Micrograph showing CLL

Results of a phase 3 study suggest that adding ofatumumab to chlorambucil can improve progression-free survival (PFS) in treatment-naïve patients with chronic lymphocytic leukemia (CLL).

Ofatumumab plus chlorambucil improved the median PFS by 71% compared to chlorambucil alone.

The combination also improved the overall response rate, duration of response, and time to next treatment.

However, patients in the combination arm had a higher rate of grade 3 or greater adverse events (AEs).

Researchers reported these results in The Lancet. The study, known as COMPLEMENT 1, was funded by GlaxoSmithKline and Genmab A/S.

The study included 447 patients with previously untreated CLL for whom fludarabine-based therapy was considered inappropriate. Patients were randomized to treatment with up to 12 cycles of ofatumumab in combination with chlorambucil (n=221) or up to 12 cycles of chlorambucil alone (n=226).

The study’s primary endpoint was the median PFS, which was 22.4 months in the combination arm and 13.1 months in the chlorambucil arm (hazard ratio [HR]=0.57, P<0.0001). This improvement in PFS was observed in most subgroups, irrespective of age, gender, disease stage, and prognostic factors.

As for secondary endpoints, patients in the combination arm had a higher overall response rate than patients in the chlorambucil arm—82% and 69%, respectively (odds ratio=2.16, P=0.001).

And combination treatment increased the duration of response compared to chlorambucil alone—22.1 months and 13.2 months, respectively (HR=0.56, P<0.001).

Patients in the combination arm also experienced a significantly longer time to next therapy compared to the chlorambucil arm—39.8 months and 24.7 months, respectively (HR=0.49, P<0.0001).

Safety data

The most common AEs (occurring in at least 2% of patients) were neutropenia, thrombocytopenia, anemia, infections, and infusion-related reactions.

Neutropenia occurred more frequently in the combination arm (27% vs 18%), as did infusion-related reactions (67% vs 0%) and infections (46% vs 42%). But thrombocytopenia and anemia were more frequent in the chlorambucil arm (26% vs 14% and 13% vs 9%, respectively).

The incidence of grade 3 or greater AEs was higher in the combination arm than the chlorambucil arm—50% and 43%, respectively.

Grade 3/4 infusion-related reactions occurred in 10% of patients in the combination arm, leading to drug withdrawal in 3% of patients and hospitalization in 2% of patients. No fatal infusion-related reactions were reported.

The most common infections were respiratory tract infections, with an incidence of 27% in the combination arm and 31% in the chlorambucil arm. There were similar frequencies of sepsis (3% and 2%, respectively) and opportunistic infections between the arms (4% and 5%, respectively).

The incidence of AEs leading to treatment withdrawal was 13% in both arms. And the incidence of death during treatment or within 60 days after the last dose was 3% in both arms.

These data formed the basis for regulatory approvals of ofatumumab (Arzerra) in the US and European Union, as well as the recent inclusion of ofatumumab plus chlorambucil in the National Comprehensive Cancer Network treatment guidelines.

Micrograph showing CLL

Results of a phase 3 study suggest that adding ofatumumab to chlorambucil can improve progression-free survival (PFS) in treatment-naïve patients with chronic lymphocytic leukemia (CLL).

Ofatumumab plus chlorambucil improved the median PFS by 71% compared to chlorambucil alone.

The combination also improved the overall response rate, duration of response, and time to next treatment.

However, patients in the combination arm had a higher rate of grade 3 or greater adverse events (AEs).

Researchers reported these results in The Lancet. The study, known as COMPLEMENT 1, was funded by GlaxoSmithKline and Genmab A/S.

The study included 447 patients with previously untreated CLL for whom fludarabine-based therapy was considered inappropriate. Patients were randomized to treatment with up to 12 cycles of ofatumumab in combination with chlorambucil (n=221) or up to 12 cycles of chlorambucil alone (n=226).

The study’s primary endpoint was the median PFS, which was 22.4 months in the combination arm and 13.1 months in the chlorambucil arm (hazard ratio [HR]=0.57, P<0.0001). This improvement in PFS was observed in most subgroups, irrespective of age, gender, disease stage, and prognostic factors.

As for secondary endpoints, patients in the combination arm had a higher overall response rate than patients in the chlorambucil arm—82% and 69%, respectively (odds ratio=2.16, P=0.001).

And combination treatment increased the duration of response compared to chlorambucil alone—22.1 months and 13.2 months, respectively (HR=0.56, P<0.001).

Patients in the combination arm also experienced a significantly longer time to next therapy compared to the chlorambucil arm—39.8 months and 24.7 months, respectively (HR=0.49, P<0.0001).

Safety data

The most common AEs (occurring in at least 2% of patients) were neutropenia, thrombocytopenia, anemia, infections, and infusion-related reactions.

Neutropenia occurred more frequently in the combination arm (27% vs 18%), as did infusion-related reactions (67% vs 0%) and infections (46% vs 42%). But thrombocytopenia and anemia were more frequent in the chlorambucil arm (26% vs 14% and 13% vs 9%, respectively).

The incidence of grade 3 or greater AEs was higher in the combination arm than the chlorambucil arm—50% and 43%, respectively.

Grade 3/4 infusion-related reactions occurred in 10% of patients in the combination arm, leading to drug withdrawal in 3% of patients and hospitalization in 2% of patients. No fatal infusion-related reactions were reported.

The most common infections were respiratory tract infections, with an incidence of 27% in the combination arm and 31% in the chlorambucil arm. There were similar frequencies of sepsis (3% and 2%, respectively) and opportunistic infections between the arms (4% and 5%, respectively).

The incidence of AEs leading to treatment withdrawal was 13% in both arms. And the incidence of death during treatment or within 60 days after the last dose was 3% in both arms.

These data formed the basis for regulatory approvals of ofatumumab (Arzerra) in the US and European Union, as well as the recent inclusion of ofatumumab plus chlorambucil in the National Comprehensive Cancer Network treatment guidelines.

Micrograph showing CLL

Results of a phase 3 study suggest that adding ofatumumab to chlorambucil can improve progression-free survival (PFS) in treatment-naïve patients with chronic lymphocytic leukemia (CLL).

Ofatumumab plus chlorambucil improved the median PFS by 71% compared to chlorambucil alone.

The combination also improved the overall response rate, duration of response, and time to next treatment.

However, patients in the combination arm had a higher rate of grade 3 or greater adverse events (AEs).

Researchers reported these results in The Lancet. The study, known as COMPLEMENT 1, was funded by GlaxoSmithKline and Genmab A/S.

The study included 447 patients with previously untreated CLL for whom fludarabine-based therapy was considered inappropriate. Patients were randomized to treatment with up to 12 cycles of ofatumumab in combination with chlorambucil (n=221) or up to 12 cycles of chlorambucil alone (n=226).

The study’s primary endpoint was the median PFS, which was 22.4 months in the combination arm and 13.1 months in the chlorambucil arm (hazard ratio [HR]=0.57, P<0.0001). This improvement in PFS was observed in most subgroups, irrespective of age, gender, disease stage, and prognostic factors.

As for secondary endpoints, patients in the combination arm had a higher overall response rate than patients in the chlorambucil arm—82% and 69%, respectively (odds ratio=2.16, P=0.001).

And combination treatment increased the duration of response compared to chlorambucil alone—22.1 months and 13.2 months, respectively (HR=0.56, P<0.001).

Patients in the combination arm also experienced a significantly longer time to next therapy compared to the chlorambucil arm—39.8 months and 24.7 months, respectively (HR=0.49, P<0.0001).

Safety data

The most common AEs (occurring in at least 2% of patients) were neutropenia, thrombocytopenia, anemia, infections, and infusion-related reactions.

Neutropenia occurred more frequently in the combination arm (27% vs 18%), as did infusion-related reactions (67% vs 0%) and infections (46% vs 42%). But thrombocytopenia and anemia were more frequent in the chlorambucil arm (26% vs 14% and 13% vs 9%, respectively).

The incidence of grade 3 or greater AEs was higher in the combination arm than the chlorambucil arm—50% and 43%, respectively.

Grade 3/4 infusion-related reactions occurred in 10% of patients in the combination arm, leading to drug withdrawal in 3% of patients and hospitalization in 2% of patients. No fatal infusion-related reactions were reported.

The most common infections were respiratory tract infections, with an incidence of 27% in the combination arm and 31% in the chlorambucil arm. There were similar frequencies of sepsis (3% and 2%, respectively) and opportunistic infections between the arms (4% and 5%, respectively).

The incidence of AEs leading to treatment withdrawal was 13% in both arms. And the incidence of death during treatment or within 60 days after the last dose was 3% in both arms.

These data formed the basis for regulatory approvals of ofatumumab (Arzerra) in the US and European Union, as well as the recent inclusion of ofatumumab plus chlorambucil in the National Comprehensive Cancer Network treatment guidelines.

Genetic analysis

Photo courtesy of NIGMS

A study of genes associated with bleeding disorders suggests it can be challenging to gauge the clinical significance of novel gene variants.

Researchers analyzed genomic data from more than 16,000 subjects, looking for missense variants in the integrin aIIbß3 receptor subunit genes ITGA2B and ITGB3.

Although the team identified close to 200 novel variants in these genes, they found it difficult to determine the functional impact of the variants.

Barry S. Coller, MD, of The Rockefeller University in New York, New York, and his colleagues described this research in PNAS.

The team analyzed genomic data from 16,108 people and found that about 1.3% of the individuals had missense variants in ITGA2B, ITGB3, or both genes.

To determine which of these missense variants were newly discovered, the researchers looked for 111 variants that were previously reported as being associated with Glanzmann thrombasthenia, 20 variants that were associated with alloimmune thrombocytopenia, and 5 variants that were associated with aniso/macrothrombocytopenia.

The results suggested the team had discovered 114 novel missense variants in ITGA2B and 68 novel variants in ITGB3. And they did not find any of the previously reported variants in the 2 genes.

“This means the disease-causing mutations previously reported are very rare and, thus, probably first appeared relatively recently—that is, in the past several hundred years,” Dr Coller said.

The researchers then used 3 different algorithms to try to predict the proportion of the missense variants that would likely have a negative impact on a person’s health by causing excess bleeding.

They got a wide range of results. Depending on the algorithm and other variables, between 27% and 71% of variants were predicted to be harmful.

To test the validity of the predictions, the team took a closer look at 3 of the variants that affect amino acids previously associated with Glanzmann thrombasthenia.

They found that 2 of the variants—aIIb P176H and ß3 C547G—severely reduced aIIbß3 expression. The third variant—aIIb P943A—partially reduced aIIbß3 expression but had no effect on fibrinogen binding.

These results show how challenging it can be to interpret genetic data, Dr Coller said.

“Some variants of these 2 genes will likely be obviously deleterious, but it may be impossible to predict whether others are deleterious,” he noted. “In those cases, we will need to use additional information to judge the likelihood of a mutation being deleterious, and, in many cases, there will be residual uncertainty.”

Genetic analysis

Photo courtesy of NIGMS

A study of genes associated with bleeding disorders suggests it can be challenging to gauge the clinical significance of novel gene variants.

Researchers analyzed genomic data from more than 16,000 subjects, looking for missense variants in the integrin aIIbß3 receptor subunit genes ITGA2B and ITGB3.

Although the team identified close to 200 novel variants in these genes, they found it difficult to determine the functional impact of the variants.

Barry S. Coller, MD, of The Rockefeller University in New York, New York, and his colleagues described this research in PNAS.

The team analyzed genomic data from 16,108 people and found that about 1.3% of the individuals had missense variants in ITGA2B, ITGB3, or both genes.

To determine which of these missense variants were newly discovered, the researchers looked for 111 variants that were previously reported as being associated with Glanzmann thrombasthenia, 20 variants that were associated with alloimmune thrombocytopenia, and 5 variants that were associated with aniso/macrothrombocytopenia.

The results suggested the team had discovered 114 novel missense variants in ITGA2B and 68 novel variants in ITGB3. And they did not find any of the previously reported variants in the 2 genes.

“This means the disease-causing mutations previously reported are very rare and, thus, probably first appeared relatively recently—that is, in the past several hundred years,” Dr Coller said.

The researchers then used 3 different algorithms to try to predict the proportion of the missense variants that would likely have a negative impact on a person’s health by causing excess bleeding.

They got a wide range of results. Depending on the algorithm and other variables, between 27% and 71% of variants were predicted to be harmful.

To test the validity of the predictions, the team took a closer look at 3 of the variants that affect amino acids previously associated with Glanzmann thrombasthenia.

They found that 2 of the variants—aIIb P176H and ß3 C547G—severely reduced aIIbß3 expression. The third variant—aIIb P943A—partially reduced aIIbß3 expression but had no effect on fibrinogen binding.

These results show how challenging it can be to interpret genetic data, Dr Coller said.

“Some variants of these 2 genes will likely be obviously deleterious, but it may be impossible to predict whether others are deleterious,” he noted. “In those cases, we will need to use additional information to judge the likelihood of a mutation being deleterious, and, in many cases, there will be residual uncertainty.”

Genetic analysis

Photo courtesy of NIGMS

A study of genes associated with bleeding disorders suggests it can be challenging to gauge the clinical significance of novel gene variants.

Researchers analyzed genomic data from more than 16,000 subjects, looking for missense variants in the integrin aIIbß3 receptor subunit genes ITGA2B and ITGB3.

Although the team identified close to 200 novel variants in these genes, they found it difficult to determine the functional impact of the variants.

Barry S. Coller, MD, of The Rockefeller University in New York, New York, and his colleagues described this research in PNAS.

The team analyzed genomic data from 16,108 people and found that about 1.3% of the individuals had missense variants in ITGA2B, ITGB3, or both genes.

To determine which of these missense variants were newly discovered, the researchers looked for 111 variants that were previously reported as being associated with Glanzmann thrombasthenia, 20 variants that were associated with alloimmune thrombocytopenia, and 5 variants that were associated with aniso/macrothrombocytopenia.

The results suggested the team had discovered 114 novel missense variants in ITGA2B and 68 novel variants in ITGB3. And they did not find any of the previously reported variants in the 2 genes.

“This means the disease-causing mutations previously reported are very rare and, thus, probably first appeared relatively recently—that is, in the past several hundred years,” Dr Coller said.

The researchers then used 3 different algorithms to try to predict the proportion of the missense variants that would likely have a negative impact on a person’s health by causing excess bleeding.

They got a wide range of results. Depending on the algorithm and other variables, between 27% and 71% of variants were predicted to be harmful.

To test the validity of the predictions, the team took a closer look at 3 of the variants that affect amino acids previously associated with Glanzmann thrombasthenia.

They found that 2 of the variants—aIIb P176H and ß3 C547G—severely reduced aIIbß3 expression. The third variant—aIIb P943A—partially reduced aIIbß3 expression but had no effect on fibrinogen binding.

These results show how challenging it can be to interpret genetic data, Dr Coller said.

“Some variants of these 2 genes will likely be obviously deleterious, but it may be impossible to predict whether others are deleterious,” he noted. “In those cases, we will need to use additional information to judge the likelihood of a mutation being deleterious, and, in many cases, there will be residual uncertainty.”

Cancer patient receiving

chemotherapy

Photo by Rhoda Baer

A bill that repeals the sustainable growth rate (SGR) formula for physician reimbursement under Medicare is a victory for cancer patients, according to oncologist groups.

The bill—known as H.R.2—passed both the US House of Representatives and the Senate with an overwhelming majority. It must still be signed into law by President Obama, but he has indicated he will sign it.

By repealing the SGR payment methodology, the bill will prevent a 21.2% reduction in physician reimbursement rates.

“Today’s courageous vote by the US Senate to finally end the sustainable growth rate formula is a vote for the millions of patients with cancer who depend on Medicare to help them fight their disease,” said Peter Paul Yu, MD, president of the American Society of Clinical Oncology.

“With Congress passing this historic legislation to finally end the 13-year SGR roller coaster ride, Medicare beneficiaries and their physicians can breathe easier knowing that they will no longer face the perennial threat of payment cuts that risk disruption of care and cause anxiety among patients.”

Under H.R. 2, Medicare’s physician reimbursements will increase by 0.5% in the second half of 2015, then an additional 0.5% annually from 2016 through the end of 2019. The 2019 rates will be maintained through 2025 with no additional increases.

The bill also includes comprehensive structural changes to Medicare’s reimbursement model that aim to promote physician participation in clinical quality improvement activities and value-based care that will take full effect in 2019.

Current Medicare programs that reward electronic health records, quality reporting, the value-based modifier, and meaningful use will be merged by 2019 to encourage participation and to reduce the administrative burden.

The bill also ensures the Children’s Health Insurance Program will receive funding for 2 more years and allocates $7.2 billion for community health centers.

“[P]assage of this legislation represents a long-awaited, historic victory for our patients,” said Bruce G. Haffty, MD, chair of the American Society for Radiation Oncology’s board of directors.

“Permanently repealing the SGR and replacing it with a stabilized reimbursement plan focused on quality will strengthen Medicare and allow us to enhance cancer care for the more than 1 million patients treated with radiation therapy each year.”

Cancer patient receiving

chemotherapy

Photo by Rhoda Baer

A bill that repeals the sustainable growth rate (SGR) formula for physician reimbursement under Medicare is a victory for cancer patients, according to oncologist groups.

The bill—known as H.R.2—passed both the US House of Representatives and the Senate with an overwhelming majority. It must still be signed into law by President Obama, but he has indicated he will sign it.

By repealing the SGR payment methodology, the bill will prevent a 21.2% reduction in physician reimbursement rates.

“Today’s courageous vote by the US Senate to finally end the sustainable growth rate formula is a vote for the millions of patients with cancer who depend on Medicare to help them fight their disease,” said Peter Paul Yu, MD, president of the American Society of Clinical Oncology.

“With Congress passing this historic legislation to finally end the 13-year SGR roller coaster ride, Medicare beneficiaries and their physicians can breathe easier knowing that they will no longer face the perennial threat of payment cuts that risk disruption of care and cause anxiety among patients.”

Under H.R. 2, Medicare’s physician reimbursements will increase by 0.5% in the second half of 2015, then an additional 0.5% annually from 2016 through the end of 2019. The 2019 rates will be maintained through 2025 with no additional increases.

The bill also includes comprehensive structural changes to Medicare’s reimbursement model that aim to promote physician participation in clinical quality improvement activities and value-based care that will take full effect in 2019.

Current Medicare programs that reward electronic health records, quality reporting, the value-based modifier, and meaningful use will be merged by 2019 to encourage participation and to reduce the administrative burden.

The bill also ensures the Children’s Health Insurance Program will receive funding for 2 more years and allocates $7.2 billion for community health centers.

“[P]assage of this legislation represents a long-awaited, historic victory for our patients,” said Bruce G. Haffty, MD, chair of the American Society for Radiation Oncology’s board of directors.

“Permanently repealing the SGR and replacing it with a stabilized reimbursement plan focused on quality will strengthen Medicare and allow us to enhance cancer care for the more than 1 million patients treated with radiation therapy each year.”

Cancer patient receiving

chemotherapy

Photo by Rhoda Baer

A bill that repeals the sustainable growth rate (SGR) formula for physician reimbursement under Medicare is a victory for cancer patients, according to oncologist groups.

The bill—known as H.R.2—passed both the US House of Representatives and the Senate with an overwhelming majority. It must still be signed into law by President Obama, but he has indicated he will sign it.

By repealing the SGR payment methodology, the bill will prevent a 21.2% reduction in physician reimbursement rates.

“Today’s courageous vote by the US Senate to finally end the sustainable growth rate formula is a vote for the millions of patients with cancer who depend on Medicare to help them fight their disease,” said Peter Paul Yu, MD, president of the American Society of Clinical Oncology.

“With Congress passing this historic legislation to finally end the 13-year SGR roller coaster ride, Medicare beneficiaries and their physicians can breathe easier knowing that they will no longer face the perennial threat of payment cuts that risk disruption of care and cause anxiety among patients.”

Under H.R. 2, Medicare’s physician reimbursements will increase by 0.5% in the second half of 2015, then an additional 0.5% annually from 2016 through the end of 2019. The 2019 rates will be maintained through 2025 with no additional increases.

The bill also includes comprehensive structural changes to Medicare’s reimbursement model that aim to promote physician participation in clinical quality improvement activities and value-based care that will take full effect in 2019.

Current Medicare programs that reward electronic health records, quality reporting, the value-based modifier, and meaningful use will be merged by 2019 to encourage participation and to reduce the administrative burden.

The bill also ensures the Children’s Health Insurance Program will receive funding for 2 more years and allocates $7.2 billion for community health centers.

“[P]assage of this legislation represents a long-awaited, historic victory for our patients,” said Bruce G. Haffty, MD, chair of the American Society for Radiation Oncology’s board of directors.

“Permanently repealing the SGR and replacing it with a stabilized reimbursement plan focused on quality will strengthen Medicare and allow us to enhance cancer care for the more than 1 million patients treated with radiation therapy each year.”

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel supported approval of cangrelor, a short-acting, intravenous antiplatelet drug, for use in patients undergoing percutaneous coronary intervention, with precautions that it not be used widely or indiscriminately.

At a meeting on April 15, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 9-2, with one abstention, that cangrelor should be approved as an adjunct to PCI “for reducing the periprocedural thrombotic events, such as MI, stent thrombosis, and ischemia-driven revascularization.” The proposed indication includes the statement that use is for patients undergoing PCI “who have not received an oral P2Y₁₂ inhibitor prior to the PCI procedure and in whom oral therapy with P2Y₁₂ inhibitors is not feasible or desirable.”

Cangrelor, a P2Y₁₂ receptor inhibitor, has a half-life of 3-6 minutes, and platelet function completely returns to normal within 1 hour of stopping the infusion, according to the product’s sponsor, the Medicines Company.

The vote was based on analyses of revised endpoints of the data from the CHAMPION PHOENIX study, which compared cangrelor to clopidogrel in more than 11,000 patients undergoing PCI. The same panel voted 7-2 against approval in February 2014, for reasons that included doubts about the clinical consequences of some of the endpoints of the trial.

At the request of the FDA, the company reanalyzed the data, dropping intraprocedural stent thrombosis and MIs that did not meet the SCAI (Society for Cardiovascular Angiography Interventions) criteria for a clinically relevant MI from the primary endpoint. At 48 hours, 1.4% of those in the cangrelor arm met this revised endpoint, vs. 2.1% of those in the clopidogrel arm, for an odds ratio of 0.69 (P = .011). Most of the panel agreed that these analyses showed the drug had a beneficial effect.

Deaths and serious adverse events were similar between cangrelor and clopidogrel, but bleeding events were more common among patients treated with cangrelor, according to the company. A risk-benefit analysis, which took into account bleeding events, provided by the FDA concluded that the “benefit of cangrelor is small, but the risk is smaller.”

“There’s a great responsibility that this gets used appropriately and [is] not overused,” said Dr. James de Lemos, who voted against approval at the last meeting but voted for approval at this meeting. Dr. de Lemos, distinguished chair in cardiology and professor of medicine at the University of Texas Southwestern Medical Center, Dallas, said that his concerns about the robustness of the primary endpoint that had been “mostly addressed” by the FDA’s and company’s analyses.

However, he added that he remained concerned by the very narrow clinical benefit of the drug "relative to the risks and relative to what I worry will be the potential use of the drug.”

”What I would hope is that this drug is used very selectively and very narrowly in circumstances where P2Y₁₂ inhibitors cannot be used appropriately,” he commented. “If it is used broadly and indiscriminately, it will not only be expensive but it [also] will expose low-risk patients to unnecessary bleeding, some of which can be quite substantial.”

The FDA usually follows the recommendations of its advisory panels. The members of the panel had no relevant disclosures.

[email protected]

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel supported approval of cangrelor, a short-acting, intravenous antiplatelet drug, for use in patients undergoing percutaneous coronary intervention, with precautions that it not be used widely or indiscriminately.

At a meeting on April 15, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 9-2, with one abstention, that cangrelor should be approved as an adjunct to PCI “for reducing the periprocedural thrombotic events, such as MI, stent thrombosis, and ischemia-driven revascularization.” The proposed indication includes the statement that use is for patients undergoing PCI “who have not received an oral P2Y₁₂ inhibitor prior to the PCI procedure and in whom oral therapy with P2Y₁₂ inhibitors is not feasible or desirable.”

Cangrelor, a P2Y₁₂ receptor inhibitor, has a half-life of 3-6 minutes, and platelet function completely returns to normal within 1 hour of stopping the infusion, according to the product’s sponsor, the Medicines Company.

The vote was based on analyses of revised endpoints of the data from the CHAMPION PHOENIX study, which compared cangrelor to clopidogrel in more than 11,000 patients undergoing PCI. The same panel voted 7-2 against approval in February 2014, for reasons that included doubts about the clinical consequences of some of the endpoints of the trial.

At the request of the FDA, the company reanalyzed the data, dropping intraprocedural stent thrombosis and MIs that did not meet the SCAI (Society for Cardiovascular Angiography Interventions) criteria for a clinically relevant MI from the primary endpoint. At 48 hours, 1.4% of those in the cangrelor arm met this revised endpoint, vs. 2.1% of those in the clopidogrel arm, for an odds ratio of 0.69 (P = .011). Most of the panel agreed that these analyses showed the drug had a beneficial effect.

Deaths and serious adverse events were similar between cangrelor and clopidogrel, but bleeding events were more common among patients treated with cangrelor, according to the company. A risk-benefit analysis, which took into account bleeding events, provided by the FDA concluded that the “benefit of cangrelor is small, but the risk is smaller.”

“There’s a great responsibility that this gets used appropriately and [is] not overused,” said Dr. James de Lemos, who voted against approval at the last meeting but voted for approval at this meeting. Dr. de Lemos, distinguished chair in cardiology and professor of medicine at the University of Texas Southwestern Medical Center, Dallas, said that his concerns about the robustness of the primary endpoint that had been “mostly addressed” by the FDA’s and company’s analyses.

However, he added that he remained concerned by the very narrow clinical benefit of the drug "relative to the risks and relative to what I worry will be the potential use of the drug.”

”What I would hope is that this drug is used very selectively and very narrowly in circumstances where P2Y₁₂ inhibitors cannot be used appropriately,” he commented. “If it is used broadly and indiscriminately, it will not only be expensive but it [also] will expose low-risk patients to unnecessary bleeding, some of which can be quite substantial.”

The FDA usually follows the recommendations of its advisory panels. The members of the panel had no relevant disclosures.

[email protected]

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel supported approval of cangrelor, a short-acting, intravenous antiplatelet drug, for use in patients undergoing percutaneous coronary intervention, with precautions that it not be used widely or indiscriminately.

At a meeting on April 15, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 9-2, with one abstention, that cangrelor should be approved as an adjunct to PCI “for reducing the periprocedural thrombotic events, such as MI, stent thrombosis, and ischemia-driven revascularization.” The proposed indication includes the statement that use is for patients undergoing PCI “who have not received an oral P2Y₁₂ inhibitor prior to the PCI procedure and in whom oral therapy with P2Y₁₂ inhibitors is not feasible or desirable.”

Cangrelor, a P2Y₁₂ receptor inhibitor, has a half-life of 3-6 minutes, and platelet function completely returns to normal within 1 hour of stopping the infusion, according to the product’s sponsor, the Medicines Company.

The vote was based on analyses of revised endpoints of the data from the CHAMPION PHOENIX study, which compared cangrelor to clopidogrel in more than 11,000 patients undergoing PCI. The same panel voted 7-2 against approval in February 2014, for reasons that included doubts about the clinical consequences of some of the endpoints of the trial.

At the request of the FDA, the company reanalyzed the data, dropping intraprocedural stent thrombosis and MIs that did not meet the SCAI (Society for Cardiovascular Angiography Interventions) criteria for a clinically relevant MI from the primary endpoint. At 48 hours, 1.4% of those in the cangrelor arm met this revised endpoint, vs. 2.1% of those in the clopidogrel arm, for an odds ratio of 0.69 (P = .011). Most of the panel agreed that these analyses showed the drug had a beneficial effect.

Deaths and serious adverse events were similar between cangrelor and clopidogrel, but bleeding events were more common among patients treated with cangrelor, according to the company. A risk-benefit analysis, which took into account bleeding events, provided by the FDA concluded that the “benefit of cangrelor is small, but the risk is smaller.”

“There’s a great responsibility that this gets used appropriately and [is] not overused,” said Dr. James de Lemos, who voted against approval at the last meeting but voted for approval at this meeting. Dr. de Lemos, distinguished chair in cardiology and professor of medicine at the University of Texas Southwestern Medical Center, Dallas, said that his concerns about the robustness of the primary endpoint that had been “mostly addressed” by the FDA’s and company’s analyses.

However, he added that he remained concerned by the very narrow clinical benefit of the drug "relative to the risks and relative to what I worry will be the potential use of the drug.”

”What I would hope is that this drug is used very selectively and very narrowly in circumstances where P2Y₁₂ inhibitors cannot be used appropriately,” he commented. “If it is used broadly and indiscriminately, it will not only be expensive but it [also] will expose low-risk patients to unnecessary bleeding, some of which can be quite substantial.”

The FDA usually follows the recommendations of its advisory panels. The members of the panel had no relevant disclosures.

[email protected]

“It’s best to let her cry it out.” Easy advice to give, but not always easy to follow. The simplest recommendations from pediatricians can pose great challenges, at least initially, for parents. As trainees in pediatrics, we learn the script, but we do not always understand the reality of implementing our advice. Before becoming a parent, “crying it out” seemed the obvious and easy choice. Now, as a parent, I have felt the desperate necessity of getting a child to fall asleep. Although I would never condone unsafe sleeping practices, I understand what drives parents to such extremes.

When the dreaded 2-month-visit came around, I also felt the angst of intentionally putting your child through pain. Sweat dripped down my forehead and my vision blurred when I first saw the nurse immunize my son. Before this, I had ordered countless vaccinations for other patients, and I heard their screaming every day in the halls of clinic as background noise. Yet, seeing my own son being held down and jabbed with a needle was hard to bear. His high-pitched scream seemed perfectly calibrated to pound me with guilt. Of course, I knew the science and I had no fear of adverse events, but seeing your own child in pain does strange things to you. It strikes the same evolutionary chord that sends parents running into traffic to save their babies.

As trainees, many of us have put off having children until later in life. There is nothing wrong with this choice; however, it means that many of us lack the firsthand experience of parenting. We may not know that something as simple as getting a toddler to sit at the dinner table to eat anything can be a night-long struggle. To better prepare new parents and to better understand seasoned parents, we ought to solicit their experiences during office visits. By simply listening for 2 minutes, we can give parents a chance to vent (often well needed and deserved), and we can store their experiences in our memory for future use. Just as we stow away the image of the lacy rash of Fifth disease, we also should stockpile parenting tidbits. The only way to empathize with people going through something foreign to us is to acquire surrogate experiences. Parents in our clinics carry expansive libraries of these experiences, and we should not waste this opportunity.

By better understanding the realities of parenting, we can learn to frame our recommendations in terms that resonate with parents. We can preface our advice with challenges the parents can expect. We can remind them that parenting is hard, but their struggles are normal. When we better understand parents, they can better understand us.

Dr. Sisk is a pediatrics resident at St. Louis Children’s Hospital. E-mail him at [email protected].

“It’s best to let her cry it out.” Easy advice to give, but not always easy to follow. The simplest recommendations from pediatricians can pose great challenges, at least initially, for parents. As trainees in pediatrics, we learn the script, but we do not always understand the reality of implementing our advice. Before becoming a parent, “crying it out” seemed the obvious and easy choice. Now, as a parent, I have felt the desperate necessity of getting a child to fall asleep. Although I would never condone unsafe sleeping practices, I understand what drives parents to such extremes.

When the dreaded 2-month-visit came around, I also felt the angst of intentionally putting your child through pain. Sweat dripped down my forehead and my vision blurred when I first saw the nurse immunize my son. Before this, I had ordered countless vaccinations for other patients, and I heard their screaming every day in the halls of clinic as background noise. Yet, seeing my own son being held down and jabbed with a needle was hard to bear. His high-pitched scream seemed perfectly calibrated to pound me with guilt. Of course, I knew the science and I had no fear of adverse events, but seeing your own child in pain does strange things to you. It strikes the same evolutionary chord that sends parents running into traffic to save their babies.

As trainees, many of us have put off having children until later in life. There is nothing wrong with this choice; however, it means that many of us lack the firsthand experience of parenting. We may not know that something as simple as getting a toddler to sit at the dinner table to eat anything can be a night-long struggle. To better prepare new parents and to better understand seasoned parents, we ought to solicit their experiences during office visits. By simply listening for 2 minutes, we can give parents a chance to vent (often well needed and deserved), and we can store their experiences in our memory for future use. Just as we stow away the image of the lacy rash of Fifth disease, we also should stockpile parenting tidbits. The only way to empathize with people going through something foreign to us is to acquire surrogate experiences. Parents in our clinics carry expansive libraries of these experiences, and we should not waste this opportunity.

By better understanding the realities of parenting, we can learn to frame our recommendations in terms that resonate with parents. We can preface our advice with challenges the parents can expect. We can remind them that parenting is hard, but their struggles are normal. When we better understand parents, they can better understand us.

Dr. Sisk is a pediatrics resident at St. Louis Children’s Hospital. E-mail him at [email protected].

“It’s best to let her cry it out.” Easy advice to give, but not always easy to follow. The simplest recommendations from pediatricians can pose great challenges, at least initially, for parents. As trainees in pediatrics, we learn the script, but we do not always understand the reality of implementing our advice. Before becoming a parent, “crying it out” seemed the obvious and easy choice. Now, as a parent, I have felt the desperate necessity of getting a child to fall asleep. Although I would never condone unsafe sleeping practices, I understand what drives parents to such extremes.

When the dreaded 2-month-visit came around, I also felt the angst of intentionally putting your child through pain. Sweat dripped down my forehead and my vision blurred when I first saw the nurse immunize my son. Before this, I had ordered countless vaccinations for other patients, and I heard their screaming every day in the halls of clinic as background noise. Yet, seeing my own son being held down and jabbed with a needle was hard to bear. His high-pitched scream seemed perfectly calibrated to pound me with guilt. Of course, I knew the science and I had no fear of adverse events, but seeing your own child in pain does strange things to you. It strikes the same evolutionary chord that sends parents running into traffic to save their babies.

As trainees, many of us have put off having children until later in life. There is nothing wrong with this choice; however, it means that many of us lack the firsthand experience of parenting. We may not know that something as simple as getting a toddler to sit at the dinner table to eat anything can be a night-long struggle. To better prepare new parents and to better understand seasoned parents, we ought to solicit their experiences during office visits. By simply listening for 2 minutes, we can give parents a chance to vent (often well needed and deserved), and we can store their experiences in our memory for future use. Just as we stow away the image of the lacy rash of Fifth disease, we also should stockpile parenting tidbits. The only way to empathize with people going through something foreign to us is to acquire surrogate experiences. Parents in our clinics carry expansive libraries of these experiences, and we should not waste this opportunity.

By better understanding the realities of parenting, we can learn to frame our recommendations in terms that resonate with parents. We can preface our advice with challenges the parents can expect. We can remind them that parenting is hard, but their struggles are normal. When we better understand parents, they can better understand us.

Dr. Sisk is a pediatrics resident at St. Louis Children’s Hospital. E-mail him at [email protected].

SNOWMASS, COLO.– The sun may be setting on the use of aspirin for thromboprophylaxis in patients with nonvalvular atrial fibrillation. The 2014 American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines are unique among the major international guidelines in giving a modest IIb, Level of Evidence C endorsement to the option of aspirin or no treatment in patients with atrial fibrillation (AF) and a CHA₂DS₂-VASc score of 1. In contrast, the 2014 U.K. NICE (National Institute for Health and Care Excellence) guidelines, the 2013 Asian Pacific Heart Rhythm Society guidelines, and the 2012 European Society of Cardiology guidelines all recommend consideration of oral anticoagulation – eschewing aspirin – in patients with a CHA₂DS₂-VASc score of 1 or more, Dr. Bernard J. Gersh noted at the Annual Cardiovascular Conference at Snowmass.

The NICE guidelines put the matter succinctly, stating, “The main departure from prior guidelines is that aspirin should not be used in AF simply to reduce the risk of stroke, as it is not as effective as NOACs [novel oral anticoagulants] ... and can cause more bleeding side effects.”

Dr. Gersh was coauthor of a recently published think piece that argued that exaggerated misperceptions of aspirin’s efficacy and safety have led to its inappropriate status as “the easy option” for stroke prevention in AF (Eur. Heart J. 2015;36:653-6).

“By giving physicians a soft option of aspirin in CHA₂DS₂-VASc 1 patients, we’re allowing them an excuse not to use an oral anticoagulant, which is what they should be using,” Dr. Gersh explained at the conference.

He noted that an analysis of more than 41,000 Medicare beneficiaries with AF in 2007-2008 showed that only 66.8% were on warfarin.

“There’s no doubt that warfarin, and for that matter the NOACs, are underutilized, and it’s possible that the misperception that aspirin is effective may contribute to that underutilization,” asserted Dr. Gersh, professor of medicine at the Mayo Clinic, Rochester, Minn.

The cardiologist added that the widely held belief that aspirin reduces stroke risk by roughly 20%, compared with placebo, in patients with AF is based upon seriously flawed data. True, a meta-analysis of six placebo-controlled randomized trials done in an earlier era concluded that aspirin reduced the relative risk of stroke by 19%, but what’s often overlooked is that aspirin significantly outperformed placebo in only one of those six studies – the SPAF 1 trial – where in one arm aspirin achieved an “almost implausible” 94% relative risk reduction.

“Nothing reduces risk by 94%,” Dr. Gersh observed, adding that the SPAF 1 methodology was, upon careful examination, “completely unacceptable” by contemporary standards.

He was a coinvestigator in a study of 7,347 AF patients on oral anticoagulation therapy in 176 U.S. practices participating in the ORBIT-AF registry (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation). The analysis showed that concomitant use of aspirin and an oral anticoagulant in patients with AF is common in everyday clinical practice, being employed in 35% of the study population. Of note, 39% of these patients had no history of CAD and therefore weren’t on aspirin for secondary cardiovascular prevention, and 17% of them were at elevated bleeding risk because of an ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) bleeding risk score of 5 or more.

The key, disturbing finding was this: The adjusted risks of major bleeding and hospitalization for bleeding were 53% and 52% greater, respectively, in patients on an oral anticoagulant plus aspirin than with an oral anticoagulant alone (Circulation 2013;128:721-8).

On the basis of this study and other evidence, Dr. Gersh believes the use of aspirin in patients with AF should be considered only in those with CAD, where a case can be made for its use in secondary prevention alongside an oral anticoagulant to reduce stroke risk. But even then, aspirin’s use is reasonable only in those at low risk of bleeding, and extra vigilance and prophylaxis with a proton pump inhibitor are called for.

“If a patient is at high risk of bleeding, I personally would not give aspirin,” the cardiologist added.

The big remaining question – and an area of current controversy – concerns the safety of halting aspirin in AF patients on an oral anticoagulant who’ve undergone coronary stenting. Ongoing studies are looking at this issue, and answers are expected within a year or 2.

Dr. Gersh reported serving as a consultant to Merck and Ortho-McNeil-Janssen and on data safety monitoring boards for Baxter, Medtronic, and Teva.

[email protected]

SNOWMASS, COLO.– The sun may be setting on the use of aspirin for thromboprophylaxis in patients with nonvalvular atrial fibrillation. The 2014 American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines are unique among the major international guidelines in giving a modest IIb, Level of Evidence C endorsement to the option of aspirin or no treatment in patients with atrial fibrillation (AF) and a CHA₂DS₂-VASc score of 1. In contrast, the 2014 U.K. NICE (National Institute for Health and Care Excellence) guidelines, the 2013 Asian Pacific Heart Rhythm Society guidelines, and the 2012 European Society of Cardiology guidelines all recommend consideration of oral anticoagulation – eschewing aspirin – in patients with a CHA₂DS₂-VASc score of 1 or more, Dr. Bernard J. Gersh noted at the Annual Cardiovascular Conference at Snowmass.

The NICE guidelines put the matter succinctly, stating, “The main departure from prior guidelines is that aspirin should not be used in AF simply to reduce the risk of stroke, as it is not as effective as NOACs [novel oral anticoagulants] ... and can cause more bleeding side effects.”

Dr. Gersh was coauthor of a recently published think piece that argued that exaggerated misperceptions of aspirin’s efficacy and safety have led to its inappropriate status as “the easy option” for stroke prevention in AF (Eur. Heart J. 2015;36:653-6).

“By giving physicians a soft option of aspirin in CHA₂DS₂-VASc 1 patients, we’re allowing them an excuse not to use an oral anticoagulant, which is what they should be using,” Dr. Gersh explained at the conference.

He noted that an analysis of more than 41,000 Medicare beneficiaries with AF in 2007-2008 showed that only 66.8% were on warfarin.

“There’s no doubt that warfarin, and for that matter the NOACs, are underutilized, and it’s possible that the misperception that aspirin is effective may contribute to that underutilization,” asserted Dr. Gersh, professor of medicine at the Mayo Clinic, Rochester, Minn.

The cardiologist added that the widely held belief that aspirin reduces stroke risk by roughly 20%, compared with placebo, in patients with AF is based upon seriously flawed data. True, a meta-analysis of six placebo-controlled randomized trials done in an earlier era concluded that aspirin reduced the relative risk of stroke by 19%, but what’s often overlooked is that aspirin significantly outperformed placebo in only one of those six studies – the SPAF 1 trial – where in one arm aspirin achieved an “almost implausible” 94% relative risk reduction.

“Nothing reduces risk by 94%,” Dr. Gersh observed, adding that the SPAF 1 methodology was, upon careful examination, “completely unacceptable” by contemporary standards.

He was a coinvestigator in a study of 7,347 AF patients on oral anticoagulation therapy in 176 U.S. practices participating in the ORBIT-AF registry (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation). The analysis showed that concomitant use of aspirin and an oral anticoagulant in patients with AF is common in everyday clinical practice, being employed in 35% of the study population. Of note, 39% of these patients had no history of CAD and therefore weren’t on aspirin for secondary cardiovascular prevention, and 17% of them were at elevated bleeding risk because of an ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) bleeding risk score of 5 or more.

The key, disturbing finding was this: The adjusted risks of major bleeding and hospitalization for bleeding were 53% and 52% greater, respectively, in patients on an oral anticoagulant plus aspirin than with an oral anticoagulant alone (Circulation 2013;128:721-8).

On the basis of this study and other evidence, Dr. Gersh believes the use of aspirin in patients with AF should be considered only in those with CAD, where a case can be made for its use in secondary prevention alongside an oral anticoagulant to reduce stroke risk. But even then, aspirin’s use is reasonable only in those at low risk of bleeding, and extra vigilance and prophylaxis with a proton pump inhibitor are called for.

“If a patient is at high risk of bleeding, I personally would not give aspirin,” the cardiologist added.

The big remaining question – and an area of current controversy – concerns the safety of halting aspirin in AF patients on an oral anticoagulant who’ve undergone coronary stenting. Ongoing studies are looking at this issue, and answers are expected within a year or 2.

Dr. Gersh reported serving as a consultant to Merck and Ortho-McNeil-Janssen and on data safety monitoring boards for Baxter, Medtronic, and Teva.

[email protected]

SNOWMASS, COLO.– The sun may be setting on the use of aspirin for thromboprophylaxis in patients with nonvalvular atrial fibrillation. The 2014 American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines are unique among the major international guidelines in giving a modest IIb, Level of Evidence C endorsement to the option of aspirin or no treatment in patients with atrial fibrillation (AF) and a CHA₂DS₂-VASc score of 1. In contrast, the 2014 U.K. NICE (National Institute for Health and Care Excellence) guidelines, the 2013 Asian Pacific Heart Rhythm Society guidelines, and the 2012 European Society of Cardiology guidelines all recommend consideration of oral anticoagulation – eschewing aspirin – in patients with a CHA₂DS₂-VASc score of 1 or more, Dr. Bernard J. Gersh noted at the Annual Cardiovascular Conference at Snowmass.

The NICE guidelines put the matter succinctly, stating, “The main departure from prior guidelines is that aspirin should not be used in AF simply to reduce the risk of stroke, as it is not as effective as NOACs [novel oral anticoagulants] ... and can cause more bleeding side effects.”

Dr. Gersh was coauthor of a recently published think piece that argued that exaggerated misperceptions of aspirin’s efficacy and safety have led to its inappropriate status as “the easy option” for stroke prevention in AF (Eur. Heart J. 2015;36:653-6).

“By giving physicians a soft option of aspirin in CHA₂DS₂-VASc 1 patients, we’re allowing them an excuse not to use an oral anticoagulant, which is what they should be using,” Dr. Gersh explained at the conference.

He noted that an analysis of more than 41,000 Medicare beneficiaries with AF in 2007-2008 showed that only 66.8% were on warfarin.

“There’s no doubt that warfarin, and for that matter the NOACs, are underutilized, and it’s possible that the misperception that aspirin is effective may contribute to that underutilization,” asserted Dr. Gersh, professor of medicine at the Mayo Clinic, Rochester, Minn.

The cardiologist added that the widely held belief that aspirin reduces stroke risk by roughly 20%, compared with placebo, in patients with AF is based upon seriously flawed data. True, a meta-analysis of six placebo-controlled randomized trials done in an earlier era concluded that aspirin reduced the relative risk of stroke by 19%, but what’s often overlooked is that aspirin significantly outperformed placebo in only one of those six studies – the SPAF 1 trial – where in one arm aspirin achieved an “almost implausible” 94% relative risk reduction.

“Nothing reduces risk by 94%,” Dr. Gersh observed, adding that the SPAF 1 methodology was, upon careful examination, “completely unacceptable” by contemporary standards.

He was a coinvestigator in a study of 7,347 AF patients on oral anticoagulation therapy in 176 U.S. practices participating in the ORBIT-AF registry (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation). The analysis showed that concomitant use of aspirin and an oral anticoagulant in patients with AF is common in everyday clinical practice, being employed in 35% of the study population. Of note, 39% of these patients had no history of CAD and therefore weren’t on aspirin for secondary cardiovascular prevention, and 17% of them were at elevated bleeding risk because of an ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) bleeding risk score of 5 or more.

The key, disturbing finding was this: The adjusted risks of major bleeding and hospitalization for bleeding were 53% and 52% greater, respectively, in patients on an oral anticoagulant plus aspirin than with an oral anticoagulant alone (Circulation 2013;128:721-8).

On the basis of this study and other evidence, Dr. Gersh believes the use of aspirin in patients with AF should be considered only in those with CAD, where a case can be made for its use in secondary prevention alongside an oral anticoagulant to reduce stroke risk. But even then, aspirin’s use is reasonable only in those at low risk of bleeding, and extra vigilance and prophylaxis with a proton pump inhibitor are called for.

“If a patient is at high risk of bleeding, I personally would not give aspirin,” the cardiologist added.

The big remaining question – and an area of current controversy – concerns the safety of halting aspirin in AF patients on an oral anticoagulant who’ve undergone coronary stenting. Ongoing studies are looking at this issue, and answers are expected within a year or 2.

Dr. Gersh reported serving as a consultant to Merck and Ortho-McNeil-Janssen and on data safety monitoring boards for Baxter, Medtronic, and Teva.

[email protected]