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CAR-T cell therapy rolls on in pediatric ALL
SAN FRANCISCO – CAR-T cell therapy drove relapsed, refractory acute lymphoblastic leukemia into complete remission in 92% or all but three of 39 children in a phase I/IIa study.
Complete responses were seen within 28 days of receiving a chimeric antigen receptor (CAR)-T cell infusion and have persisted in 15 patients for a year or more, Dr. Stephan A. Grupp reported at the annual meeting of the American Society of Hematology.
Ten relapses have occurred during follow-up of up to 31 months (median 6 months). Half were due to disappearance of the T cells, resulting in CD19-positive relapse, and half were related to antigen escape, resulting in CD19-negative relapse.
Five of the relapsed patients died. No events have been seen in patients who remain in remission after 12 months.
Importantly, CAR-T cell therapy was not used as a bridge to transplant, with only three patients subsequently going on to stem cell transplantation, Dr. Grupp, a pediatric oncologist at the Children’s Hospital of Philadelphia (CHOP) and professor of pediatrics at the University of Pennsylvania, said during a press briefing.
When asked whether CAR-T therapy could be a replacement for transplantation in the future, Dr. Grupp responded, “That would be my fondest hope. We’re not quite there yet, but we’re a lot closer than we used to be.”
The novel immunotherapy first hit the front pages in 2011 after researchers at CHOP and the University of Pennsylvania reported breakthrough results in a handful of children treated with CTL019 cells. T cells are collected from the patient and then genetically reengineered with a CAR directed against tumor B cells expressing the CD19 surface antigen.
More than 130 patients have now been treated by the Pennsylvania team with the CTL019 approach, which received breakthrough therapy status from the Food and Drug Administration in July 2014.
The updated results presented by Dr. Grupp build on those reported earlier this year (N. Engl. J. Med. 2014;371:1507-17) and involve 39 children and young adults. This includes the first 30 pediatric patients with relapsed, refractory ALL treated in the pilot trial. Their median age was 10 years and most were refractory to multiple prior therapies.
At 6 months, the duration of response was 76% and event-free survival was 70%.
The ability of patients to retain their T cells for 6 months or longer was observed in about two-thirds of patients and “is a key point in maintaining remission in these patients,” Dr. Grupp said.
Response rates were independent of disease burden at the time of infusion: 82% response in patients with more than 50% leukemia blast cells, 88% in those with more than 5% blasts, and 100% in those with 0.01%-5% blasts or less than 0.01% blasts.
Patients with higher baseline disease burden (more than 50% blasts), however, were significantly more likely to experience severe cytokine release syndrome (CRS), compared with those with lower disease burden (P < .002).
CRS has been seen across CAR-T cell studies, but there are insufficient data to determine whether this toxicity differs between adult and pediatric patients.
“The key to the cytokine release syndrome, and I believe this carries across platforms and actually may also apply to blinatumomab, is the amplification of the macrophage system through interleukin-6,” Dr. Grupp explained. “This is a classical feedback loop that is actually druggable” using the IL-6 receptor blocker tocilizumab (Actemra).
This strategy produced “remarkable control” of the CRS toxicity, with many of the severe CRS cases experiencing resolution within hours and all cases resolving within 2-3 days, he said.
B-cell aplasia was observed in all responding patients to date and was managed with intravenous immunoglobulin replacement therapy.
The two key questions for the future of CTL019 therapy are toxicity and the logistics of collecting a cell sample and sending it to a centralized manufacturing facility, Dr. Grupp said. This process has already been done on a small scale at CHOP because their cells are made at the University of Pennsylvania. Novartis, which licensed the technology, has built a cell-manufacturing facility and an ongoing phase II study is evaluating whether the technology can be safely rolled out to eight or nine pediatric centers across the country. An adult study will follow, he said.
SAN FRANCISCO – CAR-T cell therapy drove relapsed, refractory acute lymphoblastic leukemia into complete remission in 92% or all but three of 39 children in a phase I/IIa study.
Complete responses were seen within 28 days of receiving a chimeric antigen receptor (CAR)-T cell infusion and have persisted in 15 patients for a year or more, Dr. Stephan A. Grupp reported at the annual meeting of the American Society of Hematology.
Ten relapses have occurred during follow-up of up to 31 months (median 6 months). Half were due to disappearance of the T cells, resulting in CD19-positive relapse, and half were related to antigen escape, resulting in CD19-negative relapse.
Five of the relapsed patients died. No events have been seen in patients who remain in remission after 12 months.
Importantly, CAR-T cell therapy was not used as a bridge to transplant, with only three patients subsequently going on to stem cell transplantation, Dr. Grupp, a pediatric oncologist at the Children’s Hospital of Philadelphia (CHOP) and professor of pediatrics at the University of Pennsylvania, said during a press briefing.
When asked whether CAR-T therapy could be a replacement for transplantation in the future, Dr. Grupp responded, “That would be my fondest hope. We’re not quite there yet, but we’re a lot closer than we used to be.”
The novel immunotherapy first hit the front pages in 2011 after researchers at CHOP and the University of Pennsylvania reported breakthrough results in a handful of children treated with CTL019 cells. T cells are collected from the patient and then genetically reengineered with a CAR directed against tumor B cells expressing the CD19 surface antigen.
More than 130 patients have now been treated by the Pennsylvania team with the CTL019 approach, which received breakthrough therapy status from the Food and Drug Administration in July 2014.
The updated results presented by Dr. Grupp build on those reported earlier this year (N. Engl. J. Med. 2014;371:1507-17) and involve 39 children and young adults. This includes the first 30 pediatric patients with relapsed, refractory ALL treated in the pilot trial. Their median age was 10 years and most were refractory to multiple prior therapies.
At 6 months, the duration of response was 76% and event-free survival was 70%.
The ability of patients to retain their T cells for 6 months or longer was observed in about two-thirds of patients and “is a key point in maintaining remission in these patients,” Dr. Grupp said.
Response rates were independent of disease burden at the time of infusion: 82% response in patients with more than 50% leukemia blast cells, 88% in those with more than 5% blasts, and 100% in those with 0.01%-5% blasts or less than 0.01% blasts.
Patients with higher baseline disease burden (more than 50% blasts), however, were significantly more likely to experience severe cytokine release syndrome (CRS), compared with those with lower disease burden (P < .002).
CRS has been seen across CAR-T cell studies, but there are insufficient data to determine whether this toxicity differs between adult and pediatric patients.
“The key to the cytokine release syndrome, and I believe this carries across platforms and actually may also apply to blinatumomab, is the amplification of the macrophage system through interleukin-6,” Dr. Grupp explained. “This is a classical feedback loop that is actually druggable” using the IL-6 receptor blocker tocilizumab (Actemra).
This strategy produced “remarkable control” of the CRS toxicity, with many of the severe CRS cases experiencing resolution within hours and all cases resolving within 2-3 days, he said.
B-cell aplasia was observed in all responding patients to date and was managed with intravenous immunoglobulin replacement therapy.
The two key questions for the future of CTL019 therapy are toxicity and the logistics of collecting a cell sample and sending it to a centralized manufacturing facility, Dr. Grupp said. This process has already been done on a small scale at CHOP because their cells are made at the University of Pennsylvania. Novartis, which licensed the technology, has built a cell-manufacturing facility and an ongoing phase II study is evaluating whether the technology can be safely rolled out to eight or nine pediatric centers across the country. An adult study will follow, he said.
SAN FRANCISCO – CAR-T cell therapy drove relapsed, refractory acute lymphoblastic leukemia into complete remission in 92% or all but three of 39 children in a phase I/IIa study.
Complete responses were seen within 28 days of receiving a chimeric antigen receptor (CAR)-T cell infusion and have persisted in 15 patients for a year or more, Dr. Stephan A. Grupp reported at the annual meeting of the American Society of Hematology.
Ten relapses have occurred during follow-up of up to 31 months (median 6 months). Half were due to disappearance of the T cells, resulting in CD19-positive relapse, and half were related to antigen escape, resulting in CD19-negative relapse.
Five of the relapsed patients died. No events have been seen in patients who remain in remission after 12 months.
Importantly, CAR-T cell therapy was not used as a bridge to transplant, with only three patients subsequently going on to stem cell transplantation, Dr. Grupp, a pediatric oncologist at the Children’s Hospital of Philadelphia (CHOP) and professor of pediatrics at the University of Pennsylvania, said during a press briefing.
When asked whether CAR-T therapy could be a replacement for transplantation in the future, Dr. Grupp responded, “That would be my fondest hope. We’re not quite there yet, but we’re a lot closer than we used to be.”
The novel immunotherapy first hit the front pages in 2011 after researchers at CHOP and the University of Pennsylvania reported breakthrough results in a handful of children treated with CTL019 cells. T cells are collected from the patient and then genetically reengineered with a CAR directed against tumor B cells expressing the CD19 surface antigen.
More than 130 patients have now been treated by the Pennsylvania team with the CTL019 approach, which received breakthrough therapy status from the Food and Drug Administration in July 2014.
The updated results presented by Dr. Grupp build on those reported earlier this year (N. Engl. J. Med. 2014;371:1507-17) and involve 39 children and young adults. This includes the first 30 pediatric patients with relapsed, refractory ALL treated in the pilot trial. Their median age was 10 years and most were refractory to multiple prior therapies.
At 6 months, the duration of response was 76% and event-free survival was 70%.
The ability of patients to retain their T cells for 6 months or longer was observed in about two-thirds of patients and “is a key point in maintaining remission in these patients,” Dr. Grupp said.
Response rates were independent of disease burden at the time of infusion: 82% response in patients with more than 50% leukemia blast cells, 88% in those with more than 5% blasts, and 100% in those with 0.01%-5% blasts or less than 0.01% blasts.
Patients with higher baseline disease burden (more than 50% blasts), however, were significantly more likely to experience severe cytokine release syndrome (CRS), compared with those with lower disease burden (P < .002).
CRS has been seen across CAR-T cell studies, but there are insufficient data to determine whether this toxicity differs between adult and pediatric patients.
“The key to the cytokine release syndrome, and I believe this carries across platforms and actually may also apply to blinatumomab, is the amplification of the macrophage system through interleukin-6,” Dr. Grupp explained. “This is a classical feedback loop that is actually druggable” using the IL-6 receptor blocker tocilizumab (Actemra).
This strategy produced “remarkable control” of the CRS toxicity, with many of the severe CRS cases experiencing resolution within hours and all cases resolving within 2-3 days, he said.
B-cell aplasia was observed in all responding patients to date and was managed with intravenous immunoglobulin replacement therapy.
The two key questions for the future of CTL019 therapy are toxicity and the logistics of collecting a cell sample and sending it to a centralized manufacturing facility, Dr. Grupp said. This process has already been done on a small scale at CHOP because their cells are made at the University of Pennsylvania. Novartis, which licensed the technology, has built a cell-manufacturing facility and an ongoing phase II study is evaluating whether the technology can be safely rolled out to eight or nine pediatric centers across the country. An adult study will follow, he said.
AT ASH 2014
Key clinical point: CAR-T cell therapy continues to provide durable responses in early studies of children with refractory ALL.
Major finding: Complete remission occurred in 36 of 39 patients (92%) treated with CAR-T cell therapy.
Data source: Phase I/IIa a study in 39 children and young adults with relapsed, refractory acute lymphoblastic leukemia.
Disclosures: The authors reported financial ties with Novartis, the study sponsor.
VALOR: Baby step forward or misstep in AML?
SAN FRANCISCO – Adding vosaroxin to cytarabine chemotherapy increased overall survival in first relapsed or refractory acute myeloid leukemia in the phase III VALOR study.
The difference in this primary endpoint, however, failed to achieve statistically significance (median 7.5 months vs. 6.1 months; P = .06), lead study author Dr. Farhad Ravandi reported at the annual meeting of the American Society of Hematology.
More patients receiving vosaroxin (Qinprezo) and cytarabine than cytarabine alone achieved complete remission (CR) (30.1% vs. 16.3%; P < .0001).
The benefit was significant across all subgroups (age at least 60 years, refractory disease, early and late relapse), except in those aged younger than 60 years, he said.
Vosaroxin is an investigational, first-in-class anticancer quinolone derivative that was granted fast track designation by the Food and Drug Administration in 2011 for the potential treatment of relapsed or refractory acute myeloid leukemia (AML) in combination with cytarabine.
Despite missing its primary endpoint, Dr. Ravandi argued during a press briefing that VALOR was a positive trial and that the survival benefit with combination vosaroxin was “highly significant.” He described relapsed/refractory AML as the equivalent of metastatic cancer, with patients presenting with disease “all over their body, right from day 1.”
“In solid tumors, we are excited about a 1- or 2-month survival improvement and I don’t see why we shouldn’t be excited in AML as well,” said Dr. Ravandi of the University of Texas M.D. Anderson Cancer Center in Houston.
He suggested that the bar has been set high in AML because about 40% of patients are cured and that great leaps forward remain rare. “We should not discount the small steps forward in treating our patients and providing better treatment options,” he said.
Press briefing moderator Dr. David Steensma of the Dana-Farber Cancer Institute, Boston, agreed that change is often incremental in AML but countered that the magnitude of benefit wasn’t great.
“AML is a really difficult population, no question about it, but there’s also no question that seven and a half months is pretty crummy and we need to do better than that,” Dr. Steensma said.
VALOR randomly assigned 711 adult patients from 124 sites in 15 countries to IV cytarabine 1 g/m² on days 1-5 plus placebo or IV vosaroxin 90 mg/m² on days 1 and 4 for induction and 70 mg/m² for subsequent cycles. Patients had AML refractory to initial induction therapy or were in first relapse, defined as relapse within 90 days to 24 months after first CR or CR with incomplete platelet recovery.
In all, 30.1% of patients in the vosaroxin group and 29% in the placebo group underwent allogeneic stem cell transplantation (ASCT). In those younger than 60 years, rates were 46.2% and 45.4%.
When stratified by age, there was a significant overall survival benefit with the vosaroxin combination for patients aged 60 years and older, who accounted for two-thirds of the study population (median 7.1 months vs. 5.0 months; hazard ratio, 0.75; P = .003), Dr. Ravandi said.
There was no survival advantage in patients younger than 60 years (median 9.1 months vs. 7.9 months; HR, 1.08, P = .60).
In a preplanned analysis censored for ASCT, median overall survival was significantly better in patients receiving the vosaroxin combination versus cytarabine alone (6.7 months vs. 5.3 months; HR, 0.83; P = .02).
“The benefit may be underestimated by the high rate of [ASCT], particularly in the younger patients,” Dr. Ravandi concluded during the formal presentation of the late-breaking abstract. “These data support the use of vosaroxin in combination with cytarabine as a new standard for salvage therapy in older patients with relapsed or refractory AML.”
During the discussion following the presentation, session comoderator Dr. Jonathan Friedberg of the University of Rochester Medical Center in Rochester, N.Y., asked, “How do you reconcile the observation that the patients you wanted to get to transplant got there, and yet you’re blaming the transplant for poor outcomes?”
Dr. Ravandi responded that transplantation is an issue in all AML studies and that a much larger study would have been needed to show a survival difference regardless of transplant status.
Treatment-related adverse events were more common in patients on vosaroxin and were mostly infection related. Stomatitis was identified as a dose-limiting toxicity in previous studies and occurred at any grade in 49% of vosaroxin patients and 19% of controls and at grade 3/4 in 15% and 3%.
Other notable grade 3/4 events were febrile neutropenia (47% vs. 33%) and thrombocytopenia (24% vs. 25%). This increase in toxicity did not translate into worse all-cause mortality at either 30 or 60 days, Dr. Ravandi said.
Sunesis Pharmaceuticals funded the study. Dr. Ravandi and several coauthors reported financial ties with Sunesis. Dr Steensma reported financial ties with several companies. Dr. Friedberg reported no disclosures.
SAN FRANCISCO – Adding vosaroxin to cytarabine chemotherapy increased overall survival in first relapsed or refractory acute myeloid leukemia in the phase III VALOR study.
The difference in this primary endpoint, however, failed to achieve statistically significance (median 7.5 months vs. 6.1 months; P = .06), lead study author Dr. Farhad Ravandi reported at the annual meeting of the American Society of Hematology.
More patients receiving vosaroxin (Qinprezo) and cytarabine than cytarabine alone achieved complete remission (CR) (30.1% vs. 16.3%; P < .0001).
The benefit was significant across all subgroups (age at least 60 years, refractory disease, early and late relapse), except in those aged younger than 60 years, he said.
Vosaroxin is an investigational, first-in-class anticancer quinolone derivative that was granted fast track designation by the Food and Drug Administration in 2011 for the potential treatment of relapsed or refractory acute myeloid leukemia (AML) in combination with cytarabine.
Despite missing its primary endpoint, Dr. Ravandi argued during a press briefing that VALOR was a positive trial and that the survival benefit with combination vosaroxin was “highly significant.” He described relapsed/refractory AML as the equivalent of metastatic cancer, with patients presenting with disease “all over their body, right from day 1.”
“In solid tumors, we are excited about a 1- or 2-month survival improvement and I don’t see why we shouldn’t be excited in AML as well,” said Dr. Ravandi of the University of Texas M.D. Anderson Cancer Center in Houston.
He suggested that the bar has been set high in AML because about 40% of patients are cured and that great leaps forward remain rare. “We should not discount the small steps forward in treating our patients and providing better treatment options,” he said.
Press briefing moderator Dr. David Steensma of the Dana-Farber Cancer Institute, Boston, agreed that change is often incremental in AML but countered that the magnitude of benefit wasn’t great.
“AML is a really difficult population, no question about it, but there’s also no question that seven and a half months is pretty crummy and we need to do better than that,” Dr. Steensma said.
VALOR randomly assigned 711 adult patients from 124 sites in 15 countries to IV cytarabine 1 g/m² on days 1-5 plus placebo or IV vosaroxin 90 mg/m² on days 1 and 4 for induction and 70 mg/m² for subsequent cycles. Patients had AML refractory to initial induction therapy or were in first relapse, defined as relapse within 90 days to 24 months after first CR or CR with incomplete platelet recovery.
In all, 30.1% of patients in the vosaroxin group and 29% in the placebo group underwent allogeneic stem cell transplantation (ASCT). In those younger than 60 years, rates were 46.2% and 45.4%.
When stratified by age, there was a significant overall survival benefit with the vosaroxin combination for patients aged 60 years and older, who accounted for two-thirds of the study population (median 7.1 months vs. 5.0 months; hazard ratio, 0.75; P = .003), Dr. Ravandi said.
There was no survival advantage in patients younger than 60 years (median 9.1 months vs. 7.9 months; HR, 1.08, P = .60).
In a preplanned analysis censored for ASCT, median overall survival was significantly better in patients receiving the vosaroxin combination versus cytarabine alone (6.7 months vs. 5.3 months; HR, 0.83; P = .02).
“The benefit may be underestimated by the high rate of [ASCT], particularly in the younger patients,” Dr. Ravandi concluded during the formal presentation of the late-breaking abstract. “These data support the use of vosaroxin in combination with cytarabine as a new standard for salvage therapy in older patients with relapsed or refractory AML.”
During the discussion following the presentation, session comoderator Dr. Jonathan Friedberg of the University of Rochester Medical Center in Rochester, N.Y., asked, “How do you reconcile the observation that the patients you wanted to get to transplant got there, and yet you’re blaming the transplant for poor outcomes?”
Dr. Ravandi responded that transplantation is an issue in all AML studies and that a much larger study would have been needed to show a survival difference regardless of transplant status.
Treatment-related adverse events were more common in patients on vosaroxin and were mostly infection related. Stomatitis was identified as a dose-limiting toxicity in previous studies and occurred at any grade in 49% of vosaroxin patients and 19% of controls and at grade 3/4 in 15% and 3%.
Other notable grade 3/4 events were febrile neutropenia (47% vs. 33%) and thrombocytopenia (24% vs. 25%). This increase in toxicity did not translate into worse all-cause mortality at either 30 or 60 days, Dr. Ravandi said.
Sunesis Pharmaceuticals funded the study. Dr. Ravandi and several coauthors reported financial ties with Sunesis. Dr Steensma reported financial ties with several companies. Dr. Friedberg reported no disclosures.
SAN FRANCISCO – Adding vosaroxin to cytarabine chemotherapy increased overall survival in first relapsed or refractory acute myeloid leukemia in the phase III VALOR study.
The difference in this primary endpoint, however, failed to achieve statistically significance (median 7.5 months vs. 6.1 months; P = .06), lead study author Dr. Farhad Ravandi reported at the annual meeting of the American Society of Hematology.
More patients receiving vosaroxin (Qinprezo) and cytarabine than cytarabine alone achieved complete remission (CR) (30.1% vs. 16.3%; P < .0001).
The benefit was significant across all subgroups (age at least 60 years, refractory disease, early and late relapse), except in those aged younger than 60 years, he said.
Vosaroxin is an investigational, first-in-class anticancer quinolone derivative that was granted fast track designation by the Food and Drug Administration in 2011 for the potential treatment of relapsed or refractory acute myeloid leukemia (AML) in combination with cytarabine.
Despite missing its primary endpoint, Dr. Ravandi argued during a press briefing that VALOR was a positive trial and that the survival benefit with combination vosaroxin was “highly significant.” He described relapsed/refractory AML as the equivalent of metastatic cancer, with patients presenting with disease “all over their body, right from day 1.”
“In solid tumors, we are excited about a 1- or 2-month survival improvement and I don’t see why we shouldn’t be excited in AML as well,” said Dr. Ravandi of the University of Texas M.D. Anderson Cancer Center in Houston.
He suggested that the bar has been set high in AML because about 40% of patients are cured and that great leaps forward remain rare. “We should not discount the small steps forward in treating our patients and providing better treatment options,” he said.
Press briefing moderator Dr. David Steensma of the Dana-Farber Cancer Institute, Boston, agreed that change is often incremental in AML but countered that the magnitude of benefit wasn’t great.
“AML is a really difficult population, no question about it, but there’s also no question that seven and a half months is pretty crummy and we need to do better than that,” Dr. Steensma said.
VALOR randomly assigned 711 adult patients from 124 sites in 15 countries to IV cytarabine 1 g/m² on days 1-5 plus placebo or IV vosaroxin 90 mg/m² on days 1 and 4 for induction and 70 mg/m² for subsequent cycles. Patients had AML refractory to initial induction therapy or were in first relapse, defined as relapse within 90 days to 24 months after first CR or CR with incomplete platelet recovery.
In all, 30.1% of patients in the vosaroxin group and 29% in the placebo group underwent allogeneic stem cell transplantation (ASCT). In those younger than 60 years, rates were 46.2% and 45.4%.
When stratified by age, there was a significant overall survival benefit with the vosaroxin combination for patients aged 60 years and older, who accounted for two-thirds of the study population (median 7.1 months vs. 5.0 months; hazard ratio, 0.75; P = .003), Dr. Ravandi said.
There was no survival advantage in patients younger than 60 years (median 9.1 months vs. 7.9 months; HR, 1.08, P = .60).
In a preplanned analysis censored for ASCT, median overall survival was significantly better in patients receiving the vosaroxin combination versus cytarabine alone (6.7 months vs. 5.3 months; HR, 0.83; P = .02).
“The benefit may be underestimated by the high rate of [ASCT], particularly in the younger patients,” Dr. Ravandi concluded during the formal presentation of the late-breaking abstract. “These data support the use of vosaroxin in combination with cytarabine as a new standard for salvage therapy in older patients with relapsed or refractory AML.”
During the discussion following the presentation, session comoderator Dr. Jonathan Friedberg of the University of Rochester Medical Center in Rochester, N.Y., asked, “How do you reconcile the observation that the patients you wanted to get to transplant got there, and yet you’re blaming the transplant for poor outcomes?”
Dr. Ravandi responded that transplantation is an issue in all AML studies and that a much larger study would have been needed to show a survival difference regardless of transplant status.
Treatment-related adverse events were more common in patients on vosaroxin and were mostly infection related. Stomatitis was identified as a dose-limiting toxicity in previous studies and occurred at any grade in 49% of vosaroxin patients and 19% of controls and at grade 3/4 in 15% and 3%.
Other notable grade 3/4 events were febrile neutropenia (47% vs. 33%) and thrombocytopenia (24% vs. 25%). This increase in toxicity did not translate into worse all-cause mortality at either 30 or 60 days, Dr. Ravandi said.
Sunesis Pharmaceuticals funded the study. Dr. Ravandi and several coauthors reported financial ties with Sunesis. Dr Steensma reported financial ties with several companies. Dr. Friedberg reported no disclosures.
AT ASH 2014
Key clinical point: Vosaroxin plus cytarabine failed to significantly improve overall survival in relapsed or refractory AML, but may offer older patients a new option.
Major finding: Median overall survival was 7.5 months for vosaroxin plus cytarabine vs. 6.1 months for cytarabine alone (HR, 0.865; P = .06).
Data source: Randomized, phase III trial in 711 patients with first relapsed or refractory acute myeloid leukemia.
Disclosures: Sunesis Pharmaceuticals funded the study. Dr. Ravandi and several coauthors reported financial ties with Sunesis. Dr Steensma reported financial ties with several companies. Dr. Friedberg reported no disclosures.
Nursing home-onset C. difficile infections cut wide swath
PHILADELPHIA – Clostridium difficile infections among nursing home residents resulted in some 31,000 hospitalizations and 9,000 deaths nationally in 2012, population-based surveillance data suggest.
“Nursing home-onset CDI is associated with substantial morbidity and mortality,” Dr. Fernanda Lessa reported at an annual scientific meeting on infectious diseases.
Nursing home residents are at higher risk of C. difficile infections (CDI) because of advanced age, frequent healthcare utilization, extended lengths of stay, and exposure to antimicrobials. The national burden of CDI in this setting, however, is not well characterized, said Dr. Lessa of the Centers for Disease Control and Prevention, Atlanta.
The investigators, lead by the CDC’s Dr. Jennifer C. Hunter analyzed surveillance data from 10 states in the Emerging Infections Program (EIP), representing a population of 11.4 million Americans and encompassing 382 nursing homes in 2012. A regression model was used to calculate incidence controlling for identified predictors of high nursing home-onset CDI incidence that vary by region. Sampling weights were used to estimate the national burden of infections and numbers of hospitalizations, recurrences, and deaths.
Nursing home-onset CDI cases were defined as a C. difficile-positive stool sample by toxin or molecular assay during 2012 in a surveillance area resident at least one year of age without a positive test in the prior 8 weeks and a positive stool sample collected in a nursing home resident or within 3 days after hospital admission from a nursing home.
A total of 16,565 CDI cases were identified, of which 3,513 (21%) were nursing home-onset CDI, she said.
A full medical record review of 272 random nursing home-onset CDI cases revealed that most patients received antibiotics in the 12 weeks before testing positive (77%) and had onset of the disease within a month after hospital discharge (76%), Dr. Lessa observed.
Approximately 13% required hospitalization within 7 days of testing positive, 2% required ICU admission, 20% had recurrent disease within 2-8 weeks, and 8% died within 30 days of a positive specimen.
After adjusting for age and diagnostic testing methods, an estimated 115,811 cases of nursing home-onset CDI occurred in 2012, with the highest rate among those aged 65-84 years (58,857 cases; rate 157.97/100,000 population).
Of these, an estimated 31,644 patients required hospitalization, 21,103 experienced recurrence, and 9,053 died within 30 days, Dr. Lessa reported.
“Strategies to reduce unnecessary antibiotic use in both acute and long-term care settings may lead to decreases in CDI onset in nursing homes in the U.S.,” she suggested.
During a discussion of the results, it was noted that the data are very consistent with multiple other studies showing that CDI in long-term care facilities is occurring within 30 days of transfer to the hospital, raising the question of whether the major problem isn’t antibiotic stewardship in the hospital setting.
Dr. Lessa pointed out that 30% of cases were not hospitalized in the 12 weeks prior to CDI onset, but went on to say, “I think we should focus on both [settings], but I completely agree that antimicrobial stewardship in the acute care setting will likely have a major impact in reducing nursing home C. difficile rates.”
ID Week is a joint meeting of the Infectious Diseases Society of America, Society for Healthcare Epidemiology of America, HIV Medicine Association, and Pediatric Infectious Diseases Society.
PHILADELPHIA – Clostridium difficile infections among nursing home residents resulted in some 31,000 hospitalizations and 9,000 deaths nationally in 2012, population-based surveillance data suggest.
“Nursing home-onset CDI is associated with substantial morbidity and mortality,” Dr. Fernanda Lessa reported at an annual scientific meeting on infectious diseases.
Nursing home residents are at higher risk of C. difficile infections (CDI) because of advanced age, frequent healthcare utilization, extended lengths of stay, and exposure to antimicrobials. The national burden of CDI in this setting, however, is not well characterized, said Dr. Lessa of the Centers for Disease Control and Prevention, Atlanta.
The investigators, lead by the CDC’s Dr. Jennifer C. Hunter analyzed surveillance data from 10 states in the Emerging Infections Program (EIP), representing a population of 11.4 million Americans and encompassing 382 nursing homes in 2012. A regression model was used to calculate incidence controlling for identified predictors of high nursing home-onset CDI incidence that vary by region. Sampling weights were used to estimate the national burden of infections and numbers of hospitalizations, recurrences, and deaths.
Nursing home-onset CDI cases were defined as a C. difficile-positive stool sample by toxin or molecular assay during 2012 in a surveillance area resident at least one year of age without a positive test in the prior 8 weeks and a positive stool sample collected in a nursing home resident or within 3 days after hospital admission from a nursing home.
A total of 16,565 CDI cases were identified, of which 3,513 (21%) were nursing home-onset CDI, she said.
A full medical record review of 272 random nursing home-onset CDI cases revealed that most patients received antibiotics in the 12 weeks before testing positive (77%) and had onset of the disease within a month after hospital discharge (76%), Dr. Lessa observed.
Approximately 13% required hospitalization within 7 days of testing positive, 2% required ICU admission, 20% had recurrent disease within 2-8 weeks, and 8% died within 30 days of a positive specimen.
After adjusting for age and diagnostic testing methods, an estimated 115,811 cases of nursing home-onset CDI occurred in 2012, with the highest rate among those aged 65-84 years (58,857 cases; rate 157.97/100,000 population).
Of these, an estimated 31,644 patients required hospitalization, 21,103 experienced recurrence, and 9,053 died within 30 days, Dr. Lessa reported.
“Strategies to reduce unnecessary antibiotic use in both acute and long-term care settings may lead to decreases in CDI onset in nursing homes in the U.S.,” she suggested.
During a discussion of the results, it was noted that the data are very consistent with multiple other studies showing that CDI in long-term care facilities is occurring within 30 days of transfer to the hospital, raising the question of whether the major problem isn’t antibiotic stewardship in the hospital setting.
Dr. Lessa pointed out that 30% of cases were not hospitalized in the 12 weeks prior to CDI onset, but went on to say, “I think we should focus on both [settings], but I completely agree that antimicrobial stewardship in the acute care setting will likely have a major impact in reducing nursing home C. difficile rates.”
ID Week is a joint meeting of the Infectious Diseases Society of America, Society for Healthcare Epidemiology of America, HIV Medicine Association, and Pediatric Infectious Diseases Society.
PHILADELPHIA – Clostridium difficile infections among nursing home residents resulted in some 31,000 hospitalizations and 9,000 deaths nationally in 2012, population-based surveillance data suggest.
“Nursing home-onset CDI is associated with substantial morbidity and mortality,” Dr. Fernanda Lessa reported at an annual scientific meeting on infectious diseases.
Nursing home residents are at higher risk of C. difficile infections (CDI) because of advanced age, frequent healthcare utilization, extended lengths of stay, and exposure to antimicrobials. The national burden of CDI in this setting, however, is not well characterized, said Dr. Lessa of the Centers for Disease Control and Prevention, Atlanta.
The investigators, lead by the CDC’s Dr. Jennifer C. Hunter analyzed surveillance data from 10 states in the Emerging Infections Program (EIP), representing a population of 11.4 million Americans and encompassing 382 nursing homes in 2012. A regression model was used to calculate incidence controlling for identified predictors of high nursing home-onset CDI incidence that vary by region. Sampling weights were used to estimate the national burden of infections and numbers of hospitalizations, recurrences, and deaths.
Nursing home-onset CDI cases were defined as a C. difficile-positive stool sample by toxin or molecular assay during 2012 in a surveillance area resident at least one year of age without a positive test in the prior 8 weeks and a positive stool sample collected in a nursing home resident or within 3 days after hospital admission from a nursing home.
A total of 16,565 CDI cases were identified, of which 3,513 (21%) were nursing home-onset CDI, she said.
A full medical record review of 272 random nursing home-onset CDI cases revealed that most patients received antibiotics in the 12 weeks before testing positive (77%) and had onset of the disease within a month after hospital discharge (76%), Dr. Lessa observed.
Approximately 13% required hospitalization within 7 days of testing positive, 2% required ICU admission, 20% had recurrent disease within 2-8 weeks, and 8% died within 30 days of a positive specimen.
After adjusting for age and diagnostic testing methods, an estimated 115,811 cases of nursing home-onset CDI occurred in 2012, with the highest rate among those aged 65-84 years (58,857 cases; rate 157.97/100,000 population).
Of these, an estimated 31,644 patients required hospitalization, 21,103 experienced recurrence, and 9,053 died within 30 days, Dr. Lessa reported.
“Strategies to reduce unnecessary antibiotic use in both acute and long-term care settings may lead to decreases in CDI onset in nursing homes in the U.S.,” she suggested.
During a discussion of the results, it was noted that the data are very consistent with multiple other studies showing that CDI in long-term care facilities is occurring within 30 days of transfer to the hospital, raising the question of whether the major problem isn’t antibiotic stewardship in the hospital setting.
Dr. Lessa pointed out that 30% of cases were not hospitalized in the 12 weeks prior to CDI onset, but went on to say, “I think we should focus on both [settings], but I completely agree that antimicrobial stewardship in the acute care setting will likely have a major impact in reducing nursing home C. difficile rates.”
ID Week is a joint meeting of the Infectious Diseases Society of America, Society for Healthcare Epidemiology of America, HIV Medicine Association, and Pediatric Infectious Diseases Society.
AT ID WEEK 2014
Key clinical point: Nursing home-onset C. difficile infections are associated with significant morbidity and mortality.
Major finding: An estimated 115,811 cases of nursing home-onset C. difficile occurred in 2012 nationally.
Data source: Population-based surveillance data from 10 states and 382 nursing homes.
Disclosures: Dr. Lessa reported having no financial disclosures.
ICD lead extraction complication rates warrant surgical backup
CHICAGO– Transvenous lead extraction was associated with a significant risk of urgent cardiac surgery and mortality in a real-world cohort of patients undergoing procedures across a wide spectrum of centers and operators.
Among the 11,304 extractions, the major complication rate was 2.3% and mortality rate 0.9%.
While the complication rate was in line with previously published single-center registry data, the mortality rate was more than twice that reported in recent single-center studies from high-volume centers (0.9% vs. 0.4%), Dr. Nitesh Sood reported at the American Heart Association annual scientific sessions.
Of the 98 perioperative deaths, 18 occurred during the lead extraction procedure.
Another 41 patients (16%) required urgent cardiac surgery, of whom 14 (34%) died during or in the immediate postoperative period after surgery.
“Thus, while overall rate of major complications remains low, there exists a significant risk of urgent cardiac surgery and mortality during transvenous lead extractions [TLE] performed in the ‘real world.’ Appropriate training of all personnel involved and optimal cardiothoracic surgical back-up at centers performing TLE is imperative,” Dr. Sood of the Southcoast Health System, Fall River, Mass., concluded.
The analysis is the largest real-world cohort of TLE involving 11,304 patients with an implantable cardioverter defibrillator (ICD) in the American College of Cardiology Foundation’s National Cardiovascular Data Registry (NCDR) ICD Registry with lead extraction data submitted between April 2010 and July 2012. Major complication was a combined endpoint of major operative complications, postoperative or in-hospital mortality, as defined by the NCDR ICD Registry.
The 258 complications included 62 cardiac arrests, 55 pericardial tamponades, 47 pneumothoraces, and 40 cardiac perforations.
In multivariate analysis, significant predictors of any complication were female sex (adjusted odds ratio, 1.46), heart failure admission vs. lead extraction admission (OR, 2.6), noncardiac admission vs. lead extraction admission (OR, 2.4), lead-only procedure vs. extraction during generator change/upgrade (OR, 1.76), age of lead (OR, 1.08), and clinical status requiring lead replacement (OR, 2.2). Dr. Sood reported.
Among lead characteristics, multivariate predictors of major perioperative complications included at least three concurrent leads extracted (OR, 2.13), longer implant duration (OR, 1.13), flat coil design vs. round (OR, 2.68), greater proximal coil surface area (OR, 1.04), and dislodgement of other leads during extraction (OR, 3.97), he noted.
CHICAGO– Transvenous lead extraction was associated with a significant risk of urgent cardiac surgery and mortality in a real-world cohort of patients undergoing procedures across a wide spectrum of centers and operators.
Among the 11,304 extractions, the major complication rate was 2.3% and mortality rate 0.9%.
While the complication rate was in line with previously published single-center registry data, the mortality rate was more than twice that reported in recent single-center studies from high-volume centers (0.9% vs. 0.4%), Dr. Nitesh Sood reported at the American Heart Association annual scientific sessions.
Of the 98 perioperative deaths, 18 occurred during the lead extraction procedure.
Another 41 patients (16%) required urgent cardiac surgery, of whom 14 (34%) died during or in the immediate postoperative period after surgery.
“Thus, while overall rate of major complications remains low, there exists a significant risk of urgent cardiac surgery and mortality during transvenous lead extractions [TLE] performed in the ‘real world.’ Appropriate training of all personnel involved and optimal cardiothoracic surgical back-up at centers performing TLE is imperative,” Dr. Sood of the Southcoast Health System, Fall River, Mass., concluded.
The analysis is the largest real-world cohort of TLE involving 11,304 patients with an implantable cardioverter defibrillator (ICD) in the American College of Cardiology Foundation’s National Cardiovascular Data Registry (NCDR) ICD Registry with lead extraction data submitted between April 2010 and July 2012. Major complication was a combined endpoint of major operative complications, postoperative or in-hospital mortality, as defined by the NCDR ICD Registry.
The 258 complications included 62 cardiac arrests, 55 pericardial tamponades, 47 pneumothoraces, and 40 cardiac perforations.
In multivariate analysis, significant predictors of any complication were female sex (adjusted odds ratio, 1.46), heart failure admission vs. lead extraction admission (OR, 2.6), noncardiac admission vs. lead extraction admission (OR, 2.4), lead-only procedure vs. extraction during generator change/upgrade (OR, 1.76), age of lead (OR, 1.08), and clinical status requiring lead replacement (OR, 2.2). Dr. Sood reported.
Among lead characteristics, multivariate predictors of major perioperative complications included at least three concurrent leads extracted (OR, 2.13), longer implant duration (OR, 1.13), flat coil design vs. round (OR, 2.68), greater proximal coil surface area (OR, 1.04), and dislodgement of other leads during extraction (OR, 3.97), he noted.
CHICAGO– Transvenous lead extraction was associated with a significant risk of urgent cardiac surgery and mortality in a real-world cohort of patients undergoing procedures across a wide spectrum of centers and operators.
Among the 11,304 extractions, the major complication rate was 2.3% and mortality rate 0.9%.
While the complication rate was in line with previously published single-center registry data, the mortality rate was more than twice that reported in recent single-center studies from high-volume centers (0.9% vs. 0.4%), Dr. Nitesh Sood reported at the American Heart Association annual scientific sessions.
Of the 98 perioperative deaths, 18 occurred during the lead extraction procedure.
Another 41 patients (16%) required urgent cardiac surgery, of whom 14 (34%) died during or in the immediate postoperative period after surgery.
“Thus, while overall rate of major complications remains low, there exists a significant risk of urgent cardiac surgery and mortality during transvenous lead extractions [TLE] performed in the ‘real world.’ Appropriate training of all personnel involved and optimal cardiothoracic surgical back-up at centers performing TLE is imperative,” Dr. Sood of the Southcoast Health System, Fall River, Mass., concluded.
The analysis is the largest real-world cohort of TLE involving 11,304 patients with an implantable cardioverter defibrillator (ICD) in the American College of Cardiology Foundation’s National Cardiovascular Data Registry (NCDR) ICD Registry with lead extraction data submitted between April 2010 and July 2012. Major complication was a combined endpoint of major operative complications, postoperative or in-hospital mortality, as defined by the NCDR ICD Registry.
The 258 complications included 62 cardiac arrests, 55 pericardial tamponades, 47 pneumothoraces, and 40 cardiac perforations.
In multivariate analysis, significant predictors of any complication were female sex (adjusted odds ratio, 1.46), heart failure admission vs. lead extraction admission (OR, 2.6), noncardiac admission vs. lead extraction admission (OR, 2.4), lead-only procedure vs. extraction during generator change/upgrade (OR, 1.76), age of lead (OR, 1.08), and clinical status requiring lead replacement (OR, 2.2). Dr. Sood reported.
Among lead characteristics, multivariate predictors of major perioperative complications included at least three concurrent leads extracted (OR, 2.13), longer implant duration (OR, 1.13), flat coil design vs. round (OR, 2.68), greater proximal coil surface area (OR, 1.04), and dislodgement of other leads during extraction (OR, 3.97), he noted.
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point: Appropriate training and optimal cardiothoracic surgical backup is necessary at all centers performing lead extractions, because of a significant risk of urgent cardiac surgery and death.
Major finding: The major complication rate was 2.3% and mortality rate 0.9%.
Data source: Retrospective analysis of 11,304 patients with transvenous lead extraction in the NCDR ICD Registry.
Disclosures: The study was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry. Dr. Sood reported having no financial disclosures. Three coauthors reported relationships with device makers.
CABG plus mitral repair put under spotlight
CHICAGO – Early results from a randomized trial cast doubt on the benefits of routinely repairing a leaky mitral valve during coronary artery bypass grafting in patients with moderate ischemic mitral regurgitation.
At 1 year, there was no significant difference between patients undergoing CABG alone or CABG plus mitral repair in the primary endpoint of left ventricular reverse modeling, as defined by changes in LV end-systolic volume index (LVESVI) at 1 year (z score 0.50).
Both groups achieved significant reductions in LVESVI, with a median reduction of about 6 mL/m2 from baseline, Dr. Robert Michler, chair of cardiovascular and thoracic surgery at Montefiore Medical Center, New York, reported at the American Heart Association scientific sessions.
At 1 year, patients who underwent CABG and mitral valve repair had significantly less residual moderate or severe mitral regurgitation (11% vs. 31%; P < .001).
On the other hand, the combination procedure was associated with significantly higher rates of any neurologic event (9.6% vs. 3.1%; P = .03), longer cross-clamp (117 vs. 74 minutes) and cardiopulmonary bypass times (163 vs. 106 minutes; P values both < .001), and longer ICU (4.8 vs. 4.0 days; P = .006) and hospital length of stay (11.3 vs. 9.4 days; P = .002), according to the results, also published online (N. Engl. J. Med. 2014 [doi: 10.1056/NEJMoa1410490]).
“The trial did not demonstrate a clinically meaningful advantage to the routine addition of mitral valve repair to CABG,” Dr. Michler said, on behalf of the Cardiothoracic Surgical Trials Network investigators.
The 2014 AHA/American College of Cardiology mitral valve guidelines give a weak class IIb recommendation for mitral valve repair for patients with chronic mitral regurgitation (MR) who are undergoing other cardiac surgery, he noted.
The study evenly randomized 301 patients with moderate ischemic mitral regurgitation to CABG alone or CABG plus valve repair with an undersized ring (average, 28.3 mm for men and 27.1 mm for women).
The mean LVESVI at baseline was 54.8 mL/m2 in the CABG-alone group and 59.6 mL/m2 in the combined procedure group.
At 12 months, mean LVESVIs were 46.1 mL/m2 and 49.6 mL/m2, respectively.
The trial lacked a clinical primary endpoint, and longer follow-up is ongoing to determine whether the lower incidence of moderate or severe MR at 1 year will translate into a net clinical benefit for patients undergoing CABG plus mitral repair, Dr. Michler said.
Designated discussant Dr. David Adams, director of Mount Sinai Hospital’s mitral valve repair reference center in New York, cautioned the audience on the length of the study and called for a full 5 years of follow-up rather than the 2 years as planned.
“Ischemic mitral regurgitation is a disease that hurts you over time. That’s in patients that have had MI, had previous CABG, had attempted mitral valve repair, and had PCI [percutaneous coronary intervention]. So we need much longer term follow-up of this very important data set to really understand its implications,” he said.
In light of roughly half of the patients being in heart failure at baseline, session cochair Dr. Robert Bonow, vice chair of medicine, Northwestern University, Chicago, questioned whether there were differences in outcomes related to changes in baseline ejection fraction (EF) or whether improvement in EF in patients with low EF correlated with reduction in mitral regurgitation with CABG alone.
What is known right now is that mean LVEF increased to the same degree after CABG in both groups, Dr. Michler responded. This was true despite this being a “sick population of patients,” with more than half having diabetes, 50% with heart failure, 20% with renal insufficiency, 10% with prior stroke, and a mean ejection fraction of 40% in both groups.
“What we have yet to identify and plan to explore is the correlation between reverse ventricular remodeling, ejection fraction, and outcome, meaning both the degree of mitral regurgitation and whether there is any signal with respect to repeat hospitalizations, heart failure, or possibly even mortality,” Dr. Michler said.
Both Dr. Michler and Dr. Adams remarked that surgery was extremely safe for the CABG alone and CABG plus MR groups, as reflected by the low mortality at 30 days (2.7% vs. 1.3%) and 1 year (7.3% vs. 6.7%).
The composite endpoint of major adverse cardiac or cerebrovascular events was also similar between groups.
The trial was funded by the National Institutes of Health and the Canadian Institutes for Health Research. Dr. Michler reported grant support from NIH during the conduct of the study. Dr. Adams reported coinventing a mitral valve repair ring.
CHICAGO – Early results from a randomized trial cast doubt on the benefits of routinely repairing a leaky mitral valve during coronary artery bypass grafting in patients with moderate ischemic mitral regurgitation.
At 1 year, there was no significant difference between patients undergoing CABG alone or CABG plus mitral repair in the primary endpoint of left ventricular reverse modeling, as defined by changes in LV end-systolic volume index (LVESVI) at 1 year (z score 0.50).
Both groups achieved significant reductions in LVESVI, with a median reduction of about 6 mL/m2 from baseline, Dr. Robert Michler, chair of cardiovascular and thoracic surgery at Montefiore Medical Center, New York, reported at the American Heart Association scientific sessions.
At 1 year, patients who underwent CABG and mitral valve repair had significantly less residual moderate or severe mitral regurgitation (11% vs. 31%; P < .001).
On the other hand, the combination procedure was associated with significantly higher rates of any neurologic event (9.6% vs. 3.1%; P = .03), longer cross-clamp (117 vs. 74 minutes) and cardiopulmonary bypass times (163 vs. 106 minutes; P values both < .001), and longer ICU (4.8 vs. 4.0 days; P = .006) and hospital length of stay (11.3 vs. 9.4 days; P = .002), according to the results, also published online (N. Engl. J. Med. 2014 [doi: 10.1056/NEJMoa1410490]).
“The trial did not demonstrate a clinically meaningful advantage to the routine addition of mitral valve repair to CABG,” Dr. Michler said, on behalf of the Cardiothoracic Surgical Trials Network investigators.
The 2014 AHA/American College of Cardiology mitral valve guidelines give a weak class IIb recommendation for mitral valve repair for patients with chronic mitral regurgitation (MR) who are undergoing other cardiac surgery, he noted.
The study evenly randomized 301 patients with moderate ischemic mitral regurgitation to CABG alone or CABG plus valve repair with an undersized ring (average, 28.3 mm for men and 27.1 mm for women).
The mean LVESVI at baseline was 54.8 mL/m2 in the CABG-alone group and 59.6 mL/m2 in the combined procedure group.
At 12 months, mean LVESVIs were 46.1 mL/m2 and 49.6 mL/m2, respectively.
The trial lacked a clinical primary endpoint, and longer follow-up is ongoing to determine whether the lower incidence of moderate or severe MR at 1 year will translate into a net clinical benefit for patients undergoing CABG plus mitral repair, Dr. Michler said.
Designated discussant Dr. David Adams, director of Mount Sinai Hospital’s mitral valve repair reference center in New York, cautioned the audience on the length of the study and called for a full 5 years of follow-up rather than the 2 years as planned.
“Ischemic mitral regurgitation is a disease that hurts you over time. That’s in patients that have had MI, had previous CABG, had attempted mitral valve repair, and had PCI [percutaneous coronary intervention]. So we need much longer term follow-up of this very important data set to really understand its implications,” he said.
In light of roughly half of the patients being in heart failure at baseline, session cochair Dr. Robert Bonow, vice chair of medicine, Northwestern University, Chicago, questioned whether there were differences in outcomes related to changes in baseline ejection fraction (EF) or whether improvement in EF in patients with low EF correlated with reduction in mitral regurgitation with CABG alone.
What is known right now is that mean LVEF increased to the same degree after CABG in both groups, Dr. Michler responded. This was true despite this being a “sick population of patients,” with more than half having diabetes, 50% with heart failure, 20% with renal insufficiency, 10% with prior stroke, and a mean ejection fraction of 40% in both groups.
“What we have yet to identify and plan to explore is the correlation between reverse ventricular remodeling, ejection fraction, and outcome, meaning both the degree of mitral regurgitation and whether there is any signal with respect to repeat hospitalizations, heart failure, or possibly even mortality,” Dr. Michler said.
Both Dr. Michler and Dr. Adams remarked that surgery was extremely safe for the CABG alone and CABG plus MR groups, as reflected by the low mortality at 30 days (2.7% vs. 1.3%) and 1 year (7.3% vs. 6.7%).
The composite endpoint of major adverse cardiac or cerebrovascular events was also similar between groups.
The trial was funded by the National Institutes of Health and the Canadian Institutes for Health Research. Dr. Michler reported grant support from NIH during the conduct of the study. Dr. Adams reported coinventing a mitral valve repair ring.
CHICAGO – Early results from a randomized trial cast doubt on the benefits of routinely repairing a leaky mitral valve during coronary artery bypass grafting in patients with moderate ischemic mitral regurgitation.
At 1 year, there was no significant difference between patients undergoing CABG alone or CABG plus mitral repair in the primary endpoint of left ventricular reverse modeling, as defined by changes in LV end-systolic volume index (LVESVI) at 1 year (z score 0.50).
Both groups achieved significant reductions in LVESVI, with a median reduction of about 6 mL/m2 from baseline, Dr. Robert Michler, chair of cardiovascular and thoracic surgery at Montefiore Medical Center, New York, reported at the American Heart Association scientific sessions.
At 1 year, patients who underwent CABG and mitral valve repair had significantly less residual moderate or severe mitral regurgitation (11% vs. 31%; P < .001).
On the other hand, the combination procedure was associated with significantly higher rates of any neurologic event (9.6% vs. 3.1%; P = .03), longer cross-clamp (117 vs. 74 minutes) and cardiopulmonary bypass times (163 vs. 106 minutes; P values both < .001), and longer ICU (4.8 vs. 4.0 days; P = .006) and hospital length of stay (11.3 vs. 9.4 days; P = .002), according to the results, also published online (N. Engl. J. Med. 2014 [doi: 10.1056/NEJMoa1410490]).
“The trial did not demonstrate a clinically meaningful advantage to the routine addition of mitral valve repair to CABG,” Dr. Michler said, on behalf of the Cardiothoracic Surgical Trials Network investigators.
The 2014 AHA/American College of Cardiology mitral valve guidelines give a weak class IIb recommendation for mitral valve repair for patients with chronic mitral regurgitation (MR) who are undergoing other cardiac surgery, he noted.
The study evenly randomized 301 patients with moderate ischemic mitral regurgitation to CABG alone or CABG plus valve repair with an undersized ring (average, 28.3 mm for men and 27.1 mm for women).
The mean LVESVI at baseline was 54.8 mL/m2 in the CABG-alone group and 59.6 mL/m2 in the combined procedure group.
At 12 months, mean LVESVIs were 46.1 mL/m2 and 49.6 mL/m2, respectively.
The trial lacked a clinical primary endpoint, and longer follow-up is ongoing to determine whether the lower incidence of moderate or severe MR at 1 year will translate into a net clinical benefit for patients undergoing CABG plus mitral repair, Dr. Michler said.
Designated discussant Dr. David Adams, director of Mount Sinai Hospital’s mitral valve repair reference center in New York, cautioned the audience on the length of the study and called for a full 5 years of follow-up rather than the 2 years as planned.
“Ischemic mitral regurgitation is a disease that hurts you over time. That’s in patients that have had MI, had previous CABG, had attempted mitral valve repair, and had PCI [percutaneous coronary intervention]. So we need much longer term follow-up of this very important data set to really understand its implications,” he said.
In light of roughly half of the patients being in heart failure at baseline, session cochair Dr. Robert Bonow, vice chair of medicine, Northwestern University, Chicago, questioned whether there were differences in outcomes related to changes in baseline ejection fraction (EF) or whether improvement in EF in patients with low EF correlated with reduction in mitral regurgitation with CABG alone.
What is known right now is that mean LVEF increased to the same degree after CABG in both groups, Dr. Michler responded. This was true despite this being a “sick population of patients,” with more than half having diabetes, 50% with heart failure, 20% with renal insufficiency, 10% with prior stroke, and a mean ejection fraction of 40% in both groups.
“What we have yet to identify and plan to explore is the correlation between reverse ventricular remodeling, ejection fraction, and outcome, meaning both the degree of mitral regurgitation and whether there is any signal with respect to repeat hospitalizations, heart failure, or possibly even mortality,” Dr. Michler said.
Both Dr. Michler and Dr. Adams remarked that surgery was extremely safe for the CABG alone and CABG plus MR groups, as reflected by the low mortality at 30 days (2.7% vs. 1.3%) and 1 year (7.3% vs. 6.7%).
The composite endpoint of major adverse cardiac or cerebrovascular events was also similar between groups.
The trial was funded by the National Institutes of Health and the Canadian Institutes for Health Research. Dr. Michler reported grant support from NIH during the conduct of the study. Dr. Adams reported coinventing a mitral valve repair ring.
AT THE AHA SCIENTIFIC SESSIONS 2014
Key clinical point: CABG plus mitral repair did not significantly improve left ventricular remodeling at 1 year, and was associated with some untoward events.
Major finding: At 12 months, mean LVESVI was 46.1 mL/m2 with CABG alone and 49.6 mL/m2 with CABG plus mitral repair.
Data source: A randomized trial in 301 patients with moderate mitral regurgitation.
Disclosures: The trial was funded by the National Institutes of Health and the Canadian Institutes for Health Research. Dr. Michler reported grant support from NIH during the conduct of the study. Dr. Adams reported coinventing a mitral valve repair ring.
Mechanical mitral valves outshine bioprostheses in long term
CHICAGO – Biologic prostheses in patients with severe ischemic mitral regurgitation undergoing mitral valve replacement were associated with worse valve hemodynamics and decreased functional capacity, compared with mechanical prostheses, long-term follow-up data showed.
Dr. Carlo Fino reported the results of a retrospective study involving 86 consecutive patients who received mitral valve replacement with either biologic (41) or mechanical (45) prostheses for chronic ischemic mitral valve regurgitation. Their mean age was 63 years and 60 were male.
Significantly more patients with mechanical bioprostheses had a history of heart failure (53% vs. 27%), but all other baseline demographic, clinical, and echocardiographic data were similar. Patients with atrial fibrillation were excluded from the study.
Operative variables were also similar between the mechanical and biologic groups including cardiopulmonary bypass time (mean, 85 vs. 82 minutes), aortic cross clamp time (mean, 71 vs. 68 minutes), arterial grafts per patient (1.2 for both groups), anastomoses per patient (2.7 vs. 2.4), and use of intra-aortic balloon pump (2 patients vs. 1 patient).
At 32 months’ follow-up, patients with mechanical versus biologic prostheses had significantly higher left ventricular ejection fraction (49% vs. 42%) and cardiac index (4.8 vs. 4.5 L/min per square meter) during exercise, Dr. Fino reported at the American Heart Association scientific sessions.
Systolic pulmonary arterial pressure increased modestly during exercise with a mechanical valve, but was significantly higher with a biologic valve (41 vs. 59 mm Hg), as was mitral peak gradient (11.26 vs. 16 mm Hg).
An interesting finding in the study was that effective orifice area and indexed effective orifice area both increased significantly during exercise with a mechanical prosthesis, but did not increase at all with a biologic prosthesis (2.2 vs. 1.8 cm2; 1.57 vs. 1.18 cm2/m2, respectively), said Dr. Fino of Azienda Ospedaliera Papa Giovanni XXIII, in Bergamo, Italy.
“We can’t explain why this effective area does not increase with the bioprosthesis,” he said.
The findings have not changed the center’s clinical approach, but warrant bigger, longer confirmatory studies, he said.
Dr. Fino and his coauthors reported having no relevant financial disclosures.
CHICAGO – Biologic prostheses in patients with severe ischemic mitral regurgitation undergoing mitral valve replacement were associated with worse valve hemodynamics and decreased functional capacity, compared with mechanical prostheses, long-term follow-up data showed.
Dr. Carlo Fino reported the results of a retrospective study involving 86 consecutive patients who received mitral valve replacement with either biologic (41) or mechanical (45) prostheses for chronic ischemic mitral valve regurgitation. Their mean age was 63 years and 60 were male.
Significantly more patients with mechanical bioprostheses had a history of heart failure (53% vs. 27%), but all other baseline demographic, clinical, and echocardiographic data were similar. Patients with atrial fibrillation were excluded from the study.
Operative variables were also similar between the mechanical and biologic groups including cardiopulmonary bypass time (mean, 85 vs. 82 minutes), aortic cross clamp time (mean, 71 vs. 68 minutes), arterial grafts per patient (1.2 for both groups), anastomoses per patient (2.7 vs. 2.4), and use of intra-aortic balloon pump (2 patients vs. 1 patient).
At 32 months’ follow-up, patients with mechanical versus biologic prostheses had significantly higher left ventricular ejection fraction (49% vs. 42%) and cardiac index (4.8 vs. 4.5 L/min per square meter) during exercise, Dr. Fino reported at the American Heart Association scientific sessions.
Systolic pulmonary arterial pressure increased modestly during exercise with a mechanical valve, but was significantly higher with a biologic valve (41 vs. 59 mm Hg), as was mitral peak gradient (11.26 vs. 16 mm Hg).
An interesting finding in the study was that effective orifice area and indexed effective orifice area both increased significantly during exercise with a mechanical prosthesis, but did not increase at all with a biologic prosthesis (2.2 vs. 1.8 cm2; 1.57 vs. 1.18 cm2/m2, respectively), said Dr. Fino of Azienda Ospedaliera Papa Giovanni XXIII, in Bergamo, Italy.
“We can’t explain why this effective area does not increase with the bioprosthesis,” he said.
The findings have not changed the center’s clinical approach, but warrant bigger, longer confirmatory studies, he said.
Dr. Fino and his coauthors reported having no relevant financial disclosures.
CHICAGO – Biologic prostheses in patients with severe ischemic mitral regurgitation undergoing mitral valve replacement were associated with worse valve hemodynamics and decreased functional capacity, compared with mechanical prostheses, long-term follow-up data showed.
Dr. Carlo Fino reported the results of a retrospective study involving 86 consecutive patients who received mitral valve replacement with either biologic (41) or mechanical (45) prostheses for chronic ischemic mitral valve regurgitation. Their mean age was 63 years and 60 were male.
Significantly more patients with mechanical bioprostheses had a history of heart failure (53% vs. 27%), but all other baseline demographic, clinical, and echocardiographic data were similar. Patients with atrial fibrillation were excluded from the study.
Operative variables were also similar between the mechanical and biologic groups including cardiopulmonary bypass time (mean, 85 vs. 82 minutes), aortic cross clamp time (mean, 71 vs. 68 minutes), arterial grafts per patient (1.2 for both groups), anastomoses per patient (2.7 vs. 2.4), and use of intra-aortic balloon pump (2 patients vs. 1 patient).
At 32 months’ follow-up, patients with mechanical versus biologic prostheses had significantly higher left ventricular ejection fraction (49% vs. 42%) and cardiac index (4.8 vs. 4.5 L/min per square meter) during exercise, Dr. Fino reported at the American Heart Association scientific sessions.
Systolic pulmonary arterial pressure increased modestly during exercise with a mechanical valve, but was significantly higher with a biologic valve (41 vs. 59 mm Hg), as was mitral peak gradient (11.26 vs. 16 mm Hg).
An interesting finding in the study was that effective orifice area and indexed effective orifice area both increased significantly during exercise with a mechanical prosthesis, but did not increase at all with a biologic prosthesis (2.2 vs. 1.8 cm2; 1.57 vs. 1.18 cm2/m2, respectively), said Dr. Fino of Azienda Ospedaliera Papa Giovanni XXIII, in Bergamo, Italy.
“We can’t explain why this effective area does not increase with the bioprosthesis,” he said.
The findings have not changed the center’s clinical approach, but warrant bigger, longer confirmatory studies, he said.
Dr. Fino and his coauthors reported having no relevant financial disclosures.
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point: Patients with severe mitral valve regurgitation implanted with a mechanical prosthesis appear to have better cardiovascular performance in the long term than those given biologic prostheses.
Major finding: Indexed effective orifice area increased significantly during exercise with a mechanical prosthesis versus a biologic one (1.57 vs. 1.18 cm2/m2).
Data source: A retrospective study in 86 consecutive patients undergoing mitral valve replacement for severe ischemic mitral regurgitation.
Disclosures: Dr. Fino and his coauthors reported having no relevant financial disclosures.
Ofatumumab maintenance halves risk of progression in relapsed CLL
SAN FRANCISCO – Ofatumumab maintenance therapy nearly doubled progression-free survival in patients with relapsed CLL, according to a preplanned interim analysis of the phase III PROLONG study.
At a median follow-up of 19.1 months, progression-free survival was 15.2 months with the standard approach of observation alone and 29.4 months with maintenance ofatumumab (Hazard ratio, 0.50; P < .0001).
Ofatumumab (Arzerra) also significantly increased the median time to next treatment from 31.1 months to 38 months (HR, 0.66; P = .0108), Dr. Marinus van Oers reported at the annual meeting of the American Society of Hematology.
The benefit in progression-free survival (PFS) with maintenance was “statistically significant and clinical relevant” and was present in all subgroups, he said. It was independent of age, gender, number and type of prior treatment, minimal residual disease status at study entry, and “response at study entry, although we have the impression that it’s more effective in patients on PR [partial response] than in patients on CR [complete response],” he added.
The rationale for the trial lies in the fact that despite recent advances, there is still no curative treatment for chronic lymphocytic leukemia (CLL). Ofatumumab, a type 1 CD20 monoclonal antibody, has a role as maintenance in follicular lymphoma (FL), which shares similarities in biological behavior with CLL. This role is debated, but a recent meta-analysis shows ofatumumab maintenance prolongs PFS and tends to prolong overall survival in relapsed patients with FL, Dr. van Oers of the Academic Medical Center in Amsterdam, The Netherlands, observed.
PROLONG randomized 474 patients with relapsed CLL to observation or ofatumumab 300 mg in week 1 and 1,000 mg in week 2, and every 8 weeks for 2 years. All patients were in second or third remission and within 3 months of response assessment after the last reinduction treatment. Patients with refractory disease or prior maintenance therapy or stem cell transplantation were excluded.
At baseline, the median age was about 65 years, 70% had at least two prior treatments, 80% were in partial remission from their last CLL treatment, and less than 10% had poor-risk cytogenetics 11p or 17p deletions. At the time of the analysis, 25% of patients had received all 13 cycles of ofatumumab.
Adverse events of any grade were increased with the addition of ofatumumab versus placebo (86% vs. 72%; P < .0001). Sixty percent were related to study treatment, but none resulted in study withdrawal, Dr. van Oers said. In all, 17 patients on the experimental arm dropped out due to physician decision or patient wish.
Among grade 3 events, neutropenia was significantly increased with maintenance therapy versus placebo (24% vs. 10%; P < .0001) and there was a non-significant increase in infections (13% vs. 8%). Five deaths occurred in the observation arm and two in the ofatumumab arm, one due to sepsis two months after the end of treatment and the other due to unrelated GI obstruction.
Median overall survival has not been reached for either arm (HR, 0.85; P = .487), he reported on behalf of HOVON and the NORDIC CLL group, co-developers of the study.
SAN FRANCISCO – Ofatumumab maintenance therapy nearly doubled progression-free survival in patients with relapsed CLL, according to a preplanned interim analysis of the phase III PROLONG study.
At a median follow-up of 19.1 months, progression-free survival was 15.2 months with the standard approach of observation alone and 29.4 months with maintenance ofatumumab (Hazard ratio, 0.50; P < .0001).
Ofatumumab (Arzerra) also significantly increased the median time to next treatment from 31.1 months to 38 months (HR, 0.66; P = .0108), Dr. Marinus van Oers reported at the annual meeting of the American Society of Hematology.
The benefit in progression-free survival (PFS) with maintenance was “statistically significant and clinical relevant” and was present in all subgroups, he said. It was independent of age, gender, number and type of prior treatment, minimal residual disease status at study entry, and “response at study entry, although we have the impression that it’s more effective in patients on PR [partial response] than in patients on CR [complete response],” he added.
The rationale for the trial lies in the fact that despite recent advances, there is still no curative treatment for chronic lymphocytic leukemia (CLL). Ofatumumab, a type 1 CD20 monoclonal antibody, has a role as maintenance in follicular lymphoma (FL), which shares similarities in biological behavior with CLL. This role is debated, but a recent meta-analysis shows ofatumumab maintenance prolongs PFS and tends to prolong overall survival in relapsed patients with FL, Dr. van Oers of the Academic Medical Center in Amsterdam, The Netherlands, observed.
PROLONG randomized 474 patients with relapsed CLL to observation or ofatumumab 300 mg in week 1 and 1,000 mg in week 2, and every 8 weeks for 2 years. All patients were in second or third remission and within 3 months of response assessment after the last reinduction treatment. Patients with refractory disease or prior maintenance therapy or stem cell transplantation were excluded.
At baseline, the median age was about 65 years, 70% had at least two prior treatments, 80% were in partial remission from their last CLL treatment, and less than 10% had poor-risk cytogenetics 11p or 17p deletions. At the time of the analysis, 25% of patients had received all 13 cycles of ofatumumab.
Adverse events of any grade were increased with the addition of ofatumumab versus placebo (86% vs. 72%; P < .0001). Sixty percent were related to study treatment, but none resulted in study withdrawal, Dr. van Oers said. In all, 17 patients on the experimental arm dropped out due to physician decision or patient wish.
Among grade 3 events, neutropenia was significantly increased with maintenance therapy versus placebo (24% vs. 10%; P < .0001) and there was a non-significant increase in infections (13% vs. 8%). Five deaths occurred in the observation arm and two in the ofatumumab arm, one due to sepsis two months after the end of treatment and the other due to unrelated GI obstruction.
Median overall survival has not been reached for either arm (HR, 0.85; P = .487), he reported on behalf of HOVON and the NORDIC CLL group, co-developers of the study.
SAN FRANCISCO – Ofatumumab maintenance therapy nearly doubled progression-free survival in patients with relapsed CLL, according to a preplanned interim analysis of the phase III PROLONG study.
At a median follow-up of 19.1 months, progression-free survival was 15.2 months with the standard approach of observation alone and 29.4 months with maintenance ofatumumab (Hazard ratio, 0.50; P < .0001).
Ofatumumab (Arzerra) also significantly increased the median time to next treatment from 31.1 months to 38 months (HR, 0.66; P = .0108), Dr. Marinus van Oers reported at the annual meeting of the American Society of Hematology.
The benefit in progression-free survival (PFS) with maintenance was “statistically significant and clinical relevant” and was present in all subgroups, he said. It was independent of age, gender, number and type of prior treatment, minimal residual disease status at study entry, and “response at study entry, although we have the impression that it’s more effective in patients on PR [partial response] than in patients on CR [complete response],” he added.
The rationale for the trial lies in the fact that despite recent advances, there is still no curative treatment for chronic lymphocytic leukemia (CLL). Ofatumumab, a type 1 CD20 monoclonal antibody, has a role as maintenance in follicular lymphoma (FL), which shares similarities in biological behavior with CLL. This role is debated, but a recent meta-analysis shows ofatumumab maintenance prolongs PFS and tends to prolong overall survival in relapsed patients with FL, Dr. van Oers of the Academic Medical Center in Amsterdam, The Netherlands, observed.
PROLONG randomized 474 patients with relapsed CLL to observation or ofatumumab 300 mg in week 1 and 1,000 mg in week 2, and every 8 weeks for 2 years. All patients were in second or third remission and within 3 months of response assessment after the last reinduction treatment. Patients with refractory disease or prior maintenance therapy or stem cell transplantation were excluded.
At baseline, the median age was about 65 years, 70% had at least two prior treatments, 80% were in partial remission from their last CLL treatment, and less than 10% had poor-risk cytogenetics 11p or 17p deletions. At the time of the analysis, 25% of patients had received all 13 cycles of ofatumumab.
Adverse events of any grade were increased with the addition of ofatumumab versus placebo (86% vs. 72%; P < .0001). Sixty percent were related to study treatment, but none resulted in study withdrawal, Dr. van Oers said. In all, 17 patients on the experimental arm dropped out due to physician decision or patient wish.
Among grade 3 events, neutropenia was significantly increased with maintenance therapy versus placebo (24% vs. 10%; P < .0001) and there was a non-significant increase in infections (13% vs. 8%). Five deaths occurred in the observation arm and two in the ofatumumab arm, one due to sepsis two months after the end of treatment and the other due to unrelated GI obstruction.
Median overall survival has not been reached for either arm (HR, 0.85; P = .487), he reported on behalf of HOVON and the NORDIC CLL group, co-developers of the study.
AT ASH 2014
Key clinical point: Maintenance ofatumumab cuts the risk of progression in half among patients with relapsed CLL.
Major finding: Progression-free survival was 15.2 months with observation alone and 29.4 months with maintenance ofatumumab (Hazard ratio, 0.50; P < .0001).
Data source: Randomized phase III trial in 474 patients with relapsed CLL.
Disclosures: GlaxoSmithKline sponsored the study. Dr. van Oers reported having no financial disclosures.
Brentuximab changes landscape for post-transplant Hodgkin’s lymphoma patients
SAN FRANCISCO – Early post-transplant brentuximab vedotin dramatically slows Hodgkin’s lymphoma progression in patients at high risk for relapse or progression, the phase III AETHERA study shows.
After a median follow-up of about 28 months, the primary end point of progression-free survival (PFS) per independent review increased from a median of 24 months with placebo and best supportive care (BSC) to 43 months with brentuximab and BSC (Hazard ratio, 0.57; P = .001).
Per investigator assessment, median PFS was 16 months with placebo and had not been reached with brentuximab (HR, 0.50),Dr. Craig Moskowitz reported at the annual meeting of the American Society of Hematology.
The benefit of brentuximab maintenance was consistent across every subgroup. Historically, roughly half of patients who undergo an autologous stem cell transplant will relapse.
“Once this study is published, in patients who met eligibility criteria to be on this study - and once again I’ll remind you that’s remission duration less than one year, disease outside the lymph node system, or primary refractory disease - in my opinion, this will be the standard of care,” Dr. Moskowitz said during a press briefing.
Brentuximab, an anti-CD30 antibody conjugate, is already approved in the U.S. for the management of Hodgkin’s lymphoma (HL) after failure of autologous stem cell transplantation (ASCT) or at least two prior lines of multi-agent chemotherapy in patients ineligible for ASCT.
Brentuximab is also indicated for systemic anaplastic large cell lymphoma after failure of at least one multi-agent chemotherapy regimen.
In September it was announced that AETHERA met its primary end point, but this was the first full look at the absolute survival rates and safety data.
The 2-year PFS rate for the brentuximab and placebo groups is now 63% vs. 51% per independent review and 65% vs. 45% per investigator.
“The bottom line is there’s a 20% difference in progression-free survival at 2 years upon investigator review. This has never been seen in patients with relapsed, refractory lymphoma, let alone Hodgkin lymphoma,” Dr. Moskowitz, clinical director of hematology oncology at Memorial Sloan-Kettering Cancer Center in New York City, said.
Overall survival data are immature, but was the same in both groups at 2 years (P = .62). The likelihood of showing a survival difference was not expected because 85% of patients who relapsed on the placebo arm crossed over to brentuximab, as allowed per protocol, and it’s known that brentuximab alone in auto-transplant failures improves outcomes by at least a year, he said. Also, twice as many patients who failed placebo received a second transplant.
Dr. Moskowitz stressed that nearly every patient in the trial had at least three risk factors that would place them at high risk of treatment failure and that studies have shown that for patients with this many risk factors, the chance of being cured by an auto-transplant is about 25%. The risk factors are: relapsed less than 12 months or refractory to frontline therapy, best response of partial remission or stable disease to most recent salvage therapy, extranodal disease at pre-ASCT relapse, B symptoms at pre-ASCT relapse, or two or more prior salvage therapies.
Press briefing moderator Dr. Brad Kahl of the University of Wisconsin-Madison, said Aethera is the first study to show a significant benefit for a post-transplant strategy.
“The biggest question in my mind is whether the application of maintenance brentuximab vedotin is just delaying the inevitable relapse, so the patients will still relapse, just later, or has the brentuximab taken patients who are destined to relapse and turned them into a cured patient,” Dr. Kahl said. “We don’t know the answer to that question. That will become apparent with more time.”
Dr. Moscowitz observed that relapses almost never happen after two year, adding, “So if you’re in remission at two years after stem cell transplantation for Hodgkin lymphoma, you are likely to be cured.”
AETHERA enrolled 329 patients with Hodgkin’s lymphoma and randomly assigned them after ASCT to brentuximab vedotin 1.8 mg/kg or placebo given every 3 weeks for up to 16 cycles, plus BSC. All patients were required to have achieved a complete response, partial remission, or stable disease to salvage therapy prior to ASCT. Their median age was 32 years and 53% were male.
Roughly 60% were refractory to upfront therapy, 43% in the brentuximab arm and 48% of controls had received 2 or more prior systemic therapies, and a third in each arm had extranodal involvement.
Consolidation therapy with brentuximab was generally well tolerated, Dr. Moskowitz said. Peripheral sensory neuropathy was the most common side effect, experienced at any grade in 67% on brentuximab vs. 19% of controls and at grade 3 in 13% vs. 1%. There were no grade 4 events and 85% of patients had resolution or improvement with dose reductions or stopping the drug.
Other adverse events in the brentuximab and control groups were neutropenia (35% vs. 12%), upper respiratory tract infections (26% vs. 23%), and fatigue (24% vs. 18%). Two patients died within 40 days of dosing with brentuximab, one from treatment-related acute respiratory distress syndrome associated with pneumonitis and one following an episode of treatment-related acute pancreatitis that had resolved at the time of death, he reported.
Based on the results, study sponsor Seattle Genetics is expected to seek approval for brentuximab in this consolidation setting in the first half of 2015, according to a statement from the company. The ongoing phase III ECHELON-1 and ECHELON 2 trials in HL and mature T-cell lymphomas are looking at the use of brentuximab in frontline disease.
SAN FRANCISCO – Early post-transplant brentuximab vedotin dramatically slows Hodgkin’s lymphoma progression in patients at high risk for relapse or progression, the phase III AETHERA study shows.
After a median follow-up of about 28 months, the primary end point of progression-free survival (PFS) per independent review increased from a median of 24 months with placebo and best supportive care (BSC) to 43 months with brentuximab and BSC (Hazard ratio, 0.57; P = .001).
Per investigator assessment, median PFS was 16 months with placebo and had not been reached with brentuximab (HR, 0.50),Dr. Craig Moskowitz reported at the annual meeting of the American Society of Hematology.
The benefit of brentuximab maintenance was consistent across every subgroup. Historically, roughly half of patients who undergo an autologous stem cell transplant will relapse.
“Once this study is published, in patients who met eligibility criteria to be on this study - and once again I’ll remind you that’s remission duration less than one year, disease outside the lymph node system, or primary refractory disease - in my opinion, this will be the standard of care,” Dr. Moskowitz said during a press briefing.
Brentuximab, an anti-CD30 antibody conjugate, is already approved in the U.S. for the management of Hodgkin’s lymphoma (HL) after failure of autologous stem cell transplantation (ASCT) or at least two prior lines of multi-agent chemotherapy in patients ineligible for ASCT.
Brentuximab is also indicated for systemic anaplastic large cell lymphoma after failure of at least one multi-agent chemotherapy regimen.
In September it was announced that AETHERA met its primary end point, but this was the first full look at the absolute survival rates and safety data.
The 2-year PFS rate for the brentuximab and placebo groups is now 63% vs. 51% per independent review and 65% vs. 45% per investigator.
“The bottom line is there’s a 20% difference in progression-free survival at 2 years upon investigator review. This has never been seen in patients with relapsed, refractory lymphoma, let alone Hodgkin lymphoma,” Dr. Moskowitz, clinical director of hematology oncology at Memorial Sloan-Kettering Cancer Center in New York City, said.
Overall survival data are immature, but was the same in both groups at 2 years (P = .62). The likelihood of showing a survival difference was not expected because 85% of patients who relapsed on the placebo arm crossed over to brentuximab, as allowed per protocol, and it’s known that brentuximab alone in auto-transplant failures improves outcomes by at least a year, he said. Also, twice as many patients who failed placebo received a second transplant.
Dr. Moskowitz stressed that nearly every patient in the trial had at least three risk factors that would place them at high risk of treatment failure and that studies have shown that for patients with this many risk factors, the chance of being cured by an auto-transplant is about 25%. The risk factors are: relapsed less than 12 months or refractory to frontline therapy, best response of partial remission or stable disease to most recent salvage therapy, extranodal disease at pre-ASCT relapse, B symptoms at pre-ASCT relapse, or two or more prior salvage therapies.
Press briefing moderator Dr. Brad Kahl of the University of Wisconsin-Madison, said Aethera is the first study to show a significant benefit for a post-transplant strategy.
“The biggest question in my mind is whether the application of maintenance brentuximab vedotin is just delaying the inevitable relapse, so the patients will still relapse, just later, or has the brentuximab taken patients who are destined to relapse and turned them into a cured patient,” Dr. Kahl said. “We don’t know the answer to that question. That will become apparent with more time.”
Dr. Moscowitz observed that relapses almost never happen after two year, adding, “So if you’re in remission at two years after stem cell transplantation for Hodgkin lymphoma, you are likely to be cured.”
AETHERA enrolled 329 patients with Hodgkin’s lymphoma and randomly assigned them after ASCT to brentuximab vedotin 1.8 mg/kg or placebo given every 3 weeks for up to 16 cycles, plus BSC. All patients were required to have achieved a complete response, partial remission, or stable disease to salvage therapy prior to ASCT. Their median age was 32 years and 53% were male.
Roughly 60% were refractory to upfront therapy, 43% in the brentuximab arm and 48% of controls had received 2 or more prior systemic therapies, and a third in each arm had extranodal involvement.
Consolidation therapy with brentuximab was generally well tolerated, Dr. Moskowitz said. Peripheral sensory neuropathy was the most common side effect, experienced at any grade in 67% on brentuximab vs. 19% of controls and at grade 3 in 13% vs. 1%. There were no grade 4 events and 85% of patients had resolution or improvement with dose reductions or stopping the drug.
Other adverse events in the brentuximab and control groups were neutropenia (35% vs. 12%), upper respiratory tract infections (26% vs. 23%), and fatigue (24% vs. 18%). Two patients died within 40 days of dosing with brentuximab, one from treatment-related acute respiratory distress syndrome associated with pneumonitis and one following an episode of treatment-related acute pancreatitis that had resolved at the time of death, he reported.
Based on the results, study sponsor Seattle Genetics is expected to seek approval for brentuximab in this consolidation setting in the first half of 2015, according to a statement from the company. The ongoing phase III ECHELON-1 and ECHELON 2 trials in HL and mature T-cell lymphomas are looking at the use of brentuximab in frontline disease.
SAN FRANCISCO – Early post-transplant brentuximab vedotin dramatically slows Hodgkin’s lymphoma progression in patients at high risk for relapse or progression, the phase III AETHERA study shows.
After a median follow-up of about 28 months, the primary end point of progression-free survival (PFS) per independent review increased from a median of 24 months with placebo and best supportive care (BSC) to 43 months with brentuximab and BSC (Hazard ratio, 0.57; P = .001).
Per investigator assessment, median PFS was 16 months with placebo and had not been reached with brentuximab (HR, 0.50),Dr. Craig Moskowitz reported at the annual meeting of the American Society of Hematology.
The benefit of brentuximab maintenance was consistent across every subgroup. Historically, roughly half of patients who undergo an autologous stem cell transplant will relapse.
“Once this study is published, in patients who met eligibility criteria to be on this study - and once again I’ll remind you that’s remission duration less than one year, disease outside the lymph node system, or primary refractory disease - in my opinion, this will be the standard of care,” Dr. Moskowitz said during a press briefing.
Brentuximab, an anti-CD30 antibody conjugate, is already approved in the U.S. for the management of Hodgkin’s lymphoma (HL) after failure of autologous stem cell transplantation (ASCT) or at least two prior lines of multi-agent chemotherapy in patients ineligible for ASCT.
Brentuximab is also indicated for systemic anaplastic large cell lymphoma after failure of at least one multi-agent chemotherapy regimen.
In September it was announced that AETHERA met its primary end point, but this was the first full look at the absolute survival rates and safety data.
The 2-year PFS rate for the brentuximab and placebo groups is now 63% vs. 51% per independent review and 65% vs. 45% per investigator.
“The bottom line is there’s a 20% difference in progression-free survival at 2 years upon investigator review. This has never been seen in patients with relapsed, refractory lymphoma, let alone Hodgkin lymphoma,” Dr. Moskowitz, clinical director of hematology oncology at Memorial Sloan-Kettering Cancer Center in New York City, said.
Overall survival data are immature, but was the same in both groups at 2 years (P = .62). The likelihood of showing a survival difference was not expected because 85% of patients who relapsed on the placebo arm crossed over to brentuximab, as allowed per protocol, and it’s known that brentuximab alone in auto-transplant failures improves outcomes by at least a year, he said. Also, twice as many patients who failed placebo received a second transplant.
Dr. Moskowitz stressed that nearly every patient in the trial had at least three risk factors that would place them at high risk of treatment failure and that studies have shown that for patients with this many risk factors, the chance of being cured by an auto-transplant is about 25%. The risk factors are: relapsed less than 12 months or refractory to frontline therapy, best response of partial remission or stable disease to most recent salvage therapy, extranodal disease at pre-ASCT relapse, B symptoms at pre-ASCT relapse, or two or more prior salvage therapies.
Press briefing moderator Dr. Brad Kahl of the University of Wisconsin-Madison, said Aethera is the first study to show a significant benefit for a post-transplant strategy.
“The biggest question in my mind is whether the application of maintenance brentuximab vedotin is just delaying the inevitable relapse, so the patients will still relapse, just later, or has the brentuximab taken patients who are destined to relapse and turned them into a cured patient,” Dr. Kahl said. “We don’t know the answer to that question. That will become apparent with more time.”
Dr. Moscowitz observed that relapses almost never happen after two year, adding, “So if you’re in remission at two years after stem cell transplantation for Hodgkin lymphoma, you are likely to be cured.”
AETHERA enrolled 329 patients with Hodgkin’s lymphoma and randomly assigned them after ASCT to brentuximab vedotin 1.8 mg/kg or placebo given every 3 weeks for up to 16 cycles, plus BSC. All patients were required to have achieved a complete response, partial remission, or stable disease to salvage therapy prior to ASCT. Their median age was 32 years and 53% were male.
Roughly 60% were refractory to upfront therapy, 43% in the brentuximab arm and 48% of controls had received 2 or more prior systemic therapies, and a third in each arm had extranodal involvement.
Consolidation therapy with brentuximab was generally well tolerated, Dr. Moskowitz said. Peripheral sensory neuropathy was the most common side effect, experienced at any grade in 67% on brentuximab vs. 19% of controls and at grade 3 in 13% vs. 1%. There were no grade 4 events and 85% of patients had resolution or improvement with dose reductions or stopping the drug.
Other adverse events in the brentuximab and control groups were neutropenia (35% vs. 12%), upper respiratory tract infections (26% vs. 23%), and fatigue (24% vs. 18%). Two patients died within 40 days of dosing with brentuximab, one from treatment-related acute respiratory distress syndrome associated with pneumonitis and one following an episode of treatment-related acute pancreatitis that had resolved at the time of death, he reported.
Based on the results, study sponsor Seattle Genetics is expected to seek approval for brentuximab in this consolidation setting in the first half of 2015, according to a statement from the company. The ongoing phase III ECHELON-1 and ECHELON 2 trials in HL and mature T-cell lymphomas are looking at the use of brentuximab in frontline disease.
AT ASH 2014
Key clinical point: Brentuximab vedotin given immediately post-transplant significantly improves progression-free survival in patients with Hodgkin’s lymphoma at high risk for progression.
Major finding: Median progression-free survival per independent review was 24 months with placebo vs. 43 months with brentuximab (HR, 0.57; P = .001).
Data source: Randomized, double-blind, phase III study in 329 patients with Hodgkin’s lymphoma.
Disclosures: Seattle Genetics sponsored the study. Dr. Moskowitz reported research funding from Genentech and Merck, and research funding from and consultancy for Seattle Genetics. Several co-authors reported financial ties with industry, including employment with or equity ownership in Seattle Genetics.
Coordinated regional STEMI care delivers dividends
CHICAGO – Regional coordination of emergency care provided modest but significant improvements in timely reperfusion of patients with ST-elevation myocardial infarction.
In the massive Mission Lifeline: STEMI Accelerator project, in-hospital mortality was 3.6% for patients who spent 30 minutes or less between the hospital door and cardiac catheter lab door, compared with 7% for those with times spent in the emergency department of 30-45 minutes and 10.8% for patients with ED times of more than 45 minutes (P < .001), after adjustment for clinical risk factors such as cardiac arrest and cardiogenic shock among patients presenting directly to a percutaneous coronary intervention–capable hospital via emergency medical services.
“While this relationship may have residual confounding, we believe that it shows ED time is an important indicator of the coordination of care,” Dr. Matthew Sherwood said at the American Heart Association scientific sessions.
The American College of Cardiology Foundation/AHA guidelines recommend the use of regional systems of care for STEMI patients and set a system goal for first medical contact to device time of 90 minutes or less for patients presenting directly to a percutaneous intervention–capable hospital and 120 minutes or less for those transferred from a non-PCI hospital to a PCI facility.
Only half of patients are treated within guideline goals, largely because of delays related to fragmentation of the health care system and lack of coordination between EMS agencies and acute care hospitals, said Dr. Sherwood, an interventional cardiology fellow with Duke University in Durham, N.C. For example, only 17% of EMS agencies can preactivate cardiac catheter labs in all receiving hospitals.
The STEMI Accelerator study sought to improve STEMI care between 484 hospitals and 1,253 EMS agencies in 16 cities, including New York, St. Louis, Pittsburgh, and Houston, representing roughly 10% of the U.S. population.
Leaders of emergency medical services, ED physicians, and interventional cardiologists were brought together in each region to identify areas for improvement and establish a regional coordinator who would implement a feedback system. They also developed a uniform protocol for preactivation for STEMI by EMS providers and coordinated a plan for rapid transfer of all STEMI patients to appropriate facilities.
At least 70% of PCI centers were also required to enroll in the National Cardiovascular Data Registry–Action GWTG registry for data collection, Dr. Sherwood said.
The Mission Lifeline: STEMI Systems Accelerator operations manual was also distributed at the national level to assist regions in developing their own, more individualized protocols. In New York City, that involved 16 PCI hospitals in downtown Manhattan developing a plan for STEMI patients to bypass the ED and go directly to the catheter lab – a move that has paid off in improved time to device delivery, he said.
The analysis included 23,809 patients with STEMI treated from the third quarter of 2012 to the first quarter of 2014. Of these, 11,765 presented directly to a PCI center via EMS, 6,502 presented to a PCI center via their own transportation, and 5,542 transferred from a non–PCI capable facility for further care. Their median age was 60 years, 29% were female, and 16% had no insurance.
For all three patient groups, there was a modest, but significant improvement from baseline to Q1 2014 in the percentage of patients meeting first medical contact to device time goals, including: direct-presenting patients (62% vs. 65%; P = .025), direct-presenting patients transported by EMS (54% vs. 59%; P = .0046), and patients requiring hospital transfer (50% vs. 53%; P = .007), Dr. Sherwood reported.
While the overall study showed modest improvements, there was a significant amount of variation in regional time and performance improvements. For example, among patients presenting directly to a PCI hospital, some regions showed up to 20% increases in the proportion of patients treated within guideline goals, he said.
Unadjusted in-hospital mortality also declined over the study period for participating regions, compared with national rates, suggesting that regional STEMI programs can provide important improvements to public health, Dr. Sherwood concluded.
Speaking as a practitioner in one of the contributing hospitals, panelist Dr. Roxana Mehran of Mount Sinai Hospital in New York, said that the STEMI program was invaluable in expanding their focus beyond door to balloon time.
“This particular program was extremely helpful for us in not just the timing of getting the patient, but also on the post discharge, which is also a part of this program,” she said. “I must tell you it had a huge impact, and we saw our numbers change dramatically just over the few quarters we saw patients.”
The Medicines Company, AstraZeneca, Philips Healthcare, and Abiomed sponsored the study. Dr. Sherwood reported no relevant financial relationships.
CHICAGO – Regional coordination of emergency care provided modest but significant improvements in timely reperfusion of patients with ST-elevation myocardial infarction.
In the massive Mission Lifeline: STEMI Accelerator project, in-hospital mortality was 3.6% for patients who spent 30 minutes or less between the hospital door and cardiac catheter lab door, compared with 7% for those with times spent in the emergency department of 30-45 minutes and 10.8% for patients with ED times of more than 45 minutes (P < .001), after adjustment for clinical risk factors such as cardiac arrest and cardiogenic shock among patients presenting directly to a percutaneous coronary intervention–capable hospital via emergency medical services.
“While this relationship may have residual confounding, we believe that it shows ED time is an important indicator of the coordination of care,” Dr. Matthew Sherwood said at the American Heart Association scientific sessions.
The American College of Cardiology Foundation/AHA guidelines recommend the use of regional systems of care for STEMI patients and set a system goal for first medical contact to device time of 90 minutes or less for patients presenting directly to a percutaneous intervention–capable hospital and 120 minutes or less for those transferred from a non-PCI hospital to a PCI facility.
Only half of patients are treated within guideline goals, largely because of delays related to fragmentation of the health care system and lack of coordination between EMS agencies and acute care hospitals, said Dr. Sherwood, an interventional cardiology fellow with Duke University in Durham, N.C. For example, only 17% of EMS agencies can preactivate cardiac catheter labs in all receiving hospitals.
The STEMI Accelerator study sought to improve STEMI care between 484 hospitals and 1,253 EMS agencies in 16 cities, including New York, St. Louis, Pittsburgh, and Houston, representing roughly 10% of the U.S. population.
Leaders of emergency medical services, ED physicians, and interventional cardiologists were brought together in each region to identify areas for improvement and establish a regional coordinator who would implement a feedback system. They also developed a uniform protocol for preactivation for STEMI by EMS providers and coordinated a plan for rapid transfer of all STEMI patients to appropriate facilities.
At least 70% of PCI centers were also required to enroll in the National Cardiovascular Data Registry–Action GWTG registry for data collection, Dr. Sherwood said.
The Mission Lifeline: STEMI Systems Accelerator operations manual was also distributed at the national level to assist regions in developing their own, more individualized protocols. In New York City, that involved 16 PCI hospitals in downtown Manhattan developing a plan for STEMI patients to bypass the ED and go directly to the catheter lab – a move that has paid off in improved time to device delivery, he said.
The analysis included 23,809 patients with STEMI treated from the third quarter of 2012 to the first quarter of 2014. Of these, 11,765 presented directly to a PCI center via EMS, 6,502 presented to a PCI center via their own transportation, and 5,542 transferred from a non–PCI capable facility for further care. Their median age was 60 years, 29% were female, and 16% had no insurance.
For all three patient groups, there was a modest, but significant improvement from baseline to Q1 2014 in the percentage of patients meeting first medical contact to device time goals, including: direct-presenting patients (62% vs. 65%; P = .025), direct-presenting patients transported by EMS (54% vs. 59%; P = .0046), and patients requiring hospital transfer (50% vs. 53%; P = .007), Dr. Sherwood reported.
While the overall study showed modest improvements, there was a significant amount of variation in regional time and performance improvements. For example, among patients presenting directly to a PCI hospital, some regions showed up to 20% increases in the proportion of patients treated within guideline goals, he said.
Unadjusted in-hospital mortality also declined over the study period for participating regions, compared with national rates, suggesting that regional STEMI programs can provide important improvements to public health, Dr. Sherwood concluded.
Speaking as a practitioner in one of the contributing hospitals, panelist Dr. Roxana Mehran of Mount Sinai Hospital in New York, said that the STEMI program was invaluable in expanding their focus beyond door to balloon time.
“This particular program was extremely helpful for us in not just the timing of getting the patient, but also on the post discharge, which is also a part of this program,” she said. “I must tell you it had a huge impact, and we saw our numbers change dramatically just over the few quarters we saw patients.”
The Medicines Company, AstraZeneca, Philips Healthcare, and Abiomed sponsored the study. Dr. Sherwood reported no relevant financial relationships.
CHICAGO – Regional coordination of emergency care provided modest but significant improvements in timely reperfusion of patients with ST-elevation myocardial infarction.
In the massive Mission Lifeline: STEMI Accelerator project, in-hospital mortality was 3.6% for patients who spent 30 minutes or less between the hospital door and cardiac catheter lab door, compared with 7% for those with times spent in the emergency department of 30-45 minutes and 10.8% for patients with ED times of more than 45 minutes (P < .001), after adjustment for clinical risk factors such as cardiac arrest and cardiogenic shock among patients presenting directly to a percutaneous coronary intervention–capable hospital via emergency medical services.
“While this relationship may have residual confounding, we believe that it shows ED time is an important indicator of the coordination of care,” Dr. Matthew Sherwood said at the American Heart Association scientific sessions.
The American College of Cardiology Foundation/AHA guidelines recommend the use of regional systems of care for STEMI patients and set a system goal for first medical contact to device time of 90 minutes or less for patients presenting directly to a percutaneous intervention–capable hospital and 120 minutes or less for those transferred from a non-PCI hospital to a PCI facility.
Only half of patients are treated within guideline goals, largely because of delays related to fragmentation of the health care system and lack of coordination between EMS agencies and acute care hospitals, said Dr. Sherwood, an interventional cardiology fellow with Duke University in Durham, N.C. For example, only 17% of EMS agencies can preactivate cardiac catheter labs in all receiving hospitals.
The STEMI Accelerator study sought to improve STEMI care between 484 hospitals and 1,253 EMS agencies in 16 cities, including New York, St. Louis, Pittsburgh, and Houston, representing roughly 10% of the U.S. population.
Leaders of emergency medical services, ED physicians, and interventional cardiologists were brought together in each region to identify areas for improvement and establish a regional coordinator who would implement a feedback system. They also developed a uniform protocol for preactivation for STEMI by EMS providers and coordinated a plan for rapid transfer of all STEMI patients to appropriate facilities.
At least 70% of PCI centers were also required to enroll in the National Cardiovascular Data Registry–Action GWTG registry for data collection, Dr. Sherwood said.
The Mission Lifeline: STEMI Systems Accelerator operations manual was also distributed at the national level to assist regions in developing their own, more individualized protocols. In New York City, that involved 16 PCI hospitals in downtown Manhattan developing a plan for STEMI patients to bypass the ED and go directly to the catheter lab – a move that has paid off in improved time to device delivery, he said.
The analysis included 23,809 patients with STEMI treated from the third quarter of 2012 to the first quarter of 2014. Of these, 11,765 presented directly to a PCI center via EMS, 6,502 presented to a PCI center via their own transportation, and 5,542 transferred from a non–PCI capable facility for further care. Their median age was 60 years, 29% were female, and 16% had no insurance.
For all three patient groups, there was a modest, but significant improvement from baseline to Q1 2014 in the percentage of patients meeting first medical contact to device time goals, including: direct-presenting patients (62% vs. 65%; P = .025), direct-presenting patients transported by EMS (54% vs. 59%; P = .0046), and patients requiring hospital transfer (50% vs. 53%; P = .007), Dr. Sherwood reported.
While the overall study showed modest improvements, there was a significant amount of variation in regional time and performance improvements. For example, among patients presenting directly to a PCI hospital, some regions showed up to 20% increases in the proportion of patients treated within guideline goals, he said.
Unadjusted in-hospital mortality also declined over the study period for participating regions, compared with national rates, suggesting that regional STEMI programs can provide important improvements to public health, Dr. Sherwood concluded.
Speaking as a practitioner in one of the contributing hospitals, panelist Dr. Roxana Mehran of Mount Sinai Hospital in New York, said that the STEMI program was invaluable in expanding their focus beyond door to balloon time.
“This particular program was extremely helpful for us in not just the timing of getting the patient, but also on the post discharge, which is also a part of this program,” she said. “I must tell you it had a huge impact, and we saw our numbers change dramatically just over the few quarters we saw patients.”
The Medicines Company, AstraZeneca, Philips Healthcare, and Abiomed sponsored the study. Dr. Sherwood reported no relevant financial relationships.
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point: Organizing regional STEMI care results in significant improvements in the percentage of patients achieving national reperfusion goals.
Major finding: For all three patient groups, there was a modest but significant improvement from baseline to study end in the percentage of patients meeting first medical contact to device time goals.
Data source: Mission Lifeline: STEMI Accelerator, an observational study in 23,809 patients with STEMI.
Disclosures: The Medicines Company, AstraZeneca, Philips Healthcare, and Abiomed sponsored the study. Dr. Sherwood reported no relevant financial relationships.
Losartan fails in hypertrophic cardiomyopathy
CHICAGO – A year of losartan had no effect on left ventricular mass in patients with overt hypertrophic cardiomyopathy, compared with placebo, in the INHERIT trial.
The angiotensin receptor blocker did not alter any secondary endpoint, including maximal wall thickness, left ventricular fibrosis, diastolic function, and exercise capacity.
There also was no significant change in symptoms or resting left ventricular outflow tract (LVOT) gradient, Dr. Anna Axelsson reported at the American Heart Association scientific sessions.
Current therapies for hypertrophic cardiomyopathy (HCM) are palliative for symptoms only.
Losartan is known to reduce heart wall thickening in patients with hypertension, but is only used with caution in patients with HCM because of a suspicion of deleterious side effects.
INHERIT was initiated based on promising effects with angiotensin receptor blockade in animal and human studies, said Dr. Axelsson of Rigshospitalet, University of Copenhagen, and Harvard Medical School, Boston.
Losartan (Cozaar) has been shown to prevent the development of hypertrophy and fibrosis in HCM mice when started in the prehypertrophic phase. Candesartan (Atacand) use in humans was associated with regression of LV hypertrophy and improvement in LV function and exercise capacity in a small pilot study (J. Mol. Diagn. 2009;11:35-41).
INHERIT (Inhibition of the Renin Angiotensin System With Losartan in Patients With Hypertrophic Cardiomyopathy) evenly allocated 133 adults with overt HCM to daily losartan 100 mg or placebo for 12 months. LV mass was 108 g/m2 in the placebo group and 105 g/m2 in the losartan group, and 83% of patients had fibrosis.
Of the 124 patients completing the study, 93% were compliant (> 80%,) as assessed by pill count. Corroborating this was a significant decrease in blood pressure in the losartan group compared with the placebo group (P value = .001), Dr. Axelsson said.
At 12 months, both groups had a small decrease from baseline in LV mass, as assessed by magnetic resonance imaging or computed tomography, but the difference between groups was not statistically significant or clinically relevant (mean difference 1 g/m2), she said.
Adverse events were few, and comparable between the losartan and control groups. Sudden cardiac death occurred in two patients on placebo. One patient in each group had worsening of New York Heart Association class. Two controls and one losartan-treated patient had increases in LVOT gradient of at least 10 mm Hg. One patient discontinued losartan because of angioedema and two discontinued because of unspecified symptoms leading to withdrawal of consent.
“The observed safety suggests that losartan may be used for other indications in patients with obstructive physiology,” Dr. Axelsson said.
When asked whether clinicians can conclude that it’s safe to give patients with obstructive physiology a vasodilator, Dr. Axelsson said, “perhaps it shouldn’t be considered such a contraindication anymore, but it should still be done cautiously.”
Invited discussant Dr. Euan Ashley of Stanford (Calif.) University, said that only 15% of patients in the trial had an LVOT gradient of more than 30 mm Hg at baseline, “so to try and extrapolate that vasodilators are safe in older hypertrophics may be going too far.”
Finally, Dr. Axelsson said the overall results do not “close the door” to treatment with angiotensin receptor blockers in HCM, and that future trials may determine whether ARBs can prevent development of disease in preclinical or earlier stages of HCM.
The ongoing VANISH trial is evaluating valsartan (Diovan) in younger patients with early sarcomeric HCM. Also, the Liberty-HCM study will evaluate the effects of the investigational late sodium channel inhibitor, GS-6615, in patients aged 18-65 years, with symptomatic HCM.
INHERIT was funded by the Danish Heart Foundation and several other Danish research organizations. Dr. Axelsson holds stock with AstraZeneca.
CHICAGO – A year of losartan had no effect on left ventricular mass in patients with overt hypertrophic cardiomyopathy, compared with placebo, in the INHERIT trial.
The angiotensin receptor blocker did not alter any secondary endpoint, including maximal wall thickness, left ventricular fibrosis, diastolic function, and exercise capacity.
There also was no significant change in symptoms or resting left ventricular outflow tract (LVOT) gradient, Dr. Anna Axelsson reported at the American Heart Association scientific sessions.
Current therapies for hypertrophic cardiomyopathy (HCM) are palliative for symptoms only.
Losartan is known to reduce heart wall thickening in patients with hypertension, but is only used with caution in patients with HCM because of a suspicion of deleterious side effects.
INHERIT was initiated based on promising effects with angiotensin receptor blockade in animal and human studies, said Dr. Axelsson of Rigshospitalet, University of Copenhagen, and Harvard Medical School, Boston.
Losartan (Cozaar) has been shown to prevent the development of hypertrophy and fibrosis in HCM mice when started in the prehypertrophic phase. Candesartan (Atacand) use in humans was associated with regression of LV hypertrophy and improvement in LV function and exercise capacity in a small pilot study (J. Mol. Diagn. 2009;11:35-41).
INHERIT (Inhibition of the Renin Angiotensin System With Losartan in Patients With Hypertrophic Cardiomyopathy) evenly allocated 133 adults with overt HCM to daily losartan 100 mg or placebo for 12 months. LV mass was 108 g/m2 in the placebo group and 105 g/m2 in the losartan group, and 83% of patients had fibrosis.
Of the 124 patients completing the study, 93% were compliant (> 80%,) as assessed by pill count. Corroborating this was a significant decrease in blood pressure in the losartan group compared with the placebo group (P value = .001), Dr. Axelsson said.
At 12 months, both groups had a small decrease from baseline in LV mass, as assessed by magnetic resonance imaging or computed tomography, but the difference between groups was not statistically significant or clinically relevant (mean difference 1 g/m2), she said.
Adverse events were few, and comparable between the losartan and control groups. Sudden cardiac death occurred in two patients on placebo. One patient in each group had worsening of New York Heart Association class. Two controls and one losartan-treated patient had increases in LVOT gradient of at least 10 mm Hg. One patient discontinued losartan because of angioedema and two discontinued because of unspecified symptoms leading to withdrawal of consent.
“The observed safety suggests that losartan may be used for other indications in patients with obstructive physiology,” Dr. Axelsson said.
When asked whether clinicians can conclude that it’s safe to give patients with obstructive physiology a vasodilator, Dr. Axelsson said, “perhaps it shouldn’t be considered such a contraindication anymore, but it should still be done cautiously.”
Invited discussant Dr. Euan Ashley of Stanford (Calif.) University, said that only 15% of patients in the trial had an LVOT gradient of more than 30 mm Hg at baseline, “so to try and extrapolate that vasodilators are safe in older hypertrophics may be going too far.”
Finally, Dr. Axelsson said the overall results do not “close the door” to treatment with angiotensin receptor blockers in HCM, and that future trials may determine whether ARBs can prevent development of disease in preclinical or earlier stages of HCM.
The ongoing VANISH trial is evaluating valsartan (Diovan) in younger patients with early sarcomeric HCM. Also, the Liberty-HCM study will evaluate the effects of the investigational late sodium channel inhibitor, GS-6615, in patients aged 18-65 years, with symptomatic HCM.
INHERIT was funded by the Danish Heart Foundation and several other Danish research organizations. Dr. Axelsson holds stock with AstraZeneca.
CHICAGO – A year of losartan had no effect on left ventricular mass in patients with overt hypertrophic cardiomyopathy, compared with placebo, in the INHERIT trial.
The angiotensin receptor blocker did not alter any secondary endpoint, including maximal wall thickness, left ventricular fibrosis, diastolic function, and exercise capacity.
There also was no significant change in symptoms or resting left ventricular outflow tract (LVOT) gradient, Dr. Anna Axelsson reported at the American Heart Association scientific sessions.
Current therapies for hypertrophic cardiomyopathy (HCM) are palliative for symptoms only.
Losartan is known to reduce heart wall thickening in patients with hypertension, but is only used with caution in patients with HCM because of a suspicion of deleterious side effects.
INHERIT was initiated based on promising effects with angiotensin receptor blockade in animal and human studies, said Dr. Axelsson of Rigshospitalet, University of Copenhagen, and Harvard Medical School, Boston.
Losartan (Cozaar) has been shown to prevent the development of hypertrophy and fibrosis in HCM mice when started in the prehypertrophic phase. Candesartan (Atacand) use in humans was associated with regression of LV hypertrophy and improvement in LV function and exercise capacity in a small pilot study (J. Mol. Diagn. 2009;11:35-41).
INHERIT (Inhibition of the Renin Angiotensin System With Losartan in Patients With Hypertrophic Cardiomyopathy) evenly allocated 133 adults with overt HCM to daily losartan 100 mg or placebo for 12 months. LV mass was 108 g/m2 in the placebo group and 105 g/m2 in the losartan group, and 83% of patients had fibrosis.
Of the 124 patients completing the study, 93% were compliant (> 80%,) as assessed by pill count. Corroborating this was a significant decrease in blood pressure in the losartan group compared with the placebo group (P value = .001), Dr. Axelsson said.
At 12 months, both groups had a small decrease from baseline in LV mass, as assessed by magnetic resonance imaging or computed tomography, but the difference between groups was not statistically significant or clinically relevant (mean difference 1 g/m2), she said.
Adverse events were few, and comparable between the losartan and control groups. Sudden cardiac death occurred in two patients on placebo. One patient in each group had worsening of New York Heart Association class. Two controls and one losartan-treated patient had increases in LVOT gradient of at least 10 mm Hg. One patient discontinued losartan because of angioedema and two discontinued because of unspecified symptoms leading to withdrawal of consent.
“The observed safety suggests that losartan may be used for other indications in patients with obstructive physiology,” Dr. Axelsson said.
When asked whether clinicians can conclude that it’s safe to give patients with obstructive physiology a vasodilator, Dr. Axelsson said, “perhaps it shouldn’t be considered such a contraindication anymore, but it should still be done cautiously.”
Invited discussant Dr. Euan Ashley of Stanford (Calif.) University, said that only 15% of patients in the trial had an LVOT gradient of more than 30 mm Hg at baseline, “so to try and extrapolate that vasodilators are safe in older hypertrophics may be going too far.”
Finally, Dr. Axelsson said the overall results do not “close the door” to treatment with angiotensin receptor blockers in HCM, and that future trials may determine whether ARBs can prevent development of disease in preclinical or earlier stages of HCM.
The ongoing VANISH trial is evaluating valsartan (Diovan) in younger patients with early sarcomeric HCM. Also, the Liberty-HCM study will evaluate the effects of the investigational late sodium channel inhibitor, GS-6615, in patients aged 18-65 years, with symptomatic HCM.
INHERIT was funded by the Danish Heart Foundation and several other Danish research organizations. Dr. Axelsson holds stock with AstraZeneca.
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point: Losartan 100 mg daily did not alter LV mass or any secondary endpoint in patients with hypertrophic cardiomyopathy.
Major finding: At 12 months, the change in LV mass from baseline was similar between patients receiving losartan and those on placebo.
Data source: INHERIT, a double-blind, randomized, placebo controlled trial of 133 patients with hypertrophic cardiomyopathy.
Disclosures: The Danish Heart Foundation and several other Danish research organizations funded the study. Dr. Axelsson holds stock with AstraZeneca.
