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Metabolic tumor volume predicts outcome in follicular lymphoma
The total metabolic tumor volume, as quantified on PET scanning at the time that follicular lymphoma is diagnosed, is a strong independent predictor of treatment response and patient outcome, according to a report published online in Journal of Clinical Oncology.
Until now, no study has specifically examined the prognostic possibilities of PET-derived total metabolic tumor volume (TMTV) for this malignancy, either on its own or in combination with any of several existing prognostic indices. Those tools use a variety of surrogates to estimate tumor burden. Now that PET is recommended at diagnosis for all cases of follicular lymphoma and anatomic CT data are also available, it is much easier to estimate total tumor burden than it was when those indices were developed, said Michel Meignan, MD, PhD, of Hôpital Henri Mondor, Crétiel (France) and his associates.
It is crucial to identify patients likely to have a poor response to standard treatment, both to spare them the considerable adverse effects of that treatment and to select them for alternative first-line approaches. Even though patient survival has improved markedly during the past decade with the introduction of combined treatment using rituximab plus chemotherapy, approximately 20% of patients still show disease progression within 2 years, and the 5-year overall survival is only 50%, the investigators noted.
To assess the prognostic value of TMTV as assessed by PET, they pooled data from three multicenter prospective studies involving 185 patients with either a high tumor burden or advanced-stage follicular lymphoma. These participants were followed for a median of 63.5 months at 56 medical centers in France, Belgium, Australia, and Italy.
A TMTV threshold of 510 cm3 was found to have the optimal sensitivity (0.46), specificity (0.83), positive predictive value (0.67), and negative predictive value (0.67) for predicting both progression-free and overall survival. The 30% of patients who had a TMTV greater than that cutoff point had markedly inferior 5-year progression-free survival (less than 3 years), while the 70% who had a smaller TMTV had median progression-free survival of more than 6 years, Dr. Meignan and his associates said (J Clin Oncol. 2016 Aug 22. doi:10.1200/JCO.2016.66.9440).
Combining TMTV with other prognostic measures improved predictions even further. Patients who had both a high TMTV and an intermediate to high score on the Follicular Lymphoma International Prognostic Index 2 showed extremely poor outcomes, with a median progression-free survival of only 19 months. “This population can no longer be characterized as having an indolent lymphoma,” the investigators said.
No sponsor or funding source was cited for this study. Dr. Meignan reported receiving fees for travel and expenses from Roche; his associates reported ties to numerous industry sources.
The total metabolic tumor volume, as quantified on PET scanning at the time that follicular lymphoma is diagnosed, is a strong independent predictor of treatment response and patient outcome, according to a report published online in Journal of Clinical Oncology.
Until now, no study has specifically examined the prognostic possibilities of PET-derived total metabolic tumor volume (TMTV) for this malignancy, either on its own or in combination with any of several existing prognostic indices. Those tools use a variety of surrogates to estimate tumor burden. Now that PET is recommended at diagnosis for all cases of follicular lymphoma and anatomic CT data are also available, it is much easier to estimate total tumor burden than it was when those indices were developed, said Michel Meignan, MD, PhD, of Hôpital Henri Mondor, Crétiel (France) and his associates.
It is crucial to identify patients likely to have a poor response to standard treatment, both to spare them the considerable adverse effects of that treatment and to select them for alternative first-line approaches. Even though patient survival has improved markedly during the past decade with the introduction of combined treatment using rituximab plus chemotherapy, approximately 20% of patients still show disease progression within 2 years, and the 5-year overall survival is only 50%, the investigators noted.
To assess the prognostic value of TMTV as assessed by PET, they pooled data from three multicenter prospective studies involving 185 patients with either a high tumor burden or advanced-stage follicular lymphoma. These participants were followed for a median of 63.5 months at 56 medical centers in France, Belgium, Australia, and Italy.
A TMTV threshold of 510 cm3 was found to have the optimal sensitivity (0.46), specificity (0.83), positive predictive value (0.67), and negative predictive value (0.67) for predicting both progression-free and overall survival. The 30% of patients who had a TMTV greater than that cutoff point had markedly inferior 5-year progression-free survival (less than 3 years), while the 70% who had a smaller TMTV had median progression-free survival of more than 6 years, Dr. Meignan and his associates said (J Clin Oncol. 2016 Aug 22. doi:10.1200/JCO.2016.66.9440).
Combining TMTV with other prognostic measures improved predictions even further. Patients who had both a high TMTV and an intermediate to high score on the Follicular Lymphoma International Prognostic Index 2 showed extremely poor outcomes, with a median progression-free survival of only 19 months. “This population can no longer be characterized as having an indolent lymphoma,” the investigators said.
No sponsor or funding source was cited for this study. Dr. Meignan reported receiving fees for travel and expenses from Roche; his associates reported ties to numerous industry sources.
The total metabolic tumor volume, as quantified on PET scanning at the time that follicular lymphoma is diagnosed, is a strong independent predictor of treatment response and patient outcome, according to a report published online in Journal of Clinical Oncology.
Until now, no study has specifically examined the prognostic possibilities of PET-derived total metabolic tumor volume (TMTV) for this malignancy, either on its own or in combination with any of several existing prognostic indices. Those tools use a variety of surrogates to estimate tumor burden. Now that PET is recommended at diagnosis for all cases of follicular lymphoma and anatomic CT data are also available, it is much easier to estimate total tumor burden than it was when those indices were developed, said Michel Meignan, MD, PhD, of Hôpital Henri Mondor, Crétiel (France) and his associates.
It is crucial to identify patients likely to have a poor response to standard treatment, both to spare them the considerable adverse effects of that treatment and to select them for alternative first-line approaches. Even though patient survival has improved markedly during the past decade with the introduction of combined treatment using rituximab plus chemotherapy, approximately 20% of patients still show disease progression within 2 years, and the 5-year overall survival is only 50%, the investigators noted.
To assess the prognostic value of TMTV as assessed by PET, they pooled data from three multicenter prospective studies involving 185 patients with either a high tumor burden or advanced-stage follicular lymphoma. These participants were followed for a median of 63.5 months at 56 medical centers in France, Belgium, Australia, and Italy.
A TMTV threshold of 510 cm3 was found to have the optimal sensitivity (0.46), specificity (0.83), positive predictive value (0.67), and negative predictive value (0.67) for predicting both progression-free and overall survival. The 30% of patients who had a TMTV greater than that cutoff point had markedly inferior 5-year progression-free survival (less than 3 years), while the 70% who had a smaller TMTV had median progression-free survival of more than 6 years, Dr. Meignan and his associates said (J Clin Oncol. 2016 Aug 22. doi:10.1200/JCO.2016.66.9440).
Combining TMTV with other prognostic measures improved predictions even further. Patients who had both a high TMTV and an intermediate to high score on the Follicular Lymphoma International Prognostic Index 2 showed extremely poor outcomes, with a median progression-free survival of only 19 months. “This population can no longer be characterized as having an indolent lymphoma,” the investigators said.
No sponsor or funding source was cited for this study. Dr. Meignan reported receiving fees for travel and expenses from Roche; his associates reported ties to numerous industry sources.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: At diagnosis, the total metabolic tumor volume of follicular lymphoma predicts treatment response and patient outcome.
Major finding: A TMTV threshold of 510 cm3 was found to have the optimal sensitivity (0.46), specificity (0.83), positive predictive value (0.67), and negative predictive value (0.67) for predicting both progression-free and overall survival.
Data source: A pooled analysis of three multicenter prospective studies involving 185 patients with a high burden of disease.
Disclosures: No sponsor or funding source was cited for this study. Dr. Meignan reported receiving fees for travel and expenses from Roche; his associates reported ties to numerous industry sources.
Acetaminophen doesn’t exacerbate asthma in young children
As-needed use of acetaminophen for fever or pain does not exacerbate mild persistent asthma in young children, according to a report published online August 18 in the New England Journal of Medicine.
In a prospective, randomized, double-blind clinical trial performed at 18 U.S. medical centers, neither acetaminophen nor ibuprofen raised the rate of exacerbations or impaired asthma control among 300 children aged 1-5 years. This result refutes those of observational and post hoc data that linked acetaminophen to increased asthma exacerbations, daily symptoms, and need for bronchodilators in children and adults. Those findings “have led to much controversy and even alarm,” with some physicians recommending that acetaminophen be completely avoided in children with asthma until more safety data became available, said William J. Sheehan, MD, of the division of allergy and immunology, Boston Children’s Hospital and Harvard Medical School, Boston, and his associates.
The investigators performed this 2-year study to obtain such safety data. The children (median age, 40 months) were randomly assigned to receive either liquid acetaminophen (150 patients) or matching liquid ibuprofen (150 patients) as needed for pain, fever, or discomfort and were followed for 46 weeks. All the participants received standard asthma-control therapies including inhaled glucocorticoids, oral leukotriene-receptor antagonists, and as-needed inhaled glucocorticoids.
The primary outcome – the mean number of asthma exacerbations – was 0.81 in the acetaminophen group and 0.87 in the ibuprofen group, a nonsignificant difference. The rate of exacerbations also did not differ between acetaminophen and ibuprofen in the subgroup of 226 children who completed the entire trial or in the subgroup of 200 who received a study medication for pain or fever at least once during follow-up, Dr. Sheehan and his associates said (N Engl J Med. 2016 Aug 18. doi: 10.1056/NEJMoa1515990).
There also were no significant differences between the two study groups in time to first asthma exacerbation, percentage of days of good asthma control (85.8% vs. 86.8% of days), use of rescue albuterol (2.8 vs. 3.0 inhalations per week), or unscheduled health care visits for asthma (0.75 vs. 0.76 visits). No between-group differences occurred regarding adverse events or serious adverse events.
Some experts have suggested that the observational studies reporting a link between acetaminophen and asthma exacerbations may have been flawed by “confounding by indication,” because children with asthma have more symptomatic respiratory infections than do those without asthma and use more acetaminophen for fever and malaise. “We [also] observed that greater use of antipyretic, analgesic medications was associated with more apparent respiratory illnesses and that the reported respiratory illnesses were associated with asthma exacerbations.
“However, we found no evidence that acetaminophen, when used during periods of respiratory illness, was associated with a higher risk of asthma exacerbations or other asthma-related complications than was ibuprofen,” Dr. Sheehan and his associates wrote.
This study was funded by the National Institutes of Health and the National Heart, Lung, and Blood Institute. Dr. Sheehan reported having no relevant financial disclosures; his associates reported numerous ties to industry sources.
The findings of Sheehan et al. should reassure clinicians and parents who care for young children taking asthma-controlling medications that the use of acetaminophen in usual, as-needed doses will not worsen the condition.
Acetaminophen and ibuprofen can be used similarly in situations for which they are indicated.
Augusto A. Litonjua, MD, is in the Channing Division of Network Medicine, Brigham and Women’s Hospital, and at Harvard Medical School, both in Boston. Dr. Litonjua made these remarks in an editorial accompanying Dr. Sheehan’s report (N Engl J Med. 2016 Aug 18. doi: 10.1056/NEJMe1607629). He reported receiving personal fees from UpToDate, Springer Humana Press, and AstraZeneca outside this editorial.
The findings of Sheehan et al. should reassure clinicians and parents who care for young children taking asthma-controlling medications that the use of acetaminophen in usual, as-needed doses will not worsen the condition.
Acetaminophen and ibuprofen can be used similarly in situations for which they are indicated.
Augusto A. Litonjua, MD, is in the Channing Division of Network Medicine, Brigham and Women’s Hospital, and at Harvard Medical School, both in Boston. Dr. Litonjua made these remarks in an editorial accompanying Dr. Sheehan’s report (N Engl J Med. 2016 Aug 18. doi: 10.1056/NEJMe1607629). He reported receiving personal fees from UpToDate, Springer Humana Press, and AstraZeneca outside this editorial.
The findings of Sheehan et al. should reassure clinicians and parents who care for young children taking asthma-controlling medications that the use of acetaminophen in usual, as-needed doses will not worsen the condition.
Acetaminophen and ibuprofen can be used similarly in situations for which they are indicated.
Augusto A. Litonjua, MD, is in the Channing Division of Network Medicine, Brigham and Women’s Hospital, and at Harvard Medical School, both in Boston. Dr. Litonjua made these remarks in an editorial accompanying Dr. Sheehan’s report (N Engl J Med. 2016 Aug 18. doi: 10.1056/NEJMe1607629). He reported receiving personal fees from UpToDate, Springer Humana Press, and AstraZeneca outside this editorial.
As-needed use of acetaminophen for fever or pain does not exacerbate mild persistent asthma in young children, according to a report published online August 18 in the New England Journal of Medicine.
In a prospective, randomized, double-blind clinical trial performed at 18 U.S. medical centers, neither acetaminophen nor ibuprofen raised the rate of exacerbations or impaired asthma control among 300 children aged 1-5 years. This result refutes those of observational and post hoc data that linked acetaminophen to increased asthma exacerbations, daily symptoms, and need for bronchodilators in children and adults. Those findings “have led to much controversy and even alarm,” with some physicians recommending that acetaminophen be completely avoided in children with asthma until more safety data became available, said William J. Sheehan, MD, of the division of allergy and immunology, Boston Children’s Hospital and Harvard Medical School, Boston, and his associates.
The investigators performed this 2-year study to obtain such safety data. The children (median age, 40 months) were randomly assigned to receive either liquid acetaminophen (150 patients) or matching liquid ibuprofen (150 patients) as needed for pain, fever, or discomfort and were followed for 46 weeks. All the participants received standard asthma-control therapies including inhaled glucocorticoids, oral leukotriene-receptor antagonists, and as-needed inhaled glucocorticoids.
The primary outcome – the mean number of asthma exacerbations – was 0.81 in the acetaminophen group and 0.87 in the ibuprofen group, a nonsignificant difference. The rate of exacerbations also did not differ between acetaminophen and ibuprofen in the subgroup of 226 children who completed the entire trial or in the subgroup of 200 who received a study medication for pain or fever at least once during follow-up, Dr. Sheehan and his associates said (N Engl J Med. 2016 Aug 18. doi: 10.1056/NEJMoa1515990).
There also were no significant differences between the two study groups in time to first asthma exacerbation, percentage of days of good asthma control (85.8% vs. 86.8% of days), use of rescue albuterol (2.8 vs. 3.0 inhalations per week), or unscheduled health care visits for asthma (0.75 vs. 0.76 visits). No between-group differences occurred regarding adverse events or serious adverse events.
Some experts have suggested that the observational studies reporting a link between acetaminophen and asthma exacerbations may have been flawed by “confounding by indication,” because children with asthma have more symptomatic respiratory infections than do those without asthma and use more acetaminophen for fever and malaise. “We [also] observed that greater use of antipyretic, analgesic medications was associated with more apparent respiratory illnesses and that the reported respiratory illnesses were associated with asthma exacerbations.
“However, we found no evidence that acetaminophen, when used during periods of respiratory illness, was associated with a higher risk of asthma exacerbations or other asthma-related complications than was ibuprofen,” Dr. Sheehan and his associates wrote.
This study was funded by the National Institutes of Health and the National Heart, Lung, and Blood Institute. Dr. Sheehan reported having no relevant financial disclosures; his associates reported numerous ties to industry sources.
As-needed use of acetaminophen for fever or pain does not exacerbate mild persistent asthma in young children, according to a report published online August 18 in the New England Journal of Medicine.
In a prospective, randomized, double-blind clinical trial performed at 18 U.S. medical centers, neither acetaminophen nor ibuprofen raised the rate of exacerbations or impaired asthma control among 300 children aged 1-5 years. This result refutes those of observational and post hoc data that linked acetaminophen to increased asthma exacerbations, daily symptoms, and need for bronchodilators in children and adults. Those findings “have led to much controversy and even alarm,” with some physicians recommending that acetaminophen be completely avoided in children with asthma until more safety data became available, said William J. Sheehan, MD, of the division of allergy and immunology, Boston Children’s Hospital and Harvard Medical School, Boston, and his associates.
The investigators performed this 2-year study to obtain such safety data. The children (median age, 40 months) were randomly assigned to receive either liquid acetaminophen (150 patients) or matching liquid ibuprofen (150 patients) as needed for pain, fever, or discomfort and were followed for 46 weeks. All the participants received standard asthma-control therapies including inhaled glucocorticoids, oral leukotriene-receptor antagonists, and as-needed inhaled glucocorticoids.
The primary outcome – the mean number of asthma exacerbations – was 0.81 in the acetaminophen group and 0.87 in the ibuprofen group, a nonsignificant difference. The rate of exacerbations also did not differ between acetaminophen and ibuprofen in the subgroup of 226 children who completed the entire trial or in the subgroup of 200 who received a study medication for pain or fever at least once during follow-up, Dr. Sheehan and his associates said (N Engl J Med. 2016 Aug 18. doi: 10.1056/NEJMoa1515990).
There also were no significant differences between the two study groups in time to first asthma exacerbation, percentage of days of good asthma control (85.8% vs. 86.8% of days), use of rescue albuterol (2.8 vs. 3.0 inhalations per week), or unscheduled health care visits for asthma (0.75 vs. 0.76 visits). No between-group differences occurred regarding adverse events or serious adverse events.
Some experts have suggested that the observational studies reporting a link between acetaminophen and asthma exacerbations may have been flawed by “confounding by indication,” because children with asthma have more symptomatic respiratory infections than do those without asthma and use more acetaminophen for fever and malaise. “We [also] observed that greater use of antipyretic, analgesic medications was associated with more apparent respiratory illnesses and that the reported respiratory illnesses were associated with asthma exacerbations.
“However, we found no evidence that acetaminophen, when used during periods of respiratory illness, was associated with a higher risk of asthma exacerbations or other asthma-related complications than was ibuprofen,” Dr. Sheehan and his associates wrote.
This study was funded by the National Institutes of Health and the National Heart, Lung, and Blood Institute. Dr. Sheehan reported having no relevant financial disclosures; his associates reported numerous ties to industry sources.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Using acetaminophen for fever or pain doesn’t exacerbate mild persistent asthma in young children.
Major finding: The mean number of asthma exacerbations was 0.81 in the acetaminophen group and 0.87 in the ibuprofen group, a nonsignificant difference.
Data source: A 2-year multicenter, double-blind, randomized clinical trial involving 300 children aged 1-5 years.
Disclosures: This study was funded by the National Institutes of Health and the National Heart, Lung, and Blood Institute. Dr. Sheehan reported having no relevant financial disclosures; his associates reported numerous ties to industry sources.
Primary biliary cholangitis: Obeticholic acid reduces biomarkers
Obeticholic acid reduced alkaline phosphatase level, total bilirubin level, and other biomarkers of cholestasis, hepatocellular injury, inflammation, and apoptosis in patients with primary biliary cholangitis participating in a phase III clinical trial, which was reported online August 17 in the New England Journal of Medicine.
A study to assess the drug’s effects on clinical outcomes is currently enrolling patients (NCT02308111), said Frederik Nevens, MD, PhD, of University Hospitals Leuven (Belgium) and his associates.
They assessed treatment with obeticholic acid, a selective farnesoid X receptor agonist, in a manufacturer-sponsored double-blind randomized trial involving 217 patients treated at 59 sites in 13 countries. Participants were assigned to receive a once-daily oral placebo (73 patients), obeticholic acid at an initial dose of 5 mg with escalation to 10 mg if possible (71 patients), or a daily 10-mg dose of obeticholic acid (73 patients). All were also given standard ursodiol (13-15 mg per kg) at the same time, with the expectation that many would have to discontinue that drug due to adverse events. The study participants were treated for 1 year, when the double-blind phase of the study was completed and all were offered entry into a 5-year open-label phase.
The primary composite endpoint was 1) an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% below baseline level, and 2) a total bilirubin level at or below the upper limit of the normal range. After 1 year of treatment, 46% of the 5-mg group and 47% of the 10-mg group achieved this endpoint, compared with only 10% of the placebo group. The response to treatment was rapid, with patients in the active-treatment groups showing significantly lower alkaline phosphatase and bilirubin levels than the placebo group within 2 weeks of starting therapy.
In addition, the percentage of patients who showed at least a 15% reduction in alkaline phosphatase level was significantly higher with 5-10 mg active treatment (77%) and with 10 mg active treatment (77%) than with placebo (29%). And total bilirubin level progressively decreased in both active treatment groups but progressively increased in the placebo group, Dr. Nevens and his associates said (N Engl J Med. 2016 Aug 18. doi: 10.1056/NEJMoa1509840). Obeticholic acid also reduced levels of IgM and interleukin-12, as well as levels of gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase, and conjugated bilirubin. It did not induce significant symptom relief as measured by a disease-specific quality of life questionnaire, and it didn’t reduce liver fibrosis as measured by noninvasive techniques.
In the open-label extension phase of the study, treatment efficacy was similar.
The most common adverse event was pruritus, which is also characteristic of the disease itself. The incidence was higher in both active-treatment groups (56% with 5-10-mg therapy and 68% with 10-mg therapy) than in the placebo group (38%). One patient (1%) in the 5-10-mg group and seven patients (10%) in the 10-mg group discontinued treatment because of pruritus, compared with no patients in the placebo group.
The treatment’s beneficial effects persisted for 2 years, but that is a relatively short follow-up for a chronic disease that will require lifelong therapy. Future research must address longer-term benefits as well as adverse events, the investigators said.
The results of this phase III clinical trial are encouraging, but we still do not know whether or how obeticholic acid impacts clinical endpoints such as hepatic decompensation, progression to cirrhosis, symptoms, or survival.
Also unknown is whether patients with this chronic disease will be able to take obeticholic acid indefinitely. And we don’t know whether to continue treating those who don’t show a biochemical response to the drug within 1 year, who comprise approximately 50% of patients, according to the results of this trial.
The price of obeticholic acid is also a concern. At present it costs approximately $70,000 per year.
Daniel S. Pratt, MD, is at the Autoimmune and Cholestatic Liver Center at Massachusetts General Hospital and at Harvard Medical School, both in Boston. He reported having no relevant financial disclosures. Dr. Pratt made these remarks in an editorial accompanying Dr. Nevens’ report (N Engl J Med. 2016 Aug 18. doi: 10.1056/NEJMe1607744).
The results of this phase III clinical trial are encouraging, but we still do not know whether or how obeticholic acid impacts clinical endpoints such as hepatic decompensation, progression to cirrhosis, symptoms, or survival.
Also unknown is whether patients with this chronic disease will be able to take obeticholic acid indefinitely. And we don’t know whether to continue treating those who don’t show a biochemical response to the drug within 1 year, who comprise approximately 50% of patients, according to the results of this trial.
The price of obeticholic acid is also a concern. At present it costs approximately $70,000 per year.
Daniel S. Pratt, MD, is at the Autoimmune and Cholestatic Liver Center at Massachusetts General Hospital and at Harvard Medical School, both in Boston. He reported having no relevant financial disclosures. Dr. Pratt made these remarks in an editorial accompanying Dr. Nevens’ report (N Engl J Med. 2016 Aug 18. doi: 10.1056/NEJMe1607744).
The results of this phase III clinical trial are encouraging, but we still do not know whether or how obeticholic acid impacts clinical endpoints such as hepatic decompensation, progression to cirrhosis, symptoms, or survival.
Also unknown is whether patients with this chronic disease will be able to take obeticholic acid indefinitely. And we don’t know whether to continue treating those who don’t show a biochemical response to the drug within 1 year, who comprise approximately 50% of patients, according to the results of this trial.
The price of obeticholic acid is also a concern. At present it costs approximately $70,000 per year.
Daniel S. Pratt, MD, is at the Autoimmune and Cholestatic Liver Center at Massachusetts General Hospital and at Harvard Medical School, both in Boston. He reported having no relevant financial disclosures. Dr. Pratt made these remarks in an editorial accompanying Dr. Nevens’ report (N Engl J Med. 2016 Aug 18. doi: 10.1056/NEJMe1607744).
Obeticholic acid reduced alkaline phosphatase level, total bilirubin level, and other biomarkers of cholestasis, hepatocellular injury, inflammation, and apoptosis in patients with primary biliary cholangitis participating in a phase III clinical trial, which was reported online August 17 in the New England Journal of Medicine.
A study to assess the drug’s effects on clinical outcomes is currently enrolling patients (NCT02308111), said Frederik Nevens, MD, PhD, of University Hospitals Leuven (Belgium) and his associates.
They assessed treatment with obeticholic acid, a selective farnesoid X receptor agonist, in a manufacturer-sponsored double-blind randomized trial involving 217 patients treated at 59 sites in 13 countries. Participants were assigned to receive a once-daily oral placebo (73 patients), obeticholic acid at an initial dose of 5 mg with escalation to 10 mg if possible (71 patients), or a daily 10-mg dose of obeticholic acid (73 patients). All were also given standard ursodiol (13-15 mg per kg) at the same time, with the expectation that many would have to discontinue that drug due to adverse events. The study participants were treated for 1 year, when the double-blind phase of the study was completed and all were offered entry into a 5-year open-label phase.
The primary composite endpoint was 1) an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% below baseline level, and 2) a total bilirubin level at or below the upper limit of the normal range. After 1 year of treatment, 46% of the 5-mg group and 47% of the 10-mg group achieved this endpoint, compared with only 10% of the placebo group. The response to treatment was rapid, with patients in the active-treatment groups showing significantly lower alkaline phosphatase and bilirubin levels than the placebo group within 2 weeks of starting therapy.
In addition, the percentage of patients who showed at least a 15% reduction in alkaline phosphatase level was significantly higher with 5-10 mg active treatment (77%) and with 10 mg active treatment (77%) than with placebo (29%). And total bilirubin level progressively decreased in both active treatment groups but progressively increased in the placebo group, Dr. Nevens and his associates said (N Engl J Med. 2016 Aug 18. doi: 10.1056/NEJMoa1509840). Obeticholic acid also reduced levels of IgM and interleukin-12, as well as levels of gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase, and conjugated bilirubin. It did not induce significant symptom relief as measured by a disease-specific quality of life questionnaire, and it didn’t reduce liver fibrosis as measured by noninvasive techniques.
In the open-label extension phase of the study, treatment efficacy was similar.
The most common adverse event was pruritus, which is also characteristic of the disease itself. The incidence was higher in both active-treatment groups (56% with 5-10-mg therapy and 68% with 10-mg therapy) than in the placebo group (38%). One patient (1%) in the 5-10-mg group and seven patients (10%) in the 10-mg group discontinued treatment because of pruritus, compared with no patients in the placebo group.
The treatment’s beneficial effects persisted for 2 years, but that is a relatively short follow-up for a chronic disease that will require lifelong therapy. Future research must address longer-term benefits as well as adverse events, the investigators said.
Obeticholic acid reduced alkaline phosphatase level, total bilirubin level, and other biomarkers of cholestasis, hepatocellular injury, inflammation, and apoptosis in patients with primary biliary cholangitis participating in a phase III clinical trial, which was reported online August 17 in the New England Journal of Medicine.
A study to assess the drug’s effects on clinical outcomes is currently enrolling patients (NCT02308111), said Frederik Nevens, MD, PhD, of University Hospitals Leuven (Belgium) and his associates.
They assessed treatment with obeticholic acid, a selective farnesoid X receptor agonist, in a manufacturer-sponsored double-blind randomized trial involving 217 patients treated at 59 sites in 13 countries. Participants were assigned to receive a once-daily oral placebo (73 patients), obeticholic acid at an initial dose of 5 mg with escalation to 10 mg if possible (71 patients), or a daily 10-mg dose of obeticholic acid (73 patients). All were also given standard ursodiol (13-15 mg per kg) at the same time, with the expectation that many would have to discontinue that drug due to adverse events. The study participants were treated for 1 year, when the double-blind phase of the study was completed and all were offered entry into a 5-year open-label phase.
The primary composite endpoint was 1) an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% below baseline level, and 2) a total bilirubin level at or below the upper limit of the normal range. After 1 year of treatment, 46% of the 5-mg group and 47% of the 10-mg group achieved this endpoint, compared with only 10% of the placebo group. The response to treatment was rapid, with patients in the active-treatment groups showing significantly lower alkaline phosphatase and bilirubin levels than the placebo group within 2 weeks of starting therapy.
In addition, the percentage of patients who showed at least a 15% reduction in alkaline phosphatase level was significantly higher with 5-10 mg active treatment (77%) and with 10 mg active treatment (77%) than with placebo (29%). And total bilirubin level progressively decreased in both active treatment groups but progressively increased in the placebo group, Dr. Nevens and his associates said (N Engl J Med. 2016 Aug 18. doi: 10.1056/NEJMoa1509840). Obeticholic acid also reduced levels of IgM and interleukin-12, as well as levels of gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase, and conjugated bilirubin. It did not induce significant symptom relief as measured by a disease-specific quality of life questionnaire, and it didn’t reduce liver fibrosis as measured by noninvasive techniques.
In the open-label extension phase of the study, treatment efficacy was similar.
The most common adverse event was pruritus, which is also characteristic of the disease itself. The incidence was higher in both active-treatment groups (56% with 5-10-mg therapy and 68% with 10-mg therapy) than in the placebo group (38%). One patient (1%) in the 5-10-mg group and seven patients (10%) in the 10-mg group discontinued treatment because of pruritus, compared with no patients in the placebo group.
The treatment’s beneficial effects persisted for 2 years, but that is a relatively short follow-up for a chronic disease that will require lifelong therapy. Future research must address longer-term benefits as well as adverse events, the investigators said.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Obeticholic acid therapy reduced alkaline phosphatase level, total bilirubin level, and other biomarkers in primary biliary cholangitis.
Major finding: 46% of the 5-mg group and 47% of the 10-mg group achieved the primary end point, compared with only 10% of the placebo group.
Data source: A 1-year international randomized double-blind placebo-controlled phase III clinical trial involving 217 adults with primary biliary cholangitis.
Disclosures: This study was supported by Intercept Pharmaceuticals. Dr. Nevens reported having no relevant financial disclosures; his associates reported ties to numerous industry sources.
Expanded prenatal screening offers promise in detecting more disease carriers
Expanded genetic screening of prospective parents for recessive abnormalities has the potential to identify many more carriers of potentially serious genetic disorders, compared with current screening that relies on racial/ethnic background, according to a report published online Aug. 16 in JAMA.
Currently, the American College of Medical Genetics and Genomics and the American Congress of Obstetricians and Gynecologists recommend prenatal carrier testing for only for a limited number of individual diseases and primarily based on parents’ reports of their racial/ethnic background. But new technologies now allow expanded carrier screening for dozens of conditions, and do so independently of parents’ racial/ethnic background, reported Imran S. Haque, PhD, of Counsyl, South San Francisco, Calif., and his colleagues. Counsyl is a commercial laboratory that provides expanded carrier screening.
The researchers analyzed data from 346,790 individual screens performed between Jan. 1, 2012, and July 15, 2015, to create a computer model that estimates the results of expanded carrier screening. The model included 15 racial/ethnic categories, and it assessed screening results from either targeted genotyping or next-generation sequencing. The model assessed screens for up to 110 genetic abnormalities that cause up to 94 conditions known to produce profound or severe disability in affected offspring (JAMA. 2016;316[7]:734-42. doi: 10.1001/jama.2016.11139).
Across all racial/ethnic categories except African or African American or Southeast Asian, the expanded carrier screening model that included additional severe and profound diseases would be expected to detect at least twice as many hypothetical fetuses as would current professional screening recommendations (P less than .001 for all racial/ethnic categories).
For instance, among the Ashkenazi Jewish population, which has the most extensive ethnicity-specific panel, 55% of fetuses with profound or severe phenotypes would be missed using current screening (392.2 per 100,000 fetuses detected by expanded screening versus 174.8 per 100,000 with current screening). For the Middle Eastern population, 91% of fetuses with profound or severe phenotypes would be missed using the current screening (193.8 per 100,000 fetuses with expanded screening versus 17.7 per 100,000 fetuses with current screening).
Among couples of East Asian descent, expanded screening would identify genetic conditions affecting 129.9 per 100,000 fetuses, compared with 7.6 per 100,000 with current screening. Among couples of Northern European descent, expanded screening would identify genetic conditions affecting 159.2 per 100,000 fetuses, while current screening would do so in 55.2 per 100,000. Among couples of African descent, current screening misses about 13% of fetuses with profound or severe phenotypes, compared with expanded carrier screening.
The researchers noted that while carrier screening according to current guidelines targets “a number of diseases prevalent in those of European descent (such as cystic fibrosis), they do not identify risk for other conditions that may be important to diverse populations.”
“Expanded carrier screening revealed that many non-European racial/ethnic categories have a risk of a profound or severe genetic disease that may not be detected by the guidelines in place at the time of this analysis,” the researchers added.
Five of the study authors are employees of Counsyl, which funded the study. Another author disclosed ties with Natera Inc., Sequenom, Ariosa Diagnostics Inc./Roche, Illumina Inc., KellBenx, and Perinatal Quality Foundation.
The study by Haque and colleagues is an important contribution in the evolving field of prenatal testing. It provides a wealth of data on the frequency of genetic variants that can be detected in individuals of childbearing age from a diversity of racial/ethnic backgrounds. The large number of silent but potentially damaging sequence variants in every human genome went unnoticed until the last few years when high throughput DNA sequencing technology became widely available.
The study by Haque et al. was based on testing conducted by a commercial health technology company, although this does not in any way impugn the validity of the data presented. However, by using a proprietary testing strategy, some aspects of their approach are not reported in the article or otherwise ascertainable by the general public. For example, only the most frequently identified mutations are presented, and all those mutations are for disorders already offered in standard screening panels. Without supportive data to justify which diseases, genes, and mutations were selected, the screening panel may appear somewhat arbitrary and perhaps could be perceived as being driven by marketing concerns as much as by compelling scientific reasoning.
Wayne W. Grody, MD, PhD, is in the division of molecular diagnostics and at the Clinical Genomics Center at UCLA. He reported having no relevant financial disclosures. These comments are excerpted from an editorial accompanying Dr. Haque’s report (JAMA 2016;316:717-9).
The study by Haque and colleagues is an important contribution in the evolving field of prenatal testing. It provides a wealth of data on the frequency of genetic variants that can be detected in individuals of childbearing age from a diversity of racial/ethnic backgrounds. The large number of silent but potentially damaging sequence variants in every human genome went unnoticed until the last few years when high throughput DNA sequencing technology became widely available.
The study by Haque et al. was based on testing conducted by a commercial health technology company, although this does not in any way impugn the validity of the data presented. However, by using a proprietary testing strategy, some aspects of their approach are not reported in the article or otherwise ascertainable by the general public. For example, only the most frequently identified mutations are presented, and all those mutations are for disorders already offered in standard screening panels. Without supportive data to justify which diseases, genes, and mutations were selected, the screening panel may appear somewhat arbitrary and perhaps could be perceived as being driven by marketing concerns as much as by compelling scientific reasoning.
Wayne W. Grody, MD, PhD, is in the division of molecular diagnostics and at the Clinical Genomics Center at UCLA. He reported having no relevant financial disclosures. These comments are excerpted from an editorial accompanying Dr. Haque’s report (JAMA 2016;316:717-9).
The study by Haque and colleagues is an important contribution in the evolving field of prenatal testing. It provides a wealth of data on the frequency of genetic variants that can be detected in individuals of childbearing age from a diversity of racial/ethnic backgrounds. The large number of silent but potentially damaging sequence variants in every human genome went unnoticed until the last few years when high throughput DNA sequencing technology became widely available.
The study by Haque et al. was based on testing conducted by a commercial health technology company, although this does not in any way impugn the validity of the data presented. However, by using a proprietary testing strategy, some aspects of their approach are not reported in the article or otherwise ascertainable by the general public. For example, only the most frequently identified mutations are presented, and all those mutations are for disorders already offered in standard screening panels. Without supportive data to justify which diseases, genes, and mutations were selected, the screening panel may appear somewhat arbitrary and perhaps could be perceived as being driven by marketing concerns as much as by compelling scientific reasoning.
Wayne W. Grody, MD, PhD, is in the division of molecular diagnostics and at the Clinical Genomics Center at UCLA. He reported having no relevant financial disclosures. These comments are excerpted from an editorial accompanying Dr. Haque’s report (JAMA 2016;316:717-9).
Expanded genetic screening of prospective parents for recessive abnormalities has the potential to identify many more carriers of potentially serious genetic disorders, compared with current screening that relies on racial/ethnic background, according to a report published online Aug. 16 in JAMA.
Currently, the American College of Medical Genetics and Genomics and the American Congress of Obstetricians and Gynecologists recommend prenatal carrier testing for only for a limited number of individual diseases and primarily based on parents’ reports of their racial/ethnic background. But new technologies now allow expanded carrier screening for dozens of conditions, and do so independently of parents’ racial/ethnic background, reported Imran S. Haque, PhD, of Counsyl, South San Francisco, Calif., and his colleagues. Counsyl is a commercial laboratory that provides expanded carrier screening.
The researchers analyzed data from 346,790 individual screens performed between Jan. 1, 2012, and July 15, 2015, to create a computer model that estimates the results of expanded carrier screening. The model included 15 racial/ethnic categories, and it assessed screening results from either targeted genotyping or next-generation sequencing. The model assessed screens for up to 110 genetic abnormalities that cause up to 94 conditions known to produce profound or severe disability in affected offspring (JAMA. 2016;316[7]:734-42. doi: 10.1001/jama.2016.11139).
Across all racial/ethnic categories except African or African American or Southeast Asian, the expanded carrier screening model that included additional severe and profound diseases would be expected to detect at least twice as many hypothetical fetuses as would current professional screening recommendations (P less than .001 for all racial/ethnic categories).
For instance, among the Ashkenazi Jewish population, which has the most extensive ethnicity-specific panel, 55% of fetuses with profound or severe phenotypes would be missed using current screening (392.2 per 100,000 fetuses detected by expanded screening versus 174.8 per 100,000 with current screening). For the Middle Eastern population, 91% of fetuses with profound or severe phenotypes would be missed using the current screening (193.8 per 100,000 fetuses with expanded screening versus 17.7 per 100,000 fetuses with current screening).
Among couples of East Asian descent, expanded screening would identify genetic conditions affecting 129.9 per 100,000 fetuses, compared with 7.6 per 100,000 with current screening. Among couples of Northern European descent, expanded screening would identify genetic conditions affecting 159.2 per 100,000 fetuses, while current screening would do so in 55.2 per 100,000. Among couples of African descent, current screening misses about 13% of fetuses with profound or severe phenotypes, compared with expanded carrier screening.
The researchers noted that while carrier screening according to current guidelines targets “a number of diseases prevalent in those of European descent (such as cystic fibrosis), they do not identify risk for other conditions that may be important to diverse populations.”
“Expanded carrier screening revealed that many non-European racial/ethnic categories have a risk of a profound or severe genetic disease that may not be detected by the guidelines in place at the time of this analysis,” the researchers added.
Five of the study authors are employees of Counsyl, which funded the study. Another author disclosed ties with Natera Inc., Sequenom, Ariosa Diagnostics Inc./Roche, Illumina Inc., KellBenx, and Perinatal Quality Foundation.
Expanded genetic screening of prospective parents for recessive abnormalities has the potential to identify many more carriers of potentially serious genetic disorders, compared with current screening that relies on racial/ethnic background, according to a report published online Aug. 16 in JAMA.
Currently, the American College of Medical Genetics and Genomics and the American Congress of Obstetricians and Gynecologists recommend prenatal carrier testing for only for a limited number of individual diseases and primarily based on parents’ reports of their racial/ethnic background. But new technologies now allow expanded carrier screening for dozens of conditions, and do so independently of parents’ racial/ethnic background, reported Imran S. Haque, PhD, of Counsyl, South San Francisco, Calif., and his colleagues. Counsyl is a commercial laboratory that provides expanded carrier screening.
The researchers analyzed data from 346,790 individual screens performed between Jan. 1, 2012, and July 15, 2015, to create a computer model that estimates the results of expanded carrier screening. The model included 15 racial/ethnic categories, and it assessed screening results from either targeted genotyping or next-generation sequencing. The model assessed screens for up to 110 genetic abnormalities that cause up to 94 conditions known to produce profound or severe disability in affected offspring (JAMA. 2016;316[7]:734-42. doi: 10.1001/jama.2016.11139).
Across all racial/ethnic categories except African or African American or Southeast Asian, the expanded carrier screening model that included additional severe and profound diseases would be expected to detect at least twice as many hypothetical fetuses as would current professional screening recommendations (P less than .001 for all racial/ethnic categories).
For instance, among the Ashkenazi Jewish population, which has the most extensive ethnicity-specific panel, 55% of fetuses with profound or severe phenotypes would be missed using current screening (392.2 per 100,000 fetuses detected by expanded screening versus 174.8 per 100,000 with current screening). For the Middle Eastern population, 91% of fetuses with profound or severe phenotypes would be missed using the current screening (193.8 per 100,000 fetuses with expanded screening versus 17.7 per 100,000 fetuses with current screening).
Among couples of East Asian descent, expanded screening would identify genetic conditions affecting 129.9 per 100,000 fetuses, compared with 7.6 per 100,000 with current screening. Among couples of Northern European descent, expanded screening would identify genetic conditions affecting 159.2 per 100,000 fetuses, while current screening would do so in 55.2 per 100,000. Among couples of African descent, current screening misses about 13% of fetuses with profound or severe phenotypes, compared with expanded carrier screening.
The researchers noted that while carrier screening according to current guidelines targets “a number of diseases prevalent in those of European descent (such as cystic fibrosis), they do not identify risk for other conditions that may be important to diverse populations.”
“Expanded carrier screening revealed that many non-European racial/ethnic categories have a risk of a profound or severe genetic disease that may not be detected by the guidelines in place at the time of this analysis,” the researchers added.
Five of the study authors are employees of Counsyl, which funded the study. Another author disclosed ties with Natera Inc., Sequenom, Ariosa Diagnostics Inc./Roche, Illumina Inc., KellBenx, and Perinatal Quality Foundation.
FROM JAMA
Key clinical point: Expanded prenatal screening of prospective parents for genetic abnormalities would identify many more carriers of potentially serious disorders.
Major finding: An expanded carrier screening model that included additional severe and profound diseases would be expected to detect at least twice as many hypothetical fetuses as current professional screening recommendations (P less than .001 for all racial/ethnic categories).
Data source: An industry-sponsored retrospective modeling analysis involving data for 346,790 ethnically diverse men and women screened during a 3.5-year period.
Disclosures: Five of the study authors are employees of Counsyl, which funded the study. Another author disclosed ties with Natera Inc., Sequenom, Ariosa Diagnostics Inc./Roche, Illumina Inc., KellBenx, and Perinatal Quality Foundation.
Model estimates risk of pneumonia after CABG
A model incorporating 17 easily obtainable preoperative variables may help clinicians estimate patients’ risk of developing pneumonia after undergoing coronary artery bypass graft surgery, according to a report published in Annals of Thoracic Surgery.
“This model may be used to inform clinician-patient decision making and to identify opportunities for mitigating a patient’s risk,” said Raymond J. Strobel, a medical student at the University of Michigan, Ann Arbor, and his associates.
Postoperative pneumonia is the most common hospital-acquired infection following CABG, and it raises mortality risk fourfold and increases length of stay threefold. But reliable estimation of patient risk of post-CABG pneumonia has been difficult because of its low relative incidence – roughly 3% – and because most studies of the disorder are nearly a decade out of date.
To devise a predictive model using current data, Mr. Strobel and his associates assessed numerous potential risk factors and outcomes for 16,084 consecutive patients undergoing CABG at all 33 cardiac centers across Michigan during a 3-year period. They identified 531 cases of post-CABG pneumonia (3.3%) in this cohort.
The investigators performed a univariate analysis to test the associations between pneumonia and numerous factors related to patient demographics, medical history, comorbid diseases, laboratory values, cardiac anatomy, cardiac function, pulmonary function, the CABG procedure, and the institution where the procedure was performed. Variables that were found to be significantly associated with pneumonia (though usually with small absolute magnitudes) were then assessed in a multivariate analysis, which was further refined to create the final model.
The final model includes 17 factors that clearly raise the risk of post-CABG pneumonia. These include an elevated leukocyte count; a decreased hematocrit; older patient age; comorbidities such as peripheral vascular disease, diabetes, and liver disease; markers of pulmonary impairment such as cigarette smoking, the need for home oxygen therapy, and chronic lung disease; markers of cardiac dysfunction such as a recent history of arrhythmia and decreased ejection fraction; and emergency or urgent rather than elective operative status.
“This model performs well and demonstrates robustness across important clinical subgroups and centers,” the investigators said (Ann Thorac Surg. 2016 Jun 1; doi: 10.1016/j.athoracsur.2016.03.074).
In particular, this study identified preoperative leukocytosis to be a significant predictor of post-CABG pneumonia across several subgroups of patients. “We speculate that patients presenting with an elevated white blood cell count before surgery may be mounting an immune response against a pathogen and that the insult of CABG significantly increases their odds of postoperative pneumonia. ... It may be prudent to delay surgery until the source of leukocytosis is satisfactorily investigated, if not identified and treated, or the leukocytosis has otherwise resolved,” Mr. Strobel and his associates noted.
A model incorporating 17 easily obtainable preoperative variables may help clinicians estimate patients’ risk of developing pneumonia after undergoing coronary artery bypass graft surgery, according to a report published in Annals of Thoracic Surgery.
“This model may be used to inform clinician-patient decision making and to identify opportunities for mitigating a patient’s risk,” said Raymond J. Strobel, a medical student at the University of Michigan, Ann Arbor, and his associates.
Postoperative pneumonia is the most common hospital-acquired infection following CABG, and it raises mortality risk fourfold and increases length of stay threefold. But reliable estimation of patient risk of post-CABG pneumonia has been difficult because of its low relative incidence – roughly 3% – and because most studies of the disorder are nearly a decade out of date.
To devise a predictive model using current data, Mr. Strobel and his associates assessed numerous potential risk factors and outcomes for 16,084 consecutive patients undergoing CABG at all 33 cardiac centers across Michigan during a 3-year period. They identified 531 cases of post-CABG pneumonia (3.3%) in this cohort.
The investigators performed a univariate analysis to test the associations between pneumonia and numerous factors related to patient demographics, medical history, comorbid diseases, laboratory values, cardiac anatomy, cardiac function, pulmonary function, the CABG procedure, and the institution where the procedure was performed. Variables that were found to be significantly associated with pneumonia (though usually with small absolute magnitudes) were then assessed in a multivariate analysis, which was further refined to create the final model.
The final model includes 17 factors that clearly raise the risk of post-CABG pneumonia. These include an elevated leukocyte count; a decreased hematocrit; older patient age; comorbidities such as peripheral vascular disease, diabetes, and liver disease; markers of pulmonary impairment such as cigarette smoking, the need for home oxygen therapy, and chronic lung disease; markers of cardiac dysfunction such as a recent history of arrhythmia and decreased ejection fraction; and emergency or urgent rather than elective operative status.
“This model performs well and demonstrates robustness across important clinical subgroups and centers,” the investigators said (Ann Thorac Surg. 2016 Jun 1; doi: 10.1016/j.athoracsur.2016.03.074).
In particular, this study identified preoperative leukocytosis to be a significant predictor of post-CABG pneumonia across several subgroups of patients. “We speculate that patients presenting with an elevated white blood cell count before surgery may be mounting an immune response against a pathogen and that the insult of CABG significantly increases their odds of postoperative pneumonia. ... It may be prudent to delay surgery until the source of leukocytosis is satisfactorily investigated, if not identified and treated, or the leukocytosis has otherwise resolved,” Mr. Strobel and his associates noted.
A model incorporating 17 easily obtainable preoperative variables may help clinicians estimate patients’ risk of developing pneumonia after undergoing coronary artery bypass graft surgery, according to a report published in Annals of Thoracic Surgery.
“This model may be used to inform clinician-patient decision making and to identify opportunities for mitigating a patient’s risk,” said Raymond J. Strobel, a medical student at the University of Michigan, Ann Arbor, and his associates.
Postoperative pneumonia is the most common hospital-acquired infection following CABG, and it raises mortality risk fourfold and increases length of stay threefold. But reliable estimation of patient risk of post-CABG pneumonia has been difficult because of its low relative incidence – roughly 3% – and because most studies of the disorder are nearly a decade out of date.
To devise a predictive model using current data, Mr. Strobel and his associates assessed numerous potential risk factors and outcomes for 16,084 consecutive patients undergoing CABG at all 33 cardiac centers across Michigan during a 3-year period. They identified 531 cases of post-CABG pneumonia (3.3%) in this cohort.
The investigators performed a univariate analysis to test the associations between pneumonia and numerous factors related to patient demographics, medical history, comorbid diseases, laboratory values, cardiac anatomy, cardiac function, pulmonary function, the CABG procedure, and the institution where the procedure was performed. Variables that were found to be significantly associated with pneumonia (though usually with small absolute magnitudes) were then assessed in a multivariate analysis, which was further refined to create the final model.
The final model includes 17 factors that clearly raise the risk of post-CABG pneumonia. These include an elevated leukocyte count; a decreased hematocrit; older patient age; comorbidities such as peripheral vascular disease, diabetes, and liver disease; markers of pulmonary impairment such as cigarette smoking, the need for home oxygen therapy, and chronic lung disease; markers of cardiac dysfunction such as a recent history of arrhythmia and decreased ejection fraction; and emergency or urgent rather than elective operative status.
“This model performs well and demonstrates robustness across important clinical subgroups and centers,” the investigators said (Ann Thorac Surg. 2016 Jun 1; doi: 10.1016/j.athoracsur.2016.03.074).
In particular, this study identified preoperative leukocytosis to be a significant predictor of post-CABG pneumonia across several subgroups of patients. “We speculate that patients presenting with an elevated white blood cell count before surgery may be mounting an immune response against a pathogen and that the insult of CABG significantly increases their odds of postoperative pneumonia. ... It may be prudent to delay surgery until the source of leukocytosis is satisfactorily investigated, if not identified and treated, or the leukocytosis has otherwise resolved,” Mr. Strobel and his associates noted.
FROM ANNALS OF THORACIC SURGERY
Key clinical point: A model incorporating 17 easily obtainable preoperative variables helps estimate patients’ risk of developing pneumonia after coronary artery bypass surgery.
Major finding: Seventeen factors clearly raise the risk of post-CABG pneumonia, including an elevated leukocyte count, a decreased hematocrit, cigarette smoking, and the need for home oxygen therapy.
Data source: A prospective observational cohort study assessing numerous risk factors in 16,084 CABG patients.
Disclosures: This study was funded in part by the U.S. Agency for Healthcare Research and Quality, Blue Cross and Blue Shield of Michigan, and Blue Care Network. The authors’ financial disclosures were not provided.
Thymectomy improves clinical outcomes for myasthenia gravis
Thymectomy improved 3-year clinical outcomes and proved superior to medical therapy for mild to severe nonthymomatous myasthenia gravis, according to a report published online Aug. 11 in the New England Journal of Medicine.
Compared with standard prednisone therapy, thymectomy plus prednisone decreased the number and severity of symptoms, allowed the lowering of steroid doses, decreased the number and length of hospitalizations for disease exacerbations, reduced the need for immunosuppressive agents, and improved health-related quality of life in an international, randomized clinical trial, said Gil I. Wolfe, MD, of the department of neurology, State University of New York at Buffalo and his associates.
Until now, thymectomy was known to be beneficial in some cases of myasthenia gravis “but with widely varying rates of clinical improvement or remission.” And the success of immunotherapy has raised the question of whether an invasive surgery is necessary. Data from randomized, controlled studies have been sparse.
Moreover, thymectomy rarely causes adverse effects, but “the procedure can cost up to $80,000 and can be associated with operative complications that need to be weighed against benefits.” In comparison, medical therapy with glucocorticoids and other immunosuppressive agents is less invasive but is definitely associated with adverse events, including some that are life threatening, and negatively impacts quality of life, the investigators said.
To address the lack of randomized controlled trial data, they assessed 3-year outcomes in 126 patients treated at 67 medical centers in 18 countries during a 6-year period. The study participants were aged 18-65 years, had a disease duration of less than 5 years at enrollment (median duration, 1 year), and had class II (mild generalized disease) to class IV (severe generalized disease) myasthenia gravis. These patients were randomly assigned to undergo thymectomy and receive standard prednisone therapy (66 participants) or to receive standard prednisone alone (60 participants).
Thymectomy was performed using a median sternotomy “with the goal of an en bloc resection of all mediastinal tissue that could anatomically contain gross or microscopic thymus.”
At follow-up, time-weighted average scores on the Quantitative Myasthenia Gravis scale were significantly lower by 2.85 points, indicating improved clinical status, in the thymectomy group than in the control group. Time-weighted average prednisone dose also was significantly lower, at an average alternate-day dose of 44 mg in the thymectomy group and 60 mg in the control group, Dr. Wolfe and his associates said (N Engl J Med. 2016 Aug 11. doi: 10.1056/NEJMoa1602489).
On a measure of treatment-related complications, scores favored thymectomy with regard to the number of patients with symptoms, the total number of symptoms, and the distress level related to symptoms throughout the study period. Fewer patients in the thymectomy group required hospitalization for exacerbations of myasthenia gravis (9% vs. 37%), and the mean cumulative number of hospital days was lower with thymectomy (8.4 vs. 19.2).
In addition, scores on the Myasthenia Gravis Activities of Daily Living scale favored thymectomy (2.24 vs. 3.41). Fewer patients in the thymectomy group required azathioprine (17% vs. 0.48%). And the percentage of patients who reported having minimal manifestations of the disease at 3 years was significantly higher with thymectomy (67%) than with prednisone alone (47%).
This study was supported by the National Institute of Neurological Disorders and Stroke, the Muscular Dystrophy Association, and the Myasthenia Gravis Foundation of America and received no commercial support. Dr. Wolfe reported ties to Alexion Pharmaceuticals, Alpha Cancer Technologies, Argenx, Baxalta, CSL Behring, Grifols, and UCB, and his associates reported ties to numerous industry sources.
Landmark trial establishes effectiveness of thymectomy in myasthenia gravis
One of the many challenges of treating patients with myasthenia gravis (MG) is the fluctuating nature of symptoms and deficits. The neurologist or neuromuscular specialist must decide whether the disease is truly worsening, whether the patient is experiencing more pronounced symptoms from intercurrent illness or the effects of a medication known to affect the neuromuscular junction adversely, or whether the patient is concerned that there might be worsening disease when all objective measures indicate stability. These factors make treatment decisions more difficult in MG than for many other neuromuscular disorders.
Similarly, researchers considering a trial investigating treatment efficacy in MG face the complex issues of disease fluctuation in cohorts of individuals with the disease, varying levels of corticosteroid and immunosuppressant doses in different MG patients, and thorny ethical dilemmas in providing accepted therapies but not withholding effective treatments from those in need.
Dr. Wolfe and his colleagues demonstrate that they have navigated these treacherous waters. They have succeeded in completing a landmark controlled clinical trial which establishes the effectiveness of transsternal thymectomy with adjuvant corticosteroid therapy in nonthymomatous MG vs. oral prednisone without surgery. While this international 36-center trial managed to recruit 126 subjects over a 6-year period, using sound inclusion and exclusion criteria and a meticulous trial design, the number of patients is not sufficient to allow for as robust a subgroup analysis for age, gender, and a variety of clinical variables reflecting severity of disease as would have been hoped for by the MG community.
Nonetheless, this paper sets the use of thymectomy in nonthymomatous MG on firmer ground going forward. The investigators will doubtless be presenting further data from the trial, including clinical-pathologic correlates and other relevant novel observations. In addition, Wolfe et al. have opened the door for future trials of thymectomy in MG to address such issues as the benefits vs. risks of performing the operation via the traditional transsternal vs. alternative non–sternal splitting approaches.
Benn E. Smith, MD, is an associate professor of neurology at the Mayo Clinic in Scottsdale, Ariz. and is the director of the sensory laboratory there. Dr. Smith is on the Editorial Advisory Board of Clinical Neurology News.
End to an 80-year controversy
These findings from Wolfe et al. end an 80-year controversy over the effectiveness of thymectomy for patients with myasthenia gravis.
Perhaps the most important benefit for patients is that even when they require prednisone following the surgery, they can take lower doses, endure fewer glucocorticoid-related symptoms, and experience less distress from those symptoms than patients who don’t undergo thymectomy.
Unfortunately, the study results cannot offer further clarity regarding patient selection for thymectomy. The patient population in this trial was so small that subgroup analyses couldn’t allow conclusions regarding the relative effectiveness of thymectomy in men vs. women or younger vs. older patients.
Allan H. Ropper, MD, is in the department of neurology at Brigham and Women’s Hospital and Harvard Medical School, both in Boston. His financial disclosures are available at NEJM.org. Dr. Ropper made these remarks in an editorial accompanying Dr. Wolfe’s report (N Engl J Med. 2016 Aug 11. doi: 10.1056/NEJMe1607953).
Landmark trial establishes effectiveness of thymectomy in myasthenia gravis
One of the many challenges of treating patients with myasthenia gravis (MG) is the fluctuating nature of symptoms and deficits. The neurologist or neuromuscular specialist must decide whether the disease is truly worsening, whether the patient is experiencing more pronounced symptoms from intercurrent illness or the effects of a medication known to affect the neuromuscular junction adversely, or whether the patient is concerned that there might be worsening disease when all objective measures indicate stability. These factors make treatment decisions more difficult in MG than for many other neuromuscular disorders.
Similarly, researchers considering a trial investigating treatment efficacy in MG face the complex issues of disease fluctuation in cohorts of individuals with the disease, varying levels of corticosteroid and immunosuppressant doses in different MG patients, and thorny ethical dilemmas in providing accepted therapies but not withholding effective treatments from those in need.
Dr. Wolfe and his colleagues demonstrate that they have navigated these treacherous waters. They have succeeded in completing a landmark controlled clinical trial which establishes the effectiveness of transsternal thymectomy with adjuvant corticosteroid therapy in nonthymomatous MG vs. oral prednisone without surgery. While this international 36-center trial managed to recruit 126 subjects over a 6-year period, using sound inclusion and exclusion criteria and a meticulous trial design, the number of patients is not sufficient to allow for as robust a subgroup analysis for age, gender, and a variety of clinical variables reflecting severity of disease as would have been hoped for by the MG community.
Nonetheless, this paper sets the use of thymectomy in nonthymomatous MG on firmer ground going forward. The investigators will doubtless be presenting further data from the trial, including clinical-pathologic correlates and other relevant novel observations. In addition, Wolfe et al. have opened the door for future trials of thymectomy in MG to address such issues as the benefits vs. risks of performing the operation via the traditional transsternal vs. alternative non–sternal splitting approaches.
Benn E. Smith, MD, is an associate professor of neurology at the Mayo Clinic in Scottsdale, Ariz. and is the director of the sensory laboratory there. Dr. Smith is on the Editorial Advisory Board of Clinical Neurology News.
End to an 80-year controversy
These findings from Wolfe et al. end an 80-year controversy over the effectiveness of thymectomy for patients with myasthenia gravis.
Perhaps the most important benefit for patients is that even when they require prednisone following the surgery, they can take lower doses, endure fewer glucocorticoid-related symptoms, and experience less distress from those symptoms than patients who don’t undergo thymectomy.
Unfortunately, the study results cannot offer further clarity regarding patient selection for thymectomy. The patient population in this trial was so small that subgroup analyses couldn’t allow conclusions regarding the relative effectiveness of thymectomy in men vs. women or younger vs. older patients.
Allan H. Ropper, MD, is in the department of neurology at Brigham and Women’s Hospital and Harvard Medical School, both in Boston. His financial disclosures are available at NEJM.org. Dr. Ropper made these remarks in an editorial accompanying Dr. Wolfe’s report (N Engl J Med. 2016 Aug 11. doi: 10.1056/NEJMe1607953).
Landmark trial establishes effectiveness of thymectomy in myasthenia gravis
One of the many challenges of treating patients with myasthenia gravis (MG) is the fluctuating nature of symptoms and deficits. The neurologist or neuromuscular specialist must decide whether the disease is truly worsening, whether the patient is experiencing more pronounced symptoms from intercurrent illness or the effects of a medication known to affect the neuromuscular junction adversely, or whether the patient is concerned that there might be worsening disease when all objective measures indicate stability. These factors make treatment decisions more difficult in MG than for many other neuromuscular disorders.
Similarly, researchers considering a trial investigating treatment efficacy in MG face the complex issues of disease fluctuation in cohorts of individuals with the disease, varying levels of corticosteroid and immunosuppressant doses in different MG patients, and thorny ethical dilemmas in providing accepted therapies but not withholding effective treatments from those in need.
Dr. Wolfe and his colleagues demonstrate that they have navigated these treacherous waters. They have succeeded in completing a landmark controlled clinical trial which establishes the effectiveness of transsternal thymectomy with adjuvant corticosteroid therapy in nonthymomatous MG vs. oral prednisone without surgery. While this international 36-center trial managed to recruit 126 subjects over a 6-year period, using sound inclusion and exclusion criteria and a meticulous trial design, the number of patients is not sufficient to allow for as robust a subgroup analysis for age, gender, and a variety of clinical variables reflecting severity of disease as would have been hoped for by the MG community.
Nonetheless, this paper sets the use of thymectomy in nonthymomatous MG on firmer ground going forward. The investigators will doubtless be presenting further data from the trial, including clinical-pathologic correlates and other relevant novel observations. In addition, Wolfe et al. have opened the door for future trials of thymectomy in MG to address such issues as the benefits vs. risks of performing the operation via the traditional transsternal vs. alternative non–sternal splitting approaches.
Benn E. Smith, MD, is an associate professor of neurology at the Mayo Clinic in Scottsdale, Ariz. and is the director of the sensory laboratory there. Dr. Smith is on the Editorial Advisory Board of Clinical Neurology News.
End to an 80-year controversy
These findings from Wolfe et al. end an 80-year controversy over the effectiveness of thymectomy for patients with myasthenia gravis.
Perhaps the most important benefit for patients is that even when they require prednisone following the surgery, they can take lower doses, endure fewer glucocorticoid-related symptoms, and experience less distress from those symptoms than patients who don’t undergo thymectomy.
Unfortunately, the study results cannot offer further clarity regarding patient selection for thymectomy. The patient population in this trial was so small that subgroup analyses couldn’t allow conclusions regarding the relative effectiveness of thymectomy in men vs. women or younger vs. older patients.
Allan H. Ropper, MD, is in the department of neurology at Brigham and Women’s Hospital and Harvard Medical School, both in Boston. His financial disclosures are available at NEJM.org. Dr. Ropper made these remarks in an editorial accompanying Dr. Wolfe’s report (N Engl J Med. 2016 Aug 11. doi: 10.1056/NEJMe1607953).
Thymectomy improved 3-year clinical outcomes and proved superior to medical therapy for mild to severe nonthymomatous myasthenia gravis, according to a report published online Aug. 11 in the New England Journal of Medicine.
Compared with standard prednisone therapy, thymectomy plus prednisone decreased the number and severity of symptoms, allowed the lowering of steroid doses, decreased the number and length of hospitalizations for disease exacerbations, reduced the need for immunosuppressive agents, and improved health-related quality of life in an international, randomized clinical trial, said Gil I. Wolfe, MD, of the department of neurology, State University of New York at Buffalo and his associates.
Until now, thymectomy was known to be beneficial in some cases of myasthenia gravis “but with widely varying rates of clinical improvement or remission.” And the success of immunotherapy has raised the question of whether an invasive surgery is necessary. Data from randomized, controlled studies have been sparse.
Moreover, thymectomy rarely causes adverse effects, but “the procedure can cost up to $80,000 and can be associated with operative complications that need to be weighed against benefits.” In comparison, medical therapy with glucocorticoids and other immunosuppressive agents is less invasive but is definitely associated with adverse events, including some that are life threatening, and negatively impacts quality of life, the investigators said.
To address the lack of randomized controlled trial data, they assessed 3-year outcomes in 126 patients treated at 67 medical centers in 18 countries during a 6-year period. The study participants were aged 18-65 years, had a disease duration of less than 5 years at enrollment (median duration, 1 year), and had class II (mild generalized disease) to class IV (severe generalized disease) myasthenia gravis. These patients were randomly assigned to undergo thymectomy and receive standard prednisone therapy (66 participants) or to receive standard prednisone alone (60 participants).
Thymectomy was performed using a median sternotomy “with the goal of an en bloc resection of all mediastinal tissue that could anatomically contain gross or microscopic thymus.”
At follow-up, time-weighted average scores on the Quantitative Myasthenia Gravis scale were significantly lower by 2.85 points, indicating improved clinical status, in the thymectomy group than in the control group. Time-weighted average prednisone dose also was significantly lower, at an average alternate-day dose of 44 mg in the thymectomy group and 60 mg in the control group, Dr. Wolfe and his associates said (N Engl J Med. 2016 Aug 11. doi: 10.1056/NEJMoa1602489).
On a measure of treatment-related complications, scores favored thymectomy with regard to the number of patients with symptoms, the total number of symptoms, and the distress level related to symptoms throughout the study period. Fewer patients in the thymectomy group required hospitalization for exacerbations of myasthenia gravis (9% vs. 37%), and the mean cumulative number of hospital days was lower with thymectomy (8.4 vs. 19.2).
In addition, scores on the Myasthenia Gravis Activities of Daily Living scale favored thymectomy (2.24 vs. 3.41). Fewer patients in the thymectomy group required azathioprine (17% vs. 0.48%). And the percentage of patients who reported having minimal manifestations of the disease at 3 years was significantly higher with thymectomy (67%) than with prednisone alone (47%).
This study was supported by the National Institute of Neurological Disorders and Stroke, the Muscular Dystrophy Association, and the Myasthenia Gravis Foundation of America and received no commercial support. Dr. Wolfe reported ties to Alexion Pharmaceuticals, Alpha Cancer Technologies, Argenx, Baxalta, CSL Behring, Grifols, and UCB, and his associates reported ties to numerous industry sources.
Thymectomy improved 3-year clinical outcomes and proved superior to medical therapy for mild to severe nonthymomatous myasthenia gravis, according to a report published online Aug. 11 in the New England Journal of Medicine.
Compared with standard prednisone therapy, thymectomy plus prednisone decreased the number and severity of symptoms, allowed the lowering of steroid doses, decreased the number and length of hospitalizations for disease exacerbations, reduced the need for immunosuppressive agents, and improved health-related quality of life in an international, randomized clinical trial, said Gil I. Wolfe, MD, of the department of neurology, State University of New York at Buffalo and his associates.
Until now, thymectomy was known to be beneficial in some cases of myasthenia gravis “but with widely varying rates of clinical improvement or remission.” And the success of immunotherapy has raised the question of whether an invasive surgery is necessary. Data from randomized, controlled studies have been sparse.
Moreover, thymectomy rarely causes adverse effects, but “the procedure can cost up to $80,000 and can be associated with operative complications that need to be weighed against benefits.” In comparison, medical therapy with glucocorticoids and other immunosuppressive agents is less invasive but is definitely associated with adverse events, including some that are life threatening, and negatively impacts quality of life, the investigators said.
To address the lack of randomized controlled trial data, they assessed 3-year outcomes in 126 patients treated at 67 medical centers in 18 countries during a 6-year period. The study participants were aged 18-65 years, had a disease duration of less than 5 years at enrollment (median duration, 1 year), and had class II (mild generalized disease) to class IV (severe generalized disease) myasthenia gravis. These patients were randomly assigned to undergo thymectomy and receive standard prednisone therapy (66 participants) or to receive standard prednisone alone (60 participants).
Thymectomy was performed using a median sternotomy “with the goal of an en bloc resection of all mediastinal tissue that could anatomically contain gross or microscopic thymus.”
At follow-up, time-weighted average scores on the Quantitative Myasthenia Gravis scale were significantly lower by 2.85 points, indicating improved clinical status, in the thymectomy group than in the control group. Time-weighted average prednisone dose also was significantly lower, at an average alternate-day dose of 44 mg in the thymectomy group and 60 mg in the control group, Dr. Wolfe and his associates said (N Engl J Med. 2016 Aug 11. doi: 10.1056/NEJMoa1602489).
On a measure of treatment-related complications, scores favored thymectomy with regard to the number of patients with symptoms, the total number of symptoms, and the distress level related to symptoms throughout the study period. Fewer patients in the thymectomy group required hospitalization for exacerbations of myasthenia gravis (9% vs. 37%), and the mean cumulative number of hospital days was lower with thymectomy (8.4 vs. 19.2).
In addition, scores on the Myasthenia Gravis Activities of Daily Living scale favored thymectomy (2.24 vs. 3.41). Fewer patients in the thymectomy group required azathioprine (17% vs. 0.48%). And the percentage of patients who reported having minimal manifestations of the disease at 3 years was significantly higher with thymectomy (67%) than with prednisone alone (47%).
This study was supported by the National Institute of Neurological Disorders and Stroke, the Muscular Dystrophy Association, and the Myasthenia Gravis Foundation of America and received no commercial support. Dr. Wolfe reported ties to Alexion Pharmaceuticals, Alpha Cancer Technologies, Argenx, Baxalta, CSL Behring, Grifols, and UCB, and his associates reported ties to numerous industry sources.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Thymectomy improved 3-year clinical outcomes and was superior to medical therapy for mild to severe nonthymomatous myasthenia gravis.
Major finding: Scores on the Quantitative Myasthenia Gravis scale were significantly lower by 2.85 points, indicating improved clinical status, in the thymectomy group than in the control group.
Data source: An international, randomized, medication-controlled trial involving 126 patients at 67 medical centers.
Disclosures: This study was supported by the National Institute of Neurological Disorders and Stroke, the Muscular Dystrophy Association, and the Myasthenia Gravis Foundation of America and received no commercial support. Dr. Wolfe reported ties to Alexion Pharmaceuticals, Alpha Cancer Technologies, Argenx, Baxalta, CSL Behring, Grifols, and UCB, and his associates reported ties to numerous industry sources.
Solid INRs on warfarin don’t predict future stability
Six months of stable international normalized ratio values [INRs] while on warfarin therapy doesn’t predict continued INR stability, according to a Research Letter to the Editor published August 9 in JAMA.
Whether or not to switch patients with atrial fibrillation from warfarin to non–vitamin K anticoagulants remains controversial. “A common belief has been that patients with stable INRs while taking warfarin would continue to be stable and derive less benefit from switching to non–vitamin K oral anticoagulants,” said Sean D. Pokorney, MD, of the division of cardiology, Duke University Medical Center, Durham, N.C., and his associates.
But the results of their observational study of 3,749 patients enrolled in an atrial fibrillation registry show that such stability cannot be predicted, and “challenge the notion that patients who have done well taking warfarin should maintain taking warfarin,” the investigators said (JAMA. 2016;316:661-3).
They assessed INRs over the course of 3 years of follow-up using data from patients enrolled in the registry through 176 clinics. INR stability was defined as having 80% or more of INRs in the therapeutic range (2-3). The mean patient age was 75 years, and 43% were women.
A total of 968 patients showed such INR stability throughout the first 6 months of the study. However, 36% of them went on to have at least one “well out of range” INR during the following year. Even in the subgroup of 376 patients who had 100% of their INRs within the therapeutic range during the first 6 months, 33% went on to have at least one “well out of range” INR during the following year, according to Dr. Pokorney and his associates.
No sponsor was cited for this study. Dr. Pokorney reported ties to AstraZeneca, Boston Scientific, Gilead, Janssen, and Medtronic; his associates reported ties to numerous industry sources.
Six months of stable international normalized ratio values [INRs] while on warfarin therapy doesn’t predict continued INR stability, according to a Research Letter to the Editor published August 9 in JAMA.
Whether or not to switch patients with atrial fibrillation from warfarin to non–vitamin K anticoagulants remains controversial. “A common belief has been that patients with stable INRs while taking warfarin would continue to be stable and derive less benefit from switching to non–vitamin K oral anticoagulants,” said Sean D. Pokorney, MD, of the division of cardiology, Duke University Medical Center, Durham, N.C., and his associates.
But the results of their observational study of 3,749 patients enrolled in an atrial fibrillation registry show that such stability cannot be predicted, and “challenge the notion that patients who have done well taking warfarin should maintain taking warfarin,” the investigators said (JAMA. 2016;316:661-3).
They assessed INRs over the course of 3 years of follow-up using data from patients enrolled in the registry through 176 clinics. INR stability was defined as having 80% or more of INRs in the therapeutic range (2-3). The mean patient age was 75 years, and 43% were women.
A total of 968 patients showed such INR stability throughout the first 6 months of the study. However, 36% of them went on to have at least one “well out of range” INR during the following year. Even in the subgroup of 376 patients who had 100% of their INRs within the therapeutic range during the first 6 months, 33% went on to have at least one “well out of range” INR during the following year, according to Dr. Pokorney and his associates.
No sponsor was cited for this study. Dr. Pokorney reported ties to AstraZeneca, Boston Scientific, Gilead, Janssen, and Medtronic; his associates reported ties to numerous industry sources.
Six months of stable international normalized ratio values [INRs] while on warfarin therapy doesn’t predict continued INR stability, according to a Research Letter to the Editor published August 9 in JAMA.
Whether or not to switch patients with atrial fibrillation from warfarin to non–vitamin K anticoagulants remains controversial. “A common belief has been that patients with stable INRs while taking warfarin would continue to be stable and derive less benefit from switching to non–vitamin K oral anticoagulants,” said Sean D. Pokorney, MD, of the division of cardiology, Duke University Medical Center, Durham, N.C., and his associates.
But the results of their observational study of 3,749 patients enrolled in an atrial fibrillation registry show that such stability cannot be predicted, and “challenge the notion that patients who have done well taking warfarin should maintain taking warfarin,” the investigators said (JAMA. 2016;316:661-3).
They assessed INRs over the course of 3 years of follow-up using data from patients enrolled in the registry through 176 clinics. INR stability was defined as having 80% or more of INRs in the therapeutic range (2-3). The mean patient age was 75 years, and 43% were women.
A total of 968 patients showed such INR stability throughout the first 6 months of the study. However, 36% of them went on to have at least one “well out of range” INR during the following year. Even in the subgroup of 376 patients who had 100% of their INRs within the therapeutic range during the first 6 months, 33% went on to have at least one “well out of range” INR during the following year, according to Dr. Pokorney and his associates.
No sponsor was cited for this study. Dr. Pokorney reported ties to AstraZeneca, Boston Scientific, Gilead, Janssen, and Medtronic; his associates reported ties to numerous industry sources.
FROM JAMA
Key clinical point: Six months of stable INRs while on warfarin doesn’t predict continued INR stability.
Major finding: Of the 968 patients who showed INR stability throughout the first 6 months of the study, 36% went on to have at least one “well out of range” INR during the following year.
Data source: An observational cohort study involving 3,749 patients with atrial fibrillation who were followed for 3 years.
Disclosures: No sponsor was cited for this study. Dr. Pokorney reported ties to AstraZeneca, Boston Scientific, Gilead, Janssen, and Medtronic; his associates reported ties to numerous industry sources.
Lipid Screening in Young Adults Still Unsettled
The value of screening young adults for dyslipidemia remains unknown because there is still no direct evidence regarding the benefits and harms in this patient population, according to an update of the 2008 U.S. Preventive Services Task Force recommendations on lipid screening, which was published online August 8 in Annals of Internal Medicine.
In 2008, the USPSTF also could find no direct evidence regarding asymptomatic men and women aged 21-39 years, and thus could make no recommendation for or against lipid screening “because of the low likelihood of identifying lipid levels high enough to justify treatment.” Now the organization has undertaken an extensive review of all English-language articles released since then, searching the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, Medline, reference lists, and ClinicalTrials.gov, said Roger Chou, MD, lead author of the update and director of the Pacific Northwest Evidence-Based Practice Center, Oregon Health & Science University, Portland, and his associates.
They were unable to find any randomized trials, cohort studies, or case-control studies comparing lipid screening against no lipid screening, dyslipidemia treatment against no treatment, or immediate against delayed treatment that assessed mortality, cardiovascular outcomes, or harms in this age group.
Some health organizations recommend starting dyslipidemia screening in asymptomatic adults at age 20, while others don’t recommend the practice until age 35-40 for men and age 50 for women. The 2014 American College of Cardiology/American Heart Association guideline on assessing CV risk deems it “reasonable” to assess traditional risk factors including lipids beginning at age 20, Dr. Chou and his associates said (Ann Intern Med. 2016 Aug 8. doi: 10.7326/M16-0946).
However, the potential adverse effects of statin therapy that is initiated in young adulthood and continued for decades haven’t been well studied, they noted.
In addition, some experts advocate lipid screening to identify young adults who have familial hypercholesterolemia. But this condition has such a low prevalence (estimated at only 1 in 500 people), and affected patients have such a low rate of coronary heat disease events before age 40 (approximately 10%) that the potential benefits of screening for this reason are very limited, the investigators added.
This study was supported by the Agency for Healthcare Research and Quality.
The value of screening young adults for dyslipidemia remains unknown because there is still no direct evidence regarding the benefits and harms in this patient population, according to an update of the 2008 U.S. Preventive Services Task Force recommendations on lipid screening, which was published online August 8 in Annals of Internal Medicine.
In 2008, the USPSTF also could find no direct evidence regarding asymptomatic men and women aged 21-39 years, and thus could make no recommendation for or against lipid screening “because of the low likelihood of identifying lipid levels high enough to justify treatment.” Now the organization has undertaken an extensive review of all English-language articles released since then, searching the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, Medline, reference lists, and ClinicalTrials.gov, said Roger Chou, MD, lead author of the update and director of the Pacific Northwest Evidence-Based Practice Center, Oregon Health & Science University, Portland, and his associates.
They were unable to find any randomized trials, cohort studies, or case-control studies comparing lipid screening against no lipid screening, dyslipidemia treatment against no treatment, or immediate against delayed treatment that assessed mortality, cardiovascular outcomes, or harms in this age group.
Some health organizations recommend starting dyslipidemia screening in asymptomatic adults at age 20, while others don’t recommend the practice until age 35-40 for men and age 50 for women. The 2014 American College of Cardiology/American Heart Association guideline on assessing CV risk deems it “reasonable” to assess traditional risk factors including lipids beginning at age 20, Dr. Chou and his associates said (Ann Intern Med. 2016 Aug 8. doi: 10.7326/M16-0946).
However, the potential adverse effects of statin therapy that is initiated in young adulthood and continued for decades haven’t been well studied, they noted.
In addition, some experts advocate lipid screening to identify young adults who have familial hypercholesterolemia. But this condition has such a low prevalence (estimated at only 1 in 500 people), and affected patients have such a low rate of coronary heat disease events before age 40 (approximately 10%) that the potential benefits of screening for this reason are very limited, the investigators added.
This study was supported by the Agency for Healthcare Research and Quality.
The value of screening young adults for dyslipidemia remains unknown because there is still no direct evidence regarding the benefits and harms in this patient population, according to an update of the 2008 U.S. Preventive Services Task Force recommendations on lipid screening, which was published online August 8 in Annals of Internal Medicine.
In 2008, the USPSTF also could find no direct evidence regarding asymptomatic men and women aged 21-39 years, and thus could make no recommendation for or against lipid screening “because of the low likelihood of identifying lipid levels high enough to justify treatment.” Now the organization has undertaken an extensive review of all English-language articles released since then, searching the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, Medline, reference lists, and ClinicalTrials.gov, said Roger Chou, MD, lead author of the update and director of the Pacific Northwest Evidence-Based Practice Center, Oregon Health & Science University, Portland, and his associates.
They were unable to find any randomized trials, cohort studies, or case-control studies comparing lipid screening against no lipid screening, dyslipidemia treatment against no treatment, or immediate against delayed treatment that assessed mortality, cardiovascular outcomes, or harms in this age group.
Some health organizations recommend starting dyslipidemia screening in asymptomatic adults at age 20, while others don’t recommend the practice until age 35-40 for men and age 50 for women. The 2014 American College of Cardiology/American Heart Association guideline on assessing CV risk deems it “reasonable” to assess traditional risk factors including lipids beginning at age 20, Dr. Chou and his associates said (Ann Intern Med. 2016 Aug 8. doi: 10.7326/M16-0946).
However, the potential adverse effects of statin therapy that is initiated in young adulthood and continued for decades haven’t been well studied, they noted.
In addition, some experts advocate lipid screening to identify young adults who have familial hypercholesterolemia. But this condition has such a low prevalence (estimated at only 1 in 500 people), and affected patients have such a low rate of coronary heat disease events before age 40 (approximately 10%) that the potential benefits of screening for this reason are very limited, the investigators added.
This study was supported by the Agency for Healthcare Research and Quality.
FROM ANNALS OF INTERNAL MEDICINE
Lipid screening in young adults still unsettled
The value of screening young adults for dyslipidemia remains unknown because there is still no direct evidence regarding the benefits and harms in this patient population, according to an update of the 2008 U.S. Preventive Services Task Force recommendations on lipid screening, which was published online August 8 in Annals of Internal Medicine.
In 2008, the USPSTF also could find no direct evidence regarding asymptomatic men and women aged 21-39 years, and thus could make no recommendation for or against lipid screening “because of the low likelihood of identifying lipid levels high enough to justify treatment.” Now the organization has undertaken an extensive review of all English-language articles released since then, searching the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, Medline, reference lists, and ClinicalTrials.gov, said Roger Chou, MD, lead author of the update and director of the Pacific Northwest Evidence-Based Practice Center, Oregon Health & Science University, Portland, and his associates.
They were unable to find any randomized trials, cohort studies, or case-control studies comparing lipid screening against no lipid screening, dyslipidemia treatment against no treatment, or immediate against delayed treatment that assessed mortality, cardiovascular outcomes, or harms in this age group.
Some health organizations recommend starting dyslipidemia screening in asymptomatic adults at age 20, while others don’t recommend the practice until age 35-40 for men and age 50 for women. The 2014 American College of Cardiology/American Heart Association guideline on assessing CV risk deems it “reasonable” to assess traditional risk factors including lipids beginning at age 20, Dr. Chou and his associates said (Ann Intern Med. 2016 Aug 8. doi: 10.7326/M16-0946).
However, the potential adverse effects of statin therapy that is initiated in young adulthood and continued for decades haven’t been well studied, they noted.
In addition, some experts advocate lipid screening to identify young adults who have familial hypercholesterolemia. But this condition has such a low prevalence (estimated at only 1 in 500 people), and affected patients have such a low rate of coronary heat disease events before age 40 (approximately 10%) that the potential benefits of screening for this reason are very limited, the investigators added.
This study was supported by the Agency for Healthcare Research and Quality.
The value of screening young adults for dyslipidemia remains unknown because there is still no direct evidence regarding the benefits and harms in this patient population, according to an update of the 2008 U.S. Preventive Services Task Force recommendations on lipid screening, which was published online August 8 in Annals of Internal Medicine.
In 2008, the USPSTF also could find no direct evidence regarding asymptomatic men and women aged 21-39 years, and thus could make no recommendation for or against lipid screening “because of the low likelihood of identifying lipid levels high enough to justify treatment.” Now the organization has undertaken an extensive review of all English-language articles released since then, searching the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, Medline, reference lists, and ClinicalTrials.gov, said Roger Chou, MD, lead author of the update and director of the Pacific Northwest Evidence-Based Practice Center, Oregon Health & Science University, Portland, and his associates.
They were unable to find any randomized trials, cohort studies, or case-control studies comparing lipid screening against no lipid screening, dyslipidemia treatment against no treatment, or immediate against delayed treatment that assessed mortality, cardiovascular outcomes, or harms in this age group.
Some health organizations recommend starting dyslipidemia screening in asymptomatic adults at age 20, while others don’t recommend the practice until age 35-40 for men and age 50 for women. The 2014 American College of Cardiology/American Heart Association guideline on assessing CV risk deems it “reasonable” to assess traditional risk factors including lipids beginning at age 20, Dr. Chou and his associates said (Ann Intern Med. 2016 Aug 8. doi: 10.7326/M16-0946).
However, the potential adverse effects of statin therapy that is initiated in young adulthood and continued for decades haven’t been well studied, they noted.
In addition, some experts advocate lipid screening to identify young adults who have familial hypercholesterolemia. But this condition has such a low prevalence (estimated at only 1 in 500 people), and affected patients have such a low rate of coronary heat disease events before age 40 (approximately 10%) that the potential benefits of screening for this reason are very limited, the investigators added.
This study was supported by the Agency for Healthcare Research and Quality.
The value of screening young adults for dyslipidemia remains unknown because there is still no direct evidence regarding the benefits and harms in this patient population, according to an update of the 2008 U.S. Preventive Services Task Force recommendations on lipid screening, which was published online August 8 in Annals of Internal Medicine.
In 2008, the USPSTF also could find no direct evidence regarding asymptomatic men and women aged 21-39 years, and thus could make no recommendation for or against lipid screening “because of the low likelihood of identifying lipid levels high enough to justify treatment.” Now the organization has undertaken an extensive review of all English-language articles released since then, searching the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, Medline, reference lists, and ClinicalTrials.gov, said Roger Chou, MD, lead author of the update and director of the Pacific Northwest Evidence-Based Practice Center, Oregon Health & Science University, Portland, and his associates.
They were unable to find any randomized trials, cohort studies, or case-control studies comparing lipid screening against no lipid screening, dyslipidemia treatment against no treatment, or immediate against delayed treatment that assessed mortality, cardiovascular outcomes, or harms in this age group.
Some health organizations recommend starting dyslipidemia screening in asymptomatic adults at age 20, while others don’t recommend the practice until age 35-40 for men and age 50 for women. The 2014 American College of Cardiology/American Heart Association guideline on assessing CV risk deems it “reasonable” to assess traditional risk factors including lipids beginning at age 20, Dr. Chou and his associates said (Ann Intern Med. 2016 Aug 8. doi: 10.7326/M16-0946).
However, the potential adverse effects of statin therapy that is initiated in young adulthood and continued for decades haven’t been well studied, they noted.
In addition, some experts advocate lipid screening to identify young adults who have familial hypercholesterolemia. But this condition has such a low prevalence (estimated at only 1 in 500 people), and affected patients have such a low rate of coronary heat disease events before age 40 (approximately 10%) that the potential benefits of screening for this reason are very limited, the investigators added.
This study was supported by the Agency for Healthcare Research and Quality.
FROM ANNALS OF INTERNAL MEDICINE
Elbasvir-grazoprevir works effectively against HCV despite current drug use
A 12-week course of elbasvir plus grazoprevir proved effective against hepatitis C virus in 301 patients who were receiving opioid agonist therapy for injectable drug addiction, according to a report published online August 8 in Annals of Internal Medicine.
This patient population showed excellent treatment adherence and achieved sustained virologic response (SVR) rates of approximately 90%, even though most participants continued to use injectable drugs during the study. These findings demonstrate that current drug users can achieve HCV treatment outcomes that are comparable to those in the general HCV population, and “suggest that access to interferon-free direct-acting antiviral therapy should be expanded to patients receiving opioid agonist therapy, including the removal of drug use-based restrictions,” said Gregory J. Dore, MD, of the Kirby Institute, University of New South Wales, Sydney, and his associates.
They assessed elbasvir-grazoprevir (Zepatier) treatment in patients with untreated chronic HCV who were aged 18 and older and had been receiving opioid agonist therapy with methadone, buprenorphine, or buprenorphine-naloxone for at least 3 months at facilities in 13 countries. The study participants were randomly assigned in double-blind fashion to receive either immediate active treatment for 12 weeks (201 patients) or matching placebo for 12 weeks followed by 4 weeks of follow-up followed by deferred open-label active treatment for 12 weeks (100 control subjects).
All patients were followed for 6 months after they completed active treatment. All underwent frequent urine testing for illegal drugs, and more than half of both study groups tested positive for at least one drug during active treatment and follow-up. Illegal drug use was stable throughout the study period and did not affect either treatment adherence or efficacy. Nearly every participant showed excellent adherence (over 95%) to elbasvir-grazoprevir.
The primary efficacy endpoint, the SVR rate immediately after active treatment, was 91.5% in the immediate-treatment group and 89.5% in the deferred-treatment group. Both rates are substantially higher than the historical reference SVR rate of 67%, Dr. Dore and his associates noted (Ann Intern Med. 2016 Aug 8. doi: 10.7326/M16-0816).
Elbasvir-grazoprevir was equally effective against the GT1a, GT1b, and GT4 strains of HCV, but was less effective against the GT6 strain, which occurs primarily in China and Southeast Asia. It also was effective across important subgroups of patients, including those who had cirrhosis and those who carried HCV variants associated with drug resistance.
Regarding treatment safety, the rate of serious adverse events was low in both study groups (3.5% and 4.0%, respectively), and only one event in each group was deemed to be related to elbasvir-grazoprevir.
The incidence of reinfection for the 24-week period after successful treatment was 4.6 per 100 person-years, and it often was attributed to continuing use of contaminated needles or sexual contact with an infected partner. The effect of reinfection is “of considerable clinical and public health interest,” and will be further examined during a 3-year extension of the follow-up of this study, the investigators said.
“Of interest, 3 of the 6 patients categorized as having HCV reinfection subsequently had undetectable HCV-RNA levels without additional HCV treatment, indicating that not all reinfection cases develop viral persistence,” they added.
This study was funded primarily by Merck, which markets Zepatier. Dr. Dore reported ties to AbbVie, Merck, Bristol-Myers Squibb, Janssen, Roche, Gilead, GlaxoSmithKline, and Abbott, and his associates reported ties to numerous industry sources.
A 12-week course of elbasvir plus grazoprevir proved effective against hepatitis C virus in 301 patients who were receiving opioid agonist therapy for injectable drug addiction, according to a report published online August 8 in Annals of Internal Medicine.
This patient population showed excellent treatment adherence and achieved sustained virologic response (SVR) rates of approximately 90%, even though most participants continued to use injectable drugs during the study. These findings demonstrate that current drug users can achieve HCV treatment outcomes that are comparable to those in the general HCV population, and “suggest that access to interferon-free direct-acting antiviral therapy should be expanded to patients receiving opioid agonist therapy, including the removal of drug use-based restrictions,” said Gregory J. Dore, MD, of the Kirby Institute, University of New South Wales, Sydney, and his associates.
They assessed elbasvir-grazoprevir (Zepatier) treatment in patients with untreated chronic HCV who were aged 18 and older and had been receiving opioid agonist therapy with methadone, buprenorphine, or buprenorphine-naloxone for at least 3 months at facilities in 13 countries. The study participants were randomly assigned in double-blind fashion to receive either immediate active treatment for 12 weeks (201 patients) or matching placebo for 12 weeks followed by 4 weeks of follow-up followed by deferred open-label active treatment for 12 weeks (100 control subjects).
All patients were followed for 6 months after they completed active treatment. All underwent frequent urine testing for illegal drugs, and more than half of both study groups tested positive for at least one drug during active treatment and follow-up. Illegal drug use was stable throughout the study period and did not affect either treatment adherence or efficacy. Nearly every participant showed excellent adherence (over 95%) to elbasvir-grazoprevir.
The primary efficacy endpoint, the SVR rate immediately after active treatment, was 91.5% in the immediate-treatment group and 89.5% in the deferred-treatment group. Both rates are substantially higher than the historical reference SVR rate of 67%, Dr. Dore and his associates noted (Ann Intern Med. 2016 Aug 8. doi: 10.7326/M16-0816).
Elbasvir-grazoprevir was equally effective against the GT1a, GT1b, and GT4 strains of HCV, but was less effective against the GT6 strain, which occurs primarily in China and Southeast Asia. It also was effective across important subgroups of patients, including those who had cirrhosis and those who carried HCV variants associated with drug resistance.
Regarding treatment safety, the rate of serious adverse events was low in both study groups (3.5% and 4.0%, respectively), and only one event in each group was deemed to be related to elbasvir-grazoprevir.
The incidence of reinfection for the 24-week period after successful treatment was 4.6 per 100 person-years, and it often was attributed to continuing use of contaminated needles or sexual contact with an infected partner. The effect of reinfection is “of considerable clinical and public health interest,” and will be further examined during a 3-year extension of the follow-up of this study, the investigators said.
“Of interest, 3 of the 6 patients categorized as having HCV reinfection subsequently had undetectable HCV-RNA levels without additional HCV treatment, indicating that not all reinfection cases develop viral persistence,” they added.
This study was funded primarily by Merck, which markets Zepatier. Dr. Dore reported ties to AbbVie, Merck, Bristol-Myers Squibb, Janssen, Roche, Gilead, GlaxoSmithKline, and Abbott, and his associates reported ties to numerous industry sources.
A 12-week course of elbasvir plus grazoprevir proved effective against hepatitis C virus in 301 patients who were receiving opioid agonist therapy for injectable drug addiction, according to a report published online August 8 in Annals of Internal Medicine.
This patient population showed excellent treatment adherence and achieved sustained virologic response (SVR) rates of approximately 90%, even though most participants continued to use injectable drugs during the study. These findings demonstrate that current drug users can achieve HCV treatment outcomes that are comparable to those in the general HCV population, and “suggest that access to interferon-free direct-acting antiviral therapy should be expanded to patients receiving opioid agonist therapy, including the removal of drug use-based restrictions,” said Gregory J. Dore, MD, of the Kirby Institute, University of New South Wales, Sydney, and his associates.
They assessed elbasvir-grazoprevir (Zepatier) treatment in patients with untreated chronic HCV who were aged 18 and older and had been receiving opioid agonist therapy with methadone, buprenorphine, or buprenorphine-naloxone for at least 3 months at facilities in 13 countries. The study participants were randomly assigned in double-blind fashion to receive either immediate active treatment for 12 weeks (201 patients) or matching placebo for 12 weeks followed by 4 weeks of follow-up followed by deferred open-label active treatment for 12 weeks (100 control subjects).
All patients were followed for 6 months after they completed active treatment. All underwent frequent urine testing for illegal drugs, and more than half of both study groups tested positive for at least one drug during active treatment and follow-up. Illegal drug use was stable throughout the study period and did not affect either treatment adherence or efficacy. Nearly every participant showed excellent adherence (over 95%) to elbasvir-grazoprevir.
The primary efficacy endpoint, the SVR rate immediately after active treatment, was 91.5% in the immediate-treatment group and 89.5% in the deferred-treatment group. Both rates are substantially higher than the historical reference SVR rate of 67%, Dr. Dore and his associates noted (Ann Intern Med. 2016 Aug 8. doi: 10.7326/M16-0816).
Elbasvir-grazoprevir was equally effective against the GT1a, GT1b, and GT4 strains of HCV, but was less effective against the GT6 strain, which occurs primarily in China and Southeast Asia. It also was effective across important subgroups of patients, including those who had cirrhosis and those who carried HCV variants associated with drug resistance.
Regarding treatment safety, the rate of serious adverse events was low in both study groups (3.5% and 4.0%, respectively), and only one event in each group was deemed to be related to elbasvir-grazoprevir.
The incidence of reinfection for the 24-week period after successful treatment was 4.6 per 100 person-years, and it often was attributed to continuing use of contaminated needles or sexual contact with an infected partner. The effect of reinfection is “of considerable clinical and public health interest,” and will be further examined during a 3-year extension of the follow-up of this study, the investigators said.
“Of interest, 3 of the 6 patients categorized as having HCV reinfection subsequently had undetectable HCV-RNA levels without additional HCV treatment, indicating that not all reinfection cases develop viral persistence,” they added.
This study was funded primarily by Merck, which markets Zepatier. Dr. Dore reported ties to AbbVie, Merck, Bristol-Myers Squibb, Janssen, Roche, Gilead, GlaxoSmithKline, and Abbott, and his associates reported ties to numerous industry sources.
FROM ANNALS OF INTERNAL MEDICINE
Key clinical point: A 12-week course of elbasvir plus grazoprevir was effective against HCV in patients receiving opioid agonist therapy for injectable drug addiction.
Major finding: The primary efficacy endpoint, the SVR rate after active treatment, was 91.5% with immediate treatment and 89.5% with deferred treatment.
Data source: An international, randomized, placebo-controlled, double-blind trial involving 301 patients followed for 6 months.
Disclosures: This study was funded primarily by Merck, which markets Zepatier. Dr. Dore reported ties to AbbVie, Merck, Bristol-Myers Squibb, Janssen, Roche, Gilead, GlaxoSmithKline, and Abbott, and his associates reported ties to numerous industry sources.
