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Evidence Mounts on Heart Failure After Trastuzumab in Breast Cancer Survivors
Trastuzumab, whether given with or without anthracyline-based chemotherapy, was associated with significant increases in heart failure and cardiomyopathy in a large population-based, retrospective cohort study of women treated for breast cancer.
In the "real world" study, which used data from the health maintenance organization Cancer Research Network, the adjusted risk of heart failure (HF) and/or cardiomyopathy increased fourfold among women who received trastuzumab (Herceptin) alone and sevenfold in those who received anthracycline plus trastuzumab, compared with women who received no chemotherapy.
In all, the risk of anthracycline-associated HF/cardiomyopathy among women younger than 65 years was similar to results from randomized clinical trials, while the trastuzumab-associated HF/cardiomyopathy risk – whether administered alone or following an anthracycline – was greater than that previously reported.
"Our results highlight the importance of generalizability in applying clinical trial findings to community settings; although similar to clinical trial results, these population-based results cannot be attributed to any single patient in clinical practice," wrote Erin J. Aiello Bowles of Group Health Research Institute, Seattle, and her associates.
Randomized trials have typically excluded older women and those with major comorbidities, and therefore the association between the two agents and HF/cardiomyopathy in this population is not well understood, Ms. Bowles and her associates noted (J. Natl. Cancer Inst. 2012 Aug. 30 [doi:10.1093/jnci/djs317]).
The current study population comprised 12,500 women diagnosed with incident, invasive breast cancer from Jan. 1, 1999, through Dec. 31, 2007, at eight integrated Cancer Research Network health systems. Women diagnosed with HF/cardiomyopathy prior to breast cancer diagnosis or initiation of chemotherapy were excluded. They had a mean age of 60 years (range, 22-99), and 85.8% were white.
In a median follow-up of 4.4 years, nearly half (46.5%) had received no chemotherapy. Just under a third, 29.6%, had received anthracycline-based chemotherapy alone, 0.9% received trastuzumab-based therapy without anthracycline, 3.5% received anthracycline plus trastuzumab, and 19.5% received other chemotherapy.
Compared with the women who received other chemotherapy or no chemotherapy, the women who received anthracycline alone or anthracycline plus trastuzumab were younger, diagnosed at later stages, had fewer comorbidities, and were slightly more likely to receive radiation therapy. These findings "suggest substantial individualization of adjuvant chemotherapy administration by age and comorbidity in community practice," Ms. Bowles and her associates wrote.
The incidence of HF/cardiomyopathy increased with increasing follow-up time for all of the chemotherapy types, but to a greater degree with trastuzumab. The cumulative HF/cardiomyopathy incidence increased from 1.2% at year 1 to 4.3% at year 5 for the anthracycline recipients, which was similar to the increase from 1.3% to 4.5% for those on other chemotherapies. For those with no chemotherapy, the cumulative incidence rose from 0.9% to 3.1%.
In contrast, the cumulative HF/cardiomyopathy incidence among recipients of anthracycline plus trastuzumab was 6.2% after 1 year of follow-up and continued to increase to 20.1% by 5 years.
Compared with no chemotherapy, the risk of incident HF/cardiomyopathy among all women was statistically significantly increased for anthracycline alone (adjusted hazard ratio, 1.40), trastuzumab without anthracycline (HR, 4.12), anthracycline plus trastuzumab (HR, 7.19), and other chemotherapy (HR, 1.49), the investigators said.
The 5-year cumulative incidence for HF/cardiomyopathy associated with each of the chemotherapies was greater in the older age groups, but the hazard ratios for HF/cardiomyopathy associated with chemotherapy use decreased with increasing age. For example, the hazard ratio for HF/cardiomyopathy associated with anthracycline use alone was statistically significant among women younger than 55 years (HR, 2.52) but not among women 55-64 years (HR, 1.61) or older.
According to Ms. Bowles and her associates, this study demonstrates the importance of observational comparative safety and effectiveness studies in providing complementary data to those obtained in clinical trials. "Observational studies allow for estimation of risks and benefits in community practice, which includes patients who may not be eligible for clinical trials. Clinical trials may provide more relevant estimates for patients who are eligible candidates, but many people are not and still receive these treatments in community practice," they wrote.
This work was supported by the National Cancer Institute through an administrative supplement to the Cancer Research Network. Ms. Bowles did not report any financial disclosures, but one of her coauthors, Dr. Larry A. Allen, has received consulting fees from Amgen, Janssen Scientific Affairs, and the Robert Wood Johnson Foundation.
The development of trastuzumab for the treatment of nonmetastatic invasive breast cancer tumors expressing human epidermal growth factor receptor 2 has been an important step in the field of personalized medicine.
Multiple trials have documented clinically and statistically significant improvements in overall and disease-free survival for women receiving adjuvant treatment including trastuzumab, compared with those receiving other chemotherapy agents. Unlike most new cancer chemotherapies, trastuzumab’s use in early-stage HER2-positive breast cancer also appears to be cost effective (Ann. Pharmacother. 2009;43:296-303).
This benefit, however, has been offset by safety concerns, with a pooled analysis of the early breast cancer trials suggesting a fivefold increase in risk of congestive heart failure for women who receive trastuzumab versus those who do not, with consistent results across varying treatment regimens (Cochrane Database Syst. Rev. 2012;4:CD006243).
The current study adds an additional year of follow-up to previous trials, during which the incidence of congestive heart failure continues to increase with no indication of a plateau. This justifies long-term surveillance for congestive heart failure in women who have received trastuzumab, as well as extended follow-up of women enrolled in trials.
Although most previous randomized clinical trials have included anthracycline in both treatment and comparison arms, the current observational study found that, in real life, about 40% of women undergoing chemotherapy received regimens excluding anthracycline, probably due in part to the older age and higher comorbidity burden relative to participants in clinical trials.
Finally, this study raises concern in that roughly a quarter of the women who received adjuvant trastuzumab had been treated well before the publication of peer-reviewed results of relevant randomized controlled trials. Clinicians may have been basing their decision on findings from trials in women with metastatic breast cancer and preliminary data from the early breast cancer trials. The interim findings, however, were based on follow-up periods too short to account for the longer life expectancy of women with early breast cancer relative to women with metastatic disease.
There have been many instances in which new treatments disseminate based on preliminary reports of benefit, only to be withdrawn after additional safety data become available. Patients, clinicians, and researchers must temper their enthusiasm about the benefits of new cancer therapies with the recognition that estimates of the long-term risk of adverse events are based on short-term observations among carefully selected clinical trial participants.
Ann M. Geiger, Ph.D., is with the division of public health sciences at Wake Forest University, Winston Salem, N.C. She said that she has no conflicts of interest.
The development of trastuzumab for the treatment of nonmetastatic invasive breast cancer tumors expressing human epidermal growth factor receptor 2 has been an important step in the field of personalized medicine.
Multiple trials have documented clinically and statistically significant improvements in overall and disease-free survival for women receiving adjuvant treatment including trastuzumab, compared with those receiving other chemotherapy agents. Unlike most new cancer chemotherapies, trastuzumab’s use in early-stage HER2-positive breast cancer also appears to be cost effective (Ann. Pharmacother. 2009;43:296-303).
This benefit, however, has been offset by safety concerns, with a pooled analysis of the early breast cancer trials suggesting a fivefold increase in risk of congestive heart failure for women who receive trastuzumab versus those who do not, with consistent results across varying treatment regimens (Cochrane Database Syst. Rev. 2012;4:CD006243).
The current study adds an additional year of follow-up to previous trials, during which the incidence of congestive heart failure continues to increase with no indication of a plateau. This justifies long-term surveillance for congestive heart failure in women who have received trastuzumab, as well as extended follow-up of women enrolled in trials.
Although most previous randomized clinical trials have included anthracycline in both treatment and comparison arms, the current observational study found that, in real life, about 40% of women undergoing chemotherapy received regimens excluding anthracycline, probably due in part to the older age and higher comorbidity burden relative to participants in clinical trials.
Finally, this study raises concern in that roughly a quarter of the women who received adjuvant trastuzumab had been treated well before the publication of peer-reviewed results of relevant randomized controlled trials. Clinicians may have been basing their decision on findings from trials in women with metastatic breast cancer and preliminary data from the early breast cancer trials. The interim findings, however, were based on follow-up periods too short to account for the longer life expectancy of women with early breast cancer relative to women with metastatic disease.
There have been many instances in which new treatments disseminate based on preliminary reports of benefit, only to be withdrawn after additional safety data become available. Patients, clinicians, and researchers must temper their enthusiasm about the benefits of new cancer therapies with the recognition that estimates of the long-term risk of adverse events are based on short-term observations among carefully selected clinical trial participants.
Ann M. Geiger, Ph.D., is with the division of public health sciences at Wake Forest University, Winston Salem, N.C. She said that she has no conflicts of interest.
The development of trastuzumab for the treatment of nonmetastatic invasive breast cancer tumors expressing human epidermal growth factor receptor 2 has been an important step in the field of personalized medicine.
Multiple trials have documented clinically and statistically significant improvements in overall and disease-free survival for women receiving adjuvant treatment including trastuzumab, compared with those receiving other chemotherapy agents. Unlike most new cancer chemotherapies, trastuzumab’s use in early-stage HER2-positive breast cancer also appears to be cost effective (Ann. Pharmacother. 2009;43:296-303).
This benefit, however, has been offset by safety concerns, with a pooled analysis of the early breast cancer trials suggesting a fivefold increase in risk of congestive heart failure for women who receive trastuzumab versus those who do not, with consistent results across varying treatment regimens (Cochrane Database Syst. Rev. 2012;4:CD006243).
The current study adds an additional year of follow-up to previous trials, during which the incidence of congestive heart failure continues to increase with no indication of a plateau. This justifies long-term surveillance for congestive heart failure in women who have received trastuzumab, as well as extended follow-up of women enrolled in trials.
Although most previous randomized clinical trials have included anthracycline in both treatment and comparison arms, the current observational study found that, in real life, about 40% of women undergoing chemotherapy received regimens excluding anthracycline, probably due in part to the older age and higher comorbidity burden relative to participants in clinical trials.
Finally, this study raises concern in that roughly a quarter of the women who received adjuvant trastuzumab had been treated well before the publication of peer-reviewed results of relevant randomized controlled trials. Clinicians may have been basing their decision on findings from trials in women with metastatic breast cancer and preliminary data from the early breast cancer trials. The interim findings, however, were based on follow-up periods too short to account for the longer life expectancy of women with early breast cancer relative to women with metastatic disease.
There have been many instances in which new treatments disseminate based on preliminary reports of benefit, only to be withdrawn after additional safety data become available. Patients, clinicians, and researchers must temper their enthusiasm about the benefits of new cancer therapies with the recognition that estimates of the long-term risk of adverse events are based on short-term observations among carefully selected clinical trial participants.
Ann M. Geiger, Ph.D., is with the division of public health sciences at Wake Forest University, Winston Salem, N.C. She said that she has no conflicts of interest.
Trastuzumab, whether given with or without anthracyline-based chemotherapy, was associated with significant increases in heart failure and cardiomyopathy in a large population-based, retrospective cohort study of women treated for breast cancer.
In the "real world" study, which used data from the health maintenance organization Cancer Research Network, the adjusted risk of heart failure (HF) and/or cardiomyopathy increased fourfold among women who received trastuzumab (Herceptin) alone and sevenfold in those who received anthracycline plus trastuzumab, compared with women who received no chemotherapy.
In all, the risk of anthracycline-associated HF/cardiomyopathy among women younger than 65 years was similar to results from randomized clinical trials, while the trastuzumab-associated HF/cardiomyopathy risk – whether administered alone or following an anthracycline – was greater than that previously reported.
"Our results highlight the importance of generalizability in applying clinical trial findings to community settings; although similar to clinical trial results, these population-based results cannot be attributed to any single patient in clinical practice," wrote Erin J. Aiello Bowles of Group Health Research Institute, Seattle, and her associates.
Randomized trials have typically excluded older women and those with major comorbidities, and therefore the association between the two agents and HF/cardiomyopathy in this population is not well understood, Ms. Bowles and her associates noted (J. Natl. Cancer Inst. 2012 Aug. 30 [doi:10.1093/jnci/djs317]).
The current study population comprised 12,500 women diagnosed with incident, invasive breast cancer from Jan. 1, 1999, through Dec. 31, 2007, at eight integrated Cancer Research Network health systems. Women diagnosed with HF/cardiomyopathy prior to breast cancer diagnosis or initiation of chemotherapy were excluded. They had a mean age of 60 years (range, 22-99), and 85.8% were white.
In a median follow-up of 4.4 years, nearly half (46.5%) had received no chemotherapy. Just under a third, 29.6%, had received anthracycline-based chemotherapy alone, 0.9% received trastuzumab-based therapy without anthracycline, 3.5% received anthracycline plus trastuzumab, and 19.5% received other chemotherapy.
Compared with the women who received other chemotherapy or no chemotherapy, the women who received anthracycline alone or anthracycline plus trastuzumab were younger, diagnosed at later stages, had fewer comorbidities, and were slightly more likely to receive radiation therapy. These findings "suggest substantial individualization of adjuvant chemotherapy administration by age and comorbidity in community practice," Ms. Bowles and her associates wrote.
The incidence of HF/cardiomyopathy increased with increasing follow-up time for all of the chemotherapy types, but to a greater degree with trastuzumab. The cumulative HF/cardiomyopathy incidence increased from 1.2% at year 1 to 4.3% at year 5 for the anthracycline recipients, which was similar to the increase from 1.3% to 4.5% for those on other chemotherapies. For those with no chemotherapy, the cumulative incidence rose from 0.9% to 3.1%.
In contrast, the cumulative HF/cardiomyopathy incidence among recipients of anthracycline plus trastuzumab was 6.2% after 1 year of follow-up and continued to increase to 20.1% by 5 years.
Compared with no chemotherapy, the risk of incident HF/cardiomyopathy among all women was statistically significantly increased for anthracycline alone (adjusted hazard ratio, 1.40), trastuzumab without anthracycline (HR, 4.12), anthracycline plus trastuzumab (HR, 7.19), and other chemotherapy (HR, 1.49), the investigators said.
The 5-year cumulative incidence for HF/cardiomyopathy associated with each of the chemotherapies was greater in the older age groups, but the hazard ratios for HF/cardiomyopathy associated with chemotherapy use decreased with increasing age. For example, the hazard ratio for HF/cardiomyopathy associated with anthracycline use alone was statistically significant among women younger than 55 years (HR, 2.52) but not among women 55-64 years (HR, 1.61) or older.
According to Ms. Bowles and her associates, this study demonstrates the importance of observational comparative safety and effectiveness studies in providing complementary data to those obtained in clinical trials. "Observational studies allow for estimation of risks and benefits in community practice, which includes patients who may not be eligible for clinical trials. Clinical trials may provide more relevant estimates for patients who are eligible candidates, but many people are not and still receive these treatments in community practice," they wrote.
This work was supported by the National Cancer Institute through an administrative supplement to the Cancer Research Network. Ms. Bowles did not report any financial disclosures, but one of her coauthors, Dr. Larry A. Allen, has received consulting fees from Amgen, Janssen Scientific Affairs, and the Robert Wood Johnson Foundation.
Trastuzumab, whether given with or without anthracyline-based chemotherapy, was associated with significant increases in heart failure and cardiomyopathy in a large population-based, retrospective cohort study of women treated for breast cancer.
In the "real world" study, which used data from the health maintenance organization Cancer Research Network, the adjusted risk of heart failure (HF) and/or cardiomyopathy increased fourfold among women who received trastuzumab (Herceptin) alone and sevenfold in those who received anthracycline plus trastuzumab, compared with women who received no chemotherapy.
In all, the risk of anthracycline-associated HF/cardiomyopathy among women younger than 65 years was similar to results from randomized clinical trials, while the trastuzumab-associated HF/cardiomyopathy risk – whether administered alone or following an anthracycline – was greater than that previously reported.
"Our results highlight the importance of generalizability in applying clinical trial findings to community settings; although similar to clinical trial results, these population-based results cannot be attributed to any single patient in clinical practice," wrote Erin J. Aiello Bowles of Group Health Research Institute, Seattle, and her associates.
Randomized trials have typically excluded older women and those with major comorbidities, and therefore the association between the two agents and HF/cardiomyopathy in this population is not well understood, Ms. Bowles and her associates noted (J. Natl. Cancer Inst. 2012 Aug. 30 [doi:10.1093/jnci/djs317]).
The current study population comprised 12,500 women diagnosed with incident, invasive breast cancer from Jan. 1, 1999, through Dec. 31, 2007, at eight integrated Cancer Research Network health systems. Women diagnosed with HF/cardiomyopathy prior to breast cancer diagnosis or initiation of chemotherapy were excluded. They had a mean age of 60 years (range, 22-99), and 85.8% were white.
In a median follow-up of 4.4 years, nearly half (46.5%) had received no chemotherapy. Just under a third, 29.6%, had received anthracycline-based chemotherapy alone, 0.9% received trastuzumab-based therapy without anthracycline, 3.5% received anthracycline plus trastuzumab, and 19.5% received other chemotherapy.
Compared with the women who received other chemotherapy or no chemotherapy, the women who received anthracycline alone or anthracycline plus trastuzumab were younger, diagnosed at later stages, had fewer comorbidities, and were slightly more likely to receive radiation therapy. These findings "suggest substantial individualization of adjuvant chemotherapy administration by age and comorbidity in community practice," Ms. Bowles and her associates wrote.
The incidence of HF/cardiomyopathy increased with increasing follow-up time for all of the chemotherapy types, but to a greater degree with trastuzumab. The cumulative HF/cardiomyopathy incidence increased from 1.2% at year 1 to 4.3% at year 5 for the anthracycline recipients, which was similar to the increase from 1.3% to 4.5% for those on other chemotherapies. For those with no chemotherapy, the cumulative incidence rose from 0.9% to 3.1%.
In contrast, the cumulative HF/cardiomyopathy incidence among recipients of anthracycline plus trastuzumab was 6.2% after 1 year of follow-up and continued to increase to 20.1% by 5 years.
Compared with no chemotherapy, the risk of incident HF/cardiomyopathy among all women was statistically significantly increased for anthracycline alone (adjusted hazard ratio, 1.40), trastuzumab without anthracycline (HR, 4.12), anthracycline plus trastuzumab (HR, 7.19), and other chemotherapy (HR, 1.49), the investigators said.
The 5-year cumulative incidence for HF/cardiomyopathy associated with each of the chemotherapies was greater in the older age groups, but the hazard ratios for HF/cardiomyopathy associated with chemotherapy use decreased with increasing age. For example, the hazard ratio for HF/cardiomyopathy associated with anthracycline use alone was statistically significant among women younger than 55 years (HR, 2.52) but not among women 55-64 years (HR, 1.61) or older.
According to Ms. Bowles and her associates, this study demonstrates the importance of observational comparative safety and effectiveness studies in providing complementary data to those obtained in clinical trials. "Observational studies allow for estimation of risks and benefits in community practice, which includes patients who may not be eligible for clinical trials. Clinical trials may provide more relevant estimates for patients who are eligible candidates, but many people are not and still receive these treatments in community practice," they wrote.
This work was supported by the National Cancer Institute through an administrative supplement to the Cancer Research Network. Ms. Bowles did not report any financial disclosures, but one of her coauthors, Dr. Larry A. Allen, has received consulting fees from Amgen, Janssen Scientific Affairs, and the Robert Wood Johnson Foundation.
FROM THE JOURNAL OF THE NATIONAL CANCER INSTITUTE
Major Finding: The adjusted risk of heart failure (HF) and/or cardiomyopathy increased fourfold among women who received trastuzumab alone and sevenfold in those who received anthracycline plus trastuzumab, compared with women who received no chemotherapy.
Data Source: The "real world" study used data on 12,500 women from the health maintenance organization Cancer Research Network.
Disclosures: This work was supported by the National Cancer Institute through an administrative supplement to the Cancer Research Network. Ms. Bowles did not report any financial disclosures, but coauthor Dr. Larry A. Allen has received consulting fees from Amgen, Janssen Scientific Affairs, and the Robert Wood Johnson Foundation.
Adalimumab Plus Methotrexate Reduced Joint Damage in RA
Combination therapy of a tumor necrosis factor inhibitor plus methotrexate inhibited both joint erosion and joint space narrowing independent of disease activity in a 2-year, randomized, controlled trial of 638 patients with early, progressive rheumatoid arthritis.
While joint erosion (JE) has been perceived to be the most critical indicator of permanent disability in RA patients, recent data suggest that joint space narrowing (JSN) may be more important early in the disease process as a predictor of irreversible physical disability (Ann. Rheum. Dis. 2011;70:733-9). "Preventing the onset or worsening of JSN probably represents a critical aspect of effective disease management of early rheumatoid arthritis patients," Dr. Josef S. Smolen of the Medical University of Vienna and Hietzing Hospital, also in Vienna, and his associates wrote online in Annals of the Rheumatic Diseases (2012 [doi 10.1136/annrheumdis-2012-201620]).
The data came from patients enrolled in Abbott’s PREMIER trial, a 2-year, active-controlled, double-blind study of 799 methotrexate-naive patients with early, progressive RA. They were randomly assigned to either combination treatment with subcutaneous adalimumab (ADA; 40 mg every other week) plus oral methotrexate (MTX; titrated to 20 mg/week by week 8, as tolerated), adalimumab monotherapy, or methotrexate monotherapy. Study patients were 18 years of age or older, with RA duration of less than 3 years, 8 or more swollen joints, and 10 or more tender joints.
Of the 799 patients originally randomly assigned in PREMIER, the current analysis included 229 patients in the ADA plus MTX combination group, 205 on ADA monotherapy, and 204 MTX monotherapy patients, all of whom had one or more post-baseline time-averaged disease activity (DAS28) measurements and underwent radiography at baseline and week 52 and/or week 104.
At both the 52 and 104 week time points, the patients receiving combination therapy using ADA and MTX had greater mean reductions from baseline in DAS28 (–3.6 at 52 weeks, –3.8 at 104 weeks) than did those receiving patients receiving ADA monotherapy (–2.8 and –3.1, respectively) or MTX monotherapy (–2.8 and –3.1, respectively). This pattern of treatment responses was evident at week 2 and maintained throughout the 104 weeks of the trial, Dr. Smolen and his associates said.
Approximately half of the patients receiving combination therapy were in the lowest tertile of time–averaged 28-joint disease activity score (TA-DAS28), while patients receiving either adalimumab or methotrexate monotherapy were clustered in the higher TA-DAS28 tertiles. Whereas the radiographic progression of both JE and JSN increased significantly with increasing disease activity in the two monotherapy groups – more so with MTX than ADA – there was far less of a relationship between radiographic progression and disease activity in the combination treatment group, and even less so for JSN than for JE. These findings suggest that ADA plus MTX therapy may have even stronger inhibitory effects on JSN progression than on JE progression despite persistent inflammation, they commented.
While JE scores were not associated with health assessment questionnaire (HAQ-DI) scores at any of the time points examined, JSN scores were positively associated with HAQ-DI scores at both 52 and 104 weeks but not at baseline.
Of 649 patients for whom employment status was known, the presence of JSN was associated with being employed at baseline and at weeks 52 and 104 (P = .02, .007, and .04, respectively) but JE was not. The percentages of employed patients generally decreased with increasing baseline values of JE or JSN, but the relationship was more apparent for JSN (P =.02 vs. P less than .001 for the overall differences among JE and JSN tertiles, respectively). These data indicate that progression of JSN plays a more prominent role than does JE in determining employment status, Dr. Smolen and his associates said.
"Patients with RA frequently lose their jobs early in the course of the disease, with 20%-30% experiencing permanent work disability during the first 2-3 years after diagnosis (Clin. Exp. Rheumatol. 2003;21:S71-4). These data indicate that early control of JSN progression is important not only to protect patients’ physical functioning but [also] to help them maintain the lifestyle they had before RA diagnosis," the investigators said.
"Because of the clinical implications of JSN progression for disability and work impairment, protection from the onset or worsening of JSN should be an important factor when choosing between therapeutic modalities," they concluded.
The study was sponsored by Abbott. Dr. Smolen has financial relationships with Abbott, Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Glaxo, Lilly, MSD (Schering-Plough), Novo-Nordisk, Pfizer (Wyeth), Roche, Sandoz, and UCB. His coauthors have similar disclosures, and four are full-time employees of Abbott.
Combination therapy of a tumor necrosis factor inhibitor plus methotrexate inhibited both joint erosion and joint space narrowing independent of disease activity in a 2-year, randomized, controlled trial of 638 patients with early, progressive rheumatoid arthritis.
While joint erosion (JE) has been perceived to be the most critical indicator of permanent disability in RA patients, recent data suggest that joint space narrowing (JSN) may be more important early in the disease process as a predictor of irreversible physical disability (Ann. Rheum. Dis. 2011;70:733-9). "Preventing the onset or worsening of JSN probably represents a critical aspect of effective disease management of early rheumatoid arthritis patients," Dr. Josef S. Smolen of the Medical University of Vienna and Hietzing Hospital, also in Vienna, and his associates wrote online in Annals of the Rheumatic Diseases (2012 [doi 10.1136/annrheumdis-2012-201620]).
The data came from patients enrolled in Abbott’s PREMIER trial, a 2-year, active-controlled, double-blind study of 799 methotrexate-naive patients with early, progressive RA. They were randomly assigned to either combination treatment with subcutaneous adalimumab (ADA; 40 mg every other week) plus oral methotrexate (MTX; titrated to 20 mg/week by week 8, as tolerated), adalimumab monotherapy, or methotrexate monotherapy. Study patients were 18 years of age or older, with RA duration of less than 3 years, 8 or more swollen joints, and 10 or more tender joints.
Of the 799 patients originally randomly assigned in PREMIER, the current analysis included 229 patients in the ADA plus MTX combination group, 205 on ADA monotherapy, and 204 MTX monotherapy patients, all of whom had one or more post-baseline time-averaged disease activity (DAS28) measurements and underwent radiography at baseline and week 52 and/or week 104.
At both the 52 and 104 week time points, the patients receiving combination therapy using ADA and MTX had greater mean reductions from baseline in DAS28 (–3.6 at 52 weeks, –3.8 at 104 weeks) than did those receiving patients receiving ADA monotherapy (–2.8 and –3.1, respectively) or MTX monotherapy (–2.8 and –3.1, respectively). This pattern of treatment responses was evident at week 2 and maintained throughout the 104 weeks of the trial, Dr. Smolen and his associates said.
Approximately half of the patients receiving combination therapy were in the lowest tertile of time–averaged 28-joint disease activity score (TA-DAS28), while patients receiving either adalimumab or methotrexate monotherapy were clustered in the higher TA-DAS28 tertiles. Whereas the radiographic progression of both JE and JSN increased significantly with increasing disease activity in the two monotherapy groups – more so with MTX than ADA – there was far less of a relationship between radiographic progression and disease activity in the combination treatment group, and even less so for JSN than for JE. These findings suggest that ADA plus MTX therapy may have even stronger inhibitory effects on JSN progression than on JE progression despite persistent inflammation, they commented.
While JE scores were not associated with health assessment questionnaire (HAQ-DI) scores at any of the time points examined, JSN scores were positively associated with HAQ-DI scores at both 52 and 104 weeks but not at baseline.
Of 649 patients for whom employment status was known, the presence of JSN was associated with being employed at baseline and at weeks 52 and 104 (P = .02, .007, and .04, respectively) but JE was not. The percentages of employed patients generally decreased with increasing baseline values of JE or JSN, but the relationship was more apparent for JSN (P =.02 vs. P less than .001 for the overall differences among JE and JSN tertiles, respectively). These data indicate that progression of JSN plays a more prominent role than does JE in determining employment status, Dr. Smolen and his associates said.
"Patients with RA frequently lose their jobs early in the course of the disease, with 20%-30% experiencing permanent work disability during the first 2-3 years after diagnosis (Clin. Exp. Rheumatol. 2003;21:S71-4). These data indicate that early control of JSN progression is important not only to protect patients’ physical functioning but [also] to help them maintain the lifestyle they had before RA diagnosis," the investigators said.
"Because of the clinical implications of JSN progression for disability and work impairment, protection from the onset or worsening of JSN should be an important factor when choosing between therapeutic modalities," they concluded.
The study was sponsored by Abbott. Dr. Smolen has financial relationships with Abbott, Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Glaxo, Lilly, MSD (Schering-Plough), Novo-Nordisk, Pfizer (Wyeth), Roche, Sandoz, and UCB. His coauthors have similar disclosures, and four are full-time employees of Abbott.
Combination therapy of a tumor necrosis factor inhibitor plus methotrexate inhibited both joint erosion and joint space narrowing independent of disease activity in a 2-year, randomized, controlled trial of 638 patients with early, progressive rheumatoid arthritis.
While joint erosion (JE) has been perceived to be the most critical indicator of permanent disability in RA patients, recent data suggest that joint space narrowing (JSN) may be more important early in the disease process as a predictor of irreversible physical disability (Ann. Rheum. Dis. 2011;70:733-9). "Preventing the onset or worsening of JSN probably represents a critical aspect of effective disease management of early rheumatoid arthritis patients," Dr. Josef S. Smolen of the Medical University of Vienna and Hietzing Hospital, also in Vienna, and his associates wrote online in Annals of the Rheumatic Diseases (2012 [doi 10.1136/annrheumdis-2012-201620]).
The data came from patients enrolled in Abbott’s PREMIER trial, a 2-year, active-controlled, double-blind study of 799 methotrexate-naive patients with early, progressive RA. They were randomly assigned to either combination treatment with subcutaneous adalimumab (ADA; 40 mg every other week) plus oral methotrexate (MTX; titrated to 20 mg/week by week 8, as tolerated), adalimumab monotherapy, or methotrexate monotherapy. Study patients were 18 years of age or older, with RA duration of less than 3 years, 8 or more swollen joints, and 10 or more tender joints.
Of the 799 patients originally randomly assigned in PREMIER, the current analysis included 229 patients in the ADA plus MTX combination group, 205 on ADA monotherapy, and 204 MTX monotherapy patients, all of whom had one or more post-baseline time-averaged disease activity (DAS28) measurements and underwent radiography at baseline and week 52 and/or week 104.
At both the 52 and 104 week time points, the patients receiving combination therapy using ADA and MTX had greater mean reductions from baseline in DAS28 (–3.6 at 52 weeks, –3.8 at 104 weeks) than did those receiving patients receiving ADA monotherapy (–2.8 and –3.1, respectively) or MTX monotherapy (–2.8 and –3.1, respectively). This pattern of treatment responses was evident at week 2 and maintained throughout the 104 weeks of the trial, Dr. Smolen and his associates said.
Approximately half of the patients receiving combination therapy were in the lowest tertile of time–averaged 28-joint disease activity score (TA-DAS28), while patients receiving either adalimumab or methotrexate monotherapy were clustered in the higher TA-DAS28 tertiles. Whereas the radiographic progression of both JE and JSN increased significantly with increasing disease activity in the two monotherapy groups – more so with MTX than ADA – there was far less of a relationship between radiographic progression and disease activity in the combination treatment group, and even less so for JSN than for JE. These findings suggest that ADA plus MTX therapy may have even stronger inhibitory effects on JSN progression than on JE progression despite persistent inflammation, they commented.
While JE scores were not associated with health assessment questionnaire (HAQ-DI) scores at any of the time points examined, JSN scores were positively associated with HAQ-DI scores at both 52 and 104 weeks but not at baseline.
Of 649 patients for whom employment status was known, the presence of JSN was associated with being employed at baseline and at weeks 52 and 104 (P = .02, .007, and .04, respectively) but JE was not. The percentages of employed patients generally decreased with increasing baseline values of JE or JSN, but the relationship was more apparent for JSN (P =.02 vs. P less than .001 for the overall differences among JE and JSN tertiles, respectively). These data indicate that progression of JSN plays a more prominent role than does JE in determining employment status, Dr. Smolen and his associates said.
"Patients with RA frequently lose their jobs early in the course of the disease, with 20%-30% experiencing permanent work disability during the first 2-3 years after diagnosis (Clin. Exp. Rheumatol. 2003;21:S71-4). These data indicate that early control of JSN progression is important not only to protect patients’ physical functioning but [also] to help them maintain the lifestyle they had before RA diagnosis," the investigators said.
"Because of the clinical implications of JSN progression for disability and work impairment, protection from the onset or worsening of JSN should be an important factor when choosing between therapeutic modalities," they concluded.
The study was sponsored by Abbott. Dr. Smolen has financial relationships with Abbott, Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Glaxo, Lilly, MSD (Schering-Plough), Novo-Nordisk, Pfizer (Wyeth), Roche, Sandoz, and UCB. His coauthors have similar disclosures, and four are full-time employees of Abbott.
FROM ANNALS OF THE RHEUMATIC DISEASES
Major Finding: At both 52 and 104 weeks, the rheumatoid arthritis patients receiving adalimumab plus methotrexate combination therapy had greater mean reductions from baseline in DAS28 (–3.6 at 52 weeks, –3.8 at 104 weeks) than did those patients receiving ADA monotherapy (-2.8 and -3.1, respectively) or MTX monotherapy (-2.8 and -3.1, respectively). This pattern of treatment responses was evident at week 2 and was maintained throughout the 104 weeks of the trial,
Data Source: The data come from PREMIER, a 2-year, active-controlled, double-blind study of 799 methotrexate-naive patients with early, progressive RA.
Disclosures: The study was sponsored by Abbott. Dr. Smolen has financial relationships with Abbott, Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Glaxo, Lilly, MSD (Schering-Plough), Novo-Nordisk, Pfizer (Wyeth), Roche, Sandoz, and UCB. His coauthors have similar disclosures, and four are full-time employees of Abbott.
Bariatric Surgery Prevents Type 2 Diabetes
Bariatric surgery reduced the incidence of type 2 diabetes by 78% compared with usual care at 15 years in a prospective, case-matched study of more than 3,000 obese adults.
This significant risk reduction was seen with all types of bariatric surgery and regardless of baseline body mass index. And, it occurred despite the fact that the matching process unexpectedly resulted in the bariatric surgery group having a higher mean body weight and more severe risk factors at baseline than the controls.
The impact of bariatric surgery was even greater, with an 87% risk reduction, for those with impaired fasting glucose at baseline, said Dr. Lena M.S. Carlsson of the Sahlgrenska Academy at the University of Gothenburg, Sweden, and her associates (N. Engl. J. Med. 2012;367:695-704).
"Our data indicate that bariatric surgery has a preventive effect on incident type 2 diabetes, particularly in participants with impaired fasting glucose. In contrast, baseline BMI did not influence the preventive effect of bariatric surgery on type 2 diabetes, implying that anthropometric data are not useful in the selection of candidates for bariatric surgery, whereas data on impaired fasting glucose may be helpful," the authors wrote.
The finding comes from the Swedish Obese Subjects (SOS) trial, which included 1,658 patients who chose to undergo bariatric surgery and 1,771 matched controls. All patients in both groups entered the study with the intention of losing weight. None had diabetes at baseline.
In the bariatric surgery group, the types of procedures were banding in 311, vertical banded gastroplasty in 1,140, and gastric bypass in 207. Patients in the control group received the customary treatment for obesity at their primary health care centers, which in Sweden ranges from advanced lifestyle modification – including recommendations regarding eating behavior, food selection, energy intake, and physical activity – to no treatment. About half (54%) of the controls reported receiving professional guidance in attempts to lose weight.
There were several significant differences between groups at baseline. The bariatric surgery group weighed an average of 6 kg more than did the controls, and had a greater mean BMI (42.4 vs. 40.2 kg/m2). They also had higher mean blood pressures and total cholesterol and triglyceride levels, and were more likely to smoke and to be less active.
After adjustment for follow-up of less than 15 years and for death, the 15-year participation rate was 54%. At 15 years, the bariatric surgery group had lost 31 kg after 1 year, but then regained weight, so the average loss at 10 and 15 years was about 20 kg. The control group never lost or gained more than 3 kg over the entire study period, regardless of whether they had professional help.
During the follow-up, type 2 diabetes developed in 110 of the bariatric surgery patients and in 392 controls, corresponding to incidence rates of 6.8 and 28.4 cases per 1,000 person-years, respectively (P less than .001). The unadjusted hazard ratio was 0.22, which dropped to 0.17 following multivariate adjustments. Aside from treatment group, other strong univariate predictors of diabetes outcome were baseline blood glucose and the presence or absence of impaired fasting glucose, Dr. Carlsson and her associates reported.
In a sensitivity analysis performed to account for the low participation rate, the impact of treatment on the incidence of type 2 diabetes was at least as strong after 2 years and 10 years of follow-up as after 15 years. All types of bariatric surgery were associated with a reduced incidence of diabetes, with no significant differences among them. There were also no differences by receipt of professional weight-loss assistance, or by BMI at baseline, the investigators noted.
A total of 3 patients (0.2%) died within 90 days of surgery, and 245 patients in the surgery group (15%) reported at least one complication. Of those, 46 (2.8%) were serious enough to require a reoperation.
The risk reduction seen among those with impaired fasting glucose was at least twice as large as the risk reduction achieved with lifestyle interventions in large, long-term trials of moderately obese people with prediabetes (Lancet 2006;368:1673-9, Lancet 2009;374:1677-86, and Lancet 2008;371:1783-9), the investigators noted.
The ongoing SOS study is supported by grants from the Swedish Research Council, the Swedish Foundation for Strategic Research to the Sahlgrenska Center for Cardiovascular and Metabolic Research, the Swedish federal government, the VINNOVA-VINNMER program, and the Wenner-Gren Foundations. The SOS study has previously been supported by grants to one of the authors from Hoffmann-La Roche, AstraZeneca, and other companies. Dr. Carlsson reported receiving consulting fees from AstraZeneca and owning stock in Sahltech. Other coinvestigators also had financial disclosures.
The long-term findings of the SOS study are both provocative and exciting, especially the findings suggesting that bariatric surgery may prevent the conversion of abnormalities in glucose metabolism to frank diabetes.
The findings of previous studies, showing that bariatric surgery can have a prolonged, positive effect on blood sugar beyond that attainable with medication, have led to speculation about whether surgery might be considered earlier in the course of disease in patients with adult-onset diabetes.
However, it remains impractical and unjustified to contemplate the performance of bariatric surgery in the millions of eligible obese adults. And to be certain, the authors do not suggest such an approach. Rather, the current study should provide an impetus to develop a more complete understanding of the mechanisms by which the various bariatric procedures exert their beneficial effects. Such understanding will be important because it will enable the identification of individuals who are the most appropriate candidates for surgery.
The cause of type 2 diabetes is multifactorial, and this long-term study shows that surgery did not prevent the development of diabetes in all patients. Furthermore, it is possible that interventions that are even less invasive may accomplish the very desirable goal of decreasing the incidence of type 2 diabetes and its attendant complications.
Danny O. Jacobs, M.D., is chair of surgery at the Duke University School of Medicine, Durham, N.C. These remarks were taken from his editorial accompanying Dr. Carlson’s report (N. Engl. J. Med. 2012;367:764-5). Dr. Jacobs has consulting, research, and/or educational services working relationships with Ethicon, Surgisphere, and other companies.
The long-term findings of the SOS study are both provocative and exciting, especially the findings suggesting that bariatric surgery may prevent the conversion of abnormalities in glucose metabolism to frank diabetes.
The findings of previous studies, showing that bariatric surgery can have a prolonged, positive effect on blood sugar beyond that attainable with medication, have led to speculation about whether surgery might be considered earlier in the course of disease in patients with adult-onset diabetes.
However, it remains impractical and unjustified to contemplate the performance of bariatric surgery in the millions of eligible obese adults. And to be certain, the authors do not suggest such an approach. Rather, the current study should provide an impetus to develop a more complete understanding of the mechanisms by which the various bariatric procedures exert their beneficial effects. Such understanding will be important because it will enable the identification of individuals who are the most appropriate candidates for surgery.
The cause of type 2 diabetes is multifactorial, and this long-term study shows that surgery did not prevent the development of diabetes in all patients. Furthermore, it is possible that interventions that are even less invasive may accomplish the very desirable goal of decreasing the incidence of type 2 diabetes and its attendant complications.
Danny O. Jacobs, M.D., is chair of surgery at the Duke University School of Medicine, Durham, N.C. These remarks were taken from his editorial accompanying Dr. Carlson’s report (N. Engl. J. Med. 2012;367:764-5). Dr. Jacobs has consulting, research, and/or educational services working relationships with Ethicon, Surgisphere, and other companies.
The long-term findings of the SOS study are both provocative and exciting, especially the findings suggesting that bariatric surgery may prevent the conversion of abnormalities in glucose metabolism to frank diabetes.
The findings of previous studies, showing that bariatric surgery can have a prolonged, positive effect on blood sugar beyond that attainable with medication, have led to speculation about whether surgery might be considered earlier in the course of disease in patients with adult-onset diabetes.
However, it remains impractical and unjustified to contemplate the performance of bariatric surgery in the millions of eligible obese adults. And to be certain, the authors do not suggest such an approach. Rather, the current study should provide an impetus to develop a more complete understanding of the mechanisms by which the various bariatric procedures exert their beneficial effects. Such understanding will be important because it will enable the identification of individuals who are the most appropriate candidates for surgery.
The cause of type 2 diabetes is multifactorial, and this long-term study shows that surgery did not prevent the development of diabetes in all patients. Furthermore, it is possible that interventions that are even less invasive may accomplish the very desirable goal of decreasing the incidence of type 2 diabetes and its attendant complications.
Danny O. Jacobs, M.D., is chair of surgery at the Duke University School of Medicine, Durham, N.C. These remarks were taken from his editorial accompanying Dr. Carlson’s report (N. Engl. J. Med. 2012;367:764-5). Dr. Jacobs has consulting, research, and/or educational services working relationships with Ethicon, Surgisphere, and other companies.
Bariatric surgery reduced the incidence of type 2 diabetes by 78% compared with usual care at 15 years in a prospective, case-matched study of more than 3,000 obese adults.
This significant risk reduction was seen with all types of bariatric surgery and regardless of baseline body mass index. And, it occurred despite the fact that the matching process unexpectedly resulted in the bariatric surgery group having a higher mean body weight and more severe risk factors at baseline than the controls.
The impact of bariatric surgery was even greater, with an 87% risk reduction, for those with impaired fasting glucose at baseline, said Dr. Lena M.S. Carlsson of the Sahlgrenska Academy at the University of Gothenburg, Sweden, and her associates (N. Engl. J. Med. 2012;367:695-704).
"Our data indicate that bariatric surgery has a preventive effect on incident type 2 diabetes, particularly in participants with impaired fasting glucose. In contrast, baseline BMI did not influence the preventive effect of bariatric surgery on type 2 diabetes, implying that anthropometric data are not useful in the selection of candidates for bariatric surgery, whereas data on impaired fasting glucose may be helpful," the authors wrote.
The finding comes from the Swedish Obese Subjects (SOS) trial, which included 1,658 patients who chose to undergo bariatric surgery and 1,771 matched controls. All patients in both groups entered the study with the intention of losing weight. None had diabetes at baseline.
In the bariatric surgery group, the types of procedures were banding in 311, vertical banded gastroplasty in 1,140, and gastric bypass in 207. Patients in the control group received the customary treatment for obesity at their primary health care centers, which in Sweden ranges from advanced lifestyle modification – including recommendations regarding eating behavior, food selection, energy intake, and physical activity – to no treatment. About half (54%) of the controls reported receiving professional guidance in attempts to lose weight.
There were several significant differences between groups at baseline. The bariatric surgery group weighed an average of 6 kg more than did the controls, and had a greater mean BMI (42.4 vs. 40.2 kg/m2). They also had higher mean blood pressures and total cholesterol and triglyceride levels, and were more likely to smoke and to be less active.
After adjustment for follow-up of less than 15 years and for death, the 15-year participation rate was 54%. At 15 years, the bariatric surgery group had lost 31 kg after 1 year, but then regained weight, so the average loss at 10 and 15 years was about 20 kg. The control group never lost or gained more than 3 kg over the entire study period, regardless of whether they had professional help.
During the follow-up, type 2 diabetes developed in 110 of the bariatric surgery patients and in 392 controls, corresponding to incidence rates of 6.8 and 28.4 cases per 1,000 person-years, respectively (P less than .001). The unadjusted hazard ratio was 0.22, which dropped to 0.17 following multivariate adjustments. Aside from treatment group, other strong univariate predictors of diabetes outcome were baseline blood glucose and the presence or absence of impaired fasting glucose, Dr. Carlsson and her associates reported.
In a sensitivity analysis performed to account for the low participation rate, the impact of treatment on the incidence of type 2 diabetes was at least as strong after 2 years and 10 years of follow-up as after 15 years. All types of bariatric surgery were associated with a reduced incidence of diabetes, with no significant differences among them. There were also no differences by receipt of professional weight-loss assistance, or by BMI at baseline, the investigators noted.
A total of 3 patients (0.2%) died within 90 days of surgery, and 245 patients in the surgery group (15%) reported at least one complication. Of those, 46 (2.8%) were serious enough to require a reoperation.
The risk reduction seen among those with impaired fasting glucose was at least twice as large as the risk reduction achieved with lifestyle interventions in large, long-term trials of moderately obese people with prediabetes (Lancet 2006;368:1673-9, Lancet 2009;374:1677-86, and Lancet 2008;371:1783-9), the investigators noted.
The ongoing SOS study is supported by grants from the Swedish Research Council, the Swedish Foundation for Strategic Research to the Sahlgrenska Center for Cardiovascular and Metabolic Research, the Swedish federal government, the VINNOVA-VINNMER program, and the Wenner-Gren Foundations. The SOS study has previously been supported by grants to one of the authors from Hoffmann-La Roche, AstraZeneca, and other companies. Dr. Carlsson reported receiving consulting fees from AstraZeneca and owning stock in Sahltech. Other coinvestigators also had financial disclosures.
Bariatric surgery reduced the incidence of type 2 diabetes by 78% compared with usual care at 15 years in a prospective, case-matched study of more than 3,000 obese adults.
This significant risk reduction was seen with all types of bariatric surgery and regardless of baseline body mass index. And, it occurred despite the fact that the matching process unexpectedly resulted in the bariatric surgery group having a higher mean body weight and more severe risk factors at baseline than the controls.
The impact of bariatric surgery was even greater, with an 87% risk reduction, for those with impaired fasting glucose at baseline, said Dr. Lena M.S. Carlsson of the Sahlgrenska Academy at the University of Gothenburg, Sweden, and her associates (N. Engl. J. Med. 2012;367:695-704).
"Our data indicate that bariatric surgery has a preventive effect on incident type 2 diabetes, particularly in participants with impaired fasting glucose. In contrast, baseline BMI did not influence the preventive effect of bariatric surgery on type 2 diabetes, implying that anthropometric data are not useful in the selection of candidates for bariatric surgery, whereas data on impaired fasting glucose may be helpful," the authors wrote.
The finding comes from the Swedish Obese Subjects (SOS) trial, which included 1,658 patients who chose to undergo bariatric surgery and 1,771 matched controls. All patients in both groups entered the study with the intention of losing weight. None had diabetes at baseline.
In the bariatric surgery group, the types of procedures were banding in 311, vertical banded gastroplasty in 1,140, and gastric bypass in 207. Patients in the control group received the customary treatment for obesity at their primary health care centers, which in Sweden ranges from advanced lifestyle modification – including recommendations regarding eating behavior, food selection, energy intake, and physical activity – to no treatment. About half (54%) of the controls reported receiving professional guidance in attempts to lose weight.
There were several significant differences between groups at baseline. The bariatric surgery group weighed an average of 6 kg more than did the controls, and had a greater mean BMI (42.4 vs. 40.2 kg/m2). They also had higher mean blood pressures and total cholesterol and triglyceride levels, and were more likely to smoke and to be less active.
After adjustment for follow-up of less than 15 years and for death, the 15-year participation rate was 54%. At 15 years, the bariatric surgery group had lost 31 kg after 1 year, but then regained weight, so the average loss at 10 and 15 years was about 20 kg. The control group never lost or gained more than 3 kg over the entire study period, regardless of whether they had professional help.
During the follow-up, type 2 diabetes developed in 110 of the bariatric surgery patients and in 392 controls, corresponding to incidence rates of 6.8 and 28.4 cases per 1,000 person-years, respectively (P less than .001). The unadjusted hazard ratio was 0.22, which dropped to 0.17 following multivariate adjustments. Aside from treatment group, other strong univariate predictors of diabetes outcome were baseline blood glucose and the presence or absence of impaired fasting glucose, Dr. Carlsson and her associates reported.
In a sensitivity analysis performed to account for the low participation rate, the impact of treatment on the incidence of type 2 diabetes was at least as strong after 2 years and 10 years of follow-up as after 15 years. All types of bariatric surgery were associated with a reduced incidence of diabetes, with no significant differences among them. There were also no differences by receipt of professional weight-loss assistance, or by BMI at baseline, the investigators noted.
A total of 3 patients (0.2%) died within 90 days of surgery, and 245 patients in the surgery group (15%) reported at least one complication. Of those, 46 (2.8%) were serious enough to require a reoperation.
The risk reduction seen among those with impaired fasting glucose was at least twice as large as the risk reduction achieved with lifestyle interventions in large, long-term trials of moderately obese people with prediabetes (Lancet 2006;368:1673-9, Lancet 2009;374:1677-86, and Lancet 2008;371:1783-9), the investigators noted.
The ongoing SOS study is supported by grants from the Swedish Research Council, the Swedish Foundation for Strategic Research to the Sahlgrenska Center for Cardiovascular and Metabolic Research, the Swedish federal government, the VINNOVA-VINNMER program, and the Wenner-Gren Foundations. The SOS study has previously been supported by grants to one of the authors from Hoffmann-La Roche, AstraZeneca, and other companies. Dr. Carlsson reported receiving consulting fees from AstraZeneca and owning stock in Sahltech. Other coinvestigators also had financial disclosures.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Major Finding: During follow-up, type 2 diabetes developed in 110 of the bariatric surgery patients and in 392 controls, corresponding to incidence rates of 6.8 versus 28.4 cases per 1,000 person-years, respectively (P less than .001).
Data Source: The Swedish Obese Subjects (SOS) study is a prospective, case-matched 15-year comparison of diabetes incidence between 1,658 obese nondiabetic individuals who chose to undergo bariatric surgery and 1,771 who received usual weight loss management.
Disclosures: The ongoing SOS study is supported by grants from the Swedish Research Council, the Swedish Foundation for Strategic Research to the Sahlgrenska Center for Cardiovascular and Metabolic Research, the Swedish federal government, the VINNOVA-VINNMER program, and the Wenner-Gren Foundations. The SOS study has previously been supported by grants to one of the authors from Hoffmann-La Roche, AstraZeneca, and other companies. Dr. Carlsson reported receiving consulting fees from AstraZeneca and owning stock in Sahltech. Other coinvestigators also had financial disclosures.
Acne Severity Grading Scale in the Works
A group of experts has identified what they believe to be essential clinical components of an ideal severity grading scale for acne vulgaris.
Although more than 25 systems are in existence for acne grading, there is neither a gold standard nor a standardized system consistently used in research or clinical practice. "The reasons for this are multiple, including differing needs of the clinical versus research paradigms, the persistence of simpler tools with inadequate accuracy, the inefficiency of research methods such as lesion counting, and a previous lack of consensus building in this area," lead author Dr. Jerry Tan, a dermatologist at the University of Western Ontario in London, said in an interview.
The panel of 12 acne experts determined that an ideal scale should include the clinical components of primary acne lesions; their quantity, extent, and facial and extrafacial sites of involvement; and features of clinimetric properties, categorization, efficiency, and acceptance.
This consensus is considered a first step toward the development of a new acne severity grading scale. In the meantime, "this information can best be used by practicing dermatologists as an initial phase in further identifying and developing a standard for acne severity grading in the future," said Dr. Tan.
The panel arrived at this consensus via the "Delphi method," in which each member responded to a three-phase, online, anonymous survey. In the first Delphi round, they were asked open-ended questions about what components and features would be essential to the scale, and whether any current scales included the components the member deemed essential and the features deemed important (J. Am. Acad. Dermatol. 2012;67:187-93 [doi: 10.1016/j.jaad.2011.09.005]).
In the first round, the group identified primary acne lesions (evaluation of inflammatory or noninflammatory lesions together or separately), secondary lesions (such as scarring or pigmentary changes), quantity of lesions, extrafacial sites of involvement, extent of involvement, and patient experiences as being essential clinical components. Features deemed important included clinimetric properties (such as validity and reproducibility), efficiency/ease of use, categorization of severity (i.e., based on descriptive text and/or photographic examples), and acceptance (by physicians, patients, and other stakeholders).
In the next round, panel members were asked to grade each component and feature on a seven-point scale, and to provide subcategories for inclusion.
In the final consensus, the group agreed that the scale should include separate evaluation of inflammatory and noninflammatory primary lesions; determination of the quantity of lesions by counting and numerical range; grading of extrafacial sites including the chest, back, neck, and shoulders; and determination of extent of involvement using proportion descriptors such as "one third or less."
The panel also came to a consensus on excluding patient experiences, while a slight majority also opted for excluding secondary lesions. In addition, a consensus was achieved for inclusion of the clinimetric properties (validity, reproducibility, discriminatory capacity, and responsivity), efficiency, acceptability, and categorization of severity.
The agreement to exclude patient experiences was a bit of a surprise, according to Dr. Tan. The finding may reflect the focus of the group on expert-determined severity, as well as the availability of quality-of-life scales that are particular to patient experience with acne and are routinely used in conjunction with clinician-based global acne severity assessments in clinical trials.
The group also agreed that while several current acne severity grading scales contain some of these elements, none contain all. For example, the eight-point severity grade scale by Allen and Smith includes type and quantity of lesions and proportion of facial involvement, but it is limited to the face (Arch. Dermatol. 1982;118:23-5). The ECLA (Echelle de Cotation des Lésions d’Acné) scale comprises numerical ranges of primary acne lesions, and includes extrafacial sites, but it does not include proportion descriptors of anatomical sites, and the scale has not been validated (Ann. Derm. Venereol. 1999;126:136-41), they wrote.
"The next steps are to identify current systems which meet at least some of the identified clinical components and features from the Delphi process. This may then facilitate development of the ideal acne grading tool for future clinical practice and research," Dr. Tan said in the interview.
Dr. Tan is an advisory board member, speaker, consultant, and/or investigator for Bayer, Cipher, and other companies. All but two of the other panel members also reported conflicts of interest.
A group of experts has identified what they believe to be essential clinical components of an ideal severity grading scale for acne vulgaris.
Although more than 25 systems are in existence for acne grading, there is neither a gold standard nor a standardized system consistently used in research or clinical practice. "The reasons for this are multiple, including differing needs of the clinical versus research paradigms, the persistence of simpler tools with inadequate accuracy, the inefficiency of research methods such as lesion counting, and a previous lack of consensus building in this area," lead author Dr. Jerry Tan, a dermatologist at the University of Western Ontario in London, said in an interview.
The panel of 12 acne experts determined that an ideal scale should include the clinical components of primary acne lesions; their quantity, extent, and facial and extrafacial sites of involvement; and features of clinimetric properties, categorization, efficiency, and acceptance.
This consensus is considered a first step toward the development of a new acne severity grading scale. In the meantime, "this information can best be used by practicing dermatologists as an initial phase in further identifying and developing a standard for acne severity grading in the future," said Dr. Tan.
The panel arrived at this consensus via the "Delphi method," in which each member responded to a three-phase, online, anonymous survey. In the first Delphi round, they were asked open-ended questions about what components and features would be essential to the scale, and whether any current scales included the components the member deemed essential and the features deemed important (J. Am. Acad. Dermatol. 2012;67:187-93 [doi: 10.1016/j.jaad.2011.09.005]).
In the first round, the group identified primary acne lesions (evaluation of inflammatory or noninflammatory lesions together or separately), secondary lesions (such as scarring or pigmentary changes), quantity of lesions, extrafacial sites of involvement, extent of involvement, and patient experiences as being essential clinical components. Features deemed important included clinimetric properties (such as validity and reproducibility), efficiency/ease of use, categorization of severity (i.e., based on descriptive text and/or photographic examples), and acceptance (by physicians, patients, and other stakeholders).
In the next round, panel members were asked to grade each component and feature on a seven-point scale, and to provide subcategories for inclusion.
In the final consensus, the group agreed that the scale should include separate evaluation of inflammatory and noninflammatory primary lesions; determination of the quantity of lesions by counting and numerical range; grading of extrafacial sites including the chest, back, neck, and shoulders; and determination of extent of involvement using proportion descriptors such as "one third or less."
The panel also came to a consensus on excluding patient experiences, while a slight majority also opted for excluding secondary lesions. In addition, a consensus was achieved for inclusion of the clinimetric properties (validity, reproducibility, discriminatory capacity, and responsivity), efficiency, acceptability, and categorization of severity.
The agreement to exclude patient experiences was a bit of a surprise, according to Dr. Tan. The finding may reflect the focus of the group on expert-determined severity, as well as the availability of quality-of-life scales that are particular to patient experience with acne and are routinely used in conjunction with clinician-based global acne severity assessments in clinical trials.
The group also agreed that while several current acne severity grading scales contain some of these elements, none contain all. For example, the eight-point severity grade scale by Allen and Smith includes type and quantity of lesions and proportion of facial involvement, but it is limited to the face (Arch. Dermatol. 1982;118:23-5). The ECLA (Echelle de Cotation des Lésions d’Acné) scale comprises numerical ranges of primary acne lesions, and includes extrafacial sites, but it does not include proportion descriptors of anatomical sites, and the scale has not been validated (Ann. Derm. Venereol. 1999;126:136-41), they wrote.
"The next steps are to identify current systems which meet at least some of the identified clinical components and features from the Delphi process. This may then facilitate development of the ideal acne grading tool for future clinical practice and research," Dr. Tan said in the interview.
Dr. Tan is an advisory board member, speaker, consultant, and/or investigator for Bayer, Cipher, and other companies. All but two of the other panel members also reported conflicts of interest.
A group of experts has identified what they believe to be essential clinical components of an ideal severity grading scale for acne vulgaris.
Although more than 25 systems are in existence for acne grading, there is neither a gold standard nor a standardized system consistently used in research or clinical practice. "The reasons for this are multiple, including differing needs of the clinical versus research paradigms, the persistence of simpler tools with inadequate accuracy, the inefficiency of research methods such as lesion counting, and a previous lack of consensus building in this area," lead author Dr. Jerry Tan, a dermatologist at the University of Western Ontario in London, said in an interview.
The panel of 12 acne experts determined that an ideal scale should include the clinical components of primary acne lesions; their quantity, extent, and facial and extrafacial sites of involvement; and features of clinimetric properties, categorization, efficiency, and acceptance.
This consensus is considered a first step toward the development of a new acne severity grading scale. In the meantime, "this information can best be used by practicing dermatologists as an initial phase in further identifying and developing a standard for acne severity grading in the future," said Dr. Tan.
The panel arrived at this consensus via the "Delphi method," in which each member responded to a three-phase, online, anonymous survey. In the first Delphi round, they were asked open-ended questions about what components and features would be essential to the scale, and whether any current scales included the components the member deemed essential and the features deemed important (J. Am. Acad. Dermatol. 2012;67:187-93 [doi: 10.1016/j.jaad.2011.09.005]).
In the first round, the group identified primary acne lesions (evaluation of inflammatory or noninflammatory lesions together or separately), secondary lesions (such as scarring or pigmentary changes), quantity of lesions, extrafacial sites of involvement, extent of involvement, and patient experiences as being essential clinical components. Features deemed important included clinimetric properties (such as validity and reproducibility), efficiency/ease of use, categorization of severity (i.e., based on descriptive text and/or photographic examples), and acceptance (by physicians, patients, and other stakeholders).
In the next round, panel members were asked to grade each component and feature on a seven-point scale, and to provide subcategories for inclusion.
In the final consensus, the group agreed that the scale should include separate evaluation of inflammatory and noninflammatory primary lesions; determination of the quantity of lesions by counting and numerical range; grading of extrafacial sites including the chest, back, neck, and shoulders; and determination of extent of involvement using proportion descriptors such as "one third or less."
The panel also came to a consensus on excluding patient experiences, while a slight majority also opted for excluding secondary lesions. In addition, a consensus was achieved for inclusion of the clinimetric properties (validity, reproducibility, discriminatory capacity, and responsivity), efficiency, acceptability, and categorization of severity.
The agreement to exclude patient experiences was a bit of a surprise, according to Dr. Tan. The finding may reflect the focus of the group on expert-determined severity, as well as the availability of quality-of-life scales that are particular to patient experience with acne and are routinely used in conjunction with clinician-based global acne severity assessments in clinical trials.
The group also agreed that while several current acne severity grading scales contain some of these elements, none contain all. For example, the eight-point severity grade scale by Allen and Smith includes type and quantity of lesions and proportion of facial involvement, but it is limited to the face (Arch. Dermatol. 1982;118:23-5). The ECLA (Echelle de Cotation des Lésions d’Acné) scale comprises numerical ranges of primary acne lesions, and includes extrafacial sites, but it does not include proportion descriptors of anatomical sites, and the scale has not been validated (Ann. Derm. Venereol. 1999;126:136-41), they wrote.
"The next steps are to identify current systems which meet at least some of the identified clinical components and features from the Delphi process. This may then facilitate development of the ideal acne grading tool for future clinical practice and research," Dr. Tan said in the interview.
Dr. Tan is an advisory board member, speaker, consultant, and/or investigator for Bayer, Cipher, and other companies. All but two of the other panel members also reported conflicts of interest.
FROM THE JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
Drug-Eluting Stents Beat Bare-Metal in STEMI Patients
Use of biolimus-eluting stents with a biodegradable polymer resulted in a significantly lower major adverse cardiac event rate at 1 year than did use of bare-metal stents in patients with acute myocardial infarction who were undergoing primary percutaneous coronary intervention.
The finding comes from Comparison of Biolimus Eluted From an Erodible Stent Coating With Bare Metal Stents in Acute ST-Elevation Myocardial Infarction (COMFORTABLE AMI), a multicenter, randomized, assessor-blinded, superiority trial in patients presenting with STEMI who were undergoing primary PCI. The trial of more than 1,100 patients found that compared with the use of bare-metal stents, the use of biolimus-eluting stents with a biodegradable polymer was associated with a significant 4.4% absolute reduction and 51% relative reduction in the risk of major adverse cardiac events at 1 year. Use of the biolimus-eluting stents prevented 42 events per 1,000 patients at 1 year compared with bare-metal stents, said Dr. Lorenz Raber of Bern (Switzerland) University Hospital and his associates (JAMA 2012;308:777-87).
The final analysis included 575 patients with 629 infarct vessel lesions randomly assigned to biolimus-eluting stents (Bio-Matrix, Biosensors Europe SA) and 582 patients with 648 infarct-vessel lesions randomly assigned to otherwise identically designed bare-metal stents (Gazelle, Biosensors Europe SA). The patients had a mean age of 61 years, and 79% were men. The median time from symptom onset to balloon inflation was 234 minutes, and from hospital admission to balloon inflation, 44 minutes. There were no apparent differences in lesion complexity between the two groups.
At discharge, 43% of patients received prasugrel and 57% of patients received clopidogrel. In contrast with most previous trials of patients with STEMI, the use of dual antiplatelet therapy remained balanced in both treatment groups throughout the entire follow-up period up to 1 year, the investigators noted.
At 1 year, the primary end point of major adverse cardiac events (cardiac death, target vessel–related reinfarction, and ischemia-driven target-lesion revascularization) occurred in 4.3% of patients who received biolimus-eluting stents and 8.7% of patients given bare-metal stents, producing a hazard ratio of 0.49 (P = .004). For cardiac death alone, the percentages were 2.9% with biolimus-eluting stents and 3.5% for bare-metal stents (HR 0.81, P = .53).
The treatment effect in favor of patients receiving biolimus-eluting stents was attributable to significantly lower risks of target vessel–related reinfarction (0.5% vs 2.7% HR, 0.20, P =.01) and ischemia-driven target-lesion revascularization (1.6% vs 5.7%, HR 0.28). Differences between stent types with respect to the primary outcome emerged early and continued throughout the study period, Dr. Raber and his associates said.
The rates of definite stent thrombosis at 1 year did not differ significantly, at 0.9% in patients receiving biolimus-eluting stents and 2.1% in those receiving bare-metal stents. Furthermore, no differences were seen in all-cause and cardiac mortality between the groups at 1 year.
The biolimus-eluting stent used in this study is not approved by the Food and Drug Administration, but data showing that it was noninferior to the sirolimus-eluting Cypher stent (Lancet 2011;378:1940-8) provided the basis for a recommendation for its use in European guidelines on myocardial revascularization (Eur. Heart J. 2010;31:2501-5), they noted.
The COMFORTABLE AMI trial was investigator-initiated, managed by the Clinical Trials Unit, University of Bern (Switzerland), and supported by the Swiss National Science Foundation and an unrestricted research grant from Biosensors Europe SA, Morges, Switzerland. Dr. Raber is the recipient of a research fellowship funded by the Swiss National Science Foundation.
By their very nature, the biodegradable polymers used in newer generation DESs might offer the early advantages of polymers – protecting against stent thrombosis – while avoiding the very late hazards, their proinflammatory and prothrombotic effects. This may turn out to be especially useful in patients with STEMI.
Although COMFORTABLE AMI is a well done trial with convincing results, it has neither the required sample size nor the sufficient length of follow-up to provide the definitive answer about the long-term safety of the new biodegradable DES in this setting. Nonethelesss, the trial offers positive signals that, along with previous findings indicating the excellent 4-year safety of biodegradable polymer DESs, form a good basis to believe that these new DESs may belong to the "first-choice" devices in patients with STEMI.
The findings from the COMFORTABLE AMI trial and from previous trials on DESs in patients with AMI show that the efficacy of DESs versus BMSs in STEMI is already established, therefore there is almost no rationale any more for performing studies comparing a DES with a BMS.
It is also now apparent that concerns about a possible very late safety issue with DESs are apparently specific to the stent type and are mostly related to first-generation DESs. Such concerns are less justified with newer DESs.
Dr. Salvatore Cassese and Dr. Adnan Kastrati are with Deutsches Herzzentrum,Technische Universitat, Munich. These remarks are taken from their editorial accompanying the COMFORTABLE-AMI report (JAMA 2012;308:814-5). Dr Kastrati holds a patent related to polymer-free sirolimus and probucol coating and reported receiving honoraria from Abbott, Biosensors, Cordis, and Medtronic. Dr Cassese reports no conflicts.
By their very nature, the biodegradable polymers used in newer generation DESs might offer the early advantages of polymers – protecting against stent thrombosis – while avoiding the very late hazards, their proinflammatory and prothrombotic effects. This may turn out to be especially useful in patients with STEMI.
Although COMFORTABLE AMI is a well done trial with convincing results, it has neither the required sample size nor the sufficient length of follow-up to provide the definitive answer about the long-term safety of the new biodegradable DES in this setting. Nonethelesss, the trial offers positive signals that, along with previous findings indicating the excellent 4-year safety of biodegradable polymer DESs, form a good basis to believe that these new DESs may belong to the "first-choice" devices in patients with STEMI.
The findings from the COMFORTABLE AMI trial and from previous trials on DESs in patients with AMI show that the efficacy of DESs versus BMSs in STEMI is already established, therefore there is almost no rationale any more for performing studies comparing a DES with a BMS.
It is also now apparent that concerns about a possible very late safety issue with DESs are apparently specific to the stent type and are mostly related to first-generation DESs. Such concerns are less justified with newer DESs.
Dr. Salvatore Cassese and Dr. Adnan Kastrati are with Deutsches Herzzentrum,Technische Universitat, Munich. These remarks are taken from their editorial accompanying the COMFORTABLE-AMI report (JAMA 2012;308:814-5). Dr Kastrati holds a patent related to polymer-free sirolimus and probucol coating and reported receiving honoraria from Abbott, Biosensors, Cordis, and Medtronic. Dr Cassese reports no conflicts.
By their very nature, the biodegradable polymers used in newer generation DESs might offer the early advantages of polymers – protecting against stent thrombosis – while avoiding the very late hazards, their proinflammatory and prothrombotic effects. This may turn out to be especially useful in patients with STEMI.
Although COMFORTABLE AMI is a well done trial with convincing results, it has neither the required sample size nor the sufficient length of follow-up to provide the definitive answer about the long-term safety of the new biodegradable DES in this setting. Nonethelesss, the trial offers positive signals that, along with previous findings indicating the excellent 4-year safety of biodegradable polymer DESs, form a good basis to believe that these new DESs may belong to the "first-choice" devices in patients with STEMI.
The findings from the COMFORTABLE AMI trial and from previous trials on DESs in patients with AMI show that the efficacy of DESs versus BMSs in STEMI is already established, therefore there is almost no rationale any more for performing studies comparing a DES with a BMS.
It is also now apparent that concerns about a possible very late safety issue with DESs are apparently specific to the stent type and are mostly related to first-generation DESs. Such concerns are less justified with newer DESs.
Dr. Salvatore Cassese and Dr. Adnan Kastrati are with Deutsches Herzzentrum,Technische Universitat, Munich. These remarks are taken from their editorial accompanying the COMFORTABLE-AMI report (JAMA 2012;308:814-5). Dr Kastrati holds a patent related to polymer-free sirolimus and probucol coating and reported receiving honoraria from Abbott, Biosensors, Cordis, and Medtronic. Dr Cassese reports no conflicts.
Use of biolimus-eluting stents with a biodegradable polymer resulted in a significantly lower major adverse cardiac event rate at 1 year than did use of bare-metal stents in patients with acute myocardial infarction who were undergoing primary percutaneous coronary intervention.
The finding comes from Comparison of Biolimus Eluted From an Erodible Stent Coating With Bare Metal Stents in Acute ST-Elevation Myocardial Infarction (COMFORTABLE AMI), a multicenter, randomized, assessor-blinded, superiority trial in patients presenting with STEMI who were undergoing primary PCI. The trial of more than 1,100 patients found that compared with the use of bare-metal stents, the use of biolimus-eluting stents with a biodegradable polymer was associated with a significant 4.4% absolute reduction and 51% relative reduction in the risk of major adverse cardiac events at 1 year. Use of the biolimus-eluting stents prevented 42 events per 1,000 patients at 1 year compared with bare-metal stents, said Dr. Lorenz Raber of Bern (Switzerland) University Hospital and his associates (JAMA 2012;308:777-87).
The final analysis included 575 patients with 629 infarct vessel lesions randomly assigned to biolimus-eluting stents (Bio-Matrix, Biosensors Europe SA) and 582 patients with 648 infarct-vessel lesions randomly assigned to otherwise identically designed bare-metal stents (Gazelle, Biosensors Europe SA). The patients had a mean age of 61 years, and 79% were men. The median time from symptom onset to balloon inflation was 234 minutes, and from hospital admission to balloon inflation, 44 minutes. There were no apparent differences in lesion complexity between the two groups.
At discharge, 43% of patients received prasugrel and 57% of patients received clopidogrel. In contrast with most previous trials of patients with STEMI, the use of dual antiplatelet therapy remained balanced in both treatment groups throughout the entire follow-up period up to 1 year, the investigators noted.
At 1 year, the primary end point of major adverse cardiac events (cardiac death, target vessel–related reinfarction, and ischemia-driven target-lesion revascularization) occurred in 4.3% of patients who received biolimus-eluting stents and 8.7% of patients given bare-metal stents, producing a hazard ratio of 0.49 (P = .004). For cardiac death alone, the percentages were 2.9% with biolimus-eluting stents and 3.5% for bare-metal stents (HR 0.81, P = .53).
The treatment effect in favor of patients receiving biolimus-eluting stents was attributable to significantly lower risks of target vessel–related reinfarction (0.5% vs 2.7% HR, 0.20, P =.01) and ischemia-driven target-lesion revascularization (1.6% vs 5.7%, HR 0.28). Differences between stent types with respect to the primary outcome emerged early and continued throughout the study period, Dr. Raber and his associates said.
The rates of definite stent thrombosis at 1 year did not differ significantly, at 0.9% in patients receiving biolimus-eluting stents and 2.1% in those receiving bare-metal stents. Furthermore, no differences were seen in all-cause and cardiac mortality between the groups at 1 year.
The biolimus-eluting stent used in this study is not approved by the Food and Drug Administration, but data showing that it was noninferior to the sirolimus-eluting Cypher stent (Lancet 2011;378:1940-8) provided the basis for a recommendation for its use in European guidelines on myocardial revascularization (Eur. Heart J. 2010;31:2501-5), they noted.
The COMFORTABLE AMI trial was investigator-initiated, managed by the Clinical Trials Unit, University of Bern (Switzerland), and supported by the Swiss National Science Foundation and an unrestricted research grant from Biosensors Europe SA, Morges, Switzerland. Dr. Raber is the recipient of a research fellowship funded by the Swiss National Science Foundation.
Use of biolimus-eluting stents with a biodegradable polymer resulted in a significantly lower major adverse cardiac event rate at 1 year than did use of bare-metal stents in patients with acute myocardial infarction who were undergoing primary percutaneous coronary intervention.
The finding comes from Comparison of Biolimus Eluted From an Erodible Stent Coating With Bare Metal Stents in Acute ST-Elevation Myocardial Infarction (COMFORTABLE AMI), a multicenter, randomized, assessor-blinded, superiority trial in patients presenting with STEMI who were undergoing primary PCI. The trial of more than 1,100 patients found that compared with the use of bare-metal stents, the use of biolimus-eluting stents with a biodegradable polymer was associated with a significant 4.4% absolute reduction and 51% relative reduction in the risk of major adverse cardiac events at 1 year. Use of the biolimus-eluting stents prevented 42 events per 1,000 patients at 1 year compared with bare-metal stents, said Dr. Lorenz Raber of Bern (Switzerland) University Hospital and his associates (JAMA 2012;308:777-87).
The final analysis included 575 patients with 629 infarct vessel lesions randomly assigned to biolimus-eluting stents (Bio-Matrix, Biosensors Europe SA) and 582 patients with 648 infarct-vessel lesions randomly assigned to otherwise identically designed bare-metal stents (Gazelle, Biosensors Europe SA). The patients had a mean age of 61 years, and 79% were men. The median time from symptom onset to balloon inflation was 234 minutes, and from hospital admission to balloon inflation, 44 minutes. There were no apparent differences in lesion complexity between the two groups.
At discharge, 43% of patients received prasugrel and 57% of patients received clopidogrel. In contrast with most previous trials of patients with STEMI, the use of dual antiplatelet therapy remained balanced in both treatment groups throughout the entire follow-up period up to 1 year, the investigators noted.
At 1 year, the primary end point of major adverse cardiac events (cardiac death, target vessel–related reinfarction, and ischemia-driven target-lesion revascularization) occurred in 4.3% of patients who received biolimus-eluting stents and 8.7% of patients given bare-metal stents, producing a hazard ratio of 0.49 (P = .004). For cardiac death alone, the percentages were 2.9% with biolimus-eluting stents and 3.5% for bare-metal stents (HR 0.81, P = .53).
The treatment effect in favor of patients receiving biolimus-eluting stents was attributable to significantly lower risks of target vessel–related reinfarction (0.5% vs 2.7% HR, 0.20, P =.01) and ischemia-driven target-lesion revascularization (1.6% vs 5.7%, HR 0.28). Differences between stent types with respect to the primary outcome emerged early and continued throughout the study period, Dr. Raber and his associates said.
The rates of definite stent thrombosis at 1 year did not differ significantly, at 0.9% in patients receiving biolimus-eluting stents and 2.1% in those receiving bare-metal stents. Furthermore, no differences were seen in all-cause and cardiac mortality between the groups at 1 year.
The biolimus-eluting stent used in this study is not approved by the Food and Drug Administration, but data showing that it was noninferior to the sirolimus-eluting Cypher stent (Lancet 2011;378:1940-8) provided the basis for a recommendation for its use in European guidelines on myocardial revascularization (Eur. Heart J. 2010;31:2501-5), they noted.
The COMFORTABLE AMI trial was investigator-initiated, managed by the Clinical Trials Unit, University of Bern (Switzerland), and supported by the Swiss National Science Foundation and an unrestricted research grant from Biosensors Europe SA, Morges, Switzerland. Dr. Raber is the recipient of a research fellowship funded by the Swiss National Science Foundation.
FROM JAMA
Major Finding: At 1 year, the primary end point of major adverse cardiac events occurred in 4.3% of patients who received biolimus-eluting stents and in 8.7% of patients given bare-metal stents, producing a significant, 51% reduction in risk.
Data Source: COMFORTABLE AMI, a multicenter, randomized, assessor-blinded, superiority trial in more than 1,100 patients presenting with STEMI who were undergoing primary PCI.
Disclosures: COMFORTABLE AMI was supported by the Swiss National Science Foundation and an unrestricted research grant from Biosensors Europe SA. Dr. Raber has received a research fellowship from the Swiss National Science Foundation.
Length of Stay, Mortality Rise With Glycemic Variability
PHILADELPHIA – Glycemic variability appeared to be independently associated with increased length of stay and mortality in noncritically ill hospitalized patients, in a large retrospective study presented at the annual scientific sessions of the American Diabetes Association.
"Glycemic variability" refers to oscillations of blood glucose levels around the mean. Two people can have identical hemoglobin A1c values, yet one may have far greater variability than the other and therefore be considered to have poorer control because of frequent bouts of hyper- and hypoglycemia, said Dr. Carlos E. Mendez, director of the diabetes management program at the Albany (N.Y.) Stratton VA Medical Center.
Previous studies done in critical care settings have demonstrated increased mortality in patients with high glycemic variability, independent of hypo- and hyperglycemia (Crit. Care Med. 2008;36:3008-13). Both in vitro and in vivo data suggest that "rather than hyperglycemia, glycemic variability has a more profound effect and greater production of reactive oxygen species and what we think is more reactive oxidative stress," Dr. Mendez said.
To examine this phenomenon in noncritically ill patients, he and his associates retrospectively reviewed glucose values from a total of 960 patients who were admitted to medical (81%) or surgical (19%) wards during 2008-2010 and for whom a minimum of two point-of-care blood glucose values per day had been ordered. A GSD (glucose standard deviation) value was calculated as a surrogate for glycemic variability.
The patients were typical of a VA population: They had a mean age of 69.8 years, and 95% were male. Their mean blood glucose was 181.3 mg/dL, with a mean GSD of 57.4 mg/dL. Average length of stay was 5.7 days. A mean of 4.8 glucose readings per day was performed for the group as a whole. Nearly a quarter (24%) had at least one hypoglycemic episode; about two-thirds were receiving insulin. The 90-day mortality was 11%. The majority (85%) had a diagnosis of diabetes.
Length of stay increased significantly with increasing GSD, from 3.3 days for the 166 patients with the least variability (0-30 mg/dL), to 6.5 days for the 245 patients with GSD of 61-90 mg/dL, to 7.4 days for the 39 who had glycemic variability greater than 120 mg/dL. Those increases translated to a mean 6% increase in length of stay for every 10-mg/dL increase in the GSD. The relationship remained significant for patients with and without diabetes, for medical and surgical patients, and for those who had and had not experienced hypoglycemia, Dr. Mendez said.
Mortality at 90 days also increased significantly with greater GSD, from 9% in those with the lowest variability, up to 28% for the patients with the highest variability. Here, there was a 9% increased risk of death for every 10 mg/dL of increased GSD. The mortality findings were significant for the patients with diabetes and for the medical ward patients, but didn’t reach significance for nondiabetic and surgical patients, probably because of low numbers, he said.
Prospective studies using continuous glucose monitoring would confirm these results and better elucidate factors that may influence glycemic variability in noncritically ill inpatients, he concluded.
Dr. Mendez disclosed no conflict of interest.
PHILADELPHIA – Glycemic variability appeared to be independently associated with increased length of stay and mortality in noncritically ill hospitalized patients, in a large retrospective study presented at the annual scientific sessions of the American Diabetes Association.
"Glycemic variability" refers to oscillations of blood glucose levels around the mean. Two people can have identical hemoglobin A1c values, yet one may have far greater variability than the other and therefore be considered to have poorer control because of frequent bouts of hyper- and hypoglycemia, said Dr. Carlos E. Mendez, director of the diabetes management program at the Albany (N.Y.) Stratton VA Medical Center.
Previous studies done in critical care settings have demonstrated increased mortality in patients with high glycemic variability, independent of hypo- and hyperglycemia (Crit. Care Med. 2008;36:3008-13). Both in vitro and in vivo data suggest that "rather than hyperglycemia, glycemic variability has a more profound effect and greater production of reactive oxygen species and what we think is more reactive oxidative stress," Dr. Mendez said.
To examine this phenomenon in noncritically ill patients, he and his associates retrospectively reviewed glucose values from a total of 960 patients who were admitted to medical (81%) or surgical (19%) wards during 2008-2010 and for whom a minimum of two point-of-care blood glucose values per day had been ordered. A GSD (glucose standard deviation) value was calculated as a surrogate for glycemic variability.
The patients were typical of a VA population: They had a mean age of 69.8 years, and 95% were male. Their mean blood glucose was 181.3 mg/dL, with a mean GSD of 57.4 mg/dL. Average length of stay was 5.7 days. A mean of 4.8 glucose readings per day was performed for the group as a whole. Nearly a quarter (24%) had at least one hypoglycemic episode; about two-thirds were receiving insulin. The 90-day mortality was 11%. The majority (85%) had a diagnosis of diabetes.
Length of stay increased significantly with increasing GSD, from 3.3 days for the 166 patients with the least variability (0-30 mg/dL), to 6.5 days for the 245 patients with GSD of 61-90 mg/dL, to 7.4 days for the 39 who had glycemic variability greater than 120 mg/dL. Those increases translated to a mean 6% increase in length of stay for every 10-mg/dL increase in the GSD. The relationship remained significant for patients with and without diabetes, for medical and surgical patients, and for those who had and had not experienced hypoglycemia, Dr. Mendez said.
Mortality at 90 days also increased significantly with greater GSD, from 9% in those with the lowest variability, up to 28% for the patients with the highest variability. Here, there was a 9% increased risk of death for every 10 mg/dL of increased GSD. The mortality findings were significant for the patients with diabetes and for the medical ward patients, but didn’t reach significance for nondiabetic and surgical patients, probably because of low numbers, he said.
Prospective studies using continuous glucose monitoring would confirm these results and better elucidate factors that may influence glycemic variability in noncritically ill inpatients, he concluded.
Dr. Mendez disclosed no conflict of interest.
PHILADELPHIA – Glycemic variability appeared to be independently associated with increased length of stay and mortality in noncritically ill hospitalized patients, in a large retrospective study presented at the annual scientific sessions of the American Diabetes Association.
"Glycemic variability" refers to oscillations of blood glucose levels around the mean. Two people can have identical hemoglobin A1c values, yet one may have far greater variability than the other and therefore be considered to have poorer control because of frequent bouts of hyper- and hypoglycemia, said Dr. Carlos E. Mendez, director of the diabetes management program at the Albany (N.Y.) Stratton VA Medical Center.
Previous studies done in critical care settings have demonstrated increased mortality in patients with high glycemic variability, independent of hypo- and hyperglycemia (Crit. Care Med. 2008;36:3008-13). Both in vitro and in vivo data suggest that "rather than hyperglycemia, glycemic variability has a more profound effect and greater production of reactive oxygen species and what we think is more reactive oxidative stress," Dr. Mendez said.
To examine this phenomenon in noncritically ill patients, he and his associates retrospectively reviewed glucose values from a total of 960 patients who were admitted to medical (81%) or surgical (19%) wards during 2008-2010 and for whom a minimum of two point-of-care blood glucose values per day had been ordered. A GSD (glucose standard deviation) value was calculated as a surrogate for glycemic variability.
The patients were typical of a VA population: They had a mean age of 69.8 years, and 95% were male. Their mean blood glucose was 181.3 mg/dL, with a mean GSD of 57.4 mg/dL. Average length of stay was 5.7 days. A mean of 4.8 glucose readings per day was performed for the group as a whole. Nearly a quarter (24%) had at least one hypoglycemic episode; about two-thirds were receiving insulin. The 90-day mortality was 11%. The majority (85%) had a diagnosis of diabetes.
Length of stay increased significantly with increasing GSD, from 3.3 days for the 166 patients with the least variability (0-30 mg/dL), to 6.5 days for the 245 patients with GSD of 61-90 mg/dL, to 7.4 days for the 39 who had glycemic variability greater than 120 mg/dL. Those increases translated to a mean 6% increase in length of stay for every 10-mg/dL increase in the GSD. The relationship remained significant for patients with and without diabetes, for medical and surgical patients, and for those who had and had not experienced hypoglycemia, Dr. Mendez said.
Mortality at 90 days also increased significantly with greater GSD, from 9% in those with the lowest variability, up to 28% for the patients with the highest variability. Here, there was a 9% increased risk of death for every 10 mg/dL of increased GSD. The mortality findings were significant for the patients with diabetes and for the medical ward patients, but didn’t reach significance for nondiabetic and surgical patients, probably because of low numbers, he said.
Prospective studies using continuous glucose monitoring would confirm these results and better elucidate factors that may influence glycemic variability in noncritically ill inpatients, he concluded.
Dr. Mendez disclosed no conflict of interest.
AT THE ANNUAL SCIENTIFIC SESSIONS OF THE AMERICAN DIABETES ASSOCIATION
Major Finding: Length of stay increased by 6% and 90-day mortality by 9% for every 10 mg/dL increase in glucose standard deviation.
Data Source: The data come from a retrospective analysis of 960 noncritically ill patients who were admitted to medical or surgical wards in a VA hospital during 2008-2010.
Disclosures: Dr. Mendez disclosed no conflict of interest.
Pancreas-Sparing GK Activator Lowers Glucose Without Hypoglycemia
PHILADELPHIA – An investigational glucokinase activator lowered glucose levels without producing hypoglycemia in a 2-week, phase IIa study of 60 patients with type 2 diabetes.
The enzyme glucokinase (GK) is involved in glucose homeostasis via control of both pancreatic insulin secretion and glucose disposal in the liver. The compound GKM-001, under development by Advinus Therapeutics, differs from other investigational GK activators in that it specifically targets the liver and avoids the pancreas, thereby eliminating the risk for hypoglycemia, Rashmi H. Barbhaiya, Ph.D., said at the annual scientific sessions of the American Diabetes Association.
In a multiple ascending dose study, 60 patients were washed out of their prior medications, then randomized either to doses of 25, 50, 200, 600, or 1,000 mg or to placebo.
Compared with baseline, there were dose-dependent reductions in the 24-hour glucose area under the curve. At day 14, the percent reductions were 9% with 25 mg, 14% with 50 mg, 15% with 200 mg, 17% with 600 mg, and 20% with 1,000 mg, while the placebo group had a 2% increase. Significant reductions were also seen in fasting glucose levels, ranging from 23 to 46 mg/dL, reported Dr. Barbhaiya, CEO and managing director of Advinus, which is based in Bangalore, India.
No hypoglycemia was seen with any of the doses following 12 hours of overnight fasting and 2 hours of postdose fasting, he said.
Neither oral glucose tolerance tests nor dinnertime mixed-meal tolerance tests on days 1 and 14 showed any changes in C-peptide area under the curve, providing further evidence that GKM-001 is not interacting with the pancreas and that its glucose-lowering action is not due to increased insulin levels, he said.
There were also no changes in levels of plasma triglycerides, aspartate transaminase, or alanine aminotransferase.
The company will soon be initiating a phase IIb study of GKM-001 that will assess its impact on hemoglobin A1c levels when used in combination with metformin, he said.
The study was funded by Advinus Therapeutics. Dr. Barbhaiya is a cofounder and a shareholder of the company.
PHILADELPHIA – An investigational glucokinase activator lowered glucose levels without producing hypoglycemia in a 2-week, phase IIa study of 60 patients with type 2 diabetes.
The enzyme glucokinase (GK) is involved in glucose homeostasis via control of both pancreatic insulin secretion and glucose disposal in the liver. The compound GKM-001, under development by Advinus Therapeutics, differs from other investigational GK activators in that it specifically targets the liver and avoids the pancreas, thereby eliminating the risk for hypoglycemia, Rashmi H. Barbhaiya, Ph.D., said at the annual scientific sessions of the American Diabetes Association.
In a multiple ascending dose study, 60 patients were washed out of their prior medications, then randomized either to doses of 25, 50, 200, 600, or 1,000 mg or to placebo.
Compared with baseline, there were dose-dependent reductions in the 24-hour glucose area under the curve. At day 14, the percent reductions were 9% with 25 mg, 14% with 50 mg, 15% with 200 mg, 17% with 600 mg, and 20% with 1,000 mg, while the placebo group had a 2% increase. Significant reductions were also seen in fasting glucose levels, ranging from 23 to 46 mg/dL, reported Dr. Barbhaiya, CEO and managing director of Advinus, which is based in Bangalore, India.
No hypoglycemia was seen with any of the doses following 12 hours of overnight fasting and 2 hours of postdose fasting, he said.
Neither oral glucose tolerance tests nor dinnertime mixed-meal tolerance tests on days 1 and 14 showed any changes in C-peptide area under the curve, providing further evidence that GKM-001 is not interacting with the pancreas and that its glucose-lowering action is not due to increased insulin levels, he said.
There were also no changes in levels of plasma triglycerides, aspartate transaminase, or alanine aminotransferase.
The company will soon be initiating a phase IIb study of GKM-001 that will assess its impact on hemoglobin A1c levels when used in combination with metformin, he said.
The study was funded by Advinus Therapeutics. Dr. Barbhaiya is a cofounder and a shareholder of the company.
PHILADELPHIA – An investigational glucokinase activator lowered glucose levels without producing hypoglycemia in a 2-week, phase IIa study of 60 patients with type 2 diabetes.
The enzyme glucokinase (GK) is involved in glucose homeostasis via control of both pancreatic insulin secretion and glucose disposal in the liver. The compound GKM-001, under development by Advinus Therapeutics, differs from other investigational GK activators in that it specifically targets the liver and avoids the pancreas, thereby eliminating the risk for hypoglycemia, Rashmi H. Barbhaiya, Ph.D., said at the annual scientific sessions of the American Diabetes Association.
In a multiple ascending dose study, 60 patients were washed out of their prior medications, then randomized either to doses of 25, 50, 200, 600, or 1,000 mg or to placebo.
Compared with baseline, there were dose-dependent reductions in the 24-hour glucose area under the curve. At day 14, the percent reductions were 9% with 25 mg, 14% with 50 mg, 15% with 200 mg, 17% with 600 mg, and 20% with 1,000 mg, while the placebo group had a 2% increase. Significant reductions were also seen in fasting glucose levels, ranging from 23 to 46 mg/dL, reported Dr. Barbhaiya, CEO and managing director of Advinus, which is based in Bangalore, India.
No hypoglycemia was seen with any of the doses following 12 hours of overnight fasting and 2 hours of postdose fasting, he said.
Neither oral glucose tolerance tests nor dinnertime mixed-meal tolerance tests on days 1 and 14 showed any changes in C-peptide area under the curve, providing further evidence that GKM-001 is not interacting with the pancreas and that its glucose-lowering action is not due to increased insulin levels, he said.
There were also no changes in levels of plasma triglycerides, aspartate transaminase, or alanine aminotransferase.
The company will soon be initiating a phase IIb study of GKM-001 that will assess its impact on hemoglobin A1c levels when used in combination with metformin, he said.
The study was funded by Advinus Therapeutics. Dr. Barbhaiya is a cofounder and a shareholder of the company.
AT THE ANNUAL SCIENTIFIC SESSIONS OF THE AMERICAN DIABETES ASSOCIATION
Major Finding: At day 14, the percent reductions in 24-hour glucose profiles were 9% with 25 mg, 14% with 50 mg, 15% with 200 mg, 17% with 600 mg, and 20% with 1,000 mg, while the placebo group had a 2% increase. No hypoglycemia was seen at any time with any dose.
Data Source: This was a placebo-controlled ascending dose study of 60 patients with type 2 diabetes.
Disclosures: The study was funded by Advinus Therapeutics. Dr. Barbhaiya is a cofounder and a shareholder of the company.
Abatacept Delays Beta-Cell Loss in Type 1 Diabetes
PHILADELPHIA – Previous costimulation with abatacept for 24 months was associated with a continued slowing of the decline in beta-cell function 1 year after discontinuation in patients with recent-onset type 1 diabetes.
The findings suggest that abatacept might be useful in prevention studies in individuals at high risk of type 1 diabetes, or as one component in studies that use a combination of different strategies, said Dr. Tihamer Orban, principal investigator in the Type 1 Diabetes TrialNet, through which the study was conducted.
Abatacept, marketed by Bristol-Myers Squibb as Orencia, is a costimulation modulator that was approved to treat rheumatoid arthritis and juvenile idiopathic arthritis. The biologic blocks the process of T-lymphocyte activation that drives the autoimmune destruction of beta-cells leading to type 1 diabetes, according to Dr. Orban.
The current data constitute a follow-up to a randomized, double-masked trial that included 112 patients, aged 6-36 years (mean, 14 years), who had been diagnosed with type 1 diabetes within the previous 100 days. The administration of 27 intravenous infusions of abatacept over 2 years in 77 patients was associated with a 59% higher adjusted C-peptide AUC (area under the curve), compared with the 35 patients who received placebo infusions. The difference (0.378 nmol/L with abatacept vs. 0.238 nmol/L with placebo) was significant. Hemoglobin A1c was also significantly lower in the abatacept patients, with no difference in insulin use (Lancet 2011;378:412-9).
However, despite continued administration of abatacept over 24 months, the decrease in beta-cell function with abatacept was parallel to that with placebo after 6 months of treatment, causing the investigators to speculate that T-cell activation lessens with time.
The study remained double-blinded at 36 months. At that point, the mean adjusted 2-hour C-peptide AUC was 0.215 nmol/L for the 64 abatacept patients in whom it was measured, compared with 0.135 nmol/L for the 29 remaining placebo patients. The difference was still significant, said Dr. Orban, who is also an investigator in the section on immunobiology at the Joslin Diabetes Center and an instructor in medicine at Harvard Medical School, both in Boston.
Still, the major effect appeared to be within the first year of the treatment phase, and the two groups remained relatively parallel thereafter. This suggests that the drug may only be actively blocking T-cell activation around the time of diagnosis, he noted.
HbA1c was significantly lower in the abatacept-treated patients, with no difference in insulin use. In all, abatacept treatment resulted in an average 9.5 months’ delay of loss in beta-cell function, compared with placebo, Dr. Orban said.
"It seems that we may not need a full 2 years of treatment to achieve this effect. It’s very logical to try a shorter course of the drug and see if a similar effect can be achieved," Dr. Orban commented.
This study was sponsored by the Type 1 Diabetes TrialNet Study Group, a clinical trials network funded by the National Institutes of Health. Dr. Orban is founder and CEO of Orban Biotech LLC.
PHILADELPHIA – Previous costimulation with abatacept for 24 months was associated with a continued slowing of the decline in beta-cell function 1 year after discontinuation in patients with recent-onset type 1 diabetes.
The findings suggest that abatacept might be useful in prevention studies in individuals at high risk of type 1 diabetes, or as one component in studies that use a combination of different strategies, said Dr. Tihamer Orban, principal investigator in the Type 1 Diabetes TrialNet, through which the study was conducted.
Abatacept, marketed by Bristol-Myers Squibb as Orencia, is a costimulation modulator that was approved to treat rheumatoid arthritis and juvenile idiopathic arthritis. The biologic blocks the process of T-lymphocyte activation that drives the autoimmune destruction of beta-cells leading to type 1 diabetes, according to Dr. Orban.
The current data constitute a follow-up to a randomized, double-masked trial that included 112 patients, aged 6-36 years (mean, 14 years), who had been diagnosed with type 1 diabetes within the previous 100 days. The administration of 27 intravenous infusions of abatacept over 2 years in 77 patients was associated with a 59% higher adjusted C-peptide AUC (area under the curve), compared with the 35 patients who received placebo infusions. The difference (0.378 nmol/L with abatacept vs. 0.238 nmol/L with placebo) was significant. Hemoglobin A1c was also significantly lower in the abatacept patients, with no difference in insulin use (Lancet 2011;378:412-9).
However, despite continued administration of abatacept over 24 months, the decrease in beta-cell function with abatacept was parallel to that with placebo after 6 months of treatment, causing the investigators to speculate that T-cell activation lessens with time.
The study remained double-blinded at 36 months. At that point, the mean adjusted 2-hour C-peptide AUC was 0.215 nmol/L for the 64 abatacept patients in whom it was measured, compared with 0.135 nmol/L for the 29 remaining placebo patients. The difference was still significant, said Dr. Orban, who is also an investigator in the section on immunobiology at the Joslin Diabetes Center and an instructor in medicine at Harvard Medical School, both in Boston.
Still, the major effect appeared to be within the first year of the treatment phase, and the two groups remained relatively parallel thereafter. This suggests that the drug may only be actively blocking T-cell activation around the time of diagnosis, he noted.
HbA1c was significantly lower in the abatacept-treated patients, with no difference in insulin use. In all, abatacept treatment resulted in an average 9.5 months’ delay of loss in beta-cell function, compared with placebo, Dr. Orban said.
"It seems that we may not need a full 2 years of treatment to achieve this effect. It’s very logical to try a shorter course of the drug and see if a similar effect can be achieved," Dr. Orban commented.
This study was sponsored by the Type 1 Diabetes TrialNet Study Group, a clinical trials network funded by the National Institutes of Health. Dr. Orban is founder and CEO of Orban Biotech LLC.
PHILADELPHIA – Previous costimulation with abatacept for 24 months was associated with a continued slowing of the decline in beta-cell function 1 year after discontinuation in patients with recent-onset type 1 diabetes.
The findings suggest that abatacept might be useful in prevention studies in individuals at high risk of type 1 diabetes, or as one component in studies that use a combination of different strategies, said Dr. Tihamer Orban, principal investigator in the Type 1 Diabetes TrialNet, through which the study was conducted.
Abatacept, marketed by Bristol-Myers Squibb as Orencia, is a costimulation modulator that was approved to treat rheumatoid arthritis and juvenile idiopathic arthritis. The biologic blocks the process of T-lymphocyte activation that drives the autoimmune destruction of beta-cells leading to type 1 diabetes, according to Dr. Orban.
The current data constitute a follow-up to a randomized, double-masked trial that included 112 patients, aged 6-36 years (mean, 14 years), who had been diagnosed with type 1 diabetes within the previous 100 days. The administration of 27 intravenous infusions of abatacept over 2 years in 77 patients was associated with a 59% higher adjusted C-peptide AUC (area under the curve), compared with the 35 patients who received placebo infusions. The difference (0.378 nmol/L with abatacept vs. 0.238 nmol/L with placebo) was significant. Hemoglobin A1c was also significantly lower in the abatacept patients, with no difference in insulin use (Lancet 2011;378:412-9).
However, despite continued administration of abatacept over 24 months, the decrease in beta-cell function with abatacept was parallel to that with placebo after 6 months of treatment, causing the investigators to speculate that T-cell activation lessens with time.
The study remained double-blinded at 36 months. At that point, the mean adjusted 2-hour C-peptide AUC was 0.215 nmol/L for the 64 abatacept patients in whom it was measured, compared with 0.135 nmol/L for the 29 remaining placebo patients. The difference was still significant, said Dr. Orban, who is also an investigator in the section on immunobiology at the Joslin Diabetes Center and an instructor in medicine at Harvard Medical School, both in Boston.
Still, the major effect appeared to be within the first year of the treatment phase, and the two groups remained relatively parallel thereafter. This suggests that the drug may only be actively blocking T-cell activation around the time of diagnosis, he noted.
HbA1c was significantly lower in the abatacept-treated patients, with no difference in insulin use. In all, abatacept treatment resulted in an average 9.5 months’ delay of loss in beta-cell function, compared with placebo, Dr. Orban said.
"It seems that we may not need a full 2 years of treatment to achieve this effect. It’s very logical to try a shorter course of the drug and see if a similar effect can be achieved," Dr. Orban commented.
This study was sponsored by the Type 1 Diabetes TrialNet Study Group, a clinical trials network funded by the National Institutes of Health. Dr. Orban is founder and CEO of Orban Biotech LLC.
AT THE ANNUAL SCIENTIFIC SESSIONS OF THE AMERICAN DIABETES ASSOCIATION
Major Finding: At 36 months, the mean adjusted 2-hour C-peptide AUC was 0.215 nmol/L for the 64 abatacept patients in whom it was measured, compared with 0.135 nmol/L for the 29 remaining placebo patients, a significant difference.
Data Source: Data are from a 1-year follow-up to a randomized, controlled trial of abatacept vs. placebo infusions in 112 recently diagnosed patients with type 1 diabetes.
Disclosures: This study was sponsored by the Type 1 Diabetes TrialNet Study Group, a clinical trials network funded by the National Institutes of Health. Dr. Orban is founder and CEO of Orban Biotech LLC.
Tofacitinib Lowered Disease Activity in Ulcerative Colitis
Tofacitinib was associated with greater clinical response and remission rates than was placebo in a double-blind, phase II trial of patients with moderately or severely active ulcerative colitis.
Current treatment of ulcerative colitis with mesalamine, glucocorticoids, azathioprine, and anti–tumor necrosis factor (anti-TNF) agents such as infliximab and adalimumab is not always effective, and may be associated with serious toxic effects (Gastroenterology 2006;130:940-87). Thus, "additional treatments are needed," said Dr. William J. Sandborn, chief of the division of gastroenterology and professor of medicine at the University of California, San Diego and his associates (N. Engl. J. Med. 2012;367:616-24).
Tofacitinib is a selective oral inhibitor of the Janus kinase (JAK) family of enzymes that includes JAK1 and JAK3, which mediate signal-transduction activity for multiple cytokines, including several that are integral to lymphocyte activation, function, and proliferation. Although the importance of the JAK family in the pathogenesis of ulcerative colitis is unclear, tofacitinib has shown efficacy against other immune-mediated conditions, including organ allograft rejection, rheumatoid arthritis, and psoriasis.
The 8-week trial was conducted at 51 centers in 17 countries from January 2009 through September 2010 with funding from Pfizer. Subjects had to be at least 18 years of age, with a confirmed diagnosis of ulcerative colitis of 3 months’ duration or longer, a score of 6-12 on the Mayo risk calculator for ulcerative colitis,and evidence on sigmoidoscopic examination of moderately or severely active disease. In most of the patients, the use of conventional therapy (mesalamine, glucocorticoids, immunosuppressants, or anti-TNF agents used as monotherapy or in some combination) had failed, according to the investigators.
During the study, patients could receive oral mesalamine or oral prednisone at a stable dosage of 30 mg or less per day. However, patients receiving azathioprine, 6-mercaptopurine, and methotrexate discontinued them immediately before initiating therapy with tofacitinib, and patients who had previously received anti-TNF therapy were required to discontinue it for at least 8 weeks before study entry.
Patients were randomly assigned to receive twice-daily oral tofacitinib doses of 0.5 mg, 3 mg, 10 mg, or 15 mg or placebo for 8 weeks, and were then followed for 4 weeks through 12 weeks. Of the 195 patients randomized, 194 received at least one dose of the study drug or placebo and 157 completed the full 8 weeks of treatment. Across all treatment groups, 131 patients (67.5%) received concomitant aminosalicylates, and 85 (43.8%) received concomitant glucocorticoids at some point during the study, they noted.
Clinical response was defined as a decrease from baseline in the total Mayo score (defined as an absolute decrease by at least 3 points and a relative decrease by at least 30%) with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1.
The primary end point, clinical response at 8 weeks, occurred in 42% (20) of the patients who received placebo. The response was significantly greater than that seen only among the patients who received the highest doses of tofacitinib, 78% of those receiving 15 mg (P less than .001). For the lower doses, the clinical response rates were not significantly different from those with placebo (61%, 48% and 32%, respectively, for 10 mg, 3 mg and 0.5 mg).
Clinical remission, a secondary end point, was defined as a total Mayo score of 0-2, with no individual subscore exceeding 1. Clinical remission at 8 weeks occurred in 10% (5) of the placebo patients. Here, the difference from placebo with tofacitinib was significant for doses of 3 mg (33%; P = .01), 10 mg (48%; P less than .001), and 15 mg (41%; P less than .001).
Another secondary end point, endoscopic response, was defined as a decrease from baseline in the endoscopy subscore by at least 1.The secondary end point of endoscopic remission was defined as an endoscopy subscore of 0.
An endoscopic response at 8 weeks occurred in 46% with placebo, significantly lower than the responses with tofacitinib doses of 10 mg (67%; P = .07) and 15mg (78%; P = .001). Endoscopic remission at 8 weeks occurred in just 2% of the placebo group, vs. significantly greater proportions of 18% with 3 mg (P = .01), 30% with 10 mg (P less than .001), and 27% with 15 mg (P less than .001).
Rates of overall and serious adverse events, as well as adverse events from infection, were similar among the groups. Two patients receiving 10 mg of tofacitinib twice daily had serious adverse events from infection (a postoperative abscess in one and anal abscess in the other). There was a dose-dependent increase in both LDL and HDL cholesterol concentrations at 8 weeks with tofacitinib, which reversed after discontinuation of the study drug . During the study period, the absolute neutrophil count was less than 1,500 cells per cubic millimeter in three patients receiving tofacitinib, but was not less than 1,000 cells per cubic millimeter in any patient, Dr. Sandborn and his associates reported.
In previous studies of patients with rheumatoid arthritis, tofacitinib has been associated with increases in LDL cholesterol and serum creatinine, and decreases in absolute neutrophil count, whereas increased infection risk has been seen with the 15-mg, twice-daily dose. The small size and short duration of the current trial did not allow for a comprehensive assessment of the safety and tolerability of the drug in patients with ulcerative colitis, they noted.
This study was funded by Pfizer, from whom Dr. Sandborn has received grants and consulting fees. He has also served as a consultant and has additional ties to numerous other companies.
Tofacitinib was associated with greater clinical response and remission rates than was placebo in a double-blind, phase II trial of patients with moderately or severely active ulcerative colitis.
Current treatment of ulcerative colitis with mesalamine, glucocorticoids, azathioprine, and anti–tumor necrosis factor (anti-TNF) agents such as infliximab and adalimumab is not always effective, and may be associated with serious toxic effects (Gastroenterology 2006;130:940-87). Thus, "additional treatments are needed," said Dr. William J. Sandborn, chief of the division of gastroenterology and professor of medicine at the University of California, San Diego and his associates (N. Engl. J. Med. 2012;367:616-24).
Tofacitinib is a selective oral inhibitor of the Janus kinase (JAK) family of enzymes that includes JAK1 and JAK3, which mediate signal-transduction activity for multiple cytokines, including several that are integral to lymphocyte activation, function, and proliferation. Although the importance of the JAK family in the pathogenesis of ulcerative colitis is unclear, tofacitinib has shown efficacy against other immune-mediated conditions, including organ allograft rejection, rheumatoid arthritis, and psoriasis.
The 8-week trial was conducted at 51 centers in 17 countries from January 2009 through September 2010 with funding from Pfizer. Subjects had to be at least 18 years of age, with a confirmed diagnosis of ulcerative colitis of 3 months’ duration or longer, a score of 6-12 on the Mayo risk calculator for ulcerative colitis,and evidence on sigmoidoscopic examination of moderately or severely active disease. In most of the patients, the use of conventional therapy (mesalamine, glucocorticoids, immunosuppressants, or anti-TNF agents used as monotherapy or in some combination) had failed, according to the investigators.
During the study, patients could receive oral mesalamine or oral prednisone at a stable dosage of 30 mg or less per day. However, patients receiving azathioprine, 6-mercaptopurine, and methotrexate discontinued them immediately before initiating therapy with tofacitinib, and patients who had previously received anti-TNF therapy were required to discontinue it for at least 8 weeks before study entry.
Patients were randomly assigned to receive twice-daily oral tofacitinib doses of 0.5 mg, 3 mg, 10 mg, or 15 mg or placebo for 8 weeks, and were then followed for 4 weeks through 12 weeks. Of the 195 patients randomized, 194 received at least one dose of the study drug or placebo and 157 completed the full 8 weeks of treatment. Across all treatment groups, 131 patients (67.5%) received concomitant aminosalicylates, and 85 (43.8%) received concomitant glucocorticoids at some point during the study, they noted.
Clinical response was defined as a decrease from baseline in the total Mayo score (defined as an absolute decrease by at least 3 points and a relative decrease by at least 30%) with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1.
The primary end point, clinical response at 8 weeks, occurred in 42% (20) of the patients who received placebo. The response was significantly greater than that seen only among the patients who received the highest doses of tofacitinib, 78% of those receiving 15 mg (P less than .001). For the lower doses, the clinical response rates were not significantly different from those with placebo (61%, 48% and 32%, respectively, for 10 mg, 3 mg and 0.5 mg).
Clinical remission, a secondary end point, was defined as a total Mayo score of 0-2, with no individual subscore exceeding 1. Clinical remission at 8 weeks occurred in 10% (5) of the placebo patients. Here, the difference from placebo with tofacitinib was significant for doses of 3 mg (33%; P = .01), 10 mg (48%; P less than .001), and 15 mg (41%; P less than .001).
Another secondary end point, endoscopic response, was defined as a decrease from baseline in the endoscopy subscore by at least 1.The secondary end point of endoscopic remission was defined as an endoscopy subscore of 0.
An endoscopic response at 8 weeks occurred in 46% with placebo, significantly lower than the responses with tofacitinib doses of 10 mg (67%; P = .07) and 15mg (78%; P = .001). Endoscopic remission at 8 weeks occurred in just 2% of the placebo group, vs. significantly greater proportions of 18% with 3 mg (P = .01), 30% with 10 mg (P less than .001), and 27% with 15 mg (P less than .001).
Rates of overall and serious adverse events, as well as adverse events from infection, were similar among the groups. Two patients receiving 10 mg of tofacitinib twice daily had serious adverse events from infection (a postoperative abscess in one and anal abscess in the other). There was a dose-dependent increase in both LDL and HDL cholesterol concentrations at 8 weeks with tofacitinib, which reversed after discontinuation of the study drug . During the study period, the absolute neutrophil count was less than 1,500 cells per cubic millimeter in three patients receiving tofacitinib, but was not less than 1,000 cells per cubic millimeter in any patient, Dr. Sandborn and his associates reported.
In previous studies of patients with rheumatoid arthritis, tofacitinib has been associated with increases in LDL cholesterol and serum creatinine, and decreases in absolute neutrophil count, whereas increased infection risk has been seen with the 15-mg, twice-daily dose. The small size and short duration of the current trial did not allow for a comprehensive assessment of the safety and tolerability of the drug in patients with ulcerative colitis, they noted.
This study was funded by Pfizer, from whom Dr. Sandborn has received grants and consulting fees. He has also served as a consultant and has additional ties to numerous other companies.
Tofacitinib was associated with greater clinical response and remission rates than was placebo in a double-blind, phase II trial of patients with moderately or severely active ulcerative colitis.
Current treatment of ulcerative colitis with mesalamine, glucocorticoids, azathioprine, and anti–tumor necrosis factor (anti-TNF) agents such as infliximab and adalimumab is not always effective, and may be associated with serious toxic effects (Gastroenterology 2006;130:940-87). Thus, "additional treatments are needed," said Dr. William J. Sandborn, chief of the division of gastroenterology and professor of medicine at the University of California, San Diego and his associates (N. Engl. J. Med. 2012;367:616-24).
Tofacitinib is a selective oral inhibitor of the Janus kinase (JAK) family of enzymes that includes JAK1 and JAK3, which mediate signal-transduction activity for multiple cytokines, including several that are integral to lymphocyte activation, function, and proliferation. Although the importance of the JAK family in the pathogenesis of ulcerative colitis is unclear, tofacitinib has shown efficacy against other immune-mediated conditions, including organ allograft rejection, rheumatoid arthritis, and psoriasis.
The 8-week trial was conducted at 51 centers in 17 countries from January 2009 through September 2010 with funding from Pfizer. Subjects had to be at least 18 years of age, with a confirmed diagnosis of ulcerative colitis of 3 months’ duration or longer, a score of 6-12 on the Mayo risk calculator for ulcerative colitis,and evidence on sigmoidoscopic examination of moderately or severely active disease. In most of the patients, the use of conventional therapy (mesalamine, glucocorticoids, immunosuppressants, or anti-TNF agents used as monotherapy or in some combination) had failed, according to the investigators.
During the study, patients could receive oral mesalamine or oral prednisone at a stable dosage of 30 mg or less per day. However, patients receiving azathioprine, 6-mercaptopurine, and methotrexate discontinued them immediately before initiating therapy with tofacitinib, and patients who had previously received anti-TNF therapy were required to discontinue it for at least 8 weeks before study entry.
Patients were randomly assigned to receive twice-daily oral tofacitinib doses of 0.5 mg, 3 mg, 10 mg, or 15 mg or placebo for 8 weeks, and were then followed for 4 weeks through 12 weeks. Of the 195 patients randomized, 194 received at least one dose of the study drug or placebo and 157 completed the full 8 weeks of treatment. Across all treatment groups, 131 patients (67.5%) received concomitant aminosalicylates, and 85 (43.8%) received concomitant glucocorticoids at some point during the study, they noted.
Clinical response was defined as a decrease from baseline in the total Mayo score (defined as an absolute decrease by at least 3 points and a relative decrease by at least 30%) with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1.
The primary end point, clinical response at 8 weeks, occurred in 42% (20) of the patients who received placebo. The response was significantly greater than that seen only among the patients who received the highest doses of tofacitinib, 78% of those receiving 15 mg (P less than .001). For the lower doses, the clinical response rates were not significantly different from those with placebo (61%, 48% and 32%, respectively, for 10 mg, 3 mg and 0.5 mg).
Clinical remission, a secondary end point, was defined as a total Mayo score of 0-2, with no individual subscore exceeding 1. Clinical remission at 8 weeks occurred in 10% (5) of the placebo patients. Here, the difference from placebo with tofacitinib was significant for doses of 3 mg (33%; P = .01), 10 mg (48%; P less than .001), and 15 mg (41%; P less than .001).
Another secondary end point, endoscopic response, was defined as a decrease from baseline in the endoscopy subscore by at least 1.The secondary end point of endoscopic remission was defined as an endoscopy subscore of 0.
An endoscopic response at 8 weeks occurred in 46% with placebo, significantly lower than the responses with tofacitinib doses of 10 mg (67%; P = .07) and 15mg (78%; P = .001). Endoscopic remission at 8 weeks occurred in just 2% of the placebo group, vs. significantly greater proportions of 18% with 3 mg (P = .01), 30% with 10 mg (P less than .001), and 27% with 15 mg (P less than .001).
Rates of overall and serious adverse events, as well as adverse events from infection, were similar among the groups. Two patients receiving 10 mg of tofacitinib twice daily had serious adverse events from infection (a postoperative abscess in one and anal abscess in the other). There was a dose-dependent increase in both LDL and HDL cholesterol concentrations at 8 weeks with tofacitinib, which reversed after discontinuation of the study drug . During the study period, the absolute neutrophil count was less than 1,500 cells per cubic millimeter in three patients receiving tofacitinib, but was not less than 1,000 cells per cubic millimeter in any patient, Dr. Sandborn and his associates reported.
In previous studies of patients with rheumatoid arthritis, tofacitinib has been associated with increases in LDL cholesterol and serum creatinine, and decreases in absolute neutrophil count, whereas increased infection risk has been seen with the 15-mg, twice-daily dose. The small size and short duration of the current trial did not allow for a comprehensive assessment of the safety and tolerability of the drug in patients with ulcerative colitis, they noted.
This study was funded by Pfizer, from whom Dr. Sandborn has received grants and consulting fees. He has also served as a consultant and has additional ties to numerous other companies.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Major Finding: The primary end point, clinical response at 8 weeks, occurred in 42% (20) of the patients who received placebo. The response was significantly greater than that among the patients who received the highest doses of tofacitinib, 78% of those receiving 15 mg (P less than .001).
Data Source: The findings come from a randomized, double-blind phase II trial of 194 patients with moderately or severely active ulcerative colitis, most of whom had failed current therapies.
Disclosures: The study was funded by Pfizer, from whom Dr. Sandborn has received grants and consulting fees. He has also served as a consultant and has additional ties to numerous other companies.
Behavioral Problems Greater in Toddlers Who Snore
Children who snore persistently and loudly at age 2 and 3 years are more likely to have problem behaviors at age 3 years, compared with children who don’t snore or who only snore transiently.
Those findings come from a prospective analysis of 249 mother-child pairs who were part of the Cincinnati-based Health Outcomes and Measures of the Environment (HOME) Study, which enrolled the women at or before 19 weeks’ gestation. The results highlight the importance of routine screening for snoring in particular, because parents’ responses to more general sleep questions may not reflect this hallmark symptom of sleep-disordered breathing (SDB), said Dean W. Beebe, Ph.D., of Cincinnati Children’s Hospital Medical Center, and his associates (Pediatrics 2012 Aug. 13 [doi:10.1542/peds.2012-0045]).
The findings of this study, believed to be the first to examine the relationship between the persistence of snoring and behavioral functioning in preschool-aged children, also suggest that screening is particularly important for children from lower socioeconomic backgrounds who are at higher risk for persistent SDB and its associated morbidity. It is also important to document whether snoring persists, the investigators said.
Snoring was assessed when the children were aged 2 and 3 years with the validated Child Sleep Habits Questionnaire, which asked parents to report how often their child "snored loudly" during the previous week. Of the 249 children, 170 (68%) were "nonsnorers" whose parents reported that they "rarely" snored loudly over the previous week. Another 57 children (23%) were "transient snorers," who snored loudly two or more times per week at either age 2 or 3 years but not both, and 22 (9%) were "persistent snorers," who snored two or more times per week at ages 2 and 3 years.
Parents completed the validated preschool form of the Behavior Assessment System for Children, and a trained research associate administered the Bayley Scales of Infant Development. Prenatal exposure to tobacco was assessed through maternal serum cotinine measures during pregnancy, and childhood tobacco exposure was assessed through collected serum. The mothers were surveyed about breast feeding, and the children were examined at annual visits.
The three groups did not differ significantly with regard to gender, birth weight, or gestational age. In the unadjusted analysis, the persistent snorers tended toward a higher body mass index z score than did the transient snorers or the nonsnorers at both the 2-year and 3-year assessments. Persistent snorers had significantly higher prenatal and childhood cotinine levels than did either of the other two groups at both time points.
Persistent snorers were significantly more likely to be African American (55% versus 13.5% of the nonsnorers), and to have lower parental education and annual family income ($49,000 vs. $84,000). None of the children fed breast milk for more than 12 months developed persistent snoring, but nearly one-quarter of those who were never fed breast milk, or who received breast milk for less than 1 month, did so.
Persistent snorers had significantly worse overall behavioral functioning than did the nonsnorers and transient snorers. Overall Behavioral Symptoms Index (BSI) scores were 49.2 for the nonsnorers, 50.9 for the transient snorers, and 57.6 for the persistent snorers, with a P value of less than .001 for the persistent snorers versus the other two groups. The difference was particularly significant with regard to hyperactivity, depression, and attention.
"At risk" or worse overall behaviors, defined as a BSI index score of 60 or greater, were reported in 35% of persistent snorers, compared with 10% of nonsnorers and 12% of transient snorers. "Preschool behavior and emotional problems of this magnitude were once dismissed as trivial, but are now recognized as significant sources of functional impairment at the population level," Dr. Beebe and his associates noted.
These results are consistent with reports on older children, and remained significant after the researchers controlled for child gender, race, and socioeconomic status.
Definitive causal conclusions can’t be drawn from this study. However, the findings are consistent with previous data suggesting that SDB-mediated sleep disruption and intermittent hypoxia can result in elevated oxidative stress, systemic inflammation, and changes in neural and neurobehavioral functioning. An ongoing randomized trial is currently examining the effect of surgical treatment of SDB on cognitive and behavioral functioning (Sleep 2011;34:1509-17).
A simple screening tool called BEARS (Bedtime Issues, Excessive Daytime Sleepiness, Night Awakenings, Regularity and Duration of Sleep, Snoring) has shown utility for identifying sleep problems in the primary care setting (Sleep Med. 2005;6:63-9).
None of the authors have any conflicts of interest to declare.
Children who snore persistently and loudly at age 2 and 3 years are more likely to have problem behaviors at age 3 years, compared with children who don’t snore or who only snore transiently.
Those findings come from a prospective analysis of 249 mother-child pairs who were part of the Cincinnati-based Health Outcomes and Measures of the Environment (HOME) Study, which enrolled the women at or before 19 weeks’ gestation. The results highlight the importance of routine screening for snoring in particular, because parents’ responses to more general sleep questions may not reflect this hallmark symptom of sleep-disordered breathing (SDB), said Dean W. Beebe, Ph.D., of Cincinnati Children’s Hospital Medical Center, and his associates (Pediatrics 2012 Aug. 13 [doi:10.1542/peds.2012-0045]).
The findings of this study, believed to be the first to examine the relationship between the persistence of snoring and behavioral functioning in preschool-aged children, also suggest that screening is particularly important for children from lower socioeconomic backgrounds who are at higher risk for persistent SDB and its associated morbidity. It is also important to document whether snoring persists, the investigators said.
Snoring was assessed when the children were aged 2 and 3 years with the validated Child Sleep Habits Questionnaire, which asked parents to report how often their child "snored loudly" during the previous week. Of the 249 children, 170 (68%) were "nonsnorers" whose parents reported that they "rarely" snored loudly over the previous week. Another 57 children (23%) were "transient snorers," who snored loudly two or more times per week at either age 2 or 3 years but not both, and 22 (9%) were "persistent snorers," who snored two or more times per week at ages 2 and 3 years.
Parents completed the validated preschool form of the Behavior Assessment System for Children, and a trained research associate administered the Bayley Scales of Infant Development. Prenatal exposure to tobacco was assessed through maternal serum cotinine measures during pregnancy, and childhood tobacco exposure was assessed through collected serum. The mothers were surveyed about breast feeding, and the children were examined at annual visits.
The three groups did not differ significantly with regard to gender, birth weight, or gestational age. In the unadjusted analysis, the persistent snorers tended toward a higher body mass index z score than did the transient snorers or the nonsnorers at both the 2-year and 3-year assessments. Persistent snorers had significantly higher prenatal and childhood cotinine levels than did either of the other two groups at both time points.
Persistent snorers were significantly more likely to be African American (55% versus 13.5% of the nonsnorers), and to have lower parental education and annual family income ($49,000 vs. $84,000). None of the children fed breast milk for more than 12 months developed persistent snoring, but nearly one-quarter of those who were never fed breast milk, or who received breast milk for less than 1 month, did so.
Persistent snorers had significantly worse overall behavioral functioning than did the nonsnorers and transient snorers. Overall Behavioral Symptoms Index (BSI) scores were 49.2 for the nonsnorers, 50.9 for the transient snorers, and 57.6 for the persistent snorers, with a P value of less than .001 for the persistent snorers versus the other two groups. The difference was particularly significant with regard to hyperactivity, depression, and attention.
"At risk" or worse overall behaviors, defined as a BSI index score of 60 or greater, were reported in 35% of persistent snorers, compared with 10% of nonsnorers and 12% of transient snorers. "Preschool behavior and emotional problems of this magnitude were once dismissed as trivial, but are now recognized as significant sources of functional impairment at the population level," Dr. Beebe and his associates noted.
These results are consistent with reports on older children, and remained significant after the researchers controlled for child gender, race, and socioeconomic status.
Definitive causal conclusions can’t be drawn from this study. However, the findings are consistent with previous data suggesting that SDB-mediated sleep disruption and intermittent hypoxia can result in elevated oxidative stress, systemic inflammation, and changes in neural and neurobehavioral functioning. An ongoing randomized trial is currently examining the effect of surgical treatment of SDB on cognitive and behavioral functioning (Sleep 2011;34:1509-17).
A simple screening tool called BEARS (Bedtime Issues, Excessive Daytime Sleepiness, Night Awakenings, Regularity and Duration of Sleep, Snoring) has shown utility for identifying sleep problems in the primary care setting (Sleep Med. 2005;6:63-9).
None of the authors have any conflicts of interest to declare.
Children who snore persistently and loudly at age 2 and 3 years are more likely to have problem behaviors at age 3 years, compared with children who don’t snore or who only snore transiently.
Those findings come from a prospective analysis of 249 mother-child pairs who were part of the Cincinnati-based Health Outcomes and Measures of the Environment (HOME) Study, which enrolled the women at or before 19 weeks’ gestation. The results highlight the importance of routine screening for snoring in particular, because parents’ responses to more general sleep questions may not reflect this hallmark symptom of sleep-disordered breathing (SDB), said Dean W. Beebe, Ph.D., of Cincinnati Children’s Hospital Medical Center, and his associates (Pediatrics 2012 Aug. 13 [doi:10.1542/peds.2012-0045]).
The findings of this study, believed to be the first to examine the relationship between the persistence of snoring and behavioral functioning in preschool-aged children, also suggest that screening is particularly important for children from lower socioeconomic backgrounds who are at higher risk for persistent SDB and its associated morbidity. It is also important to document whether snoring persists, the investigators said.
Snoring was assessed when the children were aged 2 and 3 years with the validated Child Sleep Habits Questionnaire, which asked parents to report how often their child "snored loudly" during the previous week. Of the 249 children, 170 (68%) were "nonsnorers" whose parents reported that they "rarely" snored loudly over the previous week. Another 57 children (23%) were "transient snorers," who snored loudly two or more times per week at either age 2 or 3 years but not both, and 22 (9%) were "persistent snorers," who snored two or more times per week at ages 2 and 3 years.
Parents completed the validated preschool form of the Behavior Assessment System for Children, and a trained research associate administered the Bayley Scales of Infant Development. Prenatal exposure to tobacco was assessed through maternal serum cotinine measures during pregnancy, and childhood tobacco exposure was assessed through collected serum. The mothers were surveyed about breast feeding, and the children were examined at annual visits.
The three groups did not differ significantly with regard to gender, birth weight, or gestational age. In the unadjusted analysis, the persistent snorers tended toward a higher body mass index z score than did the transient snorers or the nonsnorers at both the 2-year and 3-year assessments. Persistent snorers had significantly higher prenatal and childhood cotinine levels than did either of the other two groups at both time points.
Persistent snorers were significantly more likely to be African American (55% versus 13.5% of the nonsnorers), and to have lower parental education and annual family income ($49,000 vs. $84,000). None of the children fed breast milk for more than 12 months developed persistent snoring, but nearly one-quarter of those who were never fed breast milk, or who received breast milk for less than 1 month, did so.
Persistent snorers had significantly worse overall behavioral functioning than did the nonsnorers and transient snorers. Overall Behavioral Symptoms Index (BSI) scores were 49.2 for the nonsnorers, 50.9 for the transient snorers, and 57.6 for the persistent snorers, with a P value of less than .001 for the persistent snorers versus the other two groups. The difference was particularly significant with regard to hyperactivity, depression, and attention.
"At risk" or worse overall behaviors, defined as a BSI index score of 60 or greater, were reported in 35% of persistent snorers, compared with 10% of nonsnorers and 12% of transient snorers. "Preschool behavior and emotional problems of this magnitude were once dismissed as trivial, but are now recognized as significant sources of functional impairment at the population level," Dr. Beebe and his associates noted.
These results are consistent with reports on older children, and remained significant after the researchers controlled for child gender, race, and socioeconomic status.
Definitive causal conclusions can’t be drawn from this study. However, the findings are consistent with previous data suggesting that SDB-mediated sleep disruption and intermittent hypoxia can result in elevated oxidative stress, systemic inflammation, and changes in neural and neurobehavioral functioning. An ongoing randomized trial is currently examining the effect of surgical treatment of SDB on cognitive and behavioral functioning (Sleep 2011;34:1509-17).
A simple screening tool called BEARS (Bedtime Issues, Excessive Daytime Sleepiness, Night Awakenings, Regularity and Duration of Sleep, Snoring) has shown utility for identifying sleep problems in the primary care setting (Sleep Med. 2005;6:63-9).
None of the authors have any conflicts of interest to declare.
FROM PEDIATRICS
Major Finding: Overall Behavioral Symptoms Index (BSI) scores were 49.2 for the nonsnorers, 50.9 for the transient snorers, and 57.6 for the persistent snorers, with a P value of less than .001 for the persistent snorers versus the other two groups.
Data Source: These findings come from a prospective analysis of 249 mother-child pairs who were part of the Cincinnati-based Health Outcomes and Measures of the Environment (HOME) Study, which enrolled the women at or before 19 weeks’ gestation.
Disclosures: None of the authors have any conflicts of interest to declare.
