Sharon Worcester

Young women who elect contralateral prophylactic mastectomy do so, in part, because they want to improve their chances for survival, even though they realize there is no convincing evidence of a survival benefit, based on results from a survey.

Moreover, many women, particularly those without a known BRCA mutation, substantially overestimate their risk of developing cancer in the unaffected breast, Shoshana M. Rosenberg, Sc.D., of the Dana-Farber Cancer Institute and the Harvard School of Public Health, both in Boston, and her colleagues reported in the Sept. 17 issue of Annals of Internal Medicine.

The findings suggest "some degree of cognitive dissonance," since almost all respondents cited both the desire to improve survival or extend life and a desire to prevent metastatic disease as extremely or very important reasons for choosing contralateral prophylactic mastectomy, while also demonstrating awareness that bilateral mastectomy would not extend survival, the researchers said. Anxiety and fear of recurrence likely influenced the decision-making process and led women to identify their desire to extend life and prevent metastatic disease as among the most important reasons for having contralateral prophylactic mastectomy.

Of 550 women diagnosed at age 40 years or younger with breast cancer in one breast, 123 (22%) who underwent bilateral mastectomy were included in the analysis. Of those women, 94% said the desire to improve survival was an extremely or very important factor in their decision to undergo contralateral prophylactic mastectomy. Yet 74% of mutation carriers and 84% of noncarriers acknowledged that most women who are diagnosed with early-stage breast cancer and undergo treatment will ultimately die of something other than breast cancer.

Also, 98% cited a desire to decrease their risk of contralateral breast cancer and 95% cited a desire for peace of mind as extremely or very important factors in their decision (Ann. Intern. Med. 2013;17:373-81).

Mutation carriers estimated their risk of developing cancer in the contralateral breast in the 5 years after unilateral treatment at 20%, noncarriers estimated that risk at 10%. The risk for women with BRCA mutations is estimated to be 24%-31%. The group without mutations overestimated their risk, which is actually about 2%-4% over 5 years. Women in both groups estimated the risk of chest wall recurrence after bilateral mastectomy at 5%, which is actually estimated at less than 1%, the researchers noted.

Survey participants were women whose median age was 37 years at cancer diagnosis and who were recruited from four academic and five community hospitals in Massachusetts, and from one academic site in Toronto between November 2006 and November 2010. The participants were recruited as part of the Helping Ourselves, Helping Others: Young Women’s Breast Cancer Study. Most had stage I or stage II breast cancer, and all were believed to have breast cancer only in one breast. About 60% of tumors were estrogen receptor–positive, and about 25% of the women were BRCAmutation carriers.

The survey was a one-time supplement to the ongoing prospective cohort study. It is one of the largest surveys to date to examine decision-making, risk perceptions, and psychosocial aspects of contralateral prophylactic mastectomy among young women with breast cancer, the investigators said. The survey findings are important, given that the rates of contralateral prophylactic mastectomy have increased dramatically in recent years, from 4%-6% in the late 1990s to 11%-25% in more recent reports, even though "the value of the procedure for most women with unilateral early-stage breast cancer is unclear," the researchers said.

The study was limited by the lack of validation of the survey, the possibility of recall bias (since the women were surveyed an average of 2 years following surgery), and the possibility of limited generalizability of the findings because the study population was primarily white, non-Hispanic, and college educated. Yet, the findings highlight a need for improved communication with patients, they said.

Although 96%-97% of participants believed they were clear about benefits and risks, and which mattered most, many women reported that several outcomes associated with surgery were worse than they had expected. For example, 33% reported needing a higher-than-expected number of operations or procedures, and 28% said that numbness or tingling in the chest was worse than expected.

"With respect to QOL outcomes, 42% reported that their sense of sexuality was worse than they expected after surgery, and nearly one-third indicated that self-consciousness about appearance was also worse than expected," the researchers reported.

Only about half of the participants indicated that their physicians had talked at least to some degree about reasons not to have contralateral prophylactic mastectomy, suggesting a potential role for "interventions that ensure women are sufficiently informed and the actual risk for contralateral disease is effectively communicated," the investigators said.

Additional clarification of these conflicting responses would be helpful, they said, suggesting that future investigation "might include focus groups or collection of qualitative data with the goal of elucidating the role of cognitive biases in making treatment decisions."

This study was primarily funded by Susan G. Komen for the Cure. Dr. Rosenberg reported receiving support from the National Cancer Institute.

Young women who elect contralateral prophylactic mastectomy do so, in part, because they want to improve their chances for survival, even though they realize there is no convincing evidence of a survival benefit, based on results from a survey.

Moreover, many women, particularly those without a known BRCA mutation, substantially overestimate their risk of developing cancer in the unaffected breast, Shoshana M. Rosenberg, Sc.D., of the Dana-Farber Cancer Institute and the Harvard School of Public Health, both in Boston, and her colleagues reported in the Sept. 17 issue of Annals of Internal Medicine.

The findings suggest "some degree of cognitive dissonance," since almost all respondents cited both the desire to improve survival or extend life and a desire to prevent metastatic disease as extremely or very important reasons for choosing contralateral prophylactic mastectomy, while also demonstrating awareness that bilateral mastectomy would not extend survival, the researchers said. Anxiety and fear of recurrence likely influenced the decision-making process and led women to identify their desire to extend life and prevent metastatic disease as among the most important reasons for having contralateral prophylactic mastectomy.

Of 550 women diagnosed at age 40 years or younger with breast cancer in one breast, 123 (22%) who underwent bilateral mastectomy were included in the analysis. Of those women, 94% said the desire to improve survival was an extremely or very important factor in their decision to undergo contralateral prophylactic mastectomy. Yet 74% of mutation carriers and 84% of noncarriers acknowledged that most women who are diagnosed with early-stage breast cancer and undergo treatment will ultimately die of something other than breast cancer.

Also, 98% cited a desire to decrease their risk of contralateral breast cancer and 95% cited a desire for peace of mind as extremely or very important factors in their decision (Ann. Intern. Med. 2013;17:373-81).

Mutation carriers estimated their risk of developing cancer in the contralateral breast in the 5 years after unilateral treatment at 20%, noncarriers estimated that risk at 10%. The risk for women with BRCA mutations is estimated to be 24%-31%. The group without mutations overestimated their risk, which is actually about 2%-4% over 5 years. Women in both groups estimated the risk of chest wall recurrence after bilateral mastectomy at 5%, which is actually estimated at less than 1%, the researchers noted.

Survey participants were women whose median age was 37 years at cancer diagnosis and who were recruited from four academic and five community hospitals in Massachusetts, and from one academic site in Toronto between November 2006 and November 2010. The participants were recruited as part of the Helping Ourselves, Helping Others: Young Women’s Breast Cancer Study. Most had stage I or stage II breast cancer, and all were believed to have breast cancer only in one breast. About 60% of tumors were estrogen receptor–positive, and about 25% of the women were BRCAmutation carriers.

The survey was a one-time supplement to the ongoing prospective cohort study. It is one of the largest surveys to date to examine decision-making, risk perceptions, and psychosocial aspects of contralateral prophylactic mastectomy among young women with breast cancer, the investigators said. The survey findings are important, given that the rates of contralateral prophylactic mastectomy have increased dramatically in recent years, from 4%-6% in the late 1990s to 11%-25% in more recent reports, even though "the value of the procedure for most women with unilateral early-stage breast cancer is unclear," the researchers said.

The study was limited by the lack of validation of the survey, the possibility of recall bias (since the women were surveyed an average of 2 years following surgery), and the possibility of limited generalizability of the findings because the study population was primarily white, non-Hispanic, and college educated. Yet, the findings highlight a need for improved communication with patients, they said.

Although 96%-97% of participants believed they were clear about benefits and risks, and which mattered most, many women reported that several outcomes associated with surgery were worse than they had expected. For example, 33% reported needing a higher-than-expected number of operations or procedures, and 28% said that numbness or tingling in the chest was worse than expected.

"With respect to QOL outcomes, 42% reported that their sense of sexuality was worse than they expected after surgery, and nearly one-third indicated that self-consciousness about appearance was also worse than expected," the researchers reported.

Only about half of the participants indicated that their physicians had talked at least to some degree about reasons not to have contralateral prophylactic mastectomy, suggesting a potential role for "interventions that ensure women are sufficiently informed and the actual risk for contralateral disease is effectively communicated," the investigators said.

Additional clarification of these conflicting responses would be helpful, they said, suggesting that future investigation "might include focus groups or collection of qualitative data with the goal of elucidating the role of cognitive biases in making treatment decisions."

This study was primarily funded by Susan G. Komen for the Cure. Dr. Rosenberg reported receiving support from the National Cancer Institute.

Young women who elect contralateral prophylactic mastectomy do so, in part, because they want to improve their chances for survival, even though they realize there is no convincing evidence of a survival benefit, based on results from a survey.

Moreover, many women, particularly those without a known BRCA mutation, substantially overestimate their risk of developing cancer in the unaffected breast, Shoshana M. Rosenberg, Sc.D., of the Dana-Farber Cancer Institute and the Harvard School of Public Health, both in Boston, and her colleagues reported in the Sept. 17 issue of Annals of Internal Medicine.

The findings suggest "some degree of cognitive dissonance," since almost all respondents cited both the desire to improve survival or extend life and a desire to prevent metastatic disease as extremely or very important reasons for choosing contralateral prophylactic mastectomy, while also demonstrating awareness that bilateral mastectomy would not extend survival, the researchers said. Anxiety and fear of recurrence likely influenced the decision-making process and led women to identify their desire to extend life and prevent metastatic disease as among the most important reasons for having contralateral prophylactic mastectomy.

Of 550 women diagnosed at age 40 years or younger with breast cancer in one breast, 123 (22%) who underwent bilateral mastectomy were included in the analysis. Of those women, 94% said the desire to improve survival was an extremely or very important factor in their decision to undergo contralateral prophylactic mastectomy. Yet 74% of mutation carriers and 84% of noncarriers acknowledged that most women who are diagnosed with early-stage breast cancer and undergo treatment will ultimately die of something other than breast cancer.

Also, 98% cited a desire to decrease their risk of contralateral breast cancer and 95% cited a desire for peace of mind as extremely or very important factors in their decision (Ann. Intern. Med. 2013;17:373-81).

Mutation carriers estimated their risk of developing cancer in the contralateral breast in the 5 years after unilateral treatment at 20%, noncarriers estimated that risk at 10%. The risk for women with BRCA mutations is estimated to be 24%-31%. The group without mutations overestimated their risk, which is actually about 2%-4% over 5 years. Women in both groups estimated the risk of chest wall recurrence after bilateral mastectomy at 5%, which is actually estimated at less than 1%, the researchers noted.

Survey participants were women whose median age was 37 years at cancer diagnosis and who were recruited from four academic and five community hospitals in Massachusetts, and from one academic site in Toronto between November 2006 and November 2010. The participants were recruited as part of the Helping Ourselves, Helping Others: Young Women’s Breast Cancer Study. Most had stage I or stage II breast cancer, and all were believed to have breast cancer only in one breast. About 60% of tumors were estrogen receptor–positive, and about 25% of the women were BRCAmutation carriers.

The survey was a one-time supplement to the ongoing prospective cohort study. It is one of the largest surveys to date to examine decision-making, risk perceptions, and psychosocial aspects of contralateral prophylactic mastectomy among young women with breast cancer, the investigators said. The survey findings are important, given that the rates of contralateral prophylactic mastectomy have increased dramatically in recent years, from 4%-6% in the late 1990s to 11%-25% in more recent reports, even though "the value of the procedure for most women with unilateral early-stage breast cancer is unclear," the researchers said.

The study was limited by the lack of validation of the survey, the possibility of recall bias (since the women were surveyed an average of 2 years following surgery), and the possibility of limited generalizability of the findings because the study population was primarily white, non-Hispanic, and college educated. Yet, the findings highlight a need for improved communication with patients, they said.

Although 96%-97% of participants believed they were clear about benefits and risks, and which mattered most, many women reported that several outcomes associated with surgery were worse than they had expected. For example, 33% reported needing a higher-than-expected number of operations or procedures, and 28% said that numbness or tingling in the chest was worse than expected.

"With respect to QOL outcomes, 42% reported that their sense of sexuality was worse than they expected after surgery, and nearly one-third indicated that self-consciousness about appearance was also worse than expected," the researchers reported.

Only about half of the participants indicated that their physicians had talked at least to some degree about reasons not to have contralateral prophylactic mastectomy, suggesting a potential role for "interventions that ensure women are sufficiently informed and the actual risk for contralateral disease is effectively communicated," the investigators said.

Additional clarification of these conflicting responses would be helpful, they said, suggesting that future investigation "might include focus groups or collection of qualitative data with the goal of elucidating the role of cognitive biases in making treatment decisions."

This study was primarily funded by Susan G. Komen for the Cure. Dr. Rosenberg reported receiving support from the National Cancer Institute.

Selenium supplementation provided no benefit over placebo for the prevention of second primary tumors in patients with completely resected stage 1 non–small cell lung cancer in a randomized phase III trial.

In 1,040 patients who were randomized to receive selenium and 521 patients randomized to receive placebo, the incidence rates of lung and overall second primary tumors (SPTs) were similar (1.62 and 3.54 per 100 person-years vs. 1.30 and 3.39 per 100 person-years, respectively). Five-year disease-free survival (DFS) rates were 74.4% and 79.6% for the selenium and placebo groups, respectively, Dr. Daniel D. Karp of the University of Texas M.D. Anderson Cancer Center, Houston, and his colleagues reported.

© Bert Folsom/Fotolia.com

The findings were published online Sept. 3 ahead of print in the Journal of Clinical Oncology.

Patients included in the double-blind study were adults aged 18 years or older who were 6-36 months out from complete resection of histologically proven stage 1A or 1B non–small cell lung cancer (NSCLC). Selenium was given at a dose of 200 mcg daily for up to 48 months (J. Clin. Oncol. 2013 Sept. 3 [doi: 10.1200/JCO.2013.49.2173]).

At a planned interim analysis in October 2009, a data monitoring committee determined that "it was highly unlikely that this study could eventually show significant evidence of benefit from selenium," and the following month accrual was discontinued and participating patients discontinued treatment and entered the follow-up phase.

At the interim analysis, there were 83 cases of lung SPT, corresponding to 46% of the originally planned end points. The incidence rates of lung SPT were 1.91 and 1.36 per 100 person-years in the selenium and placebo groups, respectively.

"Overall, the SPT incidence rate was higher in the selenium arm but not significantly. Five-year DFS was 72% for selenium and 78% for placebo," the authors noted.

At the more recent analysis in June, 2011, there were 252 reported SPTs in 224 patients. Of these, 98 were lung cancers, corresponding to 56% of the originally planned end points.

Although prior studies suggested a possible benefit of selenium for tertiary chemoprevention in completely resected NSCLC patients, the findings of the current study suggest otherwise. Although selenium treatment was safe, with similar rates of grade 1 to 2 toxicity (31% and 26%, respectively), and grade 3 or greater toxicity (2% and 3%, respectively) occurring in the treatment and placebo groups, and no increased risk of diabetes or skin cancer among those treated with selenium, no significant differences were seen with respect to SPT prevention, the investigators said.

However, a recurring theme in this and prior SPT prevention trials in lung cancer and head and neck cancer – including studies evaluating retinoids for chemoprevention – is that the lowest rates of SPTs tend to be seen in never-smokers, followed by former smokers, they noted.

In the current study, active smokers in the selenium group had a 30% risk of recurrence or SPT, compared with a 24% risk for former smokers and a 20% risk for never-smokers. Also, the 3- and 5-year overall survival rates were 85.5% and 74.9%, respectively, in those who were active smokers or who had stopped smoking within 1 year, compared with 90% and 83.6%, respectively, for never-smokers.

"It is now clear that there is no demonstrable benefit in giving supplements such as selenium or retinoids to current smokers. However, the data suggest that a better approach might be to treat never-smokers with low serum selenium levels," they said, explaining that descriptive data from the current study suggest that any beneficial effect of selenium is limited to patients with a low baseline selenium level.

"In the current era of molecularly targeted therapies for lung cancer, it seems that persisting with broad approaches in genomically unselected patient populations who continue to smoke is highly unlikely to be successful," they said.

This study was supported by Public Health Service Grants and grants from the National Cancer Institute, the National Institutes of Health, and the Department of Health and Human Services. One coauthor of this study, Dr. David H. Johnson, reported serving as a consultant or adviser for Peloton Therapeutics. The remaining authors reported having no disclosures.

Selenium supplementation provided no benefit over placebo for the prevention of second primary tumors in patients with completely resected stage 1 non–small cell lung cancer in a randomized phase III trial.

In 1,040 patients who were randomized to receive selenium and 521 patients randomized to receive placebo, the incidence rates of lung and overall second primary tumors (SPTs) were similar (1.62 and 3.54 per 100 person-years vs. 1.30 and 3.39 per 100 person-years, respectively). Five-year disease-free survival (DFS) rates were 74.4% and 79.6% for the selenium and placebo groups, respectively, Dr. Daniel D. Karp of the University of Texas M.D. Anderson Cancer Center, Houston, and his colleagues reported.

© Bert Folsom/Fotolia.com

The findings were published online Sept. 3 ahead of print in the Journal of Clinical Oncology.

Patients included in the double-blind study were adults aged 18 years or older who were 6-36 months out from complete resection of histologically proven stage 1A or 1B non–small cell lung cancer (NSCLC). Selenium was given at a dose of 200 mcg daily for up to 48 months (J. Clin. Oncol. 2013 Sept. 3 [doi: 10.1200/JCO.2013.49.2173]).

At a planned interim analysis in October 2009, a data monitoring committee determined that "it was highly unlikely that this study could eventually show significant evidence of benefit from selenium," and the following month accrual was discontinued and participating patients discontinued treatment and entered the follow-up phase.

At the interim analysis, there were 83 cases of lung SPT, corresponding to 46% of the originally planned end points. The incidence rates of lung SPT were 1.91 and 1.36 per 100 person-years in the selenium and placebo groups, respectively.

"Overall, the SPT incidence rate was higher in the selenium arm but not significantly. Five-year DFS was 72% for selenium and 78% for placebo," the authors noted.

At the more recent analysis in June, 2011, there were 252 reported SPTs in 224 patients. Of these, 98 were lung cancers, corresponding to 56% of the originally planned end points.

Although prior studies suggested a possible benefit of selenium for tertiary chemoprevention in completely resected NSCLC patients, the findings of the current study suggest otherwise. Although selenium treatment was safe, with similar rates of grade 1 to 2 toxicity (31% and 26%, respectively), and grade 3 or greater toxicity (2% and 3%, respectively) occurring in the treatment and placebo groups, and no increased risk of diabetes or skin cancer among those treated with selenium, no significant differences were seen with respect to SPT prevention, the investigators said.

However, a recurring theme in this and prior SPT prevention trials in lung cancer and head and neck cancer – including studies evaluating retinoids for chemoprevention – is that the lowest rates of SPTs tend to be seen in never-smokers, followed by former smokers, they noted.

In the current study, active smokers in the selenium group had a 30% risk of recurrence or SPT, compared with a 24% risk for former smokers and a 20% risk for never-smokers. Also, the 3- and 5-year overall survival rates were 85.5% and 74.9%, respectively, in those who were active smokers or who had stopped smoking within 1 year, compared with 90% and 83.6%, respectively, for never-smokers.

"It is now clear that there is no demonstrable benefit in giving supplements such as selenium or retinoids to current smokers. However, the data suggest that a better approach might be to treat never-smokers with low serum selenium levels," they said, explaining that descriptive data from the current study suggest that any beneficial effect of selenium is limited to patients with a low baseline selenium level.

"In the current era of molecularly targeted therapies for lung cancer, it seems that persisting with broad approaches in genomically unselected patient populations who continue to smoke is highly unlikely to be successful," they said.

This study was supported by Public Health Service Grants and grants from the National Cancer Institute, the National Institutes of Health, and the Department of Health and Human Services. One coauthor of this study, Dr. David H. Johnson, reported serving as a consultant or adviser for Peloton Therapeutics. The remaining authors reported having no disclosures.

Selenium supplementation provided no benefit over placebo for the prevention of second primary tumors in patients with completely resected stage 1 non–small cell lung cancer in a randomized phase III trial.

In 1,040 patients who were randomized to receive selenium and 521 patients randomized to receive placebo, the incidence rates of lung and overall second primary tumors (SPTs) were similar (1.62 and 3.54 per 100 person-years vs. 1.30 and 3.39 per 100 person-years, respectively). Five-year disease-free survival (DFS) rates were 74.4% and 79.6% for the selenium and placebo groups, respectively, Dr. Daniel D. Karp of the University of Texas M.D. Anderson Cancer Center, Houston, and his colleagues reported.

© Bert Folsom/Fotolia.com

The findings were published online Sept. 3 ahead of print in the Journal of Clinical Oncology.

Patients included in the double-blind study were adults aged 18 years or older who were 6-36 months out from complete resection of histologically proven stage 1A or 1B non–small cell lung cancer (NSCLC). Selenium was given at a dose of 200 mcg daily for up to 48 months (J. Clin. Oncol. 2013 Sept. 3 [doi: 10.1200/JCO.2013.49.2173]).

At a planned interim analysis in October 2009, a data monitoring committee determined that "it was highly unlikely that this study could eventually show significant evidence of benefit from selenium," and the following month accrual was discontinued and participating patients discontinued treatment and entered the follow-up phase.

At the interim analysis, there were 83 cases of lung SPT, corresponding to 46% of the originally planned end points. The incidence rates of lung SPT were 1.91 and 1.36 per 100 person-years in the selenium and placebo groups, respectively.

"Overall, the SPT incidence rate was higher in the selenium arm but not significantly. Five-year DFS was 72% for selenium and 78% for placebo," the authors noted.

At the more recent analysis in June, 2011, there were 252 reported SPTs in 224 patients. Of these, 98 were lung cancers, corresponding to 56% of the originally planned end points.

Although prior studies suggested a possible benefit of selenium for tertiary chemoprevention in completely resected NSCLC patients, the findings of the current study suggest otherwise. Although selenium treatment was safe, with similar rates of grade 1 to 2 toxicity (31% and 26%, respectively), and grade 3 or greater toxicity (2% and 3%, respectively) occurring in the treatment and placebo groups, and no increased risk of diabetes or skin cancer among those treated with selenium, no significant differences were seen with respect to SPT prevention, the investigators said.

However, a recurring theme in this and prior SPT prevention trials in lung cancer and head and neck cancer – including studies evaluating retinoids for chemoprevention – is that the lowest rates of SPTs tend to be seen in never-smokers, followed by former smokers, they noted.

In the current study, active smokers in the selenium group had a 30% risk of recurrence or SPT, compared with a 24% risk for former smokers and a 20% risk for never-smokers. Also, the 3- and 5-year overall survival rates were 85.5% and 74.9%, respectively, in those who were active smokers or who had stopped smoking within 1 year, compared with 90% and 83.6%, respectively, for never-smokers.

"It is now clear that there is no demonstrable benefit in giving supplements such as selenium or retinoids to current smokers. However, the data suggest that a better approach might be to treat never-smokers with low serum selenium levels," they said, explaining that descriptive data from the current study suggest that any beneficial effect of selenium is limited to patients with a low baseline selenium level.

"In the current era of molecularly targeted therapies for lung cancer, it seems that persisting with broad approaches in genomically unselected patient populations who continue to smoke is highly unlikely to be successful," they said.

This study was supported by Public Health Service Grants and grants from the National Cancer Institute, the National Institutes of Health, and the Department of Health and Human Services. One coauthor of this study, Dr. David H. Johnson, reported serving as a consultant or adviser for Peloton Therapeutics. The remaining authors reported having no disclosures.

Danish researchers report that rheumatoid arthritis patients’ baseline patient global score component of the Disease-Activity Score–28 tool was most strongly correlated with patient-reported outcomes and was the best predictor of a gain in quality adjusted life years following 1 year of biological therapy in a prospective observational study.

An objective C-reactive protein (CRP) measure, however, had no predictive value, and no sharp demarcation between objective and subjective variables was apparent.

The finding that patient global score at baseline may drive a gain in quality adjusted life years (QALY) could improve understanding of which disease-related factors might affect the cost per QALY gains (an important measure for comparing the cost-effectiveness of treatments) and predict treatment response, according to Dr. Louise Linde of the DANBIO Registry, Glostrup, Denmark, and her colleagues (J. Rheumatol. 2013;40:1479-86).

Of 282 patients who completed the study, 68% gained QALYs following 1 year of biological therapy (mean of 0.14), 61% were European League Against Rheumatism (EULAR) criteria responders, and 62% achieved minimally important differences based on the European Quality of Life 5 Dimensions (EQ-5D) questionnaire.

The proportion of patients achieving both a EULAR and EQ-5D response was 55%. Cross-tabulation by response groups (EULAR response/EQ-5D response, EULAR no response/EQ-5D no response, EULAR response/EQ-5D no response, and EULAR no response/EQ-5D response) showed that the mean reduction in swollen joints across the groups ranged from 0 to 6 with clinically and statistically significant differences in three of six possible comparisons.

Similar patterns were seen for tender joints and patient global score, the investigators said.

"Thus, the mean reduction in tender joints ranged from –1 to 9 across the response groups. In addition, the EULAR no response/EQ-5D response group could be discriminated from the EULAR response/EQ-5D response group, leading to significant differences (3-9 tender joints) in four of six comparisons. Similarly, the mean reduction in patient global score ranged from –0.7 to 4.0 cm across the response groups, and highly significant differences of 2.0-4.7 cm were observed between the response groups in five of six comparisons," they said.

However, the mean reduction in CRP, which ranged from 6.0 to 16.5 mg/L across the response groups, distinguished only the EULAR response/EQ-5D response from the EULAR nonresponders.

All EULAR responders experienced significant reductions in swollen and tender joints, CRP, and patient global scores – regardless of EQ-5D status – and the EULAR nonresponders who had an EQ-5D response experienced similar improvements. However, those with no EQ-5D response experienced a worsening in patient global score of 0.7.

Patient global score was strongly correlated with responses on both the EULAR and European Quality of Life 5 Dimensions EQ-5D.

Regression analysis demonstrated that "the gain in QALY after 1 year of biological therapy increased with increasing baseline patient global score and number of swollen joints, and patients with two or more extraarticular manifestations gained more QALY compared with those without such manifestations," the investigators wrote.

"This finding may reflect the likely scenario that patients with very active or severe disease have more room for improvement. This does not imply, however that such patients will have a more favorable final status than those with less active or less severe disease at baseline, a conclusion not supported by our observational data," they noted.

The mean age of the patients in this study was 55 years. They were recruited from 17 routine care sites between November 2005 and July 2007. Clinical and patient-reported data were collected at baseline and after 3, 6, and 12 months of therapy. Clinical data were obtained via the Danish DANBIO registry, which includes 90% of Danish patients with RA who are receiving biological therapy. Collected clinical data included disease duration, 28 swollen and tender joint counts, CRP, patient global score on a visual analog scale, IgM-rheumatoid factor status, number of previous biological therapies, and concomitant use of methotrexate and glucocorticoids. Self-reported patient data included marital status, education, smoking behavior, body mass index, exercise habits, extra-articular features, joint surgery, and comorbidities.

In addition to the EQ-5D, participants also completed the validated Danish Health Assessment Questionnaire.

Though limited by the factors inherent in observational study design, the study is strengthened by the nationwide recruitment, the fact that is was carried out in a clinical setting, and the fact that the study population had similar baseline demographic, clinical, and patent-reported values as have been reported for other RA patients treated with biological therapies in routine care in several other registries.

"This result suggests that our findings may be generalizable to patients with RA treated in routine care with biologicals in countries with a public healthcare system similar to the Danish model," the investigators wrote.

Danish researchers report that rheumatoid arthritis patients’ baseline patient global score component of the Disease-Activity Score–28 tool was most strongly correlated with patient-reported outcomes and was the best predictor of a gain in quality adjusted life years following 1 year of biological therapy in a prospective observational study.

An objective C-reactive protein (CRP) measure, however, had no predictive value, and no sharp demarcation between objective and subjective variables was apparent.

The finding that patient global score at baseline may drive a gain in quality adjusted life years (QALY) could improve understanding of which disease-related factors might affect the cost per QALY gains (an important measure for comparing the cost-effectiveness of treatments) and predict treatment response, according to Dr. Louise Linde of the DANBIO Registry, Glostrup, Denmark, and her colleagues (J. Rheumatol. 2013;40:1479-86).

Of 282 patients who completed the study, 68% gained QALYs following 1 year of biological therapy (mean of 0.14), 61% were European League Against Rheumatism (EULAR) criteria responders, and 62% achieved minimally important differences based on the European Quality of Life 5 Dimensions (EQ-5D) questionnaire.

The proportion of patients achieving both a EULAR and EQ-5D response was 55%. Cross-tabulation by response groups (EULAR response/EQ-5D response, EULAR no response/EQ-5D no response, EULAR response/EQ-5D no response, and EULAR no response/EQ-5D response) showed that the mean reduction in swollen joints across the groups ranged from 0 to 6 with clinically and statistically significant differences in three of six possible comparisons.

Similar patterns were seen for tender joints and patient global score, the investigators said.

"Thus, the mean reduction in tender joints ranged from –1 to 9 across the response groups. In addition, the EULAR no response/EQ-5D response group could be discriminated from the EULAR response/EQ-5D response group, leading to significant differences (3-9 tender joints) in four of six comparisons. Similarly, the mean reduction in patient global score ranged from –0.7 to 4.0 cm across the response groups, and highly significant differences of 2.0-4.7 cm were observed between the response groups in five of six comparisons," they said.

However, the mean reduction in CRP, which ranged from 6.0 to 16.5 mg/L across the response groups, distinguished only the EULAR response/EQ-5D response from the EULAR nonresponders.

All EULAR responders experienced significant reductions in swollen and tender joints, CRP, and patient global scores – regardless of EQ-5D status – and the EULAR nonresponders who had an EQ-5D response experienced similar improvements. However, those with no EQ-5D response experienced a worsening in patient global score of 0.7.

Patient global score was strongly correlated with responses on both the EULAR and European Quality of Life 5 Dimensions EQ-5D.

Regression analysis demonstrated that "the gain in QALY after 1 year of biological therapy increased with increasing baseline patient global score and number of swollen joints, and patients with two or more extraarticular manifestations gained more QALY compared with those without such manifestations," the investigators wrote.

"This finding may reflect the likely scenario that patients with very active or severe disease have more room for improvement. This does not imply, however that such patients will have a more favorable final status than those with less active or less severe disease at baseline, a conclusion not supported by our observational data," they noted.

The mean age of the patients in this study was 55 years. They were recruited from 17 routine care sites between November 2005 and July 2007. Clinical and patient-reported data were collected at baseline and after 3, 6, and 12 months of therapy. Clinical data were obtained via the Danish DANBIO registry, which includes 90% of Danish patients with RA who are receiving biological therapy. Collected clinical data included disease duration, 28 swollen and tender joint counts, CRP, patient global score on a visual analog scale, IgM-rheumatoid factor status, number of previous biological therapies, and concomitant use of methotrexate and glucocorticoids. Self-reported patient data included marital status, education, smoking behavior, body mass index, exercise habits, extra-articular features, joint surgery, and comorbidities.

In addition to the EQ-5D, participants also completed the validated Danish Health Assessment Questionnaire.

Though limited by the factors inherent in observational study design, the study is strengthened by the nationwide recruitment, the fact that is was carried out in a clinical setting, and the fact that the study population had similar baseline demographic, clinical, and patent-reported values as have been reported for other RA patients treated with biological therapies in routine care in several other registries.

"This result suggests that our findings may be generalizable to patients with RA treated in routine care with biologicals in countries with a public healthcare system similar to the Danish model," the investigators wrote.

Danish researchers report that rheumatoid arthritis patients’ baseline patient global score component of the Disease-Activity Score–28 tool was most strongly correlated with patient-reported outcomes and was the best predictor of a gain in quality adjusted life years following 1 year of biological therapy in a prospective observational study.

An objective C-reactive protein (CRP) measure, however, had no predictive value, and no sharp demarcation between objective and subjective variables was apparent.

The finding that patient global score at baseline may drive a gain in quality adjusted life years (QALY) could improve understanding of which disease-related factors might affect the cost per QALY gains (an important measure for comparing the cost-effectiveness of treatments) and predict treatment response, according to Dr. Louise Linde of the DANBIO Registry, Glostrup, Denmark, and her colleagues (J. Rheumatol. 2013;40:1479-86).

Of 282 patients who completed the study, 68% gained QALYs following 1 year of biological therapy (mean of 0.14), 61% were European League Against Rheumatism (EULAR) criteria responders, and 62% achieved minimally important differences based on the European Quality of Life 5 Dimensions (EQ-5D) questionnaire.

The proportion of patients achieving both a EULAR and EQ-5D response was 55%. Cross-tabulation by response groups (EULAR response/EQ-5D response, EULAR no response/EQ-5D no response, EULAR response/EQ-5D no response, and EULAR no response/EQ-5D response) showed that the mean reduction in swollen joints across the groups ranged from 0 to 6 with clinically and statistically significant differences in three of six possible comparisons.

Similar patterns were seen for tender joints and patient global score, the investigators said.

"Thus, the mean reduction in tender joints ranged from –1 to 9 across the response groups. In addition, the EULAR no response/EQ-5D response group could be discriminated from the EULAR response/EQ-5D response group, leading to significant differences (3-9 tender joints) in four of six comparisons. Similarly, the mean reduction in patient global score ranged from –0.7 to 4.0 cm across the response groups, and highly significant differences of 2.0-4.7 cm were observed between the response groups in five of six comparisons," they said.

However, the mean reduction in CRP, which ranged from 6.0 to 16.5 mg/L across the response groups, distinguished only the EULAR response/EQ-5D response from the EULAR nonresponders.

All EULAR responders experienced significant reductions in swollen and tender joints, CRP, and patient global scores – regardless of EQ-5D status – and the EULAR nonresponders who had an EQ-5D response experienced similar improvements. However, those with no EQ-5D response experienced a worsening in patient global score of 0.7.

Patient global score was strongly correlated with responses on both the EULAR and European Quality of Life 5 Dimensions EQ-5D.

Regression analysis demonstrated that "the gain in QALY after 1 year of biological therapy increased with increasing baseline patient global score and number of swollen joints, and patients with two or more extraarticular manifestations gained more QALY compared with those without such manifestations," the investigators wrote.

"This finding may reflect the likely scenario that patients with very active or severe disease have more room for improvement. This does not imply, however that such patients will have a more favorable final status than those with less active or less severe disease at baseline, a conclusion not supported by our observational data," they noted.

The mean age of the patients in this study was 55 years. They were recruited from 17 routine care sites between November 2005 and July 2007. Clinical and patient-reported data were collected at baseline and after 3, 6, and 12 months of therapy. Clinical data were obtained via the Danish DANBIO registry, which includes 90% of Danish patients with RA who are receiving biological therapy. Collected clinical data included disease duration, 28 swollen and tender joint counts, CRP, patient global score on a visual analog scale, IgM-rheumatoid factor status, number of previous biological therapies, and concomitant use of methotrexate and glucocorticoids. Self-reported patient data included marital status, education, smoking behavior, body mass index, exercise habits, extra-articular features, joint surgery, and comorbidities.

In addition to the EQ-5D, participants also completed the validated Danish Health Assessment Questionnaire.

Though limited by the factors inherent in observational study design, the study is strengthened by the nationwide recruitment, the fact that is was carried out in a clinical setting, and the fact that the study population had similar baseline demographic, clinical, and patent-reported values as have been reported for other RA patients treated with biological therapies in routine care in several other registries.

"This result suggests that our findings may be generalizable to patients with RA treated in routine care with biologicals in countries with a public healthcare system similar to the Danish model," the investigators wrote.

Hypermethylation in novel DNA biomarkers for prostate cancer predicted the cancer’s return after radical prostatectomy, according to a study published online Aug. 5 in the Journal of Clinical Oncology.

"To the best of our knowledge, this is the first report of a validated prognostic multigene methylation signature for [prostate cancer]," said Christa Haldrup, Ph.D., of Aarhus (Denmark) University Hospital and her colleagues (J. Clin. Oncol. 2013 Aug. 5 [doi: 10.1200/JCO.2012.47.1847]).

The study investigators identified six DNA methylation markers – hypermethylation of AOX1, C1orf114, GAS6, HAPLN3, KLF8, and MOB3B – as highly cancer specific. One of the potential markers, C1orf114 hypermethylation, and a methylation signature including the three genes AOX1, C1orf114, and HAPLN3 were independent predictors of time to biochemical recurrence after radical prostatectomy.

The researchers identified the markers using microarray-based screening and bisulfate sequencing of 20 nonmalignant tissue specimens and 29 prostate cancer (PC) tissue specimens. They then evaluated the markers’ diagnostic potential in a training cohort of 293 radical prostatectomy (RP) samples and a validation cohort of 114 RP samples.

High methylation of C1orf114 was significantly associated with biochemical recurrence of disease, according to multivariate analysis of the training cohort (hazard ratio, 3.10). This finding was confirmed in the validation cohort (HR, 3.27).

Similarly, a two-gene prognostic methylation signature (C1orf114 and HAPLN3) and the three-gene prognostic methylation signature also were significantly associated with biochemical recurrence in the training and validation cohorts.

When researchers analyzed the three-gene signature in high- and low-methylation subgroups, hypermethylation was significantly associated with recurrence in the training cohort (HR, 1.91) and validation cohort (HR, 2.33), the investigators said.

The two- and three-gene signatures performed markedly better as recurrence predictors than C10rf114 alone, and the three-gene signature performed slightly better than the two-gene signature, "suggesting that incorporation of a few genes into a simple dichotomized methylation-based test can improve robustness compared with a single-marker test," the investigators said.

"Three years after surgery, 52% and 41% of patients in the high-methylation group had experienced biochemical recurrence, compared with only 19% and 14% of patients in the low-methylation group in cohorts 1 and 2, respectively," they said.

Tissue samples for the study were collected in Denmark, Switzerland, Germany, and Finland. The training cohort consisted of "consecutive curatively intended RP of histologically verified, clinically localized PC" collected between 1993 and 2005 and previously used for tissue microarray construction. The validation cohort consisted of such samples collected from 1992 to 2003.

The six candidate genes were the most promising of eight that were initially selected for validation.

"Gene selection was based on difference in methylation levels between ADJ-N [adjacent normal] and PC samples, fold change in methylation levels between ADJ-N and PC samples, and, when possible, the presence of more than one CpG site indicating cancer-associated hypermethylation," the investigators wrote. "We preferably included genes not previously investigated in relation to PC."

For all candidate biomarkers, RP samples were significantly hypermethylated, compared with nonmalignant samples, they said.

"C1orf114 methylation as a continuous variable, and models based on dichotomized C1orf114, HAPLN3, and AOX1 methylation had significant independent prognostic value for prediction of biochemical recurrence in two RP patient cohorts from four different countries," the study authors said.

"The novel candidate methylation biomarkers were highly cancer specific" and were at level with or exceeded the known candidate PC methylation marker GSTP1 in this sample set, they added.

"The precise clinical utility of these new candidate methylation markers for PC diagnosis should be further investigated in studies including prostate biopsy, urine, or blood samples," the investigators said.

Future studies also should evaluate the prognostic potential of the markers in diagnostic biopsies. "Because only preoperative clinicopathologic parameters are available at this time, molecular markers may contribute relatively more independent prognostic information than after RP and, importantly, could be used to guide treatment decisions," the investigators said.

The Lundbeck Foundation, the John and Birthe Meyer Foundation, the Danish Cancer Society, and the Danish Council for Strategic Research supported the study. The authors reported having no disclosures.

Hypermethylation in novel DNA biomarkers for prostate cancer predicted the cancer’s return after radical prostatectomy, according to a study published online Aug. 5 in the Journal of Clinical Oncology.

"To the best of our knowledge, this is the first report of a validated prognostic multigene methylation signature for [prostate cancer]," said Christa Haldrup, Ph.D., of Aarhus (Denmark) University Hospital and her colleagues (J. Clin. Oncol. 2013 Aug. 5 [doi: 10.1200/JCO.2012.47.1847]).

The study investigators identified six DNA methylation markers – hypermethylation of AOX1, C1orf114, GAS6, HAPLN3, KLF8, and MOB3B – as highly cancer specific. One of the potential markers, C1orf114 hypermethylation, and a methylation signature including the three genes AOX1, C1orf114, and HAPLN3 were independent predictors of time to biochemical recurrence after radical prostatectomy.

The researchers identified the markers using microarray-based screening and bisulfate sequencing of 20 nonmalignant tissue specimens and 29 prostate cancer (PC) tissue specimens. They then evaluated the markers’ diagnostic potential in a training cohort of 293 radical prostatectomy (RP) samples and a validation cohort of 114 RP samples.

High methylation of C1orf114 was significantly associated with biochemical recurrence of disease, according to multivariate analysis of the training cohort (hazard ratio, 3.10). This finding was confirmed in the validation cohort (HR, 3.27).

Similarly, a two-gene prognostic methylation signature (C1orf114 and HAPLN3) and the three-gene prognostic methylation signature also were significantly associated with biochemical recurrence in the training and validation cohorts.

When researchers analyzed the three-gene signature in high- and low-methylation subgroups, hypermethylation was significantly associated with recurrence in the training cohort (HR, 1.91) and validation cohort (HR, 2.33), the investigators said.

The two- and three-gene signatures performed markedly better as recurrence predictors than C10rf114 alone, and the three-gene signature performed slightly better than the two-gene signature, "suggesting that incorporation of a few genes into a simple dichotomized methylation-based test can improve robustness compared with a single-marker test," the investigators said.

"Three years after surgery, 52% and 41% of patients in the high-methylation group had experienced biochemical recurrence, compared with only 19% and 14% of patients in the low-methylation group in cohorts 1 and 2, respectively," they said.

Tissue samples for the study were collected in Denmark, Switzerland, Germany, and Finland. The training cohort consisted of "consecutive curatively intended RP of histologically verified, clinically localized PC" collected between 1993 and 2005 and previously used for tissue microarray construction. The validation cohort consisted of such samples collected from 1992 to 2003.

The six candidate genes were the most promising of eight that were initially selected for validation.

"Gene selection was based on difference in methylation levels between ADJ-N [adjacent normal] and PC samples, fold change in methylation levels between ADJ-N and PC samples, and, when possible, the presence of more than one CpG site indicating cancer-associated hypermethylation," the investigators wrote. "We preferably included genes not previously investigated in relation to PC."

For all candidate biomarkers, RP samples were significantly hypermethylated, compared with nonmalignant samples, they said.

"C1orf114 methylation as a continuous variable, and models based on dichotomized C1orf114, HAPLN3, and AOX1 methylation had significant independent prognostic value for prediction of biochemical recurrence in two RP patient cohorts from four different countries," the study authors said.

"The novel candidate methylation biomarkers were highly cancer specific" and were at level with or exceeded the known candidate PC methylation marker GSTP1 in this sample set, they added.

"The precise clinical utility of these new candidate methylation markers for PC diagnosis should be further investigated in studies including prostate biopsy, urine, or blood samples," the investigators said.

Future studies also should evaluate the prognostic potential of the markers in diagnostic biopsies. "Because only preoperative clinicopathologic parameters are available at this time, molecular markers may contribute relatively more independent prognostic information than after RP and, importantly, could be used to guide treatment decisions," the investigators said.

The Lundbeck Foundation, the John and Birthe Meyer Foundation, the Danish Cancer Society, and the Danish Council for Strategic Research supported the study. The authors reported having no disclosures.

Hypermethylation in novel DNA biomarkers for prostate cancer predicted the cancer’s return after radical prostatectomy, according to a study published online Aug. 5 in the Journal of Clinical Oncology.

"To the best of our knowledge, this is the first report of a validated prognostic multigene methylation signature for [prostate cancer]," said Christa Haldrup, Ph.D., of Aarhus (Denmark) University Hospital and her colleagues (J. Clin. Oncol. 2013 Aug. 5 [doi: 10.1200/JCO.2012.47.1847]).

The study investigators identified six DNA methylation markers – hypermethylation of AOX1, C1orf114, GAS6, HAPLN3, KLF8, and MOB3B – as highly cancer specific. One of the potential markers, C1orf114 hypermethylation, and a methylation signature including the three genes AOX1, C1orf114, and HAPLN3 were independent predictors of time to biochemical recurrence after radical prostatectomy.

The researchers identified the markers using microarray-based screening and bisulfate sequencing of 20 nonmalignant tissue specimens and 29 prostate cancer (PC) tissue specimens. They then evaluated the markers’ diagnostic potential in a training cohort of 293 radical prostatectomy (RP) samples and a validation cohort of 114 RP samples.

High methylation of C1orf114 was significantly associated with biochemical recurrence of disease, according to multivariate analysis of the training cohort (hazard ratio, 3.10). This finding was confirmed in the validation cohort (HR, 3.27).

Similarly, a two-gene prognostic methylation signature (C1orf114 and HAPLN3) and the three-gene prognostic methylation signature also were significantly associated with biochemical recurrence in the training and validation cohorts.

When researchers analyzed the three-gene signature in high- and low-methylation subgroups, hypermethylation was significantly associated with recurrence in the training cohort (HR, 1.91) and validation cohort (HR, 2.33), the investigators said.

The two- and three-gene signatures performed markedly better as recurrence predictors than C10rf114 alone, and the three-gene signature performed slightly better than the two-gene signature, "suggesting that incorporation of a few genes into a simple dichotomized methylation-based test can improve robustness compared with a single-marker test," the investigators said.

"Three years after surgery, 52% and 41% of patients in the high-methylation group had experienced biochemical recurrence, compared with only 19% and 14% of patients in the low-methylation group in cohorts 1 and 2, respectively," they said.

Tissue samples for the study were collected in Denmark, Switzerland, Germany, and Finland. The training cohort consisted of "consecutive curatively intended RP of histologically verified, clinically localized PC" collected between 1993 and 2005 and previously used for tissue microarray construction. The validation cohort consisted of such samples collected from 1992 to 2003.

The six candidate genes were the most promising of eight that were initially selected for validation.

"Gene selection was based on difference in methylation levels between ADJ-N [adjacent normal] and PC samples, fold change in methylation levels between ADJ-N and PC samples, and, when possible, the presence of more than one CpG site indicating cancer-associated hypermethylation," the investigators wrote. "We preferably included genes not previously investigated in relation to PC."

For all candidate biomarkers, RP samples were significantly hypermethylated, compared with nonmalignant samples, they said.

"C1orf114 methylation as a continuous variable, and models based on dichotomized C1orf114, HAPLN3, and AOX1 methylation had significant independent prognostic value for prediction of biochemical recurrence in two RP patient cohorts from four different countries," the study authors said.

"The novel candidate methylation biomarkers were highly cancer specific" and were at level with or exceeded the known candidate PC methylation marker GSTP1 in this sample set, they added.

"The precise clinical utility of these new candidate methylation markers for PC diagnosis should be further investigated in studies including prostate biopsy, urine, or blood samples," the investigators said.

Future studies also should evaluate the prognostic potential of the markers in diagnostic biopsies. "Because only preoperative clinicopathologic parameters are available at this time, molecular markers may contribute relatively more independent prognostic information than after RP and, importantly, could be used to guide treatment decisions," the investigators said.

The Lundbeck Foundation, the John and Birthe Meyer Foundation, the Danish Cancer Society, and the Danish Council for Strategic Research supported the study. The authors reported having no disclosures.

Response-guided neoadjuvant chemotherapy may improve disease-free and overall survival in patients with early breast cancer, particularly in those patients with hormone receptor–positive tumors, findings from an exploratory analysis of data from the phase III GeparTrio trial suggest.

"Our exploratory analyses of this prospective trial strongly suggest that the various breast cancer phenotypes require different chemotherapy approaches and show that even patients with luminal tumors can derive greater benefit from response-guided chemotherapy," Dr. Gunter von Minckwitz of the German Breast Group, Neu-Isenburg, and his colleagues reported, noting that the findings must be tested prospectively but can be used to guide the design of future trials.

After treating 2,072 patients with two cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC), the researchers randomized 1,390 early responders to receive either four or six additional TAC cycles, and randomized 622 early nonresponders either to four additional TAC cycles or to non-cross-resistant treatment with vinorelbine and capecitabine (TAC-NX) before surgery. TAC cycles included 75 mg/m² of docetaxel, 50 mg/m² of doxorubicin, and 500 mg/m² of cyclophosphamide on day 1 every 3 weeks. NX included 25 mg/m² of vinorelbine on days 1 and 8 plus 1,000 mg/m² of capecitabine given orally twice daily on days 1-14 every 3 weeks. Sixty patients did not continue in the study after the initial TAC cycles.

Disease-free survival was better in the 686 early responders who received a total of eight TAC cycles, compared with the 704 patients who received six TAC cycles (hazard ratio, 0.78), and in 301 early nonresponders who received TAC-NX, compared with 321 early nonresponders who received six TAC cycles (HR, 0.59), the investigators reported online Sept. 3 in the Journal of Clinical Oncology.

An exploratory analysis demonstrated that both disease-free survival and overall survival were longer following either eight TAC cycles or TAC-NX, as compared with conventional chemotherapy with six TAC cycles (HRs, 0.71 and 0.79, respectively), the investigators reported (J. Clin. Oncol. 2013 Sept. 3 [doi: 10.1200/JCO.2012.45.0940]).

"Treatment effects on overall survival were less pronounced. Responders receiving TAC x 8 showed only a trend toward longer overall survival compared with those receiving TAC x 6 (hazard ratio, 0.76), whereas nonresponders receiving TAC-NX showed no improvement in overall survival compared with those receiving TAC x 6 (hazard ratio, 0.85). Response-guided chemotherapy provided significant but marginal overall survival benefit over conventional chemotherapy (hazard ratio, 0.79)," they said.

Of note, the effects of response-guided therapy on disease-free survival were apparent in all hormone receptor–positive tumors but not in hormone receptor–negative tumors, they noted (HRs for luminal A, luminal B HER2-negative, and luminal B HER2-positive tumors were 0.55, 0.40, and 0.56, respectively; HRs for nonluminal HER2-positive and triple-negative tumors were 1.01 and 0.87, respectively).

Pathological complete response (pCR) did not predict long-term outcomes; a comparison of pCR rates based on treatment strategy showed that "survival in patients with hormone receptor–positive tumors did not depend on pCR but was improved by response-guided therapy, whereas survival in patients with hormone receptor–negative tumors did depend on pCR but was not improved by response-guided therapy," they said. pCR predicted improved disease-free survival in triple-negative, nonluminal HER2-positive, and luminal B HER2-negative tumors (HRs, 6.67, 5.24, and 3.74, respectively), they reported.

Patients included in the study had unilateral or bilateral primary breast cancer confirmed by core biopsy, and had at least one additional risk factor, including age under 36, clinical tumor size more than 5 cm, estrogen receptor and progesterone receptor negativity, clinical axillary node involvement, or undifferentiated tumor grade.

The findings from the GeparTrio study demonstrate the advantage of neoadjuvant versus adjuvant chemotherapy. Response-guided treatment can only be conducted when the tumor is available for the monitoring of response, the investigators noted.

This study was supported by Amgen, Chugai, Roche, and Sanofi-Aventis. Dr. von Minckwitz and multiple coauthors reported serving as a consultant or advisor for, owning stock in, and/or receiving honoraria or research funding from Amgen, Roche, Sanofi-Aventis, and other companies.

Response-guided neoadjuvant chemotherapy may improve disease-free and overall survival in patients with early breast cancer, particularly in those patients with hormone receptor–positive tumors, findings from an exploratory analysis of data from the phase III GeparTrio trial suggest.

"Our exploratory analyses of this prospective trial strongly suggest that the various breast cancer phenotypes require different chemotherapy approaches and show that even patients with luminal tumors can derive greater benefit from response-guided chemotherapy," Dr. Gunter von Minckwitz of the German Breast Group, Neu-Isenburg, and his colleagues reported, noting that the findings must be tested prospectively but can be used to guide the design of future trials.

After treating 2,072 patients with two cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC), the researchers randomized 1,390 early responders to receive either four or six additional TAC cycles, and randomized 622 early nonresponders either to four additional TAC cycles or to non-cross-resistant treatment with vinorelbine and capecitabine (TAC-NX) before surgery. TAC cycles included 75 mg/m² of docetaxel, 50 mg/m² of doxorubicin, and 500 mg/m² of cyclophosphamide on day 1 every 3 weeks. NX included 25 mg/m² of vinorelbine on days 1 and 8 plus 1,000 mg/m² of capecitabine given orally twice daily on days 1-14 every 3 weeks. Sixty patients did not continue in the study after the initial TAC cycles.

Disease-free survival was better in the 686 early responders who received a total of eight TAC cycles, compared with the 704 patients who received six TAC cycles (hazard ratio, 0.78), and in 301 early nonresponders who received TAC-NX, compared with 321 early nonresponders who received six TAC cycles (HR, 0.59), the investigators reported online Sept. 3 in the Journal of Clinical Oncology.

An exploratory analysis demonstrated that both disease-free survival and overall survival were longer following either eight TAC cycles or TAC-NX, as compared with conventional chemotherapy with six TAC cycles (HRs, 0.71 and 0.79, respectively), the investigators reported (J. Clin. Oncol. 2013 Sept. 3 [doi: 10.1200/JCO.2012.45.0940]).

"Treatment effects on overall survival were less pronounced. Responders receiving TAC x 8 showed only a trend toward longer overall survival compared with those receiving TAC x 6 (hazard ratio, 0.76), whereas nonresponders receiving TAC-NX showed no improvement in overall survival compared with those receiving TAC x 6 (hazard ratio, 0.85). Response-guided chemotherapy provided significant but marginal overall survival benefit over conventional chemotherapy (hazard ratio, 0.79)," they said.

Of note, the effects of response-guided therapy on disease-free survival were apparent in all hormone receptor–positive tumors but not in hormone receptor–negative tumors, they noted (HRs for luminal A, luminal B HER2-negative, and luminal B HER2-positive tumors were 0.55, 0.40, and 0.56, respectively; HRs for nonluminal HER2-positive and triple-negative tumors were 1.01 and 0.87, respectively).

Pathological complete response (pCR) did not predict long-term outcomes; a comparison of pCR rates based on treatment strategy showed that "survival in patients with hormone receptor–positive tumors did not depend on pCR but was improved by response-guided therapy, whereas survival in patients with hormone receptor–negative tumors did depend on pCR but was not improved by response-guided therapy," they said. pCR predicted improved disease-free survival in triple-negative, nonluminal HER2-positive, and luminal B HER2-negative tumors (HRs, 6.67, 5.24, and 3.74, respectively), they reported.

Patients included in the study had unilateral or bilateral primary breast cancer confirmed by core biopsy, and had at least one additional risk factor, including age under 36, clinical tumor size more than 5 cm, estrogen receptor and progesterone receptor negativity, clinical axillary node involvement, or undifferentiated tumor grade.

The findings from the GeparTrio study demonstrate the advantage of neoadjuvant versus adjuvant chemotherapy. Response-guided treatment can only be conducted when the tumor is available for the monitoring of response, the investigators noted.

This study was supported by Amgen, Chugai, Roche, and Sanofi-Aventis. Dr. von Minckwitz and multiple coauthors reported serving as a consultant or advisor for, owning stock in, and/or receiving honoraria or research funding from Amgen, Roche, Sanofi-Aventis, and other companies.

Response-guided neoadjuvant chemotherapy may improve disease-free and overall survival in patients with early breast cancer, particularly in those patients with hormone receptor–positive tumors, findings from an exploratory analysis of data from the phase III GeparTrio trial suggest.

"Our exploratory analyses of this prospective trial strongly suggest that the various breast cancer phenotypes require different chemotherapy approaches and show that even patients with luminal tumors can derive greater benefit from response-guided chemotherapy," Dr. Gunter von Minckwitz of the German Breast Group, Neu-Isenburg, and his colleagues reported, noting that the findings must be tested prospectively but can be used to guide the design of future trials.

After treating 2,072 patients with two cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC), the researchers randomized 1,390 early responders to receive either four or six additional TAC cycles, and randomized 622 early nonresponders either to four additional TAC cycles or to non-cross-resistant treatment with vinorelbine and capecitabine (TAC-NX) before surgery. TAC cycles included 75 mg/m² of docetaxel, 50 mg/m² of doxorubicin, and 500 mg/m² of cyclophosphamide on day 1 every 3 weeks. NX included 25 mg/m² of vinorelbine on days 1 and 8 plus 1,000 mg/m² of capecitabine given orally twice daily on days 1-14 every 3 weeks. Sixty patients did not continue in the study after the initial TAC cycles.

Disease-free survival was better in the 686 early responders who received a total of eight TAC cycles, compared with the 704 patients who received six TAC cycles (hazard ratio, 0.78), and in 301 early nonresponders who received TAC-NX, compared with 321 early nonresponders who received six TAC cycles (HR, 0.59), the investigators reported online Sept. 3 in the Journal of Clinical Oncology.

An exploratory analysis demonstrated that both disease-free survival and overall survival were longer following either eight TAC cycles or TAC-NX, as compared with conventional chemotherapy with six TAC cycles (HRs, 0.71 and 0.79, respectively), the investigators reported (J. Clin. Oncol. 2013 Sept. 3 [doi: 10.1200/JCO.2012.45.0940]).

"Treatment effects on overall survival were less pronounced. Responders receiving TAC x 8 showed only a trend toward longer overall survival compared with those receiving TAC x 6 (hazard ratio, 0.76), whereas nonresponders receiving TAC-NX showed no improvement in overall survival compared with those receiving TAC x 6 (hazard ratio, 0.85). Response-guided chemotherapy provided significant but marginal overall survival benefit over conventional chemotherapy (hazard ratio, 0.79)," they said.

Of note, the effects of response-guided therapy on disease-free survival were apparent in all hormone receptor–positive tumors but not in hormone receptor–negative tumors, they noted (HRs for luminal A, luminal B HER2-negative, and luminal B HER2-positive tumors were 0.55, 0.40, and 0.56, respectively; HRs for nonluminal HER2-positive and triple-negative tumors were 1.01 and 0.87, respectively).

Pathological complete response (pCR) did not predict long-term outcomes; a comparison of pCR rates based on treatment strategy showed that "survival in patients with hormone receptor–positive tumors did not depend on pCR but was improved by response-guided therapy, whereas survival in patients with hormone receptor–negative tumors did depend on pCR but was not improved by response-guided therapy," they said. pCR predicted improved disease-free survival in triple-negative, nonluminal HER2-positive, and luminal B HER2-negative tumors (HRs, 6.67, 5.24, and 3.74, respectively), they reported.

Patients included in the study had unilateral or bilateral primary breast cancer confirmed by core biopsy, and had at least one additional risk factor, including age under 36, clinical tumor size more than 5 cm, estrogen receptor and progesterone receptor negativity, clinical axillary node involvement, or undifferentiated tumor grade.

The findings from the GeparTrio study demonstrate the advantage of neoadjuvant versus adjuvant chemotherapy. Response-guided treatment can only be conducted when the tumor is available for the monitoring of response, the investigators noted.

This study was supported by Amgen, Chugai, Roche, and Sanofi-Aventis. Dr. von Minckwitz and multiple coauthors reported serving as a consultant or advisor for, owning stock in, and/or receiving honoraria or research funding from Amgen, Roche, Sanofi-Aventis, and other companies.

Low-dose computed tomography reduces lung cancer mortality and all-cause mortality when used as a screening tool in asymptomatic adults at high risk for the disease, according to the results of a systematic review conducted for the U.S. Preventive Services Task Force.

In 2004, the USPSTF deemed the evidence insufficient for recommending for or against low-dose computed tomography (LDCT) for lung cancer screening in asymptomatic individuals, but the current review suggests screening has a definite benefit for most patients, Dr. Linda L. Humphrey, of Oregon Health and Science University and the Portland Veterans Affairs Medical Center, and her colleagues reported.

A draft recommendation based on the findings, published online in the Annals of Internal Medicine (2013 July 29 [doi: 10.7326/0003-4819-159-6-201309170-00690]), is available on the USPSTF website for comment.

©kutay tanir/iStockphoto.com

The researchers reviewed the literature published between 2000 and May 2013 and identified four trials that reported findings on the efficacy of LDCT screening in patients with smoking exposure for both intervention and control groups. Three small trials showed varying degrees of benefit with screening, but were underpowered; one large trial – the National Lung Screening Trial (NLST) – showed a significant 20% reduction in lung cancer mortality among those screened, as well as a 6.7% reduction in all-cause mortality.

The randomized multicenter NLST compared annual LDCT scans with annual single-view posterior-anterior chest radiographs for 3 years in more than 53,000 current or former smokers aged 55-74 years with at least a 30–pack-year history of smoking (N. Engl. J. Med. 2013;368:1980-91). One cancer death was prevented for every 320 patients who completed one screening, and one death from any cause was prevented for every 219 patients screened in that study; the trial was stopped early after 6.5 years of follow-up based on the findings.

The benefits of LDCT for lung cancer screening in this population outweighed the risks, they noted.

Harms associated with LDCT, according to findings from 7 trials and 13 cohort studies that reported on such outcomes, included radiation exposure, overdiagnosis, and a high rate of false-positive findings that were resolved by further imaging in most cases. False negatives were reported in six studies, and the rates ranged from 0% to 20%, but none of the studies evaluated the harm of false reassurance, the investigators noted. Screening benefits must be weighed against these potential harms.

Lung cancer is the leading cause of cancer-related deaths, accounting for nearly 27%. Furthermore, about 85% of U.S. lung cancer cases are attributable to smoking, and since about 20% of Americans currently smoke – and many more are former smokers who remain at increased risk because of their smoking history – "lung cancer will remain a major public health problem in this country for decades," the investigators wrote.

The studies included in this review were conducted in patients at high risk for lung cancer based on current or former smoking. However, patients at an increased risk for lung cancer, including older adults and those with a family history of lung cancer, chronic obstructive pulmonary disease, pulmonary fibrosis, and certain environmental and occupational exposures, may also benefit from LDCT screening.

"Future research to identify methods for focusing LDCT screening on persons at highest risk for disease, to improve discrimination between benign and malignant pulmonary nodules, and to find early indicators of aggressive disease is warranted," the investigators noted.

"If LDCT screening becomes routine, the risk for harms should be measured and methods to limit them identified."

The review was funded by grants from the Agency for Healthcare Research and Quality and the Portland Veterans Affairs Medical Center.

Low-dose computed tomography reduces lung cancer mortality and all-cause mortality when used as a screening tool in asymptomatic adults at high risk for the disease, according to the results of a systematic review conducted for the U.S. Preventive Services Task Force.

In 2004, the USPSTF deemed the evidence insufficient for recommending for or against low-dose computed tomography (LDCT) for lung cancer screening in asymptomatic individuals, but the current review suggests screening has a definite benefit for most patients, Dr. Linda L. Humphrey, of Oregon Health and Science University and the Portland Veterans Affairs Medical Center, and her colleagues reported.

A draft recommendation based on the findings, published online in the Annals of Internal Medicine (2013 July 29 [doi: 10.7326/0003-4819-159-6-201309170-00690]), is available on the USPSTF website for comment.

©kutay tanir/iStockphoto.com

The researchers reviewed the literature published between 2000 and May 2013 and identified four trials that reported findings on the efficacy of LDCT screening in patients with smoking exposure for both intervention and control groups. Three small trials showed varying degrees of benefit with screening, but were underpowered; one large trial – the National Lung Screening Trial (NLST) – showed a significant 20% reduction in lung cancer mortality among those screened, as well as a 6.7% reduction in all-cause mortality.

The randomized multicenter NLST compared annual LDCT scans with annual single-view posterior-anterior chest radiographs for 3 years in more than 53,000 current or former smokers aged 55-74 years with at least a 30–pack-year history of smoking (N. Engl. J. Med. 2013;368:1980-91). One cancer death was prevented for every 320 patients who completed one screening, and one death from any cause was prevented for every 219 patients screened in that study; the trial was stopped early after 6.5 years of follow-up based on the findings.

The benefits of LDCT for lung cancer screening in this population outweighed the risks, they noted.

Harms associated with LDCT, according to findings from 7 trials and 13 cohort studies that reported on such outcomes, included radiation exposure, overdiagnosis, and a high rate of false-positive findings that were resolved by further imaging in most cases. False negatives were reported in six studies, and the rates ranged from 0% to 20%, but none of the studies evaluated the harm of false reassurance, the investigators noted. Screening benefits must be weighed against these potential harms.

Lung cancer is the leading cause of cancer-related deaths, accounting for nearly 27%. Furthermore, about 85% of U.S. lung cancer cases are attributable to smoking, and since about 20% of Americans currently smoke – and many more are former smokers who remain at increased risk because of their smoking history – "lung cancer will remain a major public health problem in this country for decades," the investigators wrote.

The studies included in this review were conducted in patients at high risk for lung cancer based on current or former smoking. However, patients at an increased risk for lung cancer, including older adults and those with a family history of lung cancer, chronic obstructive pulmonary disease, pulmonary fibrosis, and certain environmental and occupational exposures, may also benefit from LDCT screening.

"Future research to identify methods for focusing LDCT screening on persons at highest risk for disease, to improve discrimination between benign and malignant pulmonary nodules, and to find early indicators of aggressive disease is warranted," the investigators noted.

"If LDCT screening becomes routine, the risk for harms should be measured and methods to limit them identified."

The review was funded by grants from the Agency for Healthcare Research and Quality and the Portland Veterans Affairs Medical Center.

Low-dose computed tomography reduces lung cancer mortality and all-cause mortality when used as a screening tool in asymptomatic adults at high risk for the disease, according to the results of a systematic review conducted for the U.S. Preventive Services Task Force.

In 2004, the USPSTF deemed the evidence insufficient for recommending for or against low-dose computed tomography (LDCT) for lung cancer screening in asymptomatic individuals, but the current review suggests screening has a definite benefit for most patients, Dr. Linda L. Humphrey, of Oregon Health and Science University and the Portland Veterans Affairs Medical Center, and her colleagues reported.

A draft recommendation based on the findings, published online in the Annals of Internal Medicine (2013 July 29 [doi: 10.7326/0003-4819-159-6-201309170-00690]), is available on the USPSTF website for comment.

©kutay tanir/iStockphoto.com

The researchers reviewed the literature published between 2000 and May 2013 and identified four trials that reported findings on the efficacy of LDCT screening in patients with smoking exposure for both intervention and control groups. Three small trials showed varying degrees of benefit with screening, but were underpowered; one large trial – the National Lung Screening Trial (NLST) – showed a significant 20% reduction in lung cancer mortality among those screened, as well as a 6.7% reduction in all-cause mortality.

The randomized multicenter NLST compared annual LDCT scans with annual single-view posterior-anterior chest radiographs for 3 years in more than 53,000 current or former smokers aged 55-74 years with at least a 30–pack-year history of smoking (N. Engl. J. Med. 2013;368:1980-91). One cancer death was prevented for every 320 patients who completed one screening, and one death from any cause was prevented for every 219 patients screened in that study; the trial was stopped early after 6.5 years of follow-up based on the findings.

The benefits of LDCT for lung cancer screening in this population outweighed the risks, they noted.

Harms associated with LDCT, according to findings from 7 trials and 13 cohort studies that reported on such outcomes, included radiation exposure, overdiagnosis, and a high rate of false-positive findings that were resolved by further imaging in most cases. False negatives were reported in six studies, and the rates ranged from 0% to 20%, but none of the studies evaluated the harm of false reassurance, the investigators noted. Screening benefits must be weighed against these potential harms.

Lung cancer is the leading cause of cancer-related deaths, accounting for nearly 27%. Furthermore, about 85% of U.S. lung cancer cases are attributable to smoking, and since about 20% of Americans currently smoke – and many more are former smokers who remain at increased risk because of their smoking history – "lung cancer will remain a major public health problem in this country for decades," the investigators wrote.

The studies included in this review were conducted in patients at high risk for lung cancer based on current or former smoking. However, patients at an increased risk for lung cancer, including older adults and those with a family history of lung cancer, chronic obstructive pulmonary disease, pulmonary fibrosis, and certain environmental and occupational exposures, may also benefit from LDCT screening.

"Future research to identify methods for focusing LDCT screening on persons at highest risk for disease, to improve discrimination between benign and malignant pulmonary nodules, and to find early indicators of aggressive disease is warranted," the investigators noted.

"If LDCT screening becomes routine, the risk for harms should be measured and methods to limit them identified."

The review was funded by grants from the Agency for Healthcare Research and Quality and the Portland Veterans Affairs Medical Center.

Treatment with the renin inhibitor aliskiren did not improve or slow the progression of coronary atherosclerosis in patients with prehypertension and coronary artery disease, according to the prospective, randomized, placebo-controlled Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study (AQUARIUS).

The change in the primary efficacy measure – percent atheroma volume (PAV) from baseline to completion – did not differ significantly in 225 subjects who were randomized to receive 300 mg of aliskiren for 104 weeks and 233 subjects who were randomized to receive a placebo (–0.33% vs. 0.11%, respectively), Dr. Stephen J. Nicholls of the South Australian Health and Medical Research Institute, Adelaide, Australia and his colleagues reported.

A secondary efficacy parameter – the change from baseline in normalized total atheroma volume (TAV) – also did not differ between the aliskiren and placebo groups (–4.1 mm³ vs. –2.1 mm³), and no significant differences were seen between the groups in the proportion of participants who experienced regression of PAV (56.9% vs. 48.9%) and TAV (64.4% vs. 57.5%), the investigators reported at the annual congress of the European Society of Cardiology.

The findings were simultaneously published online Sept. 3 in JAMA.

Patients included in AQUARIUS were adults over age 35 years with coronary artery disease and prehypertension, with systolic blood pressure of 125-139 mm Hg, and diastolic blood pressure less than 90 mm Hg, and with two additional cardiovascular risk factors. They were enrolled during March 2009–February 2011 at 103 participating academic and community hospitals in Europe, Australia, North America, and South America. At baseline, after coronary angiography, they underwent coronary intravascular ultrasound (IVUS) imaging.

A total of 613 participants were enrolled and treated with 150 mg of aliskiren for a 1-week run-in period before randomization. After 104 weeks, three-quarters of the patients, or 458, had a second IVUS on the same vessel (JAMA 2013 Sept. 3[doi:10.1001/jama.2013.277169]).

Patients with diabetes were withdrawn during the study period after a product label change warned that concomitant use of aliskiren in patients with diabetes who were treated with an ACE inhibitor or angiotensin receptor blocker was contraindicated; this alteration in the trial represents "a factor potentially confounding interpretation," the investigators noted.

Nonetheless, the study is among the first to evaluate the effect of renin inhibition on atherosclerotic plaque in patients with coronary atherosclerosis whose blood pressure was considered optimally controlled, they said.

"The benefit of additional blood pressure lowering agents in patients who have reached treatment goals has not been established. However, few trials have examined the benefits and risks of further intensifying blood pressure treatment in patient with established coronary artery disease (CAD) who are in the prehypertension range," they said.

Since renin-angiotensin-aldosterone system (RAAS) activation is known to play an important role in atherosclerosis, and since RAAS inhibition may have a direct beneficial effect on the artery wall, the investigators sought to determine if aliskiren, a direct renin inhibitor, would slow progression of coronary atherosclerosis in these patients.

"Aliskiren moderately reduced blood pressure, substantially reduced plasma renin activity, and produced a compensatory increase in plasma renin concentration," they wrote.

However, the primary and secondary IVUS endpoints failed to demonstrate a significant difference in disease progression between those who received aliskiren and those who received placebo.

"During the prespecified exploratory analysis, we observed fewer adjudicated major adverse cardiovascular events in the aliskiren group (26 vs. 50). Although these exploratory findings support the hypothesis of potential beneficial effects of renin inhibition in patients with preexisting CAD and blood pressure levels treated to goal, the current clinical findings are inconclusive. Definitive demonstration of a clinical outcome benefit will require a larger, adequately powered clinical trial with cardiovascular events prespecified as the primary end point," they said.

This study was sponsored by Novartis Pharmaceuticals. Dr. Nicholls reported receiving research support from AstraZeneca, Novartis, Eli Lilly, Anthera, LipoScience, Roche, and Resverlogix; and receiving honoraria from or serving as a consultant to AstraZeneca, Roche, Esperion, Abbott, Pfizer, Merck, Takeda, LipoScience, Omthera, Novo-Nordisk, sanofi-aventis, Atheronova, Anthera, CSL Behring, and Boehringer Ingelheim. Other authors also reported having disclosures. Details are available with the full text of the article at JAMA.com.

Treatment with the renin inhibitor aliskiren did not improve or slow the progression of coronary atherosclerosis in patients with prehypertension and coronary artery disease, according to the prospective, randomized, placebo-controlled Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study (AQUARIUS).

The change in the primary efficacy measure – percent atheroma volume (PAV) from baseline to completion – did not differ significantly in 225 subjects who were randomized to receive 300 mg of aliskiren for 104 weeks and 233 subjects who were randomized to receive a placebo (–0.33% vs. 0.11%, respectively), Dr. Stephen J. Nicholls of the South Australian Health and Medical Research Institute, Adelaide, Australia and his colleagues reported.

A secondary efficacy parameter – the change from baseline in normalized total atheroma volume (TAV) – also did not differ between the aliskiren and placebo groups (–4.1 mm³ vs. –2.1 mm³), and no significant differences were seen between the groups in the proportion of participants who experienced regression of PAV (56.9% vs. 48.9%) and TAV (64.4% vs. 57.5%), the investigators reported at the annual congress of the European Society of Cardiology.

The findings were simultaneously published online Sept. 3 in JAMA.

Patients included in AQUARIUS were adults over age 35 years with coronary artery disease and prehypertension, with systolic blood pressure of 125-139 mm Hg, and diastolic blood pressure less than 90 mm Hg, and with two additional cardiovascular risk factors. They were enrolled during March 2009–February 2011 at 103 participating academic and community hospitals in Europe, Australia, North America, and South America. At baseline, after coronary angiography, they underwent coronary intravascular ultrasound (IVUS) imaging.

A total of 613 participants were enrolled and treated with 150 mg of aliskiren for a 1-week run-in period before randomization. After 104 weeks, three-quarters of the patients, or 458, had a second IVUS on the same vessel (JAMA 2013 Sept. 3[doi:10.1001/jama.2013.277169]).

Patients with diabetes were withdrawn during the study period after a product label change warned that concomitant use of aliskiren in patients with diabetes who were treated with an ACE inhibitor or angiotensin receptor blocker was contraindicated; this alteration in the trial represents "a factor potentially confounding interpretation," the investigators noted.

Nonetheless, the study is among the first to evaluate the effect of renin inhibition on atherosclerotic plaque in patients with coronary atherosclerosis whose blood pressure was considered optimally controlled, they said.

"The benefit of additional blood pressure lowering agents in patients who have reached treatment goals has not been established. However, few trials have examined the benefits and risks of further intensifying blood pressure treatment in patient with established coronary artery disease (CAD) who are in the prehypertension range," they said.

Since renin-angiotensin-aldosterone system (RAAS) activation is known to play an important role in atherosclerosis, and since RAAS inhibition may have a direct beneficial effect on the artery wall, the investigators sought to determine if aliskiren, a direct renin inhibitor, would slow progression of coronary atherosclerosis in these patients.

"Aliskiren moderately reduced blood pressure, substantially reduced plasma renin activity, and produced a compensatory increase in plasma renin concentration," they wrote.

However, the primary and secondary IVUS endpoints failed to demonstrate a significant difference in disease progression between those who received aliskiren and those who received placebo.

"During the prespecified exploratory analysis, we observed fewer adjudicated major adverse cardiovascular events in the aliskiren group (26 vs. 50). Although these exploratory findings support the hypothesis of potential beneficial effects of renin inhibition in patients with preexisting CAD and blood pressure levels treated to goal, the current clinical findings are inconclusive. Definitive demonstration of a clinical outcome benefit will require a larger, adequately powered clinical trial with cardiovascular events prespecified as the primary end point," they said.

This study was sponsored by Novartis Pharmaceuticals. Dr. Nicholls reported receiving research support from AstraZeneca, Novartis, Eli Lilly, Anthera, LipoScience, Roche, and Resverlogix; and receiving honoraria from or serving as a consultant to AstraZeneca, Roche, Esperion, Abbott, Pfizer, Merck, Takeda, LipoScience, Omthera, Novo-Nordisk, sanofi-aventis, Atheronova, Anthera, CSL Behring, and Boehringer Ingelheim. Other authors also reported having disclosures. Details are available with the full text of the article at JAMA.com.

Treatment with the renin inhibitor aliskiren did not improve or slow the progression of coronary atherosclerosis in patients with prehypertension and coronary artery disease, according to the prospective, randomized, placebo-controlled Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study (AQUARIUS).

The change in the primary efficacy measure – percent atheroma volume (PAV) from baseline to completion – did not differ significantly in 225 subjects who were randomized to receive 300 mg of aliskiren for 104 weeks and 233 subjects who were randomized to receive a placebo (–0.33% vs. 0.11%, respectively), Dr. Stephen J. Nicholls of the South Australian Health and Medical Research Institute, Adelaide, Australia and his colleagues reported.

A secondary efficacy parameter – the change from baseline in normalized total atheroma volume (TAV) – also did not differ between the aliskiren and placebo groups (–4.1 mm³ vs. –2.1 mm³), and no significant differences were seen between the groups in the proportion of participants who experienced regression of PAV (56.9% vs. 48.9%) and TAV (64.4% vs. 57.5%), the investigators reported at the annual congress of the European Society of Cardiology.

The findings were simultaneously published online Sept. 3 in JAMA.

Patients included in AQUARIUS were adults over age 35 years with coronary artery disease and prehypertension, with systolic blood pressure of 125-139 mm Hg, and diastolic blood pressure less than 90 mm Hg, and with two additional cardiovascular risk factors. They were enrolled during March 2009–February 2011 at 103 participating academic and community hospitals in Europe, Australia, North America, and South America. At baseline, after coronary angiography, they underwent coronary intravascular ultrasound (IVUS) imaging.

A total of 613 participants were enrolled and treated with 150 mg of aliskiren for a 1-week run-in period before randomization. After 104 weeks, three-quarters of the patients, or 458, had a second IVUS on the same vessel (JAMA 2013 Sept. 3[doi:10.1001/jama.2013.277169]).

Patients with diabetes were withdrawn during the study period after a product label change warned that concomitant use of aliskiren in patients with diabetes who were treated with an ACE inhibitor or angiotensin receptor blocker was contraindicated; this alteration in the trial represents "a factor potentially confounding interpretation," the investigators noted.

Nonetheless, the study is among the first to evaluate the effect of renin inhibition on atherosclerotic plaque in patients with coronary atherosclerosis whose blood pressure was considered optimally controlled, they said.

"The benefit of additional blood pressure lowering agents in patients who have reached treatment goals has not been established. However, few trials have examined the benefits and risks of further intensifying blood pressure treatment in patient with established coronary artery disease (CAD) who are in the prehypertension range," they said.

Since renin-angiotensin-aldosterone system (RAAS) activation is known to play an important role in atherosclerosis, and since RAAS inhibition may have a direct beneficial effect on the artery wall, the investigators sought to determine if aliskiren, a direct renin inhibitor, would slow progression of coronary atherosclerosis in these patients.

"Aliskiren moderately reduced blood pressure, substantially reduced plasma renin activity, and produced a compensatory increase in plasma renin concentration," they wrote.

However, the primary and secondary IVUS endpoints failed to demonstrate a significant difference in disease progression between those who received aliskiren and those who received placebo.

"During the prespecified exploratory analysis, we observed fewer adjudicated major adverse cardiovascular events in the aliskiren group (26 vs. 50). Although these exploratory findings support the hypothesis of potential beneficial effects of renin inhibition in patients with preexisting CAD and blood pressure levels treated to goal, the current clinical findings are inconclusive. Definitive demonstration of a clinical outcome benefit will require a larger, adequately powered clinical trial with cardiovascular events prespecified as the primary end point," they said.

This study was sponsored by Novartis Pharmaceuticals. Dr. Nicholls reported receiving research support from AstraZeneca, Novartis, Eli Lilly, Anthera, LipoScience, Roche, and Resverlogix; and receiving honoraria from or serving as a consultant to AstraZeneca, Roche, Esperion, Abbott, Pfizer, Merck, Takeda, LipoScience, Omthera, Novo-Nordisk, sanofi-aventis, Atheronova, Anthera, CSL Behring, and Boehringer Ingelheim. Other authors also reported having disclosures. Details are available with the full text of the article at JAMA.com.

Neither saxagliptin nor alogliptin was associated with increased – or decreased – rates of major adverse cardiovascular events in high-risk patients with type 2 diabetes mellitus in separate randomized, double-blind, placebo-controlled trials.

The findings with respect to these recently approved antidiabetic therapies – members of the same class of selective dipeptidyl peptidase–4 (DDP-4) inhibitors – provide clinicians with important information to help guide treatment decision-making for patients with type 2 diabetes and cardiovascular risk, the authors concluded.

Both studies were mandated by the Food and Drug Administration, which in 2008 began requiring all diabetes therapies to demonstrate cardiovascular safety after concerns were raised in 2007 about a link between rosiglitazone (Avandia) and an increased risk of myocardial infarction. The results were reported at the annual congress of the European Society of Cardiology, and were simultaneously published online Sept. 2 in the New England Journal of Medicine.

SAVOR-TIMI 53

SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) randomized 16,492 patients with type 2 diabetes and a history of established cardiovascular disease or multiple risk factors for vascular disease to either saxagliptin, doses ranging from 2.5 to 5 mg daily, or placebo.

The primary endpoint – a composite of cardiovascular death, myocardial infarction, or ischemic stroke – occurred at similar rates in 613 patients randomized to receive saxagliptin treatment and 609 patients randomized to receive placebo (7.3% and 7.2%, respectively) at a median follow-up of 2.1 years, Dr. Benjamin M. Scirica of Brigham and Women’s Hospital and Harvard Medical School, Boston, and his colleagues reported on behalf of the SAVOR-TIMI 53 Steering Committee and Investigators.

A major secondary endpoint – a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure – also occurred at similar rates in the treatment and placebo groups (12.8% and 12.4%, respectively), they reported (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMoa1307684]).

However, more patients in the treatment group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%), they noted, adding that this was an unexpected finding that merits further study.

The findings demonstrate that DPP-4 inhibition with saxagliptin neither increases nor decreases the rate of ischemic events over a median 2-year period, although longer duration of treatment may have different effects.

"Together with ongoing trials of other DPP-4 inhibitors and novel antihyperglycemic agents, these data will provide a more rigorous and robust evidence base than is currently available to guide the future care of patients with diabetes," they concluded.

EXAMINE

Similarly, the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial showed that the primary endpoint – a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – did not occur significantly more often at a median follow-up of 18 months in 2,679 patients randomized to receive treatment, compared with 2,701 patients randomized to receive placebo (11.3% vs. 11.8%, respectively), Dr. William B. White of the University of Connecticut School of Medicine, Farmington, and his colleagues reported on behalf of the EXAMINE investigators.

Patients included in this noninferiority study had type 2 diabetes and a recent acute myocardial infarction or unstable angina requiring hospitalization, who received standard-of-care treatment for diabetes and cardiovascular risk factors throughout the study period. Alogliptin doses ranged from 6.25 to 25 mg daily on the basis of the patients’ estimated glomerular filtration rate at baseline.

"The alogliptin and placebo groups did not differ significantly with respect to the incidence of serious adverse events (33.6% and 35.5%, respectively)," the investigators wrote (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMoa1305889]).

In this group of patients at very high cardiovascular event risk, alogliptin did not increase or decrease cardiovascular morbidity or mortality over a median 18-month period; the findings do not rule out longer-term risks with respect to cardiovascular endpoints, they noted.

"These data can be used to help guide clinicians in choosing among the many available antidiabetic agents when treating patients with type 2 diabetes and very high cardiovascular risk," they concluded.

The SAVOR-TIMI 53 trial was supported by AstraZeneca and Bristol-Myers Squibb. The EXAMINE trial was supported by Takeda Development Center Americas. Multiple authors for both studies reported disclosures. Details are provided with the full text of each article at NEJM.org.

Neither saxagliptin nor alogliptin was associated with increased – or decreased – rates of major adverse cardiovascular events in high-risk patients with type 2 diabetes mellitus in separate randomized, double-blind, placebo-controlled trials.

The findings with respect to these recently approved antidiabetic therapies – members of the same class of selective dipeptidyl peptidase–4 (DDP-4) inhibitors – provide clinicians with important information to help guide treatment decision-making for patients with type 2 diabetes and cardiovascular risk, the authors concluded.

Both studies were mandated by the Food and Drug Administration, which in 2008 began requiring all diabetes therapies to demonstrate cardiovascular safety after concerns were raised in 2007 about a link between rosiglitazone (Avandia) and an increased risk of myocardial infarction. The results were reported at the annual congress of the European Society of Cardiology, and were simultaneously published online Sept. 2 in the New England Journal of Medicine.

SAVOR-TIMI 53

SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) randomized 16,492 patients with type 2 diabetes and a history of established cardiovascular disease or multiple risk factors for vascular disease to either saxagliptin, doses ranging from 2.5 to 5 mg daily, or placebo.

The primary endpoint – a composite of cardiovascular death, myocardial infarction, or ischemic stroke – occurred at similar rates in 613 patients randomized to receive saxagliptin treatment and 609 patients randomized to receive placebo (7.3% and 7.2%, respectively) at a median follow-up of 2.1 years, Dr. Benjamin M. Scirica of Brigham and Women’s Hospital and Harvard Medical School, Boston, and his colleagues reported on behalf of the SAVOR-TIMI 53 Steering Committee and Investigators.

A major secondary endpoint – a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure – also occurred at similar rates in the treatment and placebo groups (12.8% and 12.4%, respectively), they reported (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMoa1307684]).

However, more patients in the treatment group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%), they noted, adding that this was an unexpected finding that merits further study.

The findings demonstrate that DPP-4 inhibition with saxagliptin neither increases nor decreases the rate of ischemic events over a median 2-year period, although longer duration of treatment may have different effects.

"Together with ongoing trials of other DPP-4 inhibitors and novel antihyperglycemic agents, these data will provide a more rigorous and robust evidence base than is currently available to guide the future care of patients with diabetes," they concluded.

EXAMINE

Similarly, the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial showed that the primary endpoint – a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – did not occur significantly more often at a median follow-up of 18 months in 2,679 patients randomized to receive treatment, compared with 2,701 patients randomized to receive placebo (11.3% vs. 11.8%, respectively), Dr. William B. White of the University of Connecticut School of Medicine, Farmington, and his colleagues reported on behalf of the EXAMINE investigators.

Patients included in this noninferiority study had type 2 diabetes and a recent acute myocardial infarction or unstable angina requiring hospitalization, who received standard-of-care treatment for diabetes and cardiovascular risk factors throughout the study period. Alogliptin doses ranged from 6.25 to 25 mg daily on the basis of the patients’ estimated glomerular filtration rate at baseline.

"The alogliptin and placebo groups did not differ significantly with respect to the incidence of serious adverse events (33.6% and 35.5%, respectively)," the investigators wrote (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMoa1305889]).

In this group of patients at very high cardiovascular event risk, alogliptin did not increase or decrease cardiovascular morbidity or mortality over a median 18-month period; the findings do not rule out longer-term risks with respect to cardiovascular endpoints, they noted.

"These data can be used to help guide clinicians in choosing among the many available antidiabetic agents when treating patients with type 2 diabetes and very high cardiovascular risk," they concluded.

The SAVOR-TIMI 53 trial was supported by AstraZeneca and Bristol-Myers Squibb. The EXAMINE trial was supported by Takeda Development Center Americas. Multiple authors for both studies reported disclosures. Details are provided with the full text of each article at NEJM.org.

Neither saxagliptin nor alogliptin was associated with increased – or decreased – rates of major adverse cardiovascular events in high-risk patients with type 2 diabetes mellitus in separate randomized, double-blind, placebo-controlled trials.

The findings with respect to these recently approved antidiabetic therapies – members of the same class of selective dipeptidyl peptidase–4 (DDP-4) inhibitors – provide clinicians with important information to help guide treatment decision-making for patients with type 2 diabetes and cardiovascular risk, the authors concluded.

Both studies were mandated by the Food and Drug Administration, which in 2008 began requiring all diabetes therapies to demonstrate cardiovascular safety after concerns were raised in 2007 about a link between rosiglitazone (Avandia) and an increased risk of myocardial infarction. The results were reported at the annual congress of the European Society of Cardiology, and were simultaneously published online Sept. 2 in the New England Journal of Medicine.

SAVOR-TIMI 53

SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) randomized 16,492 patients with type 2 diabetes and a history of established cardiovascular disease or multiple risk factors for vascular disease to either saxagliptin, doses ranging from 2.5 to 5 mg daily, or placebo.

The primary endpoint – a composite of cardiovascular death, myocardial infarction, or ischemic stroke – occurred at similar rates in 613 patients randomized to receive saxagliptin treatment and 609 patients randomized to receive placebo (7.3% and 7.2%, respectively) at a median follow-up of 2.1 years, Dr. Benjamin M. Scirica of Brigham and Women’s Hospital and Harvard Medical School, Boston, and his colleagues reported on behalf of the SAVOR-TIMI 53 Steering Committee and Investigators.

A major secondary endpoint – a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure – also occurred at similar rates in the treatment and placebo groups (12.8% and 12.4%, respectively), they reported (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMoa1307684]).

However, more patients in the treatment group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%), they noted, adding that this was an unexpected finding that merits further study.

The findings demonstrate that DPP-4 inhibition with saxagliptin neither increases nor decreases the rate of ischemic events over a median 2-year period, although longer duration of treatment may have different effects.

"Together with ongoing trials of other DPP-4 inhibitors and novel antihyperglycemic agents, these data will provide a more rigorous and robust evidence base than is currently available to guide the future care of patients with diabetes," they concluded.

EXAMINE

Similarly, the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial showed that the primary endpoint – a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – did not occur significantly more often at a median follow-up of 18 months in 2,679 patients randomized to receive treatment, compared with 2,701 patients randomized to receive placebo (11.3% vs. 11.8%, respectively), Dr. William B. White of the University of Connecticut School of Medicine, Farmington, and his colleagues reported on behalf of the EXAMINE investigators.

Patients included in this noninferiority study had type 2 diabetes and a recent acute myocardial infarction or unstable angina requiring hospitalization, who received standard-of-care treatment for diabetes and cardiovascular risk factors throughout the study period. Alogliptin doses ranged from 6.25 to 25 mg daily on the basis of the patients’ estimated glomerular filtration rate at baseline.

"The alogliptin and placebo groups did not differ significantly with respect to the incidence of serious adverse events (33.6% and 35.5%, respectively)," the investigators wrote (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMoa1305889]).

In this group of patients at very high cardiovascular event risk, alogliptin did not increase or decrease cardiovascular morbidity or mortality over a median 18-month period; the findings do not rule out longer-term risks with respect to cardiovascular endpoints, they noted.

"These data can be used to help guide clinicians in choosing among the many available antidiabetic agents when treating patients with type 2 diabetes and very high cardiovascular risk," they concluded.

The SAVOR-TIMI 53 trial was supported by AstraZeneca and Bristol-Myers Squibb. The EXAMINE trial was supported by Takeda Development Center Americas. Multiple authors for both studies reported disclosures. Details are provided with the full text of each article at NEJM.org.

Pretreatment with the P2Y₁₂ antagonist prasugrel in patients with non-ST–segment elevation acute coronary syndromes did not reduce the rate of major ischemic events, but did increase the rate of major bleeding complications within 30 days of coronary angiography in the randomized, controlled, phase III ACCOAST trial.

The incidence of the primary efficacy endpoint – a composite of death from cardiovascular causes, myocardial infarction, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor rescue therapy through day 7 – was similar in 2,037 patients who were randomized to receive prasugrel before and after angiography, and in 1,996 patients who were randomized to receive treatment only after angiography (10.0% and 9.8%; respectively; hazard ratio, 1.02), Dr. Gilles Montalescot of Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, and colleagues found.

The findings were similar, with no significant differences noted between the pretreatment and control groups with respect to the primary efficacy endpoint, among the 2,770 patients managed by percutaneous coronary intervention (PCI), compared with the entire cohort ultimately managed by PCI, coronary artery bypass grafting (CABG), or medical treatment alone.

However, the rate of a key safety endpoint – thrombolysis in myocardial infarction (TIMI) major bleeding episodes through day 7 – was increased in those in the pretreatment group, compared with the control group (2.6% vs. 1.4%; hazard ratio, 1.90), the investigators said, noting that the findings, which were reported at the annual congress of the European Society of Cardiology and simultaneously published online Sept. 1 in the New England Journal of Medicine, were confirmed at 30 days.

"There was an increase by a factor of 3 in all major bleeding not related to CABG and an increase by a factor of 6 in life-threatening bleeding not related to CABG. TIMI minor bleeding events were also increased with pretreatment compared with no pretreatment (hazard ratio, 2.50)," they wrote (N. Engl. J. Med. 2013 Sept. 1 [doi:10.1056/NEJM1308075]).

Patients in the trial were adults with a mean age of 63 years who had non-ST–segment elevation (NSTE) acute coronary syndromes and a positive troponin level. They were enrolled between Dec. 6, 2009, and Nov. 16, 2012. All were scheduled to undergo coronary angiography within 2-48 hours following randomization.

Those randomized to the pretreatment group received a 30-mg loading dose with prasugrel before angiography, and an additional 30 mg at the time of PCI. Those randomized to the control group received a placebo before the angiography, and 60 mg of prasugrel at the time of PCI.

In a pharmacodynamic substudy involving 23 patients, the investigators noted that "at the time of arterial access, a median of 4.8 hours after the first loading dose, there was greater platelet inhibition in the pretreatment group than in the control group, which may have contributed to the increased rate of bleeding complications in the pretreatment group."

Of note, the lack of protection afforded by prasugrel against ischemic events was demonstrated consistently across all prespecified subgroups, including high-risk groups such as the elderly, those with diabetes, and those with a Global Registry of Acute Coronary Events (GRACE) risk score of 140 or higher.

"This suggests that stronger [than clopidogrel] antiplatelet therapy does not prevent the occurrence of a myocardial infarction before catheterization or after PCI," the investigators wrote. Nonetheless, the lack of P2Y₁₂ inhibition in the control group did notresult in an excess of ischemic events in patients who underwent CABG or medical therapy. In fact, other studies have shown that currently, the risk of ischemic events is "extremely low" because of the short time between admission to the hospital and catheterization.

The benefit of adding clopidogrel to aspirin in patients with NSTE acute coronary syndromes was demonstrated in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study, in which a small subgroup of patients received the drug prior to undergoing PCI; the significant reduction in ischemic events set a precedent for clopidogrel treatment before catheterization, although subsequent studies have not supported the finding. The pretreatment use of clopidogrel and aspirin in patients with NSTE acute coronary syndrome to help reduce ischemic events following an invasive procedure is commonplace, and is included as a class I recommendation in guidelines from the American College of Cardiology Foundation–American Heart Association. This is despite a lack of rigorous studies supporting the practice, which has often been extended to new oral P2Y₁₂ antagonists like prasugrel as well, they explained.

However, prasugrel is more potent and has a more rapid onset of action than clopidogrel. "Our results support the administration of prasugrel when the coronary anatomy is known and after PCI is selected as the treatment strategy," they concluded.

This study was supported by Daiichi Sankyo and Eli Lilly. Multiple study authors, including Dr. Montalescot, reported having disclosures.

Pretreatment with the P2Y₁₂ antagonist prasugrel in patients with non-ST–segment elevation acute coronary syndromes did not reduce the rate of major ischemic events, but did increase the rate of major bleeding complications within 30 days of coronary angiography in the randomized, controlled, phase III ACCOAST trial.

The incidence of the primary efficacy endpoint – a composite of death from cardiovascular causes, myocardial infarction, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor rescue therapy through day 7 – was similar in 2,037 patients who were randomized to receive prasugrel before and after angiography, and in 1,996 patients who were randomized to receive treatment only after angiography (10.0% and 9.8%; respectively; hazard ratio, 1.02), Dr. Gilles Montalescot of Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, and colleagues found.

The findings were similar, with no significant differences noted between the pretreatment and control groups with respect to the primary efficacy endpoint, among the 2,770 patients managed by percutaneous coronary intervention (PCI), compared with the entire cohort ultimately managed by PCI, coronary artery bypass grafting (CABG), or medical treatment alone.

However, the rate of a key safety endpoint – thrombolysis in myocardial infarction (TIMI) major bleeding episodes through day 7 – was increased in those in the pretreatment group, compared with the control group (2.6% vs. 1.4%; hazard ratio, 1.90), the investigators said, noting that the findings, which were reported at the annual congress of the European Society of Cardiology and simultaneously published online Sept. 1 in the New England Journal of Medicine, were confirmed at 30 days.

"There was an increase by a factor of 3 in all major bleeding not related to CABG and an increase by a factor of 6 in life-threatening bleeding not related to CABG. TIMI minor bleeding events were also increased with pretreatment compared with no pretreatment (hazard ratio, 2.50)," they wrote (N. Engl. J. Med. 2013 Sept. 1 [doi:10.1056/NEJM1308075]).

Patients in the trial were adults with a mean age of 63 years who had non-ST–segment elevation (NSTE) acute coronary syndromes and a positive troponin level. They were enrolled between Dec. 6, 2009, and Nov. 16, 2012. All were scheduled to undergo coronary angiography within 2-48 hours following randomization.

Those randomized to the pretreatment group received a 30-mg loading dose with prasugrel before angiography, and an additional 30 mg at the time of PCI. Those randomized to the control group received a placebo before the angiography, and 60 mg of prasugrel at the time of PCI.

In a pharmacodynamic substudy involving 23 patients, the investigators noted that "at the time of arterial access, a median of 4.8 hours after the first loading dose, there was greater platelet inhibition in the pretreatment group than in the control group, which may have contributed to the increased rate of bleeding complications in the pretreatment group."

Of note, the lack of protection afforded by prasugrel against ischemic events was demonstrated consistently across all prespecified subgroups, including high-risk groups such as the elderly, those with diabetes, and those with a Global Registry of Acute Coronary Events (GRACE) risk score of 140 or higher.

"This suggests that stronger [than clopidogrel] antiplatelet therapy does not prevent the occurrence of a myocardial infarction before catheterization or after PCI," the investigators wrote. Nonetheless, the lack of P2Y₁₂ inhibition in the control group did notresult in an excess of ischemic events in patients who underwent CABG or medical therapy. In fact, other studies have shown that currently, the risk of ischemic events is "extremely low" because of the short time between admission to the hospital and catheterization.

The benefit of adding clopidogrel to aspirin in patients with NSTE acute coronary syndromes was demonstrated in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study, in which a small subgroup of patients received the drug prior to undergoing PCI; the significant reduction in ischemic events set a precedent for clopidogrel treatment before catheterization, although subsequent studies have not supported the finding. The pretreatment use of clopidogrel and aspirin in patients with NSTE acute coronary syndrome to help reduce ischemic events following an invasive procedure is commonplace, and is included as a class I recommendation in guidelines from the American College of Cardiology Foundation–American Heart Association. This is despite a lack of rigorous studies supporting the practice, which has often been extended to new oral P2Y₁₂ antagonists like prasugrel as well, they explained.

However, prasugrel is more potent and has a more rapid onset of action than clopidogrel. "Our results support the administration of prasugrel when the coronary anatomy is known and after PCI is selected as the treatment strategy," they concluded.

This study was supported by Daiichi Sankyo and Eli Lilly. Multiple study authors, including Dr. Montalescot, reported having disclosures.

Pretreatment with the P2Y₁₂ antagonist prasugrel in patients with non-ST–segment elevation acute coronary syndromes did not reduce the rate of major ischemic events, but did increase the rate of major bleeding complications within 30 days of coronary angiography in the randomized, controlled, phase III ACCOAST trial.

The incidence of the primary efficacy endpoint – a composite of death from cardiovascular causes, myocardial infarction, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor rescue therapy through day 7 – was similar in 2,037 patients who were randomized to receive prasugrel before and after angiography, and in 1,996 patients who were randomized to receive treatment only after angiography (10.0% and 9.8%; respectively; hazard ratio, 1.02), Dr. Gilles Montalescot of Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, and colleagues found.

The findings were similar, with no significant differences noted between the pretreatment and control groups with respect to the primary efficacy endpoint, among the 2,770 patients managed by percutaneous coronary intervention (PCI), compared with the entire cohort ultimately managed by PCI, coronary artery bypass grafting (CABG), or medical treatment alone.

However, the rate of a key safety endpoint – thrombolysis in myocardial infarction (TIMI) major bleeding episodes through day 7 – was increased in those in the pretreatment group, compared with the control group (2.6% vs. 1.4%; hazard ratio, 1.90), the investigators said, noting that the findings, which were reported at the annual congress of the European Society of Cardiology and simultaneously published online Sept. 1 in the New England Journal of Medicine, were confirmed at 30 days.

"There was an increase by a factor of 3 in all major bleeding not related to CABG and an increase by a factor of 6 in life-threatening bleeding not related to CABG. TIMI minor bleeding events were also increased with pretreatment compared with no pretreatment (hazard ratio, 2.50)," they wrote (N. Engl. J. Med. 2013 Sept. 1 [doi:10.1056/NEJM1308075]).

Patients in the trial were adults with a mean age of 63 years who had non-ST–segment elevation (NSTE) acute coronary syndromes and a positive troponin level. They were enrolled between Dec. 6, 2009, and Nov. 16, 2012. All were scheduled to undergo coronary angiography within 2-48 hours following randomization.

Those randomized to the pretreatment group received a 30-mg loading dose with prasugrel before angiography, and an additional 30 mg at the time of PCI. Those randomized to the control group received a placebo before the angiography, and 60 mg of prasugrel at the time of PCI.

In a pharmacodynamic substudy involving 23 patients, the investigators noted that "at the time of arterial access, a median of 4.8 hours after the first loading dose, there was greater platelet inhibition in the pretreatment group than in the control group, which may have contributed to the increased rate of bleeding complications in the pretreatment group."

Of note, the lack of protection afforded by prasugrel against ischemic events was demonstrated consistently across all prespecified subgroups, including high-risk groups such as the elderly, those with diabetes, and those with a Global Registry of Acute Coronary Events (GRACE) risk score of 140 or higher.

"This suggests that stronger [than clopidogrel] antiplatelet therapy does not prevent the occurrence of a myocardial infarction before catheterization or after PCI," the investigators wrote. Nonetheless, the lack of P2Y₁₂ inhibition in the control group did notresult in an excess of ischemic events in patients who underwent CABG or medical therapy. In fact, other studies have shown that currently, the risk of ischemic events is "extremely low" because of the short time between admission to the hospital and catheterization.

The benefit of adding clopidogrel to aspirin in patients with NSTE acute coronary syndromes was demonstrated in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study, in which a small subgroup of patients received the drug prior to undergoing PCI; the significant reduction in ischemic events set a precedent for clopidogrel treatment before catheterization, although subsequent studies have not supported the finding. The pretreatment use of clopidogrel and aspirin in patients with NSTE acute coronary syndrome to help reduce ischemic events following an invasive procedure is commonplace, and is included as a class I recommendation in guidelines from the American College of Cardiology Foundation–American Heart Association. This is despite a lack of rigorous studies supporting the practice, which has often been extended to new oral P2Y₁₂ antagonists like prasugrel as well, they explained.

However, prasugrel is more potent and has a more rapid onset of action than clopidogrel. "Our results support the administration of prasugrel when the coronary anatomy is known and after PCI is selected as the treatment strategy," they concluded.

This study was supported by Daiichi Sankyo and Eli Lilly. Multiple study authors, including Dr. Montalescot, reported having disclosures.

Carbonation produces a decrease in the neural processing of sweetness-related signals, particularly those from sucrose, a small functional neuroimaging study shows.

The findings, which suggest that the combination of CO₂ and sucrose might increase consumption of sucrose, could have implications for dietary interventions designed to regulate caloric intake, according to Dr. Francesco Di Salle of Salerno (Italy) University and his colleagues.

To assess the interference between CO₂ and perception of sweetness, as well as the differential effects of CO₂ on sucrose and aspartame-acesulfame, (As-Ac, an artificial sweetener combination commonly used in diet beverages), the investigators performed two functional magnetic resonance imaging (fMRI) experiments to evaluate changes in regional brain activity.

The first experiment, performed in nine volunteers, analyzed the effect of carbonation in four sweet Sprite-based solutions, including one carbonated and sweetened with sucrose, one noncarbonated and sweetened with sucrose, one carbonated and sweetened with As-Ac, and one noncarbonated and sweetened with As-Ac. The second experiment evaluated the spatial location of the strongest neural effects of sour taste and CO₂ within the insular cortex of eight subjects.

On fMRI, the presence of carbonation in sweet solutions "independently of the sweetening agent, reduced neural activity in the anterior insula (AI), orbitofrontal cortex (OFC), and posterior pons ... the effect of carbonation on sucrose was much higher than on perception of As-Ac," they noted, explaining that "at the perceptual level ... carbonation reduced the perception of sweetness and the differences between the sensory profiles of sucrose and As-Ac."

This effect may increase sucrose intake, but is also favorable to diet beverage formulations being perceived as similar to regular beverage formulations, the investigators reported online May 28 ahead of print in Gastroenterology.

"It is also coherent with a process of prioritization among perceptual inputs (chemesthetic and gustatory information) deriving from the same body topography and converging to the same cortical regions (AI, OFC), they said (Gastroenterology 2013 [doi:10.1053/j.gastro.2013.05.041]).

To correlate neuroimaging with behavioral data, the ability of carbonation to modulate perception of sweetness was assessed in 14 subjects, who scored the level of perceived sweetness of the solutions on a visual analog scale ranging from 0 to 100 mm. The effect of 1,585 ppm of CO₂ added to a 10% glucose solution on the perception of sweetness was also tested in seven subjects.

CO₂ was able to significantly reduce sweet-induced taste perceptions as assessed by the volunteers’ visual analog scale recordings: The perception of Sprite-associated sweetness was significantly reduced by CO₂ (48 vs. 63 and 48 vs. 55 for As-Ac and sucrose, respectively).

"Similarly, in the presence of carbonation, sweet-induced perception of a 10% glucose solution was significantly reduced (36 vs. 53), the investigators said.

Given the widespread use of CO₂ in sweet beverages, the modulation of sweet perception by CO₂ is of interest, they noted.

The findings, which suggest that CO₂ modulates the perception of sweetness thereby reducing the global neural processing of sweetness, the processing of sucrose more than of As-Ac, and the processing difference between sweetening agents via modulation of the perception of sweetness, is "of utmost importance for designing carbonated beverages and is relevant to the regulation of caloric intake," they said.

"This effect is driven by the integration of information on gastric fullness and on nutrient depletion, conveyed to a brain network where the autonomic brainstem circuitry and tractus solitarius neurons play a critical role in homeostatic functions," they added.

It may be that taste and CO₂-related information influence food choices and intake through integration in the tractus solitarius with input from the gastrointestinal tract, they suggested, explaining that "the reduced discrimination between sucrose and As-Ac induced by CO₂ would promote the consumptions of low-calorie beverages and would converge with CO₂-induced gastric distention in limiting caloric intake."

This study was supported in part by the Coca-Cola Company. One author, Dr. Rosario Cuomo, was sponsored by the Coca-Cola Company. The remaining authors reported having no disclosures.

Carbonation produces a decrease in the neural processing of sweetness-related signals, particularly those from sucrose, a small functional neuroimaging study shows.

The findings, which suggest that the combination of CO₂ and sucrose might increase consumption of sucrose, could have implications for dietary interventions designed to regulate caloric intake, according to Dr. Francesco Di Salle of Salerno (Italy) University and his colleagues.

To assess the interference between CO₂ and perception of sweetness, as well as the differential effects of CO₂ on sucrose and aspartame-acesulfame, (As-Ac, an artificial sweetener combination commonly used in diet beverages), the investigators performed two functional magnetic resonance imaging (fMRI) experiments to evaluate changes in regional brain activity.

The first experiment, performed in nine volunteers, analyzed the effect of carbonation in four sweet Sprite-based solutions, including one carbonated and sweetened with sucrose, one noncarbonated and sweetened with sucrose, one carbonated and sweetened with As-Ac, and one noncarbonated and sweetened with As-Ac. The second experiment evaluated the spatial location of the strongest neural effects of sour taste and CO₂ within the insular cortex of eight subjects.

On fMRI, the presence of carbonation in sweet solutions "independently of the sweetening agent, reduced neural activity in the anterior insula (AI), orbitofrontal cortex (OFC), and posterior pons ... the effect of carbonation on sucrose was much higher than on perception of As-Ac," they noted, explaining that "at the perceptual level ... carbonation reduced the perception of sweetness and the differences between the sensory profiles of sucrose and As-Ac."

This effect may increase sucrose intake, but is also favorable to diet beverage formulations being perceived as similar to regular beverage formulations, the investigators reported online May 28 ahead of print in Gastroenterology.

"It is also coherent with a process of prioritization among perceptual inputs (chemesthetic and gustatory information) deriving from the same body topography and converging to the same cortical regions (AI, OFC), they said (Gastroenterology 2013 [doi:10.1053/j.gastro.2013.05.041]).

To correlate neuroimaging with behavioral data, the ability of carbonation to modulate perception of sweetness was assessed in 14 subjects, who scored the level of perceived sweetness of the solutions on a visual analog scale ranging from 0 to 100 mm. The effect of 1,585 ppm of CO₂ added to a 10% glucose solution on the perception of sweetness was also tested in seven subjects.

CO₂ was able to significantly reduce sweet-induced taste perceptions as assessed by the volunteers’ visual analog scale recordings: The perception of Sprite-associated sweetness was significantly reduced by CO₂ (48 vs. 63 and 48 vs. 55 for As-Ac and sucrose, respectively).

"Similarly, in the presence of carbonation, sweet-induced perception of a 10% glucose solution was significantly reduced (36 vs. 53), the investigators said.

Given the widespread use of CO₂ in sweet beverages, the modulation of sweet perception by CO₂ is of interest, they noted.

The findings, which suggest that CO₂ modulates the perception of sweetness thereby reducing the global neural processing of sweetness, the processing of sucrose more than of As-Ac, and the processing difference between sweetening agents via modulation of the perception of sweetness, is "of utmost importance for designing carbonated beverages and is relevant to the regulation of caloric intake," they said.

"This effect is driven by the integration of information on gastric fullness and on nutrient depletion, conveyed to a brain network where the autonomic brainstem circuitry and tractus solitarius neurons play a critical role in homeostatic functions," they added.

It may be that taste and CO₂-related information influence food choices and intake through integration in the tractus solitarius with input from the gastrointestinal tract, they suggested, explaining that "the reduced discrimination between sucrose and As-Ac induced by CO₂ would promote the consumptions of low-calorie beverages and would converge with CO₂-induced gastric distention in limiting caloric intake."

This study was supported in part by the Coca-Cola Company. One author, Dr. Rosario Cuomo, was sponsored by the Coca-Cola Company. The remaining authors reported having no disclosures.

Carbonation produces a decrease in the neural processing of sweetness-related signals, particularly those from sucrose, a small functional neuroimaging study shows.

The findings, which suggest that the combination of CO₂ and sucrose might increase consumption of sucrose, could have implications for dietary interventions designed to regulate caloric intake, according to Dr. Francesco Di Salle of Salerno (Italy) University and his colleagues.

To assess the interference between CO₂ and perception of sweetness, as well as the differential effects of CO₂ on sucrose and aspartame-acesulfame, (As-Ac, an artificial sweetener combination commonly used in diet beverages), the investigators performed two functional magnetic resonance imaging (fMRI) experiments to evaluate changes in regional brain activity.

The first experiment, performed in nine volunteers, analyzed the effect of carbonation in four sweet Sprite-based solutions, including one carbonated and sweetened with sucrose, one noncarbonated and sweetened with sucrose, one carbonated and sweetened with As-Ac, and one noncarbonated and sweetened with As-Ac. The second experiment evaluated the spatial location of the strongest neural effects of sour taste and CO₂ within the insular cortex of eight subjects.

On fMRI, the presence of carbonation in sweet solutions "independently of the sweetening agent, reduced neural activity in the anterior insula (AI), orbitofrontal cortex (OFC), and posterior pons ... the effect of carbonation on sucrose was much higher than on perception of As-Ac," they noted, explaining that "at the perceptual level ... carbonation reduced the perception of sweetness and the differences between the sensory profiles of sucrose and As-Ac."

This effect may increase sucrose intake, but is also favorable to diet beverage formulations being perceived as similar to regular beverage formulations, the investigators reported online May 28 ahead of print in Gastroenterology.

"It is also coherent with a process of prioritization among perceptual inputs (chemesthetic and gustatory information) deriving from the same body topography and converging to the same cortical regions (AI, OFC), they said (Gastroenterology 2013 [doi:10.1053/j.gastro.2013.05.041]).

To correlate neuroimaging with behavioral data, the ability of carbonation to modulate perception of sweetness was assessed in 14 subjects, who scored the level of perceived sweetness of the solutions on a visual analog scale ranging from 0 to 100 mm. The effect of 1,585 ppm of CO₂ added to a 10% glucose solution on the perception of sweetness was also tested in seven subjects.

CO₂ was able to significantly reduce sweet-induced taste perceptions as assessed by the volunteers’ visual analog scale recordings: The perception of Sprite-associated sweetness was significantly reduced by CO₂ (48 vs. 63 and 48 vs. 55 for As-Ac and sucrose, respectively).

"Similarly, in the presence of carbonation, sweet-induced perception of a 10% glucose solution was significantly reduced (36 vs. 53), the investigators said.

Given the widespread use of CO₂ in sweet beverages, the modulation of sweet perception by CO₂ is of interest, they noted.

The findings, which suggest that CO₂ modulates the perception of sweetness thereby reducing the global neural processing of sweetness, the processing of sucrose more than of As-Ac, and the processing difference between sweetening agents via modulation of the perception of sweetness, is "of utmost importance for designing carbonated beverages and is relevant to the regulation of caloric intake," they said.

"This effect is driven by the integration of information on gastric fullness and on nutrient depletion, conveyed to a brain network where the autonomic brainstem circuitry and tractus solitarius neurons play a critical role in homeostatic functions," they added.

It may be that taste and CO₂-related information influence food choices and intake through integration in the tractus solitarius with input from the gastrointestinal tract, they suggested, explaining that "the reduced discrimination between sucrose and As-Ac induced by CO₂ would promote the consumptions of low-calorie beverages and would converge with CO₂-induced gastric distention in limiting caloric intake."

This study was supported in part by the Coca-Cola Company. One author, Dr. Rosario Cuomo, was sponsored by the Coca-Cola Company. The remaining authors reported having no disclosures.