NASHVILLE, TENN. – U.S. stroke specialists now face the challenge of making endovascular embolectomy a routinely available option for selected patients with acute ischemic stroke, Dr. Pooja Khatri said in an interview at the International Stroke Conference.

During the conference, which was sponsored by the American Heart Association, new reports from three independent, randomized controlled trials, as well as data from a fourth study published in January, collectively established endovascular embolectomy as the new standard-of-care treatment for acute ischemic stroke patients with a proximal occlusion of a large, intracerebral artery. The stroke community, however, now faces the responsibility of figuring out how to make this a reality.

Among the hurdles they face are using CT imaging or other methods to identify in daily practice the specific patients who will get the biggest benefit from endovascular treatment and finding a consensus within each region on how to triage acute stroke patients to centers that can perform embolectomy, said Dr. Khatri, professor of neurology and director of acute stroke at the University of Cincinnati. In Cincinnati, Dr. Khatri and her colleagues are planning to soon hold a retreat with representatives from other area hospitals to try to work out the logistics.Dr. Khatri has received research support from Penumbra and Genentech.

[email protected]
On Twitter @mitchelzoler

NASHVILLE, TENN. – U.S. stroke specialists now face the challenge of making endovascular embolectomy a routinely available option for selected patients with acute ischemic stroke, Dr. Pooja Khatri said in an interview at the International Stroke Conference.

During the conference, which was sponsored by the American Heart Association, new reports from three independent, randomized controlled trials, as well as data from a fourth study published in January, collectively established endovascular embolectomy as the new standard-of-care treatment for acute ischemic stroke patients with a proximal occlusion of a large, intracerebral artery. The stroke community, however, now faces the responsibility of figuring out how to make this a reality.

Among the hurdles they face are using CT imaging or other methods to identify in daily practice the specific patients who will get the biggest benefit from endovascular treatment and finding a consensus within each region on how to triage acute stroke patients to centers that can perform embolectomy, said Dr. Khatri, professor of neurology and director of acute stroke at the University of Cincinnati. In Cincinnati, Dr. Khatri and her colleagues are planning to soon hold a retreat with representatives from other area hospitals to try to work out the logistics.Dr. Khatri has received research support from Penumbra and Genentech.

[email protected]
On Twitter @mitchelzoler

NASHVILLE, TENN. – U.S. stroke specialists now face the challenge of making endovascular embolectomy a routinely available option for selected patients with acute ischemic stroke, Dr. Pooja Khatri said in an interview at the International Stroke Conference.

During the conference, which was sponsored by the American Heart Association, new reports from three independent, randomized controlled trials, as well as data from a fourth study published in January, collectively established endovascular embolectomy as the new standard-of-care treatment for acute ischemic stroke patients with a proximal occlusion of a large, intracerebral artery. The stroke community, however, now faces the responsibility of figuring out how to make this a reality.

Among the hurdles they face are using CT imaging or other methods to identify in daily practice the specific patients who will get the biggest benefit from endovascular treatment and finding a consensus within each region on how to triage acute stroke patients to centers that can perform embolectomy, said Dr. Khatri, professor of neurology and director of acute stroke at the University of Cincinnati. In Cincinnati, Dr. Khatri and her colleagues are planning to soon hold a retreat with representatives from other area hospitals to try to work out the logistics.Dr. Khatri has received research support from Penumbra and Genentech.

[email protected]
On Twitter @mitchelzoler

Bone marrow harvest

Photo by Chad McNeeley

SAN DIEGO—Haploidentical bone marrow transplant (haplo-BMT) is a feasible option for patients with high-risk hematologic malignancies who don’t have timely access to an HLA-matched donor, according to a speaker at the 2015 BMT Tandem Meetings.

Haplo-BMT using myeloablative conditioning, T-cell replete grafts, and post-transplant cyclophosphamide elicited “excellent” rates of engraftment, graft-vs-host disease (GVHD), and transplant-related mortality, said Heather Symons, MD, of The Johns Hopkins University School of Medicine in Baltimore, Maryland.

Dr Symons presented these results at the meeting as abstract 6*, which was chosen as one of the meeting’s “Best Abstracts.” The research was funded by Otsuka Pharmaceuticals.

Dr Symons and her colleagues conducted a phase 2 study of 96 patients with high-risk hematologic malignancies and a median age of 42 (range, 1-65). Males made up 58% of the population.

Diagnoses included acute and chronic leukemias, lymphomas, multiple myeloma, and myelodysplastic syndromes. Some patients were in complete remission, and some were in chemo-sensitive partial remission. There was also a mix of minimal residual disease positivity and negativity.

“Given the heterogeneity of these patients, we further classified our patients by disease risk index,” Dr Symons said. “We used the revised disease risk index as published by Armand in 2013. The disease risk index, or DRI, assigned patients into overall survival risk groups based on disease type and status.”

So 6 patients had a low DRI, 61 had an intermediate DRI, and 29 had a high DRI.

For most patients (n=73), conditioning consisted of intravenous busulfan (pharmacokinetically adjusted) on days –6 to –3 and cyclophosphamide (50 mg/kg/day) on days –2 and –1. But 23 patients (those with acute lymphocytic leukemia or lymphoblastic lymphoma) received cyclophosphamide (50 mg/kg/day) on days –5 and –4 and total body irradiation (200 cGy twice daily) on days –3 to -1.

All patients received T-cell-replete bone marrow from haploidentical, related donors. The median number of HLA mismatches was 4.

Post-transplant immunosuppression consisted of cyclophosphamide (50 mg/kg/day) on days 3 and 4, followed by mycophenolate mofetil for 30 days and tacrolimus for 6 months.

‘Excellent’ outcomes

The median follow-up was 18 months (range, 3-59). The median time to neutrophil engraftment was 24 days, and the median time to platelet engraftment was 29 days. Ninety-one percent of patients had donor chimerism greater than 95% at day 60.

The cumulative incidence of acute GVHD was 17% for grades 2-4 and 7% for grades 3-4. The cumulative incidence of chronic GHVD was 15%. For moderate-to-severe chronic GVHD, it was 5%.

Twenty-four percent of patients had CMV reactivation, and 22% had hemorrhagic cystitis.

The rate of relapse was 36% at 1 year and 44% at 3 years. The transplant-related mortality rate was 6% at 100 days and 11% at 1 year.

Ten patients died—2 from GVHD, 1 of cardiomyopathy, 2 of veno-occlusive disease, 1 of drug-induced liver injury, 2 due to infection, and 2 of unknown causes.

Overall survival was 72% at 1 year, 57% at 2 years, and 51% at 3 years. Event-free survival was 56% at 1 year, 51% at 2 years, and 47% at 3 years.

A multivariate analysis revealed that overall survival decreased with increasing age and increasing DRI.

Compared to patients younger than 20, the hazard ratio (HR) was 6.3 for patients ages 20 to 50 (P=0.02) and 4.7 for patients older than 50 (P=0.04). Compared to patients with a low or intermediate DRI, the HR was 2.2 for those with a high DRI (P=0.03).

The analysis also indicated that increasing age and donor CMV-positivity conferred worse event-free survival.

Compared to patients younger than 20, the HR was 3.6 for patients ages 20 to 50 (P=0.04) and 4.0 for patients older than 50 (P=0.03). Compared to patients who had a CMV-negative donor, the HR was 2.2 for patients who had a CMV-positive donor (P=0.01).

“In conclusion, myeloablative haploidentical bone marrow transplantation with post-transplantation cyclophosphamide for high-risk hematologic malignancies has excellent rates of engraftment, graft-vs-host disease, and transplant-related mortality, with results that are similar to those described in myeloablative HLA-matched bone marrow transplantation,” Dr Symons said.

“Overall, this seems a feasible option for high-risk patients who lack timely access to an HLA-matched donor and warrants continued study. We are soon to start enrolling patients on a Pediatric Blood & Marrow Transplant Consortium trial using myeloablative conditioning, haploidentical donors, and post-transplantation cyclophosphamide.”

*Information in the abstract differs from that presented at the meeting.

Bone marrow harvest

Photo by Chad McNeeley

SAN DIEGO—Haploidentical bone marrow transplant (haplo-BMT) is a feasible option for patients with high-risk hematologic malignancies who don’t have timely access to an HLA-matched donor, according to a speaker at the 2015 BMT Tandem Meetings.

Haplo-BMT using myeloablative conditioning, T-cell replete grafts, and post-transplant cyclophosphamide elicited “excellent” rates of engraftment, graft-vs-host disease (GVHD), and transplant-related mortality, said Heather Symons, MD, of The Johns Hopkins University School of Medicine in Baltimore, Maryland.

Dr Symons presented these results at the meeting as abstract 6*, which was chosen as one of the meeting’s “Best Abstracts.” The research was funded by Otsuka Pharmaceuticals.

Dr Symons and her colleagues conducted a phase 2 study of 96 patients with high-risk hematologic malignancies and a median age of 42 (range, 1-65). Males made up 58% of the population.

Diagnoses included acute and chronic leukemias, lymphomas, multiple myeloma, and myelodysplastic syndromes. Some patients were in complete remission, and some were in chemo-sensitive partial remission. There was also a mix of minimal residual disease positivity and negativity.

“Given the heterogeneity of these patients, we further classified our patients by disease risk index,” Dr Symons said. “We used the revised disease risk index as published by Armand in 2013. The disease risk index, or DRI, assigned patients into overall survival risk groups based on disease type and status.”

So 6 patients had a low DRI, 61 had an intermediate DRI, and 29 had a high DRI.

For most patients (n=73), conditioning consisted of intravenous busulfan (pharmacokinetically adjusted) on days –6 to –3 and cyclophosphamide (50 mg/kg/day) on days –2 and –1. But 23 patients (those with acute lymphocytic leukemia or lymphoblastic lymphoma) received cyclophosphamide (50 mg/kg/day) on days –5 and –4 and total body irradiation (200 cGy twice daily) on days –3 to -1.

All patients received T-cell-replete bone marrow from haploidentical, related donors. The median number of HLA mismatches was 4.

Post-transplant immunosuppression consisted of cyclophosphamide (50 mg/kg/day) on days 3 and 4, followed by mycophenolate mofetil for 30 days and tacrolimus for 6 months.

‘Excellent’ outcomes

The median follow-up was 18 months (range, 3-59). The median time to neutrophil engraftment was 24 days, and the median time to platelet engraftment was 29 days. Ninety-one percent of patients had donor chimerism greater than 95% at day 60.

The cumulative incidence of acute GVHD was 17% for grades 2-4 and 7% for grades 3-4. The cumulative incidence of chronic GHVD was 15%. For moderate-to-severe chronic GVHD, it was 5%.

Twenty-four percent of patients had CMV reactivation, and 22% had hemorrhagic cystitis.

The rate of relapse was 36% at 1 year and 44% at 3 years. The transplant-related mortality rate was 6% at 100 days and 11% at 1 year.

Ten patients died—2 from GVHD, 1 of cardiomyopathy, 2 of veno-occlusive disease, 1 of drug-induced liver injury, 2 due to infection, and 2 of unknown causes.

Overall survival was 72% at 1 year, 57% at 2 years, and 51% at 3 years. Event-free survival was 56% at 1 year, 51% at 2 years, and 47% at 3 years.

A multivariate analysis revealed that overall survival decreased with increasing age and increasing DRI.

Compared to patients younger than 20, the hazard ratio (HR) was 6.3 for patients ages 20 to 50 (P=0.02) and 4.7 for patients older than 50 (P=0.04). Compared to patients with a low or intermediate DRI, the HR was 2.2 for those with a high DRI (P=0.03).

The analysis also indicated that increasing age and donor CMV-positivity conferred worse event-free survival.

Compared to patients younger than 20, the HR was 3.6 for patients ages 20 to 50 (P=0.04) and 4.0 for patients older than 50 (P=0.03). Compared to patients who had a CMV-negative donor, the HR was 2.2 for patients who had a CMV-positive donor (P=0.01).

“In conclusion, myeloablative haploidentical bone marrow transplantation with post-transplantation cyclophosphamide for high-risk hematologic malignancies has excellent rates of engraftment, graft-vs-host disease, and transplant-related mortality, with results that are similar to those described in myeloablative HLA-matched bone marrow transplantation,” Dr Symons said.

“Overall, this seems a feasible option for high-risk patients who lack timely access to an HLA-matched donor and warrants continued study. We are soon to start enrolling patients on a Pediatric Blood & Marrow Transplant Consortium trial using myeloablative conditioning, haploidentical donors, and post-transplantation cyclophosphamide.”

*Information in the abstract differs from that presented at the meeting.

Bone marrow harvest

Photo by Chad McNeeley

SAN DIEGO—Haploidentical bone marrow transplant (haplo-BMT) is a feasible option for patients with high-risk hematologic malignancies who don’t have timely access to an HLA-matched donor, according to a speaker at the 2015 BMT Tandem Meetings.

Haplo-BMT using myeloablative conditioning, T-cell replete grafts, and post-transplant cyclophosphamide elicited “excellent” rates of engraftment, graft-vs-host disease (GVHD), and transplant-related mortality, said Heather Symons, MD, of The Johns Hopkins University School of Medicine in Baltimore, Maryland.

Dr Symons presented these results at the meeting as abstract 6*, which was chosen as one of the meeting’s “Best Abstracts.” The research was funded by Otsuka Pharmaceuticals.

Dr Symons and her colleagues conducted a phase 2 study of 96 patients with high-risk hematologic malignancies and a median age of 42 (range, 1-65). Males made up 58% of the population.

Diagnoses included acute and chronic leukemias, lymphomas, multiple myeloma, and myelodysplastic syndromes. Some patients were in complete remission, and some were in chemo-sensitive partial remission. There was also a mix of minimal residual disease positivity and negativity.

“Given the heterogeneity of these patients, we further classified our patients by disease risk index,” Dr Symons said. “We used the revised disease risk index as published by Armand in 2013. The disease risk index, or DRI, assigned patients into overall survival risk groups based on disease type and status.”

So 6 patients had a low DRI, 61 had an intermediate DRI, and 29 had a high DRI.

For most patients (n=73), conditioning consisted of intravenous busulfan (pharmacokinetically adjusted) on days –6 to –3 and cyclophosphamide (50 mg/kg/day) on days –2 and –1. But 23 patients (those with acute lymphocytic leukemia or lymphoblastic lymphoma) received cyclophosphamide (50 mg/kg/day) on days –5 and –4 and total body irradiation (200 cGy twice daily) on days –3 to -1.

All patients received T-cell-replete bone marrow from haploidentical, related donors. The median number of HLA mismatches was 4.

Post-transplant immunosuppression consisted of cyclophosphamide (50 mg/kg/day) on days 3 and 4, followed by mycophenolate mofetil for 30 days and tacrolimus for 6 months.

‘Excellent’ outcomes

The median follow-up was 18 months (range, 3-59). The median time to neutrophil engraftment was 24 days, and the median time to platelet engraftment was 29 days. Ninety-one percent of patients had donor chimerism greater than 95% at day 60.

The cumulative incidence of acute GVHD was 17% for grades 2-4 and 7% for grades 3-4. The cumulative incidence of chronic GHVD was 15%. For moderate-to-severe chronic GVHD, it was 5%.

Twenty-four percent of patients had CMV reactivation, and 22% had hemorrhagic cystitis.

The rate of relapse was 36% at 1 year and 44% at 3 years. The transplant-related mortality rate was 6% at 100 days and 11% at 1 year.

Ten patients died—2 from GVHD, 1 of cardiomyopathy, 2 of veno-occlusive disease, 1 of drug-induced liver injury, 2 due to infection, and 2 of unknown causes.

Overall survival was 72% at 1 year, 57% at 2 years, and 51% at 3 years. Event-free survival was 56% at 1 year, 51% at 2 years, and 47% at 3 years.

A multivariate analysis revealed that overall survival decreased with increasing age and increasing DRI.

Compared to patients younger than 20, the hazard ratio (HR) was 6.3 for patients ages 20 to 50 (P=0.02) and 4.7 for patients older than 50 (P=0.04). Compared to patients with a low or intermediate DRI, the HR was 2.2 for those with a high DRI (P=0.03).

The analysis also indicated that increasing age and donor CMV-positivity conferred worse event-free survival.

Compared to patients younger than 20, the HR was 3.6 for patients ages 20 to 50 (P=0.04) and 4.0 for patients older than 50 (P=0.03). Compared to patients who had a CMV-negative donor, the HR was 2.2 for patients who had a CMV-positive donor (P=0.01).

“In conclusion, myeloablative haploidentical bone marrow transplantation with post-transplantation cyclophosphamide for high-risk hematologic malignancies has excellent rates of engraftment, graft-vs-host disease, and transplant-related mortality, with results that are similar to those described in myeloablative HLA-matched bone marrow transplantation,” Dr Symons said.

“Overall, this seems a feasible option for high-risk patients who lack timely access to an HLA-matched donor and warrants continued study. We are soon to start enrolling patients on a Pediatric Blood & Marrow Transplant Consortium trial using myeloablative conditioning, haploidentical donors, and post-transplantation cyclophosphamide.”

*Information in the abstract differs from that presented at the meeting.

Platelets (blue) in a thrombus

Image by Andre E.X. Brown

The platelet protein RASA3 is critical to treatment success with the antiplatelet drug clopidogrel (Plavix), according to research published in The Journal of Clinical Investigation.

The study shows that RASA3 is part of a cellular pathway that is crucial for platelet activity during thrombus formation.

Researchers believe this newfound information could aid the development of new antiplatelet compounds and antidotes to clopidogrel.

“We believe these findings could lead to improved strategies for treatment following a heart attack and a better understanding of why people respond differently to antiplatelet drugs such as aspirin and Plavix,” said study author Wolfgang Bergmeier, PhD, of the University of North Carolina at Chapel Hill.

Since the 1970s, scientists have known that clopidogrel has an anticlotting effect on platelets. In 2001, they found the compound’s target—the adenosine diphosphate receptor P2Y12. But they didn’t know how this receptor communicates with other proteins in the cell pathways important for platelet activation.

Researchers have since learned that P2Y12 communicates with RAP1, a small GTPase that cycles between an inactive GDP-bound form and an active GTP-bound form. RAP1 is tightly regulated by GEFs, which stimulate GTP loading, and GAPs, which catalyze GTP hydrolysis.

Dr Bergmeier’s group and others previously showed that RAP1 regulates platelet adhesion and thrombosis.

Now, his team has found evidence suggesting the GAP RASA3 is the “missing link” between P2Y12 and RAP1 in platelets. And agents that inhibit P2Y12, like clopidogrel, prevent thrombosis mainly through their effect on RASA3/RAP1 signaling.

The researchers used deep sequencing techniques to show that RASA3 was the only highly expressed GAP gene for RAP1 in platelets. And they hypothesized that a malfunctioning RASA3 protein would lead to the activation and clearance of platelets.

Experiments showed that mice with a RASA3 mutation had 3% to 5% of the typical platelet count. The rest of their platelets were being activated and cleared from circulation.

However, when the researchers disabled the major GEF proteins, platelet counts rose to normal levels. This suggests a tightly controlled balance between GEF and GAP proteins, especially RASA3, is vital for platelet activity.

“These experiments show that this RAP1 GEF-GAP pathway is crucial for platelets to jump into action to plug a hole in the endothelium,” Dr Bergmeier said. “And now we know that RASA3 is a critical negative regulator, a ‘brake’ on the process.”

“We have good reason to believe that the RAP1 ‘switch,’ controlled by the same GEF and GAP proteins, also regulates the active state of human platelets. We expect this research will provide critical information for improving antiplatelet therapies, possibly including approaches that eliminate some of the patient-to-patient variability and the increased bleeding risk associated with current antiplatelet drugs.”

Platelets (blue) in a thrombus

Image by Andre E.X. Brown

The platelet protein RASA3 is critical to treatment success with the antiplatelet drug clopidogrel (Plavix), according to research published in The Journal of Clinical Investigation.

The study shows that RASA3 is part of a cellular pathway that is crucial for platelet activity during thrombus formation.

Researchers believe this newfound information could aid the development of new antiplatelet compounds and antidotes to clopidogrel.

“We believe these findings could lead to improved strategies for treatment following a heart attack and a better understanding of why people respond differently to antiplatelet drugs such as aspirin and Plavix,” said study author Wolfgang Bergmeier, PhD, of the University of North Carolina at Chapel Hill.

Since the 1970s, scientists have known that clopidogrel has an anticlotting effect on platelets. In 2001, they found the compound’s target—the adenosine diphosphate receptor P2Y12. But they didn’t know how this receptor communicates with other proteins in the cell pathways important for platelet activation.

Researchers have since learned that P2Y12 communicates with RAP1, a small GTPase that cycles between an inactive GDP-bound form and an active GTP-bound form. RAP1 is tightly regulated by GEFs, which stimulate GTP loading, and GAPs, which catalyze GTP hydrolysis.

Dr Bergmeier’s group and others previously showed that RAP1 regulates platelet adhesion and thrombosis.

Now, his team has found evidence suggesting the GAP RASA3 is the “missing link” between P2Y12 and RAP1 in platelets. And agents that inhibit P2Y12, like clopidogrel, prevent thrombosis mainly through their effect on RASA3/RAP1 signaling.

The researchers used deep sequencing techniques to show that RASA3 was the only highly expressed GAP gene for RAP1 in platelets. And they hypothesized that a malfunctioning RASA3 protein would lead to the activation and clearance of platelets.

Experiments showed that mice with a RASA3 mutation had 3% to 5% of the typical platelet count. The rest of their platelets were being activated and cleared from circulation.

However, when the researchers disabled the major GEF proteins, platelet counts rose to normal levels. This suggests a tightly controlled balance between GEF and GAP proteins, especially RASA3, is vital for platelet activity.

“These experiments show that this RAP1 GEF-GAP pathway is crucial for platelets to jump into action to plug a hole in the endothelium,” Dr Bergmeier said. “And now we know that RASA3 is a critical negative regulator, a ‘brake’ on the process.”

“We have good reason to believe that the RAP1 ‘switch,’ controlled by the same GEF and GAP proteins, also regulates the active state of human platelets. We expect this research will provide critical information for improving antiplatelet therapies, possibly including approaches that eliminate some of the patient-to-patient variability and the increased bleeding risk associated with current antiplatelet drugs.”

Platelets (blue) in a thrombus

Image by Andre E.X. Brown

The platelet protein RASA3 is critical to treatment success with the antiplatelet drug clopidogrel (Plavix), according to research published in The Journal of Clinical Investigation.

The study shows that RASA3 is part of a cellular pathway that is crucial for platelet activity during thrombus formation.

Researchers believe this newfound information could aid the development of new antiplatelet compounds and antidotes to clopidogrel.

“We believe these findings could lead to improved strategies for treatment following a heart attack and a better understanding of why people respond differently to antiplatelet drugs such as aspirin and Plavix,” said study author Wolfgang Bergmeier, PhD, of the University of North Carolina at Chapel Hill.

Since the 1970s, scientists have known that clopidogrel has an anticlotting effect on platelets. In 2001, they found the compound’s target—the adenosine diphosphate receptor P2Y12. But they didn’t know how this receptor communicates with other proteins in the cell pathways important for platelet activation.

Researchers have since learned that P2Y12 communicates with RAP1, a small GTPase that cycles between an inactive GDP-bound form and an active GTP-bound form. RAP1 is tightly regulated by GEFs, which stimulate GTP loading, and GAPs, which catalyze GTP hydrolysis.

Dr Bergmeier’s group and others previously showed that RAP1 regulates platelet adhesion and thrombosis.

Now, his team has found evidence suggesting the GAP RASA3 is the “missing link” between P2Y12 and RAP1 in platelets. And agents that inhibit P2Y12, like clopidogrel, prevent thrombosis mainly through their effect on RASA3/RAP1 signaling.

The researchers used deep sequencing techniques to show that RASA3 was the only highly expressed GAP gene for RAP1 in platelets. And they hypothesized that a malfunctioning RASA3 protein would lead to the activation and clearance of platelets.

Experiments showed that mice with a RASA3 mutation had 3% to 5% of the typical platelet count. The rest of their platelets were being activated and cleared from circulation.

However, when the researchers disabled the major GEF proteins, platelet counts rose to normal levels. This suggests a tightly controlled balance between GEF and GAP proteins, especially RASA3, is vital for platelet activity.

“These experiments show that this RAP1 GEF-GAP pathway is crucial for platelets to jump into action to plug a hole in the endothelium,” Dr Bergmeier said. “And now we know that RASA3 is a critical negative regulator, a ‘brake’ on the process.”

“We have good reason to believe that the RAP1 ‘switch,’ controlled by the same GEF and GAP proteins, also regulates the active state of human platelets. We expect this research will provide critical information for improving antiplatelet therapies, possibly including approaches that eliminate some of the patient-to-patient variability and the increased bleeding risk associated with current antiplatelet drugs.”

Prescription medications

Photo courtesy of CDC

A large, retrospective study has shown that nonsteroidal anti-inflammatory drugs (NSAIDs) can increase the risk of bleeding and cardiovascular events in patients who are receiving antithrombotic therapy after myocardial infarction (MI).

The risks were increased regardless of the type of antithrombotic treatment patients received, the types of NSAIDs they were prescribed, or the duration of NSAID use.

Researchers reported these findings in JAMA.

Anne-Marie Schjerning Olsen, MD, PhD, of Copenhagen University Hospital Gentofte in Hellerup, Denmark, and her colleagues conducted the research. They used nationwide administrative registries in Denmark (2002-2011) to analyze patients 30 years of age or older who were admitted with first-time MI and were alive 30 days after hospital discharge.

The team looked at subsequent treatment with aspirin, clopidogrel, or other oral anticoagulants and their combinations, as well as ongoing, concomitant, prescription NSAID use. They assessed the risk of bleeding requiring hospitalization and a composite cardiovascular outcome (cardiovascular death, nonfatal recurrent MI, and stroke).

The study included 61,971 patients with a mean age of 68 years. Thirty-four percent of these patients filled at least 1 NSAID prescription.

At a median follow-up of 3.5 years, 18,105 patients (29.2%) had died. There were 5288 bleeding events (8.5%) and 18,568 cardiovascular events (30.0%).

A multivariate analysis showed that NSAID use increased the risk of bleeding (hazard ratio, 2.02) and cardiovascular events (hazard ratio, 1.40). The increased risk of these events was present regardless of the type of antithrombotic treatment, the types of NSAIDs used, or the duration of NSAID use.

Dr Schjerning Olsen and her colleagues said additional research is needed to confirm these findings, but physicians should exercise caution when prescribing NSAIDs to patients with a recent MI.

Authors of a related editorial pointed out that this study only included prescription NSAID use. In countries where NSAIDs are available over the counter, physicians may be unaware that patients are taking these drugs.

Prescription medications

Photo courtesy of CDC

A large, retrospective study has shown that nonsteroidal anti-inflammatory drugs (NSAIDs) can increase the risk of bleeding and cardiovascular events in patients who are receiving antithrombotic therapy after myocardial infarction (MI).

The risks were increased regardless of the type of antithrombotic treatment patients received, the types of NSAIDs they were prescribed, or the duration of NSAID use.

Researchers reported these findings in JAMA.

Anne-Marie Schjerning Olsen, MD, PhD, of Copenhagen University Hospital Gentofte in Hellerup, Denmark, and her colleagues conducted the research. They used nationwide administrative registries in Denmark (2002-2011) to analyze patients 30 years of age or older who were admitted with first-time MI and were alive 30 days after hospital discharge.

The team looked at subsequent treatment with aspirin, clopidogrel, or other oral anticoagulants and their combinations, as well as ongoing, concomitant, prescription NSAID use. They assessed the risk of bleeding requiring hospitalization and a composite cardiovascular outcome (cardiovascular death, nonfatal recurrent MI, and stroke).

The study included 61,971 patients with a mean age of 68 years. Thirty-four percent of these patients filled at least 1 NSAID prescription.

At a median follow-up of 3.5 years, 18,105 patients (29.2%) had died. There were 5288 bleeding events (8.5%) and 18,568 cardiovascular events (30.0%).

A multivariate analysis showed that NSAID use increased the risk of bleeding (hazard ratio, 2.02) and cardiovascular events (hazard ratio, 1.40). The increased risk of these events was present regardless of the type of antithrombotic treatment, the types of NSAIDs used, or the duration of NSAID use.

Dr Schjerning Olsen and her colleagues said additional research is needed to confirm these findings, but physicians should exercise caution when prescribing NSAIDs to patients with a recent MI.

Authors of a related editorial pointed out that this study only included prescription NSAID use. In countries where NSAIDs are available over the counter, physicians may be unaware that patients are taking these drugs.

Prescription medications

Photo courtesy of CDC

A large, retrospective study has shown that nonsteroidal anti-inflammatory drugs (NSAIDs) can increase the risk of bleeding and cardiovascular events in patients who are receiving antithrombotic therapy after myocardial infarction (MI).

The risks were increased regardless of the type of antithrombotic treatment patients received, the types of NSAIDs they were prescribed, or the duration of NSAID use.

Researchers reported these findings in JAMA.

Anne-Marie Schjerning Olsen, MD, PhD, of Copenhagen University Hospital Gentofte in Hellerup, Denmark, and her colleagues conducted the research. They used nationwide administrative registries in Denmark (2002-2011) to analyze patients 30 years of age or older who were admitted with first-time MI and were alive 30 days after hospital discharge.

The team looked at subsequent treatment with aspirin, clopidogrel, or other oral anticoagulants and their combinations, as well as ongoing, concomitant, prescription NSAID use. They assessed the risk of bleeding requiring hospitalization and a composite cardiovascular outcome (cardiovascular death, nonfatal recurrent MI, and stroke).

The study included 61,971 patients with a mean age of 68 years. Thirty-four percent of these patients filled at least 1 NSAID prescription.

At a median follow-up of 3.5 years, 18,105 patients (29.2%) had died. There were 5288 bleeding events (8.5%) and 18,568 cardiovascular events (30.0%).

A multivariate analysis showed that NSAID use increased the risk of bleeding (hazard ratio, 2.02) and cardiovascular events (hazard ratio, 1.40). The increased risk of these events was present regardless of the type of antithrombotic treatment, the types of NSAIDs used, or the duration of NSAID use.

Dr Schjerning Olsen and her colleagues said additional research is needed to confirm these findings, but physicians should exercise caution when prescribing NSAIDs to patients with a recent MI.

Authors of a related editorial pointed out that this study only included prescription NSAID use. In countries where NSAIDs are available over the counter, physicians may be unaware that patients are taking these drugs.

From left: Investigators

Kristine Crews, Barthelemy

Diouf, and William Evans

Photo by Seth Dixon

A gene variant may help predict vincristine-related toxicity in children with acute lymphoblastic leukemia (ALL).

A study of more than 300 children with ALL showed that patients with an inherited variant in the gene CEP72 were more likely to develop peripheral neuropathy after receiving the chemotherapy drug vincristine.

If these results can be replicated in additional populations, they may provide a basis for safer dosing of the drug, according to investigators.

William Evans, PharmD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and shared the results in JAMA.

The investigators analyzed patients in 2 prospective clinical trials for childhood ALL that included treatment with 36 to 39 doses of vincristine. The team performed genetic analyses and assessed vincristine-induced peripheral neuropathy in 321 patients in whom DNA data were available.

This included 222 patients with a median age of 6 years who were enrolled in a St Jude Children’s Research Hospital study from 1994 to 1998, as well as 99 patients with a median age of 11.4 years who were enrolled in a Children’s Oncology Group (COG) study from 2007 to 2010.

Grade 2 to 4 vincristine-induced peripheral neuropathy occurred in 28.8% of patients (64/222) in the St Jude cohort and in 22.2% (22/99) in the COG cohort.

The investigators found that a single nucleotide polymorphism (SNP) in the promoter region of the CEP72 gene, which encodes a centrosomal protein involved in microtubule formation, was significantly associated with vincristine-induced neuropathy (P=6.3×10^-9).

This SNP had a minor allele frequency of 37%, and 16% of patients (50/321) were homozygous for the risk allele (TT at rs924607).

Among patients with the high-risk CEP72 genotype, 56% (28/50) had at least 1 episode of grade 2 to 4 neuropathy. This was significantly higher than in patients with the CEP72 CC or CT genotypes. About 21% of those patients (58/271) had at least 1 episode of grade 2 to 4 neuropathy (P=2.4×10^-6).

In addition, the severity of neuropathy was greater in patients who were homozygous for the TT genotype than in patients with the CC or CT genotype—2.4-fold greater by Poisson regression (P<0.0001) and 2.7-fold greater based on the mean grade of neuropathy (P=0.004).

Finally, in lab experiments, the investigators found that reducing CEP72 expression in human neurons and leukemia cells increased their sensitivity to vincristine.

In a related editorial, Howard L. McLeod, PharmD, of the Moffitt Cancer Center in Tampa, Florida, noted that this study has several strengths: genome-wide discovery in patients from well-conducted clinical trials, replication in a multicenter cohort, statistical robustness, and laboratory correlative findings that contribute to biologic plausibility.

However, he also pointed out that vincristine remains a component of the most widely accepted treatment regimens for childhood ALL.

“It is not clear that vincristine can be removed from the treatment options for a child with CEP72 variants, although this study suggests that the resulting increase in leukemia cellular sensitivity makes vincristine dose reductions possible without compromising antileukemic effect,” he wrote.

“However, there is value in the association of CEP72 with vincristine-induced peripheral neuropathy (VIPN). The ability to objectively ascribe a degree of heightened VIPN risk will allow for greater transparency in discussions of risk and benefits of therapy with patients and their family members.”

“This also may lead to developmental therapeutic approaches to modulate CEP72 function as either primary prevention or treatment of chronic VIPN. This study also represents an initial robust effort to generate predictors for adverse drug reactions in cancer care.”

From left: Investigators

Kristine Crews, Barthelemy

Diouf, and William Evans

Photo by Seth Dixon

A gene variant may help predict vincristine-related toxicity in children with acute lymphoblastic leukemia (ALL).

A study of more than 300 children with ALL showed that patients with an inherited variant in the gene CEP72 were more likely to develop peripheral neuropathy after receiving the chemotherapy drug vincristine.

If these results can be replicated in additional populations, they may provide a basis for safer dosing of the drug, according to investigators.

William Evans, PharmD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and shared the results in JAMA.

The investigators analyzed patients in 2 prospective clinical trials for childhood ALL that included treatment with 36 to 39 doses of vincristine. The team performed genetic analyses and assessed vincristine-induced peripheral neuropathy in 321 patients in whom DNA data were available.

This included 222 patients with a median age of 6 years who were enrolled in a St Jude Children’s Research Hospital study from 1994 to 1998, as well as 99 patients with a median age of 11.4 years who were enrolled in a Children’s Oncology Group (COG) study from 2007 to 2010.

Grade 2 to 4 vincristine-induced peripheral neuropathy occurred in 28.8% of patients (64/222) in the St Jude cohort and in 22.2% (22/99) in the COG cohort.

The investigators found that a single nucleotide polymorphism (SNP) in the promoter region of the CEP72 gene, which encodes a centrosomal protein involved in microtubule formation, was significantly associated with vincristine-induced neuropathy (P=6.3×10^-9).

This SNP had a minor allele frequency of 37%, and 16% of patients (50/321) were homozygous for the risk allele (TT at rs924607).

Among patients with the high-risk CEP72 genotype, 56% (28/50) had at least 1 episode of grade 2 to 4 neuropathy. This was significantly higher than in patients with the CEP72 CC or CT genotypes. About 21% of those patients (58/271) had at least 1 episode of grade 2 to 4 neuropathy (P=2.4×10^-6).

In addition, the severity of neuropathy was greater in patients who were homozygous for the TT genotype than in patients with the CC or CT genotype—2.4-fold greater by Poisson regression (P<0.0001) and 2.7-fold greater based on the mean grade of neuropathy (P=0.004).

Finally, in lab experiments, the investigators found that reducing CEP72 expression in human neurons and leukemia cells increased their sensitivity to vincristine.

In a related editorial, Howard L. McLeod, PharmD, of the Moffitt Cancer Center in Tampa, Florida, noted that this study has several strengths: genome-wide discovery in patients from well-conducted clinical trials, replication in a multicenter cohort, statistical robustness, and laboratory correlative findings that contribute to biologic plausibility.

However, he also pointed out that vincristine remains a component of the most widely accepted treatment regimens for childhood ALL.

“It is not clear that vincristine can be removed from the treatment options for a child with CEP72 variants, although this study suggests that the resulting increase in leukemia cellular sensitivity makes vincristine dose reductions possible without compromising antileukemic effect,” he wrote.

“However, there is value in the association of CEP72 with vincristine-induced peripheral neuropathy (VIPN). The ability to objectively ascribe a degree of heightened VIPN risk will allow for greater transparency in discussions of risk and benefits of therapy with patients and their family members.”

“This also may lead to developmental therapeutic approaches to modulate CEP72 function as either primary prevention or treatment of chronic VIPN. This study also represents an initial robust effort to generate predictors for adverse drug reactions in cancer care.”

From left: Investigators

Kristine Crews, Barthelemy

Diouf, and William Evans

Photo by Seth Dixon

A gene variant may help predict vincristine-related toxicity in children with acute lymphoblastic leukemia (ALL).

A study of more than 300 children with ALL showed that patients with an inherited variant in the gene CEP72 were more likely to develop peripheral neuropathy after receiving the chemotherapy drug vincristine.

If these results can be replicated in additional populations, they may provide a basis for safer dosing of the drug, according to investigators.

William Evans, PharmD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and shared the results in JAMA.

The investigators analyzed patients in 2 prospective clinical trials for childhood ALL that included treatment with 36 to 39 doses of vincristine. The team performed genetic analyses and assessed vincristine-induced peripheral neuropathy in 321 patients in whom DNA data were available.

This included 222 patients with a median age of 6 years who were enrolled in a St Jude Children’s Research Hospital study from 1994 to 1998, as well as 99 patients with a median age of 11.4 years who were enrolled in a Children’s Oncology Group (COG) study from 2007 to 2010.

Grade 2 to 4 vincristine-induced peripheral neuropathy occurred in 28.8% of patients (64/222) in the St Jude cohort and in 22.2% (22/99) in the COG cohort.

The investigators found that a single nucleotide polymorphism (SNP) in the promoter region of the CEP72 gene, which encodes a centrosomal protein involved in microtubule formation, was significantly associated with vincristine-induced neuropathy (P=6.3×10^-9).

This SNP had a minor allele frequency of 37%, and 16% of patients (50/321) were homozygous for the risk allele (TT at rs924607).

Among patients with the high-risk CEP72 genotype, 56% (28/50) had at least 1 episode of grade 2 to 4 neuropathy. This was significantly higher than in patients with the CEP72 CC or CT genotypes. About 21% of those patients (58/271) had at least 1 episode of grade 2 to 4 neuropathy (P=2.4×10^-6).

In addition, the severity of neuropathy was greater in patients who were homozygous for the TT genotype than in patients with the CC or CT genotype—2.4-fold greater by Poisson regression (P<0.0001) and 2.7-fold greater based on the mean grade of neuropathy (P=0.004).

Finally, in lab experiments, the investigators found that reducing CEP72 expression in human neurons and leukemia cells increased their sensitivity to vincristine.

In a related editorial, Howard L. McLeod, PharmD, of the Moffitt Cancer Center in Tampa, Florida, noted that this study has several strengths: genome-wide discovery in patients from well-conducted clinical trials, replication in a multicenter cohort, statistical robustness, and laboratory correlative findings that contribute to biologic plausibility.

However, he also pointed out that vincristine remains a component of the most widely accepted treatment regimens for childhood ALL.

“It is not clear that vincristine can be removed from the treatment options for a child with CEP72 variants, although this study suggests that the resulting increase in leukemia cellular sensitivity makes vincristine dose reductions possible without compromising antileukemic effect,” he wrote.

“However, there is value in the association of CEP72 with vincristine-induced peripheral neuropathy (VIPN). The ability to objectively ascribe a degree of heightened VIPN risk will allow for greater transparency in discussions of risk and benefits of therapy with patients and their family members.”

“This also may lead to developmental therapeutic approaches to modulate CEP72 function as either primary prevention or treatment of chronic VIPN. This study also represents an initial robust effort to generate predictors for adverse drug reactions in cancer care.”

Even a short course of NSAIDs markedly raises the risk of major bleeding in patients receiving antithrombotic medication after having a myocardial infarction, according to a report published online Feb. 24 in JAMA.

In a nationwide Danish study, this risk was increased no matter which antithrombotic regimens the participants were taking and no matter which NSAIDs they were given. “There was no safe therapeutic window for concomitant NSAID use, because even short-term (0-3 days) treatment was associated with increased risk of bleeding,” said Dr. Anne-Marie Schjerning Olsen of Copenhagen University Hospital Gentofte, Hellerup (Denmark), and her associates.

Denise Fulton/Frontline Medical News

More research is needed to confirm the findings of this observational study, but until then “physicians should exercise appropriate caution when prescribing NSAIDs for patients who have recently experienced MI,” they noted.

The only NSAID available over the counter in Denmark during the study period was ibuprofen, and it could only be purchased in low (20-mg) doses and in limited quantities (100 tablets). In countries like the United States, where ibuprofen and other NSAIDs are available without prescriptions and where there are few restrictions on the amounts that can be purchased, these study findings are even more worrying, Dr. Schjerning Olsen and her colleagues said.

Several current guidelines discourage the use of NSAIDs in people with a history of MI, including recommendations from the American Heart Association and the European Medicines Agency. But several sources have indicated that many such patients are being exposed to the drugs. To study the issue, the investigators analyzed data in four nationwide Danish health care registries. They identified roughly 62,000 adults (mean age 67.7 years) hospitalized for recent MI in 2002-2011 and put on antithrombotic medications, of whom nearly 21,000 (33.8%) also received at least one prescription for NSAID treatment.

During a median follow-up of 3.5 years, there were 5,288 major bleeding events in the study cohort, including 799 fatal bleeding events.

The incidence of major bleeding events was 4.2 per 100 person-years among patients given NSAIDs, compared with 2.2 per 100 person-years without NSAID therapy, for a hazard ratio of 2.0. Bleeding risk was markedly increased from the first day of exposure to NSAIDs (HR of 3.37 on days 0-3), and it persisted through 90 days. This pattern was consistent across all antithrombotic regimens and regardless of whether the prescribed NSAIDs were selective COX-2 inhibitors, such as rofecoxib or celecoxib, or nonselective COX-2 inhibitors, such as ibuprofen or diclofenac (JAMA 2015 Feb. 24 [doi:10.1001/jama.2015.0809]).

When major gastrointestinal bleeding events were considered individually, the incidence was 2.1 events per 100 person-years among NSAID users, compared with only 0.8 events per 100 person-years without NSAIDs, for an HR of 2.65. The incidence of combined cardiovascular events was 11.2 per 100 person-years among NSAID users, compared with 8.3 per 100 person-years without NSAIDs, for an HR of 1.4.

These results persisted through several sensitivity analyses. They remained consistent when patients with rheumatoid arthritis were excluded from the analysis; such patients are the primary users of NSAIDs in the age group of the study population. The findings also remained consistent when patients at high risk of bleeding due to comorbidities were excluded from the analysis, including those with malignancy, acute or chronic renal failure, or a history of bleeding events.

“Although it seems unlikely that physicians can completely avoid prescription of NSAIDs, even among high-risk patients, these results highlight the importance of considering the balance of benefits and risks before initiating any NSAID treatment,” Dr. Schjerning Olsen and her associates said.

The study was funded by the Danish Council for Independent Research, the William Harvey Research Institute at Barts, and the London School of Medicine and Dentistry. Dr. Schjerning Olsen reported having no financial conflicts of interest; one of her associates reported ties to Cardiome, Merck, Sanofi, Daiichi, and Bristol-Myers Squibb.

Even a short course of NSAIDs markedly raises the risk of major bleeding in patients receiving antithrombotic medication after having a myocardial infarction, according to a report published online Feb. 24 in JAMA.

In a nationwide Danish study, this risk was increased no matter which antithrombotic regimens the participants were taking and no matter which NSAIDs they were given. “There was no safe therapeutic window for concomitant NSAID use, because even short-term (0-3 days) treatment was associated with increased risk of bleeding,” said Dr. Anne-Marie Schjerning Olsen of Copenhagen University Hospital Gentofte, Hellerup (Denmark), and her associates.

Denise Fulton/Frontline Medical News

More research is needed to confirm the findings of this observational study, but until then “physicians should exercise appropriate caution when prescribing NSAIDs for patients who have recently experienced MI,” they noted.

The only NSAID available over the counter in Denmark during the study period was ibuprofen, and it could only be purchased in low (20-mg) doses and in limited quantities (100 tablets). In countries like the United States, where ibuprofen and other NSAIDs are available without prescriptions and where there are few restrictions on the amounts that can be purchased, these study findings are even more worrying, Dr. Schjerning Olsen and her colleagues said.

Several current guidelines discourage the use of NSAIDs in people with a history of MI, including recommendations from the American Heart Association and the European Medicines Agency. But several sources have indicated that many such patients are being exposed to the drugs. To study the issue, the investigators analyzed data in four nationwide Danish health care registries. They identified roughly 62,000 adults (mean age 67.7 years) hospitalized for recent MI in 2002-2011 and put on antithrombotic medications, of whom nearly 21,000 (33.8%) also received at least one prescription for NSAID treatment.

During a median follow-up of 3.5 years, there were 5,288 major bleeding events in the study cohort, including 799 fatal bleeding events.

The incidence of major bleeding events was 4.2 per 100 person-years among patients given NSAIDs, compared with 2.2 per 100 person-years without NSAID therapy, for a hazard ratio of 2.0. Bleeding risk was markedly increased from the first day of exposure to NSAIDs (HR of 3.37 on days 0-3), and it persisted through 90 days. This pattern was consistent across all antithrombotic regimens and regardless of whether the prescribed NSAIDs were selective COX-2 inhibitors, such as rofecoxib or celecoxib, or nonselective COX-2 inhibitors, such as ibuprofen or diclofenac (JAMA 2015 Feb. 24 [doi:10.1001/jama.2015.0809]).

When major gastrointestinal bleeding events were considered individually, the incidence was 2.1 events per 100 person-years among NSAID users, compared with only 0.8 events per 100 person-years without NSAIDs, for an HR of 2.65. The incidence of combined cardiovascular events was 11.2 per 100 person-years among NSAID users, compared with 8.3 per 100 person-years without NSAIDs, for an HR of 1.4.

These results persisted through several sensitivity analyses. They remained consistent when patients with rheumatoid arthritis were excluded from the analysis; such patients are the primary users of NSAIDs in the age group of the study population. The findings also remained consistent when patients at high risk of bleeding due to comorbidities were excluded from the analysis, including those with malignancy, acute or chronic renal failure, or a history of bleeding events.

“Although it seems unlikely that physicians can completely avoid prescription of NSAIDs, even among high-risk patients, these results highlight the importance of considering the balance of benefits and risks before initiating any NSAID treatment,” Dr. Schjerning Olsen and her associates said.

The study was funded by the Danish Council for Independent Research, the William Harvey Research Institute at Barts, and the London School of Medicine and Dentistry. Dr. Schjerning Olsen reported having no financial conflicts of interest; one of her associates reported ties to Cardiome, Merck, Sanofi, Daiichi, and Bristol-Myers Squibb.

Even a short course of NSAIDs markedly raises the risk of major bleeding in patients receiving antithrombotic medication after having a myocardial infarction, according to a report published online Feb. 24 in JAMA.

In a nationwide Danish study, this risk was increased no matter which antithrombotic regimens the participants were taking and no matter which NSAIDs they were given. “There was no safe therapeutic window for concomitant NSAID use, because even short-term (0-3 days) treatment was associated with increased risk of bleeding,” said Dr. Anne-Marie Schjerning Olsen of Copenhagen University Hospital Gentofte, Hellerup (Denmark), and her associates.

Denise Fulton/Frontline Medical News

More research is needed to confirm the findings of this observational study, but until then “physicians should exercise appropriate caution when prescribing NSAIDs for patients who have recently experienced MI,” they noted.

The only NSAID available over the counter in Denmark during the study period was ibuprofen, and it could only be purchased in low (20-mg) doses and in limited quantities (100 tablets). In countries like the United States, where ibuprofen and other NSAIDs are available without prescriptions and where there are few restrictions on the amounts that can be purchased, these study findings are even more worrying, Dr. Schjerning Olsen and her colleagues said.

Several current guidelines discourage the use of NSAIDs in people with a history of MI, including recommendations from the American Heart Association and the European Medicines Agency. But several sources have indicated that many such patients are being exposed to the drugs. To study the issue, the investigators analyzed data in four nationwide Danish health care registries. They identified roughly 62,000 adults (mean age 67.7 years) hospitalized for recent MI in 2002-2011 and put on antithrombotic medications, of whom nearly 21,000 (33.8%) also received at least one prescription for NSAID treatment.

During a median follow-up of 3.5 years, there were 5,288 major bleeding events in the study cohort, including 799 fatal bleeding events.

The incidence of major bleeding events was 4.2 per 100 person-years among patients given NSAIDs, compared with 2.2 per 100 person-years without NSAID therapy, for a hazard ratio of 2.0. Bleeding risk was markedly increased from the first day of exposure to NSAIDs (HR of 3.37 on days 0-3), and it persisted through 90 days. This pattern was consistent across all antithrombotic regimens and regardless of whether the prescribed NSAIDs were selective COX-2 inhibitors, such as rofecoxib or celecoxib, or nonselective COX-2 inhibitors, such as ibuprofen or diclofenac (JAMA 2015 Feb. 24 [doi:10.1001/jama.2015.0809]).

When major gastrointestinal bleeding events were considered individually, the incidence was 2.1 events per 100 person-years among NSAID users, compared with only 0.8 events per 100 person-years without NSAIDs, for an HR of 2.65. The incidence of combined cardiovascular events was 11.2 per 100 person-years among NSAID users, compared with 8.3 per 100 person-years without NSAIDs, for an HR of 1.4.

These results persisted through several sensitivity analyses. They remained consistent when patients with rheumatoid arthritis were excluded from the analysis; such patients are the primary users of NSAIDs in the age group of the study population. The findings also remained consistent when patients at high risk of bleeding due to comorbidities were excluded from the analysis, including those with malignancy, acute or chronic renal failure, or a history of bleeding events.

“Although it seems unlikely that physicians can completely avoid prescription of NSAIDs, even among high-risk patients, these results highlight the importance of considering the balance of benefits and risks before initiating any NSAID treatment,” Dr. Schjerning Olsen and her associates said.

The study was funded by the Danish Council for Independent Research, the William Harvey Research Institute at Barts, and the London School of Medicine and Dentistry. Dr. Schjerning Olsen reported having no financial conflicts of interest; one of her associates reported ties to Cardiome, Merck, Sanofi, Daiichi, and Bristol-Myers Squibb.

Inpatients discharged from teaching hospitals on weekends experience similar postdischarge outcomes and shorter lengths of stay compared with patients discharged on weekdays, according to a recent Journal of Hospital Medicine study.

The study, led by Finlay McAlister, MSc, MD, LMCC, general internist and population health investigator at the Alberta Heritage Foundation for Medical Research in Canada, examined death or nonelective readmission rates for general medicine inpatients 30 days after weekend and weekday discharges at all seven teaching hospitals in Alberta.

Although fewer pharmacists, physicians, and therapists typically are available to assist patients discharged on weekends, Dr. McAlister and colleagues found that patients sent home on weekends do not bounce back to the hospital or the ED sooner than patients sent home on weekdays.

"If somebody is ready to go [home] on a weekend, you do not have to hold them until Monday, and nurse them and give them a false impression that that will improve their 30-day outcome," Dr. McAlister says.

In a previous study of patients with heart failure, Dr. McAlister noticed a trend that suggested better outcomes for patients discharged on weekdays. However, after studying a wider spectrum of patients with various diagnoses, he concluded there is no difference between weekend and weekday discharges in terms of patients' 30-day outcome.

Dr. McAlister suggests more research can be done to determine whether there is a difference in outcomes for weekend discharges from nonteaching hospitals.

"Because teaching hospitals may be a bit of a safety net, in terms of having house staff that is there seven days a week," he says. "The impact of reduced staffing levels may be more severe than at nonteaching hospitals."

Visit our website for more information on patient-discharge recommendations.

Inpatients discharged from teaching hospitals on weekends experience similar postdischarge outcomes and shorter lengths of stay compared with patients discharged on weekdays, according to a recent Journal of Hospital Medicine study.

The study, led by Finlay McAlister, MSc, MD, LMCC, general internist and population health investigator at the Alberta Heritage Foundation for Medical Research in Canada, examined death or nonelective readmission rates for general medicine inpatients 30 days after weekend and weekday discharges at all seven teaching hospitals in Alberta.

Although fewer pharmacists, physicians, and therapists typically are available to assist patients discharged on weekends, Dr. McAlister and colleagues found that patients sent home on weekends do not bounce back to the hospital or the ED sooner than patients sent home on weekdays.

"If somebody is ready to go [home] on a weekend, you do not have to hold them until Monday, and nurse them and give them a false impression that that will improve their 30-day outcome," Dr. McAlister says.

In a previous study of patients with heart failure, Dr. McAlister noticed a trend that suggested better outcomes for patients discharged on weekdays. However, after studying a wider spectrum of patients with various diagnoses, he concluded there is no difference between weekend and weekday discharges in terms of patients' 30-day outcome.

Dr. McAlister suggests more research can be done to determine whether there is a difference in outcomes for weekend discharges from nonteaching hospitals.

"Because teaching hospitals may be a bit of a safety net, in terms of having house staff that is there seven days a week," he says. "The impact of reduced staffing levels may be more severe than at nonteaching hospitals."

Visit our website for more information on patient-discharge recommendations.

Inpatients discharged from teaching hospitals on weekends experience similar postdischarge outcomes and shorter lengths of stay compared with patients discharged on weekdays, according to a recent Journal of Hospital Medicine study.

The study, led by Finlay McAlister, MSc, MD, LMCC, general internist and population health investigator at the Alberta Heritage Foundation for Medical Research in Canada, examined death or nonelective readmission rates for general medicine inpatients 30 days after weekend and weekday discharges at all seven teaching hospitals in Alberta.

Although fewer pharmacists, physicians, and therapists typically are available to assist patients discharged on weekends, Dr. McAlister and colleagues found that patients sent home on weekends do not bounce back to the hospital or the ED sooner than patients sent home on weekdays.

"If somebody is ready to go [home] on a weekend, you do not have to hold them until Monday, and nurse them and give them a false impression that that will improve their 30-day outcome," Dr. McAlister says.

In a previous study of patients with heart failure, Dr. McAlister noticed a trend that suggested better outcomes for patients discharged on weekdays. However, after studying a wider spectrum of patients with various diagnoses, he concluded there is no difference between weekend and weekday discharges in terms of patients' 30-day outcome.

Dr. McAlister suggests more research can be done to determine whether there is a difference in outcomes for weekend discharges from nonteaching hospitals.

"Because teaching hospitals may be a bit of a safety net, in terms of having house staff that is there seven days a week," he says. "The impact of reduced staffing levels may be more severe than at nonteaching hospitals."

Visit our website for more information on patient-discharge recommendations.

A pair of rural South Carolina hospitals that may soon shutter their doors is the latest example of the pressure on rural hospitalists, says a veteran HM director. But hospital closures also give rural hospitalists the opportunity to carve out a niche doing medical work that best serves their community.

Marlboro Park Hospital and Chesterfield General Hospital, 15 miles apart in northeastern South Carolina, are set to close this spring as Community Health Systems—which runs the hospitals and employs hospital staff—announced it would not renew its operating lease. A new operator is being sought.

The fear of a rural institution closing is a common one for hospitalists, says Dana Giarrizzi, DO, FHM, national medical director for telehospitalist services for Eagle Hospital Physicians and section leader for the rural section of SHM.

"There's always that feeling of walking the tightrope," Dr. Giarrizzi says. "It's a fine line because you can't offer everything…there aren't enough physicians."

And while hospitals' shrinking bottom lines, more intensive reporting and quality protocols, and ongoing changes to the rules of the Affordable Care Act have roiled rural hospitalists, Dr. Giarrizzi sees the current environment as one that offers rural groups an opportunity to focus on what they do best and home in on that.

"It's really important [for rural hospitalist groups] to figure out what their niche is, figure out what works for them, and then to run that well," Dr. Giarrizzi adds. "I think it hurts them when they're pushed or when they feel like they have to do everything…you don't have that ability. These small rural hospitals serve their purpose, but their purpose isn't to serve everything."

Visit our website for more information on rural hospitals.

A pair of rural South Carolina hospitals that may soon shutter their doors is the latest example of the pressure on rural hospitalists, says a veteran HM director. But hospital closures also give rural hospitalists the opportunity to carve out a niche doing medical work that best serves their community.

Marlboro Park Hospital and Chesterfield General Hospital, 15 miles apart in northeastern South Carolina, are set to close this spring as Community Health Systems—which runs the hospitals and employs hospital staff—announced it would not renew its operating lease. A new operator is being sought.

The fear of a rural institution closing is a common one for hospitalists, says Dana Giarrizzi, DO, FHM, national medical director for telehospitalist services for Eagle Hospital Physicians and section leader for the rural section of SHM.

"There's always that feeling of walking the tightrope," Dr. Giarrizzi says. "It's a fine line because you can't offer everything…there aren't enough physicians."

And while hospitals' shrinking bottom lines, more intensive reporting and quality protocols, and ongoing changes to the rules of the Affordable Care Act have roiled rural hospitalists, Dr. Giarrizzi sees the current environment as one that offers rural groups an opportunity to focus on what they do best and home in on that.

"It's really important [for rural hospitalist groups] to figure out what their niche is, figure out what works for them, and then to run that well," Dr. Giarrizzi adds. "I think it hurts them when they're pushed or when they feel like they have to do everything…you don't have that ability. These small rural hospitals serve their purpose, but their purpose isn't to serve everything."

Visit our website for more information on rural hospitals.

A pair of rural South Carolina hospitals that may soon shutter their doors is the latest example of the pressure on rural hospitalists, says a veteran HM director. But hospital closures also give rural hospitalists the opportunity to carve out a niche doing medical work that best serves their community.

Marlboro Park Hospital and Chesterfield General Hospital, 15 miles apart in northeastern South Carolina, are set to close this spring as Community Health Systems—which runs the hospitals and employs hospital staff—announced it would not renew its operating lease. A new operator is being sought.

The fear of a rural institution closing is a common one for hospitalists, says Dana Giarrizzi, DO, FHM, national medical director for telehospitalist services for Eagle Hospital Physicians and section leader for the rural section of SHM.

"There's always that feeling of walking the tightrope," Dr. Giarrizzi says. "It's a fine line because you can't offer everything…there aren't enough physicians."

And while hospitals' shrinking bottom lines, more intensive reporting and quality protocols, and ongoing changes to the rules of the Affordable Care Act have roiled rural hospitalists, Dr. Giarrizzi sees the current environment as one that offers rural groups an opportunity to focus on what they do best and home in on that.

"It's really important [for rural hospitalist groups] to figure out what their niche is, figure out what works for them, and then to run that well," Dr. Giarrizzi adds. "I think it hurts them when they're pushed or when they feel like they have to do everything…you don't have that ability. These small rural hospitals serve their purpose, but their purpose isn't to serve everything."

Visit our website for more information on rural hospitals.

Discovery of a genetic variation that may boost the risk of peripheral neuropathy for some cancer patients on vincristine therapy could lead to better treatment regimens for those patients.

Investigators uncovered the genetic variation in a study that analyzed DNA samples from 321 children with acute lymphoblastic leukemia who received standard vincristine therapy while participating in two prospective clinical trials (JAMA 2015 Feb. 24 [doi:10.1001/jama.2015.0894]).

William E. Evans, Pharm.D., and Kristine R. Crews, Pharm.D., both of St. Jude Children’s Research Hospital, Memphis, Tenn., discussed what spurred the search for genetic risk factors and what’s next for researchers looking to cut the chance of side effects associated with vincristine treatment in a video interview.

[email protected]

Discovery of a genetic variation that may boost the risk of peripheral neuropathy for some cancer patients on vincristine therapy could lead to better treatment regimens for those patients.

Investigators uncovered the genetic variation in a study that analyzed DNA samples from 321 children with acute lymphoblastic leukemia who received standard vincristine therapy while participating in two prospective clinical trials (JAMA 2015 Feb. 24 [doi:10.1001/jama.2015.0894]).

William E. Evans, Pharm.D., and Kristine R. Crews, Pharm.D., both of St. Jude Children’s Research Hospital, Memphis, Tenn., discussed what spurred the search for genetic risk factors and what’s next for researchers looking to cut the chance of side effects associated with vincristine treatment in a video interview.

[email protected]

Discovery of a genetic variation that may boost the risk of peripheral neuropathy for some cancer patients on vincristine therapy could lead to better treatment regimens for those patients.

Investigators uncovered the genetic variation in a study that analyzed DNA samples from 321 children with acute lymphoblastic leukemia who received standard vincristine therapy while participating in two prospective clinical trials (JAMA 2015 Feb. 24 [doi:10.1001/jama.2015.0894]).

William E. Evans, Pharm.D., and Kristine R. Crews, Pharm.D., both of St. Jude Children’s Research Hospital, Memphis, Tenn., discussed what spurred the search for genetic risk factors and what’s next for researchers looking to cut the chance of side effects associated with vincristine treatment in a video interview.

[email protected]

NASHVILLE, TENN. – The 10-year outcome for most giant intracranial aneurysms is rather dismal even if the lesions are initially successfully treated, according to findings from the International Study of Unruptured Intracranial Aneurysms.

Most patients lived through the first 2 years after diagnosis, but by 10 years, 37% of treated patients had died. Untreated patients had significantly higher mortality at 57%, Dr. James C. Torner said at the International Stroke Conference, which was sponsored by the American Heart Association.

“Compared to small aneurysms, the risk of all-cause mortality for these giant aneurysms is seven times greater in the first year, and the risk of hemorrhage or procedure-related death is 15 times higher. The risk does decrease over time, but it’s still elevated. It’s twice as high for death from hemorrhage and six times more likely from death due to rupture or a procedure by 10 years.”

Dr. Torner of the University of Iowa, Iowa City, presented 10-year outcomes from the International Study of Unruptured Intracranial Aneurysms (ISUIA), which followed 4,059 patients, of whom 187 had a giant unruptured intracranial aneurysm.

The mean lesion size was about 30 mm, but ranged from 25 to 63 mm. A third involved the internal carotid, and another third were cavernous. The remainder were either vestibular, posterior communicating, anterior cerebral, or middle cerebral.

Most were irregular; about 40% were a single sac. Daughter sacs were present in the rest. The volume ranged from 1,100 to 38,000 mm³, with about 10% having a volume of greater than 20,000 mm³.

Most of the patients were women (91%). Age was not related to occurrence; patients ranged from 25 to 82 years. There were some common risk factors, including smoking (in 70%), a family history of aneurysm (in 10%), a family history of coronary artery disease (in up to 45%, depending on patient age), hypertension (in up to 40%), and vascular headache. Patients aged 50 years or older were most likely to present with vascular headache (75%).

The baseline score on the modified Rankin Scale (mRS) was 1 in about 93% of the group. But 80% presented with some symptoms, including cranial nerve deficit (47%; commonly in cranial nerves III and IV), mass effect (16%), headache (44%), orbital pain (21%), and partial vision loss (25%).

Surgery was performed in 39% and endovascular treatment in 27%; the rest of the patients were initially untreated, although 3% later received endovascular treatment and 5% underwent surgical treatment during the follow-up period.

By 10 years, many of the lesions had ruptured. Posterior aneurysms were most likely to rupture (53%), while cavernous aneurysms were least likely to rupture (5%). About a third of the posterior communicating and 36% of the anterior lesions were unruptured.

The risk of rupture increased over the first 5 years, rising from almost 0% in year 1 to 20% by year 5. “Hemorrhage risk is huge over the first 5 years, even with the cavernous aneurysms – even they can rupture,” Dr. Torner said. “In those with smaller aneurysms, the risk of rupture may be high in the first 2 years, but then it subsides somewhat.”

Among the 59% of the overall group who survived, the mRS score remained excellent (1 or 2) by 10 years. Of the remainder who died, 23% died of a cranial or subarachnoid hemorrhage, and 11% of a cerebral infarct. Coronary disease, respiratory disease, and cancer were the other causes.

Treated patients generally fared better than untreated, although mortality varied significantly by lesion location. For anterior lesions, the death rate was 25% in untreated patients , 32% for surgical patients, and 19% in endovascular patients. Death rates for those with posterior communicating lesions were 90% for untreated and 50% for surgically treated patients; all of those with endovascular treatment died. For those with posterior lesions, death rates approached 100% for all groups.

Dr. Torner cautioned that because the study outcomes were collected during the 1990s, most treated patients underwent only coiling or clipping; better outcomes may be seen with more advanced therapies.

He said he had no relevant financial disclosures.

[email protected]

On Twitter @alz_gal

NASHVILLE, TENN. – The 10-year outcome for most giant intracranial aneurysms is rather dismal even if the lesions are initially successfully treated, according to findings from the International Study of Unruptured Intracranial Aneurysms.

Most patients lived through the first 2 years after diagnosis, but by 10 years, 37% of treated patients had died. Untreated patients had significantly higher mortality at 57%, Dr. James C. Torner said at the International Stroke Conference, which was sponsored by the American Heart Association.

“Compared to small aneurysms, the risk of all-cause mortality for these giant aneurysms is seven times greater in the first year, and the risk of hemorrhage or procedure-related death is 15 times higher. The risk does decrease over time, but it’s still elevated. It’s twice as high for death from hemorrhage and six times more likely from death due to rupture or a procedure by 10 years.”

Dr. Torner of the University of Iowa, Iowa City, presented 10-year outcomes from the International Study of Unruptured Intracranial Aneurysms (ISUIA), which followed 4,059 patients, of whom 187 had a giant unruptured intracranial aneurysm.

The mean lesion size was about 30 mm, but ranged from 25 to 63 mm. A third involved the internal carotid, and another third were cavernous. The remainder were either vestibular, posterior communicating, anterior cerebral, or middle cerebral.

Most were irregular; about 40% were a single sac. Daughter sacs were present in the rest. The volume ranged from 1,100 to 38,000 mm³, with about 10% having a volume of greater than 20,000 mm³.

Most of the patients were women (91%). Age was not related to occurrence; patients ranged from 25 to 82 years. There were some common risk factors, including smoking (in 70%), a family history of aneurysm (in 10%), a family history of coronary artery disease (in up to 45%, depending on patient age), hypertension (in up to 40%), and vascular headache. Patients aged 50 years or older were most likely to present with vascular headache (75%).

The baseline score on the modified Rankin Scale (mRS) was 1 in about 93% of the group. But 80% presented with some symptoms, including cranial nerve deficit (47%; commonly in cranial nerves III and IV), mass effect (16%), headache (44%), orbital pain (21%), and partial vision loss (25%).

Surgery was performed in 39% and endovascular treatment in 27%; the rest of the patients were initially untreated, although 3% later received endovascular treatment and 5% underwent surgical treatment during the follow-up period.

By 10 years, many of the lesions had ruptured. Posterior aneurysms were most likely to rupture (53%), while cavernous aneurysms were least likely to rupture (5%). About a third of the posterior communicating and 36% of the anterior lesions were unruptured.

The risk of rupture increased over the first 5 years, rising from almost 0% in year 1 to 20% by year 5. “Hemorrhage risk is huge over the first 5 years, even with the cavernous aneurysms – even they can rupture,” Dr. Torner said. “In those with smaller aneurysms, the risk of rupture may be high in the first 2 years, but then it subsides somewhat.”

Among the 59% of the overall group who survived, the mRS score remained excellent (1 or 2) by 10 years. Of the remainder who died, 23% died of a cranial or subarachnoid hemorrhage, and 11% of a cerebral infarct. Coronary disease, respiratory disease, and cancer were the other causes.

Treated patients generally fared better than untreated, although mortality varied significantly by lesion location. For anterior lesions, the death rate was 25% in untreated patients , 32% for surgical patients, and 19% in endovascular patients. Death rates for those with posterior communicating lesions were 90% for untreated and 50% for surgically treated patients; all of those with endovascular treatment died. For those with posterior lesions, death rates approached 100% for all groups.

Dr. Torner cautioned that because the study outcomes were collected during the 1990s, most treated patients underwent only coiling or clipping; better outcomes may be seen with more advanced therapies.

He said he had no relevant financial disclosures.

[email protected]

On Twitter @alz_gal

NASHVILLE, TENN. – The 10-year outcome for most giant intracranial aneurysms is rather dismal even if the lesions are initially successfully treated, according to findings from the International Study of Unruptured Intracranial Aneurysms.

Most patients lived through the first 2 years after diagnosis, but by 10 years, 37% of treated patients had died. Untreated patients had significantly higher mortality at 57%, Dr. James C. Torner said at the International Stroke Conference, which was sponsored by the American Heart Association.

“Compared to small aneurysms, the risk of all-cause mortality for these giant aneurysms is seven times greater in the first year, and the risk of hemorrhage or procedure-related death is 15 times higher. The risk does decrease over time, but it’s still elevated. It’s twice as high for death from hemorrhage and six times more likely from death due to rupture or a procedure by 10 years.”

Dr. Torner of the University of Iowa, Iowa City, presented 10-year outcomes from the International Study of Unruptured Intracranial Aneurysms (ISUIA), which followed 4,059 patients, of whom 187 had a giant unruptured intracranial aneurysm.

The mean lesion size was about 30 mm, but ranged from 25 to 63 mm. A third involved the internal carotid, and another third were cavernous. The remainder were either vestibular, posterior communicating, anterior cerebral, or middle cerebral.

Most were irregular; about 40% were a single sac. Daughter sacs were present in the rest. The volume ranged from 1,100 to 38,000 mm³, with about 10% having a volume of greater than 20,000 mm³.

Most of the patients were women (91%). Age was not related to occurrence; patients ranged from 25 to 82 years. There were some common risk factors, including smoking (in 70%), a family history of aneurysm (in 10%), a family history of coronary artery disease (in up to 45%, depending on patient age), hypertension (in up to 40%), and vascular headache. Patients aged 50 years or older were most likely to present with vascular headache (75%).

The baseline score on the modified Rankin Scale (mRS) was 1 in about 93% of the group. But 80% presented with some symptoms, including cranial nerve deficit (47%; commonly in cranial nerves III and IV), mass effect (16%), headache (44%), orbital pain (21%), and partial vision loss (25%).

Surgery was performed in 39% and endovascular treatment in 27%; the rest of the patients were initially untreated, although 3% later received endovascular treatment and 5% underwent surgical treatment during the follow-up period.

By 10 years, many of the lesions had ruptured. Posterior aneurysms were most likely to rupture (53%), while cavernous aneurysms were least likely to rupture (5%). About a third of the posterior communicating and 36% of the anterior lesions were unruptured.

The risk of rupture increased over the first 5 years, rising from almost 0% in year 1 to 20% by year 5. “Hemorrhage risk is huge over the first 5 years, even with the cavernous aneurysms – even they can rupture,” Dr. Torner said. “In those with smaller aneurysms, the risk of rupture may be high in the first 2 years, but then it subsides somewhat.”

Among the 59% of the overall group who survived, the mRS score remained excellent (1 or 2) by 10 years. Of the remainder who died, 23% died of a cranial or subarachnoid hemorrhage, and 11% of a cerebral infarct. Coronary disease, respiratory disease, and cancer were the other causes.

Treated patients generally fared better than untreated, although mortality varied significantly by lesion location. For anterior lesions, the death rate was 25% in untreated patients , 32% for surgical patients, and 19% in endovascular patients. Death rates for those with posterior communicating lesions were 90% for untreated and 50% for surgically treated patients; all of those with endovascular treatment died. For those with posterior lesions, death rates approached 100% for all groups.

Dr. Torner cautioned that because the study outcomes were collected during the 1990s, most treated patients underwent only coiling or clipping; better outcomes may be seen with more advanced therapies.

He said he had no relevant financial disclosures.

[email protected]

On Twitter @alz_gal