk of major bleeding and 54% less intracranial bleeding.

Dr. Lip and his colleagues acknowledged that their study, because it was an indirect comparison analysis, had automatic limitations, such as the fact that it could not adjust for patient demography and stroke risk of the different trial populations; nor could it account for differences in warfarin control between the trials, with mean time in therapeutic range better in some trials than others.

Although indirect comparison "is still considered a reasonable statistical tool to qualify a comparison of effects that have not yet been investigated head to head," only head-to-head comparison, they concluded, would "fully answer the question of efficacy/safety differences between the new drugs for stroke prevention in AF."

Dr. Lip disclosed having served as a consultant for Bayer, Astellas, and other companies; and having been a speaker for Bayer, Pfizer, and other companies. Two of Dr. Lip’s coauthors on the study, Dr. Torben Bjerregaard Larsen and Dr. Lars Hvilsted Rasmussen, disclosed having been speakers for BMS/Pfizer and Boehringer Ingelheim.

New clinical guidelines on the management of unstable angina/non–ST-elevation myocardial infarction recommend the antiplatelet therapy ticagrelor as an alternative to prasugrel and clopidogrel.

The guidelines, issued jointly by the American Heart Association and the American College of Cardiology Foundation, replace a 2011 update that did not include ticagrelor.

Ticagrelor (Brilinta), which like prasugrel and clopidogrel works by inhibiting the P2Y12 receptor, was approved by the Food and Drug Administration in July 2011 following the results of a large, randomized, placebo-controlled trial that showed it significantly reduced the rate of rate of death from vascular causes, myocardial infarction, or stroke compared with clopidogrel, although ticagrelor was associated with a higher risk of bleeding (N. Engl. J. Med. 2009;361:1045-57).

Similarly, prasugrel had been shown in an earlier randomized controlled trial to be superior to clopidogrel in reducing rates of ischemic events, but was associated with a higher bleeding risk (N. Engl. J. Med. 2007;357:2001-15).

Clopidogrel has been associated with variability in patient response, and the newer agents are considered to be more potent. Current European guidelines for unstable angina/non–ST-elevation myocardial infarction (UA/NSTEMI) explicitly recommend ticagrelor as the agent of choice, followed by prasugrel (in patients proceeding to percutaneous coronary intervention [PCI]) and clopidogrel (in patients who cannot receive the newer agents).

However, the ACCF/AHA (American College of Cardiology Foundation/American Heart Association) guidelines’ authors, led by Dr. Hani Jneid of the Baylor College of Medicine and Michael E. DeBakey VA Medical Center, both in Houston, emphasized that they were not endorsing any of the three recommended P2Y12 receptor inhibitors over the other for the treatment of UA/NSTEMI. Dr. Jneid and his colleagues cautioned that despite their being given equal footing in the ACCF/AHA guidelines, the agents were not interchangeable, and that their use in clinical practice "should carefully follow how they were tested."

Dr. Eric M. Bates, a cardiologist at the University of Michigan in Ann Arbor, said in an interview that the newer agents "are both more powerful than clopidogrel, and should both probably be avoided in patients with a history of [transient ischemic attack] or stroke. In patients over 75 in general you might want to go with the gentler clopidogrel. You may have a price to pay for more potent antiplatelet therapy."

As in previous guidelines issued by the AHA and ACCF, aspirin is recommended for all UA/NSTEMI patients immediately upon hospitalization, continuing as long as it is tolerated. Patients selected to undergo invasive procedures should receive dual therapy with aspirin and clopidogrel, ticagrelor, eptifibatide, or tirofiban before the procedure; prasugrel may be administered upon PCI. Ticagrelor and clopidogrel are appropriate both for patients receiving medical therapy alone and for those undergoing PCI. Patients who cannot tolerate aspirin may receive monotherapy with clopidogrel, prasugrel (in PCI-treated patients), or ticagrelor.

The new guidelines recommend that patients undergoing medical treatment continue receiving aspirin immediately and clopidogrel or ticagrelor as soon as possible after hospitalization, continuing for up to 12 months, while aspirin should be continued indefinitely. The 2011 guidelines had recommended that the antiplatelet therapy be continued for at least a year.

Another change from previous guidelines concerned patients on warfarin: "Targeting oral anticoagulant therapy to a lower INR (e.g., 2.0 to 2.5) might be reasonable in patients with UA/NSTEMI managed with aspirin and a P2Y12 inhibitor," the investigators wrote.

In a comment on the new guidelines published by the AHA, Dr. Elliott Antman of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, praised their detailed dosing recommendations for both anticoagulant and antiplatelet therapy, and called the committee’s unwillingness to recommend one agent over another as "quite reasonable, since prasugrel and ticagrelor have only been compared to clopidogrel and not to each other and were studied in different populations."

However, Dr. Antman also referred to a May 2012 editorial cautioning that there was "no safe ground" to treat patients with a previous stroke or transient ischemic attack with the newer agents (Circulation 2012;125:2821-23). "Clinicians should also note that the secondary prevention guidelines for management of patients with stroke recommend against prescribing the combination of aspirin with clopidogrel unless there are compelling cardiovascular indications," Dr. Antman wrote.

Dr. Jneid declared no conflicts of interest related to the guidelines; however, 7 of the 15 members of the guidelines writing committee disclosed relationships with pharmaceutical companies including AstraZeneca, Eli Lilly, and Bristol-Myers Squibb/Sanofi, the manufacturers, respectively, of ticagrelor, prasugrel, and clopidogrel. Dr. Bates disclosed having served as an adviser to all three companies, and Dr. Antman disclosed having received support from these companies.

New clinical guidelines on the management of unstable angina/non–ST-elevation myocardial infarction recommend the antiplatelet therapy ticagrelor as an alternative to prasugrel and clopidogrel.

The guidelines, issued jointly by the American Heart Association and the American College of Cardiology Foundation, replace a 2011 update that did not include ticagrelor.

Ticagrelor (Brilinta), which like prasugrel and clopidogrel works by inhibiting the P2Y12 receptor, was approved by the Food and Drug Administration in July 2011 following the results of a large, randomized, placebo-controlled trial that showed it significantly reduced the rate of rate of death from vascular causes, myocardial infarction, or stroke compared with clopidogrel, although ticagrelor was associated with a higher risk of bleeding (N. Engl. J. Med. 2009;361:1045-57).

Similarly, prasugrel had been shown in an earlier randomized controlled trial to be superior to clopidogrel in reducing rates of ischemic events, but was associated with a higher bleeding risk (N. Engl. J. Med. 2007;357:2001-15).

Clopidogrel has been associated with variability in patient response, and the newer agents are considered to be more potent. Current European guidelines for unstable angina/non–ST-elevation myocardial infarction (UA/NSTEMI) explicitly recommend ticagrelor as the agent of choice, followed by prasugrel (in patients proceeding to percutaneous coronary intervention [PCI]) and clopidogrel (in patients who cannot receive the newer agents).

However, the ACCF/AHA (American College of Cardiology Foundation/American Heart Association) guidelines’ authors, led by Dr. Hani Jneid of the Baylor College of Medicine and Michael E. DeBakey VA Medical Center, both in Houston, emphasized that they were not endorsing any of the three recommended P2Y12 receptor inhibitors over the other for the treatment of UA/NSTEMI. Dr. Jneid and his colleagues cautioned that despite their being given equal footing in the ACCF/AHA guidelines, the agents were not interchangeable, and that their use in clinical practice "should carefully follow how they were tested."

Dr. Eric M. Bates, a cardiologist at the University of Michigan in Ann Arbor, said in an interview that the newer agents "are both more powerful than clopidogrel, and should both probably be avoided in patients with a history of [transient ischemic attack] or stroke. In patients over 75 in general you might want to go with the gentler clopidogrel. You may have a price to pay for more potent antiplatelet therapy."

As in previous guidelines issued by the AHA and ACCF, aspirin is recommended for all UA/NSTEMI patients immediately upon hospitalization, continuing as long as it is tolerated. Patients selected to undergo invasive procedures should receive dual therapy with aspirin and clopidogrel, ticagrelor, eptifibatide, or tirofiban before the procedure; prasugrel may be administered upon PCI. Ticagrelor and clopidogrel are appropriate both for patients receiving medical therapy alone and for those undergoing PCI. Patients who cannot tolerate aspirin may receive monotherapy with clopidogrel, prasugrel (in PCI-treated patients), or ticagrelor.

The new guidelines recommend that patients undergoing medical treatment continue receiving aspirin immediately and clopidogrel or ticagrelor as soon as possible after hospitalization, continuing for up to 12 months, while aspirin should be continued indefinitely. The 2011 guidelines had recommended that the antiplatelet therapy be continued for at least a year.

Another change from previous guidelines concerned patients on warfarin: "Targeting oral anticoagulant therapy to a lower INR (e.g., 2.0 to 2.5) might be reasonable in patients with UA/NSTEMI managed with aspirin and a P2Y12 inhibitor," the investigators wrote.

In a comment on the new guidelines published by the AHA, Dr. Elliott Antman of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, praised their detailed dosing recommendations for both anticoagulant and antiplatelet therapy, and called the committee’s unwillingness to recommend one agent over another as "quite reasonable, since prasugrel and ticagrelor have only been compared to clopidogrel and not to each other and were studied in different populations."

However, Dr. Antman also referred to a May 2012 editorial cautioning that there was "no safe ground" to treat patients with a previous stroke or transient ischemic attack with the newer agents (Circulation 2012;125:2821-23). "Clinicians should also note that the secondary prevention guidelines for management of patients with stroke recommend against prescribing the combination of aspirin with clopidogrel unless there are compelling cardiovascular indications," Dr. Antman wrote.

Dr. Jneid declared no conflicts of interest related to the guidelines; however, 7 of the 15 members of the guidelines writing committee disclosed relationships with pharmaceutical companies including AstraZeneca, Eli Lilly, and Bristol-Myers Squibb/Sanofi, the manufacturers, respectively, of ticagrelor, prasugrel, and clopidogrel. Dr. Bates disclosed having served as an adviser to all three companies, and Dr. Antman disclosed having received support from these companies.

New clinical guidelines on the management of unstable angina/non–ST-elevation myocardial infarction recommend the antiplatelet therapy ticagrelor as an alternative to prasugrel and clopidogrel.

The guidelines, issued jointly by the American Heart Association and the American College of Cardiology Foundation, replace a 2011 update that did not include ticagrelor.

Ticagrelor (Brilinta), which like prasugrel and clopidogrel works by inhibiting the P2Y12 receptor, was approved by the Food and Drug Administration in July 2011 following the results of a large, randomized, placebo-controlled trial that showed it significantly reduced the rate of rate of death from vascular causes, myocardial infarction, or stroke compared with clopidogrel, although ticagrelor was associated with a higher risk of bleeding (N. Engl. J. Med. 2009;361:1045-57).

Similarly, prasugrel had been shown in an earlier randomized controlled trial to be superior to clopidogrel in reducing rates of ischemic events, but was associated with a higher bleeding risk (N. Engl. J. Med. 2007;357:2001-15).

Clopidogrel has been associated with variability in patient response, and the newer agents are considered to be more potent. Current European guidelines for unstable angina/non–ST-elevation myocardial infarction (UA/NSTEMI) explicitly recommend ticagrelor as the agent of choice, followed by prasugrel (in patients proceeding to percutaneous coronary intervention [PCI]) and clopidogrel (in patients who cannot receive the newer agents).

However, the ACCF/AHA (American College of Cardiology Foundation/American Heart Association) guidelines’ authors, led by Dr. Hani Jneid of the Baylor College of Medicine and Michael E. DeBakey VA Medical Center, both in Houston, emphasized that they were not endorsing any of the three recommended P2Y12 receptor inhibitors over the other for the treatment of UA/NSTEMI. Dr. Jneid and his colleagues cautioned that despite their being given equal footing in the ACCF/AHA guidelines, the agents were not interchangeable, and that their use in clinical practice "should carefully follow how they were tested."

Dr. Eric M. Bates, a cardiologist at the University of Michigan in Ann Arbor, said in an interview that the newer agents "are both more powerful than clopidogrel, and should both probably be avoided in patients with a history of [transient ischemic attack] or stroke. In patients over 75 in general you might want to go with the gentler clopidogrel. You may have a price to pay for more potent antiplatelet therapy."

As in previous guidelines issued by the AHA and ACCF, aspirin is recommended for all UA/NSTEMI patients immediately upon hospitalization, continuing as long as it is tolerated. Patients selected to undergo invasive procedures should receive dual therapy with aspirin and clopidogrel, ticagrelor, eptifibatide, or tirofiban before the procedure; prasugrel may be administered upon PCI. Ticagrelor and clopidogrel are appropriate both for patients receiving medical therapy alone and for those undergoing PCI. Patients who cannot tolerate aspirin may receive monotherapy with clopidogrel, prasugrel (in PCI-treated patients), or ticagrelor.

The new guidelines recommend that patients undergoing medical treatment continue receiving aspirin immediately and clopidogrel or ticagrelor as soon as possible after hospitalization, continuing for up to 12 months, while aspirin should be continued indefinitely. The 2011 guidelines had recommended that the antiplatelet therapy be continued for at least a year.

Another change from previous guidelines concerned patients on warfarin: "Targeting oral anticoagulant therapy to a lower INR (e.g., 2.0 to 2.5) might be reasonable in patients with UA/NSTEMI managed with aspirin and a P2Y12 inhibitor," the investigators wrote.

In a comment on the new guidelines published by the AHA, Dr. Elliott Antman of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, praised their detailed dosing recommendations for both anticoagulant and antiplatelet therapy, and called the committee’s unwillingness to recommend one agent over another as "quite reasonable, since prasugrel and ticagrelor have only been compared to clopidogrel and not to each other and were studied in different populations."

However, Dr. Antman also referred to a May 2012 editorial cautioning that there was "no safe ground" to treat patients with a previous stroke or transient ischemic attack with the newer agents (Circulation 2012;125:2821-23). "Clinicians should also note that the secondary prevention guidelines for management of patients with stroke recommend against prescribing the combination of aspirin with clopidogrel unless there are compelling cardiovascular indications," Dr. Antman wrote.

Dr. Jneid declared no conflicts of interest related to the guidelines; however, 7 of the 15 members of the guidelines writing committee disclosed relationships with pharmaceutical companies including AstraZeneca, Eli Lilly, and Bristol-Myers Squibb/Sanofi, the manufacturers, respectively, of ticagrelor, prasugrel, and clopidogrel. Dr. Bates disclosed having served as an adviser to all three companies, and Dr. Antman disclosed having received support from these companies.

A Cochrane Review of bevacizumab in metastatic breast cancer has found the medication helpful in prolonging progression-free survival and boosting response rates in both first and second-line treatment with certain types of chemotherapy.

However, the same review, published July 10 (doi:10.1002/14651858.CD008941.pub2) found no evidence of improvement in overall survival or quality of life associated with bevacizumab (Avastin), a vascular endothelial growth factor inhibitor whose use in metastatic breast cancer remains controversial.

The findings of improved progression-free survival without gains in overall are consistent with previous published systematic reviews and meta-analyses. The Cochrane Review, led by Dr. Anna Dorothea Wagner of the Centre Hospitalier Universitaire Vaudois in Lausanne (Switzerland) incorporates more trials, more individual patient data, and evidence from the most recent published trial of bevacizumab in breast cancer (Lancet Oncology 2011;12,4:369-76).

"Overall, the clinical value of bevacizumab in metastatic breast cancer can at best be considered as modest," the authors concluded.

In an interview about the Cochrane Review, oncologist Robert W. Carlson of Stanford (Calif.) University called the findings "very reassuring." Dr. Carlson, chair of the National Comprehensive Cancer Network (NCCN) panel that has maintained its endorsement of a bevacizumab and paclitaxel combination despite the Food and Drug Administration’s removal of bevacizumab’s breast cancer indication in November 2011, said that the "objective, independent, thorough look at the data comes up with the same conclusions that I think we already knew."

While the FDA revoked bevacizumab’s breast cancer indication in part because of a lack of evidence for an overall survival gain, the European Medicines Agency continues to recommend bevacizumab in combination with paclitaxel for first-line treatment or with capecitabine for the first-line treatment in patients for whom treatment with taxanes or anthracyclines are inappropriate.

"The question remains whether ... bevacizumab should be available for women with breast cancer. It’s interesting how different people can look at the same conclusions and make different inferences. And that’s really what this study highlights," Dr. Carlson said.

For their research, Dr. Wagner and her colleagues looked at published results from seven randomized controlled trials using bevacizumab and various chemotherapy regimen plus data from one registry and five ongoing studies. For some trials, investigators supplied Dr. Wagner and her colleagues with individual patient data. In all, 4,032 women were included in the analysis of progression-free survival (the trials’ primary end point), and 3,841 in analysis of overall survival.

In first-line chemotherapy progression-free survival was seen as significantly better in the bevacizumab trial arms than in the chemotherapy-only arms (hazard ratio, 0.67; 95% confidence interval, 0.61-0.73). For second-line treatment, a smaller but significant benefit was seen associated with bevacizumab (HR, 0.85; 95% CI, 0.73-0.98). Overall survival did not differ significantly in either first-line (HR, 0.93; 95% CI, 0.84-1.04) or second-line treatment (HR, 0.98; 95% CI, 0.83-1.16).

Patients with previous taxane chemotherapy and with hormone receptor–negative status saw significantly greater progression-free survival benefit, the study found. Quality of life data were available for only two trials and did not show a benefit for bevacizumab. Treatment deaths were lower among patients treated with bevacizumab (odds ratio, 0.60; 95% CI, 0.36-0.99), although serious adverse events were higher (OR, 1.41; 95% CI, 1.13-1.75).

Dr. Wagner and her colleagues wrote in their analysis that their findings had more implications for research priorities than for clinical practice, except to say that, in theory, "patients with a large tumor burden, at risk for local complications but without risk factors for thromboembolic or bleeding complications" should be likelier to benefit.

"If the administration of bevacizumab is considered, the combination with paclitaxel weekly, administered as first-line treatment, should be preferred," the authors said.

"Validated clinical or laboratory markers, which permit a selection of patients most likely to benefit from bevacizumab, are highly warranted," the paper concludes.

Dr. Carlson said that in the decision to use bevacizumab, in the absence of validated clinical markers predicting benefit, "relates to how important you think it is to get a response sooner rather than later, and what kind of risk do you place on the very bad but rare serious side effects – bowel perforation or thrombosis. The challenge is can you identify who those people are prospectively. I wish I could."

Although the NCCN breast cancer guideline still states that bevacizumab should remain an option, "it's not necessarily preferred," Dr Carlson said, adding that he has not prescribed bevacizumab outside a clinical trial for at least 2 years. "While my panel believes it should be available, most of us are not using it."

Dr. Wagner and her colleagues’ study was funded by the Martin Luther University Halle-Wittenberg (Germany) and the German government. One of Dr. Wagner’s coauthors, Dr. Christoph Thomssen, reported an advisory role with and funding from Roche, the parent company of Genentech. Dr. Carlson has received research funding in the past from Genentech but is not doing so currently.

A Cochrane Review of bevacizumab in metastatic breast cancer has found the medication helpful in prolonging progression-free survival and boosting response rates in both first and second-line treatment with certain types of chemotherapy.

However, the same review, published July 10 (doi:10.1002/14651858.CD008941.pub2) found no evidence of improvement in overall survival or quality of life associated with bevacizumab (Avastin), a vascular endothelial growth factor inhibitor whose use in metastatic breast cancer remains controversial.

The findings of improved progression-free survival without gains in overall are consistent with previous published systematic reviews and meta-analyses. The Cochrane Review, led by Dr. Anna Dorothea Wagner of the Centre Hospitalier Universitaire Vaudois in Lausanne (Switzerland) incorporates more trials, more individual patient data, and evidence from the most recent published trial of bevacizumab in breast cancer (Lancet Oncology 2011;12,4:369-76).

"Overall, the clinical value of bevacizumab in metastatic breast cancer can at best be considered as modest," the authors concluded.

In an interview about the Cochrane Review, oncologist Robert W. Carlson of Stanford (Calif.) University called the findings "very reassuring." Dr. Carlson, chair of the National Comprehensive Cancer Network (NCCN) panel that has maintained its endorsement of a bevacizumab and paclitaxel combination despite the Food and Drug Administration’s removal of bevacizumab’s breast cancer indication in November 2011, said that the "objective, independent, thorough look at the data comes up with the same conclusions that I think we already knew."

While the FDA revoked bevacizumab’s breast cancer indication in part because of a lack of evidence for an overall survival gain, the European Medicines Agency continues to recommend bevacizumab in combination with paclitaxel for first-line treatment or with capecitabine for the first-line treatment in patients for whom treatment with taxanes or anthracyclines are inappropriate.

"The question remains whether ... bevacizumab should be available for women with breast cancer. It’s interesting how different people can look at the same conclusions and make different inferences. And that’s really what this study highlights," Dr. Carlson said.

For their research, Dr. Wagner and her colleagues looked at published results from seven randomized controlled trials using bevacizumab and various chemotherapy regimen plus data from one registry and five ongoing studies. For some trials, investigators supplied Dr. Wagner and her colleagues with individual patient data. In all, 4,032 women were included in the analysis of progression-free survival (the trials’ primary end point), and 3,841 in analysis of overall survival.

In first-line chemotherapy progression-free survival was seen as significantly better in the bevacizumab trial arms than in the chemotherapy-only arms (hazard ratio, 0.67; 95% confidence interval, 0.61-0.73). For second-line treatment, a smaller but significant benefit was seen associated with bevacizumab (HR, 0.85; 95% CI, 0.73-0.98). Overall survival did not differ significantly in either first-line (HR, 0.93; 95% CI, 0.84-1.04) or second-line treatment (HR, 0.98; 95% CI, 0.83-1.16).

Patients with previous taxane chemotherapy and with hormone receptor–negative status saw significantly greater progression-free survival benefit, the study found. Quality of life data were available for only two trials and did not show a benefit for bevacizumab. Treatment deaths were lower among patients treated with bevacizumab (odds ratio, 0.60; 95% CI, 0.36-0.99), although serious adverse events were higher (OR, 1.41; 95% CI, 1.13-1.75).

Dr. Wagner and her colleagues wrote in their analysis that their findings had more implications for research priorities than for clinical practice, except to say that, in theory, "patients with a large tumor burden, at risk for local complications but without risk factors for thromboembolic or bleeding complications" should be likelier to benefit.

"If the administration of bevacizumab is considered, the combination with paclitaxel weekly, administered as first-line treatment, should be preferred," the authors said.

"Validated clinical or laboratory markers, which permit a selection of patients most likely to benefit from bevacizumab, are highly warranted," the paper concludes.

Dr. Carlson said that in the decision to use bevacizumab, in the absence of validated clinical markers predicting benefit, "relates to how important you think it is to get a response sooner rather than later, and what kind of risk do you place on the very bad but rare serious side effects – bowel perforation or thrombosis. The challenge is can you identify who those people are prospectively. I wish I could."

Although the NCCN breast cancer guideline still states that bevacizumab should remain an option, "it's not necessarily preferred," Dr Carlson said, adding that he has not prescribed bevacizumab outside a clinical trial for at least 2 years. "While my panel believes it should be available, most of us are not using it."

Dr. Wagner and her colleagues’ study was funded by the Martin Luther University Halle-Wittenberg (Germany) and the German government. One of Dr. Wagner’s coauthors, Dr. Christoph Thomssen, reported an advisory role with and funding from Roche, the parent company of Genentech. Dr. Carlson has received research funding in the past from Genentech but is not doing so currently.

A Cochrane Review of bevacizumab in metastatic breast cancer has found the medication helpful in prolonging progression-free survival and boosting response rates in both first and second-line treatment with certain types of chemotherapy.

However, the same review, published July 10 (doi:10.1002/14651858.CD008941.pub2) found no evidence of improvement in overall survival or quality of life associated with bevacizumab (Avastin), a vascular endothelial growth factor inhibitor whose use in metastatic breast cancer remains controversial.

The findings of improved progression-free survival without gains in overall are consistent with previous published systematic reviews and meta-analyses. The Cochrane Review, led by Dr. Anna Dorothea Wagner of the Centre Hospitalier Universitaire Vaudois in Lausanne (Switzerland) incorporates more trials, more individual patient data, and evidence from the most recent published trial of bevacizumab in breast cancer (Lancet Oncology 2011;12,4:369-76).

"Overall, the clinical value of bevacizumab in metastatic breast cancer can at best be considered as modest," the authors concluded.

In an interview about the Cochrane Review, oncologist Robert W. Carlson of Stanford (Calif.) University called the findings "very reassuring." Dr. Carlson, chair of the National Comprehensive Cancer Network (NCCN) panel that has maintained its endorsement of a bevacizumab and paclitaxel combination despite the Food and Drug Administration’s removal of bevacizumab’s breast cancer indication in November 2011, said that the "objective, independent, thorough look at the data comes up with the same conclusions that I think we already knew."

While the FDA revoked bevacizumab’s breast cancer indication in part because of a lack of evidence for an overall survival gain, the European Medicines Agency continues to recommend bevacizumab in combination with paclitaxel for first-line treatment or with capecitabine for the first-line treatment in patients for whom treatment with taxanes or anthracyclines are inappropriate.

"The question remains whether ... bevacizumab should be available for women with breast cancer. It’s interesting how different people can look at the same conclusions and make different inferences. And that’s really what this study highlights," Dr. Carlson said.

For their research, Dr. Wagner and her colleagues looked at published results from seven randomized controlled trials using bevacizumab and various chemotherapy regimen plus data from one registry and five ongoing studies. For some trials, investigators supplied Dr. Wagner and her colleagues with individual patient data. In all, 4,032 women were included in the analysis of progression-free survival (the trials’ primary end point), and 3,841 in analysis of overall survival.

In first-line chemotherapy progression-free survival was seen as significantly better in the bevacizumab trial arms than in the chemotherapy-only arms (hazard ratio, 0.67; 95% confidence interval, 0.61-0.73). For second-line treatment, a smaller but significant benefit was seen associated with bevacizumab (HR, 0.85; 95% CI, 0.73-0.98). Overall survival did not differ significantly in either first-line (HR, 0.93; 95% CI, 0.84-1.04) or second-line treatment (HR, 0.98; 95% CI, 0.83-1.16).

Patients with previous taxane chemotherapy and with hormone receptor–negative status saw significantly greater progression-free survival benefit, the study found. Quality of life data were available for only two trials and did not show a benefit for bevacizumab. Treatment deaths were lower among patients treated with bevacizumab (odds ratio, 0.60; 95% CI, 0.36-0.99), although serious adverse events were higher (OR, 1.41; 95% CI, 1.13-1.75).

Dr. Wagner and her colleagues wrote in their analysis that their findings had more implications for research priorities than for clinical practice, except to say that, in theory, "patients with a large tumor burden, at risk for local complications but without risk factors for thromboembolic or bleeding complications" should be likelier to benefit.

"If the administration of bevacizumab is considered, the combination with paclitaxel weekly, administered as first-line treatment, should be preferred," the authors said.

"Validated clinical or laboratory markers, which permit a selection of patients most likely to benefit from bevacizumab, are highly warranted," the paper concludes.

Dr. Carlson said that in the decision to use bevacizumab, in the absence of validated clinical markers predicting benefit, "relates to how important you think it is to get a response sooner rather than later, and what kind of risk do you place on the very bad but rare serious side effects – bowel perforation or thrombosis. The challenge is can you identify who those people are prospectively. I wish I could."

Although the NCCN breast cancer guideline still states that bevacizumab should remain an option, "it's not necessarily preferred," Dr Carlson said, adding that he has not prescribed bevacizumab outside a clinical trial for at least 2 years. "While my panel believes it should be available, most of us are not using it."

Dr. Wagner and her colleagues’ study was funded by the Martin Luther University Halle-Wittenberg (Germany) and the German government. One of Dr. Wagner’s coauthors, Dr. Christoph Thomssen, reported an advisory role with and funding from Roche, the parent company of Genentech. Dr. Carlson has received research funding in the past from Genentech but is not doing so currently.

All newly diagnosed melanoma patients with tumors of intermediate thickness – defined as those with a Breslow thickness of between 1 and 4 mm – should undergo sentinel lymph node biopsy, according to a new guideline from two professional societies.

The guideline, issued jointly July 9 by the American Society of Clinical Oncology and the Society of Surgical Oncology, also advises that while the use of sentinel lymph node biopsy (SLNB) in people with thicker or thinner melanomas remains contentious, both categories of patients could benefit from SLNB in some circumstances.

All melanoma patients with a positive SLNB, the guideline says, should be treated with completion lymph node dissection (CLND), the current standard of care, although, the authors noted, it is not yet known whether CLND after a positive SLN biopsy improves 10-year overall survival. This is the subject of a large, ongoing randomized trial, the Multicenter Selective Lymphadenectomy Trial II (MSLT-11).

The guideline’s authors, led by Dr. Sandra L. Wong of the University of Michigan, Ann Arbor, and Dr. Gary H. Lyman of Duke University, Durham, N.C., aimed to use the most current evidence to clarify both the indications for sentinel node biopsy and the role of completion biopsy in people with melanomas.

"It is critically important to identify those patients for whom the expected benefits of resecting regional lymph nodes outweigh the risks of surgical morbidity," they wrote in their analysis.

To this end, Dr. Wong, Dr. Lyman, and 12 other expert panel members undertook a broad literature search and identified 73 studies (most of them observational in design) that met the criteria for inclusion in their meta-analysis. Some 25,000 patients were enrolled in the included studies.

The authors found that while robust evidence supports routine use of sentinel lymph node biopsy (SLNB) in intermediate melanomas, there is also some evidence to support the procedure in patients with thin melanomas (less than 1 mm) when certain other risk factors are present, and in patients with thick melanomas (greater than 4 mm).

For people with melanomas of less than 1 mm Breslow thickness and one or more risk factors such as tumor ulceration or a mitotic rate of 1/mm² or greater, they wrote, "the benefits of pathologic staging may outweigh the potential risks of the procedure," particularly in the subgroup of patients with melanomas ranging from 0.75 mm to 0.99 mm.

Patients with melanomas of 4 mm or greater may also benefit, the guideline says. "Conventional wisdom asserts that patients with thick melanomas have a high risk of systemic disease at the time of diagnosis and that no survival benefit can be derived from removal of regional lymph nodes," the authors wrote.

"However, among patients without distant disease, it can be argued that those with thick melanomas have indications for SLN biopsy similar to those of patients with intermediate-thickness melanomas and derive the same benefits from SLN biopsy as a pathologic staging procedure. One of the main advantages of SLN biopsy in patients with thick melanomas is better regional disease control."

The guideline reiterates that CLND should remain the standard of care for patients with tumor-positive SLNs, even absent survival data from the ongoing MSLT-II trial. The authors cited in support of this evidence from studies that saw nodal recurrence after CLND of between 4.2% and 4.9%. By contrast, as Dr. Wong and colleagues reported in an earlier study, patients in whom CLND was not performed saw a 15% rate of regional nodal recurrence as a site of first metastasis and 41% overall regional nodal recurrence rate (Ann Surg Oncol 2006 13:302-309).

"Until final results of MSLT-II are available, we will not be able to determine, with higher-level evidence, the impact of CLND on regional disease control. Until that time, the best available evidence suggests that CLND is effective at achieving regional disease control in the majority of patients with positive SLNs," the authors wrote.

The guideline was commissioned by ASCO and SSO. The authors disclosed no conflicts of interest.

All newly diagnosed melanoma patients with tumors of intermediate thickness – defined as those with a Breslow thickness of between 1 and 4 mm – should undergo sentinel lymph node biopsy, according to a new guideline from two professional societies.

The guideline, issued jointly July 9 by the American Society of Clinical Oncology and the Society of Surgical Oncology, also advises that while the use of sentinel lymph node biopsy (SLNB) in people with thicker or thinner melanomas remains contentious, both categories of patients could benefit from SLNB in some circumstances.

All melanoma patients with a positive SLNB, the guideline says, should be treated with completion lymph node dissection (CLND), the current standard of care, although, the authors noted, it is not yet known whether CLND after a positive SLN biopsy improves 10-year overall survival. This is the subject of a large, ongoing randomized trial, the Multicenter Selective Lymphadenectomy Trial II (MSLT-11).

The guideline’s authors, led by Dr. Sandra L. Wong of the University of Michigan, Ann Arbor, and Dr. Gary H. Lyman of Duke University, Durham, N.C., aimed to use the most current evidence to clarify both the indications for sentinel node biopsy and the role of completion biopsy in people with melanomas.

"It is critically important to identify those patients for whom the expected benefits of resecting regional lymph nodes outweigh the risks of surgical morbidity," they wrote in their analysis.

To this end, Dr. Wong, Dr. Lyman, and 12 other expert panel members undertook a broad literature search and identified 73 studies (most of them observational in design) that met the criteria for inclusion in their meta-analysis. Some 25,000 patients were enrolled in the included studies.

The authors found that while robust evidence supports routine use of sentinel lymph node biopsy (SLNB) in intermediate melanomas, there is also some evidence to support the procedure in patients with thin melanomas (less than 1 mm) when certain other risk factors are present, and in patients with thick melanomas (greater than 4 mm).

For people with melanomas of less than 1 mm Breslow thickness and one or more risk factors such as tumor ulceration or a mitotic rate of 1/mm² or greater, they wrote, "the benefits of pathologic staging may outweigh the potential risks of the procedure," particularly in the subgroup of patients with melanomas ranging from 0.75 mm to 0.99 mm.

Patients with melanomas of 4 mm or greater may also benefit, the guideline says. "Conventional wisdom asserts that patients with thick melanomas have a high risk of systemic disease at the time of diagnosis and that no survival benefit can be derived from removal of regional lymph nodes," the authors wrote.

"However, among patients without distant disease, it can be argued that those with thick melanomas have indications for SLN biopsy similar to those of patients with intermediate-thickness melanomas and derive the same benefits from SLN biopsy as a pathologic staging procedure. One of the main advantages of SLN biopsy in patients with thick melanomas is better regional disease control."

The guideline reiterates that CLND should remain the standard of care for patients with tumor-positive SLNs, even absent survival data from the ongoing MSLT-II trial. The authors cited in support of this evidence from studies that saw nodal recurrence after CLND of between 4.2% and 4.9%. By contrast, as Dr. Wong and colleagues reported in an earlier study, patients in whom CLND was not performed saw a 15% rate of regional nodal recurrence as a site of first metastasis and 41% overall regional nodal recurrence rate (Ann Surg Oncol 2006 13:302-309).

"Until final results of MSLT-II are available, we will not be able to determine, with higher-level evidence, the impact of CLND on regional disease control. Until that time, the best available evidence suggests that CLND is effective at achieving regional disease control in the majority of patients with positive SLNs," the authors wrote.

The guideline was commissioned by ASCO and SSO. The authors disclosed no conflicts of interest.

All newly diagnosed melanoma patients with tumors of intermediate thickness – defined as those with a Breslow thickness of between 1 and 4 mm – should undergo sentinel lymph node biopsy, according to a new guideline from two professional societies.

The guideline, issued jointly July 9 by the American Society of Clinical Oncology and the Society of Surgical Oncology, also advises that while the use of sentinel lymph node biopsy (SLNB) in people with thicker or thinner melanomas remains contentious, both categories of patients could benefit from SLNB in some circumstances.

All melanoma patients with a positive SLNB, the guideline says, should be treated with completion lymph node dissection (CLND), the current standard of care, although, the authors noted, it is not yet known whether CLND after a positive SLN biopsy improves 10-year overall survival. This is the subject of a large, ongoing randomized trial, the Multicenter Selective Lymphadenectomy Trial II (MSLT-11).

The guideline’s authors, led by Dr. Sandra L. Wong of the University of Michigan, Ann Arbor, and Dr. Gary H. Lyman of Duke University, Durham, N.C., aimed to use the most current evidence to clarify both the indications for sentinel node biopsy and the role of completion biopsy in people with melanomas.

"It is critically important to identify those patients for whom the expected benefits of resecting regional lymph nodes outweigh the risks of surgical morbidity," they wrote in their analysis.

To this end, Dr. Wong, Dr. Lyman, and 12 other expert panel members undertook a broad literature search and identified 73 studies (most of them observational in design) that met the criteria for inclusion in their meta-analysis. Some 25,000 patients were enrolled in the included studies.

The authors found that while robust evidence supports routine use of sentinel lymph node biopsy (SLNB) in intermediate melanomas, there is also some evidence to support the procedure in patients with thin melanomas (less than 1 mm) when certain other risk factors are present, and in patients with thick melanomas (greater than 4 mm).

For people with melanomas of less than 1 mm Breslow thickness and one or more risk factors such as tumor ulceration or a mitotic rate of 1/mm² or greater, they wrote, "the benefits of pathologic staging may outweigh the potential risks of the procedure," particularly in the subgroup of patients with melanomas ranging from 0.75 mm to 0.99 mm.

Patients with melanomas of 4 mm or greater may also benefit, the guideline says. "Conventional wisdom asserts that patients with thick melanomas have a high risk of systemic disease at the time of diagnosis and that no survival benefit can be derived from removal of regional lymph nodes," the authors wrote.

"However, among patients without distant disease, it can be argued that those with thick melanomas have indications for SLN biopsy similar to those of patients with intermediate-thickness melanomas and derive the same benefits from SLN biopsy as a pathologic staging procedure. One of the main advantages of SLN biopsy in patients with thick melanomas is better regional disease control."

The guideline reiterates that CLND should remain the standard of care for patients with tumor-positive SLNs, even absent survival data from the ongoing MSLT-II trial. The authors cited in support of this evidence from studies that saw nodal recurrence after CLND of between 4.2% and 4.9%. By contrast, as Dr. Wong and colleagues reported in an earlier study, patients in whom CLND was not performed saw a 15% rate of regional nodal recurrence as a site of first metastasis and 41% overall regional nodal recurrence rate (Ann Surg Oncol 2006 13:302-309).

"Until final results of MSLT-II are available, we will not be able to determine, with higher-level evidence, the impact of CLND on regional disease control. Until that time, the best available evidence suggests that CLND is effective at achieving regional disease control in the majority of patients with positive SLNs," the authors wrote.

The guideline was commissioned by ASCO and SSO. The authors disclosed no conflicts of interest.

The clinical effectiveness agency for England and Wales has rejected a second bevacizumab combination for metastatic breast cancer, citing the treatment’s high cost, uncertain effect on quality of life, and lack of robust evidence for overall survival improvements.

Roche’s bevacizumab (Avastin) is a monoclonal antibody that works by inhibiting vascular endothelial growth factor (VEGF). It is licensed in the European Union in combination with Roche’s capecitabine (Xeloda) for metastatic breast cancer; however, the National Institute for Health and Clinical Excellence found that the treatment did not meet its cost-effectiveness criteria. NICE’s decision was widely expected after the agency issued negative draft guidance in April.

In 2010, NICE turned down bevacizumab in combination with a taxane for first-line treatment of metastatic breast cancer, its licensed indication at the time; the European Medicines Agency late that year limited the breast cancer indication to a combination with paclitaxel.

In April 2011, EMA said bevacizumab could also be used with capecitabine if other chemotherapy treatments are inappropriate, citing evidence from RIBBON-1, a randomized, placebo-controlled trial that showed average progression-free survival of 8.6 months in patients receiving the combination, compared with 5.7 months in those receiving capecitabine alone.

In a final appraisal published July 6, NICE acknowledged the statistically significant, 2.9-month gain in progression-free survival seen with bevacizumab in the trial. However, the agency said that quality-of-life data were not captured, and while median overall survival also improved by 2.9 months, this result was not statistically significant due in part to crossover.

The manufacturer’s submission to NICE included clinical trial evidence only for a subgroup of people who had been previously treated with a taxane, while the full indication includes both previously treated and treatment-naive patients.

The NICE reviewers said they found "no biologically plausible reason why bevacizumab plus capecitabine would be more effective" in the previously treated subgroup than in the broader population for which the combination is licensed. They also concluded that the incremental cost-effectiveness ratio for the treatment would be at least £82,000 (U.S.$127,000) per quality-adjusted life year (QALY).

Bevacizumab is administered by intravenous infusion at a recommended dose of 10 mg/kg of body weight once every 2 weeks or 15 mg/kg of body weight once every 3 weeks. The average price of bevacizumab treatment for breast cancer in the United Kingdom is £3,689 (U.S.$5,727) per month, according to NICE.

The clinical effectiveness agency for England and Wales has rejected a second bevacizumab combination for metastatic breast cancer, citing the treatment’s high cost, uncertain effect on quality of life, and lack of robust evidence for overall survival improvements.

Roche’s bevacizumab (Avastin) is a monoclonal antibody that works by inhibiting vascular endothelial growth factor (VEGF). It is licensed in the European Union in combination with Roche’s capecitabine (Xeloda) for metastatic breast cancer; however, the National Institute for Health and Clinical Excellence found that the treatment did not meet its cost-effectiveness criteria. NICE’s decision was widely expected after the agency issued negative draft guidance in April.

In 2010, NICE turned down bevacizumab in combination with a taxane for first-line treatment of metastatic breast cancer, its licensed indication at the time; the European Medicines Agency late that year limited the breast cancer indication to a combination with paclitaxel.

In April 2011, EMA said bevacizumab could also be used with capecitabine if other chemotherapy treatments are inappropriate, citing evidence from RIBBON-1, a randomized, placebo-controlled trial that showed average progression-free survival of 8.6 months in patients receiving the combination, compared with 5.7 months in those receiving capecitabine alone.

In a final appraisal published July 6, NICE acknowledged the statistically significant, 2.9-month gain in progression-free survival seen with bevacizumab in the trial. However, the agency said that quality-of-life data were not captured, and while median overall survival also improved by 2.9 months, this result was not statistically significant due in part to crossover.

The manufacturer’s submission to NICE included clinical trial evidence only for a subgroup of people who had been previously treated with a taxane, while the full indication includes both previously treated and treatment-naive patients.

The NICE reviewers said they found "no biologically plausible reason why bevacizumab plus capecitabine would be more effective" in the previously treated subgroup than in the broader population for which the combination is licensed. They also concluded that the incremental cost-effectiveness ratio for the treatment would be at least £82,000 (U.S.$127,000) per quality-adjusted life year (QALY).

Bevacizumab is administered by intravenous infusion at a recommended dose of 10 mg/kg of body weight once every 2 weeks or 15 mg/kg of body weight once every 3 weeks. The average price of bevacizumab treatment for breast cancer in the United Kingdom is £3,689 (U.S.$5,727) per month, according to NICE.

The clinical effectiveness agency for England and Wales has rejected a second bevacizumab combination for metastatic breast cancer, citing the treatment’s high cost, uncertain effect on quality of life, and lack of robust evidence for overall survival improvements.

Roche’s bevacizumab (Avastin) is a monoclonal antibody that works by inhibiting vascular endothelial growth factor (VEGF). It is licensed in the European Union in combination with Roche’s capecitabine (Xeloda) for metastatic breast cancer; however, the National Institute for Health and Clinical Excellence found that the treatment did not meet its cost-effectiveness criteria. NICE’s decision was widely expected after the agency issued negative draft guidance in April.

In 2010, NICE turned down bevacizumab in combination with a taxane for first-line treatment of metastatic breast cancer, its licensed indication at the time; the European Medicines Agency late that year limited the breast cancer indication to a combination with paclitaxel.

In April 2011, EMA said bevacizumab could also be used with capecitabine if other chemotherapy treatments are inappropriate, citing evidence from RIBBON-1, a randomized, placebo-controlled trial that showed average progression-free survival of 8.6 months in patients receiving the combination, compared with 5.7 months in those receiving capecitabine alone.

In a final appraisal published July 6, NICE acknowledged the statistically significant, 2.9-month gain in progression-free survival seen with bevacizumab in the trial. However, the agency said that quality-of-life data were not captured, and while median overall survival also improved by 2.9 months, this result was not statistically significant due in part to crossover.

The manufacturer’s submission to NICE included clinical trial evidence only for a subgroup of people who had been previously treated with a taxane, while the full indication includes both previously treated and treatment-naive patients.

The NICE reviewers said they found "no biologically plausible reason why bevacizumab plus capecitabine would be more effective" in the previously treated subgroup than in the broader population for which the combination is licensed. They also concluded that the incremental cost-effectiveness ratio for the treatment would be at least £82,000 (U.S.$127,000) per quality-adjusted life year (QALY).

Bevacizumab is administered by intravenous infusion at a recommended dose of 10 mg/kg of body weight once every 2 weeks or 15 mg/kg of body weight once every 3 weeks. The average price of bevacizumab treatment for breast cancer in the United Kingdom is £3,689 (U.S.$5,727) per month, according to NICE.

The European Medicines Agency said June 22 that it had recommended an extension of indication for the cancer drug everolimus to treat hormone receptor–positive, HER2–negative advanced breast cancer.

Everolimus (Afinitor, Novartis), already recommended by the EMA to treat pancreatic and renal cell cancers, is now recommended throughout the European Union in combination with exemestane as a second-line treatment in postmenopausal women in whom aromatase inhibitors have failed.

EMA also extended indications of agents used to treat two rheumatic diseases.

Etanercept (Enbrel), marketed by Pfizer and already licensed in Europe to treat rheumatic arthritis in adults, is now recommended as a treatment for polyarthritis (rheumatoid factor positive or negative), extended oligoarthritis, and psoriatic arthritis in children and adolescents in whom methotrexate has failed or is inappropriate. The indication for etanercept also was extended to treatment of enthesitis-related arthritis in adolescents 12 years and older not responding to conventional therapy.

Adalimumab (Humira), marketed by Abbott and licensed in Europe to treat a range of rheumatic diseases, will now be indicated for the treatment of adults with severe axial spondyloarthritis who have had an inadequate response to, or are intolerant of, nonsteroidal anti-inflammatory drugs. The new indication covers patients without radiographic evidence of axial spondyloarthritis but with evidence of inflammation determined by MRI or elevated C-reactive protein.

Also at its June meeting, the agency recommended a new six-in-one combination vaccine developed for use outside the European Union. Hexaxim, marketed by Sanofi Pasteur, will be used in children aged 6 weeks to 2 years old to inoculate against diphtheria, tetanus, pertussis, hepatitis B, polio, and diseases caused by Haemophilus influenzae type B, including meningitis. The vaccine is administered as three doses 4 or more weeks apart.

Five of the active substances in the vaccine have been used in other vaccines and have been previously combined in Pentaxim, also manufactured by Sanofi Pasteur. The new vaccine adds Hansenula polymorpha-derived recombinant hepatitis B surface antigen. Clinical trials in Argentina, Mexico, Peru, Turkey, Thailand, and South Africa found the new vaccine to be as effective and safe as Pentaxim plus a monovalent hepatitis B vaccine, EMA said.

EMA recommended three additional new medications:

• Teduglutide (Revestive, Nycomed), a subcutaneous injection to treat short-bowel syndrome, a condition in which nutrients are not absorbed as a result of severe intestinal disease or the surgical removal of a large portion of the small intestine.

• Glycopyrronium bromide (Enurev, Novartis), a maintenance bronchodilator treatment for symptom relief in adults with chronic obstructive pulmonary disease.

• Ceftaroline fosamil (Zinforo, AstraZeneca), an infusion for treatment of adults with complicated skin and soft-tissue infections and community-acquired pneumonia.

The agency also announced that it was restricting indications for two medications on safety concerns. Following reports from Germany of hypersensitivity reactions, the agency advised clinicians not to prescribe tolperisone for indications other than poststroke spasticity and to use oral formulations in place of injectable ones. Tolperisone is a muscle relaxant used in Europe since the 1960s and only available in a handful of countries.

EMA recommended restricting the use of trimetazidine to second-line, add-on therapy after reports from France of movement disorders including Parkinsonian symptoms, restless leg syndrome, tremors and gait instability associated with the medicine. Trimetazidine-containing medicines have been available since the 1970s in Europe and are used in the treatment of patients with angina pectoris. Clinicians are also advised not to prescribe in patients with these and related movement disorders, or those who have severe renal impairment.

All EMA recommendations require European Commission approval to be final.

The European Medicines Agency said June 22 that it had recommended an extension of indication for the cancer drug everolimus to treat hormone receptor–positive, HER2–negative advanced breast cancer.

Everolimus (Afinitor, Novartis), already recommended by the EMA to treat pancreatic and renal cell cancers, is now recommended throughout the European Union in combination with exemestane as a second-line treatment in postmenopausal women in whom aromatase inhibitors have failed.

EMA also extended indications of agents used to treat two rheumatic diseases.

Etanercept (Enbrel), marketed by Pfizer and already licensed in Europe to treat rheumatic arthritis in adults, is now recommended as a treatment for polyarthritis (rheumatoid factor positive or negative), extended oligoarthritis, and psoriatic arthritis in children and adolescents in whom methotrexate has failed or is inappropriate. The indication for etanercept also was extended to treatment of enthesitis-related arthritis in adolescents 12 years and older not responding to conventional therapy.

Adalimumab (Humira), marketed by Abbott and licensed in Europe to treat a range of rheumatic diseases, will now be indicated for the treatment of adults with severe axial spondyloarthritis who have had an inadequate response to, or are intolerant of, nonsteroidal anti-inflammatory drugs. The new indication covers patients without radiographic evidence of axial spondyloarthritis but with evidence of inflammation determined by MRI or elevated C-reactive protein.

Also at its June meeting, the agency recommended a new six-in-one combination vaccine developed for use outside the European Union. Hexaxim, marketed by Sanofi Pasteur, will be used in children aged 6 weeks to 2 years old to inoculate against diphtheria, tetanus, pertussis, hepatitis B, polio, and diseases caused by Haemophilus influenzae type B, including meningitis. The vaccine is administered as three doses 4 or more weeks apart.

Five of the active substances in the vaccine have been used in other vaccines and have been previously combined in Pentaxim, also manufactured by Sanofi Pasteur. The new vaccine adds Hansenula polymorpha-derived recombinant hepatitis B surface antigen. Clinical trials in Argentina, Mexico, Peru, Turkey, Thailand, and South Africa found the new vaccine to be as effective and safe as Pentaxim plus a monovalent hepatitis B vaccine, EMA said.

EMA recommended three additional new medications:

• Teduglutide (Revestive, Nycomed), a subcutaneous injection to treat short-bowel syndrome, a condition in which nutrients are not absorbed as a result of severe intestinal disease or the surgical removal of a large portion of the small intestine.

• Glycopyrronium bromide (Enurev, Novartis), a maintenance bronchodilator treatment for symptom relief in adults with chronic obstructive pulmonary disease.

• Ceftaroline fosamil (Zinforo, AstraZeneca), an infusion for treatment of adults with complicated skin and soft-tissue infections and community-acquired pneumonia.

The agency also announced that it was restricting indications for two medications on safety concerns. Following reports from Germany of hypersensitivity reactions, the agency advised clinicians not to prescribe tolperisone for indications other than poststroke spasticity and to use oral formulations in place of injectable ones. Tolperisone is a muscle relaxant used in Europe since the 1960s and only available in a handful of countries.

EMA recommended restricting the use of trimetazidine to second-line, add-on therapy after reports from France of movement disorders including Parkinsonian symptoms, restless leg syndrome, tremors and gait instability associated with the medicine. Trimetazidine-containing medicines have been available since the 1970s in Europe and are used in the treatment of patients with angina pectoris. Clinicians are also advised not to prescribe in patients with these and related movement disorders, or those who have severe renal impairment.

All EMA recommendations require European Commission approval to be final.

The European Medicines Agency said June 22 that it had recommended an extension of indication for the cancer drug everolimus to treat hormone receptor–positive, HER2–negative advanced breast cancer.

Everolimus (Afinitor, Novartis), already recommended by the EMA to treat pancreatic and renal cell cancers, is now recommended throughout the European Union in combination with exemestane as a second-line treatment in postmenopausal women in whom aromatase inhibitors have failed.

EMA also extended indications of agents used to treat two rheumatic diseases.

Etanercept (Enbrel), marketed by Pfizer and already licensed in Europe to treat rheumatic arthritis in adults, is now recommended as a treatment for polyarthritis (rheumatoid factor positive or negative), extended oligoarthritis, and psoriatic arthritis in children and adolescents in whom methotrexate has failed or is inappropriate. The indication for etanercept also was extended to treatment of enthesitis-related arthritis in adolescents 12 years and older not responding to conventional therapy.

Adalimumab (Humira), marketed by Abbott and licensed in Europe to treat a range of rheumatic diseases, will now be indicated for the treatment of adults with severe axial spondyloarthritis who have had an inadequate response to, or are intolerant of, nonsteroidal anti-inflammatory drugs. The new indication covers patients without radiographic evidence of axial spondyloarthritis but with evidence of inflammation determined by MRI or elevated C-reactive protein.

Also at its June meeting, the agency recommended a new six-in-one combination vaccine developed for use outside the European Union. Hexaxim, marketed by Sanofi Pasteur, will be used in children aged 6 weeks to 2 years old to inoculate against diphtheria, tetanus, pertussis, hepatitis B, polio, and diseases caused by Haemophilus influenzae type B, including meningitis. The vaccine is administered as three doses 4 or more weeks apart.

Five of the active substances in the vaccine have been used in other vaccines and have been previously combined in Pentaxim, also manufactured by Sanofi Pasteur. The new vaccine adds Hansenula polymorpha-derived recombinant hepatitis B surface antigen. Clinical trials in Argentina, Mexico, Peru, Turkey, Thailand, and South Africa found the new vaccine to be as effective and safe as Pentaxim plus a monovalent hepatitis B vaccine, EMA said.

EMA recommended three additional new medications:

• Teduglutide (Revestive, Nycomed), a subcutaneous injection to treat short-bowel syndrome, a condition in which nutrients are not absorbed as a result of severe intestinal disease or the surgical removal of a large portion of the small intestine.

• Glycopyrronium bromide (Enurev, Novartis), a maintenance bronchodilator treatment for symptom relief in adults with chronic obstructive pulmonary disease.

• Ceftaroline fosamil (Zinforo, AstraZeneca), an infusion for treatment of adults with complicated skin and soft-tissue infections and community-acquired pneumonia.

The agency also announced that it was restricting indications for two medications on safety concerns. Following reports from Germany of hypersensitivity reactions, the agency advised clinicians not to prescribe tolperisone for indications other than poststroke spasticity and to use oral formulations in place of injectable ones. Tolperisone is a muscle relaxant used in Europe since the 1960s and only available in a handful of countries.

EMA recommended restricting the use of trimetazidine to second-line, add-on therapy after reports from France of movement disorders including Parkinsonian symptoms, restless leg syndrome, tremors and gait instability associated with the medicine. Trimetazidine-containing medicines have been available since the 1970s in Europe and are used in the treatment of patients with angina pectoris. Clinicians are also advised not to prescribe in patients with these and related movement disorders, or those who have severe renal impairment.

All EMA recommendations require European Commission approval to be final.

Up to a tenth of parents of infants in Portland, Ore., consistently strayed from recommended vaccination schedules, and health providers accommodated them, according to findings of a cohort study.

The children of consistently shot-limiting parents were less likely to be caught up at either 9 or 19 months, the study also found.

Steve G. Robison, epidemiologist for the Oregon Health Authority’s immunization program, and his colleagues, conducted a retrospective analysis of immunization records for 97,711 children born between 2003 and 2009, published online June 18 in Pediatrics (2012;130:32-38 [doi:10.1542/peds.2011-3154]).

"Many parents have heard a lot of opinions about immunizing young children. We looked to see if parents were actually following alternative immunization schedules," Mr. Robison said in an interview.

In the cohort, 4.6% of children had received no more than two vaccine injections in a single immunization visit from birth to 9 months, a practice promoted by at least two physician authors of books aimed at parents. Episodic limiters, by contrast, were defined as having at least one visit in which the number of shots was limited, and only one or two visits with three or more injections, by 9 months.

The proportion of consistent shot limiters in the cohort increased from 2.4% to 9.5% between 2006 and 2009, the study found. Episodic limiters increased from 19.5% to 30.1% in the same period.

The study showed that the consistent shot limiters had fewer shots on average by 9 months than did those consistently adhering to or episodically limiting adherence to recommended schedules (6.4 vs. 10.4), but more provider visits (4.2 vs. 3.2). This likely means that physicians have been accommodating parents’ desires to vaccinate differently, and ultimately less, than is recommended by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

At 9 months, the consistent shot limiters were significantly less likely to be caught up for any immunization series than nonlimiters or episodic limiters, with an average relative risk (RR) of 0.55. By 19 months, the risk was attenuated for vaccinations due by 9 months (average RR, 0.72). However, the gap was again seen for vaccination due by 19 months (average RR, 0.54). For varicella, hepatitis A, or MMR in particular, consistent limiters were less likely on average to have received these at 19 months (average RR, 0.48) than episodic or nonlimiters.

"Kids with limited shots also had more visits to doctors for shots," Mr. Robison said. "This is what some alternative immunization schedules tell parents to do – to take their babies in almost every month for a shot in their first year of life. But these kids got fewer shots."

Recent national studies have shown trends toward increasing parental adoption of alternative vaccination schedules, with reports of between 13% and 21.8% of parents intentionally following alternative schedules that delay or limit vaccination (Pediatrics 2011;128:848-56 and Public Health Rep. 2010;125:534-41). Mr. Robison and his colleagues found that between 2004 and 2009, episodic and consistent limiters constituted between 24.9% and 39.6% of the Portland cohort.

Although the Portland study showed a higher proportion of limiters than did earlier studies, "we do not know if it can be generalized beyond the Portland area and certainly hope not," Mr. Robison said in an interview. The study population, he pointed out, has high vaccine exemption rates for school entry and may not be representative on a national scale.

Mr. Robison’s study also found that although two physicians have published immunization schedules deviating from ACIP recommendations, the consistent shot-limiting parents were not adhering closely to those alternative schedules. However, their tendency to have avoided certain types of shots by 19 months – particularly varicella, hepatitis A, or MMR – seemed to be consistent with the ideas promulgated by these authors.

"Dr. Stephanie Cave’s 2007 schedule specifies a total of five visits at 4, 5, 6, 7, and 8 months, and Dr. Robert Sears’s ‘Alternative Vaccine Schedule’ suggests a total of six visits at 2, 3, 4, 5, 6, and 7 months. Both Dr. Cave and Dr. Sears specify avoidance of HepB vaccines in the first 2 years of life, unless the birth mother is HepB surface antigen positive. Other specifics of Dr. Cave’s schedule, reissued in 2007, include entirely avoiding the rotavirus vaccine and delaying the pneumococcal vaccine until the second year of life. According to Dr. Sears’s schedule, infants would receive all recommended vaccines by 9 months of age except for the HepB and the polio vaccine," Mr. Robison and his colleagues related.

"There are no known benefits to delaying or spacing out shots this way," Mr. Robison said. "On the other hand, there are extra costs and time for a parent to take their kid in to the doctor. It’s also easy for a baby on an alternative schedule to fall behind and not catch-up."

Mr. Robison and his colleagues noted as limitations of their study the fact that it used a strict definition of consistent shot limiting, and excluded from its analysis children who had not received any vaccinations at all. Also, the role of providers was not examined, nor was the possibility of clustering among accommodating providers.

The study was funded by a grant from the Centers for Disease Control and Prevention. Neither Mr. Robison nor his colleagues declared conflicts of interest.

Up to a tenth of parents of infants in Portland, Ore., consistently strayed from recommended vaccination schedules, and health providers accommodated them, according to findings of a cohort study.

The children of consistently shot-limiting parents were less likely to be caught up at either 9 or 19 months, the study also found.

Steve G. Robison, epidemiologist for the Oregon Health Authority’s immunization program, and his colleagues, conducted a retrospective analysis of immunization records for 97,711 children born between 2003 and 2009, published online June 18 in Pediatrics (2012;130:32-38 [doi:10.1542/peds.2011-3154]).

"Many parents have heard a lot of opinions about immunizing young children. We looked to see if parents were actually following alternative immunization schedules," Mr. Robison said in an interview.

In the cohort, 4.6% of children had received no more than two vaccine injections in a single immunization visit from birth to 9 months, a practice promoted by at least two physician authors of books aimed at parents. Episodic limiters, by contrast, were defined as having at least one visit in which the number of shots was limited, and only one or two visits with three or more injections, by 9 months.

The proportion of consistent shot limiters in the cohort increased from 2.4% to 9.5% between 2006 and 2009, the study found. Episodic limiters increased from 19.5% to 30.1% in the same period.

The study showed that the consistent shot limiters had fewer shots on average by 9 months than did those consistently adhering to or episodically limiting adherence to recommended schedules (6.4 vs. 10.4), but more provider visits (4.2 vs. 3.2). This likely means that physicians have been accommodating parents’ desires to vaccinate differently, and ultimately less, than is recommended by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

At 9 months, the consistent shot limiters were significantly less likely to be caught up for any immunization series than nonlimiters or episodic limiters, with an average relative risk (RR) of 0.55. By 19 months, the risk was attenuated for vaccinations due by 9 months (average RR, 0.72). However, the gap was again seen for vaccination due by 19 months (average RR, 0.54). For varicella, hepatitis A, or MMR in particular, consistent limiters were less likely on average to have received these at 19 months (average RR, 0.48) than episodic or nonlimiters.

"Kids with limited shots also had more visits to doctors for shots," Mr. Robison said. "This is what some alternative immunization schedules tell parents to do – to take their babies in almost every month for a shot in their first year of life. But these kids got fewer shots."

Recent national studies have shown trends toward increasing parental adoption of alternative vaccination schedules, with reports of between 13% and 21.8% of parents intentionally following alternative schedules that delay or limit vaccination (Pediatrics 2011;128:848-56 and Public Health Rep. 2010;125:534-41). Mr. Robison and his colleagues found that between 2004 and 2009, episodic and consistent limiters constituted between 24.9% and 39.6% of the Portland cohort.

Although the Portland study showed a higher proportion of limiters than did earlier studies, "we do not know if it can be generalized beyond the Portland area and certainly hope not," Mr. Robison said in an interview. The study population, he pointed out, has high vaccine exemption rates for school entry and may not be representative on a national scale.

Mr. Robison’s study also found that although two physicians have published immunization schedules deviating from ACIP recommendations, the consistent shot-limiting parents were not adhering closely to those alternative schedules. However, their tendency to have avoided certain types of shots by 19 months – particularly varicella, hepatitis A, or MMR – seemed to be consistent with the ideas promulgated by these authors.

"Dr. Stephanie Cave’s 2007 schedule specifies a total of five visits at 4, 5, 6, 7, and 8 months, and Dr. Robert Sears’s ‘Alternative Vaccine Schedule’ suggests a total of six visits at 2, 3, 4, 5, 6, and 7 months. Both Dr. Cave and Dr. Sears specify avoidance of HepB vaccines in the first 2 years of life, unless the birth mother is HepB surface antigen positive. Other specifics of Dr. Cave’s schedule, reissued in 2007, include entirely avoiding the rotavirus vaccine and delaying the pneumococcal vaccine until the second year of life. According to Dr. Sears’s schedule, infants would receive all recommended vaccines by 9 months of age except for the HepB and the polio vaccine," Mr. Robison and his colleagues related.

"There are no known benefits to delaying or spacing out shots this way," Mr. Robison said. "On the other hand, there are extra costs and time for a parent to take their kid in to the doctor. It’s also easy for a baby on an alternative schedule to fall behind and not catch-up."

Mr. Robison and his colleagues noted as limitations of their study the fact that it used a strict definition of consistent shot limiting, and excluded from its analysis children who had not received any vaccinations at all. Also, the role of providers was not examined, nor was the possibility of clustering among accommodating providers.

The study was funded by a grant from the Centers for Disease Control and Prevention. Neither Mr. Robison nor his colleagues declared conflicts of interest.

Up to a tenth of parents of infants in Portland, Ore., consistently strayed from recommended vaccination schedules, and health providers accommodated them, according to findings of a cohort study.

The children of consistently shot-limiting parents were less likely to be caught up at either 9 or 19 months, the study also found.

Steve G. Robison, epidemiologist for the Oregon Health Authority’s immunization program, and his colleagues, conducted a retrospective analysis of immunization records for 97,711 children born between 2003 and 2009, published online June 18 in Pediatrics (2012;130:32-38 [doi:10.1542/peds.2011-3154]).

"Many parents have heard a lot of opinions about immunizing young children. We looked to see if parents were actually following alternative immunization schedules," Mr. Robison said in an interview.

In the cohort, 4.6% of children had received no more than two vaccine injections in a single immunization visit from birth to 9 months, a practice promoted by at least two physician authors of books aimed at parents. Episodic limiters, by contrast, were defined as having at least one visit in which the number of shots was limited, and only one or two visits with three or more injections, by 9 months.

The proportion of consistent shot limiters in the cohort increased from 2.4% to 9.5% between 2006 and 2009, the study found. Episodic limiters increased from 19.5% to 30.1% in the same period.

The study showed that the consistent shot limiters had fewer shots on average by 9 months than did those consistently adhering to or episodically limiting adherence to recommended schedules (6.4 vs. 10.4), but more provider visits (4.2 vs. 3.2). This likely means that physicians have been accommodating parents’ desires to vaccinate differently, and ultimately less, than is recommended by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

At 9 months, the consistent shot limiters were significantly less likely to be caught up for any immunization series than nonlimiters or episodic limiters, with an average relative risk (RR) of 0.55. By 19 months, the risk was attenuated for vaccinations due by 9 months (average RR, 0.72). However, the gap was again seen for vaccination due by 19 months (average RR, 0.54). For varicella, hepatitis A, or MMR in particular, consistent limiters were less likely on average to have received these at 19 months (average RR, 0.48) than episodic or nonlimiters.

"Kids with limited shots also had more visits to doctors for shots," Mr. Robison said. "This is what some alternative immunization schedules tell parents to do – to take their babies in almost every month for a shot in their first year of life. But these kids got fewer shots."

Recent national studies have shown trends toward increasing parental adoption of alternative vaccination schedules, with reports of between 13% and 21.8% of parents intentionally following alternative schedules that delay or limit vaccination (Pediatrics 2011;128:848-56 and Public Health Rep. 2010;125:534-41). Mr. Robison and his colleagues found that between 2004 and 2009, episodic and consistent limiters constituted between 24.9% and 39.6% of the Portland cohort.

Although the Portland study showed a higher proportion of limiters than did earlier studies, "we do not know if it can be generalized beyond the Portland area and certainly hope not," Mr. Robison said in an interview. The study population, he pointed out, has high vaccine exemption rates for school entry and may not be representative on a national scale.

Mr. Robison’s study also found that although two physicians have published immunization schedules deviating from ACIP recommendations, the consistent shot-limiting parents were not adhering closely to those alternative schedules. However, their tendency to have avoided certain types of shots by 19 months – particularly varicella, hepatitis A, or MMR – seemed to be consistent with the ideas promulgated by these authors.

"Dr. Stephanie Cave’s 2007 schedule specifies a total of five visits at 4, 5, 6, 7, and 8 months, and Dr. Robert Sears’s ‘Alternative Vaccine Schedule’ suggests a total of six visits at 2, 3, 4, 5, 6, and 7 months. Both Dr. Cave and Dr. Sears specify avoidance of HepB vaccines in the first 2 years of life, unless the birth mother is HepB surface antigen positive. Other specifics of Dr. Cave’s schedule, reissued in 2007, include entirely avoiding the rotavirus vaccine and delaying the pneumococcal vaccine until the second year of life. According to Dr. Sears’s schedule, infants would receive all recommended vaccines by 9 months of age except for the HepB and the polio vaccine," Mr. Robison and his colleagues related.

"There are no known benefits to delaying or spacing out shots this way," Mr. Robison said. "On the other hand, there are extra costs and time for a parent to take their kid in to the doctor. It’s also easy for a baby on an alternative schedule to fall behind and not catch-up."

Mr. Robison and his colleagues noted as limitations of their study the fact that it used a strict definition of consistent shot limiting, and excluded from its analysis children who had not received any vaccinations at all. Also, the role of providers was not examined, nor was the possibility of clustering among accommodating providers.

The study was funded by a grant from the Centers for Disease Control and Prevention. Neither Mr. Robison nor his colleagues declared conflicts of interest.

Baseline factors predicting functional outcome after first-episode psychosis differ depending on whether the psychosis is caused by schizophrenia or another type of disorder, a team of researchers in Spain has found.

In a study that enrolled 95 people with first-episode psychosis who were followed up for 2 years, processing speed significantly predicted most functional outcome measures in patients who were found to have schizophrenia spectrum disorders.

Among people who were later diagnosed with bipolar disorder and other nonschizophrenic syndromes, however, visuospatial functioning (spatial orientation, motion detection, and stimulus perception) was the only significant predictor of functional outcomes.

For both groups together, higher levels of negative symptoms at baseline predicted worse functional outcomes, a finding consistent with those of many previous studies.

For the current study, published in the Journal of Psychiatric Research (2012;46:774-81), Javier Peña of the University of Deusto in Bilbao, Spain, and colleagues recruited 109 patients who were admitted to one psychiatric hospital’s first-episode psychosis unit.

After patients were stabilized for positive symptoms, each underwent an extensive neuropsychological evaluation and completed a battery of cognitive tests. Subjects’ functional outcomes were measured using three standardized exams: the WHODAS (WHO Disability Assessment Schedule), the GAF (Global Assessment of Functioning) scale, and the CGI (Clinical Global Impression) scale.

Of the 95 subjects who completed follow-up and were entered into analysis, 58 were ultimately diagnosed with schizophrenia syndromes and 37 were diagnosed with nonschizophrenia psychotic syndromes (including bipolar disorder, delusional disorder, and acute/transient psychosis).

The two subgroups were closely matched in terms of age (mean, 28 years in both groups at baseline), sex, vocabulary, and duration of untreated psychosis, although the schizophrenia group had fewer years of education and worse premorbid functioning. During the follow-up period, patients were treated with atypical antipsychotic medications at doses determined by their clinicians.

The authors found that low processing speed at admission significantly predicted most functional outcome measures at follow-up in patients with schizophrenia after investigators controlled for the effects of other variables. Processing speed explained 10% and 11% of the variance, respectively, on the CGI and GAF exams at the 2-year follow-up.

But for patients without schizophrenia, visuospatial functioning was found to be the best predictor of functional outcome, explaining 21%, 40%, and 21% of the variance on the CGI, GAF, and WHODAS measures for the subgroup at last follow-up.

The investigators noted as limitations of their research the fact that the variables they sought to test – sociodemographics, clinical variables, neuropsychological domains, premorbid functioning, and duration of untreated psychosis – were not necessarily the only variables that could affect functional outcomes after first-episode psychosis.

They also noted that "scarce attention" has been given to the question of whether the same factors serve as functional outcome predictors in both schizophrenic and nonschizophrenic patient groups. However, they said, their findings suggested that regardless of diagnosis, patients suffering a first psychotic episode could benefit from rehabilitation programs intended to improve neuropsychological function.

"Obtaining symptomatic improvement as the only treatment goal incurs the risk of overestimating patients’ overall functioning," the investigators wrote in their analysis.

The study was funded by the Spanish Ministry of Health and the Basque government. The authors stated that they had no conflicts of interest.

Baseline factors predicting functional outcome after first-episode psychosis differ depending on whether the psychosis is caused by schizophrenia or another type of disorder, a team of researchers in Spain has found.

In a study that enrolled 95 people with first-episode psychosis who were followed up for 2 years, processing speed significantly predicted most functional outcome measures in patients who were found to have schizophrenia spectrum disorders.

Among people who were later diagnosed with bipolar disorder and other nonschizophrenic syndromes, however, visuospatial functioning (spatial orientation, motion detection, and stimulus perception) was the only significant predictor of functional outcomes.

For both groups together, higher levels of negative symptoms at baseline predicted worse functional outcomes, a finding consistent with those of many previous studies.

For the current study, published in the Journal of Psychiatric Research (2012;46:774-81), Javier Peña of the University of Deusto in Bilbao, Spain, and colleagues recruited 109 patients who were admitted to one psychiatric hospital’s first-episode psychosis unit.

After patients were stabilized for positive symptoms, each underwent an extensive neuropsychological evaluation and completed a battery of cognitive tests. Subjects’ functional outcomes were measured using three standardized exams: the WHODAS (WHO Disability Assessment Schedule), the GAF (Global Assessment of Functioning) scale, and the CGI (Clinical Global Impression) scale.

Of the 95 subjects who completed follow-up and were entered into analysis, 58 were ultimately diagnosed with schizophrenia syndromes and 37 were diagnosed with nonschizophrenia psychotic syndromes (including bipolar disorder, delusional disorder, and acute/transient psychosis).

The two subgroups were closely matched in terms of age (mean, 28 years in both groups at baseline), sex, vocabulary, and duration of untreated psychosis, although the schizophrenia group had fewer years of education and worse premorbid functioning. During the follow-up period, patients were treated with atypical antipsychotic medications at doses determined by their clinicians.

The authors found that low processing speed at admission significantly predicted most functional outcome measures at follow-up in patients with schizophrenia after investigators controlled for the effects of other variables. Processing speed explained 10% and 11% of the variance, respectively, on the CGI and GAF exams at the 2-year follow-up.

But for patients without schizophrenia, visuospatial functioning was found to be the best predictor of functional outcome, explaining 21%, 40%, and 21% of the variance on the CGI, GAF, and WHODAS measures for the subgroup at last follow-up.

The investigators noted as limitations of their research the fact that the variables they sought to test – sociodemographics, clinical variables, neuropsychological domains, premorbid functioning, and duration of untreated psychosis – were not necessarily the only variables that could affect functional outcomes after first-episode psychosis.

They also noted that "scarce attention" has been given to the question of whether the same factors serve as functional outcome predictors in both schizophrenic and nonschizophrenic patient groups. However, they said, their findings suggested that regardless of diagnosis, patients suffering a first psychotic episode could benefit from rehabilitation programs intended to improve neuropsychological function.

"Obtaining symptomatic improvement as the only treatment goal incurs the risk of overestimating patients’ overall functioning," the investigators wrote in their analysis.

The study was funded by the Spanish Ministry of Health and the Basque government. The authors stated that they had no conflicts of interest.

Baseline factors predicting functional outcome after first-episode psychosis differ depending on whether the psychosis is caused by schizophrenia or another type of disorder, a team of researchers in Spain has found.

In a study that enrolled 95 people with first-episode psychosis who were followed up for 2 years, processing speed significantly predicted most functional outcome measures in patients who were found to have schizophrenia spectrum disorders.

Among people who were later diagnosed with bipolar disorder and other nonschizophrenic syndromes, however, visuospatial functioning (spatial orientation, motion detection, and stimulus perception) was the only significant predictor of functional outcomes.

For both groups together, higher levels of negative symptoms at baseline predicted worse functional outcomes, a finding consistent with those of many previous studies.

For the current study, published in the Journal of Psychiatric Research (2012;46:774-81), Javier Peña of the University of Deusto in Bilbao, Spain, and colleagues recruited 109 patients who were admitted to one psychiatric hospital’s first-episode psychosis unit.

After patients were stabilized for positive symptoms, each underwent an extensive neuropsychological evaluation and completed a battery of cognitive tests. Subjects’ functional outcomes were measured using three standardized exams: the WHODAS (WHO Disability Assessment Schedule), the GAF (Global Assessment of Functioning) scale, and the CGI (Clinical Global Impression) scale.

Of the 95 subjects who completed follow-up and were entered into analysis, 58 were ultimately diagnosed with schizophrenia syndromes and 37 were diagnosed with nonschizophrenia psychotic syndromes (including bipolar disorder, delusional disorder, and acute/transient psychosis).

The two subgroups were closely matched in terms of age (mean, 28 years in both groups at baseline), sex, vocabulary, and duration of untreated psychosis, although the schizophrenia group had fewer years of education and worse premorbid functioning. During the follow-up period, patients were treated with atypical antipsychotic medications at doses determined by their clinicians.

The authors found that low processing speed at admission significantly predicted most functional outcome measures at follow-up in patients with schizophrenia after investigators controlled for the effects of other variables. Processing speed explained 10% and 11% of the variance, respectively, on the CGI and GAF exams at the 2-year follow-up.

But for patients without schizophrenia, visuospatial functioning was found to be the best predictor of functional outcome, explaining 21%, 40%, and 21% of the variance on the CGI, GAF, and WHODAS measures for the subgroup at last follow-up.

The investigators noted as limitations of their research the fact that the variables they sought to test – sociodemographics, clinical variables, neuropsychological domains, premorbid functioning, and duration of untreated psychosis – were not necessarily the only variables that could affect functional outcomes after first-episode psychosis.

They also noted that "scarce attention" has been given to the question of whether the same factors serve as functional outcome predictors in both schizophrenic and nonschizophrenic patient groups. However, they said, their findings suggested that regardless of diagnosis, patients suffering a first psychotic episode could benefit from rehabilitation programs intended to improve neuropsychological function.

"Obtaining symptomatic improvement as the only treatment goal incurs the risk of overestimating patients’ overall functioning," the investigators wrote in their analysis.

The study was funded by the Spanish Ministry of Health and the Basque government. The authors stated that they had no conflicts of interest.

Aggressive blood pressure lowering, and the degree of a patient’s adiposity, appear unrelated to cardiovascular disease outcomes in individuals with diabetes, according to a new analysis of data from the large, randomized controlled trial, Action to Control Cardiovascular Risk in Diabetes, presented at the annual meeting of the American Diabetes Association in Philadelphia.

The subanalysis follows on findings from the original blood-pressure study (n = 4,733) that showed no difference in cardiovascular disease (CVD) risk between people with diabetes mellitus whose blood pressure was treated to less than 120 mm Hg, compared with those with the standard treatment goal of less than 140 mm Hg. The primary measure of CVD outcomes looked at a composite of nonfatal MI, nonfatal stroke, or CVD death (N. Engl. J. Med. 2010;362:1575-85).

That original study, however, did not control for waist-to-height ratios. Presumably, a waist-to-height ratio of less than 50% would be associated with less CVD risk, compared with a ratio higher than 50%, postulated Dr. Joshua I. Barzilay of Emory University, Atlanta, and his colleagues.

His team analyzed data from the 4,687 people in the ACCORD blood-pressure cohort for whom waist-to-height data were available. All subjects had diabetes and hypertension; 47.7% were women; the subjects’ mean age was 62.2 years; and the mean follow-up was 4.7 years. Intensive lowering of blood pressure did not improve combined CVD risk, compared with standard treatment, they found (Diabetes Care 2012;35:1401-5).

Although the investigators found that controlling for the waist-to-height quartile did not affect risk for the combined outcome measure as they had hypothesized it would, one secondary end point in the study (CVD death) was found to be significantly related to the waist-to-height quartile (hazard ratio, 2.32; 95% confidence interval, 1.40–3.83; P = .0009 comparing the heaviest to lightest quartiles). Neither of the two other secondary outcome measures – fatal or nonfatal stroke and nonfatal MI – was affected.

The association between central obesity and increased risk of CVD death (but not MI or stroke) was "surprising, because morbidity outcomes share similar pathomechanisms with mortality outcomes." However, they wrote, the finding was in keeping with some other published studies. Increased "levels of inflammation factors are more strongly associated with fatal than with nonfatal CVD events. Greater degrees of central obesity are related to increased inflammation levels," they wrote.

The study is limited by its post hoc design, modest number of outcomes measured, and short follow-up. "The power to detect significant differences by the degree of central obesity was limited. With longer follow-up and more events, statistical significance could possibly be achieved for several outcomes."

The subanalysis was funded by the National Heart, Lung, and Blood Institute, and other federal agencies. Aside from study medicines and equipment, which were donated by various manufacturers, no conflicts of interest were reported.

Aggressive blood pressure lowering, and the degree of a patient’s adiposity, appear unrelated to cardiovascular disease outcomes in individuals with diabetes, according to a new analysis of data from the large, randomized controlled trial, Action to Control Cardiovascular Risk in Diabetes, presented at the annual meeting of the American Diabetes Association in Philadelphia.

The subanalysis follows on findings from the original blood-pressure study (n = 4,733) that showed no difference in cardiovascular disease (CVD) risk between people with diabetes mellitus whose blood pressure was treated to less than 120 mm Hg, compared with those with the standard treatment goal of less than 140 mm Hg. The primary measure of CVD outcomes looked at a composite of nonfatal MI, nonfatal stroke, or CVD death (N. Engl. J. Med. 2010;362:1575-85).

That original study, however, did not control for waist-to-height ratios. Presumably, a waist-to-height ratio of less than 50% would be associated with less CVD risk, compared with a ratio higher than 50%, postulated Dr. Joshua I. Barzilay of Emory University, Atlanta, and his colleagues.

His team analyzed data from the 4,687 people in the ACCORD blood-pressure cohort for whom waist-to-height data were available. All subjects had diabetes and hypertension; 47.7% were women; the subjects’ mean age was 62.2 years; and the mean follow-up was 4.7 years. Intensive lowering of blood pressure did not improve combined CVD risk, compared with standard treatment, they found (Diabetes Care 2012;35:1401-5).

Although the investigators found that controlling for the waist-to-height quartile did not affect risk for the combined outcome measure as they had hypothesized it would, one secondary end point in the study (CVD death) was found to be significantly related to the waist-to-height quartile (hazard ratio, 2.32; 95% confidence interval, 1.40–3.83; P = .0009 comparing the heaviest to lightest quartiles). Neither of the two other secondary outcome measures – fatal or nonfatal stroke and nonfatal MI – was affected.

The association between central obesity and increased risk of CVD death (but not MI or stroke) was "surprising, because morbidity outcomes share similar pathomechanisms with mortality outcomes." However, they wrote, the finding was in keeping with some other published studies. Increased "levels of inflammation factors are more strongly associated with fatal than with nonfatal CVD events. Greater degrees of central obesity are related to increased inflammation levels," they wrote.

The study is limited by its post hoc design, modest number of outcomes measured, and short follow-up. "The power to detect significant differences by the degree of central obesity was limited. With longer follow-up and more events, statistical significance could possibly be achieved for several outcomes."

The subanalysis was funded by the National Heart, Lung, and Blood Institute, and other federal agencies. Aside from study medicines and equipment, which were donated by various manufacturers, no conflicts of interest were reported.

Aggressive blood pressure lowering, and the degree of a patient’s adiposity, appear unrelated to cardiovascular disease outcomes in individuals with diabetes, according to a new analysis of data from the large, randomized controlled trial, Action to Control Cardiovascular Risk in Diabetes, presented at the annual meeting of the American Diabetes Association in Philadelphia.

The subanalysis follows on findings from the original blood-pressure study (n = 4,733) that showed no difference in cardiovascular disease (CVD) risk between people with diabetes mellitus whose blood pressure was treated to less than 120 mm Hg, compared with those with the standard treatment goal of less than 140 mm Hg. The primary measure of CVD outcomes looked at a composite of nonfatal MI, nonfatal stroke, or CVD death (N. Engl. J. Med. 2010;362:1575-85).

That original study, however, did not control for waist-to-height ratios. Presumably, a waist-to-height ratio of less than 50% would be associated with less CVD risk, compared with a ratio higher than 50%, postulated Dr. Joshua I. Barzilay of Emory University, Atlanta, and his colleagues.

His team analyzed data from the 4,687 people in the ACCORD blood-pressure cohort for whom waist-to-height data were available. All subjects had diabetes and hypertension; 47.7% were women; the subjects’ mean age was 62.2 years; and the mean follow-up was 4.7 years. Intensive lowering of blood pressure did not improve combined CVD risk, compared with standard treatment, they found (Diabetes Care 2012;35:1401-5).

Although the investigators found that controlling for the waist-to-height quartile did not affect risk for the combined outcome measure as they had hypothesized it would, one secondary end point in the study (CVD death) was found to be significantly related to the waist-to-height quartile (hazard ratio, 2.32; 95% confidence interval, 1.40–3.83; P = .0009 comparing the heaviest to lightest quartiles). Neither of the two other secondary outcome measures – fatal or nonfatal stroke and nonfatal MI – was affected.

The association between central obesity and increased risk of CVD death (but not MI or stroke) was "surprising, because morbidity outcomes share similar pathomechanisms with mortality outcomes." However, they wrote, the finding was in keeping with some other published studies. Increased "levels of inflammation factors are more strongly associated with fatal than with nonfatal CVD events. Greater degrees of central obesity are related to increased inflammation levels," they wrote.

The study is limited by its post hoc design, modest number of outcomes measured, and short follow-up. "The power to detect significant differences by the degree of central obesity was limited. With longer follow-up and more events, statistical significance could possibly be achieved for several outcomes."

The subanalysis was funded by the National Heart, Lung, and Blood Institute, and other federal agencies. Aside from study medicines and equipment, which were donated by various manufacturers, no conflicts of interest were reported.