In the previous two editions of this column, I have written about the new Medicare Access and CHIP Reauthorization Act (MACRA) and the changes it will bring to Medicare physician payment beginning in January 2019 with the Merit-Based Incentive Payment System (MIPS). In June’s column, three of the four MIPS performance categories were outlined. Specifically, those include the Quality, Resource Use, and Electronic Health Record Meaningful Use components and encompass the Physician Quality Reporting System (PQRS), Value-Based Modifier (VBM), Physician Quality Reporting System (PQRS), and Electronic Health Record Meaningful Use (EHR-MU) programs with which Fellows are hopefully familiar. As promised, this month I will discuss the final performance category component, namely the Clinical Practice Improvement Activities (CPIA) as well as the Alternative Payment Models program (APMs). Lastly, I wish to bring to the attention of Fellows a new web-based resource developed by the ACS Division of Advocacy and Health Policy to assist them in avoiding current law Medicare penalties.

The CPIA are designed to assess and credit surgeons according to their effort toward improving their clinical practice OR their preparation toward participating in the APMs. The menu of specific, recognized activities will be established in collaboration with the Centers for Medicare & Medicaid Services and the providers to whom the activities will be applicable. Many of the specifics are yet to be determined and will be part of the rule-making process in coming years. However, the MACRA legislation specifies that the CPIA must be applicable to all specialties and be attainable for small practices and professionals in rural and underserved areas. To support the efforts of surgeons and other providers in small or rural practice, Congress set aside $20 million dollars for each year, 2016-2020, for technical assistance to support the efforts of practices with 15 or fewer professionals to improve MIPS performance or transition to APMs.

The new law takes concerted steps to incentivize and encourage the development of and participation in APMs. As with the CPIA outlined above, the details of APMs are not yet fully clear and will be established going forward. However, in general, these programs will base payment on quality measures, not volume or intensity, and will include an element of financial risk for providers. For those surgeons who receive a significant share of their revenue from an APM, an annual 5% bonus will be available for each of the years 2019-2024. To qualify for that bonus surgeons must receive 25% of their Medicare revenue from an APM in the years 2019 and 2020, with the requirement subsequently increasing to 50% in 2021 and ultimately to 75% beginning in 2023. Providers may qualify based on a combination of private APMs and Medicare APMs as well.

In recognition of the lack of APMs in many areas or applicability for many specialties, MACRA prioritizes development of models for small practices, models that are specialty specific, and model development in conjunction with private payers as well as Medicaid-based options, all with the ultimate goal of encouraging the development of new and innovative payment models. The legislative language in MACRA is broad enough that it may allow for creation of a model based on the ACS’ Clinical Affinity Group (CAG) concept whereby providers are grouped together based on the patients or conditions that they treat, not their specialty designation.

Surgeons who meet a threshold of payment received from a qualified APM will be exempted from participation in MIPS to include most EHR-MU requirements and also receive the 5% bonus as described above. Those who participate in an APM but fail to meet the threshold necessary to receive that bonus will receive credit for such in the CPIA portion of their MIPS composite score.

Finally, even though the permanent repeal of the SGR found in MACRA represents the successful culmination of long-standing, combined advocacy efforts of the American College of Surgeons (ACS) and other medical associations toward meaningful, future Medicare physician payment reform, Fellows should be well aware that the three current law Medicare quality programs, namely the PQRS, EHR-MU, and VBM and their corresponding requirements as well as their associated penalties remain in effect until January 2019.

Surgeons who do not successfully participate in the PQRS, EHR-MU, and VBM face significant penalties on future Medicare payments. Specifically, failure to meet the requirements imposed by these three programs in 2015 could result in total penalties of up to 9% in Medicare payments in 2017.

To assist Fellows in navigating the complexities of complying with current law quality program requirements and thus avoid Medicare penalties, the ACS Division of Advocacy and Health Policy has developed a new online interactive flowchart which can be found at [WEB ADDRESS]. Fellows may wish to refer to and bookmark this page as an ongoing reference in order to familiarize themselves with current law requirements, facilitate their individual compliance with same, and thus successfully avoid penalties. As always, Fellows with questions may contact the DAHP at 202-337-2701.

Until next month ….

Dr. Bailey is a pediatric surgeon and Medical Director, Advocacy for the Division of Advocacy and Health Policy in the ACS offices in Washington, D.C.

In the previous two editions of this column, I have written about the new Medicare Access and CHIP Reauthorization Act (MACRA) and the changes it will bring to Medicare physician payment beginning in January 2019 with the Merit-Based Incentive Payment System (MIPS). In June’s column, three of the four MIPS performance categories were outlined. Specifically, those include the Quality, Resource Use, and Electronic Health Record Meaningful Use components and encompass the Physician Quality Reporting System (PQRS), Value-Based Modifier (VBM), Physician Quality Reporting System (PQRS), and Electronic Health Record Meaningful Use (EHR-MU) programs with which Fellows are hopefully familiar. As promised, this month I will discuss the final performance category component, namely the Clinical Practice Improvement Activities (CPIA) as well as the Alternative Payment Models program (APMs). Lastly, I wish to bring to the attention of Fellows a new web-based resource developed by the ACS Division of Advocacy and Health Policy to assist them in avoiding current law Medicare penalties.

The CPIA are designed to assess and credit surgeons according to their effort toward improving their clinical practice OR their preparation toward participating in the APMs. The menu of specific, recognized activities will be established in collaboration with the Centers for Medicare & Medicaid Services and the providers to whom the activities will be applicable. Many of the specifics are yet to be determined and will be part of the rule-making process in coming years. However, the MACRA legislation specifies that the CPIA must be applicable to all specialties and be attainable for small practices and professionals in rural and underserved areas. To support the efforts of surgeons and other providers in small or rural practice, Congress set aside $20 million dollars for each year, 2016-2020, for technical assistance to support the efforts of practices with 15 or fewer professionals to improve MIPS performance or transition to APMs.

The new law takes concerted steps to incentivize and encourage the development of and participation in APMs. As with the CPIA outlined above, the details of APMs are not yet fully clear and will be established going forward. However, in general, these programs will base payment on quality measures, not volume or intensity, and will include an element of financial risk for providers. For those surgeons who receive a significant share of their revenue from an APM, an annual 5% bonus will be available for each of the years 2019-2024. To qualify for that bonus surgeons must receive 25% of their Medicare revenue from an APM in the years 2019 and 2020, with the requirement subsequently increasing to 50% in 2021 and ultimately to 75% beginning in 2023. Providers may qualify based on a combination of private APMs and Medicare APMs as well.

In recognition of the lack of APMs in many areas or applicability for many specialties, MACRA prioritizes development of models for small practices, models that are specialty specific, and model development in conjunction with private payers as well as Medicaid-based options, all with the ultimate goal of encouraging the development of new and innovative payment models. The legislative language in MACRA is broad enough that it may allow for creation of a model based on the ACS’ Clinical Affinity Group (CAG) concept whereby providers are grouped together based on the patients or conditions that they treat, not their specialty designation.

Surgeons who meet a threshold of payment received from a qualified APM will be exempted from participation in MIPS to include most EHR-MU requirements and also receive the 5% bonus as described above. Those who participate in an APM but fail to meet the threshold necessary to receive that bonus will receive credit for such in the CPIA portion of their MIPS composite score.

Finally, even though the permanent repeal of the SGR found in MACRA represents the successful culmination of long-standing, combined advocacy efforts of the American College of Surgeons (ACS) and other medical associations toward meaningful, future Medicare physician payment reform, Fellows should be well aware that the three current law Medicare quality programs, namely the PQRS, EHR-MU, and VBM and their corresponding requirements as well as their associated penalties remain in effect until January 2019.

Surgeons who do not successfully participate in the PQRS, EHR-MU, and VBM face significant penalties on future Medicare payments. Specifically, failure to meet the requirements imposed by these three programs in 2015 could result in total penalties of up to 9% in Medicare payments in 2017.

To assist Fellows in navigating the complexities of complying with current law quality program requirements and thus avoid Medicare penalties, the ACS Division of Advocacy and Health Policy has developed a new online interactive flowchart which can be found at [WEB ADDRESS]. Fellows may wish to refer to and bookmark this page as an ongoing reference in order to familiarize themselves with current law requirements, facilitate their individual compliance with same, and thus successfully avoid penalties. As always, Fellows with questions may contact the DAHP at 202-337-2701.

Until next month ….

Dr. Bailey is a pediatric surgeon and Medical Director, Advocacy for the Division of Advocacy and Health Policy in the ACS offices in Washington, D.C.

In the previous two editions of this column, I have written about the new Medicare Access and CHIP Reauthorization Act (MACRA) and the changes it will bring to Medicare physician payment beginning in January 2019 with the Merit-Based Incentive Payment System (MIPS). In June’s column, three of the four MIPS performance categories were outlined. Specifically, those include the Quality, Resource Use, and Electronic Health Record Meaningful Use components and encompass the Physician Quality Reporting System (PQRS), Value-Based Modifier (VBM), Physician Quality Reporting System (PQRS), and Electronic Health Record Meaningful Use (EHR-MU) programs with which Fellows are hopefully familiar. As promised, this month I will discuss the final performance category component, namely the Clinical Practice Improvement Activities (CPIA) as well as the Alternative Payment Models program (APMs). Lastly, I wish to bring to the attention of Fellows a new web-based resource developed by the ACS Division of Advocacy and Health Policy to assist them in avoiding current law Medicare penalties.

The CPIA are designed to assess and credit surgeons according to their effort toward improving their clinical practice OR their preparation toward participating in the APMs. The menu of specific, recognized activities will be established in collaboration with the Centers for Medicare & Medicaid Services and the providers to whom the activities will be applicable. Many of the specifics are yet to be determined and will be part of the rule-making process in coming years. However, the MACRA legislation specifies that the CPIA must be applicable to all specialties and be attainable for small practices and professionals in rural and underserved areas. To support the efforts of surgeons and other providers in small or rural practice, Congress set aside $20 million dollars for each year, 2016-2020, for technical assistance to support the efforts of practices with 15 or fewer professionals to improve MIPS performance or transition to APMs.

The new law takes concerted steps to incentivize and encourage the development of and participation in APMs. As with the CPIA outlined above, the details of APMs are not yet fully clear and will be established going forward. However, in general, these programs will base payment on quality measures, not volume or intensity, and will include an element of financial risk for providers. For those surgeons who receive a significant share of their revenue from an APM, an annual 5% bonus will be available for each of the years 2019-2024. To qualify for that bonus surgeons must receive 25% of their Medicare revenue from an APM in the years 2019 and 2020, with the requirement subsequently increasing to 50% in 2021 and ultimately to 75% beginning in 2023. Providers may qualify based on a combination of private APMs and Medicare APMs as well.

In recognition of the lack of APMs in many areas or applicability for many specialties, MACRA prioritizes development of models for small practices, models that are specialty specific, and model development in conjunction with private payers as well as Medicaid-based options, all with the ultimate goal of encouraging the development of new and innovative payment models. The legislative language in MACRA is broad enough that it may allow for creation of a model based on the ACS’ Clinical Affinity Group (CAG) concept whereby providers are grouped together based on the patients or conditions that they treat, not their specialty designation.

Surgeons who meet a threshold of payment received from a qualified APM will be exempted from participation in MIPS to include most EHR-MU requirements and also receive the 5% bonus as described above. Those who participate in an APM but fail to meet the threshold necessary to receive that bonus will receive credit for such in the CPIA portion of their MIPS composite score.

Finally, even though the permanent repeal of the SGR found in MACRA represents the successful culmination of long-standing, combined advocacy efforts of the American College of Surgeons (ACS) and other medical associations toward meaningful, future Medicare physician payment reform, Fellows should be well aware that the three current law Medicare quality programs, namely the PQRS, EHR-MU, and VBM and their corresponding requirements as well as their associated penalties remain in effect until January 2019.

Surgeons who do not successfully participate in the PQRS, EHR-MU, and VBM face significant penalties on future Medicare payments. Specifically, failure to meet the requirements imposed by these three programs in 2015 could result in total penalties of up to 9% in Medicare payments in 2017.

To assist Fellows in navigating the complexities of complying with current law quality program requirements and thus avoid Medicare penalties, the ACS Division of Advocacy and Health Policy has developed a new online interactive flowchart which can be found at [WEB ADDRESS]. Fellows may wish to refer to and bookmark this page as an ongoing reference in order to familiarize themselves with current law requirements, facilitate their individual compliance with same, and thus successfully avoid penalties. As always, Fellows with questions may contact the DAHP at 202-337-2701.

Until next month ….

Dr. Bailey is a pediatric surgeon and Medical Director, Advocacy for the Division of Advocacy and Health Policy in the ACS offices in Washington, D.C.

Hematopoietic colony-stimulating factors should now be considered for patients who are over age 64 years, have diffuse aggressive lymphoma, and are receiving curative chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab), particularly those who have comorbidities.

This is one of several recommendations noted in the American Society of Clinical Oncology’s updated practice guidelines, published online in the Journal of Clinical Oncology, on the use of hematopoietic colony-stimulating factors (CSFs) to prevent or treat neutropenia and its complications in adults and children receiving chemotherapy.

This “moderately strong” recommendation is based on a single randomized clinical trial that found pegfilgrastim significantly reduced the risk of febrile neutropenia in this patient population, according to the guidelines (J. Clin. Oncol. 2015 July 13 [doi:10.1200/JCO.2015.62.3488]).

The updated guideline incorporates new evidence from 66 randomized controlled trials and meta-analyses published since its last update in 2006, said cochair Dr. Thomas J. Smith of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, and his associates on the update committee.

In addition to pegfilgrastim and filgrastim, the guideline now addresses the use of tbo-filgrastim, filgrastim-sndz, and other biosimilars as they become available. These new agents are effective at preventing chemotherapy-related febrile neutropenia, so the choice of agent depends on convenience, cost, and clinical factors, and in some cases may be dictated by the patient’s treatment schedule. Certain off-label uses of pegfilgrastim can now be considered, such as giving it on the same day as chemotherapy if that is the only feasible timing for some patients.

CSFs should only be used to enable dose-dense chemotherapy regimens “if supported by convincing efficacy data or within an appropriately designed clinical trial” – for example, to support treatment of urothelial cancer or high-risk breast cancer targeted with high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin.

In contrast, the use of CSFs to enable dose-dense chemotherapy for Hodgkin lymphoma is not recommended at this time because the current data supporting such use are limited and conflicting. Similarly, the current evidence strongly argues against giving CSFs to enable dose-dense chemotherapy for other lymphomas, lung cancer, ovarian cancer, osteosarcoma, or sarcoma.

The guideline update was supported by the American Society of Clinical Oncology. Dr. Smith reported stock or other ownership in United Healthcare; his associates reported ties to numerous industry sources.

The full guideline and supplementary material, including slide sets and clinical tools, are available at www.asco.org/guidelines/wbcgf.

Hematopoietic colony-stimulating factors should now be considered for patients who are over age 64 years, have diffuse aggressive lymphoma, and are receiving curative chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab), particularly those who have comorbidities.

This is one of several recommendations noted in the American Society of Clinical Oncology’s updated practice guidelines, published online in the Journal of Clinical Oncology, on the use of hematopoietic colony-stimulating factors (CSFs) to prevent or treat neutropenia and its complications in adults and children receiving chemotherapy.

This “moderately strong” recommendation is based on a single randomized clinical trial that found pegfilgrastim significantly reduced the risk of febrile neutropenia in this patient population, according to the guidelines (J. Clin. Oncol. 2015 July 13 [doi:10.1200/JCO.2015.62.3488]).

The updated guideline incorporates new evidence from 66 randomized controlled trials and meta-analyses published since its last update in 2006, said cochair Dr. Thomas J. Smith of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, and his associates on the update committee.

In addition to pegfilgrastim and filgrastim, the guideline now addresses the use of tbo-filgrastim, filgrastim-sndz, and other biosimilars as they become available. These new agents are effective at preventing chemotherapy-related febrile neutropenia, so the choice of agent depends on convenience, cost, and clinical factors, and in some cases may be dictated by the patient’s treatment schedule. Certain off-label uses of pegfilgrastim can now be considered, such as giving it on the same day as chemotherapy if that is the only feasible timing for some patients.

CSFs should only be used to enable dose-dense chemotherapy regimens “if supported by convincing efficacy data or within an appropriately designed clinical trial” – for example, to support treatment of urothelial cancer or high-risk breast cancer targeted with high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin.

In contrast, the use of CSFs to enable dose-dense chemotherapy for Hodgkin lymphoma is not recommended at this time because the current data supporting such use are limited and conflicting. Similarly, the current evidence strongly argues against giving CSFs to enable dose-dense chemotherapy for other lymphomas, lung cancer, ovarian cancer, osteosarcoma, or sarcoma.

The guideline update was supported by the American Society of Clinical Oncology. Dr. Smith reported stock or other ownership in United Healthcare; his associates reported ties to numerous industry sources.

The full guideline and supplementary material, including slide sets and clinical tools, are available at www.asco.org/guidelines/wbcgf.

Hematopoietic colony-stimulating factors should now be considered for patients who are over age 64 years, have diffuse aggressive lymphoma, and are receiving curative chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab), particularly those who have comorbidities.

This is one of several recommendations noted in the American Society of Clinical Oncology’s updated practice guidelines, published online in the Journal of Clinical Oncology, on the use of hematopoietic colony-stimulating factors (CSFs) to prevent or treat neutropenia and its complications in adults and children receiving chemotherapy.

This “moderately strong” recommendation is based on a single randomized clinical trial that found pegfilgrastim significantly reduced the risk of febrile neutropenia in this patient population, according to the guidelines (J. Clin. Oncol. 2015 July 13 [doi:10.1200/JCO.2015.62.3488]).

The updated guideline incorporates new evidence from 66 randomized controlled trials and meta-analyses published since its last update in 2006, said cochair Dr. Thomas J. Smith of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, and his associates on the update committee.

In addition to pegfilgrastim and filgrastim, the guideline now addresses the use of tbo-filgrastim, filgrastim-sndz, and other biosimilars as they become available. These new agents are effective at preventing chemotherapy-related febrile neutropenia, so the choice of agent depends on convenience, cost, and clinical factors, and in some cases may be dictated by the patient’s treatment schedule. Certain off-label uses of pegfilgrastim can now be considered, such as giving it on the same day as chemotherapy if that is the only feasible timing for some patients.

CSFs should only be used to enable dose-dense chemotherapy regimens “if supported by convincing efficacy data or within an appropriately designed clinical trial” – for example, to support treatment of urothelial cancer or high-risk breast cancer targeted with high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin.

In contrast, the use of CSFs to enable dose-dense chemotherapy for Hodgkin lymphoma is not recommended at this time because the current data supporting such use are limited and conflicting. Similarly, the current evidence strongly argues against giving CSFs to enable dose-dense chemotherapy for other lymphomas, lung cancer, ovarian cancer, osteosarcoma, or sarcoma.

The guideline update was supported by the American Society of Clinical Oncology. Dr. Smith reported stock or other ownership in United Healthcare; his associates reported ties to numerous industry sources.

The full guideline and supplementary material, including slide sets and clinical tools, are available at www.asco.org/guidelines/wbcgf.

PARIS – Antithrombotic therapy with bivalirudin for primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction may have been unfairly tarnished as having a high stent thrombosis rate, according to a large, prospective, observational cohort study.

A new analysis from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) showed similarly low stent thrombosis rates within 30 days following primary PCI for STEMI regardless of whether the antithrombotic regimen involved bivalirudin (Angiomax), heparin only, or a glycoprotein IIb/IIIa inhibitor, Dr. Per Grimfjard reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

Bruce Jancin/Frontline Medical News

The SCAAR analysis captured all STEMI patients undergoing primary PCI in Sweden from 2007 through mid-2014. These data reflect real-world interventional practice in Sweden and elsewhere, where bivalirudin is typically administered in a prolonged infusion to protect against early stent thrombosis. In contrast, the randomized trials that linked bivalirudin to high stent thrombosis rates featured protocols in which the drug was stopped immediately after the procedure, noted Dr. Grimfjard, an interventional cardiologist at Uppsala (Sweden) University.

“These are nationwide Swedish numbers, and they are complete. We think the numbers are reassuring in that respect,” he said.

Session chair Dr. Andreas Baumbach said the Swedish data are consistent with his own experience in using bivalirudin in primary PCI for STEMI.

“The headline last year was that bivalirudin has a high stent thrombosis rate. It made the newspapers everywhere. But we never saw that, and we always thought that the difference might be in how we used the drug. There’s a new headline now, that this high stent thrombosis rate is not seen in clinical practice. The practice differs from the randomized trials, and the outcomes differ as well,” observed Dr. Baumbach, professor of interventional cardiology at the University of Bristol (England).

In SCAAR, the 30-day rate of definite, angiographically proven stent thrombosis was 0.84% in 16,860 bivalirudin-treated patients, 0.94% in 3,182 who got heparin only, and 0.83% in 11,216 glycoprotein IIb/IIIa inhibitor recipients. These numeric differences weren’t statistically significant.

All-cause mortality 1 year post-PCI was 9.1% in patients with no stent thrombosis, 16.1% in those who experienced stent thrombosis within 1 day post PCI, and 23.0% in those whose stent thrombosis occurred on days 2-30. Dr. Grimfjard speculated that the explanation for the numerically higher 1-year all-cause mortality rate in patients whose stent thrombosis occurred on days 2-30 as opposed to day 0-1 is probably that they were more likely to have left the hospital when stent thrombosis occurred. That would translate to a longer time to repeat revascularization, hence a larger MI, more heart failure and arrhythmia, and thus a higher long-term risk of death.

Several audience members commented that they weren’t sure what to make of the observational Swedish data because of the looming presence of several potential confounders. For one, clinical practice trends changed considerably during the 7-year time frame of the study, as evidenced by the fact that the use of drug-eluting stents was far more common in bivalirudin-treated patients than in the glycoprotein IIb/IIIa inhibitor group. Also, Swedish cardiologists who put their STEMI patients on bivalirudin were more likely to utilize the more modern radial artery access in performing primary PCI; their practice may have differed from their colleagues’ in other, unrecorded ways as well, it was noted.

Dr. Grimfjard reported having no financial conflicts regarding the study, which was conducted free of commercial support.

bjancin@frontlinemedcom.com

PARIS – Antithrombotic therapy with bivalirudin for primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction may have been unfairly tarnished as having a high stent thrombosis rate, according to a large, prospective, observational cohort study.

A new analysis from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) showed similarly low stent thrombosis rates within 30 days following primary PCI for STEMI regardless of whether the antithrombotic regimen involved bivalirudin (Angiomax), heparin only, or a glycoprotein IIb/IIIa inhibitor, Dr. Per Grimfjard reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

Bruce Jancin/Frontline Medical News

The SCAAR analysis captured all STEMI patients undergoing primary PCI in Sweden from 2007 through mid-2014. These data reflect real-world interventional practice in Sweden and elsewhere, where bivalirudin is typically administered in a prolonged infusion to protect against early stent thrombosis. In contrast, the randomized trials that linked bivalirudin to high stent thrombosis rates featured protocols in which the drug was stopped immediately after the procedure, noted Dr. Grimfjard, an interventional cardiologist at Uppsala (Sweden) University.

“These are nationwide Swedish numbers, and they are complete. We think the numbers are reassuring in that respect,” he said.

Session chair Dr. Andreas Baumbach said the Swedish data are consistent with his own experience in using bivalirudin in primary PCI for STEMI.

“The headline last year was that bivalirudin has a high stent thrombosis rate. It made the newspapers everywhere. But we never saw that, and we always thought that the difference might be in how we used the drug. There’s a new headline now, that this high stent thrombosis rate is not seen in clinical practice. The practice differs from the randomized trials, and the outcomes differ as well,” observed Dr. Baumbach, professor of interventional cardiology at the University of Bristol (England).

In SCAAR, the 30-day rate of definite, angiographically proven stent thrombosis was 0.84% in 16,860 bivalirudin-treated patients, 0.94% in 3,182 who got heparin only, and 0.83% in 11,216 glycoprotein IIb/IIIa inhibitor recipients. These numeric differences weren’t statistically significant.

All-cause mortality 1 year post-PCI was 9.1% in patients with no stent thrombosis, 16.1% in those who experienced stent thrombosis within 1 day post PCI, and 23.0% in those whose stent thrombosis occurred on days 2-30. Dr. Grimfjard speculated that the explanation for the numerically higher 1-year all-cause mortality rate in patients whose stent thrombosis occurred on days 2-30 as opposed to day 0-1 is probably that they were more likely to have left the hospital when stent thrombosis occurred. That would translate to a longer time to repeat revascularization, hence a larger MI, more heart failure and arrhythmia, and thus a higher long-term risk of death.

Several audience members commented that they weren’t sure what to make of the observational Swedish data because of the looming presence of several potential confounders. For one, clinical practice trends changed considerably during the 7-year time frame of the study, as evidenced by the fact that the use of drug-eluting stents was far more common in bivalirudin-treated patients than in the glycoprotein IIb/IIIa inhibitor group. Also, Swedish cardiologists who put their STEMI patients on bivalirudin were more likely to utilize the more modern radial artery access in performing primary PCI; their practice may have differed from their colleagues’ in other, unrecorded ways as well, it was noted.

Dr. Grimfjard reported having no financial conflicts regarding the study, which was conducted free of commercial support.

bjancin@frontlinemedcom.com

PARIS – Antithrombotic therapy with bivalirudin for primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction may have been unfairly tarnished as having a high stent thrombosis rate, according to a large, prospective, observational cohort study.

A new analysis from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) showed similarly low stent thrombosis rates within 30 days following primary PCI for STEMI regardless of whether the antithrombotic regimen involved bivalirudin (Angiomax), heparin only, or a glycoprotein IIb/IIIa inhibitor, Dr. Per Grimfjard reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

Bruce Jancin/Frontline Medical News

The SCAAR analysis captured all STEMI patients undergoing primary PCI in Sweden from 2007 through mid-2014. These data reflect real-world interventional practice in Sweden and elsewhere, where bivalirudin is typically administered in a prolonged infusion to protect against early stent thrombosis. In contrast, the randomized trials that linked bivalirudin to high stent thrombosis rates featured protocols in which the drug was stopped immediately after the procedure, noted Dr. Grimfjard, an interventional cardiologist at Uppsala (Sweden) University.

“These are nationwide Swedish numbers, and they are complete. We think the numbers are reassuring in that respect,” he said.

Session chair Dr. Andreas Baumbach said the Swedish data are consistent with his own experience in using bivalirudin in primary PCI for STEMI.

“The headline last year was that bivalirudin has a high stent thrombosis rate. It made the newspapers everywhere. But we never saw that, and we always thought that the difference might be in how we used the drug. There’s a new headline now, that this high stent thrombosis rate is not seen in clinical practice. The practice differs from the randomized trials, and the outcomes differ as well,” observed Dr. Baumbach, professor of interventional cardiology at the University of Bristol (England).

In SCAAR, the 30-day rate of definite, angiographically proven stent thrombosis was 0.84% in 16,860 bivalirudin-treated patients, 0.94% in 3,182 who got heparin only, and 0.83% in 11,216 glycoprotein IIb/IIIa inhibitor recipients. These numeric differences weren’t statistically significant.

All-cause mortality 1 year post-PCI was 9.1% in patients with no stent thrombosis, 16.1% in those who experienced stent thrombosis within 1 day post PCI, and 23.0% in those whose stent thrombosis occurred on days 2-30. Dr. Grimfjard speculated that the explanation for the numerically higher 1-year all-cause mortality rate in patients whose stent thrombosis occurred on days 2-30 as opposed to day 0-1 is probably that they were more likely to have left the hospital when stent thrombosis occurred. That would translate to a longer time to repeat revascularization, hence a larger MI, more heart failure and arrhythmia, and thus a higher long-term risk of death.

Several audience members commented that they weren’t sure what to make of the observational Swedish data because of the looming presence of several potential confounders. For one, clinical practice trends changed considerably during the 7-year time frame of the study, as evidenced by the fact that the use of drug-eluting stents was far more common in bivalirudin-treated patients than in the glycoprotein IIb/IIIa inhibitor group. Also, Swedish cardiologists who put their STEMI patients on bivalirudin were more likely to utilize the more modern radial artery access in performing primary PCI; their practice may have differed from their colleagues’ in other, unrecorded ways as well, it was noted.

Dr. Grimfjard reported having no financial conflicts regarding the study, which was conducted free of commercial support.

bjancin@frontlinemedcom.com

Adult lymphoma survivors who were treated with autologous hematopoietic stem-cell transplantation had a greater than sixfold increased risk of left ventricular systolic dysfunction compared with controls, according to a study published online in the Journal of Clinical Oncology.

Among 274 adult survivors of Hodgkin or non-Hodgkin lymphoma, 16% had left ventricular systolic dysfunction (LVSD): 11% had overt heart failure (HF) and 5% had asymptomatic LVSD, defined as a left ventricular ejection fraction of less than 50%.Heart symptoms were significantly associated with exposure to doxorubicin at a cumulative dose of 300 mg/m² or more and with cardiac radiation therapy of more than 30 Gy. Recognizing these patient risk factors allows for more intensive follow-up with the goal of “identification and early treatment of asymptomatic LVSD [which] may prevent the development of HF,” wrote Dr. Klaus Murbraech of Oslo University Hospital and his colleagues (J. Clin. Oncol. 2015 July 13 [doi:10.1200/JCO.2015.60.8125]).

The investigators observed no association between lower-dose cardiac radiation therapy and LVSD. There was only a marginally significant association between the presence of two or more traditional cardiovascular disease risk factors and LVSD.

The cross-sectional multicenter cohort study is the first to assess the prevalence of LVSD, according to Dr. Murbraech and his colleagues. The study included adult survivors of Hodgkin or non-Hodgkin lymphoma, median age 56 years, who underwent autologous stem-cell transplants in Norway from 1987 to 2008. The median observation time was 13 years (range, 4-34 years). The control group consisted of initially healthy patients in an echocardiographic follow-up study. Controls were matched to patients based on age, sex, systolic blood pressure, and body mass index.

The study was supported by the South-Eastern Norway Regional Health Authority and Extrastiftelsen. Dr. Murbraech reported having no disclosures.

Adult lymphoma survivors who were treated with autologous hematopoietic stem-cell transplantation had a greater than sixfold increased risk of left ventricular systolic dysfunction compared with controls, according to a study published online in the Journal of Clinical Oncology.

Among 274 adult survivors of Hodgkin or non-Hodgkin lymphoma, 16% had left ventricular systolic dysfunction (LVSD): 11% had overt heart failure (HF) and 5% had asymptomatic LVSD, defined as a left ventricular ejection fraction of less than 50%.Heart symptoms were significantly associated with exposure to doxorubicin at a cumulative dose of 300 mg/m² or more and with cardiac radiation therapy of more than 30 Gy. Recognizing these patient risk factors allows for more intensive follow-up with the goal of “identification and early treatment of asymptomatic LVSD [which] may prevent the development of HF,” wrote Dr. Klaus Murbraech of Oslo University Hospital and his colleagues (J. Clin. Oncol. 2015 July 13 [doi:10.1200/JCO.2015.60.8125]).

The investigators observed no association between lower-dose cardiac radiation therapy and LVSD. There was only a marginally significant association between the presence of two or more traditional cardiovascular disease risk factors and LVSD.

The cross-sectional multicenter cohort study is the first to assess the prevalence of LVSD, according to Dr. Murbraech and his colleagues. The study included adult survivors of Hodgkin or non-Hodgkin lymphoma, median age 56 years, who underwent autologous stem-cell transplants in Norway from 1987 to 2008. The median observation time was 13 years (range, 4-34 years). The control group consisted of initially healthy patients in an echocardiographic follow-up study. Controls were matched to patients based on age, sex, systolic blood pressure, and body mass index.

The study was supported by the South-Eastern Norway Regional Health Authority and Extrastiftelsen. Dr. Murbraech reported having no disclosures.

Adult lymphoma survivors who were treated with autologous hematopoietic stem-cell transplantation had a greater than sixfold increased risk of left ventricular systolic dysfunction compared with controls, according to a study published online in the Journal of Clinical Oncology.

Among 274 adult survivors of Hodgkin or non-Hodgkin lymphoma, 16% had left ventricular systolic dysfunction (LVSD): 11% had overt heart failure (HF) and 5% had asymptomatic LVSD, defined as a left ventricular ejection fraction of less than 50%.Heart symptoms were significantly associated with exposure to doxorubicin at a cumulative dose of 300 mg/m² or more and with cardiac radiation therapy of more than 30 Gy. Recognizing these patient risk factors allows for more intensive follow-up with the goal of “identification and early treatment of asymptomatic LVSD [which] may prevent the development of HF,” wrote Dr. Klaus Murbraech of Oslo University Hospital and his colleagues (J. Clin. Oncol. 2015 July 13 [doi:10.1200/JCO.2015.60.8125]).

The investigators observed no association between lower-dose cardiac radiation therapy and LVSD. There was only a marginally significant association between the presence of two or more traditional cardiovascular disease risk factors and LVSD.

The cross-sectional multicenter cohort study is the first to assess the prevalence of LVSD, according to Dr. Murbraech and his colleagues. The study included adult survivors of Hodgkin or non-Hodgkin lymphoma, median age 56 years, who underwent autologous stem-cell transplants in Norway from 1987 to 2008. The median observation time was 13 years (range, 4-34 years). The control group consisted of initially healthy patients in an echocardiographic follow-up study. Controls were matched to patients based on age, sex, systolic blood pressure, and body mass index.

The study was supported by the South-Eastern Norway Regional Health Authority and Extrastiftelsen. Dr. Murbraech reported having no disclosures.

David Weinstock, MD

Photo courtesy of the

Dana-Farber Cancer Institute

A type II JAK2 inhibitor has shown activity against B-cell acute lymphoblastic leukemia (B-ALL) in preclinical experiments.

The inhibitor, known as CHZ868, works by binding JAK2 into a tightly clenched position, which prevents the protein from functioning.

Researchers tested CHZ868 in samples from patients with CRLF2-rearranged B-ALL, in mice with the disease, and in mice implanted with human B-ALL tissue.

“In each case, we saw good activity: leukemia cells died, JAK2 signaling was suspended, and survival rates increased,” said David Weinstock, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

“When we combined CHZ868 with the steroid dexamethasone, the killing of leukemia cells was much more extensive, and the animals lived longer than they did with CHZ868 alone.”

Dr Weinstock and his colleagues reported these results in Cancer Cell. Some of the researchers involved in this work are employees of, or have received research funding from, Novartis.

The team found that CHZ868 inhibited JAK2 signaling in B-ALL, both in vitro and in vivo. CHZ868 could overcome persistent JAK2 signaling where type I JAK2 inhibitors (BSK805 and BVB808) could not.

However, the researchers also identified a mutation—JAK2 L884P—that conferred resistance to CHZ868 and another type II JAK2 inhibitor, BBT594.

Nevertheless, CHZ868 suppressed the growth of CRLF2-rearranged human B-ALL cells and improved survival in mice with human or murine B-ALL.

CHZ868 worked synergistically with dexamethasone to induce apoptosis in JAK2-dependent B-ALL. The combination also improved survival in mice with B-ALL, when compared to either dexamethasone or CHZ868 alone.

The researchers noted that, when given at 30 mg/kg/day, CHZ868 was tolerated in NSG mice for up to 25 days and in immunocompetent mice for up to 44 days. And the drug had “essentially no effects” on peripheral blood counts.

This result and the tolerability of dexamethasone make CHZ868 and dexamethasone a “particularly attractive” combination that should be investigated in clinical trials, the team said.

They also speculated that CHZ868 or other type II JAK2 inhibitors could prove effective against malignancies other than B-ALL.

“JAK2 abnormalities are found in some cases of triple-negative breast cancer and Hodgkin lymphoma,” Dr Weinstock noted. “The success of CHZ868 in B-ALL suggests that it, or a compound that works by a similar mechanism, may also be effective in these cancers.”

David Weinstock, MD

Photo courtesy of the

Dana-Farber Cancer Institute

A type II JAK2 inhibitor has shown activity against B-cell acute lymphoblastic leukemia (B-ALL) in preclinical experiments.

The inhibitor, known as CHZ868, works by binding JAK2 into a tightly clenched position, which prevents the protein from functioning.

Researchers tested CHZ868 in samples from patients with CRLF2-rearranged B-ALL, in mice with the disease, and in mice implanted with human B-ALL tissue.

“In each case, we saw good activity: leukemia cells died, JAK2 signaling was suspended, and survival rates increased,” said David Weinstock, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

“When we combined CHZ868 with the steroid dexamethasone, the killing of leukemia cells was much more extensive, and the animals lived longer than they did with CHZ868 alone.”

Dr Weinstock and his colleagues reported these results in Cancer Cell. Some of the researchers involved in this work are employees of, or have received research funding from, Novartis.

The team found that CHZ868 inhibited JAK2 signaling in B-ALL, both in vitro and in vivo. CHZ868 could overcome persistent JAK2 signaling where type I JAK2 inhibitors (BSK805 and BVB808) could not.

However, the researchers also identified a mutation—JAK2 L884P—that conferred resistance to CHZ868 and another type II JAK2 inhibitor, BBT594.

Nevertheless, CHZ868 suppressed the growth of CRLF2-rearranged human B-ALL cells and improved survival in mice with human or murine B-ALL.

CHZ868 worked synergistically with dexamethasone to induce apoptosis in JAK2-dependent B-ALL. The combination also improved survival in mice with B-ALL, when compared to either dexamethasone or CHZ868 alone.

The researchers noted that, when given at 30 mg/kg/day, CHZ868 was tolerated in NSG mice for up to 25 days and in immunocompetent mice for up to 44 days. And the drug had “essentially no effects” on peripheral blood counts.

This result and the tolerability of dexamethasone make CHZ868 and dexamethasone a “particularly attractive” combination that should be investigated in clinical trials, the team said.

They also speculated that CHZ868 or other type II JAK2 inhibitors could prove effective against malignancies other than B-ALL.

“JAK2 abnormalities are found in some cases of triple-negative breast cancer and Hodgkin lymphoma,” Dr Weinstock noted. “The success of CHZ868 in B-ALL suggests that it, or a compound that works by a similar mechanism, may also be effective in these cancers.”

David Weinstock, MD

Photo courtesy of the

Dana-Farber Cancer Institute

A type II JAK2 inhibitor has shown activity against B-cell acute lymphoblastic leukemia (B-ALL) in preclinical experiments.

The inhibitor, known as CHZ868, works by binding JAK2 into a tightly clenched position, which prevents the protein from functioning.

Researchers tested CHZ868 in samples from patients with CRLF2-rearranged B-ALL, in mice with the disease, and in mice implanted with human B-ALL tissue.

“In each case, we saw good activity: leukemia cells died, JAK2 signaling was suspended, and survival rates increased,” said David Weinstock, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

“When we combined CHZ868 with the steroid dexamethasone, the killing of leukemia cells was much more extensive, and the animals lived longer than they did with CHZ868 alone.”

Dr Weinstock and his colleagues reported these results in Cancer Cell. Some of the researchers involved in this work are employees of, or have received research funding from, Novartis.

The team found that CHZ868 inhibited JAK2 signaling in B-ALL, both in vitro and in vivo. CHZ868 could overcome persistent JAK2 signaling where type I JAK2 inhibitors (BSK805 and BVB808) could not.

However, the researchers also identified a mutation—JAK2 L884P—that conferred resistance to CHZ868 and another type II JAK2 inhibitor, BBT594.

Nevertheless, CHZ868 suppressed the growth of CRLF2-rearranged human B-ALL cells and improved survival in mice with human or murine B-ALL.

CHZ868 worked synergistically with dexamethasone to induce apoptosis in JAK2-dependent B-ALL. The combination also improved survival in mice with B-ALL, when compared to either dexamethasone or CHZ868 alone.

The researchers noted that, when given at 30 mg/kg/day, CHZ868 was tolerated in NSG mice for up to 25 days and in immunocompetent mice for up to 44 days. And the drug had “essentially no effects” on peripheral blood counts.

This result and the tolerability of dexamethasone make CHZ868 and dexamethasone a “particularly attractive” combination that should be investigated in clinical trials, the team said.

They also speculated that CHZ868 or other type II JAK2 inhibitors could prove effective against malignancies other than B-ALL.

“JAK2 abnormalities are found in some cases of triple-negative breast cancer and Hodgkin lymphoma,” Dr Weinstock noted. “The success of CHZ868 in B-ALL suggests that it, or a compound that works by a similar mechanism, may also be effective in these cancers.”

Hematopoietic stem cells

in the bone marrow

Shortening the G1 phase of the cell cycle can improve the production and function of hematopoietic stem cells (HSCs), according to research published in the Journal of Experimental Medicine.

When investigators shortened the G1 phase in human HSCs, they found the cells were better able to resist differentiation in vitro and exhibited enhanced engraftment in vivo.

However, these benefits only occurred when the team shortened the early phase of G1, not the late phase.

Claudia Waskow, PhD, of Technische Universitaet Dresden in Germany, and her colleagues conducted this research to determine whether the function of human HSCs is controlled by the kinetics of cell-cycle progression.

The investigators knew that the body’s pool of HSCs is maintained through self-renewing divisions tightly regulated by enzymatically active cyclin (CCN)/cyclin-dependent kinase (CDK) complexes.

So they enforced expression of functional CCND1–CDK4 complexes, which are important for progression through the early G1 phase of the cell cycle, and CCNE1–CDK2 complexes, which are key in the transition from the G1 phase to the S phase.

Overexpression of CCND1–CDK4 complexes (also referred to as elevated 4D) promoted the transit from G0 to G1 and successfully shortened the G1 phase. However, the total length of the cell cycle did not change much, as the G2 or M phase was prolonged slightly.

The investigators also found that elevated 4D levels protected HSCs from differentiation-inducing signals in vitro and provided a “competitive advantage” in vivo.

When they transplanted HSCs with elevated 4D into mice, the team observed improved donor-leukocyte engraftment but no increase in the HSC pool. They said the improvement in engraftment was based on an elevated output of myeloid cells.

In contrast to elevated 4D, overexpression of CCNE1–CDK2 (also referred to as elevated 2E) conferred detrimental effects. Elevated 2E did accelerate cell-cycle progression, but it led to the loss of functional HSCs and poor engraftment.

The investigators said a large proportion of cells with elevated 2E contained fragmented DNA and underwent apoptosis after transduction.

In addition, many HSCs with elevated 2E exited G0 and shifted to the S–G2–M phases of the cell cycle. The G1 phase was significantly shortened, and the time HSCs spent in each cycle was reduced.

Dr Waskow and her colleagues said these results suggest transit velocity through the early and late G1 phase is an important regulator of HSC function and therefore makes an essential contribution to the maintenance of hematopoiesis.

Furthermore, alterations of G1 transition kinetics may be the basis for functional defects observed in HSCs from old mice or elderly humans.

Hematopoietic stem cells

in the bone marrow

Shortening the G1 phase of the cell cycle can improve the production and function of hematopoietic stem cells (HSCs), according to research published in the Journal of Experimental Medicine.

When investigators shortened the G1 phase in human HSCs, they found the cells were better able to resist differentiation in vitro and exhibited enhanced engraftment in vivo.

However, these benefits only occurred when the team shortened the early phase of G1, not the late phase.

Claudia Waskow, PhD, of Technische Universitaet Dresden in Germany, and her colleagues conducted this research to determine whether the function of human HSCs is controlled by the kinetics of cell-cycle progression.

The investigators knew that the body’s pool of HSCs is maintained through self-renewing divisions tightly regulated by enzymatically active cyclin (CCN)/cyclin-dependent kinase (CDK) complexes.

So they enforced expression of functional CCND1–CDK4 complexes, which are important for progression through the early G1 phase of the cell cycle, and CCNE1–CDK2 complexes, which are key in the transition from the G1 phase to the S phase.

Overexpression of CCND1–CDK4 complexes (also referred to as elevated 4D) promoted the transit from G0 to G1 and successfully shortened the G1 phase. However, the total length of the cell cycle did not change much, as the G2 or M phase was prolonged slightly.

The investigators also found that elevated 4D levels protected HSCs from differentiation-inducing signals in vitro and provided a “competitive advantage” in vivo.

When they transplanted HSCs with elevated 4D into mice, the team observed improved donor-leukocyte engraftment but no increase in the HSC pool. They said the improvement in engraftment was based on an elevated output of myeloid cells.

In contrast to elevated 4D, overexpression of CCNE1–CDK2 (also referred to as elevated 2E) conferred detrimental effects. Elevated 2E did accelerate cell-cycle progression, but it led to the loss of functional HSCs and poor engraftment.

The investigators said a large proportion of cells with elevated 2E contained fragmented DNA and underwent apoptosis after transduction.

In addition, many HSCs with elevated 2E exited G0 and shifted to the S–G2–M phases of the cell cycle. The G1 phase was significantly shortened, and the time HSCs spent in each cycle was reduced.

Dr Waskow and her colleagues said these results suggest transit velocity through the early and late G1 phase is an important regulator of HSC function and therefore makes an essential contribution to the maintenance of hematopoiesis.

Furthermore, alterations of G1 transition kinetics may be the basis for functional defects observed in HSCs from old mice or elderly humans.

Hematopoietic stem cells

in the bone marrow

Shortening the G1 phase of the cell cycle can improve the production and function of hematopoietic stem cells (HSCs), according to research published in the Journal of Experimental Medicine.

When investigators shortened the G1 phase in human HSCs, they found the cells were better able to resist differentiation in vitro and exhibited enhanced engraftment in vivo.

However, these benefits only occurred when the team shortened the early phase of G1, not the late phase.

Claudia Waskow, PhD, of Technische Universitaet Dresden in Germany, and her colleagues conducted this research to determine whether the function of human HSCs is controlled by the kinetics of cell-cycle progression.

The investigators knew that the body’s pool of HSCs is maintained through self-renewing divisions tightly regulated by enzymatically active cyclin (CCN)/cyclin-dependent kinase (CDK) complexes.

So they enforced expression of functional CCND1–CDK4 complexes, which are important for progression through the early G1 phase of the cell cycle, and CCNE1–CDK2 complexes, which are key in the transition from the G1 phase to the S phase.

Overexpression of CCND1–CDK4 complexes (also referred to as elevated 4D) promoted the transit from G0 to G1 and successfully shortened the G1 phase. However, the total length of the cell cycle did not change much, as the G2 or M phase was prolonged slightly.

The investigators also found that elevated 4D levels protected HSCs from differentiation-inducing signals in vitro and provided a “competitive advantage” in vivo.

When they transplanted HSCs with elevated 4D into mice, the team observed improved donor-leukocyte engraftment but no increase in the HSC pool. They said the improvement in engraftment was based on an elevated output of myeloid cells.

In contrast to elevated 4D, overexpression of CCNE1–CDK2 (also referred to as elevated 2E) conferred detrimental effects. Elevated 2E did accelerate cell-cycle progression, but it led to the loss of functional HSCs and poor engraftment.

The investigators said a large proportion of cells with elevated 2E contained fragmented DNA and underwent apoptosis after transduction.

In addition, many HSCs with elevated 2E exited G0 and shifted to the S–G2–M phases of the cell cycle. The G1 phase was significantly shortened, and the time HSCs spent in each cycle was reduced.

Dr Waskow and her colleagues said these results suggest transit velocity through the early and late G1 phase is an important regulator of HSC function and therefore makes an essential contribution to the maintenance of hematopoiesis.

Furthermore, alterations of G1 transition kinetics may be the basis for functional defects observed in HSCs from old mice or elderly humans.

Red and white blood cells

The American Society of Clinical Oncology (ASCO) has updated its clinical practice guideline on hematopoietic colony-stimulating factors (CSFs).

The guideline includes recommendations on the use of CSFs in the context of lymphoma, solid tumor malignancies, pediatric leukemia, and hematopoietic stem cell transplant.

There are no recommendations pertaining to adults with acute myeloid leukemia or myelodysplastic syndromes.

ASCO’s previous guideline on CSFs was issued in 2006. For the update, an ASCO expert panel conducted a formal systematic review of relevant articles from the medical literature published from October 2005 through September 2014.

Key recommendations from the resulting guideline are as follows.

Pegfilgrastim, filgrastim, tbo-filgrastim, and filgrastim-sndz (and other biosimilars, as they become available) can be used for the prevention of treatment-related febrile neutropenia.

For patients with lymphomas or solid tumors, primary prophylaxis with a CSF should be given during all cycles of chemotherapy in patients who have an approximately 20% or higher risk for febrile neutropenia on the basis of patient-, disease-, and treatment-related factors.

However, clinicians should also consider using chemotherapy regimens that do not require CSF administration but are as effective as regimens that do require a CSF.

Patients with lymphomas or solid tumors should receive secondary febrile neutropenia prophylaxis with a CSF if they experienced a neutropenic complication from a previous cycle of chemotherapy (for which they did not receive primary prophylaxis) when a reduced dose or treatment delay may compromise disease-free survival, overall survival, or treatment outcome.

However, the guideline also says that, in many clinical situations, dose reductions or delays may be a reasonable alternative.

CSFs should not be routinely used for patients with neutropenia who are afebrile or as adjunctive treatment with antibiotic therapy for patients with fever and neutropenia.

Dose-dense regimens with CSF support should only be used within an appropriately designed clinical trial or if use of the regimen is supported by convincing efficacy data. The guideline says that, for non-Hodgkin lymphoma, data on the value of dose-dense regimens with CSF support are limited and conflicting.

In the context of transplant, CSFs may be used alone, after chemotherapy, or in combination with plerixafor to mobilize peripheral blood stem cells. To reduce the duration of severe neutropenia, CSFs should be administered after autologous stem cell transplant and may be administered after allogeneic stem cell transplant.

CSFs should be avoided in patients receiving concomitant chemotherapy and radiation, particularly involving the mediastinum. CSFs may be considered in patients receiving radiation alone if the clinician expects prolonged treatment delays due to neutropenia.

Patients who are exposed to lethal doses of total-body radiotherapy, but not doses high enough to lead to certain death resulting from injury to other organs, should promptly receive CSFs or pegylated granulocyte CSFs.

Clinicians should consider prophylactic CSF for patients with diffuse aggressive lymphoma who are 65 or older and are receiving curative chemotherapy (R-CHOP), particularly if they have comorbidities.

The guideline also says the use of CSFs in pediatric patients will almost always be guided by clinical protocols. But CSFs should not be used in pediatric patients with nonrelapsed acute lymphoblastic leukemia or nonrelapsed acute myeloid leukemia who do not have an infection.

For more details, see the complete guideline. ASCO said it encourages feedback on its guidelines from oncologists, practitioners, and patients through the ASCO Guidelines Wiki.

Red and white blood cells

The American Society of Clinical Oncology (ASCO) has updated its clinical practice guideline on hematopoietic colony-stimulating factors (CSFs).

The guideline includes recommendations on the use of CSFs in the context of lymphoma, solid tumor malignancies, pediatric leukemia, and hematopoietic stem cell transplant.

There are no recommendations pertaining to adults with acute myeloid leukemia or myelodysplastic syndromes.

ASCO’s previous guideline on CSFs was issued in 2006. For the update, an ASCO expert panel conducted a formal systematic review of relevant articles from the medical literature published from October 2005 through September 2014.

Key recommendations from the resulting guideline are as follows.

Pegfilgrastim, filgrastim, tbo-filgrastim, and filgrastim-sndz (and other biosimilars, as they become available) can be used for the prevention of treatment-related febrile neutropenia.

For patients with lymphomas or solid tumors, primary prophylaxis with a CSF should be given during all cycles of chemotherapy in patients who have an approximately 20% or higher risk for febrile neutropenia on the basis of patient-, disease-, and treatment-related factors.

However, clinicians should also consider using chemotherapy regimens that do not require CSF administration but are as effective as regimens that do require a CSF.

Patients with lymphomas or solid tumors should receive secondary febrile neutropenia prophylaxis with a CSF if they experienced a neutropenic complication from a previous cycle of chemotherapy (for which they did not receive primary prophylaxis) when a reduced dose or treatment delay may compromise disease-free survival, overall survival, or treatment outcome.

However, the guideline also says that, in many clinical situations, dose reductions or delays may be a reasonable alternative.

CSFs should not be routinely used for patients with neutropenia who are afebrile or as adjunctive treatment with antibiotic therapy for patients with fever and neutropenia.

Dose-dense regimens with CSF support should only be used within an appropriately designed clinical trial or if use of the regimen is supported by convincing efficacy data. The guideline says that, for non-Hodgkin lymphoma, data on the value of dose-dense regimens with CSF support are limited and conflicting.

In the context of transplant, CSFs may be used alone, after chemotherapy, or in combination with plerixafor to mobilize peripheral blood stem cells. To reduce the duration of severe neutropenia, CSFs should be administered after autologous stem cell transplant and may be administered after allogeneic stem cell transplant.

CSFs should be avoided in patients receiving concomitant chemotherapy and radiation, particularly involving the mediastinum. CSFs may be considered in patients receiving radiation alone if the clinician expects prolonged treatment delays due to neutropenia.

Patients who are exposed to lethal doses of total-body radiotherapy, but not doses high enough to lead to certain death resulting from injury to other organs, should promptly receive CSFs or pegylated granulocyte CSFs.

Clinicians should consider prophylactic CSF for patients with diffuse aggressive lymphoma who are 65 or older and are receiving curative chemotherapy (R-CHOP), particularly if they have comorbidities.

The guideline also says the use of CSFs in pediatric patients will almost always be guided by clinical protocols. But CSFs should not be used in pediatric patients with nonrelapsed acute lymphoblastic leukemia or nonrelapsed acute myeloid leukemia who do not have an infection.

For more details, see the complete guideline. ASCO said it encourages feedback on its guidelines from oncologists, practitioners, and patients through the ASCO Guidelines Wiki.

Red and white blood cells

The American Society of Clinical Oncology (ASCO) has updated its clinical practice guideline on hematopoietic colony-stimulating factors (CSFs).

The guideline includes recommendations on the use of CSFs in the context of lymphoma, solid tumor malignancies, pediatric leukemia, and hematopoietic stem cell transplant.

There are no recommendations pertaining to adults with acute myeloid leukemia or myelodysplastic syndromes.

ASCO’s previous guideline on CSFs was issued in 2006. For the update, an ASCO expert panel conducted a formal systematic review of relevant articles from the medical literature published from October 2005 through September 2014.

Key recommendations from the resulting guideline are as follows.

Pegfilgrastim, filgrastim, tbo-filgrastim, and filgrastim-sndz (and other biosimilars, as they become available) can be used for the prevention of treatment-related febrile neutropenia.

For patients with lymphomas or solid tumors, primary prophylaxis with a CSF should be given during all cycles of chemotherapy in patients who have an approximately 20% or higher risk for febrile neutropenia on the basis of patient-, disease-, and treatment-related factors.

However, clinicians should also consider using chemotherapy regimens that do not require CSF administration but are as effective as regimens that do require a CSF.

Patients with lymphomas or solid tumors should receive secondary febrile neutropenia prophylaxis with a CSF if they experienced a neutropenic complication from a previous cycle of chemotherapy (for which they did not receive primary prophylaxis) when a reduced dose or treatment delay may compromise disease-free survival, overall survival, or treatment outcome.

However, the guideline also says that, in many clinical situations, dose reductions or delays may be a reasonable alternative.

CSFs should not be routinely used for patients with neutropenia who are afebrile or as adjunctive treatment with antibiotic therapy for patients with fever and neutropenia.

Dose-dense regimens with CSF support should only be used within an appropriately designed clinical trial or if use of the regimen is supported by convincing efficacy data. The guideline says that, for non-Hodgkin lymphoma, data on the value of dose-dense regimens with CSF support are limited and conflicting.

In the context of transplant, CSFs may be used alone, after chemotherapy, or in combination with plerixafor to mobilize peripheral blood stem cells. To reduce the duration of severe neutropenia, CSFs should be administered after autologous stem cell transplant and may be administered after allogeneic stem cell transplant.

CSFs should be avoided in patients receiving concomitant chemotherapy and radiation, particularly involving the mediastinum. CSFs may be considered in patients receiving radiation alone if the clinician expects prolonged treatment delays due to neutropenia.

Patients who are exposed to lethal doses of total-body radiotherapy, but not doses high enough to lead to certain death resulting from injury to other organs, should promptly receive CSFs or pegylated granulocyte CSFs.

Clinicians should consider prophylactic CSF for patients with diffuse aggressive lymphoma who are 65 or older and are receiving curative chemotherapy (R-CHOP), particularly if they have comorbidities.

The guideline also says the use of CSFs in pediatric patients will almost always be guided by clinical protocols. But CSFs should not be used in pediatric patients with nonrelapsed acute lymphoblastic leukemia or nonrelapsed acute myeloid leukemia who do not have an infection.

For more details, see the complete guideline. ASCO said it encourages feedback on its guidelines from oncologists, practitioners, and patients through the ASCO Guidelines Wiki.

Blood for transfusion

Photo by Elise Amendola

Results of a pilot study suggest a restrictive transfusion strategy may be safe for patients with acute upper gastrointestinal bleeding (AUGIB), but investigators say more research is needed.

In this study, known as TRIGGER, use of a restrictive transfusion strategy led to a 13% reduction in red blood cell (RBC) transfusions compared to the liberal strategy, but this difference was not statistically significant.

Likewise, there was no significant difference in clinical outcomes whether AUGIB patients received transfusions according to the restrictive strategy or the liberal one.

These results suggest a need for a large, randomized trial, according to investigators.

“If restrictive practice is proven to be safe in a large study, it could potentially safely reduce the use of red blood cell transfusions and produce cost savings . . . ,” said Vipul Jairath, MBChB, DPhil, of Oxford University Hospitals in the UK.

He and his colleagues conducted the TRIGGER trial and reported the results in The Lancet.

The study included 6 hospitals that had more than 20 AUGIB admissions monthly, more than 400 adult beds, 24-hour endoscopy, and onsite intensive care and surgery. Patients were eligible if they presented with new AUGIB (defined by hematemesis or melena) and were 18 or older. The only exclusion criterion was exsanguinating hemorrhage.

The investigators enrolled 936 patients—403 on the restrictive transfusion arm and 533 on the liberal arm. Patients in the restrictive arm were eligible to receive RBCs when their hemoglobin concentration fell below 80 g/L, with a post-transfusion target of 81-100 g/L.

Patients in the liberal arm were eligible for transfusion when their hemoglobin concentration fell below 100 g/L, with a post-transfusion target of 101-120 g/L. These thresholds were informed by UK transfusion practices.

Protocol adherence was 96% in the restrictive arm and 83% in the liberal arm. The mean last recorded hemoglobin concentration was 116 g/L for the restrictive arm and 118 g/L for the liberal arm.

The investigators noted that there was a 13% absolute reduction in the proportion of patients transfused in the restrictive arm, a reduction in the amount of RBCs transfused between the arms, and a separation in hemoglobin concentration between the arms, but none of these differences were significant.

In addition, there was no significant difference in clinical outcomes between the arms, although the trial was not powered to assess these outcomes.

All-cause mortality at day 28 was 7% in the liberal transfusion arm and 5% in the restrictive arm. The rate of serious adverse events at day 28 was 22% and 18%, respectively.

At hospital discharge, further bleeding had occurred in 6% of patients in the liberal arm and 4% in the restrictive arm. At day 28, further bleeding had occurred in 9% and 5%, respectively.

At discharge, thromboembolic or ischemic events had occurred in 5% of patients in the liberal arm and 3% in the restrictive arm. At day 28, these events had occurred in 7% and 4%, respectively.

At discharge, acute transfusion reactions had occurred in 2% of patients in the liberal arm and 1% in the restrictive arm, and infections had occurred in 24% and 26%, respectively.

By discharge, 38% of patients in the liberal arm and 32% in the restrictive arm had required some therapeutic intervention. Surgical or radiological intervention was required in 3% and 4%, respectively.

Considering these results, the investigators said the TRIGGER trial has paved the way for a phase 3 trial that could provide evidence to inform transfusion guidelines for patients with AUGIB.

Blood for transfusion

Photo by Elise Amendola

Results of a pilot study suggest a restrictive transfusion strategy may be safe for patients with acute upper gastrointestinal bleeding (AUGIB), but investigators say more research is needed.

In this study, known as TRIGGER, use of a restrictive transfusion strategy led to a 13% reduction in red blood cell (RBC) transfusions compared to the liberal strategy, but this difference was not statistically significant.

Likewise, there was no significant difference in clinical outcomes whether AUGIB patients received transfusions according to the restrictive strategy or the liberal one.

These results suggest a need for a large, randomized trial, according to investigators.

“If restrictive practice is proven to be safe in a large study, it could potentially safely reduce the use of red blood cell transfusions and produce cost savings . . . ,” said Vipul Jairath, MBChB, DPhil, of Oxford University Hospitals in the UK.

He and his colleagues conducted the TRIGGER trial and reported the results in The Lancet.

The study included 6 hospitals that had more than 20 AUGIB admissions monthly, more than 400 adult beds, 24-hour endoscopy, and onsite intensive care and surgery. Patients were eligible if they presented with new AUGIB (defined by hematemesis or melena) and were 18 or older. The only exclusion criterion was exsanguinating hemorrhage.

The investigators enrolled 936 patients—403 on the restrictive transfusion arm and 533 on the liberal arm. Patients in the restrictive arm were eligible to receive RBCs when their hemoglobin concentration fell below 80 g/L, with a post-transfusion target of 81-100 g/L.

Patients in the liberal arm were eligible for transfusion when their hemoglobin concentration fell below 100 g/L, with a post-transfusion target of 101-120 g/L. These thresholds were informed by UK transfusion practices.

Protocol adherence was 96% in the restrictive arm and 83% in the liberal arm. The mean last recorded hemoglobin concentration was 116 g/L for the restrictive arm and 118 g/L for the liberal arm.

The investigators noted that there was a 13% absolute reduction in the proportion of patients transfused in the restrictive arm, a reduction in the amount of RBCs transfused between the arms, and a separation in hemoglobin concentration between the arms, but none of these differences were significant.

In addition, there was no significant difference in clinical outcomes between the arms, although the trial was not powered to assess these outcomes.

All-cause mortality at day 28 was 7% in the liberal transfusion arm and 5% in the restrictive arm. The rate of serious adverse events at day 28 was 22% and 18%, respectively.

At hospital discharge, further bleeding had occurred in 6% of patients in the liberal arm and 4% in the restrictive arm. At day 28, further bleeding had occurred in 9% and 5%, respectively.

At discharge, thromboembolic or ischemic events had occurred in 5% of patients in the liberal arm and 3% in the restrictive arm. At day 28, these events had occurred in 7% and 4%, respectively.

At discharge, acute transfusion reactions had occurred in 2% of patients in the liberal arm and 1% in the restrictive arm, and infections had occurred in 24% and 26%, respectively.

By discharge, 38% of patients in the liberal arm and 32% in the restrictive arm had required some therapeutic intervention. Surgical or radiological intervention was required in 3% and 4%, respectively.

Considering these results, the investigators said the TRIGGER trial has paved the way for a phase 3 trial that could provide evidence to inform transfusion guidelines for patients with AUGIB.

Blood for transfusion

Photo by Elise Amendola

Results of a pilot study suggest a restrictive transfusion strategy may be safe for patients with acute upper gastrointestinal bleeding (AUGIB), but investigators say more research is needed.

In this study, known as TRIGGER, use of a restrictive transfusion strategy led to a 13% reduction in red blood cell (RBC) transfusions compared to the liberal strategy, but this difference was not statistically significant.

Likewise, there was no significant difference in clinical outcomes whether AUGIB patients received transfusions according to the restrictive strategy or the liberal one.

These results suggest a need for a large, randomized trial, according to investigators.

“If restrictive practice is proven to be safe in a large study, it could potentially safely reduce the use of red blood cell transfusions and produce cost savings . . . ,” said Vipul Jairath, MBChB, DPhil, of Oxford University Hospitals in the UK.

He and his colleagues conducted the TRIGGER trial and reported the results in The Lancet.

The study included 6 hospitals that had more than 20 AUGIB admissions monthly, more than 400 adult beds, 24-hour endoscopy, and onsite intensive care and surgery. Patients were eligible if they presented with new AUGIB (defined by hematemesis or melena) and were 18 or older. The only exclusion criterion was exsanguinating hemorrhage.

The investigators enrolled 936 patients—403 on the restrictive transfusion arm and 533 on the liberal arm. Patients in the restrictive arm were eligible to receive RBCs when their hemoglobin concentration fell below 80 g/L, with a post-transfusion target of 81-100 g/L.

Patients in the liberal arm were eligible for transfusion when their hemoglobin concentration fell below 100 g/L, with a post-transfusion target of 101-120 g/L. These thresholds were informed by UK transfusion practices.

Protocol adherence was 96% in the restrictive arm and 83% in the liberal arm. The mean last recorded hemoglobin concentration was 116 g/L for the restrictive arm and 118 g/L for the liberal arm.

The investigators noted that there was a 13% absolute reduction in the proportion of patients transfused in the restrictive arm, a reduction in the amount of RBCs transfused between the arms, and a separation in hemoglobin concentration between the arms, but none of these differences were significant.

In addition, there was no significant difference in clinical outcomes between the arms, although the trial was not powered to assess these outcomes.

All-cause mortality at day 28 was 7% in the liberal transfusion arm and 5% in the restrictive arm. The rate of serious adverse events at day 28 was 22% and 18%, respectively.

At hospital discharge, further bleeding had occurred in 6% of patients in the liberal arm and 4% in the restrictive arm. At day 28, further bleeding had occurred in 9% and 5%, respectively.

At discharge, thromboembolic or ischemic events had occurred in 5% of patients in the liberal arm and 3% in the restrictive arm. At day 28, these events had occurred in 7% and 4%, respectively.

At discharge, acute transfusion reactions had occurred in 2% of patients in the liberal arm and 1% in the restrictive arm, and infections had occurred in 24% and 26%, respectively.

By discharge, 38% of patients in the liberal arm and 32% in the restrictive arm had required some therapeutic intervention. Surgical or radiological intervention was required in 3% and 4%, respectively.

Considering these results, the investigators said the TRIGGER trial has paved the way for a phase 3 trial that could provide evidence to inform transfusion guidelines for patients with AUGIB.

Isotretinoin is a vitamin A derivative that frequently is used in the treatment of acne vulgaris.^1,2 Although isotretinoin generally is associated with favorable effects, adverse effects also have been reported.^3-5 Musculoskeletal side effects can include myalgia, sacroiliitis, back pain, diffuse idiopathic skeletal hyperostosis, ligament and tendon calcifications, bone resorption, and reduced collagen synthesis.^6,7 Elevated creatine kinase (CK) levels also have been reported in 15% to 50% of patients with isotretinoin-induced myalgia.⁸ However, there are limited data available on the effects of isotretinoin treatment on muscle strength. The objective of this study was to evaluate the impact of isotretinoin on muscle strength, fatigue, and endurance using an isokinetic dynamometer.

Methods

Study Design and Participants

The study followed a pretest-posttest design including 27 patients with acne vulgaris who were treated with oral isotretinoin (age range, 18–40 years) as well as 26 control patients for comparison. Exclusion criteria were renal or liver disease, uncontrolled hypertension, heart failure, malignancy, thyroid and bone disorders (eg, parathyroid disease, osteomalacia), use of drugs that can affect skeletal metabolism (eg, corticosteroids, heparin, anticonvulsants), and history of trauma to and/or surgery of the lower extremities. All patients were informed of the study procedure and informed consent was obtained. The study protocol was approved by the local ethics committee.

Data Collection

Participant demographics and clinical features (eg, sex, age, body mass index [BMI]) were obtained. Participants in the treatment group received oral isotretinoin 0.5 mg/kg once daily for 1 month, followed by an increased dose of 1 mg/kg once daily for 2 months. Isokinetic measurements of the knee muscles were performed on the nondominant side at baseline and at 3-month follow-up. Reports of muscular side effects were noted during the course of treatment.

Isokinetic Evaluation

A calibrated isokinetic dynamometer was used to conduct isokinetic evaluations. After performing 5 submaximal warm-up contractions, concentric peak torque (PT) values of the quadriceps and hamstrings at 60° and 180° per second angular velocities (AVs), hamstring strength to quadriceps strength ratio (H:Q ratio), and muscle fatigue were evaluated. The isokinetic test protocol included 10 repeats at 60° per second, 15 seconds of rest, and 15 repeats at 180° per second.

Statistical Analysis

Data analysis was conducted using SPSS software version 20.0. Data were expressed as mean (standard deviation [SD]). After checking normal distribution with the Kolmogorov-Smirnov test, independent t tests were used to compare the baseline parameters between the treatment and control groups. Paired t tests and Wilcoxon signed rank tests were used to compare baseline and posttreatment values where appropriate. The results were for those who completed treatment. Statistical significance was set at P<.05.

Results

Twenty-seven participants (24 female; 3 male) with newly diagnosed acne vulgaris were enrolled in the treatment group along with 26 controls (23 female; 3 male). One of the participants in the treatment group did not tolerate isotretinoin due to headache and was excluded from the study. The mean (SD) age of the participants was 20.6 (1.6) years for the treatment group and 21.3 (1.5) years for the control group, and the mean (SD) BMI for both groups was 21.8 (2.8) and 21.5 (1.8), respectively. Participant demographics and isokinetic values at baseline are presented in Table 1. No significant differences between the treatment and control groups for participant sex, age, or BMI were noted (P>.05).

Of the 26 participants in the treatment group, 5 reported myalgia and nonspecific back pain. Isokinetic measurements of the treatment group obtained using the dynamometer are shown in Table 2. Although the PT of the hamstring and quadriceps at both 60° and 180° per second AV was decreased at 3-month follow-up, there was no significant difference compared to baseline (P>.05). Additionally, no significant difference in H:Q ratio or muscle fatigue was noted (P>.05), and no significant difference in isokinetic measurements was seen in participants with myalgia (n=5) at 3-month follow-up versus baseline (P>.05). 

Comment

This study aimed to investigate the short-term effects of isotretinoin treatment on muscle strength, fatigue, and endurance in patients with acne vulgaris, which has not been widely evaluated in the literature. Although maximal PT of the hamstring  and quadriceps in the isotretinoin treatment group was decreased at 3-month follow-up, there was no statistically significant difference in all parameters (ie, PT at 60° and 180° per second, H:Q ratio, muscle fatigue) versus baseline. These findings showed that systemic isotretinoin was not associated with muscle dysfunction in this patient population.

Myalgia, particularly associated with exercise, has been seen in approximately 50% of patients treated with isotretinoin.⁶ Furthermore, Goulden et al⁹ reported that patients with higher CK levels might be at an increased risk for developing rhabdomyolysis in the setting of isotretinoin treatment. High CK levels indicate serious muscular cell damage and are usually associated with release of myoglobin from muscular cells.¹⁰ In the current study, 5 participants reported myalgia and nonspecific back pain at 3-month follow-up; however, no participants reported muscle weakness. Differences in the isokinetic measurements of participants with myalgia at baseline and at 3-month follow-up were not statistically significant.

Muscles mainly consist of type I (slow oxidative), type IIA (fast oxidative), and type IIB (fast glycolytic) muscle fibers. Type I fibers produce low force and high endurance, type IIB fibers produce high force and low endurance, and type IIA fibers fall in between the two. At low AVs (eg, 60° per second), only type II fibers contract. As the AV increases (eg, 180° per second), only type II fibers contract. Consequently, the observation of a decrease in the isokinetic test parameters at low or high AVs indicate the decrease in type I or type II contracting muscle fibers.^11,12 In our study, the isokinetic values did not significantly change. As such, we concluded that isotretinoin treatment did not result in the reduction of muscle fibers in our patient population.

The H:Q ratio is the indicator of muscle balance and dynamic stabilization of the knee. It is calculated by dividing the PT of the hamstrings by the PT of the quadriceps in concentric motion.¹³ Additionally, muscle fatigue demonstrates the endurance of the contraction of type IIB fibers (anaerobic).¹⁴ In our study, isotretinoin treatment did not impact the H:Q ratio or muscle fatigue.

This study included a few important limitations. The sample size was small, particularly concerning the number of participants who reported myalgia. The lack of laboratory evaluations (eg, creatinine kinase) also was a limitation. Finally, the short study period limited the conclusions that could be drawn from the data.

Conclusion

Results from the current study revealed that systemic isotretinoin treatment did not alter muscle strength, fatigue, or endurance. Further studies taking into account histologic evaluations with larger sample sizes and long-term follow-up are needed.

Isotretinoin is a vitamin A derivative that frequently is used in the treatment of acne vulgaris.^1,2 Although isotretinoin generally is associated with favorable effects, adverse effects also have been reported.^3-5 Musculoskeletal side effects can include myalgia, sacroiliitis, back pain, diffuse idiopathic skeletal hyperostosis, ligament and tendon calcifications, bone resorption, and reduced collagen synthesis.^6,7 Elevated creatine kinase (CK) levels also have been reported in 15% to 50% of patients with isotretinoin-induced myalgia.⁸ However, there are limited data available on the effects of isotretinoin treatment on muscle strength. The objective of this study was to evaluate the impact of isotretinoin on muscle strength, fatigue, and endurance using an isokinetic dynamometer.

Methods

Study Design and Participants

The study followed a pretest-posttest design including 27 patients with acne vulgaris who were treated with oral isotretinoin (age range, 18–40 years) as well as 26 control patients for comparison. Exclusion criteria were renal or liver disease, uncontrolled hypertension, heart failure, malignancy, thyroid and bone disorders (eg, parathyroid disease, osteomalacia), use of drugs that can affect skeletal metabolism (eg, corticosteroids, heparin, anticonvulsants), and history of trauma to and/or surgery of the lower extremities. All patients were informed of the study procedure and informed consent was obtained. The study protocol was approved by the local ethics committee.

Data Collection

Participant demographics and clinical features (eg, sex, age, body mass index [BMI]) were obtained. Participants in the treatment group received oral isotretinoin 0.5 mg/kg once daily for 1 month, followed by an increased dose of 1 mg/kg once daily for 2 months. Isokinetic measurements of the knee muscles were performed on the nondominant side at baseline and at 3-month follow-up. Reports of muscular side effects were noted during the course of treatment.

Isokinetic Evaluation

A calibrated isokinetic dynamometer was used to conduct isokinetic evaluations. After performing 5 submaximal warm-up contractions, concentric peak torque (PT) values of the quadriceps and hamstrings at 60° and 180° per second angular velocities (AVs), hamstring strength to quadriceps strength ratio (H:Q ratio), and muscle fatigue were evaluated. The isokinetic test protocol included 10 repeats at 60° per second, 15 seconds of rest, and 15 repeats at 180° per second.

Statistical Analysis

Data analysis was conducted using SPSS software version 20.0. Data were expressed as mean (standard deviation [SD]). After checking normal distribution with the Kolmogorov-Smirnov test, independent t tests were used to compare the baseline parameters between the treatment and control groups. Paired t tests and Wilcoxon signed rank tests were used to compare baseline and posttreatment values where appropriate. The results were for those who completed treatment. Statistical significance was set at P<.05.

Results

Twenty-seven participants (24 female; 3 male) with newly diagnosed acne vulgaris were enrolled in the treatment group along with 26 controls (23 female; 3 male). One of the participants in the treatment group did not tolerate isotretinoin due to headache and was excluded from the study. The mean (SD) age of the participants was 20.6 (1.6) years for the treatment group and 21.3 (1.5) years for the control group, and the mean (SD) BMI for both groups was 21.8 (2.8) and 21.5 (1.8), respectively. Participant demographics and isokinetic values at baseline are presented in Table 1. No significant differences between the treatment and control groups for participant sex, age, or BMI were noted (P>.05).

Of the 26 participants in the treatment group, 5 reported myalgia and nonspecific back pain. Isokinetic measurements of the treatment group obtained using the dynamometer are shown in Table 2. Although the PT of the hamstring and quadriceps at both 60° and 180° per second AV was decreased at 3-month follow-up, there was no significant difference compared to baseline (P>.05). Additionally, no significant difference in H:Q ratio or muscle fatigue was noted (P>.05), and no significant difference in isokinetic measurements was seen in participants with myalgia (n=5) at 3-month follow-up versus baseline (P>.05). 

Comment

This study aimed to investigate the short-term effects of isotretinoin treatment on muscle strength, fatigue, and endurance in patients with acne vulgaris, which has not been widely evaluated in the literature. Although maximal PT of the hamstring  and quadriceps in the isotretinoin treatment group was decreased at 3-month follow-up, there was no statistically significant difference in all parameters (ie, PT at 60° and 180° per second, H:Q ratio, muscle fatigue) versus baseline. These findings showed that systemic isotretinoin was not associated with muscle dysfunction in this patient population.

Myalgia, particularly associated with exercise, has been seen in approximately 50% of patients treated with isotretinoin.⁶ Furthermore, Goulden et al⁹ reported that patients with higher CK levels might be at an increased risk for developing rhabdomyolysis in the setting of isotretinoin treatment. High CK levels indicate serious muscular cell damage and are usually associated with release of myoglobin from muscular cells.¹⁰ In the current study, 5 participants reported myalgia and nonspecific back pain at 3-month follow-up; however, no participants reported muscle weakness. Differences in the isokinetic measurements of participants with myalgia at baseline and at 3-month follow-up were not statistically significant.

Muscles mainly consist of type I (slow oxidative), type IIA (fast oxidative), and type IIB (fast glycolytic) muscle fibers. Type I fibers produce low force and high endurance, type IIB fibers produce high force and low endurance, and type IIA fibers fall in between the two. At low AVs (eg, 60° per second), only type II fibers contract. As the AV increases (eg, 180° per second), only type II fibers contract. Consequently, the observation of a decrease in the isokinetic test parameters at low or high AVs indicate the decrease in type I or type II contracting muscle fibers.^11,12 In our study, the isokinetic values did not significantly change. As such, we concluded that isotretinoin treatment did not result in the reduction of muscle fibers in our patient population.

The H:Q ratio is the indicator of muscle balance and dynamic stabilization of the knee. It is calculated by dividing the PT of the hamstrings by the PT of the quadriceps in concentric motion.¹³ Additionally, muscle fatigue demonstrates the endurance of the contraction of type IIB fibers (anaerobic).¹⁴ In our study, isotretinoin treatment did not impact the H:Q ratio or muscle fatigue.

This study included a few important limitations. The sample size was small, particularly concerning the number of participants who reported myalgia. The lack of laboratory evaluations (eg, creatinine kinase) also was a limitation. Finally, the short study period limited the conclusions that could be drawn from the data.

Conclusion

Results from the current study revealed that systemic isotretinoin treatment did not alter muscle strength, fatigue, or endurance. Further studies taking into account histologic evaluations with larger sample sizes and long-term follow-up are needed.

Isotretinoin is a vitamin A derivative that frequently is used in the treatment of acne vulgaris.^1,2 Although isotretinoin generally is associated with favorable effects, adverse effects also have been reported.^3-5 Musculoskeletal side effects can include myalgia, sacroiliitis, back pain, diffuse idiopathic skeletal hyperostosis, ligament and tendon calcifications, bone resorption, and reduced collagen synthesis.^6,7 Elevated creatine kinase (CK) levels also have been reported in 15% to 50% of patients with isotretinoin-induced myalgia.⁸ However, there are limited data available on the effects of isotretinoin treatment on muscle strength. The objective of this study was to evaluate the impact of isotretinoin on muscle strength, fatigue, and endurance using an isokinetic dynamometer.

Methods

Study Design and Participants

The study followed a pretest-posttest design including 27 patients with acne vulgaris who were treated with oral isotretinoin (age range, 18–40 years) as well as 26 control patients for comparison. Exclusion criteria were renal or liver disease, uncontrolled hypertension, heart failure, malignancy, thyroid and bone disorders (eg, parathyroid disease, osteomalacia), use of drugs that can affect skeletal metabolism (eg, corticosteroids, heparin, anticonvulsants), and history of trauma to and/or surgery of the lower extremities. All patients were informed of the study procedure and informed consent was obtained. The study protocol was approved by the local ethics committee.

Data Collection

Participant demographics and clinical features (eg, sex, age, body mass index [BMI]) were obtained. Participants in the treatment group received oral isotretinoin 0.5 mg/kg once daily for 1 month, followed by an increased dose of 1 mg/kg once daily for 2 months. Isokinetic measurements of the knee muscles were performed on the nondominant side at baseline and at 3-month follow-up. Reports of muscular side effects were noted during the course of treatment.

Isokinetic Evaluation

A calibrated isokinetic dynamometer was used to conduct isokinetic evaluations. After performing 5 submaximal warm-up contractions, concentric peak torque (PT) values of the quadriceps and hamstrings at 60° and 180° per second angular velocities (AVs), hamstring strength to quadriceps strength ratio (H:Q ratio), and muscle fatigue were evaluated. The isokinetic test protocol included 10 repeats at 60° per second, 15 seconds of rest, and 15 repeats at 180° per second.

Statistical Analysis

Data analysis was conducted using SPSS software version 20.0. Data were expressed as mean (standard deviation [SD]). After checking normal distribution with the Kolmogorov-Smirnov test, independent t tests were used to compare the baseline parameters between the treatment and control groups. Paired t tests and Wilcoxon signed rank tests were used to compare baseline and posttreatment values where appropriate. The results were for those who completed treatment. Statistical significance was set at P<.05.

Results

Twenty-seven participants (24 female; 3 male) with newly diagnosed acne vulgaris were enrolled in the treatment group along with 26 controls (23 female; 3 male). One of the participants in the treatment group did not tolerate isotretinoin due to headache and was excluded from the study. The mean (SD) age of the participants was 20.6 (1.6) years for the treatment group and 21.3 (1.5) years for the control group, and the mean (SD) BMI for both groups was 21.8 (2.8) and 21.5 (1.8), respectively. Participant demographics and isokinetic values at baseline are presented in Table 1. No significant differences between the treatment and control groups for participant sex, age, or BMI were noted (P>.05).

Of the 26 participants in the treatment group, 5 reported myalgia and nonspecific back pain. Isokinetic measurements of the treatment group obtained using the dynamometer are shown in Table 2. Although the PT of the hamstring and quadriceps at both 60° and 180° per second AV was decreased at 3-month follow-up, there was no significant difference compared to baseline (P>.05). Additionally, no significant difference in H:Q ratio or muscle fatigue was noted (P>.05), and no significant difference in isokinetic measurements was seen in participants with myalgia (n=5) at 3-month follow-up versus baseline (P>.05). 

Comment

This study aimed to investigate the short-term effects of isotretinoin treatment on muscle strength, fatigue, and endurance in patients with acne vulgaris, which has not been widely evaluated in the literature. Although maximal PT of the hamstring  and quadriceps in the isotretinoin treatment group was decreased at 3-month follow-up, there was no statistically significant difference in all parameters (ie, PT at 60° and 180° per second, H:Q ratio, muscle fatigue) versus baseline. These findings showed that systemic isotretinoin was not associated with muscle dysfunction in this patient population.

Myalgia, particularly associated with exercise, has been seen in approximately 50% of patients treated with isotretinoin.⁶ Furthermore, Goulden et al⁹ reported that patients with higher CK levels might be at an increased risk for developing rhabdomyolysis in the setting of isotretinoin treatment. High CK levels indicate serious muscular cell damage and are usually associated with release of myoglobin from muscular cells.¹⁰ In the current study, 5 participants reported myalgia and nonspecific back pain at 3-month follow-up; however, no participants reported muscle weakness. Differences in the isokinetic measurements of participants with myalgia at baseline and at 3-month follow-up were not statistically significant.

Muscles mainly consist of type I (slow oxidative), type IIA (fast oxidative), and type IIB (fast glycolytic) muscle fibers. Type I fibers produce low force and high endurance, type IIB fibers produce high force and low endurance, and type IIA fibers fall in between the two. At low AVs (eg, 60° per second), only type II fibers contract. As the AV increases (eg, 180° per second), only type II fibers contract. Consequently, the observation of a decrease in the isokinetic test parameters at low or high AVs indicate the decrease in type I or type II contracting muscle fibers.^11,12 In our study, the isokinetic values did not significantly change. As such, we concluded that isotretinoin treatment did not result in the reduction of muscle fibers in our patient population.

The H:Q ratio is the indicator of muscle balance and dynamic stabilization of the knee. It is calculated by dividing the PT of the hamstrings by the PT of the quadriceps in concentric motion.¹³ Additionally, muscle fatigue demonstrates the endurance of the contraction of type IIB fibers (anaerobic).¹⁴ In our study, isotretinoin treatment did not impact the H:Q ratio or muscle fatigue.

This study included a few important limitations. The sample size was small, particularly concerning the number of participants who reported myalgia. The lack of laboratory evaluations (eg, creatinine kinase) also was a limitation. Finally, the short study period limited the conclusions that could be drawn from the data.

Conclusion

Results from the current study revealed that systemic isotretinoin treatment did not alter muscle strength, fatigue, or endurance. Further studies taking into account histologic evaluations with larger sample sizes and long-term follow-up are needed.