Sharon Worcester

Fractional flow reserve-guided percutaneous coronary intervention plus best medical therapy improved outcomes when compared with medical therapy alone in patients with stable coronary artery disease in the Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2 (FAME 2) trial.

A composite outcome of death from any cause, nonfatal myocardial infarction, or urgent revascularization within 2 years occurred in 8.1% of 447 patients who had at least one stenosis with a fractional flow reserve (FFR) of 0.80 and were randomized to undergo percutaneous coronary intervention (PCI) performed on the basis of the FFR, compared with 19.5% of 441 such patients who received medical therapy alone.

The difference was driven mainly by a 77% reduction in the need for urgent revascularization in interventional group as compared with the medical therapy group (4.0% vs. 16.3%, hazard ratio, 0.23). The overall rates of death and myocardial infarction did not differ significantly between the groups, Dr. Bernard D. Bruyne of the Cardiovascular Center Aalst, Belgium, and his colleagues reported at the annual congress of the European Society of Cardiology.

The findings of the open-label, randomized, multicenter trial were simultaneously published online Sept. 1 (N. Engl. J. Med. 2014 Sept. 1[doi:10.1056/NEJMoa1408758]).

The improved outcomes in the PCI group were the result of outcomes that occurred between 8 days and 2 years after randomization; in the first 7 days, more primary end-point events occurred in the PCI group than in the medical therapy group (2.2% vs. 0.9%, hazard ratio 2.49).

The rate of the primary endpoint was 9.0% among 332 additional patients who had an FFR of more than 0.80 in all stenoses, were enrolled into a registry, and received medical therapy alone, the researchers said.

The original FAME trial studied the procedure in patients who had already been selected for PCI. Compared with patients whose PCI was guided by angiography alone, those whose PCI was guided by FFR had significantly reduced rates of the composite end point of death, nonfatal myocardial infarction, and repeat revascularization at 1 year (N. Engl. J. Med. 2009;360:213-24).

FAME 2 evaluated use of FFR for improving the benefits of initial stenting as an alternative to noninvasive medical therapy. The trial was halted after a median of 7 months’ follow-up, when data safety and monitoring board found a highly statistically significant reduction in hospital readmission and urgent revascularization in the patients who received FFR-based stenting compared with those who received optimal medical therapy alone.

FAME 2 was supported by St. Jude Medical. Dr. De Bruyne reported that his institution receives grant support and consulting fees on his behalf from St. Jude Medical. Detailed disclosure information for several other authors is available with the full text of the article at www.NEJM.org.

Fractional flow reserve-guided percutaneous coronary intervention plus best medical therapy improved outcomes when compared with medical therapy alone in patients with stable coronary artery disease in the Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2 (FAME 2) trial.

A composite outcome of death from any cause, nonfatal myocardial infarction, or urgent revascularization within 2 years occurred in 8.1% of 447 patients who had at least one stenosis with a fractional flow reserve (FFR) of 0.80 and were randomized to undergo percutaneous coronary intervention (PCI) performed on the basis of the FFR, compared with 19.5% of 441 such patients who received medical therapy alone.

The difference was driven mainly by a 77% reduction in the need for urgent revascularization in interventional group as compared with the medical therapy group (4.0% vs. 16.3%, hazard ratio, 0.23). The overall rates of death and myocardial infarction did not differ significantly between the groups, Dr. Bernard D. Bruyne of the Cardiovascular Center Aalst, Belgium, and his colleagues reported at the annual congress of the European Society of Cardiology.

The findings of the open-label, randomized, multicenter trial were simultaneously published online Sept. 1 (N. Engl. J. Med. 2014 Sept. 1[doi:10.1056/NEJMoa1408758]).

The improved outcomes in the PCI group were the result of outcomes that occurred between 8 days and 2 years after randomization; in the first 7 days, more primary end-point events occurred in the PCI group than in the medical therapy group (2.2% vs. 0.9%, hazard ratio 2.49).

The rate of the primary endpoint was 9.0% among 332 additional patients who had an FFR of more than 0.80 in all stenoses, were enrolled into a registry, and received medical therapy alone, the researchers said.

The original FAME trial studied the procedure in patients who had already been selected for PCI. Compared with patients whose PCI was guided by angiography alone, those whose PCI was guided by FFR had significantly reduced rates of the composite end point of death, nonfatal myocardial infarction, and repeat revascularization at 1 year (N. Engl. J. Med. 2009;360:213-24).

FAME 2 evaluated use of FFR for improving the benefits of initial stenting as an alternative to noninvasive medical therapy. The trial was halted after a median of 7 months’ follow-up, when data safety and monitoring board found a highly statistically significant reduction in hospital readmission and urgent revascularization in the patients who received FFR-based stenting compared with those who received optimal medical therapy alone.

FAME 2 was supported by St. Jude Medical. Dr. De Bruyne reported that his institution receives grant support and consulting fees on his behalf from St. Jude Medical. Detailed disclosure information for several other authors is available with the full text of the article at www.NEJM.org.

Fractional flow reserve-guided percutaneous coronary intervention plus best medical therapy improved outcomes when compared with medical therapy alone in patients with stable coronary artery disease in the Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2 (FAME 2) trial.

A composite outcome of death from any cause, nonfatal myocardial infarction, or urgent revascularization within 2 years occurred in 8.1% of 447 patients who had at least one stenosis with a fractional flow reserve (FFR) of 0.80 and were randomized to undergo percutaneous coronary intervention (PCI) performed on the basis of the FFR, compared with 19.5% of 441 such patients who received medical therapy alone.

The difference was driven mainly by a 77% reduction in the need for urgent revascularization in interventional group as compared with the medical therapy group (4.0% vs. 16.3%, hazard ratio, 0.23). The overall rates of death and myocardial infarction did not differ significantly between the groups, Dr. Bernard D. Bruyne of the Cardiovascular Center Aalst, Belgium, and his colleagues reported at the annual congress of the European Society of Cardiology.

The findings of the open-label, randomized, multicenter trial were simultaneously published online Sept. 1 (N. Engl. J. Med. 2014 Sept. 1[doi:10.1056/NEJMoa1408758]).

The improved outcomes in the PCI group were the result of outcomes that occurred between 8 days and 2 years after randomization; in the first 7 days, more primary end-point events occurred in the PCI group than in the medical therapy group (2.2% vs. 0.9%, hazard ratio 2.49).

The rate of the primary endpoint was 9.0% among 332 additional patients who had an FFR of more than 0.80 in all stenoses, were enrolled into a registry, and received medical therapy alone, the researchers said.

The original FAME trial studied the procedure in patients who had already been selected for PCI. Compared with patients whose PCI was guided by angiography alone, those whose PCI was guided by FFR had significantly reduced rates of the composite end point of death, nonfatal myocardial infarction, and repeat revascularization at 1 year (N. Engl. J. Med. 2009;360:213-24).

FAME 2 evaluated use of FFR for improving the benefits of initial stenting as an alternative to noninvasive medical therapy. The trial was halted after a median of 7 months’ follow-up, when data safety and monitoring board found a highly statistically significant reduction in hospital readmission and urgent revascularization in the patients who received FFR-based stenting compared with those who received optimal medical therapy alone.

FAME 2 was supported by St. Jude Medical. Dr. De Bruyne reported that his institution receives grant support and consulting fees on his behalf from St. Jude Medical. Detailed disclosure information for several other authors is available with the full text of the article at www.NEJM.org.

A gluten-free diet benefited asymptomatic patients with serologic markers for celiac disease in a prospective randomized study.

The findings support active screening for celiac disease in patients at risk for the disease, even if symptoms aren’t present, according to Dr. Kalle Kurppa of the University of Tampere (Finland) and Tampere University Hospital.

The report is in the September issue of Gastroenterology (doi.org/10.1053/j.gastro.2014.05.003).

After 1 year, 20 adults with endomysial antibodies (EmA) who were randomized to a gluten-free diet (GFD) experienced significant increases in mean mucosal villous height:crypt depth values, significantly decreased levels of celiac-associated antibodies, and greater improvement in gastrointestinal symptoms, compared with 20 patients randomized to a gluten-containing diet. For example, mean small bowel mucosal villous height:crypt depth increased from 1.0 to about 2.8 in the GFD group, and from 0.8 to about 0.9 in the gluten-containing diet group, and total Gastrointestinal Symptoms Rating Scale scores improved significantly (–0.4 difference in mean change from baseline, favoring a GFD), as did individual scores for diarrhea, indigestion, and reflux in the GFD group, wrote Dr. Kurppa and colleagues.

The patients in the GFD group also experienced reduced indigestion, reflux, and anxiety, and better health as measured by Psychological, General Health, and Well-Being scores and most Short Form–36 scores, they noted.

Only social function scores on the Short Form–36 improved more in the gluten-containing diet group (–8.3 difference in mean change from baseline, favoring a gluten-containing diet).

The subjects in both groups had a median age of 42 years, and the groups were similar with respect to sex, medical history, and associated conditions.

No differences were seen between the two groups with respect to laboratory test results, bone mineral density, or body composition, and the subjects in the GFD group did not report any negative effects or reactions to the diet. After trial completion, 92% reported adherence to the gluten-free diet, and 85% said they expected to remain on the diet, the investigators noted.

Because celiac disease affects 1%-2% of the population, but is difficult to detect because of clinical heterogeneity, wide-scale screening with noninvasive serologic testing is frequently suggested.

"However, the only current treatment of the condition, a lifelong strict gluten-free diet, is restrictive and difficult to maintain and thus the positive effects of the screening are not straightforward," the investigators noted, adding that results of prior studies exploring the benefits of a gluten-free diet have been inconsistent – particularly for asymptomatic patients.

Another problem is that wide-scale screening often detects asymptomatic seropositive subjects with only mild enteropathy or even normal small-bowel mucosa, and it is unclear whether these individuals actually suffer from a true gluten-induced clinical disease, they said.

"The results of this randomized study showed that screen-detected and even apparently asymptomatic EmA-positive patients benefit from a gluten-free diet as measured by extensive clinical, serologic, and histologic parameters," the investigators said.

The fact that subjects who considered themselves asymptomatic experienced improvement in the current study suggests that "the patients may in fact have accepted mild symptoms as normal and recognized them as abnormal only later when on the diet," they said.

The findings support active screening for celiac disease in patients at risk, but the potential consequences of screening – particularly on social functioning, should be considered on an individual basis, they said, adding that prospective studies are needed "to unravel whether screen-detected seropositive subjects with completely normal small-bowel mucosal histology should be treated."

This study was supported by the Academy of Finland Research Council for Health, the Competitive Research Funding of the Pirkanmaa Hospital District, the Sigrid Juselius Foundation, the Finnish Foundation for Research, the Yrjö Jahnsson Foundation, the Foundation for Pediatric Research, and the Finnish Celiac Society. The authors reported having no disclosures.

A gluten-free diet benefited asymptomatic patients with serologic markers for celiac disease in a prospective randomized study.

The findings support active screening for celiac disease in patients at risk for the disease, even if symptoms aren’t present, according to Dr. Kalle Kurppa of the University of Tampere (Finland) and Tampere University Hospital.

The report is in the September issue of Gastroenterology (doi.org/10.1053/j.gastro.2014.05.003).

After 1 year, 20 adults with endomysial antibodies (EmA) who were randomized to a gluten-free diet (GFD) experienced significant increases in mean mucosal villous height:crypt depth values, significantly decreased levels of celiac-associated antibodies, and greater improvement in gastrointestinal symptoms, compared with 20 patients randomized to a gluten-containing diet. For example, mean small bowel mucosal villous height:crypt depth increased from 1.0 to about 2.8 in the GFD group, and from 0.8 to about 0.9 in the gluten-containing diet group, and total Gastrointestinal Symptoms Rating Scale scores improved significantly (–0.4 difference in mean change from baseline, favoring a GFD), as did individual scores for diarrhea, indigestion, and reflux in the GFD group, wrote Dr. Kurppa and colleagues.

The patients in the GFD group also experienced reduced indigestion, reflux, and anxiety, and better health as measured by Psychological, General Health, and Well-Being scores and most Short Form–36 scores, they noted.

Only social function scores on the Short Form–36 improved more in the gluten-containing diet group (–8.3 difference in mean change from baseline, favoring a gluten-containing diet).

The subjects in both groups had a median age of 42 years, and the groups were similar with respect to sex, medical history, and associated conditions.

No differences were seen between the two groups with respect to laboratory test results, bone mineral density, or body composition, and the subjects in the GFD group did not report any negative effects or reactions to the diet. After trial completion, 92% reported adherence to the gluten-free diet, and 85% said they expected to remain on the diet, the investigators noted.

Because celiac disease affects 1%-2% of the population, but is difficult to detect because of clinical heterogeneity, wide-scale screening with noninvasive serologic testing is frequently suggested.

"However, the only current treatment of the condition, a lifelong strict gluten-free diet, is restrictive and difficult to maintain and thus the positive effects of the screening are not straightforward," the investigators noted, adding that results of prior studies exploring the benefits of a gluten-free diet have been inconsistent – particularly for asymptomatic patients.

Another problem is that wide-scale screening often detects asymptomatic seropositive subjects with only mild enteropathy or even normal small-bowel mucosa, and it is unclear whether these individuals actually suffer from a true gluten-induced clinical disease, they said.

"The results of this randomized study showed that screen-detected and even apparently asymptomatic EmA-positive patients benefit from a gluten-free diet as measured by extensive clinical, serologic, and histologic parameters," the investigators said.

The fact that subjects who considered themselves asymptomatic experienced improvement in the current study suggests that "the patients may in fact have accepted mild symptoms as normal and recognized them as abnormal only later when on the diet," they said.

The findings support active screening for celiac disease in patients at risk, but the potential consequences of screening – particularly on social functioning, should be considered on an individual basis, they said, adding that prospective studies are needed "to unravel whether screen-detected seropositive subjects with completely normal small-bowel mucosal histology should be treated."

This study was supported by the Academy of Finland Research Council for Health, the Competitive Research Funding of the Pirkanmaa Hospital District, the Sigrid Juselius Foundation, the Finnish Foundation for Research, the Yrjö Jahnsson Foundation, the Foundation for Pediatric Research, and the Finnish Celiac Society. The authors reported having no disclosures.

A gluten-free diet benefited asymptomatic patients with serologic markers for celiac disease in a prospective randomized study.

The findings support active screening for celiac disease in patients at risk for the disease, even if symptoms aren’t present, according to Dr. Kalle Kurppa of the University of Tampere (Finland) and Tampere University Hospital.

The report is in the September issue of Gastroenterology (doi.org/10.1053/j.gastro.2014.05.003).

After 1 year, 20 adults with endomysial antibodies (EmA) who were randomized to a gluten-free diet (GFD) experienced significant increases in mean mucosal villous height:crypt depth values, significantly decreased levels of celiac-associated antibodies, and greater improvement in gastrointestinal symptoms, compared with 20 patients randomized to a gluten-containing diet. For example, mean small bowel mucosal villous height:crypt depth increased from 1.0 to about 2.8 in the GFD group, and from 0.8 to about 0.9 in the gluten-containing diet group, and total Gastrointestinal Symptoms Rating Scale scores improved significantly (–0.4 difference in mean change from baseline, favoring a GFD), as did individual scores for diarrhea, indigestion, and reflux in the GFD group, wrote Dr. Kurppa and colleagues.

The patients in the GFD group also experienced reduced indigestion, reflux, and anxiety, and better health as measured by Psychological, General Health, and Well-Being scores and most Short Form–36 scores, they noted.

Only social function scores on the Short Form–36 improved more in the gluten-containing diet group (–8.3 difference in mean change from baseline, favoring a gluten-containing diet).

The subjects in both groups had a median age of 42 years, and the groups were similar with respect to sex, medical history, and associated conditions.

No differences were seen between the two groups with respect to laboratory test results, bone mineral density, or body composition, and the subjects in the GFD group did not report any negative effects or reactions to the diet. After trial completion, 92% reported adherence to the gluten-free diet, and 85% said they expected to remain on the diet, the investigators noted.

Because celiac disease affects 1%-2% of the population, but is difficult to detect because of clinical heterogeneity, wide-scale screening with noninvasive serologic testing is frequently suggested.

"However, the only current treatment of the condition, a lifelong strict gluten-free diet, is restrictive and difficult to maintain and thus the positive effects of the screening are not straightforward," the investigators noted, adding that results of prior studies exploring the benefits of a gluten-free diet have been inconsistent – particularly for asymptomatic patients.

Another problem is that wide-scale screening often detects asymptomatic seropositive subjects with only mild enteropathy or even normal small-bowel mucosa, and it is unclear whether these individuals actually suffer from a true gluten-induced clinical disease, they said.

"The results of this randomized study showed that screen-detected and even apparently asymptomatic EmA-positive patients benefit from a gluten-free diet as measured by extensive clinical, serologic, and histologic parameters," the investigators said.

The fact that subjects who considered themselves asymptomatic experienced improvement in the current study suggests that "the patients may in fact have accepted mild symptoms as normal and recognized them as abnormal only later when on the diet," they said.

The findings support active screening for celiac disease in patients at risk, but the potential consequences of screening – particularly on social functioning, should be considered on an individual basis, they said, adding that prospective studies are needed "to unravel whether screen-detected seropositive subjects with completely normal small-bowel mucosal histology should be treated."

This study was supported by the Academy of Finland Research Council for Health, the Competitive Research Funding of the Pirkanmaa Hospital District, the Sigrid Juselius Foundation, the Finnish Foundation for Research, the Yrjö Jahnsson Foundation, the Foundation for Pediatric Research, and the Finnish Celiac Society. The authors reported having no disclosures.

Vedolizumab was not superior to placebo for inducing remission at 6 weeks in patients with Crohn’s disease who failed to respond to anti–tumor necrosis factor therapy, according to findings from the double-blind, phase III GEMINI 3 trial.

However, therapeutic benefit from the humanized, anti–alpha-4 beta-7 integrin, immunoglobulin G1 monoclonal antibody did become apparent by week 10, Dr. Bruce E. Sands of the Icahn School of Medicine at Mount Sinai, New York, and his colleagues report in the September issue of Gastroenterology (doi: 10.1053/j.gastro.2014.05.008).

Source: American Gastroenterological Association

The investigators randomized 315 patients with moderately to severely active Crohn’s disease who failed anti-TNF therapy to receive 300 mg of vedolizumab (158 patients) or placebo (157 patients) intravenously at weeks 0, 2, and 6. The results showed that 15.2% of the vedolizumab group was in remission at week 6, compared with 12.1% of the placebo group (relative risk, 1.2). At week 10, 26.6% of patients in the vedolizumab group, compared with 12.1% of those in the placebo group, were in remission (RR, 2.2), the investigators reported.

More patients in the vedolizumab group did, however, achieve at least a 100-point decrease in the Crohn’s Disease Activity Index (CDAI) score at both 6 weeks (39.2% vs. 22.3% of placebo patients; RR, 1.8) and 10 weeks (46.8% vs. 24.8%; RR, 1.4), they said.

The incidence and type of adverse events were similar in both groups.

GEMINI 3 was conducted between November 2010 and April 2012 at 107 sites in North America, Europe, Asia, Africa, and Australia. Participants were aged 18-80 years with moderately to severely active Crohn’s disease (defined in part by a CDAI score of 220-400 points), with known involvement of the ileum and/or colon at 3 or more months before enrollment.

Remission was defined by a CDAI score of 150 points or less.

Treatment with TNF antagonists has improved the care of patients with Crohn’s disease that is refractory to other treatments, but in controlled trials anti-TNF therapy failed in about two-thirds of patients. Treatment is also associated with an increased risk of serious infections in some patients. Natalizumab, another treatment used in Crohn’s disease, has been limited by its association with an increased risk of progressive multifocal leukoencephalopathy.

"Because of these limitations with TNF antagonists and natalizumab, therapies for patients with TNF antagonist failure are needed, and those that selectively inhibit lymphocyte trafficking to the gut may yield important safety benefits," the investigators said.

Vedolizumab was shown in the pivotal GEMINI 2 study to be safe and effective for induction and maintenance in patients with moderately to severely active Crohn’s disease who failed one or more prior therapies; GEMINI 3 specifically focuses on patients with prior TNF antagonist failure.

"The results of this short-term study support the safety of vedolizumab in patients with Crohn’s disease and are consistent with the drug’s postulated gut-selective mechanism of action," the investigators said.

Furthermore, several prespecified outcomes suggest that in addition to leading to clinical remission in the TNF antagonist–naive patients with Crohn’s disease, vedolizumab may lead to clinical remission at 10 weeks in those who failed TNF antagonist therapy.

"These clinically relevant response kinetics have potential implications for bridging induction therapy to vedolizumab maintenance therapy, which has established efficacy, in patients with this lifelong condition," they concluded.

This study was funded by Millennium Pharmaceuticals (doing business as Takeda Pharmaceuticals). Dr. Sands reported receiving consulting and advisory board fees, as well as clinical research/institutional grant support from AbbVie, Janssen, and Takeda. Detailed disclosures for all authors are available with the full text of the article.

Vedolizumab was not superior to placebo for inducing remission at 6 weeks in patients with Crohn’s disease who failed to respond to anti–tumor necrosis factor therapy, according to findings from the double-blind, phase III GEMINI 3 trial.

However, therapeutic benefit from the humanized, anti–alpha-4 beta-7 integrin, immunoglobulin G1 monoclonal antibody did become apparent by week 10, Dr. Bruce E. Sands of the Icahn School of Medicine at Mount Sinai, New York, and his colleagues report in the September issue of Gastroenterology (doi: 10.1053/j.gastro.2014.05.008).

Source: American Gastroenterological Association

The investigators randomized 315 patients with moderately to severely active Crohn’s disease who failed anti-TNF therapy to receive 300 mg of vedolizumab (158 patients) or placebo (157 patients) intravenously at weeks 0, 2, and 6. The results showed that 15.2% of the vedolizumab group was in remission at week 6, compared with 12.1% of the placebo group (relative risk, 1.2). At week 10, 26.6% of patients in the vedolizumab group, compared with 12.1% of those in the placebo group, were in remission (RR, 2.2), the investigators reported.

More patients in the vedolizumab group did, however, achieve at least a 100-point decrease in the Crohn’s Disease Activity Index (CDAI) score at both 6 weeks (39.2% vs. 22.3% of placebo patients; RR, 1.8) and 10 weeks (46.8% vs. 24.8%; RR, 1.4), they said.

The incidence and type of adverse events were similar in both groups.

GEMINI 3 was conducted between November 2010 and April 2012 at 107 sites in North America, Europe, Asia, Africa, and Australia. Participants were aged 18-80 years with moderately to severely active Crohn’s disease (defined in part by a CDAI score of 220-400 points), with known involvement of the ileum and/or colon at 3 or more months before enrollment.

Remission was defined by a CDAI score of 150 points or less.

Treatment with TNF antagonists has improved the care of patients with Crohn’s disease that is refractory to other treatments, but in controlled trials anti-TNF therapy failed in about two-thirds of patients. Treatment is also associated with an increased risk of serious infections in some patients. Natalizumab, another treatment used in Crohn’s disease, has been limited by its association with an increased risk of progressive multifocal leukoencephalopathy.

"Because of these limitations with TNF antagonists and natalizumab, therapies for patients with TNF antagonist failure are needed, and those that selectively inhibit lymphocyte trafficking to the gut may yield important safety benefits," the investigators said.

Vedolizumab was shown in the pivotal GEMINI 2 study to be safe and effective for induction and maintenance in patients with moderately to severely active Crohn’s disease who failed one or more prior therapies; GEMINI 3 specifically focuses on patients with prior TNF antagonist failure.

"The results of this short-term study support the safety of vedolizumab in patients with Crohn’s disease and are consistent with the drug’s postulated gut-selective mechanism of action," the investigators said.

Furthermore, several prespecified outcomes suggest that in addition to leading to clinical remission in the TNF antagonist–naive patients with Crohn’s disease, vedolizumab may lead to clinical remission at 10 weeks in those who failed TNF antagonist therapy.

"These clinically relevant response kinetics have potential implications for bridging induction therapy to vedolizumab maintenance therapy, which has established efficacy, in patients with this lifelong condition," they concluded.

This study was funded by Millennium Pharmaceuticals (doing business as Takeda Pharmaceuticals). Dr. Sands reported receiving consulting and advisory board fees, as well as clinical research/institutional grant support from AbbVie, Janssen, and Takeda. Detailed disclosures for all authors are available with the full text of the article.

Vedolizumab was not superior to placebo for inducing remission at 6 weeks in patients with Crohn’s disease who failed to respond to anti–tumor necrosis factor therapy, according to findings from the double-blind, phase III GEMINI 3 trial.

However, therapeutic benefit from the humanized, anti–alpha-4 beta-7 integrin, immunoglobulin G1 monoclonal antibody did become apparent by week 10, Dr. Bruce E. Sands of the Icahn School of Medicine at Mount Sinai, New York, and his colleagues report in the September issue of Gastroenterology (doi: 10.1053/j.gastro.2014.05.008).

Source: American Gastroenterological Association

The investigators randomized 315 patients with moderately to severely active Crohn’s disease who failed anti-TNF therapy to receive 300 mg of vedolizumab (158 patients) or placebo (157 patients) intravenously at weeks 0, 2, and 6. The results showed that 15.2% of the vedolizumab group was in remission at week 6, compared with 12.1% of the placebo group (relative risk, 1.2). At week 10, 26.6% of patients in the vedolizumab group, compared with 12.1% of those in the placebo group, were in remission (RR, 2.2), the investigators reported.

More patients in the vedolizumab group did, however, achieve at least a 100-point decrease in the Crohn’s Disease Activity Index (CDAI) score at both 6 weeks (39.2% vs. 22.3% of placebo patients; RR, 1.8) and 10 weeks (46.8% vs. 24.8%; RR, 1.4), they said.

The incidence and type of adverse events were similar in both groups.

GEMINI 3 was conducted between November 2010 and April 2012 at 107 sites in North America, Europe, Asia, Africa, and Australia. Participants were aged 18-80 years with moderately to severely active Crohn’s disease (defined in part by a CDAI score of 220-400 points), with known involvement of the ileum and/or colon at 3 or more months before enrollment.

Remission was defined by a CDAI score of 150 points or less.

Treatment with TNF antagonists has improved the care of patients with Crohn’s disease that is refractory to other treatments, but in controlled trials anti-TNF therapy failed in about two-thirds of patients. Treatment is also associated with an increased risk of serious infections in some patients. Natalizumab, another treatment used in Crohn’s disease, has been limited by its association with an increased risk of progressive multifocal leukoencephalopathy.

"Because of these limitations with TNF antagonists and natalizumab, therapies for patients with TNF antagonist failure are needed, and those that selectively inhibit lymphocyte trafficking to the gut may yield important safety benefits," the investigators said.

Vedolizumab was shown in the pivotal GEMINI 2 study to be safe and effective for induction and maintenance in patients with moderately to severely active Crohn’s disease who failed one or more prior therapies; GEMINI 3 specifically focuses on patients with prior TNF antagonist failure.

"The results of this short-term study support the safety of vedolizumab in patients with Crohn’s disease and are consistent with the drug’s postulated gut-selective mechanism of action," the investigators said.

Furthermore, several prespecified outcomes suggest that in addition to leading to clinical remission in the TNF antagonist–naive patients with Crohn’s disease, vedolizumab may lead to clinical remission at 10 weeks in those who failed TNF antagonist therapy.

"These clinically relevant response kinetics have potential implications for bridging induction therapy to vedolizumab maintenance therapy, which has established efficacy, in patients with this lifelong condition," they concluded.

This study was funded by Millennium Pharmaceuticals (doing business as Takeda Pharmaceuticals). Dr. Sands reported receiving consulting and advisory board fees, as well as clinical research/institutional grant support from AbbVie, Janssen, and Takeda. Detailed disclosures for all authors are available with the full text of the article.

The risk of lymphoma is no greater in children with inflammatory bowel disease who are treated with anti–tumor necrosis factor therapy than in adults treated with anti-TNF therapies or in children treated with other therapies for IBD, according to findings from a systematic review.

The review, which included 65 studies involving a total of 5,528 patients with 9,516 patient-years of follow-up, also showed that the rate of serious infection was lower among children with IBD who were treated with anti-TNF agents than among those treated with steroids or among adults treated with anti-TNF agents, Dr. Parambir S. Dulai of Dartmouth-Hitchcock Medical Center, Lebanon, N.H., and his colleagues reported in the September issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2014.01.021).

Source: American Gastroenterological Association

Two patients developed lymphoma, for a rate of 2.1/10,000 patient-years of follow-up (PYF), which did not differ significantly from the expected rate among children (5.8/100,000 PYF), the rate among pediatric patients receiving thiopurine monotherapy (4.5/10,000), or the rate among adults treated with anti-TNF agents (6.1/10,000), the investigators found.

The rate of serious infections was 352/10,000 PYF in pediatric patients treated with anti-TNF agents as part of prospective studies included in the review, which was similar to the expected rate in those treated with immunomodulator therapy (333/10,000 PYF), and significantly lower than the expected rate in those treated with glucocorticoids (730/10,000 PYF) and adults treated with anti-TNF agents (654/10,000 PYF).

Of seven deaths that occurred among the patients, five were considered related to treatment (four cases of sepsis, one case of arrhythmia), for a rate of 5.3/10,000 PYF.

Although anti-TNF therapy is an effective treatment option for pediatric IBD, many physicians are hesitant about prescribing anti-TNFs to children because of concerns about infection and lymphoma risk based on the adult literature and case reports of hepatosplenic T-cell lymphoma. However, the findings of this pooled analysis suggest that such concerns may be unfounded.

Older age, sex, and duration of IBD have been linked with increased risk of lymphoproliferative disorders and could help explain the observed differences between adults and pediatric IBD patients with respect to lymphoma rates after anti-TNF exposure, the investigators said.

"Overall, the risk of serious infection, lymphoma, and death with anti-TNF therapy in pediatric IBD is very low," they wrote.

However, they noted that the study is limited by a number of factors, including short duration of per-person follow-up, which means that while the data are promising, they are "not definitive in answering the question of whether anti-TNF therapy is associated with an increased risk of lymphoma, particularly with long-term use," the investigators said.

Long-term follow-up studies are needed in children to assess whether lymphoma risk is exposure dependent – as suggested by the existing literature – rather than a cumulative risk that is dependent on duration of therapy, they added.

Dr. Dulai reported having no disclosures. Coauthor Dr. Corey Siegel reported serving as an advisory board member or consultant for, and/or receiving grant support from Abbvie, Janssen, UCB, and the Agency for Healthcare Research and Quality. Dr. Marla Dubinsky serves as a consultant for Abbvie, Janssen, UCB, and Takeda.

The risk of lymphoma is no greater in children with inflammatory bowel disease who are treated with anti–tumor necrosis factor therapy than in adults treated with anti-TNF therapies or in children treated with other therapies for IBD, according to findings from a systematic review.

The review, which included 65 studies involving a total of 5,528 patients with 9,516 patient-years of follow-up, also showed that the rate of serious infection was lower among children with IBD who were treated with anti-TNF agents than among those treated with steroids or among adults treated with anti-TNF agents, Dr. Parambir S. Dulai of Dartmouth-Hitchcock Medical Center, Lebanon, N.H., and his colleagues reported in the September issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2014.01.021).

Source: American Gastroenterological Association

Two patients developed lymphoma, for a rate of 2.1/10,000 patient-years of follow-up (PYF), which did not differ significantly from the expected rate among children (5.8/100,000 PYF), the rate among pediatric patients receiving thiopurine monotherapy (4.5/10,000), or the rate among adults treated with anti-TNF agents (6.1/10,000), the investigators found.

The rate of serious infections was 352/10,000 PYF in pediatric patients treated with anti-TNF agents as part of prospective studies included in the review, which was similar to the expected rate in those treated with immunomodulator therapy (333/10,000 PYF), and significantly lower than the expected rate in those treated with glucocorticoids (730/10,000 PYF) and adults treated with anti-TNF agents (654/10,000 PYF).

Of seven deaths that occurred among the patients, five were considered related to treatment (four cases of sepsis, one case of arrhythmia), for a rate of 5.3/10,000 PYF.

Although anti-TNF therapy is an effective treatment option for pediatric IBD, many physicians are hesitant about prescribing anti-TNFs to children because of concerns about infection and lymphoma risk based on the adult literature and case reports of hepatosplenic T-cell lymphoma. However, the findings of this pooled analysis suggest that such concerns may be unfounded.

Older age, sex, and duration of IBD have been linked with increased risk of lymphoproliferative disorders and could help explain the observed differences between adults and pediatric IBD patients with respect to lymphoma rates after anti-TNF exposure, the investigators said.

"Overall, the risk of serious infection, lymphoma, and death with anti-TNF therapy in pediatric IBD is very low," they wrote.

However, they noted that the study is limited by a number of factors, including short duration of per-person follow-up, which means that while the data are promising, they are "not definitive in answering the question of whether anti-TNF therapy is associated with an increased risk of lymphoma, particularly with long-term use," the investigators said.

Long-term follow-up studies are needed in children to assess whether lymphoma risk is exposure dependent – as suggested by the existing literature – rather than a cumulative risk that is dependent on duration of therapy, they added.

Dr. Dulai reported having no disclosures. Coauthor Dr. Corey Siegel reported serving as an advisory board member or consultant for, and/or receiving grant support from Abbvie, Janssen, UCB, and the Agency for Healthcare Research and Quality. Dr. Marla Dubinsky serves as a consultant for Abbvie, Janssen, UCB, and Takeda.

The risk of lymphoma is no greater in children with inflammatory bowel disease who are treated with anti–tumor necrosis factor therapy than in adults treated with anti-TNF therapies or in children treated with other therapies for IBD, according to findings from a systematic review.

The review, which included 65 studies involving a total of 5,528 patients with 9,516 patient-years of follow-up, also showed that the rate of serious infection was lower among children with IBD who were treated with anti-TNF agents than among those treated with steroids or among adults treated with anti-TNF agents, Dr. Parambir S. Dulai of Dartmouth-Hitchcock Medical Center, Lebanon, N.H., and his colleagues reported in the September issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2014.01.021).

Source: American Gastroenterological Association

Two patients developed lymphoma, for a rate of 2.1/10,000 patient-years of follow-up (PYF), which did not differ significantly from the expected rate among children (5.8/100,000 PYF), the rate among pediatric patients receiving thiopurine monotherapy (4.5/10,000), or the rate among adults treated with anti-TNF agents (6.1/10,000), the investigators found.

The rate of serious infections was 352/10,000 PYF in pediatric patients treated with anti-TNF agents as part of prospective studies included in the review, which was similar to the expected rate in those treated with immunomodulator therapy (333/10,000 PYF), and significantly lower than the expected rate in those treated with glucocorticoids (730/10,000 PYF) and adults treated with anti-TNF agents (654/10,000 PYF).

Of seven deaths that occurred among the patients, five were considered related to treatment (four cases of sepsis, one case of arrhythmia), for a rate of 5.3/10,000 PYF.

Although anti-TNF therapy is an effective treatment option for pediatric IBD, many physicians are hesitant about prescribing anti-TNFs to children because of concerns about infection and lymphoma risk based on the adult literature and case reports of hepatosplenic T-cell lymphoma. However, the findings of this pooled analysis suggest that such concerns may be unfounded.

Older age, sex, and duration of IBD have been linked with increased risk of lymphoproliferative disorders and could help explain the observed differences between adults and pediatric IBD patients with respect to lymphoma rates after anti-TNF exposure, the investigators said.

"Overall, the risk of serious infection, lymphoma, and death with anti-TNF therapy in pediatric IBD is very low," they wrote.

However, they noted that the study is limited by a number of factors, including short duration of per-person follow-up, which means that while the data are promising, they are "not definitive in answering the question of whether anti-TNF therapy is associated with an increased risk of lymphoma, particularly with long-term use," the investigators said.

Long-term follow-up studies are needed in children to assess whether lymphoma risk is exposure dependent – as suggested by the existing literature – rather than a cumulative risk that is dependent on duration of therapy, they added.

Dr. Dulai reported having no disclosures. Coauthor Dr. Corey Siegel reported serving as an advisory board member or consultant for, and/or receiving grant support from Abbvie, Janssen, UCB, and the Agency for Healthcare Research and Quality. Dr. Marla Dubinsky serves as a consultant for Abbvie, Janssen, UCB, and Takeda.

Maintenance treatment with infliximab beyond 1 year after ileocolonic resection for Crohn’s disease was associated with reduced recurrence in a prospective, open-label long-term follow-up study.

Subjects were randomized in a prior study to receive infliximab for 1 year after ileocolonic resection performed between 2004 and 2007. At 1 year, the patients – who were blinded as to whether they had received placebo or infliximab – underwent ileocolonoscopy, were informed of the endoscopic findings, and were offered open-label infliximab every 8 weeks or other treatment.

Source: American Gastroenterological Association

Of 11 patients who had been receiving infliximab during the first year after surgery, 8 elected to stop infliximab, and all 8 experienced endoscopic recurrences at a mean of 18.2 months, including 5 who underwent re-resection. Of the three who continued on infliximab, one experienced endoscopic recurrence at the end of the first year, but stayed on treatment for control of arthritis symptoms and has not had Crohn’s disease symptoms, and two continued infliximab for the duration of long-term follow-up and remained in remission, Dr. Miguel Regueiro of the University of Pittsburgh Medical Center and his colleagues reported in the September issue of Clinical Gastroenterology and Hepatology (2014 [doi:10.1016/j.cgh.2013.12.035]).

Of 13 patients who received placebo during the first year after resection, 12 elected to initiate infliximab at 1-year follow-up, and 7 of those responded with endoscopic remission. The remaining five required another surgical resection. The patient who did not initiate infliximab ultimately progressed and underwent re-resection, the investigators said.

Overall, the time to first endoscopic recurrence was longer among those originally assigned to infliximab than among those who received placebo (1,231 days vs. 460 days). Additionally, 77.8% of colonoscopies performed on patients who received infliximab identified disease in remission, compared with only 6.1% of colonoscopies performed in patients not receiving biologic therapy.

"This analysis reflects the intermittent nature of use of infliximab and strong temporal relationship between exposure to infliximab and the probability of being in disease remission. To illustrate, compared with those not on biologic therapy, the adjusted rate ratio of patients being in remission while on infliximab was 13.47," they explained.

Also, while the rate of re-resectional surgery was similar among patients who originally received placebo and those who originally received infliximab, the time to repeat surgery was longer for those who originally received infliximab (1,798 vs. 1,058 days), and four of the five infliximab-treated patients who underwent reoperation during long-term follow-up did so after discontinuing infliximab after the initial 12 months, four of six of those without reoperation remained on infliximab for all or nearly all of the follow-up period, and five of seven patients who initially received placebo and who did not undergo reoperation received infliximab for most of the post 1-year follow-up period.

"Among patients on infliximab therapy for at least 60% of the full study period, and irrespective of initial random assignment, the rate of surgical re-resection was significantly lower, compared with those with less frequent use of infliximab (20.0% vs. 64.3%)," the investigators wrote.

The study is limited by several factors, including the small sample size and open-label design, and the fact that stopping and starting therapy was allowed at the discretion of the patient’s physician, with no restrictions placed on the use of concomitant medications.

The findings suggest, however, that patients at high risk for postoperative Crohn’s disease recurrence may benefit from long-term anti-TNF maintenance, the investigators concluded, noting that "results from postoperative anti-TNF studies with larger sample size and randomization to immediate ‘top down’ treatment vs. waiting for endoscopic recurrence are anticipated," they said.

Dr. Regueiro reported serving as a consultant for AbbVie, Janssen, Shire, Takeda, and UCB.

Maintenance treatment with infliximab beyond 1 year after ileocolonic resection for Crohn’s disease was associated with reduced recurrence in a prospective, open-label long-term follow-up study.

Subjects were randomized in a prior study to receive infliximab for 1 year after ileocolonic resection performed between 2004 and 2007. At 1 year, the patients – who were blinded as to whether they had received placebo or infliximab – underwent ileocolonoscopy, were informed of the endoscopic findings, and were offered open-label infliximab every 8 weeks or other treatment.

Source: American Gastroenterological Association

Of 11 patients who had been receiving infliximab during the first year after surgery, 8 elected to stop infliximab, and all 8 experienced endoscopic recurrences at a mean of 18.2 months, including 5 who underwent re-resection. Of the three who continued on infliximab, one experienced endoscopic recurrence at the end of the first year, but stayed on treatment for control of arthritis symptoms and has not had Crohn’s disease symptoms, and two continued infliximab for the duration of long-term follow-up and remained in remission, Dr. Miguel Regueiro of the University of Pittsburgh Medical Center and his colleagues reported in the September issue of Clinical Gastroenterology and Hepatology (2014 [doi:10.1016/j.cgh.2013.12.035]).

Of 13 patients who received placebo during the first year after resection, 12 elected to initiate infliximab at 1-year follow-up, and 7 of those responded with endoscopic remission. The remaining five required another surgical resection. The patient who did not initiate infliximab ultimately progressed and underwent re-resection, the investigators said.

Overall, the time to first endoscopic recurrence was longer among those originally assigned to infliximab than among those who received placebo (1,231 days vs. 460 days). Additionally, 77.8% of colonoscopies performed on patients who received infliximab identified disease in remission, compared with only 6.1% of colonoscopies performed in patients not receiving biologic therapy.

"This analysis reflects the intermittent nature of use of infliximab and strong temporal relationship between exposure to infliximab and the probability of being in disease remission. To illustrate, compared with those not on biologic therapy, the adjusted rate ratio of patients being in remission while on infliximab was 13.47," they explained.

Also, while the rate of re-resectional surgery was similar among patients who originally received placebo and those who originally received infliximab, the time to repeat surgery was longer for those who originally received infliximab (1,798 vs. 1,058 days), and four of the five infliximab-treated patients who underwent reoperation during long-term follow-up did so after discontinuing infliximab after the initial 12 months, four of six of those without reoperation remained on infliximab for all or nearly all of the follow-up period, and five of seven patients who initially received placebo and who did not undergo reoperation received infliximab for most of the post 1-year follow-up period.

"Among patients on infliximab therapy for at least 60% of the full study period, and irrespective of initial random assignment, the rate of surgical re-resection was significantly lower, compared with those with less frequent use of infliximab (20.0% vs. 64.3%)," the investigators wrote.

The study is limited by several factors, including the small sample size and open-label design, and the fact that stopping and starting therapy was allowed at the discretion of the patient’s physician, with no restrictions placed on the use of concomitant medications.

The findings suggest, however, that patients at high risk for postoperative Crohn’s disease recurrence may benefit from long-term anti-TNF maintenance, the investigators concluded, noting that "results from postoperative anti-TNF studies with larger sample size and randomization to immediate ‘top down’ treatment vs. waiting for endoscopic recurrence are anticipated," they said.

Dr. Regueiro reported serving as a consultant for AbbVie, Janssen, Shire, Takeda, and UCB.

Maintenance treatment with infliximab beyond 1 year after ileocolonic resection for Crohn’s disease was associated with reduced recurrence in a prospective, open-label long-term follow-up study.

Subjects were randomized in a prior study to receive infliximab for 1 year after ileocolonic resection performed between 2004 and 2007. At 1 year, the patients – who were blinded as to whether they had received placebo or infliximab – underwent ileocolonoscopy, were informed of the endoscopic findings, and were offered open-label infliximab every 8 weeks or other treatment.

Source: American Gastroenterological Association

Of 11 patients who had been receiving infliximab during the first year after surgery, 8 elected to stop infliximab, and all 8 experienced endoscopic recurrences at a mean of 18.2 months, including 5 who underwent re-resection. Of the three who continued on infliximab, one experienced endoscopic recurrence at the end of the first year, but stayed on treatment for control of arthritis symptoms and has not had Crohn’s disease symptoms, and two continued infliximab for the duration of long-term follow-up and remained in remission, Dr. Miguel Regueiro of the University of Pittsburgh Medical Center and his colleagues reported in the September issue of Clinical Gastroenterology and Hepatology (2014 [doi:10.1016/j.cgh.2013.12.035]).

Of 13 patients who received placebo during the first year after resection, 12 elected to initiate infliximab at 1-year follow-up, and 7 of those responded with endoscopic remission. The remaining five required another surgical resection. The patient who did not initiate infliximab ultimately progressed and underwent re-resection, the investigators said.

Overall, the time to first endoscopic recurrence was longer among those originally assigned to infliximab than among those who received placebo (1,231 days vs. 460 days). Additionally, 77.8% of colonoscopies performed on patients who received infliximab identified disease in remission, compared with only 6.1% of colonoscopies performed in patients not receiving biologic therapy.

"This analysis reflects the intermittent nature of use of infliximab and strong temporal relationship between exposure to infliximab and the probability of being in disease remission. To illustrate, compared with those not on biologic therapy, the adjusted rate ratio of patients being in remission while on infliximab was 13.47," they explained.

Also, while the rate of re-resectional surgery was similar among patients who originally received placebo and those who originally received infliximab, the time to repeat surgery was longer for those who originally received infliximab (1,798 vs. 1,058 days), and four of the five infliximab-treated patients who underwent reoperation during long-term follow-up did so after discontinuing infliximab after the initial 12 months, four of six of those without reoperation remained on infliximab for all or nearly all of the follow-up period, and five of seven patients who initially received placebo and who did not undergo reoperation received infliximab for most of the post 1-year follow-up period.

"Among patients on infliximab therapy for at least 60% of the full study period, and irrespective of initial random assignment, the rate of surgical re-resection was significantly lower, compared with those with less frequent use of infliximab (20.0% vs. 64.3%)," the investigators wrote.

The study is limited by several factors, including the small sample size and open-label design, and the fact that stopping and starting therapy was allowed at the discretion of the patient’s physician, with no restrictions placed on the use of concomitant medications.

The findings suggest, however, that patients at high risk for postoperative Crohn’s disease recurrence may benefit from long-term anti-TNF maintenance, the investigators concluded, noting that "results from postoperative anti-TNF studies with larger sample size and randomization to immediate ‘top down’ treatment vs. waiting for endoscopic recurrence are anticipated," they said.

Dr. Regueiro reported serving as a consultant for AbbVie, Janssen, Shire, Takeda, and UCB.

Adding ivabradine to standard background therapy did not improve outcomes in a large, randomized, placebo-controlled trial of more than 19,000 patients who had stable coronary artery disease without clinical heart failure.

At 3 months, the mean heart rate was 60.7 beats per minute in 9,550 patients in the Study Assessing the Morbidity-Mortality Benefits of the I_f Inhibitor Ivabradine in Patients with Coronary Artery Disease (SIGNIFY) who were assigned to receive ivabradine, compared with 70.6 beats per minute in 9,552 patients who received placebo. At a median of 27.8 months, the percentage of patients reaching a composite endpoint of death from cardiovascular causes or nonfatal myocardial infarction was 6.8% and 6.4% in the groups, respectively (hazard ratio,1.08), Dr. Kim Fox of Royal Brompton Hospital, London and colleagues reported at the 2014 European Society of Cardiology Congress.

The differences between the ivabradine and placebo groups were not statistically significant, but ivabradine was associated with a nonsignificant increase in the incidence of the primary end point in patients with Canadian Cardiovascular Society class II angina or higher (7.6% vs. 6.5%, hazard ratio, 1.18), the investigators said.

The findings were simultaneously published online Aug. 31 in the New England Journal of Medicine (N. Engl. J. Med 2014 Aug. 30[doi:10.1056/NEJMoa1406430].

Study participants, who were recruited from 1,139 centers in 51 countries between October 12, 2009 and April 30, 2012, were at least 55 years of age with documented and treated stable coronary artery disease, but no evidence of clinical heart failure. They also had to be in sinus rhythm, have a resting heart rate of 70 beats per minute or more on two consecutive readings, and have at least one major or two minor adverse prognostic factors.

All patients completed a 2- to 4-week placebo run-in phase then were randomized to ivabradine at a dose of 7.5 mg twice daily (or 5 mg twice daily for those over age 74 years) or placebo in addition to stable background therapy prescribed according to contemporary guidelines. Dosing was adjusted as needed to 5, 7.5, or 10 mg twice daily based on heart rate and bradycardia. The target heart rate was 55-60 beats per minute, and the mean study-drug dose throughout the trial was 8.2 mg twice daily in the ivabradine group, and 9.5 mg twice daily in the placebo group.

Adverse events occurred in significantly more patients in the ivabradine group (73.3% vs. 66.9%). Bradycardia, in particular, was increased in the ivabradine group (7.9% vs. 1.2% for symptomatic bradycardia, and 11.0% vs. 1.3% for asymptomatic bradycardia. Atrial fibrillation and phosphenes were also increased in the ivabradine group (5.3 vs. 3.8% and 5.4% vs. 0.5%, respectively).

Serious adverse events were also significantly more common in the ivabradine group, with 37.6% and 35.4% of patients in the groups, respectively, experiencing a serious adverse event. These events were classified as cardiac disorders in 19.0% and 16.7% of patients in the groups, respectively.

The SIGNIFY findings contrast with those from previous post hoc analyses that suggested ivabradine improves outcomes in patients with stable coronary artery disease.

"In addition, in patients with heart failure, the reduction in heart rate with ivabradine has been shown to improve clinical outcomes, beyond the improvements observed with beta-blockers," the investigators said.

In fact, on the basis of findings from the phase III Systolic Heart Failure Treatment with the I_f Inhibitor Ivabradine Trial (SHIFT), the U.S. Food and Drug Administration recently granted priority review designation for ivabradine for the treatment of chronic heart failure.

Ivabradine lowers heart rate without affecting blood pressure or left ventricular systolic function, by inhibiting the I_f, or pacemaker, current in the sinoatrial node. It is approved in numerous countries outside the United States and is used for reducing angina symptoms and for chronic heart failure.

A number of hypotheses may explain the SIGNIFY findings.

"It is possible that ivabradine decreased the heart rate too much or that there may be a J-shaped curve for the relationship between heart rate and outcome," the investigators said, explaining that "ivabradine may have unintended effects (e.g., adjustment of the doses of other heart-rate lowering agents) that may have affected the potential benefits of the lowering of heart rate with ivabradine."

Further, heart rate-reducing antianginal agents may have no effect on outcomes in patients with stable coronary artery disease, they said.

The findings may also reflect the fact that an elevated heart rate is due to different pathophysiological mechanisms in those with heart failure and those with stable coronary artery disease, they noted.

"Given that the primary cardiovascular effect of ivabradine is to reduce heart rate, these results suggest that an elevated heart rate is only a marker of risk – but not a modifiable determinant of outcomes- in patients who have stable coronary artery disease without clinical heart failure," they concluded.

This study was funded by Servier. Dr. Fox reported receiving personal fees and/or nonfinancial support from Servier, AstraZeneca, TaurX, Armgo, Broadview Ventures, and CellAegis. She also is director of Heart Research Lt. and Vesalius Trials Ltd. Detailed disclosures for all study authors are available at NEJM.org.

Adding ivabradine to standard background therapy did not improve outcomes in a large, randomized, placebo-controlled trial of more than 19,000 patients who had stable coronary artery disease without clinical heart failure.

At 3 months, the mean heart rate was 60.7 beats per minute in 9,550 patients in the Study Assessing the Morbidity-Mortality Benefits of the I_f Inhibitor Ivabradine in Patients with Coronary Artery Disease (SIGNIFY) who were assigned to receive ivabradine, compared with 70.6 beats per minute in 9,552 patients who received placebo. At a median of 27.8 months, the percentage of patients reaching a composite endpoint of death from cardiovascular causes or nonfatal myocardial infarction was 6.8% and 6.4% in the groups, respectively (hazard ratio,1.08), Dr. Kim Fox of Royal Brompton Hospital, London and colleagues reported at the 2014 European Society of Cardiology Congress.

The differences between the ivabradine and placebo groups were not statistically significant, but ivabradine was associated with a nonsignificant increase in the incidence of the primary end point in patients with Canadian Cardiovascular Society class II angina or higher (7.6% vs. 6.5%, hazard ratio, 1.18), the investigators said.

The findings were simultaneously published online Aug. 31 in the New England Journal of Medicine (N. Engl. J. Med 2014 Aug. 30[doi:10.1056/NEJMoa1406430].

Study participants, who were recruited from 1,139 centers in 51 countries between October 12, 2009 and April 30, 2012, were at least 55 years of age with documented and treated stable coronary artery disease, but no evidence of clinical heart failure. They also had to be in sinus rhythm, have a resting heart rate of 70 beats per minute or more on two consecutive readings, and have at least one major or two minor adverse prognostic factors.

All patients completed a 2- to 4-week placebo run-in phase then were randomized to ivabradine at a dose of 7.5 mg twice daily (or 5 mg twice daily for those over age 74 years) or placebo in addition to stable background therapy prescribed according to contemporary guidelines. Dosing was adjusted as needed to 5, 7.5, or 10 mg twice daily based on heart rate and bradycardia. The target heart rate was 55-60 beats per minute, and the mean study-drug dose throughout the trial was 8.2 mg twice daily in the ivabradine group, and 9.5 mg twice daily in the placebo group.

Adverse events occurred in significantly more patients in the ivabradine group (73.3% vs. 66.9%). Bradycardia, in particular, was increased in the ivabradine group (7.9% vs. 1.2% for symptomatic bradycardia, and 11.0% vs. 1.3% for asymptomatic bradycardia. Atrial fibrillation and phosphenes were also increased in the ivabradine group (5.3 vs. 3.8% and 5.4% vs. 0.5%, respectively).

Serious adverse events were also significantly more common in the ivabradine group, with 37.6% and 35.4% of patients in the groups, respectively, experiencing a serious adverse event. These events were classified as cardiac disorders in 19.0% and 16.7% of patients in the groups, respectively.

The SIGNIFY findings contrast with those from previous post hoc analyses that suggested ivabradine improves outcomes in patients with stable coronary artery disease.

"In addition, in patients with heart failure, the reduction in heart rate with ivabradine has been shown to improve clinical outcomes, beyond the improvements observed with beta-blockers," the investigators said.

In fact, on the basis of findings from the phase III Systolic Heart Failure Treatment with the I_f Inhibitor Ivabradine Trial (SHIFT), the U.S. Food and Drug Administration recently granted priority review designation for ivabradine for the treatment of chronic heart failure.

Ivabradine lowers heart rate without affecting blood pressure or left ventricular systolic function, by inhibiting the I_f, or pacemaker, current in the sinoatrial node. It is approved in numerous countries outside the United States and is used for reducing angina symptoms and for chronic heart failure.

A number of hypotheses may explain the SIGNIFY findings.

"It is possible that ivabradine decreased the heart rate too much or that there may be a J-shaped curve for the relationship between heart rate and outcome," the investigators said, explaining that "ivabradine may have unintended effects (e.g., adjustment of the doses of other heart-rate lowering agents) that may have affected the potential benefits of the lowering of heart rate with ivabradine."

Further, heart rate-reducing antianginal agents may have no effect on outcomes in patients with stable coronary artery disease, they said.

The findings may also reflect the fact that an elevated heart rate is due to different pathophysiological mechanisms in those with heart failure and those with stable coronary artery disease, they noted.

"Given that the primary cardiovascular effect of ivabradine is to reduce heart rate, these results suggest that an elevated heart rate is only a marker of risk – but not a modifiable determinant of outcomes- in patients who have stable coronary artery disease without clinical heart failure," they concluded.

This study was funded by Servier. Dr. Fox reported receiving personal fees and/or nonfinancial support from Servier, AstraZeneca, TaurX, Armgo, Broadview Ventures, and CellAegis. She also is director of Heart Research Lt. and Vesalius Trials Ltd. Detailed disclosures for all study authors are available at NEJM.org.

Adding ivabradine to standard background therapy did not improve outcomes in a large, randomized, placebo-controlled trial of more than 19,000 patients who had stable coronary artery disease without clinical heart failure.

At 3 months, the mean heart rate was 60.7 beats per minute in 9,550 patients in the Study Assessing the Morbidity-Mortality Benefits of the I_f Inhibitor Ivabradine in Patients with Coronary Artery Disease (SIGNIFY) who were assigned to receive ivabradine, compared with 70.6 beats per minute in 9,552 patients who received placebo. At a median of 27.8 months, the percentage of patients reaching a composite endpoint of death from cardiovascular causes or nonfatal myocardial infarction was 6.8% and 6.4% in the groups, respectively (hazard ratio,1.08), Dr. Kim Fox of Royal Brompton Hospital, London and colleagues reported at the 2014 European Society of Cardiology Congress.

The differences between the ivabradine and placebo groups were not statistically significant, but ivabradine was associated with a nonsignificant increase in the incidence of the primary end point in patients with Canadian Cardiovascular Society class II angina or higher (7.6% vs. 6.5%, hazard ratio, 1.18), the investigators said.

The findings were simultaneously published online Aug. 31 in the New England Journal of Medicine (N. Engl. J. Med 2014 Aug. 30[doi:10.1056/NEJMoa1406430].

Study participants, who were recruited from 1,139 centers in 51 countries between October 12, 2009 and April 30, 2012, were at least 55 years of age with documented and treated stable coronary artery disease, but no evidence of clinical heart failure. They also had to be in sinus rhythm, have a resting heart rate of 70 beats per minute or more on two consecutive readings, and have at least one major or two minor adverse prognostic factors.

All patients completed a 2- to 4-week placebo run-in phase then were randomized to ivabradine at a dose of 7.5 mg twice daily (or 5 mg twice daily for those over age 74 years) or placebo in addition to stable background therapy prescribed according to contemporary guidelines. Dosing was adjusted as needed to 5, 7.5, or 10 mg twice daily based on heart rate and bradycardia. The target heart rate was 55-60 beats per minute, and the mean study-drug dose throughout the trial was 8.2 mg twice daily in the ivabradine group, and 9.5 mg twice daily in the placebo group.

Adverse events occurred in significantly more patients in the ivabradine group (73.3% vs. 66.9%). Bradycardia, in particular, was increased in the ivabradine group (7.9% vs. 1.2% for symptomatic bradycardia, and 11.0% vs. 1.3% for asymptomatic bradycardia. Atrial fibrillation and phosphenes were also increased in the ivabradine group (5.3 vs. 3.8% and 5.4% vs. 0.5%, respectively).

Serious adverse events were also significantly more common in the ivabradine group, with 37.6% and 35.4% of patients in the groups, respectively, experiencing a serious adverse event. These events were classified as cardiac disorders in 19.0% and 16.7% of patients in the groups, respectively.

The SIGNIFY findings contrast with those from previous post hoc analyses that suggested ivabradine improves outcomes in patients with stable coronary artery disease.

"In addition, in patients with heart failure, the reduction in heart rate with ivabradine has been shown to improve clinical outcomes, beyond the improvements observed with beta-blockers," the investigators said.

In fact, on the basis of findings from the phase III Systolic Heart Failure Treatment with the I_f Inhibitor Ivabradine Trial (SHIFT), the U.S. Food and Drug Administration recently granted priority review designation for ivabradine for the treatment of chronic heart failure.

Ivabradine lowers heart rate without affecting blood pressure or left ventricular systolic function, by inhibiting the I_f, or pacemaker, current in the sinoatrial node. It is approved in numerous countries outside the United States and is used for reducing angina symptoms and for chronic heart failure.

A number of hypotheses may explain the SIGNIFY findings.

"It is possible that ivabradine decreased the heart rate too much or that there may be a J-shaped curve for the relationship between heart rate and outcome," the investigators said, explaining that "ivabradine may have unintended effects (e.g., adjustment of the doses of other heart-rate lowering agents) that may have affected the potential benefits of the lowering of heart rate with ivabradine."

Further, heart rate-reducing antianginal agents may have no effect on outcomes in patients with stable coronary artery disease, they said.

The findings may also reflect the fact that an elevated heart rate is due to different pathophysiological mechanisms in those with heart failure and those with stable coronary artery disease, they noted.

"Given that the primary cardiovascular effect of ivabradine is to reduce heart rate, these results suggest that an elevated heart rate is only a marker of risk – but not a modifiable determinant of outcomes- in patients who have stable coronary artery disease without clinical heart failure," they concluded.

This study was funded by Servier. Dr. Fox reported receiving personal fees and/or nonfinancial support from Servier, AstraZeneca, TaurX, Armgo, Broadview Ventures, and CellAegis. She also is director of Heart Research Lt. and Vesalius Trials Ltd. Detailed disclosures for all study authors are available at NEJM.org.

A sustained postdischarge smoking cessation intervention was more effective than standard recommendations regarding smoking cessation for hospitalized adults with a desire to quit smoking in the randomized, controlled Hospital-Initiated Assistance for Nicotine Dependence (Helping HAND) trial.

The 198 patients who were assigned to receive sustained care were more likely than the 199 who received standard care to use counseling (37% vs. 23%; relative risk, 1.63) and pharmacotherapy (79% vs. 59%; RR, 1.34) after discharge.

©milosluz/istockphoto.com

Those who received sustained care also were more likely to have biochemically validated, 7-day tobacco abstinence at 6 months (26% vs. 15%; RR, 1.71; number needed to treat, 9.4), Dr. Nancy A. Rigotti, who is director of the Tobacco Research and Treatment Center at Massachusetts General Hospital, Boston, and her colleagues reported online Aug. 20 in JAMA.

Patients in the study had a mean age of 53 years. Those assigned to the sustained-care group had an initial inpatient visit and received five supportive, automated, interactive phone calls and their choice of any approved smoking cessation medication or combination of medications for up to 90 days after discharge. The control group received recommendations for postdischarge pharmacotherapy and smoking cessation counseling, the investigators said (JAMA 2014;312:719-28).

"These findings, if replicated, suggest a translatable, low-cost approach to achieving sustained smoking cessation after a hospital stay," they concluded.

This study was supported by the National Heart, Lung, and Blood Institute and the Department of Veterans Affairs, and is part of the Consortium of Hospitals Advancing Research on Tobacco initiative, which is jointly sponsored by the National Cancer Institute, the NHLBI, and other federal agencies. Dr. Rigotti was an unpaid consultant for Pfizer and Alere Wellbeing regarding smoking cessation, received royalties from UpToDate for reviews on smoking cessation, and received travel reimbursement from Pfizer. Several coauthors were paid consultants for or received grants from Pfizer, and one coauthor was a paid consultant on tobacco policy for CVS.

A sustained postdischarge smoking cessation intervention was more effective than standard recommendations regarding smoking cessation for hospitalized adults with a desire to quit smoking in the randomized, controlled Hospital-Initiated Assistance for Nicotine Dependence (Helping HAND) trial.

The 198 patients who were assigned to receive sustained care were more likely than the 199 who received standard care to use counseling (37% vs. 23%; relative risk, 1.63) and pharmacotherapy (79% vs. 59%; RR, 1.34) after discharge.

©milosluz/istockphoto.com

Those who received sustained care also were more likely to have biochemically validated, 7-day tobacco abstinence at 6 months (26% vs. 15%; RR, 1.71; number needed to treat, 9.4), Dr. Nancy A. Rigotti, who is director of the Tobacco Research and Treatment Center at Massachusetts General Hospital, Boston, and her colleagues reported online Aug. 20 in JAMA.

Patients in the study had a mean age of 53 years. Those assigned to the sustained-care group had an initial inpatient visit and received five supportive, automated, interactive phone calls and their choice of any approved smoking cessation medication or combination of medications for up to 90 days after discharge. The control group received recommendations for postdischarge pharmacotherapy and smoking cessation counseling, the investigators said (JAMA 2014;312:719-28).

"These findings, if replicated, suggest a translatable, low-cost approach to achieving sustained smoking cessation after a hospital stay," they concluded.

This study was supported by the National Heart, Lung, and Blood Institute and the Department of Veterans Affairs, and is part of the Consortium of Hospitals Advancing Research on Tobacco initiative, which is jointly sponsored by the National Cancer Institute, the NHLBI, and other federal agencies. Dr. Rigotti was an unpaid consultant for Pfizer and Alere Wellbeing regarding smoking cessation, received royalties from UpToDate for reviews on smoking cessation, and received travel reimbursement from Pfizer. Several coauthors were paid consultants for or received grants from Pfizer, and one coauthor was a paid consultant on tobacco policy for CVS.

A sustained postdischarge smoking cessation intervention was more effective than standard recommendations regarding smoking cessation for hospitalized adults with a desire to quit smoking in the randomized, controlled Hospital-Initiated Assistance for Nicotine Dependence (Helping HAND) trial.

The 198 patients who were assigned to receive sustained care were more likely than the 199 who received standard care to use counseling (37% vs. 23%; relative risk, 1.63) and pharmacotherapy (79% vs. 59%; RR, 1.34) after discharge.

©milosluz/istockphoto.com

Those who received sustained care also were more likely to have biochemically validated, 7-day tobacco abstinence at 6 months (26% vs. 15%; RR, 1.71; number needed to treat, 9.4), Dr. Nancy A. Rigotti, who is director of the Tobacco Research and Treatment Center at Massachusetts General Hospital, Boston, and her colleagues reported online Aug. 20 in JAMA.

Patients in the study had a mean age of 53 years. Those assigned to the sustained-care group had an initial inpatient visit and received five supportive, automated, interactive phone calls and their choice of any approved smoking cessation medication or combination of medications for up to 90 days after discharge. The control group received recommendations for postdischarge pharmacotherapy and smoking cessation counseling, the investigators said (JAMA 2014;312:719-28).

"These findings, if replicated, suggest a translatable, low-cost approach to achieving sustained smoking cessation after a hospital stay," they concluded.

This study was supported by the National Heart, Lung, and Blood Institute and the Department of Veterans Affairs, and is part of the Consortium of Hospitals Advancing Research on Tobacco initiative, which is jointly sponsored by the National Cancer Institute, the NHLBI, and other federal agencies. Dr. Rigotti was an unpaid consultant for Pfizer and Alere Wellbeing regarding smoking cessation, received royalties from UpToDate for reviews on smoking cessation, and received travel reimbursement from Pfizer. Several coauthors were paid consultants for or received grants from Pfizer, and one coauthor was a paid consultant on tobacco policy for CVS.

Vaccination coverage for young children increased for some vaccines, but remained generally stable in 2013 relative to 2012, with less than 1% of children receiving no vaccinations, according to the 2013 National Immunization Survey.

However, coverage varied widely across geographic regions and by race and socioeconomic status. For example, children living below the poverty level had lower vaccination coverage than those living at or above the poverty level for many vaccines, and black children had lower coverage than white children for several vaccines, Laurie D. Elam-Evans, Ph.D., of the Centers for Disease Control and Prevention in Atlanta and her colleagues reported in the Aug. 29 issue of Morbidity and Mortality Weekly Report (MMWR Aug.29, 2014;63:741-8).

©luiscar/Thinkstockphotos.com

Coverage achieved the 90% national Healthy People 2020 target for one or more doses of measles-mumps-rubella, three or more doses of hepatitis B vaccine (HepB), three or more doses of poliovirus vaccine, and one or more doses of varicella vaccine, but was below targets for four or more doses of diphtheria, tetanus, and pertussis vaccine; four or more doses of pneumococcal conjugate vaccine; the full series of Haemophilus influenza type b vaccine; two or more doses of hepatitis A vaccine; rotavirus vaccine; and the HepB birth dose. Coverage increased for HepB birth dose and rotavirus vaccination, according to the random-digit dialed telephone survey of households with children aged 19-35 months (MMWR. 2014;63[34]:741-8).

"To sustain high coverage and improve coverage for more recently recommended vaccines and those that require booster doses after age 12 months, efforts are needed by parents, clinicians, health systems, and local and state health departments to implement the interventions recommended by the Guide to Community Preventive Services," the investigators said.

Doctors and nurses coping with the challenges they face in the course of clinical work, and parents who continue to prioritize immunization to keep their children healthy and safe are to be commended for the high immunization rates in the U.S. in 2013, according to Dr. Anne Schuchat, director of the National Center for Immunization and Respiratory Diseases.

"These people are central in keeping young children healthy by ensuring they receive the recommended vaccines on schedule," she said in a press statement regarding the report.

The investigators had no disclosures to report.

Vaccination coverage for young children increased for some vaccines, but remained generally stable in 2013 relative to 2012, with less than 1% of children receiving no vaccinations, according to the 2013 National Immunization Survey.

However, coverage varied widely across geographic regions and by race and socioeconomic status. For example, children living below the poverty level had lower vaccination coverage than those living at or above the poverty level for many vaccines, and black children had lower coverage than white children for several vaccines, Laurie D. Elam-Evans, Ph.D., of the Centers for Disease Control and Prevention in Atlanta and her colleagues reported in the Aug. 29 issue of Morbidity and Mortality Weekly Report (MMWR Aug.29, 2014;63:741-8).

©luiscar/Thinkstockphotos.com

Coverage achieved the 90% national Healthy People 2020 target for one or more doses of measles-mumps-rubella, three or more doses of hepatitis B vaccine (HepB), three or more doses of poliovirus vaccine, and one or more doses of varicella vaccine, but was below targets for four or more doses of diphtheria, tetanus, and pertussis vaccine; four or more doses of pneumococcal conjugate vaccine; the full series of Haemophilus influenza type b vaccine; two or more doses of hepatitis A vaccine; rotavirus vaccine; and the HepB birth dose. Coverage increased for HepB birth dose and rotavirus vaccination, according to the random-digit dialed telephone survey of households with children aged 19-35 months (MMWR. 2014;63[34]:741-8).

"To sustain high coverage and improve coverage for more recently recommended vaccines and those that require booster doses after age 12 months, efforts are needed by parents, clinicians, health systems, and local and state health departments to implement the interventions recommended by the Guide to Community Preventive Services," the investigators said.

Doctors and nurses coping with the challenges they face in the course of clinical work, and parents who continue to prioritize immunization to keep their children healthy and safe are to be commended for the high immunization rates in the U.S. in 2013, according to Dr. Anne Schuchat, director of the National Center for Immunization and Respiratory Diseases.

"These people are central in keeping young children healthy by ensuring they receive the recommended vaccines on schedule," she said in a press statement regarding the report.

The investigators had no disclosures to report.

Vaccination coverage for young children increased for some vaccines, but remained generally stable in 2013 relative to 2012, with less than 1% of children receiving no vaccinations, according to the 2013 National Immunization Survey.

However, coverage varied widely across geographic regions and by race and socioeconomic status. For example, children living below the poverty level had lower vaccination coverage than those living at or above the poverty level for many vaccines, and black children had lower coverage than white children for several vaccines, Laurie D. Elam-Evans, Ph.D., of the Centers for Disease Control and Prevention in Atlanta and her colleagues reported in the Aug. 29 issue of Morbidity and Mortality Weekly Report (MMWR Aug.29, 2014;63:741-8).

©luiscar/Thinkstockphotos.com

Coverage achieved the 90% national Healthy People 2020 target for one or more doses of measles-mumps-rubella, three or more doses of hepatitis B vaccine (HepB), three or more doses of poliovirus vaccine, and one or more doses of varicella vaccine, but was below targets for four or more doses of diphtheria, tetanus, and pertussis vaccine; four or more doses of pneumococcal conjugate vaccine; the full series of Haemophilus influenza type b vaccine; two or more doses of hepatitis A vaccine; rotavirus vaccine; and the HepB birth dose. Coverage increased for HepB birth dose and rotavirus vaccination, according to the random-digit dialed telephone survey of households with children aged 19-35 months (MMWR. 2014;63[34]:741-8).

"To sustain high coverage and improve coverage for more recently recommended vaccines and those that require booster doses after age 12 months, efforts are needed by parents, clinicians, health systems, and local and state health departments to implement the interventions recommended by the Guide to Community Preventive Services," the investigators said.

Doctors and nurses coping with the challenges they face in the course of clinical work, and parents who continue to prioritize immunization to keep their children healthy and safe are to be commended for the high immunization rates in the U.S. in 2013, according to Dr. Anne Schuchat, director of the National Center for Immunization and Respiratory Diseases.

"These people are central in keeping young children healthy by ensuring they receive the recommended vaccines on schedule," she said in a press statement regarding the report.

The investigators had no disclosures to report.

Approximately 75% of cancer patients with major depression are not receiving treatment for their depression, according to an analysis of data from more than 21,000 patients.

However, a novel integrated treatment program designed specifically for cancer patients was shown in two additional studies to be strikingly more effective than usual care for reducing depressive symptoms and improving quality of life – even in those with a poor prognosis.

The findings were reported online Aug. 28 in the Lancet Psychiatry, the Lancet, and the Lancet Oncology.

Of 21,151 patients (mean age, 64 years) who were attending cancer clinics in Scotland between May 2008 and August 2011, 1,538 had major depression and complete patient-reported treatment data available. Of those, 1,130 (73%) were not receiving appropriate treatment, Jane Walker, Ph.D. of the University of Oxford (England) and her colleagues reported (Lancet Psychiatry 2014 Aug. 28 [doi: 10.1016/S2215-0366(14)70313-X]).

The prevalence of major depression was highest in patients with lung cancer (13.1%), followed by those with gynecological cancer (10.9%), breast cancer (9.3%), colorectal cancer (7.0%), and genitourinary cancer (5.6%). Younger patients, those with lower social deprivation scores, and women with lung or colorectal cancer were at increased risk for major depression.

Younger patients and women were more likely than older patients and men to be receiving treatment, and those with breast cancer were most likely to receive treatment for depression (32%), while those with lung cancer were least likely to receive treatment (19%), the investigators said.

Notably, those who had been living with a cancer diagnosis for more than a year were as likely to have depression as those with a recent diagnosis, and those who had received initial curative treatment were as likely to have depression as those who received palliative treatment, they reported.

The findings suggest that major depression is substantially more common in people with cancer than in the general population, in which the estimated point prevalence is 2% and the estimated 12-month prevalence is 4%-5%.

"Perhaps our most important finding was that most cancer outpatients with depression were not in receipt of potentially effective treatment for their depression," they said, noting that major depression among cancer outpatients merits greater attention, and that systematic approaches to improving depression care for patients with cancer are urgently needed.

One such approach was evaluated by Dr. Walker and her colleagues from the Symptom Management Research Trials (SMaRT) Oncology-2 and Oncology-3 teams.

Of 231 patients with cancer and major depression who were enrolled in the SMaRT Oncology-2 randomized controlled effectiveness trial between May 2008 and May 2011 and assigned to receive integrated collaborative depression care (Depression Care for People with Cancer, or DCPC), 143 (62%) experienced at least a 50% improvement on the Symptom Checklist Depression Scale score at 24 weeks. Of 231 patients assigned to receive usual care, only 40 (17%) achieved a 50% or greater response at 24 weeks (adjusted odds ratio for treatment response, 8.5; number needed to treat, 2.24), Dr. Michael Sharpe of the University of Oxford reported on behalf of the SMaRT Oncology-2 team (Lancet 2014 Aug. 28 [doi: 10/1016/S0140-6736(14)61231-9]).

Additionally, 33% of those in the DCPC group achieved remission of their major depression, compared with 4% of those in the usual care group (odds ratio, 13.1).

Those in the DCPC group had less depression, anxiety, pain, and fatigue, and had better functioning, health, quality of life, and perceived quality of depression care at each of four time points evaluated during the course of the study, the investigators said.

DCPC is a manualized, multicomponent collaborative care treatment, delivered systematically by cancer nurses and psychiatrists, in conjunction with primary care physicians and oncologists, to provide "systematic proactive treatment and follow-up." Usual care was provided by primary care physicians and/or oncologists, who were instructed to treat the patients as they normally would, such as with antidepressants or referral for a mental health assessment.

Patients in SMaRT Oncology-2 were adults with a good prognosis who were attending cancer clinics in Scotland, and who had major depression of at least 4 weeks’ duration.

"The findings of this trial add to the accumulating evidence for the effectiveness of collaborative care approaches to the treatment of depression comorbid with medical conditions. They also provide new evidence that large and sustained treatment effects can be achieved if depression treatment is integrated with medical care, intensive, and systematically delivered by a well-trained and supervised team," the investigators concluded. The cost of DCPC as delivered in this trial was "quite modest, especially in the context of cancer treatment," they noted.

In a related trial (SMaRT Oncology-3), the investigators found that even patients with a poor prognosis respond well to DCPC. Patients in SMaRT Oncology-3 were adults with major depression attending cancer clinics in Scotland between January 2009 and September 2011. All had a diagnosis of primary lung cancer, and a predicted survival of at least 3 months.

Mean depression severity – a summary measure of each participant’s depression severity scores averaged over the course of the study (up to 32 weeks) was significantly lower in 68 patients with lung cancer who were assigned to receive DCPC than in 74 patients assigned to receive usual care (mean Symptom Checklist Depression Scale scores of 1.24 vs. 1.61; standardized mean difference, –0.62), Dr. Walker reported on behalf of the SMaRT Oncology-3 team.

In addition, significantly more patients receiving DCPC achieved at least a 50% reduction in depression severity scale scores (51% vs. 15%).

"We also recorded significant differences between the treatment groups in self-rated depression improvement, anxiety, quality of life, role functioning, and perceived quality of care, all in favor of the depression care for the people with lung cancer group," they said.

"Our findings suggest that, despite the rapid deterioration of this patient group, successful clinical trials in patients with poor-prognosis cancer and comorbid major depression are possible, through adaptation of both trial design and treatment delivery. Our results also suggest that it is possible to effectively treat major depression in this patient group. ... Large trials are now needed to estimate the effectiveness and cost-effectiveness of depression care for people with lung cancer in this population, and further adaptation of the treatment is needed to address the unmet needs of patients with major depression and a shorter life expectancy," they concluded.

The authors reported having no conflicts of interest. The Lancet Psychiatry and Lancet studies were jointly sponsored by the University of Edinburgh and NHS Lothian, and were funded by Cancer Research UK (CRUK), with additional funding from the Chief Scientist Office (CSO) of the Scottish Government and NHS Research Scotland. The Lancet Psychiatry article was also funded by CRUK and the CSO of the Scottish Government. Dr. Walker is supported by Sir Michael Sobell House Hospice, Oxford; and the NIHR Collaboration for Leadership in Applied Health Research and Care Oxford at the Oxford Health NHS Foundation Trust.

Approximately 75% of cancer patients with major depression are not receiving treatment for their depression, according to an analysis of data from more than 21,000 patients.

However, a novel integrated treatment program designed specifically for cancer patients was shown in two additional studies to be strikingly more effective than usual care for reducing depressive symptoms and improving quality of life – even in those with a poor prognosis.

The findings were reported online Aug. 28 in the Lancet Psychiatry, the Lancet, and the Lancet Oncology.

Of 21,151 patients (mean age, 64 years) who were attending cancer clinics in Scotland between May 2008 and August 2011, 1,538 had major depression and complete patient-reported treatment data available. Of those, 1,130 (73%) were not receiving appropriate treatment, Jane Walker, Ph.D. of the University of Oxford (England) and her colleagues reported (Lancet Psychiatry 2014 Aug. 28 [doi: 10.1016/S2215-0366(14)70313-X]).

The prevalence of major depression was highest in patients with lung cancer (13.1%), followed by those with gynecological cancer (10.9%), breast cancer (9.3%), colorectal cancer (7.0%), and genitourinary cancer (5.6%). Younger patients, those with lower social deprivation scores, and women with lung or colorectal cancer were at increased risk for major depression.

Younger patients and women were more likely than older patients and men to be receiving treatment, and those with breast cancer were most likely to receive treatment for depression (32%), while those with lung cancer were least likely to receive treatment (19%), the investigators said.

Notably, those who had been living with a cancer diagnosis for more than a year were as likely to have depression as those with a recent diagnosis, and those who had received initial curative treatment were as likely to have depression as those who received palliative treatment, they reported.

The findings suggest that major depression is substantially more common in people with cancer than in the general population, in which the estimated point prevalence is 2% and the estimated 12-month prevalence is 4%-5%.

"Perhaps our most important finding was that most cancer outpatients with depression were not in receipt of potentially effective treatment for their depression," they said, noting that major depression among cancer outpatients merits greater attention, and that systematic approaches to improving depression care for patients with cancer are urgently needed.

One such approach was evaluated by Dr. Walker and her colleagues from the Symptom Management Research Trials (SMaRT) Oncology-2 and Oncology-3 teams.

Of 231 patients with cancer and major depression who were enrolled in the SMaRT Oncology-2 randomized controlled effectiveness trial between May 2008 and May 2011 and assigned to receive integrated collaborative depression care (Depression Care for People with Cancer, or DCPC), 143 (62%) experienced at least a 50% improvement on the Symptom Checklist Depression Scale score at 24 weeks. Of 231 patients assigned to receive usual care, only 40 (17%) achieved a 50% or greater response at 24 weeks (adjusted odds ratio for treatment response, 8.5; number needed to treat, 2.24), Dr. Michael Sharpe of the University of Oxford reported on behalf of the SMaRT Oncology-2 team (Lancet 2014 Aug. 28 [doi: 10/1016/S0140-6736(14)61231-9]).

Additionally, 33% of those in the DCPC group achieved remission of their major depression, compared with 4% of those in the usual care group (odds ratio, 13.1).

Those in the DCPC group had less depression, anxiety, pain, and fatigue, and had better functioning, health, quality of life, and perceived quality of depression care at each of four time points evaluated during the course of the study, the investigators said.

DCPC is a manualized, multicomponent collaborative care treatment, delivered systematically by cancer nurses and psychiatrists, in conjunction with primary care physicians and oncologists, to provide "systematic proactive treatment and follow-up." Usual care was provided by primary care physicians and/or oncologists, who were instructed to treat the patients as they normally would, such as with antidepressants or referral for a mental health assessment.

Patients in SMaRT Oncology-2 were adults with a good prognosis who were attending cancer clinics in Scotland, and who had major depression of at least 4 weeks’ duration.

"The findings of this trial add to the accumulating evidence for the effectiveness of collaborative care approaches to the treatment of depression comorbid with medical conditions. They also provide new evidence that large and sustained treatment effects can be achieved if depression treatment is integrated with medical care, intensive, and systematically delivered by a well-trained and supervised team," the investigators concluded. The cost of DCPC as delivered in this trial was "quite modest, especially in the context of cancer treatment," they noted.

In a related trial (SMaRT Oncology-3), the investigators found that even patients with a poor prognosis respond well to DCPC. Patients in SMaRT Oncology-3 were adults with major depression attending cancer clinics in Scotland between January 2009 and September 2011. All had a diagnosis of primary lung cancer, and a predicted survival of at least 3 months.

Mean depression severity – a summary measure of each participant’s depression severity scores averaged over the course of the study (up to 32 weeks) was significantly lower in 68 patients with lung cancer who were assigned to receive DCPC than in 74 patients assigned to receive usual care (mean Symptom Checklist Depression Scale scores of 1.24 vs. 1.61; standardized mean difference, –0.62), Dr. Walker reported on behalf of the SMaRT Oncology-3 team.

In addition, significantly more patients receiving DCPC achieved at least a 50% reduction in depression severity scale scores (51% vs. 15%).

"We also recorded significant differences between the treatment groups in self-rated depression improvement, anxiety, quality of life, role functioning, and perceived quality of care, all in favor of the depression care for the people with lung cancer group," they said.

"Our findings suggest that, despite the rapid deterioration of this patient group, successful clinical trials in patients with poor-prognosis cancer and comorbid major depression are possible, through adaptation of both trial design and treatment delivery. Our results also suggest that it is possible to effectively treat major depression in this patient group. ... Large trials are now needed to estimate the effectiveness and cost-effectiveness of depression care for people with lung cancer in this population, and further adaptation of the treatment is needed to address the unmet needs of patients with major depression and a shorter life expectancy," they concluded.

The authors reported having no conflicts of interest. The Lancet Psychiatry and Lancet studies were jointly sponsored by the University of Edinburgh and NHS Lothian, and were funded by Cancer Research UK (CRUK), with additional funding from the Chief Scientist Office (CSO) of the Scottish Government and NHS Research Scotland. The Lancet Psychiatry article was also funded by CRUK and the CSO of the Scottish Government. Dr. Walker is supported by Sir Michael Sobell House Hospice, Oxford; and the NIHR Collaboration for Leadership in Applied Health Research and Care Oxford at the Oxford Health NHS Foundation Trust.

Approximately 75% of cancer patients with major depression are not receiving treatment for their depression, according to an analysis of data from more than 21,000 patients.

However, a novel integrated treatment program designed specifically for cancer patients was shown in two additional studies to be strikingly more effective than usual care for reducing depressive symptoms and improving quality of life – even in those with a poor prognosis.

The findings were reported online Aug. 28 in the Lancet Psychiatry, the Lancet, and the Lancet Oncology.

Of 21,151 patients (mean age, 64 years) who were attending cancer clinics in Scotland between May 2008 and August 2011, 1,538 had major depression and complete patient-reported treatment data available. Of those, 1,130 (73%) were not receiving appropriate treatment, Jane Walker, Ph.D. of the University of Oxford (England) and her colleagues reported (Lancet Psychiatry 2014 Aug. 28 [doi: 10.1016/S2215-0366(14)70313-X]).

The prevalence of major depression was highest in patients with lung cancer (13.1%), followed by those with gynecological cancer (10.9%), breast cancer (9.3%), colorectal cancer (7.0%), and genitourinary cancer (5.6%). Younger patients, those with lower social deprivation scores, and women with lung or colorectal cancer were at increased risk for major depression.

Younger patients and women were more likely than older patients and men to be receiving treatment, and those with breast cancer were most likely to receive treatment for depression (32%), while those with lung cancer were least likely to receive treatment (19%), the investigators said.

Notably, those who had been living with a cancer diagnosis for more than a year were as likely to have depression as those with a recent diagnosis, and those who had received initial curative treatment were as likely to have depression as those who received palliative treatment, they reported.

The findings suggest that major depression is substantially more common in people with cancer than in the general population, in which the estimated point prevalence is 2% and the estimated 12-month prevalence is 4%-5%.

"Perhaps our most important finding was that most cancer outpatients with depression were not in receipt of potentially effective treatment for their depression," they said, noting that major depression among cancer outpatients merits greater attention, and that systematic approaches to improving depression care for patients with cancer are urgently needed.

One such approach was evaluated by Dr. Walker and her colleagues from the Symptom Management Research Trials (SMaRT) Oncology-2 and Oncology-3 teams.

Of 231 patients with cancer and major depression who were enrolled in the SMaRT Oncology-2 randomized controlled effectiveness trial between May 2008 and May 2011 and assigned to receive integrated collaborative depression care (Depression Care for People with Cancer, or DCPC), 143 (62%) experienced at least a 50% improvement on the Symptom Checklist Depression Scale score at 24 weeks. Of 231 patients assigned to receive usual care, only 40 (17%) achieved a 50% or greater response at 24 weeks (adjusted odds ratio for treatment response, 8.5; number needed to treat, 2.24), Dr. Michael Sharpe of the University of Oxford reported on behalf of the SMaRT Oncology-2 team (Lancet 2014 Aug. 28 [doi: 10/1016/S0140-6736(14)61231-9]).

Additionally, 33% of those in the DCPC group achieved remission of their major depression, compared with 4% of those in the usual care group (odds ratio, 13.1).

Those in the DCPC group had less depression, anxiety, pain, and fatigue, and had better functioning, health, quality of life, and perceived quality of depression care at each of four time points evaluated during the course of the study, the investigators said.

DCPC is a manualized, multicomponent collaborative care treatment, delivered systematically by cancer nurses and psychiatrists, in conjunction with primary care physicians and oncologists, to provide "systematic proactive treatment and follow-up." Usual care was provided by primary care physicians and/or oncologists, who were instructed to treat the patients as they normally would, such as with antidepressants or referral for a mental health assessment.

Patients in SMaRT Oncology-2 were adults with a good prognosis who were attending cancer clinics in Scotland, and who had major depression of at least 4 weeks’ duration.

"The findings of this trial add to the accumulating evidence for the effectiveness of collaborative care approaches to the treatment of depression comorbid with medical conditions. They also provide new evidence that large and sustained treatment effects can be achieved if depression treatment is integrated with medical care, intensive, and systematically delivered by a well-trained and supervised team," the investigators concluded. The cost of DCPC as delivered in this trial was "quite modest, especially in the context of cancer treatment," they noted.

In a related trial (SMaRT Oncology-3), the investigators found that even patients with a poor prognosis respond well to DCPC. Patients in SMaRT Oncology-3 were adults with major depression attending cancer clinics in Scotland between January 2009 and September 2011. All had a diagnosis of primary lung cancer, and a predicted survival of at least 3 months.

Mean depression severity – a summary measure of each participant’s depression severity scores averaged over the course of the study (up to 32 weeks) was significantly lower in 68 patients with lung cancer who were assigned to receive DCPC than in 74 patients assigned to receive usual care (mean Symptom Checklist Depression Scale scores of 1.24 vs. 1.61; standardized mean difference, –0.62), Dr. Walker reported on behalf of the SMaRT Oncology-3 team.

In addition, significantly more patients receiving DCPC achieved at least a 50% reduction in depression severity scale scores (51% vs. 15%).

"We also recorded significant differences between the treatment groups in self-rated depression improvement, anxiety, quality of life, role functioning, and perceived quality of care, all in favor of the depression care for the people with lung cancer group," they said.

"Our findings suggest that, despite the rapid deterioration of this patient group, successful clinical trials in patients with poor-prognosis cancer and comorbid major depression are possible, through adaptation of both trial design and treatment delivery. Our results also suggest that it is possible to effectively treat major depression in this patient group. ... Large trials are now needed to estimate the effectiveness and cost-effectiveness of depression care for people with lung cancer in this population, and further adaptation of the treatment is needed to address the unmet needs of patients with major depression and a shorter life expectancy," they concluded.

The authors reported having no conflicts of interest. The Lancet Psychiatry and Lancet studies were jointly sponsored by the University of Edinburgh and NHS Lothian, and were funded by Cancer Research UK (CRUK), with additional funding from the Chief Scientist Office (CSO) of the Scottish Government and NHS Research Scotland. The Lancet Psychiatry article was also funded by CRUK and the CSO of the Scottish Government. Dr. Walker is supported by Sir Michael Sobell House Hospice, Oxford; and the NIHR Collaboration for Leadership in Applied Health Research and Care Oxford at the Oxford Health NHS Foundation Trust.

The oral fluoropyrimidine S-1 is effective as adjuvant chemotherapy for stage III colon cancer, according to findings from the randomized, open-label, phase III noninferiority trial in Japan.

Disease-free survival was 75.5% at 3 years in 758 patients with curatively resected stage III colon cancer who were randomized to receive S-1, compared with 72.5% in 760 such patients who received tegafur-uracil plus leucovorin (stratified hazard ratio for disease-free survival, 0.85), Dr. M. Yoshida of Osaka Medical College Hospital, Osaka, Japan, and colleagues, reported online Aug. 14 in Annals of Oncology. The findings were reported on behalf of the Adjuvant Chemotherapy Trial of TS-1 for Colon Cancer (ACTS-CC) study group.

The stratified hazard ratio for disease-free survival was similar even after excluding 14 patients who did not receive the allocated treatment, and after adjusting for key baseline factors (Ann. Oncol. 2014 Aug. 14 [doi:10.1003/annonc/mdu232]).

The findings demonstrate the efficacy of S-1 by confirming its noninferiority to tegafur-uracil plus leucovorin (UFT/LV), the investigators said.

Postoperative adjuvant chemotherapy for patients with stage III colon cancer is the standard of care internationally, and Western guidelines call for first-line treatment with intravenous 5-fluorouracil (5-FU) and leucovorin (LV) or capecitabine combined with oxaliplatin (the FOLFOX or CapeOX regimens). Fluoropyrimidine monotherapy is also a treatment option.

"In Japan, oral fluoropyrimidine derivatives have been preferred because of their convenience, leading to the development of several oral fluoropyrimidine derivatives with different properties," the investigators explained, noting that UFT/LV (uracil and tegafur/leucovorin) has been shown in two trials to be noninferior to intravenous 5-FU/LV, and is commonly used for adjuvant chemotherapy for stage III colon cancer patients in Japan.

"S-1 is another oral fluoropyrimidine approved in Japan for various cancers, including colorectal cancer, and for gastric cancers in a total of 38 countries," they said.

S-1, which combines tegafur, gimeracil, and oteracil, has been shown in phase III studies to be noninferior to conventional 5-FU–based regimens when used in combination with other cytotoxic agents for the treatment of advanced gastric cancer and advanced colorectal cancer.

As adjuvant chemotherapy, postoperative S-1 treatment significantly improved survival in patients with gastric cancer and pancreatic cancer, but its efficacy for colon cancer had not been established, they noted.

Patients included in the current study were aged 20-80 years (median, 66 years), and 35.3% were aged 70 years or older. Those assigned to the S-1 group received 80-120 mg daily (depending on body surface area) on days 1-28, every 42 days for four courses; those assigned to the UFT/LV group received 300-600 mg of UFT daily (depending on body surface area) and 75 mg of LV daily on days 1-28, every 35 days for five courses.

No significant differences were noted between the S-1 and UFT/LV groups with respect to safety and feasibility.

The findings suggest that S-1 could be a new treatment option – with multiple potential advantages over UFT/LV – for adjuvant chemotherapy in patients with colon cancer, the investigators said.

Among the advantages are lower cost (in Japan, the cost is half that of UFT/LV), dosing convenience (twice daily after meals vs. every 8 hours but not within 1 hour of meals for UFT/LV), and dramatically reduced risk of hand-foot syndrome, compared with capecitabine (1.3% vs. 60%), they said, noting that studies are ongoing to assess the cost-effectiveness of S-1 and to compare S-1 and capecitabine as adjuvant chemotherapy for stage III colon cancer. An age subgroup analysis is also underway to assess the potential role of oral fluoropyrimidines in adjuvant chemotherapy for elderly patients.

This study was supported by the Foundation for Biomedical Research and Innovation, Translational Research Informatics Center, under a funding contract with Taiho Pharmaceutical, Japan. Dr. Yoshida reported receiving honoraria and/or research funding from Taiho Pharmaceutical, Takeda Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, Merck Serono, Bayer Yakuhin, Daiichi Sankyo, Sanofi, Kyowa Hakko Kirin, Nippon Kayaku, Ono Pharmaceutical, and Jansen Pharmaceutical.

The oral fluoropyrimidine S-1 is effective as adjuvant chemotherapy for stage III colon cancer, according to findings from the randomized, open-label, phase III noninferiority trial in Japan.

Disease-free survival was 75.5% at 3 years in 758 patients with curatively resected stage III colon cancer who were randomized to receive S-1, compared with 72.5% in 760 such patients who received tegafur-uracil plus leucovorin (stratified hazard ratio for disease-free survival, 0.85), Dr. M. Yoshida of Osaka Medical College Hospital, Osaka, Japan, and colleagues, reported online Aug. 14 in Annals of Oncology. The findings were reported on behalf of the Adjuvant Chemotherapy Trial of TS-1 for Colon Cancer (ACTS-CC) study group.

The stratified hazard ratio for disease-free survival was similar even after excluding 14 patients who did not receive the allocated treatment, and after adjusting for key baseline factors (Ann. Oncol. 2014 Aug. 14 [doi:10.1003/annonc/mdu232]).

The findings demonstrate the efficacy of S-1 by confirming its noninferiority to tegafur-uracil plus leucovorin (UFT/LV), the investigators said.

Postoperative adjuvant chemotherapy for patients with stage III colon cancer is the standard of care internationally, and Western guidelines call for first-line treatment with intravenous 5-fluorouracil (5-FU) and leucovorin (LV) or capecitabine combined with oxaliplatin (the FOLFOX or CapeOX regimens). Fluoropyrimidine monotherapy is also a treatment option.

"In Japan, oral fluoropyrimidine derivatives have been preferred because of their convenience, leading to the development of several oral fluoropyrimidine derivatives with different properties," the investigators explained, noting that UFT/LV (uracil and tegafur/leucovorin) has been shown in two trials to be noninferior to intravenous 5-FU/LV, and is commonly used for adjuvant chemotherapy for stage III colon cancer patients in Japan.

"S-1 is another oral fluoropyrimidine approved in Japan for various cancers, including colorectal cancer, and for gastric cancers in a total of 38 countries," they said.

S-1, which combines tegafur, gimeracil, and oteracil, has been shown in phase III studies to be noninferior to conventional 5-FU–based regimens when used in combination with other cytotoxic agents for the treatment of advanced gastric cancer and advanced colorectal cancer.

As adjuvant chemotherapy, postoperative S-1 treatment significantly improved survival in patients with gastric cancer and pancreatic cancer, but its efficacy for colon cancer had not been established, they noted.

Patients included in the current study were aged 20-80 years (median, 66 years), and 35.3% were aged 70 years or older. Those assigned to the S-1 group received 80-120 mg daily (depending on body surface area) on days 1-28, every 42 days for four courses; those assigned to the UFT/LV group received 300-600 mg of UFT daily (depending on body surface area) and 75 mg of LV daily on days 1-28, every 35 days for five courses.

No significant differences were noted between the S-1 and UFT/LV groups with respect to safety and feasibility.

The findings suggest that S-1 could be a new treatment option – with multiple potential advantages over UFT/LV – for adjuvant chemotherapy in patients with colon cancer, the investigators said.

Among the advantages are lower cost (in Japan, the cost is half that of UFT/LV), dosing convenience (twice daily after meals vs. every 8 hours but not within 1 hour of meals for UFT/LV), and dramatically reduced risk of hand-foot syndrome, compared with capecitabine (1.3% vs. 60%), they said, noting that studies are ongoing to assess the cost-effectiveness of S-1 and to compare S-1 and capecitabine as adjuvant chemotherapy for stage III colon cancer. An age subgroup analysis is also underway to assess the potential role of oral fluoropyrimidines in adjuvant chemotherapy for elderly patients.

This study was supported by the Foundation for Biomedical Research and Innovation, Translational Research Informatics Center, under a funding contract with Taiho Pharmaceutical, Japan. Dr. Yoshida reported receiving honoraria and/or research funding from Taiho Pharmaceutical, Takeda Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, Merck Serono, Bayer Yakuhin, Daiichi Sankyo, Sanofi, Kyowa Hakko Kirin, Nippon Kayaku, Ono Pharmaceutical, and Jansen Pharmaceutical.

The oral fluoropyrimidine S-1 is effective as adjuvant chemotherapy for stage III colon cancer, according to findings from the randomized, open-label, phase III noninferiority trial in Japan.

Disease-free survival was 75.5% at 3 years in 758 patients with curatively resected stage III colon cancer who were randomized to receive S-1, compared with 72.5% in 760 such patients who received tegafur-uracil plus leucovorin (stratified hazard ratio for disease-free survival, 0.85), Dr. M. Yoshida of Osaka Medical College Hospital, Osaka, Japan, and colleagues, reported online Aug. 14 in Annals of Oncology. The findings were reported on behalf of the Adjuvant Chemotherapy Trial of TS-1 for Colon Cancer (ACTS-CC) study group.

The stratified hazard ratio for disease-free survival was similar even after excluding 14 patients who did not receive the allocated treatment, and after adjusting for key baseline factors (Ann. Oncol. 2014 Aug. 14 [doi:10.1003/annonc/mdu232]).

The findings demonstrate the efficacy of S-1 by confirming its noninferiority to tegafur-uracil plus leucovorin (UFT/LV), the investigators said.

Postoperative adjuvant chemotherapy for patients with stage III colon cancer is the standard of care internationally, and Western guidelines call for first-line treatment with intravenous 5-fluorouracil (5-FU) and leucovorin (LV) or capecitabine combined with oxaliplatin (the FOLFOX or CapeOX regimens). Fluoropyrimidine monotherapy is also a treatment option.

"In Japan, oral fluoropyrimidine derivatives have been preferred because of their convenience, leading to the development of several oral fluoropyrimidine derivatives with different properties," the investigators explained, noting that UFT/LV (uracil and tegafur/leucovorin) has been shown in two trials to be noninferior to intravenous 5-FU/LV, and is commonly used for adjuvant chemotherapy for stage III colon cancer patients in Japan.

"S-1 is another oral fluoropyrimidine approved in Japan for various cancers, including colorectal cancer, and for gastric cancers in a total of 38 countries," they said.

S-1, which combines tegafur, gimeracil, and oteracil, has been shown in phase III studies to be noninferior to conventional 5-FU–based regimens when used in combination with other cytotoxic agents for the treatment of advanced gastric cancer and advanced colorectal cancer.

As adjuvant chemotherapy, postoperative S-1 treatment significantly improved survival in patients with gastric cancer and pancreatic cancer, but its efficacy for colon cancer had not been established, they noted.

Patients included in the current study were aged 20-80 years (median, 66 years), and 35.3% were aged 70 years or older. Those assigned to the S-1 group received 80-120 mg daily (depending on body surface area) on days 1-28, every 42 days for four courses; those assigned to the UFT/LV group received 300-600 mg of UFT daily (depending on body surface area) and 75 mg of LV daily on days 1-28, every 35 days for five courses.

No significant differences were noted between the S-1 and UFT/LV groups with respect to safety and feasibility.

The findings suggest that S-1 could be a new treatment option – with multiple potential advantages over UFT/LV – for adjuvant chemotherapy in patients with colon cancer, the investigators said.

Among the advantages are lower cost (in Japan, the cost is half that of UFT/LV), dosing convenience (twice daily after meals vs. every 8 hours but not within 1 hour of meals for UFT/LV), and dramatically reduced risk of hand-foot syndrome, compared with capecitabine (1.3% vs. 60%), they said, noting that studies are ongoing to assess the cost-effectiveness of S-1 and to compare S-1 and capecitabine as adjuvant chemotherapy for stage III colon cancer. An age subgroup analysis is also underway to assess the potential role of oral fluoropyrimidines in adjuvant chemotherapy for elderly patients.

This study was supported by the Foundation for Biomedical Research and Innovation, Translational Research Informatics Center, under a funding contract with Taiho Pharmaceutical, Japan. Dr. Yoshida reported receiving honoraria and/or research funding from Taiho Pharmaceutical, Takeda Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, Merck Serono, Bayer Yakuhin, Daiichi Sankyo, Sanofi, Kyowa Hakko Kirin, Nippon Kayaku, Ono Pharmaceutical, and Jansen Pharmaceutical.