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Adding entacapone to intestinal gel could lower levodopa effective dose
The addition of the catechol-O-methyltransferase inhibitor entacapone to levodopa-carbidopa intestinal gel provided adequate levodopa exposure at a lower dose than with levodopa-carbidopa intestinal gel alone in a small, open-label randomized, crossover study of patients with advanced Parkinson’s disease.
Over 2 consecutive days, Marina Senek and her associates randomized 11 patients who were on stable levodopa-carbidopa intestinal gel (LCIG; Duodopa) therapy to receive 14-hour infusions of new LCIG formulation with entacapone (LECIG) followed by LCIG alone the next day or vice versa. Five patients received LECIG morning doses that corresponded to 80% of their individual morning dose of LCIG and six received 90% of their individual morning dose. They received maintenance doses that were equal to 80% of the LCIG maintenance dose and extra doses that were equal to 80% of extra LCIG doses.
Dose-adjusted levodopa exposure was significantly higher during LECIG treatment, with 9 of 11 patients exceeding the 20% increase in levodopa exposure targeted. Systemic levodopa exposure did not differ significantly between treatment types.
Sixteen adverse events were reported: 6 by two patients during LCIG treatment, and 10 by five patients during LECIG treatment. Headache was the most common adverse event, experienced by one patient in the LCIG group and by three in the LECIG group. Other adverse events related to treatment were nausea, diarrhea, and dizziness. No serious adverse events were reported.
By blocking the second-largest metabolic pathway for levodopa, the administration of entacapone leads to less levodopa conversion to 3-O-methyldopa and thereby increases the levodopa plasma concentration, the investigators said.
“Because of the short treatment time, conclusions have to be drawn with caution, and long-term comparative efficacy studies are needed to confirm the results and investigate the possible long-term side effects with the addition of entacapone,” the investigators noted.
Read the full study in Movement Disorders (doi: 10.1002/mds.26855).
The addition of the catechol-O-methyltransferase inhibitor entacapone to levodopa-carbidopa intestinal gel provided adequate levodopa exposure at a lower dose than with levodopa-carbidopa intestinal gel alone in a small, open-label randomized, crossover study of patients with advanced Parkinson’s disease.
Over 2 consecutive days, Marina Senek and her associates randomized 11 patients who were on stable levodopa-carbidopa intestinal gel (LCIG; Duodopa) therapy to receive 14-hour infusions of new LCIG formulation with entacapone (LECIG) followed by LCIG alone the next day or vice versa. Five patients received LECIG morning doses that corresponded to 80% of their individual morning dose of LCIG and six received 90% of their individual morning dose. They received maintenance doses that were equal to 80% of the LCIG maintenance dose and extra doses that were equal to 80% of extra LCIG doses.
Dose-adjusted levodopa exposure was significantly higher during LECIG treatment, with 9 of 11 patients exceeding the 20% increase in levodopa exposure targeted. Systemic levodopa exposure did not differ significantly between treatment types.
Sixteen adverse events were reported: 6 by two patients during LCIG treatment, and 10 by five patients during LECIG treatment. Headache was the most common adverse event, experienced by one patient in the LCIG group and by three in the LECIG group. Other adverse events related to treatment were nausea, diarrhea, and dizziness. No serious adverse events were reported.
By blocking the second-largest metabolic pathway for levodopa, the administration of entacapone leads to less levodopa conversion to 3-O-methyldopa and thereby increases the levodopa plasma concentration, the investigators said.
“Because of the short treatment time, conclusions have to be drawn with caution, and long-term comparative efficacy studies are needed to confirm the results and investigate the possible long-term side effects with the addition of entacapone,” the investigators noted.
Read the full study in Movement Disorders (doi: 10.1002/mds.26855).
The addition of the catechol-O-methyltransferase inhibitor entacapone to levodopa-carbidopa intestinal gel provided adequate levodopa exposure at a lower dose than with levodopa-carbidopa intestinal gel alone in a small, open-label randomized, crossover study of patients with advanced Parkinson’s disease.
Over 2 consecutive days, Marina Senek and her associates randomized 11 patients who were on stable levodopa-carbidopa intestinal gel (LCIG; Duodopa) therapy to receive 14-hour infusions of new LCIG formulation with entacapone (LECIG) followed by LCIG alone the next day or vice versa. Five patients received LECIG morning doses that corresponded to 80% of their individual morning dose of LCIG and six received 90% of their individual morning dose. They received maintenance doses that were equal to 80% of the LCIG maintenance dose and extra doses that were equal to 80% of extra LCIG doses.
Dose-adjusted levodopa exposure was significantly higher during LECIG treatment, with 9 of 11 patients exceeding the 20% increase in levodopa exposure targeted. Systemic levodopa exposure did not differ significantly between treatment types.
Sixteen adverse events were reported: 6 by two patients during LCIG treatment, and 10 by five patients during LECIG treatment. Headache was the most common adverse event, experienced by one patient in the LCIG group and by three in the LECIG group. Other adverse events related to treatment were nausea, diarrhea, and dizziness. No serious adverse events were reported.
By blocking the second-largest metabolic pathway for levodopa, the administration of entacapone leads to less levodopa conversion to 3-O-methyldopa and thereby increases the levodopa plasma concentration, the investigators said.
“Because of the short treatment time, conclusions have to be drawn with caution, and long-term comparative efficacy studies are needed to confirm the results and investigate the possible long-term side effects with the addition of entacapone,” the investigators noted.
Read the full study in Movement Disorders (doi: 10.1002/mds.26855).
FROM MOVEMENT DISORDERS
Early procalcitonin testing reduced ICU costs for sepsis patients
Procalcitonin (PCT) testing on the first day of ICU admission for adult patients with sepsis is associated with reduced length of stay, less antibiotic exposure, and reduced hospital and pharmacy costs, Robert A. Balk, MD, and his associates reported.
The researchers analyzed data on more than 15 million patients in the Premier Research Database; of those, more than 730,000 had a potential diagnosis of sepsis, systemic inflammatory response syndrome (SIRS), septicemia, or a shock-related diagnosis on ICU admission or discharge (CHEST. 2017;151[1]:23-33).
After propensity matching to reduce potential bias, a total of 33,569 patients who had received PCT testing on ICU day 1 were identified; a control group of 98,543 non-PCT tested patients were identified as well. Hospital costs were $2,759 lower for PCT-tested patients ($30,454 vs. $33,213), ICU costs were $1,310 lower ($20,155 vs. $21,465), and pharmacy costs were $331 lower ($4,238 vs. $4,568). PCT-tested patients also were more commonly discharged to home (44.1% vs. 41.3%).
The PCT-tested patients had less total antibiotic exposure, (16.2 days vs. 16.9 days) but higher laboratory costs, according to Dr. Balk, director of the division of pulmonary and critical care medicine at Rush Medical College, Chicago, and his colleagues. Laboratory costs of the PCT-tested patients were $81 greater ($1,807 vs. $1,726).
While PCT testing is cleared by the Food and Drug Administration to assist in identifying patients who are highly likely to develop sepsis, there is no approved sepsis test, Dr. Balk and his colleagues noted.
“This study is important in the validation of the ability of PCT testing to favorably impact the outcome of critically ill patients when used according to the FDA cleared guidelines,” the investigators said. “The cost savings were real and consequential, exceeding the potential increased costs of laboratory testing associated with PCT testing on ICU admission.”
All-patient analysis showed a statistically significant, but slightly increased (0.7%) risk of mortality in PCT-tested patients; however, the finding was not seen in an enhanced risk-adjusted analysis of 96% of patients, the investigators pointed out. This finding is consistent with other large prospective studies showing no difference in mortality or other clinical outcomes using PCT guidances.
PCT testing has not been uniformly adopted despite its inclusion in the 2012 Surviving Sepsis Guidelines, in part, due to cost. The lack of a “gold standard” sepsis test has resulted in diagnostic dilemmas, delayed treatment, and poor outcomes, Dr. Balk and colleagues noted.
Because patients were not randomized to PCT testing or non-PCT testing groups, additional variables could have over- or underestimated the effect of PCT on patient outcomes, the researchers added.
Dr. Balk has received advisory board fees from bioMerieux USA, Roche Diagnostics, and ThermoFisher Scientific; Zhun Cao, PhD, Craig Lipkin, MS, and Scott B. Robinson MA, MPH, are employees of Premier Research Services, in Charlotte. Samuel Bozzette is an employee of bioMerieux, which provided funding for the study.
The significant findings of Balk et al. suggest that “real world” evidence may support procalcitonin as an effective tool to improve antibiotic management and reduce costs of health care for critically ill patients. Data from public databases and patient registries can play key roles in evaluating biomarkers, since physicians preparing randomized trials may behave differently than in typical care settings.
Results of the recent randomized [Simplified Acute Physiology Score] trial in connection with real-life data reported by Dr. Balk and colleagues are convincing and should lead physicians to more widespread use of PCT protocols for management of patients in the critical care settings.
The study findings also add the U.S. experience to the knowledge base as most of the interventional research has been done in Europe and Asia.
Given the promising results from the randomized trials, it is important to know how PCT impacts the clinical management of patients in real-world settings. Such information can be used to further broaden and expand the findings from the randomized trials to usual care.
Philipp Schuetz, MD, MPH, of the University of Basel, Switzerland, receives research support from Thermo Fisher and bioMerieux, which make PCT tests. Peter M. Wahl, ScD, is a full-time employee of Covance Inc., of Princeton, N.J., which makes diagnostic tests and owns clinical laboratories. Their comments were made in an editorial accompanying Dr. Balk’s report (Chest. 2017;151[1]:6-8. doi:10.1016/j.chest.2016.07.014).
The significant findings of Balk et al. suggest that “real world” evidence may support procalcitonin as an effective tool to improve antibiotic management and reduce costs of health care for critically ill patients. Data from public databases and patient registries can play key roles in evaluating biomarkers, since physicians preparing randomized trials may behave differently than in typical care settings.
Results of the recent randomized [Simplified Acute Physiology Score] trial in connection with real-life data reported by Dr. Balk and colleagues are convincing and should lead physicians to more widespread use of PCT protocols for management of patients in the critical care settings.
The study findings also add the U.S. experience to the knowledge base as most of the interventional research has been done in Europe and Asia.
Given the promising results from the randomized trials, it is important to know how PCT impacts the clinical management of patients in real-world settings. Such information can be used to further broaden and expand the findings from the randomized trials to usual care.
Philipp Schuetz, MD, MPH, of the University of Basel, Switzerland, receives research support from Thermo Fisher and bioMerieux, which make PCT tests. Peter M. Wahl, ScD, is a full-time employee of Covance Inc., of Princeton, N.J., which makes diagnostic tests and owns clinical laboratories. Their comments were made in an editorial accompanying Dr. Balk’s report (Chest. 2017;151[1]:6-8. doi:10.1016/j.chest.2016.07.014).
The significant findings of Balk et al. suggest that “real world” evidence may support procalcitonin as an effective tool to improve antibiotic management and reduce costs of health care for critically ill patients. Data from public databases and patient registries can play key roles in evaluating biomarkers, since physicians preparing randomized trials may behave differently than in typical care settings.
Results of the recent randomized [Simplified Acute Physiology Score] trial in connection with real-life data reported by Dr. Balk and colleagues are convincing and should lead physicians to more widespread use of PCT protocols for management of patients in the critical care settings.
The study findings also add the U.S. experience to the knowledge base as most of the interventional research has been done in Europe and Asia.
Given the promising results from the randomized trials, it is important to know how PCT impacts the clinical management of patients in real-world settings. Such information can be used to further broaden and expand the findings from the randomized trials to usual care.
Philipp Schuetz, MD, MPH, of the University of Basel, Switzerland, receives research support from Thermo Fisher and bioMerieux, which make PCT tests. Peter M. Wahl, ScD, is a full-time employee of Covance Inc., of Princeton, N.J., which makes diagnostic tests and owns clinical laboratories. Their comments were made in an editorial accompanying Dr. Balk’s report (Chest. 2017;151[1]:6-8. doi:10.1016/j.chest.2016.07.014).
Procalcitonin (PCT) testing on the first day of ICU admission for adult patients with sepsis is associated with reduced length of stay, less antibiotic exposure, and reduced hospital and pharmacy costs, Robert A. Balk, MD, and his associates reported.
The researchers analyzed data on more than 15 million patients in the Premier Research Database; of those, more than 730,000 had a potential diagnosis of sepsis, systemic inflammatory response syndrome (SIRS), septicemia, or a shock-related diagnosis on ICU admission or discharge (CHEST. 2017;151[1]:23-33).
After propensity matching to reduce potential bias, a total of 33,569 patients who had received PCT testing on ICU day 1 were identified; a control group of 98,543 non-PCT tested patients were identified as well. Hospital costs were $2,759 lower for PCT-tested patients ($30,454 vs. $33,213), ICU costs were $1,310 lower ($20,155 vs. $21,465), and pharmacy costs were $331 lower ($4,238 vs. $4,568). PCT-tested patients also were more commonly discharged to home (44.1% vs. 41.3%).
The PCT-tested patients had less total antibiotic exposure, (16.2 days vs. 16.9 days) but higher laboratory costs, according to Dr. Balk, director of the division of pulmonary and critical care medicine at Rush Medical College, Chicago, and his colleagues. Laboratory costs of the PCT-tested patients were $81 greater ($1,807 vs. $1,726).
While PCT testing is cleared by the Food and Drug Administration to assist in identifying patients who are highly likely to develop sepsis, there is no approved sepsis test, Dr. Balk and his colleagues noted.
“This study is important in the validation of the ability of PCT testing to favorably impact the outcome of critically ill patients when used according to the FDA cleared guidelines,” the investigators said. “The cost savings were real and consequential, exceeding the potential increased costs of laboratory testing associated with PCT testing on ICU admission.”
All-patient analysis showed a statistically significant, but slightly increased (0.7%) risk of mortality in PCT-tested patients; however, the finding was not seen in an enhanced risk-adjusted analysis of 96% of patients, the investigators pointed out. This finding is consistent with other large prospective studies showing no difference in mortality or other clinical outcomes using PCT guidances.
PCT testing has not been uniformly adopted despite its inclusion in the 2012 Surviving Sepsis Guidelines, in part, due to cost. The lack of a “gold standard” sepsis test has resulted in diagnostic dilemmas, delayed treatment, and poor outcomes, Dr. Balk and colleagues noted.
Because patients were not randomized to PCT testing or non-PCT testing groups, additional variables could have over- or underestimated the effect of PCT on patient outcomes, the researchers added.
Dr. Balk has received advisory board fees from bioMerieux USA, Roche Diagnostics, and ThermoFisher Scientific; Zhun Cao, PhD, Craig Lipkin, MS, and Scott B. Robinson MA, MPH, are employees of Premier Research Services, in Charlotte. Samuel Bozzette is an employee of bioMerieux, which provided funding for the study.
Procalcitonin (PCT) testing on the first day of ICU admission for adult patients with sepsis is associated with reduced length of stay, less antibiotic exposure, and reduced hospital and pharmacy costs, Robert A. Balk, MD, and his associates reported.
The researchers analyzed data on more than 15 million patients in the Premier Research Database; of those, more than 730,000 had a potential diagnosis of sepsis, systemic inflammatory response syndrome (SIRS), septicemia, or a shock-related diagnosis on ICU admission or discharge (CHEST. 2017;151[1]:23-33).
After propensity matching to reduce potential bias, a total of 33,569 patients who had received PCT testing on ICU day 1 were identified; a control group of 98,543 non-PCT tested patients were identified as well. Hospital costs were $2,759 lower for PCT-tested patients ($30,454 vs. $33,213), ICU costs were $1,310 lower ($20,155 vs. $21,465), and pharmacy costs were $331 lower ($4,238 vs. $4,568). PCT-tested patients also were more commonly discharged to home (44.1% vs. 41.3%).
The PCT-tested patients had less total antibiotic exposure, (16.2 days vs. 16.9 days) but higher laboratory costs, according to Dr. Balk, director of the division of pulmonary and critical care medicine at Rush Medical College, Chicago, and his colleagues. Laboratory costs of the PCT-tested patients were $81 greater ($1,807 vs. $1,726).
While PCT testing is cleared by the Food and Drug Administration to assist in identifying patients who are highly likely to develop sepsis, there is no approved sepsis test, Dr. Balk and his colleagues noted.
“This study is important in the validation of the ability of PCT testing to favorably impact the outcome of critically ill patients when used according to the FDA cleared guidelines,” the investigators said. “The cost savings were real and consequential, exceeding the potential increased costs of laboratory testing associated with PCT testing on ICU admission.”
All-patient analysis showed a statistically significant, but slightly increased (0.7%) risk of mortality in PCT-tested patients; however, the finding was not seen in an enhanced risk-adjusted analysis of 96% of patients, the investigators pointed out. This finding is consistent with other large prospective studies showing no difference in mortality or other clinical outcomes using PCT guidances.
PCT testing has not been uniformly adopted despite its inclusion in the 2012 Surviving Sepsis Guidelines, in part, due to cost. The lack of a “gold standard” sepsis test has resulted in diagnostic dilemmas, delayed treatment, and poor outcomes, Dr. Balk and colleagues noted.
Because patients were not randomized to PCT testing or non-PCT testing groups, additional variables could have over- or underestimated the effect of PCT on patient outcomes, the researchers added.
Dr. Balk has received advisory board fees from bioMerieux USA, Roche Diagnostics, and ThermoFisher Scientific; Zhun Cao, PhD, Craig Lipkin, MS, and Scott B. Robinson MA, MPH, are employees of Premier Research Services, in Charlotte. Samuel Bozzette is an employee of bioMerieux, which provided funding for the study.
FROM CHEST
Key clinical point: Procalcitonin (PCT) testing on the first day of ICU admission for critically ill adults with sepsis is associated with reduced ICU length of stay and reduced hospital and pharmacy costs.
Major finding: Total hospital and ICU costs were $2,759 and $1,310 less, respectively, for PCT managed patients, while inpatient mortality for patients who received PCT was 19% vs. 18.3% for those who did not receive PCT.
Data source: A retrospective study of data on more than 730,000 adult patients who had a potential sepsis, SIRS, septicemia, or shock-related diagnosis on admission or discharge, and were treated in the ICU.
Disclosures: Dr. Balk has received advisory board fees from bioMerieux USA, Roche Diagnostics, and Thermo Fisher Scientific; Zhun Cao, PhD, Craig Lipkin, and Scott B. Robinson are employees of Premier Research Services. Samuel Bozzette is an employee of bioMerieux, which provided funding for the study.
All systemic steroid guidelines for RA offer little guidance
Every current guideline and consensus statement regarding systemic glucocorticoid therapy in rheumatoid arthritis falls short of offering clinicians practical, evidence-based guidance, according to a systematic review of all 15 such documents published in 2011-2015 in English, French, German, and Spanish.
Despite the abundant and convincing evidence that systemic glucocorticoids are very beneficial and despite their widespread use for rheumatoid arthritis (RA), fewer than half of the existing guidelines explicitly recommend these agents. Even fewer specify the optimal treatment duration, and about one-third don’t even provide dosage recommendations.
Their report, published in Arthritis Care & Research, does not address intra-articular administration of glucocorticoids. The 15 sets of guidelines were developed by 13 different rheumatology associations and networks across five continents (Arthritis Care Res. 2016 Dec 28. doi: 10.1002/acr.23185).
In this comprehensive review of 3,742 relevant publications, there was general agreement that initial treatment should center on disease-modifying antirheumatic drugs (DMARDs) plus systemic glucocorticoids. If remission, or at least reduced disease activity with preserved function, doesn’t occur within 3-6 months, another synthetic or a biologic DMARD should be tried, with or without concomitant glucocorticoids. But none of the guidelines adequately address the timing or frequency of use, either in early RA or in established disease.
All the guidelines refer to using “low-dose” or the “lowest possible dose” to avoid adverse effects, but what they mean by that is unclear. Some define “low-dose” as less than or equal to 7.5 mg per day, but others define it at higher levels, up to 15 mg per day. “Moderate” and “high” doses are not defined at all, and some guidelines refer to unspecified “low to moderate doses” or “moderately high” doses. This causes “considerable confusion for the practicing clinician and investigators,” Mr. Palmowski and his associates noted.
Similarly, the guidelines are unclear as to which routes of administration are preferred, or are even acceptable. Most specifically mention oral systemic glucocorticoids; four mention the intramuscular route, with one guideline calling this preferable “in certain situations” because it facilitates better dosing control. One guideline recommends intravenous glucocorticoids, but only for severe extra-articular manifestations. And another advocates parenteral methylprednisolone in patients who have “weaning difficulties,” but gives no further details about using this route.
The guidelines all are similarly vague regarding the duration of glucocorticoid therapy. Two do not address treatment duration at all; the other 13 recommend “short-term” or “the shortest possible duration,” but do not adequately define these terms. Six guidelines discuss maximum treatment duration, but they define that as anywhere from 3 to 24 months. Only 4 of the 15 guidelines discuss treatment periods of longer than 6 months, and all of them are vague and sometimes contradict each other regarding such prolonged use.
The daily timing of glucocorticoid therapy is virtually ignored in all the guidelines, even though researchers have known for more than 50 years that the time of day when these agents are taken has a considerable impact on their efficacy and safety. Similarly, the use of delayed-release prednisone and the question of single versus multiple doses per day “remain to be tackled,” Mr. Palmowski and his associates said.
Tapering of glucocorticoid therapy to avoid triggering a recurrence is another topic given short shrift. Five of the guidelines don’t address it at all, and another five merely state that glucocorticoids should be tapered “as rapidly as possible.” The three guidelines that do stress the importance of gradual dose reductions offer conflicting advice about accomplishing that.
Existing guidelines also neglect to address patient-specific factors that may require special attention. Two explicitly allow the use of these agents during pregnancy, but the other 13 do not even consider the question. Three guidelines address possible interactions with other medications, but the other 12 do not. Only one guideline discusses the use of glucocorticoids in relation to common RA-associated cormorbidities such as cardiovascular disease and diabetes. And none of the guidelines make any age- or sex-specific recommendations.
Finally, many of the current guidelines fail to fully identify their funding sources. Five that never mentioned funding at all “were published (and probably funded) by rheumatology associations.” And at least two of the guidelines that ignored funding sources did receive support from pharmaceutical companies, Mr. Palmowski and his associates said.
This study was sponsored by the GLORIA (Glucocorticoid Low-dose Outcome in RA) Project of the European Commission’s Horizon 2020 Initiative. Mr. Palmowski reported having no relevant financial disclosures; his associates reported ties to Merck, Roche, Mundipharma, Pfizer, SUN, Novartis, Bristol-Myers Squibb, Takeda, UCB, Serono, and Horizon Pharma.
Some may read the report by Mr. Palmowski and his colleagues and fault the people who wrote the guidelines for these inadequacies. But the true culprit is the lack of good data on which to base guidelines.
And the data are lacking mainly because there is no funding for studies of dosing, treatment duration, timing of therapy, and patient-specific factors. Glucocorticoids are old drugs, so no industry sources would consider laying out the multiple millions of dollars necessary to conduct adequate research. Moreover, as many as 60% of all patients who could participate in such studies are already taking these agents, and this makes it difficult to determine their unique risk profiles.
Tina D. Mahajan, MD, is in the division of rheumatology and immunology at the University of Nebraska, Omaha. James R. O’Dell, MD, is chief of that division. The authors’ financial disclosures were not provided. Dr. Mahajan and Dr. O’Dell made these remarks in an editorial accompanying the report by Mr. Palmowski and his associates (Arthritis Care Res. 2016 Dec 28. doi: 10.1002/acr.23184).
Some may read the report by Mr. Palmowski and his colleagues and fault the people who wrote the guidelines for these inadequacies. But the true culprit is the lack of good data on which to base guidelines.
And the data are lacking mainly because there is no funding for studies of dosing, treatment duration, timing of therapy, and patient-specific factors. Glucocorticoids are old drugs, so no industry sources would consider laying out the multiple millions of dollars necessary to conduct adequate research. Moreover, as many as 60% of all patients who could participate in such studies are already taking these agents, and this makes it difficult to determine their unique risk profiles.
Tina D. Mahajan, MD, is in the division of rheumatology and immunology at the University of Nebraska, Omaha. James R. O’Dell, MD, is chief of that division. The authors’ financial disclosures were not provided. Dr. Mahajan and Dr. O’Dell made these remarks in an editorial accompanying the report by Mr. Palmowski and his associates (Arthritis Care Res. 2016 Dec 28. doi: 10.1002/acr.23184).
Some may read the report by Mr. Palmowski and his colleagues and fault the people who wrote the guidelines for these inadequacies. But the true culprit is the lack of good data on which to base guidelines.
And the data are lacking mainly because there is no funding for studies of dosing, treatment duration, timing of therapy, and patient-specific factors. Glucocorticoids are old drugs, so no industry sources would consider laying out the multiple millions of dollars necessary to conduct adequate research. Moreover, as many as 60% of all patients who could participate in such studies are already taking these agents, and this makes it difficult to determine their unique risk profiles.
Tina D. Mahajan, MD, is in the division of rheumatology and immunology at the University of Nebraska, Omaha. James R. O’Dell, MD, is chief of that division. The authors’ financial disclosures were not provided. Dr. Mahajan and Dr. O’Dell made these remarks in an editorial accompanying the report by Mr. Palmowski and his associates (Arthritis Care Res. 2016 Dec 28. doi: 10.1002/acr.23184).
Every current guideline and consensus statement regarding systemic glucocorticoid therapy in rheumatoid arthritis falls short of offering clinicians practical, evidence-based guidance, according to a systematic review of all 15 such documents published in 2011-2015 in English, French, German, and Spanish.
Despite the abundant and convincing evidence that systemic glucocorticoids are very beneficial and despite their widespread use for rheumatoid arthritis (RA), fewer than half of the existing guidelines explicitly recommend these agents. Even fewer specify the optimal treatment duration, and about one-third don’t even provide dosage recommendations.
Their report, published in Arthritis Care & Research, does not address intra-articular administration of glucocorticoids. The 15 sets of guidelines were developed by 13 different rheumatology associations and networks across five continents (Arthritis Care Res. 2016 Dec 28. doi: 10.1002/acr.23185).
In this comprehensive review of 3,742 relevant publications, there was general agreement that initial treatment should center on disease-modifying antirheumatic drugs (DMARDs) plus systemic glucocorticoids. If remission, or at least reduced disease activity with preserved function, doesn’t occur within 3-6 months, another synthetic or a biologic DMARD should be tried, with or without concomitant glucocorticoids. But none of the guidelines adequately address the timing or frequency of use, either in early RA or in established disease.
All the guidelines refer to using “low-dose” or the “lowest possible dose” to avoid adverse effects, but what they mean by that is unclear. Some define “low-dose” as less than or equal to 7.5 mg per day, but others define it at higher levels, up to 15 mg per day. “Moderate” and “high” doses are not defined at all, and some guidelines refer to unspecified “low to moderate doses” or “moderately high” doses. This causes “considerable confusion for the practicing clinician and investigators,” Mr. Palmowski and his associates noted.
Similarly, the guidelines are unclear as to which routes of administration are preferred, or are even acceptable. Most specifically mention oral systemic glucocorticoids; four mention the intramuscular route, with one guideline calling this preferable “in certain situations” because it facilitates better dosing control. One guideline recommends intravenous glucocorticoids, but only for severe extra-articular manifestations. And another advocates parenteral methylprednisolone in patients who have “weaning difficulties,” but gives no further details about using this route.
The guidelines all are similarly vague regarding the duration of glucocorticoid therapy. Two do not address treatment duration at all; the other 13 recommend “short-term” or “the shortest possible duration,” but do not adequately define these terms. Six guidelines discuss maximum treatment duration, but they define that as anywhere from 3 to 24 months. Only 4 of the 15 guidelines discuss treatment periods of longer than 6 months, and all of them are vague and sometimes contradict each other regarding such prolonged use.
The daily timing of glucocorticoid therapy is virtually ignored in all the guidelines, even though researchers have known for more than 50 years that the time of day when these agents are taken has a considerable impact on their efficacy and safety. Similarly, the use of delayed-release prednisone and the question of single versus multiple doses per day “remain to be tackled,” Mr. Palmowski and his associates said.
Tapering of glucocorticoid therapy to avoid triggering a recurrence is another topic given short shrift. Five of the guidelines don’t address it at all, and another five merely state that glucocorticoids should be tapered “as rapidly as possible.” The three guidelines that do stress the importance of gradual dose reductions offer conflicting advice about accomplishing that.
Existing guidelines also neglect to address patient-specific factors that may require special attention. Two explicitly allow the use of these agents during pregnancy, but the other 13 do not even consider the question. Three guidelines address possible interactions with other medications, but the other 12 do not. Only one guideline discusses the use of glucocorticoids in relation to common RA-associated cormorbidities such as cardiovascular disease and diabetes. And none of the guidelines make any age- or sex-specific recommendations.
Finally, many of the current guidelines fail to fully identify their funding sources. Five that never mentioned funding at all “were published (and probably funded) by rheumatology associations.” And at least two of the guidelines that ignored funding sources did receive support from pharmaceutical companies, Mr. Palmowski and his associates said.
This study was sponsored by the GLORIA (Glucocorticoid Low-dose Outcome in RA) Project of the European Commission’s Horizon 2020 Initiative. Mr. Palmowski reported having no relevant financial disclosures; his associates reported ties to Merck, Roche, Mundipharma, Pfizer, SUN, Novartis, Bristol-Myers Squibb, Takeda, UCB, Serono, and Horizon Pharma.
Every current guideline and consensus statement regarding systemic glucocorticoid therapy in rheumatoid arthritis falls short of offering clinicians practical, evidence-based guidance, according to a systematic review of all 15 such documents published in 2011-2015 in English, French, German, and Spanish.
Despite the abundant and convincing evidence that systemic glucocorticoids are very beneficial and despite their widespread use for rheumatoid arthritis (RA), fewer than half of the existing guidelines explicitly recommend these agents. Even fewer specify the optimal treatment duration, and about one-third don’t even provide dosage recommendations.
Their report, published in Arthritis Care & Research, does not address intra-articular administration of glucocorticoids. The 15 sets of guidelines were developed by 13 different rheumatology associations and networks across five continents (Arthritis Care Res. 2016 Dec 28. doi: 10.1002/acr.23185).
In this comprehensive review of 3,742 relevant publications, there was general agreement that initial treatment should center on disease-modifying antirheumatic drugs (DMARDs) plus systemic glucocorticoids. If remission, or at least reduced disease activity with preserved function, doesn’t occur within 3-6 months, another synthetic or a biologic DMARD should be tried, with or without concomitant glucocorticoids. But none of the guidelines adequately address the timing or frequency of use, either in early RA or in established disease.
All the guidelines refer to using “low-dose” or the “lowest possible dose” to avoid adverse effects, but what they mean by that is unclear. Some define “low-dose” as less than or equal to 7.5 mg per day, but others define it at higher levels, up to 15 mg per day. “Moderate” and “high” doses are not defined at all, and some guidelines refer to unspecified “low to moderate doses” or “moderately high” doses. This causes “considerable confusion for the practicing clinician and investigators,” Mr. Palmowski and his associates noted.
Similarly, the guidelines are unclear as to which routes of administration are preferred, or are even acceptable. Most specifically mention oral systemic glucocorticoids; four mention the intramuscular route, with one guideline calling this preferable “in certain situations” because it facilitates better dosing control. One guideline recommends intravenous glucocorticoids, but only for severe extra-articular manifestations. And another advocates parenteral methylprednisolone in patients who have “weaning difficulties,” but gives no further details about using this route.
The guidelines all are similarly vague regarding the duration of glucocorticoid therapy. Two do not address treatment duration at all; the other 13 recommend “short-term” or “the shortest possible duration,” but do not adequately define these terms. Six guidelines discuss maximum treatment duration, but they define that as anywhere from 3 to 24 months. Only 4 of the 15 guidelines discuss treatment periods of longer than 6 months, and all of them are vague and sometimes contradict each other regarding such prolonged use.
The daily timing of glucocorticoid therapy is virtually ignored in all the guidelines, even though researchers have known for more than 50 years that the time of day when these agents are taken has a considerable impact on their efficacy and safety. Similarly, the use of delayed-release prednisone and the question of single versus multiple doses per day “remain to be tackled,” Mr. Palmowski and his associates said.
Tapering of glucocorticoid therapy to avoid triggering a recurrence is another topic given short shrift. Five of the guidelines don’t address it at all, and another five merely state that glucocorticoids should be tapered “as rapidly as possible.” The three guidelines that do stress the importance of gradual dose reductions offer conflicting advice about accomplishing that.
Existing guidelines also neglect to address patient-specific factors that may require special attention. Two explicitly allow the use of these agents during pregnancy, but the other 13 do not even consider the question. Three guidelines address possible interactions with other medications, but the other 12 do not. Only one guideline discusses the use of glucocorticoids in relation to common RA-associated cormorbidities such as cardiovascular disease and diabetes. And none of the guidelines make any age- or sex-specific recommendations.
Finally, many of the current guidelines fail to fully identify their funding sources. Five that never mentioned funding at all “were published (and probably funded) by rheumatology associations.” And at least two of the guidelines that ignored funding sources did receive support from pharmaceutical companies, Mr. Palmowski and his associates said.
This study was sponsored by the GLORIA (Glucocorticoid Low-dose Outcome in RA) Project of the European Commission’s Horizon 2020 Initiative. Mr. Palmowski reported having no relevant financial disclosures; his associates reported ties to Merck, Roche, Mundipharma, Pfizer, SUN, Novartis, Bristol-Myers Squibb, Takeda, UCB, Serono, and Horizon Pharma.
Key clinical point:
Major finding: All 15 guidelines refer to using “low-dose” or the “lowest possible dose” of glucocorticoids to avoid adverse effects, but some define that as 7.5 mg per day while others define it at higher levels, all the way up to 15 mg per day.
Data source: A comprehensive, systematic review of all 15 guidelines and consensus statements regarding glucocorticoid therapy in RA that were published in 2011-2015 in English, French, German, and Spanish.
Disclosures: This study was sponsored by the GLORIA (Glucocorticoid Low-dose Outcome in RA) Project of the European Commission’s Horizon 2020 Initiative. Mr. Palmowski reported having no relevant financial disclosures; his associates reported ties to Merck, Roche, Mundipharma, Pfizer, SUN, Novartis, Bristol-Myers Squibb, Takeda, UCB, Serono, and Horizon Pharma.
Surgical discharge data highlight stewardship need at transition
NEW ORLEANS – Most antibiotic prescriptions written at the time of patient discharge at an academic hospital were inappropriate, according to a retrospective review of 2014 discharge data.
These drugs were prescribed despite the existence of a robust inpatient antibiotic stewardship program (ASP) at the hospital, Sarah Scarpato, MD, reported at IDWeek, an annual scientific meeting on infectious diseases.
Of 9,750 prescriptions written during the study year, 86% were for oral antibiotics and 14% were for outpatient parenteral antibiotic therapy. Among a random sample of 150 patients discharged on antibiotics, 22.7% had no clinical indication of infection, 13% received an antibiotic with inappropriate spectrum of activity, 17% received an incorrect dose, 55% received an antibiotic course that was too long, and 7.3% received a course that was too short, Dr. Scarpato said at the combined annual meetings of the Infectious Diseases Society of America, the Society of Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.
A total of 57.7% of surgical patients and 57.6% of medical patients received an antibiotic prescription that was inappropriate.
“A whopping 70% of prescriptions had at least one error in drug choice, dose, indication, or duration,” she said.
“The most common scenarios in which an antibiotic use was not indicated were prolonged surgical prophylaxis and prolonged prophylaxis in patients who had neutropenic fever during their hospitalization but were no longer neutropenic on discharge. The most common infectious indications were consistent with previous data, with genitourinary, respiratory, and skin and soft tissue being the most common, followed by gastrointestinal,” Dr. Scarpato of the Hospital of the University of Pennsylvania, Philadelphia, said.
In addition, she noted, “100% of patients discharged from cardiothoracic surgery, ear/nose/throat surgery, oral and maxillofacial surgery, neurosurgery, and neurology had at least one error. Oncology was the medical service with the highest rate of inappropriate prescriptions at 80%. The rest, including infectious diseases, had error rates between 40% and 60%.”
Also in line with previous data, fluoroquinolones were the most commonly prescribed antibiotics, accounting for 23.5%, followed by cephalosporins, penicillins, trimethoprim-sulfamethoxazole, and metronidazole.
“Antibiotic prescription in the absence of an acceptable indication and inappropriate duration accounted for the vast majority – 76% – of inappropriate prescriptions,” Dr. Scarpato said, noting that this may be because of a failure by physicians to account for antibiotics given as an inpatient, a lack of familiarity with a patient’s course because of hand-offs, the writing of a prescription with a given duration expecting discharge on a different day, or a lack of familiarity with recommended treatment durations.
“On average, we saw an excess of 3.8 days of unnecessary antibiotics per patient,” she said. The range, however, was 18 days too few to 36 days too many. Further, readmission rates at days 7 and 30 were 6.4% and 19.4%, respectively, for patients discharged on antibiotics, compared with 3.70% and 13.79% hospital wide. The respective rates among those discharged on outpatient parenteral antibiotic therapy were 5.6% and 16.4%, compared with 6.5% and 19.9% among those on oral antibiotic therapy.
The higher rates among those on oral vs. parenteral therapy may be because patients on outpatient parenteral antibiotic therapy are followed closely by a team of infectious disease physicians and pharmacists, while those discharged on oral therapy are not routinely monitored, or it may reflect an unintended consequence of switching from parenteral to oral therapy at discharge, Dr. Scarpato said.
Transitions of care are vulnerable times for patients, she said, noting that “nearly a quarter of patients suffer an adverse event from an error in transition of care during hospital discharge, and up to half of those who suffer an adverse drug reaction at discharge are prescribed an antibiotic.”
Though limited by the retrospective and descriptive nature of the study, and the single-center design, the findings demonstrate “a significant and unmet need for antimicrobial stewardship at transition in care, even at institutions such as ours that have a substantial inpatient ASP,” Dr. Scarpato concluded.
Dr. Scarpato reported having no conflicts of interest.
NEW ORLEANS – Most antibiotic prescriptions written at the time of patient discharge at an academic hospital were inappropriate, according to a retrospective review of 2014 discharge data.
These drugs were prescribed despite the existence of a robust inpatient antibiotic stewardship program (ASP) at the hospital, Sarah Scarpato, MD, reported at IDWeek, an annual scientific meeting on infectious diseases.
Of 9,750 prescriptions written during the study year, 86% were for oral antibiotics and 14% were for outpatient parenteral antibiotic therapy. Among a random sample of 150 patients discharged on antibiotics, 22.7% had no clinical indication of infection, 13% received an antibiotic with inappropriate spectrum of activity, 17% received an incorrect dose, 55% received an antibiotic course that was too long, and 7.3% received a course that was too short, Dr. Scarpato said at the combined annual meetings of the Infectious Diseases Society of America, the Society of Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.
A total of 57.7% of surgical patients and 57.6% of medical patients received an antibiotic prescription that was inappropriate.
“A whopping 70% of prescriptions had at least one error in drug choice, dose, indication, or duration,” she said.
“The most common scenarios in which an antibiotic use was not indicated were prolonged surgical prophylaxis and prolonged prophylaxis in patients who had neutropenic fever during their hospitalization but were no longer neutropenic on discharge. The most common infectious indications were consistent with previous data, with genitourinary, respiratory, and skin and soft tissue being the most common, followed by gastrointestinal,” Dr. Scarpato of the Hospital of the University of Pennsylvania, Philadelphia, said.
In addition, she noted, “100% of patients discharged from cardiothoracic surgery, ear/nose/throat surgery, oral and maxillofacial surgery, neurosurgery, and neurology had at least one error. Oncology was the medical service with the highest rate of inappropriate prescriptions at 80%. The rest, including infectious diseases, had error rates between 40% and 60%.”
Also in line with previous data, fluoroquinolones were the most commonly prescribed antibiotics, accounting for 23.5%, followed by cephalosporins, penicillins, trimethoprim-sulfamethoxazole, and metronidazole.
“Antibiotic prescription in the absence of an acceptable indication and inappropriate duration accounted for the vast majority – 76% – of inappropriate prescriptions,” Dr. Scarpato said, noting that this may be because of a failure by physicians to account for antibiotics given as an inpatient, a lack of familiarity with a patient’s course because of hand-offs, the writing of a prescription with a given duration expecting discharge on a different day, or a lack of familiarity with recommended treatment durations.
“On average, we saw an excess of 3.8 days of unnecessary antibiotics per patient,” she said. The range, however, was 18 days too few to 36 days too many. Further, readmission rates at days 7 and 30 were 6.4% and 19.4%, respectively, for patients discharged on antibiotics, compared with 3.70% and 13.79% hospital wide. The respective rates among those discharged on outpatient parenteral antibiotic therapy were 5.6% and 16.4%, compared with 6.5% and 19.9% among those on oral antibiotic therapy.
The higher rates among those on oral vs. parenteral therapy may be because patients on outpatient parenteral antibiotic therapy are followed closely by a team of infectious disease physicians and pharmacists, while those discharged on oral therapy are not routinely monitored, or it may reflect an unintended consequence of switching from parenteral to oral therapy at discharge, Dr. Scarpato said.
Transitions of care are vulnerable times for patients, she said, noting that “nearly a quarter of patients suffer an adverse event from an error in transition of care during hospital discharge, and up to half of those who suffer an adverse drug reaction at discharge are prescribed an antibiotic.”
Though limited by the retrospective and descriptive nature of the study, and the single-center design, the findings demonstrate “a significant and unmet need for antimicrobial stewardship at transition in care, even at institutions such as ours that have a substantial inpatient ASP,” Dr. Scarpato concluded.
Dr. Scarpato reported having no conflicts of interest.
NEW ORLEANS – Most antibiotic prescriptions written at the time of patient discharge at an academic hospital were inappropriate, according to a retrospective review of 2014 discharge data.
These drugs were prescribed despite the existence of a robust inpatient antibiotic stewardship program (ASP) at the hospital, Sarah Scarpato, MD, reported at IDWeek, an annual scientific meeting on infectious diseases.
Of 9,750 prescriptions written during the study year, 86% were for oral antibiotics and 14% were for outpatient parenteral antibiotic therapy. Among a random sample of 150 patients discharged on antibiotics, 22.7% had no clinical indication of infection, 13% received an antibiotic with inappropriate spectrum of activity, 17% received an incorrect dose, 55% received an antibiotic course that was too long, and 7.3% received a course that was too short, Dr. Scarpato said at the combined annual meetings of the Infectious Diseases Society of America, the Society of Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.
A total of 57.7% of surgical patients and 57.6% of medical patients received an antibiotic prescription that was inappropriate.
“A whopping 70% of prescriptions had at least one error in drug choice, dose, indication, or duration,” she said.
“The most common scenarios in which an antibiotic use was not indicated were prolonged surgical prophylaxis and prolonged prophylaxis in patients who had neutropenic fever during their hospitalization but were no longer neutropenic on discharge. The most common infectious indications were consistent with previous data, with genitourinary, respiratory, and skin and soft tissue being the most common, followed by gastrointestinal,” Dr. Scarpato of the Hospital of the University of Pennsylvania, Philadelphia, said.
In addition, she noted, “100% of patients discharged from cardiothoracic surgery, ear/nose/throat surgery, oral and maxillofacial surgery, neurosurgery, and neurology had at least one error. Oncology was the medical service with the highest rate of inappropriate prescriptions at 80%. The rest, including infectious diseases, had error rates between 40% and 60%.”
Also in line with previous data, fluoroquinolones were the most commonly prescribed antibiotics, accounting for 23.5%, followed by cephalosporins, penicillins, trimethoprim-sulfamethoxazole, and metronidazole.
“Antibiotic prescription in the absence of an acceptable indication and inappropriate duration accounted for the vast majority – 76% – of inappropriate prescriptions,” Dr. Scarpato said, noting that this may be because of a failure by physicians to account for antibiotics given as an inpatient, a lack of familiarity with a patient’s course because of hand-offs, the writing of a prescription with a given duration expecting discharge on a different day, or a lack of familiarity with recommended treatment durations.
“On average, we saw an excess of 3.8 days of unnecessary antibiotics per patient,” she said. The range, however, was 18 days too few to 36 days too many. Further, readmission rates at days 7 and 30 were 6.4% and 19.4%, respectively, for patients discharged on antibiotics, compared with 3.70% and 13.79% hospital wide. The respective rates among those discharged on outpatient parenteral antibiotic therapy were 5.6% and 16.4%, compared with 6.5% and 19.9% among those on oral antibiotic therapy.
The higher rates among those on oral vs. parenteral therapy may be because patients on outpatient parenteral antibiotic therapy are followed closely by a team of infectious disease physicians and pharmacists, while those discharged on oral therapy are not routinely monitored, or it may reflect an unintended consequence of switching from parenteral to oral therapy at discharge, Dr. Scarpato said.
Transitions of care are vulnerable times for patients, she said, noting that “nearly a quarter of patients suffer an adverse event from an error in transition of care during hospital discharge, and up to half of those who suffer an adverse drug reaction at discharge are prescribed an antibiotic.”
Though limited by the retrospective and descriptive nature of the study, and the single-center design, the findings demonstrate “a significant and unmet need for antimicrobial stewardship at transition in care, even at institutions such as ours that have a substantial inpatient ASP,” Dr. Scarpato concluded.
Dr. Scarpato reported having no conflicts of interest.
AT IDWEEK 2016
Key clinical point:
Major finding: 70% of prescriptions had at least one error in drug choice, dose, indication, or duration.
Data source: A review of discharge data for 150 patients at an academic hospital.
Disclosures: Dr. Scarpato reported having no conflicts of interest.
Predicting response to cytarabine in AML patients
New research suggests the protein SAMHD1 could be used to predict which
patients with acute myeloid leukemia (AML) will respond to treatment
with cytarabine.
Researchers found that response to cytarabine
was inversely correlated with SAMHD1 expression in AML cell lines, mouse
models of the disease, and adult patients with AML.
Jindrich Cinatl, PhD, of the University of Frankfurt in Germany, and his colleagues reported these findings in Nature Medicine.
The researchers first analyzed 13 AML cell lines and found that SAMHD1 reduces the cytotoxic effect of cytarabine. When the team depleted SAMHD1 in these cell lines, they were “markedly sensitized” to cytarabine.
The researchers also cultivated cytarabine-resistant AML cell lines and found that SAMHD1 levels increased along with cytarabine resistance. However, depleting SAMHD1 resensitized the cells to cytarabine.
Investigation revealed that SAMHD1 removes the phosphate residues from the active form of cytarabine, Ara-CTP, and converts the drug to its inactive form, Ara-C.
The researchers then evaluated the role of SAMHD1 in AML in vivo. They transplanted SAMHD1-knockout AML cells and wild-type SAMHD1 AML cells into mice and treated the mice with cytarabine or phosphate-buffered saline.
Mice that received SAMHD1-knockout AML cells and cytarabine had significantly longer survival than mice that received wild-type SAMHD1 AML cells and cytarabine or either AML cell type plus phosphate-buffered saline.
Next, the researchers tested blasts isolated from the bone marrow of patients with therapy-naive AML.
The team found that basal SAMHD1 expression was significantly correlated with cytarabine IC50 values. And depleting SAMHD1 diminished cytarabine IC50 values by 3- to 15-fold.
Lastly, the researchers assessed whether SAMHD1 expression might be used to predict response to cytarabine-based therapy in patients with AML.
The team analyzed a cohort of 150 adult AML patients who had received 1 to 2 courses of induction therapy including cytarabine—either 2 cycles of 7+3 or 7+3 plus high-dose cytarabine in combination with mitoxantrone.
Analysis revealed that SAMHD1 expression was “markedly increased” among patients who did not achieve a complete remission (CR) at the end of induction.
Of the 112 patients who achieved a CR, 90 were scored as “SAMHD1 low,” and 22 were scored as “SAMHD1 high.” The CR rate was 44% in the SAMHD1-high cohort and 90% in the SAMHD1-low cohort.
In addition, the researchers found the level of SAMHD1 expression in blasts at patients’ initial diagnosis was predictive of event-free survival, relapse-free survival, and overall survival.
The team said these results suggest SAMHD1 could be used to guide treatment with cytarabine-based therapies in patients with AML. 
New research suggests the protein SAMHD1 could be used to predict which
patients with acute myeloid leukemia (AML) will respond to treatment
with cytarabine.
Researchers found that response to cytarabine
was inversely correlated with SAMHD1 expression in AML cell lines, mouse
models of the disease, and adult patients with AML.
Jindrich Cinatl, PhD, of the University of Frankfurt in Germany, and his colleagues reported these findings in Nature Medicine.
The researchers first analyzed 13 AML cell lines and found that SAMHD1 reduces the cytotoxic effect of cytarabine. When the team depleted SAMHD1 in these cell lines, they were “markedly sensitized” to cytarabine.
The researchers also cultivated cytarabine-resistant AML cell lines and found that SAMHD1 levels increased along with cytarabine resistance. However, depleting SAMHD1 resensitized the cells to cytarabine.
Investigation revealed that SAMHD1 removes the phosphate residues from the active form of cytarabine, Ara-CTP, and converts the drug to its inactive form, Ara-C.
The researchers then evaluated the role of SAMHD1 in AML in vivo. They transplanted SAMHD1-knockout AML cells and wild-type SAMHD1 AML cells into mice and treated the mice with cytarabine or phosphate-buffered saline.
Mice that received SAMHD1-knockout AML cells and cytarabine had significantly longer survival than mice that received wild-type SAMHD1 AML cells and cytarabine or either AML cell type plus phosphate-buffered saline.
Next, the researchers tested blasts isolated from the bone marrow of patients with therapy-naive AML.
The team found that basal SAMHD1 expression was significantly correlated with cytarabine IC50 values. And depleting SAMHD1 diminished cytarabine IC50 values by 3- to 15-fold.
Lastly, the researchers assessed whether SAMHD1 expression might be used to predict response to cytarabine-based therapy in patients with AML.
The team analyzed a cohort of 150 adult AML patients who had received 1 to 2 courses of induction therapy including cytarabine—either 2 cycles of 7+3 or 7+3 plus high-dose cytarabine in combination with mitoxantrone.
Analysis revealed that SAMHD1 expression was “markedly increased” among patients who did not achieve a complete remission (CR) at the end of induction.
Of the 112 patients who achieved a CR, 90 were scored as “SAMHD1 low,” and 22 were scored as “SAMHD1 high.” The CR rate was 44% in the SAMHD1-high cohort and 90% in the SAMHD1-low cohort.
In addition, the researchers found the level of SAMHD1 expression in blasts at patients’ initial diagnosis was predictive of event-free survival, relapse-free survival, and overall survival.
The team said these results suggest SAMHD1 could be used to guide treatment with cytarabine-based therapies in patients with AML.
New research suggests the protein SAMHD1 could be used to predict which
patients with acute myeloid leukemia (AML) will respond to treatment
with cytarabine.
Researchers found that response to cytarabine
was inversely correlated with SAMHD1 expression in AML cell lines, mouse
models of the disease, and adult patients with AML.
Jindrich Cinatl, PhD, of the University of Frankfurt in Germany, and his colleagues reported these findings in Nature Medicine.
The researchers first analyzed 13 AML cell lines and found that SAMHD1 reduces the cytotoxic effect of cytarabine. When the team depleted SAMHD1 in these cell lines, they were “markedly sensitized” to cytarabine.
The researchers also cultivated cytarabine-resistant AML cell lines and found that SAMHD1 levels increased along with cytarabine resistance. However, depleting SAMHD1 resensitized the cells to cytarabine.
Investigation revealed that SAMHD1 removes the phosphate residues from the active form of cytarabine, Ara-CTP, and converts the drug to its inactive form, Ara-C.
The researchers then evaluated the role of SAMHD1 in AML in vivo. They transplanted SAMHD1-knockout AML cells and wild-type SAMHD1 AML cells into mice and treated the mice with cytarabine or phosphate-buffered saline.
Mice that received SAMHD1-knockout AML cells and cytarabine had significantly longer survival than mice that received wild-type SAMHD1 AML cells and cytarabine or either AML cell type plus phosphate-buffered saline.
Next, the researchers tested blasts isolated from the bone marrow of patients with therapy-naive AML.
The team found that basal SAMHD1 expression was significantly correlated with cytarabine IC50 values. And depleting SAMHD1 diminished cytarabine IC50 values by 3- to 15-fold.
Lastly, the researchers assessed whether SAMHD1 expression might be used to predict response to cytarabine-based therapy in patients with AML.
The team analyzed a cohort of 150 adult AML patients who had received 1 to 2 courses of induction therapy including cytarabine—either 2 cycles of 7+3 or 7+3 plus high-dose cytarabine in combination with mitoxantrone.
Analysis revealed that SAMHD1 expression was “markedly increased” among patients who did not achieve a complete remission (CR) at the end of induction.
Of the 112 patients who achieved a CR, 90 were scored as “SAMHD1 low,” and 22 were scored as “SAMHD1 high.” The CR rate was 44% in the SAMHD1-high cohort and 90% in the SAMHD1-low cohort.
In addition, the researchers found the level of SAMHD1 expression in blasts at patients’ initial diagnosis was predictive of event-free survival, relapse-free survival, and overall survival.
The team said these results suggest SAMHD1 could be used to guide treatment with cytarabine-based therapies in patients with AML.
Venetoclax approved to treat CLL in Australia
venetoclax (US version)
Photo courtesy of Abbvie
The Australian Therapeutic Goods Administration (TGA) has approved the BCL-2 inhibitor venetoclax (Venclexta™, formerly ABT-199) for use in certain patients with chronic lymphocytic leukemia (CLL).
The drug is now approved to treat Australian patients with relapsed or refractory CLL who have 17p deletion or no other treatment options.
Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.
Now that venetoclax has been approved by the TGA, it can be registered on the Australian Register of Therapeutic Goods and legally marketed and sold in Australia.
To make the drug affordable to the Australian public, the manufacturer can apply to the Pharmaceutical Benefits Advisory Committee to have the cost of the drug subsidized by the Australian government on the Pharmaceutical Benefits Scheme (PBS).
Venetoclax is not listed on the PBS. Historically, the delay between TGA approval and PBS listing ranges from 14 months to 31 months for cancer drugs.
Phase 2 trials
Venetoclax has produced high objective response rates (ORR) in two phase 2 trials of CLL patients.
In one of these trials, researchers tested venetoclax in 107 patients with previously treated CLL and 17p deletion. The results were published in The Lancet Oncology in June 2016.
The ORR in this trial was 79%. At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival.
The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.
The incidence of treatment-emergent adverse events was 96%, and the incidence of serious adverse events was 55%.
Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.
In the second trial, researchers tested venetoclax in 64 patients with CLL who had failed treatment with ibrutinib and/or idelalisib. Results from this trial were presented at the 2016 ASH Annual Meeting.
The ORR was 67%. At 11.8 months of follow-up, the median duration of response, progression-free survival, and overall survival had not been reached. The estimated 12-month progression-free survival was 80%.
The incidence of adverse events was 100%, and the incidence of serious adverse events was 53%. No clinical TLS was observed, but 1 patient met Howard criteria for laboratory TLS.
In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.
However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.
venetoclax (US version)
Photo courtesy of Abbvie
The Australian Therapeutic Goods Administration (TGA) has approved the BCL-2 inhibitor venetoclax (Venclexta™, formerly ABT-199) for use in certain patients with chronic lymphocytic leukemia (CLL).
The drug is now approved to treat Australian patients with relapsed or refractory CLL who have 17p deletion or no other treatment options.
Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.
Now that venetoclax has been approved by the TGA, it can be registered on the Australian Register of Therapeutic Goods and legally marketed and sold in Australia.
To make the drug affordable to the Australian public, the manufacturer can apply to the Pharmaceutical Benefits Advisory Committee to have the cost of the drug subsidized by the Australian government on the Pharmaceutical Benefits Scheme (PBS).
Venetoclax is not listed on the PBS. Historically, the delay between TGA approval and PBS listing ranges from 14 months to 31 months for cancer drugs.
Phase 2 trials
Venetoclax has produced high objective response rates (ORR) in two phase 2 trials of CLL patients.
In one of these trials, researchers tested venetoclax in 107 patients with previously treated CLL and 17p deletion. The results were published in The Lancet Oncology in June 2016.
The ORR in this trial was 79%. At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival.
The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.
The incidence of treatment-emergent adverse events was 96%, and the incidence of serious adverse events was 55%.
Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.
In the second trial, researchers tested venetoclax in 64 patients with CLL who had failed treatment with ibrutinib and/or idelalisib. Results from this trial were presented at the 2016 ASH Annual Meeting.
The ORR was 67%. At 11.8 months of follow-up, the median duration of response, progression-free survival, and overall survival had not been reached. The estimated 12-month progression-free survival was 80%.
The incidence of adverse events was 100%, and the incidence of serious adverse events was 53%. No clinical TLS was observed, but 1 patient met Howard criteria for laboratory TLS.
In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.
However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.
venetoclax (US version)
Photo courtesy of Abbvie
The Australian Therapeutic Goods Administration (TGA) has approved the BCL-2 inhibitor venetoclax (Venclexta™, formerly ABT-199) for use in certain patients with chronic lymphocytic leukemia (CLL).
The drug is now approved to treat Australian patients with relapsed or refractory CLL who have 17p deletion or no other treatment options.
Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.
Now that venetoclax has been approved by the TGA, it can be registered on the Australian Register of Therapeutic Goods and legally marketed and sold in Australia.
To make the drug affordable to the Australian public, the manufacturer can apply to the Pharmaceutical Benefits Advisory Committee to have the cost of the drug subsidized by the Australian government on the Pharmaceutical Benefits Scheme (PBS).
Venetoclax is not listed on the PBS. Historically, the delay between TGA approval and PBS listing ranges from 14 months to 31 months for cancer drugs.
Phase 2 trials
Venetoclax has produced high objective response rates (ORR) in two phase 2 trials of CLL patients.
In one of these trials, researchers tested venetoclax in 107 patients with previously treated CLL and 17p deletion. The results were published in The Lancet Oncology in June 2016.
The ORR in this trial was 79%. At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival.
The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.
The incidence of treatment-emergent adverse events was 96%, and the incidence of serious adverse events was 55%.
Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.
In the second trial, researchers tested venetoclax in 64 patients with CLL who had failed treatment with ibrutinib and/or idelalisib. Results from this trial were presented at the 2016 ASH Annual Meeting.
The ORR was 67%. At 11.8 months of follow-up, the median duration of response, progression-free survival, and overall survival had not been reached. The estimated 12-month progression-free survival was 80%.
The incidence of adverse events was 100%, and the incidence of serious adverse events was 53%. No clinical TLS was observed, but 1 patient met Howard criteria for laboratory TLS.
In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.
However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.
NCI launches program to expedite drug research
Photo by Bill Branson
The National Cancer Institute (NCI) has launched a new drug formulary designed to provide investigators at NCI-designated cancer centers with quicker access to approved and investigational agents for use in preclinical studies and clinical trials.
The formulary will enable NCI to act as an intermediary between investigators and participating pharmaceutical companies, facilitating the arrangements for access to and use of pharmaceutical agents.
Following company approval, investigators will be able to obtain agents from the formulary and test them in preclinical or clinical studies, including studies combining formulary agents from different companies.
The NCI says having agents available through the formulary will expedite the start of clinical trials by alleviating the lengthy negotiation process—sometimes up to 18 months—that has been required for investigators to access such agents on their own.
“The NCI Formulary will help researchers begin testing promising drug combinations more quickly, potentially helping patients much sooner,” said NCI Acting Director Douglas Lowy, MD.
“Rather than spending time negotiating agreements, investigators will be able to focus on the important research that can ultimately lead to improved cancer care.”
The NCI Formulary includes 15 targeted agents:
- Alectinib (ALK inhibitor, tyrosine kinase inhibitor)
- Atezolizumab (PD-L1 blocking monoclonal antibody)
- Bevacizumab (anti-angiogenesis inhibitor, monoclonal antibody)
- Cobimetinib (MEK1/2 inhibitor)
- Ensartinib (ALK inhibitor)
- Ipilimumab (anti-CTLA-4 monoclonal antibody)
- Larotrectinib (tyrosine kinase inhibitor)
- LY3039478 (Notch inhibitor)
- Nivolumab (PD-1 blocking monoclonal antibody)
- Obinutuzumab (anti-CD20 monoclonal antibody)
- Pertuzumab (anti-HER2 monoclonal antibody)
- Prexasertib (checkpoint kinase 1 inhibitor)
- Trastuzumab (anti-HER2 monoclonal antibody)
- Vemurafenib (BRAF mutant v600 inhibitor)
- Vismodegib (Hedgehog inhibitor)
The agents are products of 6 different pharmaceutical companies: Bristol-Myers Squibb, Eli Lilly and Company, Genentech, Kyowa Hakko Kirin, Loxo Oncology, and Xcovery Holding Company LLC.
“The agreements with these companies demonstrate our shared commitment to expedite cancer clinical trials and improve outcomes for patients,” said James Doroshow, MD, NCI deputy director for clinical and translational research.
“We are very pleased that several additional pharmaceutical companies have already pledged a willingness to participate and are in various stages of negotiation with NCI. By the end of 2017, we expect to have doubled the number of partnerships and drugs available in the NCI Formulary.”
Photo by Bill Branson
The National Cancer Institute (NCI) has launched a new drug formulary designed to provide investigators at NCI-designated cancer centers with quicker access to approved and investigational agents for use in preclinical studies and clinical trials.
The formulary will enable NCI to act as an intermediary between investigators and participating pharmaceutical companies, facilitating the arrangements for access to and use of pharmaceutical agents.
Following company approval, investigators will be able to obtain agents from the formulary and test them in preclinical or clinical studies, including studies combining formulary agents from different companies.
The NCI says having agents available through the formulary will expedite the start of clinical trials by alleviating the lengthy negotiation process—sometimes up to 18 months—that has been required for investigators to access such agents on their own.
“The NCI Formulary will help researchers begin testing promising drug combinations more quickly, potentially helping patients much sooner,” said NCI Acting Director Douglas Lowy, MD.
“Rather than spending time negotiating agreements, investigators will be able to focus on the important research that can ultimately lead to improved cancer care.”
The NCI Formulary includes 15 targeted agents:
- Alectinib (ALK inhibitor, tyrosine kinase inhibitor)
- Atezolizumab (PD-L1 blocking monoclonal antibody)
- Bevacizumab (anti-angiogenesis inhibitor, monoclonal antibody)
- Cobimetinib (MEK1/2 inhibitor)
- Ensartinib (ALK inhibitor)
- Ipilimumab (anti-CTLA-4 monoclonal antibody)
- Larotrectinib (tyrosine kinase inhibitor)
- LY3039478 (Notch inhibitor)
- Nivolumab (PD-1 blocking monoclonal antibody)
- Obinutuzumab (anti-CD20 monoclonal antibody)
- Pertuzumab (anti-HER2 monoclonal antibody)
- Prexasertib (checkpoint kinase 1 inhibitor)
- Trastuzumab (anti-HER2 monoclonal antibody)
- Vemurafenib (BRAF mutant v600 inhibitor)
- Vismodegib (Hedgehog inhibitor)
The agents are products of 6 different pharmaceutical companies: Bristol-Myers Squibb, Eli Lilly and Company, Genentech, Kyowa Hakko Kirin, Loxo Oncology, and Xcovery Holding Company LLC.
“The agreements with these companies demonstrate our shared commitment to expedite cancer clinical trials and improve outcomes for patients,” said James Doroshow, MD, NCI deputy director for clinical and translational research.
“We are very pleased that several additional pharmaceutical companies have already pledged a willingness to participate and are in various stages of negotiation with NCI. By the end of 2017, we expect to have doubled the number of partnerships and drugs available in the NCI Formulary.”
Photo by Bill Branson
The National Cancer Institute (NCI) has launched a new drug formulary designed to provide investigators at NCI-designated cancer centers with quicker access to approved and investigational agents for use in preclinical studies and clinical trials.
The formulary will enable NCI to act as an intermediary between investigators and participating pharmaceutical companies, facilitating the arrangements for access to and use of pharmaceutical agents.
Following company approval, investigators will be able to obtain agents from the formulary and test them in preclinical or clinical studies, including studies combining formulary agents from different companies.
The NCI says having agents available through the formulary will expedite the start of clinical trials by alleviating the lengthy negotiation process—sometimes up to 18 months—that has been required for investigators to access such agents on their own.
“The NCI Formulary will help researchers begin testing promising drug combinations more quickly, potentially helping patients much sooner,” said NCI Acting Director Douglas Lowy, MD.
“Rather than spending time negotiating agreements, investigators will be able to focus on the important research that can ultimately lead to improved cancer care.”
The NCI Formulary includes 15 targeted agents:
- Alectinib (ALK inhibitor, tyrosine kinase inhibitor)
- Atezolizumab (PD-L1 blocking monoclonal antibody)
- Bevacizumab (anti-angiogenesis inhibitor, monoclonal antibody)
- Cobimetinib (MEK1/2 inhibitor)
- Ensartinib (ALK inhibitor)
- Ipilimumab (anti-CTLA-4 monoclonal antibody)
- Larotrectinib (tyrosine kinase inhibitor)
- LY3039478 (Notch inhibitor)
- Nivolumab (PD-1 blocking monoclonal antibody)
- Obinutuzumab (anti-CD20 monoclonal antibody)
- Pertuzumab (anti-HER2 monoclonal antibody)
- Prexasertib (checkpoint kinase 1 inhibitor)
- Trastuzumab (anti-HER2 monoclonal antibody)
- Vemurafenib (BRAF mutant v600 inhibitor)
- Vismodegib (Hedgehog inhibitor)
The agents are products of 6 different pharmaceutical companies: Bristol-Myers Squibb, Eli Lilly and Company, Genentech, Kyowa Hakko Kirin, Loxo Oncology, and Xcovery Holding Company LLC.
“The agreements with these companies demonstrate our shared commitment to expedite cancer clinical trials and improve outcomes for patients,” said James Doroshow, MD, NCI deputy director for clinical and translational research.
“We are very pleased that several additional pharmaceutical companies have already pledged a willingness to participate and are in various stages of negotiation with NCI. By the end of 2017, we expect to have doubled the number of partnerships and drugs available in the NCI Formulary.”
Intervention may improve warfarin management
Photo courtesy of NIGMS
Researchers have developed an intervention intended to help hospitals and clinicians improve the management of patients on warfarin.
The team implemented the intervention at 8 medical centers in the New England region of the Veterans Health Administration (VA).
These
centers saw an improvement in time in the therapeutic range
(TTR) that was significantly better than the improvement seen in medical
centers without the intervention.
“Insufficient attention has been given in the past to how we can improve the management of warfarin,” said Adam Rose, MD, of Boston University School of Medicine in Massachusetts.
“This study demonstrates that a relatively simple approach can have a large impact.”
Dr Rose and his colleagues described this study in the Annals of Pharmacotherapy.
Intervention
The researchers implemented the intervention at 8 VA sites in New England known as Veterans Integrated Service Network 1 (VISN 1).
The team described the intervention as performance measurement augmented by targeted audit and feedback. Performance was measured via an online reporting system—known as a dashboard—that provided real-time data to clinicians.
The dashboard reported TTR at the patient and site level. The dashboard also reported processes of care that have been linked to TTR, including timely follow-up when the international normalized ratio (INR) is very low or very high, gaps in monitoring, and the proportion of patients with a mean INR value between 2.3 and 2.7.
The dashboard allowed clinicians to call patients who had been lost to follow-up, had low TTR, or were in need of urgent follow-up as a result of extreme INR values.
Results
The researchers examined changes in anticoagulation control, measured as TTR, after the intervention was implemented. They compared changes at VISN 1 sites with 116 other VA sites.
A total of 11,794 patients within VISN 1 and 1,248,782 patients outside of VISN 1 received warfarin for at least part of the study period.
At VISN 1 sites, TTR improved from 66.4% to 69.2%. At the other sites, TTR improved from 65.9% to 66.4% (P<0.001 for the between-group difference).
The researchers said improvement in TTR correlated strongly with the extent of improvement on process-of-care measures, which varied widely across VISN 1 sites.
“Patients who used these measures did better clinically than those in the control group,” Dr Rose said. “This study serves as a model for how other sites and health networks could feasibly approach improving the management of warfarin in their systems.”
“If all anticoagulation clinics in the VA were to achieve this level of improvement, it would prevent 48 strokes and 68 major bleeding events each year, with a savings to the VA system of more than $4 million annually.”
Photo courtesy of NIGMS
Researchers have developed an intervention intended to help hospitals and clinicians improve the management of patients on warfarin.
The team implemented the intervention at 8 medical centers in the New England region of the Veterans Health Administration (VA).
These
centers saw an improvement in time in the therapeutic range
(TTR) that was significantly better than the improvement seen in medical
centers without the intervention.
“Insufficient attention has been given in the past to how we can improve the management of warfarin,” said Adam Rose, MD, of Boston University School of Medicine in Massachusetts.
“This study demonstrates that a relatively simple approach can have a large impact.”
Dr Rose and his colleagues described this study in the Annals of Pharmacotherapy.
Intervention
The researchers implemented the intervention at 8 VA sites in New England known as Veterans Integrated Service Network 1 (VISN 1).
The team described the intervention as performance measurement augmented by targeted audit and feedback. Performance was measured via an online reporting system—known as a dashboard—that provided real-time data to clinicians.
The dashboard reported TTR at the patient and site level. The dashboard also reported processes of care that have been linked to TTR, including timely follow-up when the international normalized ratio (INR) is very low or very high, gaps in monitoring, and the proportion of patients with a mean INR value between 2.3 and 2.7.
The dashboard allowed clinicians to call patients who had been lost to follow-up, had low TTR, or were in need of urgent follow-up as a result of extreme INR values.
Results
The researchers examined changes in anticoagulation control, measured as TTR, after the intervention was implemented. They compared changes at VISN 1 sites with 116 other VA sites.
A total of 11,794 patients within VISN 1 and 1,248,782 patients outside of VISN 1 received warfarin for at least part of the study period.
At VISN 1 sites, TTR improved from 66.4% to 69.2%. At the other sites, TTR improved from 65.9% to 66.4% (P<0.001 for the between-group difference).
The researchers said improvement in TTR correlated strongly with the extent of improvement on process-of-care measures, which varied widely across VISN 1 sites.
“Patients who used these measures did better clinically than those in the control group,” Dr Rose said. “This study serves as a model for how other sites and health networks could feasibly approach improving the management of warfarin in their systems.”
“If all anticoagulation clinics in the VA were to achieve this level of improvement, it would prevent 48 strokes and 68 major bleeding events each year, with a savings to the VA system of more than $4 million annually.”
Photo courtesy of NIGMS
Researchers have developed an intervention intended to help hospitals and clinicians improve the management of patients on warfarin.
The team implemented the intervention at 8 medical centers in the New England region of the Veterans Health Administration (VA).
These
centers saw an improvement in time in the therapeutic range
(TTR) that was significantly better than the improvement seen in medical
centers without the intervention.
“Insufficient attention has been given in the past to how we can improve the management of warfarin,” said Adam Rose, MD, of Boston University School of Medicine in Massachusetts.
“This study demonstrates that a relatively simple approach can have a large impact.”
Dr Rose and his colleagues described this study in the Annals of Pharmacotherapy.
Intervention
The researchers implemented the intervention at 8 VA sites in New England known as Veterans Integrated Service Network 1 (VISN 1).
The team described the intervention as performance measurement augmented by targeted audit and feedback. Performance was measured via an online reporting system—known as a dashboard—that provided real-time data to clinicians.
The dashboard reported TTR at the patient and site level. The dashboard also reported processes of care that have been linked to TTR, including timely follow-up when the international normalized ratio (INR) is very low or very high, gaps in monitoring, and the proportion of patients with a mean INR value between 2.3 and 2.7.
The dashboard allowed clinicians to call patients who had been lost to follow-up, had low TTR, or were in need of urgent follow-up as a result of extreme INR values.
Results
The researchers examined changes in anticoagulation control, measured as TTR, after the intervention was implemented. They compared changes at VISN 1 sites with 116 other VA sites.
A total of 11,794 patients within VISN 1 and 1,248,782 patients outside of VISN 1 received warfarin for at least part of the study period.
At VISN 1 sites, TTR improved from 66.4% to 69.2%. At the other sites, TTR improved from 65.9% to 66.4% (P<0.001 for the between-group difference).
The researchers said improvement in TTR correlated strongly with the extent of improvement on process-of-care measures, which varied widely across VISN 1 sites.
“Patients who used these measures did better clinically than those in the control group,” Dr Rose said. “This study serves as a model for how other sites and health networks could feasibly approach improving the management of warfarin in their systems.”
“If all anticoagulation clinics in the VA were to achieve this level of improvement, it would prevent 48 strokes and 68 major bleeding events each year, with a savings to the VA system of more than $4 million annually.”
Shorter Length of Stay May Not Mean Higher Readmission Rates
Length of stay (LOS) in hospitals may drop, but it doesn’t necessarily lead to higher readmission rates, according to a study by Kyoto University researchers.
In Japan, the researchers say, acute care hospital stays are longer than in other developed countries but have shortened over the past decade—mainly due to the Diagnosis Procedure Combination Per-Diem Payment System (DPC/PDPS). Under that system, introduced in 2003, hospital reimbursements from insurers reduce as LOS increases for individual patients.
Related: Risk of Readmission After Pneumonia
Concerns that excessive reductions might worsen the quality of health care led the researchers to investigate what the last 10 years of DPC/PDPS have meant for early-stage cancer surgical patients.
They analyzed 4 years of data from 804 hospitals on 42,585 surgical patients with gastric cancer, 40,156 with lung cancer, and 15,467 with colon cancer, comparing LOS with unplanned readmissions within 30 days.
They found LOS was reduced—although slightly—by about 0.5 d/y. Mean overall LOS for gastric cancer patients dropped from 21.85 days to 19.89; for lung cancer patients, from 15.61 to 14.25; for colon cancer patients, from 18.70 to 17.18.
Related: Survival After Long-Term Residence in an Intensive Care Unit
However, unplanned emergency readmission rates remained relatively stable at about 2% or declined slightly. Readmission rates were significantly lower only for lung cancer patients; declines were not significant for the other groups.
Both preoperative and postoperative LOS also decreased during the study period. In particular, the researchers note, improvements in postoperative care may have shortened LOS. They also suggest that downward trends reflect improvements due to better medical techniques, procedure choices, and advances in clinical pathways.
Source:
Kunisawa S, Fushimi K, Imanaka Y. PLoS One. 2016;11(11): e0166269.
doi: 10.1371/journal.pone.0166269.
Length of stay (LOS) in hospitals may drop, but it doesn’t necessarily lead to higher readmission rates, according to a study by Kyoto University researchers.
In Japan, the researchers say, acute care hospital stays are longer than in other developed countries but have shortened over the past decade—mainly due to the Diagnosis Procedure Combination Per-Diem Payment System (DPC/PDPS). Under that system, introduced in 2003, hospital reimbursements from insurers reduce as LOS increases for individual patients.
Related: Risk of Readmission After Pneumonia
Concerns that excessive reductions might worsen the quality of health care led the researchers to investigate what the last 10 years of DPC/PDPS have meant for early-stage cancer surgical patients.
They analyzed 4 years of data from 804 hospitals on 42,585 surgical patients with gastric cancer, 40,156 with lung cancer, and 15,467 with colon cancer, comparing LOS with unplanned readmissions within 30 days.
They found LOS was reduced—although slightly—by about 0.5 d/y. Mean overall LOS for gastric cancer patients dropped from 21.85 days to 19.89; for lung cancer patients, from 15.61 to 14.25; for colon cancer patients, from 18.70 to 17.18.
Related: Survival After Long-Term Residence in an Intensive Care Unit
However, unplanned emergency readmission rates remained relatively stable at about 2% or declined slightly. Readmission rates were significantly lower only for lung cancer patients; declines were not significant for the other groups.
Both preoperative and postoperative LOS also decreased during the study period. In particular, the researchers note, improvements in postoperative care may have shortened LOS. They also suggest that downward trends reflect improvements due to better medical techniques, procedure choices, and advances in clinical pathways.
Source:
Kunisawa S, Fushimi K, Imanaka Y. PLoS One. 2016;11(11): e0166269.
doi: 10.1371/journal.pone.0166269.
Length of stay (LOS) in hospitals may drop, but it doesn’t necessarily lead to higher readmission rates, according to a study by Kyoto University researchers.
In Japan, the researchers say, acute care hospital stays are longer than in other developed countries but have shortened over the past decade—mainly due to the Diagnosis Procedure Combination Per-Diem Payment System (DPC/PDPS). Under that system, introduced in 2003, hospital reimbursements from insurers reduce as LOS increases for individual patients.
Related: Risk of Readmission After Pneumonia
Concerns that excessive reductions might worsen the quality of health care led the researchers to investigate what the last 10 years of DPC/PDPS have meant for early-stage cancer surgical patients.
They analyzed 4 years of data from 804 hospitals on 42,585 surgical patients with gastric cancer, 40,156 with lung cancer, and 15,467 with colon cancer, comparing LOS with unplanned readmissions within 30 days.
They found LOS was reduced—although slightly—by about 0.5 d/y. Mean overall LOS for gastric cancer patients dropped from 21.85 days to 19.89; for lung cancer patients, from 15.61 to 14.25; for colon cancer patients, from 18.70 to 17.18.
Related: Survival After Long-Term Residence in an Intensive Care Unit
However, unplanned emergency readmission rates remained relatively stable at about 2% or declined slightly. Readmission rates were significantly lower only for lung cancer patients; declines were not significant for the other groups.
Both preoperative and postoperative LOS also decreased during the study period. In particular, the researchers note, improvements in postoperative care may have shortened LOS. They also suggest that downward trends reflect improvements due to better medical techniques, procedure choices, and advances in clinical pathways.
Source:
Kunisawa S, Fushimi K, Imanaka Y. PLoS One. 2016;11(11): e0166269.
doi: 10.1371/journal.pone.0166269.
How Many Shades of Gray?
The hyperpigmentation on both of this 56-year-old man’s legs is asymptomatic. But it has steadily worsened, causing him a great deal of distress.
A few months before the dyschromia manifested, he underwent orthopedic surgery and developed a postop infection. He was prescribed minocycline. As of today, he has been taking a 100-mg bid dose for three months.
He is otherwise healthy and not taking any other medications.
EXAMINATION
From the knees down, both legs display marked circumferential, bluish gray hyperpigmentation. It is not seen on any other areas (eg, arms, face, sclerae, or trunk).
What is the diagnosis?
This type of bluish gray hyperpigmentation is an uncommon idiosyncratic effect of minocycline ingestion. Although long-term, high-dose use of the drug is usually responsible, hyperpigmentation has been reported with short-term use at relatively low doses. The most common presentation is in acne patients taking minocycline who notice color changes in their gums, sclerae, and nail beds.
Four distinct variations of hyperpigmentation have been described: a slate gray color on the face, a circumscribed distribution on arms and legs, a diffuse muddy brown discoloration on sun-exposed skin, and development on the thorax in old scars. In addition to affecting the skin, it can stain internal organs, heart valves, joints, and bones. Biopsy will reveal pigment granules in dendritic cells and extracellularly in the dermis.
In some cases, the discoloration can be permanent, but it typically clears upon cessation of the offending drug. In this particular case, the benefits of minocycline outweighed any concern about the dyschromia. Alternately, a 755-nm Q-switched alexandrite laser has been used successfully.
There are numerous causes of dyschromia, including other drugs (eg, antimalarials, amiodarones, gold and silver salts) and medical conditions (eg, Addison disease, onchronosis).
TAKE-HOME LEARNING POINTS
- Though uncommon, there is an association between minocycline use and various forms of hyperpigmentation.
- The discoloration ranges from slate gray to muddy brown and can be seen on the sclerae, face, gums, trunk, and legs, as well as in scars.
- Though more common with long-term, high-dose use of the drug, dyschromia has been reported after as little as three months of therapy.
- Other drugs that can cause hyperpigmentation include antimalarials, amiodarone, and silver and gold salts.
- Most cases resolve upon cessation of the drug; for those that don’t, a 755-nm Q-switched alexandrite laser is effective.
The hyperpigmentation on both of this 56-year-old man’s legs is asymptomatic. But it has steadily worsened, causing him a great deal of distress.
A few months before the dyschromia manifested, he underwent orthopedic surgery and developed a postop infection. He was prescribed minocycline. As of today, he has been taking a 100-mg bid dose for three months.
He is otherwise healthy and not taking any other medications.
EXAMINATION
From the knees down, both legs display marked circumferential, bluish gray hyperpigmentation. It is not seen on any other areas (eg, arms, face, sclerae, or trunk).
What is the diagnosis?
This type of bluish gray hyperpigmentation is an uncommon idiosyncratic effect of minocycline ingestion. Although long-term, high-dose use of the drug is usually responsible, hyperpigmentation has been reported with short-term use at relatively low doses. The most common presentation is in acne patients taking minocycline who notice color changes in their gums, sclerae, and nail beds.
Four distinct variations of hyperpigmentation have been described: a slate gray color on the face, a circumscribed distribution on arms and legs, a diffuse muddy brown discoloration on sun-exposed skin, and development on the thorax in old scars. In addition to affecting the skin, it can stain internal organs, heart valves, joints, and bones. Biopsy will reveal pigment granules in dendritic cells and extracellularly in the dermis.
In some cases, the discoloration can be permanent, but it typically clears upon cessation of the offending drug. In this particular case, the benefits of minocycline outweighed any concern about the dyschromia. Alternately, a 755-nm Q-switched alexandrite laser has been used successfully.
There are numerous causes of dyschromia, including other drugs (eg, antimalarials, amiodarones, gold and silver salts) and medical conditions (eg, Addison disease, onchronosis).
TAKE-HOME LEARNING POINTS
- Though uncommon, there is an association between minocycline use and various forms of hyperpigmentation.
- The discoloration ranges from slate gray to muddy brown and can be seen on the sclerae, face, gums, trunk, and legs, as well as in scars.
- Though more common with long-term, high-dose use of the drug, dyschromia has been reported after as little as three months of therapy.
- Other drugs that can cause hyperpigmentation include antimalarials, amiodarone, and silver and gold salts.
- Most cases resolve upon cessation of the drug; for those that don’t, a 755-nm Q-switched alexandrite laser is effective.
The hyperpigmentation on both of this 56-year-old man’s legs is asymptomatic. But it has steadily worsened, causing him a great deal of distress.
A few months before the dyschromia manifested, he underwent orthopedic surgery and developed a postop infection. He was prescribed minocycline. As of today, he has been taking a 100-mg bid dose for three months.
He is otherwise healthy and not taking any other medications.
EXAMINATION
From the knees down, both legs display marked circumferential, bluish gray hyperpigmentation. It is not seen on any other areas (eg, arms, face, sclerae, or trunk).
What is the diagnosis?
This type of bluish gray hyperpigmentation is an uncommon idiosyncratic effect of minocycline ingestion. Although long-term, high-dose use of the drug is usually responsible, hyperpigmentation has been reported with short-term use at relatively low doses. The most common presentation is in acne patients taking minocycline who notice color changes in their gums, sclerae, and nail beds.
Four distinct variations of hyperpigmentation have been described: a slate gray color on the face, a circumscribed distribution on arms and legs, a diffuse muddy brown discoloration on sun-exposed skin, and development on the thorax in old scars. In addition to affecting the skin, it can stain internal organs, heart valves, joints, and bones. Biopsy will reveal pigment granules in dendritic cells and extracellularly in the dermis.
In some cases, the discoloration can be permanent, but it typically clears upon cessation of the offending drug. In this particular case, the benefits of minocycline outweighed any concern about the dyschromia. Alternately, a 755-nm Q-switched alexandrite laser has been used successfully.
There are numerous causes of dyschromia, including other drugs (eg, antimalarials, amiodarones, gold and silver salts) and medical conditions (eg, Addison disease, onchronosis).
TAKE-HOME LEARNING POINTS
- Though uncommon, there is an association between minocycline use and various forms of hyperpigmentation.
- The discoloration ranges from slate gray to muddy brown and can be seen on the sclerae, face, gums, trunk, and legs, as well as in scars.
- Though more common with long-term, high-dose use of the drug, dyschromia has been reported after as little as three months of therapy.
- Other drugs that can cause hyperpigmentation include antimalarials, amiodarone, and silver and gold salts.
- Most cases resolve upon cessation of the drug; for those that don’t, a 755-nm Q-switched alexandrite laser is effective.