Micrograph showing CML

Image by Difu Wu

The phase 3 EPIC trial, a comparison of tyrosine kinase inhibitors (TKIs), has left some questions unanswered.

The trial did not determine whether the third-generation TKI ponatinib is more effective than the first-generation TKI imatinib for patients with previously untreated chronic myeloid leukemia (CML).

The study was terminated early due to safety concerns associated with ponatinib, so the primary endpoint could only be analyzed in a small number of patients.

Results in these patients showed no significant difference in that endpoint—major molecular response (MMR) at 12 months—between the imatinib and ponatinib arms.

Results in the entire study cohort suggested that, overall, ponatinib was more toxic than imatinib. In particular, ponatinib produced more arterial occlusive events.

However, the trial’s investigators have questioned whether reducing the dose of ponatinib might change that.

Jeffrey H. Lipton, MD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada, and his colleagues reported results from the EPIC trial in The Lancet Oncology. The trial was supported by Ariad Pharmaceuticals.

Problems with ponatinib

Ponatinib was approved by the US Food and Drug Administration (FDA) in December 2012 to treat adults with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia that is resistant to or intolerant of other TKIs.

In October 2013, follow-up results from the phase 2 PACE trial suggested ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the EPIC trial, which was terminated.

That November, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. In December, the agency decided ponatinib could return to the market if new safety measures were implemented. In January 2014, ponatinib was put back on the market in the US.

EPIC trial

The trial enrolled 307 patients with newly diagnosed, chronic-phase CML. Patients were randomized to receive ponatinib at 45 mg (n=155) or imatinib at 400 mg (n=152) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met.

The median age was 55 (range, 18-89) in the ponatinib arm and 52 (range, 18-86) in the imatinib arm. Most patients were male—63% and 61%, respectively—and most had an ECOG performance status of 0—75% and 78%, respectively.

Patients were randomized between August 14, 2012, and October 9, 2013, and the trial was terminated on October 17, 2013.

Because of the early termination, only 10 patients in the ponatinib arm and 13 in the imatinib arm were evaluable for the primary endpoint—MMR at 12 months. Eighty percent (8/10) of the evaluable patients in the ponatinib arm and 38% (5/13) of those in the imatinib arm achieved an MMR at 12 months (P=0.074).

The investigators also evaluated the incidence of MMR at any time in patients with any post-baseline molecular response assessment. This time, the incidence of MMR was significantly higher in the ponatinib arm than the imatinib arm—41% (61/149) and 18% (25/142), respectively (P<0.0001).

All of the patients were evaluable for safety—154 in the ponatinib arm and 152 in the imatinib arm.

Arterial occlusive events occurred in 7% (n=11) of patients in the ponatinib arm and 2% (n=3) in the imatinib arm (P=0.052). These events were considered serious in 6% (n=10) and 1% (n=1), respectively (P=0.010).

Common grade 3/4 adverse events—in the ponatinib and imatinib arms, respectively—were increased lipase (14% vs 2%), thrombocytopenia (12% vs 7%), rash (6% vs 1%), and neutropenia (3% vs 8%).

Serious adverse events that occurred in 3 or more patients in the ponatinib arm were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). There were no serious adverse events that occurred in 3 or more patients in the imatinib arm.

Dr Lipton and his colleagues said the premature termination of the EPIC trial restricts the interpretation of its results, but the available data provide some insight into the activity and safety of ponatinib in previously untreated CML.

The investigators also noted that data from this trial and the clinical development program for ponatinib suggest that lowering doses of the drug could improve its vascular safety profile and, therefore, the benefit-risk balance.

Two ongoing trials (NCT02467270 and NCT02627677) may provide more insight. Both are investigating starting doses of ponatinib at 15 mg or 30 mg.

Micrograph showing CML

Image by Difu Wu

The phase 3 EPIC trial, a comparison of tyrosine kinase inhibitors (TKIs), has left some questions unanswered.

The trial did not determine whether the third-generation TKI ponatinib is more effective than the first-generation TKI imatinib for patients with previously untreated chronic myeloid leukemia (CML).

The study was terminated early due to safety concerns associated with ponatinib, so the primary endpoint could only be analyzed in a small number of patients.

Results in these patients showed no significant difference in that endpoint—major molecular response (MMR) at 12 months—between the imatinib and ponatinib arms.

Results in the entire study cohort suggested that, overall, ponatinib was more toxic than imatinib. In particular, ponatinib produced more arterial occlusive events.

However, the trial’s investigators have questioned whether reducing the dose of ponatinib might change that.

Jeffrey H. Lipton, MD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada, and his colleagues reported results from the EPIC trial in The Lancet Oncology. The trial was supported by Ariad Pharmaceuticals.

Problems with ponatinib

Ponatinib was approved by the US Food and Drug Administration (FDA) in December 2012 to treat adults with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia that is resistant to or intolerant of other TKIs.

In October 2013, follow-up results from the phase 2 PACE trial suggested ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the EPIC trial, which was terminated.

That November, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. In December, the agency decided ponatinib could return to the market if new safety measures were implemented. In January 2014, ponatinib was put back on the market in the US.

EPIC trial

The trial enrolled 307 patients with newly diagnosed, chronic-phase CML. Patients were randomized to receive ponatinib at 45 mg (n=155) or imatinib at 400 mg (n=152) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met.

The median age was 55 (range, 18-89) in the ponatinib arm and 52 (range, 18-86) in the imatinib arm. Most patients were male—63% and 61%, respectively—and most had an ECOG performance status of 0—75% and 78%, respectively.

Patients were randomized between August 14, 2012, and October 9, 2013, and the trial was terminated on October 17, 2013.

Because of the early termination, only 10 patients in the ponatinib arm and 13 in the imatinib arm were evaluable for the primary endpoint—MMR at 12 months. Eighty percent (8/10) of the evaluable patients in the ponatinib arm and 38% (5/13) of those in the imatinib arm achieved an MMR at 12 months (P=0.074).

The investigators also evaluated the incidence of MMR at any time in patients with any post-baseline molecular response assessment. This time, the incidence of MMR was significantly higher in the ponatinib arm than the imatinib arm—41% (61/149) and 18% (25/142), respectively (P<0.0001).

All of the patients were evaluable for safety—154 in the ponatinib arm and 152 in the imatinib arm.

Arterial occlusive events occurred in 7% (n=11) of patients in the ponatinib arm and 2% (n=3) in the imatinib arm (P=0.052). These events were considered serious in 6% (n=10) and 1% (n=1), respectively (P=0.010).

Common grade 3/4 adverse events—in the ponatinib and imatinib arms, respectively—were increased lipase (14% vs 2%), thrombocytopenia (12% vs 7%), rash (6% vs 1%), and neutropenia (3% vs 8%).

Serious adverse events that occurred in 3 or more patients in the ponatinib arm were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). There were no serious adverse events that occurred in 3 or more patients in the imatinib arm.

Dr Lipton and his colleagues said the premature termination of the EPIC trial restricts the interpretation of its results, but the available data provide some insight into the activity and safety of ponatinib in previously untreated CML.

The investigators also noted that data from this trial and the clinical development program for ponatinib suggest that lowering doses of the drug could improve its vascular safety profile and, therefore, the benefit-risk balance.

Two ongoing trials (NCT02467270 and NCT02627677) may provide more insight. Both are investigating starting doses of ponatinib at 15 mg or 30 mg.

Micrograph showing CML

Image by Difu Wu

The phase 3 EPIC trial, a comparison of tyrosine kinase inhibitors (TKIs), has left some questions unanswered.

The trial did not determine whether the third-generation TKI ponatinib is more effective than the first-generation TKI imatinib for patients with previously untreated chronic myeloid leukemia (CML).

The study was terminated early due to safety concerns associated with ponatinib, so the primary endpoint could only be analyzed in a small number of patients.

Results in these patients showed no significant difference in that endpoint—major molecular response (MMR) at 12 months—between the imatinib and ponatinib arms.

Results in the entire study cohort suggested that, overall, ponatinib was more toxic than imatinib. In particular, ponatinib produced more arterial occlusive events.

However, the trial’s investigators have questioned whether reducing the dose of ponatinib might change that.

Jeffrey H. Lipton, MD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada, and his colleagues reported results from the EPIC trial in The Lancet Oncology. The trial was supported by Ariad Pharmaceuticals.

Problems with ponatinib

Ponatinib was approved by the US Food and Drug Administration (FDA) in December 2012 to treat adults with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia that is resistant to or intolerant of other TKIs.

In October 2013, follow-up results from the phase 2 PACE trial suggested ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the EPIC trial, which was terminated.

That November, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. In December, the agency decided ponatinib could return to the market if new safety measures were implemented. In January 2014, ponatinib was put back on the market in the US.

EPIC trial

The trial enrolled 307 patients with newly diagnosed, chronic-phase CML. Patients were randomized to receive ponatinib at 45 mg (n=155) or imatinib at 400 mg (n=152) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met.

The median age was 55 (range, 18-89) in the ponatinib arm and 52 (range, 18-86) in the imatinib arm. Most patients were male—63% and 61%, respectively—and most had an ECOG performance status of 0—75% and 78%, respectively.

Patients were randomized between August 14, 2012, and October 9, 2013, and the trial was terminated on October 17, 2013.

Because of the early termination, only 10 patients in the ponatinib arm and 13 in the imatinib arm were evaluable for the primary endpoint—MMR at 12 months. Eighty percent (8/10) of the evaluable patients in the ponatinib arm and 38% (5/13) of those in the imatinib arm achieved an MMR at 12 months (P=0.074).

The investigators also evaluated the incidence of MMR at any time in patients with any post-baseline molecular response assessment. This time, the incidence of MMR was significantly higher in the ponatinib arm than the imatinib arm—41% (61/149) and 18% (25/142), respectively (P<0.0001).

All of the patients were evaluable for safety—154 in the ponatinib arm and 152 in the imatinib arm.

Arterial occlusive events occurred in 7% (n=11) of patients in the ponatinib arm and 2% (n=3) in the imatinib arm (P=0.052). These events were considered serious in 6% (n=10) and 1% (n=1), respectively (P=0.010).

Common grade 3/4 adverse events—in the ponatinib and imatinib arms, respectively—were increased lipase (14% vs 2%), thrombocytopenia (12% vs 7%), rash (6% vs 1%), and neutropenia (3% vs 8%).

Serious adverse events that occurred in 3 or more patients in the ponatinib arm were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). There were no serious adverse events that occurred in 3 or more patients in the imatinib arm.

Dr Lipton and his colleagues said the premature termination of the EPIC trial restricts the interpretation of its results, but the available data provide some insight into the activity and safety of ponatinib in previously untreated CML.

The investigators also noted that data from this trial and the clinical development program for ponatinib suggest that lowering doses of the drug could improve its vascular safety profile and, therefore, the benefit-risk balance.

Two ongoing trials (NCT02467270 and NCT02627677) may provide more insight. Both are investigating starting doses of ponatinib at 15 mg or 30 mg.

NEW YORK (Reuters Health) - Ten-year results from a comparison of coronary-artery bypass grafting (CABG) with medical therapy alone has found that bypass lowers the odds of cardiovascular death by about nine percentage points in people with ischemic cardiomyopathy.

The 16% reduction in the death rate meant volunteers who received bypass grafting typically lived nearly a year and a half longer than those who received optimal nonsurgical therapy.

The findings are based on a study population of 1,212 patients with an ejection fraction of 35% or less who received bypass grafts between 2002 and 2007.

Death from any cause, the primary endpoint, occurred in 66.1% of the control patients and 58.9% of the bypass recipients (p=0.02).

When the researchers looked exclusively at cardiovascular deaths, the rates were 49.3% in the medical-therapy group and 40.5% in the group receiving bypass in addition to standard medical care (p=0.006).

The combined odds of hospitalization or death from any cause were also lower with bypass.

For death or hospitalization for cardiovascular causes, there was a 10.4 percentage point difference (p<0.001). For death or hospitalization for heart failure, the difference was 8.6 points (p<0.002). It was for 6.4 percentage points for death or hospitalization for any cause (p=0.001).

Results from the study, known as STICHES, were released April 3 at the American College of Cardiology annual scientific session in Chicago and online by the New England Journal of Medicine.

Bypass grafting "was associated with more favorable results than medical therapy alone across all clinically relevant long-term outcomes we evaluated," said the team, led by Dr. Eric Velazquez of the Duke Clinical Research Institute at Duke University, Durham, North Carolina.

The trends "resulted from a persistent and perhaps increasing effect size over time," they said. "Thus, it appears that the operative risk associated with CABG is offset by a durable effect that translates into increasing clinical benefit to at least 10 years."

Coronary artery disease kills more than 538,000 people in the United States each year. Most of the studies establishing the benefits of bypass grafting were done more than 40 years ago.

The initial version of the new study was known as STICH and it followed patients at 99 sites in 22 countries for a median of just over four and a half years. It found no significant difference between the two treatments when it came to the rate of death from any cause. However, bypass recipients were less likely to die from a cardiovascular event or to die from any cause or be hospitalized for cardiovascular causes.

STICHES extends those results to 10 years and found that any-cause death became significant.

Median survival was 7.73 years with bypass and 6.29 years without. The researchers calculated that the number needed to treat to prevent one death was 14 patients. The number needed to prevent one death from a cardiovascular cause was 11.

Other secondary measures were the rates of death combined with specific cardiovascular events. Once again, they consistently found a benefit for bypass.

There was a 15.8 percentage point difference for any cause of death or revascularization (p<0.001). For death or nonfatal myocardial infarction the difference was 6.3 points and it was for 7.2 percentage points for death or nonfatal stroke (both p=0.03).

Among the 610 people originally assigned to the bypass group, 9% did not receive a graft before the end of the trial. In the 602 assigned to medical therapy alone, 19.8% underwent bypass surgery. Eleven percent had it within the first year.

In an accompanying editorial, Drs. Robert Guyton and Andrew Smith of Emory University in Atlanta, wrote, "The STICHES 10-year results firmly extend the survival benefit of CABG in patients with advanced coronary artery disease to patients with heart failure and severe ischemic cardiomyopathy. These findings should prompt strong consideration of coronary bypass as an addition to medical therapy in shared decision making with these patients."

The National Heart Lung and Blood Institute funded this research. Two coauthors reported disclosures.

NEW YORK (Reuters Health) - Ten-year results from a comparison of coronary-artery bypass grafting (CABG) with medical therapy alone has found that bypass lowers the odds of cardiovascular death by about nine percentage points in people with ischemic cardiomyopathy.

The 16% reduction in the death rate meant volunteers who received bypass grafting typically lived nearly a year and a half longer than those who received optimal nonsurgical therapy.

The findings are based on a study population of 1,212 patients with an ejection fraction of 35% or less who received bypass grafts between 2002 and 2007.

Death from any cause, the primary endpoint, occurred in 66.1% of the control patients and 58.9% of the bypass recipients (p=0.02).

When the researchers looked exclusively at cardiovascular deaths, the rates were 49.3% in the medical-therapy group and 40.5% in the group receiving bypass in addition to standard medical care (p=0.006).

The combined odds of hospitalization or death from any cause were also lower with bypass.

For death or hospitalization for cardiovascular causes, there was a 10.4 percentage point difference (p<0.001). For death or hospitalization for heart failure, the difference was 8.6 points (p<0.002). It was for 6.4 percentage points for death or hospitalization for any cause (p=0.001).

Results from the study, known as STICHES, were released April 3 at the American College of Cardiology annual scientific session in Chicago and online by the New England Journal of Medicine.

Bypass grafting "was associated with more favorable results than medical therapy alone across all clinically relevant long-term outcomes we evaluated," said the team, led by Dr. Eric Velazquez of the Duke Clinical Research Institute at Duke University, Durham, North Carolina.

The trends "resulted from a persistent and perhaps increasing effect size over time," they said. "Thus, it appears that the operative risk associated with CABG is offset by a durable effect that translates into increasing clinical benefit to at least 10 years."

Coronary artery disease kills more than 538,000 people in the United States each year. Most of the studies establishing the benefits of bypass grafting were done more than 40 years ago.

The initial version of the new study was known as STICH and it followed patients at 99 sites in 22 countries for a median of just over four and a half years. It found no significant difference between the two treatments when it came to the rate of death from any cause. However, bypass recipients were less likely to die from a cardiovascular event or to die from any cause or be hospitalized for cardiovascular causes.

STICHES extends those results to 10 years and found that any-cause death became significant.

Median survival was 7.73 years with bypass and 6.29 years without. The researchers calculated that the number needed to treat to prevent one death was 14 patients. The number needed to prevent one death from a cardiovascular cause was 11.

Other secondary measures were the rates of death combined with specific cardiovascular events. Once again, they consistently found a benefit for bypass.

There was a 15.8 percentage point difference for any cause of death or revascularization (p<0.001). For death or nonfatal myocardial infarction the difference was 6.3 points and it was for 7.2 percentage points for death or nonfatal stroke (both p=0.03).

Among the 610 people originally assigned to the bypass group, 9% did not receive a graft before the end of the trial. In the 602 assigned to medical therapy alone, 19.8% underwent bypass surgery. Eleven percent had it within the first year.

In an accompanying editorial, Drs. Robert Guyton and Andrew Smith of Emory University in Atlanta, wrote, "The STICHES 10-year results firmly extend the survival benefit of CABG in patients with advanced coronary artery disease to patients with heart failure and severe ischemic cardiomyopathy. These findings should prompt strong consideration of coronary bypass as an addition to medical therapy in shared decision making with these patients."

The National Heart Lung and Blood Institute funded this research. Two coauthors reported disclosures.

NEW YORK (Reuters Health) - Ten-year results from a comparison of coronary-artery bypass grafting (CABG) with medical therapy alone has found that bypass lowers the odds of cardiovascular death by about nine percentage points in people with ischemic cardiomyopathy.

The 16% reduction in the death rate meant volunteers who received bypass grafting typically lived nearly a year and a half longer than those who received optimal nonsurgical therapy.

The findings are based on a study population of 1,212 patients with an ejection fraction of 35% or less who received bypass grafts between 2002 and 2007.

Death from any cause, the primary endpoint, occurred in 66.1% of the control patients and 58.9% of the bypass recipients (p=0.02).

When the researchers looked exclusively at cardiovascular deaths, the rates were 49.3% in the medical-therapy group and 40.5% in the group receiving bypass in addition to standard medical care (p=0.006).

The combined odds of hospitalization or death from any cause were also lower with bypass.

For death or hospitalization for cardiovascular causes, there was a 10.4 percentage point difference (p<0.001). For death or hospitalization for heart failure, the difference was 8.6 points (p<0.002). It was for 6.4 percentage points for death or hospitalization for any cause (p=0.001).

Results from the study, known as STICHES, were released April 3 at the American College of Cardiology annual scientific session in Chicago and online by the New England Journal of Medicine.

Bypass grafting "was associated with more favorable results than medical therapy alone across all clinically relevant long-term outcomes we evaluated," said the team, led by Dr. Eric Velazquez of the Duke Clinical Research Institute at Duke University, Durham, North Carolina.

The trends "resulted from a persistent and perhaps increasing effect size over time," they said. "Thus, it appears that the operative risk associated with CABG is offset by a durable effect that translates into increasing clinical benefit to at least 10 years."

Coronary artery disease kills more than 538,000 people in the United States each year. Most of the studies establishing the benefits of bypass grafting were done more than 40 years ago.

The initial version of the new study was known as STICH and it followed patients at 99 sites in 22 countries for a median of just over four and a half years. It found no significant difference between the two treatments when it came to the rate of death from any cause. However, bypass recipients were less likely to die from a cardiovascular event or to die from any cause or be hospitalized for cardiovascular causes.

STICHES extends those results to 10 years and found that any-cause death became significant.

Median survival was 7.73 years with bypass and 6.29 years without. The researchers calculated that the number needed to treat to prevent one death was 14 patients. The number needed to prevent one death from a cardiovascular cause was 11.

Other secondary measures were the rates of death combined with specific cardiovascular events. Once again, they consistently found a benefit for bypass.

There was a 15.8 percentage point difference for any cause of death or revascularization (p<0.001). For death or nonfatal myocardial infarction the difference was 6.3 points and it was for 7.2 percentage points for death or nonfatal stroke (both p=0.03).

Among the 610 people originally assigned to the bypass group, 9% did not receive a graft before the end of the trial. In the 602 assigned to medical therapy alone, 19.8% underwent bypass surgery. Eleven percent had it within the first year.

In an accompanying editorial, Drs. Robert Guyton and Andrew Smith of Emory University in Atlanta, wrote, "The STICHES 10-year results firmly extend the survival benefit of CABG in patients with advanced coronary artery disease to patients with heart failure and severe ischemic cardiomyopathy. These findings should prompt strong consideration of coronary bypass as an addition to medical therapy in shared decision making with these patients."

The National Heart Lung and Blood Institute funded this research. Two coauthors reported disclosures.

Pregnant woman

Photo by Nina Matthews

After reviewing existing evidence, scientists from the US Centers for Disease Control and Prevention (CDC) have concluded that Zika virus causes

microcephaly and other severe fetal brain defects.

“This study marks a turning point in the Zika outbreak,” said Tom Frieden, MD, director of the CDC.

“It is now clear that the virus causes microcephaly. We’ve now confirmed what mounting evidence has suggested.”

Details on the CDC’s review were published in NEJM.

The report notes that no single piece of evidence provides conclusive proof that Zika virus infection is a cause of microcephaly and other fetal brain defects. Rather, increasing evidence from a number of recently published studies and a careful evaluation using established scientific criteria support the authors’ conclusions.

The finding that Zika virus infection can cause microcephaly and other severe fetal brain defects means that a woman who is infected with Zika during pregnancy has an increased risk of having a baby with these health problems.

However, as we’ve seen during the current Zika outbreak, some infected women deliver babies that appear to be healthy.

The CDC said establishing the causal relationship between Zika and fetal brain defects is an important step in driving additional prevention efforts, focusing research activities, and reinforcing the need for direct communication about the risks of Zika.

However, the agency noted that many questions about the Zika virus remain. And answering these questions will be the focus of ongoing research.

The CDC also said it is not changing its current recommendations regarding the Zika virus. Pregnant women should continue to avoid travel to areas where Zika is actively spreading.

If a pregnant woman travels to or lives in an area with active Zika virus transmission, she should talk with her healthcare provider and take steps to prevent mosquito bites and sexual transmission of the virus.

The CDC also encourages women and their partners in areas with active Zika transmission to engage in pregnancy planning and counseling with their healthcare providers so they know the risks and the ways to mitigate them.

Pregnant woman

Photo by Nina Matthews

After reviewing existing evidence, scientists from the US Centers for Disease Control and Prevention (CDC) have concluded that Zika virus causes

microcephaly and other severe fetal brain defects.

“This study marks a turning point in the Zika outbreak,” said Tom Frieden, MD, director of the CDC.

“It is now clear that the virus causes microcephaly. We’ve now confirmed what mounting evidence has suggested.”

Details on the CDC’s review were published in NEJM.

The report notes that no single piece of evidence provides conclusive proof that Zika virus infection is a cause of microcephaly and other fetal brain defects. Rather, increasing evidence from a number of recently published studies and a careful evaluation using established scientific criteria support the authors’ conclusions.

The finding that Zika virus infection can cause microcephaly and other severe fetal brain defects means that a woman who is infected with Zika during pregnancy has an increased risk of having a baby with these health problems.

However, as we’ve seen during the current Zika outbreak, some infected women deliver babies that appear to be healthy.

The CDC said establishing the causal relationship between Zika and fetal brain defects is an important step in driving additional prevention efforts, focusing research activities, and reinforcing the need for direct communication about the risks of Zika.

However, the agency noted that many questions about the Zika virus remain. And answering these questions will be the focus of ongoing research.

The CDC also said it is not changing its current recommendations regarding the Zika virus. Pregnant women should continue to avoid travel to areas where Zika is actively spreading.

If a pregnant woman travels to or lives in an area with active Zika virus transmission, she should talk with her healthcare provider and take steps to prevent mosquito bites and sexual transmission of the virus.

The CDC also encourages women and their partners in areas with active Zika transmission to engage in pregnancy planning and counseling with their healthcare providers so they know the risks and the ways to mitigate them.

Pregnant woman

Photo by Nina Matthews

After reviewing existing evidence, scientists from the US Centers for Disease Control and Prevention (CDC) have concluded that Zika virus causes

microcephaly and other severe fetal brain defects.

“This study marks a turning point in the Zika outbreak,” said Tom Frieden, MD, director of the CDC.

“It is now clear that the virus causes microcephaly. We’ve now confirmed what mounting evidence has suggested.”

Details on the CDC’s review were published in NEJM.

The report notes that no single piece of evidence provides conclusive proof that Zika virus infection is a cause of microcephaly and other fetal brain defects. Rather, increasing evidence from a number of recently published studies and a careful evaluation using established scientific criteria support the authors’ conclusions.

The finding that Zika virus infection can cause microcephaly and other severe fetal brain defects means that a woman who is infected with Zika during pregnancy has an increased risk of having a baby with these health problems.

However, as we’ve seen during the current Zika outbreak, some infected women deliver babies that appear to be healthy.

The CDC said establishing the causal relationship between Zika and fetal brain defects is an important step in driving additional prevention efforts, focusing research activities, and reinforcing the need for direct communication about the risks of Zika.

However, the agency noted that many questions about the Zika virus remain. And answering these questions will be the focus of ongoing research.

The CDC also said it is not changing its current recommendations regarding the Zika virus. Pregnant women should continue to avoid travel to areas where Zika is actively spreading.

If a pregnant woman travels to or lives in an area with active Zika virus transmission, she should talk with her healthcare provider and take steps to prevent mosquito bites and sexual transmission of the virus.

The CDC also encourages women and their partners in areas with active Zika transmission to engage in pregnancy planning and counseling with their healthcare providers so they know the risks and the ways to mitigate them.

Reza Dana, MD

Photo courtesy of

Massachusetts Eye and Ear

A topical immunosuppressant may be a feasible treatment option for ocular graft-versus-host-disease (GVHD), according to a phase 1/2 study.

The immunosuppressant, tacrolimus, proved equally as effective as the steroid methylprednisolone.

And although tacrolimus was significantly more likely to produce a burning sensation, the drug did not significantly increase intraocular pressure (IOP) the way methylprednisolone did.

These results were published in Ophthalmology. The study was supported by the National Eye Institute, National Institutes of Health, and Research to Prevent Blindness.

“We found tacrolimus to be very effective—just as good as the steroid, in the reduction of ocular symptoms of GVHD,” said study author Reza Dana, MD, of Massachusetts Eye and Ear Infirmary in Boston.

“We saw this improvement without any of the negative effects, such as a rise in pressure in the eye, as we saw with the steroid.”

The trial included 40 patients with ocular GVHD. They had received a hematopoietic stem cell transplant to treat leukemias, lymphomas, multiple myeloma, myelodysplastic syndromes, and thrombocytopenia.

The patients were randomized to receive topical tacrolimus 0.05% (n=24) or topical methylprednisolone 0.5% (n=16). Their median ages were 54±12 and 58±11, respectively. And the mean baseline ocular GVHD duration was 27±34 months and 28±33 months, respectively.

The patients received treatment for 10 weeks. Three patients were lost to follow-up in the tacrolimus group, 3 withdrew from the study because of a burning sensation when applying tacrolimus, and 1 patient from the methylprednisolone group was withdrawn due to a geographic corneal epithelial defect.

Safety/tolerability

There were no major adverse events in either treatment group, and there was no significant difference in the composite tolerability scores between the groups (P=0.06).

Tolerability scores were calculated based on patients’ reports of burning sensation, discharge, redness, itchiness, and foreign body sensation (scale, 0-4 for each variable).

The burning sensation score was higher in the tacrolimus group than the methylprednisolone group. At week 5, the scores were 3.6 and 1.6, respectively (P<0.001). At week 10, they were 3.5 and 2.2, respectively (P=0.002).

There was no significant change from baseline in the mean IOP in the tacrolimus group at week 5 (P=0.50) or week 10 (P=0.20). But there was a significant change in the methylprednisolone group at both time points (P=0.04 for both).

Still, this did not amount to a significant difference between the treatment groups. In the tacrolimus group, the mean IOP was 15.6 mmHg at baseline, 16 mmHg at week 5, and 16.5 at week 10. In the methylprednisolone group the mean IOPs were 15.3 mmHg, 17.5 mmHg, and 17 mmHg, respectively.

Efficacy

The main efficacy endpoints were corneal fluorescein staining (CFS), tear film break-up time (TBUT), Schirmer test results, and expression of the ocular surface inflammatory markers human leukocyte antigen-DR (HLA-DR) and intercellular adhesion molecule-1 (ICAM-1).

Topical tacrolimus was more effective than methylprednisolone in reducing the CFS score from baseline to week 10. CFS scores were reduced by 55% and 23%, respectively (P=0.01).

There was a significant increase in TBUT from baseline to week 10 in the tacrolimus group (0.7-2.6 seconds, P=0.003) but not in the methylprednisolone group (0.6-1.0 seconds, P=0.42). However, there was no significant difference in TBUT changes between the treatment groups (P=0.06).

Schirmer test scores did not change significantly in either treatment group.

ICAM-1 expression decreased significantly from baseline in both the tacrolimus group (39% reduction, P=0.003) and the methylprednisolone group (40% reduction, P=0.008).

HLA-DR expression decreased significantly in the tacrolimus group (46% reduction, P=0.03) but not the methylprednisolone group (24% reduction, P=0.09).

“The problem with steroid treatment for ocular GVHD is that it can cause the pressure in the eye to rise, and it can also cause cataracts,” Dr Dana noted.

“The results of this trial give us reassurance that [tacrolimus] is another effective treatment for GVHD, without the negative side effects of steroids. This is a game-changer in terms of managing their care.”

Reza Dana, MD

Photo courtesy of

Massachusetts Eye and Ear

A topical immunosuppressant may be a feasible treatment option for ocular graft-versus-host-disease (GVHD), according to a phase 1/2 study.

The immunosuppressant, tacrolimus, proved equally as effective as the steroid methylprednisolone.

And although tacrolimus was significantly more likely to produce a burning sensation, the drug did not significantly increase intraocular pressure (IOP) the way methylprednisolone did.

These results were published in Ophthalmology. The study was supported by the National Eye Institute, National Institutes of Health, and Research to Prevent Blindness.

“We found tacrolimus to be very effective—just as good as the steroid, in the reduction of ocular symptoms of GVHD,” said study author Reza Dana, MD, of Massachusetts Eye and Ear Infirmary in Boston.

“We saw this improvement without any of the negative effects, such as a rise in pressure in the eye, as we saw with the steroid.”

The trial included 40 patients with ocular GVHD. They had received a hematopoietic stem cell transplant to treat leukemias, lymphomas, multiple myeloma, myelodysplastic syndromes, and thrombocytopenia.

The patients were randomized to receive topical tacrolimus 0.05% (n=24) or topical methylprednisolone 0.5% (n=16). Their median ages were 54±12 and 58±11, respectively. And the mean baseline ocular GVHD duration was 27±34 months and 28±33 months, respectively.

The patients received treatment for 10 weeks. Three patients were lost to follow-up in the tacrolimus group, 3 withdrew from the study because of a burning sensation when applying tacrolimus, and 1 patient from the methylprednisolone group was withdrawn due to a geographic corneal epithelial defect.

Safety/tolerability

There were no major adverse events in either treatment group, and there was no significant difference in the composite tolerability scores between the groups (P=0.06).

Tolerability scores were calculated based on patients’ reports of burning sensation, discharge, redness, itchiness, and foreign body sensation (scale, 0-4 for each variable).

The burning sensation score was higher in the tacrolimus group than the methylprednisolone group. At week 5, the scores were 3.6 and 1.6, respectively (P<0.001). At week 10, they were 3.5 and 2.2, respectively (P=0.002).

There was no significant change from baseline in the mean IOP in the tacrolimus group at week 5 (P=0.50) or week 10 (P=0.20). But there was a significant change in the methylprednisolone group at both time points (P=0.04 for both).

Still, this did not amount to a significant difference between the treatment groups. In the tacrolimus group, the mean IOP was 15.6 mmHg at baseline, 16 mmHg at week 5, and 16.5 at week 10. In the methylprednisolone group the mean IOPs were 15.3 mmHg, 17.5 mmHg, and 17 mmHg, respectively.

Efficacy

The main efficacy endpoints were corneal fluorescein staining (CFS), tear film break-up time (TBUT), Schirmer test results, and expression of the ocular surface inflammatory markers human leukocyte antigen-DR (HLA-DR) and intercellular adhesion molecule-1 (ICAM-1).

Topical tacrolimus was more effective than methylprednisolone in reducing the CFS score from baseline to week 10. CFS scores were reduced by 55% and 23%, respectively (P=0.01).

There was a significant increase in TBUT from baseline to week 10 in the tacrolimus group (0.7-2.6 seconds, P=0.003) but not in the methylprednisolone group (0.6-1.0 seconds, P=0.42). However, there was no significant difference in TBUT changes between the treatment groups (P=0.06).

Schirmer test scores did not change significantly in either treatment group.

ICAM-1 expression decreased significantly from baseline in both the tacrolimus group (39% reduction, P=0.003) and the methylprednisolone group (40% reduction, P=0.008).

HLA-DR expression decreased significantly in the tacrolimus group (46% reduction, P=0.03) but not the methylprednisolone group (24% reduction, P=0.09).

“The problem with steroid treatment for ocular GVHD is that it can cause the pressure in the eye to rise, and it can also cause cataracts,” Dr Dana noted.

“The results of this trial give us reassurance that [tacrolimus] is another effective treatment for GVHD, without the negative side effects of steroids. This is a game-changer in terms of managing their care.”

Reza Dana, MD

Photo courtesy of

Massachusetts Eye and Ear

A topical immunosuppressant may be a feasible treatment option for ocular graft-versus-host-disease (GVHD), according to a phase 1/2 study.

The immunosuppressant, tacrolimus, proved equally as effective as the steroid methylprednisolone.

And although tacrolimus was significantly more likely to produce a burning sensation, the drug did not significantly increase intraocular pressure (IOP) the way methylprednisolone did.

These results were published in Ophthalmology. The study was supported by the National Eye Institute, National Institutes of Health, and Research to Prevent Blindness.

“We found tacrolimus to be very effective—just as good as the steroid, in the reduction of ocular symptoms of GVHD,” said study author Reza Dana, MD, of Massachusetts Eye and Ear Infirmary in Boston.

“We saw this improvement without any of the negative effects, such as a rise in pressure in the eye, as we saw with the steroid.”

The trial included 40 patients with ocular GVHD. They had received a hematopoietic stem cell transplant to treat leukemias, lymphomas, multiple myeloma, myelodysplastic syndromes, and thrombocytopenia.

The patients were randomized to receive topical tacrolimus 0.05% (n=24) or topical methylprednisolone 0.5% (n=16). Their median ages were 54±12 and 58±11, respectively. And the mean baseline ocular GVHD duration was 27±34 months and 28±33 months, respectively.

The patients received treatment for 10 weeks. Three patients were lost to follow-up in the tacrolimus group, 3 withdrew from the study because of a burning sensation when applying tacrolimus, and 1 patient from the methylprednisolone group was withdrawn due to a geographic corneal epithelial defect.

Safety/tolerability

There were no major adverse events in either treatment group, and there was no significant difference in the composite tolerability scores between the groups (P=0.06).

Tolerability scores were calculated based on patients’ reports of burning sensation, discharge, redness, itchiness, and foreign body sensation (scale, 0-4 for each variable).

The burning sensation score was higher in the tacrolimus group than the methylprednisolone group. At week 5, the scores were 3.6 and 1.6, respectively (P<0.001). At week 10, they were 3.5 and 2.2, respectively (P=0.002).

There was no significant change from baseline in the mean IOP in the tacrolimus group at week 5 (P=0.50) or week 10 (P=0.20). But there was a significant change in the methylprednisolone group at both time points (P=0.04 for both).

Still, this did not amount to a significant difference between the treatment groups. In the tacrolimus group, the mean IOP was 15.6 mmHg at baseline, 16 mmHg at week 5, and 16.5 at week 10. In the methylprednisolone group the mean IOPs were 15.3 mmHg, 17.5 mmHg, and 17 mmHg, respectively.

Efficacy

The main efficacy endpoints were corneal fluorescein staining (CFS), tear film break-up time (TBUT), Schirmer test results, and expression of the ocular surface inflammatory markers human leukocyte antigen-DR (HLA-DR) and intercellular adhesion molecule-1 (ICAM-1).

Topical tacrolimus was more effective than methylprednisolone in reducing the CFS score from baseline to week 10. CFS scores were reduced by 55% and 23%, respectively (P=0.01).

There was a significant increase in TBUT from baseline to week 10 in the tacrolimus group (0.7-2.6 seconds, P=0.003) but not in the methylprednisolone group (0.6-1.0 seconds, P=0.42). However, there was no significant difference in TBUT changes between the treatment groups (P=0.06).

Schirmer test scores did not change significantly in either treatment group.

ICAM-1 expression decreased significantly from baseline in both the tacrolimus group (39% reduction, P=0.003) and the methylprednisolone group (40% reduction, P=0.008).

HLA-DR expression decreased significantly in the tacrolimus group (46% reduction, P=0.03) but not the methylprednisolone group (24% reduction, P=0.09).

“The problem with steroid treatment for ocular GVHD is that it can cause the pressure in the eye to rise, and it can also cause cataracts,” Dr Dana noted.

“The results of this trial give us reassurance that [tacrolimus] is another effective treatment for GVHD, without the negative side effects of steroids. This is a game-changer in terms of managing their care.”

Isabel Meininger

Photo courtesy of

Helmholtz Zentrum München

Researchers say they have gained new insights into the workings of MALT1, a protein that controls the activation of lymphocytes.

The team found that, through alternative splicing, two variants of MALT1 may arise, and one has a stronger effect than the other.

The researchers say understanding this process is important because previous research has suggested MALT1 may be a therapeutic

target for lymphomas and other diseases.

Isabel Meininger, a doctoral student at Helmholtz Zentrum München in Neuherberg, Germany, and her colleagues described their MALT1-related findings in Nature Communications.

“To our surprise, we showed that MALT1 is regulated by post-transcriptional splicing,” Meininger said. “Depending on which MALT1 variant is expressed, the immune system is activated more or less.”

The researchers explained that most pre-messenger RNAs in mammals are prone to alternative splicing, which results in the generation of multiple transcripts and proteins with diverse functions.

In the case of MALT1, the variants MALT1A and MALT1B differ only through the presence of exon 7, a short sequence that encodes 11 amino acids.

If exon 7 is missing, as in the case of MALT1B, the protein’s ability to stimulate T cells is impaired. So MALT1A has a stronger effect on T cells than MALT1B.

The researchers also found that a molecule called hnRNP U (heterogeneous nuclear ribonucleoprotein U) regulates which of the two variants is preferably expressed.

If hnRNP U is present in small amounts, higher levels of MALT1A are expressed, resulting in stronger activation of T cells. With higher levels of hnRNP U, higher levels of MALT1B are expressed, and the response of the T cells is weaker.

“Our findings contribute to a better understanding of the function of MALT1 and enable us to better assess the potential impact of a pharmacological effect on this promising drug candidate,” said study author Daniel Krappmann, PhD, of Helmholtz Zentrum München.

In a previous study, Dr Krappmann and his team identified small molecules that can inhibit MALT1 to treat diffuse large B-cell lymphoma.

In future studies, the researchers want to confirm, in a preclinical model, the effects of MALT1 splicing on the immune system and disease development.

Isabel Meininger

Photo courtesy of

Helmholtz Zentrum München

Researchers say they have gained new insights into the workings of MALT1, a protein that controls the activation of lymphocytes.

The team found that, through alternative splicing, two variants of MALT1 may arise, and one has a stronger effect than the other.

The researchers say understanding this process is important because previous research has suggested MALT1 may be a therapeutic

target for lymphomas and other diseases.

Isabel Meininger, a doctoral student at Helmholtz Zentrum München in Neuherberg, Germany, and her colleagues described their MALT1-related findings in Nature Communications.

“To our surprise, we showed that MALT1 is regulated by post-transcriptional splicing,” Meininger said. “Depending on which MALT1 variant is expressed, the immune system is activated more or less.”

The researchers explained that most pre-messenger RNAs in mammals are prone to alternative splicing, which results in the generation of multiple transcripts and proteins with diverse functions.

In the case of MALT1, the variants MALT1A and MALT1B differ only through the presence of exon 7, a short sequence that encodes 11 amino acids.

If exon 7 is missing, as in the case of MALT1B, the protein’s ability to stimulate T cells is impaired. So MALT1A has a stronger effect on T cells than MALT1B.

The researchers also found that a molecule called hnRNP U (heterogeneous nuclear ribonucleoprotein U) regulates which of the two variants is preferably expressed.

If hnRNP U is present in small amounts, higher levels of MALT1A are expressed, resulting in stronger activation of T cells. With higher levels of hnRNP U, higher levels of MALT1B are expressed, and the response of the T cells is weaker.

“Our findings contribute to a better understanding of the function of MALT1 and enable us to better assess the potential impact of a pharmacological effect on this promising drug candidate,” said study author Daniel Krappmann, PhD, of Helmholtz Zentrum München.

In a previous study, Dr Krappmann and his team identified small molecules that can inhibit MALT1 to treat diffuse large B-cell lymphoma.

In future studies, the researchers want to confirm, in a preclinical model, the effects of MALT1 splicing on the immune system and disease development.

Isabel Meininger

Photo courtesy of

Helmholtz Zentrum München

Researchers say they have gained new insights into the workings of MALT1, a protein that controls the activation of lymphocytes.

The team found that, through alternative splicing, two variants of MALT1 may arise, and one has a stronger effect than the other.

The researchers say understanding this process is important because previous research has suggested MALT1 may be a therapeutic

target for lymphomas and other diseases.

Isabel Meininger, a doctoral student at Helmholtz Zentrum München in Neuherberg, Germany, and her colleagues described their MALT1-related findings in Nature Communications.

“To our surprise, we showed that MALT1 is regulated by post-transcriptional splicing,” Meininger said. “Depending on which MALT1 variant is expressed, the immune system is activated more or less.”

The researchers explained that most pre-messenger RNAs in mammals are prone to alternative splicing, which results in the generation of multiple transcripts and proteins with diverse functions.

In the case of MALT1, the variants MALT1A and MALT1B differ only through the presence of exon 7, a short sequence that encodes 11 amino acids.

If exon 7 is missing, as in the case of MALT1B, the protein’s ability to stimulate T cells is impaired. So MALT1A has a stronger effect on T cells than MALT1B.

The researchers also found that a molecule called hnRNP U (heterogeneous nuclear ribonucleoprotein U) regulates which of the two variants is preferably expressed.

If hnRNP U is present in small amounts, higher levels of MALT1A are expressed, resulting in stronger activation of T cells. With higher levels of hnRNP U, higher levels of MALT1B are expressed, and the response of the T cells is weaker.

“Our findings contribute to a better understanding of the function of MALT1 and enable us to better assess the potential impact of a pharmacological effect on this promising drug candidate,” said study author Daniel Krappmann, PhD, of Helmholtz Zentrum München.

In a previous study, Dr Krappmann and his team identified small molecules that can inhibit MALT1 to treat diffuse large B-cell lymphoma.

In future studies, the researchers want to confirm, in a preclinical model, the effects of MALT1 splicing on the immune system and disease development.

Children with better adherence to asthma treatments tended to have more severe asthma symptoms, according to Dr. Marjolein Engelkes of Erasmus University, Rotterdam (The Netherlands) and her associates.

Of the 14,303 children with asthma included in the study, short-acting beta2-agonists and inhaled corticosteroids were the most commonly prescribed treatments at 38 users/100 person-years and 31 users/100 person-years, respectively. Inhaled corticosteroid prescriptions were most common during the winter and in September, and decreased as children increased in age.

©tupungato/Thinkstock.com

The median medication possession ratio (MPR) for inhaled corticosteroids was 56%. Children with an MPR over 87% were significantly more likely to be younger at the start of inhaled corticosteroid treatment, visit specialists more often, and to have more exacerbations than children with an MPR less than 37%.

“These findings indicate that there is room for improvement of adherence to treatment, especially in children with milder forms of asthma,” the investigators concluded.

Find the full study in Pediatric Allergy and Immunology (2016 Mar. doi: 10.1111/pai.12507).

lfranki@frontlinemedcom.com

Children with better adherence to asthma treatments tended to have more severe asthma symptoms, according to Dr. Marjolein Engelkes of Erasmus University, Rotterdam (The Netherlands) and her associates.

Of the 14,303 children with asthma included in the study, short-acting beta2-agonists and inhaled corticosteroids were the most commonly prescribed treatments at 38 users/100 person-years and 31 users/100 person-years, respectively. Inhaled corticosteroid prescriptions were most common during the winter and in September, and decreased as children increased in age.

©tupungato/Thinkstock.com

The median medication possession ratio (MPR) for inhaled corticosteroids was 56%. Children with an MPR over 87% were significantly more likely to be younger at the start of inhaled corticosteroid treatment, visit specialists more often, and to have more exacerbations than children with an MPR less than 37%.

“These findings indicate that there is room for improvement of adherence to treatment, especially in children with milder forms of asthma,” the investigators concluded.

Find the full study in Pediatric Allergy and Immunology (2016 Mar. doi: 10.1111/pai.12507).

lfranki@frontlinemedcom.com

Children with better adherence to asthma treatments tended to have more severe asthma symptoms, according to Dr. Marjolein Engelkes of Erasmus University, Rotterdam (The Netherlands) and her associates.

Of the 14,303 children with asthma included in the study, short-acting beta2-agonists and inhaled corticosteroids were the most commonly prescribed treatments at 38 users/100 person-years and 31 users/100 person-years, respectively. Inhaled corticosteroid prescriptions were most common during the winter and in September, and decreased as children increased in age.

©tupungato/Thinkstock.com

The median medication possession ratio (MPR) for inhaled corticosteroids was 56%. Children with an MPR over 87% were significantly more likely to be younger at the start of inhaled corticosteroid treatment, visit specialists more often, and to have more exacerbations than children with an MPR less than 37%.

“These findings indicate that there is room for improvement of adherence to treatment, especially in children with milder forms of asthma,” the investigators concluded.

Find the full study in Pediatric Allergy and Immunology (2016 Mar. doi: 10.1111/pai.12507).

lfranki@frontlinemedcom.com

Officials at the Centers for Disease Control and Prevention have determined that Zika virus infection is a cause of microcephaly in babies born to infected mothers, following a systematic review of the latest research on Zika virus.

The CDC released findings from that review in a peer-reviewed special report published online April 13 in the New England Journal of Medicine (2016. doi: 10.1056/NEJMsr1604338). The report, CDC officials said, incorporated evidence from as recently as the past week.

Sumaia Villela/Agência Brasil/CC BY 3.0 BR

In a press conference in April, CDC director Tom Frieden said there was “no longer any doubt” that Zika virus causes microcephaly. Dr. Frieden’s statements reflect what appears to be a growing scientific consensus. On March 31, the World Health Organization reported that there was a “strong” consensus that Zika virus can cause microcephaly, Guillain-Barré syndrome, and other neurological disorders. New microcephaly cases in Colombia – with 32 reported by the end of March – are among the findings cited by both the WHO and the CDC.

Dr. Frieden stressed that no single piece of evidence was seen to provide conclusive proof of causation, but that the CDC scientists’ conclusions were based on “a thorough review of the best available evidence” subjected to established criteria.

For its review published in the New England Journal of Medicine, CDC scientists led by Dr. Sonja Rasmussen subjected available evidence to two separate criteria to determine the relationship of Zika virus to the spikes in microcephaly cases seen in countries where Zika is spreading. Shepard’s criteria were used to prove teratogenicity, and the Bradford Hill criteria were used to show evidence of causation.

The CDC has not made any changes to its guidance on Zika virus prevention, which includes advising pregnant women to avoid travel to regions where Zika transmission is occurring, take steps to prevent infection if they live in areas where Zika virus is present, and use condoms to prevent sexual transmission of Zika from a partner. On April 13, the CDC added St. Lucia to its growing list of countries to be avoided by pregnant women.

The full spectrum of defects caused by congenital Zika infection is still poorly understood. Additional studies are underway at CDC, Dr. Frieden said, to better understand the severe phenotype of microcephaly seen in babies born to Zika-infected mothers and “to determine whether children who have microcephaly born to mothers infected by the Zika virus is the tip of the iceberg of what we could see in damaging effects on the brain.”

Officials at the Centers for Disease Control and Prevention have determined that Zika virus infection is a cause of microcephaly in babies born to infected mothers, following a systematic review of the latest research on Zika virus.

The CDC released findings from that review in a peer-reviewed special report published online April 13 in the New England Journal of Medicine (2016. doi: 10.1056/NEJMsr1604338). The report, CDC officials said, incorporated evidence from as recently as the past week.

Sumaia Villela/Agência Brasil/CC BY 3.0 BR

In a press conference in April, CDC director Tom Frieden said there was “no longer any doubt” that Zika virus causes microcephaly. Dr. Frieden’s statements reflect what appears to be a growing scientific consensus. On March 31, the World Health Organization reported that there was a “strong” consensus that Zika virus can cause microcephaly, Guillain-Barré syndrome, and other neurological disorders. New microcephaly cases in Colombia – with 32 reported by the end of March – are among the findings cited by both the WHO and the CDC.

Dr. Frieden stressed that no single piece of evidence was seen to provide conclusive proof of causation, but that the CDC scientists’ conclusions were based on “a thorough review of the best available evidence” subjected to established criteria.

For its review published in the New England Journal of Medicine, CDC scientists led by Dr. Sonja Rasmussen subjected available evidence to two separate criteria to determine the relationship of Zika virus to the spikes in microcephaly cases seen in countries where Zika is spreading. Shepard’s criteria were used to prove teratogenicity, and the Bradford Hill criteria were used to show evidence of causation.

The CDC has not made any changes to its guidance on Zika virus prevention, which includes advising pregnant women to avoid travel to regions where Zika transmission is occurring, take steps to prevent infection if they live in areas where Zika virus is present, and use condoms to prevent sexual transmission of Zika from a partner. On April 13, the CDC added St. Lucia to its growing list of countries to be avoided by pregnant women.

The full spectrum of defects caused by congenital Zika infection is still poorly understood. Additional studies are underway at CDC, Dr. Frieden said, to better understand the severe phenotype of microcephaly seen in babies born to Zika-infected mothers and “to determine whether children who have microcephaly born to mothers infected by the Zika virus is the tip of the iceberg of what we could see in damaging effects on the brain.”

Officials at the Centers for Disease Control and Prevention have determined that Zika virus infection is a cause of microcephaly in babies born to infected mothers, following a systematic review of the latest research on Zika virus.

The CDC released findings from that review in a peer-reviewed special report published online April 13 in the New England Journal of Medicine (2016. doi: 10.1056/NEJMsr1604338). The report, CDC officials said, incorporated evidence from as recently as the past week.

Sumaia Villela/Agência Brasil/CC BY 3.0 BR

In a press conference in April, CDC director Tom Frieden said there was “no longer any doubt” that Zika virus causes microcephaly. Dr. Frieden’s statements reflect what appears to be a growing scientific consensus. On March 31, the World Health Organization reported that there was a “strong” consensus that Zika virus can cause microcephaly, Guillain-Barré syndrome, and other neurological disorders. New microcephaly cases in Colombia – with 32 reported by the end of March – are among the findings cited by both the WHO and the CDC.

Dr. Frieden stressed that no single piece of evidence was seen to provide conclusive proof of causation, but that the CDC scientists’ conclusions were based on “a thorough review of the best available evidence” subjected to established criteria.

For its review published in the New England Journal of Medicine, CDC scientists led by Dr. Sonja Rasmussen subjected available evidence to two separate criteria to determine the relationship of Zika virus to the spikes in microcephaly cases seen in countries where Zika is spreading. Shepard’s criteria were used to prove teratogenicity, and the Bradford Hill criteria were used to show evidence of causation.

The CDC has not made any changes to its guidance on Zika virus prevention, which includes advising pregnant women to avoid travel to regions where Zika transmission is occurring, take steps to prevent infection if they live in areas where Zika virus is present, and use condoms to prevent sexual transmission of Zika from a partner. On April 13, the CDC added St. Lucia to its growing list of countries to be avoided by pregnant women.

The full spectrum of defects caused by congenital Zika infection is still poorly understood. Additional studies are underway at CDC, Dr. Frieden said, to better understand the severe phenotype of microcephaly seen in babies born to Zika-infected mothers and “to determine whether children who have microcephaly born to mothers infected by the Zika virus is the tip of the iceberg of what we could see in damaging effects on the brain.”

The benefit of adding lumbar fusion surgery to decompression surgery for spinal stenosis was nonexistent in one large clinical trial and very modest in another, according to separate reports published online April 13 in the New England Journal of Medicine.

Both studies indicated that, given the considerable cost and the potential complications associated with lumbar fusion, it may not be worthwhile to add it to decompression surgery for spinal stenosis. “The goal of surgery in lumbar spinal stenosis is to improve walking distance and to relieve pain by decompression of the nerve roots. The addition of instrumented fusion – ‘just to be sure’ – for the treatment of the most frequent forms of lumbar spinal stenosis does not create any added value for patients and might be regarded as an overcautious and unnecessary treatment,” Dr. Wilco C. Peul and Dr. Wouter A. Moojen said in an editorial accompanying the two reports.

Surgical decompression of spinal stenosis using laminectomy is increasingly being supplemented with lumbar fusion, which is thought to firm up spinal instability and minimize the risk of future deformity. In the United States, approximately half of patients who have surgery for spinal stenosis undergo fusion procedures. Of those who also show degenerative spondylolisthesis on preoperative imaging studies, 96% undergo fusion procedures because many spine surgeons see this as a sign of instability and a mandatory indication for fusion. However, the evidence supporting the use of fusion plus decompression, as opposed to decompression alone, is weak, according to the investigators who conducted the Swedish Spinal Stenosis Study. The other study in the New England Journal of Medicine, the Spinal Laminectomy Versus Instrumented Pedicle Screw (SLIP) trial, was conducted in the United States.

Both of those clinical trials were performed to shed further light on the issue.

In the Swedish Spinal Stenosis Study, the investigators assessed outcomes in 247 patients aged 50-80 years who were treated at seven Swedish hospitals over the course of 6 years. This open-label, superiority trial randomly assigned 124 patients to decompression surgery alone and 123 to decompression plus fusion. The primary outcome measure was score on the Oswestry Disability Index (ODI), which measures disability and quality of life in patients with low-back pain, 2 years after surgery. The ODI scale runs from 0 to 100, with higher scores indicating more severe disability, said Dr. Peter Försth of the department of surgical sciences at Uppsala (Sweden) University and the Stockholm Spine Center and his associates.

At 2 years, there was no significant difference between the two study groups; the decompression-only group had a mean ODI score of 24, and the fusion group had a mean score of 27. The ODI scores in both groups had improved from baseline to a similar degree: by 17 points with decompression alone and by 15 points with fusion. In addition, fusion surgery was not superior to decompression alone regardless of whether patients had any degree of spondylolisthesis and regardless of whether they had severe spondylolisthesis involving a vertebral slip of 7.4 mm or more, the investigators reported (N Engl J Med. 2016 April 13. doi: 10.1056/NEJMoa1513721).The two study groups also showed no significant differences in secondary outcome measures, including performance on the 6-minute walk test and subjective patient assessment of improvement in walking ability. Moreover, these results persisted in the 144 patients who were assessed at 5-year follow-up.

In contrast, decompression alone was associated with fewer complications than decompression plus fusion. Postoperative wound infection developed in only 4% of the decompression-only group, compared with 10% of the fusion group. Although this study wasn’t adequately powered to draw firm conclusions regarding complications, a previous analysis of registry data reported that adding fusion surgery to decompression surgery doubles the risk of severe adverse events in older patients, Dr. Försth and his associates said.

Decompression alone also was markedly less expensive than fusion surgery. Mean direct costs were $6,800 higher for fusion than for decompression alone, because of the additional operating time needed, the extended hospital stay, and the cost of the implant.

In the SLIP trial, the researchers compared outcomes in 66 patients aged 50-80 years who all had spinal stenosis with grade 1 degenerative spondylolisthesis. The participants were randomly assigned to undergo decompression alone (35 patients) or decompression plus fusion (31 patients) at five U.S. medical centers, said Dr. Zoher Ghogawala of the Alan and Jacqueline B. Stuart Spine Research Center in the department of neurosurgery at Lahey Hospital and Medical Center, Burlington, Mass., and his associates.

The primary outcome measure was the physical-component summary score on the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) 2 years after surgery. This scale also runs from 0 to 100, but higher scores indicate better physical health. Five points was prespecified as the minimal clinically important difference on the SF-36.

At 2 years, patients in the fusion group showed a small but significant advantage of 5.7 points on the SF-36, with a mean score of 15.2, compared with patients in the decompression-only group (mean score, 9.5). However, the ODI scores, a secondary outcome measure in this study, were not significantly different between the two study groups, Dr. Ghogawala and his associates reported (N Engl J Med. 2016 April 13. doi: 10.1056/NEJMoa1508788).Surgical complications, blood loss, and length of stay all were significantly greater with fusion than with decompression alone.

Dr. Försth’s study was supported by Uppsala University, Uppsala County Council, the Stockholm Spine Center, and Johnson & Johnson. Two of his associates reported ties to Medtronic and Quantify Research. Dr. Ghogawala’s study was supported by the Jean and David Wallace Foundation, the Greenwich Lumbar Stenosis SLIP Study Fund. His associates reported ties to numerous industry sources.

The benefit of adding lumbar fusion surgery to decompression surgery for spinal stenosis was nonexistent in one large clinical trial and very modest in another, according to separate reports published online April 13 in the New England Journal of Medicine.

Both studies indicated that, given the considerable cost and the potential complications associated with lumbar fusion, it may not be worthwhile to add it to decompression surgery for spinal stenosis. “The goal of surgery in lumbar spinal stenosis is to improve walking distance and to relieve pain by decompression of the nerve roots. The addition of instrumented fusion – ‘just to be sure’ – for the treatment of the most frequent forms of lumbar spinal stenosis does not create any added value for patients and might be regarded as an overcautious and unnecessary treatment,” Dr. Wilco C. Peul and Dr. Wouter A. Moojen said in an editorial accompanying the two reports.

Surgical decompression of spinal stenosis using laminectomy is increasingly being supplemented with lumbar fusion, which is thought to firm up spinal instability and minimize the risk of future deformity. In the United States, approximately half of patients who have surgery for spinal stenosis undergo fusion procedures. Of those who also show degenerative spondylolisthesis on preoperative imaging studies, 96% undergo fusion procedures because many spine surgeons see this as a sign of instability and a mandatory indication for fusion. However, the evidence supporting the use of fusion plus decompression, as opposed to decompression alone, is weak, according to the investigators who conducted the Swedish Spinal Stenosis Study. The other study in the New England Journal of Medicine, the Spinal Laminectomy Versus Instrumented Pedicle Screw (SLIP) trial, was conducted in the United States.

Both of those clinical trials were performed to shed further light on the issue.

In the Swedish Spinal Stenosis Study, the investigators assessed outcomes in 247 patients aged 50-80 years who were treated at seven Swedish hospitals over the course of 6 years. This open-label, superiority trial randomly assigned 124 patients to decompression surgery alone and 123 to decompression plus fusion. The primary outcome measure was score on the Oswestry Disability Index (ODI), which measures disability and quality of life in patients with low-back pain, 2 years after surgery. The ODI scale runs from 0 to 100, with higher scores indicating more severe disability, said Dr. Peter Försth of the department of surgical sciences at Uppsala (Sweden) University and the Stockholm Spine Center and his associates.

At 2 years, there was no significant difference between the two study groups; the decompression-only group had a mean ODI score of 24, and the fusion group had a mean score of 27. The ODI scores in both groups had improved from baseline to a similar degree: by 17 points with decompression alone and by 15 points with fusion. In addition, fusion surgery was not superior to decompression alone regardless of whether patients had any degree of spondylolisthesis and regardless of whether they had severe spondylolisthesis involving a vertebral slip of 7.4 mm or more, the investigators reported (N Engl J Med. 2016 April 13. doi: 10.1056/NEJMoa1513721).The two study groups also showed no significant differences in secondary outcome measures, including performance on the 6-minute walk test and subjective patient assessment of improvement in walking ability. Moreover, these results persisted in the 144 patients who were assessed at 5-year follow-up.

In contrast, decompression alone was associated with fewer complications than decompression plus fusion. Postoperative wound infection developed in only 4% of the decompression-only group, compared with 10% of the fusion group. Although this study wasn’t adequately powered to draw firm conclusions regarding complications, a previous analysis of registry data reported that adding fusion surgery to decompression surgery doubles the risk of severe adverse events in older patients, Dr. Försth and his associates said.

Decompression alone also was markedly less expensive than fusion surgery. Mean direct costs were $6,800 higher for fusion than for decompression alone, because of the additional operating time needed, the extended hospital stay, and the cost of the implant.

In the SLIP trial, the researchers compared outcomes in 66 patients aged 50-80 years who all had spinal stenosis with grade 1 degenerative spondylolisthesis. The participants were randomly assigned to undergo decompression alone (35 patients) or decompression plus fusion (31 patients) at five U.S. medical centers, said Dr. Zoher Ghogawala of the Alan and Jacqueline B. Stuart Spine Research Center in the department of neurosurgery at Lahey Hospital and Medical Center, Burlington, Mass., and his associates.

The primary outcome measure was the physical-component summary score on the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) 2 years after surgery. This scale also runs from 0 to 100, but higher scores indicate better physical health. Five points was prespecified as the minimal clinically important difference on the SF-36.

At 2 years, patients in the fusion group showed a small but significant advantage of 5.7 points on the SF-36, with a mean score of 15.2, compared with patients in the decompression-only group (mean score, 9.5). However, the ODI scores, a secondary outcome measure in this study, were not significantly different between the two study groups, Dr. Ghogawala and his associates reported (N Engl J Med. 2016 April 13. doi: 10.1056/NEJMoa1508788).Surgical complications, blood loss, and length of stay all were significantly greater with fusion than with decompression alone.

Dr. Försth’s study was supported by Uppsala University, Uppsala County Council, the Stockholm Spine Center, and Johnson & Johnson. Two of his associates reported ties to Medtronic and Quantify Research. Dr. Ghogawala’s study was supported by the Jean and David Wallace Foundation, the Greenwich Lumbar Stenosis SLIP Study Fund. His associates reported ties to numerous industry sources.

The benefit of adding lumbar fusion surgery to decompression surgery for spinal stenosis was nonexistent in one large clinical trial and very modest in another, according to separate reports published online April 13 in the New England Journal of Medicine.

Both studies indicated that, given the considerable cost and the potential complications associated with lumbar fusion, it may not be worthwhile to add it to decompression surgery for spinal stenosis. “The goal of surgery in lumbar spinal stenosis is to improve walking distance and to relieve pain by decompression of the nerve roots. The addition of instrumented fusion – ‘just to be sure’ – for the treatment of the most frequent forms of lumbar spinal stenosis does not create any added value for patients and might be regarded as an overcautious and unnecessary treatment,” Dr. Wilco C. Peul and Dr. Wouter A. Moojen said in an editorial accompanying the two reports.

Surgical decompression of spinal stenosis using laminectomy is increasingly being supplemented with lumbar fusion, which is thought to firm up spinal instability and minimize the risk of future deformity. In the United States, approximately half of patients who have surgery for spinal stenosis undergo fusion procedures. Of those who also show degenerative spondylolisthesis on preoperative imaging studies, 96% undergo fusion procedures because many spine surgeons see this as a sign of instability and a mandatory indication for fusion. However, the evidence supporting the use of fusion plus decompression, as opposed to decompression alone, is weak, according to the investigators who conducted the Swedish Spinal Stenosis Study. The other study in the New England Journal of Medicine, the Spinal Laminectomy Versus Instrumented Pedicle Screw (SLIP) trial, was conducted in the United States.

Both of those clinical trials were performed to shed further light on the issue.

In the Swedish Spinal Stenosis Study, the investigators assessed outcomes in 247 patients aged 50-80 years who were treated at seven Swedish hospitals over the course of 6 years. This open-label, superiority trial randomly assigned 124 patients to decompression surgery alone and 123 to decompression plus fusion. The primary outcome measure was score on the Oswestry Disability Index (ODI), which measures disability and quality of life in patients with low-back pain, 2 years after surgery. The ODI scale runs from 0 to 100, with higher scores indicating more severe disability, said Dr. Peter Försth of the department of surgical sciences at Uppsala (Sweden) University and the Stockholm Spine Center and his associates.

At 2 years, there was no significant difference between the two study groups; the decompression-only group had a mean ODI score of 24, and the fusion group had a mean score of 27. The ODI scores in both groups had improved from baseline to a similar degree: by 17 points with decompression alone and by 15 points with fusion. In addition, fusion surgery was not superior to decompression alone regardless of whether patients had any degree of spondylolisthesis and regardless of whether they had severe spondylolisthesis involving a vertebral slip of 7.4 mm or more, the investigators reported (N Engl J Med. 2016 April 13. doi: 10.1056/NEJMoa1513721).The two study groups also showed no significant differences in secondary outcome measures, including performance on the 6-minute walk test and subjective patient assessment of improvement in walking ability. Moreover, these results persisted in the 144 patients who were assessed at 5-year follow-up.

In contrast, decompression alone was associated with fewer complications than decompression plus fusion. Postoperative wound infection developed in only 4% of the decompression-only group, compared with 10% of the fusion group. Although this study wasn’t adequately powered to draw firm conclusions regarding complications, a previous analysis of registry data reported that adding fusion surgery to decompression surgery doubles the risk of severe adverse events in older patients, Dr. Försth and his associates said.

Decompression alone also was markedly less expensive than fusion surgery. Mean direct costs were $6,800 higher for fusion than for decompression alone, because of the additional operating time needed, the extended hospital stay, and the cost of the implant.

In the SLIP trial, the researchers compared outcomes in 66 patients aged 50-80 years who all had spinal stenosis with grade 1 degenerative spondylolisthesis. The participants were randomly assigned to undergo decompression alone (35 patients) or decompression plus fusion (31 patients) at five U.S. medical centers, said Dr. Zoher Ghogawala of the Alan and Jacqueline B. Stuart Spine Research Center in the department of neurosurgery at Lahey Hospital and Medical Center, Burlington, Mass., and his associates.

The primary outcome measure was the physical-component summary score on the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) 2 years after surgery. This scale also runs from 0 to 100, but higher scores indicate better physical health. Five points was prespecified as the minimal clinically important difference on the SF-36.

At 2 years, patients in the fusion group showed a small but significant advantage of 5.7 points on the SF-36, with a mean score of 15.2, compared with patients in the decompression-only group (mean score, 9.5). However, the ODI scores, a secondary outcome measure in this study, were not significantly different between the two study groups, Dr. Ghogawala and his associates reported (N Engl J Med. 2016 April 13. doi: 10.1056/NEJMoa1508788).Surgical complications, blood loss, and length of stay all were significantly greater with fusion than with decompression alone.

Dr. Försth’s study was supported by Uppsala University, Uppsala County Council, the Stockholm Spine Center, and Johnson & Johnson. Two of his associates reported ties to Medtronic and Quantify Research. Dr. Ghogawala’s study was supported by the Jean and David Wallace Foundation, the Greenwich Lumbar Stenosis SLIP Study Fund. His associates reported ties to numerous industry sources.

CHICAGO – Early intravenous administration of the beta-blocker metoprolol before primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction (STEMI) was safe but did not reduce infarct size in the randomized, placebo-controlled Early-BAMI trial.

No difference was seen in infarct size, as measured by magnetic resonance imaging at 30 days, between 336 patients with STEMI who presented within 12 hours of symptom onset and were randomized to receive intravenous metoprolol (2 vials with 5 mg) before undergoing angioplasty, and 347 such patients who received placebo (left ventricular volume, 15.3% and 14.9%, respectively), Dr. Vincent Roolvink of Isala Hospital, Zwolle, the Netherlands, reported at the annual meeting of the American College of Cardiology.

No differences were seen between the groups for the secondary endpoints of blood flow from the left ventricle or levels of cardiac enzymes, Dr. Roolvink noted.

Further, while significantly fewer cases of ventricular arrhythmia occurred in the metoprolol patients (3.6% vs. 6.9%), this difference was not clinically significant, he said.

No significant differences were seen with respect to safety endpoints, including abnormally slow heart rate, low blood pressure, or cardiogenic shock.

The Early-BAMI subjects had a mean age of 62 years, and most (75%) were men. They were enrolled at centers throughout the Netherlands and Spain.

“In this nonrestricted STEMI population, early intravenous metoprolol before primary percutaneous intervention did not reduce infarct size,” Dr Roolvink said, noting that the findings follow conflicting results from prior studies, with some suggesting that beta-blockers could reduce heart attack severity or improve blood flow from the left ventricle when given to STEMI patients prior to angioplasty.

However only one randomized trial took place in the primary percutaneous coronary intervention era, and that trial – METOCARD-CNIC (Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction) – involved only patients with STEMIs involving the anterior wall of the left ventricle (J Am Coll Cardiol. 2014;63[22]:2356-62).

Early-BAMI (The Effect of Early Administration of Intravenous Beta Blockers in Patients with ST-elevation Myocardial Infarction Before Primary Percutaneous Coronary Intervention) was the first double blind, placebo-controlled international multicenter study to test this approach.

“Our results do not confirm the effect observed in the METOCARD-CNIC trial,” Dr. Roolvink said.

He noted, however, that the current findings are limited by the fact that study subjects had lower than expected overall heart attack severity.

Additional large randomized trials are needed to clarify whether early beta-blocker treatment is of benefit before angioplasty in STEMI patients. The safety profile, low cost of beta-blocker administration, and the reduction of acute malignant arrhythmias among those receiving beta-blocker treatment in the current trial should encourage the performance of additional larger trials, he said.

The findings were simultaneously published online (J Am Coll Cardiol. 2016 Apr 3. doi:10.1016/j.jacc.2016.03.522)

Early-BAMI was funded by the Dutch Heart Foundation and Medtronic. Dr. Roolvink reported having no disclosures.

sworcester@frontlinemedcom.com

CHICAGO – Early intravenous administration of the beta-blocker metoprolol before primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction (STEMI) was safe but did not reduce infarct size in the randomized, placebo-controlled Early-BAMI trial.

No difference was seen in infarct size, as measured by magnetic resonance imaging at 30 days, between 336 patients with STEMI who presented within 12 hours of symptom onset and were randomized to receive intravenous metoprolol (2 vials with 5 mg) before undergoing angioplasty, and 347 such patients who received placebo (left ventricular volume, 15.3% and 14.9%, respectively), Dr. Vincent Roolvink of Isala Hospital, Zwolle, the Netherlands, reported at the annual meeting of the American College of Cardiology.

No differences were seen between the groups for the secondary endpoints of blood flow from the left ventricle or levels of cardiac enzymes, Dr. Roolvink noted.

Further, while significantly fewer cases of ventricular arrhythmia occurred in the metoprolol patients (3.6% vs. 6.9%), this difference was not clinically significant, he said.

No significant differences were seen with respect to safety endpoints, including abnormally slow heart rate, low blood pressure, or cardiogenic shock.

The Early-BAMI subjects had a mean age of 62 years, and most (75%) were men. They were enrolled at centers throughout the Netherlands and Spain.

“In this nonrestricted STEMI population, early intravenous metoprolol before primary percutaneous intervention did not reduce infarct size,” Dr Roolvink said, noting that the findings follow conflicting results from prior studies, with some suggesting that beta-blockers could reduce heart attack severity or improve blood flow from the left ventricle when given to STEMI patients prior to angioplasty.

However only one randomized trial took place in the primary percutaneous coronary intervention era, and that trial – METOCARD-CNIC (Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction) – involved only patients with STEMIs involving the anterior wall of the left ventricle (J Am Coll Cardiol. 2014;63[22]:2356-62).

Early-BAMI (The Effect of Early Administration of Intravenous Beta Blockers in Patients with ST-elevation Myocardial Infarction Before Primary Percutaneous Coronary Intervention) was the first double blind, placebo-controlled international multicenter study to test this approach.

“Our results do not confirm the effect observed in the METOCARD-CNIC trial,” Dr. Roolvink said.

He noted, however, that the current findings are limited by the fact that study subjects had lower than expected overall heart attack severity.

Additional large randomized trials are needed to clarify whether early beta-blocker treatment is of benefit before angioplasty in STEMI patients. The safety profile, low cost of beta-blocker administration, and the reduction of acute malignant arrhythmias among those receiving beta-blocker treatment in the current trial should encourage the performance of additional larger trials, he said.

The findings were simultaneously published online (J Am Coll Cardiol. 2016 Apr 3. doi:10.1016/j.jacc.2016.03.522)

Early-BAMI was funded by the Dutch Heart Foundation and Medtronic. Dr. Roolvink reported having no disclosures.

sworcester@frontlinemedcom.com

CHICAGO – Early intravenous administration of the beta-blocker metoprolol before primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction (STEMI) was safe but did not reduce infarct size in the randomized, placebo-controlled Early-BAMI trial.

No difference was seen in infarct size, as measured by magnetic resonance imaging at 30 days, between 336 patients with STEMI who presented within 12 hours of symptom onset and were randomized to receive intravenous metoprolol (2 vials with 5 mg) before undergoing angioplasty, and 347 such patients who received placebo (left ventricular volume, 15.3% and 14.9%, respectively), Dr. Vincent Roolvink of Isala Hospital, Zwolle, the Netherlands, reported at the annual meeting of the American College of Cardiology.

No differences were seen between the groups for the secondary endpoints of blood flow from the left ventricle or levels of cardiac enzymes, Dr. Roolvink noted.

Further, while significantly fewer cases of ventricular arrhythmia occurred in the metoprolol patients (3.6% vs. 6.9%), this difference was not clinically significant, he said.

No significant differences were seen with respect to safety endpoints, including abnormally slow heart rate, low blood pressure, or cardiogenic shock.

The Early-BAMI subjects had a mean age of 62 years, and most (75%) were men. They were enrolled at centers throughout the Netherlands and Spain.

“In this nonrestricted STEMI population, early intravenous metoprolol before primary percutaneous intervention did not reduce infarct size,” Dr Roolvink said, noting that the findings follow conflicting results from prior studies, with some suggesting that beta-blockers could reduce heart attack severity or improve blood flow from the left ventricle when given to STEMI patients prior to angioplasty.

However only one randomized trial took place in the primary percutaneous coronary intervention era, and that trial – METOCARD-CNIC (Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction) – involved only patients with STEMIs involving the anterior wall of the left ventricle (J Am Coll Cardiol. 2014;63[22]:2356-62).

Early-BAMI (The Effect of Early Administration of Intravenous Beta Blockers in Patients with ST-elevation Myocardial Infarction Before Primary Percutaneous Coronary Intervention) was the first double blind, placebo-controlled international multicenter study to test this approach.

“Our results do not confirm the effect observed in the METOCARD-CNIC trial,” Dr. Roolvink said.

He noted, however, that the current findings are limited by the fact that study subjects had lower than expected overall heart attack severity.

Additional large randomized trials are needed to clarify whether early beta-blocker treatment is of benefit before angioplasty in STEMI patients. The safety profile, low cost of beta-blocker administration, and the reduction of acute malignant arrhythmias among those receiving beta-blocker treatment in the current trial should encourage the performance of additional larger trials, he said.

The findings were simultaneously published online (J Am Coll Cardiol. 2016 Apr 3. doi:10.1016/j.jacc.2016.03.522)

Early-BAMI was funded by the Dutch Heart Foundation and Medtronic. Dr. Roolvink reported having no disclosures.

sworcester@frontlinemedcom.com

CHICAGO – The benefit from dual-antiplatelet therapy in high-risk patients following a myocardial infarction was especially apparent in post-MI patients with diabetes in a prespecified secondary analysis from a multicenter trial of ticagrelor with more than 21,000 patients.

Among post-MI patients with diabetes, treatment with ticagrelor plus aspirin led to an absolute 1.5% reduction in the rate of cardiovascular death, MI, or stroke during a median 33-month follow-up, compared with an absolute 1.1% cut in patients without diabetes, Dr. Deepak L. Bhatt said at the annual meeting of the American College of Cardiology. The relative risk reduction, compared with placebo was 16% in both the diabetes and no diabetes subgroups, statistically significant differences in both subgroups.

Mitchel L. Zoler/Frontline Medical News

“Long-term treatment with ticagrelor reduced the composite of cardiovascular death, MI, or stroke in diabetic patients with a greater absolute risk reduction than in nondiabetic patients,” said Dr. Bhatt, professor of medicine at Harvard Medical School and executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital in Boston. Treatment with ticagrelor plus aspirin in post-MI patients with diabetes also led to an increased number of major bleeding episodes, compared with patients on aspirin alone, but no excess of intracerebral hemorrhages or fatal bleeds, he noted.

This finding of a significant benefit from ticagrelor in post-MI patients with diabetes confirms similar, prior findings with other antiplatelet drugs (including clopidogrel, prasugrel, and vorapaxar) and prior findings with ticagrelor, Dr. Bhatt noted.

The new analysis used data collected in the Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial. The primary results from PEGASUS-TIMI 54 had shown that adding ticagrelor to aspirin treatment of high-risk post-MI patients, including those who both had or did not have diabetes, significantly cut the composite rate of cardiovascular death, MI, and stroke, compared with aspirin alone (N Engl J Med. 2015 May 7;372[19]:1791-800). The study group included 6,806 patients with diabetes (type 2 diabetes in 99% of these patients), and 14,355 without diabetes. All patients had their MI 1-3 years before entering the study.

Dr. Bhatt and his associates examined the incidence of the various clinical endpoints measured in the study among only the patients with diabetes divided into those who received any dosage of ticagrelor (60 mg b.i.d. or 90 mg b.i.d.) or placebo, and also among the patients without diabetes. In addition to the primary endpoint, the new analysis showed that the rate of cardiovascular death during follow-up was 3.9% in the diabetes patients on dual therapy and 5.0% among the diabetes patients on aspirin only, a 22% relative risk reduction with ticagrelor added that was statistically significant. In contrast, among patients without diabetes the rates of cardiovascular death between those on and not on ticagrelor only differed by 0.2%, a 9% relative risk reduction that was not statistically significant. The same pattern occurred for the endpoint of death from coronary artery disease.

Concurrent with Dr. Bhatt’s report, the results appeared in an article published online (J Am Coll Cardiol. 2016 Apr; doi: 10.1016/S0735-1097[16]30023-7).

A new study, THEMIS, is examining the safety and efficacy of combined ticagrelor and aspirin treatment in a lower-risk group of patients with diabetes, those with coronary artery disease who have not had a prior MI. Those results may be available in 2018.

PEGASUS-TIMI 54 was sponsored by AstraZeneca, the company that markets ticagrelor (Brilinta). Dr. Bhatt has been an advisor to Cardax and Regado Biosciences and has received research support from AstraZeneca and several other companies.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

CHICAGO – The benefit from dual-antiplatelet therapy in high-risk patients following a myocardial infarction was especially apparent in post-MI patients with diabetes in a prespecified secondary analysis from a multicenter trial of ticagrelor with more than 21,000 patients.

Among post-MI patients with diabetes, treatment with ticagrelor plus aspirin led to an absolute 1.5% reduction in the rate of cardiovascular death, MI, or stroke during a median 33-month follow-up, compared with an absolute 1.1% cut in patients without diabetes, Dr. Deepak L. Bhatt said at the annual meeting of the American College of Cardiology. The relative risk reduction, compared with placebo was 16% in both the diabetes and no diabetes subgroups, statistically significant differences in both subgroups.

Mitchel L. Zoler/Frontline Medical News

“Long-term treatment with ticagrelor reduced the composite of cardiovascular death, MI, or stroke in diabetic patients with a greater absolute risk reduction than in nondiabetic patients,” said Dr. Bhatt, professor of medicine at Harvard Medical School and executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital in Boston. Treatment with ticagrelor plus aspirin in post-MI patients with diabetes also led to an increased number of major bleeding episodes, compared with patients on aspirin alone, but no excess of intracerebral hemorrhages or fatal bleeds, he noted.

This finding of a significant benefit from ticagrelor in post-MI patients with diabetes confirms similar, prior findings with other antiplatelet drugs (including clopidogrel, prasugrel, and vorapaxar) and prior findings with ticagrelor, Dr. Bhatt noted.

The new analysis used data collected in the Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial. The primary results from PEGASUS-TIMI 54 had shown that adding ticagrelor to aspirin treatment of high-risk post-MI patients, including those who both had or did not have diabetes, significantly cut the composite rate of cardiovascular death, MI, and stroke, compared with aspirin alone (N Engl J Med. 2015 May 7;372[19]:1791-800). The study group included 6,806 patients with diabetes (type 2 diabetes in 99% of these patients), and 14,355 without diabetes. All patients had their MI 1-3 years before entering the study.

Dr. Bhatt and his associates examined the incidence of the various clinical endpoints measured in the study among only the patients with diabetes divided into those who received any dosage of ticagrelor (60 mg b.i.d. or 90 mg b.i.d.) or placebo, and also among the patients without diabetes. In addition to the primary endpoint, the new analysis showed that the rate of cardiovascular death during follow-up was 3.9% in the diabetes patients on dual therapy and 5.0% among the diabetes patients on aspirin only, a 22% relative risk reduction with ticagrelor added that was statistically significant. In contrast, among patients without diabetes the rates of cardiovascular death between those on and not on ticagrelor only differed by 0.2%, a 9% relative risk reduction that was not statistically significant. The same pattern occurred for the endpoint of death from coronary artery disease.

Concurrent with Dr. Bhatt’s report, the results appeared in an article published online (J Am Coll Cardiol. 2016 Apr; doi: 10.1016/S0735-1097[16]30023-7).

A new study, THEMIS, is examining the safety and efficacy of combined ticagrelor and aspirin treatment in a lower-risk group of patients with diabetes, those with coronary artery disease who have not had a prior MI. Those results may be available in 2018.

PEGASUS-TIMI 54 was sponsored by AstraZeneca, the company that markets ticagrelor (Brilinta). Dr. Bhatt has been an advisor to Cardax and Regado Biosciences and has received research support from AstraZeneca and several other companies.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

CHICAGO – The benefit from dual-antiplatelet therapy in high-risk patients following a myocardial infarction was especially apparent in post-MI patients with diabetes in a prespecified secondary analysis from a multicenter trial of ticagrelor with more than 21,000 patients.

Among post-MI patients with diabetes, treatment with ticagrelor plus aspirin led to an absolute 1.5% reduction in the rate of cardiovascular death, MI, or stroke during a median 33-month follow-up, compared with an absolute 1.1% cut in patients without diabetes, Dr. Deepak L. Bhatt said at the annual meeting of the American College of Cardiology. The relative risk reduction, compared with placebo was 16% in both the diabetes and no diabetes subgroups, statistically significant differences in both subgroups.

Mitchel L. Zoler/Frontline Medical News

“Long-term treatment with ticagrelor reduced the composite of cardiovascular death, MI, or stroke in diabetic patients with a greater absolute risk reduction than in nondiabetic patients,” said Dr. Bhatt, professor of medicine at Harvard Medical School and executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital in Boston. Treatment with ticagrelor plus aspirin in post-MI patients with diabetes also led to an increased number of major bleeding episodes, compared with patients on aspirin alone, but no excess of intracerebral hemorrhages or fatal bleeds, he noted.

This finding of a significant benefit from ticagrelor in post-MI patients with diabetes confirms similar, prior findings with other antiplatelet drugs (including clopidogrel, prasugrel, and vorapaxar) and prior findings with ticagrelor, Dr. Bhatt noted.

The new analysis used data collected in the Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial. The primary results from PEGASUS-TIMI 54 had shown that adding ticagrelor to aspirin treatment of high-risk post-MI patients, including those who both had or did not have diabetes, significantly cut the composite rate of cardiovascular death, MI, and stroke, compared with aspirin alone (N Engl J Med. 2015 May 7;372[19]:1791-800). The study group included 6,806 patients with diabetes (type 2 diabetes in 99% of these patients), and 14,355 without diabetes. All patients had their MI 1-3 years before entering the study.

Dr. Bhatt and his associates examined the incidence of the various clinical endpoints measured in the study among only the patients with diabetes divided into those who received any dosage of ticagrelor (60 mg b.i.d. or 90 mg b.i.d.) or placebo, and also among the patients without diabetes. In addition to the primary endpoint, the new analysis showed that the rate of cardiovascular death during follow-up was 3.9% in the diabetes patients on dual therapy and 5.0% among the diabetes patients on aspirin only, a 22% relative risk reduction with ticagrelor added that was statistically significant. In contrast, among patients without diabetes the rates of cardiovascular death between those on and not on ticagrelor only differed by 0.2%, a 9% relative risk reduction that was not statistically significant. The same pattern occurred for the endpoint of death from coronary artery disease.

Concurrent with Dr. Bhatt’s report, the results appeared in an article published online (J Am Coll Cardiol. 2016 Apr; doi: 10.1016/S0735-1097[16]30023-7).

A new study, THEMIS, is examining the safety and efficacy of combined ticagrelor and aspirin treatment in a lower-risk group of patients with diabetes, those with coronary artery disease who have not had a prior MI. Those results may be available in 2018.

PEGASUS-TIMI 54 was sponsored by AstraZeneca, the company that markets ticagrelor (Brilinta). Dr. Bhatt has been an advisor to Cardax and Regado Biosciences and has received research support from AstraZeneca and several other companies.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler